Hormone replacement therapy (male-to-female)

Hormone replacement therapy of the male-to-female type (MTF HRT) is a type of hormone replacement therapy for transgender and transsexual people. It changes the balance of sex hormones in the body. Some intersex people also receive HRT, either starting in childhood to confirm the assigned sex, or later, if the 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).

Formal requirements for HRT

The requirements for hormone replacement therapy vary immensely, often psychological counselling is required.

Under WPATH guidelines, mental health providers require individuals to satisfy two sets of criteria — eligibility and readiness — to undertake any stage of transition including hormone replacement therapy. Eligibility involves the patient meeting requirements from a major diagnostic tool, such as the ICD-10, DSM-IV-R or the DSM-V. ICD-10 requirements are for either Transsexualism or Gender identity disorder of childhood.^[1]

The ICD-10 criteria for Transsexualism include the individual having a transsexual identity of over 2 years, a strong and persistent desire to live as a member of the opposite sex, usually accompanied by the desire to make their body as congruent as possible with the preferred sex through surgery and hormone treatments. These individuals cannot be diagnosed with Transsexualism if it is believed to be a result of another mental disorder, or a genetic, intersex or chromosomal abnormality.

The ICD-10 criteria for Gender identity disorder of childhood in males include the individual being pre-pubescent and having intense and persistent distress about being a boy. The distress must be present for at least six months. The child must either:

1. Have a preoccupation with stereotypical female activities, as shown by crossdressing, simulating female attire, or an intense desire to join in the games and pastimes of girls, rejecting male games and pastimes.
2. Have persistent denial relating to their male anatomy. This can be shown through believing they will grow up to be a woman, that their penis or testes are disgusting or will disappear, or that it would be better not to have a penis.

The DSM-IV-R criteria for Gender Identity Disorder includes four main criteria. The DSM-IV-R also requests that the individual's sexuality is noted.

Strong and persistent cross-gender identity

In children this may be demonstrated by them meeting four or more of the following criteria:

1. An insistence that one is or desires to be the other sex.
2. Girls(MTFs) must display a preference crossdressing or simulating female attire, and boys(FTMs) must persistently wear only stereotypical male clothing.
3. Persistent fantasies of being the other sex, or strong and persistent preference for cross-sex roles in make-believe play.
4. Intense desire to participate in stereotypical games of the other sex.

adolescents and adults must display a persistent desire to be the other sex, frequent passing as the other sex, desire to live or be treated as the other sex, or the conviction that they have the typical feelings and reactions of the other sex.

Persistent discomfort with their sex or a sense of inappropriateness in the gender role of that sex

In boys this may manifest as an assertion that their penis or testes are disgusting or will disappear, or asserting that it is better not to have a penis.

In adults and adolescents this manifests as a preoccupation with removing primary or secondary sex characteristics, such as a demand for surgery or hormone replacement therapy.

The disturbance causes clinically significant distress or impairment in social, occupational or important areas of functioning

The DSM-V moves from Gender Identity Disorder to Gender Dysphoria to avoid the implication that gender nonconformity is in itself a mental disorder, but a similar entry remains in the DSM-V so that individuals may still seek treatment.^[2] The DSM-V, unlike the DSM-IV and ICD-10, separates Gender Dysphoria from sexual paraphilias, and diagnoses on the basis of a strong desire that one has feelings and convictions typical of the other sex, or that one strongly desires to be treated as the other sex or be rid of one's sex characteristics.

The readability of patients to transition is also relevant to undertake hormone replacement therapy, which includes the patient's likelihood to take hormones in a responsible manner, have made progress in mastering other identified problems that leads to improving or continuing stable mental health, and have had further consolidation of gender identity during psychotherapy or Real Life Experience of their desired gender role.^[3]

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 (WPATH). This period is sometimes called the Real Life Experience (RLE). The Endocrine Society in 2009 specified that individuals should either have a documented 3 months Real Life Experience or a period of psychotherapy of length specified by their mental health provider, usually a minimum of 3 months.^[3]

Some people, especially individuals from the transgender community, say that RLE is psychologically harmful and is a form of "gatekeeping" — effectively barring people from transitioning for as long as possible, if not permanently.

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. As many individuals must pay for evaluation and care out-of-pocket, expense can also be prohibitive to pursuing such therapy.

