Hormone replacement therapy (male-to-female)
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Hormone replacement therapy (HRT) for transgender and transsexual people changes the balance of sex hormones in their bodies. Some intersex people also receive HRT, either starting in childhood to confirm the sex to which they were assigned, or later, if this assignment has proven to be incorrect.
Its purpose is to cause the development of the secondary sex characteristics of the desired sex. It cannot undo many of the changes produced by the first natural occurring puberty, which may necessitate surgery and/or epilation (see below). The effects of hormonal therapy are often much more satisfying to trans men than trans women, as it is easier to produce secondary male sexual characteristics with androgens than it is to rid trans women of those established characteristics.
Formal requirements for HRT 
The requirements for hormone replacement therapy vary immensely, often at least a certain time of psychological counseling is required. Some organizations still require a period of time living as the desired gender role, based on standards such as the Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. This period is sometimes called the Real Life Experience (RLE). Some people, especially individuals from the transgender community, say that RLE is psychologically harmful and is a form of "gatekeeping" — effectively barring the person from transitioning for as long as possible, if not permanently.[who?]
Some individuals choose to self-administer their medication ("do-it-yourself"), often because available doctors have too little experience in this matter, or no doctor is available in the first place. Sometimes, trans persons choose to self-administer because their doctor will not prescribe hormones without a letter from the patient's therapist stating that the patient meets the diagnostic criteria for GID and is making an informed decision to transition. Many therapists require at least three months of continuous psychotherapy and/or a real life test in order to write such a letter as is suggested in the HBIGDA Standards of Care. In these circumstances, the individual may self-administer until they can get these authorizations, feeling that they shouldn't have to wait for a medical professional to be convinced of their situation. In addition, as many individuals must pay for evaluation and care out-of-pocket, expense can also be prohibitive to pursuing such therapy.
However, self-administration of hormones is potentially dangerous and orally delivered hormones can cause an elevation in liver enzymes.
Medical contraindications 
- Absolute: history of estrogen-sensitive cancer (for example breast cancer), history of thromboembolic disease (unless provided with concurrent anti-coagulation therapy), or history of macroprolactinoma.
- Relative: Liver, kidney, or heart disease and stroke (or any of the risk factors for heart disease: high cholesterol, diabetes, obesity, smoking); Strong family history of breast cancer or thromboembolic disease; Gallbladder disease; circulation or clotting conditions such as peripheral vascular disease, polycythemia vera, sickle cell anaemia, paroxysmal nocturnal hemoglobinuria, hyperlipidemia/hypercholesterolemia, hyperlipoproteinaemia, hypertension, factor V leiden, prothrombin mutation, antiphospholipid antibodies, anticardiolipin antibodies, lupus anticoagulants, plasminogen or fibrinolysis disorders, protein C deficiency, protein S deficiency, or antithrombin III deficiency.
Types of therapy 
- The dosages used are often higher than replacement doses for natal women, although the official guideline for endocrinologists recommends "maintain[ing] sex hormone levels within the normal range for the person’s desired gender". Usually the dosage is reduced after an orchiectomy (the removal of the testes) or sex reassignment surgery. However, the practice of lowering estrogen doses after such operations has been carried over from the days when very high doses of estrogen were required to decrease testosterone since antiandrogens were not used. In fact, high doses (though using a less potent estrogen, estradiol, that is endogenous to the human body rather than the risky ethinyl estradiol and conjugated estrogens used in the past) are recommended during the first ten or so years of HRT to fully develop, with or without having had an orchiectomy or sex reassignment. After usually ten years or so the dosages can be reduced.
- Many different variations of estradiol exist as well as other types of estrogens although the ones most commonly used are either micronized estradiol, estradiol acetate, estradiol valerate, estradiol cypionate, estradiol enanthate, conjugated estrogens, esterified estrogens, and ethinyl estradiol.
- Injectable, implanted, nasal, oral, sub lingual, gel, spray, and transdermal patch formulations are available.
- As dosage increases, risks increase as well. Therefore, those with relative contraindications should start at lower doses and increase dosage more gradually.
