Hormone replacement therapy (male to female)

Medical uses

Contraindications

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

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

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

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

Interactions

Inducers of CYP3A4 and other cytochrome P450 enzymes can reduce the effects of MTF HRT. (For a list of CYP3A4 inducers, see here.)

Estrogens

Estrogen is one of the two major sex hormones in women (the other being progesterone), and is responsible for the development and maintenance of female secondary sexual characteristics, such as breasts, wide hips, and a feminine pattern of fat distribution. Estrogens act by binding to and activating the estrogen receptor (ER), their biological target in the body. A variety of different forms of estrogen are available and used medically. The most common estrogens used in transgender women include estradiol (which is the predominant natural estrogen in women) and estradiol esters such as estradiol valerate and estradiol cypionate (which are prodrugs of estradiol). Conjugated equine estrogens (CEEs), marketed as Premarin, and ethinylestradiol are also sometimes used, but this is becoming less common. Estrogens may be administered orally, sublingually, transdermally (via patch), topically (via gel), by intramuscular or subcutaneous injection, or by an implant.

Prior to sex reassignment surgery, dosages of estrogen for transgender people are often higher than replacement dosages used for cisgender women. Hembree et al. (2009) recommend "maintain[ing] sex hormone levels within the normal range for the person’s desired gender". Dosages are typically reduced after an orchiectomy (removal of the testes) or sex reassignment surgery. However, that practice has been carried over from an era in which very high doses of estrogen were required to decrease testosterone, since antiandrogens were not used concurrently. Today, high doses of a less potent estrogen – estradiol, which is endogenous to the human body, rather than the riskier ethinylestradiol and conjugated estrogens used in the past – are recommended during the first ten or so years of HRT, with or without an orchiectomy or sex reassignment. After that period, dosages can be reduced.

Antiandrogens

Androgens, such as testosterone and dihydrotestosterone (DHT), are the major sex hormones in men, and are responsible for the development and maintenance of male secondary sexual characteristics, such as a deep voice, broad shoulders, and a masculine pattern of hair, muscle, and fat distribution. In addition, they stimulate sex drive and the frequency of spontaneous erections and are responsible for acne, body odor, and male-pattern scalp hair loss. Androgens act by binding to and activating the androgen receptor (AR), their biological target in the body. In contrast to androgens, antiandrogens are drugs that prevent the effects of androgens in the body. They do this by preventing androgens from binding to the AR or by preventing the production of androgens. The most commonly used antiandrogens in transgender women are cyproterone acetate, spironolactone, and GnRH analogues.

Steroidal antiandrogens

The most commonly used antiandrogens for transgender women are steroidal: spironolactone and cyproterone acetate. Spironolactone, which is relatively safe and inexpensive, is the most frequently used antiandrogen in the United States. Cyproterone acetate, which is unavailable in the United States, is more commonly used in the rest of the world.

Spironolactone is a potassium-sparing diuretic that is mainly used to treat low-renin hypertension, edema, hyperaldosteronism, and low potassium levels caused by other diuretics. It can cause high potassium levels (hyperkalemia) and is therefore contraindicated in people who have renal failure or already-elevated potassium levels. Spironolactone prevents the formation of androgens in the testes (though not in the adrenal glands) by inhibiting enzymes involved in androgen production. It is also an androgen receptor antagonist (that is, it prevents androgens from binding to and activating the androgen receptor).

Cyproterone acetate is a powerful antiandrogen and progestin that suppresses gonadotropin levels (which in turn reduces androgen levels), blocks androgens from binding to and activating the androgen receptor, and inhibits enzymes in the androgen biosynthesis pathway. It has been used as a means of androgen deprivation therapy to treat prostate cancer. If used long-term in dosages of 150 mg or higher, it can cause liver damage or failure.

