ࡱ> }~ fbjbjVV "<<t**mm4h7K`d"\s':'''1)*D[*$[c]c]c]c]c]c]c$zfiRc*-)-)**cm|'L'4d999*$''[c9*[c99RWZ'. XGc0d0`dXni2pni<ZZni]0**9*****cc9***`d****ni********** 3: Transgender Cross-Sex Hormone Therapy Use February 2012 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives Background According to VHA Directive 2011-024 Providing Health Care for Transgender and Intersex Veterans, it is VHA policy that medically necessary care is provided to enrolled or otherwise eligible intersex and transgender Veterans, including hormonal therapy, mental health care, preoperative evaluation, and medically necessary post-operative and long-term care following sex reassignment surgery. Sex reassignment surgery cannot be performed or funded by VHA or VA. The purpose of this PBM document is to provide additional information on the safe use of cross-sex hormone therapy in Veteran patients. Definitions: Transgender: a term used to describe people whose gender identity (sense of themselves as male or female) or gender expression differs from that usually associated with their sex assigned at birth. Transsexual (Male-to-Female, MtF): Male-to-female (MTF) transsexuals are individuals who are male sex at birth, but self-identify as female and often take steps to socially or medically transition to female, including feminizing hormone therapy, electrolysis, and surgeries (e.g., vaginoplasty, breast augmentation). Transsexual (Female-to-Male, FtM): Female-to-male (FTM) transsexuals are individuals who are female sex at birth, but self-identify as male and often take steps socially or medically transition to male, including masculinizing hormone therapy and surgeries (e.g., phalloplasty, mastectomy). Gender Identity Disorder (GID): GID is a conflict between a persons physical sex and the gender with which the person identifies. Untreated and/or undertreated GID is associated with increased morbidity including depression, anxiety, and suicidality and increased mortality., Hormonal treatment is used to reduce or eliminate the symptoms of gender dysphoria through changes in hormonally-sensitive sex characteristics (i.e., reducing characteristics of the original sex and inducing those of the opposite sex). Cross-sex hormone therapy may be used across all spectrums of transition: those desiring hormone therapy only or planning on future sex-reassignment surgery, or those who are post sex-reassignment surgery. Patients may desire varying extents of change in cross-sex characteristics from suppression of the original sex only to complete transition to the desired sex. No prospective, randomized, controlled trials were located that have evaluated the safety and efficacy of the use of cross-sex hormones to produce physical effects in transgender patients. Available information on the use of cross-sex hormone therapy in transgender patients has been derived primarily from observational study or has been extrapolated from use of hormones for indications in the same biologic sex (e.g., estrogen in females; testosterone in males). Various regimens and products have been used. Clinical guidelines on the use of cross-sex hormone treatment in transgender patients have been published by the Endocrine Society (ESG), the World Professional Association for Transgender Health (WPATH)., Very low quality evidence suggests that cross-sex hormone therapy and sex reassignment have a positive impact on quality of life and psychosocial outcomes. In a 2010 meta-analysis including 28 non-randomized, observational studies (which were mostly uncontrolled), improvements were shown in the majority of studies in measures including resolution of gender dysphoria, psychiatric comorbidities, quality of life, and satisfaction with sexual function. NOTEREF _Ref308458632 \h  \* MERGEFORMAT 3 The impact of hormone therapy alone (without sex reassignment surgery) could not be assessed since most of the studies reported on both of the interventions as a whole. The few studies that reported worsening in quality of life were primarily noted in MtF patients. Though suicide attempt rates improved post-transition, they remained higher than the standard population rate. Patients with psychiatric co-morbidities tended to have worse outcomes post-transition. Mortality rates in a transsexual population receiving long-term cross-sex hormone therapy was evaluated and compared to the general population. There were a total of 1331 patients (72% MtF) in this Netherlands population followed for a median duration of 18.5 years providing over 25,000 patient-years of data. A 51% increase in total mortality was observed in the MtF population compared to adjusted expected mortality of the general population (95% confidence interval [CI] 1.47-1.55), primarily due to higher rates of suicide, illicit drug use, and AIDS. Death due to ischemic heart disease was also higher in the MtF population compared to the general population, and current use of ethinyl estradiol was independently associated with an increase in cardiovascular mortality. The mortality rates in the MtF group due to malignant cancers overall were not increased compared to the general population, although a statistical increase in lung and hematological cancer deaths were noted. No increased mortality was observed in the FtM population compared to expected rates, but limited to no conclusions could be drawn due to the overall small numbers of events in these patients. The FtM group tended to be younger than the MtF. Goal of Cross-Sex Hormone Therapy: To reduce or eliminate the symptoms of gender dysphoria through changes in hormonally-sensitive sex characteristics (i.e., reducing characteristics of the original sex and inducing those of the opposite sex) General Principles of Management: Effective clinical care of transgender patients with GID who are receiving cross-sex hormone therapy requires an interdisciplinary, coordinated treatment approach with special attention to the needs of each patient and collaboration among multiple specialties, notably: gynecology, mental health, primary and specialty care, womens health, pharmacy and urology. Patients must be carefully evaluated for eligibility and readiness of cross-sex hormone therapy by a qualified mental healthcare professional or other qualified healthcare professional with expertise in the treatment of transgender patients. Patients must be fully informed on the risks, benefits, limitations, unknowns, expectations of therapy and consent to treatment. Patients must be agreeable to adherence to recommended regimen and avoidance of use of additional hormone treatments obtained through other means (to avoid intentional or unintentional supratherapeutic dosing). Concurrent medical and/or psychiatric conditions should be evaluated, addressed, and adequately controlled prior to initiation. Modifiable risk factors that could