Testosterone Wiki

A living synthesis mined nightly by VaultMiner. Domain: Testosterone and androgen research. Primary focus: testosterone in women (menopause, libido, mood, cognition, bone, muscle) and in trans men (gender-affirming testosterone therapy). Secondary: testosterone in men (hypogonadism, TRT, aging) and androgen receptor / steroidogenesis mechanism.

Last updated: 2026-08-11

Testosterone in Women: Clinical Use and Safety

• testosterone prescribing for U.S. women rose 2.6-fold from 2016 to 2025 (50.0 to 130.8 per 100,000), with a +58.7% increase in 2025 alone, based on Epic Cosmos data from over 300 million records. Measured cardiovascular disease outcomes in women were zero; all safety data is extrapolated from male trials like TRAVERSE. The only women's cardiovascular trial, BLISS/LibiGel, was completed but never published. (source: 10-1016_j-jacadv-2026-102724.md)
• A 2026 systematic review of 13 RCTs (n=2,628 cisgender women, transdermal testosterone, 8-52 weeks) found no cardiovascular deaths, but certainty is moderate and short-term; 13 observational cohort studies in transgender men (n=7,837, long-term) reported 34 cardiovascular deaths (incidence 1.81 per 1,000 person-years), with low to very low certainty. The evidence differs by study design and follow-up, not by definitive comparative risk. (source: viana-2026-cardiovascular-mortality-associated-with-testosterone-therapy-in-cisg.md)
• A 2026 systematic review concludes testosterone is effective for female sexual dysfunction in both pre- and postmenopausal women, but the premenopausal evidence rests on only 2 small, old RCTs (n=31-261) and is described as 'preliminary.' The postmenopausal evidence is solid (7 RCTs). (source: 10-1093_jsxmed_qdag206.md)
• A 2026 RCT (n=47) of compounded transdermal testosterone for postmenopausal sexual desire found that while serum testosterone rose (p=0.001) and some FSFI domains improved, desire was a secondary outcome and the study was not powered for it. The authors note that compounded-hormone variability undermined interpretation, and the 2019 consensus states compounded testosterone 'cannot be recommended.' (source: 10-1016_j-ejogrb-2026-115242.md)
• The 2005 North American Menopause Society position statement concluded that postmenopausal women with decreased sexual desire and personal distress may be candidates for testosterone therapy, but it could not be recommended without concomitant estrogen therapy due to lack of evidence. Transdermal patches and gels are preferred over oral products due to first-pass hepatic effects. (source: anon-2005-the-role-of-testosterone-therapy-in-postmenopausal-women.md)
• The 2014 Endocrine Society clinical practice guideline on androgen therapy in women, developed with GRADE methodology, provides evidence-based recommendations for therapeutic androgen use. (source: wierman-2014-androgen-therapy-in-women-a-reappraisal-an-endocrine.md)
• A 2017 systematic review and meta-analysis of 7 RCTs (n=3,035) found that transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder significantly improved satisfying sexual episodes, sexual activity, orgasms, and desire, and reduced personal distress. It was associated with androgenic adverse events like acne and hair growth, but not with any serious adverse events. (source: achilli-2017-efficacy-and-safety-of-transdermal-testosterone-in-postmenopausal.md)
• A 2026 cross-sectional study (AWMYS, n=731, LC-MS/MS) found that blood testosterone, Dehydroepiandrosterone, and androstenedione are NOT associated with sexual desire in midlife women, suggesting these should not be measured in a routine workup. The null result had a positive control (the same assay did track orgasm/arousal), but the study excluded women with depression, on psychotropics, or with oophorectomy. (source: 10-1016_j-fertnstert-2026-05-156.md)
• A 2016 narrative review argues that estrogen-only therapies producing periovulatory levels of circulating estradiol increase sexual desire in postmenopausal women, and that testosterone at supraphysiological, but not physiological, levels enhances the effectiveness of low-dose estrogen therapies. The authors conclude that the focus on androgen therapies for female sexual desire disorders may be misplaced. (source: cappelletti-2016-increasing-women-s-sexual-desire-the-comparative-effectiveness.md)
• Testosterone is vital to female physiology, and its role in female health is often ignored. Emerging research shows that testosterone plays a crucial role in female reproduction, cardiovascular health, bone remodeling, muscle mass, and brain function. (source: faucett-2026-testosterone-vital-to-female-physiology.md)
• A 2011 study (n=300) found that continuous subcutaneous testosterone implant therapy was effective for relief of hormone deficiency symptoms in both pre- and postmenopausal women, as measured by the validated Menopause Rating Scale (MRS), with higher doses correlating with greater improvement. (source: glaser-2011-beneficial-effects-of-testosterone-therapy-in-women-measured.md)
• A 2024 retrospective cohort study (n=510) in a UK specialist menopause clinic found that transdermal testosterone therapy added to existing HRT for 4 months was associated with improvements in mood (47% of women improved), cognition (39% improved), and libido (52% improved), with mean symptom scores decreasing by 34%, 22%, and 33%, respectively. (source: glynne-2024-effect-of-transdermal-testosterone-therapy-on-mood-and.md)
• A 2026 retrospective cohort study (n=47) found that transdermal testosterone therapy in perimenopausal and postmenopausal women with a history of breast cancer was associated with significant reductions in night sweats, anxiety/panic, depression, anhedonia, and palpitations, as well as a decrease in mean Menopause Symptom Questionnaire score from 30.81 to 20.47 after ~3.7 months. (source: glynne-2026-use-of-transdermal-testosterone-to-treat-menopausal-symptoms.md)
• Flibanserin, a serotonin 1A agonist/2A antagonist, is effective and safe for hypoactive sexual desire disorder in women, according to a 2015 meta-analysis of 4 RCTs (n=3,414) showing improvements in satisfying sexual events, desire scores, and distress. (source: gao-2015-efficacy-and-safety-of-flibanserin-in-women-with.md)
• The largest documented case of deliberate supraphysiologic androgen administration to female bodies was the GDR state-sponsored doping program (1966-1989), where several thousand athletes, including minors, were given androgens with emphasis on women and adolescent girls, with damaging side effects recorded. (source: franke-1997-clinchem-GDR-hormonal-doping-androgenization-athletes.md)
• A qualitative study of 16 women with current or past anabolic-androgenic steroid use documents irreversible masculinizing effects: voice deepening, clitoral enlargement, hirsutism, and menstrual disruption. Initiation was typically mediated by male partners, friends, or coaches. Clitoral enlargement produced shame and reduced self-esteem, moderated by partner response. (source: havnes-2020-ijdp-women-AAS-masculinizing-gonadal-sexual-effects.md)
• Antidepressant-associated sexual dysfunction is a common side effect of psychotropics, with significant impact on quality of life, relationships, and mental health. Reported problems include decreased sexual desire, decreased excitement, diminished or delayed orgasm, and erection or delayed ejaculation problems. (source: higgins-2010-antidepressant-associated-sexual-dysfunction-impact-effects-and-tre.md)
• The 2019 Islam meta-analysis of 36 RCTs (n=8,480) confirms that testosterone significantly improves sexual function in postmenopausal women, including satisfactory sexual event frequency, desire, pleasure, arousal, orgasm, and reduces distress, while oral testosterone worsens lipid profiles and non-oral routes are neutral. Safety data do not extend beyond 24 months. (source: islam-2019-lancetde-testosterone-women-metaanalysis.md)
• A 1991 study of 9 female weight lifters self-administering testosterone and anabolic steroids found 30-fold elevations of serum testosterone in those injecting testosterone, with 3 exceeding the upper limit of the normal male range, plus a compensatory fall in SHBG, decreased thyroid-binding proteins, and a 39% decrease in HDL-C. (source: malarkey-1991-ajog-female-weight-lifters-self-administered-androgens.md)
• The 2021 International Society for the Study of Women's Sexual Health (ISSWSH) clinical practice guideline, building on the Global Position Statement, recommends systemic transdermal testosterone for women with hypoactive sexual desire disorder not primarily related to modifiable factors or comorbidities. It supports use in late reproductive age premenopausal women, notes a moderate therapeutic benefit, and states that a total testosterone level should not be used to diagnose HSDD but as a baseline for monitoring. Compounded products cannot be recommended due to lack of efficacy and safety data. (source: parish-2021-international-society-for-the-study-of-women-s-sexual.md)
• A 2024 narrative review of 9 RCTs and systematic reviews concludes that current evidence recommends systemic transdermal testosterone within the postmenopausal physiological range for postmenopausal women with hypoactive sexual desire disorder (HSDD) / female sexual interest and arousal disorder (FSIAD), with moderate therapeutic benefit and no short-term severe adverse effects, though long-term safety data is lacking. (source: ribera-2024-systemic-testosterone-for-the-treatment-of-female-sexual.md)
• In women, the androgens testosterone and Dehydroepiandrosterone (DHEA) play important physiologic roles in reproductive tissues, mood, cognition, the breast, bone, muscle, vasculature, and other systems. (source: smith-2020-prescribing-testosterone-and-dhea-the-role-of-androgens.md)
• A 1985 prospective crossover study of 53 surgically menopausal women found that exogenous androgen enhanced the intensity of sexual desire and arousal and the frequency of sexual fantasies, but did not affect physiologic response or interpersonal aspects of sexual behavior, suggesting the major impact of androgen in women is on sexual motivation. (source: sherwin-1985-androgen-enhances-sexual-motivation-in-females-a-prospective.md)
• A 2022 review concludes that testosterone replacement therapy is an effective treatment for hypoactive sexual desire disorder in postmenopausal women, with limited data in premenopausal women, and calls for long-term safety research. (source: uloko-2022-the-clinical-management-of-testosterone-replacement-therapy-in.md)
• A 2026 survey of 1,213 Brazilian gynecologists found that 95% sometimes prescribe testosterone for hypoactive sexual desire disorder, 93.9% for perimenopausal/postmenopausal women, 90.1% for premenopausal women, and 66% for breast cancer patients. 93.9% used compounded gels or creams, and 72% believed an approved TT treatment for women is needed, highlighting reliance on unapproved formulations. _(source: valadares-2026-a-survey-of-brazilian-gynecologists-prescribing-practices-and.md)

