Hormone replacement therapy (trans)

Hormone replacement therapy (HRT) for transgender and transsexual people replaces the hormones naturally occurring in their bodies with those of the other sex. Its purpose is to cause the development of the secondary sex characteristics of the desired gender. It can not undo the changes produced by the first natural occurring puberty of transgender people, this is done by sexual reassignment surgery and for transwomen by epilation. Some intersex people also receive HRT, either starting in childhood to confirm the gender they were assigned, or later, if this assignment has proven to be incorrect.

While some argue that hormonal therapy does not truly masculinize or feminize, the question is one of definitions. If by masculinize and feminize one means to completely reproduce the male or female biological state, that cannot be done with current medical or surgical therapy. However, the goal of HRT, and indeed all somatic treatments, is to provide patients with a more satisfying body that is more congruent with their true psychological gender identity. It should be noted that the effects of hormonal therapy are often much more satisfying to transgender men than transgender women. It is easier to produce secondary male sexual characteristics with androgens than it is to rid transgender 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 counselling is required, and so is a time of living in the desired gender role, if that is at all possible, in order to assure that they can psychologically function in that gender role. This period is sometimes called the Real Life Experience (RLE). See also Standards of care for gender identity disorders.

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 3 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. Individuals seeking physicians who are knowledgeable and willing to treat transgender patients may wish to consult transgender support groups or a directory of LGBT-friendly doctors, in the USA for example the Gay and Lesbian Medical Association's referral service at GLMA.org.

Changes established at puberty
A number of skeletal and cartilaginous changes take place after the onset of puberty at various rates and times. Sometime in the late teen years epiphyseal clusure (in other words, the ends of bones are fused closed) takes place and the length of bones is fixed for life. Consequently total height and the length of arms, legs, hands, and feet are not affected by HRT. However, details of bone shape change throughout life, bones becoming heavier and more deeply sculptured under the influence of testosterone. Many of these differences are described in the Desmond Morris book Manwatching.


 * Pelvis: The pelvis in females tends to be wider than in males and tilted forward; the pelvis in males tends to be more circular and tilted upwards.
 * Hands: Male hands and feet tend to be larger than female hands and feet in persons of equal height.
 * Upper Arm: The upper arm in females tends to be significantly longer (about 1") than in males of the same height.
 * Head: Females tend to have smaller heads than males of the same height.
 * Chest: Female ribcages tend to be narrower than those of males.  (Need to know if this is true for individuals of the same body size.)

Facial changes develop gradually over time, and sexual dimorphism (physical difference between the sexes) tends to increase with age. Within a population of similar body size and ethnicity:


 * Brow: Males tend to develop heavier bony brows than females.
 * Cheeks: Female cheeks tend to be fuller and more rounded.  Under the influence of estrogen, fat is deposited beneath the skin and overall facial and body contours become softer.
 * Nose: The tips of the nasal bones tend to grow more in males than females, creating a larger (longer or wider) nose.
 * Jaw: The jaw in males tends to grow wider and more deeply sculptured than in females.
 * Larynx: At puberty, the bones and cartilage of the voicebox tend to enlarge less in females than males. In some males, the larynx becomes visible as a bony "adam's apple."

HRT female-to-male
For transmen, taking androgens (i.e. testosterone) causes reversible and irreversible changes.

Irreversible changes

 * deepening of the voice,
 * growth of facial and body hair,
 * male pattern baldness (in some individuals),
 * an enlargement of the clitoris,
 * growth spurt and closure of growth plates if given before the end of puberty, and
 * possible shrinking and/or softening of breasts, although this is due to changes in fat tissue.

Reversible changes

 * increased libido,
 * redistribution of body fat,
 * cessation of ovulation and menstruation,
 * further muscle development (especially upper body),
 * increased sweat and changes in body odor,
 * prominence of veins and coarser skin,
 * acne (especially in the first few years of therapy),
 * alterations in blood lipids (cholesterol and triglycerides), and
 * increased red blood cell count.

The psychological changes are harder to define, since HRT is usually the first physical action that takes place when transitioning. This fact alone has a significant psychological impact, which is hard to distinguish from hormonally induced changes. Most transmen report an increase of energy and an increased sex drive. Many also report feeling more confident.

