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Feminizing hormone therapy

January 01, 1970

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 edit

Main articles: Transgender hormone therapy § Requirements, and Transgender hormone therapy § Accessibility

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 edit

Medications and dosages used in transgender women[1][3][5][6][12][a]
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]
  1. ^ Additional sources:[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]
  2. ^ Lower starting doses may be used in adolescents if being used in combination with a GnRH agonist or antagonist.
  3. ^ a b c d e Also available under other brand names.
  4. ^ For induction of lactation to allow for breastfeeding specifically.
  5. ^ Administered in divided doses.

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 edit

See also: Estrogen (medication) § Transgender women, and Estradiol (medication) § Transgender women
 
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.[46] 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.[47] The dashed purple line is the upper limit for the female/castrate range (~50 ng/dL) and the dashed grey line is the testosterone level in a comparison group of post-operative transgender women (21.7 ng/dL).[47]

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 edit

See also: Antiandrogen § Transgender hormone therapy

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 edit

See also: Spironolactone § Transgender hormone therapy, and Cyproterone acetate § Transgender hormone therapy

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]

 
Testosterone levels with estradiol (E2) alone or in combination with an antiandrogen (AA) in the form of spironolactone (SPL) or cyproterone acetate (CPA) in transfeminine people.[89] Estradiol was used in the form of oral estradiol valerate (EV) in almost all cases.[89] The dashed horizontal line is the upper limit of the female/castrate range (~50 ng/dL).

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 edit

See also: Bicalutamide medical uses § Transgender hormone therapy, Nilutamide § Transgender hormone therapy, and Flutamide § Transgender hormone therapy

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 edit

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 edit

See also: Finasteride § Transgender hormone therapy, and Dutasteride § Transgender hormone therapy

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 edit

See also: Progesterone (medication) § Transgender women

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 edit

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 edit

Further information: CYP3A4 § CYP3A4 ligands

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 edit

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:

Effects of feminizing hormone therapy in transfeminine people
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
Changes in mood, emotionality, and behavior Unspecified Unspecified Reversible
Decreased sex drive 1–3 months Temporary[274] Reversible
Decreased spontaneous/morning erections 1–3 months 3–6 months Reversible
Erectile dysfunction and decreased ejaculate volume 1–3 months Variable Reversible
Decreased sperm production/fertility Unknown >3 years Reversible or permanent[g]
Decreased testicle size 3–6 months 2–3 years Unknown
Decreased penis size None[h] Not applicable Not applicable
Decreased prostate gland size Unspecified Unspecified Unspecified
Voice changes None[i] Not applicable Not applicable
Footnotes and sources
Footnotes:
  1. ^ a b Estimates represent published and unpublished clinical observations.
  2. ^ Time at which further changes are unlikely at maximum maintained dose. Maximum effects vary widely depending on genetics, body habitus, age, and status of gonad removal. Generally, older individuals with intact gonads may have less feminization overall.
  3. ^ Complete removal of male facial and body hair requires electrolysis, laser hair removal, or both. Temporary hair removal can be achieved with shaving, epilating, waxing, and other methods.
  4. ^ Familial scalp hair loss may occur if estrogens are stopped.
  5. ^ Varies significantly depending on the amount of physical exercise.
  6. ^ Occurs only in individuals of pubertal age who have not yet completed epiphyseal closure.
  7. ^ Additional research is needed to determine permanency, but a permanent impact of estrogen therapy on sperm quality is likely and sperm preservation options should be counseled on and considered before initiation of therapy.
  8. ^ Conflicting reports, with none reported observed in transgender women but significant albeit minor reduction of penis size reported in men with prostate cancer on androgen deprivation therapy.[275][276][277][278]
  9. ^ Treatment by speech pathologists for voice training is effective.
Sources: Guidelines:[1][2][6] Reviews/book chapters: [4][279][210][280][57][255][281][211] Studies:[282][283]

Breast development edit

See also: Breast development § Biochemistry
 
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.[285]

Breast development in transgender women begins within two to three months of the start of hormone therapy and continues for up to two years.[286][211] Breast development seems to be better in transgender women who have a higher body mass index.[286][211] 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.[286][211] Different estrogens, such as estradiol valerate, conjugated estrogens, and ethinylestradiol, appear to produce equivalent results in terms of breast sizes in transgender women.[286][235][176] The sudden discontinuation of estrogen therapy has been associated with onset of galactorrhea (lactation).[286][211]

Skin changes edit

Estrogens cause the accumulation of subcutaneous fat and an increased epidermal thickness, softening the skin.[285][287] Some skin conditions, including melasma, are found in trans women at the same rate at cisgender women.[288]

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.[285][289]

Hair changes edit

Antiandrogens affect existing facial hair only slightly; patients may see slower growth and some reduction in density and coverage. This reduction of density is due to the decreasing hair diameter and slower terminal growth rate. Effects on hair size and density were noticeable in the first four months following the start of hormone therapy, but later subsided, with measurements staying constant.[288] In patients in their teens or early twenties, antiandrogens prevent new facial hair from developing if testosterone levels are within the normal female range.[285][289]

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.[285][289] Eyebrows do not change because they are not androgenic hair.[290]

Eye changes edit

The lens of the eye changes in curvature.[291][292][293][287] 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.[294][295][296][297][298]

Fat changes edit

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. The body begins to burn old adipose tissue in the waist, shoulders, and back, making those areas smaller.[285]

