Feminizing hormone therapy

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    • Feminizing hormone therapy, also known as transfeminine hormone therapy, is

    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

    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

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

    Many physicians operate by the

    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

    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

    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. induction of lactation to allow for breastfeeding
      specifically.
    5. ^ Administered in divided doses.

    A variety of different

    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

    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]

    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

    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

    See also: Antiandrogen § Transgender hormone therapy

    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

    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

    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

    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

    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

    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

    safety relative to flutamide and nilutamide, as well as in comparison to cyproterone acetate.[153][154][155] It has few to no side effects in women.[141][142] Despite its greatly improved tolerability and safety profile however, bicalutamide does still have a small risk of elevated liver enzymes and association with rare cases of serious liver damage and lung disease.[15][149][156]

    Nonsteroidal antiandrogens like bicalutamide may be a particularly favorable option for transgender women who wish to preserve

    sex drive, sexual function, and/or fertility, relative to antiandrogens that suppress testosterone levels and can greatly disrupt these functions such as cyproterone acetate and GnRH modulators.[157][158][159] However, estrogens suppress testosterone levels and at high doses can markedly disrupt sex drive and function and fertility on their own.[160][161][162][163] Moreover, disruption of gonadal function and fertility by estrogens may be permanent after extended exposure.[162][163]

    GnRH modulators

    GnRH analogues.[164] However, not all clinically used GnRH modulators are analogues of GnRH.[167]

    There are two types of GnRH modulators:

    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

    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

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

    3α-androstanediol, respectively.[194][195]

    5α-Reductase inhibitors include

    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.

    suicidality.[222][57]

    Progestogens

    See also: Progesterone (medication) § Transgender women

    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

    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

    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

    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

    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

    5α-reductase inhibitors such as finasteride in transfeminine people.[183]

    Interactions

    Further information: CYP3A4 § CYP3A4 ligands

    Many of the medications used in feminizing hormone therapy, such as

    St. John's wort, among others, may decrease circulating levels of these medications and thereby decrease their effects. Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes, such as cimetidine, clotrimazole, grapefruit juice, itraconazole, ketoconazole, and ritonavir, among others, may increase circulating levels of these medications and thereby increase their effects.[citation needed
    ] The concomitant use of a cytochrome P450 inducer or inhibitor with feminizing hormone therapy may necessitate medication dosage adjustments.

    Effects

    The spectrum of effects of hormone therapy in transfeminine people depend on the specific medications and dosages used. In any case, the main effects of hormone therapy in transfeminine people are

    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
    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
    morning erections
    		 1–3 months 3–6 months Reversible
    decreased ejaculate volume
    		 1–3 months Variable Reversible
    Decreased
    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. 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. physical exercise
      .
    6. epiphyseal closure
      .
    7. 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. 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

    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

    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

    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]

    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

    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

    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

    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

    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

    The most significant cardiovascular risk for transgender women is the prothrombotic effect (increased

    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

    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

    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

    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

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

    Metabolic changes

    Cancer risk

    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

    ovarian failure and hypogonadism rather than to genetics.[339]

    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

    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

    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

    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
    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

    Effective pharmaceutical female sex-hormonal medications, including androgens, estrogens, and progestogens, first became available in the 1920s and 1930s.

    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

    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

    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]