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- Progestogens include progesterone and progestins (synthetic analogs of progesterone or 17α-hydroxyprogesterone). There are oral, sublingual, suppository, gel, and injectable formulations available.
- Progestogens, in conjunction with prolactin, are involved in the maturation of the lobules, acini, and alveoli during pregnancy, which are mammary structures that estrogen has little to no effect on. However, there is at present no clinical evidence that either progesterone or progestins enhance breast size, shape, or appearance in either trans women or cisgender women, and one study found no benefit to breast hemicircumference over estrogen alone in a small sample of trans women given both an estrogen and an oral progestogen (usually 10 mg/day medroxyprogesterone acetate). However, the authors of the paper state that the sample size was too small to make any definitive conclusions, and that further studies should be carried out to confirm whether progestogens do significantly affect breast size and/or shape in trans women or not. As of 2012, no additional study has looked at the issue again.
- Progestogens are involved in fat distribution, increase female libidinal feelings, increase appetite, slight increase in skin oil, increases blood flow to the skin, increases the ability to sweat and lose extra heat, increase in body temperature enabling one to better tolerate the cold, healthier nails, produce a sense of calm and promote sleep, and increase energy. However, progestogens may increase skin oil and libido too much for some and there may be acne breakouts due to the increase in skin oil. In addition, these effects may actually be the result of androgenic action, which may be undesirable for most trans women.
- Progesterone in particular is essential for bone health and seems to have a role in skin elasticity, and nerve tissue. Other effects that have been seen with progesterone in particular (not the synthetics) include reducing spasms and relaxing smooth muscle tone, gallbladder activity is reduced, bronchi are widened (helps respiration), an anti-inflammatory agent and reduces the immune response, normalizing blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy. Progesterone also assists in thyroid function and bone building by osteoblasts.
- Progestins (synthetic progestogens) are associated with an increased risk in breast cancer, which is not seen with progesterone (a bioidentical or natural progestogen).
- Spironolactone is the most frequently used antiandrogen in the United States because it is relatively safe and inexpensive. Cyproterone acetate is more commonly used outside of the US.
- Spironolactone is a 'potassium-sparing diuretic' that is also used to treat low-renin hypertension, edema, hyperaldosteronism, and low potassium levels caused by other diuretics. It can cause high potassium levels, hyperkalemia, and is therefore contra-indicated in people with renal failure or who otherwise have elevated potassium levels. Spironolactone prevents the formation of testosterone in the testis (though not in the adrenals) by inhibiting enzymes involved in its production and is an androgen receptor antagonist (prevents androgens from binding to androgen receptors).
- Cyproterone acetate is derived from 17α hydroxyprogesterone and suppresses gonadotropin levels (which in turn reduces testosterone levels), blocks androgens from binding to androgen receptors, and is a weak progestin. It has been used to treat prostate cancer. If used long-term in dosages of 150 milligrams or higher it can possibly lead to liver damage or failure.
- Other antiandrogens include bicalutamide, flutamide, and nilutamide. Unlike the two medications above, these do not lower testosterone levels but rather prevent testosterone and dihydrotestosterone from binding to androgen receptors. Because these have a weak action at the brain they do not lower libido or decrease erections. Two other antiandrogens that are rarely prescribed are ketoconazole and cimetidine. Ketoconazole has been used in those with prostatic cancer and hirsutism. Cimetidine has also been used in hirsutism. Ketoconazole has the potential of liver toxicity over long-term use and cimetidine is a relatively weak antiandrogen.
- Certain antiandrogens do not lower testosterone levels or prevent its action upon tissues but rather its metabolite, dihydrotestosterone (DHT), from forming. These medications can be used when the patient has male-pattern hair loss (androgenetic alopecia) and/or an enlarged prostate (benign prostatic hyperplasia). DHT contributes to the manifestation and exacerbation of both. Two medications are currently available to prevent the creation of DHT, finasteride and dutasteride. DHT levels can be lowered up to approximately 60-75% with the former depending upon dosage and up to 93-94% with the latter.
