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Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine.[1][2][3][4][5][6] It is a common type of transgender hormone therapy (another being masculinizing hormone therapy) and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.
The purpose of the therapy is to cause the development of the secondary sex characteristics of the desired sex, such as breasts and a feminine pattern of hair, fat, and muscle distribution. It cannot undo many of the changes produced by naturally occurring puberty, which may necessitate surgery and other treatments to reverse (see below). The medications used for feminizing hormone therapy include estrogens, antiandrogens, progestogens, and gonadotropin-releasing hormone modulators (GnRH modulators).
Feminizing hormone therapy has been empirically shown to reduce the distress and discomfort associated with gender dysphoria in transfeminine individuals.[7][8][9]
Requirements
Many physicians operate by the World Professional Association of Transgender Health (WPATH) Standards of Care (SoC) model and require psychotherapy and a letter of recommendation from a psychotherapist in order for a transgender person to obtain hormone therapy.[2] Other physicians operate by an informed consent model and have no requirements for transgender hormone therapy aside from consent.[2]
Medications used in transgender hormone therapy are also sold without a prescription on the Internet by unregulated online pharmacies, and some transgender women purchase these medications and treat themselves using a do-it-yourself (DIY) or self-medication approach.[10][11] One reason that many transgender people turn to DIY hormone therapy is due to long waiting lists of up to years for standard physician-based hormone therapy in some parts of the world such as the United Kingdom, as well as due to the often high costs of seeing a physician and the restrictive criteria that make some ineligible for treatment.[10][11]
The accessibility of transgender hormone therapy differs throughout the world and throughout individual countries.[2]
Medications
| Medication | Brand name | Type | Route | Dosage[b] |
|---|---|---|---|---|
| Estradiol | Various | Estrogen | Oral | 2–10 mg/day |
| Various | Estrogen | Sublingual | 1–8 mg/day | |
| Climara[c] | Estrogen | TD patch | 25–400 μg/day | |
| Divigel[c] | Estrogen | TD gel | 0.5–5 mg/day | |
| Various | Estrogen | SC implant | 50–200 mg every 6–24 mos | |
| Estradiol valerate | Progynova | Estrogen | Oral | 2–10 mg/day |
| Progynova | Estrogen | Sublingual | 1–8 mg/day | |
| Delestrogen[c] | Estrogen | IM, SC | 2–10 mg/wk or 5–20 mg every 2 wks | |
| Estradiol cypionate | Depo-Estradiol | Estrogen | IM, SC | 2–10 mg/wk or 5–20 mg every 2 wks |
| Estradiol dipropionate | Agofollin | Estrogen | IM, SC | 2–10 mg/wk or 5–20 mg every 2 wks |
| Estradiol benzoate | Progynon-B | Estrogen | IM, SC | 0.5–1.5 mg every 2–3 days |
| Estriol | Ovestin[c] | Estrogen | Oral | 4–6 mg/day |
| Spironolactone | Aldactone | Antiandrogen | Oral | 100–400 mg/day |
| Cyproterone acetate | Androcur | Antiandrogen; Progestogen |
Oral | 5–100 mg/day |
| Androcur Depot | IM | 300 mg/month | ||
| Bicalutamide | Casodex | Antiandrogen | Oral | 25–50 mg/day |
| Enzalutamide | Xtandi | Antiandrogen | Oral | 160 mg/day |
| GnRH analogue | Various | GnRH modulator | Various | Variable |
| Elagolix | Orilissa | GnRH antagonist | Oral | 150 mg/day or 200 mg twice daily |
| Finasteride | Propecia | 5αR inhibitor | Oral | 1–5 mg/day |
| Dutasteride | Avodart | 5αR inhibitor | Oral | 0.25–0.5 mg/day |
| Progesterone | Prometrium[c] | Progestogen | Oral | 100–400 mg/day |
| Medroxyprogesterone acetate | Provera | Progestogen | Oral | 2.5–40 mg/day |
| Depo-Provera | Progestogen | IM | 150 mg every 3 mos | |
| Depo-SubQ Provera 104 | Progestogen | SC | 104 mg every 3 mos | |
| Hydroxyprogesterone caproate | Proluton | Progestogen | IM | 250 mg/wk |
| Dydrogesterone | Duphaston | Progestogen | Oral | 20 mg/day |
| Drospirenone | Slynd | Progestogen | Oral | 3 mg/day |
| Domperidone[d] | Motilium | Prolactin releaser | Oral | 30–80 mg/day[e] |
| ||||
A variety of different sex-hormonal medications are used in feminizing hormone therapy for transgender women.[1][2][3][4] These include estrogens to induce feminization and suppress testosterone levels; antiandrogens such as androgen receptor antagonists, antigonadotropins, GnRH modulators, and 5α-reductase inhibitors to further oppose the effects of androgens like testosterone; and progestogens for various possible though uncertain benefits.[1][2][3][4] An estrogen in combination with an antiandrogen is the mainstay of feminizing hormone therapy for transgender women.[44][45]
