Masculinizing hormone therapy

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Masculinizing hormone therapy, also called masculinizing hormone replacement therapy, androgen hormone therapy, transgender hormone therapy of the masculinizing type, transmasculine hormone therapy, or female-to-male (FTM) hormone therapy, is a form of hormone therapy or hormone replacement therapy (HRT). Masculinizing hormone therapy means taking certain kinds of medicine to make a person physically look, sound, and even smell masculine, so that one is generally seen as a man by most people.

Some nonbinary people who were assigned female at birth go on this hormone therapy as part of their transition, and this article focuses on that. Such nonbinary people are said to be on the female-to-male transition spectrum, and that they are trans-masculine. Masculinizing hormone therapy is also a common part of transition for transgender men, who experience it in much the same way as trans-masculine nonbinary people. The category of "trans-masculine" also includes trans men, and is the term used throughout most of this article for the people who take this therapy, except when referring to a specific group. One shortcoming of using this term for this article is that not all people who go on masculinizing HRT consider themselves masculine, but the HRT itself is masculinizing.

Some other kinds of people who do not necessarily consider themselves trans-masculine may go on masculinizing hormone therapy, such as some intersex people, and people who were assigned male at birth who have had their testicles removed (which can be due to illness, injury, or gender dysphoria). Members of these two groups may or may not consider themselves transgender. For this reason, this article usually uses the language "masculinizing HRT" rather than terms that could exclude these groups.

The World Professional Association for Transgender Health (WPATH), which sets the standards for transgender care in all countries, says that HRT is "a medically necessary intervention for many transsexual, transgender, and gender-nonconforming individuals with gender dysphoria [...] Some people seek maximum feminization/masculinization, while others experience relief with an androgynous presentation resulting from hormonal minimization of existing secondary sex characteristics".

Effects of masculinizing hormone therapy

When a trans-masculine person goes on masculinizing hormone therapy, this has a variety of physical effects that make the person look, sound, and even smell like a cisgender man. The person's risk for certain health conditions changes to that of the risk level of a cisgender man. Physical changes caused by HRT happen at different times, similar to the process by which a cisgender man goes through puberty.

Permanent and temporary changes

For transmasculine people, taking masculinizing hormone therapy causes some changes that are temporary, meaning that they will only last while they are taking that therapy. It also causes some changes that are permanent, meaning that they will last even if they stop taking that therapy. Depending on what changes they seek, some transmasculine people find that going on HRT for a specific period of time and then stopping is effective to give them some changes they want (such as deepening their voice to a degree they find satisfactory) while avoiding some other changes that they do not want (such as male-pattern balding).

Permanent changes

• deepening of the voice,
• growth of facial and body hair,
• male pattern baldness (in some individuals),
• an enlargement of the clitoris, and
• growth spurt and closure of growth plates if given before the end of puberty.

Temporary 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),
• increased red blood cell count, and
• shrinking and/or softening of breasts (in some individuals), though this is due to changes in fat tissue.

Voice deepening

Most individuals on testosterone will experience a gradual deepening of the voice, caused by growth of the larynx (voice box). In most cases, this begins after 3 to 12 months, and finished after 1 to 2 years. The changes are permanent, meaning a trans-masculine person's voice will stay as low as it got even if they stop taking HRT. Many individuals who do not want the full effect of voice deepening will take testosterone until their voice deepens to their desired resonance and then stop.

Skin changes

Masculinizing HRT causes increased activity of oil and sweat glands, like that of a cisgender man, especially during the first two years of HRT, similar to puberty.

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

The WPATH says that masculinizing HRT causes a likely increased risk of acne. Acne is generally worse during only the first two years of testosterone therapy, as with 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.

Increased skin oiliness and acne happens only when the person is first starting HRT, similar to how cisgender men have oiliness and acne during puberty. Trans-masculine people usually see oiliness and acne start in 1 to 6 months of starting HRT. Then the oiliness and acne usually goes away after 1 to 2 years of HRT.

Hair changes

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 hair loss will develop. Testosterone is converted (within the cells of the hair follicle's dermal papilla) by 5α-reductase to DHT. There are two forms of this enzyme: type 1 and 2. However, type 2 is the form that is most important to the development of male pattern hair loss. Males with congenital 5α-reductase type 2 deficiency (but functional 5α-reductase type 1) never develop male-pattern hair loss.^{[citation needed]}

A trans-masculine person usually starts growing more facial and body hair in 3 to 6 months after starting HRT. When they reach 3 to 5 years on HRT, they usually have as much facial and body hair as they are going to have.

