Feminizing hormone therapy

[1][4][14] Conjugated estrogens (Premarin), which are used in menopausal hormone therapy, and ethinylestradiol, which is used in birth control pills, have been used in transgender women in the past, but are no longer recommended and are rarely used today due to their higher risks of blood clots and cardiovascular problems.

[14][15][16][17] Parenteral (non-oral) routes are practically preferred, owing to a minimal or negligible risk of blood clots and cardiovascular issues.

[74][75] In addition, androgens stimulate sex drive and the frequency of spontaneous erections and are responsible for acne, body odor, and androgen-dependent scalp hair loss.

[72][118] However, this occurs mostly in prostate cancer patients who take very high doses of cyproterone acetate; liver toxicity has not been reported in transgender women.

[72] Cyproterone acetate also has a variety of other adverse effects, such as fatigue and weight gain, and risks, such as blood clots and benign brain tumors, among others.

[130][136] The nonsteroidal antiandrogens that have been used in transgender women include the first-generation medications flutamide (Eulexin), nilutamide (Anandron, Nilandron), and bicalutamide (Casodex).

[38][137][5][3]Newer and even more efficacious second-generation nonsteroidal antiandrogens like enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) also exist, but are very expensive due to generics being unavailable and have not been used in transgender women.

[154] As a result of this, GnRH modulators are able to completely shut-down gonadal sex hormone production, and can decrease testosterone levels in men and transgender women by about 95%, or to an equivalent extent as surgical castration.

[160] Antigonadotropins such as estrogens and cyproterone acetate as well as nonsteroidal antiandrogens such as flutamide and bicalutamide can be used beforehand and concomitantly to reduce or prevent the effects of the testosterone flare caused by GnRH agonists.

[1][165] GnRH agonists are prescribed as standard practice for transgender women in the United Kingdom however, where the National Health Service (NHS) covers them.

The eighth edition of the World Professional Association for Transgender Health's Standards of Care permit its use from Tanner stage 2 and recommends GnRH agonists as the preferred method of puberty blocking.

[171][172] However, 5α-reductase is expressed only in specific tissues, such as skin, hair follicles, and the prostate gland, and for this reason, conversion of testosterone into DHT happens only in certain parts of the body.

[191] Dutasteride has been found to be significantly more effective than finasteride in the treatment of scalp hair loss in men, which has been attributed to its more complete inhibition of 5α-reductase and by extension decrease in DHT production.

[2][212] Some patients and clinicians believe, on the basis of anecdotal and subjective claims, that progestogens may provide benefits such as improved breast and/or nipple development, mood, and libido in transgender women.

[64][228][212] A study found full lobuloalveolar maturation of the mammary glands on histological examination in transgender women treated with an estrogen and high-dose cyproterone acetate.

[229] In terms of the effects of progestogens on sex drive, one study assessed the use of dydrogesterone to improve sexual desire in transgender women and found no benefit.

[238][239] Because of their potential detrimental effects and lack of supported benefits, some researchers have argued that, aside from the purpose of testosterone suppression, progestogens should not generally be used or advocated in transgender women or should only be used for a limited duration (e.g., 2–3 years).

[236][197][5][6][216] Conversely, other researchers have argued that the risks of progestogens in transgender women are likely minimal, and that in light of potential albeit hypothetical benefits, should be used if desired.

[14] Galactogogues such as the peripherally selective D2 receptor antagonist and prolactin releaser domperidone can be used to induce lactation in transgender women who wish to breastfeed.

[251][228][250][64][252] The World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8), released in September 2022, recommends against therapeutic strategies including supraphysiological estradiol levels (>200 pg/mL), use of progesterone (including rectal progesterone), use of bicalutamide, and monitoring of the ratio of estrone to estradiol.

[236] Several studies have found that hormone therapy in transgender women causes the structure of the brain to change in the direction of female proportions.

[272] The age of starting and stopping hormone therapy seems to be a significant factor, but no direct causation has been found between length of treatment and ability to reproduce.

[279] Transgender individuals are encouraged to ingest at least 1g of Calcium and 1000 IU of Vitamin D daily, engage regularly in weight-bearing physical activity, and reduce alcohol and smoking consumption.

Effects on hair size and density were noticeable in the first four months following the start of hormone therapy, but later subsided, with measurements staying constant.

[277] In patients in their teens or early twenties, antiandrogens prevent new facial hair from developing if testosterone levels are within the normal female range.

[292][153][20] Increased risk of VTE with estrogens is thought to be due to their influence on liver protein synthesis, specifically on the production of coagulation factors.

[198] A 2018 cohort study of 2842 transfeminine individuals in the United States treated with a mean follow-up of 4.0 years observed an increased risk of VTE, stroke, and heart attack relative to a cisgender reference population.

[74][313] The risk of breast cancer in women with Turner syndrome (45,XO karyotype) also appears to be significantly decreased, though this could be related to ovarian failure and hypogonadism rather than to genetics.

Transgender individuals who have undergone male puberty often opt for vocal training, though this may take many years of practice to achieve the desired results.

[327][328][329][330] Additional reports of hormone therapy in transgender women were published by Hamburger, the German-American endocrinologist Harry Benjamin, and other researchers in the mid-to-late 1960s.

Estradiol blood levels with rectal administration.
Estradiol levels with oral versus sublingual routes of administration of estradiol in postmenopausal women.
Testosterone levels in relation to estradiol levels (and corresponding estradiol dosages) during therapy with oral estradiol alone or in combination with an antiandrogen in transgender women. [ 28 ] The dashed purple line is the upper limit for the female/castrate range (~50 ng/dL) and the dashed grey line is the testosterone level in a comparison group of post-operative transgender women (21.7 ng/dL). [ 28 ]
Estradiol and testosterone levels over 12 weeks after a single intramuscular injection of 320 mg polyestradiol phosphate , a polymeric estradiol ester and prodrug, in men with prostate cancer. [ 71 ] Demonstrates the suppression of testosterone levels by parenteral estradiol.
Testosterone levels with estradiol (E2) alone or in combination with an antiandrogen (AA) in the form of spironolactone (SPL) or cyproterone acetate (CPA) in transfeminine people. [ 90 ] Estradiol was used in the form of oral estradiol valerate (EV) in almost all cases. [ 90 ] The dashed horizontal line is the upper limit of the female/castrate range (~50 ng/dL).
Well-developed breasts of transgender woman induced by hormone therapy.