While a high level of testosterone is often associated with an increase in aggression, this is not a noticeable effect in most transmen. HRT doses of testosterone are much lower than the typical doses taken by steroid-using athletes, and create testosterone levels comparable to those of most non-trans men. These levels of testosterone have not been proven to cause more aggression than comparable levels of estrogen. It is assumed that the effect of the start of physical treatment is such a relief, and decreases pre-existing aggression so much, that the overall level of aggression actually decreases.

Some transmen are unable to pass as men without hormones. The most commonly cited reason for this is that their voice may reveal them.

Contraindications
Several contraindications to androgen therapy exist. An absolute medical contraindication is pregnancy

Relative medical contraindications are:
 * androgen sensitive epilepsy,
 * migraines,
 * sleep apnea,
 * polycythemia (elevated red blood cell count,)
 * cardiac failure, renal failure, or severe hypertension susceptible to salt retention and fluid overload
 * significant liver disease
 * coronary artery disease or risk factors for CAD
 * history of uterine cancer
 * bleeding disorders (for injected testosterone)
 * significant history of violent behavior
 * history of breast cancer (testosterone has anti-proliferative effects on most but not all breast cancers)

Types of androgen therapy
The half-life of testosterone in blood is about 70 minutes, so it is necessary to have a continuous supply of the hormone for masculinization.

Injected
'Depot' drug formulations are created by mixing a substance with the drug that slows its release and prolongs the action of the drug. The two primarily used forms in the US are the testosterone esters testosterone cypionate (Depo-Testosterone) and testosterone enanthate (Delatestryl) which are almost interchangeable. Enanthate is purported to be slightly better with respect to even testosterone release, but this is probably more of a concern for bodybuilders who use the drugs at higher doses (250-1000 mg/week) than the replacement doses used by transgender men (50-100mg/week.) They are mixed with different oils, so some individuals may tolerate one better than the other. Enanthate costs more than cypionate and is more typically the one prescribed for hypogonadal males in the US. Cypionate is more popular in the US than elsewhere (especially amongst bodybuilders.) Other formulations exist but are more difficult to come by in the US. Sustanon is a formulation that mixes shorter acting and longer acting testosterone preparations that gives more even levels of testosterone with injections given every three weeks. A newly marketed formulation of injected testosterone available in Europe, Nebido (testosterone undecanoate in oil) provides significantly improved testosterone delivery with far less variation outside the eugonadal range than other formulations with injections required only four times yearly. However, each quarterly dose requires injection of 4ml which may require multiple simultaneous injections. Nebido is also much more expensive and currently unavailable in the United States.

The adverse side effects of injected testosterone esters are generally associated with high peak levels in the first few days after an injection. Some side effects may be ameliorated by using a shorter dosing interval (weekly or every ten days instead of twice monthly with enanthate or cypionate.) 100 mg weekly gives a much lower peak level of testosterone than does 200 mg every two weeks, while still maintaining the same total dose of androgen. This benefit must be weighed against the discomfort and inconvenience of doubling the number of injections.

Injected testosterone esters should be started at a low dose and titrated upwards based on trough levels (blood levels drawn just before your next shot.) A trough level of 500 ng/dl is sought. (Normal range for a biological male is 290 to 900 ng/dl.)

Transdermal
Both testosterone patches and gels are available. Both approximate normal physiological levels of testosterone better than the higher peaks associated with injection. Both can cause local skin irritation (more so with the patches.)

Patches slowly diffuse testosterone through the skin and are replaced daily. The cost varies, as with all medication, from country to country, it is about $150/month in the US, and about 60 Euros in Germany.

Transdermal testosterone is available in the United States under the brand names Androgel and Testim. Both are absorbed quickly when applied and produce a temporary drug depot in the skin which diffuses into the circulation, peaking at 4 hours and decreasing slowly over the rest of the day. The cost varies, as with all medication, from country to country, it is about $150/month in the US for either brand name drug. However, certain pharmacies are able to compound the drug more cheaply.

Transdermal testosterone poses a risk of inadvertent exposure to others who come in contact with the patient's skin. This is most important for patients whose intimate partners are pregnant or those who are parents of young children as both of these groups are more vulnerable to the masculinizing effects of androgens. Case reports of significant virilization of young children after exposure to topical androgen preparations (both prescription and 'supplement' products) used by their caregivers demonstrates this very real risk.

Testosterone pellets
6-12 pellets are inserted under the skin every three months. This must be done in a physicians office, but is a relatively minor procedure done under local anesthetic. Pellets cost about $20 each, so the cost is greater than injected testosterone when the cost of the physician visit and procedure are included. The primary advantages of Testopel are that it gives a much more constant blood level of testosterone yet requires attention only four times yearly.

