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Hormone replacement therapy (trans)

Hormone replacement therapy (HRT) for transgendered and transsexual people replaces the hormones naturally occuring in their bodies with those of the other sex. Its purpose is to cause the development of the secondary sexual characteristics of the desired gender. It can not undo the changes produced by the first natural ocurring puberty of transgendered 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 assigment has proven to be incorrect.

Formal requirements for HRT

The requirements for hormone replacement therapy vary very much, often at least a certain time of psychological counceling 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 Test (RLT). 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. However, this route is potentially dangerous.

HRT female-to-male

For transmen, taking androgens (i.e. testosterone) causes reversible and irreversible changes.

Changes

Irreversible changes:

• deepening of the voice,
• growth of facial and body hair,
• male pattern baldness,
• 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 in most transmen this is largely unnoticable.

Reversible changes:

• increased libido and changes in sexual behavior,
• redistribution of body fat,
• further muscle development and conditioning (especially upper body),
• increased sweat and body odor,
• weight gain and fluid retention,
• 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 incease 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. It is assumed that the effect of the start of physical treatment is so much of a relief, and therefore decreases pre-existing aggression so much, that even if the testosterone itself causes an increase in aggression, the total amount of aggression actually decreases.

Many transmen are unable to pass as men without hormones, especially their voice often gives them away. Also, the redistributing of facial fat can be very important for passing.

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

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 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 body-builders who abuse 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.

The adverse side effects of injected testosterone 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 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 gel 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. Cost is about $150/month in the US.

Androgel is absorbed quickly when it is applied and produces 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. Cost is about $150/month in the US.

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 most western countries. 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

Non-Testosterone Hormonal Therapy

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 GID, GnRH agonists can be used to delay pubertal changes which will make subsequent therapy in adulthood more effective. 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.

Progesterone depots:

Progesterone injected every three months as contraception. Generally after the first cycle, menses are greatly reduced or eliminated. 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.

Testosterone Effects:

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. (This doesn’t mean it’s not there, just that the study didn’t show it. A small to moderate detrimental effect is quite possible, 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 worse 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.
• For health maintenance and screening it is probably best to assume that a transman's cardiovascular risk is no worse than that of a male of similar age and health status but greater than that of a biological woman of similar age and health status.
• 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. In addition to the cardiovascular benefits though, tobacco abuse decreases testosterone uptake and increases its metabolism.

Hair:

• The action of testosterone on hair follicles is mainly due to the more potent androgen, dihydrotestosterone, DHT.
• Testosterone is converted (within the cells of the hair follicle) by Type II 5-a-Reductase to DHT.
• With androgen therapy, genetics primarily determines how much hair will develop (and where) as well as whether male pattern baldness will develop.
• Propecia (Finasteride) is a Type-2, 5-a-Reductase inhibitor that works by blocking the conversion of testosterone to DHT. While it will not make facial hair growth that has occurred regress, it 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. It is about $2.35/pill in the US (or $0.60/day if you cut tablets into quarters to take 1.25 mg day.) As ‘Propecia’ it is $1.60/1 mg tablet ($1.60/day to take 1mg/day – the recommended dose for hair loss.) At the 1-1.25mg/day dose it may also decrease libido.
• Rogaine (Minoxidil – available without a prescription in the US) is a topical preparation of a potent 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 an increased risk of ovarian and possibly 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 will probably never be known 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. In particular, however, it is important to remember that 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 must 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.
• Any transman with a uterus/cervix must have a Pap smear yearly. This interval may be increased to every 2-3 years on the advice of a gynecologist.
• 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. While estrogen supplementation is not usually necessary, some of the injected testosterone will be aromatized into estrogen sufficient to maintain bone (as it does in biological men.)
• 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 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.

• 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.)

Testosterone can also alter the effects of other drugs:

• 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.

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.)

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 body-builders 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.

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.

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