Transgender hormone therapy (male-to-female)

Transgender hormone therapy of the male-to-female (MTF) type, also known as feminizing hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sexual characteristics of transgender people from masculine (or androgynous) to feminine.[1][2][3][4][5][6] It is one of two types of transgender hormone therapy (the other being female-to-male) and is predominantly used to treat transgender women and other transfeminine individuals. Some intersex people also 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 the MTF therapy include estrogens, antiandrogens, progestogens, and gonadotropin-releasing hormone modulators (GnRH modulators).

While the therapy cannot undo the effects of a person's first puberty, developing secondary sex characteristics associated with a different gender can relieve some or all of the distress and discomfort associated with gender dysphoria, and can help the person to "pass" or be seen as the gender they identify with. Introducing exogenous hormones into the body impacts it at every level and many patients report changes in energy levels, mood, appetite, etc. The goal of the therapy, and indeed all somatic treatments, is to provide patients with a more satisfying body that is more congruent with their gender identity.

Medical uses

Requirements and accessibility

Contraindications

Some medical conditions may be a reason to withhold hormone replacement therapy because of the harm it could cause to the patient. Such interfering factors are described in medicine as contraindications.

Absolute contraindications – those that can cause life-threatening complications, and in which hormone replacement therapy should never be used – include histories of estrogen-sensitive cancer (e.g., breast cancer), thrombosis or embolism (unless the patient receives concurrent anticoagulants), or macroprolactinoma. In such cases, the patient should be monitored by an oncologist, hematologist or cardiologist, or neurologist, respectively.

Relative contraindications – in which the benefits of HRT may outweigh the risks, but caution should be used – include:

As dosages increase, risks increase as well. Therefore, patients with relative contraindications may start at low dosages and increase gradually.

Safety

Hormone therapy for transgender individuals has been shown in medical literature to be safe when supervised by a qualified medical professional.[7]

Interactions

Inducers of CYP3A4 and other cytochrome P450 enzymes can reduce the effects of MTF HRT.

Types of therapy

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]

Medications and dosages used in hormone therapy for transgender women
MedicationBrand namesTypeRouteDosage
EstradiolVariousEstrogenOral0.25–8 mg/day
VariousSublingual0.25–8 mg/day
Climara, Vivelle, othersTransdermal (patches)6.25–400 μg/day
Divigel, EstroGel, SandrenaTransdermal (gel)0.5–4.5 mg/day
Estradiol valerateProgynovaEstrogenOral0.25–8 mg/day
Delestrogen, Progynon DepotInjection (IM or SC)2–10 mg/week or 5–30 mg/2 weeks
Estradiol cypionateDepo-EstradiolEstrogenInjection (IM or SC)2–10 mg/week or 5–30 mg/2 weeks
Estradiol benzoateProgynon-BEstrogenInjection (IM or SC)0.5–1.5 mg/2–3 days
Conjugated estrogensaPremarinEstrogenOral0.625–10 mg/day
EthinylestradiolaVariousEstrogenOral20–100 μg/day
EstriolOvestin, SynapauseEstrogenOral4–6 mg/day
SpironolactoneAldactoneAntiandrogenOral100–400 mg/day
Cyproterone acetateAndrocurAntiandrogen; ProgestogenOral25–50 mg/day
FlutamideaEulexinAntiandrogenOral125–750 mg/day (divided doses)
NilutamideaAnandron, NilandronAntiandrogenOral300 mg/day
BicalutamideCasodexAntiandrogenOral50 mg/day
GnRH analogueVariousGnRH modulatorParenteral (various)Variable
ElagolixOrilissaGnRH antagonistOral150 mg/day or 200 mg/twice a day[8]
FinasteridePropecia5α-Reductase inhibitorOral1–5 mg/day
DutasterideAvodart5α-Reductase inhibitorOral0.25–0.5 mg/day
ProgesteronePrometrium, UtrogestanProgestogenOral100–400 mg/day
Medroxyprogesterone acetateProveraProgestogenOral2.5–40 mg/day
Depo-ProveraInjection (IM)150 mg/3 months
Depo-SubQ Provera 104Injection (SC)104 mg/3 months
Hydroxyprogesterone caproateProlutonProgestogenInjection (IM)250 mg/week
DydrogesteroneDuphastonProgestogenOral20 mg/day
Footnotes: a = No longer recommended for use in transgender women. Miscellaneous: Direct link to table. Sources: Guidelines: [1][3][5][6][9] Reviews/book chapters: [4][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]

Estrogens

Estradiol and testosterone levels over the course of 12 weeks following a single intramuscular injection of 320 mg polyestradiol phosphate, a polymeric estradiol ester and prodrug, in men with prostate cancer.[27] Demonstrates the suppression of testosterone levels by parenteral estradiol.
Testosterone levels as a function of estradiol levels during 1 to 8 mg/day oral estradiol therapy in transgender women.[28] Demonstrates the suppression of testosterone levels by oral estradiol.