Oral
Not frequently used in the US, sometimes used in Europe. Once absorbed from the GI tract testosterone is shunted (at very high blood levels) to the liver where it can cause liver damage and worsens some of the adverse effects of testosterone - lower SHBG levels, lower HDL (good) cholesterol. In addition, the ‘first pass’ metabolism of the liver also may result in testosterone levels too low to provide satisfactory masculinization and suppress menses. The safest of the oral formulations is Andriol (testosterone undecanoate) which is not available in the US.

Sublingual/Buccal
In 2003 the FDA approved a buccal form of testosterone (Striant®.) Sublingual testosterone can also be made by some compounding pharmacies. Cost for Striant® is greater than other formulations ($180-210/month.) Testosterone is absorbed through the oral mucosa and avoids the 'first pass metabolism' in the liver which is cause of many of the adverse effect with oral testosterone. The lozenges can cause gum irritation, taste changes, and headache but most side effects diminish after two weeks. The lozenge is 'mucoadhesive' and must be applied twice daily.

GnRH agonists
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 agonists, such as nafarelin can be used to suspend the advance of sex steroid induced, inappropriate pubertal changes for a period without inducing any changes in the gender-appropriate direction. GnRH agonists work by initially over stimulating the pituitary then rapidly desensitizing it to the effects of GnRH. Over a period of weeks, gonadal androgen production is greatly reduced. There is considerable controversy over the earliest age, and for how long it is clinically, morally and legally safe to do this. The Harry Benjamin International Gender Dysphoria Association Standards of Care permit from Tanner Stage 2, but do not allow the addition of gender-appropriate hormones until 16, which could be five or more years. The sex steroids do have important other functions. The high cost of GnRH agonists is often a significant factor.

Progestin injections
Depo-Provera (depot medroxyprogesterone acetate, or DMPA) may be injected every three months just as it is used for contraception. Generally after the first cycle, menses are greatly reduced or eliminated. This may be useful for transgender men prior to initiation of testosterone therapy.

Supplements
Andro ‘Pro-hormones’: Androstenedione, 4-androstenediol, 5-androstenediol, 19-androstenediol, and 19-norandrostenediol are sold as supplements that are purported to increase serum testosterone, increase muscle mass, decrease fat, elevate mood, and increase sexual performance (i.e. many of the effects transgender men seek with androgen therapy.) However, there is no good medical evidence that the pro-hormones do any of these things. However, there is evidence that ingestion of these substances can cause elevated estrogen levels, and decreases in HDL (good) cholesterol.

Cardiovascular

 * In biological men, testosterone levels that are either significantly above or below normal are associated with increase cardiovascular risk. This may be causative or simply a correlation.
 * A single retrospective study in the medical literature of 293 transmen treated with testosterone (range of 2 months to 41 years) by the Amsterdam Gender Dysphoria Clinic from 1975 to 1994 showed no increase in cardiovascular mortality or morbidity when compared with the general female Dutch population. (As with all scientific studies, this does not conclusively prove that no causal link exists. A small to moderate detrimental effect remains a possibility, though a very large effect is more unlikely.)
 * Androgen therapy does adversely affect the blood lipid profile by causing decreases in HDL (good) cholesterol, increases in LDL (bad) cholesterol, and increases in triglycerides.
 * Androgen therapy redistributes the fat toward abdominal obesity, which is associated with increased cardiovascular risk than fat carried on the buttocks and hips.
 * Androgen therapy can cause weight gain and decreased insulin sensitivity (perhaps worsening a predisposition to develop Type II diabetes.)
 * Androgen therapy effects are not all negative, however. Acutely it causes dilation of the coronary arteries, and in men with testosterone levels within the normal physiological range, higher levels are actually associated with a slight decrease in cardiovascular disease.
 * Supra-physiological levels of androgens (generally due to abuse) are associated with significantly increased risks of strokes and heart attacks (even in the young.) More is not better!
 * Cardiovascular risk factors are more than additive. (If high blood pressure is worth 10 and smoking is worth 10, together they are worth more than 20.) So for transgender men, the addition of risk with androgen therapy makes improving modifiable risk factors more important.
 * The most important modifiable risk factor for many men is smoking.

