By Aly W. | First published August 4, 2018 | Last modified September 23, 2022
Sex hormones such as estrogen, testosterone, and progesterone are produced by the gonads. The sex hormones mediate the development of the secondary sexual characteristics. Testosterone causes masculinization, while estradiol causes feminization and breast development. Males have high amounts of testosterone, while females have low testosterone but high amounts of estradiol. These hormonal differences are responsible for the physical differences between males and females. Sex hormones and other hormonal medications are used in transfeminine people to shift the hormonal profile from a male-typical one to a female-typical profile. This causes feminization and demasculinization and allows for alleviation of gender dysphoria. The changes caused by transfeminine hormone therapy occur over a period of months to years. There are many different types and forms of hormonal medications, and these medications can be administered by a variety of different routes. Examples include as pills taken by mouth, as patches or gel applied to the skin, and as injections, among others. Different hormonal medications, routes, and doses have differences in efficacy, side effects, risks, costs, convenience, and availability. Hormone therapy should ideally be regularly monitored in transfeminine people with blood tests to ensure effectiveness and safety and to allow for adjustment as necessary.
The sex hormones include the estrogens (E), progestogens (P), and androgens. A person’s hormonal profile is a product of the type of gonads that they are born with. Natal males have testes while natal females have ovaries. Testes produce large amounts of androgens and small amounts of estrogens whereas ovaries produce high amounts of estrogens and progesterone and low amounts of androgens.
The major estrogen in the body is estradiol (E2), the main progestogen is progesterone (P4), and the major androgens are testosterone (T) and dihydrotestosterone (DHT). The sex hormones are responsible for and determine the secondary sex characteristics. They mediate their effects by acting as agonists (or activators) of receptors inside of cells. These receptors include the androgen receptor (AR), the estrogen receptors (ERs), and the progesterone receptors (PRs). Following their activation, these receptors modulate gene expression to influence cells and tissues.
Estrogens cause feminization. This includes breast development, softening of the skin, a feminine pattern of fat distribution (concentrated in the breasts, hips, thighs, and buttocks), widening of the hips (in those whose growth plates have not yet fused), and other changes (Wiki).
Progestogens have essentially no known role in feminization or pubertal breast development. Rather than acting as mediators of feminization, progestogens have important effects in the female reproductive system and are essential hormones during pregnancy (Wiki). They also oppose the actions of estrogens in certain parts of the body, such as the uterus, vagina, and breasts (Wiki).
Androgens cause masculinization. This includes growth of the penis, broadening of the shoulders, expansion of the rib cage, muscle growth, voice deepening, a masculine pattern of fat distribution (concentrated in the stomach and waist), and facial/body hair growth (Wiki). Androgens also cause a variety of generally undesirable skin and hair effects, including oily skin, acne, seborrhea, scalp hair loss, and body odor. They additionally oppose breast development mediated by estrogens.
In addition to their effects on the body, sex hormones have actions in the brain. These actions influence cognition, emotions, and behavior. For instance, androgens produce pronounced sexual desire and arousal (including spontaneous erections) in men, while estrogens appear to be the major hormones responsible for sexual desire in women (Cappelletti & Wallen, 2016). Sex hormones also have important effects on health, which can be both positive and negative. For instance, estrogens maintain bone strength and likely protect against heart disease in women (NAMS, 2022), but also increase the risk of breast cancer (Aly W., 2020) and can increase the risk of blood clots (Aly W., 2020).
Estrogens, progestogens, and androgens also have antigonadotropic effects. That is, they inhibit the gonadotropin-releasing hormone (GnRH)-induced secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the pituitary gland in the brain. The gonadotropins signal the gonads to make sex hormones and to supply the sperm and egg cells necessary for fertility. Hence, lower levels of the gonadotropins will result in reduced gonadal sex hormone production and diminished fertility. If gonadotropin levels are sufficiently suppressed, the gonads will no longer make sex hormones at all and fertility will cease. The vast majorities of the quantities of estradiol, testosterone, and progesterone in the body are produced by the gonads. Most of the small remaining amounts of these hormones are produced via the adrenal glands, which are located at the tops of the kidneys.
In cisgender females, the sex hormones are largely absent during childhood, gradually ramp up in production in late childhood and adolescence, are present in a cyclical manner during adulthood, and then largely stop being produced following the menopause. Hormone levels vary substantially but in a predictable manner during the normal menstrual cycle in adult premenopausal women. The menstrual cycle lasts about 28 days on average and consists of the following parts:
- Follicular phase—first half of the cycle or days 1–14
- Mid-cycle—middle of the cycle or days 12–16 or so
- Luteal phase—latter half of the cycle or days 14–28
Hormone levels during the menstrual cycle are shown in the following graph:
|Figure 1: Median estradiol and progesterone levels throughout the menstrual cycle in premenopausal cisgender women (Stricker et al., 2006; Abbott, 2009). The horizontal dashed lines are the average levels over the spanned periods. Other figures available elsewhere show variation between individuals (Graph; Graph; Graph).|
As can be seen in the graph, estradiol levels are relatively low and progesterone levels are very low during the follicular phase; estradiol but not progesterone levels briefly surge to very high levels and trigger ovulation during mid-cycle; and estradiol and progesterone levels both undergo a bump and are relatively high during the luteal phase (though estradiol is not as high as during the mid-cycle peak).
The table below shows the circulating levels and production rates of estradiol, progesterone, and testosterone in women and men and allows for comparison between them.
Table 1: Ranges for circulating levelsa and estimated production ratesb of the major sex hormones:
|Hormone||Group||Time||Levels (mass/vol)c||Levels (mol/vol)c||Production rates|
|Estradiol||Womend||Follicular phase||5–180 pg/mL||20–660 pmol/L||30–170 μg/daye|
|Mid-cycle||45–750 pg/mL||170–2,750 pmol/L||320–950 μg/daye|
|Luteal phase||20–300 pg/mL||73–1100 pmol/L||250–300 μg/daye|
|Men||–||8–35 pg/mL||30–130 pmol/L||10–60 μg/day|
|Progesterone||Womend||Follicular phase||≤0.3 ng/mL||≤1.0 nmol/L||0.75–5 mg/day|
|Mid-cycle||0.1–1.5 ng/mL||0.3–4.8 nmol/L||4 mg/day|
|Luteal phase||3.5–38 ng/mL||11–120 nmol/L||15–50 mg/dayf|
|Men||–||≤0.5 ng/mL||≤1.6 nmol/L||0.75–3 mg/day|
|Testosterone||Womend||Menstrual cycle||5–55 ng/dL||0.2–1.9 nmol/L||190–260 μg/day|
|Men||–||250–1100 ng/dL||8.7–38 nmol/L||5–7 mg/day|
a Sources for hormone levels: Zhang & Stanczyk, 2013; Nakamoto, 2016; Styne, 2016; LabCorp, 2020. b Sources for production rates: Aufrère & Benson, 1976; Powers et al., 1985; Lauritzen, 1988; Carr, 1993; O’Connell, 1995; Kuhl, 2003; Norman & Henry, 2015a; Norman & Henry, 2015b; Strauss & FitzGerald, 2019. c With liquid chromatography–mass spectrometry (LC–MS) (state-of-the-art blood tests). d During the menstrual cycle in the adult premenopause (age ~18–50 years). e Average production rate of estradiol over the whole menstrual cycle is roughly 200 μg/day or 6 mg/month (Rosenfield, Cooke, & Radovich, 2021). f Average production rate of progesterone during the luteal phase of the menstrual cycle is about 25 mg/day (Carr, 1993).
Mean integrated estradiol levels are around 100 pg/mL (367 pmol/L) in premenopausal women and around 25 pg/mL (92 pmol/L) in men. The 95% range for mean estradiol levels in women is around 50 to 250 pg/mL (180–918 pmol/L) (e.g., Abbott, 2009 (Graph); Verdonk et al., 2019 (Graph)). The average production of estradiol by the ovaries in premenopausal women is about 6 mg over the course of one menstrual cycle (i.e., one month) (Rosenfield et al., 2008). This corresponds to a mean rate of about 200 μg/day. Estradiol levels increase slowly during normal female puberty, when breast development and feminization take place. Mean estradiol levels during the different stages of female puberty are quite low—less than about 50 to 60 pg/mL (180–220 pmol/L) until late puberty (Aly W., 2020). In postmenopausal women, whose ovaries no longer produce considerable quantities of estrogens, estradiol levels are generally less than 10 to 20 pg/mL (37–73 pmol/L) (Nakamoto, 2016).
Mean testosterone levels are around 30 ng/dL (1.0 nmol/L) in women and 600 ng/dL (21 nmol/L) in men. Based on these values, testosterone levels are on average about 20-fold higher in men than in women. In men who have undergone gonadectomy (castration/gonadal removal), testosterone levels are similar to those in women (<50 ng/dL [1.7 nmol/L]) (Nishiyama, 2014; Itty & Getzenberg, 2020). The mean or median levels of testosterone in women with symptoms of androgen excess (e.g., excessive facial/body hair growth) due to polycystic ovary syndrome (PCOS) range from 41 to 75 ng/dL (150–275 pmol/L) per different studies (Balen et al., 1995; Steinberger et al., 1998; Legro et al., 2010; Loh et al., 2020). Hence, it appears that even testosterone levels that are marginally elevated relative to normal female levels may have the potential to produce undesirable androgenic effects.
The goal of hormone therapy for transfeminine people, otherwise known as feminizing hormone therapy (FHT) or (more in the past) as male-to-female (MtF) hormone replacement therapy (HRT), is to produce feminization and demasculinization of the body as well as alleviation of gender dysphoria. Medication therapy with sex hormones and other sex-hormonal medications is used to mediate these changes. Transfeminine people are given estrogens, progestogens, and antiandrogens (AAs) to supersede gonadal sex hormone production and shift the hormonal profile from male-typical to female-typical.
Transfeminine hormone therapy aims to achieve estradiol and testosterone levels within the normal female range. Commonly recommended ranges for transfeminine people in the literature are 100 to 200 pg/mL (367–734 pmol/L) for estradiol levels and less than 50 ng/dL (1.7 nmol/L) for testosterone levels (Table). However, higher estradiol levels of more than 200 pg/mL (734 pmol/L) can be useful in transfeminine hormone therapy to help suppress testosterone levels. Lower estradiol levels (≤50–60 pg/mL [≤180–220 pmol/L]) are recommended and more appropriate for pubertal and adolescent transfeminine individuals. Sex hormone levels in the blood can be measured with blood tests, in which blood is drawn from a vein using a needle and then analyzed in a laboratory. This is useful in transfeminine people to ensure that the hormonal profile has been satisfactorily altered in line with therapeutic goals—specifically that hormone levels are within female ranges.