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.[29] A variety of different forms of estrogens are available and used medically.[29] 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][29] 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.[29][10][30][31][32] Parenteral (non-oral) routes are preferred, owing to a minimal or negligible risk of blood clots and cardiovascular issues.[5][33][34][35][36]

In addition to producing feminization, estrogens have antigonadotropic effects and suppress gonadal sex hormone production.[10][28][16] They are mainly responsible for the suppression of testosterone levels in transgender women.[10][16] 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.[37][38] Lower levels of estradiol can also considerably but incompletely suppress testosterone production.[28] When testosterone levels are insufficiently suppressed by estradiol alone, antiandrogens can be used to suppress or block the effects of residual testosterone.[10] Oral estradiol often has difficulty adequately suppressing testosterone levels, due to the relatively low estradiol levels achieved with it.[28][39][40]

Prior to orchiectomy or sex reassignment surgery, the doses of estrogens used in transgender women are often higher than replacement doses used in cisgender women.[17][41][42] This is to help suppress testosterone levels.[41] 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 physiological levels of estradiol are unable to suppress testosterone levels into the female range.[1] In addition, the Endocrine Society recommends dosages of injected estradiol esters that result in estradiol levels that can markedly exceed the normal female range (e.g., 10 mg/week estradiol valerate, which results in peak estradiol levels of 1,250 pg/mL on average).[1][43][44] Dosages of estrogens can be reduced after an orchiectomy (surgical removal of the gonads) or sex reassignment surgery, when testosterone suppression is no longer needed.[5]

Antiandrogens

Androgens, such as testosterone and dihydrotestosterone (DHT), are the major sex hormones in people with testes, and are responsible for the development and maintenance of masculine secondary sexual characteristics, such as a deep voice, broad shoulders, and a masculine pattern of hair, muscle, and fat distribution. In addition, they stimulate sex drive and the frequency of spontaneous erections and are responsible for acne, body odor, and scalp hair loss. Androgens act by binding to and activating the androgen receptor, their biological target in the body.

In contrast to androgens, antiandrogens are medications that prevent the effects of androgens in the body.[45][46] They do this by blocking androgens from binding to the androgen receptor and/or by inhibiting or suppressing the production of androgens.[45] Antiandrogens that directly block the androgen receptor are known as androgen receptor antagonists, while antiandrogens that inhibit the enzymatic synthesis of androgens are known as androgen synthesis inhibitors and antiandrogens that suppress androgen production in the gonads are known as antigonadotropins.[46] Estrogens and progestogens are antigonadotropins and hence are functional antiandrogens.[10][47][48][49]

The purpose of antiandrogens is to suppress or block residual testosterone that is not suppressed by estrogens alone.[10][45][16] Antiandrogens are not necessarily needed if testosterone levels are in the normal female range with an estrogen alone.[10][45][16]

Steroidal antiandrogens

Steroidal antiandrogens are antiandrogens that resemble steroid hormones like testosterone and progesterone in chemical structure.[50] 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.[51][52] Cyproterone acetate (Androcur), which is unavailable in the United States, is widely used in Europe, Canada, and the rest of the world.[2][45][51][53] Medroxyprogesterone acetate (Provera, Depo-Provera), a similar medication, is sometimes used in place of cyproterone acetate in the United States.[54][55]

