Transgender hormone therapy (male-to-female)

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.[14] Demonstrates the suppression of testosterone levels by parenteral estradiol.

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.[15] 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 pg/mL).[15]

Estrogens are the major sex hormones in women, and are responsible for the development and maintenance of feminine secondary sexual characteristics, such as breasts, wide hips, and a feminine pattern of fat distribution.[4] Estrogens act by binding to and activating the estrogen receptor (ER), their biological target in the body.[16] A variety of different forms of estrogens are available and used medically.[16] The most common estrogens used in transgender women include estradiol, which is the predominant natural estrogen in women, and estradiol esters such as estradiol valerate and estradiol cypionate, which are prodrugs of estradiol.[1][4][16] 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.[4][1][2][5] Estrogens may be administered orally, sublingually, transdermally/topically (via patch or gel), rectally, by intramuscular or subcutaneous injection, or by an implant.[16][17][18][19][20] Parenteral (non-oral) routes are preferred, owing to a minimal or negligible risk of blood clots and cardiovascular issues.[5][21][22][23][24]

In addition to producing feminization, estrogens have antigonadotropic effects and suppress gonadal sex hormone production.[17][15][25] They are mainly responsible for the suppression of testosterone levels in transgender women.[17][25] Levels of estradiol of 200 pg/mL and above suppress testosterone levels by about 90%, while estradiol levels of 500 pg/mL and above suppress testosterone levels by about 95%, or to an equivalent extent as surgical castration and GnRH modulators.[26][27] Lower levels of estradiol can also considerably but incompletely suppress testosterone production.[15] When testosterone levels are insufficiently suppressed by estradiol alone, antiandrogens can be used to suppress or block the effects of residual testosterone.[17] Oral estradiol often has difficulty adequately suppressing testosterone levels, due to the relatively low estradiol levels achieved with it.[15][28][29]

Prior to orchiectomy (surgical removal of the gonads) or sex reassignment surgery, the doses of estrogens used in transgender women are often higher than replacement doses used in cisgender women.[30][31][32] This is to help suppress testosterone levels.[31] The Endocrine Society (2017) recommends maintaining estradiol levels roughly within the normal average range for premenopausal women of about 100 to 200 pg/mL.[1] However, it notes that these physiological levels of estradiol are usually unable to suppress testosterone levels into the female range.[1] A 2018 Cochrane review proposal questioned the notion of keeping estradiol levels lower in transgender women, which results in incomplete suppression of testosterone levels and necessitates the addition of antiandrogens.[33] The review proposal noted that high-dose parenteral estradiol is known to be safe.[33] The Endocrine Society itself recommends dosages of injected estradiol esters that result in estradiol levels markedly in excess of the normal female range, for instance 10 mg per week estradiol valerate by intramuscular injection.[1] A single such injection results in estradiol levels of about 1,250 pg/mL at peak and levels of around 200 pg/mL after 7 days.[34][35] Dosages of estrogens can be reduced after an orchiectomy or sex reassignment surgery, when gonadal testosterone suppression is no longer needed.[5]

Antiandrogens are medications that prevent the effects of androgens in the body.[36][37] Androgens, such as testosterone and dihydrotestosterone (DHT), are the major sex hormones in individuals with testes, and are responsible for the development and maintenance of masculine secondary sex characteristics, such as a deep voice, broad shoulders, and a masculine pattern of hair, muscle, and fat distribution.[38][39] 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.[38][39] They also have functional antiestrogenic effects in the breasts and oppose estrogen-mediated breast development, even at low levels.[40][41][42][43] Androgens act by binding to and activating the androgen receptor, their biological target in the body.[44] Antiandrogens work by blocking androgens from binding to the androgen receptor and/or by inhibiting or suppressing the production of androgens.[36]

Antiandrogens that directly block the androgen receptor are known as androgen receptor antagonists or blockers, while antiandrogens that inhibit the enzymatic biosynthesis of androgens are known as androgen synthesis inhibitors and antiandrogens that suppress androgen production in the gonads are known as antigonadotropins.[37] Estrogens and progestogens are antigonadotropins and hence are functional antiandrogens.[17][45][46][47] The purpose of the use of antiandrogens in transgender women is to block or suppress residual testosterone that is not suppressed by estrogens alone.[17][36][25] Additional antiandrogen therapy is not necessarily required if testosterone levels are in the normal female range or if the person has undergone orchiectomy.[17][36][25] However, individuals with testosterone levels in the normal female range and with persisting androgen-dependent skin and/or hair symptoms, such as acne, seborrhea, oily skin, or scalp hair loss, can potentially still benefit from the addition of an antiandrogen, as antiandrogens can reduce or eliminate such symptoms.[48][49][50]

Steroidal antiandrogens are antiandrogens that resemble steroid hormones like testosterone and progesterone in chemical structure.[51] They are the most commonly used antiandrogens in transgender women.[2] Spironolactone (Aldactone), which is relatively safe and inexpensive, is the most frequently used antiandrogen in the United States.[52][53] Cyproterone acetate (Androcur), which is unavailable in the United States, is widely used in Europe, Canada, and the rest of the world.[2][36][52][54] Medroxyprogesterone acetate (Provera, Depo-Provera), a similar medication, is sometimes used in place of cyproterone acetate in the United States.[55][56]

