Cross-Sex Hormone Therapy: Female Hormones

Scope Of Report

For the purposes of this report, we’re looking at cross-gender hormone therapy for assigned-male-at-birth individuals — that is, estrogen and anti-androgens, as they are generally taken by transgender women and others seeking to feminize their bodies.  I’ll look into the evidence for the medical and psychological risks and benefits of these drugs.

Bottom Lines

  • hormone therapy consisting of estrogen and an anti-androgen is mostly safe: the biggest risk is cardiovascular problems
  • the anti-androgen cyproterone acetate is riskier than other anti-androgens: it’s associated with venous thromboembolism, hyperprolactinemia, and possibly impaired mood and cognitive ability. It can be substituted with spironolactone, or in some cases with no anti-androgen at all.
  • hormone therapy for trans women improves mood and agreeableness, reduces gender dysphoria, and has some feminizing effects on appearance
  • hormone therapy does change brain size but doesn’t impair cognitive performance
  • trying to get an “androgynous” outcome by taking anti-androgens without estrogen is a bad idea and does cause cognitive impairment and depression.

Risks of Hormone Therapy: Venous Thromboembolism

The most common risk of hormone therapy in trans women is venous thromboembolism. This is when a blood clot in a vein breaks loose and travels in the blood; if it reaches the lungs it is called a pulmonary embolism and can be very dangerous. About 5% of people with venous thromboembolisms die.[1]

In the largest study, 1076 individuals, the rate of venous thromboembolism is 1%; smaller studies find 5-6% rates.[2]  Some small studies (162 individuals) suggest that transdermal estrogen has less risk of venous thromboembolism than oral estrogen.

The risk of venous thromboembolism is also elevated in hormonal birth control, which, like hormone therapy, contains female hormones.  Current users of estrogen-containing birth control have about double the yearly risk of venous thromboembolism of female non-users. Birth control containing the progestin cyproterone acetate is associated with 1.88x the venous thromboembolism risk of birth control with other progestins.[3]  This is relevant because cyproterone acetate is also an anti-androgen sometimes used in cross-gender hormone therapy; avoiding cyproterone acetate could reduce the risk of venous thromboembolism.

Risks of Hormone Therapy: Osteoporosis

Estrogen is associated with osteoporosis: 25% of 100 transgender women had osteoporosis after more than 10 years of HRT, whereas transgender men did not.[2]

Risks of Hormone Therapy: Hyperprolactinemia

The anti-androgen cyproterone acetate can cause hyperprolactinemia.

High levels of the hormone prolactin can cause symptoms such as breast discharge, erectile dysfunction and reduced libido, infertility, breast growth, decreased body hair and muscle mass, and headaches. (Not all of these may be undesirable for trans women, of course.)  It is not otherwise dangerous, and can be treated with dopamine agonists such as bromocriptine.

In a total of 1109 trans women across six studies, there were elevated prolactin levels in 19.5%. [5]  Trans women on hormone therapy have much higher rates of migraine than the baseline population: 26% out of 50, as opposed to a baseline rate of 6%.  This may be due to higher prolactin levels.[6] 14/47, or 30% of trans women reported new sources of pain after going on hormones, in particular headaches, breast pain, and musculoskeletal pain.[7] This may also be a result of hyperprolactinemia, or it may be related to other hormonal-balance issues (women generally are more pain-sensitive than men.)

Cyproterone acetate increases prolactin levels; spironolactone does not. (p = 0.0002).[8]  Avoiding cyproterone acetate seems likely to reduce the risk of hyperprolactinemia.

Risks of Hormone Therapy: Infertility

Estrogen therapy usually eliminates the production of sperm.  In 7 out of 10 trans women on estrogen, there was no spermatogenesis.[53] A single male given estrogen had a pronounced drop in sperm motility and density by 4 weeks of estrogen treatment, though it did recover after discontinuation of treatment.[54] As of 2009, there have been no studies of restoration of spermatogenesis after prolonged treatment with estrogen. [52]

Benefits of Hormone Therapy: Improved Mood

Hormone treatment (transdermal estradiol + cyproterone acetate) reduced anxiety and depression scores (p < 0.001) in a cohort study of 107 trans women.[16]

Estrogen has a complex relationship to mood even in cis women.  One credible model is that estrogen fluctuations (for example, around the menstrual cycle, or around the start of menopause) cause mood disorders.  Increased vulnerability to depression in women begins with puberty and ends with menopause, though the perimenopause period is associated both with new onset of depression and increased depression symptoms. [17]  For this reason, estrogen supplementation in cis women is sometimes an effective treatment for mood disorders associated with hormone fluctuations. Estrogen has been consistently shown to be effective as a treatment for PMS, for postpartum depression, and for the milder mood problems associated with menopause, but not with severe menopausal depression or non-reproductive-related major depressive disorder.[18]

Higher doses of estrogen, on the other hand, tend to make mood problems in cis women worse. 3 mg estradiol vs. 2 mg estradiol in HRT for perimenopausal women significantly (p < 0.001) increased tension, irritability, and depressed mood, and decreased friendliness. [19] In postmenopausal women treated with 2 mg/day estrogen or placebo for three months, there was no difference in baseline mood, but the estrogen-treated group had stronger negative emotion responses to a social stress test.[20]  Chronic administration of E2 to ovariectomized female rats and mice at much higher than physiologic doses increases anxious and depressive behaviors.[21]  It’s not clear how this translates to trans women, but it may be preferable to err on the side of lower estrogen doses when possible.

