Name: Team FPS
Posts by Team FPS:
- 3 cups water, filtered
- 1 1/2 cups NON-Hydrolyzed Gelatin (I recommend Great Lakes)
- 3 cups sugar, organic, raw (addition by FPS – use refined white sugar)
- ½ cup strawberries, chopped and diced
- 2 cups orange juice, pulp-free
- 1/4 cup lime juice, pulp-free
- Reducing levels of norepinephrine, serotonin and dopamine does not actually produce depression in humans, even though it appeared to do so in animals.
- The theory cannot explain why there are drugs that alleviate depression despite the fact that they have little or no effect on either serotonin or norepinephrine.
- Drugs that raise serotonin and norepinephrine levels, such as amphetamine and cocaine, do not alleviate depression.
- No one has explained why it takes a relatively long time before antidepressant drugs produce any elevation of mood. Antidepressants produce their maximum elevation of serotonin and norepinephrine in only a day or two, but it often takes several weeks before any improvement in mood occurs.
- Although some depressed patients have low levels of serotonin and norepinephrine, the majority do not. Estimates vary, but a reasonable average from several studies indicates that only about 25 percent of depressed patients actually have low levels of these metabolites.
- Some depressed patients actually have abnormally high levels of serotonin and norepinephrine, and some patients with no history of depression at all have low levels of these amines.
- Although there have been claims that depression may be caused by excessive levels of monoamine oxydase (the enzyme that breaks down serotonin and norepinephrine), this is only true in some depressed patients and not in others.
- Antidepressants produce a number of different effects other than increasing norepinephrine and serotonin activity that have not been accounted for when considering their activity on depression.
Long Chain Fats Decrease Insulin Metabolism
February 21st, 2012Endocrinology. 2003 Jun;144(6):2404-8.
In vitro inhibition of insulin-degrading enzyme by long-chain fatty acids and their coenzyme A thioesters.
Hamel FG, Upward JL, Bennett RG.
Insulin-degrading enzyme is responsible for initiating insulin degradation in cells, but little is known about the factors controlling its activity. Because obesity and high levels of free fatty acids decrease insulin clearance, we examined the effect of some common free fatty acids and their acyl-coenzyme A thioesters on insulin-degrading enzyme partially purified from the livers of male Sprague Dawley rats. Octanoic acid (C8:0) had no effect on activity. Long-chain free fatty acids (C16-C20) inhibited between 50% and 90% of the insulin degradation with IC(50) values in the range of 10-50 micro M. In general, the corresponding acyl-coenzyme A thioesters had lower IC(50) values and were slightly more efficacious. (125)I-insulin cross-linking studies showed free fatty acids did not inhibit hormone binding to insulin-degrading enzyme. Kinetic analysis showed a noncompetitive type of inhibition. Furthermore, fatty acids eliminated the ability of insulin to inhibit the proteasome. These results suggest that when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells. This mechanism may contribute to the hyperinsulinemia and insulin resistance seen with elevated fatty acids and obesity.
Fish – Elongase and Desaturase Enzymes
February 21st, 2012Aquaculture Volume 290, Issues 1–2, 4 May 2009, Pages 122–131
Physiological roles of fatty acyl desaturases and elongases in marine fish: Characterisation of cDNAs of fatty acyl Δ6 desaturase and elovl5 elongase of cobia (Rachycentron canadum)
Xiaozhong Zheng, Zhaokun Ding, Youqing Xu, Oscar Monroig, Sofia Morais, Douglas R. Tocher
In the present paper, we investigated the expression of fatty acyl desaturase and elongase genes in a marine teleost, cobia, a species of great interest due to its considerable aquaculture potential. A cDNA was cloned that, when expressed in yeast, was shown to result in desaturation of 18:3n−3 and 18:2n−6, indicating that it coded for a Δ6 desaturase enzyme. Very low desaturation of 20:4n−3 and 20:3n−6 indicated only trace Δ5 activity. Another cloned cDNA enabled elongation of 18:4n−3, 18:3n−6, 20:5n−3 and 20:4n−6 in the yeast expression system, indicating that it had C18–20 and C20–22 elongase activity. Sequence comparison and phylogenetic analysis confirmed that it was homologous to human ELOVL5 elongase. However, the cobia Elovl5 elongase also had low activity toward C24 HUFA. The cobia Δ6 desaturase had a preference for 18:3n−3, but the elongase was generally equally active with both n−3 and n−6 substrates. Expression of both genes was 1–2 orders of magnitude greater in brain than other tissues suggesting an important role, possibly to ensure sufficient docosahexaenoic acid (DHA, 22:6n−3) synthesis in neural tissues through elongation and desaturation of eicosapentaenoic acid (EPA; 20:5n−3).
Estrogen and PCOS
February 17th, 2012Am J Obstet Gynecol. 1993 Nov;169(5):1223-6.
Excessive estradiol secretion in polycystic ovarian disease.
Benjamin F, Toles AW, Seltzer VL, Deutsch S.
Polycystic ovarian disease is both a hyperestrogenic and a hyperandrogenic syndrome, and all studies have shown that hyperestrogenemia is the result of an elevation of estrone with plasma estradiol levels in the normal follicular range. Because a literature search failed to reveal any report of polycystic ovarian disease with significantly elevated estradiol levels, we report a case in which the plasma estradiol was so massively elevated as to mimic an estrogen-producing neoplasm. This case also suggests that although polycystic ovarian disease is a very rare cause of such excessive estradiol production, it should be included in the differential diagnosis of estrogen-producing neoplasms.
J Clin Endocrinol Metab. 1995 Feb;80(2):603-7.
The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome.
Ditkoff EC, Fruzzetti F, Chang L, Stancyzk FZ, Lobo RA.
Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO. Eight patients with PCO and seven matched controls received ovine corticotropin-releasing hormone (oCRH; 0.1 micrograms/kg) iv before and after hypoestrogenism was induced by leuprolide acetate (LA; 1 mg, sc, each day). In patients with PCO, a third oCRH test was repeated after transdermal estradiol (E2; 0.1 mg) had been applied for a week, during which time LA was continued. At baseline, patients with PCO had increased responses of 11 beta-hydroxyandrostenedione and dehydroepiandrosterone (P < 0.03 and P < 0.02) and increased delta maximal ratios of androstenedione (A4)/ACTH and dehydroepiandrosterone/ACTH (P < 0.01) after oCRH treatment. After LA administration to patients with PCO, these ratios were significantly suppressed (P < 0.01) and returned to baseline after E2 was added. There were no changes in controls. Steroid ratio responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal E2 administration. There was a significant positive correlation between changes in E2 levels and delta maximum change in the ratios of A4/17-OHP after oCRH treatment, signifying 17,20-desmolase activity (r = 0.58, P < 0.02). In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome.
Endocrinology. 1993 Dec;133(6):2696-703.
Ovarian steroidal response to gonadotropins and beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic innervation.
Barria A, Leyton V, Ojeda SR, Lara HE.
Experimental induction of a polycystic ovarian syndrome (PCOS) in rodents by the administration of a single dose of estradiol valerate (EV) results in activation of the peripheral sympathetic neurons that innervate the ovary. This activation is evidenced by an increased capacity of ovarian nerve terminals to incorporate and release norepinephrine (NE), an increase in ovarian NE content, and a decrease in ovarian beta-adrenergic receptor number in the ovarian compartments receiving catecholaminergic innervation. The present experiments were undertaken to examine the functional consequences of this enhanced sympathetic outflow to the ovary. The steroidal responses of the gland to beta-adrenergic receptor stimulation and hCG were examined in vitro 60 days after EV administration, i.e. at the time when follicular cysts are well established. EV-treated rats exhibited a remarkable increase in ovarian progesterone and androgen responses to isoproterenol, a beta-adrenergic receptor agonist, with no changes in estradiol responsiveness. Basal estradiol release was, however, 50-fold higher than the highest levels released from normal ovaries at any phase of the estrous cycle. The ovarian progesterone and androgen responses to hCG were enhanced in EV-treated rats, as were the responses to a combination of isoproterenol and hCG. Transection of the superior ovarian nerve (SON), which carries most of the catecholaminergic fibers innervating endocrine ovarian cells, dramatically reduced the exaggerated responses of all three steroids to both beta-adrenergic and gonadotropin stimulation. SON transection also reduced the elevated levels of ovarian NE resulting from EV treatment and caused up-regulation of beta-adrenoreceptors. Most importantly, SON transection restored estrous cyclicity and ovulatory capacity. The results indicate that the increased output of ovarian steroids in PCOS is at least in part due to an enhanced responsiveness of the gland to both catecholaminergic and gonadotropin stimulation. The ability of SON transection to restore a normal response indicates that the alteration in steroid output results from a deranged activation of selective components of the noradrenergic innervation to the ovary. These findings support the concept that an alteration in the neurogenic control of the ovary contributes to the etiology of PCOS.
Br J Obstet Gynaecol. 1976 Aug;83(8):593-602.
Polycystic ovarian disease.
Duignan NM.
Sex hormone binding globulin (SHBG) capacity was reduced in 9 of 31 patients with polycystic ovarian (PCO) disease and the mean level in PCO patients was significantly less (p less than 0.001) than normal. Serum testosterone levels were elevated in 21 of 32 PCO patients and the mean level was significantly elevated (p less than 0.001). Serum androstenedione values were raised in 17 of 31 patients and the mean value was also significantly raised (p less than 0.001). Serum dehydroepiandrosterone sulphate (DHAS) concentrations were elevated in only 2 of 14 patients. Urinary 17-oxo and 17-oxogenic steroids were normal in all patients studied. Basal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were normal but LH release following injection of luteinizing hormone-releasing hormone (LH-RH) was enhanced. A highly significant negative correlation (r=–0.449; p less than 0.01) was found between the logarithm of testosterone and the logarithm of LH levels. Serum prolactin concentrations were elevated in 4 of 21 PCO patients. Thyroid-stimulating hormone (TSH) values were normal. Eighteen of 20 patients ovulated following treatment with clomiphene and nine became pregnant. Five of 12 of patients treated with oestrogen/progesterone preparations noticed an improvement in their hirsutism. It is suggested that the normal cyclical release of LH is inhibited in PCO disease by a negative feedback by androgens to the hypothalamus or the pituitary, and that wedge resection should be reserved for patients in whom other forms of treatment have failed.
Akush Ginekol (Mosk). 1990 Sep;(9):61-3.
[The therapeutic effect of parlodel in the polycystic ovary syndrome].
[Article in Russian]
Soboleva EL, Komarov EK, Potin VV, Svechnikova FA.
Parlodel (2.5-50 mg/day) has been given for 1 to 7 days to 33 patients with the polycystic ovary syndrome (POS). The ovulatory menstrual cycle returned in 10 (30%) patients and 4 of them conceived. Pretreatment cycle disturbance persisted in 6 (18%) patients. Parlodel reduced mid-follicular mean blood LH levels to values of normal women. Some decrease in blood testosterone levels occurred only in the second phase of the cycle. Estradiol test in 6 patients showed normal positive and negative feedbacks in the hypothalamic-pituitary-ovarian axis. Parlodel treatment reduced basal and estradiol stimulated pituitary gonadotropin secretion. It is suggested that parlodel may be used in ovulation induction in a proportion of POS patients.
Obstet Gynecol. 1980 May;55(5):579-82.
Prolactin release in polycystic ovary.
Falaschi P, del Pozo E, Rocco A, Toscano V, Petrangeli E, Pompei P, Frajese G.
Ten normoprolactinemic and 10 hyperprolactinemic patients, all with polycystic ovary syndrome (PCO), were subjected to prolactin (PRL) stimulatory tests with thyrotropin-releasing hormone (TRH), 200 microgram intravenously, and haloperidol (a dopamine-blocking agent), 1 mg intramuscularly. The results were compared with those of 8 women with idiopathic hyperprolactinemia and 10 normal female volunteers. Distinctive features of PCO were elevated plasma concentrations of luteinizing hormone, estrone, and testosterone in the presence of normal estradiol, whereas in idiopathic hyperprolactinemia estradiol was reduced. Both groups of patients with PCO exhibited responses to TRH and haloperidol significantly higher than the controls (P less than .001), whereas only the hyperprolactinemic PCO patients reacted with an excessive PRL discharge (P less than .001). As expected, the response to both secretagogue agents was blunted in patients with idiopathic hyperprolactinemia. The present report discusses the possible implication of estrogen and the dopaminergic system in the mechanisms leading to hyperprolactinemia and enhanced PRL release in PCO.
The Journal of Clinical Endocrinology & Metabolism September 1, 1996 vol. 81 no. 9 3299-3306
The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome.
A Dunaif, D Scott, D Finegood, B Quintana and R Whitcomb
We performed this study to investigate the hypothesis that insulin resistance plays a role in the pathogenesis of reproductive abnormalities in women with the polycystic ovary syndrome (PCOS). Twenty-five women with PCOS were enrolled in a double-blind randomized 3-month trial of two doses of the insulin-sensitizing agent, troglitazone, 21 of whom completed the study: 200 mg, n = 10; 400 mg, n = 11. Baseline hormonal parameters and glucose tolerance were compared with 12 age- and weight-matched ovulatory control women. There were no significant changes in body mass index during the study. Fasting (P < 0.01) and 2-h post-75-g glucose load insulin levels (P < 0.05), as well as integrated insulin responses to the glucose load, decreased (P < 0.05), and insulin sensitivity assessed by a frequently sampled iv glucose tolerance test increased significantly (P < 0.001) during troglitazone treatment. This was accompanied by significant decreases in the levels of nonsex hormone-binding globulin-bound testosterone (P < 0.01), dehydroepiandrosterone sulfate (P < 0.001), estradiol (P < 0.01), and estrone (P < 0.001). Stepwise regression analysis indicated that decreases in nonsex hormone-binding globulin testosterone levels were significantly correlated with decreases in integrated insulin responses to the glucose load (r2 0.44, P < 0.01). The only significant changes at the 200-mg troglitazone dose were an increase in insulin sensitivity (P < 0.05) and decreases in dehydro-epiandrosterone sulfate (P < 0.01) and estrone (P < 0.05) levels. At the 400-mg dose, in addition to the changes noted in the entire troglitazone treatment group, increases in the disposition index (the product of insulin sensitivity and secretion) achieved significance, as did decreases in androstenedione (P < 0.01) and LH (P < 0.05) levels and increases in sex hormone-binding globulin levels (P < 0.01). Two PCOS women had ovulatory menses. We conclude that 1) troglitazone improves total body insulin action in PCOS, resulting in lower circulating insulin levels; 2) insulin resistance, probably via hyperinsulinemia, results in a general augmentation of steroidogenesis and LH release in PCOS; and 3) insulin-sensitizing agents, such as troglitazone, may provide a novel therapy for PCOS.
Shock Increases Estrogen
February 17th, 2012Since Selye’s work, it has been known that estrogen creates the same conditions as occur in the shock phase of the stress reaction. (And shock, in a potential vicious circle, can increase the level of estrogen.) -Ray Peat, PhD
Circ Shock. 1994 Aug;43(4):171-8.
Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock.
Fourrier F, Jallot A, Leclerc L, Jourdain M, Racadot A, Chagnon JL, Rime A, Chopin C.
METHODS:
Estrone (E1), estradiol (E2), testosterone (T), FSH, and LH levels were daily measured during a ten day period in 50 critically ill patients (38 men, 12 post-menopausal women). Patients were separated into four groups: A) no circulatory failure, no sepsis, B) sepsis syndrome without circulatory failure, C) circulatory failure without sepsis syndrome, D) septic shock. Results of hormonal measurements were compared 1) among the 4 groups, 2) between male and female patients, 3) between septic and nonseptic patients. The potential for the infusion of the vasoactive drug dobutamine to induce sex hormonal changes was documented in ten additional septic shock patients by measuring cortisol, E1, and T at base-line and after dobutamine infusion. Changes in active renin and plasma renin activity (PRA) were used as indirect witness of the dobutamine-induced beta 2-stimulation.
RESULTS:
A dramatic increase in E1 and E2 levels was observed in women of groups B and D, and only in male patients of group D. In the septic patients, estrogen levels peaked at days 1 and 2 and trended to normal from day 6 after the onset of sepsis, while FSH and LH decreased. No difference was found between survivors and non-survivors. Whatever the group, male patients had low T levels throughout the study. Dobutamine induced a significant increase in active renin levels and a decrease in the regression slope between renin and PRA. Cortisol levels remained normal. No significant change in E1 and T was observed after dobutamine.
CONCLUSIONS:
High estrogen levels were specifically observed in patients with sepsis and septic shock, either males or females. Decreased LH and FSH levels were consistent with the negative feed-back effect of high estrogen levels on pituitary secretion. Circulating T levels were decreased in all male patients. We found no correlation between sequential estrogen levels and outcome. These levels were not modified by a dobutamine-induced beta-2 stimulation.
Bisphenol A (BPA), Estrogen, and Development
February 17th, 2012The estrogenic effects of bisphenol A (BPA) create a potential model of estrogen’s harm of mother and fetus.
Arch Toxicol. 2006 Oct;80(10):647-55. Epub 2006 Apr 8.
Toxicokinetics of bisphenol A in pregnant DA/Han rats after single i.v. application.
Moors S, Diel P, Degen GH.
Bisphenol A (BPA) is an important chemical in the production of epoxy resins and polycarbonate plastics, and basic monomers which are used for a variety of applications. Consumer exposure to BPA may be possible from migration of BPA from dental sealants or from polycarbonate or epoxy-lined food and drink containers. BPA is known to act as weak estrogen mimic in rodents, and there is a concern of adverse endocrine effects, especially from prenatal exposure to this potential ‘endocrine disruptor’. To address this concern, we have studied the disposition and transplacental transfer of BPA in pregnant DA/Han rats on day 18 of gestation. The BPA concentrations were determined by GC/MS analysis in maternal blood, maternal organs (liver, kidney, uterus), placenta and fetuses (fetal liver and residual tissues) at different time-points (5-360 min) after intravenous administration of 10 mg BPA/kg body weight. Total BPA (aglycone and conjugates) was analyzed in all tissue samples after enzymatic hydrolysis and liquid/liquid extraction; in maternal plasma, total BPA and BPA aglycone were analyzed in parallel samples (with/without hydrolysis). Soon (5 min) after the i.v. injection a mean total BPA concentration of 3.8 microg/ml was found in maternal plasma; it declined in the first 2 h to 0.7 microg/ml. Early after injection, the majority of circulating BPA (almost 80%) was still in the aglycone form, but, metabolism by phase II enzymes decreased the BPA aglycone concentration to 0.3 microg/ml after 2 h. Despite this efficient conjugation, BPA was rapidly distributed in the organism: In well perfused organs peak concentrations for total BPA were attained 20-30 min after intravenous administration, with mean values of about 9.7 microg/g in maternal liver, 8.6 microg/g in kidneys, and 6.2 microg/g in the uterus. The peak values in other tissues were lower, with 4.0 microg/g for placenta, 3.3 microg/g for fetal liver, and 2.4 microg/g for residual fetus homogenate. The BPA levels in all tissues thereafter declined more or less in parallel with those in maternal blood. The rather similar concentration time course in placenta and fetal liver indicates that BPA is readily transferred across the placenta of DA/Han rats to the fetus. Our data on BPA disposition in DA/Han rats are discussed in the context of other kinetic studies with BPA in pregnant rats, and in relation to the previous results from our laboratory (Degen et al. Arch Toxicol 76:23-29, 2002a, b, c) demonstrating comparable transplacental transfer of daidzein, a phytoestrogen that accounts for a significant portion of total human exposure to potential endocrine disruptors.
Neuroscience. 2010 May 19;167(3):741-9. Epub 2010 Feb 26.
Corticosterone-regulated actions in the rat brain are affected by perinatal exposure to low dose of bisphenol A.
Poimenova A, Markaki E, Rahiotis C, Kitraki E.
The estrogen-mimicking endocrine disrupter bisphenol A (BPA) which is used in the manufacture of plastic and epoxy resins, is one of the world’s most heavily produced synthetic chemicals. BPA is detected in animal tissues, and its bio-accumulation has shown to be higher in the fetus than the mother. Exposure to doses below the daily safe limit has been reported to affect the sexual differentiation of the brain and modify the behavior of the exposed rodent offspring. The aim of the present study was to investigate in the rat the possible organizational effects of low BPA exposure on glucocorticoid-regulated responses. Female breeders were exposed to 40 microg/kg b.w. BPA daily throughout pregnancy and lactation. Plasma corticosterone levels and the two types of hippocampal corticosteroid receptors (GR and MR) were determined in mid-adolescent offspring under basal conditions and following a Y-maze task. BPA treated females had higher corticosterone levels than control females and BPA males and lower GR levels than BPA males, under basal conditions. Following the mildly stressful experience of Y-maze, corticosterone levels were increased in BPA-treated animals of both sexes, compared to the controls. GR levels were also increased in BPA-treated females compared to males. No effect of BPA was observed on MR levels, whereas the Y-maze experience significantly decreased receptors’ levels in both female groups. The animals’ performance in the task was also evaluated. BPA exposure significantly impaired the spatial recognition memory in both sexes, and modified the behavioural coping in a sex-dependent manner. Female BPA-treated offspring exhibited increased “anxiety-like” behaviour and dramatic loss of exploration attitude during the task, in comparison to males. This study provides for the first time evidence that corticosterone and its actions in the brain are sensitive to the programming effects of BPA at a dose below the currently acceptable daily intake.
Synapse. 2010 Jun;64(6):432-9.
Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice.
Tian YH, Baek JH, Lee SY, Jang CG.
Bisphenol A (BPA), an environmental endocrine-disrupting chemical, has been extensively evaluated for reproductive toxicity and carcinogenicity. However, little is known about the behavioral and neurochemical effects of BPA exposure. This study examined whether chronic daily exposure to an environmental endocrine-disrupting chemical, bisphenol A [(BPA); 100 microg/kg/day or 500 microg/kg/day, p.o.], from prenatal Day 7 to postnatal Day 36 would lead to changes in anxiety and memory in mice. First, we observed the behavioral alterations of BPA-treated mice using two anxiety-related models, the open field test and elevated plus maze (EPM) test. In the open field test, BPA treatment (100 microg/kg/day) increased movement in the central zone. BPA treatment (500 microg/kg/day) also increased the time spent in the open arms in the EPM test. Second, we measured cognitive ability in the Y-maze test and novel object test. BPA-treated mice showed decreased alternation behavior in the Y-maze at both of doses, indicating working memory impairment. BPA-treated mice (100 microg/kg/day) also showed decreased novel object recognition as expressed by central locomotion and frequency in the central zone, showing recognition memory impairment. Finally, to measure changes in the dopaminergic and NMDAergic systems in the brain, we performed autoradiographic receptor binding assays for dopamine D(1) and D(2) receptors, the NMDA receptor, and the dopamine transporter. BPA treatment increased D(2) receptor binding in the caudate putamen (CPu) but decreased DAT binding. BPA treatment also decreased NMDA receptor binding in the frontal cortex and CA1, CA3, and DG of the hippocampus. Taken together, our results suggest that long-term BPA exposure in mice can induce anxiolytic behaviors, cognitive deficits and changes in the dopaminergic and NMDAergic systems.
Horm Behav. 2010 Jul;58(2):326-33. Epub 2010 Mar 3.
Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl-D-aspartate receptors of hippocampus in male offspring mice.
Xu XH, Zhang J, Wang YM, Ye YP, Luo QQ.
Bisphenol-A (BPA) has been shown to influence development of the brain and behaviors. The purpose of the present report was to investigate the effects of perinatal exposure to BPA on learning/memory and its mechanism of action, especially focusing on N-methyl-d-aspartate receptor (NMDAR). Perinatal maternal exposure to BPA at 0.5, 5, and 50mg/kg/d significantly extended the escape length to find the hidden platform in Morris water maze, and BPA at 0.5 or 5mg/kg/d markedly decreased the percentage of time spent in the quadrant where the platform had been during training both in postnatal day (PND) 21 and PND 56 mice. The results of passive avoidance test showed that the error frequency to step down from a platform after received footshock was significantly increased, and the latency of the step-down response onto the grid floor 24h after received footshock was obviously reduced by exposure to BPA at 5 and 50mg/kg/d (P<0.01) in the PND 21 offspring or at 50mg/kg/d in the PND 56 offspring (P<0.01). Furthermore, perinatal exposure to BPA significantly inhibited the expressions of NMDAR subunits NR1, NR2A, and 2B in the hippocampus during the development stage, especially in PND 56 mice. The expressions of estrogen receptor beta (ERbeta) in both PND 21 and PND 56 mice were markedly down-regulated by BPA at 0.5, 5, and 50mg/kg/d. These results indicate that perinatal exposure to BPA affects normal behavioral development in both spatial memory and avoidance memory, and also permanently influences the behavior of offspring in adulthood. The inhibition of expressions of NMDAR subunits and ERbeta in hippocampus during postnatal development stage may be involved.
Environ Health Perspect. 2001 Jul;109(7):675-80.
Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels.
Rubin BS, Murray MK, Damassa DA, King JC, Soto AM.