Male-pattern hair loss, also called male-pattern baldness or androgenic alopecia, is a genetic condition that is expressed in people who have a hormone balance with more testosterone than estrogen, if they have ancestors who had it too, and once they are old enough for it to happen. Since it is genetic, people who do not have any ancestors who had male-pattern hair loss will most likely never have it themselves. Trans-masculine people who carry the gene for male-pattern hair loss will see a likely increased risk of expressing that gene when on masculinizing HRT, and they will usually start seeing it happen more than 12 months after starting HRT. This varies a great deal depending on the person's age.

Increased muscle mass and strength

People who have a hormone balance with more testosterone than estrogen tend to develop more muscle mass. The amount of muscle mass and strength that a trans-masculine person develops depends a great deal on how much exercise they get. Going on HRT alone will not cause a person to develop much muscle. It still requires some self-discipline to attain. A trans-masculine person usually starts developing more muscle mass and strength 6 to 12 months after starting HRT. When they reach 2 to 5 years on HRT, they usually have as much as they are going to have.

Fat redistribution

Sex hormone balance determines the areas where a person's fat is located on their body and face. Fat distribution is one of the main sexual characteristics that people look at when they make a quick decision about whether they think someone looks like a man or a woman. A trans-masculine person usually starts seeing their fat redistribute in 3 to 6 months after starting HRT. When they reach 2 to 5 years on HRT, their fat has usually settled into where it is going to be from then on. The WPATH says that trans-masculine people find that HRT causes them to have less body fat and more muscle, but also that there is a likely increased risk of weight gain on HRT. (Note that muscle is denser and weighs more than fat.) The fat redistributes away from the chest, thighs, buttocks, and hips, toward the belly and waistline. This raises the person's center of gravity, and changes the fit of the waistline of their clothes. Fat redistribution can make the breasts very slightly smaller. Masculinizing HRT can redistribute fat toward a person's face and neck in a way that can raise their risk for having trouble breathing while they sleep (sleep apnea) to what it would be if they had been assigned male at birth.

Reproductive system changes

Menstrual changes

The menstrual cycle usually stops in 3 to 6 months after starting masculinizing HRT. If bleeding continues past 6 months, this is a sign to check on one's hormone levels to see if the HRT dosage is too low to cause masculinization. This can also be a sign to see a gynecologist, to see if some other health condition is causing the bleeding.

Clitoris changes

The clitoris grows in size, called clitaromegaly. This eventually causes the clitoris to resemble a small penis (in cisgender men, called a micropenis). HRT cannot change where the opening for urine (urethra) is located. For people who were assigned female at birth, the urethra is a separate hole, between the clitoris and the vagina. A trans-masculine person usually starts seeing their clitoris grow in 3 to 6 months after starting HRT. When they reach 1 to 2 years on HRT, it has reached its maximum size.

Vaginal atrophy

Masculinizing HRT can sometimes cause vaginal atrophy and dryness. Vaginal atrophy means that the inside of the vagina becomes more weak, delicate, fragile, and dry, and less elastic. On masculinizing HRT, the vagina and vulva are not as wet, but can still become wet when aroused. Vaginal atrophy is also common for cisgender women to have when they go through menopause. A trans-masculine person may start having vaginal atrophy 3 to 6 months after starting HRT, with maximum effect at 1 to 2 years after starting HRT.

If a trans-masculine person receives vaginal penetration, this may be more painful (dyspareunia), which can cause tiny rips (microtears) in the skin inside the vagina. Microtears increase the risk of communicating sexually transmitted infections (STIs). It is important for trans-masculine people to use lubrication to help make sure that sex is comfortable, and to use condoms specifically to protect against STIs, even when using other forms of birth control.^{[citation needed]}

Vaginal atrophy can be treated with topical estrogen cream.

Changes to feelings about sex

Many trans-masculine people report an increased desire for sex (libido) after starting HRT. Some report that this decreases somewhat after several years on testosterone, so this is equivalent to the raised libido that cisgender men feel during puberty. Some trans-masculine people do not notice that HRT causes any changes in their libido: those who were always disinterested in sex may remain asexual.

