Gender-Affirming Hormone Therapy (GAHT)
Gender-affirming hormone therapy (GAHT) encompasses feminizing regimens (estrogen ± antiandrogens) and masculinizing regimens (testosterone) used to align physical characteristics with gender identity. The Endocrine Society 2017, WPATH Standards of Care Version 8 (2022), ACOG 2021, and AAFP 2023 all recognize GAHT as medically necessary care that improves psychological functioning, quality of life, and reduces gender dysphoria.[1][2][3][4]
This article is the pharmacology reference for the reconstructive urologist and urogynecologist who participates in GAHT-management decisions perioperatively or longitudinally. For surgical detail, see Gender-Affirming Surgery overview. For related hormonal-therapy topics, see Testosterone replacement, Vaginal and topical estrogen, and Androgen adjuncts.
Feminizing GAHT — estrogen ± antiandrogen
Estrogen formulations
The primary agent is 17β-estradiol. Ethinyl estradiol and conjugated estrogens are specifically not recommended — the former carries ~20× higher VTE risk, and both agents preclude serum-level monitoring.[1][5][3]
| Formulation | Dose | Route | Notes |
|---|---|---|---|
| Oral estradiol | 2–6 mg/day (start 2 mg, ↑ to 4 mg after 2 wk) | PO | Most commonly prescribed; higher VTE risk than transdermal[1][5] |
| Transdermal estradiol | 0.1–0.4 mg/24 h patch | Transdermal | Preferred for age >45, smokers, VTE risk factors, BMI >30[1][5] |
| Estradiol valerate | 5–30 mg IM q2 wk (or 10 mg/wk) | IM / SC | Reliable therapeutic levels; VTE risk likely similar to oral[1] |
| Estradiol cypionate | 2–10 mg IM q1–2 wk | IM / SC | Similar to valerate[1] |
| Ethinyl estradiol | — | — | Do not use — ~20× VTE risk; cannot monitor levels[3] |
| Conjugated estrogens | — | — | Not recommended — monitoring impossible; higher thrombotic risk[3] |
Target serum levels (Endocrine Society):[1][5]
- Estradiol 100–200 pg/mL (wider range may be acceptable for individual goals)
- Testosterone <50 ng/dL
Antiandrogen agents
Estrogen alone is usually insufficient to suppress testosterone into the female range — adjunctive antiandrogen is standard.[1]
| Agent | Dose | Mechanism | Key considerations |
|---|---|---|---|
| Spironolactone | 50–200 mg BID (typ. 100 mg BID) | AR antagonist; weak T-synthesis inhibitor | US first-line; monitor K⁺ (hyperkalemia rare in healthy adults); weak estrogenic activity[1][5][3] |
| Cyproterone acetate | 25–50 mg/day | Progestational antiandrogen; suppresses gonadotropins | European first-line; not available in the US; hepatotoxicity, meningioma, and prolactinoma risks[1][4] |
| GnRH agonists (leuprolide, goserelin) | Leuprolide 11.25–22.5 mg IM q3 mo | Suppress LH/FSH → profound T suppression | Most effective suppression; very expensive in US; preferred in adolescents for puberty suppression[1][5] |
| Finasteride | 1–5 mg/day | 5α-reductase inhibitor (T → DHT block) | Does not lower T; useful for scalp-hair and body-hair goals once T is already suppressed[5][3] |
| Progesterone / progestins | Variable | Gonadotropin suppression | Anecdotal breast-development and mood benefit; no well-designed studies; MPA has WHI CV signal[6] |
Timeline of feminizing changes[1][5]
| Change | Onset | Max effect | Reversibility |
|---|---|---|---|
| Breast growth | 3–6 mo | 2–3 y | Irreversible |
| Decreased libido / erections | 1–3 mo | 3–6 mo | Reversible |
| Skin softening / ↓ oiliness | 3–6 mo | Unknown | Reversible |
| Fat redistribution (female) | 3–6 mo | 2–5 y | Reversible |
| Decreased body / facial hair | 6–12 mo | >3 y (usually needs laser / electrolysis) | Reversible |
| Decreased muscle mass / strength | 3–6 mo | 1–2 y | Reversible |
| Testicular atrophy | 3–6 mo | 2–3 y | Irreversible |
| Male-pattern baldness (slowing) | 1–3 mo | 1–2 y | Variable |
| Voice | — | — | N/A — estrogen does not raise pitch; speech therapy required |
Masculinizing GAHT — testosterone
Regimens mirror the treatment of male hypogonadism but target the normal physiologic male range (320–1,000 ng/dL).[1][5] See also Testosterone replacement for the underlying pharmacology.
