Non-feminizing Estrogens Research Articles

Evidence-based neuroprotective potential of nonfeminizing estrogens: In vitro and in vivo studies.

Menopause weakens the brain's structural integrity and increases its susceptibility to a range of degenerative and mental illnesses. 17β estradiol (17βE2) exhibits potent neuroprotective properties. Exogenous estrogen supplementation provides neuroprotection, but the findings presented by the Million Women Study (MWS) and the Women's Health Initiative (WHI), as well as the increased risk of endometrial cancer, breast cancer and venous thromboembolism associated with estrogen use, have cast doubt on its clinical use for neurological disorders. Thus, the objective of our review article is to compile all in vitro and in vivo studies conducted till date demonstrating the neuroprotective potential of nonfeminizing estrogens. This objective has been achieved by gathering various research and review manuscripts from different records such as PubMed, Embase, Scopus, Google Scholar, Web of Science and OVID, using different terms like 'estrogen deficiency, 17β estradiol, non-feminising estrogens, and brain disorder'. However, recent evidence has revealed the contribution of numerous non-estrogen receptor-dependent pathways in neuroprotective effects of estrogen. In conclusion, synthetic nonfeminizing estrogens that have little or no ER binding but are equally powerful (and in some cases more potent) in delivering neuroprotection are emerging as viable and potential alternatives.

17α-estradiol does not adversely affect sperm parameters or fertility in male mice: implications for reproduction-longevity trade-offs.

17α-estradiol (17α-E2) is referred to as a nonfeminizing estrogen that was recently found to extend healthspan and lifespan in male, but not female, mice. Despite an abundance of data indicating that 17α-E2 attenuates several hallmarks of aging in male rodents, very little is known with regard to its effects on feminization and fertility. In these studies, we evaluated the effects of 17α-E2 on several markers of male reproductive health in two independent cohorts of mice. In alignment with our previous reports, chronic 17α-E2 treatment prevented gains in body mass, but did not adversely affect testes mass or seminiferous tubule morphology. We subsequently determined that chronic 17α-E2 treatment also did not alter plasma 17β-estradiol or estrone concentrations, while mildly increasing plasma testosterone levels. We also determined that chronic 17α-E2 treatment did not alter plasma follicle-stimulating hormone or luteinizing hormone concentrations, which suggests 17α-E2 treatment does not alter gonadotropin-releasing hormone neuronal function. Sperm quantity, morphology, membrane integrity, and various motility measures were also unaffected by chronic 17α-E2 treatment in our studies. Lastly, two different approaches were used to evaluate male fertility in these studies. We found that chronic 17α-E2 treatment did not diminish the ability of male mice to impregnate female mice, or to generate successfully implanted embryos in the uterus. We conclude that chronic treatment with 17α-E2 at the dose most commonly employed in aging research does not adversely affect reproductive fitness in male mice, which suggests 17α-E2 does not extend lifespan or curtail disease parameters through tradeoff effects with reproduction.

Modulatory role of 17α‐estradiol (non‐feminizing estrogen) on 6‐OHDA‐induced Parkinsonism in ovariectomized rats