Spironolactone is an antimineralocorticoid (antagonist of the mineralocorticoid receptor) and potassium-sparing diuretic, which is mainly used to treat high blood pressure, edema, high aldosterone levels, and low potassium levels caused by other diuretics, among other uses.[57] Spironolactone is an antiandrogen as a secondary and originally unintended action.[57] It works as an antiandrogen mainly by acting as an androgen receptor antagonist.[58] The medication is also a weak steroidogenesis inhibitor, and inhibits the enzymatic synthesis of androgens.[59][58][60] However, this action is of very low potency, and spironolactone has mixed and highly inconsistent effects on hormone levels.[59][58][60][61][62] In any case, testosterone levels are usually unchanged by spironolactone.[59][58][60][61][62] In accordance, a relatively large study found no effect of spironolactone on testosterone levels in transgender women.[15] Spironolactone is described as a relatively weak antiandrogen.[63][64][65] It is widely used in the treatment of acne, excessive hair growth, and hyperandrogenism in women, who have much lower testosterone levels than men.[61][62] Because of its antimineralocorticoid activity, spironolactone has antimineralocorticoid side effects[66] and can cause high potassium levels.[67][68] Hospitalization and/or death can potentially result from high potassium levels due to spironolactone,[67][68][69] but the risk of high potassium levels in people taking spironolactone appears to be minimal in those without risk factors for it.[62][70][71] As such, monitoring of potassium levels may not be necessary in most cases.[62][70][71] Spironolactone has been found to decrease the bioavailability of high doses of oral estradiol.[15] Although widely employed, the use of spironolactone as an antiandrogen in transgender women has recently been questioned due to the various shortcomings of the medication for such purposes.[15]

Testosterone and luteinizing hormone levels with 100 mg/day oral cyproterone acetate in men.[72]

Testosterone levels with 100–300 mg/day oral cyproterone acetate and low-dose oral estrogen in men with prostate cancer.[73] The estrogen used was 0.1 mg/day diethylstilbestrol,[73] which has been described as an "extremely low" dosage.[74]

Cyproterone acetate is an antiandrogen and progestin which is used in the treatment of numerous androgen-dependent conditions and is also used as a progestogen in birth control pills.[75][76] It works primarily as an antigonadotropin, secondarily to its potent progestogenic activity, and strongly suppresses gonadal androgen production.[75][25] Cyproterone acetate at a dosage of 5 to 10 mg/day has been found to lower testosterone levels in men by about 50 to 70%,[77][78][79][80] while a dosage of 100 mg/day has been found to lower testosterone levels in men by about 75%.[81][82] The combination of 25 mg/day cyproterone acetate and a moderate dosage of estradiol has been found to suppress testosterone levels in transgender women by about 95%.[83] In addition to its actions as an antigonadotropin, cyproterone acetate is an androgen receptor antagonist.[75][36] However, this action is relatively insignificant at low dosages, and is more important at the high doses of cyproterone acetate that are used in the treatment of prostate cancer (100–300 mg/day).[84][85] Cyproterone acetate can cause elevated liver enzymes and liver damage, including liver failure.[36][86] 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.[36] 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.[25][36][87] Periodic monitoring of liver enzymes and prolactin levels may be advisable during cyproterone acetate therapy.

Medroxyprogesterone acetate is a progestin that is related to cyproterone acetate and is sometimes used as an alternative to it.[55][56] It is specifically used as an alternative to cyproterone acetate in the United States, where cyproterone acetate is not approved for medical use and is unavailable.[55][56] Medroxyprogesterone acetate suppresses testosterone levels in transgender women similarly to cyproterone acetate.[56][15] Oral medroxyprogesterone acetate has been found to suppress testosterone levels in men by about 30 to 75% across a dosage range of 20 to 100 mg/day.[88][89][90][91][92] In contrast to cyproterone acetate however, medroxyprogesterone acetate is not also an androgen receptor antagonist.[16][93] Medroxyprogesterone acetate has similar side effects and risks as cyproterone acetate, but is not associated with liver problems.[94][66]

Numerous other progestogens and by extension antigonadotropins have been used to suppress testosterone levels in men and are likely useful for such purposes in transgender women as well.[95][96][97][98][99][100][101] Progestogens alone are in general able to suppress testosterone levels in men by a maximum of about 70 to 80%, or to just above female/castrate levels when used at sufficiently high doses.[102][103][104] The combination of a sufficient dosage of a progestogen with very small doses of an estrogen (e.g., as little as 0.5–1.5 mg/day oral estradiol) is synergistic in terms of antigonadotropic effect and is able to fully suppress gonadal testosterone production, reducing testosterone levels to the female/castrate range.[74][105]

Nonsteroidal antiandrogens are antiandrogens which are nonsteroidal and hence unrelated to steroid hormones in terms of chemical structure.[51][106] These medications are primarily used in the treatment of prostate cancer,[106] but are also used for other purposes such as the treatment of acne, excessive facial/body hair growth, and high androgen levels in women.[107][108][109][110] Unlike steroidal antiandrogens, nonsteroidal antiandrogens are highly selective for the androgen receptor and act as pure androgen receptor antagonists.[106][111] Similarly to spironolactone however, they do not lower androgen levels, and instead work exclusively by preventing androgens from activating the androgen receptor.[106][111] Nonsteroidal antiandrogens are more efficacious androgen receptor antagonists than are steroidal antiandrogens,[51][112] and for this reason, in conjunction with GnRH modulators, have largely replaced steroidal antiandrogens in the treatment of prostate cancer.[106][113]