Hair
With either minoxidil or finasteride the beneficial effect will be lost within months upon ceasing use of product. With either, best results occur when they are started before significant hair loss has occurred.
 * The action of testosterone on hair follicles is mainly due to the more potent androgen, dihydrotestosterone, DHT.
 * With androgen therapy, genetics primarily determines how much hair will develop (and where) as well as whether male pattern baldness will develop.
 * Testosterone is converted (within the cells of the hair follicle's dermal papilla) by 5-alpha reductase to DHT. There are two forms of this enzyme: type 1 and 2. However, type 2 is the form that is important to the development of male pattern baldness. Male pseudohermaphrodites with congenital deficiency of type 2 5-alpha reductase (but functional Type 1) never develop male pattern baldness.
 * Propecia (Finasteride) and Avodart (Dutasteride) are Type-2, 5-a-Reductase inhibitors that work by blocking the conversion of testosterone to DHT. While they will not make facial hair growth that has occurred regress, they may slow or prevent further development of new facial hair. Finasteride is sold as 5mg tablets as ‘Proscar’ which is used to treat prostate enlargement and ‘Propecia’ as 1 mg tablet to treat baldness. The cost of 'Propecia' per mg is significantly higher than 'Proscar' so some patients split tablets into quarters. At the 1-1.25mg/day dose it may also decrease libido.
 * Saw palmetto is a naturally occurring 5-alpha reductase inhibitor which is used by some to treat male pattern baldness and prostate enlargement.
 * Rogaine (Minoxidil – available without a prescription in the US) is a topical preparation of a potent blood pressure medicine. It is sold as 2% and 5% solutions. The 5% solution is not recommended for use by women because it may cause the adverse effect of unwanted facial hair growth in a small percentage of women. It may also cause skin irritation and itching. One ml is applied twice daily to the scalp (predominantly in the areas where hair loss is greatest.) It may take several months to show effects and may cause a slight paradoxical worsening of hair loss initially (that does eventually recover.)

Gynecological effects

 * Menses should cease within 5 months of testosterone therapy (often sooner.) If bleeding continues past 5 months, transmen must see a gynecologist.
 * Clitoromegaly occurs, and frequently reaches its apex within 2-3 years of therapy. Sizes generally range from 3-8 cm with 4-5 cm being about average. This is genetically determined, but some physicians advocate topical clitoral testosterone as an adjunct to growth before metaidioplasty. However, this testosterone is absorbed and should be calculated into your total regimen.
 * After long-term androgen therapy, ovaries may develop polycystic ovary syndrome (PCOS) morphology. (In both PCOS and transgender men there is an up-regulation of testosterone receptors in the ovaries.)
 * Untreated PCOS is associated with a possibly increased risk of endometrial cancer as well as decreased fertility.
 * It is unknown whether the risk of ovarian cancer is increased, decreased or unchanged in transgender men compared to women. It is unlikely to be determined in the near future because ovarian cancer is a relatively rare disease and the population of transgender men is too small to do the appropriate study. However, it has been recommended by some physicians that transgender men have an oophorectomy within 2-5 years of starting androgen therapy due to the possible increased risk. (Note: Testosterone dose can frequently be decreased after oophorectomy.)
 * The risk of endometrial cancer is similarly unknown. However, A high prevalence of endometrial hyperplasia has been noted in a small study of transgender men undergoing hysterectomy. (Futterweit W, and Deligdisch L. “Histopathological effects of exogenously administered testosterone in 19 female to male transsexuals.” J Clin Endo & Metab. 62(1):16-21. 1986.)

Frequently the first sign of endometrial cancer is bleeding in post-menopausal women. Transgender men who have any bleeding after the cessation of menses with androgen therapy should have an endometrial biopsy (and possibly an ultrasound) done to rule-out endometrial cancer.
 * Some sources recommend endometrial ultrasounds every two years. Testosterone usually causes atrophy of the endometrium. Any transgender man with an endometrium that is not thinned on ultrasound should have a biopsy to evaluate for endometrial cancer and possibly use progesterone to cause sloughing of the endometrium. Vaginal bleeding from progesterone may be emotionally uncomfortable for a transman, but it is preferable to developing endometrial cancer.
 * Until recently, any adult with a uterus/cervix was advised to have a Pap smear yearly. This interval might be increased to every 2-3 years for certain people on the advice of a gynecologist. However, recent research has linked cervical cancer to a sexually transmitted virus; transmen who have never had vaginal sex may not be at risk.  However, since the long-term effects of testosterone on cervical tissues are not well understood, Pap smears may be considered a general precaution.
 * Some transgender men report a decrease in breast size with androgen therapy. However, no morphological changes were found when this was studied and likely it is due to loss of fat in the breasts.
 * Androgen therapy (and suppression of estrogen production) may cause vaginal atrophy and dryness, which may result in dyspareunia (painful vaginal intercourse.) This can be alleviated with topical estrogen cream.
 * Most transgender men report a significantly increased libido. Some report that this decreases somewhat after several years on testosterone. (Natural testosterone levels peak in women just before ovulation which may account for the mid-cycle increase in libido many women experience.)