Some transgender people notice that after going on HRT, their feelings about sex change, they may feel more comfortable with having sex. Some transgender people say they see different kinds of people as sexually attractive than they had noticed before they were on HRT, that is, a change in their sexual orientation. These changes in feelings about sex is not necessarily caused by the HRT itself, but may represent a relaxing of a person's anxieties in response to HRT helping them to experience less distress from gender dysphoria.

Effect on ability to get pregnant

Masculinizing HRT decreases ovulation, and stops menstrual bleeding. However, masculinizing HRT can't prevent pregnancy. It is not an approved form of birth control (contraception). Trans-masculine people who engage in sex which places them at risk for pregnancy should use other means of birth control. All methods for birth control are acceptable for use together with masculinizing HRT.

If a trans-masculine person has not had their uterus removed and ovaries removed, they may regain fertility after stopping masculinizing HRT. 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. Previously using the "slow-freezing" cryopreservation method there were very poor survival rates of banked oocytes. However, the advent of vitrification, a rapid freezing process, has made oocyte cryopreservation a viable option for fertility preservation. It allows the possibility for eggs to later be fertilized and be placed in a surrogate, as opposed to a transgender man having to carry the pregnancy himself.
• Embryo banking. Oocyte harvest as above with immediate fertilization and banking of the embryo. The sperm donor must be chosen before oophorectomy. Allows the possibility for embryos to later be placed in a surrogate, as opposed to a transgender man having to carry the pregnancy himself.
• 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 replantation into the transgender man for stimulation and harvest, but may eventually be possible in a lab as techniques for tissue culture improve. This option does not usually allow for placement into a surrogate as it may require the use of immunosuppressants on the part of the surrogate.

Question of risk of cancer in uterus or ovaries

Doctors once speculated that masculinizing hormone therapy might increase the risk of a trans-masculine person getting cancer in their uterus or ovaries. As a result, doctors used to advise trans-masculine people to have their uterus removed after they had been on HRT for five years. Studies now show that there is no proof of a correlation between this HRT and those cancers. The WPATH says that there is no increased risk or that it is inconclusive whether masculinizing HRT might increase the risk of cervical cancer, ovarian cancer, or uterine cancer.

The risk of endometrial cancer is similarly unknown. A large multicenter study along with review of previous studies, noted no increased prevalence of endometrial hyperplasia or malignancy in transgender men undergoing hysterectomy. However while the endometrial linings in these studies were noted to be thin, they remained histologically active.

Frequently the first sign of endometrial cancer is bleeding in post-menopausal women. Trans-masculine people who have any bleeding after the cessation of menses with masculinizing HRT should be evaluated for age appropriate causes of abnormal uterine bleeding as per cisgender female guidelines.

All adults with a uterus or cervix are advised to have a Pap smear per guidelines, to check for human papillomavirus (HPV) infection. Use of testosterone is no exception to this rule.

Question of relationship with PCOS

Polycystic ovary syndrome (PCOS), also called polycystic ovarian syndrome, is a set of symptoms with no known cause, and no known cure as of 2020. It correlates with high testosterone levels in people who were assigned female at birth. Diagnosis is based on two of the following three findings: no ovulation, high androgen levels, and ovarian cysts. Its symptoms are associated with high testosterone, such as growing extra body hair, menstrual problems, and fertility problems. Some people informally consider PCOS a intersex condition, even though PCOS usually develops later in life, rather than at birth, as most intersex conditions do. PCOS itself is not harmful, unless if the androgenic symptoms are found distressing by the person who has them, but it does cause a higher risk of obesity, and therefore of Type II diabetes. Treatment for PCOS involves lifestyle changes and medications to reduce those risks. For cisgender women, some treatments for PCOS aim to undo masculinization, but that is not desirable to undo for trans-masculine people.

The WPATH says that an increased prevalence of PCOS has been noted among trans-masculine people, even in those who have never taken masculinizing hormone therapy, according to studies from 1993, 1997, and 2007. This correlation has raised questions of cause and effect: whether going on masculinizing HRT causes PCOS, and whether having PCOS could cause someone to question their gender identity. However, the WPATH says, "there is no evidence that PCOS is related to the development of a transsexual transgender, or gender-nonconforming identity".

