A variety of different
sex-hormonal medications are used in feminizing hormone therapy for
transgender women.
Estrogens Estrogens are the major sex hormones in women, and are responsible for the development and maintenance of feminine secondary sexual characteristics, such as breasts, wide hips, and a feminine pattern of fat distribution. The
pharmacokinetics of estradiol's routes of administration vary greatly.
Sublingual and rectal administration result in peak concentrations up to ten times higher than oral administration, and higher
trough concentrations. This makes frequent, small sublingual or rectal doses, a very efficient way to create a stable and constant increase in trough levels. A large amount of estradiol consumed sublingually, and especially
orally is
converted by the GI tract into estrone and other compounds, causing a higher estrone:estradiol (E1:E2) ratio. This means oral doses are more subject to individual variances in enzymes and physiological chemistry. The extent of the estrone ratio's effects are unclear but, as a weaker estrogen agonist than estradiol, a high estrone level can reduce feminization by
competitive antagonism. A high estrone ratio is linked to reduced skeletal growth in pubertal boys and insulin resistance in
PCOS. The ratio is also known to be higher in early female puberty (~1:3), and lower in the later stages (~1-5). An average dose
intramuscular injection can vary from far above to far below the average female range over the course of a week, depending on an individual's body. Lower levels of estradiol can also considerably but incompletely suppress testosterone production.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 review proposal noted that high-dose parenteral estradiol is known to be safe. Dosages of estrogens can be reduced after an orchiectomy or sex reassignment surgery, when gonadal testosterone suppression is no longer needed. Demonstrates the suppression of testosterone levels by parenteral estradiol.
Antiandrogens Antiandrogens are medications that prevent the effects of
androgens in the body. In addition, androgens stimulate
sex drive and the frequency of
spontaneous erections and are responsible for
acne,
body odor, and
androgen-dependent scalp hair loss. Androgens act by binding to and activating the
androgen receptor, their
biological target in the body. Antiandrogens work by blocking androgens from binding to the androgen receptor and/or by inhibiting or suppressing the
production of androgens.
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.
Steroidal antiandrogens Steroidal antiandrogens are antiandrogens that resemble
steroid hormones like testosterone and
progesterone in
chemical structure. They are the most commonly used antiandrogens in transgender women.
Cyproterone acetate (Androcur), which is unavailable in the United States, is widely used in
Europe,
Canada, and the rest of the world.
Medroxyprogesterone acetate (Provera, Depo-Provera), a similar medication, is sometimes used in place of cyproterone acetate in the United States. Estradiol was used in the form of oral
estradiol valerate (EV) in almost all cases. Spironolactone is an antiandrogen as a secondary and originally unintended action. The medication is also a weak
steroidogenesis inhibitor, and inhibits the
enzymatic synthesis of androgens. However, this action is of low
potency, and spironolactone has mixed and inconsistent effects on hormone levels. In any case, testosterone levels are usually unchanged by spironolactone. It is widely used in the treatment of
acne,
excessive hair growth, and
hyperandrogenism in women, who have much lower testosterone levels than men. Hospitalization and/or death can potentially result from high potassium levels due to spironolactone, but the risk of high potassium levels in people taking spironolactone appears to be minimal in those without risk factors for it. As such, monitoring of potassium levels may not be necessary in most cases. It works primarily as an antigonadotropin, secondarily to its potent progestogenic activity, and strongly suppresses gonadal androgen production. 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 combination with estrogen, 10, 25, and 50 mg/day cyproterone acetate have all shown the same degree of testosterone suppression. In addition to its actions as an antigonadotropin, cyproterone acetate is an androgen receptor antagonist. 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. High dosages of cyproterone-based medication have been linked with
meningioma. 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. 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.