Childbearing

 * As the age at which transgender people begin therapy decreases, retention of reproductive potential becomes more important.
 * If a transgender man has not undergone hysterectomy and oophorectomy, he may regain fertility on cessation of testosterone. With the ovarian changes of long-term androgen therapy, however it may require months of cessation of testosterone and possibly assistive reproductive technology to become pregnant. Testosterone must be withheld for the duration of pregnancy.
 * If a transgender man is planning on having a hysterectomy/oophorectomy, future reproduction may still be preserved by:
 * Oocyte banking – hormonal stimulation to ‘hyper-ovulate’ with transvaginal oocyte harvest for freezing. Very poor survival of banked oocytes.
 * Embryo banking – oocyte harvest as above with immediate fertilization and banking of the embryo. Much better survival, but the sperm donor must be chosen before oophorectomy.
 * Ovarian tissue banking – probably the best option. Ovarian tissue is frozen after oophorectomy. Even after long term androgen therapy, ovaries usually retain usable follicles. Eventual use of frozen ovaries will require replantation into the transgender man for stimulation and harvest, but may eventually be possible in a lab as techniques for tissue culture improve.

Bone

 * 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.)
 * Testosterone may cause an increase in cortical bone thickness in transgender men (however this does not necessarily translate to a greater mechanical stability.)
 * Transgender men who have been oophorectomized must continue androgen therapy to avoid premature osteoporosis. Estrogen supplementation is theoretically not usually necessary, as some of the injected testosterone will be aromatized into estrogen sufficient to maintain bone (as it does in biological men.) However, a single small study of transmen after oophorectomy demonstrated that androgens alone may be insufficient to retard bone loss. (van Kesteren P, et al. “Long-term follow-up of bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones.” Clin Endocrin. 48(3):347-54. 1998.) It is likely the case that pre-oophorectomy, residual estrogen production is protective. However, after oophorectomy, some transmen may have insufficient estrogen to retard bone loss.
 * Some physicians advocate a Dexa (bone density) scan at the time of oophorectomy and every year or two thereafter to diagnose osteoporosis before it becomes severe enough to be symptomatic. This is important because treatment of osteoporosis is most effective if done early.
 * Daily calcium supplementation and possibly Vitamin D is probably a good idea for most transgender men, but it is even more important after removal of the ovaries.

Drug interactions
Testosterone (and all the sex steroids) are metabolized by the Cytochrome P-450 enzyme system in the liver. (Specifically CYP3A.) There are certain drugs that increase or decrease the activity of this enzyme and may cause increased or decreased levels of testosterone and other sex steroids. Testosterone can also alter the effects of other drugs: Because of these interactions, it is imperative that transmen tell any health care provider that he sees for any reason that he is on androgen therapy (and any other medication or supplement that he takes.)
 * Cyt P-450 Inducers – May cause decreased levels of testosterone (and other sex steroid) levels: Phenobarbital and Dilantin (seizure medicines,) Rifampin (antibiotic,) and Alcohol!
 * Cyt P-450 Inhibitors – May cause increased levels of testosterone: Serzone, Prozac, Paxil (antidepressants,) Sporanox, Diflucan, and other ‘azole’ antifungals, Tagamet (anti-ulcer agent that can cause gynecomastia in men because of this effect.) Biaxin and other ‘erythromycin type’ antibiotics, Protease Inhibitors (HIV treatment.)
 * Increases the blood thinning effect of Coumadin (warfarin.)
 * Decreases the effectiveness of Inderal (propranolol) a blood-pressure medicine.
 * Increases the effect of some oral medicines for diabetes and can cause dangerously low blood sugar levels.