The anti-androgen spironolactone is used to treat symptoms of PMS in cis women, such as irritability, depression, feeling of swelling, breast tenderness, and food craving. Unlike other anti-androgens such as cyproterone acetate or finasteride, it has not been connected with negative effects on mood or cognition.[22]

Benefits of Hormone Therapy: Reduced Gender Dysphoria

Cross-hormone therapy resulted in less body uneasiness in trans women, in a study of 125 subjects.[23]  Adolescents (mean age 17) treated vs. rejected for cross-sex hormone therapy had less gender dysphoria at follow-up in both groups, but significantly less in the treated group.  The treated group were more satisfied with their bodies.[24]

Benefits of Hormone Therapy: Higher Agreeableness

Androgen deprivation and estrogen supplementation in males (e.g. treated for prostate cancer) correlates with higher agreeableness on the Big Five personality test.[25]

Benefits of Hormone Therapy: Altered Sexual Patterns

Estrogen treatment inhibits sexual activity, spontaneous erections, and nocturnal penile tumescence.[4]   Androgen deprivation therapy in cis men (as part of treatment for prostate cancer) consistently causes reduced libido and lower frequency of early morning erections, p < 0.0001.[51] However, trans women have no higher rates of hypoactive sexual desire syndrome than cis women[47]; it may simply be that estrogen causes a more female-typical sex pattern.

Benefits of Hormone Therapy: Physical Appearance Changes

Estrogen and anti-androgens reduce hair on the trunk and limbs, but don’t completely remove it on the face; electrolysis or shaving is still usually necessary.[26]

Breast growth is usually present, with a mean hemicircumference of 18 cm after a year of hormone therapy — this is still a few centimeters less than the mean for cis women.[26]  Most trans women are dissatisfied with the final size of their breast development.[30]

Hormone therapy significantly (p < 0.01, Cohen’s d = 1) improved the “physical appearance score” for gender compatibility of transgender people, a composite made of hair, facial hair, larynx, voice, figure, height, skin, hands/feet, muscularity, chin, nose, jaw, speech, and gestures/movement.[27]

Breast growth, redistribution of body fat, and decrease in muscle mass begin at 3-6 months and peak at 2 years; decreased hair growth begins at 6-12 months and peaks at >3 years.[28]

Trans women, compared to cis men, had similar BMI but higher body fat percentage: 29% vs. 21%, p < 0.001. They also had lower grip, biceps, and quadriceps strength (p < 0.001).[29]

Non-Effects of Hormone Therapy: Cognitive Ability

A study of 35 trans men and 15 trans women at the beginning of hormone treatment, as well as 20 control (cis) men and 20 cis women, found that the trans men’s spatial rotation ability increased during 12 weeks of hormone treatment, while the trans women’s spatial rotation ability slightly declined (p < 0.01), from an average score of 101.9 to 98.5, or a 3% drop.  In this study, trans women were treated with with 100 ug/day of ethinyl estradiol and 100 ug/day of cyproterone acetate.[31]

A study of 51 trans people given hormone therapy and 29 cis controls found no effect on cognitive abilities of hormone treatment over the course of a year. Trans women were given 100 ug/day of oral ethinyl estradiol.[32]

A study of 103 trans women, treated with conjugated equine estrogens or ethinyl estradiol, and in some cases cyproterone acetate and/or medroxyprogesterone acetate, found a slight improvement in digit span after going on estrogen (6.70 on estrogen, 6.00 off estrogen), and a slight improvement in a visual recall test after going off estrogen, but mostly found no effect on a large battery of cognitive tests.[34]

The anti-androgens leuprorelin, goserelin, and cyproterone acetate, when given to men with prostate cancer, caused a drop in one or more cognitive tests in 24/50 men randomized to active treatment, compared to none of the men randomized to placebo.[33]  However, when men treated with anti-androgens were subsequently given estrogen, their memory performance improved.[50]

It seems likely that estrogen has little or no effect on cognitive abilities. Cyproterone acetate taken alone has a negative effect on cognition in cis men, and may contribute to a slight drop in spatial rotation ability in the context of hormone therapy for trans women.

Non-Effects of Hormone Therapy: All-Cause Mortality

In a retrospective study of 816 trans women and 293 trans men, all-cause mortality was not different than in the general population.[47]  In a long-term follow-up study of 2236 trans women and 876 trans men, there was no elevated mortality compared to the general population.[49] In a cohort study of 966 trans women and 365 trans men, the trans women group had 51% higher mortality than the general population, due mostly to suicide, cardiovascular disease, AIDS, and drug abuse; but the use of estrogen among trans women was not an independent predictor of mortality generally or of any cause of mortality except for cardiovascular disease. In other words, trans women are an at-risk population for problems like suicide, drug abuse, and AIDS, but hormone users are at no higher risk than non-users.[48]

Neutral Effects of Hormone Therapy: Brain Morphology

Men and women have structural brain differences. Men have larger brain volumes (and smaller ventricles) than women; they have larger hypothalamuses; and they have a higher fraction of white matter relative to gray matter.