The nonsteroidal antiandrogens that have been used in transgender women include the first-generation medications flutamide (Eulexin), nilutamide (Anandron, Nilandron), and bicalutamide (Casodex).[107][114][5][3][115]^:477 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.[116][117] Flutamide and nilutamide have relatively high toxicity, including considerable risks of liver damage and lung disease.[118][108] Due to its risks, the use of flutamide in cisgender and transgender women is now limited and discouraged.[107][108][5] Flutamide and nilutamide have largely been superseded by bicalutamide in clinical practice,[119][120] with bicalutamide accounting for almost 90% of nonsteroidal antiandrogen prescriptions in the United States by the mid-2000s.[121][111] Bicalutamide is said to have excellent tolerability and safety relative to flutamide and nilutamide, as well as in comparison to cyproterone acetate.[122][123][124] It has few to no side effects in women.[109][110] Despite its greatly improved tolerability and safety profile however, bicalutamide does still have a small risk of elevated liver enzymes and association with very rare cases of liver damage and lung disease.[107][118][125]

Nonsteroidal antiandrogens like bicalutamide may be a particularly favorable option for transgender women who wish to preserve sex drive, sexual function, and/or fertility, relative to antiandrogens that suppress testosterone levels and can greatly disrupt these functions such as cyproterone acetate and GnRH modulators.[126][127][128] However, estrogens suppress testosterone levels and at high doses can markedly disrupt sex drive and function and fertility on their own.[129][130][131][132] Moreover, disruption of gonadal function and fertility by estrogens may be permanent after extended exposure.[131][132]

GnRH modulators are powerful antigonadotropins and hence functional antiandrogens.[133] In both males and females, gonadotropin-releasing hormone (GnRH) is produced in the hypothalamus and induces the secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland.[133] The gonadotropins signal the gonads to make sex hormones such as testosterone and estradiol.[133] GnRH modulators bind to and inhibit the GnRH receptor, thereby preventing gonadotropin release.[133] 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.[133][134][135] GnRH modulators are also commonly known as GnRH analogues.[133] However, not all clinically used GnRH modulators are analogues of GnRH.[136]

There are two types of GnRH modulators: GnRH agonists and GnRH antagonists.[133] These medications have the opposite action on the GnRH receptor but paradoxically have the same therapeutic effects.[133] GnRH agonists, such as leuprorelin (Lupron), goserelin (Zoladex), and buserelin (Suprefact), are GnRH receptor superagonists, and work by producing profound desensitization of the GnRH receptor such that the receptor becomes non-functional.[133][134] This occurs because GnRH is normally released in pulses, but GnRH agonists are continuously present, and this results in excessive downregulation of the receptor and ultimately a complete loss of function.[137][138][133] At the initiation of treatment, GnRH agonists are associated with a "flare" effect on hormone levels due to acute overstimulation of the GnRH receptor.[133][139] In men, LH levels increase by up to 800%, while testosterone levels increase to about 140 to 200% of baseline.[140][139] Gradually however, the GnRH receptor desensitizes; testosterone levels peak after about 2 to 4 days, return to baseline after about 7 to 8 days, and are reduced to castrate levels within 2 to 4 weeks.[139] 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.[141][140][142][143][17][144] In contrast to GnRH agonists, GnRH antagonists, such as degarelix (Firmagon) and elagolix (Orilissa), work by binding to the GnRH receptor without activating it, thereby displacing GnRH from the receptor and preventing its activation.[133] Unlike with GnRH agonists, there is no initial surge effect with GnRH antagonists; the therapeutic effects are immediate, with sex hormone levels being reduced to castrate levels within a few days.[133][134]

GnRH modulators are highly effective for testosterone suppression in transgender women and have few or no side effects when sex hormone deficiency is avoided with concomitant estrogen therapy.[1][145] However, GnRH modulators tend to be very expensive (typically US$10,000 to US$15,000 per year in the United States), and are often denied by medical insurance.[1][146][147][148] GnRH modulator therapy is much less economical than surgical castration, and is less convenient than surgical castration in the long-term as well.[149] Because of their costs, many transgender women cannot afford GnRH modulators and must use other, often less effective options for testosterone suppression.[1][146] GnRH agonists are prescribed as standard practice for transgender women in the United Kingdom however, where the National Health Service (NHS) covers them.[146][150] This is in contrast to the rest of Europe and to the United States.[150] Another drawback of GnRH modulators is that most of them are peptides and are not orally active, requiring administration by injection, implant, or nasal spray.[142] However, non-peptide and orally active GnRH antagonists, elagolix (Orilissa) and relugolix (Relumina), were introduced for medical use in 2018 and 2019, respectively. But they are under patent protection and, as with other GnRH modulators, are very expensive at present.[151]

In adolescents of either sex with relevant indicators, GnRH modulators can be used to stop undesired pubertal changes for a period without inducing any changes toward the sex with which the patient currently identifies. There is considerable controversy over the earliest age at which it is clinically, morally, and legally safe to use GnRH modulators, and for how long. The sixth edition of the World Professional Association for Transgender Health's Standards of Care permit it from Tanner stage 2 but do not allow the addition of hormones until age 16, which could be five or more years later. Sex steroids have important functions in addition to their role in puberty, and some skeletal changes (such as increased height) that may be considered masculine are not hindered by GnRH modulators.