Neurological changes

A 2006 study found that HRT in trans men correlates with in an increase in brain volume up to male proportions.

On the other hand, the reality of distinct differences between the brains of men and women is disputed by various neurologists. British neuroscientist Gina Rippon, author of the 2019 book Gendered Brain: The New Neuroscience that Shatters the Myth of the Female Brain, argues that there is not a "single item type as a male brain or a female brain", instead that "everybody is actually made up of a whole pattern of things, which is maybe due to their biology and maybe due to their different experiences in life." She puts forward the idea that "every brain is different from every other brain". Rippon is opposed to the "continued emphasis on 'essentialist', brain-based explanations in both public communication of, and research into, many forms of gender imbalance."

Effects on migraines

Migraines are a poorly-understood type of headache with a neurological origin. The symptoms of a migraine can include hallucinations, light sensitivity, nausea, and vomiting. The cause of migraines is not well understood, but seems to correlate with a person's hormone balance. Many cisgender men and women who have had migraines find that their migraines change in frequency and severity after puberty or menopause. Usually, cisgender boys have worse migraines before puberty, whereas cisgender women have worse migraines between puberty and menopause. Many cisgender women have migraines just before a menstrual period, as part of premenstrual syndrome (PMS).

Transgender people can see a change in the frequency or severity of migraines when they go on HRT, and during the time they are adapting to a new HRT regimen.

Effects on epilepsy

Some seizure disorders are androgen-dependent. These may be worsened or (very rarely) unmasked with androgen therapy.^{[citation needed]}

Sleep deprivation worsens almost all seizure disorders, so concurrent obstructive sleep apnea caused or worsened by androgen therapy may also be responsible.

Psychological and emotional changes

The psychological changes are hard to define, for a variety of reasons. These types of changes are more subjective and difficult to quantify. During any gender transition, there are usually other factors in a person's life that have effects on their emotions, stress levels, and mental health. An extremely high level of testosterone is often associated with an increase in aggression, but this is not a noticeable effect in most trans-masculine people. 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 cisgender men (men who are not transgender). These levels of testosterone have not been proven to cause more aggression than comparable levels of estrogen.

Some trans-masculine people report mood swings, increased anger, and increased aggressiveness just after starting androgen therapy. Studies are limited and small scale, however, based on self reporting over a short period of time (7 months). In a study by Motta et al, trans men also reported better anger control. Many transgender men, however, report improved mood, decreased emotional lability, and a lessening of anger and aggression.^{[citation needed]}

The WPATH says that if someone already has has certain psychiatric disorders, masculinizing HRT carries a possible increased risk of destabilization of those certain psychiatric disorders. The WPATH says this "includes bipolar, schizoaffective, and other disorders that may include manic or psychotic symptoms. This adverse event appears to be associated with higher doses or supraphysiologic blood levels of testosterone." That is, HRT is only known to destabilize those disorders if someone is on a higher dose than is recommended to match that of healthy cisgender men's testosterone levels. This means that trans-masculine people with these disorders can safely avoid destabilization by working with their endocrinologist to make sure that their testosterone level is like that of a healthy cisgender man.

Cardiovascular changes

The WPATH says that masculinizing HRT carries a possible increased risk of high cholesterol, also called hyperlipidemia, which means abnormally high levels of fats (lipids) in the blood. High cholesterol can be inherited, or can be caused by unhealthy habits (including eating mostly unhealthy foods, not getting enough exercise, drinking too much alcohol, and smoking). This means that trans-masculine people on HRT have reason to make healthy choices about food, exercise, and substances, just as cisgender men do.

The WPATH says that if there is a presence of other risk factors, then masculinizing HRT carries a possible increased risk of cardiovascular disease.

The WPATH says that if there is a presence of other risk factors, then masculinizing HRT carries a possible increased risk of hypertension.

In cisgender 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 trans men 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 can 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 rather than fat carried on the buttocks and hips.

The WPATH says that if there is a presence of other risk factors, then masculinizing HRT carries a possible increased risk of Type II diabetes. This is because androgen therapy can cause weight gain and decreased insulin sensitivity, which could possibly worsen a predisposition to develop Type II diabetes.

Androgen therapy 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). 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 pre-clinical models, testosterone XHT has been shown to lead to adverse cardiovascular effects, but adding a low-dose estrogen to that hormone therapy completely mitigated those effects.