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    179. ISBN 978-1-118-53857-9
      . Treatment is expensive, with costs typically in the range of $10,000–$15,000 per year.
    180. ISBN 978-3-642-55780-4
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    181. ^
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    186. ISBN 978-1-61779-222-9
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      PMID 16985920
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    188. ISBN 978-0-471-13320-9
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    189. PMID 11469812
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    190. PMID 1551803
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    191. S2CID 41352599
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    192. S2CID 1093345
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    193. S2CID 54356569
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      S2CID 25793400
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      S2CID 28841145
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    198. S2CID 51968365
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    199. S2CID 205537645
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    200. ^
      S2CID 30008068
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    201. ^
      PMID 28294070
      .
    202. ^
      S2CID 207263793
      .
    203. S2CID 31245042
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    204. ISBN 978-3-540-46911-7
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    205. ISBN 978-1-4822-3199-1
      .
    206. ISBN 978-3-319-03233-7
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      . [...] caution is recommended while prescribing oral finasteride to male-to-female transsexuals, as the drug has been associated with inducing depression, anxiety and suicidal ideation, symptoms that are particularly common in patients with gender dysphoria, who are already at a high risk.[9]
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      . It has been suggested that progestins be added during the last week of each cycle of estrogen therapy in order to develop more rounded breasts rather than the conical breasts many of these patients develop, but we have been unable to detect any difference in breast contour with or without progestins.
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    247. ^
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      . Experimentally I have been able to induce lactogenesis in a male transvestite whose testes had been removed some years before and whose breasts had been well developed over a long period with stilbestrol and ethisterone.9 In July, 1955, 600 mg. of estradiol was implanted subcutaneously and weekly injections of 50 mg. of progesterone were given for four months. For the next month daily injections of 10 mg. estradiol dipropionate and 50 mg. progesterone were given. These injections were continued for another month, increasing progesterone to 100 mg. daily. Both hormones were then withdrawn, and daily injections of increasing doses of prolactin and somatotropin were given for four days; at the same time, the patient used a breast bump four times daily for 5 minutes on both sides. During this time the mammary veins were visibly enlarged and on the sixth and seventh days 1 to 2 cc. of milky fluid was collected.
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    259. ^ Kuhl H (2011). "Pharmacology of Progestogens" (PDF). Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology. 8 (1): 157–177.
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    264. ISSN 1574-8855
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    269. ^
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      . [...] castration and feminizing plastic surgery of the external genitalia was performed [...] Some time after the operation, the patient developed a renewed interest in life. After the surgical and hormonal correction, the patient irresistibly developed maternal instincts. Unmarried, the patient obtained permission for the adoption of a child, simulated pregnancy, and was discharged from the maternity hospital with a son. From the first days after the "birth", galactorrhea sharply increased, and spontaneous outflow of milk appeared, with galactorrhea (+++). The baby was breastfed up to 6 months of age. [...] Our message is the second in the world literature describing galactorrhea in a male patient with transsexualism. The first description of this kind was made in 1983 by R. [Flückiger] et al. (6). This observation demonstrates the independence of the mechanism of lactation development from one's genetic sex and is alarming with regard to the possibility of drug-induced galactorrhea development in men.
    270. ^ Foss GL (January 1956). "Abnormalities of form and function of the human breast". Journal of Endocrinology. 14 (1): R6–R9. Based on the theories of lactogenesis and stimulated by the success of Lyons, Li, Johnson & Cole [1955], who succeeded in producing lactation in male rats, an attempt was made to initiate lactogenesis in a male transvestist. Six years ago this patient had been given oestrogens. Both testes and penis were then removed and an artificial vagina was constructed by plastic surgery. The patient was implanted with 500 mg oestradiol in September 1954, and 600 mg in July 1955. The breasts were then developed more intensively with daily injections of oestradiol dipropionate and progesterone for 6 weeks. Immediately following withdrawal of this treatment, prolactin 22·9 mg was injected daily for 3 days without effect. After a second month on oestradiol and progesterone daily, combined injections of prolactin and somatotrophin were given for 4 days and suction was applied by a breast pump-four times daily. On the 4th and 5th days a few drops of colostrum were expressed from the right nipple.
    271. ^ Gardiner-Hill H (1958). Modern Trends in Endocrinology. Butterworth. p. 192. Recently, an attempt has been made by Foss (1956) to initiate lactation in a castrated male transvestist. He was given an implant of 500 milligrams of oestradiol, and 10 months later, a further 600 milligrams of oestradiol, followed by daily injections of oestradiol dipropionate and progesterone for 6 weeks. Immediately after withdrawal of this treatment, 22·9 milligrams of prolactin were injected daily for 3 days but without effect. After a second month of treatment with oestradiol and progesterone daily, he was given combined injections of prolactin and somatotrophin for 4 days, suction with a breast-pump being employed 4 times daily. On the fourth and fifth days a few drops of colostrum were expressed from the right nipple. There is a possible application here of modern hormone knowledge to man, and further trials would be of interest.
    272. ISBN 978-3-540-11071-2
      . [...] An observation (Wyss and Del Pozo unpublished) in a male transsexual showed that induction of lactation can be similarly achieved in the human male. [...]
    273. ISBN 978-0-19-990805-9
      . Just 2 years later, Winfrey would feature another interview that elicited many of the same audience reactions. In this 2010 episode, lesbian partners Dr. Christine McGinn and Lisa Bortz beamed with joy as they held their infant twins. Again, audience members' jaws dropped when it was revealed that beautiful Christine was a male-to-female transsexual who used to be a handsome military officer Chris, and that Lisa had given birth to the couple's biological children using sperm Chris banked prior to gender confirmation surgeries.10 And it was Winfrey's chin that nearly hit the floor as she watched video of Christine breastfeeding the couples' children (the episode is referred to online as "The Mom Who Fathered Her Own Children"). [...]
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      . Estrogen is given to MTF transsexuals orally as conjugated estrogens, or 17b-estradiol, as transdermal estrogen, or as parenteral estrogen esters to feminize the body.5 There is no evidence that progestin has beneficial effects on treatment with estrogen in MTF transsexuals; however, progestins were administered to some of MTF transsexuals. Because administration of antiandrogen to MTF transsexuals is not common in Japan, we could exclude the modification with antiandrogen in the present study.

    Further reading

    External links
    Retrieved from "https://en.wikipedia.org/w/index.php?title=Feminizing_hormone_therapy&oldid=1216955200"