Estrogens
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.[48] A variety of different forms of estrogens are available and used medically.[48] 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][48] 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.[48][49][50][51][52] Parenteral (non-oral) routes are preferred, owing to a minimal or negligible risk of blood clots and cardiovascular issues.[5][53][54][55][56]
In addition to producing feminization, estrogens have antigonadotropic effects and suppress gonadal sex hormone production.[49][47][57] They are mainly responsible for the suppression of testosterone levels in transgender women.[49][57] 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.[58][59] Lower levels of estradiol can also considerably but incompletely suppress testosterone production.[47] When testosterone levels are insufficiently suppressed by estradiol alone, antiandrogens can be used to suppress or block the effects of residual testosterone.[49] Oral estradiol often has difficulty adequately suppressing testosterone levels, due to the relatively low estradiol levels achieved with it.[47][60][61]
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.[62][63][64] This is to help suppress testosterone levels.[63] 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.[65] The review proposal noted that high-dose parenteral estradiol is known to be safe.[65] 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.[66][67] Dosages of estrogens can be reduced after an orchiectomy or sex reassignment surgery, when gonadal testosterone suppression is no longer needed.[5]
Antiandrogens
Antiandrogens are medications that prevent the effects of androgens in the body.[68][69] 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.[70][71] 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.[70][71] Androgens also have functional antiestrogenic effects in the breasts and oppose estrogen-mediated breast development, even at low levels.[72][73][74][75] Androgens act by binding to and activating the androgen receptor, their biological target in the body.[76] Antiandrogens work by blocking androgens from binding to the androgen receptor and/or by inhibiting or suppressing the production of androgens.[68]
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.[69] Estrogens and progestogens are antigonadotropins and hence are functional antiandrogens.[49][77][78][79] The purpose of the use of antiandrogens in transgender women is to block or suppress residual testosterone that is not suppressed by estrogens alone.[49][68][57] Additional antiandrogen therapy is not necessarily required if testosterone levels are in the normal female range or if the person has undergone orchiectomy.[49][68][57] 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.[80][81][82]
Steroidal antiandrogens
Steroidal antiandrogens are antiandrogens that resemble steroid hormones like testosterone and progesterone in chemical structure.[83] 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.[84][85] Cyproterone acetate (Androcur), which is unavailable in the United States, is widely used in Europe, Canada, and the rest of the world.[2][68][84][86] Medroxyprogesterone acetate (Provera, Depo-Provera), a similar medication, is sometimes used in place of cyproterone acetate in the United States.[87][88]
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.[90] Spironolactone is an antiandrogen as a secondary and originally unintended action.[90] It works as an antiandrogen mainly by acting as an androgen receptor antagonist.[91] The medication is also a weak steroidogenesis inhibitor, and inhibits the enzymatic synthesis of androgens.[92][91][93] However, this action is of low potency, and spironolactone has mixed and inconsistent effects on hormone levels.[92][91][93][94][95] In any case, testosterone levels are usually unchanged by spironolactone.[92][91][93][94][95] Studies in transgender women have found testosterone levels to be unaltered with spironolactone[47] or to be decreased.[89] Spironolactone is described as a relatively weak antiandrogen.[96][97][98] It is widely used in the treatment of acne, excessive hair growth, and hyperandrogenism in women, who have much lower testosterone levels than men.[94][95] Because of its antimineralocorticoid activity, spironolactone has antimineralocorticoid side effects[99] and can cause high potassium levels.[100][101] Hospitalization and/or death can potentially result from high potassium levels due to spironolactone,[100][101][102] but the risk of high potassium levels in people taking spironolactone appears to be minimal in those without risk factors for it.[95][103][104] As such, monitoring of potassium levels may not be necessary in most cases.[95][103][104] Spironolactone has been found to decrease the bioavailability of high doses of oral estradiol.[47] 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.[47]