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.[56] Spironolactone is an antiandrogen as a secondary and originally unintended action.[56] It works as an antiandrogen mainly by acting as an androgen receptor antagonist.[57] The medication is also a weak steroidogenesis inhibitor, and inhibits the enzymatic synthesis of androgens.[58][57][59] However, this action is of very low potency, and spironolactone has mixed and highly inconsistent effects on hormone levels.[58][57][59][60][61] In any case, testosterone levels are usually unchanged by spironolactone.[58][57][59][60][61] In accordance, a relatively large study found no effect of spironolactone on testosterone levels in transgender women.[28] Spironolactone is described as a relatively weak antiandrogen.[62][63][64] It is widely used in the treatment of acne, excessive hair growth, and hyperandrogenism in women, who have much lower testosterone levels than men.[60][61] Because of its antimineralocorticoid activity, spironolactone has antimineralocorticoid side effects[65] and can cause high potassium levels.[66][67] Hospitalization and/or death can result from high potassium levels,[66][67][68] but the risk of high potassium levels in people taking spironolactone appears to be minimal in those without risk factors for it.[61][69][70] As such, monitoring of potassium levels may not be necessary in most cases.[61][69][70] Spironolactone has been found to decrease the bioavailability of oral estradiol.[28] Although widely employed, the use of spironolactone as an antiandrogen in transgender women has recently been questioned due to its various shortcomings.[28]

Testosterone and luteinizing hormone levels with 100 mg/day oral cyproterone acetate in men.[71]
Testosterone levels with intramuscular 100 mg/month estradiol undecylate or 300 mg/week cyproterone acetate in older men with prostate cancer.[72] Solid lines are average levels and dashed lines are highest and lowest levels.[72]

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.[73][74] It works primarily as an antigonadotropin, secondarily to its potent progestogenic activity, and strongly suppresses gonadal androgen production.[73][16] Cyproterone acetate at a dosage of 10 mg/day has been found to lower testosterone levels in men by about 50 to 70%,[75][76][77][78] while a dosage of 100 mg/day has been found to lower testosterone levels in men by about 75%.[79][72] 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%.[80] In addition to its actions as an antigonadotropin, cyproterone acetate is an androgen receptor antagonist.[73][45] 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).[81][82] Cyproterone acetate can cause elevated liver enzymes and liver damage, including liver failure.[45][83] However, this occurs mostly in prostate cancer patients who take very high doses of cyproterone acetate, and liver toxicity has not been reported in transgender women.[45] Cyproterone acetate also has a variety of other adverse effects and risks, such as depression, blood clots, benign brain tumors, glucocorticoid side effects, and cardiovascular side effects, among others.[16][45][84] 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.[54][55] 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.[54][55] Medroxyprogesterone acetate suppresses testosterone levels in transgender women similarly to cyproterone acetate.[55][28] 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.[85][86][87][88][89] In contrast to cyproterone acetate however, medroxyprogesterone acetate is not an androgen receptor antagonist, and instead has very weak androgenic activity.[29][90] However, the clinical relevance of this androgenic activity is doubtful at typical clinical dosages.[90] Medroxyprogesterone acetate has similar side effects and risks as cyproterone acetate, but lacks the liver issues of cyproterone acetate and does not seem to share its risk of depression.[91][92][65]

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.[93][94][95][96][97][98][99] 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.[100][101][102]

Nonsteroidal antiandrogens

Nonsteroidal antiandrogens are antiandrogens that are nonsteroidal and hence unrelated to steroid hormones in terms of chemical structure.[50][103] These medications are primarily used in the treatment of prostate cancer,[103] but are also used for other purposes such as the treatment of acne, excessive facial/body hair growth, and high androgen levels in women.[104][105][106] Unlike steroidal antiandrogens, nonsteroidal antiandrogens are highly selective for the androgen receptor and act as pure androgen receptor antagonists.[103][107] Similarly to spironolactone however, they do not lower androgen levels, and instead work exclusively by preventing androgens from activating the androgen receptor.[103][107] The nonsteroidal antiandrogens are more efficacious androgen receptor antagonists than are the steroidal antiandrogens,[50][108] and for this reason, in conjunction with GnRH modulators, have largely replaced steroidal antiandrogens in the treatment of prostate cancer.[103][109]