5α-Reductase inhibitors are inhibitors of the enzyme 5α-reductase, and are a type of specific androgen synthesis inhibitor.[152][153] 5α-Reductase is an enzyme that is responsible for the conversion of testosterone into the more potent androgen dihydrotestosterone (DHT).[152][153] There are three different isoforms of 5α-reductase, types 1, 2, and 3, and these three isoforms show different patterns of expression in the body.[152] Relative to testosterone, DHT is about 2.5- to 10-fold more potent as an agonist of the androgen receptor.[152][153][154] As such, 5α-reductase serves to considerably potentiate the effects of testosterone.[152][153] 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.[152][153][155] Furthermore, circulating levels of total and free DHT in men are very low at about 1/10th and 1/20th those of testosterone, respectively,[153][156][152] and DHT is efficiently inactivated into weak androgens in various tissues such as muscle, fat, and liver.[152][134][157] As such, it is thought that DHT plays little role as a systemic androgen hormone and serves more as a means of locally potentiating the androgenic effects of testosterone in a tissue-specific manner.[152][158][159] Conversion of testosterone into DHT by 5α-reductase plays an important role in male reproductive system development and maintenance (specifically of the penis, scrotum, prostate gland, and seminal vesicles), male-pattern facial/body hair growth, and scalp hair loss, but has little role in other aspects of masculinization.[152][153][155][160][161] Besides the involvement of 5α-reductase in androgen signaling, it is also required for the conversion of steroid hormones such as progesterone and testosterone into neurosteroids like allopregnanolone and 3α-androstanediol, respectively.[162][163]

5α-Reductase inhibitors include finasteride and dutasteride.[152][153] Finasteride is a selective inhibitor of 5α-reductase types 2 and 3, while dutasteride is an inhibitor of all three isoforms of 5α-reductase.[152][164][165] Finasteride can decrease circulating DHT levels by up to 70%, whereas dutasteride can decrease circulating DHT levels by up to 99%.[164][165] Conversely, 5α-reductase inhibitors do not decrease testosterone levels, and may actually increase them slightly.[1][15][25][166] 5α-Reductase inhibitors are used primarily in the treatment of benign prostatic hyperplasia, a condition in which the prostate gland becomes excessively large due to stimulation by DHT and causes unpleasant urogenital symptoms.[164][167] They are also used in the treatment of androgen-dependent scalp hair loss in men and women.[168][169][170] The medications are able to prevent further scalp hair loss in men and can restore some scalp hair density.[168][169][171] Conversely, the effectiveness of 5α-reductase inhibitors in the treatment of scalp hair loss in women is less clear.[170][153] This may be because androgen levels are much lower in women, in whom they may not play as important of a role in scalp hair loss.[170][153] 5α-Reductase inhibitors are also used to treat hirsutism (excessive body/facial hair growth) in women, and are very effective for this indication.[172] 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.[173][174][106] In addition to their antiandrogenic uses, 5α-reductase inhibitors have been found to reduce adverse affective symptoms in premenstrual dysphoric disorder in women.[175][176] This is thought to be due to prevention by 5α-reductase inhibitors of the conversion of progesterone into allopregnanolone during the luteal phase of the menstrual cycle.[175][176]

5α-Reductase inhibitors are sometimes used as a component of feminizing hormone therapy for transgender women in combination with estrogens and/or other antiandrogens.[4][177][32] They may have beneficial effects limited to improvement of scalp hair loss, body hair growth, and possibly skin symptoms such as acne.[178][2][179][32] However, little clinical research on 5α-reductase inhibitors in transgender women has been conducted, and evidence of their efficacy and safety in this group is limited.[177][180] Moreover, 5α-reductase inhibitors have only mild and specific antiandrogenic activity, and are not recommended as general antiandrogens.[180]

5α-Reductase inhibitors have minimal side effects and are well-tolerated in both men and women.[181][182] In men, the most common side effect is sexual dysfunction (0.9–15.8% incidence), which may include decreased libido, erectile dysfunction, and reduced ejaculate.[181][182][183][184][185] Another side effect in men is breast changes, such as breast tenderness and gynecomastia (2.8% incidence).[182] Due to decreased levels of androgens and/or neurosteroids, 5α-reductase inhibitors may slightly increase the risk of depression (~2.0% incidence).[184][186][187][181][184][163] There are reports that a small percentage of men may experience persistent sexual dysfunction and adverse mood changes even after discontinuation of 5α-reductase inhibitors.[185][188][186][189][184][183][163] Some of the possible side effects of 5α-reductase inhibitors in men, such as gynecomastia and sexual dysfunction, are actually welcome changes for many transgender women.[107] In any case, caution may be warranted in using 5α-reductase inhibitors in transgender women, as this group is already at a high risk for depression and suicidality.[190][25]

Progesterone, a progestogen, is the other of the two major sex hormones in women.[142] It is mainly involved in the regulation of the female reproductive system, the menstrual cycle, pregnancy, and lactation.[142] The non-reproductive effects of progesterone are fairly insignificant.[191] Unlike estrogens, progesterone is not known to be involved in the development of female secondary sexual characteristics, and hence is not believed to contribute to feminization in women.[2][56] One area of particular interest in terms of the effects of progesterone in women is breast development.[192][193][194] Estrogens are responsible for the development of the ductal and connective tissues of the breasts and the deposition of fat into the breasts during puberty in girls.[192][193] Conversely, high levels of progesterone, in conjunction with other hormones such as prolactin, are responsible for the lobuloalveolar maturation of the mammary glands during pregnancy.[192][193] This allows for lactation and breastfeeding after childbirth.[192][193] Although progesterone causes the breasts to change during pregnancy, the breasts undergo involution and revert to their pre-pregnancy composition and size after the cessation of breastfeeding.[192][195][193] Every pregnancy, lobuloalveolar maturation occurs again anew.[192][193]