Aside from economic factors, self-medication can occur due to poor access to medication, even where health care is provided free. In a UK NHS patient survey conducted in 2008, 5% of respondents acknowledged resorting to self-medication. The report also highlights that 46% of NHS patients were dissatisfied with the duration endured in order to receive hormone therapy. In acknowledgement of this problem, the report in part concludes that "The NHS must provide a service that is easy to access so that vulnerable patients do not feel forced to turn to DIY remedies such as buying drugs online with all the risks that entails. Patients must be able to access professional help and advice so that they can make informed decisions about their care, whether they wish to take the NHS or private route without putting their health and indeed their lives in danger." ^[4] This recognizes that self-administration of certain medications (namely ethinyl estradiol) and antiandrogens (namely spironolactone, cyproterone acetate, flutamide, and nilutamide) is potentially dangerous and can cause an elevation in liver enzymes or other potentially dangerous adverse effects.^[5]

Medical contraindications

Some medical conditions may serve as a reason to withhold hormone replacement therapy due to the resultant harm that would be caused to the patient. These interfering factors are described in medicine as a contraindication.

• 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. In such cases the patient should be concurrently followed by an oncologist, hematologist or cardiologist, or neurologist, respectively.
• 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

Estrogens

• The dosages used are often higher than replacement doses for cisgender women, although the official guideline for endocrinologists recommends "maintain[ing] sex hormone levels within the normal range for the person’s desired gender".^[6] 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, and esterified estrogens.
• Injectable, implanted, nasal, oral, sublingual, 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.

Progestogens

• Progestogens include progesterone and progestins (synthetic progestogens). There are oral, sublingual, suppository, gel, and injectable formulations available.
• Progestogens, in conjunction with the hormone prolactin, are involved in the maturation of the lobules, acini, and areola during pregnancy, which are mammary structures that estrogen has little to no direct effect on.^[7] 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).^[8] 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.^[8] As of 2014, no additional study has looked at the issue again.^[9] Anecdotal evidence from trans women has suggested that those who take progesterone supplements may experience more full breast development, including development beyond Tanner stage 4 (as many trans women do not develop Tanner 5 breasts). However, there have been no formal studies with sufficiently large sample sizes to indicate whether this merits closer investigation.
• Progestogens are involved in fat distribution (e.g., along with estrogen, increased fat deposition in gluteofemoral (buttock/thigh) regions),^[10][11] increase sex drive (only progesterone – via its active metabolite allopregnanolone (does not occur through activation of the progesterone receptor)),^[12][13] increase appetite and weight gain (only in the presence of estrogen),^[11] and produce a sense of calm (i.e., anxiolysis) and promote sleep (i.e., sedation/hypnotic effects).^{[14][15][16][17]}
• Progesterone in particular is essential for bone health and seems to have a role in skin elasticity and nervous system function.^[18] 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),^[19] 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.
• High doses of progestogens, via exerting negative feedback on the hypothalamic-pituitary-gonadal axis (HPG axis) through activation of the progesterone receptor, have antigonadotropic properties – that is, they suppress the gonadal production of sex hormones such as androgens. As such, sufficient dosages of progestogens, such as cyproterone acetate, megestrol acetate, medroxyprogesterone acetate, chlormadinone acetate, spironolactone, and progesterone, can help to reduce androgen levels.
• Certain progestins, including 19-nortestosterone derivatives, like levonorgestrel, norgestrel, norethisterone, and norethisterone acetate, as well as, to a lesser extent, the 17-hydroxyprogesterone derivative, medroxyprogesterone acetate (MPA), have weak androgenic properties via binding to and activating the androgen receptor similarly to testosterone, and can produce androgenic side effects such as acne, hirsutism, and increased sex drive.^[20][21][22] Conversely, certain other progestins, such as cyproterone acetate, megestrol acetate, and drospirenone, have antiandrogenic properties via binding to and blocking the activation of the androgen receptor.^[23]
• Androgenic progestins, such as medroxyprogesterone acetate and levonorgestrel, have been associated with an increased risk of breast cancer, which is not seen with progesterone (i.e., bioidentical or natural progestogen).^[24][25][26]
• Cyproterone acetate and spironolactone, in addition to their actions as antiandrogens, are also progestins, the former strongly and the latter relatively weakly so but still significantly.