Reference Ranges

• The most-cited reference ranges for serum testosterone in premenopausal women come from a 2011 study of 161 normally cycling women aged 18-49. For a 30-year-old, the 5th-95th percentiles are: total testosterone 15-46 ng/dL, free testosterone 1.2-6.4 pg/mL, calculated free testosterone 1.3-5.6 pg/mL, bioavailable testosterone 1.12-7.62 ng/dL, and SHBG 18-86 nmol/L. Testosterone declines with age while SHBG remains stable. (source: braunstein-2011-jsm-premenopausal-T-reference-ranges.md)
• The SHIP cohort (n=985 women aged 20-80) provides age-specific reference ranges for total testosterone and androstenedione measured by LC-MS/MS, and calculated free testosterone. Whole-range free testosterone was 0.0025-0.0253 nmol/L (~0.7-7.3 pg/mL), with a distinct decline across every 10-year age band. (source: haring-2012-jcem-age-specific-T-androstenedione-women.md)
• A 2022 study (n=17) using equilibrium dialysis and LC-MS/MS sampled every 3 days across 2 cycles found that peak total testosterone at midcycle was 43.6 ± 16.2 ng/dL and free testosterone 15.6 ± 11.9 pg/mL, higher than previously reported, calling for menstrual phase-specific reference ranges. (source: jasuja-2022-fertstert-DHT-T-freeT-menstrual-cycle.md)
• A 2019 cross-sectional study (n=588 women aged 18-39, LC-MS/MS) found median total testosterone was 0.34 nmol/L (range 0.04-1.01). All C19 steroids were significantly lower at 35-39 than at 18-25, and overweight women had lower levels, supporting the need for age-specific reference ranges. (source: skiba-2019-jcem-androgens-reproductive-years-normal.md)
• NHANES 2011-2012 data (LC-MS/MS) found 10th-90th percentiles for total testosterone in women aged ≥20 years were 7.1-49.8 ng/dL. (source: vesper-2015-serum-total-testosterone-concentrations-in-the-us-household.md)
• A 1995 study of 33 healthy premenopausal women (age 21-51) found that 24-hour mean plasma testosterone declines steeply with age, with the expected concentration at age 40 being about half that at age 21 (0.61 vs 1.3 nmol/L), based on a fitted regression. Percent free testosterone did not vary with age, so free testosterone fell in parallel. Plasma DHEA and DHEAS also declined with age. This is a small study and does not inform decline after age 40. _(source: zumoff-1995-jcem-24h-mean-testosterone-declines-with-age.md)

Testosterone in Women: Mechanisms and Physiology

• The human ovary does not secrete 11-oxygenated androgens. A 2022 study of four hyperandrogenism cases confirmed that 11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT) are not biosynthesized by the ovary, and proposes the testosterone/11-KT ratio to help identify adrenal versus ovarian androgen excess. (source: auer-2022-11-oxygenated-androgens-are-not-secreted-by-the-human.md)
• Ovarian secretion of testosterone increases during the menopausal transition. A 1998 study found ovarian vein testosterone levels were highest in postmenopausal women (median 2.5 nmol/l) and were significantly associated with ovarian stromal hyperplasia, though these high levels were not reflected in peripheral venous blood. (source: ala-fossi-1998-ovarian-testosterone-secretion-during-perimenopause.md)
• A 2026 narrative review found that endogenous hyperandrogenism in women (from PCOS, congenital adrenal hyperplasia, or differences of sex development) is associated with greater lean body mass, higher hemoglobin concentrations, and better aerobic capacity compared to nonhyperandrogenemic women, though effects vary by condition. (source: galas-2026-endogenous-hyperandrogenism-in-women-and-its-influence-on.md)
• Women with hypermobile Ehlers-Danlos syndrome (hEDS) have significantly lower levels of multiple androgen sulfate metabolites compared to controls, driven largely by those aged 30-49, possibly due to downregulation of enzymes involved in androgen biosynthesis, metabolism, and disposition. (source: hannon-2026-lower-androgen-sulfate-metabolites-in-women-with-hypermobile.md)
• Topical testosterone administration ameliorates atopic dermatitis in KFRS4 rats by increasing sebaceous gland number, epidermal thickening, and inducing androgen receptor-positive cells, while enhancing skin barrier function and modulating Th2 and Th17 immune responses. (source: hayashi-2026-topical-administration-of-testosterone-ameliorates-atopic-dermatiti.md)
• A 2020 study found that 10 weeks of testosterone administration in young women induced fiber type-specific hypertrophy (type II) and increased capillarization in skeletal muscle, supporting its performance-enhancing role. (source: horwath-2020-fiber-type-specific-hypertrophy-and-increased-capillarization-in-sk.md)
• Sex hormones, including estradiol, progesterone, and testosterone, have organizational and activational effects on the human brain, impacting cognition, emotion, and reward processing, as reviewed in a 2020 handbook chapter. (source: hornung-2020-sex-hormones-and-human-brain-function.md)
• A 2026 study in mice found that testosterone is essential for pain-related empathetic behaviors (social sniffing, allolicking, allogrooming) in males, while estrogen inhibits these behaviors in intact males; in females, testosterone selectively enhances allogrooming but not allolicking. (source: li-2026-roles-of-testosterone-in-pain-related-empathetic-behaviors-in.md)
• A 2026 study in the equine fetal gonad found that downregulation of DHCR7, the last enzyme in cholesterol synthesis, may drive accumulation of 7-dehydrocholesterol (7-DHC) and the synthesis of B-ring unsaturated steroids, a phenomenon resembling Smith-Lemli-Opitz Syndrome in humans. (source: malin-2026-compartmentalization-of-dhcr7-links-7-dhc-metabolism-to-b-ring.md)
• A 2026 study using NHANES data (n=4,330) found that bioavailable testosterone (FAI) and bioavailable estradiol (FEI) predict muscle strength in both sexes, and that older females with a history of menopausal hormone therapy had 1.9 kg greater grip strength than those without, an advantage that widened with age. (source: logue-2026-sex-hormones-and-menopause-hormone-therapy-predict-muscle.md)
• A 2016 study of 114 women with PCOS and 49 controls found that 11-oxygenated C19 steroids (11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone) are significantly higher in PCOS, representing the majority of circulating androgens [53.0% vs 44.0% in controls], and correlate with markers of insulin resistance. (source: o-reilly-2016-11-oxygenated-c19-steroids-are-the-predominant-androgens-in.md)
• A 2026 study of patients with borderline personality disorder (BPD) examined hair testosterone levels and social behavior, finding that testosterone may modulate social behavior in BPD. (source: wingenfeld-2026-testosterone-in-patients-with-borderline-personality-disorder-fr.md)

Genetics and Testosterone

• A 2020 Mendelian randomization study used human genetics to understand the disease impacts of testosterone in men and women. (source: the-2020-using-human-genetics-to-understand-the-disease-impacts.md)

