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 Male-to-Female Transition


The endocrine treatment of male-to-female (MtF) patients is complex, with many options, and should be individualized based on patient desires and expected outcomes. The cornerstone agent in the feminization of MtF patients is estrogen. Antiandrogens inhibit the actions of androgen and are often used with estrogens to further reduce endogenous testosterone levels, thereby boosting the feminizing effects of estrogen. Many patients believe that progestins have a role in transition to female habitus by increasing breast tissue development; however, evidence regarding the role of progestins is limited, and studies show no benefit in feminization, with possible harmful metabolic effects.[3,8] Current guidelines do not address the preferential order in which therapies should be chosen. Patient characteristics and clinical response should guide drug selection decisions. Prescribers should be aware that no drugs are approved by the United States Food and Drug Administration for treatment of transsexualism and that any pharmacotherapy used is prescribed off-label.

The goals of treatment revolve around reducing the secondary sex characteristics of the assigned birth gender and inducing those of the patient's gender identity. In MtF patients, this is achieved by maintaining serum estradiol levels within the normal range for healthy premenopausal women (<200 pg/ml) and suppressing testosterone levels to those normally found in women (<55 ng/dl). Both estradiol and testosterone levels should be monitored regularly in order to avoid supraphysiologic levels and to minimize the risk of adverse effects. In addition, the physical signs of feminization should be closely monitored to help guide the treatment of MtF persons. Physical changes expected to occur include decreased body and facial hair, decreased oiliness of the skin, induction of breast growth, decreased muscle mass and strength, and a redistribution of body fat to more closely resemble the female habitus.[1] Table 2 provides a timeline of these expected changes.

Estrogen Therapy Many commercially available estrogen formulations are available (Table 3). Oral, transdermal, and intramuscular estradiol or its esters can be monitored by serum estradiol levels. Conjugated and synthetic estrogens cannot be monitored through blood tests and therefore are of limited use in patients being treated for GID.[1] Oral ethinyl estradiol has been shown to carry a higher risk for venous thromboembolism in the MtF population, and due to the high doses necessary to treat these individuals, it is not recommended for use.[9] Therefore, 17β-estradiol as an oral, transdermal, or injectable preparation is the recommended treatment of choice for MtF individuals.[1,10] Evidence suggests that the lowest thromboembolic risk is with transdermal preparations. This method of administration should be favored, especially for those at greatest risk for thromboembolic events, including individuals older than 40 years, those who smoke, and those who have diabetes mellitus or liver disease.[1]

The dose of estrogen needed for the treatment of MtF patients is about 2–3 times the recommended doses for hormone replacement therapy in postmenopausal women.[11] The recommended dose for oral 17β-estradiol is 2–6 mg/day. The recommended dosage for transdermal 17β-estradiol is 0.1–0.4 mg topically twice/week, and the recommended dosage of injectable estradiol is 5–20 mg intramuscularly every 2 weeks. Doses should be titrated individually based on serum estradiol and testosterone levels, as well as the physical degree of feminization.[1] If intramuscular forms are used, it is recommended to measure levels midway between injections to avoid measuring peaks or troughs of drug concentrations seen immediately after and before injections, respectively. If using transdermal or oral formulations, serum levels may be sampled at any time during the course of therapy due to the steady-state concentration being achieved within 1 week after initiation of therapy. The time of day at which levels are sampled does not significantly impact hormone concentrations.[1]

To our knowledge, no studies exist comparing the use of injectable estradiol with either transdermal or oral preparations in MtF individuals. Some patients do not achieve hormonal goals despite use of the maximum recommended dose of either oral or transdermal estrogen preparations. Many MtF patients prefer injectable estrogen therapy as this may provide higher levels of circulating estrogens; however, this formulation may take longer to reach steady state, as it is injected in a depot form intramuscularly and has a higher potential for abuse or overdose.[10,11] If minimal breast development is seen after the first 2 years of estrogen therapy, some clinicians advocate a temporary switch to injectable estrogen in an attempt to boost breast development, but the effectiveness of this approach has not been determined.[11] Injectable estradiol may also be considered if hormonal goals cannot be achieved on maximum doses of transdermal or oral preparations.