The nonsteroidal estrogenic compound bisphenol A (BPA) is a monomer used in the manufacture of polycarbonate plastics and resins. BPA may be ingested by humans as it reportedly leaches from the lining of tin cans into foods, from dental sealants into saliva, and from polycarbonate bottles into their contents. Because BPA is weakly estrogenic–approximately 10,000-fold less potent than 17beta-estradiol–current environmental exposure levels have been considered orders of magnitude below the dose required for adverse effects on health. Herein we demonstrate measurable effects on the offspring of Sprague-Dawley female rats that were exposed, via their drinking water, to approximately 0.1 mg BPA/kg body weight (bw)/day (low dose) or 1.2 mg BPA/kg bw/day (high dose) from day 6 of pregnancy through the period of lactation. Offspring exposed to BPA exhibited an increase in body weight that was apparent soon after birth and continued into adulthood. In addition, female offspring exposed perinatally to the high dose of BPA exhibited altered patterns of estrous cyclicity and decreased levels of plasma luteinizing hormone (LH) in adulthood. Administration of neither the doses of BPA that caused effects during perinatal exposure nor a 10-fold higher dose was able to evoke a uterotropic response in ovariectomized postpubertal females. These data indicate an increased sensitivity to BPA during the perinatal period and suggest the need for careful evaluation of the current levels of exposure to this compound.
Environ Res. 2008 Oct;108(2):150-7.
Effects of developmental exposure to bisphenol A on brain and behavior in mice.
Palanza P, Gioiosa L, vom Saal FS, Parmigiani S.
Bisphenol A (BPA) is a widespread estrogenic chemical used in the production of polycarbonate, and epoxy resins lining food and beverage cans and in dental sealants. During fetal life the intrauterine environment is critical for the normal development, and even small changes in the levels of hormones, such as estradiol or estrogen-mimicking chemicals, can lead to changes in brain function and consequently in behavior. We review here a series of ethological studies on the effects of maternal oral exposure during the last part of gestation (prenatal exposure) or from gestation day 11 to postnatal day 7 (perinatal exposure) to a low, environmentally relevant dose of BPA (10 microg/kg bw/day) on behavioral responses of CD-1 mouse offspring. We examined both male and female offspring and found that maternal exposure to BPA affected: (1) behavioral responses to novelty before puberty and, as adults; (2) exploration and activity in a free-exploratory open field; (3) exploration in the elevated plus maze and (4) sensitivity to amphetamine-induced reward in the conditioned place preference test. A consistent effect of the maternal exposure to BPA is that in all these different experimental settings, while a significant sex difference was observed in the control group, exposure to BPA decreased or eliminated the sex difference in behavior. In addition, exposure of female mice to BPA in both adulthood or during fetal life altered subsequent maternal behavior. These findings, together with those from other laboratories, are evidence of long-term consequences of maternal exposure to low-dose BPA at the level of neurobehavioral development.
Horm Behav. 2007 Sep;52(3):307-16. Epub 2007 May 22.
Developmental exposure to low-dose estrogenic endocrine disruptors alters sex differences in exploration and emotional responses in mice.
Gioiosa L, Fissore E, Ghirardelli G, Parmigiani S, Palanza P.
Estrogenic endocrine disruptors (EEDs) are naturally occurring or man-made compounds present in the environment that are able to bind to estrogen receptors and interfere with normal cellular development in target organs and tissues. There is mounting evidence that EEDs can interfere with the processes of sexual differentiation of brain and behavior in different animal models. We investigated the effects of maternal exposure to EEDs, at concentrations within the range of human exposure and not patently teratogenic, on behavioral responses of male and female house mice (Mus musculus domesticus) before and after puberty. Pregnant dams were trained to spontaneously drink daily doses of corn oil with or without the estrogenic plastic derivative, bisphenol A (BPA 10 microg/kg), or the estrogenic insecticide methoxychlor (MXC 20 microg/kg) from gestation day 11 to postpartum day 8. Their male and female offspring were examined at different ages to examine several components of explorative and emotional behaviors in 3 experimental paradigms: a novelty test before puberty and, as adults, a free-exploratory open-field test and the elevated plus maze test. The main results are sex differences in control mice on a number of behavioral responses at both ages and in all experimental paradigms, while perinatal exposure to BPA or MXC decreased or eliminated such sex differences. The present findings are evidence of long-term consequences of developmental exposure to BPA and MXC on neurobehavioral development and suggest a differential effect of low-dose exposure to these estrogenic chemicals in males and females.
Bisphenol A (BPA), Estrogen, and Diabetes
February 17th, 2012Mol Cell Endocrinol. 2011 Dec 31. [Epub ahead of print]
Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways.
Alonso-Magdalena P, Ropero AB, Soriano S, García-Arévalo M, Ripoll C, Fuentes E, Quesada I, Nadal A.
Bisphenol-A (BPA) is an estrogenic monomer commonly used in the manufacture of numerous consumer products such as food and beverage containers. Widespread human exposure to significant doses of this compound has been reported. Traditionally, BPA has been considered a weak estrogen, based on its lower binding affinity to the nuclear estrogen receptors (ERs) compared to 17-β estradiol (E2) as well as its low transcriptional activity after ERs activation. However, in vivo animal studies have demonstrated that it can interfere with endocrine signaling pathways at low doses during fetal, neonatal or perinatal periods as well as in adulthood. In addition, mounting evidence suggests a variety of pathways through which BPA can elicit cellular responses at very low concentrations with the same or even higher efficiency than E2. Thus, the purpose of the present review is to analyze with substantiated scientific evidence the strong estrogenic activity of BPA when it acts through alternative mechanisms of action at least in certain cell types.
Endocrinology. 2006 Jun;147(6 Suppl):S56-69. Epub 2006 May 11.
Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure.
Welshons WV, Nagel SC, vom Saal FS.
Over 6 billion pounds per year of the estrogenic monomer bisphenol A (BPA) are used to manufacture polycarbonate plastic products, in resins lining metal cans, in dental sealants, and in blends with other types of plastic products. The ester bond linking BPA molecules in polycarbonate and resins undergoes hydrolysis, resulting in the release of free BPA into food, beverages, and the environment, and numerous monitoring studies now show almost ubiquitous human exposure to biologically active levels of this chemical. BPA exerts estrogenic effects through the classical nuclear estrogen receptors, and BPA acts as a selective estrogen receptor modulator. However, BPA also initiates rapid responses via estrogen receptors presumably associated with the plasma membrane. Similar to estradiol, BPA causes changes in some cell functions at concentrations between 1 pM and 1 nM, and the mean and median range of unconjugated BPA measured by multiple techniques in human pregnant maternal, fetal, and adult blood and other tissues exceeds these levels. In contrast to these published findings, BPA manufacturers persist in describing BPA as a weak estrogen and insist there is little concern with human exposure levels. Our concern with human exposure to BPA derives from 1) identification of molecular mechanisms mediating effects in human and animal tissues at very low doses, 2) in vivo effects in experimental animals caused by low doses within the range of human exposure, and 3) widespread human exposure to levels of BPA that cause adverse effects in animals.
Reprod Toxicol. 2007 Aug-Sep;24(2):199-224. Epub 2007 Jun 26.
In vivo effects of bisphenol A in laboratory rodent studies.
Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser-Kuntz DR, vom Saal FS.
Concern is mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical used in synthesis of plastics. We have reviewed the growing literature on effects of low doses of BPA, below 50 mg/(kg day), in laboratory exposures with mammalian model organisms. Many, but not all, effects of BPA are similar to effects seen in response to the model estrogens diethylstilbestrol and ethinylestradiol. For most effects, the potency of BPA is approximately 10-1000-fold less than that of diethylstilbestrol or ethinylestradiol. Based on our review of the literature, a consensus was reached regarding our level of confidence that particular outcomes occur in response to low dose BPA exposure. We are confident that adult exposure to BPA affects the male reproductive tract, and that long lasting, organizational effects in response to developmental exposure to BPA occur in the brain, the male reproductive system, and metabolic processes. We consider it likely, but requiring further confirmation, that adult exposure to BPA affects the brain, the female reproductive system, and the immune system, and that developmental effects occur in the female reproductive system.
Environ Health Perspect. 2006 Jan;114(1):106-12.
The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance.
Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A.
The function of the pancreatic beta-cell is the storage and release of insulin, the main hormone involved in blood glucose homeostasis. The results in this article show that the widespread environmental contaminant bisphenol-A (BPA) imitates 17beta-estradiol (E2) effects in vivo on blood glucose homeostasis through genomic and nongenomic pathways. The exposure of adult mice to a single low dose (10 microg/kg) of either E2 or BPA induces a rapid decrease in glycemia that correlates with a rise of plasma insulin. Longer exposures to E2 and BPA induce an increase in pancreatic beta-cell insulin content in an estrogen-receptor-dependent manner. This effect is visible after 2 days of treatment and starting at doses as low as 10 microg/kg/day. After 4 days of treatment with either E2 or BPA, these mice developed chronic hyperinsulinemia, and their glucose and insulin tolerance tests were altered. These experiments unveil the link between environmental estrogens and insulin resistance. Therefore, either abnormal levels of endogenous estrogens or environmental estrogen exposure enhances the risk of developing type 2 diabetes mellitus, hypertension, and dyslipidemia.
Int J Androl. 2008 Apr;31(2):194-200. Epub 2007 Oct 31.
Bisphenol-A disruption of the endocrine pancreas and blood glucose homeostasis.
Ropero AB, Alonso-Magdalena P, García-García E, Ripoll C, Fuentes E, Nadal A.
The link between endocrine disruptors and altered blood glucose homeostasis has been recently suggested. Epidemiological studies have correlated levels of phthalates, dioxins and persistent organic pollutants with alterations of blood glucose homeostasis in humans. Environmentally relevant doses of the ubiquitous endocrine disruptor bisphenol-A (BPA) have profound effects on mice endocrine pancreas–an essential tissue involved in glucose metabolism. BPA exerts rapid non-genomic effects on insulin releasing beta-cells and glucagon releasing alpha-cells within freshly isolated islets of Langerhans. In vivo, a single BPA injection of 10 microg/kg rapidly increases plasma insulin and concomitantly decreases glycaemia. When mice were treated with BPA 100 microg/kg/day for 4 days, the environmental oestrogen produced an increase in beta-cell insulin content along with a post-prandial hyperinsulinaemia and insulin resistance. The results reviewed here demonstrate that doses well below the current lowest observed adverse effect level considered by the US-EPA, disrupt pancreatic beta-cell function producing insulin resistance in male mice. Therefore, this altered blood glucose homeostasis by BPA exposure may enhance the risk of developing type II diabetes.
Mol Cell Endocrinol. 2009 May 25;304(1-2):63-8. Epub 2009 Mar 9.
The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes.
Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, Ropero AB.
The estrogen receptor ERalpha is emerging as a key molecule involved in glucose and lipid metabolism. The main functions of pancreatic beta-cells are the biosynthesis and release of insulin, the only hormone that can directly decrease blood glucose levels. Estrogen receptors ERalpha and ERbeta exist in beta-cells. The role of ERbeta is still unknown, yet ERalpha plays an important role in the regulation of insulin biosynthesis, insulin secretion and beta-cell survival. Activation of ERalpha by 17beta-estradiol (E2) and the environmental estrogen bisphenol-A (BPA) promotes an increase of insulin biosynthesis through a non-classical estrogen-activated pathway that involves phosphorylation of ERK1/2. The activation of ERalpha by physiological concentrations of E2 may play an important role in the adaptation of the endocrine pancreas to pregnancy. However, if ERalpha is over stimulated by an excess of E2 or the action of an environmental estrogen such as BPA, it will produce an excessive insulin signaling. This may provoke insulin resistance in the liver and muscle, as well as beta-cell exhaustion and therefore, it may contribute to the development of type II diabetes.
PLoS One. 2008 Apr 30;3(4):e2069.
Pancreatic insulin content regulation by the estrogen receptor ER alpha.
Alonso-Magdalena P, Ropero AB, Carrera MP, Cederroth CR, Baquié M, Gauthier BR, Nef S, Stefani E, Nadal A.
The function of pancreatic beta-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ER alpha and ER beta, are important molecules involved in glucose metabolism, yet their role in pancreatic beta-cell physiology is still greatly unknown. In this report we show that both ER alpha and ER beta are present in pancreatic beta-cells. Long term exposure to physiological concentrations of 17beta-estradiol (E2) increased beta-cell insulin content, insulin gene expression and insulin release, yet pancreatic beta-cell mass was unaltered. The up-regulation of pancreatic beta-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ER alpha and ER beta agonists as well as ER alphaKO and ER betaKO mice suggests that the estrogen receptor involved is ER alpha. The up-regulation of pancreatic insulin content by ER alpha activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.
Also see here – Estrogen Stimulates Insulin, Lowers Blood Sugar, Depletes Glycogen
How to Strain Orange Juice
February 16th, 2012Source – Danny Roddy
Valentine’s Day Strawberry Gummies
February 15th, 2012I LOVE every day, so Valentine’s Day is a great day to reflect on matters of the heart and not of the mind. A healthy heart-shaped, heart healthy recipe version of the popular gummy was inspired by my recent interest in gelatin.
Gelatin, the cooked form of collagen, is beneficial at reducing inflammation in the body.
Most gummy items purchased at the store are sweetened with corn syrup, high fructose corn syrup, etc…and I strongly believe you should avoid all products with any corn sweeteners. This is a great recipe to try with you kids or to whip up for your loved ones all year round!
Here it is, comment with questions!
EATgredients:
Directions:
1.) In medium bowl, mix water and gelatin, stirring until it forms a semi-hard substance (1 minute of stirring should be good) Let sit for 10 minutes.
2.) In medium sauce pan add sugar, orange juice, and lime juice. Mix and bring to a boil. Let boil for 2 minutes, turn off heat.
3.) Add in gelatin mix and strawberries and stir for 1-2 minutes, until there are no more clumps of gelatin. Turn off heat and cool for 5 minutes.
4.) Pour mixture in coconut oil greased pan (slightly greased). Depending on thickness of gummies you can use multiple pans/pyrex/etc…
5.) Allow to cool for 5 minutes and place in refrigerator. Gummies should be ready in an hour!
Note: I purchased the heart cut outs at Michaels for a couple of bucks!
Carbohydrate Lowers Free Tryptophan
February 15th, 2012J Sports Sci. 1995 Summer;13 Spec No:S49-53.
Central and peripheral factors in fatigue.
Davis JM.
The causes of fatigue during muscular exercise include factors that reside in the brain (central mechanisms) as well as the muscles themselves (peripheral mechanisms). Central fatigue is largely unexplored, but there is increasing evidence that increased brain serotonin (5-HT) can lead to central (mental) fatigue, thereby causing a deterioration in sport and exercise performance. Although there are also strong theoretical grounds for a beneficial role of nutrition in delaying central fatigue, the data are much more tenuous. Dietary supplementation with branched-chain amino acids (BCAA) in low doses produces small and probably inconsequential effects on peripheral markers of brain 5-HT synthesis (plasma free tryptophan/BCAA), whereas larger doses are likely to be unpalatable, reduce the absorption of water in the gut, and may increase potentially toxic ammonia concentrations in the plasma. Alternatively, carbohydrate supplementation results in large reductions in plasma free tryptophan/BCAA and exercise time to fatigue is significantly longer, but it is difficult to distinguish between the effects of carbohydrate feedings on central fatigue mechanisms and the well-established beneficial effects of carbohydrate supplements on the contracting muscle. These data support the exciting possibility that relationships exist among nutrition, brain neurochemistry and sport performance. However, while the evidence is intriguing and makes good intuitive sense, our knowledge in this area is rudimentary at best.
Am J Clin Nutr. 2000 Aug;72(2 Suppl):573S-8S.
Serotonin and central nervous system fatigue: nutritional considerations.
Davis JM, Alderson NL, Welsh RS.
Fatigue from voluntary muscular effort is a complex phenomenon involving the central nervous system (CNS) and muscle. An understanding of the mechanisms within muscle that cause fatigue has led to the development of nutritional strategies to enhance performance. Until recently, little was known about CNS mechanisms of fatigue, even though the inability or unwillingness to generate and maintain central activation of muscle is the most likely explanation of fatigue for most people during normal daily activities. A possible role of nutrition in central fatigue is receiving more attention with the development of theories that provide a clue to its biological mechanisms. The focus is on the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] because of its role in depression, sensory perception, sleepiness, and mood. Nutritional strategies have been designed to alter the metabolism of brain 5-HT by affecting the availability of its amino acid precursor. Increases in brain 5-HT concentration and overall activity have been associated with increased physical and perhaps mental fatigue during endurance exercise. Carbohydrate (CHO) or branched-chain amino acid (BCAA) feedings may attenuate increases in 5-HT and improve performance. However, it is difficult to distinguish between the effects of CHO on the brain and those on the muscles themselves, and most studies involving BCAA show no performance benefits. It appears that important relations exist between brain 5-HT and central fatigue. Good theoretical rationale and data exist to support a beneficial role of CHO and BCAA on brain 5-HT and central fatigue, but the strength of evidence is presently weak.
Tryptophan, Fatigue, Training, and Performance
February 15th, 2012Am J Clin Nutr. 2000 Aug;72(2 Suppl):573S-8S.
Serotonin and central nervous system fatigue: nutritional considerations.
Davis JM, Alderson NL, Welsh RS.
Fatigue from voluntary muscular effort is a complex phenomenon involving the central nervous system (CNS) and muscle. An understanding of the mechanisms within muscle that cause fatigue has led to the development of nutritional strategies to enhance performance. Until recently, little was known about CNS mechanisms of fatigue, even though the inability or unwillingness to generate and maintain central activation of muscle is the most likely explanation of fatigue for most people during normal daily activities. A possible role of nutrition in central fatigue is receiving more attention with the development of theories that provide a clue to its biological mechanisms. The focus is on the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] because of its role in depression, sensory perception, sleepiness, and mood. Nutritional strategies have been designed to alter the metabolism of brain 5-HT by affecting the availability of its amino acid precursor. Increases in brain 5-HT concentration and overall activity have been associated with increased physical and perhaps mental fatigue during endurance exercise. Carbohydrate (CHO) or branched-chain amino acid (BCAA) feedings may attenuate increases in 5-HT and improve performance. However, it is difficult to distinguish between the effects of CHO on the brain and those on the muscles themselves, and most studies involving BCAA show no performance benefits. It appears that important relations exist between brain 5-HT and central fatigue. Good theoretical rationale and data exist to support a beneficial role of CHO and BCAA on brain 5-HT and central fatigue, but the strength of evidence is presently weak.
Med Sci Sports Exerc. 1997 Jan;29(1):45-57.
Possible mechanisms of central nervous system fatigue during exercise.
Davis JM, Bailey SP.
Fatigue of voluntary muscular effort is a complex phenomenon. To date, relatively little attention has been placed on the role of the central nervous system (CNS) in fatigue during exercise despite the fact that the unwillingness to generate and maintain adequate CNS drive to the working muscle is the most likely explanation of fatigue for most people during normal activities. Several biological mechanisms have been proposed to explain CNS fatigue. Hypotheses have been developed for several neurotransmitters including serotonin (5-HT; 5-hydroxytryptamine), dopamine, and acetylcholine. The most prominent one involves an increase in 5-HT activity in various brain regions. Good evidence suggests that increases and decreases in brain 5-HT activity during prolonged exercise hasten and delay fatigue, respectively, and nutritional manipulations designed to attenuate brain 5-HT synthesis during prolonged exercise improve endurance performance. Other neuromodulators that may influence fatigue during exercise include cytokines and ammonia. Increases in several cytokines have been associated with reduced exercise tolerance associated with acute viral or bacterial infection. Accumulation of ammonia in the blood and brain during exercise could also negatively effect the CNS function and fatigue. Clearly fatigue during prolonged exercise is influenced by multiple CNS and peripheral factors. Further elucidation of how CNS influences affect fatigue is relevant for achieving optimal muscular performance in athletics as well as everyday life.
Amino Acids. 2001;20(1):25-34.
Amino acids and central fatigue.
Blomstrand E.
There is an increasing interest in the mechanisms behind central fatigue, particularly in relation to changes in brain monoamine metabolism and the influence of specific amino acids on fatigue. Several studies in experimental animals have shown that physical exercise increases the synthesis and metabolism of brain 5-hydroxytryptamine (5-HT). Support for the involvement of 5-HT in fatigue can be found in studies where the brain concentration of 5-HT has been altered by means of pharmacological agents. When the 5-HT level was elevated in this way the performance was impaired in both rats and human subjects, and in accordance with this a decrease in the 5-HT level caused an improvement in running performance in rats. The precursor of 5-HT is the amino acid tryptophan and the synthesis of 5-HT in the brain is thought to be regulated by the blood supply of free tryptophan in relation to other large neutral amino acids (including the branched-chain amino acids, BCAA) since these compete with tryptophan for transport into the brain. Studies in human subjects have shown that the plasma ratio of free tryptophan/BCAA increases during and, particularly, after sustained exercise. This would favour the transport of tryptophan into the brain and also the synthesis and release of 5-HT which may lead to central fatigue. Attempts have been made to influence the 5-HT level by giving BCAA to human subjects during different types of sustained heavy exercise. The results indicate that ingestion of BCAA reduces the perceived exertion and mental fatigue during exercise and improves cognitive performance after the exercise. In addition, in some situations ingestion of BCAA might also improve physical performance; during exercise in the heat or in a competitive race when the central component of fatigue is assumed to be more pronounced than in a laboratory experiment. However, more experiments are needed to further clarify the effect of BCAA and also of tryptophan ingestion on physical performance and mental fatigue.
Adv Exp Med Biol. 1995;384:315-20.
Tryptophan, 5-hydroxytryptamine and a possible explanation for central fatigue.
Newsholme EA, Blomstrand E.
In prolonged exercise the plasma level of branched-chain amino acids (BCAA) may fall and that of fatty acid increases: the latter increases the free tryptophan level, so that the plasma concentration ratio, free tryptophan/BCAA may increase leading to higher levels of tryptophan and therefore of 5-hydroxytryptamine (5-HT) in brain. The latter increases the activity of some 5-HT neurons in the brain which can cause sleep and which could, therefore, increase the mental effort necessary to maintain athletic activity. Drinks containing branched-chain amino acids should restore vigor to athletes whose performance is depressed by an excess of cerebral 5-HT. Recent work suggests that intake of branched-chain amino acids may improve performance in slower runners in the marathon and decrease perceived physical and mental exertion in laboratory experiments. This suggestion is supported by pharmacological manipulations that result in either increased or decreased physical performance.
Brain Res Bull. 1997;43(1):43-6.
Changes in the albumin binding of tryptophan during postoperative recovery: a possible link with central fatigue?
Yamamoto T, Castell LM, Botella J, Powell H, Hall GM, Young A, Newsholme EA.
Erratum in
Brain Res Bull 1997;44(6):735.
Tryptophan is the precursor of the neurotransmitter 5-hydroxytryptamine (5-HT), known to be involved in sleep and fatigue. In the blood, tryptophan binds to albumin, and that which does not, free tryptophan, competes with branched chain amino acids (BCAA) for entry into the brain. The plasma concentrations of albumin, free tryptophan, total tryptophan, and BCAA were measured before and after major surgery in nine elderly and nine coronary artery bypass graft (CABG) patients. In both the elderly and the CABG patients plasma free tryptophan concentrations were increased after surgery, compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased significantly after surgery. Plasma albumin concentrations were decreased significantly after surgery in both the elderly and the CABG patients. Plasma BCAA concentrations were not affected by surgery in either group. The effect of exercising to exhaustion on 5-HT and tryptophan were investigated in Nagase analbuminemic rats (NAR). The intrasynaptosomal concentration of tryptophan, 5-hydroxy-tryptophan, and 5-HT was increased by fatigue after exercise. In addition, running time to exhaustion was shortened in NAR. These data suggest that free tryptophan uptake and 5-HT synthesis were enhanced in the nerve terminal. A decrease in plasma albumin may account for the increase in plasma-free tryptophan levels. An increase in plasma free tryptophan, resulting in an enhanced plasma concentration ratio of free tryptophan/BCAA, may lead to a higher 5-HT concentration in some parts of the brain and, consequently, to central fatigue. It is suggested that provision of BCAA as a dietary supplement may counteract the increase in plasma free tryptophan and thus improve the status of some patients after major surgery.
Adv Exp Med Biol. 1999;467:697-704.
The role of tryptophan in fatigue in different conditions of stress.
Castell LM, Yamamoto T, Phoenix J, Newsholme EA.
Tryptophan is the precursor for the neurotransmitter 5-hydroxytryptamine (5-HT), which is involved in fatigue and sleep. It is present in bound and free from in the blood, where the concentration is controlled by albumin binding to tryptophan. An increase in plasma free tryptophan leads to an increased rate of entry of tryptophan into the brain. This should lead to a higher level of 5-HT which may cause central fatigue. Central fatigue is implicated in clinical conditions such as chronic fatigue syndrome and post-operative fatigue. Increased plasma free tryptophan leads to an increase in the plasma concentration ratio of free tryptophan to the branched chain amino acids (BCAA) which compete with tryptophan for entry into the brain across the blood-brain barrier. The plasma concentrations of these amino acids were measured in chronic fatigue syndrome patients (CFS) before and after exercise (Castell et al., 1998), and in patients undergoing major surgery (Yamamoto et al., 1997). In the CFS patients, the pre-exercise concentration of plasma free tryptophan was higher than in controls (p < 0.05) but did not change during or after exercise. This might indicate an abnormally high level of brain 5-HT in CFS patients leading to persistent fatigue. In the control group, plasma free tryptophan was increased after maximal exercise (p < 0.001), returning towards baseline levels 60 min later. The apparent failure of the CFS patients to change the plasma free tryptophan concentration or the free tryptophan/BCAA ratio during exercise may indicate increased sensitivity of brain 5-HT receptors, as has been demonstrated in other studies (Cleare et al., 1995). In post-operative recovery after major surgery plasma free tryptophan concentrations were markedly increased compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased after surgery. Plasma albumin concentrations were decreased after surgery: this may account for the increase in plasma free tryptophan levels. Provision of BCAA has improved mental performance in athletes after endurance exercise (Blomstrand et al., 1995, 1997). It is suggested that BCAA supplementation may help to counteract the effects of an increase in plasma free tryptophan, and may thus improve the status of patients during or after some clinically stressful conditions.
