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Case 4: Discussion

HIV Risk Factors and Prevalence among Transgender Women

Male-to-female (MTF) transgender women have an increased risk for HIV infection[1,2,3,4]. The largest and most comprehensive study to date of HIV prevalence and risk behaviors among transgender persons was carried out in San Francisco and revealed an HIV prevalence of 35% among MTF transgender women[1]. This prevalence exceeds that of other high-risk groups living in the same community, including gay men and injection drug users. The estimated incidence of new HIV infection among transgender women in United States urban areas ranges from 3.4-7.8 per 100 person-years[2,3], rates that rival those observed in gay men during the height of the United States HIV epidemic in the 1980's[4]. Investigators have identified four risk factors that are highly associated with HIV seropositivity in transgender women: African American race, a history of injection drug use, multiple sex partners, and low education level (Figure 1). Studies of HIV prevalence in transgender women also reveal an alarmingly high proportion of commercial sex work in this group[1]. Moreover, one small study conducted in Atlanta in the early 1990's reported that 36 (68%) of the 53 MTF sex workers tested positive for HIV[5]. Qualitative risk assessment efforts have shown that transgender women, when compared with homosexual males or heterosexual females, have more sexual partners and more frequently engage in high-risk sexual behaviors[6]. Reasons cited for these high risk behaviors include dependence on income from sex work for survival, reinforcement of femininity and attractiveness, and higher financial incentives for riskier sexual acts[6,7]. The risk of HIV transmission through injection hormone use appears to vary regionally, with lower risk detected in cities with needle exchange programs and public health clinics offering low-cost hormone therapy[1].

Barriers to Health Care for Transgender Women

Multiple barriers to adequate health care exist for the transgender population. These include social isolation, fear of exposure, denial of insurance coverage, competing priorities (such as housing and employment), stigma of going to a gender reassignment clinic, a lack of clinical research and medical literature related to transgender individuals, as well as provider ignorance regarding the care of these patients. The Harry Benjamin International Gender Dysphoria Association (HBIGDA) has set minimal standards of care for transgender persons, including guidelines for initiation of hormonal reassignment therapy ( The HBIGDA has established the following suggested criteria prior to initiating therapy: (1) age of 18 years or older; (2) knowledge of social and medical benefits; (3) an understanding of the potential risks of therapy; and (4) undergoing psychotherapy for a minimum of 3 months, or documenting a real life experience whereby they adopt their new or evolving gender in everyday life for at least 3 months. This real life experience should include maintaining employment (or performing volunteer work), documenting awareness of their cross gender identity by people other than therapist, and acquiring and using a new gender appropriate first name. Ideally, cross-gender hormonal therapy should be undertaken in conjunction with a provider experienced in its use. Although the main goal of hormonal therapy is to improve quality of life, frequent medical monitoring of cross-gender hormone therapy can also improve adherence with treatment for chronic illnesses commonly encountered in this population, such as HIV infection, depression, and substance abuse, as well as to increase opportunities for preventive health care.

General Principles of Hormonal Reassignment Therapy

A thorough discussion of cross-hormonal and surgical reassignment protocols is beyond the scope of this article, but some clear principles of management have been established[9,10]. To date, no randomized controlled trials comparing various hormonal reassignment protocols have been conducted and management remains largely experience-based. The mainstay of all feminization protocols is estrogen therapy. Potential beneficial effects of estrogen therapy in this context include breast development, redistribution of body fat, softening of the skin, loss of erections, testicular atrophy and slowing of scalp hair loss. Risks of estrogen therapy are well documented and are dose related (Figure 2). Many patients harbor the misconception that "more is better" and will commonly take multiple estrogen formulations obtained from a variety of sources, often exceeding medically recommended doses[10]. Transgender women require life-long estrogen therapy, even after orchiectomy. Following orchiectomy, significantly lower estrogen doses are required. The decision to take cross-gender hormones is a major event in a transgender person's life, and education regarding the risks and benefits of therapy is essential prior to starting treatment. Medical providers must consider the gravity of the psychological need for hormone therapy in these patients and should make every effort to manage potential risks in order not to restrict access to hormonal gender transition.

Gender Transitioning with Hormone Therapy

Most transgender women will transition with either estrogen alone or in combination with an antiandrogen such as spironolactone (Aldactone). The estrogen dose required for transition is very difficult to predict. Thus, all patients should be started on low doses and titrated to higher doses every few months, depending on their response to the hormones, including breast development, body fat redistribution, presence of morning erections, and softening of skin. Transition is a very slow process and the full benefit from estrogen therapy will not be appreciated until the patient has taken an adequate dose for two years. After maximum feminization is evident, estrogen doses can then be reduced to a minimum required maintenance dose in an attempt to reduce risks of therapy.

