Gender Dysphoria and Gender Reassignment Surgery

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Currently, the local Medicare Administrative Contractors (MACs) determine coverage of gender reassignment surgery on a case-by-case basis. We received a complete, formal request to make a national coverage determination on surgical remedies for gender identity disorder (GID), now known as gender dysphoria. The Centers for Medicare & Medicaid Services (CMS) is not issuing a National Coverage Determination (NCD) at this time on gender reassignment surgery for Medicare beneficiaries with gender dysphoria because the clinical evidence is inconclusive for the Medicare population. In the absence of a NCD, coverage determinations for gender reassignment surgery, under section 1862(a)(1)(A) of the Social Security Act (the Act) and any other relevant statutory requirements, will continue to be made by the local MACs on a case-by-case basis. To clarify further, the result of this decision is not national non-coverage rather it is that no national policy will be put in place for the Medicare program. In the absence of a national policy, MACs will make the determination of whether or not to cover gender reassignment surgery based on whether gender reassignment surgery is reasonable and necessary for the individual beneficiary after considering the individual’s specific circumstances. For Medicare beneficiaries enrolled in Medicare Advantage (MA) plans, the initial determination of whether or not surgery is reasonable and necessary will be made by the MA plans. Consistent with the request CMS received, the focus of this National Coverage Analysis (NCA) was gender reassignment surgery. Specific types of surgeries were not individually assessed. We did not analyze the clinical evidence for counseling or hormone therapy treatments for gender dysphoria. As requested by several public commenters, we have modified our final decision memorandum to remove language that was beyond the scope of the specific request. We are not making a national coverage determination related to counseling, hormone therapy treatments, or any other potential treatment for gender dysphoria. While we are not issuing a NCD, CMS encourages robust clinical studies that will fill the evidence gaps and help inform which patients are most likely to achieve improved health outcomes with gender reassignment surgery, which types of surgery are most appropriate, and what types of physician criteria and care setting(s) are needed to ensure that patients achieve improved health outcomes.

Decision Memo: I. Decision Currently, the local Medicare Administrative Contractors (MACs) determine coverage of gender reassignment surgery on a case-by-case basis. We received a complete, formal request to make a national coverage determination on surgical remedies for gender identity disorder (GID), now known as gender dysphoria. The Centers for Medicare & Medicaid Services (CMS) is not issuing a National Coverage Determination (NCD) at this time on gender reassignment surgery for Medicare beneficiaries with gender dysphoria because the clinical evidence is inconclusive for the Medicare population. In the absence of a NCD, coverage determinations for gender reassignment surgery, under section 1862(a)(1)(A) of the Social Security Act (the Act) and any other relevant statutory requirements, will continue to be made by the local MACs on a case-by-case basis. To clarify further, the result of this decision is not national non-coverage rather it is that no national policy will be put in place for the Medicare program. In the absence of a national policy, MACs will make the determination of whether or not to cover gender reassignment surgery based on whether gender reassignment surgery is reasonable and necessary for the individual beneficiary after considering the individual’s specific circumstances. For Medicare beneficiaries enrolled in Medicare Advantage (MA) plans, the initial determination of whether or not surgery is reasonable and necessary will be made by the MA plans. Consistent with the request CMS received, the focus of this National Coverage Analysis (NCA) was gender reassignment surgery. Specific types of surgeries were not individually assessed. We did not analyze the clinical evidence for counseling or hormone therapy treatments for gender dysphoria. As requested by several public commenters, we have modified our final decision memorandum to remove language that was beyond the scope of the specific request. We are not making a national coverage determination related to counseling, hormone therapy treatments, or any other potential treatment for gender dysphoria. While we are not issuing a NCD, CMS encourages robust clinical studies that will fill the