Int J Sport Nutr Exerc Metab. 2007 Aug;17 Suppl:S37-46.
Amino acids and the brain: do they play a role in “central fatigue”?
Meeusen R, Watson P.
It is clear that the cause of fatigue is complex, influenced by both events occurring in the periphery and the central nervous system (CNS). It has been suggested that exercise-induced changes in serotonin (5-HT), dopamine (DA), and noradrenaline (NA) concentrations contribute to the onset of fatigue during prolonged exercise. Serotonin has been linked to fatigue because of its documented role in sleep, feelings of lethargy and drowsiness, and loss of motivation, whereas increased DA and NA neurotransmission favors feelings of motivation, arousal, and reward. 5-HT has been shown to increase during acute exercise in running rats and to remain high at the point of fatigue. DA release is also elevated during exercise but appears to fall at exhaustion, a response that may be important in the fatigue process. The rates of 5-HT and DA/NA synthesis largely depend on the peripheral availability of the amino acids tryptophan (TRP) and tyrosine (TYR), with increased brain delivery increasing serotonergic and DA/NA activity, respectively. TRP, TYR, and the branched-chained amino acids (BCAAs) use the same transporter to pass through the blood-brain barrier, meaning that the plasma concentration ratio of these amino acids is thought to be a very important marker of neurotransmitter synthesis. Pharmacological manipulation of these neurotransmitter systems has provided support for an important role of the CNS in the development of fatigue. Work conducted over the last 20 y has focused on the possibility that manipulation of neurotransmitter precursors may delay the onset of fatigue. Although there is evidence that BCAA (to limit 5-HT synthesis) and TYR (to elevate brain DA/NA) ingestion can influence perceived exertion and some measures of mental performance, the results of several apparently well-controlled laboratory studies have yet to demonstrate a clear positive effect on exercise capacity or performance. There is good evidence that brain neurotransmitters can play a role in the development of fatigue during prolonged exercise, but nutritional manipulation of these systems through the provision of amino acids has proven largely unsuccessful.
J Sports Sci. 1995 Summer;13 Spec No:S49-53.
Central and peripheral factors in fatigue.
Davis JM.
The causes of fatigue during muscular exercise include factors that reside in the brain (central mechanisms) as well as the muscles themselves (peripheral mechanisms). Central fatigue is largely unexplored, but there is increasing evidence that increased brain serotonin (5-HT) can lead to central (mental) fatigue, thereby causing a deterioration in sport and exercise performance. Although there are also strong theoretical grounds for a beneficial role of nutrition in delaying central fatigue, the data are much more tenuous. Dietary supplementation with branched-chain amino acids (BCAA) in low doses produces small and probably inconsequential effects on peripheral markers of brain 5-HT synthesis (plasma free tryptophan/BCAA), whereas larger doses are likely to be unpalatable, reduce the absorption of water in the gut, and may increase potentially toxic ammonia concentrations in the plasma. Alternatively, carbohydrate supplementation results in large reductions in plasma free tryptophan/BCAA and exercise time to fatigue is significantly longer, but it is difficult to distinguish between the effects of carbohydrate feedings on central fatigue mechanisms and the well-established beneficial effects of carbohydrate supplements on the contracting muscle. These data support the exciting possibility that relationships exist among nutrition, brain neurochemistry and sport performance. However, while the evidence is intriguing and makes good intuitive sense, our knowledge in this area is rudimentary at best.
Vitamin C and Iron Absorption
February 15th, 2012Int J Vitam Nutr Res Suppl. 1989;30:103-8.
The role of vitamin C in iron absorption.
Hallberg L, Brune M, Rossander L.
Iron requirements remain the same despite the current lower energy requirement. This means that more iron must be absorbed per unit energy. A higher bioavailability of the dietary iron can be achieved by increasing the content of food components enhancing iron absorption (ascorbic acid, meat/fish) or by decreasing the content of inhibitors (e.g., phytates, tannins). The latter is not feasible considering the recent and reasonable trend toward increasing the intake of dietary fibre. The key role of ascorbic acid for the absorption of dietary nonheme iron is generally accepted. The reasons for its action are twofold: (1) the prevention of the formation of insoluble and unabsorbable iron compounds and (2) the reduction of ferric to ferrous iron, which seems to be a requirement for the uptake of iron into the mucosal cells.
Fed Proc. 1983 Apr;42(6):1716-20.
An overview of current information on bioavailability of dietary iron to humans.
Morris ER.
Bioavailability factors can greatly modify the absorption of dietary iron consumed in different meals by an individual. A greater percentage is generally absorbed of heme iron from animal tissues than of nonheme iron of either animal or plant food. The amount of meat in a meal is the only bioavailability factor known to influence absorption of heme iron. Absorption of iron from the exchangeable nonheme iron pool of a meal is influenced by both enhancing and inhibiting substances or factors. Ascorbic acid, meat, fish, and poultry enhance absorption of nonheme iron, and meals may be classified according to relative bioavailability depending on the content of meat, fish, poultry, and/or ascorbic acid. Some low-molecular-weight organic acids may also increase the bioavailability of nonheme iron. Synthetic metal-chelating agents added to foods and the beverages tea and coffee will inhibit absorption of nonheme iron in a concentration-dependent manner. Wheat bran, soy products, cow’s milk, and egg tend to decrease bioavailability of nonheme iron when included in a meal. However, the effect of compounds thought to be responsible for the inhibition in purified form (phytate, fiber, phosphoproteins) is dependent on chemical form and concentration. In some foods there may be as yet unidentified inhibitors or interaction between compounds to inhibit absorption of nonheme iron. Currently available information permits estimation of relative bioavailable iron in a meal.
Ann N Y Acad Sci. 1980;355:32-44.
Interaction of vitamin C and iron.
Lynch SR, Cook JD.
Food iron is absorbed by the intestinal mucosa from two separate pools of heme and nonheme iron. Heme iron, derived from hemoglobin and myoglobin, is well absorbed and relatively little affected by other foods eaten in the same meal. On the other hand, the absorption of nonheme iron, the major dietary pool, is greatly influenced by meal composition. Ascorbic acid is a powerful enhancer of nonheme iron absorption and can reverse the inhibiting effect of such substances as tea and calcium/phosphate. Its influence may be less pronounced in meals of high iron availability–those containing meat, fish, or poultry. The enhancement of iron absorption from vegetable meals is directly proportional to the quantity of ascorbic acid present. The absorption of soluble inorganic iron added to a meal increases in parallel with the absorption of nonheme iron, but ascorbic acid has a much smaller effect on insoluble iron compounds, such as ferric oxide or ferric hydroxide, which are common food contaminants. Ascorbic acid facilitates iron absorption by forming a chelate with ferric iron at acid pH that remains soluble at the alkaline pH of the duodenum. High cost and instability during food storage are the major obstacles to using ascorbic acid in programs designed to combat nutritional iron deficiency anemia.
Thyroid Status and Oxidized LDL
February 13th, 2012J Clin Endocrinol Metab. 1997 Oct;82(10):3421-4.
Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation.
Sundaram V, Hanna AN, Koneru L, Newman HA, Falko JM.
Hypothyroidism is frequently associated with hypercholesterolemia and an increased risk for atherosclerosis, whereas hyperthyroidism is known to precipitate angina or myocardial infarction in patients with underlying coronary heart disease. We have shown previously that L-T4 functions as an antioxidant in vitro and inhibits low density lipoprotein (LDL) oxidation in a dose-dependent fashion. The present study was designed to evaluate the changes in LDL oxidation in subjects with hypothyroidism and hyperthyroidism. Fasting blood samples for LDL oxidation analyses, lipoprotein determinations, and thyroid function tests were collected at baseline and after the patients were rendered euthyroid. The lag phase (mean +/- SEM hours) of the Cu+2-catalyzed LDL oxidation in the hypothyroid state and the subsequent euthyroid states were 4 +/- 0.0.65 and 14 +/- 0.68 h, respectively (P < 0.05). The lag phase during the hyperthyroid phase was 6 +/- 0.55 h, and that during the euthyroid phase was 12 +/- 0.66 h (P < 0.05). The total and LDL cholesterol levels were higher in hypothyroidism than in euthyroidism and were lower in hyperthyroidism than in the euthyroid state. We conclude that LDL has more susceptibility to oxidation in both the hypothyroid and hyperthyroid states. Thus, the enhanced LDL oxidation may play a role in the cardiac disease process in both hypothyroidism and hyperthyroidism.
J Clin Endocrinol Metab. 1998 May;83(5):1752-5.
Increased oxidizability of low-density lipoproteins in hypothyroidism.
Diekman T, Demacker PN, Kastelein JJ, Stalenhoef AF, Wiersinga WM.
Hypothyroidism leads to an increase of plasma low-density lipoprotein (LDL) cholesterol levels. Oxidation of LDL particles changes their intrinsic properties, thereby enhancing the development of atherosclerosis. T4 has three specific binding sites on apolipoprotein B; furthermore it inhibits LDL oxidation in vitro. We therefore hypothesized that T4 deficiency not only results in elevated LDL-cholesterol levels but also in increased LDL oxidation. Ten patients with overt hypothyroidism were studied when untreated (TSH 76 +/- 13 mU/L, T4 40 +/- 6 nmol/L) and again when they were euthyroid for at least 3 months during T4 treatment (TSH 2.7 +/- 0.5 mU/L, T4 115 +/- 11 nmol/L). Plasma lipids and lipoproteins and the oxidizability and chemical composition of LDL were determined. The transition from the hypothyroid to the euthyroid state was associated with a decrease (mean +/- SE) of plasma total cholesterol (5.8 +/- 0.3 vs. 4.8 +/- 0.2 mmol/L, P < 0.005), LDL cholesterol (3.8 +/- 0.3 vs. 2.9 +/- 0.2 nmol/L, P < 0.005) and apolipoprotein B (1.2 +/- 0.1 vs. 0.9 +/- 0.1 g/L, P < 0.005); plasma high-density lipoprotein cholesterol, apolipoprotein A-1, and triglycerides did not change. The actual content of dienes in LDL particles was increased in hypothyroidism, with a decrease after T4 suppletion [median (range) = 257 (165-346) vs. 188 (138-254) nmol/mg LDL protein, P < 0.005; reference range 140-180]. The lag time, an estimate of the resistance of LDL against oxidation in vitro, was shortened when hypothyroid but normalized after T4 treatment [29 (19-90) vs. 77 (42-96) min, P < 0.005; reference range 67-87]. The density, the relative fatty acid content, and the vitamin E content of LDL particles did not change. In conclusion, the hypothyroid state is not only associated with a quantitative increase of LDL particles, but it also changes their quality by increasing LDL oxidizability.
Arterioscler Thromb Vasc Biol. 1998 May;18(5):732-7.
Effect of thyroid function on LDL oxidation.
Costantini F, Pierdomenico SD, De Cesare D, De Remigis P, Bucciarelli T, Bittolo-Bon G, Cazzolato G, Nubile G, Guagnano MT, Sensi S, Cuccurullo F, Mezzetti A.
In this study, the effect of different levels of thyroid hormone and metabolic activity on low density lipoprotein (LDL) oxidation was investigated. Thus, in 16 patients with hyperthyroidism, 16 with hypothyroidism, and 16 age- and sex-matched healthy normolipidemic control subjects, the native LDL content in lipid peroxides, vitamin E, beta-carotene, and lycopene, as well as the susceptibility of these particles to undergo lipid peroxidation, was assessed. Hyperthyroidism was associated with significantly higher lipid peroxidation, as characterized by a higher native LDL content in lipid peroxides, a lower lag phase, and a higher oxidation rate than in the other two groups. This elevated lipid peroxidation was associated with a lower LDL antioxidant concentration. Interestingly, hypothyroid patients showed an intermediate behavior. In fact, in hypothyroidism, LDL oxidation was significantly lower than in hyperthyroidism but higher than in the control group. Hypothyroidism was also characterized by the highest beta-carotene LDL content, whereas vitamin E was significantly lower than in control subjects. In hyperthyroidism but not in the other two groups, LDL oxidation was strongly influenced by free thyroxine blood content. In fact in this group, the native LDL lipid peroxide content and the lag phase were directly and indirectly, respectively, related to free thyroxine blood levels. On the contrary, in hypothyroidism LDL oxidation was strongly and significantly related to serum lipids. In conclusion, both hypothyroidism and hyperthyroidism are characterized by higher levels of LDL oxidation when compared with normolipidemic control subjects. In hyperthyroid patients, the increased lipid peroxidation was strictly related to free thyroxine levels, whereas in hypothyroidism it was strongly influenced by serum lipids.
Endocr Res. 2004 Aug;30(3):481-9.
Effect of thyroid function on LDL oxidation in hypothyroidism and hyperthyroidism.
Oge A, Sozmen E, Karaoglu AO.
Oxidized low-density lipoproteins (LDL) are highly suspected of initiating the atherosclerosis process. Hypothyroidism is frequently associated with hypercholesterolemia and carries increased risk for atherosclerosis. In contrast to hypothyroidism, hyperthyroidism is not associated with increased LDL cholesterol, but is associated with increased oxidized LDL. This study was designed to evaluate the changes in LDL oxidation in subjects with hypothyroidism or hyperthyroidism, and to reveal the effects of treatment in hypothyroidism and hyperthyroidism on LDL oxidation and lipid profiles. Thirty-two patients with hypothyroidism and 16 patients with hyperthyroidism were studied before the therapy and thereafter, when they were euthyroid with appropriate treatment. Plasma lipids and lipoproteins, and the oxidizability of LDL by determining the levels of malonaldehyde bis (dimethyacetyl) (MDA) and diene conjugation, were determined at baseline and after the patients were rendered euthyroid. The actual content of dienes in LDL particles was increased in hypothyroidism, with a decrease after T4 supplementation (p < .001). Dienes in LDL particles were increased in hyperthyroidism, with a decrease after treatment (p < .05). In hypothyroid patients, the lag phase was shorter in the pretreatment period than in the euthyroid period (p > .05). The lag phase of hyperthyroid patients was shorter in the pretreatment period than in the euthyroid period and hypothyroid state (p < .001). The Cu2+-catalyzed dienes of LDL and MDA oxidation in the hypothyroid state and the subsequent euthyroid states were decreased (p < .001). The Cu2+-catalyzed dienes of LDL (p < .01) and MDA oxidation (p < .001) in hyperthyroid patients after treatment were decreased. The enhanced LDL oxidation may play a role in the cardiac disease process in both hypothyroidism and hyperthyroidism.
180 Nutrition Program Testimonial – Yeast Infections, Digestion, PMS
February 12th, 2012Female, 34, Southern California
What was the primary benefit of doing the Program for you?
Reoccurring vaginal yeast infections have ceased completely. Bloating and gas that was previously frequent only occurs if I eat the wrong foods.
How long did you spend in calendar time on the Program?
4 months
What were your body temperature and pulse changes during the Program?
Starting temperature was in the low 96s. Currently, I have consistent temperatures in the high 97s and low 98s depending upon where I am in my menstrual cycle.
Summarize your experience with the program as a testimonial to be used with your permission.
I’ve come a long way. Being very frustrated about the direction of my health for nine months was extremely taxing for me both physically and emotionally. My health had always been good and this was the first time that I had a long stretch of time where I couldn’t correct my problems quickly.
For nine months, I had reoccurring vaginal yeast infections, which were accompanied by thinning of my hair, and frequent gas and bloating. I also noticed flare ups seemed to be worst during certain parts of my menstrual cycle. Doctors did little to help or explain why this was occurring and maybe in this case actually put me going in the wrong direction. Nothing I did dietary seemed to be beneficial despite being strict with an “anti-yeast” diet, which varies depending upon what website you go to. That created some confusion on my part.
A girlfriend of mine told me about some of the information that FPS was putting out on their blog and Facebook page. I contacted Rob to see if he felt some of his recommendations would be of any benefit. He didn’t make any promises but was confident we could make some positive changes after he reviewed my assessment documentation.
Well, within two months my symptoms drastically lessened and by the end of four months I no longer had any symptoms. At the current time, I’ve been healthy for a period of eight months now. I didn’t want to write my testimonial too soon for fear that I would jinx myself or something, but Rob’s recommendations were definitely the key to my health reversal. Most of his coaching was the exact opposite of what I was doing previously including eating sugars from ripe fruits, orange juice, milk and consuming saturated fats which I thought weren’t healthy for me. I know better now though.
Rob was able to explain to me the big picture of how these symptoms can come about and then created a step by step program to that was initially a big change but with each day it became much easier for me to put into action. I had to increase my metabolism, eat digestible foods to improve my gut health, and balance my blood sugar if I was going to getting better. The foods were tasty and most were easy to find at my local grocery store. I know what to look for on labels to tell real from imposter health foods. My perspective on food has changed completely and for the better. I cannot believe how good health eating tastes! All of my girlfriends are asking me for my recipes.
Another added benefit is that my PMS is virtually gone. The only time I have menstrual issues is when I have a period of time when my diet isn’t the way it should be. I have the knowledge of what to eat and why to balance my hormones.
I hope this testimonial can help someone else that is in my shoes, b/c I was getting so frustrated and didn’t know where else to turn. I am glad that I found this information and hope others can approach this information with an open mind because it really works. You’ll have to be a little patient as health correction doesn’t happen overnight, but the results are worth the wait. Thanks FPS!
Preparing Powdered Eggshells for Calcium
February 7th, 2012The “chemical imbalance” myth
February 7th, 2012
“A theory that is wrong is considered preferable to admitting our ignorance.” – Elliot Vallenstein, Ph.D.
The idea that depression and other mental health conditions are caused by an imbalance of chemicals in the brain is so deeply ingrained in our psyche that it seems almost sacrilegious to question it.
Direct-to-consumer-advertising (DCTA) campaigns, which have expanded the size of the antidepressant market (Donohue et al., 2004), revolve around the claim that SSRIs (the most popular class of antidepressants) alleviate depression by correcting a deficiency of serotonin in the brain.
For example, Pfizer’s television advertisement for Zoloft states that “depression is a serious medical condition that may be due to a chemical imbalance”, and that “Zoloft works to correct this imbalance.”
Other SSRI advertising campaigns make similar claims. The Effexor website even has a slick video explaining that “research suggests an important link between depression and an imbalance in some of the brain’s chemical messengers. Two neurotransmitters believed to be involved in depression are serotonin and norepinephrine.” The video goes on to explain that Effexor works by increasing serotonin levels in the synapse, which is “believed to relieve symptoms of depression over time.”
These days serotonin is widely promoted as the way to achieve just about every personality trait that is desirable, including self-confidence, creativity, emotional resilience, success, achievement, sociability and high energy. And the converse is also true. Low serotonin levels have been implicated in almost every undesirable mental state and behavioral pattern, such as depression, aggressiveness, suicide, stress, lack of self-confidence, failure, low impulse control, binge eating and other forms of substance abuse.
In fact, the idea that low levels of serotonin cause depression has become so widespread that it’s not uncommon to hear people speak of the need to “boost their serotonin levels” through exercise, herbal supplements or even sexual activity. The “chemical imbalance” theory is so well established that it is now part of the popular lexicon.
It is, after all, a neat theory. It takes a complex and heterogeneous condition (depression) and boils it down to a simple imbalance of two to three neurotransmitters (out of more than 100 that have been identified), which, as it happens, can be “corrected” by long-term drug treatment. This clear and easy-to-follow theory is the driving force behind the $12 billion worth of antidepressant drugs sold each year.
However, there is one (rather large) problem with this theory: there is absolutely no evidence to support it. Recent reviews of the research have demonstrated no link between depression, or any other mental disorder, and an imbalance of chemicals in the brain (Lacasse & Leo, 2005; (Valenstein, 1998).
The ineffectiveness of antidepressant drugs when compared to placebo cast even more doubt on the “chemical imbalance” theory. (See my recent articles Placebos as effective as antidepressants and A closer look at the evidence for more on this.)
Folks, at this point you might want to grab a cup of tea. It’s going to take a while to explain the history of this theory, why it is flawed, and how continues to persist in light of the complete lack of evidence to support it. I will try to be as concise as possible, but there’s a lot of material to cover and a lot of propaganda I need to disabuse you of.
Ready? Let’s start with a bit of history.
The history of the “chemical imbalance” theory
The first antidepressant, iproniazid, was discovered by accident in 1952 after it was observed that some tubercular patients became euphoric when treated with this drug. A bacteriologist named Albert Zeller found that iproniazid was effective in inhibiting the enzyme monoamine oxydase. As its name implies, monoamine oxydase plays an essential role in inactivating monoamines such as epinephrine and norepinephrine. Thus, iproniazid raised levels of epinephrine and norepinephrine which in turn led to stimulation of the sympathetic nervous system – an effect thought to be responsible for the antidepressant action of the drug.
At around the same time, an extract from the plant Rauwolfia serpentina was introduced into western psychiatry. This extract had been used medicinally in India for more than a thousand years and was thought to have a calming effect useful to quite babies, treat insomnia, high blood pressure, insanity and much more. In 1953 chemists at Ciba, a pharmaceutical company, isolated the active compound from this herb and called it reserpine.
In 1955 researchers at the National Institutes of Health reported that reserpine reduces the levels of serotonin in the brains of animals. It was later established that all three of the major biogenic amines in the brain, norepinephrine, serotonin, and dopamine, were all decreased by reserpine (again, in animals).
In animal studies conducted at around the same time, it was found that animals administered reserpine showed a short period of increased excitement and motor activity, followed by a prolonged period of inactivity. The animals often had a hunched posture and an immobility that was thought to resemble catatonia (Valenstein, 1998). Since reserpine lowered levels of serotonin, norepinephrine and dopamine, and caused the effects observed in animals, it was concluded that depression was a result of low levels of biogenic amines. Hence, the “chemical imbalance” theory is born.
However, it was later found that reserpine only rarely produces a true clinical depression. Despite high doses and many months of treatment with reserpine, only 6 percent of the patients developed symptoms even suggestive of depression. In addition, an examination of these 6 percent of patients revealed that all of them had a previous history of depression. (Mendels & Frazer, 1974) There were even reports from a few studies that reserpine could have anantidepressant effect (in spite of reducing levels of serotonin, norepinephrine and dopanmine).
As it turns out, that is only the tip of the iceberg when it comes to revealing the inadequacies of the “chemical imbalance” theory.
The fatal flaws of “chemical imbalance” theory
As Elliot Valenstein Ph.D., Professor Emeritus of psychology and neuroscience at Michigan University, points out in his seminal book Blaming the Brain, “Contrary to what is often claimed, no biochemical, anatomical or functional signs have been found that reliably distinguish the brains of mental patients.” (p. 125)
In his book, Valenstein clearly and systematically dismantles the chemical imbalance theory:
Another problem is that it is not now possible to measure serotonin and norepinephrine in the brains of patients. Estimates of brain neurotransmitters can only be inferred by measuring the biogenic amine breakdown products (metabolites) in the urine and cerebrospinal fluid. The assumption underlying this measurement is that the level of biogenic amine metabolites in the urine and cerebrospinal fluid reflects the amount of neurotransmitters in the brain. However, less than one-half of the serotonin and norepinephrine metabolites in the urine or cerebrospinal fluid come from the brain. The other half come from various organs in the body. Thus, there are serious problems with what is actually being measured.
Finally, there is not a single peer-reviewed article that can be accurately cited to support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence. Furthermore, theDiagnostic and Statistical Manual of Mental Disorders (DSM) does not list serotonin as the cause of any mental disorder. The American Psychiatric Press Textbook of Clinical Psychiatry addresses serotonin deficiency as an unconfirmed hypothesis, stating “Additional experience has not confirmed the monoamine depletion hypothesis” (Lacasse & Leo, 2005).
When all of this evidence is taken in full, it should be abundantly clear that depression is not caused by a chemical imbalance.
But, as Valenstein shrewdly observes, “there are few rewards waiting for the person who claims that “the emperor is really nude” or who claims that we really do not know what causes depression or why an antidepressant sometimes helps to relieve this condition.”
How have we been fooled?
There are several reasons the idea that mental disorders are caused by a chemical imbalance has become so widespread (and none of them have anything to do with the actual scientific evidence, as we have seen).
It is known that people suffering from mental disorders and especially their families prefer a diagnosis of “physical disease” because it does not convey the stigma and blame commonly associated with “psychological problems”. A “physical disease” may suggest a more optimistic prognosis, and mental patients are often more amenable to drug treatment when they are told they have a physical disease.
Patients are highly susceptible to Direct-to-Consumer-Advertising (DCTA). It has been reported that patients are now presenting to their doctors with a self-described “chemical imbalance” (Kramer, 2002). This is important because studies show that patients who are convinced they are suffering from a neurotransmitter defect are likely to request a prescription for antidepressants, and may be skeptical of physicians who suggest other interventions such as cognitive behavioral therapy (DeRubeis et al., 2005). It has also been shown that anxious and depressed patients “are probably more susceptible to the controlling influence of advertisements (Hollon MF, 2004).
The benefit of the chemical imbalance theory for insurance companies and the pharmaceutical industry is primarily economic. Medical insurers are primarily concerned with cost, and they want to discourage treatments (such as psychotherapy) that may involve many contact hours and considerable expense. Their control over payment schedules enables insurance companies to shift treatment toward drugs and away from psychotherapy.