GnRH analogues 
- In both sexes, the hypothalamus releases GnRH (gonadotropin-releasing hormone) to stimulate the pituitary to produce LH (luteinizing hormone) and FSH (follicle-stimulating hormone) which in turn cause the gonads to produce sex steroids. In adolescents of either sex with relevant indicators, GnRH analogues, such as goserelin acetate can be used to suspend the advance of sex steroid-induced, inappropriate pubertal changes for a period without inducing any changes towards the sex with which the patient currently identifies. GnRH agonists work by initially over stimulating the pituitary then rapidly desensitizing it to the effects of GnRH. After an initial surge, over a period of weeks, gonadal androgen production is greatly reduced. On the other hand, GnRH antagonists act by blocking the action of GnRH in the pituitary. There is considerable controversy over the earliest age, and for how long it is clinically, morally and legally safe to do this. The current, sixth edition of the World Professional Association for Transgender Health Standards of Care permit from Tanner stage 2, but do not allow the addition of hormones until 16, which could be five or more years. The sex steroids do have important other functions. Also, some skeletal changes (such as increased height), which may be considered masculine, are not hindered by GnRH analogues.
- GnRH analogues are often prescribed to prevent the reactivation of testicular function where surgeons require the cessation of estrogens prior to surgery.
- The high cost of GnRH analogues is often a significant factor.
Effects of HRT 
- The growth of breasts, with concomitant enlargement of the nipples.
- Redistribution of body fat.
- Thinning of skin.
Irreversible changes 
Partially reversible changes 
- Breast development (may need reconstructive surgery to reverse the effect) 
Reversible changes 
- Decreased libido
- Redistribution of body fat
- Reduced muscle development
- Various skin changes
- Significantly reduced and lightened body hair
- Change in body odor and sweat production
- Less prominence of veins
- Ocular changes
- Reduced gonadal size
The psychological changes are harder to define, because HRT is usually the first physical action that takes place when transitioning and the act itself of beginning HRT has a significant psychological effect, which is difficult to distinguish from hormonally induced changes.
What HRT cannot change 
- HRT cannot reverse bone changes that have already been established by puberty. Consequently, total height, the length of the arms, legs, hands, and feet, and the width/size of the shoulders and rib cage are all not affected by HRT. However, details of bone shape change throughout life, with bones becoming heavier and more deeply sculptured under the influence of androgens, and HRT will prevent such changes from developing any further.
- The width of the hips are not affected in individuals in whom epiphyseal closure (fusion and closure of the ends of bones, which prevents any further lengthening) has taken place, an event which occurs in most people between 18 and 25 years of age. In addition, already established changes to the shape of the hips cannot be reversed by HRT whether epiphyseal closure has taken place yet or not.
- Already established changes to the sculpture of the bone structure of the face are not affected by HRT, nor is the prominence of the thyroid cartilage (Adam's apple) affected. These changes may be reversed by surgery (facial feminization surgery and tracheal shave, respectively) instead.
- During puberty, the voice deepens in pitch and becomes more resonant, effects which are permanent and are not affected by HRT.
- Facial hair develops during puberty, and this is a change that is not significantly affected by HRT. Facial hair may be permanently removed with electrolysis or laser hair removal instead.
- The most significant cardiovascular risk for transgender women is the pro-thrombotic effect of estrogens (Increased blood clotting.) This manifests most significantly as an increased risk for thromboembolic disease: deep venous thrombosis (DVT) and pulmonary embolism (PE) which occurs when DVTs break off and migrate through the venous system to the lungs. It is important for any person on female hormones to immediately seek medical care if she develops pain or swelling of one leg (especially calf) as this is the predominant symptom of a DVT, or if she develops symptoms of PE: chest pain, shortness of breath, fainting, or palpitations (even without leg pain or swelling).
- In practice this becomes very important to transgender women undergoing surgery. Ethinyl and conjugated oral estrogens should be withheld for a week before and until two weeks after surgery.
- DVTs occur more frequently in the first year of treatment with estrogens. However this may represent a 'screening by treatment' of patients who may have genetic predispositions to thromboembolic disease, with those who are more likely to develop DVTs doing so early on in therapy. However, if patients have a family history of thromboembolic disease, screening for known disease may be appropriate.