BackgroundEpidemiological studies have reported that the incidence of Parkinson’s disease (PD) is 1.5 times more in men as compared to women. It suggests that gonadal hormones influence the development and progression of PD. Estrogen replacement therapies have a protective effect against dopaminergic toxins and can be protective in Parkinsonism. However, there are multiple unresolved issues regarding the safety of ERT. Thus, there is a essential need to find alternatives that would avoid these health risks.ObjectivesThus main objective of study was to assess effect of 17α‐estradiol, a non‐feminizing estrogen, in attenuating PD employing an animal model of surgical menopause.Methodology17α‐estradiol and 17β‐estradiol was injected 10 µg/kg/s.c. for 14 days in ovariectomized 6‐OHDA rats. After 14 days of drug administration behavioral parameters of Parkinsonism (sensorimotor activity, motor coordination, and locomotor activity) were performed. These behavioral parameters were further correlated with various biochemical and molecular markers in postmenopausal Parkinsonism. Uterine weight and serum estradiol levels were also assessed to determine estrogenic effect of both the drugs peripherally. Effect of both drugs on expression of ER‐α and ER‐β in striatum was also evaluated. Further the differential effect of 17α‐estradiol and 17β‐estradiol was evaluated in postmenopausal Parkinsonism.Results17α‐estradiol and 17β‐estradiol equally modulated behavioral changes and attenuated rise in oxidative stress markers, inflammatory markers, improving neurotrophic factors and modulation of striatal neuron morphology. 17β‐estradiol treatment restored the uterine weight and serum estradiol levels towards normal, however 17α‐estradiol did not show any effect on uterine horns and serum estradiol levels. No effect of 17α‐estradiol was observed on expression of ER‐α and ER‐β in the striatum, indicates receptor independent effect of 17α‐estradiolConclusionBoth 17α‐estradiol and 17β‐estradiol are equally effective in Parkinsonism, however, 17α‐estradiol may prove to be safer alternative of 17β‐estradiol in Parkinsonism due to lack of feminizing effect.

Role of non-feminizing estrogens in brain protection from cerebral ischemia and Alzheimer’s disease neuropathology

SAMP8 mice exhibit changes that commonly occur with normal aging late in life, but do so at a much earlier age. These changes include impairments in learning and memory as early as 8 months of age and so the SAMP8 is a useful model to investigate those age-related brain changes that may affect cognition. As brain insulin signaling and memory decline with aging, the SAMP8 model is useful for investigating these changes and interventions that might prevent the decline. This review will summarize the SAMP8 mouse model, highlight changes in brain insulin signaling and its role in memory, and discuss intranasal insulin delivery in investigating effects on insulin metabolism and memory in the SAMP8 mice.

A novel mechanism of non-feminizing estrogens in neuroprotection

Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in an in vitro assay using a panel of >70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large bulky group at the C2 or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C or D rings either reduced or did not markedly change neuroprotection. Collectively, there was a negative correlation between binding to ERs and neuroprotection with the more potent compounds showing no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. We demonstrated that these non-feminizing estrogens engage in a redox cycle with glutathione, using the hexose monophosphate shunt to apply cytosolic reducing potential to cellular membranes. Together, these results demonstrate that non-feminizing estrogens are neuroprotective and protect brain from the induction of ischemic- and Alzheimer's disease (AD)-like neuropathology in an animal model. These features of non-feminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, as they are not expected to show the side effects of chronic estrogen therapy that are mediated by ER actions in the liver, uterus and breast.

17α-Estradiol: A candidate neuroserm and non-feminizing estrogen for postmenopausal neuronal complications

Extensive evidence suggests that decline in ovarian function with menopause is associated with neuronal dysfunction. Major cause of this is rise in oxidative stress and inflammatory cytokines because of estrogen deficiency. 17β-Estradiol (E2, hormone with potent antioxidant and anti-inflammatory activity) has profound protective actions on multiple organ systems, but feminizing side effects of β-estradiol limits its clinical efficacy. 17α-Estradiol (E2α), a non feminizing congener, gives a ray of hope to the scientific community as an alternative strategy to treat menopause associated neuronal pathologies. We assessed the protective actions of 17α-estradiol (5, 10μg/kg) against cognitive deficits, depression and motor coordination after 4weeks of ovariectomy in rats and compared its efficacy with E2 at same doses. After the behavioral assay animals were sacrificed and their brains were harvested for biochemical studies. Uterine weights were also assessed. E2 and E2α (5, 10μg/kg) were equally protective against attenuating cognitive deficits, depressive symptoms and motor incoordination in OVX rats. Both demonstrated significant antioxidant activity and E2, but not E2α, increased serum estradiol levels and proliferated uterine weights, markers of feminizing action. It can thus be concluded that E2α offers safe alternative to E2 in protecting against menopausal neuropathologies.