Menopause and Hormone Therapy

• Genitourinary Syndrome of Menopause (GSM) is a key condition addressed by local estrogen therapy. (source: ashraf-2026-genitourinary-syndrome-of-menopause.md)
• Locally delivered vaginal estrogen (tablets, capsules, rings, pessaries, creams) is the most common and highly recommended treatment for Genitourinary Syndrome of Menopause. The lowest effective dose of 17β-estradiol is recommended for long-term treatment to minimize risk. (source: abdelgader-2023-intravaginal-drug-delivery-systems-to-treat-the-genitourinary.md)
• A 2024 scoping review on GSM treatment notes that first-line therapies include lubricants and moisturizers for short-term relief, while unresolved or severe cases may warrant hormonal treatment. Topical hormonal treatments have fewer side effects than systemic alternatives. Selective estrogen receptor modulators like ospemifene and steroid hormones like Dehydroepiandrosterone (DHEA) show benefit, and innovative approaches like laser treatment are discussed. Safety in women with a history or risk of breast cancer is addressed, noting the need for more research. (source: cuccu-2024-update-on-genitourinary-syndrome-of-menopause-a-scoping.md)
• A 2009 review found that local estrogen therapy relieves symptoms of atrophic vaginitis, improves quality of life, and may have favorable effects on sexuality, urinary tract infections, vaginal surgery, and incontinence. (source: krause-2009-local-effects-of-vaginally-administered-estrogen-therapy.md)
• A 2024 study of 10 million senior Medicare women (2007-2020) found that HRT use beyond age 65 has varying effects by type, route, and dose. estrogen monotherapy was associated with reduced mortality (19%), breast cancer (16%), and dementia (2%). Estrogen plus progestin increased breast cancer risk by 10-19%, but this was mitigated with low-dose transdermal or vaginal preparations. Risk reductions were generally greater with low doses and vaginal or transdermal routes. (source: baik-2024-use-of-menopausal-hormone-therapy-beyond-age-65.md)
• HRT is being investigated as a treatment for depression in perimenopausal women. (source: anon-2022-hormone-replacement-therapy-treatment-for-depression-in-perimenopausal.md)
• A 2023 nationwide nested case-control study in the BMJ examined the link between menopausal hormone therapy and dementia. (source: anon-2023-menopausal-hormone-therapy-and-dementia-nationwide-nested-case-control.md)
• A 2013 nationwide prospective cohort study in Taiwan (n=5,837 women with symptomatic menopausal transition vs 23,348 controls) found that symptomatic menopausal transition was an independent risk factor for major depression (HR 2.18, 95% CI 1.79-2.65) and any depressive disorder (HR 2.34, 95% CI 2.08-2.63) after adjusting for confounders. Medical comorbidities like cerebrovascular disease, cardiovascular disease, congestive heart failure, and liver disease further increased risk. (source: chen-2013-symptomatic-menopausal-transition-increases-the-risk-of-new-onset.md)
• A 2025 themed issue in the British Journal of Psychiatry examines the impact of ovarian hormone fluctuations on women's mental health across puberty, menstrual cycle, pregnancy, postpartum, and menopause, highlighting critical gaps and calling for sex-specific approaches in reproductive psychiatry and hormone-informed mental care. (source: comasco-2025-psychiatric-symptoms-on-the-ovarian-hormone-roller-coaster.md)
• A 2023 review highlights that hormonal fluctuations in the perimenopause are associated with physical and psychological symptoms. Those with pre-existing mental disorders may experience changes in symptoms and treatment response during perimenopause and postmenopause. The oestradiol-suppressing effect of many psychotropics on the hypothalamic-pituitary-gonadal axis may compound the transition. A collaborative approach between primary care and secondary mental health services is recommended, potentially including lifestyle measures and/or HRT. (source: behrman-2023-severe-mental-illness-and-the-perimenopause.md)
• Surgical menopause (risk-reducing bilateral salpingo-oophorectomy) is associated with more severe psychological, vasomotor, and somatic climacteric symptoms and more significant sexual dysfunction compared to natural menopause, according to a 2009 study (n=48 surgical vs 60 natural menopause). However, the procedure did not affect overall perceived quality of life and decreased anxiety and cancer fear. (source: benshushan-2009-climacteric-symptoms-in-women-undergoing-risk-reducing-bilateral.md)
• A 2010 review discusses the central effects of estradiol in regulating food intake, body weight, and adiposity. Men and postmenopausal women accumulate more intra-abdominal fat than premenopausal women, increasing risk of metabolic syndrome. The review highlights sexual dimorphisms in body weight regulation. (source: brown-2010-central-effects-of-estradiol-in-the-regulation-of.md)
• A 2025 retrospective cohort study (n=920) from a UK specialist menopause clinic found that initiating or optimizing menopausal hormone therapy (17β-estradiol ± progestogen, with or without transdermal testosterone) was associated with a 44.59% decrease in mean Meno-D depression scores after ~107 days, with significant improvements in mood symptoms regardless of regimen. (source: glynne-2025-transdermal-oestradiol-and-testosterone-therapy-for-menopausal-depre.md)
• The KEEPS-Continuation Study (n=275) found that short-term (4 years) exposure to menopausal hormone therapy (oral conjugated equine estrogens or transdermal 17β-estradiol with micronized Progesterone) initiated within 3 years of menopause did not influence cognitive performance approximately 10 years later, compared to placebo. (source: gleason-2024-long-term-cognitive-effects-of-menopausal-hormone-therapy-findings.md)
• A 2025 consensus statement from a 25-member multidisciplinary panel concluded that some women with a history of breast cancer may choose to take menopausal hormone therapy (off-label) after shared decision-making, accepting an increased risk of relapse for relief of menopausal symptoms, and that all patients considering MHT after breast cancer should be registered in a clinical study (e.g., MENO-ABC trial). (source: glynne-2025-menopausal-hormone-therapy-for-breast-cancer-patients-what.md)
• A systematic review comparing transdermal versus oral HRT routes in postmenopausal women found that venous thromboembolism risk is higher with the oral route, while bone mineral density, glucose metabolism, lipid profile, breast cancer, endometrial disease, and cardiovascular risk show no clear difference. (source: gold-tajn-2022-effects-of-transdermal-versus-oral-hormone-replacement-therapy.md)
• A 2026 narrative review on perimenopausal depression describes it as a distinct subtype of major depressive disorder with a hormonal aetiology, recommending accurate diagnosis using tools like the Meno-D scale and treatment including lifestyle support, menopausal hormone therapy, trauma-informed psychotherapy, and psychotropics when appropriate. (source: kulkarni-2026-the-primary-care-management-of-perimenopausal-depression.md)
• The Meno-D scale, a 12-item questionnaire validated in 2018, measures perimenopausal depression with five sub-scales: somatic, cognitive, self, sleep, and sexual, with high internal consistency and discriminant validity. (source: kulkarni-2018-development-and-validation-of-a-new-rating-scale.md)
• A 2024 review on menopause-associated depression highlights that erratic fluctuations in estrogen and progesterone during the perimenopausal stage trigger proinflammatory mediators and induce oxidative stress, leading to progressive neuronal damage, and calls for agents targeting these specific pathologies. (source: liang-2024-menopause-associated-depression-impact-of-oxidative-stress-and-neuroi.md)
• A 2019 review on allopregnanolone (ALLO), a 3-α reduced metabolite of progesterone and a strong allosteric modulator of the GABA-A receptor, finds that ALLO dysregulation is identified across reproductive transitions (menarche, menstrual cycle, peripartum, menopausal transition) and is associated with mood symptoms, though evidence of its exact role and directionality is inconsistent. (source: mcevoy-2019-allopregnanolone-and-reproductive-psychiatry-an-overview.md)
• A 2024 BMJ article discusses whether vaginal estrogen is a treatment on the rise and questions its safety. (source: meaidi-2024-vaginal-oestrogen-is-a-treatment-on-the-rise.md)
• A 2017 book chapter covers the management of Genitourinary Syndrome of Menopause (GSM). (source: lukas-2017-management-of-genitourinary-syndrome-of-menopause-gsm.md)
• A 2025 narrative review explores the neurobiological effects of estrogen and progesterone on the brain and discusses therapeutic approaches for premenstrual dysphoric disorder (PMDD), postnatal depression (PND), and menopausal depression. (source: mu-2025-using-estrogen-and-progesterone-to-treat-premenstrual-dysphoric.md)
• The 2011 VIVA international survey (n=3,520 postmenopausal women aged 55-65) found that 45% reported vaginal symptoms, but only 4% attributed them to vaginal atrophy, and 63% failed to recognize it as a chronic condition. Almost half (46%) lacked knowledge about local estrogen therapy, and 30% would consider taking it, with vaginal tablets being the preferred option. (source: nappi-2011-vaginal-health-insights-views-attitudes-viva-results.md)
• A 2019 review of studies using LC or GC/MS/MS found that mean basal estradiol levels in postmenopausal women are 3.1-4.9 pg/mL. Low-dose vaginal estrogens produce dose-dependent systemic absorption: 25 μg softgel capsule gives 7.1-9.1 pg/mL, 25 μg tablet gives 16.7-22.7 pg/mL, 10 μg softgel gives 4.6-7.4 pg/mL, 10 μg tablet gives 6.6-14.8 pg/mL, and 4 μg softgel gives 3.6-3.9 pg/mL. Absorption may be influenced by placement in the vagina. (source: santen-2019-systemic-estradiol-levels-with-low-dose-vaginal-estrogens.md)
• A 2021 study from the SWAN Study Heart study (n=362 women) found that abdominal visceral adipose tissue (VAT) accelerates 2 years before the final menstrual period, increasing by 8.2% per year from 2 years before to menopause, and 5.8% per year after menopause. This menopause-related VAT increase was associated with greater internal carotid artery intima-media thickness (ICA-IMT), a measure of subclinical atherosclerosis. (source: samargandy-2021-abdominal-visceral-adipose-tissue-over-the-menopause-transition.md)
• A 2021 sub-analysis of the ELITE trial found that oral 17β-estradiol 1 mg/day plus vaginal micronized progesterone gel 45 mg/day for 10 days/month in healthy postmenopausal women led to progressive increases in endometrial thickness and a higher rate of endometrial hyperplasia compared to placebo, suggesting this vaginal progesterone dose is insufficient to fully oppose the endometrial effects of oral estradiol. (source: sriprasert-2021-use-of-oral-estradiol-plus-vaginal-progesterone-in.md)
• A 2022 review on HRT and cognition/mood notes that the 'critical window' hypothesis is compelling: HRT may positively impact cognition when initiated in perimenopause or early postmenopause but may have negative effects in older postmenopausal women. Evidence for a positive effect of HRT on mood is more convincing, though possibly more efficacious in younger women. (source: sharma-2022-the-effect-of-hormone-replacement-therapy-on-cognition.md)
• A 2020 review on progesterone and psychiatric illness finds that the literature does not support an association between exogenous progesterone and negative mood in the general population, but indicates a subset of women may be vulnerable. Research is lacking on women with psychiatric illness. (source: standeven-2020-progesterone-reproduction-and-psychiatric-illness.md)