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.[105][106] It works primarily as an antigonadotropin, secondarily to its potent progestogenic activity, and strongly suppresses gonadal androgen production.[105][57] 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%,[107][108][109][110] while a dosage of 100 mg/day has been found to lower testosterone levels in men by about 75%.[111][112] 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%.[113] In combination with estrogen, 10, 25, and 50 mg/day cyproterone acetate have all shown the same degree of testosterone suppression.[114] In addition to its actions as an antigonadotropin, cyproterone acetate is an androgen receptor antagonist.[105][68] 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).[115][116] Cyproterone acetate can cause elevated liver enzymes and liver damage, including liver failure.[68][117] 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.[68] 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.[57][68][118] High dosages of cyproterone-based medication have been linked with meningioma.[119] 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.[87][88] 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.[87][88] Medroxyprogesterone acetate suppresses testosterone levels in transgender women similarly to cyproterone acetate.[88][47] 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.[120][121][122][123][124] In contrast to cyproterone acetate however, medroxyprogesterone acetate is not also an androgen receptor antagonist.[48][125] Medroxyprogesterone acetate has similar side effects and risks as cyproterone acetate, but is not associated with liver problems.[126][99]
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.[127][128][129][130][131][132][133] 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.[134][135][136] 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.[137][138]
Nonsteroidal antiandrogens
Nonsteroidal antiandrogens are antiandrogens which are nonsteroidal and hence unrelated to steroid hormones in terms of chemical structure.[83][139] These medications are primarily used in the treatment of prostate cancer,[139] but are also used for other purposes such as the treatment of acne, excessive facial/body hair growth, and high androgen levels in women.[15][140][141][142] Unlike steroidal antiandrogens, nonsteroidal antiandrogens are highly selective for the androgen receptor and act as pure androgen receptor antagonists.[139][143] Similarly to spironolactone however, they do not lower androgen levels, and instead work exclusively by preventing androgens from activating the androgen receptor.[139][143] Nonsteroidal antiandrogens are more efficacious androgen receptor antagonists than are steroidal antiandrogens,[83][144] and for this reason, in conjunction with GnRH modulators, have largely replaced steroidal antiandrogens in the treatment of prostate cancer.[139][145]
The nonsteroidal antiandrogens that have been used in transgender women include the first-generation medications flutamide (Eulexin), nilutamide (Anandron, Nilandron), and bicalutamide (Casodex).[15][20][5][3][146]: 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.[147][148] Flutamide and nilutamide have relatively high toxicity, including considerable risks of liver damage and lung disease.[149][140] Due to its risks, the use of flutamide in cisgender and transgender women is now limited and discouraged.[15][140][5] Flutamide and nilutamide have largely been superseded by bicalutamide in clinical practice,[150][151] with bicalutamide accounting for almost 90% of nonsteroidal antiandrogen prescriptions in the United States by the mid-2000s.[152][143] Bicalutamide is said to have excellent tolerability and safety relative to flutamide and nilutamide, as well as in comparison to cyproterone acetate.[153][154][155] It has few to no side effects in women.[141][142] Despite its greatly improved tolerability and safety profile however, bicalutamide does still have a small risk of elevated liver enzymes and association with rare cases of serious liver damage and lung disease.[15][149][156]
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.[157][158][159] However, estrogens suppress testosterone levels and at high doses can markedly disrupt sex drive and function and fertility on their own.[160][161][162][163] Moreover, disruption of gonadal function and fertility by estrogens may be permanent after extended exposure.[162][163]
