“In the 1930s, it was demonstrated that estrogen, even in small doses, produced abortions, and that when it is given early enough, even a very small dose will prevent implantation of the fertilized embryo. Progesterone was known, by the early 1940s, to protect against the many toxic effects of estrogen, including abortion, but it was also known as nature’s contraceptive, since it can prevent pregnancy without harmful side-effects, by different mechanisms, including prevention of sperm entry into the uterus. That is, progesterone prevents the miscarriages which result from excess estrogen (1,2), but if used before intercourse, it prevents conception, and thus is a true contraceptive, while estrogen is an abortifacient, not a contraceptive.” -Ray Peat, PhD
Fertil Steril. 1986 Jan;45(1):69-74. Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/estrogen ratios in humans and mice. Gidley-Baird AA, O’Neill C, Sinosich MJ, Porter RN, Pike IL, Saunders DM.
Daily blood samples were taken for progesterone (P) and estradiol (E2) measurements from women who showed a platelet response consistent with the presence of viable embryos after in vitro fertilization and embryo transfer procedures. A comparison of steroid levels between those women who became pregnant and those who did not revealed the following: at and after the time of transfer, women who failed to become pregnant had significantly higher E2 levels and a lower ratio of P/E2 than women who became pregnant. The P/E2 ratio was a better predictor of implantation failure than was the absolute level of either hormone. Experiments were done in mice to test the hypothesis that P could protect implantation of the embryo against the inhibitory effects of high E2. In mice, implantation was inhibited by relatively high levels of E2. This effect was overcome by concomitant administration of P. There was a significant dose-response-related interaction of P with the E2.
Fertil Steril. 1985 Aug;44(2):185-9. Early luteal serum progesterone concentrations are higher in pregnancy cycles. Yovich JL, McColm SC, Yovich JM, Matson PL.
In a consecutive series of 167 patients reaching the stage of embryo transfer after in vitro fertilization and embryo transfer, 19 clinical pregnancies ensued. The serum progesterone (P) levels were significantly greater on the first and second (P less than 0.01) and third (P less than 0.05) postaspiration days for those who conceived. Higher circulating levels of P were achieved on days 1, 2, and 3 (P less than 0.05) by the daily injection of P, 50 mg in oil, given for 5 consecutive days, beginning immediately after follicle aspiration. Both pregnancy and nonpregnancy cycles demonstrated high circulating P levels, but the study implies that relatively higher levels are required for conception, and such levels can be achieved by the use of intramuscular P.
arly Pregnancy. 1996 Jun;2(2):113-20. Relationship of estradiol and progesterone levels to uterine blood flow during early pregnancy
Dickey RP, Hower JF.
The purpose of this study was to examine the relationship of uterine blood flow to serum estradiol and progesterone during early pregnancy. Recumbent uterine artery average velocity, diameter, blood flow volume and uterine and spiral artery resistance were measured using vaginal Doppler ultrasound 118 times in 43 patients during gestational (postmenstrual) weeks 5 to 16. Relationships to serum progesterone and estrogen were analyzed before and after week 10, when intervillous circulation begins, by multiple linear regression analysis and analysis of covariance (ANCOVA) to correct for the effect of gestational age. After correction for gestational age, estradiol was negatively related to uterine artery flow volume (p < 0.05), diameter (p < 0.05), pulsatility index (p < 0.05) and resistance index (p < 0.01) for weeks 5-16 and to diameter (p < 0.05) after week 9. Progesterone was positively related to volume (p < 0.05) and velocity (p < 0.01) for weeks 5-16 and to volume (p < 0.05) for weeks 5 to 9. Spiral artery indices of resistance were unrelated to hormone levels. These results indicate that before the 10th gestational week, uterine blood flow volume is related to progesterone, but not estradiol levels, and suggest that high estradiol levels during and after the 10th week may be associated with decreased uterine blood flow volume.
Proc Soc Exp Biol Med. 1958 Nov;99(2):478-82. Anti-progestational activity of estrogens in rabbit endometrium. MIYAKE T, PINCUS G. 1) The anti-progestational activity of 4 estrogens—estrone, estradiol, estriol, and stilbestrol—administered subcutaneously along with progesterone into Clauberg rabbits has been demonstrated by estimation of endometrial carbonic anhydrase content and simultaneous measurement of uterine G/M ratio. 2) All these estrogens inhibit the effect of progesterone on carbonic anhydrase content and G/M ratio of the endometrium. Intensity of inhibition depends upon dosage. 3) The anti-progestational activities of these estrogens are approximately the same. 4) When administered alone, these estrogens produce no significant change in either carbonic anhydrase titers or G/M ratios of the endometrium. 5) The linear relationship with negative slope which is obtained between the logarithmic dose of the estrogens and the endometrial carbonic anhydrase content of the progesterone-treated Clauberg rabbit suggests the usefulness of the carbonic anhydrase method as an assay procedure for anti-progestational activity. 6) Comparison of the log-dose-response curves of progesterone with and without estradiol indicates that estrogen may depress reactivity of the endometrium to progesterone rather than neutralize or inactivate progesterone in the body.
Fertil Steril. 1956 Jul-Aug;7(4):301-11. Effect of various steroids on gestation and litter size in rats. VELARDO JT, RANEY NM, SMITH BG, STURGIS SH.
The purpose of this investigation was to ascertain the action of estriol and various ratios of pregnane-3-a-20-a-diol: pregnanedione on gestation and the number of living young born in each treatment group of rats. These substances, in the doses here used, did not affect the mating response or length of gestation. Combinations of the 2 pregnanes tended to reduce the size of the litters compared with untreated controls both when given for a week before mating and also on the day of mating only. When estriol was given prior to mating, it caused a more marked reduction in live births, and when this steroid was employed after mating and daily through time of implantation, the litters decreased to 33% of the control size. In the same animals, the incidence of placental scars, abortions, and stillbirths further bears witness to the possibility that the steroids employed interfered with the optimum differentiation of progestational endometrial changes, rather than affecting any suppression of ovulatory mechanisms. It is postulated that faulty metabolism of either estrogenic or progestational hormones may play a role in certain clinical problems of miscarriage and abortion by a similar interference with the development of the maternal bed.
Domest Anim Endocrinol. 2003 Nov;25(4):329-43. Effects of endocrine disrupting compounds on the pathology and oestrogen receptor alpha and beta distribution in the uterus and cervix of ewe lambs.
Morrison AG, Callanan JJ, Evans NP, Aldridge TC, Sweeney T.
A number of chemicals have been classed as endocrine disrupting compounds due to their ability to mimic the actions of endogenous hormones in vivo and in vitro. The objective of this experiment was to determine the pathological changes and oestrogen receptor (ER) distribution in the cervix and uterus of prepubertal ovariectomised ewe lambs following exposure to a range of compounds with a predominantly oestrogenic effect. Lambs were exposed to diethylstilbestrol (0.175 mg/kg biweekly), bisphenol-A (3.5mg/kg biweekly) or octylphenol (3.5mg/kg biweekly) for 6 weeks. Following sacrifice, uterine and cervical tissue pathology was assessed. The endometrial and myometrial areas were quantified and the distribution of ERalpha and ERbeta assessed by immunohistochemistry. No differences were observed between control and octylphenol-exposed lambs in uterine gross pathology and histopathology. Uteri from bisphenol-A- and diethylstilbestrol-exposed lambs were heavier than both control and octylphenol-exposed lambs. In the bisphenol-A-exposed lambs, endometrial oedema accounted for a significant increase in the endometrial cross-sectional area over the other groups. Uteri from animals exposed to diethylstilbestrol showed variable pathology including oedema and cellular proliferation. Keratinisation of the cervical epithelium was observed in both bisphenol-A- and diethylstilbestrol-exposed lambs. Exposure to diethylstilbestrol and bisphenol-A was associated with a diffuse intracellular distribution of ERalpha and ERbeta in the uterine endometrium. This was in addition to the strong cytoplasmic staining of uterine epithelial cells and nuclear staining of specific sub-epithelial cells observed in all groups. We conclude that a 6-week exposure of lambs to bisphenol-A and diethylstilbestrol altered the uterocervical environment and has the potential to disrupt subsequent reproductive function. Pathological changes could not be detected in the uterus or cervix of lambs exposed to octylphenol.
Environ Health Perspect. 2011 Dec 15. [Epub ahead of print] Identification of Phthalates in Medications and Dietary Supplement Formulations in the U.S. and Canada.
Kelley KE, Hernández-Díaz S, Chaplin EL, Hauser R, Mitchell AA.
Background: In experimental animals, some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), are demonstrated reproductive and developmental toxicants. Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients.
Objective: The objective of this study was to identify and describe the scope of prescription (RX) and non-prescription (OTC) medicinal products and dietary supplements marketed in the United States and Canada since 1995 that include phthalates as excipients. Methods: Lists of modified-release drug products were used to identify potential drug products. Inclusion of phthalates was verified using available electronic databases, print references, published package inserts, product packages, and direct communication from manufacturers. Additional products were identified using Internet searches utilizing keywords for phthalates.
