Endogenous Estrogen Production Research Articles

The effect of estrogen signaling modulation on female‐specific microglial heterogeneity in the mouse hippocampus

AbstractBackgroundEstrogens, such as 17β‐estradiol, are the primary female sex hormones predominantly synthesized by mature ovarian follicular cells. The natural exhaustion of ovarian follicular cells during menopause causes a rapid decline in endogenous estrogen levels. This decline in estrogen levels is associated with an increase in chronic, age‐related pathologies, including inflammation in the brain. Studies suggest that estrogens can temper inflammatory processes in the brain by activating estrogen receptor α (ERα), a nuclear transcription factor expressed by microglia, the brain’s primary resident macrophage. However, the pathways responsible for estrogens’ anti‐inflammatory effects in microglia remain unresolved. Here, we hypothesize that estrogen signaling through microglial ERα suppresses pro‐inflammatory signaling pathways. We believe that ablation of endogenous estrogens during menopause induces neuroinflammation and promotes the transition of microglia to activated phenotypes, contributing to various brain diseases, including Alzheimer’s disease (AD).MethodTo test the effect of estrogenic depletion on microglial heterogeneity in mice, we: 1) knocked out ERα, 2) depleted endogenous estrogens with 4‐vinylcyclohexene diepoxide (VCD) treatment, and 3) compared to untreated female C57BL/6 controls. We then examined the changes in hippocampal microglial phenotypic states using 10X single‐cell transcriptomic sequencing (scRNA‐seq).ResultscRNA‐seq data were quality filtered, and unbiased clustering analyses (i.e., UMAP) identified five hippocampal microglial subtypes. Interestingly, the expression of specific microglial phenotypic state (stage 1 disease‐associated microglia) was increased upon ablation of endogenous estrogen production by VCD or knockout of ERα.ConclusionSuch skewing of microglia towards reactive phenotype suggests that loss of estrogen‐ ERα signaling may encourage “priming” of microglia to transition to the stage 1 DAM phenotype, which is then more susceptible to becoming “reactive” DAMs (stage 2 DAMs).

Histological features of the Purkinje neurons of the Albino rat (Rattus norvegicus) following letrozole administration.

Aromatase inhibitors are increasingly being used as adjuvant therapy for hormone-responsive cancers. These drugs may reduce the endogenous estrogen production in the cerebellum. Prolonged use has been associated with symptoms such as ataxia, poorer balance performance and diminished verbal memory, suggesting impaired cerebellar function. Thus, this study sought to outline the structural basis for the cerebellar deficits observed. Twenty-seven male rats (3 baseline, 15 experimental, 9 control) aged three months were recruited with the intervention group receiving 0.5 mg/kg of letrozole daily for 50 days by oral gavage while the control group received normal saline. Their cerebella were harvested for histological processing on days 20, 35, and 50. Photomicrographs were taken and analysed using Fiji ImageJ software. The dendritic spine densities and Purkinje linear densities were coded and analyzed using IBM SPSS Statistics version 25.0. A P-value of ≤0.05 was considered significant. A temporal decline in the Purkinje linear density as well as pyknosis and cytoplasmic eosinophilia was noted in the intervention group (P=0.1). Further, the dendritic spine density of the Purkinje neurons in the intervention group was markedly reduced (P=0.01). The reduction in the linear cell density and the dendritic spine density of the Purkinje cells following letrozole administration may provide an anatomical basis for the functional cerebellar deficits seen in chronic aromatase inhibitor use.