Testosterone and Anhedonia/Reward

• A 2016 study on adolescent neural response to reward found that while boys showed increased nucleus accumbens BOLD response compared to girls, sex hormones (testosterone and estradiol) did not mediate this effect. Motivation to earn money partially mediated the sex effect on nucleus accumbens activity. (source: alarc-n-2016-adolescent-neural-response-to-reward-is-related-to.md)
• A 2024 study of early adolescents (ABCD study, 15,844 observations) found that boys had higher reward motivation than girls. Pubertal stage and testosterone levels were positively associated with reward motivation behavior, but there were no significant associations between pubertal development and neural activation during reward anticipation and feedback. (source: barendse-2024-sex-and-pubertal-variation-in-reward-related-behavior-and.md)
• The separable, nonlinear, and interactive effects of testosterone and cortisol during status competition in humans were examined in a 2026 study. The results suggest that testosterone increases sensitivity to opponent status while decreasing sensitivity to gains and losses. Cortisol moderates testosterone's effects on status sensitivity while independently increasing reward sensitivity. (source: elahi-2026-separable-nonlinear-and-interactive-effects-of-testosterone-and.md)
• A 2018 rat study found that chronic 17β-estradiol treatment enhanced saccharin preference (indicating reduced anhedonia) and novel object recognition memory in ovariectomized rats, but had no effect on passive coping in the forced swim test. (source: gogos-2018-differential-effects-of-chronic-17-oestradiol-treatment-on-rat.md)
• A 2025 study in male mice found that absence of estrogen receptor β renders male mice susceptible to stress-induced maladaptive reward processing, and that brain-selective delivery of 17β-estradiol or an ERβ-specific agonist prevents these effects, implicating estradiol (not testosterone per se) in stress susceptibility. (source: georgiou-2025-estradiol-via-estrogen-receptor-signaling-mediates-stress-suscepti.md)
• A 2025 study (n=137) using ecological momentary assessments over 90 days found that amplifying positivity (positive rumination) is associated with fluctuations and instability in anhedonia over time, while dampening and difficulties regulating negative emotions were not related to anhedonia dynamics in individuals with major depressive disorder. (source: gallagher-2025-anhedonia-in-flux-understanding-the-associations-of-emotion.md)
• A 2019 RCT (n=99) found no significant differences in response to intravenous ketamine for treatment-resistant depression between women and men, nor between pre- and postmenopausal women. (source: freeman-2019-sex-differences-in-response-to-ketamine-as-a.md)
• Exogenous testosterone administration (0.5 mg sublingual) in healthy women increases ventral striatal BOLD response during reward anticipation, and this effect interacts with levels of self-reported intrinsic appetitive motivation. (source: hermans-2010-effects-of-exogenous-testosterone-on-the-ventral-striatal.md)
• In adolescents (n=810, ages 13-20), reward sensitivity was more strongly associated with sensation seeking in males, and self-reported pubertal development was positively associated with reward sensitivity in both sexes. testosterone showed a positive association with sensation seeking, while estradiol showed a negative association. (source: harden-2017-developmental-differences-in-reward-sensitivity-and-sensation-seekin.md)
• A biopsychosocial study (n=94, ages 18-34) found that motivation in an effort-based decision-making task decreased during periovulatory and luteal menstrual cycle phases, with females showing more sustained effort and males more opportunistic reward seeking. Endogenous estradiol, progesterone, and testosterone levels explained little variance beyond task incentives and sex/gender associations. (source: grahlow-2026-motivation-and-reward-processing-across-sex-gender-and-the.md)
• Ketamine and its active metabolites (2R,6R)-HNK and (2S,6S)-HNK are novel ligands for estrogen receptor α (ERα), binding with IC50 values of 2.31-3.53 µM. Estrogen plus ketamine or its metabolites induces additive effects on AMPA receptor gene expression, and this effect is lost when ERα is knocked down, suggesting a positive feedback loop involving estrogen-inducible enzymes that metabolize ketamine. (source: ho-2018-ketamine-and-ketamine-metabolites-as-novel-estrogen-receptor.md)
• Ketamine and its active metabolites regulate the type I interferon pathway in human microglia via STAT3, and this signaling may contribute to ketamine's antidepressant effects through augmentation of BDNF expression and promotion of synaptic proteins. (source: ho-2019-ketamine-and-active-ketamine-metabolites-regulate-stat3-and.md)
• A 2023 study (n=192 men) found that a single dose of testosterone (150 mg) eliminated strategic prosocial behavior (feigned prosociality) when being watched, by impacting choice consistency in a reinforcement learning task, without deteriorating learning per se. (source: kutlikova-2023-testosterone-eliminates-strategic-prosocial-behavior-through-impa.md)
• A 2022 enrichment-loss rat model study found that flexible coping animals in enriched environments had higher Dehydroepiandrosterone/corticosterone (DHEA/CORT) ratios, consistent with adaptive stress responses, while enrichment-loss led to blunted CORT responses and less exploratory behavior. (source: kent-2022-the-emotional-impact-of-disrupted-environmental-contexts-enrichment.md)
• A 2018 review on sex differences and effects of estradiol on striatal function highlights that the caudate-putamen, nucleus accumbens core, and shell all express membrane-associated estrogen receptors, and that behaviors mediated by these regions differ by sex or are sensitive to gonadal hormones like 17β-estradiol and testosterone. (source: meitzen-2018-sex-differences-and-the-effects-of-estradiol-on.md)
• A 2023 rat study found that the medial preoptic area (mPOA) efferents to the ventral tegmental area (VTA) are sexually dimorphic in their sex-steroid hormone receptor content: females have a greater percentage of efferents expressing estrogen receptor α (ERα), while males have a greater percentage expressing androgen receptor (AR), particularly in the central mPOA. (source: martz-2023-sex-steroid-hormone-receptor-content-of-medial-preoptic.md)
• A 2023 mouse study found that fluoxetine combined with swimming exercise synergistically reduces LPS-induced depressive-like behavior (including anhedonia) by normalizing the HPA axis and reducing brain inflammation, with the combination more effectively increasing testosterone and IL-10 and decreasing corticosterone and TNF-α than either alone. (source: mahdirejei-2023-fluoxetine-combined-with-swimming-exercise-synergistically-reduc.md)
• A 2021 study (n=106) found that menopausal status did not influence overall response to intravenous ketamine for treatment-resistant depression: premenopausal and postmenopausal women had similar response rates (30% and 26%) and remission rates (both 13%), though premenopausal women improved in social function more rapidly and postmenopausal women reduced suicidal ideation more rapidly. (source: lipsitz-2021-intravenous-ketamine-for-postmenopausal-women-with-treatment-resist.md)
• A 2026 longitudinal study (n=126 adolescents, 216 scans over 2 years) found that puberty moderates the link between mesocorticolimbic resting-state functional connectivity and reward/punishment sensitivity in males but not females. testosterone levels moderated the association between anterior ventromedial PFC-NAcc RSFC and reward sensitivity, such that weaker RSFC related to higher reward sensitivity in males with lower testosterone than expected for their age and pubertal status. (source: ojha-2026-mesocorticolimbic-connectivity-and-motivational-sensitivity-sex-specif.md)
• A 2017 study found that ginsenoside Rg1 exerts antidepressive effects by regulating the HPA axis and hypothalamic-pituitary-gonadal axis, counteracting the persistent glucocorticoid increase and HPG dysfunction seen in major depression. (source: mou-2017-antidepressive-effects-of-ginsenoside-rg1-via-regulation-of.md)
• A 2022 pharmaco-fMRI study (n=30 women) simulated pregnancy and postpartum hormonal states by inducing hypogonadism, adding back estradiol and progesterone for 8 weeks, then withdrawing both. Women with a history of postpartum depression (PPD+) showed increased anhedonia during addback and withdrawal compared to those without. During reward feedback, both hormone-sensitive and non-sensitive groups showed decreased activation in the right putamen and left postcentral and supramarginal gyri at withdrawal scans relative to pre-treatment. (source: schiller-2022-effects-of-gonadal-steroids-on-reward-circuitry-function.md)
• A 2025 narrative review on anhedonia treatments covers current and future pharmacological and neuromodulation approaches for this transdiagnostic symptom. (source: serretti-2025-anhedonia-current-and-future-treatments.md)
• A 2004 double-blind placebo-controlled crossover study in 12 healthy young women found that a single administration of testosterone shifted decision-making toward disadvantageous choices on the Iowa Gambling Task, indicating reduced punishment sensitivity and enhanced reward dependency. (source: van-2004-testosterone-shifts-the-balance-between-sensitivity-for-punishment.md)
• A 2020 study in 96 men found that a single dose of testosterone gel (50 mg) decreased resting-state functional connectivity between the right dorsolateral prefrontal cortex and right amygdala, and between the ventromedial prefrontal cortex and left inferior parietal lobule, disrupting fronto-subcortical and fronto-parietal circuits implicated in emotion regulation. (source: votinov-2020-effects-of-exogenous-testosterone-application-on-network-connectivi.md)
• In a 2022 double-blind RCT of 50 men undergoing severe energy deficit, testosterone enanthate (200 mg/week) did not alter risky choice between lives and cash, but increased sensitivity to negative feedback following risky choices, suggesting modulation of feedback processing. (source: vartanian-2022-effect-of-exogenous-testosterone-in-the-context-of.md)
• The Effort-Expenditure for Rewards Task (EEfRT) is a validated behavioral measure of reward motivation, with higher trait anhedonia associated with reduced willingness to expend effort for rewards. (source: treadway-2009-worth-the-eefrt-the-effort-expenditure-for-rewards.md)
• In a mouse model of chronic restraint stress, both C57BL/6J and BALB/c mice showed increased hair testosterone levels after stress, but only BALB/c mice exhibited anhedonia-like behavior in the sucrose preference test, suggesting strain differences in stress susceptibility despite similar testosterone responses. (source: tsuchimine-2020-comparison-of-physiological-and-behavioral-responses-to-chronic.md)
• A 2019 mouse study found that testosterone-dependent lower excitability of ventral hippocampus (vHPC) to nucleus accumbens (NAc) neurons underlies male resilience to stress-induced anhedonia (reduced sucrose preference). Chemogenetic inhibition of this circuit prevented stress-induced anhedonia in female mice. (source: williams-2019-androgen-dependent-excitability-of-mouse-ventral-hippocampal-affer.md)
• Toludesvenlafaxine, a triple reuptake inhibitor, increased testosterone levels and improved anhedonia and sexual function in rat models of depression. (source: zhu-2021-pharmacological-characterization-of-toludesvenlafaxine-as-a-triple-reup.md)