There are two types of progestogens: progesterone, which is the natural and bioidentical hormone in the body; and progestins, which are synthetic progestogens.[16] There are dozens of clinically used progestins.[16][196][197] Certain progestins, namely cyproterone acetate and medroxyprogesterone acetate and as described previously, are used at high doses as functional antiandrogens due to their antigonadotropic effects to help suppress testosterone levels in transgender women.[55][56] Aside from the specific use of testosterone suppression however, there are no other indications of progestogens in transgender women at present.[2] In relation to this, the use of progestogens in transgender women is controversial, and they are not otherwise routinely prescribed or recommended.[2][5][6][178][180][198] Besides progesterone, cyproterone acetate, and medroxyprogesterone acetate, other progestogens that have been reported to have been used in transgender women include hydroxyprogesterone caproate, dydrogesterone, and norethisterone acetate.[199][200][180][201][5] Progestins in general largely have the same progestogenic effects however, and in theory, any progestin could be used in transgender women.[16]

Clinical research on the use of progestogens in transgender women is very limited.[2][194] 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.[4][3][194] There are no clinical studies to support such reports at present.[2][4][194] No clinical study has assessed the use of progesterone in transgender women, and only a couple of studies have compared the use of progestins (specifically cyproterone acetate and medroxyprogesterone acetate) versus the use of no progestogen in transgender women.[194][202][145] These studies, albeit limited in the quality of their findings, reported no benefit of progestogens on breast development in transgender women.[194][145][178] This has also been the case in limited clinical experience.[203] These reports are in accordance with the normal and even above-average breast development in women with complete androgen insensitivity syndrome, who lack progesterone and have no lobuloalveolar development of the mammary glands on histological examination.[40][204] It is noteworthy that epithelial tissue, which makes up lobuloalveolar tissue, normally (outside of pregnancy and lactation) comprises only about 10 to 15% of the tissue of the breasts.[205][206][207][208] Although the influence of progesterone on breast development is uncertain, progesterone is thought to cause reversible breast enlargement during the menstrual cycle due to local fluid retention in the breasts.[209][210] This may give a misleading appearance of breast growth, and might contribute to anecdotal reports of improved breast size and/or shape with progesterone in transgender women.[209][210]

Progestogens have some antiestrogenic effects in the breasts, for instance decreasing expression of the estrogen receptor and increasing expression of estrogen-metabolizing enzymes,[211][212][213][214] and for this reason, have been used to treat breast pain and benign breast disorders.[215][216][217][218] Progesterone levels during female puberty do not normally increase importantly until near the end of puberty in cisgender girls, a point by which most breast development has already been completed.[219] In addition, concern has been expressed that premature exposure to progestogens during the process of breast development is unphysiological and might compromise final breast growth outcome, although this notion presently remains theoretical.[107][194][220] Though the role of progestogens in pubertal breast development is uncertain, progesterone is essential for lobuloalveolar maturation of the mammary glands during pregnancy.[192] Hence, progestogens are required for any transgender woman who wishes to lactate or breastfeed.[221][222][194] 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.[223][224][225] However, lobuloalveolar development reversed with discontinuation of cyproterone acetate, indicating that continued progestogen exposure is necessary to maintain the tissue.[223]

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.[201] Another study likewise found that oral progesterone did not improve sexual function in cisgender women.[226]

Progestogens can have adverse effects.[178][180][16][196][227][19] Oral progesterone has inhibitory neurosteroid effects and can produce side effects such as sedation, mood changes, and alcohol-like effects.[16][228][229] Many progestins have off-target activity, such as androgenic, antiandrogenic, glucocorticoid, and antimineralocorticoid activity, and these activities likewise can contribute unwanted side effects.[16][196] Furthermore, the addition of a progestin to estrogen therapy has been found to increase the risk of blood clots, cardiovascular disease (e.g., coronary heart disease and stroke), and breast cancer compared to estrogen therapy alone in postmenopausal women.[230][180][178][231] Although it is unknown if these health risks of progestins occur in transgender women similarly, it cannot be ruled out that they do.[230][180][178] High-dose progestogens increase the risk of benign brain tumors including prolactinomas and meningiomas as well.[232][233] 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).[230][178][5][6][230][198] 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.[3] In general, some transgender women respond favorably to the effects of progestogens, while others respond negatively.[3]

Progesterone is most commonly taken orally.[16][231] However, oral progesterone has very low bioavailability, and produces only weak and inadequate progestogenic effects even at high doses.[234][235][231][236][237] In accordance, and in contrast to progestins, oral progesterone has no antigonadotropic effects in men even at high doses.[228][238] Progesterone can also be taken by various parenteral (non-oral) routes, including sublingually, rectally, and by intramuscular or subcutaneous injection.[16][217][239] These routes do not have the bioavailability and efficacy issues of oral progesterone, and accordingly, can produce considerable antigonadotropic and other progestogenic effects.[16][236][240] Transdermal progesterone is poorly effective, owing to absorption issues.[16][217][237] Progestins are usually taken orally.[16] In contrast to progesterone, most progestins have high oral bioavailability, and can produce full progestogenic effects with oral administration.[16] Some progestins, such as medroxyprogesterone acetate and hydroxyprogesterone caproate, are or can be used by intramuscular or subcutaneous injection instead.[241][217] Almost all progestins, with the exception of dydrogesterone, have antigonadotropic effects.[16]

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.[242][243][221] An extended period of combined estrogen and progestogen therapy is necessary to mature the lobuloalveolar tissue of the breasts before this can be successful.[222][221][244][223] There are several published reports of lactation and/or breastfeeding in transgender women.[245][246][222][244][221][247][248]

Breast development induced by hormone therapy in transgender women. [249]

Well-developed breasts of transgender woman induced by hormone therapy.