Antiandrogens

• The most commonly used antiandrogens as a component of HRT for trans women include the steroidal antiandrogens spironolactone and cyproterone acetate. Spironolactone is the most frequently used antiandrogen in the United States. It is relatively safe and inexpensive. Cyproterone acetate, which is unavailable in the United States, is more commonly used in the rest of the world.
• Spironolactone is a potassium-sparing diuretic that is mainly used to treat low-renin hypertension, edema, hyperaldosteronism, and low potassium levels caused by other diuretics. It can cause high potassium levels, hyperkalemia, and is therefore contraindicated in people with renal failure or who otherwise have elevated potassium levels. Spironolactone prevents the formation of androgens in the testes (though not in the adrenals) by acting as a progestin and by inhibiting enzymes involved in androgen production,^[27][28][29] and is also an androgen receptor antagonist (that is, it prevents androgens from binding to and activating the androgen receptor).^{[30][31][32][33][34]}
• Cyproterone acetate is powerful antiandrogen and progestin that suppresses gonadotropin levels (which in turn reduces androgen levels), blocks androgens from binding to and activating the androgen receptor, and inhibits enzymes in the androgen biosynthesis pathway. It has been used as a means of androgen deprivation therapy to treat prostate cancer. If used long-term in dosages of 150 mg or higher it can possibly lead to liver damage or failure.^{[35][36][37][38][39][40][41][42][43]}
• Other antiandrogens that are used as a component of HRT for trans women include flutamide, nilutamide, and bicalutamide, all three of which are primarily used in the treatment of prostate cancer.^[44][45] Unlike spironolactone and cyproterone acetate, these antiandrogens are non-steroidal, pure androgen receptor antagonists and do not lower androgen levels but rather act solely to block androgens from binding to and activating the androgen receptor. However, they are very potent in doing so, and are highly effective as antiandrogens. Moreover, bicalutamide, due in part to its high selectivity for the androgen receptor, has improved tolerability and safety profiles relative to spironolactone and cyproterone acetate. Notably, bicalutamide has largely replaced flutamide and nilutamide in clinical practice, similarly due to improved tolerability and especially safety. Enzalutamide is a newer non-steroidal antiandrogen with greater antiandrogen efficacy that is still on-patent and is extremely expensive. Non-steroidal antiandrogens may be an appealing option for those who wish to better preserve sex drive and function^[46] and/or fertility,^[47] as well as for those who desire more selective action with a reduced side effect profile relative to the profiles of spironolactone and cyproterone acetate (which increase the risk of depressive symptoms, among other undesirable adverse effects).^[48]
• 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. These medications have also been found to be effective in the treatment of hirsutism in women.

GnRH analogues

• In both sexes, the hypothalamus releases gonadotropin-releasing hormone (GnRH) to stimulate the pituitary gland to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) which in turn cause the gonads to produce sex steroids such as androgens and estrogens. In adolescents of either sex with relevant indicators, GnRH analogues, such as goserelin acetate can be used to 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 previous, 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 a significant factor in their relative lack of use in transgender and transsexual individuals. However GnRH analogues are used as standard practice in the United Kingdom.

Effects of HRT

A trans woman before and after 28 months of HRT.

Overview

For trans women, taking estrogens causes, among other changes:

• Redistribution of body fat in a feminine pattern.
• Growth of the breasts, with accompanying enlargement of the nipples.
• Changes to androgenic (body) hair.
• Widening of the pelvis (in those who have not yet experienced epiphyseal closure).
• Thinning of the skin.

For male-to-female transgender people, HRT often includes antiandrogens in addition to the estrogens and progestogens mentioned above.

HRT does not usually cause facial hair growth to be impeded or the voice to change.

Partially reversible changes

• Breast development (may need reconstructive surgery to reverse the effect)^[49]
• Infertility, eventually leading to chemically induced aspermatogenesis. The reversibility of this effect depends on the length of time and effects of androgen suppressing substances. Androgen suppressing drugs are not a substitute for other birth control methods.

Reversible changes

• Decreased libido
• Redistribution of body fat (most of time)
• 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 "gonads" 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. A significant majority of the craniofacial changes occur during adolescence, although continual through much of adult life postadolescenct growth is considerably slower and minimal by comparison.^[50] Also unaffected is the prominence of the thyroid cartilage (Adam's apple). These changes may be reversed by surgery (facial feminization surgery and tracheal shave, respectively) instead.
• During puberty, the voice deepens in pitch and becomes more resonant, effects which are permanent and are not affected by HRT. Voice therapy and optionally surgery may be used instead to achieve a more female sounding voice.
• Facial hair develops during puberty, and this is a change that is only slightly affected by HRT. Facial hair may be near-permanently removed with laser hair removal or permanently with electrolysis instead.

Cardiovascular

• 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.^[51]
• 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 (i.e., without any other drugs).^[52] A study of prostate cancer patients also showed an increased number of deaths unrelated to cancer among patients taking 150 mg/day bicalutamide.^[53] This prompted Health Canada to withdraw its approval for 150 mg bicalutamide as monotherapy.^[54] The increased death rate has not been observed when bicalutamide is combined with a method of reducing androgen production, such as a GnRH analogue or orchiectomy. The reason for the increased rate of heart failure and death seen with bicalutamide monotherapy is not well-understood.

Hair

• 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 race generally lacks a significant amount of facial hair may 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.^[55][56]
• 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.^[55][56]
• 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.
• Eyebrows will not change as they are not androgenic.^[57]

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 may or may not be possible depending on the amount of hormones and/or antiandrogens being taken; it varies a lot depending on individual biochemistry, dosing, and anatomy.
• Testi volume is reduced by about 25% with typical dosages and as much as 50% in higher dosages, especially after a year of HRT.^[55] 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

• Childbearing, as experienced by cisgender women, is speculative with current 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. As of now, the first uterine transplant, done on October 4, in Sweden proved to be successful.^{[58][59][60][61]} 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.