Testosterone formulations
| Formulation | Dose | Route | Notes |
|---|---|---|---|
| Cypionate | 50–100 mg SC/IM weekly (or 100–200 mg q2 wk) | SC or IM | US first-line; SC increasingly preferred (smaller needle, less pain)[5][3] |
| Enanthate | 50–100 mg SC/IM weekly (or 100–200 mg q2 wk) | SC or IM | Interchangeable with cypionate[1][5] |
| Undecanoate | 1,000 mg IM initially, at 6 wk, then q12 wk | IM only | Long-acting; US REMS required (POME / anaphylaxis)[1][4] |
| Transdermal gel / patch | Gel 50–100 mg/d; patch 2.5–7.5 mg/d | Transdermal | More uniform levels; may not virilize fully; transfer risk to contacts[1][5] |
| Pellets | 150–450 mg SC q3–6 mo | SC implant | Less common; requires minor procedure[5] |
- Testosterone 320–1,000 ng/dL (for injectable esters, measure midway between injections; target 400–700 ng/dL)
- Avoid supraphysiologic levels — erythrocytosis, acne, adverse lipid profile
Timeline of masculinizing changes[1][5]
| Change | Onset | Max effect | Reversibility |
|---|---|---|---|
| Cessation of menses | 2–6 mo | — | Reversible |
| Clitoral enlargement | 3–6 mo | 1–2 y | Irreversible |
| Voice deepening | 3–12 mo | 1–2 y | Irreversible |
| Facial / body hair growth | 6–12 mo | 4–5 y | Irreversible |
| Increased muscle mass | 6–12 mo | 2–5 y | Reversible |
| Fat redistribution (male) | 3–6 mo | 2–5 y | Reversible |
| Acne | 1–6 mo | 1–2 y | Reversible |
| Increased libido | 1–3 mo | Variable | Reversible |
| Male-pattern baldness | 6–12 mo | Variable | Irreversible (genetic) |
| Vaginal atrophy | 3–6 mo | 1–2 y | Reversible |
If menses persist despite adequate T levels, add a progestational agent (e.g., MPA, norethindrone) or consider endometrial ablation.[1][5]
Puberty suppression in adolescents
GnRH agonists (leuprolide, triptorelin, goserelin, histrelin implant) reversibly suppress endogenous puberty beginning at Tanner stage 2.[1][7][8]
Rationale
- Prevents irreversible development of undesired secondary sex characteristics (breast development, voice deepening, facial hair, skeletal changes)
- Extends the diagnostic window for gender-identity exploration
- Improves psychological functioning — reduces depression, anxiety, suicidality
- Improves cosmetic outcomes if the patient later proceeds to GAHT
Key considerations
- Fully reversible — endogenous puberty resumes after cessation
- Bone mineral density declines during treatment (particularly in AMAB individuals); generally recovers with subsequent sex-hormone administration
- Fertility implications — GnRHa inhibits spermatogenesis and ovulation; fertility preservation counseling before initiation
- Growth — height velocity slows during treatment; final height generally within genetic target
Signal from real-world data
Nos 2022 (JAMA Netw Open, n = 2,688 transgender adolescents) — GnRHa use was associated with a longer median time before starting GAHT, supporting the concept that puberty suppression functions as a true "pause" rather than a commitment device to GAHT.[9]
Cardiovascular and thromboembolic risk — the dominant safety concern
Feminizing GAHT — VTE
Transfeminine persons on estrogen have higher VTE incidence than cisgender women or cisgender men, with the highest risk in the first year after initiation. Much of the historical signal reflects ethinyl estradiol — which is no longer recommended. Transdermal estradiol has a substantially better risk profile.[10]
van Zijverden 2025 Dutch cohort (n = 2,714 transfeminine; 23,907 person-years):[11]
- MI: SIR 0.50 (95% CI 0.32–0.71) — lower than general-population men
