Hormone replacement therapy (trans male)

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This article is about hormone replacement therapy for trans men.

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 behaviour
• 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 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. 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.

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.)

A newer form of injected testosterone, Nebido (testosterone undecanoate in oil) provides better testosterone delivery with much less variation outside the normal male range, with injections required only every twelve weeks. 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.

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.

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. The cost varies, as with all medication, from country to country, it is about $150/month in the US.

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 or 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 but be applied twice daily.

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 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.

Testosterone effects

Overview

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,
• 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 and changes in sexual behaviour,
• redistribution of body fat,
• further muscle development and conditioning (especially upper body),
• increased sweat and body odour,
• 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 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. It is assumed that the effect of the start of physical treatment is such a relief, and decreases pre-existing aggression so much, that even if the testosterone itself causes an increase in aggression, the overall level 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.

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.

Hair

• 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) is a Type-2, 5-α-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 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. 1 cc 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.)

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.

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 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. 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 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 for transmen over 30 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.
• Anti-mullerian hormone (AMH) is thought to reflect the size of one’s remaining egg supply, also known as “ovarian reserve.” (Further elaboration on AMH may be found here) AMH is a factor in determining whether one is a good candidate for certain fertility treatment options.
• 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. While there is typically a lower survival rate than that of cryopreserved embryos, advances in oocyte cryopreservation technology, specifically with vitrification (a “rapid freezing” technology) have opened up oocyte banking as a viable option. Oocyte cryopreservation may be done prior to or post testosterone hormone therapy, but testosterone hormone therapy would likely have to cease for the duration of IVF treatment for oocyte cryopreservation. (A blog of one man’s experience of IVF for oocyte cryopreservation can be found here)
  • Embryo banking – oocyte harvest as above with immediate fertilization and banking of the embryo. The sperm donor must be chosen before oophorectomy.
  • Ovarian tissue banking – Ovarian tissue is frozen after oophorectomy. Even after long term androgen therapy, ovaries usually retain usable follicles. Eventual use of frozen ovaries will require reimplantation into the transgender man for stimulation and harvest, but may eventually be possible in a lab as techniques for tissue culture improve. Implantation into a surrogate may be possible, but is more complicated and typically involves immune system suppressant to reduce to risk of rejection.

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.

• 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.)

Sleep apnea

• Sleep apnea (obstructive sleep apnea or 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

• 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 odour – 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 and 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.
• 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.)

External links

• FTM Informational Network
• FTM Hormone Information – Very informative with different topics than this article