Testosterone in Men: Hypogonadism and Aging

• A 2026 narrative review distinguishes between late-onset hypogonadism (LOH) and functional hypogonadism in aging men. It highlights that progressive testosterone decline interacts bidirectionally with circadian disruption, sleep disorders (including Obstructive sleep apnea), and metabolic imbalance. Functional hypogonadism may be partially reversible through weight reduction, metabolic optimization, physical activity, and sleep-focused interventions. (source: andersen-2026-late-onset-and-functional-hypogonadism-in-aging-men-an.md)
• A 2026 review proposes that stem Leydig cells (SLCs) are a potential therapeutic target for late-onset hypogonadism (LOH), as their functional decline in the aging microenvironment is a key mechanism of testosterone decline. (source: xu-2026-restoring-testosterone-homeostasis-the-therapeutic-potential-of-stem.md)
• The endocrinology of the aging male is a recognized field of study. (source: anon-2007-endocrinology-of-the-aging-male-an-overview.md)
• A 2024 review on age-related testosterone decline highlights that aging affects the hypothalamic-pituitary-gonadal axis and Leydig cells, leading to testosterone reduction. Exogenous testosterone supplementation can partially ameliorate age-related deficiency, but long-term safety remains contentious. Preserving endogenous testosterone production during aging is a potential intervention strategy. (source: cheng-2024-age-related-testosterone-decline-mechanisms-and-intervention-strategi.md)
• A 2026 systematic review of 11 RCTs (n>600 men) found that testosterone therapy significantly improved depressive symptoms in men with treatment-resistant depression (p<0.05) and enhanced specific cognitive domains, particularly verbal memory and visuospatial processing, in older or hypogonadal men. Global cognition and anxiety showed inconsistent effects. Quality of life and sexual function consistently improved. Adverse events were mild and transient. The authors conclude TT should be considered a complementary approach under endocrinological supervision. (source: canal-2026-psychiatric-and-cognitive-effects-of-testosterone-therapy-in.md)
• Individualizing injectable testosterone replacement therapy in primary care is crucial, and the goal is to achieve physiologic replacement with stable symptoms, interpretable laboratory results, tolerable treatment burden, and appropriate safety monitoring. (source: farzam-2026-individualizing-injectable-testosterone-replacement-therapy-in-prima.md)
• Pituitary macroadenoma with panhypopituitarism can present with psychiatric symptoms mimicking schizophrenia, as in a 2023 case report of a 42-year-old man who improved with dopamine agonist and steroid therapy. (source: ghimire-2023-pituitary-macroadenoma-with-panhypopituitarism-masquerading-as-schi.md)
• Erectile dysfunction in elderly men is linked to age-related changes and risk factors including hypertension, dyslipidemia, diabetes mellitus, and atherosclerotic heart disease. (source: g-k-e-2019-erectile-dysfunction-in-the-elderly-male.md)
• A 2026 narrative review describes a secular, age-independent decline in testosterone levels across populations, linked to modifiable factors including obesity, physical inactivity, unhealthy diet, chronic stress, poor sleep, and exposure to endocrine-disrupting chemicals. (source: fraile-mart-nez-2026-understanding-the-secular-decline-in-testosterone-mechanism.md)
• A Mendelian randomization study found that genetically proxied abundance of the Eubacterium rectale group in the gut microbiome is associated with greater odds of detectable male estradiol (OR 1.36), and Alistipes finegoldii with heel bone mineral density, suggesting microbial influences on male reproductive endocrine and skeletal physiology. (source: ha-2026-gut-microbiome-associations-in-male-reproductive-endocrine-skeletal-phys.md)
• A 2025 review on Leydig cell aging and obesity-related hypogonadism highlights that oxidative stress, inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress drive Leydig cell aging, and that obesity may accelerate this through chronic inflammation and endocrine changes. (source: huang-2025-mechanisms-of-leydig-cell-aging-and-obesity-related-hypogonadism.md)
• A 2014 study of 4,241 men with erectile dysfunction found that aging males benefited more from medical treatment (sildenafil) than younger males, with improvement rates of 107% in IIEF-EF, 83.1% in erection hardness, and 116.5% in sexual satisfaction, suggesting age is not a limiting factor. (source: jiang-2014-medical-management-of-erectile-dysfunction-in-aging-males.md)
• A 2023 editorial discusses metabolic factors in erectile dysfunction. (source: meng-2023-editorial-metabolic-factors-in-erectile-dysfunction.md)
• A 2025 comparative review of new oral testosterone formulations (Jatenzo, Tlando, Kyzatrex) for symptomatic male hypogonadism reports that clinical trials restore eugonadal levels in 80-88% of patients. Shared risks include hypertension, polycythemia, and lipid changes. Differences in dosing, titration, and insurance coverage influence choice. (source: rosen-2025-treatment-of-symptomatic-male-hypogonadism-with-new-oral.md)
• A 2026 retrospective study of active-duty military personnel (n=13,209 males) found that current or prior androgen therapy was associated with increased risk of tendon rupture (adjusted hazard ratio 1.85; 95% CI 1.71-2.00). (source: rebello-2026-tendon-injury-is-associated-with-sex-hormone-therapy.md)
• A 2020 review highlights that testosterone plays a pivotal role in mood, behaviour, self-perception, and quality of life in men. Low testosterone in older men (functional hypogonadism) is associated with depressive symptoms, anxiety, and reduced quality of life, and testosterone substitution can improve quality of life in older hypogonadal men. (source: zitzmann-2020-testosterone-mood-behaviour-and-quality-of-life.md)
• A 2022 review found that lower testosterone concentrations in middle-aged and older men are associated with higher prevalence and incidence of cognitive decline and dementia, including Alzheimer's disease. Men on androgen deprivation therapy for prostate cancer had a higher risk of dementia. Small intervention studies of testosterone on cognitive function have yielded mixed results. (source: yeap-2022-testosterone-cognitive-decline-and-dementia-in-ageing-men.md)
• A 2026 study demonstrated that chronic subcutaneous kisspeptin-10 administration (daily 8 h infusions for 12 days) sustained increases in LH, FSH, and testosterone in healthy men, suggesting kisspeptin-based therapies may be developed for treating reproductive disorders like hypogonadism. (source: yeung-2026-chronic-subcutaneous-kisspeptin-10-stimulates-gonadotropin-secretion.md)
• A 2026 study (NHANES 2011-2014, n=1,001 men aged 40-59) found that higher total testosterone levels were positively associated with higher handgrip strength (HGS), with stronger links in the 50-59 year olds. Per European Association of Urology guidelines, men with testosterone levels above deficiency (≥230 ng/dL) had higher odds of increased appendicular lean soft tissue index (ALSTI) versus those with deficiency. Normal testosterone (>346 ng/dL) was linked to higher HGS overall and in men aged 50-59. (source: prokopidis-2026-association-of-testosterone-with-lean-soft-tissue-and.md)
• A 2026 cross-sectional comparative study of hospitalized men in Poland (2013 vs 2023) found that most associated old age with declining testosterone levels and considered andropause a natural process. Psychological symptoms of aging were reported by 80.5% in 2013 and 75.9% in 2023, while sexual dysfunction by 65.8% and 63.3%. More than half had no depressive symptoms. (source: bejda-2026-changes-in-bio-psycho-social-aspects-of-male-aging-a.md)