The nonsteroidal antiandrogens that have been used in transgender women include the first-generation medications flutamide (Eulexin), nilutamide (Anandron, Nilandron), and bicalutamide (Casodex).[11][5][3][110]:477 Newer and even more efficacious second-generation nonsteroidal antiandrogens like enzalutamide (Xtandi) and apalutamide (Erleada) have also been introduced, but are very expensive due to generics being unavailable, and have not been used in transgender women.[111][112] Flutamide and nilutamide have relatively high toxicity, including considerable risks of liver damage and lung disease.[113][104] Due to its risks, the use of flutamide in cisgender and transgender women is now discouraged.[104][5] Flutamide and nilutamide have largely been superseded by bicalutamide in clinical practice,[114][115] with it accounting for almost 90% of nonsteroidal antiandrogen prescriptions in the United States by the mid-2000s.[116][107] Bicalutamide is said to have excellent tolerability and safety relative to flutamide and nilutamide, as well as in comparison to cyproterone acetate.[117][118][119] It has few to no side effects in women.[105][106] The medication does have a small risk of elevated liver enzymes and has been associated with very rare cases of liver damage and lung disease however.[113][120]

Nonsteroidal antiandrogens like bicalutamide may be a favorable option in particular 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 like cyproterone acetate and GnRH modulators.[121][122][123]

GnRH modulators

GnRH modulators are powerful antigonadotropins and hence functional antiandrogens.[124] 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.[124] The gonadotropins signal the gonads to make sex hormones such as testosterone and estradiol.[124] GnRH modulators bind to and inhibit the GnRH receptor, thereby preventing gonadotropin release.[124] 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.[124][125][126] GnRH modulators are also commonly known as GnRH analogues.[124] However, not all clinically used GnRH modulators are analogues of GnRH.[127][128]

There are two types of GnRH modulators: GnRH agonists and GnRH antagonists.[124] These medications have the opposite action on the GnRH receptor but paradoxically have the same therapeutic effects.[124] 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.[124][125] 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.[129][130][124] At the initiation of treatment, GnRH agonists are associated with a "flare" effect on hormone levels due to acute overstimulation of the GnRH receptor.[124][131] In men, LH levels increase by up to 800%, while testosterone levels increase to about 140 to 200% of baseline.[132][131] 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.[131] Antigonadotropins such as estrogens and cyproterone acetate can be used to diminish or prevent the testosterone flare caused by GnRH agonists.[133][134][10][135] 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.[124] Unlike with GnRH agonists, there is no initial surge effect with GnRH antagonists, and the therapeutic effects are immediate; sex hormone levels are reduced to castrate levels within a few days.[124][125]

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][136] However, GnRH modulators tend to be very expensive, and are often denied by medical insurance.[1][137] GnRH modulator therapy is much less economical than surgical castration, and is less convenient than surgical castration in the long-term as well.[138] Because of their costs, many transgender women cannot afford GnRH modulators and must use other, often less effective options for testosterone suppression.[1][137] GnRH agonists are prescribed as standard practice for transgender women in the United Kingdom however, where the National Health Service (NHS) covers them.[137] 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.[133] However, the first non-peptide and orally active GnRH antagonist, elagolix (Orilissa), has recently been introduced for medical use.[128] As with other GnRH modulators, it is currently very expensive.[139]

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

5α-Reductase inhibitors

5α-Reductase inhibitors, a type of androgen synthesis inhibitor, work not by decreasing testosterone levels but rather by preventing the conversion and hence potentiation of testosterone into the more potent androgen dihydrotestosterone (DHT) in certain tissues such as the skin, hair follicles, and prostate gland. They are used in the treatment of prostate disorders and pattern hair loss in men, and have also been found to be effective in the treatment of excessive hair growth in women. Since they do not decrease testosterone levels however, they do not affect the actions of testosterone in most of the body. The two main 5α-reductase inhibitors that are used clinically are finasteride (Propecia) and dutasteride (Avodart). DHT levels can be lowered up to about 70% with finasteride and by up to about 99% or more with dutasteride.[140][141] Dutasteride has been found to be more effective than finasteride in the treatment of pattern hair loss.[142][143]

Progestogens

Progesterone, a progestogen, is the other of the two major sex hormones in women.[133] It is mainly involved in the regulation of the female reproductive system, the menstrual cycle, pregnancy, and lactation.[133] The non-reproductive effects of progesterone are fairly insignificant.[144] 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][55] One area of particular interest in terms of the effects of progesterone in women is breast development.[145][146][147] 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.[145][146] 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.[145][146] This allows for lactation and breastfeeding after childbirth.[145][146] 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.[145][148][146] Every pregnancy, lobuloalveolar maturation occurs again anew.[145][146]