The motivation of the pharmaceutical companies should be fairly obvious. As mentioned previously, the market for antidepressant drugs is now $12 billion. All publicly traded for-profit companies are required by law to increase the value of their investor’s stock. Perhaps it goes without saying, but it is a simple fact that pharmaceutical companies will do anything they legally (and sometimes illegally) can to maximize revenues.
Studies have shown that the advertisements placed by drug companies in professional journals or distributed directly to physicians are often exaggerated or misleading and do not accurately reflect scientific evidence (Lacasse & Leo, 2005). While physicians deny they are being influenced, it has been shown repeatedly that their prescription preferences are heavily affected by promotional material from drug companies (Moynihan, 2003). Research also suggests that doctors exposed to company reps are more likely to favor drugs over non-drug therapy, and more likely to prescribe expensive medications when equally effective but less costly ones are available (Lexchin, 1989). Some studies have even shown an association between the dose and response: in other words, the more contact between doctors and sales reps the more doctors latch on to the “commercial” messages as opposed to the “scientific” view of a product’s value (Wazana, 2000).
The motivation of psychiatrists to accept the chemical imbalance theory is somewhat more subtle. Starting around 1930, psychiatrists became increasingly aware of growing competition from nonmedical therapists such as psychologists, social workers and counselors. Because of this, psychiatrists have been attracted to physical treatments like drugs and electroshock therapy that differentiate them from nonmedical practitioners. Psychiatry may be the least respected medical specialty (U.S. General Accounting Office report). Many Americans rejected Fruedian talk therapy as quackery, and the whole field of psychiatry lacks the quality of research (randomized, placebo-controlled, double-blind experiments) that serves as the gold-standard in other branches of medicine.
Dr. Colin Ross, a psychiatrist, describes it this way:
“I also saw how badly biological psychiatrists want to be regarded as doctors and accepted by the rest of the medical profession. In their desire to be accepted as real clinical scientists, these psychiatrists were building far too dogmatic an edifice… pushing their certainty far beyond what the data could support.”
Of course there are also many “benefits” to going along with the conventional “chemical imbalance” theory, such as free dinners, symphony tickets, and trips to the Caribbean; consultancy fees, honoraria and stock options from the pharmaceutical companies; and a much larger, growing private practice as the $20 billion spent by drug companies on advertising brings patients to the office. Psychiatrists are just human, like the rest of us, and not many of them can resist all of these benefits.
In sum, the idea that depression is caused by a chemical imbalance is a myth. Pharmaceutical ads for antidepressants assert that depression is a physical diseases because that serves as a natural and easy segue to promoting drug treatment. There may well be biological factors which predispose some individuals toward depression, but predisposition is not a cause. The theory that mental disorders are physical diseases ignores the relevance of psychosocial factors and implies by omission that such factors are of little importance.
Stay tuned for future articles on the psychosocial factors of depression, the loss of sadness as a normal response to life, and the branding of new psychological conditions as a means of increasing drug sales.
Making a Killing: The Untold Story of Psychotropic Drugging
February 7th, 2012This video provides the facts about psychotropic drugs and the huge profits they create for the pharmaceutical industry. These drugs are not safe and have not been on the market long enough to provide sufficient long term studies regarding their effects. These drugs do cause addiction, however most “doctors” would call this dependence because you do not have to take an increasing dose over time. They are completely fine with you being addicted to the same amount of any given drug on a daily basis. Over half of the people that commit suicide in the United States are prescribed to psychotropic drugs. (Ex: Paxil (Paroxetine), Zoloft (Sertraline), Prozac, Wellbutrin (Bupropion), Effexor, Seroquil, Ultram (Tramadol), etc.)
180 Nutrition Program Testimonial – Digestion, Sleep, Energy, Libido
February 6th, 2012Male, 30 years old, Southern California
What was the primary benefit of doing the Program for you?
The knowledge of how the human body really works, and what it takes to truly nourish your body so it can heal.
Did you experience changes in energy, appetite, emotional balance and mental sharpness?
Yes, I experienced an increase in all 4.
Did you have identified problems upon entering the Program, and were they changed?
I had digestion and evacuation issues, and also sleep problems. They all greatly improved on the program, and fairly quickly.
What is your next major plan for improving your health now, after the Program, if you have
one?
The program has become a way of life for me, so I will be continuing to implement what I have learned in the program in the future.
What were your body temperature changes during the Program?
My average waking temp is now between 97.8-98.0 an increase from 97. During the day my temp is now up to 98.6.
What is your normal pulse rate now? Did this change?
Pulse is also up to an average of 75 bpm. Up from around 60 bpm.
Would you recommend the Program to others?
l would highly recommend this program.
Summarize your experience with the program.
Before I began the program I had a lot of health concerns. I wasn’t digesting well, sleeping well, and I had lost my energy and libido as well. All this at the age of only 29! I was seen by many doctors and had lots of tests done, but they could find nothing. So I began surfing the web hoping to find a solution to my problems. I started trying just about everything out there, from a vegetarian diet to even a raw food diet, but nothing seemed to work. ln fact, it seemed to make things worse.
Then I came across the work of Ray Peat. As I read through a lot of his work a lot of things really made sense to me. The problem was that there was also a good portion of his work that I didn’t understand as well. As I kept researching his work and surfing the web some more trying to piece it all together so that I can implement his findings into my daily life I came across the Functional Performance Systems web page. lt was full of information on the findings of Ray Peats work. As I looked through the site, I saw that they offered a program that would help piece it all together for me so I could finally really put his work to the test.
That was when I decided to give FPS a call and give the program a try. That ended up being the best choice I made in my search to better health. That was when I met Rob Turner of FPS. Rob was the best teacher on the work of Ray Peat that I could have hoped for! He was with me every step of the program and really helped me understand how the human body really works and how to really heal your body by fixing your metabolism. Each week Rob went through each step of the program at my pace and really made it very easy to understand.
That was when things really started to change in the right direction for me. I was finally giving my body the fuel it needed to begin to heal. ln just a few weeks I started digesting better, sleeping better and my energy was coming back as well. Rob showed me how I can track my progress through my body temperature and pulses. As my temps and pulses began to rise my problems were getting better. I was finally healing my broken metabolism. I couldn’t believe that it could be done by just eating the way the body was designed to be feed. Even when there were bumps in the road Rob was always there to walk me through the problem and get me through it. I learned so much in this program and would highly recommend it to anyone who was looking to truly better their health!
Thumbs Up: Fructose
February 3rd, 2012Diabetes Care. 2007 Jun;30(6):1406-11. Epub 2007 Mar 23.
Orange juice or fructose intake does not induce oxidative and inflammatory response.
Ghanim H, Mohanty P, Pathak R, Chaudhuri A, Sia CL, Dandona P.
OBJECTIVE:
We have previously shown that 300 kcal from glucose intake induces a significant increase in reactive oxygen species (ROS) generation and nuclear factor-kappaB (NF-kappaB) binding in the circulating mononuclear cells in healthy normal subjects. We hypothesized that the intake of 300 calories as orange juice or fructose, the other major carbohydrate in orange juice, would induce a significantly smaller response than that of glucose.
RESEARCH DESIGN AND METHODS:
Four groups (eight subjects each) of normal-weight subjects were given a 300-cal drink of glucose (75 g), fructose (75 g), or orange juice or water sweetened with saccharin (control group) to drink, and then blood samples were collected.
RESULTS:
There was a significant increase in ROS generation by mononuclear cells (by 130 +/- 18%, P < 0.001), polymorph nuclear cells (by 95 +/- 22%, P < 0.01), and in NF-kappaB binding in mononuclear cells by 82 +/- 16% (P < 0.01) over the baseline after 2 h of glucose intake. These changes were absent following fructose, orange juice, or water intake. There was significantly lower ROS generation and NF-kappaB binding following orange juice, fructose, and water compared with glucose (P < 0.001 for all). Furthermore, incubation of mononuclear cells in vitro with 50 mmol/l of the flavonoids hesperetin or naringenin reduced ROS generation by 52 +/- 7% and 77 +/- 8% (P < 0.01), respectively, while fructose or ascorbic acid did not cause any change.
CONCLUSIONS:
Caloric intake in the form of orange juice or fructose does not induce either oxidative or inflammatory stress, possibly due to its flavonoids content and might, therefore, represent a potentially safe energy source.
Am J Hypertens. 2008 Jun;21(6):708-14. Epub 2008 Apr 10.
Hepatic effects of a fructose diet in the stroke-prone spontaneously hypertensive rat.
Brosnan MJ, Carkner RD.
BACKGROUND:
Feeding stroke-prone spontaneously hypertensive rats (SHRSP) a diet rich in fructose results in a profound glucose intolerance not observed in the normotensive Wistar Kyoto (WKY) strain. The aim of this study was to investigate the role of the liver in the underlying mechanisms in the SHRSP.
METHODS:
SHRSP and WKY rats were fed either 60% fructose or regular chow for 2 weeks with blood pressure being measured using tail-cuff plethysmography and radiotelemetry. Intraperitoneal glucose tolerance tests were performed and livers harvested for analysis of expression of inflammatory mediators and antioxidant proteins by western blotting and quantitative reverse transcriptase-PCR. The serum triglyceride content and fatty acid profiles were also measured.
RESULTS:
Feeding SHRSP and WKY on 60% fructose for 2 weeks resulted in glucose intolerance with no increases in levels of blood pressure. Serum triglycerides were increased in both strains of fructose-fed rats with the highest levels being observed in the SHRSP. The serum fatty acid profiles were changed with large increases in the amounts of oleic acid (18.1) and reductions in linoleic acid (18.2). Levels of expression of c-jun N-terminal kinase/stress activated protein kinase (JNK/SAPK), and nuclear factor kappaB (NF-kappaB) were shown to be unchanged between the livers of the chow and fructose-fed groups. In contrast, protein levels of the three isoforms of superoxide dismutase (SOD) were upregulated in liver of SHRSP fed on fructose while only manganese SOD (MnSOD) was upregulated in fructose-fed WKY rats.
CONCLUSIONS:
These results demonstrate that the major contribution of the liver in the early pathogenesis of metabolic syndrome may be an increased secretion of triglyceride containing altered proportions of fatty acid pools. Feeding rats a diet rich in fructose does not affect hepatic expression of inflammatory pathways and the increased hepatic SOD expression may constitute an early protective mechanism.
Am J Clin Nutr. 1989 Jun;49(6):1290-4.
Dietary fructose or starch: effects on copper, zinc, iron, manganese, calcium, and magnesium balances in humans.
Holbrook JT, Smith JC Jr, Reiser S.
A balance study was conducted to assess the effects of consuming low-copper diets, high in fructose or cornstarch. The study involved 19 apparently healthy males, aged 21-57 y. The two experimental diets averaged 0.35 mg Cu/1000 kcal and provided 20% of the calories from fructose or cornstarch. Cu, zinc, calcium, magnesium, and iron balances were determined 1 wk before the study (pretest) when the subjects consumed self-selected diets and after consuming the experimental diets for 6 wk. No major differences in mineral balances were evident between the two groups during the pretest study when the subjects ate self-selected diets. In contrast, when fed the test diets, the group consuming the low-Cu fructose diet had significantly more positive balances for all minerals studied than the group fed the low-Cu cornstarch diet. The results indicate that dietary fructose enhances mineral balance.
Anaesthesist. 1995 Nov;44(11):770-81.
[Fructose vs. glucose in total parenteral nutrition in critically ill patients].
[Article in German]
Adolph M, Eckart A, Eckart J.
Parenteral nutrition required following surgery or injury should not only meet post-aggression caloric requirements but also match the specific metabolic needs so as not to worsen the metabolic disruptions already present in this situation. The primary objective of parenteral nutrition is body protein maintenance or restoration by reduction of protein catabolism or promotion of protein synthesis or both. Whether all parenteral energy donors, ie., glucose, fructose, other polyols, and lipid emulsions, are equally capable of achieving this objective continues to be a controversial issue. The objective of the present study was to answer the following questions: (1) Do glucose and fructose differ in their effects on the metabolic changes seen following surgery or injury, the changes in glucose metabolism in particular? (2) Can the observation of poorer glucose utilization in the presence of lipids be confirmed in ICU patients?
PATIENTS, MATERIALS AND METHODS:
A prospective, randomized clinical trial has been conducted in 20 aseptic surgical ICU patients to generate an objective database along these lines by performing a detailed analysis of the metabolic responses to different parenteral nutrition protocols. The effects of a glucose solution+lipid emulsion regimen vs fructose solution+lipid emulsion regimen on a number of carbohydrate and lipid metabolism variables were evaluated for an isocaloric (carbohydrates: 0.25 g/kg body weight/h; lipids: 0.166g/kg body weight/h) and isonitrogenous (amino acids: 0.0625 g/kg body weight/h) total nutrient supply over a 10-h study period.
RESULTS:
A significantly smaller rise in blood glucose concentrations (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids n.s.) suggested that fructose had a small effect, if any at all, on glucose metabolism. Serum insulin activity showed significant differences as a function of carbohydrate regimen, i.e. infusion of fructose instead of glucose produced a less pronounced increase in insulin activity (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids P<0.01). Impairment of glucose utilization by concomitant administration of lipids was observed neither in patients who first received glucose nor in those who first received fructose.
CONCLUSIONS:
As demonstrated, parenteral fructose, unlike parenteral glucose, has a significantly less adverse impact than glucose on the glucose balance, which is disrupted initially in the post-aggression state. In addition, the less pronounced increase in insulin activity during fructose infusion than during glucose infusion can be assumed to facilitate mobilization of endogenous lipid stores and lipid oxidation. Earlier workers pointed out that any rise in free fatty acid and ketone body concentrations in the serum produces inhibition of muscular glucose uptake and oxidation, and of glycolysis. These findings were recorded in a rat model and could not be confirmed in our post-aggression state patients receiving lipid doses commensurate with the usual clinical infusion rates. The serious complications that can result from hereditary fructose intolerance are completely avoidable if a careful patient history is taken before the first parenteral use of fructose. If the patient or family members and close friends, are simply asked whether he/she can tolerate fruit and sweet dishes, hereditary fructose intolerance can be ruled out beyond all reasonable doubt. Only in the extremely rare situations in which it is not possible to question either the patient or any significant other, a test dose will have to be administered to exclude fructose intolerance. The benefits of fructose-specific metabolic effects reported in the literature and corroborated by the results of our own study suggest that fructose is an important nutrient that contributes to metabolic stabilization, especially in the post-aggression phase and in septic patients.
Bone. 2008 May;42(5):960-8. Epub 2008 Feb 15.
The effect of feeding different sugar-sweetened beverages to growing female Sprague-Dawley rats on bone mass and strength.
Tsanzi E, Light HR, Tou JC.
Consumption of sugar beverages has increased among adolescents. Additionally, the replacement of sucrose with high fructose corn syrup (HFCS) as the predominant sweetener has resulted in higher fructose intake. Few studies have investigated the effect of drinking different sugar-sweetened beverages on bone, despite suggestions that sugar consumption negatively impacts mineral balance. The objective of this study was to determine the effect of drinking different sugar-sweetened beverages on bone mass and strength. Adolescent (age 35d) female Sprague-Dawley rats were randomly assigned (n=8-9/group) to consume deionized distilled water (ddH2O, control) or ddH2O containing 13% w/v glucose, sucrose, fructose or high fructose corn syrup (HFCS-55) for 8weeks. Tibia and femur measurements included bone morphometry, bone turnover markers, determination of bone mineral density (BMD) and bone mineral content (BMC) by dual energy X-ray absorptiometry (DXA) and bone strength by three-point bending test. The effect of sugar-sweetened beverage consumption on mineral balance, urinary and fecal calcium (Ca) and phosphorus (P) was measured by inductively coupled plasma optical emission spectrometry. The results showed no difference in the bone mass or strength of rats drinking the glucose-sweetened beverage despite their having the lowest food intake, but the highest beverage and caloric consumption. Only in comparisons among the rats provided sugar-sweetened beverage were femur and tibia BMD lower in rats drinking the glucose-sweetened beverage. Differences in bone and mineral measurements appeared most pronounced between rats drinking glucose versus fructose-sweetened beverages. Rats provided the glucose-sweetened beverage had reduced femur and tibia total P, reduced P and Ca intake and increased urinary Ca excretion compared to the rats provided the fructose-sweetened beverage. The results suggested that glucose rather than fructose exerted more deleterious effects on mineral balance and bone.
Ann Nutr Aliment. 1975;29(4):305-12.
[Effects of administering diets with starch or sucrose basis on certain parameters of calcium metabolism in the young, growing rat].
[Article in French]
Artus M.
The important role of many carbohydrates on calcium metabolism has been demonstrated by FOURNIER and DUPUIS. Starch, however, neither influences the absorption nor the retention of calcium. Less is known about the effects of sucrose. In this study the influence of starch on calcium metabolsim has been compared with that of sucrose. Male weanling Wistar rats were divided into three groups according to their diets. The first group received a refined and well-balanced diet (except for the absence of vitamin D), containing 68 p. 100 of starch. The second group received the same diet except sucrose was substituted for the starch. The third group received the same diet as Group 1, with the addition of vitamin D. Plasma calcium citrate and urinary citrate and calcium were determined. At the age of 2 months after one night of fasting, each group of rats was injected intraperitoneally with a 1 ml, aqueous solution containing 1 mg calcium and 0, 6 mu Ci45Ca. Twenty-four hours later the animals were sacrificed and the calcium femur percentage, radioactivity p. 1,000 of the injected dose of 45Ca, and specific radioactivity were determined. When performance data from Group 3 were compared to Group 1 and Group 2, the following results were obtained: –Group 1 (starch diet without vitamin D) had very low plasma calcium levels; urinary calcium, plasma citrate and urinary citrate levels were lowered, and the calcium femur percentage was smaller. Bone avidity for calcium was found. –Group 2 (sucrose diet without vitamin D) had normal plasma calcium levels. Urinary calcium and citrate and plasma citrate did not show significant differences from those of animals receiving vitamin D. No significant differences were found in the specific radioactivity and radioactivity p. 1,000 of the administered dose. Contrary to starch, sucrose maintained calcium homeostasis, and apparently, normal ossification, although the femur was lighter than those of animals receiving vitamin D. Further work is necessary to determine whether the fructose component of the sucrose molecule is responsible for the increased calcium utilization and, if so, what levels of ingestion are necessary for this activity.
Carbohydr Res. 2009 Sep 8;344(13):1676-81. Epub 2009 Jun 3.
Protective role of fructose in the metabolism of astroglial C6 cells exposed to hydrogen peroxide.
Spasojević I, Bajić A, Jovanović K, Spasić M, Andjus P.
Astroglial cells represent the main line of defence against oxidative damage related to neurodegeneration. Therefore, protection of astroglia from an excess of reactive oxygen species could represent an important target of the treatment of such conditions. The aim of our study was to compare the abilities of glucose and fructose, the two monosaccharides used in diet and infusion, to protect C6 cells from hydrogen peroxide (H(2)O(2))-mediated oxidative stress. It was observed using confocal microscopy with fluorescent labels and the MTT test that fructose prevents changes of oxidative status of the cells exposed to H(2)O(2) and preserves their viability. Even more pronounced protective effects were observed for fructose 1,6-bis(phosphate). We propose that fructose and its intracellular forms prevent H(2)O(2) from participating in the Fenton reaction via iron sequestration. As fructose and fructose 1,6-bis(phosphate) are able to pass the blood-brain barrier, they could provide antioxidative protection of nervous tissue in vivo. So, in contrast to the well-known negative effects of frequent consumption of fructose under physiological conditions, acute infusion or ingestion of fructose or fructose 1,6-bis(phosphate) could be of benefit in the cytoprotective therapy of neurodegenerative disorders related to oxidative stress.
Brundin, et al. (1993) compared the effects of glucose and fructose in healthy people, and saw a greater oxygen consumption with fructose, and also an increase in the temperature of the blood, and a greater increase in carbon dioxide production. -Ray Peat, PhD
AJP – Endo April 1993 vol. 264 no. 4 E504-E513
Whole body and splanchnic oxygen consumption and blood flow after oral ingestion of fructose or glucose
T. Brundin and J. Wahren
The contribution of the splanchnic tissues to the initial 2-h rise in whole body energy expenditure after ingestion of glucose or fructose was examined in healthy subjects. Indirect calorimetry and catheter techniques were employed to determine pulmonary gas exchange, cardiac output, splanchnic blood flow, splanchnic oxygen uptake, and blood temperatures before and for 2 h after ingestion of 75 g of either fructose or glucose in water solution or of water only. Fructose ingestion was found to increase total oxygen uptake by an average of 9.5% above basal levels; the corresponding increase for glucose was 8.8% and for water only 2.5%. The respiratory exchange ratio increased from 0.84 in the basal state to 0.97 at 45 min after fructose ingestion and rose gradually after glucose to 0.86 after 120 min. The average 2-h thermic effect, expressed as percent of ingested energy, was 5.0% for fructose and 3.7% for glucose (not significant). Splanchnic oxygen consumption did not increase measurably after ingestion of either fructose or glucose. The arterial concentration of lactate rose, arterial pH fell, and PCO2 remained essentially unchanged after fructose ingestion. Glucose, but not fructose, elicited increases in cardiac output (28%) and splanchnic blood flow (56%). Fructose, but not glucose, increased arterial blood temperature significantly. It is concluded that both fructose and glucose-induced thermogenesis occurs exclusively in extrasplanchnic tissues. Compared with glucose, fructose ingestion is accompanied by a more marked rise in CO2 production, possibly reflecting an increased extrasplanchnic oxidation of lactate and an accumulation of heat in the body.
Am J Clin Nutr. 1993 Nov;58(5 Suppl):766S-770S.
Fructose and dietary thermogenesis.
Tappy L, Jéquier E.
Ingestion of nutrients increases energy expenditure above basal metabolic rate. Thermogenesis of carbohydrate comprises two distinct components: an obligatory component, which corresponds to the energy cost of carbohydrate absorption, processing, and storage; and a facultative component, which appears to be related with a carbohydrate-induced stimulation of the sympathetic nervous system, and can be inhibited by beta-adrenergic antagonists. Fructose ingestion induces a greater thermogenesis than does glucose. This can be explained by the hydrolysis of 3.5-4.5 mol ATP/mol fructose stored as glycogen, vs 2.5 mol ATP/mol glucose stored. Therefore the large thermogenesis of fructose corresponds essentially to an increase in obligatory thermogenesis. Obese individuals and obese patients with non-insulin-dependent diabetes mellitus commonly have a decrease in glucose-induced thermogenesis. These individuals in contrast display a normal thermogenesis after ingestion of fructose. This may be explained by the fact that the initial hepatic fructose metabolism is independent of insulin. This observation indicates that insulin resistance is likely to play an important role in the decreased glucose-induced thermogenesis of these individuals.
Diabetes Metab. 2005 Apr;31(2):178-88.
Consumption of carbohydrate solutions enhances energy intake without increased body weight and impaired insulin action in rat skeletal muscles.
Ruzzin J, Lai YC, Jensen J.
OBJECTIVES:
In the present study, we investigated whether replacement of tap water by fructose or sucrose solutions affect rat body weight and insulin action in skeletal muscles.
METHODS:
Rats were fed standard rodent chow ad libitum with water, or water containing fructose (10.5% or 35%) or sucrose (10.5% or 35%) for 11 weeks. Body weight and energy intake from chow and drinking solutions were measured. Urinary catecholamines secretion was determined after 50-60 days. At the end of the feeding period, soleus and epitrochlearis were removed for in vitro measurements of glucose uptake (with tracer amount of 2-[3H]-deoxy-D-glucose) and PKB Ser473 phosphorylation (assessed by Western Blot) with or without insulin.
RESULTS:
Fructose and sucrose solutions enhanced daily energy intake by about 15% without increasing rat body weight. Secretion of urinary noradrenaline was higher in rats drinking a 35% sucrose solution than in rats drinking water. In the other groups, urinary noradrenaline secretion was similar to rats consuming water. Urinary adrenaline secretion was similar in all groups. Insulin-stimulated glucose uptake and insulin-stimulated PKB phosphorylation were not reduced by intake of fructose or sucrose solution.
CONCLUSIONS:
Fructose and sucrose solutions enhanced energy intake but did not increase body weight. Although noradrenaline may regulate body weight in rats drinking 35% sucrose solution, body weight seems to be regulated by other mechanisms. Intake of fructose or sucrose solution did not impair insulin-stimulated glucose uptake or signaling in skeletal muscles.
Minerva Endocrinol. 1990 Oct-Dec;15(4):273-7.
[Postprandial thermogenesis and obesity: effects of glucose and fructose].
[Article in Italian]
Macor C, De Palo C, Vettor R, Sicolo N, De Palo E, Federspil G.
In order to check whether reduced postprandial thermogenesis, as found in obese subjects depends on insulin resistance, the study tested whether the thermogenetic response to glucose in a group of obese subjects and a group of normal weight subjects differed from that obtained using an insulin-independent monosaccharide such as fructose. Nine obese subjects and 6 control subjects were included in the study. An oral glucose tolerance and fructose tolerance test (75 g) was performed in all subjects on different days. Energy expenditure was calculated both in basal conditions and during the test (resting metabolic rate: RMR) using indirect calorimetry expressed per kg of lean weight, as assessed using bioimpedance measurement techniques. Blood samples were collected to assay glycemia and insulinemia. Results show that increased RMR induced by glucose was significantly reduced in the group of obese subjects compared to controls. In the same group of obese subjects, RMR was found to be significantly higher following fructose in comparison to the glucose response but did not differ from that in controls. Data confirm the existence of reduced thermogenesis in obese subjects induced by glucose. The fact that this phenomenon was not recorded in the same subjects following the fructose tolerance test, whose metabolism is insulin-independent, supports the hypothesis that reduced glucose-induced thermogenesis in obese subjects may depend on insulin resistance.