Bone/skeletal changes edit

Sex hormones play an important role in bone growth and maintenance. The effects of hormone therapy on bone health are not fully understood, and may depend on whether hormone therapy is started before or after puberty.[299] Significant changes to bone structure have been observed,[300][301][302] and transgender women have statistically poorer bone health even before beginning the transition process, possibly due to a lack of physical exercise[303] or other risk factors such as low vitamin D, eating disorders, and substance abuse.[304]

Approximately 14% of transgender women suffer from osteoporosis.[304] Transgender women below the age of 50 show increased fracture risk compared to age-matched cisgender women, equal to the risk to cisgender men of equivalent age. Transgender women above the age of 50 have a similar fracture risk to post-menopausal women — higher than that of age-matched cis men. In both cases, trans women's fracture patterns follow that of cis women, suffering long-term stress fractures concentrated in the hip, spine, and arms, typical of chronic low bone mineral density, rather than the fracture patterns typical of external injury suffered by cis men.[305] Current clinical guidelines are for bone health to be monitored regularly throughout the transition process, particularly if risk factors are present.[299] Transgender individuals are encouraged to ingest at least 1g of Calcium and 1000 IU of Vitamin D daily, engage regularly in weight-bearing physical activity, and reduce alcohol and smoking consumption.[306]

The effects of hormone therapy on bone health are reversible should treatment be interrupted. However, withdrawing hormone therapy after gonadectomy can lead to bone loss,[307] and poor compliance with prescribed hormone therapy after gonadectomy may account in part for the observed fracture risk.[308]

Mental changes edit

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.[309]

Side effects of hormone therapy 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.[310] Some transgender women report a significant reduction in libido, depending on the dosage of antiandrogens.[311] The effects of long-term hormonal regimens have not been conclusively studied and are difficult to estimate because research on the long-term use of hormonal therapy has not been noted.[255] One study found that sex drive returned to baseline after three years of hormone therapy. [274] It is possible to approximate outcomes of these therapies on transgender people based on their observed effect in cisgender men and women.[310] Firstly, if one is to decrease testosterone in feminizing 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.[310] To date there have not been any randomized clinical trials looking at the relationship between type and dose of transgender hormone therapy, so the relationship between them remains unclear.[310] Typically, the estrogens given for feminizing gender transition are 2 to 3 times higher than the recommended dose for HRT in postmenopausal women.[255] Pharmacokinetic studies indicate taking these increased doses may lead to a higher boost in plasma estradiol levels; however, the long-term side effects have not been studied and the safety of this route is unclear.[255]

Several studies have found that hormone therapy in transgender women causes the structure of the brain to change in the direction of female proportions.[312][313][314][315][316] 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.[312][309]

Cardiovascular effects edit

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.[317][163][55] 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.[48] Non-bioidentical estrogens such as conjugated estrogens and especially ethinylestradiol have markedly disproportionate effects on liver protein synthesis relative to estradiol.[48] 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.[48][318]

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.[211]

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.[319][320][15][54] The estrogens used included oral estradiol (1 to 10 mg/day) and other estrogen formulations.[54] Other medications such as antiandrogens like spironolactone were also used.[54]

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.[321] 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.[321][322] 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., sex, age, smoking status, weight) corresponding to known risk factors for VTE.[321] 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 may be an overestimate.[321]

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.[323][324] The dosage of oral estradiol used was 2 to 8 mg/day.[324] 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).[324] The findings of this study suggest that the incidence of VTE is low in transgender women taking oral estradiol.[323][324]

Cardiovascular health in transgender women has been reviewed in recent publications.[325][53]

Gastrointestinal effects edit

Estrogens may increase the risk of gallbladder disease, especially in older and obese people.[287]

Metabolic changes edit

Cancer risk edit

Studies are mixed on whether the risk of breast cancer is increased with hormone therapy in transgender women.[326][327][328][329] Two cohort studies found no increase in risk relative to cisgender men,[327][328] 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.[329][326] There is no evidence that breast cancer risk in transgender women is greater than in cisgender women.[330] Twenty cases of breast cancer in transgender women have been reported as of 2019.[326][331]

Cisgender men with gynecomastia have not been found to have an increased risk of breast cancer.[332] 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).[332] 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).[332][333][334] The incidences of breast cancer in karyotypical men, men with Klinefelter's syndrome, and karyotypical women are approximately 0.1%,[335] 3%,[333] and 12.5%,[336] 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,[337] yet have not been reported to develop breast cancer.[70][338] The risk of breast cancer in women with Turner syndrome (45,XO karyotype) also appears to be significantly decreased, though this could be related to ovarian failure and hypogonadism rather than to genetics.[339]

Prostate cancer is extremely rare in gonadectomized transgender women who have been treated with estrogens for a prolonged period of time.[1][340][341] Whereas as many as 70% of men show prostate cancer by their 80s,[151] only a handful of cases of prostate cancer in transgender women have been reported in the literature.[1][340][341] 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][340][341]

The risks of certain types of benign brain tumors including meningioma and prolactinoma are increased with hormone therapy in transgender women.[342] These risks have mostly been associated with the use of cyproterone acetate.[342]

Estrogens and progestogens can cause prolactinomas, which are benign, prolactin-secreting tumors of the pituitary gland.[citation needed] 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.