There are two types of progestogens: progesterone, which is the natural and bioidentical hormone in the body; and progestins, which are synthetic progestogens.[29] There are dozens of clinically used progestins.[29][149][150] 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.[54][55] 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][14][18][151] Besides progesterone, cyproterone acetate, and medroxyprogesterone acetate, other progestogens that have been reported to have been used in transgender women include hydroxyprogesterone caproate, dydrogesterone, and norethisterone acetate.[152][153][18][154][5] Progestins in general largely have the same progestogenic effects however, and in theory, any progestin could be used in transgender women.[29]

The clinical research that has studied the use of progestogens in transgender women is very limited.[2][147] 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][147] There are no clinical studies to support such reports at present.[2][4][147] 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.[147][155][136] These studies, albeit limited in the quality of their findings, found no benefit of progestogens on breast development in transgender women.[147][136][14] This has also been the case in limited clinical experience.[156] These reports are in accordance with the normal and even above-average breast development in women with complete androgen insensitivity syndrome, who lack progesterone and have no lobuloalveolar development of the mammary glands on histological examination.[157][158] It is noteworthy that epithelial tissue, which makes up lobuloalveolar tissue, normally comprises only about 10 to 15% of the tissue of the breasts.[159][160][161][162] Progestogens have some antiestrogenic effects in the breasts, for instance decreasing expression of the estrogen receptor and increasing expression of estrogen-metabolizing enzymes,[163][164][165][166] and for this reason, have been used to treat breast pain and benign breast disorders.[167][168][169][170] Progesterone levels during female puberty do not normally increase importantly until near the end of puberty in cisgender girls,[171] a point by which most or all breast development has already been completed, and there has been some concern that premature exposure to progestogens is unphysiological and might compromise ultimate breast growth.[147][172] Although the influence of progesterone on breast development is uncertain, progesterone is thought to cause reversible breast enlargement during the menstrual cycle due to local fluid retention in the breasts.[173][174] This may give a misleading appearance of breast growth, and might contribute to anecdotal reports of improved breast size and/or shape with progesterone in transgender women.[173][174] 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.[154] Another study likewise found that oral progesterone did not improve sexual function in cisgender women.[175]

Though the role of progestogens in visible breast development is uncertain, progestogens are essential for lobuloalveolar maturation of the mammary glands, and hence are required for any transgender woman who wishes to lactate or breastfeed.[145][176][147] 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.[177][178][179]

Progestogens can have adverse effects.[14][18][29][149][180][31] Oral progesterone has inhibitory neurosteroid effects and can produce side effects such as sedation, mood changes, and alcohol-like effects.[29][181][182] Many progestins have off-target activity, such as androgenic, antiandrogenic, glucocorticoid, and antimineralocorticoid activity, and these activities likewise can contribute unwanted side effects.[29][149] 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.[20][18][14][183] Although it is unknown if these health risks of progestins occur in transgender women similarly, it cannot be ruled out that they do.[20][18][14] High-dose progestogens increase the risk of benign brain tumors including prolactinomas and meningiomas as well.[184][185] 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).[20][14][5][6][20][151] 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.[29][183] However, oral progesterone has very low bioavailability, and produces only weak and inadequate progestogenic effects even at high doses.[186][187][183][188][189] In accordance, and in contrast to progestins, oral progesterone has no antigonadotropic effects in men even at high doses.[181][190] Progesterone can also be taken by various parenteral (non-oral) routes, including sublingually, rectally, and by intramuscular or subcutaneous injection.[29][169][191] These routes do not have the bioavailability issues of oral progesterone, and accordingly, can produce considerable antigonadotropic and other progestogenic effects.[29][188][192] Transdermal progesterone is poorly effective, owing to absorption issues.[29][169][189] Progestins are usually taken orally.[29] In contrast to progesterone, most progestins have high oral bioavailability, and can produce full progestogenic effects with oral administration.[29] Some progestins, such as medroxyprogesterone acetate and hydroxyprogesterone caproate, are or can be used by intramuscular or subcutaneous injection instead.[193][169] Almost all progestins, with the exception of dydrogesterone, have antigonadotropic effects.[29]

Effects

A transgender woman before and after 28 months of HRT.