- Stroke: SIR 0.94 (0.72–1.19) — similar
- VTE: SIR 1.81 (1.33–2.35) — higher
Masculinizing GAHT — CV
Same Dutch cohort (n = 1,617 transmasculine; 13,457 person-years):[11]
- MI: SIR 4.20 (2.72–6.01) — significantly higher than general-population women
- Stroke: SIR 1.55 (1.01–2.20) — higher
- VTE: SIR 1.00 (0.53–1.61) — similar
Testosterone is also associated with erythrocytosis (most common AE), adverse lipid profile (↓HDL, ↑LDL), and higher BP.[1][3][12]
Risk-mitigation
- Transdermal estradiol over oral for age >45, smokers, BMI >30, VTE risk[5][10]
- Avoid ethinyl estradiol and conjugated estrogens entirely[1][10]
- Smoking cessation strongly encouraged[5]
- Monitor hematocrit in transmasculine patients — target <54%; reduce dose or investigate if higher[1][3]
- Discontinue estrogen 4–6 weeks before major surgery with high VTE risk[13]
- Standard CV risk-factor management (lipids, BP, diabetes screening)[1][12]
Monitoring protocols
Feminizing GAHT[1][5]
| Parameter | Frequency | Target / action |
|---|---|---|
| Serum estradiol | q3 mo × 1 y, then 1–2×/y | 100–200 pg/mL |
| Serum testosterone | q3 mo × 1 y, then 1–2×/y | <50 ng/dL |
| Potassium (if on spironolactone) | q3 mo × 1 y, then annually | Monitor for hyperkalemia |
| Prolactin | Periodically | Monitor for prolactinoma (rare) |
| Fasting lipids, glucose / HbA1c | Baseline then periodically | Standard CV-risk assessment |
| LH | Consider at follow-ups | Helps assess gonadal suppression |
| CBC | Baseline then annually | Hemoglobin may decrease |
| BMD | Baseline if risk factors; age 60 if low-risk; after gonadectomy without hormone replacement | Osteoporosis screening |
Masculinizing GAHT[1][5]
| Parameter | Frequency | Target / action |
|---|---|---|
| Serum testosterone | q3 mo × 1 y, then 1–2×/y | 400–700 ng/dL (midway between ester injections) |
| Hematocrit / hemoglobin | q3 mo × 1 y, then 1–2×/y | Hct <54%; reduce dose or investigate if higher |
| Fasting lipids | Baseline then periodically | ↓ HDL, ↑ LDL / TG expected |
| Weight, BP | Every visit | Hypertension and weight gain surveillance |
| BMD | If T discontinued, non-compliant, or risk factors | Osteoporosis screening |
| Cervical screening (if cervix present) | Per ACOG | T-induced atrophy → 10× higher unsatisfactory Pap rate; self-collected HPV may be preferable[3] |
Cancer screening — screen organs present, not identity
Screening is based on the anatomy present, regardless of gender identity.[14][15][16]
Breast
- Transfeminine — breast cancer incidence is lower than cisgender women (~4.1 vs 155 per 100,000 person-years) but higher than cisgender men. Screening mammography after age 50 + ≥5 years of feminizing GAHT. Dense breast tissue (60%) may increase false negatives.[14][15]
- Transmasculine — if breast tissue remains (reduction mammoplasty, not mastectomy), follow cisgender female guidelines. After mastectomy, limited data support routine screening beyond clinical chest exam.[15]
Cervical
All individuals with a cervix should follow standard screening guidelines. Transmasculine patients have lower screening rates due to discomfort and structural barriers; testosterone-induced atrophy drives a 10-fold higher rate of unsatisfactory Paps. Self-collected HPV testing may improve adherence.[14][3]
Prostate
Transfeminine patients retain their prostate regardless of surgery. PSA is substantially lowered by feminizing GAHT — median 0.02 ng/mL in one series. A PSA >1 ng/mL should be regarded as the upper limit of normal in this population; rising PSA warrants attention. Standard age-appropriate shared decision-making applies.[14][16][17]