Unaffected characteristics edit

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.[343]

Facial hair develops during puberty and is only slightly affected by HRT.[289]

A person's voice is unaffected by feminizing hormone therapy. Transgender individuals who have undergone male puberty often opt for vocal training, though this may take many years of practice to achieve the desired results. Some may also opt for vocal surgery, though this is to be done in addition to vocal training, not instead of.[344][345][346]

Monitoring edit

Especially in the early stages of feminizing hormone therapy, blood work is done frequently to assess hormone levels and liver function. The Endocrine Society recommends that patients have blood tests every three months in the first year of HRT for estradiol and testosterone, and that spironolactone, if used, be monitored every two to three months in the first year.[1] Recommended ranges for total estradiol and total testosterone levels include but are not limited to the following:

Target ranges for hormone levels in hormone therapy for transgender women
Source Place Estradiol, total Testosterone, total
Endocrine Society United States 100–200 pg/mL <50 ng/dL
World Professional Association for Transgender Health (WPATH) United States "[T]estosterone levels [...] below the upper limit of the normal female range and estradiol levels within a premenopausal female range but well below supraphysiologic levels." "[M]aintain levels within physiologic ranges for a patient's desired gender expression (based on goals of full feminization/masculinization)."
Center of Excellence for Transgender Health (UCSFTooltip University of California, San Francisco) United States "The interpretation of hormone levels for transgender individuals is not yet evidence based; physiologic hormone levels in non-transgender people are used as reference ranges." "Providers are encouraged to consult with their local lab(s) to obtain hormone level reference ranges for both 'male' and 'female' norms, [which can vary,] and then apply the correct range when interpreting results based on the current hormonal sex, rather than the sex of registration."
Fenway Health United States 100–200 pg/mL <55 ng/dL
Callen-Lorde United States "Some guidelines recommend checking estradiol and testosterone levels at baseline and throughout the monitoring of estrogen therapy. We have not found a clinical use for routine hormone levels that justifies the expense. However, we recognize that individual providers may adjust their prescribing and monitoring practices as needed to comply with guidelines or when guided by patient need."
International Planned Parenthood Federation (IPPF) United Kingdom <200 pg/mL 30–100 ng/dL
National Health Service (NHS) Foundation Trusts United Kingdom 55–160 pg/mL 30–85 ng/dL
Royal College of Psychiatry (RCP) United Kingdom 80–140 pg/mL "Well below normal male range"
Vancouver Coastal Health (VCH) Canada ND <1.5 nmol/L
Sources: See template.

The optimal ranges for estrogen apply only to individuals taking estradiol (or an ester of estradiol), and not to those taking synthetic or other non-bioidentical preparations (e.g., conjugated estrogens or ethinylestradiol).[1]

Physicians also recommend broader medical monitoring, including complete blood counts; tests of renal function, liver function, and lipid and glucose metabolism; and monitoring of prolactin levels, body weight, and blood pressure.[1][347]

If prolactin levels are greater than 100 ng/mL, estrogen therapy should be stopped and prolactin levels should be rechecked after 6 to 8 weeks.[347] If prolactin levels remain high, an MRI scan of the pituitary gland to check for the presence of a prolactinoma should be ordered.[347] Otherwise, estrogen therapy may be restarted at a lower dosage.[347] Cyproterone acetate is particularly associated with elevated prolactin levels, and discontinuation of cyproterone acetate lowers prolactin levels.[342][258][348] In contrast to cyproterone acetate, estrogen and spironolactone therapy is not associated with increased prolactin levels.[348][349]

History edit

Effective pharmaceutical female sex-hormonal medications, including androgens, estrogens, and progestogens, first became available in the 1920s and 1930s.[350] One of the earliest reports of hormone therapy in transgender women was published by Danish endocrinologist Christian Hamburger in 1953.[351] One of his patients was Christine Jorgensen, who he had treated starting in 1950.[352][353][354][355] Additional reports of hormone therapy in transgender women were published by Hamburger, the German-American endocrinologist Harry Benjamin, and other researchers in the mid-to-late 1960s.[356][357][358][359][360][361] However, Benjamin had several hundred transgender patients under his care by the late 1950s,[88] and had treated transgender women with hormone therapy as early as the late 1940s or early 1950s.[362][363][364][352] In any case, Hamburger is said to be the first to treat transgender women with hormone therapy.[365]

One of the first transgender health clinics was opened in the mid-1960s at the Johns Hopkins School of Medicine.[366][88] By 1981, there were almost 40 such centers.[367] A review of the hormonal regimens of 20 of the centers was published that year.[356][367] The first International Symposium on Gender Identity, chaired by Christopher John Dewhurst, was held in London in 1969,[368] and the first medical textbook on transgenderism, titled Transsexualism and Sex Reassignment and edited by Richard Green and John Money, was published by Johns Hopkins University Press in 1969.[369][370] This textbook included a chapter on hormone therapy written by Christian Hamburger and Harry Benjamin.[361] The Harry Benjamin International Gender Dysphoria Association (HBIGDA), now known as the World Professional Association for Transgender Health (WPATH), was formed in 1979, with the first version of the Standards of Care published the same year.[352] The Endocrine Society published guidelines for the hormonal care of transgender people in 2009, with a revised version in 2017.[356][371][1]