At sufficiently high exposure, estrogens and androgens are able to completely suppress gonadal sex hormone production, while progestogens by themselves are able to partially but substantially suppress gonadal sex hormone production. More specifically, studies in cisgender men and transfeminine people have found that estradiol levels of around 200 pg/mL (734 pmol/L) generally suppress testosterone levels by about 90% (to ~50 ng/dL [1.7 nmol/L]), while estradiol levels of around 500 pg/mL (1,840 pmol/L) suppress testosterone levels by about 95% on average (to ~20–30 ng/dL [0.7–1.0 nmol/L]) (Wiki; Graphs). Estradiol levels of below 200 pg/mL (734 pmol/L) also suppress testosterone levels, although to a reduced extent compared to higher levels (Aly W., 2019; Aly W., 2019; Aly W., 2020).
|Figure 2: Estradiol and testosterone levels after a single injection of 320 mg polyestradiol phosphate (PEP) (a long-acting prodrug of estradiol) in men with prostate cancer (Stege et al., 1996). The maximal decrease in testosterone levels occurred with estradiol levels of greater than 200 pg/mL (734 pmol/L) and was about 90% (to roughly 50 ng/dL [1.7 nmol/L]). This figure demonstrates the ability of estradiol to concentration-dependently suppress gonadal testosterone production and circulating testosterone levels in people with testes.|
Progestogens on their own are able to maximally suppress testosterone levels by about 50 to 70% (to ~150–300 ng/dL [5.2–10.4 nmol/L] on average) (Aly W., 2019; Wiki). In combination with relatively small amounts of estrogen however, there is synergism in the antigonadotropic effect—the suppression of gonadal testosterone production with maximally effective doses of progestogens becomes complete, and testosterone levels are reduced by about 95% (to ~20–30 ng/dL [0.7–1.0 nmol/L]) (Aly W., 2019). Hence, the combination of an estrogen and a progestogen can be used to achieve maximal testosterone suppression at lower doses than would be necessary if an estrogen or progestogen were used alone.
The antigonadotropic effects of estrogens and progestogens are taken advantage of in transfeminine hormone therapy to suppress gonadal testosterone production and attain testosterone levels that are more consistent with those in cisgender women. It should be noted that the preceding numbers on testosterone suppression with estrogens and progestogens are averages and there is significant variation between individuals in terms of testosterone suppression. In other words, some may need more or less in terms of hormonal dosages to achieve the same decrease in testosterone levels.
During normal puberty in both males and females, sex hormone exposure increases slowly over a period of several years (Aly W., 2020). In relation to this, sexual maturation occurs gradually during normal puberty. In non-adolescent transgender people, adult or higher amounts of hormones are generally administered right away, and this can result in changes in secondary sex characteristics happening more quickly. The table below is reproduced from literature sources with slight modification and is commonly cited as a timeline for the effects of hormone therapy in transfeminine people (Table). It is based on a mixture of anecdotal clinical experience, expert opinion, and available clinical studies of hormone therapy in transfeminine people. Due to limited research characterizing the effects of transfeminine hormone therapy at present, the table may or may not be completely accurate.
Table 2: Effects of hormone therapy at typical doses in adult transfeminine people (Wiki):
|Breast development||2–6 months||2–3 years||Permanent|
|Reduced and slowed growth of facial and body hair||3–12 months||>3 yearsb||Reversible|
|Cessation and reversal of scalp hair loss||1–3 months||1–2 years||Reversible|
|Softening of skin and decreased skin oiliness and acne||3–6 months||Unknown||Reversible|
|Redistribution of body fat in a feminine pattern||3–6 months||2–5 years||Reversible|
|Decreased muscle mass and strength||3–6 months||1–2 yearsc||Reversible|
|Widening and rounding of the pelvisd||Unknown||Unknown||Permanent|
|Changes in mood, emotionality, and behavior||Immediate||Unknown||Reversible|
|Decreased sex drive and spontaneous erections||1–3 months||3–6 months||Reversible|
|Erectile dysfunction and decreased ejaculate volume||1–3 months||Variable||Reversible|
|Decreased sperm production and infertility||Unknown||>3 years||Mixede|
|Decreased testicular volume||3–6 months||2–3 years||Unknown|
|Voice changes (e.g., decreased pitch/resonance)||Nonef||N/A||N/A|
|Height changes (e.g., decrease)||Noneg||N/A||N/A|
a May vary significantly between individuals due to factors like genetics, diet/nutrition, hormone levels, etc. b Hormone therapy usually has little influence on facial hair density in transfeminine people. Complete removal of facial and body hair can be achieved with laser hair removal and electrolysis. Temporary hair removal can be achieved with shaving, epilating, waxing, and other methods. c May vary significantly depending on amount of physical exercise. d Occurs only in young individuals who have not yet completed growth plate closure (may not occur at all in post-adolescent people). e Only estrogens, particularly at high doses, seem to have the potential for long-lasting or irreversible infertility; impaired fertility caused by antiandrogens is usually readily reversible with discontinuation. f Voice training can be an effective means of feminizing the voice. g Sources: Gooren & Bunck (2004); Ingram & Thomas (2019); Hilton & Lundberg (2021).
The medications that are used in transfeminine hormone therapy include estrogens, progestogens, and antiandrogens. Estrogens produce feminization and testosterone suppression. Progestogens and antiandrogens do not mediate feminization themselves but further suppress and/or block testosterone. Testosterone suppression causes demasculinization and disinhibition of estrogen-mediated feminization. Androgens are sometimes used at low doses in transfeminine people who have low testosterone levels, although they are not required and benefits are uncertain. There are many different types of these hormonal medications available for transfeminine hormone therapy, with different benefits and risks.
Estrogens, progestogens, and antiandrogens are available in a variety of different formulations and for use by many different routes of administration in transfeminine people. The route of administration influences the absorption, distribution, metabolism, and elimination of the hormone in the body, resulting in significant differences between routes in terms of bioavailability, hormone levels in blood and specific tissues, and patterns of metabolites. These differences can have important therapeutic consequences.
Table 3: Major routes of administration of hormonal medications for transfeminine people:
|Oral administration||PO||Swallowed||Tablet, capsule|
|Sublingual administration||SL||Held and absorbed under tongue||Tablet|
|Buccal administration||BUC||Held and absorbed in cheek or under lips||Tablet|
|Transdermal administration||TD||Applied to and absorbed through the skin||Patch, gel, cream|
|Rectal administration||REC||Inserted into and absorbed by rectum||Suppository|
|Intramuscular injection||IM||Injected into muscle (e.g., buttocks, thigh, arm)||Solution (vial/amp.)|
|Subcutaneous injection||SC||Injected into fat under skin||Solution (vial/amp.)|
|Subcutaneous implant||SCi||Insertion via surgical incision into fat under skin||Pellet|
Vaginal administration is a major additional route of administration of hormonal medications in cisgender women. While vaginal administration via a natal vagina is of course not possible in transfeminine people, neovaginal administration is a possiblility in those who have undergone vaginoplasty. However, the lining of the neovagina is not the vaginal epithelium of natal females but instead is usually skin or colon—depending on the type of vaginoplasty performed (penile inversion or sigmoid colon vaginoplasty, respectively). For this reason, neovaginal administration in transfeminine people is likely more similar in its properties to transdermal and rectal administration—depending on the type of neovagina—than to vaginal administration in cisgender women. It is noteworthy that the vaginal and rectal routes are said to be similar in their properties for hormonal medications however (Goletiani, Keith, & Gorsky, 2007; Wiki). Moreover, absorption of estradiol via neovaginas constructed from peritoneum (internal abdominal lining)—a less commonly employed vaginoplasty approach in transfeminine people—was reported in one study to be similar to that with vaginal administration of estradiol in cisgender women (Willemsen et al., 1985). As such, neovaginal administration may be an additional possible route for certain transfeminine people depending on the circumstances. However, this route still remains to be more adequately characterized.
Estradiol, the primary bioidentical form normally found in the human body, is the main estrogen that is used in transfeminine hormone therapy. Estradiol hemihydrate (EH) is another form that is essentially identical to and interchangeable with estradiol. Estradiol esters are also sometimes used in place of estradiol. They are prodrugs of estradiol (i.e., are converted into estradiol in the body) and have identical biological activity to estradiol. However, they have longer durations when used by injection due to slower absorption from the injection site, and this allows them to be administered less often. Examples of estradiol esters include estradiol valerate (EV; Progynova, Progynon Depot, Delestrogen), estradiol cypionate (EC; Depo-Estradiol), estradiol enanthate (EEn), and estradiol benzoate (EB; Progynon-B). Polyestradiol phosphate (PEP; Estradurin) is an injectable estradiol prodrug in the form of a polymer (i.e., linked chain of estradiol molecules) which is metabolized slowly and has a very long duration.
Non-bioidentical estrogens such as ethinylestradiol (EE; found in birth control pills), conjugated estrogens (CEEs; Premarin; used in menopausal hormone therapy), and diethylstilbestrol (DES; widely used previously but now abandoned) are resistant to metabolism in the liver and have disproportionate effects on estrogen-modulated liver synthesis when compared to bioidentical estrogens like estradiol (Aly W., 2020). As a result, they have stronger influence on coagulation and greater risk of certain health problems like blood clots and associated cardiovascular issues (Aly W., 2020). For this reason, as well as the fact that relatively high doses of estrogens may be needed for testosterone suppression, non-bioidentical estrogens should ideally never be used in transfeminine hormone therapy.
Physiological levels of estradiol are usually not sufficient to suppress testosterone levels into the female range in gonadally intact transfeminine people. As a result, estradiol is generally used in combination with an antiandrogen or progestogen in transfeminine hormone therapy. This results in partial suppression of testosterone levels by estradiol and further suppression or blockade of the remaining testosterone by the antiandrogen or progestogen. The addition of an antiandrogen or progestogen to estradiol therapy however also adds the side effects, risks, and costs of these medications. An alternative to the combination of estradiol with an antiandrogen or progestogen which may be used in transfeminine people is high-dose estradiol monotherapy. This is an approach in which estradiol is used alone at supraphysiological doses. These high doses can allow for greater testosterone suppression and reduction of testosterone levels into the female range with estradiol alone.