Many studies have found that sucrose is less fattening than starch or glucose, that is, that more calories can be consumed without gaining weight. During exercise, the addition of fructose to glucose increases the oxidation of carbohydrate by about 50% (Jentjens and Jeukendrup, 2005). -Ray Peat, PhD
Br J Nutr. 2005 Apr;93(4):485-92.
High rates of exogenous carbohydrate oxidation from a mixture of glucose and fructose ingested during prolonged cycling exercise.
Jentjens RL, Jeukendrup AE.
A recent study from our laboratory has shown that a mixture of glucose and fructose ingested at a rate of 1.8 g/min leads to peak oxidation rates of approximately 1.3 g/min and results in approximately 55% higher exogenous carbohydrate (CHO) oxidation rates compared with the ingestion of an isocaloric amount of glucose. The aim of the present study was to investigate whether a mixture of glucose and fructose when ingested at a high rate (2.4 g/min) would lead to even higher exogenous CHO oxidation rates (>1.3 g/min). Eight trained male cyclists (VO2max: 68+/-1 ml/kg per min) cycled on three different occasions for 150 min at 50% of maximal power output (60+/-1% VO2max) and consumed either water (WAT) or a CHO solution providing 1.2 g/min glucose (GLU) or 1.2 g/min glucose+1.2 g/min fructose (GLU+FRUC). Peak exogenous CHO oxidation rates were higher (P<0.01) in the GLU+FRUC trial compared with the GLU trial (1.75 (SE 0.11) and 1.06 (SE 0.05) g/min, respectively). Furthermore, exogenous CHO oxidation rates during the last 90 min of exercise were approximately 50% higher (P<0.05) in GLU+FRUC compared with GLU (1.49 (SE 0.08) and 0.99 (SE 0.06) g/min, respectively). The results demonstrate that when a mixture of glucose and fructose is ingested at high rates (2.4 g/min) during 150 min of cycling exercise, exogenous CHO oxidation rates reach peak values of approximately 1.75 g/min.
Am J Physiol. 1987 Sep;253(3 Pt 1):G390-6.
Fructose prevents hypoxic cell death in liver.
Anundi I, King J, Owen DA, Schneider H, Lemasters JJ, Thurman RG.
Perfusion of livers from fasted rats with nitrogen-saturated buffer caused hepatocellular damage within 30 min. Lactate dehydrogenase (LDH) was released at maximal rates of approximately 300 U . g-1 . h-1 under these conditions, and virtually all cells in periportal and pericentral regions of the liver lobule were stained with trypan blue. Infusion of glucose, xylitol, sorbitol, or mannitol (20 mM) did not appreciably change the time course or extent of damage due to perfusion with nitrogen-saturated perfusate. However, fructose (20 mM) completely prevented damage assessed by LDH release, trypan blue uptake, and ultrastructural changes for at least 2 h of perfusion. Neither glucose, xylitol, sorbitol, nor mannitol (20 mM) increased lactate formation above basal levels during hypoxia. On the other hand, fructose (0.4-20 mM) caused a concentration-dependent increase in lactate formation that reached maximal rates of approximately 180 mumol . g-1 . h-1. The dose-dependent increase in glycolytic lactate production from fructose correlated well with cellular protection reflected by decreases in LDH release. ATP:ADP ratios were also increased from 0.4 to 1.8 in a dose-dependent manner by fructose. The results indicate that fructose protects the liver against hypoxic cell death by the glycolytic production of ATP in the absence of oxygen.
Biochem J. 1967 January; 102(1): 177–180.
The influence of fructose and its metabolites on ethanol metabolism in vitro
H. I. D. Thieden and F. Lundquist
1. Fructose caused an increase in the rate of ethanol oxidation by rat-liver slices, and d-glyceraldehyde was found to have a similar effect. 2. Addition of glycerol lowered the rate of ethanol oxidation if the incubation medium contained fructose and ethanol, but no such effect was found if it contained glucose and ethanol. 3. The formation of glycerol by the slices during incubation and the concentration of α-glycerophosphate in the slices were highest in medium containing fructose and ethanol. 4. In experiments without ethanol in the incubation medium, fructose strongly increased the pyruvate concentration, which resulted in a decrease of the lactate/pyruvate concentration ratio. Addition of ethanol to the medium resulted in a marked decrease in pyruvate concentration. 5. Oxygen consumption is greater in slices incubated in medium containing fructose and ethanol than in slices incubated in medium containing glucose and ethanol.
Am J Physiol Endocrinol Metab. 2005 Jun;288(6):E1160-7. Epub 2005 Jan 25.
Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic glucose uptake in the presence of relative insulin deficiency in dog.
Shiota M, Galassetti P, Igawa K, Neal DW, Cherrington AD.
The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 microg.kg(-1).min(-1)) was given along with basal insulin (1.8 pmol.kg(-1).min(-1)) and glucagon (0.5 ng.kg(-1).min(-1)). After a control period, glucose (36.1 micromol.kg(-1).min(-1)) was continuously given intraportally for 4 h with (2.2 micromol.kg(-1).min(-1)) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from <16 to 176 +/- 11. The infusion of glucose alone (the control group) elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.3 to 11.2 +/- 0.6 during the first 2 h after which it remained at 11.6 +/- 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.2 to 7.4 +/- 0.6 during the first 1 h after which it decreased to 6.1 +/- 0.4 by 180 min. With glucose infusion, net hepatic glucose balance (micromol.kg(-1).min(-1)) switched from output (8.9 +/- 1.7 and 13.3 +/- 2.8) to uptake (12.2 +/- 4.4 and 29.4 +/- 6.7) in the control and fructose groups, respectively. Average NHGU (micromol.kg(-1).min(-1)) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 +/- 3.3 and 14.5 +/- 1.4) than in the control group (15.0 +/- 4.4 and 5.9 +/- 1.8). Glucose 6-phosphate and glycogen content (micromol glucose/g) in the liver and glucose incorporation into hepatic glycogen (micromol glucose/g) were higher in the fructose (218 +/- 2, 283 +/- 25, and 109 +/- 26, respectively) than in the control group (80 +/- 8, 220 +/- 31, and 41 +/- 5, respectively). In conclusion, small amounts of fructose can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised.
J Clin Endocrinol Metab. 2000 Dec;85(12):4515-9.
Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults.
Moore MC, Cherrington AD, Mann SL, Davis SN.
In animal models, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to the glucose load. Therefore, we examined the effect of fructose on glucose tolerance in 11 healthy human volunteers (5 men and 6 women). Each subject underwent an oral glucose tolerance test (OGTT) on 2 separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without 7.5 g fructose (OGTT+F or OGTT-F), in random order. Arterialized blood samples were obtained from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 2 h afterward. The area under the curve (AUC) of the change in plasma glucose was 19% less in OGTT+F vs. OGTT-F (P: < 0.05). Glucose tolerance was improved by fructose in 9 subjects and worsened in 2. All 6 subjects with the largest glucose AUC during OGTT-F had a decreased response during OGTT+F (31 +/- 5% decrease). The insulin AUC did not differ between the 2 studies. Of the 9 subjects with improved glucose tolerance during the OGTT+F, 5 had smaller insulin AUC during the OGTT+F than the OGTT-F. Plasma glucagon concentrations declined similarly during OGTT-F and OGTT+F. The blood lactate response was about 50% greater during the OGTT+F (P: < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTT. In conclusion, low dose fructose improves the glycemic response to an oral glucose load in normal adults without significantly enhancing the insulin or triglyceride response. Fructose appears most effective in those normal individuals who have the poorest glucose tolerance.
Diabetes Care. 2001 Nov;24(11):1882-7.
Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes.
Moore MC, Davis SN, Mann SL, Cherrington AD.
OBJECTIVE:
In normal adults, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to a glucose load, especially in those with the poorest glucose tolerance. We hypothesized that an acute catalytic dose of fructose would also improve glucose tolerance in individuals with type 2 diabetes.
RESEARCH DESIGN AND METHODS:
Five adults with type 2 diabetes underwent an oral glucose tolerance test (OGTT) on two separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without the addition of 7.5 g fructose (OGTT + F or OGTT – F), in random order. Arterialized blood samples were collected from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 3 h afterward.
RESULTS:
The area under the curve (AUC) of the plasma glucose response was reduced by fructose administration in all subjects; the mean AUC during the OGTT + F was 14% less than that during the OGTT – F (P < 0.05). The insulin AUC was decreased 21% with fructose administration (P = 0.2). Plasma glucagon concentrations declined similarly during OGTT - F and OGTT + F. The incremental AUC of the blood lactate response during the OGTT - F was approximately 50% of that observed during the OGTT + F (P < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTTs.
CONCLUSIONS:
Low-dose fructose improves the glycemic response to an oral glucose load in adults with type 2 diabetes, and this effect is not a result of stimulation of insulin secretion.
Diabet Med. 1989 Aug;6(6):506-11.
Dietary fructose as a natural sweetener in poorly controlled type 2 diabetes: a 12-month crossover study of effects on glucose, lipoprotein and apolipoprotein metabolism.
Osei K, Bossetti B.
The metabolic effects of fructose incorporated in the normal diets of 13 poorly controlled, Type 2 diabetic patients were studied in a 6-month, randomized, crossover study. Patients used 60 g day-1 of crystalline fructose in divided amounts as part of their isocaloric (1400-3900 kcal), weight-maintaining diet. During fructose supplementation, the distribution of carbohydrate-derived calories was 35% complex and 15% simple, the latter solely from fructose. This was compared with the patients’ values on their usual diabetic diet (carbohydrate 50% (mostly complex), fat 38%, and protein 12%). After 6 months of taking fructose, fasting serum glucose decreased from 12.6 +/- 1.1 (+/- SE) to 9.8 +/- 1.3 mmol l-1 (p less than 0.02), while it was unchanged on normal diet (11.0 +/- 0.1 vs 11.6 +/- 0.9 mmol l-1, NS). Glycosylated haemoglobin was also reduced from 11.3 +/- 0.4 to 9.9 +/- 0.5% (p less than 0.05) on fructose, but unchanged on the control diet (10.4 +/- 0.7 vs 11.2 +/- 0.7%, NS). No significant long-term deleterious changes were observed in the fasting serum lipids, lipoproteins, and apolipoproteins A-1 and B-100. Fructose was well tolerated without significant effects on body weight, or lactic acid and uric acid levels.
American Journal of Clinical Nutrition, Vol 59, 753S-757S
Fructose in the diabetic diet
MI Uusitupa
Fructose is an energy-yielding sweetener coming from different natural sources (fruit, berries, and vegetables) or is added to soft drinks, bakery products, and candies. The current content of fructose in the diabetic diet seems to be within recommendations. Because of the low glycemic index of fructose, fructose may be an alternative as a sweetener for those diabetic patients who like sweet foods but are liable to high postprandial glucose concentrations. In patients with mild non-insulin-dependent diabetes mellitus, fructose may result in lower postprandial glucose and insulin responses than will most other carbohydrate sources. In clinical studies, fructose has either improved metabolic control of diabetic patients or caused no significant changes. In patients susceptible to hypertriglyceridemia high doses of fructose should be avoided because of a potential hypertriglyceridemic effect. Long-term experiences about the use of fructose from large scale controlled studies on diabetic patients are lacking.
If fructose can by-pass the fatty acids’ inhibition of glucose metabolism, to be oxidized when glucose can’t, and if the metabolism of diabetes involves the oxidation of fatty acids instead of glucose, then we would expect there to be less than the normal amount of fructose in the serum of diabetics, although their defining trait is the presence of an increased amount of glucose. According to Osuagwu and Madumere (2008), that is the case. If a fructose deficiency exists in diabetes, then it is appropriate to supplement it in the diet. -Ray Peat, PhD
Nigerian Journal of Biochemistry and Molecular Biology 23 (1): 12 – 14, 2008. ISSN 0189-475
Depleted Blood Fructose in Diabetes
C. G. Osuagwu and H. E. O. Madumere
The whole blood and plasma concentrations of two hexoses, glucose and fructose, were estimated and compared in 61 non-diabetics (30 males and 31 females) and 61 diabetics (30 males and 31 females). For non-diabetics, the whole blood and plasma concentration of glucose (mg/dl) were 72.52 ± 8.90 and 87 .54 ± 12.26 while for diabetics they were 130.08 ± 34.27 and 141.03 ± 31.68, respectively. Blood and plasma fructose levels (mg/dl) for non -diabetics were 1.34 ± 0.54 and 1.34 ± 0.32, while for diabetics the values were 0.51 ± 0.33 and 0.51 ± 0.33, respectively. This finding indicates that diminished glucose utilization results to compensatory fructose utilization and depletion in diabetes. Fructose has the more stable, and same, concentrations over time in both blood and plasma than glucose. The glucose/fructose ratio for non-diabetic blood and plasma were 52.13 ± 3.30 and 65.12 ± 4.30 while the ratios for diabetics were 466.46 ± 388.76 and 501.38 ± 382.38. In all conditions considered, the differences in the blood and plasma concentrations of these hexoses between diabetics and non-diabetics were highly significant (p < 0.001). Diabetes is a hexose metabolism derangement syndrome, and not simple glucose metabolism disease. This fact should be borne in mind in diabetes management. A parameter combining glucose and fructose factors is a more efficient measure of diabetes than one of glucose alone; glucose/fructose ratio is such an index that can be employed in diagnosis.
Diabetes Care. 1980 Sep-Oct;3(5):575-82.
Effects of oral fructose in normal, diabetic, and impaired glucose tolerance subjects.
Crapo PA, Kolterman OG, Olefsky JM.
We studied the acute effects of oral ingestion of 50-g loads of dextrose, sucrose, and fructose on post-prandial serum glucose, insulin, and plasma glucagon responses in 9 normal subjects, 10 subjects with impaired glucose tolerance, and 17 non-insulin-dependent diabetic subjects. The response to each carbohydrate was quantified when the respective carbohydrate was given alone in a drink or when given in combination with protein and fat in a test meal. The data demonstrate that (1) fructose ingestion resulted in significantly lower serum glucose and insulin responses than did sucrose or dextrose ingestion in all study groups, either when given alone or in the test meal; (2) although fructose ingestion always led to the least glycemic response compared with the other hexoses, the serum glucose response to fructose was increased the more glucose intolerant the subject; (3) urinary glucose excretion during the 3 h after carbohydrate ingestion was greatest after dextrose and least after fructose in all groups. In conclusion, fructose ingestion results in markedly lower serum glucose and insulin responses and less glycosuria than either dextrose or sucrose, both when given alone or as a constituent in a test meal. However, as glucose tolerance worsens, an increasingly greater glycemic response to fructose is seen.
Am J Clin Nutr. 1982 Aug;36(2):256-61.
Comparison of the metabolic responses to fructose and sucrose sweetened foods.
Crapo PA, Scarlett JA, Kolterman OG.
We studied the acute effects of oral ingestion of fructose and sucrose sweetened cakes and ice creams on postprandial serum glucose and insulin responses in 10 normal subjects, six subjects with impaired glucose tolerance, and 10 noninsulin-dependent diabetic subjects. The data demonstrate that: 1) ingestion of fructose cakes and ice creams resulted in lower serum glucose and insulin responses than did the sucrose cakes and ice creams in all study groups; 2) when comparing cakes to ice creams, the serum glucose and insulin responses after ice cream ingestion were lower than responses after cake ingestion. In conclusion, when fructose is incorporated as a sweetener in a complex food product, it is associated with significantly lower serum glucose and insulin responses as compared to comparable sucrose sweetened foods.
Diabetes Care. 1982 Sep-Oct;5(5):512-7.
The effects of oral fructose, sucrose, and glucose in subjects with reactive hypoglycemia.
Crapo PA, Scarlett JA, Kolterman OG, Sanders LR, Hofeldt FD, Olefsky JM.
We have evaluated the acute effects of orally administered 100-g loads of fructose, sucrose, or glucose given as drinks and of 100-g loads of fructose and sucrose given in cakes on the postprandial serum glucose, insulin, and cortisol responses in seven subjects with reactive hypoglycemia. We defined reactive hypoglycemia as a serum glucose nadir of 65 mg/dl or less, symptoms compatible with hypoglycemia occurring at or after the serum glucose nadir, a hypoglycemic index of greater than 1.0, and a rise in serum cortisol to greater than 20 micrograms/dl after the serum glucose nadir. The data demonstrated that (1) pure fructose given as a drink resulted in relatively flat serum glucose and insulin responses and did not cause a hypoglycemic reaction in any of the subjects, compared with the glucose drink, which caused a hypoglycemic reaction in any of the subjects; (2) ingestion of pure sucrose as a drink elicited significantly flatter serum glucose and insulin responses than did the glucose drink and was associated with some episodes of chemical hypoglycemia and symptoms, but did not result in a hypoglycemic reaction by our definition in any patient; and (3) ingestion of fructose cake led to serum glucose and insulin responses that were lower than those caused by ingestion of sucrose cake, but ingestion of neither fructose nor sucrose cake led to a hypoglycemic reaction by our definition in any patient. In conclusion, the use of fructose as a sweetening agent given either alone, in a drink, or with other nutrients in a cake resulted in markedly flatter serum glucose and insulin responses in subjects with reactive hypoglycemia. Fructose may thus prove useful as a sweetening agent in the dietary treatment of selected patients with reactive hypoglycemia.
When rats were fed for 8 weeks on a diet with 18% fructose and 11% saturated fatty acids, the content of polyunsatured fats in the blood decreased, as they had in the Brown, et al., experiment, and their total antioxidant status was increased (Girard, et al., 2005). -Ray Peat, PhD
Nutrition. 2005 Feb;21(2):240-8.
Changes in lipid metabolism and antioxidant defense status in spontaneously hypertensive rats and Wistar rats fed a diet enriched with fructose and saturated fatty acids.
Girard A, Madani S, El Boustani ES, Belleville J, Prost J.
OBJECTIVE:
Larger doses of fructose and saturated fat have been associated with oxidative stress and development of hypertension. The effects of modest amounts of fructose and saturated fatty acids on oxidative stress are unknown.
METHODS:
To increase knowledge on this question, 10-wk-old spontaneously hypertensive rats and Wistar rats were fed for 8 wk with a control diet or an experimental diet enriched with fructose (18%) and saturated fatty acids (11%; FS diet). The total antioxidant status of organs and red blood cells was assayed by monitoring the rate of free radical-induced red blood cell hemolysis. Sensitivity of very low-density lipoprotein and low-density lipoprotein (VLDL-LDL) to copper-induced lipid peroxidation was determined as the production of thiobarbituric acid-reactive substances. Antioxidant enzymes and vitamins were also measured to establish the oxidative stress effect.
RESULTS:
The FS diet did not affect blood pressure in either strain, but it increased plasma insulin concentrations only in Wistar rats without affecting those of glucose of either strain. The FS diet significantly enhanced plasma and VLDL-LDL triacylglycerol concentrations without affecting concentrations of VLDL-LDL thiobarbituric acid-reactive substances. The decreased content of arachidonic acid and total polyunsaturated fatty acids in VLDL-LDL by the FS diet may have prevented lipid peroxidation in this fraction. Moreover, FS consumption by both strains was accompanied by a significant increase in total antioxidant capacity of adipose tissue, muscle, heart, and liver. This may have resulted from increased tissue ascorbic acid levels and glutathione peroxidase and glutathione reductase activities in tissues.
CONCLUSIONS:
These findings clearly indicate that the FS diet did not alter blood pressure of spontaneously hypertensive rats and Wistar rats. The FS diet resulted in hypertriglyceridemia but increased the total antioxidant status, which may prevent lipid peroxidation in these rats.
In 1963 and 1964, experiments (Carroll, 1964) showed that the effects of glucose and fructose were radically affected by the type of fat in the diet. Although 0.6% of calories as
polyunsaturated fat prevents the appearance of the Mead acid (which is considered to indicate a deficiency of essential fats) the “high fructose” diets consistently add 10% or more corn oil or other highly unsaturated fat to the diet. These large quantities of PUFA aren’t necessary to prevent a deficiency, but they are needed to obscure the beneficial effects of fructose. -Ray Peat, PhD
J Nutr. 1963 Jan;79:93-100.
Influences of dietary carbohydrate-fat combinations on various functions associated with glycolysis and lipogenesis in rats. I. Effects of substituting sucrose for rice starch with unsaturated and with saturated fat.
CARROLL C.
ABSTRACT Weanling rats were fed diets differing only in source of carbohydrate
and fat for 2 to 4 weeks. Livers were assayed for glucose-6-phosphatase and fructose
diphosphatase activities, and for content of glycogen and lipids. Effects on enzyme
activities of substituting fructose for glucose were similar to those observed on sub
stituting sucrose for rice starch (previous report). Feeding either hydrogenated
coconut oil (HCO) or hydrogenated peanut oil (HPO) in place of corn oil (CO)
modified the enzymatic responses to dietary fructose. Results with HPO were some what different than those with HCO. Labile phosphorus values were highest in groups
fed sucrose or fructose with CO, and lowest in those fed rice starch or glucose with
HPO. Effects of dietary carbohydrate on accumulation of lipid in liver appeared to be
a function of the type of fat fed, namely, substitution of a fructose source for a
direct glucose source resulted in the accumulation of less fat in livers of rats fed CO,
but of more fat in livers of rats fed a hydrogenated oil. Proportions of phospholipid
and cholesterol in liver lipid, and concentration of cholesterol in serum also varied with the combination of carbohydrate and fat fed.
Sucrose: Infant Pain Reliever
February 2nd, 2012Sucrose (and sometimes honey) is increasingly being used to reduce pain in newborns, for minor things such as injections (Guala, et al., 2001; Okan, et al., 2007; Anand, et al., 2005; Schoen and Fischell, 1991). -Ray Peat, PhD
Clin Ther. 2005 Jun;27(6):844-76.
Analgesia and local anesthesia during invasive procedures in the neonate.
Anand KJ, Johnston CC, Oberlander TF, Taddio A, Lehr VT, Walco GA.
BACKGROUND:
Preterm and full-term neonates admitted to the neonatal intensive care unit or elsewhere in the hospital are routinely subjected to invasive procedures that can cause acute pain. Despite published data on the complex behavioral, physiologic, and biochemical responses of these neonates and the detrimental short- and long-term clinical outcomes of exposure to repetitive pain, clinical use of pain-control measures in neonates undergoing invasive procedures remains sporadic and suboptimal. As part of the Newborn Drug Development Initiative, the US Food and Drug Administration and the National Institute of Child Health and Human Development invited a group of international experts to form the Neonatal Pain Control Group to review the therapeutic options for pain management associated with the most commonly performed invasive procedures in neonates and to identify research priorities in this area.
OBJECTIVE:
The goal of this article was to review and synthesize the published clinical evidence for the management of pain caused by invasive procedures in preterm and full-term neonates.
METHODS:
Clinical studies examining various therapies for procedural pain in neonates were identified by searches of MEDLINE (1980-2004), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2004), the reference lists of review articles, and personal files. The search terms included specific drug names, infant-newborn, infant-preterm, and pain, using the explode function for each key word. The English-language literature was reviewed, and case reports and small case series were discarded.
RESULTS:
The most commonly performed invasive procedures in neonates included heel lancing, venipuncture, IV or arterial cannulation, chest tube placement, tracheal intubation or suctioning, lumbar puncture, circumcision, and SC or IM injection. Various drug classes were examined critically, including opioid analgesics, sedative/hypnotic drugs, nonsteroidal anti-inflammatory drugs and acetaminophen, injectable and topical local anesthetics, and sucrose. Research considerations related to each drug category were identified, potential obstacles to the systematic study of these drugs were discussed, and current gaps in knowledge were enumerated to define future research needs. Discussions relating to the optimal design for and ethical constraints on the study of neonatal pain will be published separately. Well-designed clinical trials investigating currently available and new therapies for acute pain in neonates will provide the scientific framework for effective pain management in neonates undergoing invasive procedures.
Eur J Pediatr. 2007 Oct;166(10):1017-24. Epub 2007 Jan 4.
Analgesia in preterm newborns: the comparative effects of sucrose and glucose.
Okan F, Coban A, Ince Z, Yapici Z, Can G.
The aim of this study was to evaluate the effectiveness of different oral carbohydrate solutions for alleviation of pain in healthy preterm babies. Thirty-one preterm infants who were having blood drawn by heel prick were given 2 ml of solution A (20% sucrose), solution B (20% glucose) or solution C (placebo, sterile water) into the mouth, 2 min before lancing. Behavioural responses to this painful stimulus were measured by duration of crying and facial expressions (Neonatal Facial Coding System, NFCS) and physiological responses were measured by heart rate (HR), respiratory rate (RR), and oxygen saturation changes (SaO(2)). Infants had a mean birth weight (+/-SD) of 1,401 g (406), gestational age of 30.5 weeks (2.7); at the time of the procedure the postmenstrual age was 32.3 weeks (1.5). There was no significant difference in the time spent squeezing the heel between the three groups (P = 0.669). After the heel prick of both the sucrose and glucose groups the duration of first cry and total crying time was significantly reduced (P = 0.005 and P = 0.007). When the babies received placebo they showed a significantly higher NFCS score at 4 and 5 min after the heel prick (P = 0.009 and 0.046 respectively). Following painful stimulus HR increased significantly in the first 3 min compared with baseline, and at the first minute the mean of the HR was found to be significantly higher in the placebo group than in the sucrose and glucose groups (P = 0.007). We concluded that both sucrose and glucose administered orally before a heel prick reduce the pain response in preterm infants.