Results: Labeling information for 6 RX drug products included DBP as an excipient, while 45 labels specified the use of diethyl phthalate (DEP). Phthalate polymers with no known toxicity, hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP), were noted in 75 RX products. Three OTC drug and dietary supplement products listed DBP, 64 listed DEP, and over 90 indicated inclusion of polymers.
Conclusions: Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms. The potential effects of human exposure to these phthalates through medications are unknown and warrant further investigation.
Environ Health Perspect. 2004 May;112(6):751-3. Medications as a source of human exposure to phthalates. Hauser R, Duty S, Godfrey-Bailey L, Calafat AM.
Phthalates are a group of multifunctional chemicals used in consumer and personal care products, plastics, and medical devices. Laboratory studies show that some phthalates are reproductive and developmental toxicants. Recently, human studies have shown measurable levels of several phthalates in most of the U.S. general population. Despite their widespread use and the consistent toxicologic data on phthalates, information is limited on sources and pathways of human exposure to phthalates. One potential source of exposure is medications. The need for site-specific dosage medications has led to the use of enteric coatings that allow the release of the active ingredients into the small intestine or in the colon. The enteric coatings generally consist of various polymers that contain plasticizers, including triethyl citrate, dibutyl sebacate, and phthalates such as diethyl phthalate (DEP) and dibutyl phthalate (DBP). In this article we report on medications as a potential source of exposure to DBP in a man who took Asacol [active ingredient mesalamine (mesalazine)] for the treatment of ulcerative colitis. In a spot urine sample from this man collected 3 months after he started taking Asacol, the concentration of monobutyl phthalate, a DBP metabolite, was 16,868 ng/mL (6,180 micro g/g creatinine). This concentration was more than two orders of magnitude higher than the 95th percentile for males reported in the 1999-2000 National Health and Nutrition Examination Survey (NHANES). The patient’s urinary concentrations of monoethyl phthalate (443.7 ng/mL, 162.6 micro g/g creatinine), mono-2-ethylhexyl phthalate (3.0 ng/mL, 1.1 micro g/g creatinine), and monobenzyl phthalate (9.3 ng/mL, 3.4 micro g/g creatinine) were unremarkable compared with the NHANES 1999-2000 values. Before this report, the highest estimated human exposure to DBP was more than two orders of magnitude lower than the no observable adverse effect level from animal studies. Further research is necessary to determine the proportional contribution of medications, as well as personal care and consumer products, to a person’s total phthalate burden.
Environ Health Perspect. 2009 Feb;117(2):185-9. Epub 2008 Oct 7. Medications as a potential source of exposure to phthalates in the U.S. population. Hernández-Díaz S, Mitchell AA, Kelley KE, Calafat AM, Hauser R.
BACKGROUND: Widespread human exposure to phthalates, some of which are developmental and reproductive toxicants in experimental animals, raises concerns about potential human health risks. Underappreciated sources of exposure include phthalates in the polymers coating some oral medications.
OBJECTIVE:
The objective of this study was to evaluate whether users of phthalate-containing medications have higher urinary concentrations of phthalate metabolites than do nonusers.
METHODS:
We used publically available files from the National Health and Nutrition Examination Survey for the years 1999-2004. For certain survey periods, participants were asked to recall use of prescription medication during the past 30 days, and for a subsample of individuals, the urinary concentrations of phthalate metabolites were measured. We a priori identified medications potentially containing phthalates as inactive ingredients and then compared the mean urinary concentration of phthalate metabolites between users and nonusers of those medications.
RESULTS:
Of the 7,999 persons with information on urinary phthalate concentrations, 6 reported using mesalamine formulations, some of which may include dibutyl phthalate (DBP); the mean urinary concentration of monobutyl phthalate, the main DBP metabolite, among these mesalamine users was 50 times higher than the mean for nonusers (2,257 microg/L vs. 46 microg/L; p < 0.0001). Users of didanosine, omeprazole, and theophylline products, some of which may contain diethyl phthalate (DEP), had mean urinary concentrations of monoethyl phthalate, the main DEP metabolite, significantly higher than the mean for nonusers.
CONCLUSION: Select medications might be a source of high exposure to some phthalates, one of which, DBP, shows adverse developmental and reproductive effects in laboratory animals. These results raise concern about potential human health risks, specifically among vulnerable segments of the general population and particularly pregnant women and children.
Instructions:
1. Line strainer with cheesecloth and place into bowl.
2. Scoop yogurt into lined strainer.
3. Allow yogurt to strain overnight in refrigerator.
4. Remove yogurt from cheesecloth in morning and store in separate bowl.
5. Enjoy resulting thick yogurt with fresh fruit or honey.
Homemade Ricotta Cheese
C = 4g P = 14g F = 16g
214 calories per serving
Serves 4
Ingredients:
2 qts whole milk
1 c heavy cream
½ t salt
3 T fresh lemon juice
Materials:
Large fine-mesh strainer
Fine-mesh cheesecloth
Large bowl
6-qt heavy pot
Instructions:
1. Line strainer with layer of cheesecloth and place into large bowl.
2. Slowly bring milk, cream and salt to rolling boil in pot over moderate heat, stirring occasionally to prevent scorching.
3. Add lemon juice, reduce heat to low and simmer, stirring constantly until mixture curdles, about 2 minutes.
4. Pour mixture into lined strainer and let drain for 1 hour.
5. After discarding liquid, cover ricotta and chill. Ricotta will keep in refrigerator for 3 days.
“When cancer cells are implanted into a healthy host, they seldom grow, but when implanted into a host who already has cancer, they grow. (Hakim, 1988.) The healthy host provides many restorative factors, the sick host provides additional harmful factors, but few restorative factors (Chekulaev, et aI., 1987.)” -Ray Peat, PhD
Cancer. 1988 Feb 15;61(4):689-701. Peripheral blood lymphocytes from patients with cancer lack interleukin-2 receptors. Hakim AA. When tumor cells develop in healthy adults, they activate the cellular immune system–natural killer (NK) cells, antigen-specific cytotoxic lymphocytes (CTL), and the synthesis of antigen specific cytotoxic antibodies. These are aimed at killing the intruding cells. However, in cancer patients the tumor continues to grow. As tumor cells proliferate, they were shown to release factors that mediate the inactivation of the host immune defense systems. The study documented in this article examined peripheral blood lymphocytes, mononuclear cells (MNC), NK cells, T-helper cells (THC). This study confirmed the interaction of the released inhibitor factors with these mononuclear cells. NULL cells from healthy adults responding to interleukin-2 (IL-2) and NILL cells from patients with metastatic breast carcinoma nonresponsive to IL-2 were also isolated by the standard antibodies-pinning technique. The cells were obtained from age-matched subjects: ten healthy adults; ten patients each from Stage I, II, III, and IV metastatic breast carcinoma (BCa-I, BCa-II, BCa-III, and BCa-IV or MBCa); and ten patients with benign breast disease (BBD). The responsiveness of these THC, PBMNC, NK, NULL, and NILL cells in vitro to graded levels of phytohemagglutinin (PHA), Concanavalin A (Con A), and recombinant interleukin-2 (rIL-2) was examined. Responsiveness was monitored by 3H-thymidine (3H-TdR) uptake, production and release of IL-2, interleukin-2 receptor (IL-2R), and cytotoxic activities against K-562 cells and breast carcinoma short-term cell lines. A lack of functional IL-2R in peripheral blood lymphocytes from patients with metastatic breast carcinoma was confirmed by nonsignificant anti-Tac antibody binding. An elevation in the expression of cell surface antigen GP-120 has been observed to be associated with the activation in vitro of T-cells from healthy adults and from patients with benign breast disease, but not of T-cells from patients with breast carcinoma. Biochemical studies of the GP-120 using high performance liquid chromatography combined with nitrocellulose blotting confirmed that the glycoprotein was resistant to trypsin and chymotrypsin, but susceptible to pronase. It contained sialic acid and lactosaminoglycan as O-linked sugars. It could be labeled with pariodate/NaB(3H4) and is recognized by MAbT-305 monoclonal antibodies. It contained sialic acid linked (2—3) to galactose.(ABSTRACT TRUNCATED AT 400 WORDS)
Biokhimiia. 1987 Sep;52(9):1501-11. [Activation of lipolysis and ketogenesis in tumor-bearing animals as a reflection of chronic stress states]. [Article in Russian]
Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS.