8548 Breast Development in Infant Girls: Does Endogenous Estrogen Production During Minipuberty Play a Role?

Abstract Disclosure: M. Goldberg: None. S. Zhao: None. A. Kelly: None. V.A. Stallings: None. D.M. Umbach: None. W.J. Rogan: None. N. Shaw: None. D.P. Sandler: None. Background: Breast tissue, present at birth in most term infants, regresses during infancy but persists longer in girls than boys. In girls, this persistence is thought to be due in part to stimulation by estradiol (E2) produced during minipuberty, the postnatal activation of the hypothalamic-pituitary-gonadal axis. Empirical data are sparse, however. Because E2 concentrations in infant girls fluctuate, repeated E2 measures may be necessary to adequately characterize production across minipuberty and to detect effects on estrogen-sensitive breast tissue. Hypothesis: Higher average exposure to E2 during minipuberty is associated with larger breast bud diameter in late infancy in term females. Methods: We leveraged data from 136 girls from the Infant Feeding and Early Development (IFED) Study, a prospective cohort of reproductive development in term infants enrolled during 2010-2013 from the Philadelphia area. We measured E2 in serum samples collected at study visits every 2-4 weeks from age 2-32 weeks. We assessed breast bud diameter via ultrasound at the 32-week visit. For data analysis, we log2-transformed both E2 and breast bud diameter. For E2 concentrations below the limit of detection (2.99 pg/mL, 35% of samples), we applied multiple imputation. We first calculated the intraclass correlation coefficient (ICC) of repeated E2 to understand the relative magnitude of total variation from within subjects. We then calculated subject-specific mean of E2 across time and estimated associations with breast bud diameter at the 32-week visit using both age- and multivariable-adjusted linear regression models. We present results as percent change in breast bud diameter per doubling in average E2 concentration ([2β-1] x 100%). Results: Most infants were Black (71%) and formula-fed (76%). The median number of E2 measures per girl was 9 (range: 5-10). Most of the variation in E2 concentrations was due to within-individual variation (ICC=0.27). The geometric mean E2 concentration from 2-32 weeks of age was 5.1 pg/mL (95% confidence interval [CI]: 4.7-5.4). The median breast bud diameter at the 32-week visit was 13.7mm (range: 4.4-30.5). A doubling in average E2 concentration across minipuberty was associated with a 26% larger breast bud diameter (95% CI 10-43%). This association was similar after adjustment for feeding method, race, gestational age, neonatal weight, and breast bud diameter at the neonatal visit (percent change: 28%, 95% CI: 12-46%). Conclusions: Our results suggest that endogenous estrogen production in females during minipuberty stimulates the infant breast bud. More research is needed to investigate the potential biologic relevance of this hormonal stimulation of infant breast tissue to later breast development and risk of malignant and benign breast disorders. Presentation: 6/1/2024

Red Wine as an Aromatase Inhibitor: A Narrative Review.

As estrogen-dependent breast cancer is more affected by the local production of estrogen via aromatase than serum estrogen, aromatase inhibitors for treating breast carcinomas in postmenopausal women have been developed. As the aromatase enzyme converts endogenous androgen to estrogenic compounds, its blockade lowers the in situ production of estrogen, demonstrated to encourage tumor proliferation. Red wine, but not white wine, may have aromatase-inhibiting properties that are being elucidated, although the exact mechanisms of action are not known. Polyphenols, tannins, and resveratrol have all been implicated as aromatase blockers, and there may also be synergistic interplay among selected constituents. The role of red wine would be in chemoprevention, the use of natural or synthetic substances to retard, block, or reverse cancer. One gene encodes aromatase, so aromatase inhibition would stop endogenous estrogen production. The role of aromatase inhibition in breast cancer in premenopausal women is not clear. While animal studies have demonstrated that red wine contains constituents that could block aromatase in vivo, the benefits also exist with nonalcoholic grape seed extract. Further investigation is needed but there are challenges in designing appropriate clinical trials for a substance as variable as red wine. While there is insufficient evidence to advocate for red wine as an aromatase inhibitor, there is sufficient evidence to warrant further investigation.

Tipping the balance — the move of aging females towards higher ERβ:ERα ratio and away from estrogen mediated vascular protection

Objective: The menopausal transition, marked by the cessation of endogenous estrogen production, is a hallmark of vascular aging in women, as the vascular function radically declines in the years hereafter (Parker et al. 2010). Primarily based on animal and in-vitro studies (Novella et al. 2012; Novensà et al. 2011; Park et al. 2017) it has been hypothesized that this is linked to menopause-dependent changes in the balance between the two dominant estrogen receptors, ERα and ERβ; as previous studies suggest that ERα favors NO-bioavailability whereas ERβ mediates increases in oxidative stress. However, it remains unresolved how aging actually influences changes in the balance between ERα and ERβ in skeletal muscle of females and how changes are related to downstream protein targets such as eNOS and NADPH oxidases. Study design: We measured skeletal muscle protein expression of estrogen receptors, androgen receptors, eNOS, SOD2, GPX1, gp91phox/-NOX2 and NOX4 in 82 females ranging from 20-70 yrs. of age. For age comparisons, data from the muscle biopsies were grouped by 5-year intervals. Statistical analyses were conducted by on one-way ANOVA and Pearson’s product moment correlations Results: The ERβ:ERα ratio was significantly higher in the 65+ yrs. compared to all other groups (p<0.01) and correlation analysis revealed that the ERβ/ERα ratio increased with aging (p=0.02, R2=0.07). The 65+ yrs. group presented a lower eNOS expression (p<0.05) than the 20-54 yrs. groups and correlation analysis showed a decrease in eNOS expression with aging (p=0.0002 R2=0.16). Gp91phox/-NOX2 expression correlated with ERβ and the expression of gp91phox/NOX2 (p=<0.0001 R2=0.4) was lower in the three middle groups, 45-59 yrs., compared with both the younger and older groups (p<0.05). ERα correlated with the antioxidants SOD2 and GPX1 (p=0.0001 R2=0.18 and p=<0.0001 R2=0.21, respectively). Conclusions: This study is the first to show that skeletal muscle expression of ERβ:ERα increases with age and that the expression of eNOS in skeletal muscle declines as a function of age in females. Our data also provides indirect support for that aging is associated with a shift from a more prominent ERα coupled antioxidant effect, through - SOD2/GPX1 related mechanisms, towards a more pro-oxidant environment through an ERβ mediated upregulation of Gp91phox/-NOX2. This shift, combined with the observation of an age induced decline in eNOS expression, could be mechanisms underlying reduced NO bioavailability in aging females. Further analyses are ongoing to throw light in these mechanisms and additional studies are warranted to fully elucidate the mechanistic pathways involved. Funding The study was funded by The Danish Ministry of Culture Fund for Research in Sports, The Independent Research Fund Denmark, Eva and Henry Frænkel Memorial Fund, and the Toyota Foundation. The study is part of The Copenhagen Women Study for which fi- nancial support was provided by the University of Copenhagen Excellence Programme for Interdisciplinary Research. The study was also supported by The Danish Ministry of Culture: Sports Research. Financial support is greatly appreciated from the Aarhus University Research Foundation (AUFF); the Hartmann Foundation; the A.P. Møller Foundation; the Toyota-Fonden, Denmark; and the Augustinus Foundation and Team Denmark. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

THU576 Anabolic Androgenic Steroid Abuse In Cis-gender Female Bodybuilder

Abstract Disclosure: E.M. Niedzialkowska: None. D. Shelden: None. Introduction: Anabolic androgenic steroids (AAS) are used in bodybuilders to increase muscle mass. Abuse has surged as they are regarded as potent image enhancement drugs. There are a variety of illegal AAS available. Their true content is often unknown and dosing regimens frequently include concurrent use of multiple hormonally active agents. Use among female body builders is rarely reported. Having significantly lower levels of natural testosterone, females may be more susceptible to side effects and toxicity associated with AAS abuse. Clinical case: 36 year old cis-gender female presented to the Endocrinology clinic for evaluation of fatigue. The patient worked as a personal trainer at a gym and began participating in bodybuilding competitions. A year prior to the visit the patient was started on a steroid regimen by a friend at the gym. The patient’s regimen included testosterone cypionate (250mg-350mg a week) and trenbolone acetate. Anastozole was added to limit conversion to estrogen but was not administered on a regular basis. The patient reported no gender dysphoria. She has not had a menstrual period since she started the AAS. The patient was also diagnosed with acute kidney injury at the time of AAS initiation and further work up showed negative ANA, C3, C4, normal UA and protein/creatinine ratio. Her kidney injury was deemed to be related to NSAID and testosterone use. At the time of the visit laboratory results were significant for testosterone of >1500 ng/dl (N 240-1080), IGF-1 359 ng/ml (N 63-223), LH <0.1 mUI/ml (N>0.6), FSH <0.5 mUI/ml (N>1.4), estradiol 47 pg/ml (N 21-251), prolactin 10.8 ng/ml (N 3-30), hemoglobin 17.4 g/dl (N 12-15.1), platelets 416 bil/L (150-400), TSH 0.75 uIU/ml (N 0.4-4.5), creatinine 1.33 mg/dl (N 0.5-1.1), eGFR 53 ml/min/1.73m2. The patient's testosterone regimen was gradually decreased to 100 mg weekly with plans to further decrease the dose and with close follow up and monitoring of gonadotropins. Treatment to stimulate endogenous estrogen production may be necessary despite her current value being within normal limits as this may be a function of peripheral conversion of exogenous testosterone. Conclusion: AAS abuse is infrequent among cis-gender females. Its use in female bodybuilders increases muscle strength and athletic performance. Exogenous administration of synthetic testosterone results in negative feedback on the hypothalamic-pituitary axis, inhibiting GnRH, leading to inhibition of FSH and LH production leading to amenorrhea in females. AAS has also been associated with kidney injury with reports from animal studies suggesting testosterone induced podocyte damage and apoptosis. The steroid regimens used by bodybuilders differ and include multiple hormonally active agents. Its abuse among cis-gender women is uncommon and further research is needed to evaluate its toxicity among this group. Presentation Date: Thursday, June 15, 2023

Skeletal Muscle Endogenous Estrogen Production Ameliorates the Metabolic Consequences of a High-Fat Diet in Male Mice.

The role of skeletal muscle estrogen and its ability to mitigate the negative impact of a high-fat diet (HFD) on obesity-associated metabolic impairments is unknown. To address this, we developed a novel mouse model to determine the role of endogenous 17β-estradiol (E2) production in males in skeletal muscle via inducible, skeletal muscle-specific aromatase overexpression (SkM-Arom↑). Male SkM-Arom↑ mice and littermate controls were fed a HFD for 14 weeks prior to induction of SkM-Arom↑ for a period of 6.5 weeks. Glucose tolerance, insulin action, adipose tissue inflammation, and body composition were assessed. Indirect calorimetry and behavioral phenotyping experiments were performed using metabolic cages. Liquid chromatography mass spectrometry was used to determine circulating and tissue (skeletal muscle, hepatic, and adipose) E2 and testosterone concentrations. SkM-Arom↑ significantly increased E2 in skeletal muscle, circulation, the liver, and adipose tissue. SkM-Arom↑ ameliorated HFD-induced hyperglycemia, hyperinsulinemia, impaired glucose tolerance, adipose tissue inflammation, and reduced hepatic lipid accumulation while eliciting skeletal muscle hypertrophy. Enhanced skeletal muscle aromatase activity in male mice induces weight loss, improves metabolic and inflammatory outcomes and mitigates the negative effects of a HFD. Additionally, our data demonstrate for the first time skeletal muscle E2 has anabolic effects on the musculoskeletal system.

Pubertal induction in Turner syndrome without gonadal function: A possibility of earlier, lower-dose estrogen therapy.

Delayed and absent puberty and infertility in Turner syndrome (TS) are caused by primary hypogonadism. A majority of patients with TS who are followed at hospitals during childhood will not experience regular menstruation. In fact, almost all patients with TS need estrogen replacement therapy (ERT) before they are young adults. ERT in TS is administered empirically. However, some practical issues concerning puberty induction in TS require clarification, such as how early to start ERT. The present monograph aims to review current pubertal induction therapies for TS without endogenous estrogen production and suggests a new therapeutic approach using a transdermal estradiol patch that mimics incremental increases in circulating, physiological estradiol. Although evidence supporting this approach is still scarce, pubertal induction with earlier, lower-dose estrogen therapy more closely approximates endogenous estradiol secretion.

Bacterial Vaginosis in Postmenopausal Women.

Bacterial vaginosis (BV) is the most common vaginal infection worldwide, but most research has been conducted in premenopausal women. After menopause, endogenous estrogen production decreases, often leading to the genitourinary syndrome of menopause (GSM), characterized by vulvovaginal dryness and irritation. The estrogen-deficient postmenopausal state results in an elevated vaginal pH and depletion of vaginal lactobacilli. Use of traditional BV diagnostics (Amsel criteria, Nugent score) is difficult in post-menopausal women, especially those not on estrogen replacement therapy, as these methods were originally developed in premenopausal women. In this review, we discuss recent clinical data on BV in postmenopausal women, difficulties in diagnosis using traditional methods, the role of BV molecular diagnostics, and our current expert opinion for managing BV in this population. BV prevalence has been found to range between 2%-57% among postmenopausal women per Amsel and Nugent criteria. This is likely an over-estimate of the true prevalence due to limitations in these criteria which were only validated in pre-menopausal women. Despite increasing diagnostic options for BV in recent years, including highly sensitive and specific BV nucleic acid amplification tests (NAATs), the physiologic changes of menopause and limited inclusion of postmenopausal women in clinical studies, diagnosis is difficult in this population. Recent studies utilizing 16s rRNA gene sequencing suggest that the vaginal microbiota of premenopausal and postmenopausal women is quite different, even if BV is not present. Data also suggest that obese postmenopausal women have significantly lower rates of BV compared to non-obese postmenopausal women, although further research is needed in this area. Multiple treatment options exist for vaginal atrophy and BV in this population. Data are limited regarding optimal diagnostic approaches for BV in postmenopausal women; BV NAATs and 16s rRNA gene sequencing may have a role for diagnosing BV in symptomatic women although further studies are needed. Menopausal women with characteristic vaginal symptoms and an elevated vaginal pH should be initially treated for estrogen deficiency prior to considering a diagnosis of BV; subsequent treatment for BV should be driven by symptoms.

High-Intensity Exercise Training Improves Basal Platelet Prostacyclin Sensitivity and Potentiates the Response to Dual Anti-Platelet Therapy in Postmenopausal Women.

The risk of thrombotic events dramatically increases with age and may be accelerated in women by the cessation of endogenous estrogen production at menopause. Patients at risk of thrombosis are prescribed dual anti-platelet therapy (DAPT; aspirin and a P2Y12 antagonist) and are encouraged to participate in regular physical activity, as these modalities improve nitric oxide and prostacyclin-mediated inhibition of platelet aggregation. Methods: We assessed prostacyclin sensitivity as well as basal platelet reactivity with and without in vitro DAPT before and after an 8-week high-intensity exercise training program in 13 healthy, sedentary postmenopausal women. The training intervention consisted of three 1 h sessions per week. Isolated platelets were analyzed for thromboxane A2 receptor, thromboxane A2 synthase, cyclooxygenase-1, and prostacyclin receptor protein expression. Additionally, plasma 6-keto prostaglandin F1α and thromboxane B2 levels were determined. Results: Exercise training made platelets more sensitive to the inhibitory effects of prostacyclin on thromboxane-, collagen-, and adenosine 5′-diphosphate (ADP)-induced aggregation, as well as thrombin-receptor activator peptide 6- and ADP-induced aggregation with DAPT. However, there was no change in protein expression from isolated platelets or plasma thromboxane B2 and prostacyclin levels following training. Conclusion: Together, these findings emphasize the importance of promoting physical activity as a tool for reducing thrombotic risk in postmenopausal women and suggest that training status should be considered when prescribing DAPT in this cohort.