In a study of eight trans women and six trans men, receiving estrogen and cyproterone acetate, and testosterone, respectively, as well as 9 cis male and 6 cis female controls, the trans women had significantly reduced brain and hypothalamus volume, while the trans men had significantly increased brain volume.  Brain volume decreased by a mean of 25 mL in trans women, from 1300 mL to 1275 mL, or about a 2% drop, leaving brain volume somewhere between that of cis men and cis women.[35]  Another study, of 15 trans men on testosterone and 14 trans women on estrogen and an anti-androgen, found that testosterone increased cortical thickness while estrogen and anti-androgens decreased it and increased ventricle size.[36]

While brain volume correlates with IQ,[37] and while some studies find slightly higher mean IQ in men than women (about 3.63 IQ points, extrapolated from the differences in SAT scores in a sample of 100,000)[38], the more common position among IQ researchers is that there are no significant sex differences in mean IQ.[39]  It’s not at all clear that hormone therapy’s effect on shrinking brain volume significantly impairs cognition.

Nonstandard Cases of Cross-Gender Hormone Use

Anti-Androgens May Not Be Necessary

Lower estrogen doses (0.625 mg conjugated estrogen daily) without cyproterone acetate, given to trans women, are sufficient to keep estrogen levels in the normal range for premenopausal women.[9]  7/10 trans women on estrogen alone, without anti-androgens, had testosterone levels drop into the normal female range.[10]  Given that anti-androgens, particularly cyproterone acetate, are responsible for many of the negative side effects of hormone therapy, taking estrogen alone may be a lower-risk approach to hormone therapy.

Risks of Anti-Androgens Without Estrogen: Depression and Cognitive Impairment

Men being treated for prostate cancer are regularly given anti-androgens to suppress the tumor. These men experience significantly elevated rates of anxiety and depression. (This is in contrast to trans women given anti-androgens along with estrogen, who generally experience significant psychological benefit.)

Chemical castration in men significantly reduces estrogen and testosterone levels, and causes significant increases in depression and anxiety scores (though generally subclinical.)[11]  Compared to controls, prostate cancer patients treated with anti-androgens had significant drops in spatial reasoning and executive function, more depressed mood and irritability, less energy and vigor.[12]

The anti-androgen finasteride, given to men as a treatment for hair loss, produced depressive symptoms in 64% of users and 0% of controls in responses to an internet survey (though there may be significant response bias in who chooses to take the survey); finasteride users reported sexual dysfunction, problems with attention and memory, anxiety, depression, and suicidality.[13]  An Iranian prospective study on finasteride found that it increased scores on the Beck depression inventory (p < 0.001) and HADS depression scores (p = 0.005)[14]  A meta-analysis of randomized trials found that finasteride increased the rate of erectile dysfunction, with a relative risk of 2.22 compared to placebo.[55]

Cyproterone acetate in men treated for prostate cancer is associated with declines (compared to placebo) in attention and memory.[15]

Tamoxifen

Tamoxifen is an selective estrogen-receptor modulator; its primary use is as a breast cancer drug, but it also prevents gynecomastia related to estrogen or anti-androgen use.[40]  It might in principle be possible that if one combines tamoxifen with estrogen, one can get some of estrogen’s feminizing effects without growing breasts, but I couldn’t find any case studies of this being done successfully.

Tamoxifen taken alone does not have feminizing effects on men.  It increases both serum estrogen and testosterone levels in men, and increases sperm count.[41]

Female Hormone Use in Men

Male cross-dressers do sometimes use female hormones, and in past decades the social concept of “transgender” was less sharp than it is today. In early-1990’s radical contexts, “transgender” was considered an umbrella term that would include transvestites, drag queens, feminine gay men, butch lesbians, and other gender-nonconforming people who would not usually be considered “trans” today.[43]

In a 1992 sample of 1032 male cross-dressers, 43% said they “would like to use” hormones and 9% had used or were using hormones; in a 1972 sample of of 504 male cross-dressers, 50% said they “would like to use” hormones and 9% had used or were using hormones. However, the majority of these people viewed themselves as “a man with a feminine side” rather than “a woman trapped in a man’s body,” and did not plan to live full-time as women.[42]

From a biological standpoint, there’s no strong reason to believe that hormones would have different effects depending on whether they’re taken by a person who identifies as trans or not.  Men given estrogen for medical reasons (coronary heart disease) had similar side effects as trans women do, including breast tenderness and growth, testicular shrinkage, sexual dysfunction, and depression upon discontinuing estrogen,[44] but there was no evidence of psychological disturbance as a result of taking estrogen.[45]

 

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