In order to elucidate the peculiarities of brain metabolism in tumour-bearing organisms, the arterio-venous (A-V) content of glucose, acetoacetate (Ac-Ac), beta-hydroxybutyrate (beta-HB) and non-esterified fatty acids (NEFA) in growing Zajdela ascite hepatoma (ZAH) and solid hepatoma 27 (H-27) was compared. Analysis of metabolic patterns of healthy, starving and fed recipients (ZAH and H-27) revealed the inadequacy of the concepts on anorexia as being the cause of carbohydrate-lipid metabolic disturbances. In tumour-bearing organisms lipolysis and ketogenesis reflect the tumour-induced chronic stress. Absorption of beta-HB and release of Ac-Ac by brain were observed at all stages of malignant growth. This is probably due to a partial switch-over of brain metabolism to non-carbohydrate energy sources. Besides, certain stages of tumour growth are associated with active assimilation of NEFA by brain. A correlation between the A-V difference with respect to glucose and Ac-Ac as well as between the glucose and NEFA contents was established. It was assumed that the A-V difference in glucose is the main regulator of ketone body metabolism.
Science. 1978 Jul 28;201(4353):358-60. Brain edema: induction in cortical slices by polyunsaturated fatty acids. Chan PH, Fishman RA.
The presence of polyunsaturated and saturated fatty acids in leukocytic membranes prompted study of their possible role in the induction of brain edema. Polyunsaturated fatty acids including sodium arachidonate, sodium linoleate, sodium linolenate, and docasahexaenoic acids induced edma in slices of rat brain cortex. This cellular edema was specific, since neither saturated fatty acids nor a fatty acid containing a single double bond had such effect.
Ann Neurol. 1983 Jun;13(6):625-32. Induction of brain edema following intracerebral injection of arachidonic acid.
Chan PH, Fishman RA, Caronna J, Schmidley JW, Prioleau G, Lee J. The effects of polyunsaturated fatty acids on brain edema formation have been studied in rats. Intracerebral injection of polyunsaturated fatty acids (PUFAs), including linolenic acid (18:3) and arachidonic acid (20:4), caused significant increases in cerebral water and sodium content concomitant with decreases in potassium content and Na+- and K+- dependent adenosine triphosphatase activity. There was gross and microscopic evidence of edema. Saturated fatty acids and monounsaturated fatty acid were not effective in inducing brain edema. The [125I]-bovine serum albumin spaces increased twofold and threefold at 24 hours with 18:3 and 20:4, respectively, indicating vasogenic edema with increased permeability of brain endothelial cells. Staining of the brain was observed five minutes after injection of Evans blue dye followed by arachidonic acid perfusion. A major decrease in brain potassium content was evidence of concurrent cellular (cytotoxic) edema as well. The induction of brain edema by arachidonic acid was dose dependent and maximal between 24 and 48 hours after perfusion. Dexamethasone (10 mg/kg) was effective in ameliorating the brain edema, whereas a cyclooxygenase inhibitor, indomethacin (10 mg/kg), was not. These data indicate that arachidonic acid and other PUFAs have the ability to induce vasogenic and cellular brain edema and further support the hypothesis that the degradation of phospholipids and accumulation of PUFAs, particularly arachidonic acid, initiate the development of brain edema in various disease states.
Neurochem Res. 1980 Jun;5(6):629-40. Arachidonic acid-induced swelling in incubated rat brain cortical slices. Effect of bovine serum albumin.
Chan PH, Fishman RA, Lee JL, Quan SC.
The influence of bovine serum albumin (BSA) on the rat brain cortical swelling induced by sodium arachidonate and polyunsaturated fatty acids has been studied. Coincubation of arachidonate with BSA at a molar ratio of 5 (arachidonate/BSA) or less greater inhibited the arachidonate-induced swelling. As the molar ratio of arachidonate/BSA increased, the degree of swelling increased. The swelling was not reversed by BSA, although the BSA released 46% of the previously incorporated [3H]arachidonic acid from the cortical slices. The entry of [3H]arachidonate into the slice was completely abolished by 0.1 mM BSA or partially inhibited by exogenous arachidonate. It is concluded that the induction of brain swelling by arachidonate requires the intracellular transport of exogenous arachidonate.
J Neurochem. 1980 Oct;35(4):1004-7. Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling.
Chan PH, Fishman RA.
The involvement of superoxide free radicals and lipid peroxidation in brain swelling induced by free fatty acids has been studied in brain slices and homogenates. The polyunsaturated fatty acids linoleic acid (18:2), linolenic acid (18:3), arachidonic acid (20:4), and docosahexaenoic acid (22:6) caused brain swelling concomitant with increases in superoxide and membrane lipid peroxidation. Palmitic acid (16:0) and oleic acid (18:1) had no such effect. Furthermore, superoxide formation was stimulated by NADPH and scavenged by the addition of exogenous superoxide dismutase in cortical slice homogenates. These in vitro data support the hypothesis that both superoxide radicals and lipid peroxidation are involved in the mechanism of polyunsaturated fatty acid-induced brain edema.
J Neurochem. 1982 Feb;38(2):525-31. Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices. Chan PH, Yurko M, Fishman RA.
Cellular edema and increased lactate production were induced in rat brain cortical slices by xanthine oxidase and xanthine, in the presence of ferric dialdehyde, was increased 174%. Among the various subcellular fractions of brain cortex, xanthine oxidase-stimulated lipid peroxidation was highest in myelin, mitochondria, and synaptosomes, followed by microsomes and nuclei. Antioxidants, catalase, chlorpromazine, and butylated hydroxytoluene inhibited lipid peroxidation in both homogenates and synaptosomes, indicating H2O2 and radicals were involved. Further, several free fatty acids, especially oleic acid (18:1), arachidonic acid (20:4), and docosahexaenoic acid (22:6) were released from the phospholipid pool concomitant with the degradation of membrane phospholipids in xanthine oxidase-treated synaptosomes. These data suggest that lipases are activated by free radicals and lipid peroxides in the pathogenesis of cellular swelling.
J Neurosci Res. 1984;12(4):595-605. Release of polyunsaturated fatty acids from phospholipids and alteration of brain membrane integrity by oxygen-derived free radicals. Chan PH, Fishman RA, Schmidley JW, Chen SF.
We studied the effects of oxygen-derived free radicals on the ultrastructure of brain cortical slices and the release of fatty acids from phospholipids of crude synaptosomes. Xanthine oxidase, hypoxanthine, and ADP-Fe3+, a free-radical-generating system, caused swelling of cellular processes and mitochondria. The oxygen-derived free radicals also caused the rapid release and accumulation of endogenous polyunsaturated fatty acids (PUFA) from membrane phospholipids as determined by high-performance liquid chromatography (HPLC). Furthermore, [3H]-arachidonic acid was also rapidly released from prelabeled phospholipids concomitant with a decrease in radioactivity in various phospholipid fractions. The radioactivities of neutral lipids including diacylglycerols were unchanged by free radicals. These data indicate that the activation of phospholipase A2 and the release of PUFA may have overt effect on membrane integrity and the subsequent development of cellular injury and brain edema.
“When the brain is injured, DHA and arachidonic acid contribute to brain edema, weakening the blood-brain-barrier, increasing protein breakdown, inflammation, and peroxidation, while a similar amount of stearic acid in the same situation caused no harm (Yang, et al., 2007).” -Ray Peat, PhD
Neurotoxicology. 2007 Nov;28(6):1220-9. Epub 2007 Aug 10. Detrimental effects of post-treatment with fatty acids on brain injury in ischemic rats. Yang DY, Pan HC, Yen YJ, Wang CC, Chuang YH, Chen SY, Lin SY, Liao SL, Raung SL, Wu CW, Chou MC, Chiang AN, Chen CJ. Studies have illustrated that fatty acids, especially polyunsaturated fatty acids (PUFA), have a role in regulating oxidative stress via the enhancement of antioxidative defense capacity or the augmentation of oxidative burden. Elevated oxidative stress has been implicated in the pathogenesis of brain injury associated with cerebral ischemia/reperfusion (I/R). The objective of this study was to assess whether treatment with fatty acids after focal cerebral I/R induced by occlusion of the common carotid arteries and the middle cerebral artery has effects on brain injury in a rat model. PUFA, including arachidonic acid (AA) and docosahexaenoic acid (DHA), and the saturated fatty acid, stearic acid (SA), were administrated 60 min after reperfusion via intraperitoneal injection. AA and DHA aggravated cerebral ischemic injury, which manifested as enlargement of areas of cerebral infarction and increased impairment of motor activity, in a concentration-dependent manner. However, there were no remarkable differences in post-ischemic alterations between the SA and saline groups. The post-ischemic augmentation of injury in AA and DHA treatment groups was accompanied by increases in the permeability of the blood-brain barrier (BBB), brain edema, metalloproteinase (MMP) activity, inflammatory cell infiltration, cyclooxygenase 2 (COX-2) expression, caspase 3 activity, and malondialdehyde (MDA) production, and by a decrease in the brain glutathione (GSH) content.Furthermore, we found that either AA or DHA alone had little effect on free radical generation in neuroglia, but they greatly increased the hydrogen peroxide-induced oxidative burden. Taken together, these findings demonstrate the detrimental effect of PUFA such as AA and DHA in post-ischemic progression and brain injury after cerebral I/R is associated with augmentation of cerebral I/R-induced alterations, including oxidative changes.