evidence gaps and help inform which patients are most likely to achieve improved health outcomes with gender reassignment surgery, which types of surgery are most appropriate, and what types of physician criteria and care setting(s) are needed to ensure that patients achieve improved health outcomes. II. Background Below is a list of acronyms used throughout this document. AHRQ - Agency for Healthcare Research and Quality AIDS - Acquired Immune Deficiency Syndrome ANOVA - Analysis of Variance APA - American Psychiatric Association APGAR - Adaptability, Partnership Growth, Affection, and Resolve test BIQ - Body Image Questionnaire BSRI - Bem Sex Role Inventory CCEI - Crown Crips Experimental Index CDC – Centers for Disease Control CHIS - California Health Interview Survey CI - Confidence Interval CMS - Centers for Medicare & Medicaid Services DAB - Departmental Appeals Board DSM - Diagnostic and Statistical Manual of Mental Disorders EMBASE - Exerpta Medica dataBASE FBeK - Fragebogen zur Beurteilung des eigenen Korpers FDA - Food and Drug Administration FPI-R - Freiburg Personality Inventory FSFI - Female Sexual Function Index GAF - Global Assessment of Functioning GID - Gender Identity Disorder GIS - Gender Identity Trait Scale GRS - Gender Reassignment Surgery GSI - Global Severity Indices HADS - Hospital Anxiety Depression Scale HHS - U.S. Department of Health and Human Services HIV - Human Immunodeficiency Virus IIP - Inventory of Interpersonal Problems IOM - Institute of Medicine KHQ - King’s Health Questionnaire LGB - Lesbian, Gay, and Bisexual LGBT - Lesbian, Gay, Bisexual, and Transgender MAC - Medicare Administrative Contractor MMPI - Minnesota Multiphasic Personality Inventory NCA - National Coverage Analysis NCD - National Coverage Determination NICE - National Institute for Health Care Excellence NIH - National Institutes of Health NZHTA - New Zealand Health Technology Assessment PIT - Psychological Integration of Trans-sexuals QOL - Quality of Life S.D. - Standard Deviation SADS - Social Anxiety Depression Scale SCL-90R - Symptom Check List 90-Revised SDPE - Scale for Depersonalization Experiences SES - Self Esteem Scale SF - Short Form SMR - Standardized Mortality Ratio SOC – Standards of Care STAI-X1 - Spielberger State and Trait Anxiety Questionnaire STAI-X2 - Spielberger State and Trait Anxiety Questionnaire TSCS - Tennessee Self-Concept Scale U.S. - United States VAS - Visual Analog Scale WHOQOL-BREF - World Health Organization Quality of Life - Abbreviated version of the WHOQOL-100 WPATH - World Professional Association for Transgender Health A. Diagnostic Criteria The criteria for gender dysphoria or spectrum of related conditions as defined by the American Psychiatric Association (APA) in the Diagnostic and Statistical Manual of Mental Disorders (DSM) has changed over time (See Appendix A). Gender dysphoria (previously known as gender identity disorder) is a classification used to describe persons who experience significant discontent with their biological sex and/or gender assigned at birth. Although there are other therapeutic options for gender dysphoria, consistent with the NCA request, this decision only focuses on gender reassignment surgery. B. Prevalence of Transgender Individuals For estimates of transgender individuals in the U.S., we looked at several studies. The Massachusetts Behavior Risk Factor Surveillance Survey (via telephone) (2007 and 2009) identified 0.5% individuals as transgender (Conron et al., 2012). Derivative data obtained from the 2004 California Lesbian Gay Bisexual and Transgender (LGBT) Tobacco Survey (via telephone) and the 2009 California Health Interview Survey (CHIS) (via telephone) suggested the LGB population constitutes 3.2% of the California population and that transgender subjects constitute approximately 2% of the California LGBT population and 0.06% of the overall California population (Bye et al., 2005; CHIS 2009; Gates, 2011). Most recently, the Williams Institute published a report that utilized data from the Centers for Disease Control’s (CDC) Behavioral Risk Factor Surveillance System (BRFSS). Overall, they found that 0.6% or 1.4 million U.S. adults identify as transgender. The report further estimated 0.7% of adults between the ages of 18-25 identify as transgender, 0.6% of adults between the ages of 25-65 identify as transgender, and 0.5% of adults age 65 or older identify as transgender (Flores et al., 2016). In a recent review of Medicare claims data, CMS estimated that in calendar year 2013 there were at least 4,098 transgender beneficiaries (less than 1% of the Medicare population) who utilized services paid for by Medicare, of which 90% had confirmatory diagnosis, billing codes, or evidence of a hormone therapy prescription. The