The main effects of hormone therapy in transgender women are feminization and demasculinization, and are as follows:

Effects of feminizing hormone therapy in transgender women
EffectTime to expected
onset of effecta		Time to expected
maximum effecta,b		Permanency if hormone
therapy is stopped
Breast development and nipple/areolar enlargement2–6 months1–3 yearsPermanent
Thinning/slowed growth of facial/body hair4–12 months>3 yearscReversible
Cessation/reversal of male-pattern scalp hair loss1–3 months1–2 yearsdReversible
Softening of skin/decreased oiliness and acne3–6 monthsUnknownReversible
Redistribution of body fat in a feminine pattern3–6 months2–5 yearsReversible
Decreased muscle mass/strength3–6 months1–2 yearseReversible
Widening and rounding of the pelvisfUnspecifiedUnspecifiedPermanent
Changes in mood, emotionality, and behaviorUnspecifiedUnspecifiedReversible
Decreased sex drive1–3 months3–6 monthsReversible
Decreased spontaneous/morning erections1–3 months3–6 monthsReversible
Erectile dysfunction and decreased ejaculate volume1–3 monthsVariableReversible
Decreased sperm production/fertilityUnknown>3 yearsReversible or permanentg
Decreased testicle size3–6 months2–3 yearsUnknown
Decreased penis sizeNonehNot applicableNot applicable
Decreased prostate gland sizeUnspecifiedUnspecifiedUnspecified
Voice changesNoneiNot applicableNot applicable
Footnotes: a = Estimates represent published and unpublished clinical observations. b = 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. c = 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. d = Familial scalp hair loss may occur if estrogens are stopped. e = Varies significantly depending on the amount of physical exercise. f = Occurs only in individuals of pubertal age who have not yet completed epiphyseal closure. g = 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 h = 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.[194][195][196][197] i = Treatment by speech pathologists for voice training is effective. Miscellaneous: Direct link to table. Sources: Guidelines: [1][2][6] Reviews/book chapters: [4][198][14][199][16][20][23][24] Studies: [200][201]

Physical changes

Breast development

Breast development induced by hormone therapy in transgender women. [202]

Highly 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.[203]

In clinical trials, cisgender women have used stem cells from fat to regrow their breasts after mastectomies. This could someday eliminate the need for implants for transgender women.[204]

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

Skin changes

The uppermost layer of skin, the stratum corneum, becomes thinner and more translucent. Spider veins may appear or be more noticeable as a result. Collagen decreases, and tactile sensation increases. The skin becomes softer,[205] more susceptible to tearing and irritation from scratching or shaving, and slightly lighter in color because of a slight decrease in melanin.

Sebaceous gland activity (which is triggered by androgens) lessens, reducing oil production on the skin and scalp. Consequently, the skin becomes less prone to acne. It also becomes drier, and lotions or oils may be necessary.[203][206] The pores become smaller because of the lower quantities of oil being produced. Many apocrine glands – a type of sweat gland – become inactive, and body odor decreases. Remaining body odor becomes less metallic, sharp, or acrid, and more sweet and musky.

As subcutaneous fat accumulates,[203] dimpling, or cellulite, becomes more apparent on the thighs and buttocks. Stretch marks (striae distensae) may appear on the skin in these areas. Susceptibility to sunburn increases, possibly because the skin is thinner and less pigmented.

Hair changes

Antiandrogens affect existing facial hair only slightly; patients may see slower growth and some reduction in density and coverage. Those who are less than a decade past puberty and/or lack a significant amount of facial hair may have better results. Patients taking antiandrogens tend to have better results with electrolysis and laser hair removal than those who are not. In patients in their teens or early twenties, antiandrogens prevent new facial hair from developing if testosterone levels are within the normal female range.[203][206]

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.[203][206]

Head hair may change slightly in texture, curl, and color. This is especially likely with hair growth from previously bald areas. Eyebrows do not change because they are not androgenic.[207]

Eye changes

The lens of the eye changes in curvature.[208][209][210][211] 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.[212][213][214][215][216]

Fat changes

The distribution of adipose (fat) tissue changes slowly over months and years. HRT causes the body to accumulate new fat in a typically feminine pattern, including in the hips, thighs, buttocks, pubis, upper arms, and breasts. (Fat on the hips, thighs, and buttocks has a higher concentration of omega-3 fatty acids and is meant to be used for lactation.) The body begins to burn old adipose tissue in the waist, shoulders, and back, making those areas smaller.[203]

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

Muscle changes

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

Bone/skeletal changes

Male-to-female hormone therapy causes the hips to rotate slightly forward because of changes in the tendons. Hip discomfort is not uncommon. This can cause a reduction in total body height.