Antiandrogen Therapy Antiandrogens have been shown to be effective in reducing testosterone levels and decreasing male pattern hair growth.[1] In Europe, the most widely used agent is cyproterone acetate, which is used in many studies involving MtF patients; however, this agent is not available in the United States because of concerns for liver toxicity. Often started in conjunction with estradiol, spironolactone inhibits testosterone secretion and androgen binding to receptors and may exhibit some estrogenic activity. Typical spironolactone doses are 100–400 mg/day.[1,8] If clinical goals are not achieved with this combination, finasteride may be used to slow male pattern balding by blocking the conversion of testosterone to dihydrotestosterone. Finasteride is usually dosed at 2.5–5 mg/day, and evidence of efficacy is limited.[8]

Less frequently used, flutamide inhibits androgen binding but has not been shown to lower serum testosterone levels, is associated with liver toxicity, and has not demonstrated efficacy in MtF patients.[1] Gonadotropin-releasing hormone agonists given with estrogen also are infrequently used for the treatment of MtF transition. One report of 60 MtF transsexual patients treated with subcutaneous injections of goserelin acetate 3.8 mg every 4 weeks along with oral 17β-estradiol for 24 months found this regimen to be effective in reducing testosterone levels, with a low rate of adverse events.[12] The physical change of breast development was also assessed; however, 70% of study subjects were dissatisfied with the degree of development and sought breast augmentation. As with estrogen therapy, doses of goserelin are titrated based on laboratory response and markers of feminization.

Progestin Therapy Progestins are sometimes used in the treatment of MtF patients, citing enhanced breast growth. In contrast, the combination of progestin with estrogen has not shown benefit in small studies of MtF populations. The Women's Health Initiative demonstrated an increased risk of coronary heart disease, stroke, thromboembolic events, and breast cancer when treating postmenopausal women with combined estrogen and progestin.[10,11,13] These data have not been replicated in the MtF population; however, it is possible that this increased risk would be paralleled in MtF individuals. There is also concern with adverse effects, such as increased risk of depression, and metabolic consequences, such as weight gain and lipid changes.[8] Because of these risks and lack of data on effectiveness, the use of progestins is not recommended in current guidelines and should not be advocated.[1,10,11]

Effectiveness of Therapy

Breast formation begins within the first 3–6 months of cross-sex hormone therapy.[8] Maximal growth is usually achieved after 2 years of hormone administration. However, 50–60% of MtF transsexual patients will find breast growth insufficient with hormone therapy alone. This may be due to the disproportion between breast size and height and male dimensions of the chest in MtF individuals. At this point, breast augmentation is often considered.[14]

Sexual hair growth becomes thinner and lighter as hormone treatment continues and may eventually diminish.[15] However, even with combined estrogens and antiandrogens, the elimination of male facial hair is difficult to achieve. Additional measures such as electrolysis or laser treatment are commonly necessary to eliminate this masculine trait.

Neither estrogens nor antiandrogens have any effect on the properties of voice in MtF transsexual patients.[16] Voice training with a speech or language therapist is the most effective means for developing a healthy voice within the frequency ranges for a biologic female. Laryngeal surgery may also be used to alter the frequency of the voice, but effectiveness, patient satisfaction, and quality-of-life measures with this option have not yet been determined.

Monitoring and Safety

Serious adverse effects seen with long-term cross-sex hormone treatment in MtF transsexual patients may include weight gain, emotional lability, migraines, infertility, hepatic dysfunction, hyperprolactinemia, cholelithiasis, thromboembolic events, and rarely suicide. One should also consider the risk of cardiovascular disease and hormone-related tumors.[17,18,19,20,21] Monitoring schedules have been recommended by the Endocrine Society in an attempt to avoid any potential adverse effects from occurring in those receiving cross-sex hormone therapy. Clinical and laboratory monitoring should be conducted every 3 months during the first year of endocrine treatment and then once or twice/year thereafter. At these visits, serum testosterone and estradiol levels should be measured with the goal of obtaining normal physiologic values for women (<55 ng/dl and <200 pg/ml respectively).[1] Other recommendations for routine monitoring are outlined in Table.4

There have been conflicting reports on the cardiovascular effects of estrogens in MtF patients. A prospective study of MtF patients found favorable changes in lipid profiles with increased high-density lipoprotein cholesterol (HDL) and decreased low-density lipoprotein cholesterol (LDL) levels.[22] However, these changes are accompanied by increased weight, body mass index, total body fat, blood pressure (both systolic and diastolic), triglyceride levels, and markers of insulin resistance.[10,17,22,23] The decrease in LDL levels may have also been associated with transition to smaller, more dense LDL particle size.[22] Oral estrogen therapy has been shown to increase levels of the inflammatory and hemostatic markers interleukin-6, C-reactive protein, and factor IX, all of which may be predictive of future cardiovascular disease. These effects were not seen in groups treated with transdermal estrogen, further advocating for the use of this preparation.[24,25] A large cohort of MtF individuals treated with either oral or transdermal estrogen, followed for 10 years showed no increase in cardiovascular mortality despite a 32% prevalence of tobacco use.[17] Thus, the conflicting data make it difficult to determine if estrogen is protective or detrimental in terms of cardiovascular health in MtF persons. Patients should have a baseline evaluation of traditional cardiovascular risk factors, as highlighted in Table 4, before beginning any cross-sex hormone treatment.