Breast, nipple, and areolar development varies considerably depending on genetics, body composition, age of HRT initiation, and many other factors. Development can take a couple years to nearly a decade for some. However, many transgender women report there is often a "stall" in breast growth during transition, or significant breast asymmetry. Transgender women on HRT often experience less breast development than cisgender women (especially if started after young adulthood). For this reason, many seek breast augmentation. Transgender patients opting for breast reduction are rare. Shoulder width and the size of the rib cage also play a role in the perceivable size of the breasts; both are usually larger in transgender women, causing the breasts to appear proportionally smaller. Thus, when a transgender woman opts to have breast augmentation, the implants used tend to be larger than those used by cisgender women.[250]

In clinical trials, cisgender women have used stem cells from fat to regrow their breasts after mastectomies. This could someday eliminate the need for implants for transgender women.[251]

In transgender women on HRT, as in cisgender women during puberty, breast ducts and Cooper's ligaments develop under the influence of estrogen. Progesterone causes the milk sacs (mammary alveoli) to develop, and with the right stimuli, a transgender woman may lactate. Additionally, HRT often makes the nipples more sensitive to stimulation.

Breast development in transgender women begins within 2 to 3 months of the start of hormone therapy and continues for up to 2 years.[252][179] Breast development seems to be better in transgender women who have a higher body mass index.[252][179] As a result, it may be beneficial to breast development for thin transgender women to gain some weight in the early phases of hormone therapy.[252][179] Different estrogens, such as estradiol valerate, conjugated estrogens, and ethinylestradiol, appear to produce equivalent results in terms of breast sizes in transgender women.[252][202][145] The sudden discontinuation of estrogen therapy has been associated with onset of galactorrhea (lactation).[252][179]

The uppermost layer of skin, the stratum corneum, becomes thinner and more translucent. Spider veins may appear or be more noticeable as a result. Collagen decreases, and tactile sensation increases. The skin becomes softer,[253] more susceptible to tearing and irritation from scratching or shaving, and slightly lighter in color because of a slight decrease in melanin.

Sebaceous gland activity (which is triggered by androgens) lessens, reducing oil production on the skin and scalp. Consequently, the skin becomes less prone to acne. It also becomes drier, and lotions or oils may be necessary.[250][254] The pores become smaller because of the lower quantities of oil being produced. Many apocrine glands – a type of sweat gland – become inactive, and body odor decreases. Remaining body odor becomes less metallic, sharp, or acrid, and more sweet and musky.

As subcutaneous fat accumulates,[250] dimpling, or cellulite, becomes more apparent on the thighs and buttocks. Stretch marks (striae distensae) may appear on the skin in these areas. Susceptibility to sunburn increases, possibly because the skin is thinner and less pigmented.

Antiandrogens affect existing facial hair only slightly; patients may see slower growth and some reduction in density and coverage. Those who are less than a decade past puberty and/or lack a significant amount of facial hair may have better results. Patients taking antiandrogens tend to have better results with electrolysis and laser hair removal than those who are not. In patients in their teens or early twenties, antiandrogens prevent new facial hair from developing if testosterone levels are within the normal female range.[250][254]

Body hair (on the chest, shoulders, back, abdomen, buttocks, thighs, tops of hands, and tops of feet) turns, over time, from terminal ("normal") hairs to tiny, blonde vellus hairs. Arm, perianal, and perineal hair is reduced but may not turn to vellus hair on the latter two regions (some cisgender women also have hair in these areas). Underarm hair changes slightly in texture and length, and pubic hair becomes more typically female in pattern. Lower leg hair becomes less dense. All of these changes depend to some degree on genetics.[250][254]

Head hair may change slightly in texture, curl, and color. This is especially likely with hair growth from previously bald areas. Eyebrows do not change because they are not androgenic hair.[255]

The lens of the eye changes in curvature.[256][257][258][253] Because of decreased androgen levels, the meibomian glands (the sebaceous glands on the upper and lower eyelids that open up at the edges) produce less oil. Because oil prevents the tear film from evaporating, this change may cause dry eyes.[259][260][261][262][263]

The distribution of adipose (fat) tissue changes slowly over months and years. HRT causes the body to accumulate new fat in a typically feminine pattern, including in the hips, thighs, buttocks, pubis, upper arms, and breasts. (Fat on the hips, thighs, and buttocks has a higher concentration of omega-3 fatty acids and is meant to be used for lactation.) The body begins to burn old adipose tissue in the waist, shoulders, and back, making those areas smaller.[250]

Subcutaneous fat increases in the cheeks and lips, making the face appear rounder, with slightly less emphasis on the jaw as the lower portion of the cheeks fills in.

HRT causes a reduction in muscle mass and distribution towards female proportions.

Male-to-female hormone therapy causes the hips to rotate slightly forward because of changes in the tendons. Hip discomfort is common. This can cause a reduction in total body height.

If estrogen therapy is begun prior to pelvis ossification, which occurs around the age of 25, the pelvic outlet and inlet open slightly. The femora also widen, because they are connected to the pelvis. The pelvis retains some masculine characteristics, but the end result of HRT is wider hips than a cisgender man and closer to those of a cisgender woman.