GnRH modulators
GnRH modulators are antigonadotropins and hence functional antiandrogens.[164] 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.[164] The gonadotropins signal the gonads to make sex hormones such as testosterone and estradiol.[164] GnRH modulators bind to and inhibit the GnRH receptor, thereby preventing gonadotropin release.[164] 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.[164][165][166] GnRH modulators are also commonly known as GnRH analogues.[164] However, not all clinically used GnRH modulators are analogues of GnRH.[167]
There are two types of GnRH modulators: GnRH agonists and GnRH antagonists.[164] These medications have the opposite action on the GnRH receptor but paradoxically have the same therapeutic effects.[164] 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.[164][165] 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.[168][169][164] At the initiation of treatment, GnRH agonists are associated with a "flare" effect on hormone levels due to acute overstimulation of the GnRH receptor.[164][170] In men, LH levels increase by up to 800%, while testosterone levels increase to about 140 to 200% of baseline.[171][170] 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.[170] 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.[172][171][173][174][49][175] 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.[164] 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.[164][165]
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][176] 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][177][178][179] GnRH modulator therapy is much less economical than surgical castration, and is less convenient than surgical castration in the long-term as well.[180] Because of their costs, many transgender women cannot afford GnRH modulators and must use other, often less effective options for testosterone suppression.[1][177] GnRH agonists are prescribed as standard practice for transgender women in the United Kingdom however, where the National Health Service (NHS) covers them.[177][181] This is in contrast to the rest of Europe and to the United States.[181] 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.[173] 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.[182]
In adolescents of either sex, GnRH modulators can be used to suppress puberty. 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.[183]
5α-Reductase inhibitors
5α-Reductase inhibitors are inhibitors of the enzyme 5α-reductase, and are a type of specific androgen synthesis inhibitor.[184][185] 5α-Reductase is an enzyme that is responsible for the conversion of testosterone into the more potent androgen dihydrotestosterone (DHT).[184][185] 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.[184] Relative to testosterone, DHT is about 2.5- to 10-fold more potent as an agonist of the androgen receptor.[184][185][186] As such, 5α-reductase serves to considerably potentiate the effects of testosterone.[184][185] 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.[184][185][187] Furthermore, circulating levels of total and free DHT in men are very low at about one-tenth and one-twentieth those of testosterone, respectively,[185][188][184] and DHT is efficiently inactivated into weak androgens in various tissues such as muscle, fat, and liver.[184][165][189] 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.[184][190][191] 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.[184][185][187][192][193] 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.[194][195]
5α-Reductase inhibitors include finasteride and dutasteride.[184][185] Finasteride is a selective inhibitor of 5α-reductase types 2 and 3, while dutasteride is an inhibitor of all three isoforms of 5α-reductase.[184][196][197] Finasteride can decrease circulating DHT levels by up to 70%, whereas dutasteride can decrease circulating DHT levels by up to 99%.[196][197] Conversely, 5α-reductase inhibitors do not decrease testosterone levels, and may actually increase them slightly.[1][47][57][198] 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.[196][199] They are also used in the treatment of androgen-dependent scalp hair loss in men and women.[200][201][202] The medications are able to prevent further scalp hair loss in men and can restore some scalp hair density.[200][201][203] Conversely, the effectiveness of 5α-reductase inhibitors in the treatment of scalp hair loss in women is less clear.[202][185] 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.[202][185] 5α-Reductase inhibitors are also used to treat hirsutism (excessive body/facial hair growth) in women, and are very effective for this indication.[204] 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.[205][206][139] In addition to their antiandrogenic uses, 5α-reductase inhibitors have been found to reduce adverse affective symptoms in premenstrual dysphoric disorder in women.[207][208] 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.[207][208]