Fertility preservation — counsel before initiating
Transfeminine
- Estrogen + antiandrogens cause increased sperm abnormalities, reduced count and motility, or azoospermia. Spermatogenesis may partially recover after cessation but is not guaranteed[18][19]
- Sperm cryopreservation should be offered before starting GAHT[4][20]
Transmasculine
- Testosterone causes ovarian cortical / stromal changes but persistent folliculogenesis is observed in most studies. Successful oocyte stimulation, fertilization, and live birth have been reported both with and without T discontinuation[18]
- Oocyte or embryo cryopreservation should be offered before starting GAHT[4][20]
- Testosterone is NOT reliable contraception — pregnancies have occurred during T therapy[5][4]
- Discontinue T before a planned pregnancy until after delivery and any chest-feeding[4]
Urologic considerations
Feminizing GAHT
- Decreased erectile function and testicular atrophy are expected[5]
- Prostate undergoes atrophy over time (diffuse atrophy + basal-cell hyperplasia on histology)[15]
- After vaginoplasty, the shortened neourethra is generally uneventful, but urinary complications can occur[21]
Masculinizing GAHT
- Vaginal atrophy is common — dyspareunia, dryness, and urinary symptoms[5][22]
- da Silva 2024 cross-section (n = 68 transmasculine on T) — 94.1% prevalence of pelvic-floor dysfunction: storage symptoms 69.1%, sexual dysfunction 52.9%, anorectal symptoms 45.6%, urinary incontinence substantial[22]
- After phalloplasty, urethral lengthening drives fistulae, strictures, meatal stenosis, and post-voiding dribble — see the reconstructive literature[21]
Bone health
- Feminizing: adequate estrogen maintains BMD. Screen at baseline if risk factors; at age 60 if low-risk; after gonadectomy without hormone replacement[1]
- Masculinizing: adequate testosterone maintains BMD. Screen if T discontinued, non-compliant, or other risk factors[1]
- GnRHa in adolescents: BMD declines during treatment, generally recovering with subsequent sex-hormone administration[8]
Drug interactions
| Interaction | Effect | Practical |
|---|---|---|
| Boosted PI antiretrovirals | May decrease estradiol and increase T | Adjust monitoring; check levels[23] |
| NNRTIs (efavirenz, etravirine, nevirapine) | May decrease both estradiol and T | Same — monitor[23] |
| Spironolactone + ACE-I / ARB / K⁺ supp / NSAIDs | Hyperkalemia | Monitor K⁺[1] |
| Smoking | Increases VTE risk synergistically with estrogen | Strongly encourage cessation[5] |
| Perioperative | Estrogen — discontinue 4–6 wk before high-VTE surgery; T generally continued perioperatively | Individualize[13] |
Mental-health outcomes
Multiple longitudinal and cross-sectional studies demonstrate that GAHT is associated with:[24][8]
- Reduced depression, anxiety, suicidality
- Improved global psychological functioning
- Improved QoL and body satisfaction
- Reduced gender dysphoria
The 2019 NEJM review (Safer & Tangpricha) summarized that gender-affirming care — including hormone therapy — is supported by multiple medical societies as medically necessary treatment that improves well-being.[3]
Evidence Summary
| Domain | Evidence level | Key source |
|---|---|---|
| Guideline framework | Level 1 | Endocrine Society 2017[1]; WPATH v8 (via Dakkak 2023)[4]; ACOG 2021[2] |
| Feminizing regimens and targets | Level 2 | Goldstein 2025[5]; Safer 2019[3] |
| Masculinizing regimens and targets | Level 2 | Endocrine Society[1]; Irwig 2017[25] |