Nonsteroidal antiandrogens Nonsteroidal antiandrogens are antiandrogens which are
nonsteroidal and hence unrelated to steroid hormones in terms of
chemical structure. Unlike steroidal antiandrogens, nonsteroidal antiandrogens are highly
selective for the androgen receptor and act as pure androgen receptor antagonists. and for this reason, in conjunction with GnRH modulators, have largely replaced steroidal antiandrogens in the treatment of prostate cancer. The nonsteroidal antiandrogens that have been used in transgender women include the first-generation medications
flutamide (Eulexin),
nilutamide (Anandron, Nilandron), and
bicalutamide (Casodex). Flutamide and nilutamide have relatively high
toxicity, including considerable risks of
liver damage and
lung disease. 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. 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. In both males and females,
gonadotropin-releasing hormone (GnRH) is produced in the
hypothalamus and induces the
secretion of the
gonadotropins
luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) from the
pituitary gland. GnRH modulators are also commonly known as
GnRH analogues. There are two types of GnRH modulators:
GnRH agonists and
GnRH antagonists. 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. However, GnRH modulators tend to be very expensive (typically to per year in the
United States), and are often denied by
medical insurance. Because of their costs, many transgender women cannot afford GnRH modulators and must use other, often less effective options for testosterone suppression. This is in contrast to the United States. In adolescents of either sex, GnRH modulators can be used to
suppress puberty. The eighth edition of the
World Professional Association for Transgender Health's Standards of Care permit its use from Tanner stage 2 and recommends GnRH agonists as the preferred method of puberty blocking. 5α-Reductase is an enzyme that is responsible for the conversion of
testosterone into the more
potent androgen
dihydrotestosterone (DHT). As such, 5α-reductase serves to considerably potentiate the effects of testosterone. Furthermore, circulating levels of total and free DHT in men are very low at about one-tenth and one-twentieth those of testosterone, respectively, As such, it is thought that DHT plays little role as a systemic androgen hormone and serves more as a means of locally potentiating the androgenic effects of testosterone in a
tissue-specific manner. Conversion of testosterone into DHT by 5α-reductase plays an important role in
male reproductive system development and maintenance (specifically of the
penis,
scrotum,
prostate gland, and
seminal vesicles),
male-pattern facial/body hair growth, and
scalp hair loss, but has little role in other aspects of
masculinization. Besides the involvement of 5α-reductase in androgen signaling, it is also required for the conversion of
steroid hormones such as
progesterone and testosterone into
neurosteroids like
allopregnanolone and
3α-androstanediol, respectively. Finasteride can decrease circulating DHT levels by up to 70%, whereas dutasteride can decrease circulating DHT levels by up to 99%. 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. 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. In men, the most common side effect is
sexual dysfunction (0.9–15.8% incidence), which may include
decreased libido,
erectile dysfunction, and
reduced ejaculate. Another side effect in men is
breast changes, such as
breast tenderness and
gynecomastia (2.8% incidence). There are reports that a small percentage of men may experience persistent sexual dysfunction and adverse
mood changes even after discontinuation of 5α-reductase inhibitors. Unlike estrogens, progesterone is not known to be involved in the development of female
secondary sexual characteristics, and hence is not believed to contribute to
feminization in women. Conversely, high levels of progesterone, in conjunction with other hormones such as
prolactin, are responsible for the
lobuloalveolar maturation of the
mammary glands during pregnancy. Certain progestins, namely
cyproterone acetate and
medroxyprogesterone acetate and as described previously, are used at high doses as functional
antiandrogens due to their
antigonadotropic effects to help suppress testosterone levels in transgender women. Besides progesterone, cyproterone acetate, and medroxyprogesterone acetate, other progestogens that have been reported to have been used in transgender women include
hydroxyprogesterone caproate,
dydrogesterone,
norethisterone acetate, and
drospirenone. 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. Progestogens have some
antiestrogenic effects in the breasts, for instance decreasing
expression of the
estrogen receptor and increasing expression of estrogen-
metabolizing enzymes, 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. However, lobuloalveolar development reversed with discontinuation of cyproterone acetate, indicating that continued progestogen exposure is necessary to maintain the tissue. Progestogens can have
adverse effects. Oral progesterone has
inhibitory neurosteroid effects and can produce side effects such as
sedation,
mood changes, and
alcohol-like effects. Many progestins have
off-target activity, such as
androgenic,
antiandrogenic,
glucocorticoid, and
antimineralocorticoid activity, and these activities likewise can contribute unwanted side effects. Because of their potential detrimental effects and lack of supported benefits, some researchers have argued that, aside from the purpose of testosterone suppression, progestogens should not generally be used or advocated in transgender women or should only be used for a limited duration (e.g., 2–3 years). Progesterone is most commonly taken orally. In accordance, and in contrast to progestins, oral progesterone has no antigonadotropic effects in males 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. The
World Professional Association for Transgender Health (WPATH)
Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8), released in September 2022, recommends against therapeutic strategies including
supraphysiological estradiol levels (>200 pg/mL), use of
progesterone (including
rectal progesterone), use of
bicalutamide, and monitoring of the ratio of
estrone to
estradiol. This is due to lack of data to support these approaches in transfeminine people as well as potential risks. The WPATH SOC8 also recommends against the use of
5α-reductase inhibitors such as
finasteride in transfeminine people. == Interactions ==