HRT does not reverse bone changes that have already been established by puberty. Consequently, it does not affect height; the length of the arms, legs, hands, and feet; or the width of the shoulders and rib cage. However, details of bone shape change throughout life, with bones becoming heavier and more deeply sculptured under the influence of androgens, and HRT does prevent such changes from progressing further.

The width of the hips is not affected in individuals for whom epiphyseal closure (fusion and closure of the ends of bones, which prevents any further lengthening) has taken place. This occurs in most people between 18 and 25 years of age. Already-established changes to the shape of the hips cannot be reversed by HRT whether epiphyseal closure has taken place or not.

Established changes to the bone structure of the face are also unaffected by HRT. A significant majority of craniofacial changes occur during adolescence. Post-adolescent growth is considerably slower and minimal by comparison.[264] Also unaffected is the prominence of the thyroid cartilage (Adam's apple). These changes may be reversed by surgery (facial feminization surgery and tracheal shave, respectively).

During puberty, the voice deepens in pitch and becomes more resonant. These changes are permanent and are not affected by HRT. Voice therapy and/or surgery may be used instead to achieve a more female-sounding voice.

Facial hair develops during puberty and is only slightly affected by HRT. It may, however, be eliminated nearly permanently with laser hair removal, or permanently with electrolysis.

The psychological effects of feminizing hormone therapy are harder to define than physical changes. Because hormone therapy is usually the first physical step taken to transition, the act of beginning it has a significant psychological effect, which is difficult to distinguish from hormonally induced changes.

Changes in mood and well-being occur with hormone therapy in transgender women.[265]

Some transgender women report a significant reduction in libido, depending on the dosage of antiandrogens. A small number of post-operative transgender women take low doses of testosterone to boost their libido. Many pre-operative transgender women wait until after reassignment surgery to begin an active sex life. Raising the dosage of estrogen or adding a progestogen raises the libido of some transgender women.

Spontaneous and morning erections decrease significantly in frequency, although some patients who have had an orchiectomy still experience morning erections. Voluntary erections may or may not be possible, depending on the amount of hormones and/or antiandrogens being taken.

Managing long-term hormonal regimens have not been studied and are difficult to estimate because research on the long-term use of hormonal therapy has not been noted.[230] However, it is possible to speculate the outcomes of these therapies on transgender people based on the knowledge of the current effects of gonadal hormones on sexual functioning in cisgender men and women.[266]

Firstly, if one is to decrease testosterone in male-to-female gender transition, it is likely that sexual desire and arousal would be inhibited; alternatively, if high doses of estrogen negatively impact sexual desire, which has been found in some research with cisgender women, it is hypothesized that combining androgens with high levels of estrogen would intensify this outcome.[266] Unfortunately, to date there haven't been any randomized clinical trials looking at the relationship between type and dose of transgender hormone therapy, so the relationship between them remains unclear.[266] Typically, the estrogens given for male-to-female gender transition are 2 to 3 times higher than the recommended dose for HRT in postmenopausal women.[230] Pharmacokinetic studies indicate taking these increased doses may lead to a higher boost in plasma estradiol levels; however, the long-term side effects haven't been studied and the safety of this route is unclear.[230]

As with any pharmacological or hormone therapy, there are potential side effects, which in the case of transgender hormone therapy include changes in sexual functioning. These have the ability to significantly impact sexual functioning, either directly or indirectly through the various side effects, such as cerebrovascular disorders, obesity, and mood fluctuations.[266] In addition, some research has found an onset of diabetes following feminizing hormone therapy, which impairs sexual response. Whatever route an individual and their doctor choose to take, it is important to consider both the medical risks of hormone therapy as well as the psychological needs of the patient.

Several studies have found that hormone therapy in transgender women causes the structure of the brain to change in the direction of female proportions.[267][268][269][270][271] In addition, studies have found that hormone therapy in transgender women causes performance in cognitive tasks, including visuospatial, verbal memory, and verbal fluency, to shift in a more female direction.[267][265]

A number of health changes and adverse effects can occur with feminizing hormone therapy.

A 2015 review concluded that hormone therapy for transgender people is safe when supervised by a qualified medical professional.[272]

The most significant cardiovascular risk for transgender women is the prothrombotic effect (increased blood clotting) of estrogens. This manifests most significantly as an increased risk for venous thromboembolism (VTE): deep vein thrombosis (DVT) and pulmonary embolism (PE), which occurs when blood clots from DVT break off and migrate to the lungs. Symptoms of DVT include pain or swelling of one leg, especially the calf. Symptoms of PE include chest pain, shortness of breath, fainting, and heart palpitations, sometimes without leg pain or swelling.

VTE occurs more frequently in the first year of treatment with estrogens. The risk of VTE is higher with oral non-bioidentical estrogens such as ethinylestradiol and conjugated estrogens than with parenteral formulations of estradiol such as injectable, transdermal, implantable, and intranasal.[273][274][275][276][277][278][279][280][281][282][283][132][284][285][286][287][288][23][289][290][291][292] VTE risk also increases with age and in patients who smoke, so many clinicians advise using the safer estrogen formulations in smokers and patients older than 40. In addition, VTE risk is increased by progestins and increases with the dosages of both estrogens and progestins. Obesity increases the risk of VTE as well. 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.[16] Non-bioidentical estrogens such as conjugated estrogens and especially ethinylestradiol have markedly disproportionate effects on liver protein synthesis relative to estradiol.[16] In addition, oral estradiol has a 4- to 5-fold increased impact on liver protein synthesis than does transdermal estradiol and other parenteral estradiol routes.[16][293]