| Puberty suppression | Level 2 | Tornese 2025 SR[8]; Nos 2022[9] |
| CV and VTE risk | Level 2 (large cohort) | van Zijverden 2025 Dutch cohort[11]; Skeith 2026 NEJM review[10] |
| Fertility preservation | Level 2 | De Roo 2025 systematic review[18] |
| Pelvic-floor dysfunction on testosterone | Level 3 | da Silva 2024[22] |
| Cancer screening | Level 3 (consensus) | Leone 2023 JAMA Oncol[14]; NCCN[15][17] |
Clinical Positioning
- Use 17β-estradiol, never ethinyl estradiol or conjugated estrogens — the historical VTE signal largely traces to ethinyl estradiol, and monitoring requires 17β-estradiol assays.[1][10]
- Prefer transdermal estradiol in patients >45 y, smokers, BMI >30, or with VTE risk factors. Oral is acceptable in low-risk patients, with full informed consent.[5][10]
- Spironolactone is US first-line antiandrogen; GnRH agonist is the most effective T-suppression; cyproterone is the European standard but unavailable in the US and carries meningioma / hepatotoxicity flags.[1]
- Testosterone in transmasculine adults mirrors male-hypogonadism care — target 400–700 ng/dL midway between ester injections; hematocrit is the dose-limiting lab at >54%.[1]
- Testosterone is NOT contraception. Counsel explicitly and provide contraception separately if pregnancy avoidance is desired.[4][5]
- Fertility-preservation counseling must precede GAHT initiation — sperm cryopreservation (transfeminine) or oocyte / embryo cryopreservation (transmasculine). See Androgen adjuncts for the post-treatment fertility-recovery armamentarium.[4][18]
- Cancer screening follows anatomy, not identity. Prostate, cervix, and breast all require organ-based screening. PSA >1 ng/mL is the upper limit in transfeminine patients on estrogen.[14][16]
- CV risk is higher in both populations — Dutch cohort shows a ~4× MI-risk elevation in transmasculine patients (vs cis women) and a ~1.8× VTE-risk elevation in transfeminine patients (vs general population). Actively manage traditional CV risk factors alongside GAHT.[11][12]
- For perioperative management of a major surgery with high VTE risk, discontinue estrogen 4–6 weeks preoperatively; testosterone generally continues.[13]
- Transmasculine pelvic-floor dysfunction is nearly universal (94% per da Silva 2024) and should be actively screened and treated — pelvic-floor PT, vaginal estrogen if acceptable, and counseling about dyspareunia and vaginal atrophy.[22]
- Puberty suppression in adolescents is fully reversible and extends the diagnostic window; it is not a commitment device — Nos 2022 shows it delays rather than accelerates progression to GAHT.[9]
- Monitoring cadence is q3 months in year 1, then 1–2×/year for both feminizing and masculinizing regimens, with the parameters above.[1][5]
See Also
- Vaginal and topical estrogen
- Vaginal DHEA
- Ospemifene
- Testosterone replacement
- Androgen adjuncts — fertility-preserving alternatives
References
1. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. "Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline." J Clin Endocrinol Metab. 2017;102(11):3869–3903. doi:10.1210/jc.2017-01658
2. American College of Obstetricians and Gynecologists. Health care for transgender and gender-diverse individuals. Cronin B, Stockdale CK. ACOG; 2021.
3. Safer JD, Tangpricha V. "Care of transgender persons." N Engl J Med. 2019;381(25):2451–2460. doi:10.1056/NEJMcp1903650
4. Dakkak M, Kriegel DL, Tauches K. "Caring for transgender and gender-diverse people: guidelines from WPATH." Am Fam Physician. 2023;108(6):626–629.