exacerbate adverse effects of treatment should be addressed prior to and during treatment (e.g., smoking cessation, weight, illicit drug use) Ongoing monitoring is an essential component of the safe use of treatment. Note: The use of cross-sex hormones for transgender patients is non-FDA approved, or off-label. See PBM Guidance on off-label use for more information:  HYPERLINK "http://vaww.national.cmop.va.gov/PBM/Directives%20Policies%20and%20Information%20Letters/Guidance%20on%20Off%20Label%20Prescribing.pdf" http://vaww.national.cmop.va.gov/PBM/Directives%20Policies%20and%20Information%20Letters/Guidance%20on%20Off%20Label%20Prescribing.pdf Eligibility, Readiness, and Informed Consent All patients seeking feminizing/masculinizing hormone therapy must have a careful mental health and medical evaluation prior to initiation of treatment. Candidates for hormone therapy should fulfill the diagnostic criteria for GID (DSM IV or ICD-10), as determined by a qualified mental health care professional or other qualified professional with expertise in the treatment of transgender patients. Transgender patients with intersex conditions are excluded from the GID diagnosis by DSM IV criteria. Transgender patients with intersex conditions who are seeking hormonal treatment should fulfill criteria for GID, not otherwise specified (NOS). If additional psychiatric or medical co-morbidities are present, they should be evaluated, addressed and adequately-controlled prior to initiation of cross-sex hormone treatment. Ongoing psychotherapy may or may not be indicated. Patients need to be fully informed of and clearly understand the physical, psychological, and social implications, risks, benefits, limitations, and unknowns of hormone therapy and the expectations of ongoing monitoring of treatment. It is important that the patients informed consent for use of hormone therapy be documented in the medical record. MtF Expected Effects of Endocrine Therapy Patients should be educated on the realistic expectations and anticipated onset of the physical changes induced by hormone therapy. Within the first 6 months of therapy, expected changes include redistribution of body fat and decreased muscle mass, reduced upper body strength, decreased libido, male sexual dysfunction, decreased facial and body hair, decreased oiliness of the skin, breast tissue growth, testicular atrophy, decreased sperm production, and decreased spontaneous erections. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308459784 \h  \* MERGEFORMAT 5 Maximal expected effects are observed at approximately 2-3 years. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, Most effects are reversible upon cessation of endocrine treatment, though breast development is permanent and impaired fertility may be permanent. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Limitations of hormone therapy include the lack of effect on the voice, and variability in breast growth and development. Breast growth development is usually not as pronounced as in biological females. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Thinning and slowing of body hair growth is typically insufficiently altered by hormone therapy alone, particularly facial hair. Other effects of estrogen include favorable changes to the lipid profile (increased high density lipoprotein [HDL] and decreased low density lipoprotein [LDL]) and preservation of bone mineral density (BMD). (see Risks of Endocrine Therapy for more information on negative effects) Estrogen Estrogen is the primary hormonal therapy for inducing feminization in MtF transgender patients. Several estrogen products are available for administration by the oral, transdermal, or injectable route. Given the lack of evidence evaluating the efficacy of feminization of one preparation over another (e.g., conjugated vs. ethinyl estradiol vs. 17-estradiol), providers should consider the safety concerns and potential adverse effects of the various products. The use of estrogens is associated with an increased risk of venous thromboembolism (VTE), which appears to be dose-related and higher with oral vs. transdermal administration. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 In transgender patients, it has been observed that ethinyl estradiol products may be associated with a high risk of VTE. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308459784 \h  \* MERGEFORMAT 5 Current use of ethinyl estradiol was independently associated with an increased risk of cardiovascular death in a long-term observational study. NOTEREF _Ref308463357 \h  \* MERGEFORMAT 6 Because of the potential safety concerns and the inability to regulate estrogen dose based on serum levels, ethinyl estradiol preparations are generally no longer recommended. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308459784 \h  \* MERGEFORMAT 5, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7, The use of estradiol (also known as 17-estradiol) usually given orally or transdermally in the lowest effective dose is typically preferred over ethinyl estradiol or conjugated estrogens due to the ability to monitor serum estradiol levels. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Observational data suggest a lower risk of VTE with transdermal products and lower doses of estrogen. In choosing an estrogen product, transdermal estradiol may be preferred in patients at increased risk of thromboembolism or vascular events (e.g., age >35-40 years, smoker, obesity, etc.). Oral estradiol may be used in patients at lower risk of thromboembolism and when oral administration is desired. Intramuscular (IM) injection of estradiol valerate or cypionate is an alternative option, though there may be greater fluctuations in hormone levels between injections and resulting undesirable effects. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Large doses of estradiol transdermal gel would be required for cross-sex hormone therapy and would not be practical in most situations. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Similar to the use of estrogen in biologic females, cross-hormone therapy should be individualized considering the patient-specific goals, co-morbid conditions, risk for adverse events, etc. Initiate estrogen at low doses and titrate up slowly depending on response and tolerance. (see Appendix for more dosing information) Given the lack of evidence from randomized controlled trials regarding optimal dose and outcomes in transgender patients, it is recommended that serum estrogen levels be monitored in attempt to minimize the risk for adverse events over time. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Serum estrogen levels should not exceed physiologic pre-menopausal female levels. Dosing of estrogen in transgender patients may often exceed the dosing range typically used for hypogonadal females. Following orchiectomy, estrogen doses are significantly reduced. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Androgen suppression The use of agents that directly or indirectly suppress the effects of androgens are often used in combination with estrogen in order to reduce male sexual characteristics and allow for more effective use and potentially lower doses of estrogen to achieve the desired effects. Sometimes androgen suppression is used alone in patients who only desire suppression of masculine characteristics and prefer a more androgynous appearance. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Several options are available. (see Appendix for additional information) Spironolactone is commonly used for its anti-androgenic properties and may also increase estrogen levels. When used in combination with estrogen, spironolactone was shown to further reduce testosterone levels and allow for smaller doses of estrogen to maintain or improve desired effects (e.g., male pattern hair loss, breast enlargement, feminization, decreased erections) in an observational 12-month study of 50 MtF patients. Monthly injections of gonadotropin-releasing hormone (GnRH) agonists given along with estrogen have been shown to reduce gonadotropin and testosterone levels without a negative impact on bone-mineral density, as reported in MtF patients treated with goserelin and followed over a two-year period., Other effects observed with GnRH agonist therapy were increased body mass index (BMI) and fat mass with a low incidence of adverse reactions. Evidence evaluating the use of finasteride in MtF transgender patients is lacking, though its use may improve male pattern balding. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Flutamide inhibits the binding of androgens to the receptor site, though does not lower testosterone levels. In addition, due to its hepatotoxicity and lack of demonstrated effectiveness in MtF transgender patients, use is generally not recommended. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Progestins have been used in some cross-sex hormone regimens, but their use is controversial and more recently not routinely recommended (with the exception of cyproterone, not available in the US). NOTEREF _Ref308459784 \h  \* MERGEFORMAT 5 Though expected to improve breast growth and development, the benefits of progestins added to cross-sex hormone therapy have not been clearly demonstrated. Considering the uncertain benefit along with the potential risks of progestin addition (e.g., depression, weight gain, lipid changes, cardiovascular risk, and questionable cancer risk), progestins are not routinely recommended. A situation where a progestin may be considered may be in a patient that has reached maximal estrogen doses or is intolerant of estrogen-based regimen and who is not a candidate for other androgen-suppressive therapy. Similar recommendations on the use of progestins have been proposed by the Vancouver guidelines. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Anti-androgen therapy is often used along with estrogens as a means to reduce the amount of estrogen needed for the desired effects. It is anticipated that the incorporation of anti-androgen therapy into the MtF regimen may be safer since lower estrogen doses are used. However, with the exception of spironolactone and GnRH agonists, evidence evaluating the safety of combination regimens is not available. Following orchiectomy, the need for and dose of androgen suppression therapy needs to be re-evaluated, as endogenous androgens are significantly reduced. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Risks of MtF Estrogen Treatment Some of the risks associated with the use of cross-sex hormones in MtF patients are expected to be similar to those associated with hormone replacement therapy in biologic females. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 In attempt to reduce the risk of adverse effects, supraphysiologic doses of estrogen should be avoided. Any co-existing medical conditions that could be exacerbated by hormone therapy or increase risk of adverse events with hormone therapy should be addressed and managed prior to initiating treatment (e.g., blood pressure, lipids, smoking, diabetes, etc.). (see Appendix for adverse effects of anti-androgen treatment) Risks of MtF Estrogen Treatment Established risks of estrogen treatmentVTE Hyperprolactinemia Cholelithiasis Elevations in liver function tests (LFT) Weight gain Fluid retention Hypertension Elevated TG Migraines (may also exacerbate existing condition) Fertility impairment (may or may not be permanent)Potential risks of estrogen treatment (Concerns exist; however, evidence evaluating these risks is not well established) Cardiovascular/cerebrovascular disease (likely) Hormone-sensitive tumors (e.g., prolactinoma, prostate, breast) Increased insulin resistance There is concern of an increased risk of hormonally sensitive tumors including prolactinoma, breast cancer, and prostate, though evidence is limited to case reports, and causality has not been established. Estrogen therapy in MtF patients has been associated with hyperprolactinemia, and several case reports of lactotroph hyperplasia and adenoma (prolactinoma) in MtF patients on cross-sex hormone therapy have been published. NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13,,,, Two cases of meningioma (a tumor theorized to be influenced by hormones) in MtF patients treated with cross-sex hormones were identified., Breast cancer in MtF patients on cross-sex hormone therapy has been rarely reported. NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13,, Benign prostate hyperplasia (BPH) and prostate cancer have been rarely reported in older MtF patients who were on cross-sex hormone therapy, some for many years. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13 The cases of prostate cancer occurred in patients who started estrogen therapy after the age of 50, and it was unclear whether cancer was present prior to initiation of therapy. Another report found small prostate size and no pre-malignant prostate changes in a small group of MtF patients on estrogen therapy. It is unclear how other tumors that are theorized to be affected by sex hormones (e.g., lung, colon, bladder, brain) are influenced by cross-sex hormone therapy in transgender patients. NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13 An increased incidence of death due to lung and hematologic cancers in MtF patients compared to expected population rates were observed in a large, long-term Netherlands study. NOTEREF _Ref308463357 \h  \* MERGEFORMAT 6 Overall, cancers have been rarely reported in transgender patients receiving cross-sex hormone therapy, though this may be in part due to the relatively recent use of cross-sex hormone therapy and short duration of therapy, small numbers of patients, and under-reporting. Given the biologic plausibility of increased risk of some of the hormonally sensitive tumors and cancers and the lack of sufficient evidence evaluating the risk, regular monitoring has been recommended. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13 Prolactin levels should be checked regularly; elevated levels often return to normal with reduction in estrogen dose or discontinuation. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Breast self-exam, clinical breast exam at regular appointments and routine mammogram screening should continue in MtF patients on cross-sex hormone therapy, the same as recommendations for screening in biologic females. Factors that may increase breast cancer risk may also be considered in determining the monitoring plan for a particular patient (e.g., duration of estrogen therapy, family history of breast cancer, obesity). NOTEREF _Ref308459784 \h  \* MERGEFORMAT 5 Prostate cancer screening should continue per accepted guidelines in all MtF patients, the same as recommended for biologic males. It appears that estrogen administration may be associated with an increased cardiovascular risk in MtF patients. A long-term observational study from the Netherlands found a 64% increase in cardiovascular mortality in MtF patients on various cross-sex hormone therapy regimens compared to expected population mortality rates. Several of the patients who died had known cardiovascular risk factors (smoking, hypercholesterolemia, previous MI). In the same study, current use of ethinyl estradiol was independently associated with an increased risk of cardiovascular death. NOTEREF _Ref308463357 \h  \* MERGEFORMAT 6 A systematic review of the literature found insufficient data to evaluate the effect of cross-sex hormone therapy in MtF patients on cardiovascular outcomes. Estrogen is associated with elevated triglycerides (though favorable increases in HDL and reductions in LDL), an increase in visceral fat, fluid retention, increased blood pressure, and possibly decreased insulin sensitivity. Given these known undesirable effects of estrogen that are associated with increased cardiovascular risk, all patients should be evaluated for cardiovascular risk factors and be managed according to established guidelines. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 The effects of estrogen (with or without progestin) on insulin sensitivity, blood glucose levels, and the development of diabetes in MtF transgender patients are uncertain. Insulin sensitivity was shown to be reduced in a small study of MtF patients on an estrogen plus a progestin which is not available in the US. Diabetes is a strong cardiovascular risk factor. Because estrogen is associated with other changes that can increase cardiovascular risk (e.g., increased visceral fat, elevated triglycerides, hypertension), it is important to know whether patients considering or using cross-sex hormones have or are at risk for diabetes. Current guidelines recommend monitoring of blood glucose in all patients (or hemoglobin A1C in patients with diabetes) as part of cross-sex hormone pre-screening and routine care. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Monitoring Parameters Individual goals of the patient (e.g., the extent of masculine suppression and feminine induction desired) as well as any co-existing medical conditions (e.g., smoking, liver disease, diabetes, cardiovascular disease, cancer history, etc.) need to be considered. The lowest doses of hormones to achieve the desired effects should be used. In attempt to minimize long-term complications, it has been recommended to monitor cross-sex hormone levels, maintain levels within the normal physiologic range of the desired sex and avoid supraphysiologic levels. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Patients undergoing sex-reassignment surgery with gonad removal will require significant reductions in cross-sex hormone doses after surgery. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Prior to de novo initiation of MtF cross-sex hormone therapy, a thorough medical evaluation should be completed. Considerations should include (but may not be limited to): history of or risk factors for VTE, cardiovascular disease (hypertension, myocardial infarction, stroke), diabetes, dyslipidemia, hepatic or renal disease, migraine, estrogen-dependent cancer, or cholelithiasis. Any co-existing medical conditions or modifiable risk factors (e.g., smoking, obesity) that could be exacerbated by hormone therapy or increase risk of adverse events with hormone therapy should be addressed and managed prior to initiating treatment. Because smoking increases the risk of VTE and cardiovascular disease particularly in patients on hormone therapy, smoking cessation should be strongly encouraged. Suggested medical monitoring for MtF patients on cross-hormone therapy NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 TimeframeMonitoringBaseline, pre-screeningRoutine health screening and physical exam including general health screening for biologic males, blood pressure, weight, medication history, etc. Fasting blood glucose (hemoglobin A1C for patients with diabetes), lipid profile, LFTs, testosterone, prolactin Additional lab tests as clinically indicated (e.g., electrolytes and renal function for spironolactone, thyroid function tests in patients on thyroid replacement)Regular Monitoring Q1-3 months after initiation or after change in regimen (unless otherwise noted), then q6-12 months once stablePhysical exam for signs of feminization and adverse effects of hormone therapy Weight, blood pressure Fasting blood glucose (hemoglobin A1C for patients with diabetes), lipid profile, LFTs Prolactin levels q6-12 months Additional lab tests as clinically indicated, for example: Electrolytes and renal function for spironolactone (1 wk after initiation and dose change) Thyroid function tests in patients on thyroid replacement Testosterone and estradiol levels q3 months until stable Testosterone levels goal: <55 ng/dL (normal female range) Estradiol levels: not to exceed 200 pg/mL (mean level for premenopausal females) Health maintenance and screening as clinically appropriate, including: Routine cancer screening (i.e., prostate, breast, testicular, colon) Bone mineral density (BMD) testing if at risk for osteoporotic fracture, age 60 and older, or those who stop hormone therapy (i.e., noncompliance, after sex-reassignment surgery) FtM Expected Effects of Endocrine Therapy Patients should be educated on the realistic expectations and anticipated onset of the physical changes induced by hormone therapy. Within the first 6 months of therapy, expected changes include redistribution of body fat, increased libido, oily skin and acne, clitoral enlargement, vaginal atrophy, cessation of menses, and reduced fertility. Within the first year of therapy, additional changes expected include increased muscle mass, increased facial and body hair, male pattern baldness, and deepening of voice. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308459784 \h  \* MERGEFORMAT 5, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Maximal expected effects are observed over several years. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Deepening of the voice and the changes to facial and scalp hair are permanent, and effects on fertility may be permanent. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Testosterone Testosterone is the mainstay of cross-sex hormone therapy for FtM patients. In the US, several testosterone products are available for administration via intramuscular injection or transdermal routes. Evidence is lacking on the comparative efficacy or safety of one product over another in the transgender population. Long-acting intramuscular testosterone products (cypionate or enanthate) have been observed to be effective, although may be associated with cyclical fluctuations in levels and resultant effects (e.g., changes in mood, energy, libido). Administering half of the dose every week or use of transdermal preparations can be tried to minimize the fluctuations if bothersome. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 The transdermal testosterone patch provides a more consistent 24-hour release of testosterone that mimics hormonal release in biologic males, though the patch is commonly associated with skin irritation. Several transdermal gel products and a solution product are available, which deliver more consistent release of testosterone. The concern with the use of topical testosterone gel or solution is the potential for secondary transfer and exposure to unintended contacts such as children or women. Special precautions are needed to avoid secondary exposure from treated areas or unwashed clothing. Choice of testosterone product should be made considering the advantages and disadvantages of the route of administration for the patient, adverse effects, and cost. Testosterone is contraindicated in pregnancy. Although testosterone usually suppresses menses within the first few months of treatment in FtM patients, ovulation may still occur. Effective contraception for biologic females of childbearing potential is required. Similar to the use of testosterone in males, cross-sex hormone therapy should be individualized considering the patient-specific goals, co-morbid conditions, risk for adverse events, etc. Initiate testosterone at low doses and titrate up slowly depending on response and tolerance. Given the lack of evidence from randomized controlled trials regarding optimal dose and outcomes in transgender patients, it is recommended that serum testosterone levels be monitored in attempt to minimize the risk for adverse events over time. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Serum testosterone levels should be maintained in the normal physiologic male range. Following oophorectomy, testosterone doses are reduced to achieve levels within the lower-middle end of the biologic male range. Vancouver guidelines also recommend a similar, lower goal for testosterone levels for maintenance of non-surgical patients who are on long-term treatment (2 years or more). NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Doses of testosterone used in transgender FtM patients are typically within the range of dosing used for hypogonadal males. Progestins and GnRH agonists Progestins are not typically included in FtM hormone regimens; however, short term use may sometimes be useful for facilitating menstrual cessation. Depot medroxyprogesterone acetate (DMPA) 150 mg IM injection may be given every 3 months for 1 or 2 doses at the beginning of testosterone therapy. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 DMPA also provides an effective form of contraception when dosed every 3 months. Other protocols have reported use of medroxyprogesterone acetate orally in varying regimens. GnRH agonists may also be used to suppress menses. Risks of FtM Endocrine Treatment Some of the risks associated with the use of cross-sex hormones in FtM patients are expected to be similar to those associated with hormone replacement therapy in biologic males. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 In attempt to reduce the risk of adverse effects, supraphysiologic levels of testosterone should be avoided. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Any co-existing medical conditions that could be exacerbated by hormone therapy or increase risk of adverse events with hormone therapy should be addressed and managed prior to initiating treatment (e.g., blood pressure, lipids, smoking, sleep apnea etc.). Risks of FtM Testosterone Treatment Established risks of testosterone treatmentErythrocytosis Liver dysfunction (more common with oral products) Hypertension Salt retention Weight gain (increased visceral fat) Adverse psychological changes Lipid changes (reduced HDL, elevated TG) Induction or worsening of sleep apnea Fertility impairment (may or may not be permanent) Teratogenicity during pregnancyPotential risks of testosterone treatment (Concerns exist; however, evidence evaluating these risks is not well established) Hormone-sensitive cancers (e.g., ovarian, breast, and endometrial) Increased cardiovascular risk There is concern of an increased risk of hormonally sensitive cancers including ovarian cancer, breast cancer, and endometrial cancer, though evidence is limited to case reports, and causality has not been established. NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13 Although there is concern of the presence of unopposed estrogen in the endometrium of FtM patients receiving testosterone due to the aromatization of testosterone to estradiol, no published case reports of endometrial cancer in FtM patients were located. Endometrial atrophy has actually been observed in testosterone-treated patients undergoing hysterectomy. NOTEREF _Ref308501951 \h  \* MERGEFORMAT 25, A case of breast cancer has been reported in a FtM patient on long-term testosterone therapy following mastectomy. Three case reports of ovarian cancer in FtM patients treated with testosterone have been identified., It is unclear how other tumors that are theorized to be affected by sex hormones (e.g., lung, colon, bladder, brain) are influenced by cross-sex hormone therapy in transgender patients. NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13 Overall, cancers have been rarely reported in transgender patients receiving cross-sex hormone therapy, though this may be due to the relatively recent use of hormone therapy and short duration of therapy, small numbers of patients, and under-reporting. Given the biologic plausibility of increased risk of hormonally sensitive cancers and the lack of sufficient evidence evaluating the risk, regular monitoring has been recommended. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13 In addition, oophorectomy NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308465673 \h  \* MERGEFORMAT 13 and potentially total hysterectomy NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 have been suggested as a preventative measure in FtM patients receiving long term testosterone therapy (18-24 months or longer). It is unclear whether testosterone administration is associated with an increased cardiovascular risk in FtM patients. Evidence from a long-term Netherlands study found no increase in cardiovascular mortality in FtM patients, though limited to no conclusions could be drawn due to the overall small numbers of events in these patients. NOTEREF _Ref308463357 \h  \* MERGEFORMAT 6 A systematic review of the literature found insufficient data to evaluate the effect of testosterone in FtM patients on cardiovascular outcomes. NOTEREF _Ref308502517 \h  \* MERGEFORMAT 23 However, testosterone is associated with undesirable changes in lipids (decreased HDL, elevated TG), an increase in visceral fat, salt retention/edema, and increased blood pressure. Given these known undesirable effects of testosterone that are associated with increased cardiovascular risk, all patients should be evaluated for cardiovascular risk factors and be managed according to established guidelines. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Monitoring Parameters Individual goals of the patient (e.g., the extent of feminine suppression and masculine induction desired) as well as any co-existing medical conditions (e.g., smoking, liver disease, diabetes, cardiovascular disease, cancer history, etc.) need to be considered. The lowest doses of hormones to achieve the desired effects should be used. In attempt to minimize long-term complications, it has been recommended to monitor cross-sex hormone levels, maintain levels within the normal physiologic range of the desired sex and avoid supraphysiologic levels. NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4 Patients undergoing sex-reassignment surgery with gonad removal will require significant reductions in cross-sex hormone doses after surgery. NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 Prior to de novo initiation of FtM cross-sex hormone therapy, a thorough medical evaluation should be completed. Considerations should include (but may not be limited to): history of or risk factors for erythrocytosis, cardiovascular disease (hypertension, heart failure, myocardial infarction, stroke), diabetes, dyslipidemia, hepatic or renal disease, hormone-sensitive cancer, and sleep apnea. Any co-existing medical conditions or modifiable risk factors (e.g., smoking, obesity, diet) that could be exacerbated by hormone therapy or increase risk of adverse effects with hormone therapy should be addressed and managed prior to initiating treatment. Because smoking increases the risk of cardiovascular disease, smoking cessation should be strongly encouraged. Suggested medical monitoring for FtM patients on cross-sex hormone therapy NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 TimeframeMonitoringBaseline, pre-screeningRoutine health screening and physical exam including general health screening for females, blood pressure, weight, medication history, etc. Complete blood count, LFTs, lipid profile, fasting blood glucose (hemoglobin A1C for patients with diabetes), may consider baseline testosterone level Additional lab tests as clinically indicated Regular Monitoring Q1-3 months after initiation or after change in regimen (unless otherwise noted), then q6-12 months once stablePhysical exam for signs of virilization and adverse effects of hormone therapy Weight, blood pressure Fasting blood glucose (hemoglobin A1C for patients with diabetes), lipid profile, LFTs Testosterone levels until stable Testosterone level goal: normal male range - 320-1000 ng/dL Issues for consideration in checking testosterone levels: IM injection (cypionate or enanthate) check level mid-way between injections Transdermal check level anytime after one week of treatment Total testosterone level may be elevated in some patients due to high levels of sex hormone binding globulin, but free testosterone levels are normal (for first 3-9 months of treatment) Estradiol levels during first 6 months or until there has been no uterine bleeding for 6 months Estradiol level goal: <50 pg/mL Health maintenance and screening as clinically appropriate, including: Routine cancer screening (i.e., breast, cervical, colon); additional cancer screening as appropriate: endometrial, ovarian BMD testing if at risk for osteoporotic fracture, age 60 and older, or those who stop or reduce hormone therapy (i.e., noncompliance, after sex-reassignment surgery) References APPENDIX MtF Estrogen Therapy DrugDosing Guidance Issues for considerationEstradiol, oral* (17- estradiol) Initiate at 1-2 mg/day; gradually increase Usual (oral): 2-4 mg/day, up to 6 mg/day noted Contraindications: breast cancer or estrogen-dependent neoplasm, VTE (active or past), active or recent stroke or MI Consider factors that increase risk for AEs including increased age, smoking, obesity, hypercholesterolemia, hypertension, diabetes, cardiovascular disease, etc. Consider holding estrogen therapy 4 wks prior to surgery and restarting when patient is mobile to reduce risk of VTE Choice of product: Estradiol (also known as 17- estradiol) products are preferred over ethinyl estradiol (as in contraceptive products) and conjugated estrogens (e.g., Premarin) due to ability to monitor serum levels and potentially lower risk of VTE Transdermal estradiol may be preferred in patients with increased risk of VTE including age >35-40 yrs, smoking, etc. IM estradiol products may cause cyclical fluctuations in hormone levels and adverse effects Dosing considerations: Use lowest effective dose Monitor serum levels Avoid supraphysiologic levels Hormone level goals: Testosterone levels goal <55 ng/dL Estradiol level NTE physiologic range for pre-menopausal females, 200 pg/mLEstradiol, transdermal* (17-  estradiol) Products available for weekly or twice weekly adminInitiate at 0.1 mg/24h; gradually increase Usual (transdermal): 0.1-0.2 mg/24h, up to 0.4 mg/24h noted Estradiol, injectable* (17-  estradiol) Valerate or cypionateUsual injectable (valerate) 5-20 mg IM q2 wks; up to 40 mg noted Usual injectable (cypionate): 2-10 mg IM qwk *Drug is on VA National Formulary; Note: MtF estrogen doses are often higher than usual doses for hypogonadal conditions in biologic females. Doses required post-orchiectomy are lower, and