Neuroprotection and Sex Steroid Hormones: Evidence of Estradiol- Mediated Protection in Hypertensive Encephalopathy

Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension. Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the spontaneously hypertensive rat (SHR). In the dentate gyrus of the hippocampus, SHR present decreased neurogenesis, astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus and increased basal levels of the estrogen-synthesizing enzyme aromatase, with respect to the Wistar Kyoto (WKY) normotensive strain. In the hypothalamus, SHR show increased expression of the hypertensinogenic peptide arginine vasopressin (AVP) and its V1b receptor. From the therapeutic point of view, it was highly rewarding that estradiol treatment decreased blood pressure and attenuated brain abnormalities of SHR, rendering hypertension a suitable model to test estrogen neuroprotection. When estradiol treatment was given for 2 weeks, SHR normalized their faulty brain parameters. This was shown by the enhancement of neurogenesis in the dentate gyrus, according to increased bromodeoxyuridine incorporation and doublecortin labeling, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus, increased neuronal number in the hilus of the dentate gyrus and a further hyperexpression of aromatase. The presence of estradiol receptors in hippocampus and hypothalamus suggests the possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive rats should encourage the treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated diseases.

Neuroprotective Effects of Nonfeminizing Estrogens in Retinal Photoreceptor Neurons

Retinal diseases such as macular degeneration and glaucoma are disorders that target specific retinal neurons that can ultimately lead to vision loss. Under these conditions and pathologies, retinal neurons can die via apoptosis that may be due to increased oxidative stress. The neuroprotective effects of 17β-estradiol (E2) and three synthetic nonfeminizing estrogen analogs (ZYC-26, ZYC-23, and ZYC-3) were investigated to examine their abilities to protect retinal neurons against glutamate toxicity. Using an in vitro model of glutamate-induced cell death in 661W cells, a mouse cone photoreceptor cell line, shown to express both estrogen receptors (ERs) via immunoblotting, was pretreated with E2 and its analogs and cell viability were assessed. It was observed that E2 and estrogen analogs, ZYC-26 and ZYC-3, were protective against a 5 mM glutamate insult in 661W cells. The neuroprotective abilities of ZYC-26 and ZYC-3 were autonomous of estrogen receptor-α (ERα) and ERβ demonstrated by their ability to protect in the presence of ICI 182780, a pan-ER antagonist with a high affinity for the estrogen receptor. Treatment with PPT and DPN, ERα- and ERβ-specific agonists, respectively, did not protect the 661W cells from the glutamate insult. Studying the membrane ER (mER) or GPR30 did show that activation of the receptor by G1 protected the retinal neuron from insult, whereas G15, an antagonist of the mER was not able to antagonize the protection previously seen. These data demonstrate that nonfeminizing estrogens may emerge as useful compounds for neuroprotection of retinal cells.

Effects of estrogens on cholinergic neurons in the rat basal nucleus

Estrogen replacement in postmenopausal women may help prevent or delay development of Alzheimer's disease. Because loss of basal forebrain cholinergic neurons with reductions in choline acetyltransferase (ChAT) concentration are associated with Alzheimer's disease, we investigated the effect of estradiol (E 2) and J 861, a non-feminizing estrogen, on cholinergic neurons in the basal forebrain. Ovariectomized rats received E 2, J 861 or vehicle, and basal forebrain sections through the substantia innominata, medial septum, and nucleus of the diagonal band were immunostained for ChAT. ChAT-immunoreactive cells in the basal forebrain were significantly reduced in the ovariectomized rats compared to intact rats, but those ovariectomized rats receiving estrogen replacement with E 2 and J 861 had near normal levels of ChAT-positive neurons. While retrograde tracing experiments with fluorogold injected into the prefrontal cortex showed no significant differences in the number of fluorogold-labeled cells among the groups, ChAT-immunoreactive cells and double-labeled cells were significantly lower in OVX rats than in intact and E 2 rats. Some substantia innominata cells in the J 861 rats were ChAT/estrogen receptor α-positive. These results suggest that E 2 and J 861 have positive effects on cholinergic neurons that project from the basal nucleus to the forebrain cortex.