Non-steroidal antiandrogens

Non-steroidal antiandrogens used in HRT for transgender women include flutamide, nilutamide, and bicalutamide, all three of which are primarily used in the treatment of prostate cancer in cisgender men. Unlike steroidal antiandrogens such as spironolactone and cyproterone acetate, these drugs are pure androgen receptor antagonists. They do not lower androgen levels; rather, they act solely by preventing the binding of androgens to the androgen receptor. However, they do so very strongly, and are highly effective antiandrogens. Bicalutamide has improved tolerability and safety profiles relative to cyproterone acetate, as well as to flutamide and nilutamide, and has largely replaced the latter two in clinical practice for this reason. Enzalutamide is a more recently introduced non-steroidal antiandrogen with even greater potency and efficacy as an antiandrogen than bicalutamide, but it is still under patent protection and in relation to this is currently (and for the foreseeable future) extremely expensive. Moreover, enzalutamide has been found to act as a negative allosteric modulator of the GABA receptor and has been associated with central side effects such as anxiety, insomnia, and, most notably, seizures (in ~1% of patients), properties that it does not share with bicalutamide.

Non-steroidal antiandrogens may be an appealing option for those who wish to preserve sex drive and function and/or fertility, as well as for those who desire more selective action with fewer side effects than spironolactone and cyproterone acetate (which increase the risk of depressive symptoms, among other adverse effects). Bicalutamide specifically may also be a safer drug than cyproterone acetate or spironolactone, as it has a much lower risk of hepatotoxicity relative to cyproterone acetate and, unlike spironolactone, has no risk of hyperkalemia or other antimineralocorticoid-associated adverse reactions. However, bicalutamide does have a very small risk of hepatotoxicity itself, as well as of interstitial pneumonitis.

GnRH analogues

In both sexes, the hypothalamus produces gonadotropin-releasing hormone (GnRH) to stimulate the pituitary gland to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This in turn cause the gonads to produce sex steroids such as androgens and estrogens. In adolescents of either sex with relevant indicators, GnRH analogues such as goserelin acetate can be used to stop undesired pubertal changes for a period without inducing any changes toward the sex with which the patient currently identifies. GnRH agonists work by initially overstimulating the pituitary gland, then rapidly desensitizing it to the effects of GnRH. After an initial surge, over a period of weeks, gonadal androgen production is greatly reduced. Conversely, GnRH antagonists act by blocking the action of GnRH in the pituitary gland.

There is considerable controversy over the earliest age at which it is clinically, morally, and legally safe to use GnRH analogues, 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 analogues.

GnRH analogues are often prescribed to prevent the reactivation of testicular function when surgeons require the cessation of estrogens prior to surgery.

The high cost of GnRH analogues is a significant factor in their relative lack of use in transgender people. However, they are prescribed as standard practice in the United Kingdom.

5α-Reductase inhibitors

Certain antiandrogens do not reduce testosterone or prevent its action upon tissues, but instead prevent its metabolite, dihydrotestosterone (DHT), from forming. These medications can be used when the patient has male-pattern hair loss and/or an enlarged prostate (benign prostatic hyperplasia), both of which DHT exacerbates. Two medications are currently available to prevent the creation of DHT: finasteride and dutasteride. DHT levels can be lowered up to 60–75% with the former, and up to 93–94% with the latter. These medications have also been found to be effective in the treatment of hirsutism in women.

Progestogens

Progesterone, a progestogen, is the other of the two major sex hormones in women. Unlike estrogen, progesterone is not overtly involved in the development of female secondary sexual characteristics, and is instead involved mainly in the menstrual cycle and pregnancy. For this reason, progestogens are not commonly prescribed for transgender women. However, there may be a role of progestogens in breast development (though controversial and disputed) and in regulation of skin and hair, and progesterone specifically may have positive effects on sex drive, sleep, and levels of anxiety. Moreover, due to their antigonadotropic and/or antiandrogen effects, progestogens can be useful in helping to suppress the effects of androgens in the body. The most common progestogens used in transgender women include progesterone and progestins (synthetic progestogens) like CPA and medroxyprogesterone acetate (MPA). These drugs are usually taken orally, but may also be administered by intramuscular injection.