In one study, the occurrence of venous thromboembolism increased 20-fold in MtF patients treated with estrogens and antiandrogens.[17] Most thromboembolic events occurred within the first year of therapy. Again, the rate was higher in those treated with oral estrogen than in those treated with transdermal preparations.[9,17,26] The rate of thromboembolic events in MtF patients has also been shown to be higher in those aged older than 40 years, similar to patterns seen in biologic women treated with estrogens.[9,26,27] Health care professionals should obtain a very thorough personal and family history, including thromboembolic events, in patients beginning cross-sex hormone treatment.[17] Screening for inherited thrombophilia is not routinely recommended but may be considered, especially in those with a family history positive for thromboembolic events.

Alterations in mood and memory have been associated with estrogen therapy in women. A recent study found no association between memory or a change in cognitive abilities that show sex differences with the use of estrogen in MtF patients.[28] Studies have found increased mortality of transsexual patients receiving treatment compared with the published rate for the general population, primarily due to an increased risk of suicide in MtF persons aged 25–39 years.[17,29] Special attention to emotional health should be taken during the treatment of MtF individuals, with referral to mental health providers as appropriate.

Because of the presence of estrogen receptors on pituitary lactotroph cells, up to 20% of MtF patients treated with estrogen may see an increase in prolactin levels. In most cases, prolactin levels return to the normal range after estrogen doses are decreased or the drug is discontinued.[1,30] In one case report, a dopamine agonist was effectively used when levels did not return to normal after stopping estrogen.[20] The risk of prolactinomas is thought to be very low; however, it is important to monitor prolactin levels, which should be obtained at baseline, at 6 and 12 months, and annually thereafter. Concomitant use of psychotropic drugs may also increase the risk of elevated prolactin levels.[1,30]

Hormone-dependent cancers are a concern in MtF patients treated with long-term estrogen therapy. A few cases of breast cancer in MtF persons being treated with estrogen for 5–11 years have been published.[1,10,31,32] The risk in MtF patients is thought to be low, but firm conclusions have not been determined.[31] In addition to an annual medical examination, self-examination of the breast should be done regularly as is recommended for biologic women.[1,31] The prostate is not removed in sex reassignment surgery as it is a cumbersome procedure. Therefore, the risks for benign prostatic hyperplasia and prostate cancer still exist. Prostate cancer is rare, especially in those starting androgen deprivation therapy before age 40 years, but cases of prostate cancer and benign prostatic hyperplasia have been reported in MtF individuals.[31] It is uncertain whether the condition was present before the initiation of cross-sex hormone therapy. Prostate-specific antigen levels should be monitored and routine prostate examinations performed, as recommended for biologic men.[1,14,31] Based on a recent U.S. Food and Drug Administration warning, a risk for high-grade tumors exists with the use of finasteride.[33] Thus, appropriate screening for prostate cancer before initiation of finasteride is essential. The prevalence of hormone-dependent tumors appears to be low, but it is very possible that cases are underreported.[31]

Effects of estrogen use on bone mineral density (BMD) and osteoporosis risk in MtF patients show mixed results. It is generally accepted that the use of estrogen provides protective effects on BMD. A few studies have actually shown a decrease in BMD in the MtF population, thereby concluding that these patients are at a higher risk for developing osteoporosis and related fractures.[34,35] Other studies have shown an increase in BMD after cross-sex hormone treatment, supporting the hypothesis that estrogen is beneficial for bone health.[10,12] Bone health should be a condition of interest and appropriately monitored in the long-term follow-up of MtF persons. Because of the lack of experience with MtF patients of advanced age, the Endocrine Society suggests testing BMD at baseline if risk factors for osteoporosis exist. If risk factors are not present, the guidelines state that testing should begin at age 60 years or in those not compliant with hormone therapy.[1]


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