A Nonfeminizing Estrogen Analog Protects against Ethanol Withdrawal Toxicity in Immortalized Hippocampal Cells

We have shown that 17beta-estradiol protects against ethanol withdrawal toxicity in rats. Here, we investigated whether a cellular model of ethanol withdrawal could be developed in a cultured hippocampal cell line (HT22) and whether an adamantyl-containing nonfeminizing estrogen analog, ZYC26 [(3-hydroxy-2-adamantyl(1)-4-methyl-estra-1,3,5(10)-17-one], protects against ethanol withdrawal toxicity. HT22 cells were exposed to ethanol (0-500 mM) for 24 h in the presence or absence of ZYC26 or 17beta-estradiol. The ethanol solution was then removed from the cells for 4 h to create ethanol withdrawal. Samples were collected at the end of a 24-h ethanol exposure or at 4 h of ethanol withdrawal to assess cell viability using a calcein assay, lipid peroxidation by measuring malondialdehyde, and protein oxidation by measuring carbonyl contents. When tested, ethanol concentrations were constantly maintained during a 24-h ethanol exposure and eliminated at 4 h of ethanol withdrawal. Ethanol withdrawal decreased cell viability and increased the levels of malondialdehyde and carbonyls more than ethanol exposure. ZYC26 reduced the cell death and malondialdehyde levels at a lower dose (1 microM) than 17beta-estradiol (10 microM). The increased carbonyl contents were reduced only by ZYC26 treatment. These data suggest that ethanol withdrawal can be created in HT22 cells in a manner that is more toxic than ethanol exposure and that ZYC26 is a more potent cytoprotectant than 17beta-estradiol against cell death and oxidative damage induced by ethanol withdrawal. Therefore, ZYC26 can be a potential alternative estrogen therapy for a cellular and oxidative imbalance associated with ethanol withdrawal.

Neuroprotective Effects of 17β-Estradiol and Nonfeminizing Estrogens against H2O2Toxicity in Human Neuroblastoma SK-N-SH Cells

Neuroprotective effects of estrogens have been shown in various in vitro and in vivo models, but the mechanisms underlying protection by estrogen are not clear. Mounting evidence suggests antioxidant effects contribute to the neuroprotective effects of estrogens. In the present study, we assessed the protective effects of estrogens against H2O2-induced toxicity in human neuroblastoma cells and the potential mechanisms involved in this protection. We demonstrate that 17beta-estradiol (17beta-E2) increases cell survival against H2O2 toxicity in human neuroblastoma cells. 17beta-E2 effectively reduced lipid peroxidation induced by 5-min H2O2 exposure. Furthermore, 17beta-E2 exerts the protective effects by maintaining intracellular Ca2+ homeostasis, attenuating ATP depletion, ablating mitochondrial calcium overloading, and preserving mitochondrial membrane potential. Two nonfeminizing estrogens, 17alpha- and ent-estradiol, were as effective as 17beta-E2 in increasing cell survival, alleviating lipid peroxidation, preserving mitochondrial function, and maintaining intracellular glutathione levels and Ca2+ homeostasis against H2O2 insult. Moreover, the estrogen receptor antagonist fulvestrant (ICI 182,780) did not block effects of 17beta-E2, but increased cell survival and blunted intracellular Ca2+ increases. However, these estrogens failed to reduce cytosolic reactive oxygen species, even at concentrations as high as 10 microM. In conclusion, estrogens exert protective effects against oxidative stress by inhibiting lipid peroxidation and subsequently preserving Ca2+ homeostasis, mitochondrial membrane potential, and ATP levels.