Fed Proc. 1984 Feb;43(2):210-3. The role of arachidonic acid in vasogenic brain edema.
Chan PH, Fishman RA. Arachidonic acid is released rapidly from cellular membrane phospholipids after pathological insults associated with the delayed development of brain edema. Intracerebral injection of arachidonic acid caused significant increases in brain water and sodium content with decreases in potassium content and Na+,K+-ATPase activity. The 125I-labeled bovine serum albumin spaces in brain (a measure of blood-brain barrier permeability) rose threefold 24 h after arachidonic acid injection. There was gross and microscopic evidence of edema. Saturated fatty acids and monounsaturated fatty acids were not effective. These data indicate that the endothelial cells of the blood-brain barrier are target sites for the action of arachidonic acid. It is hypothesized that the increased permeability of endothelial cells to macromolecules and water results from alterations of membrane phospholipids and increased vesicular transport, changes that are responsible for the delayed development of vasogenic edema.
J Clin Endocrinol Metab. 1998 Dec;83(12):4474-80. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. Zeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE.
Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17beta-estradiol, in endometriotic tissues. It was previously demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through conversion to estrone in eutopic endometrial epithelial cells…In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone.
Reproductive Biology and Endocrinology 2011, 9:87 The emerging use of aromatase inhibitors for endometriosis treatment Warren B Nothnick Endometriosis is defined as the growth of endometrial tissue outside of the uterine cavity. The disease occurs primarily in women of reproductive age but recurrent endometriosis is also detected in post-menopausal women. Regardless of age, endometriosis is associated with pain and reduces the quality of life for millions of women world-wide. Conventional therapies focus on reducing systemic levels of estrogen which results in cessation of endometriotic implant growth and pain symptoms associated with the disease. However, these treatments are not effective in all women and are not without side effects. Based upon the discovery that endometriotic tissue over-expresses aromatase, an enzyme critical for estrogen production, emphasis has been placed upon the use of aromatase inhibitors for the treatment of endometriosis and its associated symptoms. This article will review the rationale behind the use of aromatase inhibitors in treating endometriosis and summarize those studies which have evaluated the use of aromatase inhibitors in the treatment of endometriosis and its associated symptoms.
Drugs. 2009 May 29;69(8):943-52. doi: 10.2165/00003495-200969080-00001. Pharmacological treatment of endometriosis: experience with aromatase inhibitors. Ferrero S, Venturini PL, Ragni N, Camerini G, Remorgida V.
Current treatment of endometriosis is mainly based on surgery and ovarian suppressive agents. In the last 10 years, it has been demonstrated that aromatase P450, a key enzyme for estrogen biosynthesis, may have a pathogenic role in endometriosis because it is aberrantly expressed in endometriotic implants and in eutopic endometrium of women with endometriosis. Therefore, inhibition of aromatase activity may represent a new therapeutic option for endometriosis. Case reports and observational studies have shown that pain symptoms caused by endometriosis quickly improve after administration of aromatase inhibitors. Limited data are available on the long-term course of pain symptoms after completion of treatment with aromatase inhibitors; however, some recent studies suggest that symptoms may recur at short-term follow-up. A range of results are reported on the effects of aromatase inhibitors on endometriotic lesions, with some authors describing improvements and other authors reporting persistence of pelvic lesions at second-look laparoscopy after treatment. No severe adverse effect has been reported during treatment with aromatase inhibitors both in pre- and postmenopausal women. On the basis of the available data, administration of aromatase inhibitors should now be offered only to the small number of women who have severe pain despite previous surgical and hormonal therapies. Further research in the form of randomized controlled trials will be required before recommending the routine use of these agents.
Endocr Relat Cancer. 1999 Jun;6(2):293-301. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Bulun SE, Zeitoun K, Takayama K, Noble L, Michael D, Simpson E, Johns A, Putman M, Sasano H. Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored the continuous production of estrogen and prostaglandin (PG)E2 in the endometriotic stromal cells. The enzyme, aromatase, is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of PGE2. PGE2, in turn, is a potent inducer of aromatase activity in endometriotic stromal cells. Aromatase is not expressed in the eutopic endometrium. Aromatase expression in endometriosis and its inhibition in eutopic endometrium are controlled by the competitive binding of a stimulatory transcription factor, steroidogenic factor-1, and an inhibitory factor, chicken ovalbumin upstream promoter-transcription factor to a regulatory element in the aromatase P450 gene promoter. In addition, we find that endometriotic tissue is deficient in 17beta-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrial glandular cells and inactivates estradiol-17beta to estrone. This deficiency is another aberration that favors higher levels of estradiol-17beta in endometriotic tissues in comparison with the eutopic endometrium. The clinical relevance of local aromatase expression in endometriosis was exemplified by the successful treatment of an unusually aggressive form of recurrent endometriosis in a postmenopausal woman using an aromatase inhibitor.
Expert Opin Emerg Drugs. 2004 May;9(1):167-77. Emerging drugs for endometriosis.
Fedele L, Berlanda N. Medical treatment of endometriosis relies on drugs that suppress ovarian steroids and induce an hypoestrogenic state that causes atrophy of ectopic endometrium. Gonadotrophin-releasing hormone (GnRH) analogues, danazol, progestogens and oestrogen-progestin combinations have all proven effective in relieving pain and reducing the extent of endometriotic implants. However, symptoms often recur after discontinuation of therapy and hypoestrogenism-related side effects limit the long-term use of most medications. Furthermore, these therapies are of limited value in patients with a desire to become pregnant because they inhibit ovulation. An important target for current research is to identify effective therapies that can be safely administered in the long term. GnRH analogues with add-back therapy, progestogens and continuous oral contraceptive are options available for a medium or long-term systemic treatment. Mifepristone, an antiprogestogen, may constitute an alternative if encouraging preliminary data on its effectiveness and tolerability are confirmed. A very appealing area of interest is the possibility of treating endometriosis without suppressing ovarian function. Aromatase inhibitors might have such characteristics as they have been shown to inhibit oestrogen production selectively in endometriotic lesions, without affecting ovarian function; the clinical role of these drugs in the treatment of endometriosis is under evaluation. Levonorgestrel medicated intrauterine device has proven effective in relieving dysmenorrhoea associated with endometriosis, as well as pain associated with rectovaginal endometriosis. Although a systemic absorption is present determining side effects, this approach is promising in the long-term management of this condition. A fundamental objective of research in endometriosis treatment is to develop new therapeutic approaches based on the findings from experimental studies on the aetiopathogenesis of the disease; current research is focusing on anti-inflammatory drugs and modulators of the immune system. TNF-binding protein-1 and IL-12 have proved effective in reducing endometriotic lesions in animal models, while pentoxifylline and INF-alpha 2b have shown encouraging results in clinical studies. This area may be of paramount importance in the near future in order to develop a therapy that could prevent or eradicate endometriosis rather than merely relieving the symptoms.
Fertil Steril. 1999 Dec;72(6):961-9. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target.
Zeitoun KM, Bulun SE.
OBJECTIVE:
To provide a clinically useful model illustrating the molecular aberrations affecting estrogen biosynthesis and metabolism in endometriosis and to discuss the therapeutic role of aromatase inhibitors.
DESIGN:
Literature review.
RESULT(S): Several molecular aberrations were found in endometriotic lesions (in contrast to eutopic endometrium) that favor increased local concentrations of E2. Endometriotic stromal cells aberrantly express aromatase, which converts C19, steroids to estrogens. Aromatase activity in these cells is stimulated by prostaglandin (PG)E2. Estrogen stimulates cyclooxygenase-2, giving rise to increased PGE2 formation. Thus, this positive feedback loop produces increasing quantities of E2 and PGE2 in endometriosis. The lack of aromatase expression in eutopic endometrium is maintained by binding of an inhibitory transcription factor, COUP-TF, to the aromatase promoter. In endometriosis, however, an aberrantly expressed factor, SF-1, displaces COUP-TF to bind to this same promoter and activates aromatase expression and thus local estrogen biosynthesis. Additionally, endometriotic glandular cells are deficient in 17beta-hydroxysteroid dehydrogenase type 2, which converts E2 to estrone in the eutopic endometrium in response to P. Deficiency of this enzyme in endometriosis impairs the inactivation of E2 and may be a consequence of insensitivity to P.
CONCLUSION(S): Molecular aberrations that increase local E2 concentrations may be important in the etiology of endometriosis. These molecules may be targeted to develop novel therapeutic strategies. The clinical relevance of aromatase expression in endometriosis was shown recently by the successful treatment of an unusually aggressive case of postmenopausal endometriosis with use of an aromatase inhibitor.
J Clin Endocrinol Metab. 1997 Feb;82(2):600-6. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. Noble LS, Takayama K, Zeitoun KM, Putman JM, Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr BR, Bulun SE.