Reference Ranges for Men

• Free testosterone reference intervals measured by standardized equilibrium dialysis in healthy nonobese men: normative range 66-309 pg/mL (229-1072 pmol/L) for all men, and 120-368 pg/mL (415-1274 pmol/L) for men aged 19-39 years, with a negative association with BMI, age, and SHBG. (source: jasuja-2023-andrology-free-T-reference-intervals-standardized-ED.md)
• NHANES 2011-2012 data found 10th-90th percentiles for total testosterone in men aged ≥20 years were 150-698 ng/dL, with covariate-adjusted levels peaking at age 55-60, possibly reflecting increased exogenous testosterone use. (source: vesper-2015-serum-total-testosterone-concentrations-in-the-us-household.md)
• In NHANES 2011-2012, non-Hispanic Asian children had the highest total testosterone among children, while non-Hispanic Asian men had the lowest among men, indicating race/ethnic variations. (source: vesper-2015-serum-total-testosterone-concentrations-in-the-us-household.md)

Prostate Cancer and Androgen Receptor Targeting

• Multiple phase 3 studies have shown that early use of androgen receptor (AR) pathway inhibitors (ARPIs) results in marked improvement in overall survival for men with metastatic androgen pathway modulation-sensitive (APMS) prostate cancer (formerly castration-sensitive prostate cancer). However, resistance to these agents and progression to androgen pathway modulation-resistant (APMR) prostate cancer (formerly castration-resistant prostate cancer) inevitably occurs. As such, patients previously treated with an ARPI for APMS prostate cancer have inherently more resistant disease. AR still remains a relevant therapeutic target in most patients with APMR prostate cancer, and several novel therapies targeting both AR-dependent and -independent mechanisms of resistance are under clinical development. These include hormonal therapies that appear effective in the setting of well-characterized ARPI resistance mutations (e.g., AR ligand binding domain mutations), and include non-ligand binding domain inhibitors, AR degraders and next-generation extra-gonadal androgen biosynthesis inhibitors. Combinatorial approaches utilizing ARPIs and newer agents designed to suppress key resistance mechanisms (e.g., epigenetic therapies) and emerging data on the use of supraphysiological testosterone to both exert an antitumor effect and "re-sensitize" APMR prostate cancer to downstream ARPIs are also discussed. (source: paras-2026-beyond-androgen-deprivation-therapy-next-generation-hormonal-therapie.md)

Androgen Mechanism and Steroidogenesis

• A 2026 animal study found that L-arginine protects against codeine-induced testicular toxicity and preserves steroidogenesis in male Wistar rats by suppressing oxidative stress, inflammation, and apoptosis, and by modulating transcription factors like Nrf2 and NF-kB. (source: akhigbe-2026-l-arginine-improves-prenatal-and-pre-pubertal-codeine-induced-stero.md)
• The mechanisms of penile erection involve a balance between contractant and relaxant factors in the corpora cavernosa. Nitric oxide is the most important factor for relaxation, and erectile dysfunction can be classified as psychogenic, vasculogenic, neurologic, or endocrinologic. (source: andersson-2011-mechanisms-of-penile-erection-and-basis-for-pharmacological.md)
• Testosterone is metabolized in the central nervous system by 5α-reductase to DHT and by aromatase to estrogens. A 1991 study found that 5α-reductase is concentrated in brain white matter, associated with myelin membranes, and that neurons are more active than glial cells in converting testosterone to DHT. Only neurons possess aromatase activity. (source: celotti-1991-testosterone-metabolism-in-brain-cells-and-membranes.md)
• A 2000 study found sex differences in the distribution of androgen receptor immunoreactivity in the human hypothalamus, with men showing more intense nuclear staining in most areas, particularly in the lateromamillary and medial mamillary nuclei. (source: fern-ndez-guasti-2000-sex-differences-in-the-distribution-of-androgen-receptors.md)
• A 2026 review on local synthesis of neuro-estrogen and neuro-androgen in the hippocampus reports that neuro-estradiol (nE2) concentrations are higher in male hippocampus than female, and that nE2 and neuro-dihydrotestosterone (nDHT) have opposing effects on long-term potentiation (LTP), nE2 stimulates LTP via membrane estrogen receptor and protein kinase signaling, while nDHT inhibits LTP via membrane androgen receptor. Both rapidly increase dendritic spines. Aging-dependent cognitive decline is linked to decreases in neuro-testosterone in males and neuro-estradiol in females. (source: kawato-2026-local-synthesis-and-function-of-neuro-estrogen-and-neuro-androgen.md)
• A 2011 study on neuroactive steroids found that Dehydroepiandrosterone (DHEA) levels in CSF correlate with both unconjugated and conjugated serum DHEA, indicating that peripheral DHEA influences CNS levels, while brain synthesis may provide a minimal level of neurosteroids. (source: kancheva-2011-neuroactive-steroids-in-periphery-and-cerebrospinal-fluid.md)
• A 2021 review on 5α-reduced metabolites of testosterone in the nervous system highlights that neuroactive metabolites synthesized by 5α-reductase and 3α/3β-hydroxysteroid oxidoreductase exert effects on myelination, brain maturation, neurotransmission, reproductive behavior, and stress responses, and exhibit neuroprotective effects in several neuropathological animal models. (source: melcangi-2021-synthesis-and-actions-of-5-reduced-metabolites-of-testosterone.md)
• A 2019 study (n=22 males) found only weak to very weak correlations between serum and CSF levels of estradiol, progesterone, and testosterone, suggesting that peripheral concentrations do not parallel central compartments. (source: martin-2019-weak-correlations-between-serum-and-cerebrospinal-fluid-levels.md)
• A 2023 study (n=47 men) using GC-MS/MS quantified sex steroids in matched CSF and serum samples. DHEA was the major sex steroid in CSF (73.5 pg/mL), followed by androstenedione (61.4 pg/mL) and testosterone (49.5 pg/mL). Strong associations between CSF and serum levels were found for all sex steroids except estradiol, suggesting that CSF testosterone is derived from circulating testosterone, CSF DHT from local conversion, and CSF estradiol from local conversion of androstenedione. (source: ryberg-2023-sex-steroid-levels-in-corresponding-cerebrospinal-fluid-and.md)
• A 2026 systematic review of 5α-reductase isoenzymes (SRD5A1, SRD5A2, SRD5A3) found that impaired neurosteroidogenesis due to 5α-R inhibition may underlie vulnerability to anxiety, depression, and suicidality. Pharmacovigilance data strengthen the association between finasteride/dutasteride and persistent psychiatric and sexual adverse effects (post-finasteride syndrome). (source: rodriguez-cerdeira-2026-5-reductase-isoenzymes-from-neurosteroid-biosynthesis-to.md)
• A 2014 mouse brain study found that aromatase-expressing neurons are widely distributed, with densest populations in the bed nucleus of the stria terminalis and medial amygdala. Males had higher densities in some regions. Aromatase-positive cells co-expressed estrogen receptor α and β, or androgen receptor, and single-labelled ER- or AR-positive cells were often surrounded by aromatase-positive nerve fibres, suggesting local brain estrogen synthesis acts via pre- and post-synaptic receptors. (source: stani-2014-characterization-of-aromatase-expression-in-the-adult-male.md)
• A 2026 mouse study found that courtship singing by male mice is predicted by independent effects of housing quality and androgen-related physical traits. (source: cai-2026-courtship-singing-by-male-mice-mus-musculus-is.md)

Intracrinology and Testosterone Pellet Therapy

• Intracrinology refers to the local synthesis, activation, and inactivation of sex steroids within peripheral tissues from precursor hormones like Dehydroepiandrosterone (DHEA) and testosterone, largely independent of circulating hormone levels. (source: glaser-2026-intracrinology-and-testosterone-pellet-therapy-an-enzyme-aware-sympt.md)
• Continuous-release subcutaneous testosterone pellet therapy delivers stable physiologic levels for 3-6 months, allowing tissues to produce DHT and estradiol on demand according to local enzyme activity, avoiding peaks and troughs of other formulations. (source: glaser-2026-intracrinology-and-testosterone-pellet-therapy-an-enzyme-aware-sympt.md)
• A 2004 study of 136 androgen-deficient men found that testosterone pellets release testosterone at a steady rate of 1.34 mg per 200 mg pellet per day, with a duration of action of about 6 months, and that extruded pellets shorten the cycle. (source: kelleher-2004-testosterone-release-rate-and-duration-of-action-of.md)
• A 2010 multi-institutional observational study examined testosterone levels after Testopel™ pellet insertion. (source: mccullough-2010-1497-a-multi-institutional-observational-study-on-testosterone-l.md)