Role of Nonfeminizing Estrogens in Brain Protection from Cerebral Ischemia: An Animal Model of Alzheimer's Disease Neuropathology

Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, bulky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Abeta production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.

Neuroprotective effects of an estratriene analog are estrogen receptor independent in vitro and in vivo

Estrogens are potent neuroprotectants both in vitro and in vivo. In the present study, we compared the potency and efficacy of a non-feminizing estrogen, 2-(1-adamantyl)-4-methylestrone (ZYC-26), with its parent estrogen, estrone, and an expected non-neuroprotective 3- O-methyl analog of (17β)-2-(1-adamantyl)estradiol (ZYC-23). These estratriene derivatives were tested for their ability to protect in an in vitro lipid peroxidation model, to neuroprotect against oxidative stress in cell culture models, to bind the estrogen receptors (ERα and ERβ), to elicit uterotrophic effects, and to affect brain damage from transient middle cerebral artery occlusion. We observed that in contrast to estrone, neither ZYC-26 nor ZYC-23 bound to either estrogen receptors (ER) and both failed to elicit a uterotrophic response. In vitro, the active estrogen analogue ZYC-26 was more potent that estrogen in its ability to inhibit lipid peroxidation and to protect HT-22 cells from either glutamate or iodoacetic acid (IAA) toxicity. Further, ZYC-26 was as active in preventing brain damage from transient middle cerebral artery occlusion (MCAO) as was estrone. Collectively, these studies suggest that the antioxidant activity, rather than ER binding of non-feminizing estrogens such as ZYC-26, mediates their potent neuroprotective activity. Further, in view of the now known toxicities of chronic feminizing estrogen use in older women, non-feminizing estrogens may be a useful alternative for estrogen-induced brain protection.

Progestins and estrogens and Alzheimer's disease

Sex-specific incidence rates for Alzheimer's disease (AD) are higher in women than men. Many fundamental researches and some clinical investigations have reported therapeutic and preventive effects of estrogens on AD. But WHIMS [S.A. Shumaker, C. Legault, S.R. Rapp, L. Thal, R.B. Wallace, J.K. Ockene, S.L. Hendrix, B.N. Jones IIIrd, A.R. Assaf, R.D. Jackson, J.M. Kotchen, S. Wabertheil-Smoller, J. Wactawsk-Wende, WHIMS investigators, Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The women's health initiative memory study: a randomized controlled trial, JAMA 289 (2003) 2651–2662], which used daily continuous hormone replacement therapy (HRT), reported that the hazard ratio of the HRT for probable dementia was 2.05. Effect of progestins, and continuous (not cyclically) HRT, even only with estrogen should be reconsidered. In our clinical study, conjugated equine estrogen (CEE) alone showed good changes of psychiatric tests for AD on the 3rd week, but addition of medroxyprogesterone acetate (MPA) or norethindrone since 4th week suppressed these tests. Using human umbilical vein epithelial cell (HUVEC), levonorgestrel (LNG), norethindrone acetate (NETA), MPA increased intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion melocule-1 (VCAM-1) and E-secretin but dienogest (DNG) showed no effect. In vitro flow system, estradiol (E 2), suppressed adhesion of white cell, but LNG, NETA, MPA increased the adhesions. DNG showed less effect. Non-feminizing estrogen J 861, which has Δ8,9 double bond and straight in its structure and has less effect on sexual organs. J 861 has shown ameliorative effects on central nervous system (CNS) (increasing of cholineacetyltransferase immunoreactive cells in substantia innominata (SI), etc.) like E 2. More investigations about progestins and estrogens and AD should be done.