C19 steroids are converted to estrogens by aromatase P450 (P450arom). Aromatase expression in humans is regulated by use of tissue-specific promoters in the placenta (promoter I.1), adipose tissue (promoters I.4, I.3, and II), and gonads (promoter II). The use of each promoter gives rise to a population of P450arom messenger ribonucleic acid (mRNA) species with a unique untranslated 5′-terminus. Aromatase is not expressed in the endometrium of disease-free women. We demonstrated, however, the presence of P450arom mRNA in pelvic endometriotic implants and eutopic endometrial curettings of women with endometriosis. In the current report, aromatase activity and P450arom gene expression were investigated in cultured stromal cells derived from eutopic endometrium and ovarian endometriomas of women with pelvic endometriosis. We also investigated the hormonal regulation of aromatase expression and alternative promoter use in these cells. The effects of interleukin-1 beta (IL-1 beta), IL-2, IL-6, IL-11, oncostatin M, IL-15, tumor necrosis factor-alpha, PGE2, estradiol, R5020, dexamethasone, and dibutyryl cAMP (Bt2cAMP) on aromatase activity in endometriosis-derived stromal cells were assessed. We chose treatments with PGs and ILs because of the inflammatory nature of endometriosis. PGE2 stimulated aromatase activity in endometriosis-derived stromal cells by 19- to 44-fold (37-221 pmol/mg protein-4 h), whereas Bt2cAMP induction was 26- to 60-fold the baseline level. No stimulation was observed by estradiol or R5020 or by IL-1 beta, IL-2, IL-6, IL-11, IL-15, or TNF alpha in the presence or absence of glucocorticoids. A modest induction of aromatase activity (2-fold) was observed in dexamethasone- plus oncostatin M-treated cells. These changes in aromatase activity were accompanied by comparable changes in the levels of P450arom mRNA levels, determined by a quantitative reverse transcription-PCR method. Promoter-specific 5′-ends of P450arom transcripts in total RNA from endometriosis-derived stromal cells treated with PGE2 and Bt2cAMP were amplified employing a novel modified rapid amplification of cDNA5′-ends/Southern hybridization method using exon-specific oligonucleotide probes. The majority of P450arom transcripts in these cells contained the gonadal-type promoter II-specific sequences, whereas very few transcripts contained adipose-type promoter I.3- and I.4-specific sequences. PGE2 appears to be the most potent known stimulator of aromatase in endometriosis. Aromatase expression in PGE2-stimulated stromal cells of endometriosis is regulated primarily by the classically located promoter II, which, in turn, is regulated by cAMP. As PGE2 is known to increase intracellular cAMP levels, estrogen biosynthesis in endometriosis may be primarily regulated by PGE2 that is locally produced. Consequent local estrogen production may promote the growth of endometriotic implants.
========================================== Endometrial Cancer & Estrogen:
Br J Obstet Gynaecol. 1993 Dec;100(12):1115-9. Plasma oestrogens in postmenopausal women with endometrial cancer. Nyholm HC, Nielsen AL, Lyndrup J, Dreisler A, Hagen C, Haug E.
OBJECTIVE:
To study plasma levels of estrogens and androgens, sex hormone-binding globulin (SHBG) and follicle stimulating hormone (FSH) in postmenopausal patients with endometrial cancer.
DESIGN:
Patients and controls were matched for age, body mass index, parity and years since menopause.
SETTING:
Department of Obstetrics and Gynaecology, Hvidovre Hospital, Denmark.
SUBJECTS:
Fifty postmenopausal patients with endometrial cancer and 54 matching controls.
MEASUREMENTS:
Plasma levels of SHBG, FSH, oestrone, oestradiol, oestrone-sulphate, dehydro-epiandrosterone sulphate, testosterone, and androstenedione were measured by radio-immunoassays. Free fractions of oestradiol and testosterone were calculated according to levels of SHBG and albumin.
RESULTS: The levels of oestradiol, free oestradiol, and oestrone were elevated (P < 0.001) in patients compared with controls (oestradiol: 51 (45-59) vs 37 (34-41) pmol/l; free oestradiol: 0.69 (0.59-0.80) vs 0.48 (0.42-0.54) pmol/l; oestrone: 180 (159-204) vs 119 (107-133) pmol/l (mean values (95% CI) in patients vs controls)). Furthermore, an increased oestrone:androstenedione ratio (0.095 vs 0.072, P < 0.01) was found in patients. SHBG correlated negatively (P < 0.001) with body mass, while the free fractions of oestradiol and testosterone correlated positively (P < 0.01) with body mass, in both patients and controls. Multiple regression analysis showed that the differences in oestrogen levels between the two groups persisted when controlling for the effect of body mass, age, years since menopause, parity, and levels of SHBG and FSH.
CONCLUSION: Patients with endometrial cancer exhibit increased plasma levels of oestradiol and oestrone. Speculatively, these oestrogens may result from an increased oestrone conversion from androstenedione, an increased ovarian and adrenal secretion of androstenedione, or alternative oestrogen production routes. The present findings support the hypothetical role for oestrogens in the aetiology of endometrial cancer.
Quotes by Ray Peat, PhD: “For more than 20 years he didn’t find anything that helped, but in 1992 a student, Robin Roof, did experiments showing that progesterone injections reduced or prevented brain edema after a brain contusion. Pseudopregnancy, in which there is a high ratio of progesterone to estrogen, also prevented brain edema. An oxidative breakdown products of arachidonic acid, isoprostane, associated with dementia was reduce by 2/3 in the animals treated with progesterone (Roof, et al., 1997)”
“Marian Diamond’s work with rats clearly showed that increased exposure to estrogen during pregnancy reduced the size of the cerebral cortex and the animals’ ability to learn, while progesterone increased the brain size and intelligence. Zamenhof’s studies suggested that these hormones probably have their effects largely through their actions on glucose, though they also affect the availability of oxygen in the same way, and have a variety of direct effects on brain cells that would operate toward the same end.”
“Estrogen’s brain-toxic effects have been known since the 1950s, or earlier. Text-books in the 1960s discussed experiments in which either estrogen or insulin stopped growth of the fetus’s brain, and also in the 1960s experiments were showing that progesterone fosters brain growth and intelligence. Zamenhoff’s work showed that the prenatal abundance of glucose is a central factor in brain growth. Since estrogen and insulin lower blood sugar, and progesterone and thyroid sustain it, Zamenhoff’s work showed that the level of glucose was a common factor in many of the previous experiments, though other factors, including blood volume and body temperature, are also important. The epidemiological evidence is clear that women with toxemia of pregnancy, which involves inadequate delivery of glucose to the fetus, have babies with subnormal intelligence. Among obstetricians, it used to be common knowledge (before insulin treatment became common) that diabetic women were likely to have intellectually precocious children. As the work of Shanklin, Hodin, and the Brewers shows, there is a large group of Americans with neurological damage resulting from their mothers’ treatment during pregnancy.”
“Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen, lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.”
“By the 1970s, there was clear evidence of progesterone’s brain-protective effects, and of the neurotoxic effects of unopposed estrogen mostly from animal studies. A few people were using progesterone supplements to treat neurological diseases. It was known that the brain’s concentration of progesterone and DHEA was much higher than their concentration in the blood, but it was only in the 1980s that it was shown that they are synthesized in the brain, and a few years later, they were shown to be synthesized in the peripheral nerves. The concentration of these steroids decreases with age, but diabetes causes an exaggerated and premature decrease of them in the brain and peripheral nerves (Caruso, et al., 2008; Pesaresi, et al., 2010).”
“Progesterone is being used to treat brain injuries, very successfully. It protects against inflammation, and in an early study, compared to placebo, lowered mortality by more than half.”
“Progesterone is the basic brain-protective antiestrogen. It works to protect the brain at many levels (preventing lipid peroxidation, exitotoxicity, nitric oxide damage, energy deficit, edema, etc.) and it promotes repair and recovery.
Progesterone in most cases has effects opposite to estrogen’s, improving mitochondrial energy production while preventing excessive excitation. Along with pregnenolone, progesterone is recognized as a neurosteroid with anti-excitotoxic actions, with the ability to promote repair and regeneration of the nervous system. (Roof, Stein, Faden; Schumacher, et al.; Baulieu.)”
Estrogen:
Biol Reprod. 1993 Oct;49(4):647-52. Pathologic effect of estradiol on the hypothalamus. Brawer JR, Beaudet A, Desjardins GC, Schipper HM.
Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproductive function. In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component.