Hormone therapy for transgender women was initially done using high-dose estrogen therapy with oral estrogens such as conjugated estrogens, ethinylestradiol, and diethylstilbestrol and with parenteral estrogens such as estradiol benzoate, estradiol valerate, estradiol cypionate, and estradiol undecylate.[359][360][361][367][372] Progestogens, such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and other progestins, were also sometimes included.[351][359][360][367][373][281][255] The antiandrogen and progestogen cyproterone acetate was first used in transgender women by 1977.[374][375][376] Its use was standard at the Center of Expertise on Gender Dysphoria (CEGD; Kennis- en Zorgcentrum Genderdysforie, or KZcG) in Amsterdam, the Netherlands by 1985.[377][372] Spironolactone, another antiandrogen, was first used in transgender women by 1986.[378][373][372][279][379] These agents were described as allowing the use of much lower doses of estrogen than previously required, and this was considered advantageous due to risks of high doses of estrogens such as cardiovascular complications.[373][372][376] Antiandrogens were well-established in hormone therapy for transgender women by the early 1990s.[281][255][380] Estrogen doses in transgender women were reduced following the introduction of antiandrogens.[citation needed] Ethinylestradiol, conjugated estrogens, and other non-bioidentical estrogens largely stopped being used in transgender women in favor of estradiol starting around 2000 due to their greater risks of blood clots and cardiovascular issues.[280][325][321]

In modern times, hormone therapy in transgender women is usually done with the combination of an estrogen and an antiandrogen.[381] In some places however, such as Japan, use of antiandrogens is uncommon, and estrogen monotherapy, for instance with high-dose injectable estradiol esters, is still frequently used.[382]