Because the risks of warfarin – which is used to treat blood clots – in a relatively young and otherwise healthy population are low, while the risk of adverse physical and psychological outcomes for untreated transgender patients is high, prothrombotic mutations (such as factor V Leiden, antithrombin III, and protein C or S deficiency) are not absolute contraindications for hormonal therapy.[179]

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.[294][295][107][22] The estrogens used included oral estradiol (1 to 10 mg/day) and other estrogen formulations.[22] Other medications such as antiandrogens like spironolactone were also used.[22]

A 2019 systematic review and meta-analysis found an incidence rate of VTE of 2.3 per 1000 person-years with feminizing hormone therapy in transgender women.[296] For comparison, the rate in the general population has been found to be 1.0–1.8 per 1000 person-years, and the rate in premenopausal women taking birth control pills has been found to be 3.5 per 1000 patient-years.[296][297] As such, it appears that the risk of VTE with feminizing hormone therapy in transgender women is less than that with birth control pills.[296] The risk of VTE with birth control pills in premenopausal women is considered to be an acceptable level of risk.[296] There was significant heterogeneity in the rates of VTE across the included studied, and the meta-analysis was unable to perform subgroup analyses between estrogen type, estrogen route, estrogen dosage, concomitant antiandrogen or progestogen use, or patient characteristics (e.g., age, smoking status, weight) corresponding to known risk factors for VTE.[296] Due to the inclusion of some studies using ethinylestradiol, which is more thrombotic and is no longer used in transgender women, the researchers noted that the VTE risk found in their study is likely to be an overestimate.[296]

In a 2016 study that specifically assessed oral estradiol, the incidence of VTE in 676 transgender women who were treated for an average of 1.9 years each was only one individual, or 0.15% of the group, with an incidence of 7.8 events per 10,000 person-years.[298][299] The dosage of oral estradiol used was 2 to 8 mg/day.[299] Almost all of the transgender women were also taking spironolactone (94%), a subset were also taking finasteride (17%), and fewer than 5% were also taking a progestogen (usually oral progesterone).[299] The findings of this study suggest that the incidence of VTE is low in transgender women taking oral estradiol.[298][299]

Cardiovascular health in transgender women has been reviewed in recent publications.[300][21]

Estrogens may increase the risk of gallbladder disease, especially in older and obese people.[253] They may also increase transaminase levels, indicating liver toxicity, especially when taken in oral form.

A patient's metabolic rate may change, causing an increase or decrease in weight and energy levels, changes to sleep patterns, and temperature sensitivity. Androgen deprivation leads to slower metabolism and a loss of muscle tone. Building muscle takes more work. The addition of a progestogen may increase energy, although it may increase appetite as well.

Both estrogens and androgens are necessary in all humans for bone health. Young, healthy women produce about 10 mg of testosterone monthly, and higher bone mineral density in males is associated with higher serum estrogen. Both estrogen and testosterone help to stimulate bone formation, especially during puberty. Estrogen is the predominant sex hormone that slows bone loss, even in men.

Studies are mixed on whether the risk of breast cancer is increased with hormone therapy in transgender women.[301][302][303][304] Two cohort studies found no increase in risk relative to cisgender men,[302][303] whereas another cohort study found an almost 50-fold increase in risk such that the incidence of breast cancer was between that of cisgender men and cisgender women.[304][301] There is no evidence that breast cancer risk in transgender women is greater than in cisgender women.[305] Twenty cases of breast cancer in transgender women have been reported as of 2019.[301][306]

Cisgender men with gynecomastia have not been found to have an increased risk of breast cancer.[307] It has been suggested that a 46,XY karyotype (one X chromosome and one Y chromosome) may be protective against breast cancer compared to having a 46,XX karyotype (two X chromosomes).[307] Men with Klinefelter's syndrome (47,XXY karyotype), which causes hypoandrogenism, hyperestrogenism, and a very high incidence of gynecomastia (80%), have a dramatically (20- to 58-fold) increased risk of breast cancer compared to karyotypical men (46,XY), closer to the rate of karyotypical women (46,XX).[307][308][309] The incidences of breast cancer in karyotypical men, men with Klinefelter's syndrome, and karyotypical women are approximately 0.1%,[310] 3%,[308] and 12.5%,[311] respectively. Women with complete androgen insensitivity syndrome (46,XY karyotype) never develop male sex characteristics and have normal and complete female morphology, including breast development,[312] yet have not been reported to develop breast cancer.[38][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 necessarily than to genetics.[314]

Prostate cancer is extremely rare in gonadectomized transgender women who have been treated with estrogens for a prolonged period of time.[1][315][316] Whereas as many as 70% of men show prostate cancer by their 80s,[120] only a handful of cases of prostate cancer in transgender women have been reported in the literature.[1][315][316] As such, and in accordance with the fact that androgens are responsible for the development of prostate cancer, HRT appears to be highly protective against prostate cancer in transgender women.[1][315][316]

The risks of certain types of benign brain tumors including meningioma and prolactinoma are increased with hormone therapy in transgender women.[317] These risks have mostly been associated with the use of cyproterone acetate.[317]

Estrogens and progestogens can cause prolactinomas, which are prolactin-secreting tumors of the pituitary gland. Milk discharge from the nipples can be a sign of elevated prolactin levels. If a prolactinoma becomes large enough, it can cause visual changes (especially decreased peripheral vision), headaches, depression or other mood changes, dizziness, nausea, vomiting, and symptoms of pituitary failure, like hypothyroidism.