Medical Management of Adult Transsexual Persons

Emily L. Knezevich, Pharm.D; Laura K. Viereck, Pharm.D; Andjela T. Drincic, M.D.


Pharmacotherapy. 2012;32(1):54-66. 

In This Article

Drug Management for Female-to-Male Transition


The agent primarily used for endocrine treatment of female-to-male (FtM) patients is testosterone. The goals of medical management of the FtM transition are to maintain testosterone levels in a range considered physiologically normal for men (320–1000 ng/dl) as well as to avoid potential adverse effects that can occur with testosterone therapy. Because of the wide range of testosterone levels accepted as normal, other physical attributes of men, such as increased virilization, deepening of voice pitch, male-pattern hair growth, and male body contour, as well as cessation of menses are desired and often guide decisions for therapeutic management.[1,11,14]

Numerous preparations of testosterone are available commercially. In the United States, oral testosterone is not available due to its risk of hepatic toxicity; thus, FtM patients in the United States can use either transdermal and injectable testosterone.[11] Table 5 lists commercially available testosterone supplements in the United States, the standard dosages used for FtM transition, and adverse effects commonly associated with their use.[36]

When determining the appropriate method of testosterone delivery, many considerations should be taken into account. Transdermal testosterone is available in either patch or topical gel formulation and has been shown to provide less variation in serum testosterone levels compared with injectable preparations. In addition, testosterone administered transdermally more closely mimics physiologic testosterone levels.[11] Barriers to transdermal testosterone include site irritability seen in up to 66% of patients using transdermal patches.[37] Transdermal patches also have been found to achieve low-normal ranges of testosterone levels in hypogonadal men, which may translate to a lessened change in physical appearance and virilization in the FtM patient.[38] Transdermal testosterone administered by topical gel achieves levels of testosterone in the mid-moderate range of normal; however, some limitations exist with this formulation as well.[38] Although it is less frequent than with patches, gel formulations can result in skin irritation (~5–6%), and application can result in a musky odor.[37] A more significant concern of topical gel testosterone formulations is the risk of interpersonal transfer after administration to shoulders and upper arms. Although skin contact after the gel has dried is generally accepted as safe, these products do contain a black-box warning stemming from reports of secondary exposure to children, resulting in inappropriate sexual development.[37,39] All transdermal formulations of testosterone can be quite costly for patients who can not apply prescription insurance benefits for this elective therapy.

The most well-described formulation of testosterone therapy used to treat FtM patients is intramuscular injection of testosterone esters (cypionate or enanthate). These injections are given every 1–2 weeks based on patient response and adverse effects. Dosing may be administered at 1-week intervals if patients sense peaks and troughs in their testosterone levels, translating to cyclic variations in mood or virilism.[8,37] Injection site reactions can be common with intramuscular testosterone, with up to 33% of hypogonadal men who received the injections having local reactions.[37] Because of the viscous nature of the injectable formulation and the need to inject into muscle to obtain an extended duration, a 1.5-inch, 22-gauge needle is often used. This can be a deterrent to some people despite the infrequent dosing. In addition, if the patient is unable to self-administer, although injectable testosterone is less expensive than transdermal, the cost of office visit charges to administer the drug can be a financial burden to the patient.[37]

Other supplemental agents have been used with testosterone if menses does not cease. In fact, supplemental therapy is very frequently needed to stop menses.[14] Depot medroxyprogesterone has shown efficacy in stopping menses and reducing estrogen levels to concentrations found biologically in men. Intramuscular medroxyprogesterone 150 mg every 3 months can be given when starting testosterone and is usually discontinued after the patient has had 3–6 months of testosterone therapy. Exposure of medroxyprogesterone should be limited in an attempt to reduce the risk of endometrial hyperplasia.

Effectiveness of Therapy

Evaluation of FtM patients using testosterone therapy has provided an accepted timeline of when physical sex characteristics of men should present. Table 2 demonstrates this timeline of expected changes.[1]

The testosterone preparations vary in their effectiveness, with injectable formulations typically associated with the most substantial increases in testosterone levels and more rapid physical changes in the FtM patient. Although no substantial, published data currently demonstrate the effectiveness of injectable formulations compared with other formulations, patient and provider reports consistently demonstrate this trend.

Monitoring and Safety

Commonly described effects noted in FtM patients using testosterone include development or worsening of acne, increased musculature, increased hair growth, enlargement of the clitoris, vaginal tissue atrophy, and possible psychiatric changes (aggressive behavior).[38,40] Although rare, cases of ovarian cancer in FtM patients treated with androgens have been reported. If a patient desires to undergo surgical sex reassignment, the ovaries typically would be removed 18–24 months after the start of testosterone administration.[10] If ovarian removal does not occur, patients should be followed and screened for ovarian cancer by a gynecologist experienced in the management of transsexual persons. Monitoring schedules have been recommended by the Endocrine Society in an attempt to avoid any adverse effects from occurring in those receiving testosterone therapy. A recommended timeline for monitoring is shown in Table 6 . Patients should be monitored every 2–3 months in the first year of therapy to assess therapy effectiveness and monitor for potential adverse reactions. As stated previously, at these visits, serum testosterone levels should be measured with the goal of obtaining a concentration within a target range of 350 – 700 ng/dl.[1]

One must consider pharmacokinetic properties of the hormone delivery system when obtaining serum testosterone levels. Deciding when to measure levels follows the same principles as outlined in the MtF section describing estrogen therapy. In addition, estradiol levels should be measured after initiation of testosterone to ensure that decreases occur. This should be continued for the first 6 months of therapy or until uterine bleeding has stopped for 6 months. Estradiol levels should be less than 50 pg/ml for maximal effectiveness of therapy and inhibition of female sex characteristics to occur.[1]

Other patient monitoring is performed to avoid adverse effects that may occur with hormone replacement therapy. Baseline BMD testing should be done if other fracture risks exist. One must also remember that patients who have cervical tissue and have not undergone mastectomy must still undergo women's health screenings such as Pap smears and mammograms as recommended by the American College of Obstetricians and Gynecologists and the American Cancer Society.[1] Although liver dysfunction has been reported with the use of oral testosterone, it is not thought to be an issue with injectable and transdermal forms of the hormone. However, up to 15% of FtM patients see an increase in liver enzyme levels, so periodic monitoring is suggested.[1,17]

Testosterone use may increase cardiovascular risk due to increased atherogenicity of lipid parameters and potential for worsening insulin sensitivity.[22,27] Testosterone administration may also increase cardiovascular risk due to its erythropoietic effects and potential for lowering total homocysteine levels.[41] In addition, increased circulating androgen frequently results in weight gain, which can, in turn, increase blood pressure and further complicate insulin resistance and sleep apnea.[27] A recent meta-analysis reported no significant effect of hormones on cardiovascular outcomes during the treatment of GID using cross-sex hormones.[23] This analysis evaluated 16 studies that included 651 FtM patients. Lipid profiles in the FtM patients demonstrated statistically significant decreases in HDL levels and increases in triglyceride levels, as well as a slight increase in systolic blood pressure (1.74 mm Hg). However, the authors were unable to find a direct link to more important cardiovascular outcomes such as death, stroke, myocardial infarction, or venous thromboembolism. The authors concluded that the evidence reported in the trials was inconclusive and stated that additional study is warranted.


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