The feminizing effects of estradiol appear to be maximal at low levels in the absence of androgens. Higher doses of estradiol, aside from allowing for greater testosterone suppression, are not known to result in better feminization in transfeminine people (e.g., Nolan & Cheung, 2021). In fact, there is indication that higher estrogen doses early into hormone therapy could actually result in worse breast development, a topic that will be covered in-depth in a future article on this site. Hence, the therapeutic emphasis in transfeminine hormone therapy is more on testosterone suppression than on achieving a certain estradiol level. Higher doses of estrogens, including estradiol, also have a greater risk of adverse health effects such as blood clots and cardiovascular problems (Aly W., 2020). As such, the use of physiological doses of estradiol is optimal. At the same time however, high estrogen doses can be useful for testosterone suppression. Moreover, the absolute risks in the case of non-oral bioidentical estradiol are low and are more important in people with specific risk factors. Examples of such risk factors include older age, physical inactivity, obesity, concomitant progestogen use, smoking, surgery, and rare thrombophilic abnormalities. In healthy young people without relevant risk factors, limitedly supraphysiological doses of non-oral estradiol may be more acceptably safe (Aly W., 2020).
Estradiol and estradiol esters are usually used orally, sublingually, transdermally, by injection (intramuscularly or subcutaneously), or by implant in transfeminine hormone therapy (Wiki).
Estradiol is used orally in the form of tablets of estradiol (Wiki; Graphs). Alternatively, oral estradiol valerate tablets are used in some countries, for instance in many European countries. The only real differences between these oral estradiol forms is that estradiol valerate contains slightly less estradiol by weight (~76%) due to its ester component and hence requires somewhat higher doses (~1.3-fold) in comparison for equivalent estradiol levels (Wiki; Table). Oral estradiol has a duration suitable for once-daily administration. Oral administration of estradiol is a very convenient and inexpensive route, which makes it the most popular and widely used form of estradiol in transfeminine people. Oral estradiol has relatively low bioavailability (~5%), and there is substantial variability between people in terms of estradiol levels achieved with the same dose. Hence, in some transfeminine people estradiol levels may be low with oral estradiol, and testosterone suppression may be inadequate depending on the antiandrogen.
A major drawback of oral estradiol is that it results in excessive levels of estradiol in the liver due to the first pass that occurs with oral administration and has a disproportionate impact on estrogen-modulated liver synthesis (Aly W., 2020). This in turn increases coagulation and the risk of associated health issues like blood clots and cardiovascular problems (Aly W., 2020). These particular health concerns are largely allayed if estradiol is taken non-orally at reasonable doses. Hence non-oral forms of estradiol, like transdermal estradiol, although less convenient and often more expensive than oral estradiol, are preferrable in transfeminine hormone therapy. It has been recommended that all transfeminine people who are over 40 years of age use non-oral routes due to the greater risk of blood clots and cardiovascular problems that occurs with age (Aly W., 2020). Oral estradiol is not a good choice for high-dose estradiol monotherapy in transfeminine people due to the high estradiol levels required and the greater risks than with non-oral routes. In addition to its disproportionate liver impact, oral estradiol results in unphysiological levels of estradiol metabolites like estrone and estrone sulfate when compared to non-oral forms. The clinical implications of this, if any, are unknown. Oral and non-oral estradiol have in any case been found to have similar efficacy in terms of feminization and breast development in transfeminine people in available studies (Sam S., 2020; Aly W., 2019).
Oral estradiol tablets can be taken sublingually instead of orally. Sublingual use of estradiol tablets has several-fold higher bioavailability relative to oral administration and hence achieves much higher overall estradiol levels in comparison (Sam S., 2021; Wiki; Graphs). Sublingual use of oral estradiol tablets can be employed instead of oral administration to reduce doses and hence medication costs or to produce higher estradiol levels for the purpose of achieving better testosterone suppression when needed. However, sublingual estradiol is very spiky in terms of estradiol levels when compared to oral estradiol and has a short duration of highly elevated estradiol levels. As such, it may be advisable for sublingual estradiol to be used in divided doses multiple times throughout the day in order to maintain at least somewhat steadier estradiol levels. The therapeutic implications for transfeminine people of the spikiness of sublingual estradiol, for instance in terms of testosterone suppression and health risks, have been little-studied and are mostly unknown. Oral estradiol valerate tablets can be taken sublingually instead of orally similarly to estradiol and are likewise highly effective when used in this way (Aly W., 2019; Wiki). Due to partial swallowing of tablets, sublingual estradiol may in practice be a mixture of sublingual and oral administration and may have some of the same health risks of oral estradiol (Wiki). Buccal administration of estradiol appears to have similar properties as sublingual administration but is much less researched in comparison and is not used as often in transfeminine people (Wiki).
Transdermal estradiol is available in the form of patches, gel, emulsions, and sprays (Wiki). These forms are usually applied to skin areas such as the arms, abdomen, or buttocks. Gel, emulsions, and sprays are applied and left to dry for a short period, whereas patches are applied and remain adhesed to the skin for a specified amount of time. Due to rate-limited absorption through the skin, there is a depot effect with transdermal estradiol and this route has a long duration with very steady estradiol levels. As a result, estradiol gel, emulsions, and sprays are all suitable for once-daily use. Patches stay applied and continuously deliver estradiol for either 3–4 days or 7 days depending on the patch brand (Table). Transdermal estradiol is more expensive than oral estradiol. Gel, emulsions, and sprays may be less convenient than oral administration, but patches can be more convenient due to their infrequent application. However, patches can sometimes cause application site problems like redness and irritation and can occasionally come off prematurely due to adhesive failure. As with oral estradiol, there is substantial variability in estradiol levels with transdermal estradiol, and some transfeminine people may have poor absorption, low estradiol levels, and inadequate testosterone suppression with this route. Estradiol sprays, such as Lenzetto, have been found to achieve very low estradiol levels that are probably not therapeutically adequate for use in transfeminine hormone therapy (Aly W., 2020; Graph).
Transdermal estradiol is the form of estradiol most commonly used in transfeminine people who are over 40 years of age due to its lower health risks relative to oral estradiol. Transdermal estradiol gel is not a favorable option for high-dose estradiol monotherapy as it has difficulty achieving the high estradiol levels needed for adequate testosterone suppression (Aly W., 2019). On the other hand, transdermal estradiol patches can be an effective option for high-dose estradiol monotherapy if multiple 100 μg/day patches are used (Wiki). Different skin sites absorb transdermal estradiol to different extents (Wiki). Genital application of transdermal estradiol, specifically to the scrotum or neolabia, is particularly better-absorbed than conventional skin sites and can result in much higher estradiol levels than usual (Aly W., 2019). This can be useful for reducing doses and hence medication costs or for achieving higher estradiol levels for better testosterone suppression when needed. Transdermal estradiol should not be applied to the breasts as this is not known to result in improved breast development and the potential health consequences of doing so are unknown (e.g., influence on breast cancer risk).
Injectable estradiol preparations can be administered via either intramuscular or subcutaneous injection (Wiki; Wiki; Graphs). There is a depot effect with injectable estradiol esters such that they are slowly absorbed from the injection site and have a prolonged duration. This ranges from days to months depending on the ester in question. Commonly used injectable estradiol esters, which all have short to moderate durations, include estradiol valerate, estradiol cypionate, estradiol enanthate, and estradiol benzoate. Longer-acting injectable estradiol esters, such as estradiol undecylate (EU) and polyestradiol phosphate, have been discontinued and are no longer available. In the case of intramuscular injection, common injection sites include the deltoid muscle (upper arm), vastus lateralis and rectus femoris muscles (thigh), and ventrogluteal muscle (buttocks). Subcutaneous injection of estradiol preparations, while less commonly used, has comparable pharmacokinetics to intramuscular injection and is easier, less painful, and more convenient in comparison (Wiki). However, the maximum volume that can be safely and comfortably injected subcutaneously is less than that which can be injected intramuscularly (depending on the site up to 1.5–3 mL and up to 2–5 mL, respectively) (Hopkins, & Arias, 2013; Usach et al., 2019). Injectable estradiol preparations tend to be fairly inexpensive, but may be less convenient than other routes due to the need for regular injections. However, they have been discontinued in many parts of the world (e.g., most of Europe), and their availability is limited. In recent years, many transfeminine people have turned to black market homebrewed injectable estradiol preparations.
Injectable estradiol preparations are typically used at higher doses than other forms of estradiol, and can easily achieve very high levels of estradiol. This can be useful for testosterone suppression, making this form of estradiol arguably the best choice for high-dose estradiol monotherapy in transfeminine people. However, the high doses that are possible with injectable estradiol preparations can also easily lead to overdosage and unnecessarily increased health risks (e.g., Aly W., 2020). Resources are available for guiding selection of appropriate doses and intervals of injectable estradiol esters in transfeminine hormone therapy (Aly W., 2021; Aly W., 2021; Aly W., 2020). It is notable that currently recommended doses and intervals for injectable estradiol esters by transgender care guidelines appear to be highly excessive and too widely spaced, and are likely to be therapeutically inadvisable (Aly W., 2021).
Estradiol implants are pellets of pure crystalline hormone and are surgically placed into subcutaneous fat by a physician (Wiki). They are slowly absorbed by the body following implantation, and new implants are given once every 4 to 6 months. Due to the need for minor surgery, their high cost, and limited availability, estradiol implants are not as commonly used as other estradiol routes. Notably, almost all pharmaceutical estradiol implants throughout the world have been discontinued, and the implants that remain available are almost exclusively compounded products provided by compounding pharmacies. Dosage adjustment with estradiol implants is also more difficult than with other estradiol routes. Despite their various practical limitations however, estradiol implants allow for very steady estradiol levels, and their very long duration can allow for unusual convenience among available estradiol forms.
