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 is to provide patients with a more satisfying body that is more congruent with their gender identity.
The accessibility of transgender hormone therapy differs throughout the world and throughout individual countries.
Some medical conditions may be a reason to not to take feminizing hormone therapy because of the harm it could cause to the individual. Such interfering factors are described in medicine as contraindications.
^The starting dosage of estradiol and other estrogens is lower in combination with a GnRH agonist or antagonist in adolescents, for instance 0.25 mg/day for oral and sublingual estradiol and 6.25 μg/day for transdermal estradiol patches.
^ abcDiscontinued and hence no longer available for medical use.
^ abcdeNo longer recommended due to toxicity/safety concerns.
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. 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. The dashed purple line is the upper limit for the female/castrate range (~50 ng/dL) and the dashed grey line is the testosterone level in a comparison group of post-operative transgender women (21.7 pg/mL).
In addition to producing feminization, estrogens have antigonadotropic effects and suppress gonadalsex hormone production. They are mainly responsible for the suppression of testosterone levels in transgender women. 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. Lower levels of estradiol can also considerably but incompletely suppress testosterone production. When testosterone levels are insufficiently suppressed by estradiol alone, antiandrogens can be used to suppress or block the effects of residual testosterone. Oral estradiol often has difficulty adequately suppressing testosterone levels, due to the relatively low estradiol levels achieved with it.
Prior to orchiectomy (surgical removal of the gonads) or sex reassignment surgery, the doses of estrogens used in transgender women are often higher than replacement doses used in cisgender women. This is to help suppress testosterone levels. The Endocrine Society (2017) recommends maintaining estradiol levels roughly within the normal average range for premenopausal women of about 100 to 200 pg/mL. However, it notes that these physiological levels of estradiol are usually unable to suppress testosterone levels into the female range. 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. The review proposal noted that high-dose parenteral estradiol is known to be safe. 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. 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. Dosages of estrogens can be reduced after an orchiectomy or sex reassignment surgery, when gonadal testosterone suppression is no longer needed.
Antiandrogens that directly block the androgen receptor are known as androgen receptor antagonists or blockers, while antiandrogens that inhibit the enzymaticbiosynthesis of androgens are known as androgen synthesis inhibitors and antiandrogens that suppress androgen production in the gonads are known as antigonadotropins.Estrogens and progestogens are antigonadotropins and hence are functional antiandrogens. The purpose of the use of antiandrogens in transgender women is to block or suppress residual testosterone that is not suppressed by estrogens alone. Additional antiandrogen therapy is not necessarily required if testosterone levels are in the normal female range or if the person has undergone orchiectomy. However, individuals with testosterone levels in the normal female range and with persisting androgen-dependent skin and/or hair symptoms, such as acne, seborrhea, oily skin, or scalp hair loss, can potentially still benefit from the addition of an antiandrogen, as antiandrogens can reduce or eliminate such symptoms.
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. It works primarily as an antigonadotropin, secondarily to its potent progestogenic activity, and strongly suppresses gonadal androgen production. Cyproterone acetate at a dosage of 5 to 10 mg/day has been found to lower testosterone levels in men by about 50 to 70%, while a dosage of 100 mg/day has been found to lower testosterone levels in men by about 75%. 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%. In addition to its actions as an antigonadotropin, cyproterone acetate is an androgen receptor antagonist. 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). Cyproterone acetate can cause elevated liver enzymes and liver damage, including liver failure. However, this occurs mostly in prostate cancer patients who take very high doses of cyproterone acetate; liver toxicity has not been reported in transgender women. Cyproterone acetate also has a variety of other adverse effects, such as fatigue and weight gain, and risks, such as blood clots and benignbrain tumors, among others. 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. 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. Medroxyprogesterone acetate suppresses testosterone levels in transgender women similarly to cyproterone acetate. 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. In contrast to cyproterone acetate however, medroxyprogesterone acetate is not also an androgen receptor antagonist. Medroxyprogesterone acetate has similar side effects and risks as cyproterone acetate, but is not associated with liver problems.
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. 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. 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.
The nonsteroidal antiandrogens that have been used in transgender women include the first-generation medications flutamide (Eulexin), nilutamide (Anandron, Nilandron), and bicalutamide (Casodex).:477 Newer and even more efficacious second-generation nonsteroidal antiandrogens like enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) also exist, but are very expensive due to generics being unavailable and have not been used in transgender women. Flutamide and nilutamide have relatively high toxicity, including considerable risks of liver damage and lung disease. Due to its risks, the use of flutamide in cisgender and transgender women is now limited and discouraged. Flutamide and nilutamide have largely been superseded by bicalutamide in clinical practice, with bicalutamide accounting for almost 90% of nonsteroidal antiandrogen prescriptions in the United States by the mid-2000s. Bicalutamide is said to have excellent tolerability and safety relative to flutamide and nilutamide, as well as in comparison to cyproterone acetate. It has few to no side effects in women. Despite its greatly improved tolerability and safety profile however, bicalutamide does still have a small risk of elevated liver enzymes and association with very rare cases of liver damage and lung disease.