See also edit

References edit

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January 01, 1970
feminizing, hormone, therapy, this, article, cites, sources, does, provide, page, references, help, providing, page, numbers, existing, citations, january, 2024, learn, when, remove, this, message, also, known, transfeminine, hormone, therapy, hormone, therapy. This article cites its sources but does not provide page references You can help providing page numbers for existing citations January 2024 Learn how and when to remove this message 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 Contents 1 Requirements 2 Medications 2 1 Estrogens 2 2 Antiandrogens 2 2 1 Steroidal antiandrogens 2 2 2 Nonsteroidal antiandrogens 2 2 3 GnRH modulators 2 2 4 5a Reductase inhibitors 2 3 Progestogens 2 4 Miscellaneous 3 Interactions 4 Effects 4 1 Breast development 4 2 Skin changes 4 3 Hair changes 4 4 Eye changes 4 5 Fat changes 4 6 Bone skeletal changes 4 7 Mental changes 4 8 Cardiovascular effects 4 9 Gastrointestinal effects 4 10 Metabolic changes 4 11 Cancer risk 4 12 Unaffected characteristics 5 Monitoring 6 History 7 See also 8 References 9 Further reading 10 External linksRequirements editMain articles Transgender hormone therapy Requirements and Transgender hormone therapy Accessibility 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 editvte Medications and dosages used in transgender women 1 3 5 6 12 a 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 mg 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 or5 20 mg every 2 wks Estradiol cypionate Depo Estradiol Estrogen IM SC 2 10 mg wk or5 20 mg every 2 wks Estradiol dipropionate Agofollin Estrogen IM SC 2 10 mg wk or5 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 or200 mg twice daily Finasteride Propecia 5aR inhibitor Oral 1 5 mg day Dutasteride Avodart 5aR 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 Additional sources 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Lower starting doses may be used in adolescents if being used in combination with a GnRH agonist or antagonist a b c d e Also available under other brand names For induction of lactation to allow for breastfeeding specifically Administered in divided doses 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 5a 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 edit See also Estrogen medication Transgender women and Estradiol medication Transgender women nbsp 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 46 Demonstrates the suppression of testosterone levels by parenteral estradiol nbsp 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 47 The dashed purple line is the upper limit for the female castrate range 50 ng dL and the dashed grey line is the testosterone level in a comparison group of post operative transgender women 21 7 ng dL 47 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 edit See also Antiandrogen Transgender hormone therapy 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 edit See also Spironolactone Transgender hormone therapy and Cyproterone acetate Transgender hormone therapy 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 nbsp Testosterone levels with estradiol E2 alone or in combination with an antiandrogen AA in the form of spironolactone SPL or cyproterone acetate CPA in transfeminine people 89 Estradiol was used in the form of oral estradiol valerate EV in almost all cases 89 The dashed horizontal line is the upper limit of the female castrate range 50 ng dL 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 edit See also Bicalutamide medical uses Transgender hormone therapy Nilutamide Transgender hormone therapy and Flutamide Transgender hormone therapy 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 edit 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 5a Reductase inhibitors edit See also Finasteride Transgender hormone therapy and Dutasteride Transgender hormone therapy 5a Reductase inhibitors are inhibitors of the enzyme 5a reductase and are a type of specific androgen synthesis inhibitor 184 185 5a 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 5a 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 5a reductase serves to considerably potentiate the effects of testosterone 184 185 However 5a 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 5a 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 5a reductase in androgen signaling it is also required for the conversion of steroid hormones such as progesterone and testosterone into neurosteroids like allopregnanolone and 3a androstanediol respectively 194 195 5a Reductase inhibitors include finasteride and dutasteride 184 185 Finasteride is a selective inhibitor of 5a reductase types 2 and 3 while dutasteride is an inhibitor of all three isoforms of 5a 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 5a reductase inhibitors do not decrease testosterone levels and may actually increase them slightly 1 47 57 198 5a 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 5a 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 5a 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 5a reductase and by extension decrease in DHT production 205 206 139 In addition to their antiandrogenic uses 5a 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 5a reductase inhibitors of the conversion of progesterone into allopregnanolone during the luteal phase of the menstrual cycle 207 208 5a 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 5a reductase inhibitors in transgender women has been conducted and evidence of their efficacy and safety in this group is limited 209 212 Moreover 5a reductase inhibitors have only mild and specific antiandrogenic activity and are not recommended as general antiandrogens 212 5a 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 5a 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 5a reductase inhibitors 217 220 218 221 216 215 195 Some of the possible side effects of 5a 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 5a reductase inhibitors in transgender women as this group is already at a high risk for depression and suicidality 222 57 Progestogens edit See also Progesterone medication Transgender women 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 edit 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 gt 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 5a reductase inhibitors such as finasteride in transfeminine people 183 Interactions editFurther information CYP3A4 CYP3A4 ligands 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 editThe 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 Effects of feminizing hormone therapy in transfeminine people Effect Time to expectedonset of effect a Time to expectedmaximum effect a b Permanency if hormonetherapy 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 gt 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 Changes in mood emotionality and behavior Unspecified Unspecified Reversible Decreased sex drive 1 3 months Temporary 274 Reversible Decreased spontaneous morning erections 1 3 months 3 6 months Reversible Erectile dysfunction and decreased ejaculate volume 1 3 months Variable Reversible Decreased sperm production fertility Unknown gt 3 years Reversible or permanent g Decreased testicle size 3 6 months 2 3 years Unknown Decreased penis size None h Not applicable Not applicable Decreased prostate gland size Unspecified Unspecified Unspecified Voice changes None i Not applicable Not applicable Footnotes and sourcesFootnotes a b Estimates represent published and unpublished clinical observations Time at which further changes are unlikely at maximum maintained dose Maximum effects vary widely depending on genetics body habitus age and status of gonad removal Generally older individuals with intact gonads may have less feminization overall Complete removal of male facial and body hair requires electrolysis laser hair removal or both Temporary hair removal can be achieved with shaving epilating waxing and other methods Familial