Table 4: Available forms and recommended doses of estradiol for adulta transfeminine people:
|Sublingual or buccal||Tablets||0.5–6 mg/dayb|
|SC implant||Pellet||25–150 mg/6 months|
|Estradiol valerate||Oral||Tablets||3–10 mg/dayd|
|Sublingual or buccal||Tablets||1–8 mg/dayb,d|
|IM or SC injection||Oil solution||0.75–4 mg/5 days; or|
1–6 mg/7 days; or
1.5–9 mg/10 days
|Estradiol cypionate||IM or SC injection||Oil solution||1–6 mg/7 days; or|
1.5–9 mg/10 days; or
2–12 mg/14 days
|Estradiol enanthate||IM or SC injection||Oil solution||1–6 mg/7 days; or|
1.5–9 mg/10 days; or
2–12 mg/14 days
|Estradiol benzoate||IM or SC injection||Oil solution||0.15–0.75 mg/day; or|
0.3–1.5 mg/2 days; or
0.45–2.25 mg/3 days
|Polyestradiol phosphate||IM injection||Water solution||40–160 mg/monthe|
a Estradiol doses in pubertal adolescent transfeminine people should be lower to mimic estradiol exposure during normal female puberty (Aly W., 2020). b May be advisable to use divided doses 2 to 4 times per day (i.e., once every 6 to 12 hours) instead of once per day (Sam S., 2021). c This estradiol form achieves very low estradiol levels at typical doses that don’t appear to be well-suited for transfeminine hormone therapy (Aly W., 2020; Graph). d Estradiol valerate contains about 75% of the same amount of estradiol as estradiol so doses are about 1.3-fold higher for the same estradiol levels (Aly W., 2019; Sam S., 2021). e A higher initial loading dose of e.g., 240 or 320 mg can be used for the first one or two injections to reach steady-state estradiol levels more quickly. However, this preparation has recently been discontinued and appears to no longer be available.
There is high variability between individuals in the levels of estradiol achieved during estradiol therapy. That is, estradiol levels during treatment with the same dosage of estradiol can differ substantially between individuals. This variability is greatest with oral and transdermal estradiol but is also considerable even with injectable estradiol preparations and other estradiol forms. As such, estradiol doses are not absolute and should be individualized on a case-by-case basis in conjunction with blood work as a guide. It should also be noted that due to fluctuations in estradiol concentrations with certain routes, levels of estradiol can vary considerably from one blood test to another. This is most notable with sublingual estradiol and injectable estradiol. The fluctuations in estradiol levels with these routes are predictable and must be understood when interpreting blood work results. Differences in blood test results can be minimized with informed and consistent timing of blood draws.
If or when the gonads are surgically removed, testosterone suppression is no longer needed in transfeminine people. As a result, estradiol doses, if they are high or supraphysiological, can be lowered to more closely approximate normal physiological levels in cisgender women.
Progestogens include progesterone and progestins. Progestins are synthetic progestogens derived from structural modification of progesterone or testosterone. There are dozens of different progestins and these progestins can be divided into a variety of different structural classes with varying properties (Table). Examples of some major progestins of different classes include medroxyprogesterone acetate (MPA; Provera, Depo-Provera), norethisterone (NET; many brand names), dydrogesterone (Duphaston), and drospirenone (Slynd, Yasmin) (Aly W., 2019). Progestins were developed because they have a more favorable disposition in the body than progesterone for use as medications. Only a few clinically used progestins have been used in transfeminine hormone therapy, although progestogens largely have the same progestogenic actions and theoretically any progestogen could be employed.
Most clinically used progestogens have off-target activities in addition to their progestogenic activity, and these activities may be desirable or undesirable depending on the action in question (Kuhl, 2005; Stanczyk et al., 2013; Wiki; Table). Progesterone has a variety of neurosteroid as well as other activities that can result in central nervous system effects among others which are not shared by progestins. MPA as well as NET and its derivatives have weak androgenic activity, which is unfavorable in the context of transfeminine hormone therapy. NET and certain related progestins produce EE as a metabolite at high doses and hence can produce EE-like estrogenic effects, including increased risk of blood clots and associated cardiovascular problems. Other off-target actions of progestogens include antiandrogenic, glucocorticoid, and antimineralocorticoid activities. These actions can result in differences in therapeutic effectiveness (e.g., androgen suppression or blockade) as well as side effects and health risks.
The addition of progestogens to estrogen therapy has been associated with a number of unfavorable health effects. These include increased risk of blood clots (Wiki; Aly W., 2020), coronary heart disease (Wiki), and breast cancer (Wiki; Aly W., 2020). High doses of progestogens are also associated with increased risk of certain non-cancerous brain tumors including meningiomas and prolactinomas (Wiki; Aly W., 2020). The coronary heart disease risk may be due to changes in blood lipids caused by the weak androgenic activity of specific progestogens, but the rest of the aforementioned risks are probably due to their progestogenic activity (Stanczyk et al., 2013; Jiang & Tian, 2017). Aside from health risks, progestogens have also been associated with adverse mood changes (Wiki; Wiki). However, these effects are controversial and are not well-supported by evidence (Wiki; Wiki). Progestogens are otherwise generally well-tolerated and produce little in the way of side effects.
In contrast to certain progestins, progesterone has no unfavorable off-target activities. Due to its lack of androgenic activity, progesterone has no adverse influence on blood lipids and is not thought to increase the risk of coronary heart disease. The addition of oral progesterone to estrogen therapy notably has not been associated with increased risk of blood clots (Wiki). In addition, oral progesterone seems to have less risk of breast cancer than progestins with short-term therapy, although this is notably not the case with longer-term exposure (Wiki; Aly W., 2020). Consequently, it has been suggested that progesterone, for reasons that have yet to be fully elucidated, may be a safer progestogen than progestins and that it should be the preferred progestogen for hormone therapy in cisgender women and transfeminine people. However, there are also theoretical arguments against such notions. Oral progesterone is known to produce very low progesterone levels and have only weak progestogenic effects overall at typical doses (Aly W., 2018; Wiki). The seemingly better safety of oral progesterone may simply be an artifact of the low progesterone levels that occur with it and hence of progestogenic dosage. Non-oral progesterone at doses resulting in physiological and full progestogenic strength has never been properly evaluated in terms of health outcomes and may have equivalent risks to progestins (Aly W., 2018; Wiki).
Besides helping with testosterone suppression, progestogens are of no clear or known benefit for feminization or breast development in transfeminine people. While some transfeminine people anecdotally claim to experience improved breast development with progestogens, an involvement of these agents in breast size or shape is controversial and not supported by theory or evidence at present (Wiki; Aly W., 2020; Aly W., 2020). It’s possible that premature introduction of progestogens could actually have an unfavorable influence on breast development (Aly W., 2019). Many transfeminine people have also anecdotally claimed that progestogens have a beneficial effect on their sexual desire. However, a review of the literature showed that neither progesterone nor progestins positively influence sexual desire (Aly W., 2020). Instead, the available evidence indicates the opposite—an inhibitory influence of progestogens on sexual desire—although this may be specific to high doses (Aly W., 2020).
Due to their lack of influence on feminization and breast development and their adverse effects and health risks, progestogens are not routinely used in transfeminine hormone therapy at present. There is however a major exception to this in the form of cyproterone acetate (CPA; Androcur), an antiandrogen which is widely used in transfeminine hormone therapy and which happens to be a powerful progestogen at typical therapeutic doses. CPA will be described in the section below on antiandrogens. Although progestogens have various health risks, cisgender women of course have progesterone and the absolute risks of progestogens are very low in healthy young people. Risks like breast cancer also take many years to develop. Moreover, the testosterone suppression provided by progestogens can be very useful in transfeminine people. A limited duration of progestogen therapy, for instance a few years to help suppress testosterone levels before gonadectomy, may be quite acceptable in transfeminine people.
Progesterone can be used in transfeminine people by the oral route, by the rectal route, or by intramuscular or subcutaneous injection (Wiki). Progestins are usually used by the oral route but certain progestins are also available in injectable formulations.
Levels of progesterone with the oral route have been found using state-of-the-art assays (LC–MS) to be very low (<2 ng/mL [<6.4 nmol/L] at 100 mg/day) and inadequate for satisfactory progestogenic effects (Wiki; Aly W., 2018). In accordance, even high doses of oral progesterone showed no antigonadotropic effect in cisgender men (Wiki). This is in major contrast to non-oral progesterone and to progestins. Additionally, oral progesterone is excessively converted into potent neurosteroid metabolites like allopregnanolone and pregnanolone, and this can result in undesirable alcohol-like side effects such as sedation, cognitive/memory impairment, and mood changes (Wiki; Wiki). As such, while inconvenient, non-oral routes are preferable in the case of progesterone similarly to estradiol. Conversely, progestins have high oral bioavailability and are resistant to metabolism in the liver. In addition, in contrast to the estrogen receptors, the progesterone receptors are expressed minimally or not at all in the liver, and there is no known first pass influence of progestogenic activity on liver synthesis (Lax, 1987). For these reasons, there are no apparent problems with the oral route in the case of progestins.
Sublingual progesterone tablets exist but are only available in a couple of Eastern European countries (Wiki). In contrast to estradiol, oral progesterone is formulated as oil-filled capsules. This makes them difficult and unpleasant to use by the sublingual route.
Progesterone can be used rectally in the form of suppositories. Oral progesterone capsules can be taken rectally and this can allow for much higher progesterone levels than would be achieved orally (Aly W., 2018). While certainly inconvenient, rectal use is probably the best route of administration for progesterone for transfeminine people.
Progesterone by injection is available in both intramuscular and subcutaneous forms. However, injectable progesterone has a relatively short duration and must be given once every one to three days. This makes it too inconvenient to use for most people. Unlike with estradiol, progesterone esters with longer durations than progesterone itself by injection are not chemically possible. Injectable progestins, on the other hand, have durations ranging from weeks to months.
Table 5: Available forms and recommended doses of progestogens for transfeminine people:
|Progesterone||Oral||Oil-filled capsules||100–300 mg 1–2x/day|
|Rectal||Suppositories; Oil-filled capsules||100–200 mg 1–2x/day|
|IM injection||Oil solution||25–75 mg/1–3 days|
|SC injection||Water solution||25 mg/day|
|Progestins||Oral; IM or SC injection||Tablets; Oil solution; Water solution||Various|
As with estradiol, there is high variability between individuals in progesterone levels. Conversely, there is relatively little variability between individuals in the case of progestins.
After removal of the gonads, progestogen doses can be lowered or adjusted to approximate normal female physiological exposure or they can be discontinued entirely.