Antiandrogenic and androgenic effects

High doses of progestogens exert negative feedback on the hypothalamic-pituitary-gonadal axis by activating the progesterone receptor. As a result, they have antigonadotropic effects – that is, they suppress the gonadal production of sex hormones such as androgens. As such, sufficient dosages of progestogens, such as cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, megestrol acetate, and MPA, can considerably lower androgen levels. In addition, certain other progestogens, such as cyproterone acetate, megestrol acetate, drospirenone, and nomegestrol acetate, bind to and block the activation of the androgen receptor. On the other hand, certain other progestogens, including 19-nortestosterone derivatives like levonorgestrel, norgestrel, norethisterone, and norethisterone acetate, as well as, to a lesser extent, the 17α-hydroxyprogesterone derivative MPA, have weak androgenic activity because they bind to and activate the androgen receptor similarly to testosterone, and may produce androgenic effects such as acne, hirsutism, and increased sex drive.

Role in breast development

Progestogens, in conjunction with the hormone prolactin, are involved in the maturation of the lobules, acini, and areola during pregnancy: mammary structures that estrogen has little to no direct effect on. However, there is no clinical evidence that progestogens enhance breast size, shape, or appearance in either transgender women or cisgender women, and one study found no benefit to breast hemicircumference over estrogen alone in a small sample of transgender women given both an estrogen and an oral progestogen (usually 10 mg/day medroxyprogesterone acetate). However, the authors of the paper stated that the sample size was too small to make any definitive conclusions, and that further studies should be carried out to confirm whether progestogens significantly affect breast size and/or shape in transgender women. As of 2014, no additional study had looked at the issue. Anecdotal evidence from transgender women suggests that those who take progesterone supplements may experience more full breast development, including stage IV on the Tanner scale (many transgender women do not develop Tanner stage V breasts). However, there have been no formal studies with sufficiently large sample sizes to confirm this.

Other effects

Progestogens reportedly alter fat distribution (e.g., by increasing fat in the buttocks and thighs), increase sex drive (specifically progesterone, via its active metabolite allopregnanolone; this does not occur through activation of the progesterone receptor), cause increased appetite and weight gain (only in combination with estrogen), produce a sense of calm (i.e., anxiolysis), and promote sleep (i.e., sedative and hypnotic effects).

Progesterone specifically is essential for bone health and seems to have a role in skin elasticity and nervous system function. Other effects seen with progesterone include reducing spasms and relaxing smooth muscle tone; reducing gallbladder activity; widening bronchi, which helps respiration; reducing inflammation and immune response; and normalizing blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy. Progesterone also assists in thyroid function and bone building by osteoblasts.

Effects

The main effects of HRT of the MTF type are as follows:

The psychological effects of hormone replacement therapy are harder to define than physical changes. Because HRT 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.

Breast development

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

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

Skin changes

The uppermost layer of skin, the stratum corneum, becomes thinner and more translucent. Spider veins may appear or be more noticeable as a result. Collagen decreases, and tactile sensation increases. The skin becomes softer, 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.

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

Hair changes

Antiandrogens affect existing facial hair only slightly; patients may see slower growth and some reduction in density and coverage. Those who are less than a decade past puberty and/or whose race generally lacks 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.

Eye changes

The lens of the eye changes in curvature. 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.

Fat changes

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

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

Muscle changes

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

Bone/skeletal changes

Male-to-female hormone therapy causes the hips to rotate slightly forward because of changes in the tendons. Hip discomfort is not uncommon.

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.

Reproductive changes

Testicle volume is reduced by about 25% with typical dosages and as much as 50% with higher dosages, especially after a year of HRT. This is in response to a decrease in Leydig cells, Sertoli cells, and interstitial tissue, which produce both sperm and testosterone. When testosterone is dramatically reduced, spermatogenesis is halted almost completely, and when the cells that are involved in these processes go unused, they atrophy.

The prostate and bladder shrink. The line that runs down the underside of the penis and down the middle of the scrotum – the peno-scrotal raphe, where the urogenital folds fused early in the womb – darkens. Minor water retention is likely, but spironolactone tends to counter this effect because it is a diuretic.

HRT can cause infertility, eventually leading to chemically induced aspermatogenesis. The reversibility of this effect may depend on the duration of treatment. HRT of the MTF type is not a substitute for other birth control methods.

Childbearing, as experienced by cisgender women, is speculative with current technology. Pre-operative sperm banking, however, can allow for the use of artificial insemination with a female partner at a later date.