scalp hair loss may occur if estrogens are stopped Varies significantly depending on the amount of physical exercise Occurs only in individuals of pubertal age who have not yet completed epiphyseal closure Additional research is needed to determine permanency but a permanent impact of estrogen therapy on sperm quality is likely and sperm preservation options should be counseled on and considered before initiation of therapy Conflicting reports with none reported observed in transgender women but significant albeit minor reduction of penis size reported in men with prostate cancer on androgen deprivation therapy 275 276 277 278 Treatment by speech pathologists for voice training is effective Sources Guidelines 1 2 6 Reviews book chapters 4 279 210 280 57 255 281 211 Studies 282 283 Breast development edit See also Breast development Biochemistry nbsp 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 285 Breast development in transgender women begins within two to three months of the start of hormone therapy and continues for up to two years 286 211 Breast development seems to be better in transgender women who have a higher body mass index 286 211 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 286 211 Different estrogens such as estradiol valerate conjugated estrogens and ethinylestradiol appear to produce equivalent results in terms of breast sizes in transgender women 286 235 176 The sudden discontinuation of estrogen therapy has been associated with onset of galactorrhea lactation 286 211 Skin changes edit Estrogens cause the accumulation of subcutaneous fat and an increased epidermal thickness softening the skin 285 287 Some skin conditions including melasma are found in trans women at the same rate at cisgender women 288 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 285 289 Hair changes edit Antiandrogens affect existing facial hair only slightly patients may see slower growth and some reduction in density and coverage This reduction of density is due to the decreasing hair diameter and slower terminal growth rate Effects on hair size and density were noticeable in the first four months following the start of hormone therapy but later subsided with measurements staying constant 288 In patients in their teens or early twenties antiandrogens prevent new facial hair from developing if testosterone levels are within the normal female range 285 289 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 285 289 Eyebrows do not change because they are not androgenic hair 290 Eye changes edit The lens of the eye changes in curvature 291 292 293 287 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 294 295 296 297 298 Fat changes edit 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 The body begins to burn old adipose tissue in the waist shoulders and back making those areas smaller 285 Bone skeletal changes edit Sex hormones play an important role in bone growth and maintenance The effects of hormone therapy on bone health are not fully understood and may depend on whether hormone therapy is started before or after puberty 299 Significant changes to bone structure have been observed 300 301 302 and transgender women have statistically poorer bone health even before beginning the transition process possibly due to a lack of physical exercise 303 or other risk factors such as low vitamin D eating disorders and substance abuse 304 Approximately 14 of transgender women suffer from osteoporosis 304 Transgender women below the age of 50 show increased fracture risk compared to age matched cisgender women equal to the risk to cisgender men of equivalent age Transgender women above the age of 50 have a similar fracture risk to post menopausal women higher than that of age matched cis men In both cases trans women s fracture patterns follow that of cis women suffering long term stress fractures concentrated in the hip spine and arms typical of chronic low bone mineral density rather than the fracture patterns typical of external injury suffered by cis men 305 Current clinical guidelines are for bone health to be monitored regularly throughout the transition process particularly if risk factors are present 299 Transgender individuals are encouraged to ingest at least 1g of Calcium and 1000 IU of Vitamin D daily engage regularly in weight bearing physical activity and reduce alcohol and smoking consumption 306 The effects of hormone therapy on bone health are reversible should treatment be interrupted However withdrawing hormone therapy after gonadectomy can lead to bone loss 307 and poor compliance with prescribed hormone therapy after gonadectomy may account in part for the observed fracture risk 308 Mental changes edit 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 309 Side effects of hormone therapy 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 310 Some transgender women report a significant reduction in libido depending on the dosage of antiandrogens 311 The effects of long term hormonal regimens have not been conclusively studied and are difficult to estimate because research on the long term use of hormonal therapy has not been noted 255 One study found that sex drive returned to baseline after three years of hormone therapy 274 It is possible to approximate outcomes of these therapies on transgender people based on their observed effect in cisgender men and women 310 Firstly if one is to decrease testosterone in feminizing 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 310 To date there have not been any randomized clinical trials looking at the relationship between type and dose of transgender hormone therapy so the relationship between them remains unclear 310 Typically the estrogens given for feminizing gender transition are 2 to 3 times higher than the recommended dose for HRT in postmenopausal women 255 Pharmacokinetic studies indicate taking these increased doses may lead to a higher boost in plasma estradiol levels however the long term side effects have not been studied and the safety of this route is unclear 255 Several studies have found that hormone therapy in transgender women causes the structure of the brain to change in the direction of female proportions 312 313 314 315 316 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 312 309 Cardiovascular effects edit 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 317 163 55 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 48 Non bioidentical estrogens such as conjugated estrogens and especially ethinylestradiol have markedly disproportionate effects on liver protein synthesis relative to estradiol 48 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 48 318 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 211 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 319 320 15 54 The estrogens used included oral estradiol 1 to 10 mg day and other estrogen formulations 54 Other medications such as antiandrogens like spironolactone were also used 54 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 321 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 321 322 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 sex age smoking status weight corresponding to known risk factors for VTE 321 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 may be an overestimate 321 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 323 324 The dosage of oral estradiol used was 2 to 8 mg day 324 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 324 The findings of this study suggest that the incidence of VTE is low in transgender women taking oral estradiol 323 324 Cardiovascular health in transgender women has been reviewed in recent publications 325 53 Gastrointestinal effects edit Estrogens may increase the risk of gallbladder disease especially in older and obese people 287 Metabolic changes edit This section is empty You can help by adding to it December 2022 Cancer risk edit Studies are mixed on whether the risk of breast cancer is increased with hormone therapy in transgender women 326 327 328 329 Two cohort