- DVT risk is higher with oral estrogen (particularly ethinyl estradiol and conjugated estrogens) rather than injectable, transdermal, implantable, and nasal estrogens.
- DVT risk also increases with age and with smoking, so many clinicians advise using the safer estrogen formulations in patients who smoke or are older than age 40.
- If screening is undertaken for known pro-thrombotic mutations such as Factor V-Leiden, antithrombin III, and protein C or S deficiency, it should be done so to increase the safety of hormonal therapy and not as a screen for who may undertake hormonal therapy. Given that the risk of warfarin treatment in a relatively young, well-informed, and otherwise healthy population is quite low and that the risk of adverse physical and psychological outcome for untreated transgender patients is high, a prothrombotic mutation is not an absolute contraindication for hormonal therapy. (See: Levy, et al. “Endocrine Intervention for Transsexuals” Clin Endo 2003. 59:409-418.)
- The antiandrogen bicalutamide is associated with an increased risk of heart failure when used as monotherapy (without any other drugs). A study of prostate cancer patients also showed an increased number of deaths unrelated to cancer among patients taking 150 mg/day bicalutamide. This prompted Health Canada to withdraw its approval for 150 mg bicalutamide as monotherapy. The increased death rate has not been observed where bicalutamide was combined with a method of reducing androgen production. The exact reasons for the heart failure and deaths have not been completely determined, however a likely cause is acute adrenal insufficiency and hypotension due to the action of DHT during episodes of bicalutamide withdrawal. Because bicalutamide is extremely lipophilic, it is difficult to avoid periods of low serum concentration due to the uptake of bicalutamide into fat cells.
- Current facial hair is only slightly affected (some reduction in density, coverage, and slower growth) by antiandrogens. Those who are less than a decade past puberty and/or whose ethnicity generally lacks a significant amount of facial hair will have better results with antiandrogens. Those taking antiandrogens will have better results with electrolysis/laser hair removal than those who are not. If one is still in their teens or early twenties, there will be prevention of new facial hairs from developing if testosterone levels are within the female range.
- Body hair (chest, periareolar, shoulders, back, abdomen, buttocks, thighs, tops of hands, tops of feet) will, over time, turn from terminal ("normal") hairs to vellus hairs (very tiny, blonde "baby" hairs). Hair on the arms, perianal, and perineal will reduce but may not turn to vellus hair on the latter two regions (some natal females also have some hair in these areas). Underarm hair will slightly change in texture and length, pubic hair becomes more typically female in pattern. Lower leg hair becomes less dense in concentration. All depend upon genetics.
- Head hair may slightly change in texture, curl, and color (new hairs that is, not hair that has already formed and reached the surface prior to HRT), this is especially likely with hair growth from previously bald areas.
- Eyebrow hair becomes less "bushy" or scattered.
Urogynecological effects 
- Transgender women report a sometimes significant reduction in libido, all depending on the dosage of antiandrogens. A small number of post-operative transsexual women may take small amounts of testosterone to boost the libido. Many pre-operative transsexual women simply wait until after sex-reassignment surgery to begin an active sex life (due to how they feel towards their genitals and/or an aversion to other sex acts) and for newly post-operative women how satisfied they are with the results. Raising estrogen dosage or adding a progestogen has also raised the libido of some trans women.
- Spontaneous and morning erections decrease in frequency significantly, however some who have had an orchiectomy still experience morning erections. Voluntary erections can be maintained since the brain is the most important sex organ; a developed repertoire of fantasies and good visualization is a must. It also depends on how one views their own genitals (disgust, strong aversion to, tolerable, enjoyable, etc.).
- Testi volume is reduced by about 25% with typical dosages and as much as 50% in higher dosages, especially after a year of HRT. This is in response to the decrease in Leydig cells, Sertoli cells, and interstitial tissue, which produce both sperm and testosterone. When testosterone is dramatically reduced spermatogenesis is halted almost completely, when the cells that are involved in these processes go unused they atrophy (shrink).
- The prostate shrinks.
- The bladder shrinks.
- The line that runs down the underside of the penis and down the middle of the scrotum, the peno-scrotal raphe (where the urogenital folds fused early in the womb), will darken.