Minerva Pediatr. 2001 Aug;53(4):271-4.
Glucose or sucrose as an analgesic for newborns: a randomised controlled blind trial.
Guala A, Pastore G, Liverani ME, Giroletti G, Gulino E, Meriggi AL, Licardi G, Garipoli V.
BACKGROUND:
To evaluate the effect of different oral glucose or sucrose solutions on the pain response to heelstick in newborns.
METHODS:
DESIGN:
randomised double blind placebo controlled trial of water (control) versus one of three solutions of glucose – namely 5, 33 and 50% – or one of two solutions of sucrose (33% and 50%) or nothing.
SETTING:
postnatal ward.
PATIENTS:
seven groups of 20 healthy newborns (gestational age 38-41, weighing over 2500 g) were randomised to receive 2 ml of one of the six solutions on the tongue inmediately before heelstick procedure. Main outcome measure: heart rate before, during and three minutes after the procedure.
RESULTS:
Even if the trend of the cardiac rates did not reach statistic significance, glucose solution 33 and 50% proved to be the most effective in reducing pain response.
CONCLUSIONS:
Sweet solutions may be an easy, useful, safe and cheap analgesic for minor invasive procedures in newborns.
CLIN PEDIATR July 1991 vol. 30 no. 7 429-432
Pain in Neonatal Circumcision
Edgar J. Schoen, MD, Anne A. Fischell, MD
Because newborn circumcision is a quick and safe surgical procedure, any method to relieve pain must be almost risk-free in order to be acceptable. General anesthesia and narcotic analgesia are not appropriate. Dorsal penile nerve block (DPNB) with lidocaine hydrochloride is probably the most effective and safest form of anesthesia for newborn circumcision currently available, but it can cause significant local and systemic reactions. Only a limited number of cases of DPNB have been reported and we feel that this procedure should be used cautiously until there is more published evidence of its safety. Alternative methods of pain relief including oral acetaminophen and topical anesthesia should also be studied. Of special interest is recent evidence that a sucrose-flavored pacifier is an effective analgesic during newborn circumcision.
Ray Peat, PhD: Quotes Relating to Exercise
February 1st, 2012Change your perspective on exercise with this informative compilation of quotes from the writings of Ray Peat, PhD.
“Since fat has a very low rate of metabolism, people who lose muscle by fasting are going to have increasing difficulty in losing weight, since they will have less active tissue to consume fat. Building up muscle and lymph tissue for optimal health – even if it initially causes a slight weight gain – will make reducing easier by increasing mass of metabolically active tissue.”
“However, in Russia, physiologist always remember to include the brain in their calculations, and it turns out that a walk through interesting and pleasant surroundings consumes more energy than does harder but more boring exercise. An active brain consumes a tremendous amount of fuel.”
“Stress uses progesterone and can cause menstrual periods to stop. Girls who begin regular exercise (such as dancing) before puberty have later sexual development.”
“Lactic acid and carbon dioxide have opposing effects. Intense exercise damages cells in ways that cumulatively impair metabolism. There is clear evidence that glycolysis, producing lactic acid from glucose, has toxic effects, suppressing respiration and killing cells. Within five minutes, exercise lowers the activity of enzymes that oxidize glucose. Diabetes, Alzheimer’s disease, and general aging involve increased lactic acid production and accumulated metabolic (mitochondrial) damage.”
“Since lactic acid is produced by the breakdown of glucose, a high level of lactate in the blood means that a large amount of sugar is being consumed; in response, the body mobilizes free fatty acids as an additional source of energy. An increase of free fatty acids suppresses the oxidation of glucose. (This is called the Randle effect, glucose-fatty acid cycle, substrate-competition cycle, etc.) Women, with higher estrogen and growth hormone, usually have more free fatty acids than men, and during exercise oxidize a higher proportion of fatty acids than men do. This fatty acid exposure “decreases glucose tolerance,” and undoubtedly explains women’s higher incidence of diabetes. While most fatty acids inhibit the oxidation of glucose without immediately inhibiting glycolysis, palmitic acid is unusual, in its inhibition of glycolysis and lactate production without inhibitng oxidation. I assume that this largely has to do with its important function in cardiolipin and cytochrome oxidase.”
“In the last century, Sechenov found that exercising one hand strengthens not only that hand, but also the other. Brain activity stimulates growth and alteration of tissues, such as muscles.”
“The stressful conditions that physiologically harm mitochondria are now being seen as the probable cause for the mitochondrial genetic defects that accumulate with aging. Stressful exercise, which has been known to cause breakage of the nuclear chromosomes, is now seen to damage mitochondrial genes, too. Providing energy, while reducing stress, seems to be all it takes to reverse the accumulated mitochondrial genetic damage. Fewer mitochondrial problems will be considered to be inherited, as we develop an integral view of the ways in which mitochondrial physiology is disrupted. Palmitic acid, which is a major component of the cardiolipin which regulates the main respiratory enzyme, becomes displaced by polyunsaturated fats as aging progresses. Copper tends to be lost from this same enzyme system, and the state of the water is altered as the energetic processes change.”
“Many health conscious people become hypothyroid with a synergistic program of undercooked vegetables, legumes instead of animal proteins, oils instead of butter, carotene instead of vitamin A, and breathless exercise instead of stimulating life.”
“Exercise, like aging, obesity, and diabetes, increases the levels of circulating free fatty acids and lactate. But ordinary activity of an integral sort, activates the systems in an organized way, increasing carbon dioxide and circulation and efficiency. Different types of exercise have been identified as destructive or reparative to the mitochondria; “concentric” muscular work is said to be restorative to the mitochondria. As I understand it, this means contraction with a load, and relaxation without a load. The heart’s contraction follows this principle, and this could explain the observation that heart mitochondria don’t change in the course of ordinary aging.”
“The idea of the “oxygen debt” produced by exercise or stress as being equivalent to the accumulation of lactic acid is far from accurate, but it’s true that activity increases the need for oxygen, and also increases the tendency to accumulate lactic acid, which can then be disposed of over an extended time, with the consumption of oxygen. This relationship between work and lactic acidemia and oxygen deficit led to the term “lactate paradox” to describe the lower production of lactic acid during maximal work at high altitude when people are adapted to the altitude. Carbon dioxide, retained through the Haldane effect, accounts for the lactate paradox, by inhibiting cellular excitation and sustaining oxidative metabolism to consume lactate efficiently.”
“The polyunsaturated oils interact closely with serotonin and tryptophan, and the short and medium chain saturated fatty acids have antihistamine and antiserotonin actions. Serotonin liberates free fatty acids from the tissues, especially the polyunsaturated fats, and these in turn liberate serotonin from cells such as the platelets, and liberate tryptophan from serum albumin, increasing its uptake and the formation of serotonin in the brain. Saturated fats don’t liberate serotonin, and some of them, such as capric acid found in coconut oil, relax blood vessels, while linoleic acid constricts blood vessels and promotes hypertension. Stress, exercise, and darkness, increase the release of free fatty acids, and so promote the liberation of tryptophan and formation of serotonin. Increased serum linoleic acid is specifically associated with serotonin-dependent disorders such as migraine.”
“Mental stress, exercise, estrogen, and serotonin activate both the formation and dissolution of clots.”
“Many dietitians claim that exercise doesn’t increase the need for protein, but the Russians have found that a combination of exercise and increased protein intake can increase the muscle mass. In a woman, this process can not only improve grace and body proportions, but it also increases the body’s ability to burn up fat. Other nutrients are needed for using protein properly, and for maintaining optimum nerve functioning. However, if the exercise produces too much stress and not enough muscle action, muscle will atrophy as a result of cortisone’s shifting amino acid metabolism into glucose production. Lactic acid production (getting out of breath) is the main signal of the need to produce new glucose. Therefore, “aerobic” exercise is the most stressful. Cortisone not only causes atrophy of the skin, muscles, and immune system, but it even has been found the accelerate aging changes in the brain.”
“Estrogen promotes vascular permeability by a variety of mechanisms. Serotonin, histamine, lactic acid, and various cytokines and prostaglandins contribute to the leakage stimulated by estrogen, trauma, irradiation, poisoning, oxygen deprivation, and other factors that can induce shock. Even exercise, mental stress, and aging can increase the tendency of capillaries to leak.”
“Leakage of fluid out of the blood is one of the main features of shock, and at first it is mainly the loss of water and volume that creates a problem, by reducing the oxygenation of tissue and increasing the viscosity of the remaining blood. Blood becomes more concentrated during strenuous exercise, during the night, and in the winter, increasing the viscosity, and increasing the risk of strokes and other thrombotic problems. The absence of light causes the metabolic and hormonal changes typical of stress.”
“In the resting state, muscles consume mainly fats, so maintaining relatively large muscles is important for preventing the accumulation of fats.”
“Even on the mornings that you don’t drop dead, there is reduced adaptive capacity and functional impairment before eating breakfast. For example, men who went for a run before breakfast were found to have broken chromosomes in their blood cells, but if they ate breakfast before running, their chromosomes weren’t damaged.”
“Exercise physiologists, without mentioning functional systems, have recently discovered some principles that extend the discoveries of Meerson and Anokhin. They found that “concentric” contraction, that is, causing the muscle to contract against resistance, improves the muscle’s function, without injuring it. (Walking up a mountain causes concentric contractions to dominate in the leg muscles. Walking down the mountain injures the muscles, by stretching them, forcing them to elongate while bearing a load; they call that eccentric contraction.) Old people, who had extensively damaged mitochondrial DNA, were given a program of concentric exercise, and as their muscles adapted to the new activity, their mitochondrial DNA was found to have become normal.”
“I’m not sure who introduced the term “aerobic” to describe the state of anaerobic metabolism that develops during stressful exercise, but it has had many harmful repercussions. In experiments, T3 production is stopped very quickly by even “sub-aerobic” exercise, probably because of the combination of a decrease of blood glucose and an increase in free fatty acids. In a healthy person, rest will tend to restore the normal level of T3, but there is evidence that even very good athletes remain in a hypothyroid state even at rest. A chronic increase of lactic acid and cortisol indicates that something is wrong. The “slender muscles” of endurance runners are signs of a catabolic state, that has been demonstrated even in the heart muscle. A slow heart beat very strongly suggests hypothyroidism. Hypothyroid people, who are likely to produce lactic acid even at rest, are especially susceptible to the harmful effects of “aerobic” exercise. The good effect some people feel from exercise is probably the result of raising the body temperature; a warm bath will do the same for people with low body temperature.”
“This is where the issue of cell water comes in. Carbon dioxide, produced by oxidative cell metabolism, is associated with the high energy state of the cell. When something interferes with oxidative metabolism, lactic acid is produced instead of carbon dioxide. If the cell stays very long in this low oxygen state, it swells, taking up water. (The fatigued muscle, for example, can take up so much water in a short time that it weighs 20% more than before it began working so intensely that its energy needs far exceeded the availability of oxygen. This swelling is what causes the soreness and tightness of intense exercise. The swelling persists long after the liver has cleared the lactic acid from the blood.) This swelling from taking up water is involved in one type of “edema,” and in inflammation, or activation of the cells by hormones, as well as by simple oxygen deprivation. When the eyes have been closed for several hours, the cornea swells, because it depends on direct contact with the air for its oxygen, and the eyelid, whose circulation provides oxygen for its own cells, doesn’t provide enough for the cornea.”
“Sometimes progesterone seems to be chronically deficiency (leading to slight-though possibly prolonged-menstruation, or amenorrhea), in women who exercise hard. Since progesterone can be converted into cortisone to handle stress, this would explain why well trained athletes (who need lots of cortisone) so often miss periods. It seems to be a simple over-consumption of progesterone, which is probably a reasonable biological adaptation, preventing pregnancy during times of stress.”
“Athletic training is known to slow the pulse. Cortisone, produced by stress, inhibits the thyroid gland. (When the thyroid is low, less oxygen is needed, so this is a useful adaptation for increasing endurance.) These hormonal changes are now known to produce sterility in both men and women”
“Stress and starvation lead to a relative reliance on the fats stored in the tissues, and the mobilization of these as circulating free fatty acids contributes to a slowing of metabolism and a shift away from the use of glucose for energy. This is adaptive in the short term, since relatively little glucose is stored in the tissues (as glycogen), and the proteins making up the body would be rapidly consumed for energy, if it were not for the reduced energy demands resulting from the effects of the free fatty acids.”
“Exercise increases blood clotting, and so can increase the risk of strokes and heart attacks. Some doctors have been reporting increase incidence of flat feet, varicose veins, and prolapsed uterus among runners. Walking is a better form of exercise.”
“Histamine mimics estrogen’s effects on the uterus, and antihistamines block estrogen’s effects (Szego, 1965, Szego and Davis, 1967). Estrogen mimics the shock reaction. Stress, exercise, and toxins cause a rapid increase in estrogen. Males often have as much estrogen as females, especially when they are tired or sick. Estrogen increases the brain’s susceptibility to epileptic seizures, and recent research shows that it (and cortisol) promote the effects of the “excitotoxins,” which are increasingly implicated in degenerative brain diseases.”
Whey, Trytophan, & Serotonin
February 1st, 2012Am J Clin Nutr. 2000 Jun;71(6):1536-44.
The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress.
Markus CR, Olivier B, Panhuysen GE, Van Der Gugten J, Alles MS, Tuiten A, Westenberg HG, Fekkes D, Koppeschaar HF, de Haan EE.
BACKGROUND:
Increased brain serotonin may improve the ability to cope with stress, whereas a decline in serotonin activity is involved in depressive mood. The uptake of the serotonin precursor, tryptophan, into the brain is dependent on nutrients that influence the cerebral availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). Therefore, a diet-induced increase in tryptophan availability may increase brain serotonin synthesis and improve coping and mood, particularly in stress-vulnerable subjects.
OBJECTIVE:
We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, may increase the plasma Trp-LNAA ratio and reduce depressive mood and cortisol concentrations in stress-vulnerable subjects under acute stress.
DESIGN:
Twenty-nine highly stress-vulnerable subjects and 29 relatively stress-invulnerable subjects participated in a double-blind, placebo-controlled study. Subjects were exposed to experimental stress after the intake of a diet enriched with either alpha-lactalbumin or sodium-caseinate. Diet-induced changes in the plasma Trp-LNAA ratio and prolactin were measured. Changes in mood, pulse rate, skin conductance, and cortisol concentrations were assessed before and after the stressor.
RESULTS:
The plasma Trp-LNAA ratio was 48% higher after the alpha-lactalbumin diet than after the casein diet (P = 0.0001). In stress-vulnerable subjects this was accompanied by higher prolactin concentrations (P = 0.001), a decrease in cortisol (P = 0.036), and reduced depressive feelings (P = 0.007) under stress.
CONCLUSIONS:
Consumption of a dietary protein enriched in tryptophan increased the plasma Trp-LNAA ratio and, in stress-vulnerable subjects, improved coping ability, probably through alterations in brain serotonin.
Physiol Behav. 2004 Jun;81(4):585-93.
Alpha-lactalbumin combined with a regular diet increases plasma Trp-LNAA ratio.
Beulens JW, Bindels JG, de Graaf C, Alles MS, Wouters-Wesseling W.
Brain serotonin influences food intake and mood. It is synthesised from tryptophan (Trp) of which uptake in the brain is dependent on plasma ratio of tryptophan to the sum of other large neutral amino acids (Trp-LNAA). A carbohydrate-rich diet increases this ratio, whereas a protein-rich diet decreases it. Yet, if the protein source is alpha-lactalbumin the ratio increases. It is, however, unknown whether this also happens in the context of a regular diet (15% protein). We studied the effect of an alpha-lactalbumin supplement combined with regular diet on plasma Trp-LNAA ratio, serum prolactin (marker of serotonin synthesis), food intake, appetite, macronutrient preference and mood. Eighteen healthy males participated in a double-blind, randomised, placebo-controlled, crossover study. One hour after breakfast they received a drink containing alpha-lactalbumin and carbohydrates (AS) or carbohydrates (PS) only. Plasma Trp-LNAA ratio, serum prolactin, food intake, appetite, macronutrient preference and mood were assessed before and 90 min after consumption of the supplement. Changes of plasma Trp-LNAA ratio differed (P<.001) between both supplements, increasing by 16% after AS and decreasing by 17% after PS. Decrease of serum prolactin was slightly smaller after AS than after PS (P=.083). Appetite, food intake, macronutrient preference or mood did not differ between supplements. We conclude that an alpha-lactalbumin-enriched supplement combined with a regular diet increases plasma Trp-LNAA ratio and may influence serum prolactin, but we could not demonstrate effects on appetite, food intake, macronutrient preference and mood.
Am J Clin Nutr. 2002 Jun;75(6):1051-6.
Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects.
Markus CR, Olivier B, de Haan EH.
BACKGROUND:
Cognitive performance often declines under chronic stress exposure. The negative effect of chronic stress on performance may be mediated by reduced brain serotonin function. The uptake of the serotonin precursor tryptophan into the brain depends on nutrients that influence the availability of tryptophan by changing the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). In addition, a diet-induced increase in tryptophan may increase brain serotonergic activity levels and improve cognitive performance, particularly in high stress-vulnerable subjects.
OBJECTIVE:
We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, would increase the plasma Trp-LNAA ratio and improve cognitive performance in high stress- vulnerable subjects.
DESIGN:
Twenty-three high stress-vulnerable subjects and 29 low stress-vulnerable subjects participated in a double-blind, placebo-controlled, crossover study. All subjects conducted a memory-scanning task after the intake of a diet enriched with either alpha-lactalbumin (alpha-lactalbumin diet) or sodium caseinate (control diet). Blood samples were taken to measure the effect of dietary manipulation on the plasma Trp-LNAA ratio.
RESULTS:
A significantly greater increase in the plasma Trp-LNAA ratio after consumption of the alpha-lactalbumin diet than after the control diet (P = 0.0001) was observed; memory scanning improved significantly only in the high stress-vulnerable subjects (P = 0.019).
CONCLUSION:
Because an increase in the plasma Trp-LNAA ratio is considered to be an indirect indication of increased brain serotonin function, the results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities.
Am J Clin Nutr. 2005 May;81(5):1026-33.
Evening intake of alpha-lactalbumin increases plasma tryptophan availability and improves morning alertness and brain measures of attention.
Markus CR, Jonkman LM, Lammers JH, Deutz NE, Messer MH, Rigtering N.
BACKGROUND:
Brain serotonin function is thought to promote sleep regulation and cognitive processes, whereas sleep abnormalities and subsequent behavioral decline are often attributed to deficient brain serotonin activity. Brain uptake of the serotonin precursor tryptophan is dependent on nutrients that influence the availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp:LNAA).
OBJECTIVE:
We tested whether evening consumption of alpha-lactalbumin protein with an enriched tryptophan content of 4.8 g/100 g increases plasma Trp:LNAA and improves alertness and performance on the morning after sleep, particularly in subjects with sleep complaints.
DESIGN:
Healthy subjects with (n = 14) or without (n = 14) mild sleep complaints participated in a double-blind, placebo-controlled study. The subjects slept at the laboratory for 2 separate nights so that morning performance could be evaluated after an evening diet containing either tryptophan-rich alpha-lactalbumin or tryptophan-low placebo protein. Evening dietary changes in plasma Trp:LNAA were measured. Behavioral (reaction time and errors) and brain measures of attention were recorded during a continuous performance task.
RESULTS:
Evening alpha-lactalbumin intake caused a 130% increase in Trp:LNAA before bedtime (P = 0.0001) and modestly but significantly reduced sleepiness (P = 0.013) and improved brain-sustained attention processes (P = 0.002) the following morning. Only in poor sleepers was this accompanied by improved behavioral performance (P = 0.05).
CONCLUSION:
Evening dietary increases in plasma tryptophan availability for uptake into the brain enhance sustained alertness early in the morning after an overnight sleep, most likely because of improved sleep.
Unsaturated Fats and Heart Damage
January 31st, 2012The American Journal of Cardiology (May 1969), 23 (5), pg. 719-722
Sensitization by corn oil for the production of cardiac necroses by various steroids and sodium salts
Hans Selye; Árpád Somogyi; Gaston Côté
In the rat, the production of extensive and usually fatal myocardial necroses by fluorocortisol or desoxycorticosterone in combination with Na2HPO4 is greatly accelerated and aggravated by the oral administration of corn oil. Cortisol, progesterone and methyltestosterone do not produce myocardial necroses under these conditions even if, in addition to Na2HPO4, corn oil is given.
Not all sodium salts are equally potent in producing myocardial necroses when administered in combination with fluorocortisol and fat supplements. In this respect, NaH2PO4, Na2HPO4, NaClO4 and NaHSO4 are most effective, NaHCO3 is somewhat less active, whereas NaCl is inactive under otherwise comparable conditions.
Lipids. 1982 May;17(5):372-82.
Reduction of myocardial necrosis in male albino rats by manipulation of dietary fatty acid levels.
Kramer JK, Farnworth ER, Thompson BK, Corner AH, Trenholm HL.
A comprehensive statistical analysis had shown a significant correlation between the incidence of myocardial lesions in male albino rats and the concentration of certain dietary fatty acids. To test this result under controlled conditions, male rats were fed for 16 weeks diets containing 20% by weight soybean oil or a low erucic acid rapeseed (LEAR) oil. Both dietary oils contained substantial amounts of linolenic acid, and both groups developed a high incidence of myocardial necrosis. The addition of dietary saturated fatty acids to the oil in the form of cocoa butter significantly lowered the incidence of heart lesions in both groups. The addition of cocoa butter resulted in increased absorption of saturates and increased growth. Replacement of the cocoa butter by at least an equal amount of synthetic triolein resulted in no significant changes in the cardiopathogenic response compared to the original oils, thus ensuring that the reduction in heart lesions associated with the addition of cocoa butter was not due to dilution of cardiopathogenic compounds in the original vegetable oils. These results support the hypothesis that myocardial lesions in male rats are related to the balance of dietary fatty acids and not to cardiotoxic contaminants in the oils. Changes in the dietary fatty acids did not appear to influence the proportion of the cardiac phospholipids, but their fatty acid composition was markedly influenced. Dietary linolenic acid affected the C22 polyunsaturated fatty acids (PUFA) and dietary saturates increased the level of saturates in cardiac phospholipids. The level of arachidonic acid and total C22 PUFA did not appear to be affected by diet.
J Nutr. 1982 Feb;112(2):231-40.
Role of dietary saturated fatty acids on lowering the incidence of heart lesions in male rats.
Farnworth ER, Kramer JK, Thompson BK, Corner AH.
Male weanling rats were fed soybean or low erucic acid rapeseed oils alone or in combination with cocoa butter (a source high in saturates) or triolein for 16 weeks. All diets contained 20% by weight of the test oils. The apparent digestibility of all diets and test oils increased with the age of the rat. The apparent digestibility of saturated fatty acids was lower in rats fed the diets containing cocoa butter. The relative organ weights, however, were not affected by diet, but growth was improved by supplementing the vegetable oils with cocoa butter. This growth difference was significant for the addition of cocoa butter to low erucic acid rapeseed oil. After 16 weeks all groups of rats developed myocardial necrosis. A dramatic lowering of myocardial lesion incidence was observed in rats fed diets enriched with saturated fatty acids. The results of the present experiment suggest that enriching a vegetable oil with saturated fatty acids affects both nutritional and cardiopathological properties of the oil.
Lipids. 1980 Sep;15(9):651-60.
Comparative studies on composition of cardiac phospholipids in rats fed different vegetable oils.
Kramer JK.
Male Sprague-Dawley rats were fed diets for 1 or 16 weeks, containing 20% by weight vegetable oils differing widely in their oleic, linoleic and linolenic acid content. No significant changes were observed in the level of the cardiac lipid classes. The fatty acid composition of the 2 major phospholipids, phosphatidylcholine and phosphatidylethanolamine, showed a remarkable similarity between diets in the concentration of total saturated, C22 polyunsaturated and arachidonic acids. Monounsaturated acids were incorporated depending on their dietary concentration, but the increases were moderate. Dietary linolenic acid rapidly substituted C22 polyunsaturated fatty acids of the linoleic acid family (n-6) with those from the linolenic acid family (n-3). The results suggest that dietary linolenic acid of less than 15% does not inhibit the conversion of linoleic to arachidonic acid but the subsequent conversion of arachidonic acid to the C22 polyunsaturates was greatly reduced. Significant amounts of dietary monounsaturated fatty acids were incorporated into cardiac cardiolipin accompanied by increases in polyunsaturated fatty acids, apparently to maintain an average of 2 double bonds/molecule. The cardiac sphingomyelins also accumulated monounsaturated fatty acids depending on the dietary concentration. It is quite evident from the results of this study that the incorporation of oleic acid and the substitution of linolenic for linoleic acid-derived C22 polyunsaturated fatty acids into cardiac phospholipids was related to the dietary concentration of these fatty acids and was not peculiar to any specific oil. Even though it is impossible to estimate the effect of such changes in cardiac phospholipids on membrane structure and function, results are discussed which suggest that the resultant membrane in the Spragu-Dawley male rat is more fragile, leading to greater cellular breakdown and focal necrosis.
Biull Eksp Biol Med. 1983 Apr;95(4):46-8.
[Calcium and lipid peroxidation in the heart mitochondrial and microsomal membranes].
[Article in Russian]
Kagan VE, Savov VM, Didenko VV, Arkhipenko IuV, Meerson FZ.