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. However, estrogens suppress testosterone levels and at high doses can markedly disrupt sex drive and function and fertility on their own. Moreover, disruption of gonadal function and fertility by estrogens may be permanent after extended exposure.
There are two types of GnRH modulators: GnRH agonists and GnRH antagonists. These medications have the opposite action on the GnRH receptor but paradoxically have the same therapeutic effects.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. 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. At the initiation of treatment, GnRH agonists are associated with a "flare" effect on hormone levels due to acute overstimulation of the GnRH receptor. In men, LH levels increase by up to 800%, while testosterone levels increase to about 140 to 200% of baseline. 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. 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. 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. 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.
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. However, GnRH modulators tend to be very expensive (typically US$10,000 to US$15,000 per year in the United States), and are often denied by medical insurance. GnRH modulator therapy is much less economical than surgical castration, and is less convenient than surgical castration in the long-term as well. Because of their costs, many transgender women cannot afford GnRH modulators and must use other, often less effective options for testosterone suppression. GnRH agonists are prescribed as standard practice for transgender women in the United Kingdom however, where the National Health Service (NHS) covers them. This is in contrast to the rest of Europe and to the United States. 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. However, non-peptide and orally active GnRH antagonists, elagolix (Orilissa) and relugolix (Relumina), were introduced for medical use in 2018 and 2019, respectively. But they are under patent protection and, as with other GnRH modulators, are very expensive at present.
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 include finasteride and dutasteride. Finasteride is a selective inhibitor of 5α-reductase types 2 and 3, while dutasteride is an inhibitor of all three isoforms of 5α-reductase. Finasteride can decrease circulating DHT levels by up to 70%, whereas dutasteride can decrease circulating DHT levels by up to 99%. Conversely, 5α-reductase inhibitors do not decrease testosterone levels, and may actually increase them slightly. 5α-Reductase inhibitors are used primarily in the treatment of benign prostatic hyperplasia, a condition in which the prostate gland becomes excessively large due to stimulation by DHT and causes unpleasant urogenital symptoms. They are also used in the treatment of androgen-dependent scalp hair loss in men and women. The medications are able to prevent further scalp hair loss in men and can restore some scalp hair density. Conversely, the effectiveness of 5α-reductase inhibitors in the treatment of scalp hair loss in women is less clear. 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. 5α-Reductase inhibitors are also used to treat hirsutism (excessive body/facial hair growth) in women, and are very effective for this indication. 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. In addition to their antiandrogenic uses, 5α-reductase inhibitors have been found to reduce adverse affective symptoms in premenstrual dysphoric disorder in women. 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.
5α-Reductase inhibitors are sometimes used as a component of feminizing hormone therapy for transgender women in combination with estrogens and/or other antiandrogens. They may have beneficial effects limited to improvement of scalp hair loss, body hair growth, and possibly skin symptoms such as acne. 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. Moreover, 5α-reductase inhibitors have only mild and specific antiandrogenic activity, and are not recommended as general antiandrogens.
Clinical research on the use of progestogens in transgender women is very limited. 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. There are no clinical studies to support such reports at present. 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. These studies, albeit limited in the quality of their findings, reported no benefit of progestogens on breast development in transgender women. This has also been the case in limited clinical experience. 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. It is noteworthy that epithelial tissue, which makes up lobuloalveolar tissue, normally (outside of pregnancy and lactation) comprises only about 10 to 15% of the tissue of the breasts. 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. 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.
Progestogens have some antiestrogenic effects in the breasts, for instance decreasing expression of the estrogen receptor and increasing expression of estrogen-metabolizingenzymes, and for this reason, have been used to treat breast pain and benign breast disorders. 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. 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. Though the role of progestogens in pubertal breast development is uncertain, progesterone is essential for lobuloalveolar maturation of the mammary glands during pregnancy. Hence, progestogens are required for any transgender woman who wishes to lactate or breastfeed. 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. However, lobuloalveolar development reversed with discontinuation of cyproterone acetate, indicating that continued progestogen exposure is necessary to maintain the tissue.
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. Another study likewise found that oral progesterone did not improve sexual function in cisgender women.
Progesterone is most commonly taken orally. However, oral progesterone has very low bioavailability, and produces only weak and inadequate progestogenic effects even at high doses. In accordance, and in contrast to progestins, oral progesterone has no antigonadotropic effects in men even at high doses. Progesterone can also be taken by various parenteral (non-oral) routes, including sublingually, rectally, and by intramuscular or subcutaneous injection. These routes do not have the bioavailability and efficacy issues of oral progesterone, and accordingly, can produce considerable antigonadotropic and other progestogenic effects. Transdermal progesterone is poorly effective, owing to absorption issues. Progestins are usually taken orally. In contrast to progesterone, most progestins have high oral bioavailability, and can produce full progestogenic effects with oral administration. Some progestins, such as medroxyprogesterone acetate and hydroxyprogesterone caproate, are or can be used by intramuscular or subcutaneous injection instead. Almost all progestins, with the exception of dydrogesterone, have antigonadotropic effects.