Two recent studies indicate the potential for elevated risk of cardiovascular events in response to masculinizing HRT. Nota, et al (2019) found that transgender men taking testosterone had an increased risk of cardiovascular events compared to cisgender women, with 11 vs. 3 cardiovascular events per 100,000 person-years, though the risk was less than that of cisgender men. Researchers were not able to control for smoking status or stressors. Another recent study (Alzahrani, 2019) found elevated risk of heart attacks among self-identified transgender men—which persisted even after adjusting for age, diabetes mellitus, chronic kidney disease, smoking, hypertension, hypercholesterolemia, and exercise—though the study did not include data about whether the subjects were undergoing hormone therapy and did not control for stressors. The study found that transgender men have a >4-fold and 2-fold increased odds of having a myocardial infarction when compared with cisgender women and cisgender men, respectively. Since testosterone for transgender men is intended to be used over an individual's entire lifespan, the full range of risks of such lengthy testosterone administration is not yet known.

Gastrointestinal changes

The WPATH says that masculinizing HRT carries a possible increased risk of elevated liver enzymes.

The risk of causing liver damage or liver cancer from masculinizing HRT is minimal. Only oral pills for testosterone have a high risk for these, which is why oral testosterone pills stopped being common or used in most countries decades ago. Excessively high levels of testosterone could also raise these risks. 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.

Metabolic changes

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 cisgender 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 of hormonal treatment.

Bone changes

The WPATH says that there is no increased risk or that it is inconclusive whether masculinizing HRT might increase the risk of loss of bone density.

Both estrogens and androgens are necessary in cisgender 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 resorption. Estrogen is the predominant sex hormone that slows bone loss (even in cisgender 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). Trans-masculine people who have had their ovaries removed 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 cisgender men). However, a single small study of trans men after oophorectomy demonstrated that androgens alone may be insufficient to retard bone loss. It is likely the case that pre-oophorectomy, residual estrogen production is protective. However, after oophorectomy, some trans men may have insufficient estrogen to retard bone loss. Pre-clinical research has suggested the importance of low-dose estrogen supplementation for those beginning cross-sex hormone therapy (XHT) during adolescence (Goetz LG et al. "Cross-sex testosterone therapy in ovariectomized mice: addition of low-dose estrogen preserves bone architecture." American journal of physiology Endocrinology and metabolism. 2017;313(5):E540-e51.). 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 D3 and K2 are probably a good idea for most transgender men, but it is even more important after removal of the ovaries.

Obstructive sleep apnea

The WPATH says that masculinizing HRT carries a likely increased risk of sleep apnea.

Obstructive sleep apnea (OSA) may be worsened or unmasked by androgen therapy. Risk is higher in trans-masculine people who are obese, smoke, or have Chronic Obstructive Pulmonary Disease (COPD). 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.^{[citation needed]}

Polycythemia

The WPATH says that masculinizing HRT likely increases the risk of 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.^{[citation needed]}

Question of risk of breast cancer

The WPATH says that there is no increased risk or that it is inconclusive whether masculinizing HRT might increase the risk of breast cancer. The WPATH says, "Because the aromatization of testosterone to estrogen may increase risk in patients with a history of breast or other estrogen dependent cancers (Moore et al., 2003), consultation with an oncologist may be indicated prior to [masculinizing] hormone use."

Types of masculinizing hormone therapy

The safest, most effective, most affordable, and most common method of taking masculinizing hormone therapy is injection. People who are unable to do this because of a fear of needles can choose methods in which they absorb the HRT through their skin, in the form of patches and gels. Masculinizing hormone therapy is no longer commonly available in the form of an oral pill, because taking it by this route added some health risks.

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 United States are the testosterone esters testosterone cypionate (Depo-Testosterone) and testosterone enanthate (Delatestryl) which are almost interchangeable. Testosterone 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 (50–100 mg/week). These testosterone esters are mixed with different oils, so some individuals may tolerate one better than the other. Testosterone enanthate costs more than testosterone cypionate and is more typically the one prescribed for hypogonadal males in the United States. Testosterone cypionate is more popular in the United States than elsewhere (especially amongst bodybuilders). Other formulations exist but are more difficult to come by in the United States. A formulation of injected testosterone available in Europe and the United States, testosterone undecanoate (Nebido, Aveed) 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 4 mL of oil which may require multiple simultaneous injections. Testosterone undecanoate is also much more expensive as it is still under patent protection. Testosterone propionate is another testosterone ester that is widely available, including in the United States, Canada, and Europe, but it is very short-acting compared to the other testosterone esters and must be administered once every 2 or 3 days, and for this reason, is rarely used.