Brain Res. 1994 Jul 25;652(1):161-3. The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic beta-endorphin in adult female rats. Schipper HM, Desjardins GC, Beaudet A, Brawer JR. A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats. We have hypothesized that peroxidase-positive astrocytes in this brain region oxidize estrogens and catecholestrogens to semiquinone radicals which mediate oxidative neuronal injury. In the present study, dietary administration of the potent antioxidant 21-aminosteroid, U-74389F, completely blocked EV-induced beta-endorphin depletion in the hypothalami of adult female rats. Neither EV nor 21-aminosteroid treatment had any effect on hypothalamic concentrations of neuropeptide Y and Met-enkephalin, confirming that the estradiol lesion is fairly selective for the beta-endorphin cell population. The present findings support the hypothesis that the toxic effect of estradiol on hypothalamic beta-endorphin neurons is mediated by free radicals.
J Steroid Biochem Mol Biol. 1999 Jan;68(1-2):65-75. Purification and identification of an estrogen binding protein from rat brain: oligomycin sensitivity-conferring protein (OSCP), a subunit of mitochondrial F0F1-ATP synthase/ATPase.
Zheng J, Ramirez VD.
Early studies have suggested the presence in the central nervous system of possible estrogen binding sites/proteins other than classical nuclear estrogen receptors (nER). We report here the isolation and identification of a 23 kDa membrane protein from digitonin-solubilized rat brain mitochondrial fractions that binds 17beta-estradiol conjugated to bovine serum albumin at C-6 position (17beta-E-6-BSA), a ligand that also specifically binds nER. This protein was partially purified using affinity columns coupled with 17beta-E-6-BSA and was recognized by the iodinated 17beta-E-6-BSA (17beta-E-6-[125I]BSA) in a ligand blotting assay. The binding of 17beta-E-6-BSA to this protein was specific for the 17beta-estradiol portion of the conjugate, not BSA. Using N-terminal sequencing and immunoblotting, this 23 kDa protein was identified as the oligomycin-sensitivity conferring protein (OSCP). This protein is a subunit of the FOF1 (F-type) mitochondrial ATP synthase/ATPase required for the coupling of a proton gradient across the F0 sector of the enzyme in the mitochondrial membrane to ATP synthesis in the F1 sector of the enzyme. Studies using recombinant bovine OSCP (rbOSCP) in ligand blotting revealed that rbOSCP bound 17beta-E-6-[125I]BSA with the same specificity as the purified 23 kDa protein. Further, in a ligand binding assay, 17beta-E-6-[125I]BSA also bound rbOSCP and it was displaced by both 17beta-E-6-BSA and 17alpha-E-6-BSA as well as partially by 17beta-estradiol and diethylstilbestrol (DES), but not by BSA. This finding opens up the possibility that estradiol, and probably other compounds with similar structures, in addition to their classical genomic mechanism, may interact with ATP synthase/ATPase by binding to OSCP, and thereby modulating cellular energy metabolism. Current experiments are addressing such an issue.
Acta Neurol Scand. 1976 Oct;54(4):321-47. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Bäckström T.
Nine periods in seven women with partial epilepsy have been invetigated with respect to frequency of fits, and estrogen-progesterone levels in blood plasma. Six cycles with ovulation showed a positive correlation between the number of secondary generalized seizures and the mean estrogen/progesterone (E/P) ratios and a negative correlation to plasma progesterone levels. Three periods without ovulation showed an increase in the number of fits during days of high estrogen. The number of fits seemed not to be correlated to changes in body weight.
J Gerontol A Biol Sci Med Sci(2011) 66A (12): 1343-1349.
doi: 10.1093/gerona/glr140 Long-term Cognitive Impairment in Older Adult Twins Discordant for Gynecologic Cancer Treatment Keiko Kurita1, Beth E. Meyerowitz, Per Hall, and Margaret Gatz
Background. Research has found that patients treated for cancer generally have an increased risk for cognitive problems. However, many studies have focused on cognitive performance of cancer patients under the age of 65 who received chemotherapy treatment. Less studied is the extent to which cancer diagnosis may be associated with cognitive impairment as a late effect for older adults.
Methods. In this retrospective, co-twin design study, twin pairs 65 years of age and older discordant for cancer were identified from the Swedish Twin Registry. A pair was included if both twins participated in cognitive screening, and the twin with the cancer history was screened at least 3 years after cancer diagnosis and treatment.
Results. Female, but not male, survivors of cancer were significantly (odds ratio = 2.42, 95% confidence interval = 1.23–4.74) more likely to exhibit cognitive impairment 3 or more years after cancer diagnosis and treatment as their co-twin without a history of cancer. In particular, risk was higher among survivors of gynecologic cancers (odds ratio = 10.00, 95% confidence interval = 1.28–78.11) and those who had treatments directly or potentially affecting ovarian functioning (odds ratio = 13.00, 95% confidence interval = 1.70–99.36) compared with their respective co-twins.
Conclusions. These findings suggest that localized treatments and other cancer-related factors should be explored as determinants that underlie the association between cancer diagnosis and long-term cognitive impairment.
Endocrinology August 1, 1992vol. 131 no. 2 662-668 Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus. N G Weiland Estradiol alters cognitive function and lowers the threshold for seizures in women and laboratory animals. Both of these activities are modulated by the excitatory neurotransmitter glutamate in the hippocampus. To assess the hypothesis that estradiol increases the sensitivity of the hippocampus to glutamate activation by increasing glutamate binding sites, the densities of N-methyl-D-aspartate (NMDA) agonist sites (determined by NMDA displaced glutamate), competitive antagonist sites (CGP 39653), noncompetitive antagonist sites (MK801) as well as the non-NMDA glutamate receptors for kainate and AMPA (using kainate and CNQX, respectively) were measured using autoradiographic procedures. Two days of estradiol treatment increased the density of NMDA agonist, but not of competitive nor noncompetitive NMDA antagonist binding sites exclusively in the CA1 region of the hippocampus. The density of noncompetitive NMDA antagonist sites, however, was decreased in the dentate gyrus by estradiol treatment. Ovarian steroids had no effect on the density of kainate or AMPA receptors in any region of the hippocampus examined. These data indicate that the agonist and antagonist binding sites on the NMDA receptor/ion channel complex are regulated independently by an as yet unidentified mechanism, and that this regulation exhibits regional specificity in the hippocampus. The increase in NMDA agonist sites with ovarian hormone treatment should result in an increase in the sensitivity of the hippocampus to glutamate activation which may mediate some of the effects of estradiol on learning and epileptic seizure activity.
Ann Neurol. 2006 Sep;60(3):346-55. Endogenous sex hormones, cognitive decline, and future dementia in old men. Geerlings MI, Strozyk D, Masaki K, Remaley AT, Petrovitch H, Ross GW, White LR, Launer LJ.
OBJECTIVE: To estimate the association of endogenous levels of bioavailable testosterone and estradiol with risk for cognitive decline and dementia in old men.
METHODS:
Within the population-based, prospective Honolulu-Asia Aging Study, 2,974 men, aged 71 to 93 years, without dementia were reexamined 3 times over an average of 6 years for development of dementia and cognitive decline. Cognitive decline was measured with the Cognitive Abilities Screening Instrument. Incident dementia was diagnosed according to standard criteria. A total of 134 men experienced development of Alzheimer’s disease (AD; including 40 cases with contributing cerebrovascular disease) and 44 experienced development of vascular dementia.
RESULTS:
Adjusting for age and other covariates, testosterone was not associated with risk for dementia (using Cox regression analyses) or cognitive decline (using random coefficient analyses). However, higher levels of estradiol were associated with risk for AD (hazard ratio per standard deviation increase, 1.25; 95% confidence interval, 1.05-1.47) and AD with cerebrovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.02-1.38). Also, compared with the lowest tertile of estradiol, men in the middle and highest tertile of estradiol had 0.24 and 0.28 points lower Cognitive Abilities Screening Instrument scores, respectively, for each year increase in age.
INTERPRETATION: In old men, endogenous testosterone levels are not associated with risk for cognitive decline and AD, whereas higher estrogen levels increase risk for cognitive decline and AD.
Eur J Pharmacol 1999 Feb 26;368(1):95-102. Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na+, K+ -ATPase of porcine cortex.
Zheng J, Ramirez VD. The data indicate that the ubiquitous mitochondrial F0F1-ATPase is a specific target site for estradiol and related estrogenic compounds; however, under this in vitro condition, the effect seems to require pharmacological concentrations.
Progesterone:
Exp Neurol. 1994 Sep;129(1):64-9. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Roof RL, Duvdevani R, Braswell L, Stein DG. The ability of progesterone to reduce the cerebral edema associated with traumatic brain damage first became apparent when we observed that males had significantly more edema than females after cortical contusion. In addition, edema was almost absent in pseudopregnant female rats, a condition in which progesterone levels are high relative to estrogen. Progesterone injections given after injury also reduced edema and were equally effective in both males and females. The present experiment was done to determine if the progesterone-induced reduction in edema could also prevent secondary neuronal degeneration and reduce the behavioral impairments that accompany contusion of the medial frontal cortex. Progesterone-treated rats were less impaired on a Morris water maze spatial navigation task than rats treated with the oil vehicle. Progesterone-treated rats also showed less neuronal degeneration 21 days after injury in the medial dorsal thalamic nucleus, a structure that has reciprocal connections with the contused area.