The spectrum of effects of hormone therapy in transgender women depend on the specific medications and dosages used. In any case, 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
^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.
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.
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.
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, 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. 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.
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.
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.
Head hair may change slightly in texture, curl, and color. This is especially likely with hair growth from previously bald areas.Eyebrows do not change because they are not androgenic hair.
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.
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.
Male-to-female hormone therapy causes the hips to rotate slightly forward because of changes in the tendons. Hip discomfort is common. This can cause a reduction in total body height.
If estrogen therapy is begun prior to pelvis ossification, which occurs around the age of 25, the pelvic outlet and inlet open slightly. The femora also widen, because they are connected to the pelvis. The pelvis retains some masculine characteristics, but the end result of HRT is wider hips than a cisgender man and closer to those of a cisgender woman.
HRT does not reverse bone changes that have already been established by puberty. Consequently, it does not affect height; the length of the arms, legs, hands, and feet; or the width of the shoulders and rib cage. However, details of bone shape change throughout life, with bones becoming heavier and more deeply sculptured under the influence of androgens, and HRT does prevent such changes from progressing further.
The width of the hips is not affected in individuals for whom epiphyseal closure (fusion and closure of the ends of bones, which prevents any further lengthening) has taken place. This occurs in most people between 18 and 25 years of age. Already-established changes to the shape of the hips cannot be reversed by HRT whether epiphyseal closure has taken place or not.
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.
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.
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. 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.
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. 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. 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. 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.
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. In addition, some research has found an onset of diabetes following feminizing hormone therapy, which impairs sexual response. Whatever route an individual and their doctor choose to take, it is important to consider both the medical risks of hormone therapy as well as the psychological needs of the patient.
Several studies have found that hormone therapy in transgender women causes the structure of the brain to change in the direction of female proportions. 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.
A number of health changes and adverse effects can occur with feminizing hormone therapy.
A 2015 review concluded that hormone therapy for transgender people is safe when supervised by a qualified medical professional.
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. VTE risk also increases with age and in patients who smoke, so many clinicians advise using the safer estrogen formulations in smokers and patients older than 40. In addition, VTE risk is increased by progestins and increases with the dosages of both estrogens and progestins. Obesity increases the risk of VTE as well. Increased risk of VTE with estrogens is thought to be due to their influence on liver protein synthesis, specifically on the production of coagulation factors. Non-bioidentical estrogens such as conjugated estrogens and especially ethinylestradiol have markedly disproportionate effects on liver protein synthesis relative to estradiol. 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.
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.
A 2018 cohort study of 2842 transfeminine individuals in the United States treated with a mean follow-up of 4.0 years observed an increased risk of VTE, stroke, and heart attack relative to a cisgender reference population. The estrogens used included oral estradiol (1 to 10 mg/day) and other estrogen formulations. Other medications such as antiandrogens like spironolactone were also used.
A 2019 systematic review and meta-analysis found an incidence rate of VTE of 2.3 per 1000 person-years with feminizing hormone therapy in transgender women. For comparison, the rate in the general population has been found to be 1.0–1.8 per 1000 person-years, and the rate in premenopausal women taking birth control pills has been found to be 3.5 per 1000 patient-years. As such, it appears that the risk of VTE with feminizing hormone therapy in transgender women is less than that with birth control pills. The risk of VTE with birth control pills in premenopausal women is considered to be an acceptable level of risk. There was significant heterogeneity in the rates of VTE across the included studied, and the meta-analysis was unable to perform subgroup analyses between estrogen type, estrogen route, estrogen dosage, concomitant antiandrogen or progestogen use, or patient characteristics (e.g., age, smoking status, weight) corresponding to known risk factors for VTE. Due to the inclusion of some studies using ethinylestradiol, which is more thrombotic and is no longer used in transgender women, the researchers noted that the VTE risk found in their study is likely to be an overestimate.
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. The dosage of oral estradiol used was 2 to 8 mg/day. 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). The findings of this study suggest that the incidence of VTE is low in transgender women taking oral estradiol.
Cardiovascular health in transgender women has been reviewed in recent publications.
A patient's metabolic rate may change, causing an increase or decrease in weight and energy levels, changes to sleep patterns, and temperature sensitivity. Androgen deprivation leads to slower metabolism and a loss of muscle tone. Building muscle takes more work. The addition of a progestogen may increase energy, although it may increase appetite as well.
Both estrogens and androgens are necessary in all humans for bone health. Young, healthy women produce about 10 mg of testosterone monthly, and higher bone mineral density in males is associated with higher serum estrogen. Both estrogen and testosterone help to stimulate bone formation, especially during puberty. Estrogen is the predominant sex hormone that slows bone loss, even in men.