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 testosterone enanthate or testosterone 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 cisgender male is 290 to 900 ng/dL).

Transdermal

Both testosterone patches, creams 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 throughout the world under the brand names Andromen Forte, Androgel, Testogel and Testim. They 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, from as little as $50/month to about $280/month (in US Dollars).

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.

Implants

Implants, as subcutaneous pellets, can be used to deliver testosterone (brand name Testopel). 6 to 12 pellets are inserted under the skin every three months. This must be done in a physician's office, but is a relatively minor procedure done under local anesthetic. Pellets cost about $60 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. One common risk of any kind of implants is that the body can reject them. This often happens with testosterone implants, causing the implant to emerge from deep and painful skin lesions. One trans-masculine blogger, K-CON, posted weekly blog updates about being on Testopel for over a year, and his resulting complications (pellets failing to dissolve at the rate claimed by the manufacturer, implant rejection, leading to infection, pain, and surgery under general anesthesia to remove the pellets and the damaged tissue). He summarized his experience in a post where he explains why he would not recommend Testopel to anyone.

Oral

Oral testosterone is provided exclusively as testosterone undecanoate. It is available in Europe and Canada, but not in the United States. Once absorbed from the gastrointestinal tract, testosterone is shunted (at very high blood levels) to the liver where it can cause liver damage (albeit very rarely) and worsens some of the adverse effects of testosterone, like 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. Because of the short terminal half-life of testosterone, oral testosterone undecanoate must be administered two to four times per day, preferably with food (which improves its absorption).

Sublingual and 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 undecanoate. 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.

Alternative androgens

Synthetic androgens

Synthetic androgens/anabolic steroids (AAS), like nandrolone (as an ester like nandrolone decanoate or nandrolone phenylpropionate), are agonists of the androgen receptor (AR) similarly to testosterone but are not usually used in HRT for transgender men or for androgen replacement therapy (ART) in cisgender men. However, they can be used in place of testosterone with similar effects, and can have certain advantages like less or no local potentiation in so-called androgenic tissues that express 5α-reductase like the skin and hair follicles (which results in a reduced rate of skin and hair-related side effects like excessive body hair growth and scalp hair loss), although this can also be disadvantageous in certain aspects of masculinization like facial hair growth and normal body hair growth). Although many AAS are not potentiated in androgenic tissues, they have similar effects to testosterone in other tissues like bone, muscle, fat, and the voice box. Also, many AAS, like nandrolone esters, are aromatized into estrogens to a greatly reduced extent relative to testosterone or not at all, and for this reason, are associated with reduced or no estrogenic effects (e.g., gynecomastia). AAS that are 17α-alkylated like methyltestosterone, oxandrolone, and stanozolol are orally active but carry a high risk of liver damage, whereas AAS that are not 17α-alkylated, like nandrolone esters, must be administered by intramuscular injection (via which they act as long-lasting depots similarly to testosterone esters) but have no more risk of liver damage than does testosterone.

For the sake of clarification, the term "anabolic–androgenic steroid" is essentially synonymous with "androgen" (or with "anabolic steroid"), and that natural androgens like testosterone are also AAS. These drugs all share the same core mechanism of action of acting as agonists of the AR and have similar effects, although their potency, pharmacokinetics, oral activity, ratio of anabolic to androgenic effects (due to differing capacities to be locally metabolized and potentiated by 5α-reductase), capacity for aromatization (i.e., conversion into an estrogen), and potential for liver damage may all differ.

Dihydrotestosterone

Dihydrotestosterone (DHT) (referred to as androstanolone or stanolone when used medically) can also be used in place of testosterone as an androgen. The availability of DHT is limited; it is not available in the United States or Canada, for instance, but it is available in certain European countries, including the United Kingdom, France, Spain, Belgium, Italy, and Luxembourg. DHT is available in formulations including topical gel, buccal or sublingual tablets, and as esters in oil for intramuscular injection. Relative to testosterone, and similarly to many synthetic AAS, DHT has the potential advantages of not being locally potentiated in so-called androgenic tissues that express 5α-reductase (as DHT is already 5α-reduced) and of not being aromatized into an estrogen (it is not a substrate for aromatase).