studies found no increase in risk relative to cisgender men 327 328 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 329 326 There is no evidence that breast cancer risk in transgender women is greater than in cisgender women 330 Twenty cases of breast cancer in transgender women have been reported as of 2019 326 331 Cisgender men with gynecomastia have not been found to have an increased risk of breast cancer 332 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 332 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 332 333 334 The incidences of breast cancer in karyotypical men men with Klinefelter s syndrome and karyotypical women are approximately 0 1 335 3 333 and 12 5 336 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 337 yet have not been reported to develop breast cancer 70 338 The risk of breast cancer in women with Turner syndrome 45 XO karyotype also appears to be significantly decreased though this could be related to ovarian failure and hypogonadism rather than to genetics 339 Prostate cancer is extremely rare in gonadectomized transgender women who have been treated with estrogens for a prolonged period of time 1 340 341 Whereas as many as 70 of men show prostate cancer by their 80s 151 only a handful of cases of prostate cancer in transgender women have been reported in the literature 1 340 341 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 1 340 341 The risks of certain types of benign brain tumors including meningioma and prolactinoma are increased with hormone therapy in transgender women 342 These risks have mostly been associated with the use of cyproterone acetate 342 Estrogens and progestogens can cause prolactinomas which are benign prolactin secreting tumors of the pituitary gland citation needed 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 Unaffected characteristics edit This section needs expansion You can help by adding to it December 2022 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 343 Facial hair develops during puberty and is only slightly affected by HRT 289 A person s voice is unaffected by feminizing hormone therapy Transgender individuals who have undergone male puberty often opt for vocal training though this may take many years of practice to achieve the desired results Some may also opt for vocal surgery though this is to be done in addition to vocal training not instead of 344 345 346 Monitoring editEspecially in the early stages of feminizing hormone therapy blood work is done frequently to assess hormone levels and liver function The Endocrine Society recommends that patients have blood tests every three months in the first year of HRT for estradiol and testosterone and that spironolactone if used be monitored every two to three months in the first year 1 Recommended ranges for total estradiol and total testosterone levels include but are not limited to the following vte Target ranges for hormone levels in hormone therapy for transgender women Source Place Estradiol total Testosterone total Endocrine Society United States 100 200 pg mL lt 50 ng dL World Professional Association for Transgender Health WPATH United States T estosterone levels below the upper limit of the normal female range and estradiol levels within a premenopausal female range but well below supraphysiologic levels M aintain levels within physiologic ranges for a patient s desired gender expression based on goals of full feminization masculinization Center of Excellence for Transgender Health UCSFTooltip University of California San Francisco United States The interpretation of hormone levels for transgender individuals is not yet evidence based physiologic hormone levels in non transgender people are used as reference ranges Providers are encouraged to consult with their local lab s to obtain hormone level reference ranges for both male and female norms which can vary and then apply the correct range when interpreting results based on the current hormonal sex rather than the sex of registration Fenway Health United States 100 200 pg mL lt 55 ng dL Callen Lorde United States Some guidelines recommend checking estradiol and testosterone levels at baseline and throughout the monitoring of estrogen therapy We have not found a clinical use for routine hormone levels that justifies the expense However we recognize that individual providers may adjust their prescribing and monitoring practices as needed to comply with guidelines or when guided by patient need International Planned Parenthood Federation IPPF United Kingdom lt 200 pg mL 30 100 ng dL National Health Service NHS Foundation Trusts United Kingdom 55 160 pg mL 30 85 ng dL Royal College of Psychiatry RCP United Kingdom 80 140 pg mL Well below normal male range Vancouver Coastal Health VCH Canada ND lt 1 5 nmol L Sources See template The optimal ranges for estrogen apply only to individuals taking estradiol or an ester of estradiol and not to those taking synthetic or other non bioidentical preparations e g conjugated estrogens or ethinylestradiol 1 Physicians also recommend broader medical monitoring including complete blood counts tests of renal function liver function and lipid and glucose metabolism and monitoring of prolactin levels body weight and blood pressure 1 347 If prolactin levels are greater than 100 ng mL estrogen therapy should be stopped and prolactin levels should be rechecked after 6 to 8 weeks 347 If prolactin levels remain high an MRI scan of the pituitary gland to check for the presence of a prolactinoma should be ordered 347 Otherwise estrogen therapy may be restarted at a lower dosage 347 Cyproterone acetate is particularly associated with elevated prolactin levels and discontinuation of cyproterone acetate lowers prolactin levels 342 258 348 In contrast to cyproterone acetate estrogen and spironolactone therapy is not associated with increased prolactin levels 348 349 History editEffective pharmaceutical female sex hormonal medications including androgens estrogens and progestogens first became available in the 1920s and 1930s 350 One of the earliest reports of hormone therapy in transgender women was published by Danish endocrinologist Christian Hamburger in 1953 351 One of his patients was Christine Jorgensen who he had treated starting in 1950 352 353 354 355 Additional reports of hormone therapy in transgender women were published by Hamburger the German American endocrinologist Harry Benjamin and other researchers in the mid to late 1960s 356 357 358 359 360 361 However Benjamin had several hundred transgender patients under his care by the late 1950s 88 and had treated transgender women with hormone therapy as early as the late 1940s or early 1950s 362 363 364 352 In any case Hamburger is said to be the first to treat transgender women with hormone therapy 365 One of the first transgender health clinics was opened in the mid 1960s at the Johns Hopkins School of Medicine 366 88 By 1981 there were almost 40 such centers 367 A review of the hormonal regimens of 20 of the centers was published that year 356 367 The first International Symposium on Gender Identity chaired by Christopher John Dewhurst was held in London in 1969 368 and the first medical textbook on transgenderism titled Transsexualism and Sex Reassignment and edited by Richard Green and John Money was published by Johns Hopkins University Press in 1969 369 370 This textbook included a chapter on hormone therapy written by Christian Hamburger and Harry Benjamin 361 The Harry Benjamin International Gender Dysphoria Association HBIGDA now known as the World Professional Association for Transgender Health WPATH was formed in 1979 with the first version of the Standards of Care published the same year 352 The Endocrine Society published guidelines for the hormonal care of transgender people in 2009 with a revised version in 2017 356 371 1 Hormone therapy for transgender women was initially done using high dose estrogen therapy with oral estrogens such as conjugated estrogens ethinylestradiol and diethylstilbestrol and with parenteral estrogens such