Studies are mixed on whether the risk of breast cancer is increased with hormone therapy in transgender women. Two cohort studies found no increase in risk relative to cisgender men, 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. There is no evidence that breast cancer risk in transgender women is greater than in cisgender women. Twenty cases of breast cancer in transgender women have been reported as of 2019.
Cisgender men with gynecomastia have not been found to have an increased risk of breast cancer. It has been suggested that a 46,XY karyotype (one X chromosome and one Y chromosome) may be protective against breast cancer compared to having a 46,XX karyotype (two X chromosomes). Men with Klinefelter's syndrome (47,XXY karyotype), which causes hypoandrogenism, hyperestrogenism, and a very high incidence of gynecomastia (80%), have a dramatically (20- to 58-fold) increased risk of breast cancer compared to karyotypical men (46,XY), closer to the rate of karyotypical women (46,XX). The incidences of breast cancer in karyotypical men, men with Klinefelter's syndrome, and karyotypical women are approximately 0.1%, 3%, and 12.5%, respectively. Women with complete androgen insensitivity syndrome (46,XY karyotype) never develop male sex characteristics and have normal and complete female morphology, including breast development, yet have not been reported to develop breast cancer. The risk of breast cancer in women with Turner syndrome (45,XO karyotype) also appears to be significantly decreased, though this could be related to ovarian failure and hypogonadism rather necessarily than to genetics.
Prostate cancer is extremely rare in gonadectomized transgender women who have been treated with estrogens for a prolonged period of time. Whereas as many as 70% of men show prostate cancer by their 80s, only a handful of cases of prostate cancer in transgender women have been reported in the literature. 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.
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 2 to 3 months in the first year. Recommended ranges for total estradiol and total testosterone levels include but are not limited to the following:
Target ranges for hormone levels in feminizing hormone therapy for transgender women
"[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)."
"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."
"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."
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).
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.
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. If prolactin levels remain high, an MRI scan of the pituitary gland to check for the presence of a prolactinoma should be ordered. Otherwise, estrogen therapy may be restarted at a lower dosage. Cyproterone acetate is particularly associated with elevated prolactin levels, and discontinuation of cyproterone acetate lowers prolactin levels. In contrast to cyproterone acetate, estrogen and spironolactone therapy is not associated with increased prolactin levels.
Effective pharmaceutical female sex-hormonal medications first became available in the 1920s and 1930s. The first reports of hormone therapy in transgender women were published by clinicians such as Harry Benjamin and Christian Hamburger in the 1960s. However, Harry Benjamin is reported to have treated transgender woman with cross-sex hormone therapy as early as the 1920s and 1930s.
^Lauritzen C (December 1986). "Die Behandlung der klimakterischen Beschwerden durch vaginale, rektale und transdermale Ostrogensubstitution" [Treatment of disorders of the climacteric by vaginal, rectal and transdermal estrogen substitution]. Gynakologe (in German). 19 (4): 248–53. ISSN0017-5994. PMID3817597.
^ abOckrim J, Lalani EN, Abel P (October 2006). "Therapy Insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy". Nat Clin Pract Oncol. 3 (10): 552–63. doi:10.1038/ncponc0602. PMID17019433.
^Lycette JL, Bland LB, Garzotto M, Beer TM (December 2006). "Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities?". Clin Genitourin Cancer. 5 (3): 198–205. doi:10.3816/CGC.2006.n.037. PMID17239273.
^Liang JJ, Jolly D, Chan KJ, Safer JD (February 2018). "Testosterone Levels Achieved by Medically Treated Transgender Women in a United States Endocrinology Clinic Cohort". Endocr Pract. 24 (2): 135–142. doi:10.4158/EP-2017-0116. PMID29144822.
^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. PMID17986639.
^ abWylie, Kevan Richard; Fung, Robert; Boshier, Claudia; Rotchell, Margaret (2009). "Recommendations of endocrine treatment for patients with gender dysphoria". Sexual and Relationship Therapy. 24 (2): 175–187. doi:10.1080/14681990903023306. ISSN1468-1994.
^ abPavone-Macaluso M, de Voogt HJ, Viggiano G, Barasolo E, Lardennois B, de Pauw M, Sylvester R (September 1986). "Comparison of diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: final analysis of a randomized phase III trial of the European Organization for Research on Treatment of Cancer Urological Group". J. Urol. 136 (3): 624–31. doi:10.1016/S0022-5347(17)44996-2. PMID2942707.
^ abLainscak M, Pelliccia F, Rosano G, Vitale C, Schiariti M, Greco C, Speziale G, Gaudio C (2015). "Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone". Int. J. Cardiol. 200: 25–9. doi:10.1016/j.ijcard.2015.05.127. PMID26404748.
^Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA (2004). "Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study". N. Engl. J. Med. 351 (6): 543–51. doi:10.1056/NEJMoa040135. PMID15295047.
^ abZaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R (2016). "Guidelines of care for the management of acne vulgaris". J. Am. Acad. Dermatol. 74 (5): 945–73.e33. doi:10.1016/j.jaad.2015.12.037. PMID26897386.
^ abGoldenberg SL, Bruchovsky N, Rennie PS, Coppin CM (December 1988). "The combination of cyproterone acetate and low dose diethylstilbestrol in the treatment of advanced prostatic carcinoma". J. Urol. 140 (6): 1460–5. doi:10.1016/S0022-5347(17)42073-8. PMID2973529.
^ abSchröder, Fritz H.; Radlmaier, Albert (2009). "Steroidal Antiandrogens". In V. Craig Jordan; Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 325–346. doi:10.1007/978-1-59259-152-7_15. ISBN978-1-60761-471-5. CPA, as mentioned earlier, leads to an incomplete suppression of plasma testosterone levels, which decrease by about 70% and remain at about three times castration values. [Rennie et al.] found that the combination of CPA with an extremely low dose (0.1 mg/d) of DES led to a very effective withdrawal of androgens in terms of plasma testosterone and tissue dihydrotestosterone. [...] this regimen combines the testosterone-reducing effects of two compounds, therefore, only small amounts of estrogen are required to bring down plasma testosterone to approximately castrate levels.
^ abcNeumann F (1994). "The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research". Exp. Clin. Endocrinol. 102 (1): 1–32. doi:10.1055/s-0029-1211261. PMID8005205.
^Koch UJ, Lorenz F, Danehl K, Ericsson R, Hasan SH, Keyserlingk DV, Lübke K, Mehring M, Römmler A, Schwartz U, Hammerstein J (1976). "Continuous oral low-dosage cyproterone acetate for fertility regulation in the male? A trend analysis in 15 volunteers". Contraception. 14 (2): 117–35. doi:10.1016/0010-7824(76)90081-0. PMID949890.
^Moltz, L.; Römmler, A.; Schwartz, U.; Hammerstein, J. (1978). "Effects of Cyproterone Acetate (CPA) on Pituitary Gonadotrophin Release and on Androgen Secretion Before and After LH-RH Double Stimulation Tests in Men". International Journal of Andrology. 1 (s2b): 713–719. doi:10.1111/j.1365-2605.1978.tb00518.x. ISSN0105-6263.
^Moltz L, Römmler A, Post K, Schwartz U, Hammerstein J (April 1980). "Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men". Contraception. 21 (4): 393–413. doi:10.1016/s0010-7824(80)80017-5. PMID6771095.
^Knuth UA, Hano R, Nieschlag E (1984). "Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men". J. Clin. Endocrinol. Metab. 59 (5): 963–9. doi:10.1210/jcem-59-5-963. PMID6237116.
^Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R (1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial". Br J Urol. 52 (3): 208–15. doi:10.1111/j.1464-410x.1980.tb02961.x. PMID7000222.
^Fung, Raymond; Hellstern-Layefsky, Miriam; Lega, Iliana (2017). "Is a lower dose of cyproterone acetate as effective at testosterone suppression in transgender women as higher doses?". International Journal of Transgenderism. 18 (2): 123–128. doi:10.1080/15532739.2017.1290566. ISSN1553-2739.
^Lothstein, Leslie M. (1996). "Antiandrogen treatment for sexual disorders: Guidelines for establishing a standard of care". Sexual Addiction & Compulsivity. 3 (4): 313–331. doi:10.1080/10720169608400122. ISSN1072-0162.
^Novak E, Hendrix JW, Chen TT, Seckman CE, Royer GL, Pochi PE (October 1980). "Sebum production and plasma testosterone levels in man after high-dose medroxyprogesterone acetate treatment and androgen administration". Acta Endocrinol. 95 (2): 265–70. doi:10.1530/acta.0.0950265. PMID6449127.
^Kirschner MA, Schneider G (February 1972). "Suppression of the pituitary-Leydig cell axis and sebum production in normal men by medroxyprogesterone acetate (provera)". Acta Endocrinol. 69 (2): 385–93. doi:10.1530/acta.0.0690385. PMID5066846.
^Kemppainen JA, Langley E, Wong CI, Bobseine K, Kelce WR, Wilson EM (March 1999). "Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone". Mol. Endocrinol. 13 (3): 440–54. doi:10.1210/mend.13.3.0255. PMID10077001.
^Westhoff C (August 2003). "Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety". Contraception. 68 (2): 75–87. doi:10.1016/S0010-7824(03)00136-7. PMID12954518.
^Wu FC, Balasubramanian R, Mulders TM, Coelingh-Bennink HJ (January 1999). "Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism". J. Clin. Endocrinol. Metab. 84 (1): 112–22. doi:10.1210/jcem.84.1.5412. PMID9920070.