Medical advances may one day make it possible for transgender women to become pregnant with a donor uterus, as anti-rejection drugs do not seem to affect the fetus. The first successful uterine transplant took place in Turkey in 2011. The DNA in a donated ovum can be removed and replaced with the DNA of the receiver. In the future, stem cell biotechnology may make this possible with no need for anti-rejection drugs. However, problems may arise with the structure of the hip bones, as cisgender women generally have larger hip bones to accommodate pregnancy.

Unaffected characteristics

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

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

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

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

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

Psychological changes

Mood changes, including depression, can occur with hormone replacement therapy. However, many transgender women report significant mood-lifting effects as well. The risk of depressive side effects is more common in patients who take progestins. Medroxyprogesterone acetate, in particular, has been shown to cause depression in certain individuals, perhaps by affecting dopamine levels.

Sexual changes

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

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

Neurological changes

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

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

Cardiovascular effects

The most significant cardiovascular risk for transgender women is the pro-thrombotic effect (increased blood clotting) of estrogens. This manifests most significantly as an increased risk for thromboembolic disease: deep vein thrombosis (DVT) and pulmonary embolism, which occurs when blood clots from DVT break off and migrate to the lungs. Symptoms of DVT include pain or swelling of one leg, especially the calf. Symptoms of pulmonary embolism include chest pain, shortness of breath, fainting, and heart palpitations, sometimes without leg pain or swelling.

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

Because the risks of warfarin – which is used to treat blood clots – in a relatively young and otherwise healthy population are low, while the risk of adverse physical and psychological outcomes for untreated transgender patients is high, pro-thrombotic mutations (such as factor V Leiden, antithrombin III, and protein C or S deficiency) are not absolute contraindications for hormonal therapy.

Gastrointestinal/metabolic changes

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

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

Bone changes

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

Risk of hormone-sensitive cancers

In spite of the induction of breast development, HRT in transgender women does not appear to increase the risk of breast cancer. Only a handful of cases of breast cancer have ever been described in transgender women. This is in accordance with research in cisgender men in which gynecomastia has been found not to be associated with an increased risk of breast cancer. On the other hand, men with Klinefelter's syndrome, who have two X chromosomes (similarly to cisgender women) in addition to hypoandrogenism, hyperestrogenism, and a very high incidence of gynecomastia (80%), show a dramatically (20- to 58-fold) increased risk of breast cancer that is between that of cisgender men and cisgender women (though closer to that of the latter). The incidences of breast cancer in cisgender men (46,XY karyotype), men with Klinefelter's syndrome (47,XXY karyotype), and cisgender women (46,XX karyotype) are approximately 0.1%, 3%, and 12.5%, respectively. Also of potential relevance is the case of women with complete androgen insensitivity syndrome, who are genetically male (i.e., 46,XY karyotype) and have normal and complete morphological breast development and in fact breast sizes that are on average larger than those of cisgender women yet, similarly to cisgender men, appear to have little (or possibly even no) incidence of breast cancer. The risk of breast cancer in women with Turner syndrome (45,XO karyotype) also appears to be significantly decreased, though this may be related to ovarian failure/hypogonadism rather necessarily than to genetics.

Similarly to the case of breast cancer, prostate cancer is extremely rare in transgender women who have been treated with HRT for a prolonged period of time. Whereas as many as 70% of men show prostate cancer by their 80's, 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.

Other changes

Migraines can be made worse or unmasked by estrogen therapy.

Estrogens can also cause prolactinomas. Milk discharge from the nipples can be a sign of elevated prolactin levels. If a prolactinoma becomes large enough, it can cause visual changes (especially decreased peripheral vision), headaches, depression or other mood changes, dizziness, nausea, vomiting, and symptoms of pituitary failure, like hypothyroidism.

Hormone levels

Especially in the early stages of hormone replacement therapy, blood work is done frequently to assess hormone levels and liver function. The Endocrine Society recommends that patients have blood tests every three months in the first year of HRT for estradiol and testosterone, and that spironolactone, if used, be monitored every 2–3 months in the first year. The optimal ranges for estradiol and testosterone are:

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

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.