- Minor water retention is likely. (If spironolactone is used as an antiandrogen then it will tend to counter this effect, since it is a diuretic.)
- Childbearing, as experienced by women, is impossible with today's technology. Pre-operative sperm banking can be done, however, allowing artificial insemination to be used to produce genetic offspring with someone else at a later date. Medical advances in the near future may one day make this possible by using a donor uterus long enough to carry a child to term as anti-rejection drugs do not seem to affect the fetus. The DNA in a donated ovum can be removed and replaced with the DNA of the receiver. Further in the future stem cell biotechnology may also make this possible, with no need for anti-rejection drugs.
- Both estrogens and androgens are necessary in both biological males and females for healthy bone. (Young healthy women produce about 10 mg of testosterone monthly. Higher bone mineral density in males is associated with higher serum estrogen.)
- Bone is not static. It is constantly being reabsorbed and created. Osteoporosis results when bone formation occurs at a rate less than bone reabsorption.
- Estrogen is the predominant sex hormone that slows bone loss (even in men.)
- Both estrogen and testosterone help stimulate bone formation (T, especially at puberty.)
- The hips will rotate slightly forward due to changes in the tendons so hip discomfort is not uncommon.
Drug interactions 
- Any drug can cause adverse reactions with other medications so it is wise to check with a doctor or pharmacist when starting any new medication.
- Of the estrogen formulations commonly used, ethinyl estradiol (commonly found in birth control pills) has the greatest number of adverse reactions.
- The uppermost layer of skin, the stratum corneum, becomes thinner and therefore more translucent and pinkish (spider veins may appear or be more noticeable), less collagen, more susceptible to tearing and irritation from scratching or shaving, increased tactile sensation, and slightly lighter in color due to a slight decrease in melanin (pigment).
- Skin becomes softer.
- Sebaceous gland activity (which is triggered by androgens) lessens which lowers the amount of sebum (oil) production on the skin and scalp, consequently the skin becomes less prone to the formation of acne due to the less quantity of oil that is produced. Dry skin becomes a problem and lotions and oils may be necessary.
- The skin's pores become smaller due to the low quantities of sebum produced
- Body odor (skin, sweat, and urine) will become less "metallic," "sharp," or "acrid" and more "sweet" and "musky."
- Many apocrine glands (type of sweat glands) become inactive and body odor decreases. Sebum also contributes to body odor, the production of which is reduced by antiandrogens (as described above).
- More subcutaneous (under skin) adipose (fat) tissue accumulates. This gives a more puffy/softer appearance. Consequently dimpling, or cellulite, will be more apparent on the thighs and buttocks due to this along with the thinness of the skin.
- Susceptibility to sunburn increases possibly due to the thinner skin and/or less skin pigment.
- Because of the increase in adipose tissue in the hips, thighs, and rear, stretch marks (striae distensae) may appear on the skin in these areas.
Ocular changes 
- The lens of the eyes changes in curvature.
- Due to decreased androgens, the meibomian glands (aka., tarsal, palpebral, or tarsoconjunctival glands. A type of sebaceous gland on the upper and lower eyelids that open at the edges of the lids) produce less oil (oil that makes up the lipid layer of tear film which prevents the evaporation of the watery layer beneath) and a tendency for dry eyes may be a problem.
- Sensitivity to male body odor(s) (including male pheromones) may be positively correlated with elevated estrogen levels. Overall, olfactory senses may increase. Progestogens, however, often lower the sensitivity to male pheromones.
Mammary gland development 
- Breast, nipple, and areolar development takes 4–6 years to complete depending upon genetics, and sometimes as long as 10 years. It is normal for there to be a "stall" in breast growth during feminization, or for the size of one breast to be a little bigger than the other. Trans females who undergo HRT often experience breast development which is below the comparable cis female norm (many seek breast augmentation); it is rare for a HRT patient to opt for breast reduction. The size of the rib cage and shoulder width also play a role in the perceivable "size" of the breasts; both characteristics are usually smaller in cis females, i.e., if a cis female and a trans female were to have the same cup size, the trans female's breasts would most likely appear smaller. Thus when a trans woman opts to have breast augmentation, the implants used are, on the average, larger than those commonly used by cis females.