Effect of the lipid peroxidation (LP) on the Ca2+-transport and the effect of different Ca2+-concentrations on the LP activation were studied in microsomes and mitochondria of the heart. A slight accumulation of LP-products in the microsomal fraction results in a complete inhibition of the membrane calcium-transport activity. Preliminary administration of antioxidants (4-methyl 2,6-ditretbutylphenol and alpha-tocopherol) prevents both the accumulation of LP-products and damage of the Ca2+-transport system. Calcium at 10(-6) M to 5 X 10(-5) M concentrations stimulates LP and while being increased to 2 X 10(-3) M it inhibits LP. The data obtained evidence an interrelation between alterations of the Ca2+-concentrations and LP activation in cardiomyocytes.
Diet and Exercise
January 30th, 2012by Matt Labosco of Optimal Performance Systems
Saturated fat in the diet and serum cholesterol concentration: a critical examination of the literature
January 24th, 2012The American Journal of Clinical Nutrition 26: MAY 1973, pp. 524-555.
Saturated fat in the diet and serum cholesterol concentration: a critical examination of the literature
Raymond Reiser, Ph.D
Thyroid Status and Cardiovascular Disease
January 22nd, 2012
J Clin Endocrinol Metab. 2006 Jun;91(6):2126-32. Epub 2006 Mar 14.
Subclinical hypothyroidism, arterial stiffness, and myocardial reserve.
Owen PJ, Rajiv C, Vinereanu D, Mathew T, Fraser AG, Lazarus JH.
CONTEXT:
Subclinical hypothyroidism (SCH) is associated with increased risk of cardiac disease; its impact on arterial function is less clear.
OBJECTIVE:
The objective of the study was the assessment of arterial and cardiac function.
DESIGN:
The study was a 6-month controlled observational study using pulse wave analysis and tissue Doppler dobutamine stress echocardiography.
SETTING:
The study was conducted at a thyroid clinic.
PATIENTS:
Nineteen female SCH patients with raised TSH, normal free T(4), and no cardiovascular disease [aged 49.2 +/- 3.8 yr; body mass index (BMI) 29.9 +/- 6.7 kg/m(2)] were recruited from the thyroid clinic, and 10 female controls (aged 50.2 +/- 3.4 yr; BMI 29.7 +/- 7.2 kg/m(2)) also participated in the study.
INTERVENTIONS:
Incremental doses of l-thyroxine were used.
MAIN OUTCOME MEASURES:
Indices of vascular stiffness and left ventricular echocardiographic function were measured.
RESULTS:
Baseline augmentation gradient was elevated in SCH, compared with controls [10.3 +/- 5.1 (sd) mm Hg vs. 8.0 +/- 4.2, P < 0.05]; when euthyroid (mean T(4) dose 114 mug/d), it fell to 8.8 +/- 5.3 mm Hg (P < 0.05). Heart rate-corrected augmentation index was 26.7 +/- 9.9 vs. 18.8 +/- 9.9% (P < 0.02), falling to 19.7 +/- 9.6% (P < 0.001) after treatment. Time of travel of the reflected wave was 139.3 +/- 11.7 msec, compared with 141.5 +/- 8.8 msec in controls (P < 0.05), increasing to 144.9 +/- 11.9 msec (P < 0.05). There were no differences in resting global, regional left ventricular function, or regional myocardial velocities during maximal dobutamine stress between SCH patients and controls, or in treated patients, compared with baseline.
CONCLUSIONS:
Arterial stiffness was increased in SCH and improved with l-thyroxine, which may be beneficial, whereas myocardial functional reserve was similar to controls and remained unaltered after treatment.
Endocrine. 2004 Jun;24(1):1-13.
Hypothyroidism as a risk factor for cardiovascular disease.
Biondi B, Klein I.
The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T4 replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The “traditional” risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH >10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels <10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of L-thyroxine outweigh the risk.
Arch Intern Med. 2000 Feb 28;160(4):526-34.
The Colorado thyroid disease prevalence study.
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC.
CONTEXT:
The prevalence of abnormal thyroid function in the United States and the significance of thyroid dysfunction remain controversial. Systemic effects of abnormal thyroid function have not been fully delineated, particularly in cases of mild thyroid failure. Also, the relationship between traditional hypothyroid symptoms and biochemical thyroid function is unclear.
OBJECTIVE:
To determine the prevalence of abnormal thyroid function and the relationship between (1) abnormal thyroid function and lipid levels and (2) abnormal thyroid function and symptoms using modern and sensitive thyroid tests.
DESIGN:
Cross-sectional study.
PARTICIPANTS:
Participants in a statewide health fair in Colorado, 1995 (N = 25 862).
MAIN OUTCOME MEASURES:
Serum thyrotropin (thyroid-stimulating hormone [TSH]) and total thyroxine (T4) concentrations, serum lipid levels, and responses to a hypothyroid symptoms questionnaire.
RESULTS:
The prevalence of elevated TSH levels (normal range, 0.3-5.1 mIU/L) in this population was 9.5%, and the prevalence of decreased TSH levels was 2.2%. Forty percent of patients taking thyroid medications had abnormal TSH levels. Lipid levels increased in a graded fashion as thyroid function declined. Also, the mean total cholesterol and low-density lipoprotein cholesterol levels of subjects with TSH values between 5.1 and 10 mIU/L were significantly greater than the corresponding mean lipid levels in euthyroid subjects. Symptoms were reported more often in hypothyroid vs euthyroid individuals, but individual symptom sensitivities were low.
CONCLUSIONS:
The prevalence of abnormal biochemical thyroid function reported here is substantial and confirms previous reports in smaller populations. Among patients taking thyroid medication, only 60% were within the normal range of TSH. Modest elevations of TSH corresponded to changes in lipid levels that may affect cardiovascular health. Individual symptoms were not very sensitive, but patients who report multiple thyroid symptoms warrant serum thyroid testing. These results confirm that thyroid dysfunction is common, may often go undetected, and may be associated with adverse health outcomes that can be avoided by serum TSH measurement.
Endocr Pract. 2008 Jul-Aug;14(5):570-5.
Increased atherogenic low-density lipoprotein cholesterol in untreated subclinical hypothyroidism.
Mikhail GS, Alshammari SM, Alenezi MY, Mansour M, Khalil NA.
OBJECTIVE:
To evaluate the effects of physiologic doses of levothyroxine replacement on the lipoprotein profile in patients with subclinical hypothyroidism (SCH).
METHODS:
In a prospective, double-blind, placebo-controlled study, we enrolled 120 patients–mostly, but not exclusively, premenopausal women–with SCH. Patients were randomly assigned to either a levothyroxine-treated group (n = 60) or a placebo (control) group (n = 60). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured before and 52 weeks after assignment to either group.
RESULTS:
In the levothyroxine-treated group, the lipoprotein mean values before and after the 52-week study were as follows: TC, 5.05 +/- 0.98 mmol/L versus 4.74 +/- 0.87 mmol/L (P<.0001); LDL-C, 3.30 +/- 0.90 mmol/L versus 2.89 +/- 0.59 mmol/L (P<.01); TG, 1.18 +/- 0.71 mmol/L versus 0.95 +/- 0.53 mmol/L (P<.002); and HDL-C, 1.20 +/- 0.33 mmol/L versus 1.19 +/- 0.32 mmol/L (P = .29). In the control group, TC, HDL-C, and TG values remained unchanged after 52 weeks in comparison with baseline, but LDL-C mean values increased from 2.79 +/- 0.60 mmol/L to 3.11 +/- 0.77 mmol/L, a change that was statistically significant (P<.001). At the end of the study, the lipid profile changes between levothyroxine-treated and control groups were compared. Total cholesterol and LDL-C were significantly lower in the levothyroxine-receiving group (P<.029 and P<.0001, respectively) in comparison with the control group. The difference did not reach statistical significance for TG and HDL-C values.
CONCLUSION:
In premenopausal women, SCH has a negative effect on the lipoprotein profile and may translate into a sizable cardiovascular risk if left untreated.
Ann Intern Med. 1999 Sep 7;131(5):348-51.
Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism.
Hussein WI, Green R, Jacobsen DW, Faiman C.
BACKGROUND:
Hyperhomocysteinemia is an independent risk factor for coronary, peripheral, and cerebrovascular disease. Elevated plasma homocysteine levels were described in a preliminary report on primary hypothyroidism.
OBJECTIVE:
To determine whether restoration of euthyroidism by L-thyroxine replacement therapy would reduce or normalize plasma homocysteine levels.
DESIGN:
Prospective cohort study.
SETTING:
Outpatient endocrinology department of a tertiary center.
PATIENTS:
14 patients (10 women and 4 men; 25 to 77 years of age): 4 with newly diagnosed chronic (Hashimoto) hypothyroidism and 10 who had been rendered acutely hypothyroid (thyroid-stimulating hormone level > 25 mU/L) by total thyroidectomy for thyroid carcinoma.
MEASUREMENTS:
Total plasma homocysteine levels were measured at baseline and 3 to 9 months later, after euthyroidism had been attained by L-thyroxine replacement therapy.
RESULTS:
Median baseline plasma homocysteine levels in both sexes (women, 11.65 micromol/L [range, 7.2 to 26.5 micromol/L]; men, 15.1 micromol/L [range, 14.1 to 16.3 micromol/L]) were higher (P = 0.002) than those in healthy female (n = 35) and male (n = 36) volunteers (women, 7.52 micromol/L [range, 4.3 to 14.0 micromol/L]; men, 8.72 micromol/L [range, 5.94 to 14.98 micromol/L]). Eight patients (57%) had baseline plasma homocysteine levels that exceeded the upper limit of sex-specific reference ranges. Upon attainment of euthyroidism, all patients had a diminution in plasma homocysteine levels. The median overall change of -5.5 micromol/L (range, -15.4 to -1.8 micromol/L) corresponds to a difference of -44% (range, -58% to -13%) (P < 0.001). Homocysteine levels returned to normal in 7 of the 8 patients with elevated pretreatment values.
CONCLUSIONS:
Hypothyroidism may be a treatable cause of hyperhomocysteinemia, and elevated plasma homocysteine levels may be an independent risk factor for the accelerated atherosclerosis seen in primary hypothyroidism.
Thyroid. 2002 May;12(5):421-5.
Risk factors for cardiovascular disease in women with subclinical hypothyroidism.
Luboshitzky R, Aviv A, Herer P, Lavie L.
Overt hypothyroidism may result in accelerated atherosclerosis and coronary heart disease (CHD) presumably because of the associated hypertension, hypercholesterolemia, and hyperhomocysteinemia. As many as 10%-15% of older women have subclinical hypothyroidism (SH) and thyroid autoimmunity. Whether SH is associated with risk for CHD is controversial. We examined 57 women with SH and 34 healthy controls. SH was defined as an elevated thyrotropin (TSH) (>4.5 mU/L) and normal free thyroxine (FT(4)) level (8.7-22.6 nmol/L). None of the patients had been previously treated with thyroxine. In all participants we determined blood pressure, body mass index (BMI), and fasting TSH, FT(4), antibodies to thyroid peroxidase and thyroglobulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, folic acid, vitamin B(12), creatinine, and total plasma homocysteine levels. The SH and control groups did not differ in their total homocysteine values. Mean diastolic blood pressure was increased in SH patients versus controls (82 vs. 75 mm Hg; p < 0.01). Mean values of TC, HDL-C, LDL-C, triglycerides, TC/HDL-C, and LDL-C/HDL-C were not different in patients with SH compared with controls. Individual analysis revealed that the percentage of patients with SH having hypertension (20%), hypertriglyceridemia (26.9%), elevated TC/HDL-C (11.5%), and LDL-C/HDL-C (4%) ratios were higher than the percentages in controls. Hyperhomocysteinemia (> or = 10.98 micromol/L) was observed in 29.4% of SH and was not significantly different from the percentage in controls (21.4%). No significant correlation between TSH and biochemical parameters was detected. We conclude that subclinical hypothyroidism in middle-aged women is associated with hypertension, hypertriglyceridemia, and elevated TC/HDL-C ratio. This may increase the risk of accelerated atherosclerosis and premature coronary artery disease in some patients.
Vojnosanit Pregl. 2007 Nov;64(11):749-52.
[Cardiovascular risk factors in patients with subclinical hypothyroidism].
[Article in Serbian]
Pesić M, Antić S, Kocić R, Radojković D, Radenković S.
BACKGROUND/AIMS:
Overt hypothyroidism is disease associated with accelerated arteriosclerosis and coronary heart disease. Whether subclinical hypothyroidism (SH) is associated with increased cardiovascular risk is contraversial. As SH is a high prevalence thyroid dysfunction, specially in older women, it is important to evaluate cardiovascular risk factors in these patients and that was the aim of this study.
METHODS:
We examined 30 patients with SH and 20 healthy controls. Subclinical hypothireoidism was defined as an elevated thyrotropin (TSH) (> 4.5 mU/L) and normal free thyroxine (FT4) level. In all the participants we determined body mass index (BMI), blood pressure, TSH, FT4, antibodies to thyroid peroxidase, antibodies to thyroglobulin, total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglicerides, total cholesterol/HDL cholesterol ratio and LDL/HDL cholesterol ratio.
RESULTS:
Mean BMI in patients with SH was significantly higher (p < 0.05), as well as diastolic blood pressure (p < 0.01) compared with the controls. Average levels of total cholesterol (5.40 +/- 0.62 vs 5.06 +/- 0.19 mmol/l, p < 0.01) and triglycerides (2.16 +/- 0.56 vs 1.89 +/- 0.24 mmol/l, p < 0.05) were also significantly higher in the group with SH. Individual analysis revealed that the percentage of patients with SH having borderline elevated total cholesterol (63.33%), hypertrigliceridemia (43.33%) and elevated total cholesterol/HDL cholesterol ratio (26.67%) were significantly higher than the percentage in the controls. No significant correlation between TSH and lipid parameters was detected.
CONCLUSION:
Subclinical hypothyroidism was associated with higher BMI, diastolic hypertension, higher total cholesterol and triglicerides levels and higher total cholesterol/HDL cholesterols ratio. This might increase the risk of accelerated arteriosclerosis in patients with SH.
J Endocrinol Invest. 2004 Nov;27(10):897-903.
The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism.
Serter R, Demirbas B, Korukluoglu B, Culha C, Cakal E, Aral Y.
The aim of our study was to assess the changes in serum lipid profiles after replacement therapy with L-T4 in patients with subclinical hypothyroidism (SCH), and to see whether there is an improvement in dyslipidemia based cardiovascular risk. Thirty non-smoker pre-menopausal women with newly diagnosed SCH (TSH between 4 and 10 microIU/ml) were involved in our study; twenty-six euthyroid healthy subjects were used as control group. TSH, free T3 (FT3), free T4 (FT4), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were measured before and after 6 months of L-T4 (50-100 microg/ day) therapy. TSH levels were targeted as < 2.0 microIU/ml. LDL-C was calculated using the Friedewald formula, while the cardiovascular risk was assessed with the TC/HDL-C ratio. Pre-treatment serum TC and LDL-C concentrations in SCH patients were significantly higher than those of euthyroid subjects (199.8 +/- 22.2 vs 181.5 +/- 24.6 mg/dl, p < 0.01; 146.3 +/- 26.1 vs 124.8 +/- 12 mg/dl, p < 0.001, respectively). TC, LDL-C levels and the TC/HDL-C ratio were reduced significantly after 6-month replacement therapy (-21.1 +/- 34.4 mg/dl or -10.5%, p < 0.01; -21.5 +/- 30.3 mg/dl or -14.7%, p < 0.001, respectively; and TC/HDL-C from 4.8 +/- 0.6 to 4.1 +/- 0.5 mg/dl, p < 0.01), while body mass index (BMI) values did not change. In conclusion, even mild elevations of TSH are associated with changes in lipid profile significant enough to raise the cardiovascular risk ratio, and these changes are corrected once the patients have been rendered euthyroid.
Thyroid. 2005 May;15(5):455-60.
Thyroid substitution therapy induces high-density lipoprotein-associated platelet-activating factor-acetylhydrolase in patients with subclinical hypothyroidism: a potential antiatherogenic effect.
Milionis HJ, Tambaki AP, Kanioglou CN, Elisaf MS, Tselepis AD, Tsatsoulis A.
BACKGROUND:
Subclinical hypothyroidism (SH) has been associated with an increased risk of ischemic heart disease, which has been partly attributed to lipid abnormalities. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme associated with lipoproteins (both low-density lipoproteins [LDL], and high-density lipoproteins [HDL]). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL.
OBJECTIVE:
To evaluate qualitative changes in lipoprotein metabolism with respect to PAF-AH and PON1 activities in patients with SH before and after the restoration of euthyroidism.
DESIGN AND METHODS:
We determined the PAF-AH activity in plasma and on HDL and PON1 activities as well as the lipid profile patients with SH at baseline and after 6 months of levothyroxine substitution therapy. Thirty normolipidemic healthy individuals comprised the control group.
RESULTS:
Compared to controls, patients with SH showed higher levels of total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B. Triglycerides were significantly reduced after levothyroxine treatment. Patients with SH exhibited higher plasma baseline PAF-AH activity (63.0 +/- 16.5 versus 44.3 +/- 9.5 nmol/mL per minute p < 0.0001) and lower baseline HDL associated PAF-AH (2.9 +/- 1.1 versus 3.6 +/- 0.9 nmol/mL per minute p = 0.02) compared to the control group. PON1 activities were similar in both groups. Levothyroxine treatment had no effect on plasma PAF-AH activity or PON1 activities but resulted in a significant elevation of HDL-associated PAF-AH activity (from 2.9 +/- 1.1 to 3.5 +/- 1.0 nmol/mL per minute, p = 0.003).
CONCLUSIONS:
Patients with SH exhibit increased plasma PAF-AH activity and low HDL-associated PAF-AH activity. Levothyroxine induces a significant increase in HDL-PAF-AH activity. This action may represent a potential antiatherogenic effect of thyroid.
The Journal of Clinical Endocrinology & Metabolism 88(6):2438 –244
Hypothyroidism and Atherosclerosis
ANNE R. CAPPOLA AND PAUL W. LADENSON
For 125 yr, physicians have appreciated that there is a relationship between hypothyroidism and atherosclerosis. Our growing understanding of thyroid hormone’s regulation of lipid and homocysteine metabolism, effects on vascular reactivity and blood pressure, and modulation of other atherosclerotic factors now provide partial explanations for how hypothyroidism predisposes patients to cardiovascular
disease. In addition to this pathogenic relationship, the multiple direct and indirect actions of thyroid hormone on cardiac and peripheral vascular functions can complicate management of hypothyroid patients with atherosclerotic coronary disease. Despite these advances, today’s clinicians managing patients with hypothyroidism and atherosclerosis are still guided more by medical folklore than evidence based medicine.
The Journal of Clinical Endocrinology & Metabolism August 1, 2008 vol. 93 no. 8 2998-3007
The Influence of Age on the Relationship between Subclinical Hypothyroidism and Ischemic Heart Disease: A Metaanalysis
Salman Razvi, Abdul Shakoor, Mark Vanderpump, Jolanta U. Weaver and Simon H. S. Pearce
Context: Subclinical hypothyroidism (SCH) is a common condition that has been associated with ischemic heart disease (IHD) in some, but not all, studies. This may be due to differences in study design and the characteristics of participants.
Objective: Our objective was to investigate whether age and gender influence IHD prevalence, incidence, and mortality in people with SCH.
Data Sources: Computerized (PubMed, EMBASE, and Cochrane Library) and manual searches of the literature to May 2007, published in English, were performed.
Study Selection: Epidemiological studies that quantified thyroid status and IHD events in adults were performed.
Data Extraction: Two authors independently reviewed articles and abstracted data. Results were compared across two groups based on the minimum age of participants studied (younger than 65 yr and 65 yr or older).
Data Synthesis: There were 15 studies included for analysis with 2,531 SCH participants and 26,491 euthyroid individuals. IHD incidence and prevalence were higher in SCH subjects compared with euthyroid participants from studies including those younger than 65 yr, but not studies of subjects aged older than 65 yr [odds ratio (95% confidence interval)]: 1.57 (1.19–2.06) vs. 1.01 (0.87–1.18) and 1.68 (1.27–2.23) vs. 1.02 (0.85–1.22), respectively. Cardiovascular/all-cause mortality was also elevated in participants from the younger than 65-yr studies, but not from the studies of older people: odds ratio 1.37 (1.04–1.79) vs. 0.85 (0.56–1.29). Prevalent IHD was higher in SCH participants of both genders, although this was statistically significant only in women.
Conclusions: SCH is associated with increased IHD (both prevalence and incidence) and cardiovascular mortality only in subjects from younger populations. These data suggest that increased vascular risk may only be present in younger individuals with SCH.
Can J Cardiol. 1997 Mar;13(3):273-6.
The effect of thyroid hormone therapy on angiographic coronary artery disease progression.
Perk M, O’Neill BJ.
OBJECTIVE:
To study the effect of adequacy of thyroid hormone replacement therapy on coronary atherosclerosis.
DESIGN:
Retrospective cohort study of elderly hypothyroid patients with coexisting coronary artery disease. The association between the adequacy of thyroid replacement and the progression of angiographic coronary artery disease was investigated. Fisher’s exact test was used for statistical analysis.
SETTING:
Coronary angiographies were performed at the Cardiac Catheterization Laboratory of the Victoria General Hospital, Halifax, Nova Scotia, the only tertiary referral centre for Nova Scotia and Prince Edward Island. Information about the past and current thyroid status of the subjects was collected from their family physicians.
PATIENTS:
Of 4103 patients admitted for coronary angiography during 1992 and 1993, 25 were on thyroid replacement therapy to treat hypothyroidism. Ten patients who underwent more than one coronary arteriography were selected (seven females and three males, mean age 65 +/- 10 years).
RESULTS:
Of five patients inadequately treated for hypothyroidism, all demonstrated angiographic evidence of coronary atherosclerosis progression. However, five of seven who were treated adequately did not show atherosclerosis progression (P = 0.02, OR = 0.72, 95% CI 1.36 to infinity). Decreasing or maintaining the dose of L-thyroxine at 100 micrograms or less resulted in coronary atherosclerosis progression in six of six patients, whereas five of six patients taking fixed or increasing doses of L-thyroxine 150 micrograms or higher were spared from disease progression (P = 0.015, OR = 0.41, 95% CI 2.4 to infinity).
CONCLUSIONS:
Angiographic coronary artery disease progression may be prevented by adequate thyroid replacement in hypothyroidism. With the help of modern, sensitive thyroid stimulating hormone assays higher doses of L-thyroxine may be safer and more effective in the atherosclerosis management of this patient population. Thyroid hormones can protect against atherosclerosis, presumably due to their metabolic affects on plaque progression.
Eur J Endocrinol. 2011 Jul;165(1):115-21. Epub 2011 Apr 13.
Impact of subclinical hypothyroidism on the coronary artery disease in apparently healthy subjects.
Park YJ, Lee YJ, Choi SI, Chun EJ, Jang HC, Chang HJ.
OBJECTIVE:
Cardiovascular disease (CVD) occurs frequently and may progress more rapidly in overt hypothyroidism (OVH). However, the role of mild thyroid failure as a risk factor for CVD is not clear. This study is aimed at exploring the association between subclinical hypothyroidism (SCH) and coronary artery disease (CAD), as detected by cardiac computed tomography (CT), in apparently healthy subjects.
SUBJECTS AND METHODS:
We retrospectively enrolled 2404 asymptomatic subjects who underwent cardiac CT with an intermediate to high risk (Framingham 10-year risk ≥10%) of developing CAD but with no known CAD or thyroid disease. Coronary artery calcium score (CACS) was assessed by calcium scan, and the presence of the plaques (CAD), with ≥50% stenosis being indicative of obstructive CAD, was assessed by coronary CT angiography.
RESULTS:
Of the 2404 subjects, 2355 subjects were euthyroid (Eu; 53±9 years, 83 females) and 49 had SCH (58±12 years, seven females). CAD and CACS >100 were more prevalent in SCH subjects than in Eu subjects (Eu vs SCH: CAD, 948 (40.6%) vs 31 (63.3%), P=0.002; CACS >100, 239 (10.3%) vs 10 (20.4%), P=0.031). SCH was also an independent risk factor for CAD after a multivariate analysis (odds ratio: 2.125, 95% confidence interval: 1.049-4.307, P=0.036).
CONCLUSIONS:
SCH subjects who were at an intermediate-to-high risk of developing CAD were significantly more likely to exhibit occult CAD than Eu subjects, especially in men with SCH. These findings suggest that mild thyroid failure also independently contributes to the development of CAD.
JAMA. 2010 Sep 22;304(12):1365-74.
Subclinical hypothyroidism and the risk of coronary heart disease and mortality.
Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration.
CONTEXT:
Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants’ age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.
OBJECTIVE:
To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.
DATA SOURCES AND STUDY SELECTION:
The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.
DATA EXTRACTION:
Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.
RESULTS:
Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.
CONCLUSIONS:
Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.
Arch Intern Med. 2005 Nov 28;165(21):2460-6.
Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death.
Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, Bauer DC.
BACKGROUND:
Subclinical hypothyroidism has been associated with systolic and diastolic cardiac dysfunction and an elevated cholesterol level, but data on cardiovascular outcomes and death are limited.
METHODS:
We studied 2730 men and women, aged 70 to 79 years, with baseline thyrotropin (TSH) measurements and 4-year follow-up data to determine whether subclinical hypothyroidism was associated with congestive heart failure (CHF), coronary heart disease, stroke, peripheral arterial disease, and cardiovascular-related and total mortality. After the exclusion of participants with abnormal thyroxine levels, subclinical hypothyroidism was defined as a TSH level of 4.5 mIU/L or greater, and was further classified according to TSH levels (4.5-6.9, 7.0-9.9, and > or = 10.0 mIU/L).
