Categories:

The Brain – Estrogen’s Harm and Progesterone’s Protection

Also see:
Ray Peat Articles
Estrogen’s Role in Seizures
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy)
Nutrition and Brain Growth in Chick Embryos
Brain Swelling Induced by Polyunsaturated Fats (PUFA)
PUFA, Fish Oil, and Alzheimers

Women, Estrogen, and Circulating DHA
The healing hormone

‘Spectacular’ Recovery for State Fair Stage Collapse Victim
SyNAPSe

Progesterone could become tool versus brain cancer
The Streaming Organism

MORE VIDEOS AVAILABLE AT THE END OF THIS BLOG

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.







Posted in General.

Tagged with , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .