Fractional CO₂ laser monotherapy versus combination therapy with vaginal oestrogen for genitourinary syndrome of menopause: A prospective observational cohort study conducted over two years.

In the United States, postmenopausal women represent the largest group affected by recurrent urinary tract infections (rUTIs). Limited evidence supports long-term use of antibiotics for rUTI prophylaxis in this population. In addition to being expensive, repeated antibiotic use contributes to antimicrobial resistance, posing additional concerns for postmenopausal women who may be at higher risk for serious infection or complications from resistant infections. Topical estrogen, which directly addresses the pathophysiologic changes associated with rUTIs in this population, offers an effective and cost-efficient option for postmenopausal patients while avoiding the dangers of antimicrobial resistance.

BackgroundTestosterone-associated vulvovaginitis is an under-recognised cause of genital symptoms in transmasculine patients receiving testosterone as gender-affirming hormone therapy, with 5-years prevalence 64-78%. BASHH's Gender and Sexual Minorities Special Interest Group convened sexual health, gender, gynaecological and primary care experts and patient representatives to formulate a first-in-world best practice statement.MethodWe searched Medline, Embase, CINAHL, UpToDate, Trip Medical Database and Cochrane, to April 2025, regarding testosterone's impact on transmasculine people's vaginal histology and microbiomes, symptoms, and management. Papers on cis- or transgender women, editorials, and study protocols were excluded. Included studies were assessed using the Critical Appraisal Skills Programme tool. Recommendations for best practice were graded using GRADE methodology where possible, and supplemented by expert group consensus where evidence was limited.Results14 papers were included, of which 11 were descriptive/non-management focused. Testosterone is associated with vaginal Lactobacilli depletion, increased speciation, pH changes, atrophy, inflammation, and epithelial cell differentiation shift. The diagnosis of testosterone-associated vulvovaginitis is clinical; symptom severity does not reliably correlate with any of the above, nor other markers such as hormone levels. Two small case series and one cohort study (total n = 12) discussed treatment; topical estrogen reduced vaginal symptoms and increased Lactobacilli, with some refractory inflammatory cases requiring topical clindamycin +/- topical steroids. Presumed efficacy and safety are extrapolated from topical estrogen use in cisgender menopausal women.ConclusionSpecific evidence for testosterone-associated vulvovaginitis management is lacking; we suggest a culturally competent approach, considering it as a differential in any transmasculine people on testosterone with genitourinary symptoms. Offer examination (if possible) to exclude infection or dermatoses; offer first-line treatment with topical vaginal estrogens. Adjunctive/alternative measures include emollients and lubricants; topical clindamycin +/- topical steroids for refractory cases or aerobic/desquamative vaginitis. Long-term maintenance therapy and review is advised. Robust trans-specific clinical trials are needed to strengthen the evidence and optimise long-term outcomes.

Screening for cervical cancer using the Papanicolaou (Pap) smear has reduced morbidity and mortality associated with cervical cancer. However, anatomical and hormonal changes with age make diagnosis more complex in elderly women. This narrative review used a structured literature search of databases including PubMed, Scopus, Google Scholar, and ScienceDirect from 2010 to 2024. It included studies related to the impact of age on cervical cytology and HPV prevalence, the importance of cervical sampling adequacy, the diagnostic difficulties encountered in postmenopausal women, and the use of adjunctive cervical screening methods such as liquid-based cytology (LBC), high-risk HPV (HR-HPV) DNA testing, and topical estrogen therapy. Clinical practice guidelines from various organizations, including ACS, USPSTF, and WHO, were also reviewed. Studies have shown that menopause-related estrogen deficiency causes atrophy, reduced cellularity, and transformation zone (TZ) recession, resulting in a high number of unsatisfactory smears and false-positive interpretations that may mask HSIL. Although HPV prevalence decreases with age, persistent and re-emerging high-risk HPV types among older women are strongly associated with CIN2+. Both HR-HPV testing and LBC have demonstrated higher sensitivity for detecting cervical lesions in postmenopausal women compared with conventional cytology. Evidence also indicates that short-term topical estrogen therapy facilitates transformation zone visualization and improves sample adequacy. Gaps in screening persist among women aged 65 and older. To optimize cervical cancer prevention in this aging demographic, it is important to develop individualized cervical screening strategies that take into consideration hormone status, high-risk HPV persistence, and improved diagnostic techniques to strengthen the protection of elderly women who remain at risk.

Breast cancer incidence is lower in women living in Asia than women living in North America and Northern Europe. However, large differences exist within Asia, for example, Mongolia's breast cancer rate is even lower than China's. Endogenous estrogens in Asian populations have been hypothesized to explain the disparity because of their strong positive correlations with breast cancer, though few studies have compared estrogen metabolites (EM) within Asia or between Asia and higher breast cancer risk countries. We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 EM (non-parent estrogens) formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in premenopausal women living in Ulaanbaatar, Mongolia (n = 282), Shanghai, China (n = 121), and the United Kingdom (n = 125). We performed analysis of variance (ANOVA) using a generalized linear model procedure to assess differences in hormone concentrations between British and Asian (Chinese and Mongolian), and Chinese and Mongolian. Exponentiated least square means were used to calculate percent differences. We compared differences in overall means adjusted for age, body mass index, and parity by country during the follicular, peri-ovulatory, and luteal phases. Total, parent, and non-parent estrogen concentrations were generally higher in British than Asian women, while the non-parent to parent ratio was lower. While parent estrogens appeared higher in Chinese compared with Mongolian women, differences did not reach statistical significance except for peri-ovulatory estrone; total estrogen metabolites in the 2-, 4-, and 16-pathways were higher in Mongolian than Chinese women. The non-parent to parent ratio was highest in Mongolian women followed by Chinese women, with British women having the lowest ratio. Total urinary estrogens, both parent and their metabolites, were higher in British compared with Asian women. Our data showing the ratio of non-parent to parent estrogens, possibility reflecting greater estrogen metabolism, in women living in Mongolia, with one of the lowest breast cancer rates globally, than in women living in China, and in Chinese compared with British women, are consistent with their relative breast cancer risks and suggestive of a potentially protective metabolic profile.

In silico, in vitro, and in vivo profiling of endocrine activity and toxicity of selected oxygenated polycyclic aromatic compounds frequently encountered in PAH-contaminated soils.

Mestranol induces a reversible lysosomal storage-like state in zebrafish microglia.

Endometriosis (EM) is a chronic, estrogen-dependent inflammatory disorder affecting approximately 6-10% of women of reproductive age in the general population and remains a major cause of chronic pelvic pain and infertility. High recurrence rates and enduring symptoms despite current treatments underscore the need for a more thorough understanding of its intricate biology. There is growing evidence that the interaction among oxidative stress (OS), microbiome dysbiosis, and epigenetic dysregulation contributes to immunological activation, hormonal imbalance, and the persistence of ectopic lesions. Important disease mechanisms, such as progesterone resistance, inflammatory signaling, and aberrant cellular proliferation, are influenced by epigenetic changes, which include aberrant DNA methylation, histone modifications, and dysregulated non-coding RNAs. Simultaneously, high levels of reactive oxygen species (ROS) reinforce lesion survival and chronic inflammation by promoting angiogenesis, fibrosis, and tissue damage. Changes in the microbiome also affect immunological responses, oxidative balance, estrogen metabolism, and epigenetic control, indicating the existence of interrelated pathogenic loops. This narrative review presents an integrated mechanistic framework for endometriosis, summarizing the available data that connect these pathways. Furthermore, the growing implications of non-invasive biomarkers and precision medicine techniques highlight the potential for improved diagnosis, disease classification, and targeted treatment approaches.

Due to lipid-rich and severe matrix interference, the accurate determination of trace estrogens in cosmetics is highly challenging. Although solid-phase extraction (SPE) is widely used to mitigate the matrix interference, conventional adsorbents are often limited to cosmetic matrices. To this end, polymeric high internal phase emulsions modified with a hydrogen-bonded organic framework (polyHIPEs@HOF) were used as an adsorbent for the SPE of five estrogenic compounds. Benefiting from the hypercrosslinked architecture with interconnected macroporosity of polyHIPEs and hydrophilicity of HOF, the synthesized composites were suitable for SPE of estrogen in a cosmetic sample. Under optimized conditions, polyHIPEs@HOF enabled the rapid extraction of five estrogens from complex cosmetic samples, achieving adsorption equilibrium within 4min, and the extraction recoveries exceeded 78.28%. The adsorption capacities for estrogens ranged from 8.44 to 15.39mg g-1, and the adsorption involved multiple interactions (hydrogen bonding, π-π stacking, and hydrophobic effects). Furthermore, the polyHIPEs@HOF composite was able to eliminate the interference of the complex cosmetic matrix, and the extraction efficiency remained stable over 10 consecutive reuse cycles. These results confirm that the polyHIPEs@HOF composite is a highly efficient and reusable adsorbent for the extraction of estrogens in complex sample matrices.

Emerging evidence establishes hepatic dysfunction as a critical modulator of breast cancer (BC) progression through metabolic, endocrine, and inflammatory crosstalk, yet the molecular mediators remain incompletely characterized. This review systematically examines the liver-BC axis to identify mechanistic drivers and therapeutic opportunities for patients with comorbid conditions. We conducted an integrated analysis combining a comprehensive literature review with computational biology approaches, including protein-protein interaction network analysis, functional pathway enrichment (KEGG/GO), and multi-omics data mining from GEO, TCGA, and CPTAC databases, supplemented by experimental validations from preclinical models. Our analysis revealed hepatic dysfunction promotes BC progression through five interconnected pathways: insulin resistance-driven IGF1-PI3K/AKT activation, estrogen metabolism imbalance via CYP19A1/ESR1, IL6-STAT3/NLRP3-mediated inflammation, HMOX1/APOE-dependent metabolic rewiring, and FAK-Src/MMP9-regulated ECM remodeling. Key molecular mediators include nuclear receptors (ESR1), cytokines (IL-1β), growth factors (HGF), and receptor tyrosine kinases, with SPP1 and PTPN2 emerging as potential circulating biomarkers linking hepatic dysfunction to aggressive BC phenotypes. The crosstalk between hepatic dysfunction and BC is mediated by a network of proteins and pathways, offering potential targets for therapeutic intervention. Future research should focus on translational validation and personalized strategies for BC patients with comorbid liver conditions. This mechanistic insight may advance early diagnosis and precision treatment paradigms.

A novel three-dimensional amino-functionalized conjugated microporous polymer for efficient stir bar sorptive extraction of estrogens from chicken meat.

Endometriosis is a common estrogen-dependent disorder that typically affects women of reproductive age and generally resolves following menopause. This report describes a rare case of postmenopausal bladder endometriosis (BE) occurring in a woman with a normal body mass index and no history of exogenous estrogen use. A postmenopausal woman with a normal body mass index and no history of estrogen replacement therapy presented with dysuria. Clinical examination and imaging suggested bladder endometriosis. The patient underwent laparoscopic partial cystectomy with total hysterectomy and bilateral salpingo-oophorectomy. Postoperative histopathology confirmed the diagnosis of endometriosis. This case demonstrates that BE can occur in postmenopausal women in the absence of exogenous estrogen or obesity. The coexistence of liver cirrhosis, associated with impaired estrogen metabolism, and diabetes, characterized by chronic inflammation, may synergistically contribute to a pro-inflammatory microenvironment that sustains local estrogen activity, enabling lesion persistence. Clinicians should consider such systemic factors in non-obese postmenopausal women presenting with symptoms suggestive of endometriosis.

HighlightsPublic Health Relevance—How does this work relate to a public health issue?Millions of women worldwide use these hormones as contraceptive methods and for hormone therapy, which highlights the continuous and abundant introduction of these compounds into the environment, both through their excretion by the human body and through the direct disposal of unused or expired medications.Public health significance—Why is this work of significance to public health?Several studies demonstrate that these hormones exhibit variable removal efficiencies in water and wastewater treatment plants; however, even at any measurable concentration, they may still be sufficient to cause numerous adverse effects on aquatic organisms, such as changes in fertilization rates, behavioral modifications, histopathological alterations, immunosuppression, development of female sexual characteristics in males, and inhibition of sexual organ development. In humans, the earlier onset of puberty and the decline in semen quality over the last century have also emerged as central topics in this discussion, suggesting a possible relationship with exposure to these hormones.Public health implications—What are the key implications or messages for practitioners, policy makers and/or researchers in public health?There is an increasing need for the development of technologies capable of efficiently removing these hormones from aquatic matrices while maintaining low operational costs, so that they can be considered feasible and applicable for use in water and wastewater treatment plants.Emerging contaminants pose significant risks to ecosystems yet are not routinely included in standard monitoring or regulatory frameworks. Among these substances, endocrine disruptors such as β-estradiol and 17α-ethinylestradiol threaten both human and environmental health by interfering with metabolism, reproduction, and development across multiple species. These hormones are continuously released into the environment through excretion and improper disposal, and conventional water treatment processes are largely ineffective at removing them. As a result, they can accumulate in aquatic organisms and enter the human food chain. Recent studies have demonstrated that banana peel, Pleurotus ostreatus biomasses, and the nanomaterial δ-FeOOH are efficient, low-cost materials for the removal of toxic metals, suggesting their potential applicability for eliminating estrogenic compounds. Therefore, this study aimed to evaluate the removal of β-estradiol and 17α-ethinylestradiol using filters composed of banana peel and P. ostreatus biomass combined with δ-FeOOH. Hormone removal efficiency was assessed by LC-MS, and toxicity reduction was evaluated through bioassays. The results showed up to 100% removal of hormone concentrations and a significant decrease in sample toxicity, indicating that this filtration system represents a safe and effective alternative for removing organic contaminants from water.

Estrogens are global regulators of cellular signaling pathways, impacting fundamental processes and phenotypes that are essential for tissue remodeling and homeostasis. Traditional cell culture media contains estrogen-mimetic compounds, including phenol red and endogenous estrogen in fetal bovine serum (FBS). However, the potential of these compounds to bias in vitro studies, particularly when considering sex as a biological variable, remains unclear. This gap in understanding critically impacts the culture of human mesenchymal stromal cells (hMSCs), whose basic functions and differentiation potential, central to cell therapy and tissue engineering, are sensitive to perturbations in the culture conditions. Despite this, the effect of estrogens from cell culture media on male and female hMSCs is not currently considered in cell processing for clinical trials. As such, a baseline understanding of these estrogen-mimetic media influences on hMSCs is critical for clinical efficacy and adequate study design in research. To this end, we investigated the effects of phenol red and fetal bovine serum on the proliferation, metabolism, senescence, and differentiation capacity of male and female hMSCs. Phenol red, FBS, donor sex, and 17β-estradiol (E2) supplementation all had significant impacts on hMSC health and differentiation potential in culture. Notably, dosing with estrogen at the levels found in FBS did not recover most of the hMSC metrics tested. The notable outcomes that were significantly impacted by sex for the overall analysis include proliferation, metabolism, senescence, osteogenic differentiation, adipogenic differentiation, and gene expression for Col1a1, ESR1, Col10a1, RUNX2, FABP4, and PPARγ. Donor variability was a main driver in all the outcomes tested, highlighting the need for personalized medicine in research investigating cellular response to hormone signaling. Overall, these findings reveal the sex-biased effects of estrogen and estrogen-mimetic compounds in traditional culture media, underscoring a current gap in considering sex as a biological variable in cell therapy and tissue engineering research and manufacturing.

Recurrent urinary tract infections (rUTIs) are a prevalent condition in women, historically managed with continuous low-dose antibiotic prophylaxis. However, the global rise in antimicrobial resistance (AMR) necessitates the evaluation of non-antibiotic alternatives. This study was aimed at evaluating the efficacy and safety of non-antibiotic therapies, specifically D-mannose, cranberry products, probiotics, topical estrogen, methenamine hippurate, and immunoprophylaxis in preventing rUTIs in adult women. A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. We searched PubMed, Europe PMC, Science Direct, and the Cochrane Library for randomized controlled trials (RCTs) and high-quality observational studies published up to 31 January 2025. Studies were assessed for risk of bias using the Cochrane RoB 2 tool and the Newcastle-Ottawa Scale. The primary outcome was the reduction in UTI recurrence rates. Twelve studies met the inclusion criteria (10 RCTs, 2 observational studies). Methenamine hippurate was found to be non-inferior to daily antibiotic prophylaxis in preventing rUTIs. Immunoprophylaxis with the sublingual vaccine MV140 significantly reduced recurrence compared with placebo, with 56-58% of women remaining UTI free in a large RCT. Vaginal estrogen proved effective for postmenopausal women, significantly reducing recurrence, despite small sample sizes in recent trials. D-mannose demonstrated efficacy equivalent to antibiotics in specialist settings, but showed no benefit over placebo in a broad primary care population. Cranberry products were generally less effective than antibiotics but prevented the development of resistant fecal flora. Probiotics significantly prolonged the time to first recurrence. Non-antibiotic therapies offer viable, safe, and effective alternatives to long-term antibiotics. The evidence supports a stratified approach: methenamine hippurate and vaginal estrogen (in postmenopausal women) are supported by level 1 evidence as first-line non-antibiotic alternatives. MV140 immunoprophylaxis demonstrates high efficacy in recurrent phenotypes. D-mannose and cranberry show mixed efficacy and should be reserved for selected patient populations, particularly in specialist settings.

Introduction Testosterone is the mainstay of gender-affirming hormone therapy for transmasculine people. Administration of testosterone suppresses circulating estrogen and leads to the development of male secondary sex characteristics, but the impact of testosterone on the vagina and the symptomatic impact of these changes is largely unknown. Current treatment of vaginal symptoms in transmasculine people is informed by evidence for treating genitourinary syndrome of menopause. The objective of this systematic review is to evaluate evidence for the impact of testosterone on the vagina of transmasculine individuals and the assessment and management of these changes. Methods Medline, Embase, CINAHL, UpToDate, Trip Medical Database, and Cochrane Library of Systematic Reviews were searched up to April 2025. Manuscripts concerning the vagina of transmasculine people using testosterone were included. Studies focused on cis women or trans women were excluded. Reference lists of the identified studies were searched for the inclusion of additional studies. Expert opinion was sought to identify any unpublished literature relevant to this review. The Critical Appraisal Skills Programme (CASP) checklists were used to assess bias. Data were extracted and tabulated by a single researcher. Results Fourteen papers were included. Testosterone use is associated with a vaginal microbiome depleted in Lactobacilli sp. The vaginal epithelium of transmasculine individuals using testosterone shows atrophic changes and shifts in epithelial cell differentiation. A single cohort study showed topical estrogen reduced vaginal symptoms and increased colonization with Lactobacilli sp. in the vagina of transmasculine people. Discussion There is a lack of robust evidence for the impact of testosterone on the vagina of transmasculine individuals and for the assessment and treatment of vaginal symptoms. Future collaborative research with members of the transmasculine community is needed, with a focus on associated symptoms. Standardized assessment criteria must be validated in transmasculine people to evaluate the impact of testosterone on the vagina and the treatment of vaginal symptoms.

Ashwagandha (Withania somnifera), a traditional Ayurvedic adaptogen, is increasingly investigated in hormone-sensitive malignancies such as breast cancer. Its bioactive constituents, particularly withaferin A, exhibit diverse effects relevant to hormonal regulation, tumor suppression, and systemic balance. This review explores Ashwagandha's tri-axial roles in hormonal modulation, gut microbiota interaction, and direct anticancer activity across breast cancer subtypes. Preclinical findings show that withaferin A suppresses estrogen receptor alpha (ERα), inhibits STAT3 and NF-κB signaling, induces ROS-mediated apoptosis, and alters epigenetic regulators. In HER2-positive and triple-negative models, it reduces cancer stem cell activity, epithelial-to-mesenchymal transition (EMT), and pro-inflammatory mediators. Ashwagandha also influences the hypothalamic-pituitary-gonadal axis, raising LH, FSH, estrogen, and progesterone, while lowering cortisol and normalizing thyroid function. Immunologically, it enhances CD8⁺ T cell activity, reduces myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), and may synergize with checkpoint inhibitors. Effects on gut microbiota suggest additional roles in estrogen metabolism and inflammatory regulation. Toxicity data indicate high tolerability (LD₅₀ > 2000mg/kg), though rare hepatic and thyroid adverse events occur. Regulatory oversight remains inconsistent, with limited phytochemical standardization. Ashwagandha shows multidimensional promise but requires rigorous, standardized clinical validation.