Obstructive sleep apnea

 * OSA may be worsened or unmasked by androgen therapy.
 * Risk is greater in transgender men who are obese, smoke, or have COPD (Chronic Obstructive Pulmonary Disease.)
 * Untreated OSA may have significant adverse effects on the heart, blood pressure, mood, and may cause headaches and worsen seizure disorders.
 * Symptoms of OSA are noisy sleeping (snoring,) excessive daytime sleepiness, morning headache, personality changes, and problems with judgment, memory, and attention.

Polycythemia

 * Increased red blood cell mass usually from overproduction by the bone marrow.
 * Testosterone (frequently in large doses) was previously used to treat anemia from bone marrow failure.
 * A transgender man’s hematocrit (the percentage of whole blood made up of red blood cells) should be judged against normal age adjusted values for men.
 * Therapy is via phlebotomy (periodic therapeutic blood draws similar to blood donation.)
 * Tendency to become polycythemic worsens with age.
 * Worse with injected testosterone (especially with longer intervals between doses) than with oral, transdermal, or Testopel. (Increase in RBCs occurs with the very high peaks from injection. So decreasing dose and interval to 7-10 days instead of 14 may help.)
 * Severe polycythemia predisposes to both venous and arterial thrombosis (blood clots) such as: deep venous thrombosis, pulmonary embolism, heart attack, and stroke.
 * Aspirin may decrease the risk

Skin

 * Increased activity of oil and sweat glands.
 * Change in body odor – less sweet and musky, more metallic and acrid.
 * If severe odor is a problem, an antibacterial soap like chlorhexidine may be used in the armpits when showering. After 1-2 weeks of daily use, a noticeable decrease in odor should occur.
 * Acne: generally worse the first few years of testosterone therapy (mimicking a second puberty.) Can be treated with standard acne therapy. Initial treatment is with increased cleansing (at least twice daily) with an anti-acne or oil reducing scrub. If this doesn’t work, additional therapy may be prescribed by a physician.
 * Some physicians see acne as a contraindication to increasing testosterone dose.

Gastrointestinal

 * There is a risk of liver damage and liver cancer with all testosterone formulations, but this is minimal with all forms except oral or unless very high levels are administered. However, as with any drug that carries even a small risk of liver damage, liver function tests (or at least ALT) should be periodically monitored.

Neurological/Psychiatric

 * Headaches: Pre-existing migraine headaches can be significantly worsened with androgen therapy. Headaches can also become problematic in men without prior headache disorders.
 * Epilepsy: some seizure disorders are androgen-dependent. These may be worsened or (very rarely) unmasked with androgen therapy.
 * Sleep deprivation worsens almost all seizure disorders, so concurrent obstructive sleep apnea caused or worsened by androgen therapy may also be responsible.
 * Some transgender men report mood swings, increased anger, and increased aggressiveness after starting androgen therapy (similarly to the effects reported with body builders who abuse androgens.) This is much less severe however than the ‘roid rage’ experienced by bodybuilders because with transgender men significantly supraphysiologic levels are not present.
 * Many transgender men, however, report improved mood, decreased emotional lability, and a lessening of anger and aggression. Likely this is not a physiologic effect but rather the alleviation of emotional distress from long-standing gender dysphoria.
 * Recent studies have indicated that cross-hormone therapy in transmen may result in an increase in brain volume towards male proportions.

Metabolic

 * Testosterone increases body weight (and increases appetite.) The form that this weight gain will take depends on diet and exercise as well as genetic factors. Since testosterone has anabolic effects, gain of lean muscle mass will be easier than it previously was for transgender men. Moderate amounts of exercise will cause greater gains and will ameliorate some of the adverse effects of testosterone.
 * Many transgender men report an increased energy level, decreased need for sleep, and increased alertness after testosterone therapy.
 * In biological men, abnormally high or low levels of testosterone are both associated with insulin resistance (which eventually can result in Type II diabetes.) So mid-normal levels of testosterone are the target for androgen therapy.
 * In women, increased levels of either estrogen or androgens are associated with decreased insulin sensitivity (which may predispose to diabetes.) In a study of transgender males and females, decreased insulin sensitivity was found in both populations after four months or hormonal treatment. (Polderman K, et al. “Induction of insulin resistance by androgens and estrogens.” J Clin Endo Metab. 79(1):265-71. 1994.)

HRT male-to-female
For transwomen, taking estrogens causes among other changes:
 * the growth of breasts, with concomitant enlargement of the nipples, and
 * redistribution of body fat.
 * thinning of skin.