Correlation Between BMI And LH Level and LH/FSH Ratio-A Cross-Sectional Study

Background: Polycystic ovarian syndrome is the most common reproductive endocrinopathy of women during their childbearing age. Elevated LH/FSH ratio, abnormally high androgen level and relatively high endogenous estrogen production are indicative of PCOS. The diagnosis of polycystic ovarian syndrome remains controversial with some considering transvaginal sonography with the combination of clinical criteria for diagnosis. In this study, we tried to determine whether there is any impact of BMI on LH or LH/FSH ratio in PCOS for better management in the future.
 Materials and Methods: This is a cross-sectional study. Those clinically presented as obese, hirsute, and with menstrual disturbances were non-smokers and had not been on any medications for the last three months before the study. Age groups ˂20 and ˃40 years, non-PCOS with infertility, and nonobese patients were excluded from the study.
 Results: Among the total 58 patients, BMI in the range of 25-28 kg/m 2 was found in the highest frequency in 44 cases (75.9%), high LH level group in 33 cases (56.9%). LH/FSH ratio ˃2 found in 27 cases (46.66%). The correlation between BMI and LH/FSH ratio showed the highest frequency in 21 cases in the BMI group (25-28kg/m 2 ) (p ˂0.009). Random LH level amplitude was found higher in low BMI (25-28kg/m 2 ) than lower in higher BMI (28-34kg/m 2 ) (p ˂0.003).
 Conclusion:Assessments of basal LH levels and the LH/FSH ratio in hyperandrogenic anovulatory women would be clinically meaningful when BMI is taken into account.
 TAJ 2022; 35: No-1: 71-76

Effects of Hormone Therapy and Exercise on Bone Mineral Density in Healthy Women-A Systematic Review and Meta-analysis.

There is some evidence that an adequate "anabolic hormonal milieu" is essential for the mechanosensitivity/transduction/response of bone tissue. This work aimed to determine whether enhancing hormone therapy (HT) with exercise increases the isolated effect of HT on bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN). A comprehensive search of 6 electronic databases according to the PRISMA statement up to April 28, 2021, included controlled trials longer than 6 months with 3 study arms: (a) HT, (b) exercise, and (c) HT plus exercise (HT + E). Apart from HT, no pharmaceutic therapy or diseases with relevant osteoanabolic or osteocatabolic effect on bone metabolism were included. The present analysis was conducted as a random-effects meta-analysis. Outcome measures were standardized mean differences (SMD) for BMD changes at the LS and FN. Our search identified 6 eligible studies (n = 585). Although the effect of HT + E was more pronounced in the LS (SMD: 0.19; 95% C,: -0.15 to 0.53) and FN-BMD (0.18; -0.09 to 0.44) compared to the HT group, we did not observe significant differences between the 2 groups. We observed a low (I2: 29%) or moderate (I2: 49%) level of heterogeneity between the trials for FN or LS. We do not observe a significant effect of HT + E vs HT alone. We largely attribute this result to varying HT supplementation and hormonal status. Bearing in mind that synergistic/additive effects between HT and mechanical stimulation can only be expected in situations of hormonal insufficiency, further clinical studies should consider baseline endogenous estrogen production but also HT dosing more carefully.

Isoliquiritigenin Decreases Bone Resorption and Osteoclast Differentiation.

A dose-ranging study is performed using young estrogen-depleted rats to determine whether dietary isoliquiritigenin (ILQ) alters bone metabolism and if the effects are associated with estrogen receptor signaling. Six-week-old rats (ovariectomized at 4 weeks of age) are fed diets containing 0, 100, 250, or 750ppm ILQ (n = 5/treatment) for 7 days. Gene expression in femur and uterus, blood markers of bone turnover, body composition, and uterine weight and epithelial cell height are determined. Because ILQ lowers bone resorption, the effect of ILQ on in vitro differentiation of osteoclasts from bone marrow of mice is assessed. Treatment resulted in a dose-dependent increases in serum ILQ but no changes in serum osteocalcin, a marker of global bone formation. Contrastingly, ILQ administration results in reduced serum CTX-1, a marker of global bone resorption, and reduces tartrate resistant acid phosphatase expression in osteoclast culture. ILQ treatment and endogenous estrogen production had limited overlap on gene expression in femur and uterus. However, uterine epithelial cell hyperplasia is observed in two of five animals treated with 750ppm. In conclusion, dietary ILQ reduces bone resorption in vivo and osteoclast differentiation in vitro, by mechanisms likely differing from actions of ovarian hormones.

Cyp17a1 is Required for Female Sex Determination and Male Fertility by Regulating Sex Steroid Biosynthesis in Fish.

In teleost fish, sex steroids are involved in sex determination, sex differentiation, and fertility. Cyp17a1 (Cytochrome P450 family 17 subfamily A member 1) is thought to play essential roles in fish steroidogenesis. Therefore, to further understand its roles in steroidogenesis, sex determination, and fertility in fish, we constructed a cyp17a1 gene mutant in Nile tilapia (Oreochromis niloticus). In XX fish, mutation of the cyp17a1 gene led to a female-to-male sex reversal with a significant decline in 17β-estradiol (E2) and testosterone (T) production, and ectopic expression of male-biased markers (Dmrt1 and Gsdf) in gonads from the critical window of sex determination. Sex reversal was successfully rescued via T or E2 administration, and ovarian characteristics were maintained after termination of E2 supplementation in the absence of endogenous estrogen production in cyp17a1-/- XX fish. Likewise, deficiencies in T and 11-ketotestosterone (11-KT) production in both cyp17a1-/- XX sex-reversed males and cyp17a1-/- XY mutants resulted in meiotic initiation delays, vas deferens obstruction and sterility due to excessive apoptosis and abnormal mitochondrial morphology. However, 11-KT treatment successfully rescued the dysspermia to produce normal sperm in cyp17a1-/- male fish. Significant increases in gonadotropic hormone (gth) and gth receptors in cyp17a1-/- mutants may excessively upregulate steroidogenic gene expression in Leydig cells through a feedback loop. Taken together, our findings demonstrate that Cyp17a1 is indispensable for E2 production, which is fundamental for female sex determination and differentiation in XX tilapia. Additionally, Cyp17a1 is essential for T and 11-KT production, which further promotes spermatogenesis and fertility in XY males.

The Impact of Whey Protein and/or Omega-3 Fatty Acid Supplementation on Body Composition, Energy Expenditure and Metabolic Health in Postmenopausal Women (SHAPE Study)

Abstract Objectives Age-related deleterious shifts in body composition can lead to sarcopenia, which is the age-related loss of muscle mass, strength, and function. Furthermore, declines in endogenous estrogen production during the menopausal transition are associated with muscle mass loss and increased central adiposity, putting postmenopausal women at increased risk for negative health outcomes such as cardiovascular disease and type-2 diabetes mellitus. The objective of this study was to determine the effect of protein and/or omega-3 fatty acid (O3FA) supplementation on metabolic health in postmenopausal women. Methods Thirty-nine postmenopausal women (age: 61.3 ± 8.7 years; BMI: 27.6 ± 6.6 kg/m2) were randomly allocated to one of 5 groups: 1) control (CON; no intervention free-living; n = 6), 2) whey protein isolate (PRO; 25 g/d; n = 7), 3) O3FA (DHA/EPA; 4.3 g/d; n = 10), 4) PRO + placebo soybean oil (PRO + PLA; 4.1 g/d; n = 7), or 5) PRO + O3FA (n = 9). Energy expenditure via indirect calorimetry, dietary intake via 3-day weighed dietary records, hand grip strength (HGS), and metabolic health were assessed at 0, 4, 8, 12, and 16 weeks. Body composition was measured via dual x-ray absorptiometry at 0 and 16 weeks. Metabolic health was assessed using waist-to-hip ratio and biomarkers such as plasma glucose, insulin, free fatty acids, and cholesterol. Results There was not an effect of treatment effect on anthropometrics, body composition, HGS, or resting energy expenditure. However, a decrease in android fat % was observed in PRO compared to baseline (P < 0.05) in the absence of anthropometric change (BMI, weight, waist, hip). A significant group by time effect was observed on resting fat oxidation (P < 0.05); O3FAs (+34.6%; P < 0.05) and PRO + O3FAs (+55.6%; P < 0.05) significantly increased and PRO decreased (−37.8%; P < 0.05) from baseline to 16 weeks. There was a significant (P < 0.05) decrease in cholesterol in all groups compared to CON. Conclusions Although not significant, the data suggests individual and combined supplementation of protein and O3FA have the potential to improve body composition and substrate oxidation in postmenopausal women. NCT0303041 Funding Sources Arkansas Biosciences Institute

Hormonal contraceptive use, bone density and biochemical markers of bone metabolism in British Army recruits

IntroductionHormonal contraceptive use might impair bone health and increase the risk of stress fracture by decreasing endogenous oestrogen production, a central regulator of bone metabolism. This cross-sectional study investigated bone...