RESULTS:
Subclinical hypothyroidism was present in 338 (12.4%) of the participants. Compared with euthyroid participants, CHF events occurred more frequently among those with a TSH level of 7.0 mIU/L or greater (35.0 vs 16.5 per 1000 person-years; P = .006), but not among those with TSH levels between 4.5 and 6.9 mIU/L. In multivariate analyses, the risk of CHF was higher among those with high TSH levels (TSH of 7.0-9.9 mIU/L: hazard ratio, 2.58 [95% confidence interval, 1.19-5.60]; and TSH of > or = 10.0 mIU/L: hazard ratio, 3.26 [95% confidence interval, 1.37-7.77]). Among the 2555 participants without CHF at baseline, the hazard ratio for incident CHF events was 2.33 (95% confidence interval, 1.10-4.96; P = .03) in those with a TSH of 7.0 mIU/L or greater. Subclinical hypothyroidism was not associated with increased risk for coronary heart disease, stroke, peripheral arterial disease, or cardiovascular-related or total mortality.
CONCLUSIONS:
Subclinical hypothyroidism is associated with an increased risk of CHF among older adults with a TSH level of 7.0 mIU/L or greater, but not with other cardiovascular events and mortality. Further investigation is warranted to assess whether subclinical hypothyroidism causes or worsens preexisting heart failure.
Arch Intern Med. 2005 Nov 28;165(21):2467-72.
Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.
Walsh JP, Bremner AP, Bulsara MK, O’Leary P, Leedman PJ, Feddema P, Michelangeli V.
BACKGROUND:
There have been few large epidemiological studies examining the association between thyroid dysfunction and cardiovascular disease. In particular, it is uncertain if subclinical hypothyroidism is a risk factor for cardiovascular disease.
METHODS:
Serum thyrotropin and free thyroxine concentrations were measured in 2108 archived serum samples from a 1981 community health survey in Busselton, Western Australia (Busselton Health Study). In a cross-sectional study, we examined the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction. In a longitudinal study, we examined the risk of cardiovascular mortality and coronary heart disease events (fatal and nonfatal combined) to the end of 2001 (excluding subjects who had coronary heart disease at baseline).
RESULTS:
In the cross-sectional analysis, subjects with subclinical hypothyroidism (n = 119) had a significantly higher prevalence of coronary heart disease than euthyroid subjects (n = 1906) (age- and sex-adjusted prevalence odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). In the longitudinal analysis of subjects with subclinical hypothyroidism (n = 101), there were 21 cardiovascular deaths observed compared with 9.5 expected (age- and sex-adjusted hazard ratio, 1.5; 95% confidence interval, 1.0-2.4; P = .08) and 33 coronary heart disease events observed compared with 14.7 expected (age- and sex-adjusted hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P < .01). The increased risk of coronary heart disease events remained significant after further adjustment for standard cardiovascular risk factors. Subjects with subclinical hyperthyroidism (n = 39) had no adverse outcomes.
CONCLUSION:
Subclinical hypothyroidism may be an independent risk factor for coronary heart disease.
Heart. 1997 March; 77(3): 189–190.
Hypothyroidism, thyroxine treatment, and the heart.
M. Gammage and J. Franklyn
Hypothyroidism is a common condition; surveys indicate that approximately 1% of the general population and 4% of people 60 years and older are prescribed thyroxine long
term. Hypothyroidism has cardiovascular consequences resulting from both direct influences of thyroid hormone deficiency on the heart, and adverse effects on circulating lipid concentrations. Furthermore, with the advent of improved tests of thyroid function, it has become clear that even when patients with hypothyroidism are treated with thyroxine long term, about half have serum thyrotrophin concentrations above or below the normal range, indicating a degree of under or over treatment with thyroxine. Although little importance has been attached to these minor biochemical abnormalities, recent evidence suggests that they may have considerable clinical significance.
Lancet. 1967 Oct 14;2(7520):800-2.
Coronary-artery disease in hypothyroidism. Observations in clinical myxoedema.
Vanhaelst L, Neve P, Chailly P, Bastenie PA.
The relation of coronary-artery disease to hypothyroidism has been investigated in 87 patients with clinical myxœdema and in 25 necropsies on patients who died with inadequately treated myxœdema. The clinical and the pathological findings were compared with those in matched controls. Independently of sex, age, and associated disorders, spontaneous hypothyroidism strongly favoured the development of coronary-artery atherosclerosis. In untreated myxœdema, however, despite increased atherosclerosis and myocardial ischæmia, the incidence of myocardial infarcts was not increased.
Br Heart J. 1981 August; 46(2): 202–206.
Borderline low thyroid function and thyroid autoimmunity. Risk factors for coronary heart disease?
M Tièche, G A Lupi, F Gutzwiller, P J Grob, H Studer, and H Bürgi
Assessments were made of 945 consecutive hospital patients with regard to a relation between borderline low thyroid function (recognised by a slightly raised thyroid stimulating hormone), thyroid autoimmunity, serum cholesterol, and coronary heart disease. Men and women with a thyroid autoimmunity, serum cholesterol, and coronary heart disease. Men and women with a thyroid stimulating hormone of 4.0 mU/l or over had a higher prevalence of coronary heart disease than did age-matched controls, and this difference was significant in women. The excess of coronary heart disease was not explained by an excess of other risk factors such as a high cholesterol, hypertension, smoking, and diabetes. Women with thyroid antibodies had a slightly higher prevalence of coronary heart disease despite the unexpected finding of a lower serum cholesterol. The data point to an association between borderline thyroid function and autoimmunity and coronary heart disease which is not mediated through a raised serum cholesterol.
J Gerontol A Biol Sci Med Sci. 2002 Oct;57(10):M658-9.
Subclinical hypothyroidism is associated with coronary artery disease in older persons.
Mya MM, Aronow WS.
BACKGROUND:
We report the prevalence of coronary artery disease (CAD) associated with subclinical hypothyroidism in older persons.
METHODS:
We investigated the prevalence of subclinical hypothyroidism and its association with dyslipidemia and with CAD in 170 women and 110 men, mean age 75 +/- 9 years, in an academic nursing home.
RESULTS:
Of 280 persons, 18 (6%) had subclinical hypothyroidism, 18 (6%) had treated clinical hypothyroidism, 13 (5%) had subclinical hyperthyroidism, and 231 (83%) were euthyroid. Dyslipidemia occurred in 15 of 18 persons (83%) with subclinical hypothyroidism, in nine of 18 persons (50%) treated for hypothyroidism, in six of 13 persons (46%) with subclinical hyperthyroidism, and in 128 of 231 euthyroid persons (55%) (p <.025 comparing subclinical hypothyroidism with euthyroidism and p <.005 comparing subclinical hypothyroidism with treated hypothyroidism and with subclinical hyperthyroidism). CAD was present in 10 of 18 persons (56%) with subclinical hypothyroidism, in nine of 18 persons (50%) with treated hypothyroidism, in 5 of 13 persons (38%) with subclinical hyperthyroidism, and in 38 of 231 euthyroid persons (16%) (p <.001 comparing subclinical hypothyroidism with euthyroidism; p <.005 comparing treated hypothyroidism with euthyroidism; and p <.05 comparing subclinical hyperthyroidism with euthyroidism).
CONCLUSIONS:
Subclinical hypothyroidism was associated with a high prevalence of dyslipidemia and a high prevalence of CAD.
February 15, 2000 vol. 132 no. 4 270-278
Subclinical Hypothyroidism Is an Independent Risk Factor for Atherosclerosis and Myocardial Infarction in Elderly Women: The Rotterdam Study
A. Elisabeth Hak, MD, MSc; Huibert A.P. Pols, MD, PhD; Theo J. Visser, MD, PhD; Hemmo A. Drexhage, MD, PhD; Albert Hofman, MD, PhD; and Jacqueline C.M. Witteman, PhD
Background: Overt hypothyroidism has been found to be associated with cardiovascular disease. Whether subclinical hypothyroidism and thyroid autoimmunity are also risk factors for cardiovascular disease is controversial.
Objective: To investigate whether subclinical hypothyroidism and thyroid autoimmunity are associated with aortic atherosclerosis and myocardial infarction in postmenopausal women.
Design: Population-based cross-sectional study.
Setting: A district of Rotterdam, the Netherlands.
Participants: Random sample of 1149 women (mean age ± SD, 69.0 ± 7.5 years) participating in the Rotterdam Study.
Measurements: Data on thyroid status, aortic atherosclerosis, and history of myocardial infarction were obtained at baseline. Subclinical hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>4.0 mU/L) and a normal serum free thyroxine level (11 to 25 pmol/L [0.9 to 1.9 ng/dL]). In tests for antibodies to thyroid peroxidase, a serum level greater than 10 IU/mL was considered a positive result.
Results: Subclinical hypothyroidism was present in 10.8% of participants and was associated with a greater age-adjusted prevalence of aortic atherosclerosis (odds ratio, 1.7 [95% CI, 1.1 to 2.6]) and myocardial infarction (odds ratio, 2.3 [CI, 1.3 to 4.0]). Additional adjustment for body mass index, total and high-density lipoprotein cholesterol level, blood pressure, and smoking status, as well as exclusion of women who took β-blockers, did not affect these estimates. Associations were slightly stronger in women who had subclinical hypothyroidism and antibodies to thyroid peroxidase (odds ratio for aortic atherosclerosis, 1.9 [CI, 1.1 to 3.6]; odds ratio for myocardial infarction, 3.1 [CI, 1.5 to 6.3]). No association was found between thyroid autoimmunity itself and cardiovascular disease. The population attributable risk percentage for subclinical hypothyroidism associated with myocardial infarction was within the range of that for known major risk factors for cardiovascular disease.
Conclusion: Subclinical hypothyroidism is a strong indicator of risk for atherosclerosis and myocardial infarction in elderly women.
Curr Opin Endocrinol Diabetes Obes. 2007 Jun;14(3):197-208.
Subclinical hypothyroidism.
Papi G, Uberti ED, Betterle C, Carani C, Pearce EN, Braverman LE, Roti E.
PURPOSE OF REVIEW:
Mild or subclinical hypothyroidism is characterized by normal serum free thyroxine concentrations with elevated serum thyroid-stimulating hormone concentrations. Subclinical hypothyroidism is relatively prevalent in the general population, especially among women and the elderly. The main cause of subclinical hypothyroidism is autoimmune chronic thyroiditis. The present report reviews the most important and recent studies on subclinical hypothyroidism, and discusses the most controversial aspects of this topic.
RECENT FINDINGS:
Several studies have demonstrated that subclinical hypothyroidism may affect both diastolic and systolic cardiac function. It may also worsen many risk factors for cardiovascular disease, including hypertension, abnormal endothelial function, and elevated low-density lipoprotein cholesterol concentrations. Furthermore, a growing body of evidence suggests that subclinical hypothyroidism may cause symptoms or progress to symptomatic overt hypothyroidism.
SUMMARY:
Prompt treatment of subclinical hypothyroidism in pregnant women is mandatory to decrease risks for pregnancy complications and impaired cognitive development in offspring. Children with subclinical hypothyroidism should be treated to prevent growth retardation. Whether nonpregnant adult patients with subclinical hypothyroidism should be treated, and at what thyroid-stimulating hormone values, is debatable.
J Clin Endocrinol Metab. 2002 Oct;87(10):4662-6.
Increased central arterial stiffness in hypothyroidism.
Obuobie K, Smith J, Evans LM, John R, Davies JS, Lazarus JH.
Hypothyroidism is associated with cardiovascular dysfunction. It is increasingly apparent that stiffening of central arteries may lead to increased afterload and cardiac dysfunction. We noninvasively studied the peripheral and central pressure waveforms in 12 untreated hypothyroid patients as well as in 12 age-, sex-, and body mass index-matched controls using the technique of pulse wave analysis from recordings at the radial artery. Indexes of arterial stiffness, augmentation index (AI) and augmentation of central arterial pressure (AG), were derived as well as time of travel of the reflected wave (TR), a direct estimate of aortic pulse wave velocity. At baseline, there were no significant differences between the 2 groups in brachial and aortic blood pressures. Hypothyroid patients had significantly higher AI than controls (mean +/- SEM[SCAP], 32.0 +/- 3.4% vs. 17.0 +/- 2.4%; P < 0.0005) even when corrected for heart rate (AI(C); 28.0 +/- 3.2% vs. 17.0 +/- 2.4%; P < 0.006) and AG (13.0 +/- 2.2 vs. 7.0 +/- 2.1 mm Hg; P < 0.03) together with a lower TR (132.0 +/- 4.1 vs. 142.0 +/- 1.5 msec; P < 0.03). After 6 months of therapy with T(4), all patients were euthyroid. AI(C) had decreased in the patient group (23.0 +/- 3.2% vs. 28.0 +/- 3.2%; P < 0.01) as had AG (9.0 +/- 1.5 vs. 13.0 +/- 2.2 mm Hg; P < 0.008), but TR was significantly higher (142.0 +/- 3.0 vs. 132.0 +/- 4.1 msec; P < 0.008). AI correlated with age in all groups (hypothyroid group: r = 0.937; P < 0.0005; control group: r = 0.804; P < 0.0005), but correlated with TSH level only among controls (r = 0.591; P < 0.05). This study confirms that hypothyroidism is associated with increased cardiovascular risk, as evidenced by increased augmentation of central aortic pressures and central arterial stiffness. Furthermore, these abnormalities are reversed after adequate T(4) replacement.
Thyroid. 1996 Oct;6(5):505-12.
Acute effects of thyroid hormone on vascular smooth muscle.
Ojamaa K, Klemperer JD, Klein I.
The enhanced cardiovascular hemodynamics associated with triiodo-L-thyronine (T3) treatment is in part mediated by a decrease in systemic vascular resistance. To determine the molecular mechanisms for the vasoactive properties of T3, we studied primary cultures of aortic endothelial and vascular smooth muscle (VSM) cells. Active tension development by the VSM cells was measured by deformation lines within a siloxane matrix on which the cells were grown. Exposure to T3 (10(-10) M) resulted in cellular relaxation within 10 min. Hormone binding studies to purified VSM cell plasma membranes identified two binding sites specific for T3 with Kd of 1 x 10(-11) and 6.1 x 10(-8) M. L-Thyroxine and reverse T3 did not compete for the L-T3 binding sites. To determine an intracellular signaling pathway of T3 action, cAMP and cGMP content were measured in VSM cell cultures treated with T3. No quantitative changes were observed in a time frame known to cause VSM cell relaxation. The level of myosin light chain phosphorylation is a major determinant of smooth muscle contraction. Thus, treatment of VSM cells with isoproterenol, a vasodilator, caused a significant decrease in radiolabeled phosphate incorporation into the myosin light chains, whereas T3 had no effect on phosphorylation of these proteins. Primary cultures of vascular endothelial cells exposed to T3 showed no nitric oxide production as measured by cellular cGMP content and nitrite release, suggesting that T3 acted directly on the VSM cell to cause vascular relaxation.
Am J Med. 1990 Jun;88(6):638-41.
Recognition and management of cardiovascular disease related to thyroid dysfunction.
Ladenson PW.
Hypothyroidism and hyperthyroidism are both associated with clinically significant cardiovascular derangements. In hypothyroidism, these include pericardial effusion, heart failure, and the complex interrelationship between hypothyroidism and ischemic heart disease. Cardiovascular disorders associated with hyperthyroidism include atrial tachyarrhythmias, mitral valve dysfunction, and heart failure. Although these usually occur in individuals with intrinsic heart disease, thyroid dysfunction alone rarely causes serious but reversible cardiovascular dysfunction. Patients with commonly encountered cardiac disorders, e.g., idiopathic cardiomyopathy and atrial fibrillation, should be screened for potentially contributing subclinical thyroid diseases. In patients with heart failure and hypothyroidism, initial management should focus on diagnosis and optimal management of any primary cardiac disease, whereas in hyperthyroidism, aggressive measures to control excess thyroid hormone action should generally have the highest priority.
Recent Prog Horm Res. 2004;59:31-50.
Effects of thyroid hormone on the cardiovascular system.
Fazio S, Palmieri EA, Lombardi G, Biondi B.
Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias – namely, atrial fibrillation – whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism (“subclinical hypothyroidism”) or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring (“subclinical hyperthyroidism”), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease.
Thyroid. 1995 Dec;5(6):443-7.
Silent myocardial ischemia in hypothyroidism.
Bernstein R, Müller C, Midtbø K, Smith G, Haug E, Hertzenberg L.
In some patients with severe hypothyroidism thyroxine replacement therapy precipitates or aggravates angina pectoris, whereas in other patients angina pectoris is ameliorated or even disappears. The reason for this paradox is unknown. It has been attributed either to reversible endocrine cardiomyopathy in the form of asymmetric septal hypertrophy (ASH) or reversible anatomical narrowing of the coronary arteries. The results of a recent investigation, in which myocardial performance was surveyed by radionuclide ventriculography throughout early thyroxine replacement therapy in severe hypothyroidism, were compatible with the presence of reversible coronary dysfunction rather than of ASH. The aim of the present investigation was to confirm these findings. In six severely hypothyroid patients, without echocardiographic evidence of ASH or evidence of concomitant coronary artery disease (CAD), exercise and redistribution tomographic myocardial thallium-201 imaging (SPECT) was performed before thyroxine replacement therapy and repeated after 10 days and again after 2 months during therapy. In four patients substantial regional perfusion defects were demonstrated after exercise that were normalized at rest both before, and in one subject also after 10 days, on thyroxine. With restoration of euthyroidism, exercise and redistribution SPECT were normal in every patient. Determination of exact confidence limits reveals that the proportional incidence of myocardial perfusion defects in hypothyroidism, indicating myocardial ischemia, will at least be 22% with 95% probability. Despite the relatively low specificity of SPECT it seems pertinent to conclude that impaired myocardial perfusion as assessed by SPECT probably is due to reversible coronary dysfunction inherent in the hypothyroid state, and that this is not an infrequent manifestation of severe hypothyroidism.
J Clin Endocrinol Metab. 2000 May;85(5):1822-7.
Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging.
Bengel FM, Nekolla SG, Ibrahim T, Weniger C, Ziegler SI, Schwaiger M.
Thyroid hormones influence cardiac performance directly and indirectly via changes in peripheral circulation. Little, however, is known about the effect on myocardial oxidative metabolism and its relation to cardiac function and geometry. Patients with a history of thyroidectomy for thyroid cancer present a unique model to investigate the cardiac effects of hypothyroidism. Ten patients without heart disease were investigated in the hypothyroid state and again 4-6 weeks later under euthyroid conditions. Myocardial oxidative metabolism was measured by positron emission tomography with [11C]acetate and the clearance constant k(mono). Cine magnetic resonance imaging was applied to determine left ventricular geometry. A stroke work index (SWI = stroke volume x systolic blood pressure/ventricular mass) was calculated. Then, to estimate myocardial efficiency, a work metabolic index [WMI = SWI x heart rate/k(mono)] was obtained. Compared to hormone replacement, systemic vascular resistance and left ventricular mass were significantly higher in hypothyroidism. Ejection fraction and SWI were significantly lower. Despite an additional reduction of k(mono), the WMI was significantly lower, too. In summary, cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Estimates of cardiac work are more severely suppressed than those of oxidative metabolism, suggesting decreased efficiency. These findings may provide an explanation for development or worsening of heart failure in hypothyroid patients with preexisting heart disease.
Acta Med Scand. 1975 Jan-Feb;197(1-2):15-7.
The adhesiveness of human blood platelets and thyroid function.
Hellem AJ, Segaard E, Solem JH.
Hypothyroidism is associated with severe coronary atherosclerosis. In spite of this the reported incidence of angina pectoris and myocardial infarction in untreated hypothyroidism is small. Since many authors consider the formation of a thrombus in coronary arteries to be the final event of the process which leads to myocardial infarction, changes in the platelet function may explain the paradoxical rarity of myocardial infarction in untreated hypothyroidism. To evaluate this hypothesis, platelet adhesiveness has been estimated before and after treatment in 9 hypothyroid and 16 thyrotoxic patients. In thyrotoxicosis the platelet adhesiveness was significantly increased, but decreased to normal after treatment. In hypothyroidism platelet adhesiveness was abnormally low but increased to normal value after thyroid hormone replacement. This may be an important factor in precipitating myocardial infarction in patients with hypothyroidism and coronary artery atherosclerosis.
Metabolism. 1997 Oct;46(10):1128-31.
Alteration of platelet aggregation in patients with thyroid disorders.
Masunaga R, Nagasaka A, Nakai A, Kotake M, Sawai Y, Oda N, Mokuno T, Shimazaki K, Hayakawa N, Kato R, Hirano E, Hagiwara M, Hidaka H.
To determine whether Graves’ disease or primary hypothyroidism influence platelet function, we evaluated platelet aggregation in the platelet-rich plasma (PRP) from such patients. Platelet aggregation induced by adenosine diphosphate (ADP) in blood obtained from patients with untreated Graves’ disease was significantly lower than normal, whereas that in patients with untreated primary hypothyroidism was relatively increased. The magnitude of platelet aggregation induced by collagen in both groups of patients resembled that induced by ADP. However, significant differences were evident between the two diseases (P < .05). In addition, we observed a significant inverse correlation between the extent of platelet aggregation and plasma levels of thyroid hormones (triiodothyronine [T3], thyroxine [T4], and free T3). Platelet aggregation returned to normal when the euthyroid condition was obtained in the patients following administration of antithyroid drugs or thyroid hormone. The findings are consistent with the possibility that thyroid hormones influence platelet aggregation partly via inhibition of myosin light-chain kinase (MLCK).
J Clin Endocrinol Metab. 2010 Jan;95(1):186-93. Epub 2009 Nov 11.
Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy.
Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP.
CONTEXT:
For patients on T(4) replacement, the dose is guided by serum TSH concentrations, but some patients request higher doses due to adverse symptoms.
OBJECTIVE:
The aim of the study was to determine the safety of patients having a low but not suppressed serum TSH when receiving long-term T(4) replacement.
DESIGN:
We conducted an observational cohort study, using data linkage from regional datasets between 1993 and 2001.
SETTING:
A population-based study of all patients in Tayside, Scotland, was performed.
PATIENTS:
All patients taking T(4) replacement therapy (n = 17,684) were included.
MAIN OUTCOME MEASURES:
Fatal and nonfatal endpoints were considered for cardiovascular disease, dysrhythmias, and fractures. Patients were categorized as having a suppressed TSH (
RESULTS:
Cardiovascular disease, dysrhythmias, and fractures were increased in patients with a high TSH: adjusted hazards ratio, 1.95 (1.73-2.21), 1.80 (1.33-2.44), and 1.83 (1.41-2.37), respectively; and patients with a suppressed TSH: 1.37 (1.17-1.60), 1.6 (1.10-2.33), and 2.02 (1.55-2.62), respectively, when compared to patients with a TSH in the laboratory reference range. Patients with a low TSH did not have an increased risk of any of these outcomes [hazards ratio: 1.1 (0.99-1.123), 1.13 (0.88-1.47), and 1.13 (0.92-1.39), respectively].
CONCLUSIONS:
Patients with a high or suppressed TSH had an increased risk of cardiovascular disease, dysrhythmias, and fractures, but patients with a low but unsuppressed TSH did not. It may be safe for patients treated with T(4) to have a low but not suppressed serum TSH concentration.
Thyroid. 2002 Apr;12(4):287-93.
Thyroid disease and lipids.
Duntas LH.
The composition and the transport of lipoproteins are seriously disturbed in thyroid diseases. Overt hypothyroidism is characterized by hypercholesterolaemia and a marked increase in low-density lipoproteins (LDL) and apolipoprotein B (apo A) because of a decreased fractional clearance of LDL by a reduced number of LDL receptors in the liver. The high-density lipoprotein (HDL) levels are normal or even elevated in severe hypothyroidism because of decreased activity of cholesteryl-ester transfer protein (CETP) and hepatic lipase (HL), which are enzymes regulated by thyroid hormones. The low activity of CETP, and more specifically of HL, results in reduced transport of cholesteryl esters from HDL(2) to very low-density lipoproteins (VLDL) and intermediate low-density lipoprotein (IDL), and reduced transport of HDL(2) to HDL(3). Moreover, hypothyroidism increases the oxidation of plasma cholesterol mainly because of an altered pattern of binding and to the increased levels of cholesterol, which presents a substrate for the oxidative stress. Cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Hypothyroidism is often accompanied by diastolic hypertension that, in conjunction with the dyslipidemia, may promote atherosclerosis. However, thyroxine therapy, in a thyrotropin (TSH)-suppressive dose, usually leads to a considerable improvement of the lipid profile. The changes in lipoproteins are correlated with changes in free thyroxine (FT(4)) levels. Hyperthyroidism exhibits an enhanced excretion of cholesterol and an increased turnover of LDL resulting in a decrease of total and LDL cholesterol, whereas HDL are decreased or not affected. The action of thyroid hormone on Lp(a) lipoprotein is still debated, because both decrease or no changes have been reported. The discrepancies are mostly because of genetic polymorphism of apo(a) and to the differences between the various study groups. Subclinical hypothyroidism (SH) is associated with lipid disorders that are characterized by normal or slightly elevated total cholesterol levels, increased LDL, and lower HDL. Moreover, SH has been associated with endothelium dysfunction, aortic atherosclerosis, and myocardial infarction. Lipid disorders exhibit great individual variability. Nevertheless, they might be a link, although it has not been proved, between SH and atherosclerosis.