- The nipples often become more sensitive to stimulation.
Adipose tissue distribution 
- Fat distribution in the body slowly changes over months and years. The body will now tend to accumulate new adipose tissue (fat) in a typically female pattern. This includes the hips, thighs, rear, pubis, upper arms, and breasts. The body will now tend to use/burn the old adipose tissue in the waist making the waist appear smaller as well as on the shoulders and back.
- Subcutaneous adipose tissue increases in the face (cheeks and lips) making the face appear puffier, appears to "round out" the face, and the face appears less "drawn" or "hollow" with slightly less emphasis on the jaw due to the lower portion of the cheeks having filled in.
- Estrogens may predispose to gallbladder disease - especially in older and obese people.
- Estrogens (especially oral forms) may cause elevations in transaminases (liver function tests) indicating liver toxicity. LFTs should therefore be periodically monitored in transgender women.
- Mood changes can occur, such as the development of depression. However, many trans women report significant mood-lifting effects from HRT as well. In addition, the risk of depressive side effects is more particularly common in those who take progestins. Medroxyprogesterone acetate, in particular, has been shown to cause depression in certain individuals, perhaps due to its possible effect on dopamine levels; though, this effect may be largely reliant on its strong inhibitory effects on sex hormone production, something that would not apply to trans women because they replace their endogenous hormones with exogenous sources.
- Migraines can be made worse or unmasked by estrogen therapy.
- Estrogens can induce the development of prolactinomas, which is why prolactin levels should periodically be monitored in transgender women. Milk discharge from the nipples can be a sign of elevated prolactin levels. If a prolactinoma becomes large enough, it can cause visual changes (especially decreased peripheral vision), headaches, mood changes, depression, dizziness, nausea, vomiting, and symptoms of pituitary failure like hypothyroidism.
- Some people have noticed a feeling of calmness/self-contentment after starting HRT.
- Recent studies have indicated that cross-hormone therapy in trans women may result in a reduction in brain volume towards female proportions.
- Estrogen therapy causes decreased insulin sensitivity which places transgender women at increased risk of developing type II diabetes.
- One's metabolism slows down and one tends to gain weight, lose energy, need more sleep, and become cold more easily. Due to androgen deprivation a loss of muscle tone, a slower metabolism, and physical weakness becomes more evident. Building muscle will take more work than before. The addition of a progestogen may increase energy although an increase in appetite may be seen as well.
Hormone levels 
Israel et al. have suggested that for pre-castration MTF individuals, therapeutic estrogen levels should optimally be above the normal female range but not more than twice the maximum for the female range, and testosterone levels should optimally fall within the normal female range. However, before castration, it may prove difficult to the extent of being impractical to fully suppress testosterone levels, in which case they may be allowed to fall between the high female and low male ranges instead. In post-castration MTF persons, Israel et al. recommend that both estrogen and testosterone levels fall exactly within the normal female ranges. See the table below for all of the precise values they suggest.
|Hormone||Bio. female ref. range||Bio. male ref. range||Optimal trans. female (MTF) range||Optimal trans. male (FTM) range|
|Estrogen (total)||40–450 pg/mL||< 40 pg/mL||400–800 pg/mL (pre-castration)
40–400 pg/mL (post-castration)
|< 400 pg/mL (pre-castration)
< 40 pg/mL (post-castration)
|Testosterone (total)||25–95 ng/dL||225–900 ng/dL||95–225 ng/dL (pre-castration)
25–95 ng/dL (post-castration)
|225–900 ng/dL (pre-castration)
225–900 ng/dL (post-castration)
The optimal ranges listed for estrogen only apply to individuals taking bioidentical hormones (i.e., estradiol, including esters) and do not apply to those taking synthetic or other non-bioidentical preparations (e.g., ethinyl estradiol or conjugated equine estrogens (Premarin)).
Male and female reference ranges for hormones and other compounds are not exact and usually vary slightly depending on the source referenced. The same applies to optimal MTF (and FTM) ranges, naturally.
See also 
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