Oral Estradiol Impact on Mitigating Unloading-Induced Bone Loss in Ovary-Intact Rats.

BACKGROUND: The impact of the spaceflight environment on endogenous estrogen production in female crewmembers and the resulting impact on other adaptations, like bone loss, is an under-investigated topic. Hence, we investigated the interaction of exogenous 17- estradiol (E2) treatment and disuse to test the hypothesis that E2 treatment would mitigate disuse-induced bone loss.METHODS: There were 40 virgin female Sprague-Dawley rats (5 mo old) randomized to placebo (PL; 0 ppm E2) or estrogen (E2; 10 ppm E2) treatments, delivered via custom-made rodent diets; half of each group was randomized to either weightbearing (WB) or hindlimb unloading (HU) for 39 d.RESULTS: We observed expected lower values after HU (615%) in volumetric BMD and cross-sectional areas at the proximal tibia metaphysis (PTM, by pQCT), 20% lower %BV/TV (nonsignificant) at the PTM, and 11% lower femoral neck maximal load; none of these HU-induced impacts were modified by E2. Impaired PTM periosteal expansion was observed in all E2-treated rats, with smaller (13 to 18%) cross-sectional areas. Midshaft tibial geometry was unaffected by E2 treatment, but large reductions (73 to 81%) in periosteal bone formation indices were observed in E2-treated rats.DISCUSSION: In summary, modest supplementation of exogenous E2 did not mitigate decrements in volumetric BMD, PTM cross-sectional geometry, or femoral neck strength observed with HU. However, numerous independent impacts of E2 treatment were observed, with significant suppression of periosteal bone formation indices. If maintained over time, this might impact negatively on cortical bone integrity during prolonged nonweightbearing.Mantri AV, Allaway HCM, Brezicha JE, Hogan HA, Bloomfield SA. Oral estradiol impact on mitigating unloading-induced bone loss in ovary-intact rats. Aerosp Med Hum Perform. 2021; 92(2):6574.

Nocturia through the menopausal transition and beyond: a narrative review.

Nocturia, defined as the act of waking to pass urine during sleeping, is a common problem in older women and is associated with significant morbidity and impairments in health-related quality of life. The aim of this review was to synthesize the current evidence regarding the incidence, impact, pathophysiology, and specific diagnostic approach of nocturia in the postmenopausal population. We searched PubMed and Web of Science databases to identify relevant studies published through June 2020. Reference lists of the reviews obtained were screened for other articles deemed pertinent by the authors. Genitourinary symptoms attributed to the menopause have been reported to occur in nearly 90% of postmenopausal women, and nocturia is one of the most common. The relative deficiency in endogenous estrogen production after the menopause is thought to exacerbate all major pathophysiological mechanisms that may underlie nocturia, including reduced bladder capacity, nocturnal polyuria, global polyuria, and sleep disorders. Diminished estrogen may induce anatomical and physiological bladder changes, contributing to a reduction in functional bladder capacity. Excess nocturnal urine production can also be provoked by estrogen depletion, either via free water-predominant diuresis by an impaired secretion of antidiuretic hormone, or a salt-predominant diuresis owing to diminished activation of the renin-angiotensin-aldosterone axis. Additionally, a relationship between the transition to menopause and impaired sleep has been described, mediated by increased incidence in vasomotor symptoms and obstructive sleep apnea signs during the menopause. Further research is necessary to better characterize and manage nocturia in postmenopausal women.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Estrogen Receptors and Endometriosis.

Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.