Aside from estrogens and progestogens, there is another class of hormonal medications used in transfeminine hormone therapy known as antiandrogens (AAs). These medications nullify the effects of androgens in the body by either decreasing androgen production and lowering androgen levels or by directly blocking the actions of androgens. They work via a variety of different mechanisms of action, and include androgen receptor antagonists, antigonadotropins, and androgen synthesis inhibitors.
Androgen receptor antagonists act by directly blocking the effects of androgens, including testosterone, DHT, and other androgens, at the level of their biological target. They bind to the androgen receptor without activating it, thereby displacing androgens from the receptor. Due to the nature of their mechanism of action as competitive blockers of androgens, the antiandrogenic efficacy of androgen receptor antagonists is both highly dose-dependent and fundamentally dependent on testosterone levels. They do not act by lowering testosterone levels, although some androgen receptor antagonists may have additional antiandrogenic actions that result in decreased testosterone levels. Because androgen receptor antagonists do not work by lowering testosterone levels, blood work can be less informative for them compared to antiandrogens that suppress testosterone levels. Androgen receptor antagonists include steroidal antiandrogens (SAAs) like spironolactone (Aldactone) and cyproterone acetate (CPA; Androcur) and nonsteroidal antiandrogens (NSAAs) like bicalutamide (Casodex).
Antigonadotropins suppress the gonadal production of androgens by inhibiting the GnRH-mediated secretion of gonadotropins from the pituitary gland. They include estrogens and progestogens. In addition, GnRH agonists such as leuprorelin (Lupron) and GnRH antagonists such as elagolix (Orilissa) act similarly and could likewise be described as antigonadotropins.
Androgen synthesis inhibitors inhibit the enzyme-mediated synthesis of androgens. They include 5α-reductase inhibitors (5α-RIs) like finasteride (Propecia) and dutasteride (Avodart). There are also other types of androgen synthesis inhibitors, for instance potent 17α-hydroxylase/17,20-lyase inhibitors like ketoconazole (Nizoral) and abiraterone acetate (Zytiga). However, these agents have limitations (e.g., toxicity, high cost, and lack of experience) and have not been used in transfeminine hormone therapy.
Although antigonadotropins and androgen synthesis inhibitors have antiandrogenic effects secondary to decreased androgen levels, they are not usually referred to as “antiandrogens”. Instead, this term is most commonly reserved to refer specifically to androgen receptor antagonists. However, antigonadotropins and androgen synthesis inhibitors may nonetheless be described as antiandrogens as well.
After removal of the gonads, antiandrogens can be discontinued. If unwanted androgen-dependent symptoms, such as acne, seborrhea, or scalp hair loss, persist despite full suppression or ablation of gonadal testosterone, then a lower dose of an androgen receptor antagonist, such as 100 to 200 mg/day spironolactone or 12.5 to 25 mg/day bicalutamide, can be continued to treat these symptoms.
Table 6: Available forms and recommended doses of antiandrogens for transfeminine people:
|Spironolactone||Androgen receptor antagonist; Weak androgen synthesis inhibitor||Oral||Tablets||100–400 mg/daya,b|
|Bicalutamide||Androgen receptor antagonist||Oral||Tablets||12.5–50 mg/daya|
|Cyproterone acetate||Progestogen; Androgen receptor antagonist||Oral||Tablets||2.5–12.5 mg/dayc|
a For spironolactone and bicalutamide, it is assumed that testosterone levels are substantially suppressed (≤200 ng/dL [<6.9 nmol/L]). If not testosterone levels are not suppressed to this range, then higher doses may be warranted. b Spironolactone and its metabolites have relatively short half-lives, and twice-daily administration in divided doses (e.g., 100–200 mg twice per day) is recommended. c For CPA, this dose range is specifically one-quarter of a 10-mg tablet to one full 10-mg tablet per day (2.5–10 mg/day) or a quarter of a 50-mg tablet every other day or every 2 to 3 days (4.2–12.5 mg/day). A dosage of 5–10 mg/day or 6.25–12.5 mg/day is likely to ensure maximal testosterone suppression, while lower doses may be less effective (Aly W., 2019).
|Figure 3: Suppression of gonadal testosterone production and circulating testosterone levels (ng/dL) with estradiol in combination with different antiandrogens over one year of hormone therapy in transfeminine people (Sofer et al., 2020 [PDF]). The estradiol forms included oral tablets 2–8 mg/day, transdermal gel 2.5–5 mg/day, and transdermal patches 50–200 μg/day. The antiandrogens included spironolactone 50–200 mg/day (n=16), cyproterone acetate (n=41), and GnRH agonists (specifically triptorelin 3.75 mg/month or goserelin 3.6 mg/month by injection) (n=10) (Sofer et al., 2020). It should be noted that lower doses of cyproterone acetate (10–12.5 mg/day) show equal testosterone suppression to higher doses (25–100 mg/day) and higher doses should no longer be used (Aly W., 2019). The dashed horizontal line corresponds to the upper limit of the normal female range for testosterone levels.|
Cyproterone acetate (CPA; Androcur) is a progestogen that at much higher doses also acts as an androgen receptor antagonist (Aly W., 2019). It has been used at relatively high doses in transfeminine people to take advantage of its androgen receptor antagonism (Aly W., 2019). As a result of the strong progestogenic exposure that occurs with typical doses of CPA, the medication substantially suppresses testosterone levels in addition to its androgen receptor antagonism (Aly W., 2019). Relatively low doses of CPA (e.g., 5–10 mg/day) are able to maximally suppress testosterone levels in combination with even low doses of an estrogen (Aly W., 2019). Due to a variety of dose-dependent risks with CPA, doses of the medication have come down substantially in recent years. Lower doses of CPA are likely to be purely progestogenic and have minimal or no significant androgen receptor antagonism. However, the androgen receptor antagonism of higher doses is unnecessary since the combination of CPA with estradiol results in suppression of testosterone levels well into the female range.
CPA has been reported to produce fatigue and slight weight gain as side effects (Belisle & Love, 1986; Hammerstein, 1990). It may result in sexual dysfunction (Wiki; Aly W., 2019) and have a small risk of depressive mood changes (Wiki; Aly W., 2019). CPA produces pregnancy-like breast changes (Kanhai et al., 2000) and sometimes causes lactation as a side effect in transfeminine people (Gooren, Harmsen-Louman, & van Kessel, 1985; Schlatterer et al., 1998; Bazarra-Castro, 2009). As with other progestogens, the addition of low doses of CPA to estrogen therapy is associated with increased risk of blood clots and breast cancer (Wiki; Wiki; Aly W., 2020). Higher doses of CPA appear to have a greater risk of blood clots than low doses (Wiki). CPA is also associated with high prolactin levels (Wiki) and with certain generally non-cancerous brain tumors including prolactinomas and meningiomas (Wiki; Aly W., 2020). High doses of CPA are associated with abnormal liver changes and have resulted in rare cases of liver toxicity (Wiki). This probably isn’t an issue at doses of less than 20 mg/day however (Wiki). Monitoring of prolactin levels to detect prolactinomas and monitoring of liver function to detect liver toxicity is advisable during CPA therapy. The side effects and risks of CPA may be minimized by using the lowest effective dosage, which is much lower than what has conventionally been used (Aly W., 2019).
CPA is notably not approved for use in the United States, but is available in most other countries. It is taken orally in the form of tablets (e.g., 10, 50, and 100 mg) (Wiki).
Spironolactone (Aldactone) is an antiandrogen and antimineralocorticoid. It is widely used as an antiandrogen in cisgender women for treatment of androgen-dependent hair and skin conditions like acne, hirsutism (excessive facial/body hair growth), and scalp hair loss, in cisgender women for treatment of hyperandrogenism (high androgen levels) due to polycystic ovary syndrome (PCOS), and in transfeminine people as a component of hormone therapy. Spironolactone is particularly widely used in transfeminine people in the United States, where it is the most commonly used antiandrogen in this population. As an antimineralocorticoid, the original and primary use of spironolactone in medicine, it is used to treat heart failure, high blood pressure, high mineralocorticoid levels, low potassium levels, and edematous conditions like nephrotic syndrome and ascites, among others (Wiki). In terms of its antiandrogenic actions, spironolactone is a relatively weak androgen receptor antagonist as well as a weak androgen synthesis inhibitor (Wiki). The androgen synthesis inhibition of spironolactone is mediated specifically via inhibition of 17α-hydroxylase and 17,20-lyase (Wiki). Spironolactone does not appear to have meaningful progestogenic activity, 5α-reductase inhibition, or direct estrogenic activity. However, indirect estrogenic effects secondary to its antiandrogenic activity (e.g., breast development and feminization) can occur with it at sufficiently high doses.
Spironolactone shows limited and highly inconsistent effects on testosterone levels in clinical studies in cisgender men, cisgender women, and transfeminine people, with most studies finding no change, some studies finding a decrease, and a small number even finding an increase (Aly W., 2018; Aly W., 2020). Hence, the primary mechanism of action of spironolactone as an antiandrogen appears to be androgen receptor blockade. In transfeminine people taking spironolactone as an antiandrogen, the estrogen component of the regimen is likely the main or possibly sole agent suppressing testosterone production. This is in part based on studies in transfeminine people comparing estradiol plus spironolactone to estradiol alone (e.g., Leinung, 2014; Leinung, Feustel, & Joseph, 2018; Angus et al., 2019) and studies comparing testosterone levels with different doses of spironolactone (e.g., Liang et al., 2018; SoRelle et al., 2019). In relation to the preceding, testosterone levels are not usually suppressed into the female range in transfeminine people taking estradiol plus spironolactone, with levels often remaining well above this range (Leinung, 2014; Leinung, Feustel, & Joseph, 2018; Liang et al., 2018; Angus et al., 2019; Jain, Kwan, & Forcier, 2019; SoRelle et al., 2019; Sofer et al., 2020; Burinkul et al., 2021).