^Kumamoto Y, Yamaguchi Y, Sato Y, Suzuki R, Tanda H, Kato S, Mori K, Matsumoto H, Maki A, Kadono M (February 1990). "[Effects of anti-androgens on sexual function. Double-blind comparative studies on allylestrenol and chlormadinone acetate Part I: Nocturnal penile tumescence monitoring]". Hinyokika Kiyo (in Japanese). 36 (2): 213–26. PMID1693037.
^Geller J, Albert J, Geller S (1982). "Acute therapy with megestrol acetate decreases nuclear and cytosol androgen receptors in human BPH tissue". The Prostate. 3 (1): 11–5. doi:10.1002/pros.2990030103. PMID6176985.
^Wenderoth, U. K.; Jacobi, G. H. (1983). "Gonadotropin-releasing hormone analogues for palliation of carcinoma of the prostate". World Journal of Urology. 1 (1): 40–48. doi:10.1007/BF00326861. ISSN0724-4983.
^Melamed AJ (March 1987). "Current concepts in the treatment of prostate cancer". Drug Intell Clin Pharm. 21 (3): 247–54. doi:10.1177/106002808702100302. PMID3552544. [Megestrol acetate] produces a transient reduction in plasma testosterone to levels somewhat higher than those in castrated men. When used in a dose of 40 mg tid, in combination with estradiol 0.5–1.5 mg/d, it acts synergistically to suppress pituitary gonadotropins and maintain plasma testosterone at castration levels for periods up to one year.
^ abMoretti C, Guccione L, Di Giacinto P, Simonelli I, Exacoustos C, Toscano V, Motta C, De Leo V, Petraglia F, Lenzi A (March 2018). "Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial". J. Clin. Endocrinol. Metab. 103 (3): 824–838. doi:10.1210/jc.2017-01186. PMID29211888.
^Gretarsdottir, Helga M.; Bjornsdottir, Elin; Bjornsson, Einar S. (2018). "Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect". Case Reports in Gastroenterology. 12 (2): 266–270. doi:10.1159/000485175. ISSN1662-0631.
^Gao Y, Maurer T, Mirmirani P (January 2018). "Understanding and Addressing Hair Disorders in Transgender Individuals". Am J Clin Dermatol. 19 (4): 517–527. doi:10.1007/s40257-018-0343-z. PMID29352423. Non-steroidal antiandrogens include flutamide, nilutamide, and bicalutamide, which do not lower androgen levels and may be favorable for individuals who want to preserve sex drive and fertility .
^Iversen P, Melezinek I, Schmidt A (Jan 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID11121992.
^Morgante, E; Gradini, R; Realacci, M; Sale, P; D'eramo, G; Perrone, G A; Cardillo, M R; Petrangeli, E; Russo, Ma; Di Silverio, F (2001). "Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study". Histopathology. 38 (3): 195–201. doi:10.1046/j.1365-2559.2001.01077.x. ISSN0309-0167. PMID11260298.
^Jones CA, Reiter L, Greenblatt E (2016). "Fertility preservation in transgender patients". International Journal of Transgenderism. 17 (2): 76–82. doi:10.1080/15532739.2016.1153992. ISSN1553-2739. Traditionally, patients have been advised to cryopreserve sperm prior to starting cross-sex hormone therapy as there is a potential for a decline in sperm motility with high-dose estrogen therapy over time (Lubbert et al., 1992). However, this decline in fertility due to estrogen therapy is controversial due to limited studies.
^Payne AH, Hardy MP (28 October 2007). The Leydig Cell in Health and Disease. Springer Science & Business Media. pp. 422–431. ISBN978-1-59745-453-7. Estrogens are highly efficient inhibitors of the hypothalamic-hypophyseal-testicular axis (212–214). Aside from their negative feedback action at the level of the hypothalamus and pituitary, direct inhibitory effects on the testis are likely (215,216). [...] The histology of the testes [with estrogen treatment] showed disorganization of the seminiferous tubules, vacuolization and absence of lumen, and compartmentalization of spermatogenesis.
^ abSalam MA (2003). Principles & Practice of Urology: A Comprehensive Text. Universal-Publishers. pp. 684–. ISBN978-1-58112-412-5. Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce LH secretion and testicular androgen synthesis. [...] Interestingly, if the treatment with estrogens is discontinued after 3 yr. of uninterrupted exposure, serum testosterone may remain at castration levels for up to another 3 yr. This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells.
^Ezzati M, Carr BR (January 2015). "Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain". Womens Health (Lond). 11 (1): 19–28. doi:10.2217/whe.14.68. PMID25581052.
^Reilly DR, Delva NJ, Hudson RW (August 2000). "Protocols for the use of cyproterone, medroxyprogesterone, and leuprolide in the treatment of paraphilia". Can J Psychiatry. 45 (6): 559–63. doi:10.1177/070674370004500608. PMID10986575. [...] estrogen or antiandrogen treatment prior to the first leuprolide injection may reduce [the risk of symptoms caused by the testosterone "flare" at the initiation of treatment] (16).