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][209][64] They may have beneficial effects limited to improvement of scalp hair loss, body hair growth, and possibly skin symptoms such as acne.[210][2][211][64] 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.[209][212] Moreover, 5α-reductase inhibitors have only mild and specific antiandrogenic activity, and are not recommended as general antiandrogens.[212]
5α-Reductase inhibitors have minimal side effects and are well tolerated in both men and women.[213][214] 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.[213][214][215][216][217] Another side effect in men is breast changes, such as breast tenderness and gynecomastia (2.8% incidence).[214] Due to decreased levels of androgens and/or neurosteroids, 5α-reductase inhibitors may slightly increase the risk of depression (~2.0% incidence).[216][218][219][213][195] 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.[217][220][218][221][216][215][195] 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.[15] 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.[222][57]
Progestogens
Progesterone, a progestogen, is the other of the two major sex hormones in women.[173] It is mainly involved in the regulation of the female reproductive system, the menstrual cycle, pregnancy, and lactation.[173] The non-reproductive effects of progesterone are fairly insignificant.[223] 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][88] One area of particular interest in terms of the effects of progesterone in women is breast development.[224][225][226] 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.[224][225] 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.[224][225] This allows for lactation and breastfeeding after childbirth.[224][225] 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.[224][227][225] Every pregnancy, lobuloalveolar maturation occurs again anew.[224][225]
There are two types of progestogens: progesterone, which is the natural and bioidentical hormone in the body; and progestins, which are synthetic progestogens.[48] There are dozens of clinically used progestins.[48][228][229] 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.[87][88] 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][210][212][230] Besides progesterone, cyproterone acetate, and medroxyprogesterone acetate, other progestogens that have been reported to have been used in transgender women include hydroxyprogesterone caproate, dydrogesterone, norethisterone acetate, and drospirenone.[231][232][212][233][5][234] Progestins in general largely have the same progestogenic effects however, and in theory, any progestin could be used in transgender women.[48]
Clinical research on the use of progestogens in transgender women is very limited.[2][226] 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][226] There are no clinical studies to support such reports at present.[2][4][226] 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.[226][235][176] These studies, albeit limited in the quality of their findings, reported no benefit of progestogens on breast development in transgender women.[226][176][210] This has also been the case in limited clinical experience.[236]
Progestogens have some antiestrogenic effects in the breasts, for instance decreasing expression of the estrogen receptor and increasing expression of estrogen-metabolizing enzymes,[237][238][239][240] and for this reason, have been used to treat breast pain and benign breast disorders.[241][242][243][244] 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.[245] 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.[15][226][246] Though the role of progestogens in pubertal breast development is uncertain, progesterone is essential for lobuloalveolar maturation of the mammary glands during pregnancy.[224] Hence, progestogens are required for any transgender woman who wishes to lactate or breastfeed.[41][247][226] 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.[248][249][250] However, lobuloalveolar development reversed with discontinuation of cyproterone acetate, indicating that continued progestogen exposure is necessary to maintain the tissue.[248]
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.[233] Another study likewise found that oral progesterone did not improve sexual function in cisgender women.[251]