However, a problem may arise with the structure of hip bones, since cisgender women generally have larger hip bones to accommodate pregnancy.

Bone

• Both estrogens and androgens are necessary in all humans 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.
• If estrogen therapy is conducted prior to the pelvis ossification that occurs around the age of 25, the pelvic outlet and inlet open slightly. This widening will also widen the femora as they are connected to the pelvis. The pelvis will still have some masculine characteristics by default but the end result will be wider hips than a normal male and closer to a cis female.

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.

Skin

• 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.^[62]
• 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.^[55][56]
• 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 fat tissue accumulates.^[55] 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.^{[63][64][65][66]}
• Due to the decreased androgens, the meibomian glands (that is the sebaceous gland on the upper and lower eyelids that open up at the edges) produce less oil, which is necessary for the tear film preventing the evaporation of the watery layer, causing the eyes to dry up more often.^{[67][68][69][70][71]}

Senses

• Sensitivity to male body odor(s) (including male pheromones) may be positively correlated with elevated estrogen levels. Overall, olfactory senses may increase.

Breast 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 transition, or for the size of one breast to be a little bigger than the other. Transwomen who undergo HRT often experience breast development which is below the comparable cis female norm (many seek breast augmentation); it is rare for an 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, causing the transwoman's breasts to most likely appear proportionally 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.^[55]
• The nipples often become more sensitive to stimulation.
• Many women in clinical trials used stem cells from fat to regrow breasts from total mastectomies. This would replace the need for artificial implantation.^[72]
• As in a cisgender woman during puberty, ducts and coopers ligaments will develop under the influence of estrogen. Progesterone will cause the actual milk sacks (alveoli) to grow and develop and given the right stimuli, the breasts can lactate as in a cis woman.

Fat tissue distribution

• Adipose (fat) tissue 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.^[55]
• 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.
• Gleuteofemoral fat ( fat on hips, thighs and buttocks) will begin to accumulate. This fat has a higher content of omega-3 fatty acids and its purpose is to be used for lactation.

Gastrointestinal

• Estrogens may predispose to gallbladder disease - especially in older and obese people.^[73]
• Estrogens (especially oral forms) may cause elevations in transaminases (liver function tests) indicating liver toxicity. LFTs should therefore be periodically monitored in transgender women.

Neurological/Psychiatric

• 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,^{[74][75][76][77][78]} perhaps due to its possible effect on dopamine levels;^[79] though, this effect may be largely reliant on its strong inhibitory effects on sex hormone production.
• 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.
• Recent studies have indicated that cross-hormone therapy in trans women may result in a reduction in brain volume towards female proportions.^[80]

Metabolic

• Estrogen therapy causes decreased insulin sensitivity which places transgender women at increased risk of developing type II diabetes.
• Metabolic rate can alter causing an increase or decrease in weight, energy levels, changes to sleep patterns and also temperature sensitivity. 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

During HRT, especially in the early stages of treatment, blood work should be consistently done to assess hormone levels and liver function. It is suggested by Endocrine Society that individuals have blood tests every 3 months in the first year of hormone replacement therapy for estradiol and testosterone and monitor spironolactone, if used, every 2–3 months in the first year.^[3]

Hormone	Endocrine Society [81]	Royal College of Psychiatry [82]
Estradiol Level (pg/ml)	Less than 200pg/ml	80-140pg/ml
Testosterone Level (ng/dl)	Less than 55 ng/dl	"Well below normal male range"

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)). While the ranges given are optimal, the Endocrine Society further state that estrogen levels of 200pg/ml ought not to be exceeded.^[83]

There should also be medical monitoring, including complete blood counts, renal and liver function, lipid and glucose metabolism, as well as monitoring prolactin levels, body weight and blood pressure.^[84]

See also

• Hormone replacement therapy (female-to-male)

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External links

• Hembree W, Cohen-Kettenis P, Delemarre-van de Waal H, Gooren L, Meyer III W, Spack N, Tangpricha V, Montori V (September 2009). "Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline" (PDF). The Endocrine Society/Journal of Clinical Endocrinology & Metabolism. Retrieved 20 July 2011.
• Dahl M, Feldman J, Goldberg J, Jaberi A, Bockting W, Knudson G, Goldberg J (January 2006). "Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines" (PDF). Vancouver Coastal Health Authority. Retrieved 20 July 2011.
• Tom Waddell Clinic Transgender Protocol - MTF and FTM clinical protocols aimed at providers
• Moore E, Wisniewski A, Dobs A (August 2003). "Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects". J. Clin. Endocrinol. Metab. 88 (8): 3467–73. doi:10.1210/jc.2002-021967. PMID 12915619. Retrieved 31 October 2013.