GnRH analogues

In all people, the hypothalamus releases GnRH (gonadotropin-releasing hormone) to stimulate the pituitary to produce LH (luteinizing hormone) and FSH (follicle-stimulating hormone) which in turn cause the gonads to produce sex steroids. In adolescents of either sex with relevant indicators, GnRH analogues, such as leuprorelin 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 analogues 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 analogues is often a significant factor.

Antiestrogens

Antiestrogens (or so-called "estrogen blockers") like aromatase inhibitors (AIs) (e.g., anastrozole) or selective estrogen receptor modulators (SERMs) (e.g., tamoxifen) can be used to reduce the effects of high levels of endogenous estrogen (e.g., breast development, feminine fat distribution) in transgender men. In addition, in those who have not yet undergone or completed epiphyseal closure (which occurs during adolescence and is mediated by estrogen), antiestrogens can prevent hip widening as well as increase final height (estrogen limits height by causing the epiphyses to fuse).

Others

5α-Reductase inhibitors

5α-Reductase inhibitors like finasteride and dutasteride can be used to slow or prevent scalp hair loss and excessive body hair growth in transgender men taking testosterone. However, they may also slow or reduce certain aspects of masculinization, such as facial hair growth, normal male-pattern body hair growth, and possibly clitoral growth. A potential solution is to start taking a 5α-reductase inhibitor after these desired aspects of masculinization have been well-established.

Progestogens

Progestogens can be used to control menstruation in transgender men. Depot medroxyprogesterone acetate (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.

Growth hormone

Young people stop growing after their bones go through a change called epiphyseal closure. Complete fusion happens on average between ages 12–18 for cisgender girls (with the most common being 15-16 years) and 14–19 for cisgender boys (with the most common being 18-19 years). Once that happens, a person's bones cannot grow anymore, so they can't get any taller. For young people who have not yet started or completed epiphyseal closure, they can take growth hormone, potentially together with an aromatase inhibitor or a GnRH analogue, to increase final height.

Getting HRT

Eligibility for HRT

Formal requirements for HRT

The World Professional Association for Transgender Health (WPATH) Standards of Care, 7th edition, sets the standard used in all countries for what doctors see as the requirements for a trans person to be allowed to go on HRT. The WPATH says that these are the four criteria for HRT:

1. Persistent, well-documented gender dysphoria;

2. Capacity to make a fully informed decision and to consent for treatment;

3. Age of majority in a given country (if younger, puberty blockers are the preferred option, until they are of age);

4. If significant medical or mental health concerns are present, they must be reasonably well-controlled. The WPATH says that if someone has mental health concerns, this does not mean that person is not allowed to get HRT. Rather, these concerns need to be managed before, or at the same time as, getting HRT.

The WPATH says that in some circumstances, it can be an acceptable practice to let a person go on HRT who does not meet all these criteria.

Medical necessity

The WPATH recognizes that HRT "is a medically necessary intervention for many transsexula, transgender, and gender-nonconforming inividuals with gender dysphoria," citing studies from 1998 and 2006

Health insurance companies may require a trans-masculine person to prove that HRT is medically necessary, in order to cover it.

Ineligibility and contraindications

Masculinizing HRT largely switches a person's health risks to be the same as if they had been assigned male at birth. This means that very few conditions would make it impossible or less safe for a person to take masculinizing HRT. The WPATH says HRT is only contraindicated in rare cases, due to serious health conditions. There are a few conditions that have been seen as contraindications to masculinizing HRT.The only absolute medical contraindications currently recognized by the WPATH are pregnancy, and unstable coronary artery disease and untreated polycythemia with a hematocrit of 55% or higher, as further described below. Even in situations where going on masculinizing HRT could have an effect on someone's risk factors for certain conditions, usually this is not a reason to not go on HRT, and all that is needed is a conversation with a doctor to make sure the patient is aware of those risks, and knows how to mitigate the risks, such as through other healthy lifestyle choices.