Progestogens can have adverse effects.[210][212][48][228][252][51] Oral progesterone has inhibitory neurosteroid effects and can produce side effects such as sedation, mood changes, and alcohol-like effects.[48][253][254] Many progestins have off-target activity, such as androgenic, antiandrogenic, glucocorticoid, and antimineralocorticoid activity, and these activities likewise can contribute unwanted side effects.[48][228] 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.[255][212][210][256] Although it is unknown if these health risks of progestins occur in transgender women similarly, it cannot be ruled out that they do.[255][212][210] High-dose progestogens increase the risk of benign brain tumors including prolactinomas and meningiomas as well.[257][258] 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).[255][210][5][6][230] 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.[48][256] However, oral progesterone has very low bioavailability, and produces relatively weak progestogenic effects even at high doses.[259][260][256][261][262] In accordance, and in contrast to progestins, oral progesterone has no antigonadotropic effects in men even at high doses.[253][263] Progesterone can also be taken by various parenteral (non-oral) routes, including sublingually, rectally, and by intramuscular or subcutaneous injection.[48][243][264] These routes do not have the bioavailability and efficacy issues of oral progesterone, and accordingly, can produce considerable antigonadotropic and other progestogenic effects.[48][261][265] Transdermal progesterone is poorly effective, owing to absorption issues.[48][243][262] Progestins are usually taken orally.[48] In contrast to progesterone, most progestins have high oral bioavailability, and can produce full progestogenic effects with oral administration.[48] Some progestins, such as medroxyprogesterone acetate and hydroxyprogesterone caproate, are or can be used by intramuscular or subcutaneous injection instead.[266][243] Almost all progestins, with the exception of dydrogesterone, have antigonadotropic effects.[48]
Miscellaneous
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.[267][268][41] An extended period of combined estrogen and progestogen therapy is necessary to mature the lobuloalveolar tissue of the breasts before this can be successful.[247][41][269][248] There are several published reports of lactation and/or breastfeeding in transgender women.[270][271][247][269][41][272][273]
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.[183] This is due to lack of data to support these approaches in transfeminine people as well as potential risks.[183] The WPATH SOC8 also recommends against the use of 5α-reductase inhibitors such as finasteride in transfeminine people.[183]
Interactions
Many of the medications used in feminizing hormone therapy, such as estradiol, cyproterone acetate, and bicalutamide, are substrates of CYP3A4 and other cytochrome P450 enzymes. As a result, inducers of CYP3A4 and other cytochrome P450 enzymes, such as carbamazepine, phenobarbital, phenytoin, rifampin, rifampicin, and St. John's wort, among others, may decrease circulating levels of these medications and thereby decrease their effects. Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes, such as cimetidine, clotrimazole, grapefruit juice, itraconazole, ketoconazole, and ritonavir, among others, may increase circulating levels of these medications and thereby increase their effects.[citation needed] The concomitant use of a cytochrome P450 inducer or inhibitor with feminizing hormone therapy may necessitate medication dosage adjustments.
Effects
The spectrum of effects of hormone therapy in transfeminine people depend on the specific medications and dosages used. In any case, the main effects of hormone therapy in transfeminine people are feminization and demasculinization, and are as follows:
| Effect | Time to expected onset of effect[a] |
Time to expected maximum effect[a][b] |
Permanency if hormone therapy is stopped |
|---|---|---|---|
| Breast development and nipple/areolar enlargement | 2–6 months | 1–5 years | Surgically reversible |
| Thinning/slowed growth of facial/body hair | 4–12 months | >3 years[c] | Reversible |
| Cessation/reversal of male-pattern scalp hair loss | 1–3 months | 1–2 years[d] | Reversible |
| Softening of skin/decreased oiliness and acne | 3–6 months | Unknown | Reversible |
| Redistribution of body fat in a feminine pattern | 3–6 months | 2–5 years | Reversible |
| Decreased muscle mass/strength | 3–6 months | 1–2 years[e] | Reversible |
| Widening and rounding of the pelvis[f] | Unspecified | Unspecified | Permanent |