Estrogens in Hormonal Reassignment Therapy

Many options for estrogen therapy exist for use in hormonal reassignment therapy, and the doses used are generally at least 2-3 times higher than doses used for hormone replacement therapy in postmenopausal women (Figure 3). Although numerous different products are available, these agents have activity at the same receptors and will generate similar effects if used at an equipotent dose. Oral estrogen, either ethinyl estradiol (Estinyl) or conjugated equine estrogen (Premarin), is the most commonly used formulation, as it is relatively inexpensive and easily titrated. The main risk of estrogen therapy is venous thromboembolic disease. Transdermal estradiol patches (Alora, Climera, Esclim, Estraderm, Vivelle, Vivelle-Dot) produce fewer changes in hemostatic variables than ethinyl estradiol and are associated with a lower risk of venous thromboembolic disease[14]. Thus, transdermal estrogen is strongly recommended for transgender women at higher baseline risk of thromboembolism, namely smokers and those older than 40[10]. Some experts have argued all patients receiving estrogen therapy should use transdermal estrogen[15]. Injectable estrogen also has a low risk for causing thromboembolic complications and is an excellent alternative to transdermal estrogen in situations of high baseline risk for thromboembolism. In addition, some providers prefer the use of injectable estrogen in the initial transition period. Estrogens are contraindicated in any transgender woman with known estrogen-responsive cancer, a history of thromboembolism, or severe thrombophlebitis (unless they are on anticoagulation therapy), and should be used with caution in those with diabetes, liver disease, renal disease, cardiac disease, hyperlipidemia, pre-existing biliary disease, or a strong family history of estrogen responsive malignancy. Risks and benefits must be reviewed with these patients, but for many, the need for estrogen therapy will outweigh the potential risks even in the context of chronic illness. Although hyperprolactinemia is a relatively common side effect of estrogen therapy, most cases do not require estrogen withdrawal, and the occurrence of true prolatinomas is rare[12].

Anti-Androgen Agents in Hormonal Reassignment Therapy

Anti-androgen agents are often used in combination with estrogens in hormonal reassignment therapy to further decrease male secondary sexual characteristics (Figure 4). These anti-androgen agents presumably exert their action by lowering serum testosterone levels and by blocking testosterone binding to the androgen receptor[10]. Effective agents include spironolactone, progesterone, testosterone uptake inhibitors, growth hormone releasing antagonists, and cyproterone (not available in United States). Most experts recommend spironolactone as the anti-androgen agent of choice for patients living in the in the United States. Spironolactone is typically started at 25 mg PO bid, and increased after several weeks to a typical maintenance dose of 50 mg PO bid; the maximum dose is 200 mg PO bid. Potential benefits of spironolactone therapy include mild to modest breast development, the softening of body and facial hair, decreased progression of male pattern baldness, and decreased erections. Risks of spironolactone therapy include hypotension and hyperkalemia, and the drug is contraindicated in those with renal insufficiency or baseline serum potassium of greater than 5.5 mEq/L. Use of progesterone does not contribute significantly to feminization and is not generally recommended for gender transition. For patients with wasting syndrome or who might otherwise require megestrol acetate (Megace), progesterone may be a useful alternative. Those individuals with loss of scalp hair may benefit from finasteride (Propecia), topical minoxidil (Rogaine), or a combination of both. Cyproterone, testosterone uptake inhibitors, and growth hormone releasing antagonists are not widely use for gender transition.

Monitoring of Patients on Hormonal Reassignment Therapy

Regardless of the exact regimen chosen, all patients receiving cross-sex hormone treatment require close monitoring to minimize the risks of therapy. Recommended lab monitoring includes baseline and intermittent measurement of complete blood count, liver panel, renal panel, lipid profile, fasting glucose and prolactin level. More detailed descriptions of specific hormonal gender reassignment protocols and recommended monitoring can be found in published literature[9,10], as well as through the Tom Waddell Health Center Transgender clinic protocols (Figure 5).

Primary Care for Transgender Women

In addition to hormonal therapy, transgender women require routine primary care specific to both their biologic and acquired genders. Although a clear increased risk of breast cancer has not been established, cases of breast cancer amongst transgender women have been reported[16,17,18]. As such, breast symptoms should be elicited, clinical breast exams should be performed and patients should be educated regarding breast self-examination. Any patient with suspicious findings on examination should undergo mammogram, and some providers recommend annual mammograms for those over age 50 who have been on hormonal therapy for more than 10 years[16]. Although combined estrogen treatment and androgen suppression may theoretically provide some protection against the development of prostate cancer, the magnitude of this protection is unknown, and cases of prostate cancer have been reported in transgender women[19,20,21]. Prostate cancer screening should thus be offered as in the general male population. At every visit the clinician should review the warning signs of deep venous thrombosis and pulmonary embolism with the patient. For post-surgical patients, care of the neovagina, including consistent dilation to prevent stenosis, adequate use of lubrication, and barrier protection during sexual intercourse should be addressed. Some transgender women harbor the misconception that the neovagina is resistant to HIV, but dilation and sexual activity can cause micro-tears in the neovagina, creating ideal conditions for HIV transmission. Moreover, a thorough sexual history should be taken at each visit, and sexually transmitted diseases screening should be carried out as appropriate for the reported risk behaviors. There are no data to suggest the natural history of HIV infection differs in transgender women compared with age-matched controls. Thus, recommendations regarding the timing of initiation of antiretroviral therapy do not differ for transgender individuals.