Moreover, due to its relatively weak androgen receptor antagonism, spironolactone is likely best-suited for blocking female-range or somewhat-higher testosterone levels (e.g., <100 ng/dL [<3.5 nmol/L]) (Aly W., 2018). This is based on clinical dose-ranging studies of spironolactone (typically using 50–200 mg/day) in healthy cisgender women and cisgender women with PCOS (Goodfellow et al., 1984; Lobo et al., 1985; Hammerstein, 1990; James, Jamerson, & Aguh, 2022) as well as comparative studies of spironolactone against the more-potent antiandrogen flutamide (Cusan et al., 1994; Erenus et al., 1994; Shaw, 1996). The clinical antiandrogenic efficacy of spironolactone has been very limitedly assessed in transfeminine people to date, and is largely unknown (Angus et al., 2021). In any case, the antiandrogenic efficacy of spironolactone in cisgender women with androgen-dependent hair and skin conditions is well-established, and the medication thus does appear to be effective so long as testosterone levels are not too high (Brown et al., 2009; van Zuuren & Fedorowicz, 2016; Layton et al., 2017; Barrionuevo et al., 2018; James, Jamerson, & Aguh, 2022). In addition, higher doses of spironolactone (e.g., 300–400 mg/day) may be more useful for blocking higher testosterone levels in transfeminine people and are allowed for by several transgender care guidelines.
However, estradiol plus spironolactone regimens will likely not be fully effective in terms of testosterone suppression for many transfeminine people, and this is liable to result in suboptimal demasculinization, feminization, and breast development. Other antiandrogenic approaches, such as bicalutamide, CPA, GnRH modulators, and high-dose estradiol monotherapy, will likely be more effective in these cases owing to their ability to more potently block androgens or their capacity to reliably reduce testosterone levels into the female range. If testosterone levels are still too high with estradiol plus spironolactone, a switch to a different antiandrogen, increasing to a higher dosage of estradiol, or addition of a clinically antigonadotropic progestogen (e.g., non-oral progesterone) should be considered.
Spironolactone is a strong antimineralocorticoid, or antagonist of the mineralocorticoid receptor, the biological target of the mineralocorticoid steroid hormones aldosterone and 11-deoxycorticosterone. This is an action that spironolactone shares with progesterone, although spironolactone is a much more potent antimineralocorticoid than progesterone. The mineralocorticoid receptor is involved in regulating electrolyte and fluid balances. Although spironolactone is usually well-tolerated, it can sometimes produce antimineralocorticoid side effects such as lowered blood pressure, dizziness, fatigue, urinary frequency, and increased cortisol levels, among others (Kellner & Wiedemann, 2008; Kim & Del Rosso, 2012; Zaenglein et al., 2016; Layton et al., 2017; James, Jamerson, & Aguh, 2022). It has been argued by some in the online transgender community that spironolactone, via its antimineralocorticoid activity and increased cortisol levels, may increase visceral fat deposition in transfeminine people, but evidence does not support this hypothetical side effect at present (Aly W., TBD). Available data also do not support spironolactone stunting breast development in transfeminine people (Aly W., 2019) or having serious neuropsychiatric side effects such as depressive mood changes (Aly W., 2019).
The most important risk of spironolactone, which is consequent to its antimineralocorticoid activity, is hyperkalemia (high potassium levels) (Wiki). This complication is rare and is mostly limited to those who have specific risk factors for it, but is serious and can result in hospitalization or death. Monitoring of blood potassium levels during spironolactone therapy is advisable in those with risk factors for hyperkalemia, but does not appear to be necessary in people without such risk factors (Plovanich, Weng, & Mostaghimi, 2015; Zaenglein et al., 2016; Layton et al., 2017; Millington, Liu, & Chan, 2019; Wang & Lipner, 2020; Gupta et al., 2022; Hayes et al., 2022). Risk factors for hyperkalemia include older age (>45 years), reduced kidney function, concomitant use of other potassium-elevating drugs, and intake of potassium supplements or potassium-containing salt substitutes. Other notable potassium-elevating drugs include other potassium-sparing diuretics (e.g., amiloride (Midamor), triamterene (Dyrenium), other antimineralocorticoids), ACE inhibitors, angiotensin II receptor blockers, and the antibiotic trimethoprim (Bactrim), among others (Kim & Rosso, 2012; Salem et al., 2014). As an example drug interaction, serious hyperkalemia and sudden death can occur in elderly people (>65 years of age) concomitantly taking spironolactone and trimethoprim (Antoniou et al., 2011; Antoniou et al., 2015).
In people who are at-risk for hyperkalemia, dietary restriction to limit intake of potassium-rich foods is often recommended (Roscioni et al., 2012; Cupisti et al., 2018). This is often encountered in transgender health as transfeminine people being told “not to eat bananas”, which are said to be high in potassium. However, limiting dietary potassium with spironolactone to avoid hyperkalemia is theoretical and not actually evidence-based, with data so far contradicting its efficacy (St-Jules, Goldfarb, & Sevick, 2016; St-Jules & Fouque, 2021; Babich, Kalantar-Zadeh, & Joshi, 2022; St-Jules & Fouque, 2022). As such, routine restriction of dietary potassium with spironolactone is probably not warranted.
Spironolactone is taken orally in the form of tablets (e.g., 25, 50, and 100 mg) (Wiki). It is a prodrug of several active metabolites, including 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone, and canrenone (7α-desthioacetyl-δ6-spironolactone) (Wiki). Spironolactone and these active metabolites have elimination half-lives of 1.4 hours, 13.8 hours, 15.0 hours, and 16.5 hours, respectively (Wiki). Due to the relatively short duration of elevated drug levels with spironolactone and its active metabolites (Graph), twice-daily administration of spironolactone in divided doses may be more optimal than once-daily intake and is advised (Reiter et al., 2010).
Bicalutamide (Casodex) is a nonsteroidal antiandrogen (NSAA) which acts as a potent and highly selective androgen receptor antagonist (Wiki). It is primarily used in the treatment of prostate cancer in cisgender men. Prostate cancer is an androgen-dependent cancer which antiandrogens can help to slow the progression of, and this use constitutes the vast majority of prescriptions for bicalutamide (Wiki). In addition to prostate cancer, although to a much lesser extent, bicalutamide has been used in the treatment of hirsutism, scalp hair loss, and PCOS in cisgender women, peripheral precocious puberty (a rare form of precocious puberty in which antigonadotropins such as GnRH agonists are not effective) in cisgender boys, and priapism in cisgender men (Wiki). Bicalutamide is also becoming increasingly adopted for use as an antiandrogen in transfeminine people (Aly W., 2020; Wiki). However, its use in this population is still very limited, and well-regarded transgender health guidelines either recommend against its use (Deutsch, 2016—UCSF guidelines; Coleman et al., 2022—WPATH SOC8) or are only cautiously permissive of its use (Thompson et al., 2021—Fenway Health guidelines) due to a lack of studies of it in transfeminine people and potential risks. Nonetheless, a small but growing number of clinicians are using bicalutamide in transfeminine people or are willing to prescribe it, with these clinicians located particularly in the United States (Aly W., 2018). A single small clinical study has assessed bicalutamide in transfeminine people so far, specifically as a puberty blocker in adolescents who were denied insurance coverage for GnRH agonists (Neyman, Fuqua, & Eugster, 2019).
Bicalutamide is a much more potent androgen receptor antagonist than either spironolactone or CPA (Wiki; Neyman, Fuqua, & Eugster, 2019). It is typically used in transfeminine people at a dosage of 25 to 50 mg/day, although this dosage has been arbitrarily selected and is not based on data (Aly W., 2018; Aly W., 2019). Nonetheless, due to its relatively high potency as an androgen receptor antagonist and concomitant suppression of testosterone levels by estradiol, these doses may be adequate for many transfeminine people. At higher doses (>50 mg/day), bicalutamide is able to substantially block male-range testosterone levels (>300 ng/dL [>10.4 nmol/L]) per studies of bicalutamide monotherapy in men with prostate cancer (Aly W., 2018; Aly W., 2019; Wiki). This is something that spironolactone and CPA are not capable of in the same way. Owing to its selectivity for the androgen receptor, bicalutamide has no off-target hormonal activity and produces almost no side effects in women (Erem, 2013; Moretti et al., 2018). This is also in contrast to other mainstream antiandrogens like spironolactone and CPA, which have off-target hormonal effects like antimineralocorticoid activity or strong progestogenic activity as well as associated side effects and risks. As a selective androgen receptor antagonist, bicalutamide does not decrease testosterone levels, but rather increases them due to the body detecting a deficit in androgen signaling and attempting to compensate for it by upregulating androgen synthesis (Wiki). However, bicalutamide more than blocks the effects of any increase in testosterone it causes (Wiki; Aly W., 2019). In addition, increased testosterone levels will not occur if bicalutamide is combined with an adequate dose of an antigonadotropin such as estradiol (Aly W., 2018; Wiki). Although bicalutamide has no other important hormonal activity, it can produce robust indirect estrogenic effects (e.g., feminization and breast development) secondary to its antiandrogenic activity (Wiki; Wiki; Neyman, Fuqua, & Eugster, 2019).
Bicalutamide has certain health risks, which has been a major reason that it has not been more readily adopted in transfeminine hormone therapy (Aly W., 2020). It has a small risk of liver toxicity (Wiki; Aly W., 2020) and of lung toxicity (Wiki). Abnormal liver function tests (LFTs), such as elevated liver enzymes and elevated bilirubin, occurred in about 3.4% of men with bicalutamide monotherapy plus standard care versus 1.9% of men with placebo plus standard care in the Early Prostate Trial clinical programme (Wiki). In clinical trials, treatment with bicalutamide had to be discontinued in about 0.3 to 1.4% of men due to LFTs that became too highly elevated and could have progressed to serious liver toxicity (Wiki). To date, there are around 10 published case reports of serious liver toxicity, including cases of death, with bicalutamide, all of which have been in men with prostate cancer (Wiki; Table; Aly W., 2018). There have also been a couple of unpublished reports of death due to liver failure with bicalutamide in transfeminine people (Aly W., 2020). However, these reports have not been unconfirmed, and may or may not be reliable. Abnormal LFTs with bicalutamide usually occur within the first 3 to 6 months of treatment (Kolvenbag & Blackledge, 1996; Casodex FDA Label), and all case reports of liver toxicity with bicalutamide have had an onset of less than 6 months (Table). The liver toxicity of bicalutamide is not known to be dose-dependent across its clinically used dose range (Wiki), and abnormal LFTs have occurred with it even at relatively low doses in cisgender women (e.g., 10–50 mg/day) (Aly W., 2018). Due to its risk of liver toxicity, periodic liver monitoring is strongly advised with bicalutamide, especially within the first 6 months of treatment. Possible signs of liver toxicity include nausea, vomiting, abdominal pain, fatigue, appetite loss, flu-like symptoms, dark urine, and jaundice (yellowing of the skin/eyes) (Wiki).