Congenital Adrenal Hyperplasia

• A 2026 diagnostic accuracy study (n=203 children with premature pubarche, 85% female) found that basal 17OHP provides excellent diagnostic accuracy for 21OHD-nonclassic congenital adrenal hyperplasia (AUC 0.98). A dual-threshold strategy is supported: 170 ng/dL (5.1 nmol/L) as optimal screening cutoff (97% sensitivity, 91% specificity) and 410 ng/dL (12.4 nmol/L) as highly specific diagnostic threshold (100% specificity), potentially obviating ACTH stimulation testing. (source: chagas-2026-genotype-refined-17ohp-cut-offs-diagnosing-nonclassical-cah-due-to.md)
• A 2026 cohort study (n=29 patients with congenital adrenal hyperplasia, 20 females) found reduced left CA4 and bilateral subiculum hippocampal volumes, with females showing reduced volumes in bilateral subiculum, CA1, and left CA3 and CA4. Hippocampal structural alterations were not associated with memory performance. (source: savoia-2026-hippocampal-volume-and-white-matter-impairments-in-patients.md)
• Two case reports of 17α-hydroxylase deficiency (17-OHD) presenting with hypertension, absent breast development, primary amenorrhea, low estrogen and testosterone, elevated progesterone, ACTH, and low cortisol, due to CYP17A1 mutations. Glucocorticoid replacement controlled blood pressure and potassium. (source: zhang-2026-be-alert-to-hypertension-caused-by-17-hydroxylase-deficiency.md)

17β-Hydroxysteroid Dehydrogenase Deficiency

• Deficiency of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a rare autosomal recessive disorder of sex development in 46,XY individuals, caused by pathogenic variants in the HSD17B3 gene that impair conversion of Δ4-androstenedione to testosterone. A 2026 case report describes a patient raised female who masculinized at puberty, with compound heterozygous mutations (p.I60T and exon 1 deletion). After counseling, sex reassignment to male was performed with orchidopexy and urethroplasty; at 1-year follow-up the patient was satisfied. For early-diagnosed patients, premature gonadectomy is not recommended due to very low malignancy risk. (source: tao-2026-clinical-management-and-genetic-variation-analysis-of-patients.md)

Neuromodulation and Other Topics

• rTMS is a noninvasive neuromodulation probe and intervention. (source: anon-2011-repetitive-transcranial-magnetic-stimulation-rtms-a-noninvasive-neurom.md)
• Sex/gender influences rTMS treatment outcome: women, especially during high estradiol phases, appear more sensitive to therapeutic effects, possibly due to closer scalp-to-cortex distance, greater prefrontal gray matter density, and estradiol-facilitated cortical excitability. (source: hanlon-2022-sex-gender-as-a-factor-that-influences-transcranial-magnetic.md)
• In adolescents with major depressive disorder, improvement in anhedonia symptoms over 6 weeks of rTMS treatment (1Hz or 10Hz over left dorsolateral prefrontal cortex) predicted treatment response, with both frequencies showing significant anhedonia improvement. (source: hecker-2025-an-examination-of-anhedonia-as-a-predictor-of.md)
• A 2008 study (n=47) found that postmenopausal women with treatment-resistant depression had 0% response to rTMS, while premenopausal women and men had 70.6% and 68.8% response respectively, with greater improvement associated with higher estradiol/progesterone ratio, suggesting menopausal status and ovarian steroids are key determinants. (source: huang-2008-effect-of-age-gender-menopausal-status-and-ovarian.md)
• A 2025 study developed ketamine-loaded nanodroplets combined with low-intensity focused ultrasound (LIFU) targeting the lateral habenula in mice, achieving targeted brain delivery and antidepressant effects with reduced systemic side effects. (source: wu-2025-the-antidepressant-effect-of-targeted-release-of-ketamine-loaded.md)

Androgenetic Alopecia

• Androgenetic alopecia (AGA) is characterized by progressive follicular miniaturization. A 2026 review discusses emerging treatments including cell-derived exosomes, mesenchymal stromal cell-conditioned media, peptide-based formulations, growth-factor concentrates, PRP, and the investigational androgen receptor modulator KX-826 (pyrilutamide) which provides targeted androgen receptor modulation without systemic hormonal suppression. (source: burshtein-2026-emerging-pharmacotherapies-and-regenerative-solutions-for-promoti.md)

Gender-Affirming Hormone Therapy

• A 2026 cohort study in the Lazio Region, Italy (n=365 individuals with gender dysphoria, median age 26) found that 72.1% received at least one medication within one year of hospitalization for GD, compared to 43.1% in the general population. Among those assigned female at birth (AFAB), testosterone was more frequently prescribed, while among assigned male at birth (AMAB), estrogens and anti-androgens were common. (source: belleudi-2026-pharmacological-therapy-in-patients-with-gender-dysphoria-a.md)
• The Amsterdam Cohort of Gender Dysphoria Study (1972-2015, n=6,793) found that the estimated prevalence of transgender people receiving gender-affirming treatment in the Netherlands in 2015 was 1:3,800 for transwomen and 1:5,200 for transmen. Regret after gonadectomy was 0.6% for transwomen and 0.3% for transmen, and did not increase over time. (source: wiepjes-2018-jsm-amsterdam-cohort-gender-dysphoria.md)
• Erythrocytosis is a known adverse effect of testosterone therapy in trans men. A 2021 letter discusses prevalence, determinants, and exposure years in a large cohort of trans men. (source: giovanelli-2021-letter-to-the-editor-from-giovanelli-and-quinton.md)
• The Endocrine Society guideline for gender-dysphoric/gender-incongruent persons recommends titrating total testosterone to 400-700 ng/dL (the cisgender male range) for masculinizing hormone therapy. (source: hembree-2017-jcem-endocrine-society-gender-incongruent-guideline.md)
• In trans men on stable testosterone therapy (≥1 year), reference intervals for cisgender men can be applied for total and free testosterone and SHBG, but estradiol requires a transmasculine-specific interval (upper limit 168 pg/mL by LC-MS/MS). (source: greene-2021-jalm-repro-endo-reference-intervals-trans-men.md)
• A 2022 study of transgender men on testosterone (n=82) and transgender women on estradiol (n=93) for ≥12 months found that creatinine rises in trans men, while DHEAS, FSH, LH, SHBG fall, and HDL-C decreases consistently. (source: humble-2022-jalm-clinical-chemistry-reference-intervals-transgender.md)
• A 2026 review on trans-inclusion in sports finds that current eligibility regulations (hormone thresholds, open categories, puberty-based exclusions, blanket bans) are rarely based on direct scientific evidence. Studies on gender-affirming hormone therapy's effects on physical fitness are limited by cross-sectional designs, small cohorts, and short follow-up, making sport-specific policies difficult. (source: krishna-2026-trans-inclusion-in-sports-history-scientific-evidence-and-future.md)
• A 2021 cohort study (n=1,073 trans men, 20-year follow-up) found that erythrocytosis occurred in 11% (hematocrit >0.50 L/L), 3.7% (>0.52 L/L), and 0.5% (>0.54 L/L). Risk factors included tobacco use (OR 2.2), long-acting undecanoate injections (OR 2.9), age at initiation (OR 5.9), BMI (OR 3.7), and pulmonary conditions (OR 2.5). Hematocrit increased most in the first year (0.39 to 0.45 L/L), but the probability of developing erythrocytosis still increased over 20 years (10% after 1 year, 38% after 10 years). (source: madsen-2021-jcem-erythrocytosis-trans-men-testosterone.md)
• A 2026 prospective study (n=14 transmasculine adolescents and young adults) found that testosterone therapy lowered speaking fundamental frequency (F0) by 3 months (mean -32.9 Hz) and plateaued by 9 months, with improved voice-gender congruence (TVQ improved from 51.3 to 26.5) and decreased anxiety, though depression scores did not change. (source: ma-2026-evaluation-of-the-effects-of-testosterone-on-voice.md)
• A 2024 systematic review found that all testosterone formulations increase hematocrit in trans men, with short-acting IM esters (enanthate, cypionate) producing supraphysiologic peaks and larger increases (up to 6.9%) compared to undecanoate (up to 5%) and transdermal. Erythrocytosis is associated with tobacco use, age at initiation, BMI, and pulmonary conditions, and trans men have a hazard ratio of 7.4 for developing erythrocytosis compared to cisgender men. (source: okano-2025-andrology-testosterone-formulations-hematocrit-systematic-review.md)
• A 2022 retrospective study (n=67, Melbourne) found that 78% of trans and gender diverse individuals on 1% testosterone gel started below the standard hypogonadal-male dose (median start 25 mg/day), achieving a median total testosterone of 11.9 nmol/L (~343 ng/dL), with 52% having a nonbinary identity. This provides real-world evidence that many people masculinize satisfactorily below the 400-700 ng/dL guideline band. (source: nolan-2022-taem-testosterone-gel-concentrations-trans-gender-diverse.md)
• A 2026 cross-sectional study (n=73: 43 transgender men, 15 cisgender men, 15 cisgender women) found that transgender men on gender-affirming hormone therapy had higher neck circumference, waist-to-hip ratio, waist-to-height ratio, and atherogenic index of plasma compared to cisgender women, with a profile more closely resembling cisgender men. The observed reduction in HDL-C may be of clinical interest, but findings should be interpreted as descriptive differences, not evidence of increased cardiovascular risk. (source: muradov-2026-cross-sectional-comparison-of-cardiometabolic-markers-in-transgende.md)
• A 2026 review on gender-affirming hormone therapy and vascular health finds that GAHT alters leukocyte activation and cytokine secretion, impacting vascular responsiveness, with distinct effects in feminizing and masculinizing regimens. Changes in the gut microbiome and body composition may further modulate inflammatory states with consequences for cardiovascular health. (source: santos-2026-vascular-health-and-gender-affirming-hormone-therapy-the-immune.md)
• A 2017 retrospective cohort study (n=63 FTM transgender patients) found that subcutaneous testosterone cypionate or enanthate injections (median dose 75-80 mg/week) achieved serum total testosterone within the normal male range in all patients, across a wide BMI range (19.0-49.9 kg/m²). Among 22 patients who switched from IM to SC, all preferred SC injections. (source: spratt-2017-subcutaneous-injection-of-testosterone-is-an-effective-and.md)
• A 2026 systematic review of 13 observational cohort studies (n=7,837 transgender men on long-term testosterone therapy) reported 34 cardiovascular deaths, incidence 1.81 per 1,000 person-years, with low to very low certainty of evidence. (source: viana-2026-cardiovascular-mortality-associated-with-testosterone-therapy-in-cisg.md)
• A 2026 prospective study (n=245 transmasculine, 250 transfeminine) found that masculinizing gender-affirming hormone therapy was associated with increased LDL, triglycerides, waist, HbA1c, and decreased HDL over 36 months. Feminizing GAHT was associated with increased weight, BMI, waist, hip, but decreased total cholesterol and triglycerides. (source: christensen-2026-prospective-short-and-long-term-changes-in-cardiometabolic-risk.md)