as estradiol benzoate estradiol valerate estradiol cypionate and estradiol undecylate 359 360 361 367 372 Progestogens such as hydroxyprogesterone caproate medroxyprogesterone acetate and other progestins were also sometimes included 351 359 360 367 373 281 255 The antiandrogen and progestogen cyproterone acetate was first used in transgender women by 1977 374 375 376 Its use was standard at the Center of Expertise on Gender Dysphoria CEGD Kennis en Zorgcentrum Genderdysforie or KZcG in Amsterdam the Netherlands by 1985 377 372 Spironolactone another antiandrogen was first used in transgender women by 1986 378 373 372 279 379 These agents were described as allowing the use of much lower doses of estrogen than previously required and this was considered advantageous due to risks of high doses of estrogens such as cardiovascular complications 373 372 376 Antiandrogens were well established in hormone therapy for transgender women by the early 1990s 281 255 380 Estrogen doses in transgender women were reduced following the introduction of antiandrogens citation needed Ethinylestradiol conjugated estrogens and other non bioidentical estrogens largely stopped being used in transgender women in favor of estradiol starting around 2000 due to their greater risks of blood clots and cardiovascular issues 280 325 321 In modern times hormone therapy in transgender women is usually done with the combination of an estrogen and an antiandrogen 381 In some places however such as Japan use of antiandrogens is uncommon and estrogen monotherapy for instance with high dose injectable estradiol esters is still frequently used 382 See also edit nbsp Transgender portal Menopausal hormone therapy Androgen replacement therapy Masculinizing hormone therapyReferences edit a b c d e f g h i j k l m n o p q r s t u Hembree WC Cohen Kettenis PT Gooren L Hannema SE Meyer WJ Murad MH et al November 2017 Endocrine Treatment of Gender Dysphoric Gender Incongruent Persons An Endocrine Society Clinical Practice Guideline The Journal of Clinical Endocrinology and Metabolism 102 11 3869 3903 doi 10 1210 jc 2017 01658 PMID 28945902 S2CID 3726467 a b c d e f g h i j k l m n o p Coleman E Bockting W Botzer M Cohen Kettenis P DeCuypere G Feldman J et al 2012 Standards of Care for the Health of Transsexual Transgender and Gender Nonconforming People Version 7 PDF International Journal of Transgenderism 13 4 165 232 doi 10 1080 15532739 2011 700873 ISSN 1553 2739 S2CID 39664779 a b c d e f g h Deutsch M 17 June 2016 Guidelines for the Primary and Gender Affirming Care of Transgender and Gender Nonbinary People PDF 2nd ed University of California San Francisco Center of Excellence for Transgender Health p 28 a b c d e f g h i j Wesp LM Deutsch MB March 2017 Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons The Psychiatric Clinics of North America 40 1 99 111 doi 10 1016 j psc 2016 10 006 PMID 28159148 a b c d e f g h i j Dahl M Feldman JL Goldberg J Jaberi A Bockting WO Knudson G 2015 Endocrine Therapy for Transgender Adults in British Columbia Suggested Guidelines PDF Vancouver Coastal Health Retrieved 15 August 2018 a b c d e Bourns A 2015 Guidelines and Protocols for Comprehensive Primary Care for Trans Clients PDF Sherbourne Health Centre Retrieved 15 August 2018 Murad MH Elamin MB Garcia MZ Mullan RJ Murad A Erwin PJ Montori VM February 2010 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Retrieved 29 December 2018 a b Newman R Jeory T 16 November 2016 Fears of DIY transitioning as hormone drugs sold to transgender women without checks The Independent Retrieved 29 December 2018 Wylie K Barrett J Besser M Bouman WP Bridgman M Clayton A et al 2014 Good Practice Guidelines for the Assessment and Treatment of Adults with Gender Dysphoria PDF Sexual and Relationship Therapy 29 2 154 214 doi 10 1080 14681994 2014 883353 ISSN 1468 1994 S2CID 144632597 Archived from the original PDF on 2018 09 02 Wesp LM Deutsch MB March 2017 Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons The Psychiatric Clinics of North America 40 1 99 111 doi 10 1016 j psc 2016 10 006 PMID 28159148 Unger CA December 2016 Hormone therapy for transgender patients Translational Andrology and Urology 5 6 877 884 doi 10 21037 tau 2016 09 04 PMC 5182227 PMID 28078219 a b c d e f g h Randolph JF December 2018 Gender Affirming Hormone Therapy for Transgender Females 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Bicalutamide Associated Acute Liver Injury and Migratory Arthralgia A Rare but Clinically Important Adverse Effect Case Reports in Gastroenterology 12 2 266 270 doi 10 1159 000485175 hdl 20 500 11815 1492 ISSN 1662 0631 S2CID 81661015 Gao Y Maurer T Mirmirani P August 2018 Understanding and Addressing Hair Disorders in Transgender Individuals American Journal of Clinical Dermatology 19 4 517 527 doi 10 1007 s40257 018 0343 z PMID 29352423 S2CID 6467968 Non steroidal antiandrogens include flutamide nilutamide and bicalutamide which do not lower androgen levels and may be favorable for individuals who want to preserve sex drive and fertility 9 Iversen P Melezinek I Schmidt A January 2001 Nonsteroidal antiandrogens a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function BJU International 87 1 47 56 doi 10 1046 j 1464 410x 2001 00988 x PMID 11121992 S2CID 28215804 Morgante E Gradini R Realacci M Sale P D Eramo G Perrone GA et al March 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Aside from their negative feedback action at the level of the hypothalamus and pituitary direct inhibitory effects on the testis are likely 215 216 The histology of the testes with estrogen treatment showed disorganization of the seminiferous tubules vacuolization and absence of lumen and compartmentalization of spermatogenesis a b Salam MA 2003 Principles amp Practice of Urology A Comprehensive Text Universal Publishers pp 684 ISBN 978 1 58112 412 5 Estrogens act primarily through negative feedback at the hypothalamic pituitary level to reduce LH secretion and testicular androgen synthesis Interestingly if the treatment with estrogens is discontinued after 3 yr of uninterrupted exposure serum testosterone may remain at castration levels for up to another 3 yr This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells a b c Cox RL Crawford ED December 1995 Estrogens in the treatment of prostate cancer The Journal of Urology 154 6 1991 1998 doi 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and Treatment CRC Press pp 308 ISBN 978 1 85317 422 3 Reilly DR Delva NJ Hudson RW August 2000 Protocols for the use of cyproterone medroxyprogesterone and leuprolide in the treatment of paraphilia Canadian Journal of Psychiatry 45 6 559 563 doi 10 1177 070674370004500608 PMID 10986575 S2CID 27710792 estrogen or antiandrogen treatment prior to the first leuprolide injection may reduce the risk of symptoms caused by the testosterone flare at the initiation of treatment 16 a b c d Dittrich R Binder H Cupisti S Hoffmann I Beckmann MW Mueller A December 2005 Endocrine treatment of male to female transsexuals using gonadotropin releasing hormone agonist Experimental and Clinical Endocrinology amp Diabetes 113 10 586 592 doi 10 1055 s 2005 865900 PMID 16320157 a b c Schechter LS Safa B 23 June 2018 Gender Confirmation Surgery An Issue of Clinics in Plastic Surgery E Book Elsevier Health Sciences pp 314 ISBN 978 0 323 61075 9 Emans SJ Laufer MR 5 January 2012 Emans Laufer Goldstein s Pediatric and Adolescent Gynecology Lippincott Williams amp Wilkins pp 365 ISBN 978 1 4511 5406 1 Archived from the original on 16 May 2016 Therapy with GnRH analogs is expensive and requires intramuscular injections of depot formulations the insert of a subcutaneous implant yearly or much less commonly daily subcutaneous injections Hillard PJ 29 March 2013 Practical Pediatric and Adolescent Gynecology John Wiley amp Sons pp 182 ISBN 978 1 118 53857 9 Treatment is expensive with costs typically in the range of 10 000 15 000 per year cite, wikipedia, wiki, book, books, library,

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