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

Unaffected characteristics

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

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

Established changes to the bone structure of the face are also unaffected by HRT. A significant majority of craniofacial changes occur during adolescence. Post-adolescent growth is considerably slower and minimal by comparison.[217] Also unaffected is the prominence of the thyroid cartilage (Adam's apple). These changes may be reversed by surgery (facial feminization surgery and tracheal shave, respectively).

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

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

Psychological changes

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.

Mood changes

Mood changes, including depression, may occur with feminizing hormone therapy. However, many transgender women report mood benefits as well.

Sexual changes

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

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

Managing long-term hormonal regimens have not been studied and are difficult to estimate because research on the long-term use of hormonal therapy has not been noted.[20] However, it is possible to speculate the outcomes of these therapies on transgender people based on the knowledge of the current effects of gonadal hormones on sexual functioning in cisgender men and women.[218]

Firstly, if one is to decrease testosterone in male-to-female gender transition, it is likely that sexual desire and arousal would be inhibited; alternatively, if high doses of estrogen negatively impact sexual desire, which has been found in some research with cisgender women, it is hypothesized that combining androgens with high levels of estrogen would intensify this outcome.[218] Unfortunately, to date there haven’t been any randomized clinical trials looking at the relationship between type and dose of transgender hormone therapy, so the relationship between them remains unclear.[218] Typically, the estrogens given for male-to-female gender transition are 2 to 3 times higher than the recommended dose for HRT in postmenopausal women.[20] Pharmacokinetic studies indicate taking these increased doses may lead to a higher boost in plasma estradiol levels; however, the long-term side effects haven’t been studied and the safety of this route is unclear.[20]

As with any pharmacological or hormone therapy, there are potential side effects, which in the case of transgender hormone therapy include changes in sexual functioning. These have the ability to significantly impact sexual functioning, either directly or indirectly through the various side effects, such as cerebrovascular disorders, obesity, and mood fluctuations.[218] In addition, some research has found an onset of diabetes following feminizing hormone therapy, which impairs sexual response. Whatever route an individual and their doctor choose to take, it is important to consider both the medical risks of hormone therapy as well as the psychological needs of the patient.

Neurological changes

Recent studies have indicated that hormone therapy in transgender women may reduce brain volume toward female proportions.[219]

All aforementioned physical changes can, and reportedly do, change the experience of sensation compared to prior to HRT. Areas affected include, but aren't limited to, the basic senses, erogenous stimulus, perception of emotion, perception of social interaction, and processing of feelings and experiences.

Cardiovascular effects

The most significant cardiovascular risk for transgender women is the pro-thrombotic effect (increased blood clotting) of estrogens. This manifests most significantly as an increased risk for thromboembolic disease: deep vein thrombosis (DVT) and pulmonary embolism, 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 pulmonary embolism include chest pain, shortness of breath, fainting, and heart palpitations, sometimes without leg pain or swelling.

Deep vein thrombosis occurs more frequently in the first year of treatment with estrogens. The risk is higher with oral estrogens (particularly ethinylestradiol and conjugated estrogens) than with injectable, transdermal, implantable, and nasal formulations.[220] DVT risk also increases with age and in patients who smoke, so many clinicians advise using the safer estrogen formulations in smokers and patients older than 40.

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, pro-thrombotic mutations (such as factor V Leiden, antithrombin III, and protein C or S deficiency) are not absolute contraindications for hormonal therapy.[221]

Gastrointestinal/metabolic changes

Estrogens may increase the risk of gallbladder disease, especially in older and obese people.[222] They may also increase transaminase levels, indicating liver toxicity, especially when taken in oral form.

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

Bone changes

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

Risk of hormone-sensitive cancers

In spite of the induction of breast development, transgender women who undergo HRT do not have an increased risk of breast cancer.[1][223][224] Only a handful of cases of breast cancer have ever been described in transgender women who have undergone male-to-female HRT.[223][224] This is in accordance with research in cisgender men in which gynecomastia has been found not to be associated with an increased risk of breast cancer, suggesting a protective role of the male sex-determination chromosome.[225] On the other hand, men with Klinefelter's syndrome (two X chromosomes and one Y chromosome), 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 men with one X chromosome, closer to the rate of homogametic females.[225][226][227] The incidences of breast cancer in karyotypical men (46,XY karyotype), men with Klinefelter's syndrome (47,XXY karyotype), and karyotypical women (46,XX karyotype) are approximately 0.1%,[228] 3%,[226] and 12.5%,[229] respectively. Individuals with the 46,XY karyotype affected by complete androgen insensitivity syndrome never develop male sex characteristics and have normal and complete female morphology, and accelerated breast growth during puberty,[230][231] but appear to have little (or possibly even no) incidence of breast cancer.[232][233] The risk of breast cancer in women with Turner syndrome (45,XO karyotype) also appears to be significantly decreased, though this may be related to ovarian failure/hypogonadism rather necessarily than to genetics.[234]