5. Goldstein Z, Krasowski MD, Greene DN. "Gender-affirming feminizing hormone therapy." JAMA Intern Med. 2025;185(8):1027–1028. doi:10.1001/jamainternmed.2025.1161
6. Crandall CJ, Mehta JM, Manson JE. "Management of menopausal symptoms: a review." JAMA. 2023;329(5):405–420. doi:10.1001/jama.2022.24140
7. Turban JL, Thornton J, Ehrensaft D. "Biopsychosocial assessments for pubertal suppression to treat adolescent gender dysphoria." J Am Acad Child Adolesc Psychiatry. 2025;64(1):12–16. doi:10.1016/j.jaac.2024.03.016
8. Tornese G, Di Mase R, Munarin J, et al. "Use of gonadotropin-releasing hormone agonists in transgender and gender-diverse youth: a systematic review." Front Endocrinol. 2025;16:1555186. doi:10.3389/fendo.2025.1555186
9. Nos AL, Klein DA, Adirim TA, et al. "Association of gonadotropin-releasing hormone analogue use with subsequent use of gender-affirming hormones among transgender adolescents." JAMA Netw Open. 2022;5(11):e2239758. doi:10.1001/jamanetworkopen.2022.39758
10. Skeith L, Bates SM. "Sex hormone influences on venous thrombotic and cardiovascular risk." N Engl J Med. 2026;394(15):1514–1528. doi:10.1056/NEJMra2202438
11. van Zijverden LM, Thijs A, van Diemen JJK, Wiepjes CM, den Heijer M. "Transgender persons receiving gender-affirming hormone therapy: risk of acute cardiovascular events in a Dutch cohort study." Eur Heart J. 2025;ehaf837. doi:10.1093/eurheartj/ehaf837
12. Glintborg D, Christensen LL, Andersen MS. "Transgender healthcare: metabolic outcomes and cardiovascular risk." Diabetologia. 2024;67(11):2393–2403. doi:10.1007/s00125-024-06212-6
13. Rosendale N, Goldman S, Ortiz GM, Haber LA. "Acute clinical care for transgender patients: a review." JAMA Intern Med. 2018;178(11):1535–1543. doi:10.1001/jamainternmed.2018.4179
14. Leone AG, Trapani D, Schabath MB, et al. "Cancer in transgender and gender-diverse persons: a review." JAMA Oncol. 2023;9(4):556–563. doi:10.1001/jamaoncol.2022.7173
15. National Comprehensive Cancer Network. NCCN clinical practice guidelines: genetic / familial high-risk assessment — breast, ovarian, pancreatic, and prostate. Updated 2026-02-19.
16. National Comprehensive Cancer Network. NCCN clinical practice guidelines: prostate cancer early detection. Updated 2026-02-18.
17. Leone AG, Casolino R, Trapani D, et al. "Position paper of the Italian Association of Medical Oncology on health disparities among transgender and gender-diverse people: the Assisi Recommendations." EClinicalMedicine. 2023;65:102277. doi:10.1016/j.eclinm.2023.102277
18. De Roo C, Schneider F, Stolk THR, et al. "Fertility in transgender and gender-diverse people: systematic review of the effects of gender-affirming hormones on reproductive organs and fertility." Hum Reprod Update. 2025;31(3):183–217. doi:10.1093/humupd/dmae036
19. Ainsworth AJ, Allyse M, Khan Z. "Fertility preservation for transgender individuals: a review." Mayo Clin Proc. 2020;95(4):784–792. doi:10.1016/j.mayocp.2019.10.040
20. Schwartz AR, Moravek MB. "Reproductive potential and fertility preservation in transgender and nonbinary individuals." Curr Opin Obstet Gynecol. 2021;33(4):327–334. doi:10.1097/GCO.0000000000000729
21. Trum HW, Hoebeke P, Gooren LJ. "Sex reassignment of transsexual people from a gynecologist's and urologist's perspective." Acta Obstet Gynecol Scand. 2015;94(6):563–567. doi:10.1111/aogs.12618
22. da Silva LMB, Freire SND, Moretti E, Barbosa L. "Pelvic floor dysfunction in transgender men on gender-affirming hormone therapy: a descriptive cross-sectional study." Int Urogynecol J. 2024;35(5):1077–1084. doi:10.1007/s00192-024-05779-3
23. Horberg M, Thompson M, Agwu A, et al. "Primary care guidance for providers of care for persons with HIV: 2024 update by the HIV Medicine Association of the Infectious Diseases Society of America." Clin Infect Dis. 2024;ciae479. doi:10.1093/cid/ciae479
24. T'Sjoen G, Arcelus J, Gooren L, Klink DT, Tangpricha V. "Endocrinology of transgender medicine." Endocr Rev. 2019;40(1):97–117. doi:10.1210/er.2018-00011
25. Irwig MS. "Testosterone therapy for transgender men." Lancet Diabetes Endocrinol. 2017;5(4):301–311. doi:10.1016/S2213-8587(16)00036-X