Role of nonfeminizing estrogen analogues in neuroprotection of rat retinal ganglion cells against glutamate-induced cytotoxicity

Glaucoma is a family of eye disorders whose ultimate cause of vision loss is apoptosis of retinal ganglion cells. Although several etiologies of glaucoma exist, oxidative stress is thought to be a key mechanism by which ganglion cells die. From this perspective, the work presented here was designed to examine the efficacy of 17β-estradiol and three synthetic estrogen analogues (ZYC-1, ZYC-3, ZYC-10) as retinal ganglion cell neuroprotectants. Compound ZYC-1 and its enantiomer ZYC-10, containing an additional double bond in the steroid C ring of 17β-estradiol, had similar (ZYC-1) or modestly reduced (ZYC-10) affinity for estrogen receptors compared to the parent estrogen. In the case of ZYC-3, the addition of an adamantyl group to the C2 position of the A ring of estrone abolished its binding to the estrogen receptors. RGC-5 cells (an established clonal rat retinal ganglion cell line) and rat retinas were shown to predominantly express estrogen receptor α, with minimal detectable levels of estrogen receptor β. The affinity of the synthetic compounds for estrogen receptors was as follows: ZYC-3 < ZYC-10 < ZYC-1. An in vitro model of glutamate-induced RGC-5 cell death was used. Glutamate treatment resulted in 50–60% RGC-5 cell death with respect to control untreated cells. 17β-Estradiol and the three estrogen analogues (0.5 to 1.0 μM) protected the RGC-5 cells against glutamate cytotoxicity. The efficacy of neuroprotection by the estrogen analogues was as follows: ZYC-3 > ZYC-1 > ZYC-10. EC 50 values for inhibition of TBARS levels were as follows: ZYC-3 > ZYC-10 > ZYC-1. Furthermore, these compounds worked independent of estrogen receptors, as inclusion of 100 nM ICI 182,780 did not reverse their neuroprotective properties against glutamate insult. These compounds seem to affect neuroprotection via pathways independent of the classical estrogen receptors. The data support the hypothesis that estrogen analogues may be useful in the treatment of neurodegenerative diseases, particularly in neuroprotection of retinal ganglion cells in ocular pathologies such as glaucoma.

Estrogen-like compounds for ischemic neuroprotection.

We have synthesized a library of estrogen analogues, including enantiomers of estradiol and A-ring substituted estrogens. These compounds have reduced or no binding to either estrogen receptor-alpha or estrogen receptor-beta, exhibit enhanced neuroprotective activity in in vitro models, and are potent in protecting brain tissue from cerebral ischemia/reperfusion injury. These potent, nonfeminizing estrogen analogues are prime candidates for use in stroke neuroprotection.

The use of estrogens and related compounds in the treatment of damage from cerebral ischemia.

There are 750,000 new cases of stroke each year in the United States, and brain damage from stroke leads to high health care costs and disabilities. Needed, but currently not available, are therapies that can be administered prior to, during, or after cerebral ischemia that reduce or eliminate neuronal damage from stroke. To address this issue, we began to assess the neuroprotective effects of estrogens and related compounds in stroke neuroprotection to determine whether these compounds had potential for clinical application. First, we demonstrated that 17 beta-estradiol (E2) pretreatment exerted potent neuroprotection of the cerebral cortex over a wide dose range and pretreatment interval. Thereafter, we assessed the ability of a variety of non-feminizing estrogens to protect brain tissue from stroke. We observed that pretreatment with 17 alpha-estradiol, the complete enantiomer of E2 (ENT-E2), 2-adamantylestrone, and the enantiomer of 17-desoxyestradiol, were as effective as E2 in pretreatment protection from stroke damage. These data suggest that non-estrogen receptor mechanisms are involved in brain neuroprotection under our treatment conditions. We then determined whether the observed E2 protection could be extended to times after the onset of the cerebral ischemic event. Using a formulation of E2 that rapidly delivers the steroid, a necessary condition for acute therapy of an ongoing stroke, we demonstrated that 100 mg E2/kg could protect brain tissue for up to 3 h after the onset of the stroke. To determine whether this therapeutic window could be extended with higher doses of the steroid, we conducted a dose-response assessment of E2 when administered at 6 h after the onset of the ischemic event. While the effectiveness of the 100 micro g E2/kg was reduced at this time interval, higher doses of E2 were effective. E2, at doses of 500 and 1000 micro g/kg, reduced infarct volume by more than 50%, even with this 6-h delay in treatment. Collectively, these data indicate that estrogens could prove to be useful therapies in preventing brain damage from strokes.