Prostate cancer is extremely rare in orchidectomized transgender women who have been treated with estrogens for a prolonged period of time.[1][235][236] Whereas as many as 70% of men show prostate cancer by their 80's,[237] only a handful of cases of prostate cancer in transgender women have been reported in the literature.[1][235][236] 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][235][236]

Other changes

Migraines can be made worse or unmasked by estrogen therapy.

Estrogens can also cause prolactinomas. 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.

Hormone levels

Especially in the early stages of hormone replacement 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 2 to 3 months in the first year.[1] The optimal ranges for estradiol and testosterone are not limited to but include the following:

HormoneEndocrine Society[1]Royal College of Psychiatry[9]
Estradiol100–200 pg/mL80–140 pg/mL
Testosterone<50 ng/dL"Well below normal male range"

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., CEEs 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]

See also

References

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Further reading

  • Gooren LJ, Giltay EJ, Bunck MC (January 2008). "Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience". J. Clin. Endocrinol. Metab. 93 (1): 19–25. doi:10.1210/jc.2007-1809. PMID 17986639.
  • Gooren LJ (March 2011). "Clinical practice. Care of transsexual persons". N. Engl. J. Med. 364 (13): 1251–7. doi:10.1056/NEJMcp1008161. PMID 21449788.
  • Wierckx K, Gooren L, T'Sjoen G (2014). "Clinical review: Breast development in trans women receiving cross-sex hormones". J Sex Med. 11 (5): 1240–7. doi:10.1111/jsm.12487. PMID 24618412.
  • Fabris B, Bernardi S, Trombetta C (March 2015). "Cross-sex hormone therapy for gender dysphoria". J. Endocrinol. Invest. 38 (3): 269–82. doi:10.1007/s40618-014-0186-2. PMID 25403429.
  • Tangpricha V, den Heijer M (April 2017). "Oestrogen and anti-androgen therapy for transgender women". Lancet Diabetes Endocrinol. 5 (4): 291–300. doi:10.1016/S2213-8587(16)30319-9. PMC 5366074. PMID 27916515.
  • Unger CA (December 2016). "Hormone therapy for transgender patients". Transl Androl Urol. 5 (6): 877–884. doi:10.21037/tau.2016.09.04. PMC 5182227. PMID 28078219.
  • Wesp LM, Deutsch MB (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". Psychiatr. Clin. North Am. 40 (1): 99–111. doi:10.1016/j.psc.2016.10.006. PMID 28159148.
  • Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG (November 2017). "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline" (PDF). J. Clin. Endocrinol. Metab. 102 (11): 3869–3903. doi:10.1210/jc.2017-01658. PMID 28945902.
  • Coleman, E.; Bockting, W.; Botzer, M.; Cohen-Kettenis, P.; DeCuypere, G.; Feldman, J.; Fraser, L.; Green, J.; Knudson, G.; Meyer, W. J.; Monstrey, S.; Adler, R. K.; Brown, G. R.; Devor, A. H.; Ehrbar, R.; Ettner, R.; Eyler, E.; Garofalo, R.; Karasic, D. H.; Lev, A. I.; Mayer, G.; Meyer-Bahlburg, H.; Hall, B. P.; Pfaefflin, F.; Rachlin, K.; Robinson, B.; Schechter, L. S.; Tangpricha, V.; van Trotsenburg, M.; Vitale, A.; Winter, S.; Whittle, S.; Wylie, K. R.; Zucker, K. (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.
  • 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.
  • Dahl, M; Feldman, JL; Goldberg, J; Jaberi, A (2015). "Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines" (PDF). Vancouver Coastal Health. Retrieved 15 August 2018.
  • Bourns, Amy (2015). "Guidelines and Protocols for Comprehensive Primary Care for Trans Clients" (PDF). Sherbourne Health Centre. Retrieved 15 August 2018.
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