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

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

Irreversible changes

 * breast development,
 * enlarged nipples and areolae
 * stretch marks (for some)

Reversible changes

 * decreased libido,
 * redistribution of body fat,
 * reduced muscle development,
 * various skin changes,
 * significantly reduced body hair,
 * change in body odor and sweat production,
 * less prominence of veins,
 * ocular changes,
 * genital size

The psychological changes are harder to define, since HRT is usually the first physical action that takes place when transitioning. This fact alone has a significant psychological impact, which is hard to distinguish from hormonally induced changes. Many also report feeling more confident.

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.

Estrogens

 * Doses are often higher than replacement doses for cisgender women. 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 anti-androgens 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, sublingual, gel, and transdermal patch formulations are available.
 * As dosage increases, risks increase as well. Therefore, women with relative contraindications should start at lower doses and increase dosage more gradually.
 * Transdermal estrogen may be preferable in older transwomen and smokers as it may have less of an increase in risk for thromboembolism. However, the number of patches needed and cost may make this less practical. Furthermore, transdermal estrogen carries the risk of localised skin irritation.

Progestogens

 * Progestogens include progesterone and progestins (synthetic analogs of progesterone or 17-alpha hydroxyprogesterone). There are oral, sublingual, suppository, gel, and injectable formulations available.
 * Progestogens are involved in the full maturation of the breasts, particularly the mammary structures lobules, acini, and alveoli.
 * Progestogens also help 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 increase energy. Progesterone in particular is essential for bone health and seems to have a role in skin elasticity, nerve tissue, and respiration. 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. 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.

Anti-androgens

 * Spironolactone is the most frequently used anti-androgen 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 one of the enzymes involved in its production   and is a weak androgen receptor antagonist (prevents androgens from binding to androgen receptors).
 * Cyproterone acetate is derived from 17-alpha hydroxyprogesterone and suppresses luteinizing hormone (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 anti-androgens 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 anti-androgens 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 anti-androgen.
 * Certain anti-androgens 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 agonists

 * 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 agonists, 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 in the gender-appropriate direction. 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. 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 Harry Benjamin International Gender Dysphoria Association Standards of Care permit from Tanner stage 2, but do not allow the addition of gender-appropriate hormones until 16, which could be five or more years. The sex steroids do have important other functions. Also skeletal growth, which is often considered to be masculinising, is not hindered by GnRH agonists.
 * GnRH agonists 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 agonists is often a significant factor.

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. Hormones should be withheld for a week before 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 greater with oral rather than transdermal or injectable estrogens.
 * DVT risk also increases with age and with smoking, so many clinicians advise using the safer transdermal 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 150mg/day bicalutamide. This prompted Health Canada to withdraw its approval for 150mg 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 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.

Hair

 * Current facial hair is only slightly affected (some reduction in density, coverage, and slower growth) by anti-androgens. 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 anti-androgens. Those taking anti-androgens 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, rear, 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 upon the dosage of anti-androgens. 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, for heterosexual or bisexual transsexual women, an aversion to anal sex) and for post-operative transsexual women how satisfied they are with the results. Raising estrogen dosage or adding a progestogen has also raised the libido of some transwomen.
 * Spontaneous and morning erections decrease in frequency significantly, however some who have had an orchiectomy still experience morning erections. Voluntary erections can be maintaned 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, 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

Childbearing

 * Childbearing, as experienced by cisgender 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.

Bone

 * 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.

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 suscepitable 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 anti-androgens (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.

Senses

 * Sensitivity to male body odor(s) (including male pheromones) may be positively correlated with elevated estrogen levels. Overall, olefactory senses may increase. Progestogens, however, often lowers 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. MtF who undergo HRT often experience breast development which is below the comparable natal 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 than in natal females, i.e., if a natal female and a transsexual female were to have the same cup size, the transsexual female's breasts would most likely appear smaller. Thus when a transsexual female opts to have breast augmentation, the implants used, are on the average, larger than those commonly used by natal females.
 * The nipples will 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.

Gastrointestinal

 * 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

Neurological/Psychiatric

 * Mood changes can occur - including the development of depression, particularly in those who take progestins
 * 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 transwomen may result in a reduction in brain volume towards female proportions.

Metabolic

 * 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 twice as much work than before. However, the addition of a progestogen may increase energy although an increase in appetite may be seen as well.