LGBTQIA+ Cancer Care and Pharmacist Role

• LGBTQIA+ cancer patients often require concurrent therapies including gender-affirming hormone therapy (GAHT), antiretroviral therapy (ART), and oncology treatments, creating risks of drug interactions, cumulative toxicities, and altered pharmacokinetics. Pharmacists must adopt inclusive, culturally competent practices to optimize medication safety. (source: shrestha-2026-beyond-neutrality-in-lgbtqia-cancer-care-optimising-outcomes.md)

Masculinizing Top Surgery

• The Lahey modification for masculinizing top surgery, adapted from the modified Robertson technique for reduction mammoplasty, preserves a sensate and dynamic nipple using an inferiorly-based, bell curve pedicle. A retrospective review of 38 patients (72 nipples) found partial necrosis in 9.7%, decreased sensation in 9.7%, and complete loss of sensation in 1.4%, with no complete nipple loss and high patient satisfaction. (source: kuhn-2026-the-lahey-modification-for-masculinizing-top-surgery-a.md)

Lower Urinary Tract and Genital Symptoms in Trans Men

• A 2026 cross-sectional survey of 322 transgender men in Japan (median age 33) found that 80% reported at least one lower urinary tract symptom (LUTS), 46% reported a bothersome symptom, and 14% had a CLSS global QOL score ≥4. Vaginal symptoms occurred in 13%, and 20% reported activity restriction due to toilet-related concerns. Higher LUTS burden was associated with poorer urinary-related QOL and activity restriction. (source: kobayashi-2026-burden-of-lower-urinary-tract-and-genital-symptoms.md)

Bone Health in Transgender Adolescents

• A 2026 systematic review and meta-analysis of 10 cohorts (n=751 transgender adolescents, 427 AFAB, 324 AMAB) found that GnRHa-based pubertal suppression led to a decline in lumbar spine z scores (AFAB: -0.97, AMAB: -0.73) despite stable BMD. After gender-affirming hormone therapy, BMD increased (AFAB: +0.09 g/cm², AMAB: +0.13 g/cm²), with partial z-score recovery, but values remained below baseline. Higher BMI, shorter GnRHa duration, and longer GAHT exposure were associated with more favorable bone outcomes. The authors recommend timely GAHT initiation. (source: tienforti-2026-bone-accrual-during-puberty-suppression-and-gender-affirming-ther.md)

Turner Syndrome and Androgens

• A 2010 randomized, placebo-controlled, double-blind study (n=133 girls with Turner syndrome) found that the weak androgen oxandrolone (0.03 or 0.06 mg/kg/d) added to growth hormone therapy did not cause evident psychological virilizing side effects. Problem behavior, frequently present in untreated girls, decreased during therapy, but total and internalizing problem behavior remained increased. (source: menke-2010-the-effect-of-the-weak-androgen-oxandrolone-on.md)

Anabolic Steroid Use Disorder

• Problematic anabolic-androgenic steroid (AAS) use is coded under Other (or Unknown) Substance Use Disorder in the DSM-5, with specification of AAS. Global lifetime prevalence of AAS use is estimated at 1-5%, with higher prevalence among males and a notable shift toward initiation for aesthetic or lifestyle reasons rather than athletic competition. (source: parmar-2026-anabolic-steroid-use-disorder.md)
• Nonmedical AAS use typically involves supraphysiologic dosing, cyclic administration, stacking, and prolonged exposure, and is linked to persistent cardiometabolic, endocrine, and neuropsychiatric sequelae. Withdrawal manifestations include fatigue, depressed mood, anhedonia, insomnia, libido changes, severe depression, and suicidality, supporting recognition of AAS misuse as a dependence-like syndrome. (source: parmar-2026-anabolic-steroid-use-disorder.md)
• An exploratory cross-sectional study of female weightlifters (n=32, 16 with reported anabolic-androgenic steroid use) found that AAS users had higher levels of externalizing and internalizing psychopathology, including antisocial and attention problems, and aggressive traits. Dependence symptoms included time spent on AAS activities (50%), using more than planned (42.9%), and were associated with aggressive behavior, attention problems, and anxious/depressive symptoms. (source: scarth-2025-psychological-traits-associated-with-anabolic-androgenic-steroid-use.md)
• A 2021 phenomenological study of 12 women who used anabolic-androgenic steroids found that a sense of pride in achieving goals drives use, creating a tension between suffering and success. (source: womens-experiences-2021-fspor-anabolic-androgenic-steroids.md)

Sarcopenia and Muscle Health

• A 2026 longitudinal study from the Women's Health Initiative (n=1,565 postmenopausal women not on hormone therapy, 3 lean body mass measurements over 6 years) found that higher baseline free testosterone (highest quartile) was associated with 55% lower odds of sarcopenia (OR 0.45), and higher free estradiol with 54% lower odds (OR 0.46). Conversely, higher baseline SHBG was associated with lower total lean mass and higher odds of sarcopenia. (source: osmancevic-2026-endogenous-sex-hormones-sex-hormone-binding-globulin-and-muscle.md)
• A 2025 systematic review on sarcopenia in menopausal women (12 studies, 2015-2025) found prevalence in India ranging from 10% to 43.6%, higher in rural settings and among diabetics. Hormonal declines in estrogen, testosterone, Dehydroepiandrosterone (DHEA), progesterone, and growth hormone/IGF-1, coupled with increased cortisol, contribute to muscle loss. Effective interventions include protein intake of 0.8-1.2 g/kg/day, vitamin D 800-1000 IU/day, 150 min/week aerobic plus resistance training, and hormone therapy. (source: shrikhande-2025-sarcopenia-in-menopausal-women-prevalence-risk-factors-hormonal.md)

Panhypopituitarism and Psychiatric Presentation

• Panhypopituitarism from tuberculous meningitis can present with psychiatric symptoms including apathy and secondary amenorrhea, as in a 2018 case report of a 24-year-old woman with multiple hormonal deficiencies (hypothyroidism, hypocortisolism, hypogonadotropic hypogonadism, hypoprolactinemia) who improved with anti-tuberculosis treatment. (source: sonkar-2018-panhypopituitarism-an-unusual-presenation-of-tuberculous-meningitis.md)

Cardiovascular-Kidney-Metabolic Syndrome and Sex Hormones

• A 2026 NHANES cohort study (n=2,545 patients with cardiovascular-kidney-metabolic syndrome (CKM), mean follow-up 4.78 years) found that higher free androgen index (FAI) was associated with lower all-cause mortality (HR 0.46), and in men aged >60, elevated FAI and testosterone-to-estradiol ratio were each independently associated with reduced all-cause mortality. (source: xie-2026-association-between-endogenous-sex-hormones-and-cardiovascular-kidney-m.md)

Endocrine-Disrupting Chemicals and Sex Hormones

• In NHANES 2013-2016 (n=3,884), urinary metabolites of household pesticides (TCPY, PNP, 3-PBA) were negatively associated with serum total testosterone, estradiol, and free androgen index, and positively associated with SHBG. Associations were more consistent in non-obese individuals. (source: zheng-2026-association-of-exposure-to-household-pesticides-with-concentration.md)