ABSTRACTPurposeThis case–control study investigated whether ovarian endometriosis is associated with altered estrogen metabolism and gut or urogenital microbiota by analyzing enzyme activity, bacterial composition, and variations of estrogen metabolites in fecal, vaginal, and urinary samples.MethodsThirty‐eight reproductive‐aged women were enrolled, including 24 with pathologically confirmed ovarian endometriosis and 14 controls. Stool, urine, and vaginal samples were collected preoperatively. Gut β‐glucuronidase and β‐glucosidase activities were measured, estrogen and 14 metabolites were quantified using liquid chromatography–mass spectrometry, and gut and vaginal microbiota were analyzed by 16S rRNA gene sequencing. Microbial composition, diversity, and abundance were compared between groups.ResultsGut β‐glucuronidase activity and overall microbial diversity were comparable between groups; however, the control group showed a higher prevalence of the genus Rothia, whereas several genera, including Megamonas and [Eubacterium] coprostanoligenes_group, were enriched in the ovarian endometriosis group. In contrast, vaginal samples from patients with ovarian endometriosis demonstrated significantly reduced bacterial abundance and diversity, accompanied by lower levels of 4‐methoxyestrone, 2‐methoxyestrone, and 2‐hydroxyestrone‐3‐methyl ether.ConclusionsAlthough overt dysbiosis was not observed, specific microbial shifts and altered estrogen metabolites may reflect disturbances in estrogen metabolism and urogenital–gastrointestinal microbiota in ovarian endometriosis.

Endogenous estrogens are implicated in carcinogenesis through both estrogen receptor-mediated cell proliferation and the direct genotoxicity of reactive metabolites. Oxidative metabolism of estrogens produces catechol estrogens that are further converted to electrophilic ortho-quinones capable of alkylating DNA. The prevailing model of mutagenesis proposes that these N3Ade and N7Gua adducts depurinate to form abasic sites that induce mutations initiating hormone-related cancers. However, the mutation spectrum observed in experimental data is inconsistent with this mechanism, and synthetic studies of estrogen-DNA adducts have relied on acidic conditions that artificially promote depurination, leaving stable N7-dG lesions poorly understood. To address this, we synthesized stable N7-dG catechol and estrone adducts using 2′-fluorinated deoxyguanosine, a modification that inhibits N-glycosidic bond cleavage. ROESY 2D NMR spectroscopy revealed through-space correlations consistent with a preferred anti-conformation in solution, supported by molecular modeling. Structural analysis suggests that these cationic aryl adducts likely preserve the Watson–Crick base pairing edge but may promote tautomerization capable of altering base pairing and generating G-to-A mutations. These findings provide the first synthesized stable models of N7-dG estrogen adducts and may support an alternative mechanism of estrogen-induced mutagenesis independent of depurination, enabling future biochemical investigations of related DNA repair and mutagenesis.

Androgens and estrogens rapidly influence brain function and behaviors critical to social species, including social recognition, which is essential for group living and modulating social interactions. The specific brain regions involved and their hormonal regulation remain poorly understood. This regulation is complex, as the main circulating androgen, testosterone (T), is metabolized into estrogenic (17β-estradiol, E2) and androgenic (dihydrotestosterone, DHT) compounds, meaning its actions can be mediated through both androgen (AR) and estrogen receptors (ERs). This study identifies an estrogen-regulated, social recognition-specific brain circuit, demonstrating that T and E2, but not DHT, interact with the arginine-vasopressin (AVP) system in the bed nucleus of the stria terminalis (BNST)-lateral septum (LS) pathway to promote social recognition in male mice. T, E2, and DHT all facilitated social recognition and impaired object recognition within forty minutes of infusion into the BNST, but only the effects of T and E2 were blocked by an AVP receptor 1a (V1aR) antagonist, suggesting distinct mechanisms underlie the facilitation of social recognition by estrogens and androgens. Using CRISPR/Cas9 to selectively knock down AR, ERα, ERβ, or G protein-coupled estrogen receptor (GPER) in the BNST of male mice four weeks before steroid infusion, we found that ERα and ERβ (but not GPER) are necessary for T and E2 to rapidly facilitate social recognition, whereas DHT acts through AR. Our findings highlight the distinct roles of AR and ERs in the modulation of social recognition by steroid hormones, revealing redundant and nonoverlapping mechanisms of androgens and estrogens in the functioning of the male social brain.