Cross-Gender Hormones and Treatments for HIV

The main pathway of metabolism for estrogens occurs via the cytochrome P450 enzyme system, and thus a potential drug-drug interaction can exist with estrogens and any medication (including antiretroviral agents) that also undergo metabolism via the cytochrome P450 system. Since the nucleoside and nucleotide) reverse transcriptase inhibitors (NRTIs and NtRTIs) do not undergo metabolism via the cytochrome P450 enzyme system, they do not have significant drug-drug interactions with estrogens. In contrast, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs) can interact with estrogens; most of the available data related to interactions between antiretroviral drugs and estrogen have involved studies with oral contraceptives (Figure 6). Similar trends in interactions would likely occur with gender reassignment estrogen therapy and antiretroviral medications, with the exception that more pronounced interactions may take place because of the higher levels of estrogens used with gender reassignment hormonal therapy. Although numerous antiretroviral medications can alter estrogen levels, the effect of estrogen compounds on antiretroviral medication levels appears to be limited to a few antiretroviral medications, namely amprenavir (Agenerase) and the amprenavir pro-drug fosamprenavir (Lexiva). Co-administration of amprenavir and ethinyl estradiol to 10 patients for 28 days resulted in significant decrease in serum concentrations of amprenavir[22], suggesting that this drug combination may lead a loss of virologic control and possible amprenavir resistance. Amprenavir has been largely replaced by fosamprenavir, but the drug interaction issues are presumably the same. Although this combination has not definitively been shown to lead to virologic failure in the treatment setting, the DHHS Antiretroviral Therapy Guidelines recommend that oral contraceptives and amprenavir (or fosamprenavir) not be co-administered. Because estrogens have not been shown to significantly effect levels of other antiretroviral medications, cross-gender hormonal therapy is not contraindicated in HIV-infected persons taking antiretroviral therapy. Numerous other medications commonly prescribed for HIV-infected individuals can affect estrogen levels (Figure 7). There is no known significant drug-drug interaction between the most commonly used anti-androgen, spironolactone, and any anti-retroviral agent or other medication commonly used to treat HIV-infected individuals.

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    Figure 1. Factors Independently Associated with HIV Seropositivity in MTF Transgender Women in San Francisco, 1997

    This table shows risk factors independently associated with HIV infection among 392 male-to-female transgender women recruited in the San Francisco area. This study is the largest quantitative study published to date to describe HIV prevalence and risk factors in transgender individuals.
    Data from Clements-Nolle K, Marx R, Guzman R, Katz M. HIV Prevalence, Risk Behaviors, Health Care Use, and Mental Health Status of Transgender Persons: Implications for Public Health Intervention. Am J Pub Health. 2001;91:915-21.

    Figure 1
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    Figure 2. Morbidity in 816 MTF Transgender Women Treated with Cross-Gender

    This table shows the observed morbidity for a subset of disorders in 816 Dutch male-to-female transsexuals treated with cross-gender hormones compared with morbidity observed in the general male population. The standardized incidence ratio (SIR) with 95% confidence intervals are shown. Data from: van Kesteren P, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf). 1997;47:337-42.

    Figure 2
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    Figure 3. Estrogen Preparations for Use in Male-to-Female Gender Reassignment Therapy

    Note: The equivalent maximum dose of the injectable estradiol valerate in the table is less than calculated more for safety reasons and lack of information using the higher doses. Also, the maximum dose of the estradiol patch is less than calculated due to the impractical number of patches and prohibitive cost.
    The figure is reproduced and adapted from Tom Waddell Health Center Transgender Team. Protocols for hormonal reassignment of gender (July 2001). Reproduced with permission.

    Figure 3
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    Figure 4. Anti-androgen and Progestin Use in Male-to-Female Gender Reassignment Therapy

    This table lists the most commonly used anti-androgen agents in cross-hormonal therapy. Note that spironolactone is the agent of choice in the United States. Although theoretically effective in blocking the action of testosterone, testosterone uptake inhibitors and growth hormone releasing antagonists are not commonly used.

    Figure 4
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    Figure 5. Recommended Monitoring for MTF Transgender Persons Taking Hormonal Reassignment Therapy
    Figure 5
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    Figure 6. Interactions Between Oral Contraceptives and Antiretroviral Medications

    Information for this table derived from Bartlett JG, Lane HC, and the Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 6, 2005.

    Figure 6
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    Figure 7. Interactions Between Estrogens and Drugs Commonly Used by HIV-Infected Persons

    This table shows both documented and theoretical interactions between different estrogen formulations and drugs commonly used among HIV-infected persons. Interactions with estrogens and antiretroviral drugs are listed in Figure 6. This table is not a complete listing of all possible interactions.

    Figure 7