Brain Res. 2005 Jul 5;1049(1):112-9. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone given after traumatic brain injury (TBI) has been shown to reduce the initial cytotoxic surge of inflammatory factors. We used Western blot techniques to analyze how progesterone might affect three inflammation-related factors common to TBI: complement factor C3 (C3), glial fibrillary acidic protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after bilateral injury to the medial frontal cortex, adult male rats were given injections of progesterone (16 mg/kg) for 2 days. Brains were harvested 48 h post-TBI, proteins were extracted from samples, each of which contained tissue from both the contused and peri-contused areas, then measured by Western blot densitometry. Complete C3, GFAP, and NFkappaB p65 were increased in all injured animals. However, in animals given progesterone post-TBI, NFkappaB p65 and the inflammatory metabolites of C3 (9 kDa and 75 kDa) were decreased in comparison to vehicle-treated animals. Measures of NFkappaB p50 showed no change after injury or progesterone treatment, and progesterone did not alter the expression of GFAP. The therapeutic benefit of post-TBI progesterone administration may be due to its salutary effect on inflammatory proteins known to increase immune cell invasion and cerebral edema.
Experimental Neurology
Volume 138, Issue 2, April 1996, Pages 246-251 Progesterone Rapidly Decreases Brain Edema: Treatment Delayed up to 24 Hours Is Still Effective Robin L. Roof1, Revital Duvdevani, John W. Heyburn, Donald G. Stein
Cerebral edema is a serious side effect of traumatic brain injury. We have previously established that progesterone injections, initiated within 1 h after cortical contusion injury, reduced edema when assessed 3 days later. To determine how rapidly progesterone can reduce edema, male and female rats were given the hormone 1 h after damage to the medial frontal cortex, and edema levels were assessed between 2 h and 7 days postinjury. Progesterone decreased edema within 6 h of the injury and continued to be effective for the duration of treatment. In addition, we assessed whether progesterone injections are effective when delays are imposed between injury and initiation of treatment. Male and female rats received progesterone after postinjury delays of 6, 24, or 48 h. Progesterone was effective in reducing edema when treatment was delayed until 24 h after injury.
Mol Chem Neuropathol. 1997 May;31(1):1-11. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Roof RL, Hoffman SW, Stein DG. The gonadal hormone, progesterone, has been shown to have neuroprotective effects in injured nervous system, including the severity of postinjury cerebral edema. Progesterone’s attenuation of edema is accompanied by a sparing of neurons from secondary neuronal death and with improvements in cognitive outcome. In addition, we recently reported that postinjury blood-brain barrier (BBB) leakage, as measured by albumin immunostaining, was significantly lower in progesterone treated than in nontreated rats, supporting a possible protective action of progesterone on the BBB. Because lipid membrane peroxidation is a major contributor to BBB breakdown, we hypothesized that progesterone limits this free radical-induced damage. An antioxidant action, neuroprotective in itself, would also account for progesterone’s effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterone’s possible antiperoxidation effect, we compared brain levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a marker of lipid peroxidation, 24, 48, and 72 h after cortical contusion in male rats treated with either progesterone or the oil vehicle. The brains of progesterone treated rats contained approximately one-third of the 8-isoPGF2 alpha found in oil-treated rats. These data suggest progesterone has antioxidant effects and support its potential as a treatment for brain injury.
Brain Res. 1996 Sep 30;735(1):101-7. Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rats. Jiang N, Chopp M, Stein D, Feit H.
Progesterone (PROG) is a neurosteroid, possessing a variety of functions in the central nervous system. Exogenous PROG has been shown to reduce secondary neuronal loss in conjunction with attenuated brain edema after cerebral contusion and to reduce brain edema after focal cerebral ischemia. In the present study, we assessed the neuroprotective potential of PROG in a model of focal cerebral ischemia in the rat. Forty-eight male Wistar rats were randomly assigned to 4 groups, i.e. pretreatment with water soluble PROG, or dimethyl sulfoxide (DMSO) dissolved PROG, or DMSO as control or delayed treatment with DMSO dissolved PROG. Middle cerebral artery occlusion (MCAO) was induced by insertion of an intraluminal suture and reperfusion was performed by withdrawing the suture. Pretreatments were initiated 30 min before MCAO via intraperitoneal injection. Delayed treatment was initiated upon reperfusion following 2 h of MCAO. Infarct volume, body weight loss, and neurological deficit were measured 48 h after MCAO. Pre- and delayed treatment with DMSO dissolved PROG resulted in a 39% (P < 0.05) and 34% (P < 0.05) reduction in cerebral infarction, respectively, along with decreased body weight loss and improved neurological function as compared to control animals, whereas no statistically significant reduction in infarct volume by water soluble PROG was found. We demonstrated that administration of PROG to the male rat before or 2 hours after onset of MCAO reduces ischemic cell damage and improves physiological and neurological function 2 days after stroke. These results suggests potential therapeutic properties of PROG in the management of stroke.
Steroids. 2011 Aug;76(9):845-55. Epub 2011 Mar 1. Progesterone inhibition of voltage-gated calcium channels is a potential neuroprotective mechanism against excitotoxicity. Luoma JI, Kelley BG, Mermelstein PG. The therapeutic use of progesterone following traumatic brain injury has recently entered phase III clinical trials as a means of neuroprotection. Although it has been hypothesized that progesterone protects against calcium overload following excitotoxic shock, the exact mechanisms underlying the beneficial effects of progesterone have yet to be determined. We found that therapeutic concentrations of progesterone to be neuroprotective against depolarization-induced excitotoxicity in cultured striatal neurons. Through use of calcium imaging, electrophysiology and the measurement of changes in activity-dependent gene expression, progesterone was found to block calcium entry through voltage-gated calcium channels, leading to alterations in the signaling of the activity-dependent transcription factors NFAT and CREB. The effects of progesterone were highly specific to this steroid hormone, although they did not appear to be receptor mediated. In addition, progesterone did not inhibit AMPA or NMDA receptor signaling. This analysis regarding the effect of progesterone on calcium signaling provides both a putative mechanism by which progesterone acts as a neuroprotectant, as well as affords a greater appreciation for its potential far-reaching effects on cellular function.
Growth. 1979 Mar;43(1):58-61. The effect of progesterone on brain and body growth of chick embryos.
Ahmad G, Zamenhof S. It has been suggested that in the embryo hormonal steroids may act also as control factors for the growth of neural systems. In the present work progesterone was introduced onto the chorioallantoic membrane of the chick embryo on day 7 or days 7 and 10 of incubation. The embryo, dissected at day 10, showed significant increases in body weight and cerebral hemispheres weight. The response at day 13 was less pronounced; male embryos responded to progesterone more than the female embryos. Progesterone is a precursor to other corticosteroids, but corticosterone itself had a significant harmful effect on embryonal growth. Several possible explanations of these results have been offered. It appears that progesterone itself promotes the growth of the early embryo, but the effect depends on its age and sex.
Biomed Environ Sci. 2007 Oct;20(5):432-8. Inhibitory effect of progesterone on inflammatory factors after experimental traumatic brain injury.
Pan DS, Liu WG, Yang XF, Cao F.
OBJECTIVE: Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in young people. Inflammatory cytokines play an important part in the pathophysiology of TBI. Recent studies demonstrate that progesterone significantly reduces cerebral edema and enhances functional recovery from TBI and stroke in several animal models. This study was designed to investigate the inhibitory effect of progesterone on inflammatory response after traumatic brain injury.
METHODS:
Progesterone was injected intraperitoneally using rats as a model of traumatic brain injury, and Western blot technique was applied to detect the expression of three inflammation-related factors: nuclear factor kappa B p65 (NFkappaB p65), glial fibrillary acidic protein (GFAP), and tumor necrosis factor-alpha (TNF-alpha). The water content of injured brain was also examined. A neurological severity score was recorded to evaluate the effect of progesterone on neurodeficit recovery.
RESULTS: NFkappaB p65, GFAP, and TNF-alpha were increased in all injured animals. In rats treated with progesterone, the expression level of NFkappaB p65 and TNF-alpha were reduced significantly in comparison with vehicle-treated rats. However, progesterone did not alter the expression of GFAP in the injured rats. Progesterone also reduced the water content of injured brain and the lesion volume. In addition, progesterone-treated injured rats showed significant improvements in the Neurological Severity Score test, compared with vehicle-treated ones.
CONCLUSIONS: Progesterone inhibits the inflammatory response after experimental traumatic brain injury and mitigates the severity of brain damage.