In terms of its lung toxicity risk, bicalutamide has been associated rarely with interstitial pneumonitis, which can lead to pulmonary fibrosis and can be fatal, and also less often with eosinophilic lung disease (Wiki; Table; Aly W., 2018). As of writing, 15 published case reports of interstitial pneumonitis and 2 case reports of eosinophilic lung disease in association with bicalutamide therapy exist, likewise all in men with prostate cancer (Table). It has been estimated that interstitial pneumonitis with bicalutamide occurs at a rate of around 1 in 10,000 people, although this may be an underestimate due to under-reporting (Wiki; Aly W., 2018). Asian people may be especially likely to experience lung toxicity with bicalutamide and other NSAAs, as much higher incidences have been observed in this population (Mahler et al., 1996; Wu et al., 2022). There is no laboratory test for routine monitoring of lung changes with bicalutamide. Possible signs of relevant lung toxicity include dyspnea (difficulty breathing or shortness of breath), coughing, and pharyngitis (inflammation of the throat, typically manifesting as sore throat) (Wiki).
Bicalutamide is taken orally in the form of tablets (e.g., 50 and 150 mg) (Wiki). Due to saturation of absorption in the gastrointestinal tract, the oral bioavailability of bicalutamide progressively starts to decrease above a dosage of about 150 mg/day, and there is no further increase in bicalutamide levels above 300 mg/day (Wiki; Graph). Bicalutamide has a very long elimination half-life of about 6 to 10 days (Wiki; Graphs). As a result, it does not necessarily have to be taken daily, and can be dosed less often (in proportionally higher doses)—for instance twice weekly or even once weekly—for convenience if this is desired (Aly W., 2018). Due to its long half-life, bicalutamide requires about 4 to 12 weeks to fully reach steady-state levels (Aly W., 2018; Graph; Wiki). However, about 50% of steady state is reached within 1 week of administration of bicalutamide and 80 to 90% is reached after 3 to 4 weeks (Aly W., 2018; Graph; Wiki). Loading doses of bicalutamide can be taken to reach steady state more quickly if this is desired. Animal studies originally suggested that bicalutamide did not cross the blood–brain barrier and hence was peripherally selective (i.e., did not block androgen receptors in the brain) (Wiki). However, subsequent clinical studies found that this was not similarly the case in humans, in whom bicalutamide shows clear and robust centrally mediated antiandrogenic effects (Wiki).
Older NSAAs related to bicalutamide like flutamide (Eulexin) and nilutamide (Anandron, Nilandron) have much greater risks in comparison to bicalutamide and should not be used in transfeminine people. Nilutamide was previously characterized as an antiandrogen in transfeminine people in several studies, but was not further pursued probably due to its very high incidence of lung toxicity and other side effects (Aly W., 2020; Wiki; Wiki). Flutamide has been used limitedly as an antiandrogen in transfeminine people in the past, but should no longer be used due to a much higher risk of liver toxicity than bicalutamide as well as other side effects and drawbacks (Aly W., 2020; Wiki). Other newer and more-potent NSAAs like enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) also have risks and have not been studied or used outside of prostate cancer, although darolutamide may be a promising candidate for use as an antiandrogen in transfeminine people someday in the future (Aly W., 2019).
Testosterone is converted into DHT within certain tissues in the body (Swerdloff et al., 2017). DHT is an androgen metabolite of testosterone with several-fold higher activity than testosterone. The transformation of testosterone into DHT is mediated by the enzyme 5α-reductase. The tissues in which 5α-reductase is present and testosterone is converted into DHT are limited but most importantly include the skin, hair follicles, and prostate gland. Although DHT is more potent than testosterone, it is thought to have minimal biological role as a circulating hormone (Horton, 1992; Swerdloff et al., 2017). Instead, testosterone serves as the main circulating androgen, and the role of DHT is thought to be mainly via local metabolism and potentiation of testosterone into DHT within certain tissues.
5α-Reductase inhibitors (5α-RIs), such as finasteride (Proscar, Propecia) and dutasteride (Avodart), inhibit 5α-reductase and thereby block the conversion of testosterone into DHT. This results in marked decreases in circulating and within-tissue levels of DHT. Due to the primary role of DHT as a mediator in tissues rather than as circulating hormone, the antiandrogenic efficacy of 5α-RIs is limited. This is evidenced by the fact that they are well-tolerated in cisgender men and do not cause notable demasculinization in these individuals (Hirshburg, 2016). The medical use of 5α-RIs is mainly restricted to the treatment of scalp hair loss in men and women, hirsutism (excessive facial/body hair) in women, and prostate enlargement in men. They might also be useful for acne in women, but evidence of this is very limited (Wiki). Due to their specificity, 5α-RIs are inappropriate as general antiandrogens in transfeminine people. Moreover, DHT levels decrease in tandem with testosterone levels with suppression of testosterone production in transfeminine hormone therapy, and routine use of 5α-RIs in transfeminine people with testosterone levels within the female range is of limited usefulness and can be considered unnecessary (Gooren et al., 2016; Irwig, 2020; Prince & Safer, 2020; Glintborg et al., 2021). In any case, 5α-RIs may be useful in transfeminine people on hormone therapy who have persistent body hair growth or scalp hair loss—as they have been shown to be in cisgender women (Barrionuevo et al., 2018; Prince & Safer, 2020). However, it is notable that evidence of effectiveness in cisgender women is better for androgen receptor antagonists for such indications (van Zuuren et al., 2015). This is intuitive as androgen receptor antagonists block both testosterone and DHT whereas 5α-RIs only prevent conversion of testosterone into DHT. Hence, although 5α-RIs strongly reduce or eliminate DHT and their net effect is antiandrogenic, they do not decrease testosterone levels and in fact increase them.
There are three subtypes of 5α-reductase. Dutasteride inhibits all three subtypes of 5α-reductase whereas finasteride only inhibits two of the subtypes. As a result of this, dutasteride is a more complete 5α-RI than finasteride. Dutasteride decreases DHT levels in the blood by up to 98% while finasteride can only decrease them by around 65 to 70%. As nearly all circulating DHT originates from synthesis in peripheral tissues, these decreases indicate parallel reductions in tissue DHT production (Horton, 1992). In accordance with these findings, dutasteride has been found to be more effective than finasteride in the treatment of scalp hair loss in men (Zhou et al., 2018; Dhurat et al., 2020; Wiki). For these reasons, although both finasteride and dutasteride are effective 5α-RIs, dutasteride may be the preferable choice if a 5α-RI is used (Zhou et al., 2018; Dhurat et al., 2020).
A potentially undesirable effect of 5α-RIs in transfeminine people is that they may increase circulating testosterone levels to a degree in those in whom testosterone production isn’t fully suppressed (Leinung, Feustel, & Joseph, 2018; Aly W., 2019; Traish et al., 2019; Irwig, 2020; Glintborg et al., 2021). It appears that DHT adds significantly to negative feedback on gonadotropin secretion in the pituitary gland in people with testes who have low testosterone levels relative to the normal male range (Traish et al., 2019). The therapeutic implications of this for transfeminine people, if any, are uncertain.
Another potentially undesirable action of 5α-RIs is that they inhibit not only the production of DHT but also of certain neurosteroids. Neurosteroids are steroids that act on the nervous system—most notably the brain. Examples of neurosteroids that 5α-RIs inhibit the synthesis of include allopregnanolone, which is formed from progesterone, and 3α-androstanediol, which is derived from testosterone and DHT. Research suggests that these neurosteroids have significant biological modulatory roles in mood, anxiety, stress, and other cognitive/emotional processes (King, 2013). Possibly in relation to this, 5α-RIs have been associated with a small risk of depression (Welk et al., 2018; Deng et al., 2020; Dyson, Cantrell, & Lund, 2020; Nguyen et al., 2020; Wiki). Claims of other, more significant and persistent side effects with 5α-RIs, which are termed “post-finasteride syndrome” (PFS) in the case of finasteride, also exist (Traish, 2020). However, they are based on low-quality reports and are controversial (Fertig et al., 2016; Rezende, Dias, & Trüeb, 2018). The nocebo effect is likely to worsen perceptions of side effects with 5α-RIs (Kuhl & Wiegratz, 2017; Maksym et al., 2019; Aly W., 2020).
Clinical dose-ranging studies have found that lower doses of finasteride and dutasteride than are typically used still provide substantial or near-maximal 5α-reductase inhibition (Gormley et al., 1990; Vermeulen et al., 1991; Sudduth & Koronkowski, 1993; Drake et al., 1999; Roberts et al., 1999; Clark et al., 2004; Frye, 2006; Olsen et al., 2006; Harcha et al., 2014; Kuhl & Wiegratz, 2017). In one study with finasteride for instance, DHT levels decreased by 49.5% at 0.05 mg/day, 68.6% at 0.2 mg/day, 71.4% at 1 mg/day, and 72.2% at 5 mg/day (Drake et al., 1999). Parallel reductions in DHT levels were seen locally in the scalp (Drake et al., 1999). In a study with dutasteride, DHT levels were decreased by 52.9% at 0.05 mg/day, 94.7% at 0.5 mg/day, 97.7% at 2.5 mg/day, and 98.4% at 5 mg/day (Clark et al., 2004). Based on these findings, 5α-RIs can potentially be taken at lower doses to help reduce medication costs if needed. Finasteride tablets can be split to achieve smaller doses. Conversely, dutasteride cannot be split as it is formulated as an oil capsule. However, dutasteride has a long half-life, and instead of dividing pills, it can be taken less frequently (e.g., once every few days) as a means of reducing dosage.
5α-Reductase inhibitors are taken orally in the form of tablets and capsules. Compounded topical formulations of finasteride also exist (Marks et al., 2020). However, caution is advised with these preparations as they have been found to be excessively dosed and to produce equivalent systemic DHT suppression as oral finasteride formulations (Marks et al., 2020). Lower-concentration formulations of topical finsteride on the other hand may be more locally selective (Marks et al., 2020).