Estrogen and non-feminizing estrogen for Alzheimer's disease.

The preventive effect of estrogen on Alzheimer's disease (AD) has become clearer with many epidemiological reports. However, the therapeutic effects of estrogen have been controversial until now. In our trials, estrogen treatment showed a beneficial therapeutic effect for women with mild to moderate AD. Improvement of cognitive function was recognized during the third week from the beginning of administration and maintained as long as estrogen treatment continued. The longer the duration of HRT, the more HRT is useful for the prevention and therapy of AD. However, in most cases, administration of estrogen is discontinued because of the adverse effects on the uterus and breast. J 861 is a derivative of estradiol-17alpha, which has little effect on the sexual organs. The effects of estradiol-17beta (E2) and J 861 on neuronal function and vascular factors were investigated. J 861 was suggested to prevent both the intracellular calcium increase and peroxidation induced by amyloid beta (Abeta), more effectively than E2. The effect of J 861 may be related with both the direct non-genomic and the ER-mediated systems. J 861 showed neurotrophic effects like E2. J 861 inhibited the adhesion of monocytes to vascular endothelium, more effectively than E2. Also, J 861 suppressed the expression of adhesive factors, such as E-selectin and intercellular cell adhesion molecule-1 (ICAM-1), more effectively than E2.

Selected aspects of endocrine pharmacology of the aging male

This minireview explores the endocrinology and the clinical consequences of age-related hypogonadism (hypotestosteronemia). In addition, pharmacological and clinical applicability of new androgen formulations is described briefly. Other topics include selective androgen receptor modulators, non-feminizing estrogens, and the possible use of selective aromatase modulators. Finally, a theoretical concept of hormone displacement (i.e. excessive hormone production) is introduced using cortisol as an example.

Is there a role for estrogens in the maintenance of men's health?

This paper gives an overview of our own studies and theliterature on the biosynthesis and metabolism of estrogensin elderly men, the estrogen action in the male, and theclinical usefulness of estrogen therapy, including thephytoestrogens. Finally, the paper includes a short reviewof our knowledge of xenoestrogens and men's sexualhealth.A strong estrogen-deficient status is seen in malepatients with mutations of the estrogen receptors or in casesof deviations of the aromatase gene. On the other hand,there are no clear age-dependent changes in estrogen secretion.But, in men with disorders of glucose metabolismand also of increased body mass index, the serum estrogenconcentrations are significantly elevated. There are alsostrong positive correlations between serum estrogenlevels and bone density, including prevalence of fracturesand mood in men. New fields of interest are natural fattyesters of endogenous estrogens, e.g. lipoprotein-associatedestrogens, and the role and clinical significance oftissue-specific, local estrogen biosynthesis (e.g. differentpromoters of the aromatase gene).Exogenous estrogen treatment is focused today onpatients with normal testosterone and low levels of circulatingestrogens documented on several occasions and withclinical symptoms of hormone deficiency; male-to-femaletranssexuals; and selected patients with prostate cancer.Some clinical studies show the benefits of estrogentreatment on some cardiovascular parameters and for treatingselected signs of mental stress. An indirect estrogenreplacement can occur if dehydroepiandrosterone is givenorally to men. The clinical usefulness of dissociatedestrogens, including non-feminizing estrogens and selectiveestrogen receptor modulators, is still an open question.The beneficial action of phytoestrogens in lowering theclinical symptoms of benign prostatic hyperplasia is welldocumented. Finally, the question about the definitiveinfluence of so-called endocrine disruptors (xenoestrogens)on sexual functions in men is also discussed.