Exp Neurol. 2004 Oct;189(2):404-12. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG. Following a traumatic brain injury (TBI), the excessive release of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) is a major cause of cerebral edema, which, in turn, can cause permanent neuronal loss and cognitive deficits in laboratory rats. This study examined the changes in expression of the proinflammatory cytokines IL-1beta and TNF-alpha after progesterone (8 mg/kg) or allopregnanolone (4 mg/kg) treatment in brain-injured rats at 3, 8, and 12 h and 6 days post-injury. Adult male rats received either bilateral prefrontal cortical contusion or sham surgery. The hormones were given intraperitoneally at 1 and 6 h, and continued once per day for up to 5 days. The gene expression of IL-1beta and TNF-alpha was measured by mRNA using real-time quantitative reverse transcripted polymerase chain reaction (RT-PCR). The protein concentrations of IL-1beta and TNF-alpha were measured using enzyme-linked immunosorbent assay (ELISA) to confirm the translation from mRNA to protein. The results indicated that progesterone and allopregnanolone reduce both IL-1beta and TNF-alpha at 3 h post-injury, when the expression of these cytokines peaks. At 8 and 12 h post-injury, IL-1beta and TNF-alpha gene expression in injured rats was still elevated compared to shams. By the sixth day post-injury, cytokine expression was back to the level of intact rats. We conclude that progesterone and allopregnanolone may attenuate the production of proinflammatory cytokines early after TBI, and this may be one mechanism by which progesterone and allopregnanolone reduce cerebral edema and promote functional recovery from TBI.
Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2. Epub 2006 Sep 29. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG.
STUDY OBJECTIVE:
Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury.
METHODS:
This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury.
RESULTS: Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo.
CONCLUSION: In this small study, progesterone caused no discernible harm and showed possible signs of benefit.
Crit Care. 2008;12(2):R61. doi: 10.1186/cc6887. Epub 2008 Apr 30. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Xiao G, Wei J, Yan W, Wang W, Lu Z.
BACKGROUND:
Severe traumatic brain injury (TBI) has been increasing with greater incidence of injuries from traffic or sporting accidents. Although there are a number of animal models of TBI using progesterone for head injury, the effects of progesterone on neurologic outcome of acute TBI patients remain unclear. The aim of the present clinical study was to assess the longer-term efficacy of progesterone on the improvement in neurologic outcome of patients with acute severe TBI.
METHODS:
A total of 159 patients who arrived within 8 hours of injury with a Glasgow Coma Score The modified Functional Independence Measure scores in the progesterone group were higher than those in the placebo group at both 3-month and 6-month follow-up (P < 0.05 and P < 0.01). The mortality rate of the progesterone group was significantly lower than that of the placebo group at 6-month follow-up (P < 0.05). The mean intracranial pressure values 72 hours and 7 days after injury were lower in the progesterone group than in the placebo group, but there was no statistical significance between the two groups (P > 0.05). Instances of complications and adverse events associated with the administration of progesterone were not found.
CONCLUSION: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug.
TRIAL REGISTRATION:
ACTRN12607000545460.
Crit Care. 2008;12(3):153. doi: 10.1186/cc6899. Epub 2008 May 29. Progesterone in traumatic brain injury: time to move on to phase III trials. Vandromme M, Melton SM, Kerby JD.
There are several candidate neuroprotective agents that have been shown in preclinical testing to improve outcomes following traumatic brain injury (TBI). Xiao and colleagues have performed an in hospital, double blind, randomized, controlled clinical trial utilizing progesterone in the treatment of patients sustaining TBI evaluating safety and long term clinical outcomes. These data, combined with the results of the previously published ProTECT trial, show progesterone to be safe and potentially efficacious in the treatment of TBI. Larger phase III trials will be necessary to verify results prior to clinical implementation. Clinical trials networks devoted to the study of TBI are vital to the timely clinical testing of these candidate agents and need to be supported.
“Early research had also shown that estrogen diminishes liver glycogen storage while progesterone increases both blood sugar and liver glycogen…Estrogen is also a promoter of insulin release and action, lowering blood sugar and promoting fat synthesis.” -Ray Peat, PhD
“With aging, the loss of glycogen in the brain has serious consequences, including insomnia. Estrogen’s depletion of glycogen in other tissues is probably important for their functioning, and thyroid and progesterone are known to help maintain the glycogen stores.” -Ray Peat, PhD
J Endocrinol September 1, 1974 62 439-449 SHORT-TERM EFFECTS OF OESTRADIOL BENZOATE IN NORMAL, HYPOPHYSECTOMIZED AND ALLOXAN-DIABETIC MALE RATS
M. N. GOODMAN and R. L. HAZELWOOD
Studies were undertaken to determine the effects and possible mode of action of 17β-oestradiol benzoate (OEB) in alloxan-diabetic male rats. Adlibitum or pair-fed normal, diabetic, and hypophysectomized rats received daily subcutaneous injections of 10 μg OEB for 10 days. In normal rats, OEB decreased plasma glucose, increased plasma immunoreactive insulin, growth hormone and corticosteroid levels, increased pancreatic β-cell granulation, and enhanced glucose stimulation of insulin release in vitro. In alloxan-diabetic rats, OEB treatment decreased urinary glucose excretion, increased plasma growth hormone and corticosteroid levels and slightly enlarged the pancreatic islets of Langerhans. In hypophysectomized rats, OEB decreased plasma glucose, increased plasma insulin levels, and slightly enlarged the pancreatic islets of Langerhans.
These results suggest that OEB affects experimental diabetes by a direct action on the pancreas, promoting insulin formation, and possibly by an indirect action mediated through hypophysial secretions.
“Broda Barnes, more than 60 years ago, summed up the major effects of hypothyroidism on health very neatly when he pointed out that if hypothyroid people don’t die young from infectious diseases, such as tuberculosis, they die a little later from cancer or heart disease.” -Ray Peat, PhD
“A high level of serum cholesterol is practically diagnostic of hypothyroidism, and can be seen as an adaptive attempt to maintain adequate production of the protective steroids. Broda Barnes’ work clearly showed that hypothyroid populations are susceptible to infections, heart disease, and cancer.” -Ray Peat, PhD
“One of my recurring objects of thought has been the slowness with which raw knowledge is assimilated. For example, I have been thinking about Broda Barnes’s work on the prevention of heart disease with thyroid extract. He did solve much of ‘the riddle of heart attacks,’ but recent statements by the Heart Association show that the dominant forces in the health business haven’t learned anything at all from his work, which he began 50 years ago. His work is clearly presented, not hard to understand, and it is scientifically so sound that no one challenges it, at least not on the scientific level. It is ignored, rejected by people who choose not to be bothered to read it. How many people have died from heart disease, since his work first became available? (And how many more from cancer, tuberculosis, and other diseases he showed occur mainly among hypothyroid people?)” -Ray Peat, PhD
“Barnes, and Barnes point out that the tremendous rise in heart attacks in the 20th century has been due to survival of hypothyroid patiens who formerly who have died at an early age from one of the infectious diseases.” -Barnes and Barnes in “Hope for Hypoglycemia”
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Prior to the introduction of antibiotics in the 1940s, individuals with a low metabolic rate would die of a variety of infections, including tuberculosis, because thyroid deficiency results in increased susceptibility to infection as Broda Barnes’ work discusses. The introduction of antibiotics began saving the lives of those with a low metabolic rate.
These individuals that no longer die due to infection are now prone to getting other complications from a slowed metabolism like diabetes, heart attacks, stroke, cancer, and other chronic degenerative conditions that pervade modern life. The work of thyroid expert Broda Barnes, MD, PhD makes this point very clear.
After several years of analyzing 70,000 autopsies from the town of Graz, Austria where autopsy of all who died was mandated by law, Dr. Barnes discovered that prior to 1945 when antibiotics were introduced people dying of tuberculosis had stage four atherosclerosis in their coronary arteries. After the introduction of antibiotics which prevented these deaths, deaths from heart attacks increased significantly from one in 125 deaths to one in 14 deaths.
Barnes also found that those who died from a heart attack had evidence that they had had tuberculosis in their lungs. Hypothyroidism, in Barnes’ opinion, was the cause of both conditions. Barnes’ medical practice points to hypothyroidism’s role in the other major killers these days – stroke, diabetes, and cancer.
There has been a marked shift in death from infectious disease to death from chronic degenerative diseases as result of the introduction of antibiotics. The same underlying issue that killed people from infection (low metabolism) prior to 1940 is now killing people later in life from degenerative diseases. Supporting the health of the thyroid and metabolism is at the forefront of maintaining optimal health.
Another important note is that Dr. Mark Starr indicates that the intervention by antibiotics in the “survival of the fittest” began the perpetuation of a population that is progressively more and more hypothyroid and susceptible to disease. The passing down of dysfunctional energy producing DNA may be playing a role in health and disease in today’s population.
Resources:
Barnes BO, Ratzenhofer M, Gisi R. The role of natural consequences in the changing death patterns. J Am Geriatr Soc. 1974 Apr;22(4):176-9.
Broda Barnes, MD and Lawrence Galton, “Hypothyroidism: The Unsuspected Illness”
“The Thyroid and Atherosclerotic Heart Disease”, Menof 1973