The WPATH considers pregnancy an absolute medical contraindication, based on a 2004 study. Masculinizing HRT can affect the developing fetus. It is still possible for someone to get pregnant while on HRT, and after having been on HRT, because HRT does not prevent pregnancy. People on masculinizing HRT need highly effective birth control to prevent getting pregnant while on HRT. People on masculinizing HRT should temporarily stop taking that HRT while pregnant or trying to get pregnant.

The WPATH considers unstable coronary artery disease and untreated polycythemia with a hematocrit of 55% or higher to be absolute medical contraindications, based on a 2004 study.

It is important for patients to know that certain conditions are not contraindications, in order to prevent doctors from unethically withholding access to HRT. The WPATH says "it is unethical to deny availability or eligibility for hormone therapy solely on the basis of blood seropositivity for blood-borne infections such as HIV or hepatitis B or C."

Clinicians differ in any additional conditions that they consider to be contraindications. Additional conditions that some clinicians may consider to be contraindications may include breast feeding, active known androgen sensitive breast cancer, or active endometrial cancer. Conditions that some clinicians may consider to be relative contraindications may include androgen sensitive epilepsy, severe obstructive sleep apnea, severe hypertension due to the salt retaining effects of testosterone, active substance abuse, personal or significant family history of androgen sensitive breast cancer, history of uterine cancer, or bleeding disorders (for injected testosterone only). Many of these conditions are believed to worsen in response to a normal male level of testosterone, which is sometimes only conjecture based on limited evidence.

Finding a doctor

Many transgender groups maintain lists of LGBT-friendly doctors and other services such as legal aid. In the United States, the Gay and Lesbian Medical Association maintains a referral service.

Hormone levels

During HRT, especially in the early stages of treatment, blood work should be consistently done to assess hormone levels and liver function.

Israel et al. have suggested that for trans men who have not had their ovaries removed, therapeutic testosterone levels should optimally fall within the normal male range, whereas estrogen levels should optimally fall within the normal female range. Before oophorectomy, it is difficult and frequently impractical to fully suppress estrogen levels into the normal male range, especially with exogenous testosterone aromatizing into estrogen, hence why the female ranges are referenced instead. In post-oophorectomy trans men, Israel et al. recommend that both testosterone and estrogen levels fall exactly within the normal male ranges. See the table below for all of the precise values they suggest.

Hormone	Cis female range	Cis male range	Optimal trans female range	Optimal trans male range
Estrogen (total)	40–450 pg/mL	< 40 pg/mL	400–800 pg/mL (pre-orchiectomy) 40–400 pg/mL (post-orchiectomy)	< 400 pg/mL (pre-oophorectomy) < 40 pg/mL (post-oophorectomy)
Testosterone (total)	25–95 ng/dL	225–900 ng/dL	95–225 ng/dL (pre-orchiectomy) 25–95 ng/dL (post-orchiectomy)	225–900 ng/dL (pre-oophorectomy) 225–900 ng/dL (post-oophorectomy)

The optimal ranges listed for testosterone only apply to individuals taking bioidentical hormones in the form of testosterone (including esters) and do not apply to those taking synthetic AAS (e.g., nandrolone) or dihydrotestosterone.

See also

• Transition
• Hormone therapy
• Puberty blockers
• Feminizing hormone therapy

References

• Androgen Treatment of Female-to-Male^{[Dead link]} by Louis J.G. Gooren, and Erik J. Giltay (Journal of Sexual Medicine, Volume 5 Issue 4, Oct 2007)
• Hormone-related tumors in transsexuals receiving treatment with cross-sex hormones by Andreas Mueller and Louis Gooren (European Journal of Endocrinology, Vol 159, Issue 3, 197-202)
• Testosterone and Breast Cancer^{[Dead link]} by Susan A. Hall, Andre B. Araujo, Varant Kupelian, Nancy N. Maserejian, and Thomas G. Travison (Journal of Sexual Medicine, Not yet in print)
• Absorption of Testosterone Gel 1% (Testim) from Three Different Application Sites^{[Dead link]} by Andre T. Guay, Ted M. Smith, and Laura A. Offutt (Journal of Sexual Medicine, Volume 6 Issue 9, Jun 2009)

External links

• FTM Informational Network
• FTM Hormone Information - Very informative with different topics than this article
• Tom Waddell Clinic Transgender Protocol - MTF and FTM clinical protocols aimed at providers
• Medical Therapy and Health Maintenance for Transgender Men: A Guide For Health Care Providers: a free online medical book.