Table 7: Available forms and recommended doses of 5α-reductase inhibitors for transfeminine people:
GnRH agonists and antagonists (GnRHa), also known as GnRH receptor agonists and antagonists or GnRH modulators, are antiandrogens which work by preventing the effects of GnRH in the pituitary gland and thereby suppressing LH and FSH secretion. Receptor agonists normally activate receptors while receptor antagonists block and thereby inhibit the activation of receptors. Due to a physiological quirk however, GnRH agonists and antagonists have the same effects in the pituitary gland. This is because GnRH is secreted in pulses under normal physiological circumstances, and when the GnRH receptor is unnaturally activated in a continuous manner, as with exogenous GnRH agonists, the GnRH receptor in the pituitary gland is strongly desensitized to the point of becoming inactive. Consequently, both GnRH agonists and GnRH antagonists have the effect of abolishing gonadal sex hormone production. This, in turn, reduces testosterone levels into the castrate or normal female range (both <50 ng/dL or <1.7 nmol/L) in people with testes. GnRHa are like a reversible gonadectomy, and for this reason, are also sometimes referred to as “medical castration”. Provided that an estrogen is taken in combination with a GnRHa to prevent sex hormone deficiency, these medications have essentially no side effects or risks. For these reasons, GnRHa are the ideal antiandrogens for use in transfeminine people.
GnRHa are widely used to suppess puberty in adolescent transgender individuals. Unfortunately however, they are very expensive (e.g., ~US$10,000 per year) and medical insurance does not usually cover them for adult transgender people. Consequently, GnRHa are not commonly used in adult transfeminine people at this time. An exception is in the United Kingdom, where GnRH agonists are covered for all adult transgender people by the National Health Service (NHS). Another exception is buserelin (Suprefact), which has become available very inexpensively in its nasal spray form from certain Eastern European online pharmacies in recent years (Aly W., 2018).
GnRH agonists cause a brief flare in testosterone levels at the start of therapy prior to the GnRH receptors in the pituitary gland becoming desensitized (Wiki). Testosterone levels increase by up to about 1.5- to 2-fold for about 1 week and then decrease thereafter (Wiki). Castrate or female-range levels of testosterone are generally reached within 2 to 4 weeks (Wiki). In contrast to GnRH agonists, there is no testosterone flare with GnRH antagonists and testosterone levels start decreasing immediately, reaching castrate levels within a few days (Wiki; Graph). This is because GnRH antagonists work by blocking the GnRH receptor without initially activating it, and hence desensitization of the receptor is not necessary for their action. If desired, the testosterone flare at the initiation of GnRH agonist therapy can be prevented or blunted with the use of antigonadotropins, for instance estrogens and progestogens, as well as with potent androgen receptor antagonists such as bicalutamide (Wiki).
GnRH agonists must be injected subcutaneously or intramuscularly once per day or once every one to six months depending on the formulation employed (buserelin, goserelin, leuprorelin, triptorelin). Alternatively, they can be surgically implanted once a year (histrelin, leuprorelin) or used as a nasal spray two to three times per day (buserelin, nafarelin). The first GnRH antagonists were developed for use by once-monthly intramuscular or subcutaneous injection (abarelix, degarelix). More recently, orally administered GnRH antagonists such as elagolix and relugolix have been introduced for medical use (Aly W., 2018; Aly W., 2019). They are taken in the form of tablets once or twice daily.
Table 8: Available forms and recommended doses of GnRH agonists for transfeminine people:
|Buserelin||Suprefact, others||SC injection||Solution||200 μg/daya|
|Implant||6.3 mg/2 months|
|9.45 mg/3 months|
|Intranasal||Nasal spray||400 µg 3x/dayb,c|
|Goserelin||Zoladex||SC injection||Implant||3.6 mg/month|
|10.8 mg/3 months|
|Histrelin||Supprelin LA, Vantas||SC implant||Implant||50 mg/year|
|Leuprorelin||Lupron, others||IM injection||Solution||1 mg/day|
|Eligard, Lupron Depot, others||IM/SC injection||Suspension||3.75–7.5 mg/month|
|11.25–22.5 mg/3 months|
|30 mg/4 months|
|45 mg/6 months|
|Viadur||SC implant||Implant||65 mg/year|
|Nafarelin||Synarel||Intranasal||Nasal spray||400–600 μg 2–3x/day|
|Triptorelin||Decapeptyl, Trelstar Depot/LA||IM injection||Suspension||3.75 mg/month|
|11.25 mg/3 months|
a 500 μg 3x/day for the first week then 200 μg/day. b 800 μg 3x/day for the first week then 400 μg 3x/day. c 500 μg 2x/day can be used instead of 400 μg 3x/day but is less effective (70% decrease in testosterone levels (to ~180 ng/dL [6.2 nmol/L]) instead of 90% decrease (to ~50 ng/dL [1.7 nmol/L]) per available studies of buserelin in men with prostate cancer) (Aly W., 2018; Wiki).
Table 9: Available forms and recommended doses of GnRH antagonists for transfeminine people:
|Abarelix||Plenaxis||IM injection||Suspension||113 mg/month|
|Degarelix||Firmagon||SC injection||Solution||80 mg/montha|
|Elagolix||Orilissa||Oral||Tablets||150–200 mg 1–2x/dayb|
a First month is 240 mg then 80 mg per month thereafter. b 150 mg 1x/day is less effective than 200 mg 2x/day (which provides full gonadal sex-hormone suppression in cisgender women) (Wiki). c 80–120 mg/day for full gonadal sex-hormone suppression and 20–40 mg/day for substantial but partial gonadal sex-hormone suppression (MacLean et al., 2015; DailyMed).
In addition to estrogens, progestogens, and antiandrogens, androgens/anabolic steroids (AAS) are sometimes added to transfeminine hormone therapy. This is when testosterone levels are low (e.g., below the female average of 30 ng/dL [1.0 nmol/L]) and androgen replacement is desired. It has been proposed that adequate levels of testosterone may provide benefits such as increased sexual desire, improved mood and energy, positive effects on skin health and cellulite (Avram, 2004), and increased muscle size and strength (Huang & Basaria, 2017). However, there is insufficient clinical evidence to support such benefits at present, and androgens can produce adverse effects in cisgender women and transfeminine people, for instance acne, hirsutism, scalp hair loss, and masculinization (Wiki). For transfeminine people who nonetheless desire androgen replacement therapy, possible options for androgen medications include testosterone and its esters, dehydroepiandrosterone (DHEA; prasterone), and nandrolone esters such as nandrolone decanoate (ND) (Aly W., 2020; Table), among others.
Transfeminine people on hormone therapy should undergo regular laboratory monitoring in the form of blood work to assess efficacy and monitor for safety. Total estradiol levels and total testosterone levels should be measured to assess the effectiveness of therapy—that is, whether hormone levels are in appropriate ranges for cisgender females—and determine whether medication adjustments may be necessary. Levels of free testosterone, free estradiol, estrone (E1), dihydrotestosterone (DHT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) can also be measured to provide further information although they’re not absolutely necessary. If progesterone is used as a part of hormone therapy, progesterone levels can be measured to provide insight on the degree of progesterone exposure. In addition to hormone blood tests, transfeminine people can monitor their physical changes with hormone therapy, such as breast development and other aspects of feminization, using various physical and digital measurement methods (e.g., Aly W., 2020).
In transfeminine people taking bicalutamide or high doses of CPA (≥20 mg/day), liver function tests (LFTs), such as aspartate transaminase (AST) and alanine transaminase (ALT) levels, should be regularly performed to monitor for liver toxicity. In those who are taking spironolactone and have relevant risk factors for hyperkalemia (high potassium levels), such as older age, reduced kidney function, or concomitant use of potassium-elevating medications or potassium supplements, potassium levels should be regularly monitored to assess for hyperkalemia. Conversely, in healthy young people without such risk factors who are taking spironolactone, potassium monitoring seems to be of limited usefulness (Plovanich, Weng, & Mostaghimi, 2015; Zaenglein et al., 2016; Layton et al., 2017; Millington, Liu, & Chan, 2019; Wang & Lipner, 2020; Gupta et al., 2022; Hayes et al., 2022). In transfeminine people taking high doses of estrogens or progestogens—particularly CPA—prolactin levels should be regularly measured to monitor for hyperprolactinemia (high prolactin levels) and prolactinoma (Aly W., 2020). In people taking high doses of CPA (>12.5 mg/day), periodic magnetic resonance imaging (MRI) exams should be performed to monitor for development of meningiomas (Aly W., 2020). If the preceding tests come back abnormal, depending on the situation and its severity, medication doses should be reduced or specific medications should be discontinued or replaced with alternatives.
Certain therapeutic situations can result in inaccurate lab blood work results. Monitoring of progesterone levels with oral progesterone using immunoassay-based blood tests can result in falsely high readings for progesterone levels due to cross-reactivity with high levels of progesterone metabolites such as allopregnanolone (Aly W., 2018; Wiki). Instead of immunoassay-based tests, mass spectrometry-based tests should be used to determine progesterone levels with oral progesterone (Aly W., 2018; Wiki). Conversely, either type of test may be used to measure progesterone levels with non-oral progesterone therapy. High-dose biotin (vitamin B7) supplements can interfere with the accuracy of immunoassay-based hormone blood tests, causing falsely low or falsely high readings (Samarasinghe et al., 2017; Avery, 2019; Bowen et al., 2019; FDA, 2019; Luong, Male, & Glennon, 2019). Transdermal estradiol formulations applied to the arm can result in contamination of blood draws taken from the same arm and can result in falsely high readings for estradiol levels (Vihtamäkia, Luukkaala, & Tuimala, 2004).
Certain cancers are known to be hormone-sensitive and their incidence can be influenced by hormone therapy. Screening for breast and prostate cancer is recommended in transfeminine people (Sterling & Garcia, 2020; Iwamoto et al., 2021). The risk of breast cancer appears to be dramatically increased with transfeminine hormone therapy, perhaps especially with progestogens (Aly W., 2020). However, the risk still remains lower than in cisgender women (Aly W., 2020). The incidence of prostate cancer is greatly decreased with hormone therapy in transfeminine people as a consequence of androgen deprivation, but the risk is not abolished and prostate cancer can still occur (de Nie et al., 2020; Sam S., 2020). The prostate gland is not removed with vaginoplasty, so transfeminine people who have undergone vaginoplasty will also require monitoring for prostate cancer still. Testicular cancer is not known to be a hormone-dependent cancer and its incidence does not appear to be increased with hormone therapy in transfeminine people (Bensley et al., 2021; de Nie et al., 2021; Jacoby et al., 2021).