^ abcdDittrich R, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Mueller A (December 2005). "Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist". Exp. Clin. Endocrinol. Diabetes. 113 (10): 586–92. doi:10.1055/s-2005-865900. PMID16320157.
^Liang, Jennifer J.; Rasmusson, Ann M. (2018). "Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone". Chronic Stress. 2: 247054701881855. doi:10.1177/2470547018818555. ISSN2470-5470.
^ abcBartsch G, Rittmaster RS, Klocker H (April 2000). "Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia". Eur. Urol. 37 (4): 367–80. doi:10.1159/000020181. PMID10765065.
^ abYamana K, Labrie F, Luu-The V (August 2010). "Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride". Horm Mol Biol Clin Investig. 2 (3): 293–9. doi:10.1515/HMBCI.2010.035. PMID25961201.
^Traish AM, Krakowsky Y, Doros G, Morgentaler A (August 2018). "Do 5α-Reductase Inhibitors Raise Circulating Serum Testosterone Levels? A Comprehensive Review and Meta-Analysis to Explaining Paradoxical Results". Sex Med Rev. 7 (1): 95–114. doi:10.1016/j.sxmr.2018.06.002. PMID30098986.
^Azzouni F, Mohler J (September 2012). "Role of 5α-reductase inhibitors in benign prostatic diseases". Prostate Cancer Prostatic Dis. 15 (3): 222–30. doi:10.1038/pcan.2012.1. PMID22333687.
^ abcdefgMeriggiola MC, Gava G (November 2015). "Endocrine care of transpeople part II. A review of cross-sex hormonal treatments, outcomes and adverse effects in transwomen". Clin. Endocrinol. (Oxf). 83 (5): 607–15. doi:10.1111/cen.12754. PMID25692882.
^ abcTrost L, Saitz TR, Hellstrom WJ (May 2013). "Side Effects of 5-Alpha Reductase Inhibitors: A Comprehensive Review". Sex Med Rev. 1 (1): 24–41. doi:10.1002/smrj.3. PMID27784557.
^ abLiu L, Zhao S, Li F, Li E, Kang R, Luo L, Luo J, Wan S, Zhao Z (September 2016). "Effect of 5α-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials". J Sex Med. 13 (9): 1297–1310. doi:10.1016/j.jsxm.2016.07.006. PMID27475241.
^ abTraish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML (March 2011). "Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients". J Sex Med. 8 (3): 872–84. doi:10.1111/j.1743-6109.2010.02157.x. PMID21176115.
^ abTraish, Abdulmaged M. (2018). "The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption". Current Sexual Health Reports. 10 (3): 88–103. doi:10.1007/s11930-018-0161-6. ISSN1548-3584.
^Traish AM, Melcangi RC, Bortolato M, Garcia-Segura LM, Zitzmann M (September 2015). "Adverse effects of 5α-reductase inhibitors: What do we know, don't know, and need to know?". Rev Endocr Metab Disord. 16 (3): 177–98. doi:10.1007/s11154-015-9319-y. PMID26296373.
^Trüeb RM (June 2017). "Discriminating in favour of or against men with increased risk of finasteride-related side effects?". Exp. Dermatol. 26 (6): 527–528. doi:10.1111/exd.13155. PMID27489125. [...] 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.
^Cox DB, Kent JC, Casey TM, Owens RA, Hartmann PE (March 1999). "Breast growth and the urinary excretion of lactose during human pregnancy and early lactation: endocrine relationships". Exp. Physiol. 84 (2): 421–34. doi:10.1017/S0958067099018072. PMID10226182.
^ abKronawitter D, Gooren LJ, Zollver H, Oppelt PG, Beckmann MW, Dittrich R, Mueller A (August 2009). "Effects of transdermal testosterone or oral dydrogesterone on hypoactive sexual desire disorder in transsexual women: results of a pilot study". Eur. J. Endocrinol. 161 (2): 363–8. doi:10.1530/EJE-09-0265. PMID19497984.
^ abMeyer WJ, Webb A, Stuart CA, Finkelstein JW, Lawrence B, Walker PA (April 1986). "Physical and hormonal evaluation of transsexual patients: a longitudinal study". Archives of Sexual Behavior. 15 (2): 121–38. doi:10.1007/bf01542220. PMID3013122.
^Daniel R. Mishell; Val Davajan (1979). Reproductive endocrinology, infertility, and contraception. F. A. Davis Co. p. 224. ISBN978-0-8036-6235-3. 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.
^Lorincz AM, Sukumar S (2006). "Molecular links between obesity and breast cancer". Endocrine-Related Cancer. 13 (2): 279–92. doi:10.1677/erc.1.00729. PMID16728564. Adipocytes make up the bulk of the human breast, with epithelial cells accounting for only approximately 10% of human breast volume.
^Howard BA, Gusterson BA (2000). "Human breast development". Journal of Mammary Gland Biology and Neoplasia. 5 (2): 119–37. doi:10.1023/A:1026487120779. PMID11149569. In the stroma, there is an increase in the amount of fibrous and fatty tissue, with the adult nonlactating breast consisting of 80% or more of stroma.