anti-androgen therapy may be discontinued. Patients using reduced doses should be monitored for osteoporosis. AE=adverse effects; MI=myocardial infarction; NTE=not to exceed; VTE=venous thromboembolism MtF Androgen Suppression Therapy Drug/ClassMOADosing GuidanceAdverse EffectsMonitoring ParametersIssues for considerationSpironolactone*Decreases testosterone synthesis; inhibits androgen binding at the receptor site; may increase estrogen levels Usual: 100-200 mg/day Initiate at 50/day (or 25 mg/day if low BP) Use lowest effective dose Max 400-600 mg/day has been used but little info on long term safety Max 400 mg/dayHyperkalemia, gynecomastia (may be irreversible), dehydration, hypotension, renal impairment, possibly tumirogenicSerum electrolytes, BUN/SCr, BP Check periodically and after increase in doseHyperkalemia: Concomitant use of meds that increase potassium (e.g., ACEI/ARB, NSAIDs, potassium-sparing diuretics) may increase risk of hyperkalemia; low doses and careful monitoring requiredGnRH agonists Decrease gonadotropin and testosterone levelsStudied: goserelin 3.6 mg SQ monthly Duration: up to 2 years has been reported to be well toleratedNot well reported in TG; in general, peripheral edema, headache, mood change, depression, site reactionBMD, although BMD was not shown to be adversely affected when used in MtF in combination with estrogenNone ProgestinSuppress GnRH productionMedroxyprogesterone*: 5-30 mg/day (divide higher doses) Micronized progesterone: 100-400 mg/dayMood changes, depression, fluid retention, headache In combo with estrogen, concern for increased risk of MI, stroke, PE, breast cancer from WHIBP, weight, lipids, blood glucose, LFTs*Not routinely recommended for use due to lack of clear benefit and concerns for harm*Finasteride*Blocks conversion of testosterone to 5-alpha dihydrotestosteroneUsual: 2.5-5 mg/day Lower doses, 2.5 mg every other day, have been used for alopecia onlyNot reported in TG; in general decreased libido, sexual dysfunction, breast tenderness, breast enlargementNone required when not used for BPHNo studies have been published in TG patients; use is extrapolated from alopecia indication in biologic males, hirsute non-TG females Teratogenic drug; should not be crushed or handled by women*Drug is on VA National Formulary; Note: doses required post-orchiectomy are lower, and anti-androgen therapy may be discontinued; BMD=bone mineral density; BP=blood pressure; LFT=liver function tests; MI=myocardial infarction; TG=transgender; VTE=venous thromboembolism; WHI=Womens Health Initiative FtM Testosterone Therapy NOTEREF _Ref308459782 \h  \* MERGEFORMAT 4, NOTEREF _Ref308460155 \h  \* MERGEFORMAT 7 DrugDosing GuidanceIssues for considerationTestosterone, injection in oil* (cypionate or enanthate) Initiate at 50-80 mg q2 wks (or 50% weekly); gradually increase monthly Usual dose: 100-200 mg q2 wks (or 50% weekly) Older, higher dose regimens of 250 mg IM q2 wks notedContraindications: breast cancer, prostate cancer, pregnancy, breast-feeding Precautions: lung disease (sleep apnea), heart failure, hypertension, cardiovascular disease Consider factors that increase risk for AEs including increased age, smoking, obesity, hypercholesterolemia, hypertension, diabetes, cardiovascular disease, etc. Drug interactions: warfarin Choice of product: IM testosterone products may cause cyclical fluctuations in hormone levels and adverse effects ; transdermal products produce more consistent hormone levels Transdermal patches commonly cause skin irritation Secondary exposure with transdermal gel/solution: Risks of secondary exposure to women and children via unclothed application site or unwashed clothing. Special precautions necessary. See product information for details. Buccal system may cause mouth and gum irritation; clinical and safety data are limited Dosing considerations: Initiate at lower end of dosing range if co-morbid conditions are present Use lowest effective dose Monitor serum levels Avoid supraphysiologic levels Hormone level goals: Testosterone levels goal: 320 1000 ng/dL See specific product information for recommendations on timing of testingTestosterone, transdermal patch*Usual dose 2.5-7.5 mg q24 hrs Doses up to 10 mg/day notedTestosterone, transdermal gel*, solutionSeveral products available with varying dosing; check specific product information for dosing instructionsTestosterone, buccal systemUsual dose (non TG): 30 mg (one) q12 hr *Drug on VA National Formulary; Note: FtM testosterone doses are typically within the usual dosing range for hypogonadal conditions in biologic males. Upon chronic use (2 yrs or more) or post-oophorectomy, reduced doses may be used to keep testosterone levels at lower end of physiologic male range. Patients using reduced doses should be monitored for osteoporosis. AE=adverse effects VA Drug Costs for Cross-Sex Hormone Therapy in MtF patients DrugDosing GuidanceProducts$ Cost/unit$ Cost/pt/wk$ Cost/pt/monthEstradiol, oral*Initiate at 1-2 mg/day Usual (oral): 2-4 mg/day, up to 6 mg/day notedEstradiol tab 0.5 mg, 1 mg 2 mg (costs for 1-2 tabs/day)0.04/tab (all strengths)0.28 0.56 1.20 2.40 Estradiol, transdermal patch*Initiate at 0.1 mg/24h Usual (transdermal): 0.1-0.2 mg/24h, up to 0.4 mg/24h notedEstradiol (Climara) 0.1 mg/day patch (once weekly) (costs shown for 1-2 patches/wk)3.24/patch3.24 6.4812.96 - 25.60Estradiol (Alora) 0.1 mg/day patch (twice weekly) (costs shown for 2-4 patches/wk)3.20/patch6.40 12.8025.60 51.20Estradiol valerate, injectable* Usual injectable (valerate) 5-20 mg IM q2 wks; up to 40 mg noted Estradiol valerate (Delestrogen) 10 mg/ml, 20 mg/ml, 40 mg/ml - 5 ml multi-dose vials (costs using 20 mg/ml strength, dosing of 5-20 mg q2wk)0.63/mg1.58 6.306.30 25.20 Estradiol cypionate, injectable*Usual injectable (cypionate): 2-10 mg IM qwkEstradiol cypionate (Depo-Estradiol) 5 mg/ml 5 ml MDV (costs using dosing of 2-10 mg qwk)0.99/mg1.98 9.907.92 39.60Spironolactone100 200 mg/day; up to 400-600 mg/day notedSpironolactone 100 mg tab0.17/tab1.19 2.385.10 10.20Goserelin 3.6 mg injection3.6 mg SQ monthlyGoserelin 3.6 mg SQ monthly179.41n/a179.41Finasteride oral2.5 mg 5 mg dailyFinasteride 5 mg tab0.251.7552.50Medroxyprogesterone5 30 mg/dayMedroxyprogesterone acetate 5 mg, 10 mg tabs (costs using 5-30 mg/day)0.04 (all strengths)0.28 0.841.20 3.60Progesterone, micronized100 400 mg/dayPrometrium 100 mg, 200 mg caps (costs using 100 mg/day)1.228.5436.60Prometrium 200 mg caps (costs using 200-400 mg/day)2.3316.31 32.6269.90 139.80*VA pricing as of 11/8/11; check  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov for current pricing. Products with the lowest costs are shown when more than one product is available. Costs calculated based on usual doses. VA Drug Costs for Testosterone Therapy in FtM Patients DrugDosing GuidanceProducts$ Cost/unit$ Cost/pt/wk$ Cost/pt/monthTestosterone cypionate, injection* Initiate at 50-80 mg q2 wks (or 50% weekly); Usual dose: 100-200 mg q2 wks (or 50% weekly) Older, higher dose regimens of 250 mg IM q2 wks notedTestosterone cypionate 100 mg/mL, 200 mg/mL 10 mL multi-dose vials (costs using 100-200 mg q2wks using 200 mg/mL strength)<0.01/mg0.25 0.51 - 2Testosterone enanthate, injection* Initiate at 50-80 mg q2 wks (or 50% weekly); gradually increase monthly Usual dose: 100-200 mg q2 wks (or 50% weekly) Older, higher dose regimens of 250 mg IM q2 wks notedTestosterone enanthate 200mg/ml 5 ml multi-dose vial (costs using 100-200 mg q2 wks)<0.01/mg0.40 0.801.60 3.20Testosterone, transdermal patch*Usual dose 2.5-7.5 mg q24 hrs Doses up to 10 mg/day notedTestosterone patch (Androderm) (costs using 2.5 7.5 mg/day)1.50/2.5 mg patch10.50 31.5045.00 135.003.00/5 mg patchTestosterone, transdermal gel, solutionSeveral products available with varying dosing; check specific product information for dosing instructionsAndrogel 1% (75 gm pump; costs using 5-10gm/day)1.10/gm38.50 77.00165.00 330.00Testim 1% gel (5 gm pkg; costs using 5-10 gm/day)0.76/gm26.60 53.20114.00 228.00Androgel 1.62% (75 gm pump; costs using 2 4 pumps/day2.76/pump38.64 77.28165.60 331.20Fortesta 2% gel (60 gm pump; costs using 4-7 pumps/day)0.83/pump23.24 40.6799.60 174.30Axiron solution (60 pump bottle; costs using 2-4 pumps/day3.42/pump47.88 95.76205.20 410.40*VA pricing as of 11/8/11; check  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov for current pricing. Products with the lowest costs are shown when more than one product is available. Costs calculated based on usual doses.     Transgender Cross-Sex Hormone Therapy Recommendations Updated version may be found at  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or  HYPERLINK "http://vaww.pbm.va.gov" http://vaww.pbm.va.gov  PAGE 10 . VHA Directive 2011-024 Providing Health Care for Transgender and Intersex Veterans, June 9, 2011 . Institute of Medicine. The health of lesbian, gay, bisexual, and transgender people: Building a foundation for better understanding. 2011 Washington, DC: The National Academies Press. Found at (HYPERLINK "http://www.iom.edu/Reports/2011/The-Health-of-Lesbian-Gay-Bisexual-and-Transgender-People.aspx"HYPERLINK "http://www.iom.edu/Reports/2011/The-Health-of-Lesbian-Gay-Bisexual-and-Transgender-People.aspx"http://www.iom.edu/Reports/2011/The-Health-of-Lesbian-Gay-Bisexual-and-Transgender-People.aspx) . Murad MH, Elamin MB, Garcia MZ et al. Hormonal therapy and sex reassignment: a systematic review and meta-analysis of quality of life and psychosocial outcomes. Clin Endocrinol. 2010;72:214-31. . Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endocrine treatment of transsexual persons: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(9):3132-54. . World Professional Association for Transgender Health's Standards of Care for Gender Identity Disorders, Version 7 released 9/27/2011. Available at  HYPERLINK "http://www.wpath.org/" www.WPATH.org. . Asscheman H, Giltay EJ, Megens JAJ, et al. A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol. 2011;164:635-42. . Dahl M, Feldman JL, Goldberg JM, et al. Physical aspects of transgender endocrine therapy. International Journal of Transgenderism. 2006;9:111-34. . Louis J. Gooren. Care of transgender persons. N Engl J Med. 2011; 364:1251-1257. HYPERLINK "http://www.nejm.org/toc/nejm/364/13/"   . North American Menopause Society Position Statement 2010: Estrogen and progestogen use in postmenopausal women. Menopause. 2010;17(2):242-255. . Prior JC, Vigna YM, Watson D. Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Arch Sex Behav. 1989;18(1):49-57. . Dittrich R, Binder H, Cupisti S, et al. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Exp Clin Endocrinol Diabetes. 2005;113:586-92. . Mueller A, Zollver H, Kronawitter D, et al. Body composition and bone mineral density in male-to-female transsexuals during cross-sex hormone therapy using gonadotrophin-releasing hormone agonist. Exp Clin Endocrinol Diabetes. 2011;119:95-100. . Mueller A, Gooren L. Hormone related tumors in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol. 2008;159:197-202. . Gooren LJ, Assies J, Asscheman H, et al. Estrogen-induced prolactinoma in a man. J Clin Endocrinol Metabl. 1988;66(2):444-6. . Garcia-Malpartida K, Martin-Gorgojo A, Rocha M, et al. Prolactinoma induced by estrogen and cyproterone acetate in a male-to-female transsexual. Fertil Steril. 2010;94:1097. . Kovacs K, Stefaneanu L, Ezzat S, et al. Prolactin-producing pituitary adenoma in a male-to-female transsexual patient with protracted estrogen administration. A morphologic study. Arch Pathol Lab Med. 1994;118:562-65. . Serri O, Noiseux D, Robert F, et al. Lactotroph hyperplasia in an estrogen treated male-to-female transsexual patient. J Clin Endocrinol Metab. 1996;81:3177-79. . Delpolyi AR, Han SJ, Parsa AT. Development of a symptomatic intracranial meningioma in a male-to-female transsexual after initiation of hormone therapy. J Clin Neurosci. 2010;17(10):1324-6. . Gazzeri R and Galurza M. Growth of a meningioma in a transsexual patient after estrogen-progestin therapy. N Engl J Med. 2007;357(23):2411-12. . Ganly I and Taylor EW. Breast cancer in a trans-sexual man receiving hormone-replacement therapy. Br J Surg. 1995;82(3):341. . Pritchard TJ, Pankowsky DA, Crowe JP, et al. Breast cancer in a male-to-female transsexual. 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JAMA. 1988;259(15):2278-80. . van Kesteren P, Meinhardt W, van der Valk P, et al. Effects of estrogens only on the prostates of aging men. J Urol. 1996;156:1349-53. . Elamin MB, Garcia MZ, Murad MH, et al. Effect of sex steroid use on cardiovascular risk in transsexual individuals: a systematic review and meta-analysis. Clin Endocrinol. 2010;72:1-10. . Elbers JMH, Giltay EJ, Teerlink E, et al. Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol. 2003;58:562-71. . Miller N, Bedard YC, Cooter NB, et al. Histological changes in the genital tract in transsexual women following androgen therapy. Histopathology. 1986;10(7):661-9. . Perrone AM, Cerpolini S, Maria Salfi NC, et al. Effect of long-term testosterone administration on the endometrium of female-to-male (FtM) transsexuals. J Sex Med. 2009;6(11):3193-200. . Burcombe RJ, Makris A, Pittam M, et al. Breast cancer after bilateral subcutaneous mastectomy in a female-to-male trans-sexual. Breast. 2003;12(4):290-3. . Dizon DS, Tejada-Berges T, Koelliker S, et al. Ovarian cancer associated with testosterone supplementation in a female-to-male transsexual patient. Gynecol Obstet Invest. 2006;62:226-228. . Hage JJ, Dekker JJML, Karim RB, et al. Ovarian cancer in female-to-male transsexuals: report of two cases. Gynecol Oncol. 2000;76:413-15. 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