^Sperling MA (10 April 2014). Pediatric Endocrinology. Elsevier Health Sciences. pp. 598–. ISBN978-1-4557-5973-6. Estrogen stimulates the nipples to grow, mammary terminal duct branching to progress to the stage at which ductules are formed, and fatty stromal growth to increase until it constitutes about 85% of the mass of the breast. [...] Lobulation appears around menarche, when multiple blind saccular buds form by branching of the terminal ducts. These effects are due to the presence of progesterone. [...] Full alveolar development normally only occurs during pregnancy under the influence of additional progesterone and prolactin.
^Hagisawa S, Shimura N, Arisaka O (2012). "Effect of excess estrogen on breast and external genitalia development in growth hormone deficiency". Journal of Pediatric and Adolescent Gynecology. 25 (3): e61–3. doi:10.1016/j.jpag.2011.11.005. PMID22206682. Estrogen stimulates growth of the nipples, progression of mammary duct branching to the stage at which ductiles are formed, and fatty stromal growth until it constitutes about 85% of the mass of the breast.
^ abLee-Ellen C. Copstead-Kirkhorn; Jacquelyn L. Banasik (25 June 2014). Pathophysiology - E-Book. Elsevier Health Sciences. pp. 660–. ISBN978-0-323-29317-4. Throughout the reproductive years, some women note swelling of the breast around the latter part of each menstrual cycle before the onset of menstruation. The water retention and subsequent swelling of breast tissue during this phase of the menstrual cycle are thought to be due to high levels of circulating progesterone stimulating the secretory cells of the breast.12
^ abcFoss GL (March 1958). "Disturbances of lactation". Clin Obstet Gynecol. 1 (1): 245–54. doi:10.1097/00003081-195803000-00021. PMID13573669. 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.
^ abcKanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW (January 2000). "Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men". The American Journal of Surgical Pathology. 24 (1): 74–80. doi:10.1097/00000478-200001000-00009. PMID10632490.
^Worsley R, Santoro N, Miller KK, Parish SJ, Davis SR (March 2016). "Hormones and Female Sexual Dysfunction: Beyond Estrogens and Androgens--Findings from the Fourth International Consultation on Sexual Medicine". J Sex Med. 13 (3): 283–90. doi:10.1016/j.jsxm.2015.12.014. PMID26944460.
^Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G (2014). "Allopregnanolone and mood disorders". Prog. Neurobiol. 113: 88–94. doi:10.1016/j.pneurobio.2013.07.005. PMID23978486.
^ abcdefgMoore E, Wisniewski A, Dobs A (August 2003). "Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects". The Journal of Clinical Endocrinology and Metabolism. 88 (8): 3467–73. doi:10.1210/jc.2002-021967. PMID12915619.
^Nota NM, Wiepjes CM, de Blok CJ, Gooren LJ, Peerdeman SM, Kreukels BP, den Heijer M (July 2018). "The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment". Brain. 141 (7): 2047–2054. doi:10.1093/brain/awy108. PMID29688280.
^Kuhl H (2011). "Pharmacology of Progestogens"(PDF). Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology. 8 (1): 157–177.
^ abHermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML, Bertino JS (2005). "Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product". J Clin Pharmacol. 45 (6): 614–9. doi:10.1177/0091270005276621. PMID15901742.
^Tollan A, Oian P, Kjeldsen SE, Eide I, Maltau JM (1993). "Progesterone reduces sympathetic tone without changing blood pressure or fluid balance in men". Gynecol. Obstet. Invest. 36 (4): 234–8. doi:10.1159/000292636. PMID8300009.
^Unfer, Vittorio; di Renzo, Gian; Gerli, Sandro; Casini, Maria (2006). "The Use of Progesterone in Clinical Practice: Evaluation of its Efficacy in Diverse Indications Using Different Routes of Administration". Current Drug Therapy. 1 (2): 211–219. doi:10.2174/157488506776930923. ISSN1574-8855.
^Brady BM, Anderson RA, Kinniburgh D, Baird DT (2003). "Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male". Clin. Endocrinol. (Oxf). 58 (4): 506–12. doi:10.1046/j.1365-2265.2003.01751.x. PMID12641635.
^ abKozlov GI, Mel'nichenko GA, Golubeva IV (1985). "Sluchai laktorei u bol'nogo muzhskogo pola s transseksualizmom" [Case of galactorrhea in a transsexual male patient]. Probl Endokrinol (Mosk) (in Russian). 31 (1): 37–8. ISSN0375-9660. PMID4039061. [...] 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. Flüskiger 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.
^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 , 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.
^Harold Gardiner-Hill (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.
^Carla A. Pfeffer (2017). Queering Families: The Postmodern Partnerships of Cisgender Women and Transgender Men. Oxford University Press. pp. 19–. ISBN978-0-19-990805-9. 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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