Medicare transgender population is racially and ethnically diverse (e.g., 74% White, 15% African American) and spans the entire country. Nearly 80% of transgender beneficiaries are under age 65, including approximately 23% ages 45-54. (CMS Office of Minority Health 2015). For international comparison purposes, recent estimates of transgender populations in other countries are similar to those in the United States. New Zealand researchers, using passport data, reported a prevalence of 0.0275% for male-to-female adults and 0.0044% female-to-male adults (6:1 ratio) (Veale, 2008). Researchers from a centers of transgender treatment and reassignment surgery in Belgium conducted a survey of regional plastic surgeons and reported a prevalence of 0.008% male-to-female and 0.003% female-to-male (ratio 2.7:1) surgically reassigned transsexuals in Belgium (De Cuypere et al., 2007). Swedish researchers, using national mandatory reporting data on those requesting reassignment surgery, reported secular changes over time in that the number of completed reassignment surgeries per application increased markedly in the 1990s; the male-to- female/female-to-male sex ratio changed from 1:1 to 2:1; the age of male-to-female and female-to-male applicants was initially similar, but increased by eight years for male-to-female applicants; and the proportion of foreign born applicants increased (Olsson and Moller 2003). III. History of Medicare Coverage Date Action August 1, 1989 CMS published the initial NCD, titled “140.3, Transsexual Surgery" in the Federal Register. (54 Fed. Reg. 34,555, 34,572) May 30, 2014 The HHS Departmental Appeals Board (DAB) determined that the NCD denying coverage for all transsexual surgery was not valid. As a result, MACs determined coverage on a case-by-case basis. CMS does not currently have a NCD on gender reassignment surgery. A. Current Request On December 3, 2015, CMS accepted a formal complete request from a beneficiary to initiate a NCA for gender reassignment surgery. CMS opened this National Coverage Analysis (NCA) to thoroughly review the evidence to determine whether or not gender reassignment surgery may be covered nationally under the Medicare program. B. Benefit Category Medicare is a defined benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories as outlined in the Act. For gender reassignment surgery, the following are statutes are applicable to coverage: Under §1812 (Scope of Part A) Under §1832 (Scope of Part B) Under §1861(s) (Definition of Medical and Other Health Services) Under §1861(s)(1) (Physicians’ Services) This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Timeline of Medicare Coverage Policy Actions for Gender Reassignment Surgery Date Action December 3, 2015 CMS accepts an external request to open a NCD. A tracking sheet was posted on the web site and the initial 30 day public comment period commenced. January 2, 2016 Initial comment period closed. CMS received 103 comments. June 2, 2016 Proposed Decision Memorandum posted on the web site and the final 30 day public comment period commenced. July 2, 2016 Final comment period closed. CMS received 45 comments. V. FDA Status Surgical procedures per se are not subject to the Food and Drug Administration’s (FDA) approval. Inflatable penile prosthetic devices, rigid penile implants, testicular prosthetic implants, and breast implants have been approved and/or cleared by the FDA. VI. General Methodological Principles In general, when making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. (§ 1862 (a)(1)(A)). The evidence may consist of external technology assessments, internal review of published and unpublished studies, recommendations from the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC), evidence-based guidelines, professional society position statements, expert opinion, and public comments. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) specific clinical question relevant to the coverage request can be answered conclusively; and 2) the extent to which we are confident that the intervention will improve health outcomes for patients. A detailed account of the methodological principles of study design the agency staff utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix B. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, blinding of readers of the index test, and reference test results. VII. Evidence A. Introduction Below is a summary of the evidence we considered during our review, primarily articles about clinical trials published in peer- reviewed medical journals. We also considered articles cited by the requestor, articles identified in public comments, as well as those found by a CMS literature review. Citations are detailed below. B. Literature Search Methods CMS staff extensively searched for primary studies for gender dysphoria. The emphasis focused less on specific surgical techniques and more on functional outcomes unless specific techniques altered those types of outcomes. The reviewed evidence included articles obtained by searching literature databases and technology review databases from PubMed (1965 to current date), EMBASE, the Agency for Healthcare Research and Quality (AHRQ), the Blue Cross/Blue Shield Technology Evaluation Center, the Cochrane Collection, the Institute of Medicine, and the National Institute for Health and Care Excellence (NICE) as well as the source material for commentary, guidelines, and formal evidence-based documents published by professional societies. Systematic reviews were used to help locate some of the more obscure publications and abstracts. Keywords used in the search included: Trans-sexual, transgender, gender identity disorder (syndrome), gender dysphoria and/or hormone therapy, gender surgery, genital surgery, gender reassignment (surgery), sex reassignment (surgery) and/or quality of life, satisfaction-regret, psychological function (diagnosis of mood disorders, psychopathology, personality disorders), suicide (attempts), mortality, and adverse events-reoperations. After the identification of germane publications, CMS also conducted searches on the specific psychometric instruments used by investigators. Psychometric instruments are scientific tools used to measure individuals' mental capabilities and behavioral style. They are usually in the form of questionnaires that numerically capture responses. These tools are used to create a psychological profile that can address questions about a person’s knowledge, abilities, attitudes and personality traits. In the evaluation of patients with gender dysphoria, it is important that both validity and reliability be assured in the construction of the tool (validity refers to how well the tool actually measures what it was designed to measure, or how well it reflects the reality it claims to represent, while reliability refers to how accurately results of the tool would be replicated in a second identical piece of research). Reliability and validity are important because when evaluating patients with gender dysphoria most of the variables of interest (e.g., satisfaction, anxiety, depression) are latent in nature (not directly observed but are rather inferred) and difficult to quantify objectively. Studies with robust study designs and larger, defined patient populations assessed with objective endpoints or validated test instruments were given greater weight than small, pilot studies. Reduced consideration was given to studies that were underpowered for the assessment of differences or changes known to be clinically important. Studies with fewer than 30 patients were reviewed and delineated, but excluded from the major analytic framework. Oral presentations, unpublished white papers, and case reports were excluded. Publications in languages other than English were excluded. The CMS initial internal search for the proposed decision memorandum was limited to articles published prior to March 21, 2016. The CMS internal search for the final decision memorandum continued through articles published prior to July 22, 2016. Included studies were limited to those with adult subjects. Review and discussion of the management of children and adolescents with the additional considerations of induced pubertal delay are outside the scope of this NCD. In cases where the same population was studied for multiple reasons or where the patient population was expanded over time, the latest and/or most germane sections of the publications were analyzed. The excluded duplicative publications are delineated. CMS also searched Clinicaltrials.gov to identify relevant clinical trials. CMS looked at trial status including early termination, completed, ongoing with sponsor update, and ongoing with estimated date of completion. Publications on completed trials were sought. For this final decision, CMS also reviewed all evidence submitted via public comment. C. Discussion of Evidence The development of an assessment in support of Medicare coverage determinations is based on the same general question for almost all national coverage analyses (NCAs): "Is the evidence sufficient to conclude that the application of the item or service under study will improve health outcomes for Medicare patients?" For this specific NCA, CMS is interested in answering the following question: Is there sufficient evidence to conclude that gender reassignment surgery improves health outcomes for Medicare beneficiaries with gender dysphoria? The evidence reviewed is directed towards answering this question. 1. Internal Technology Assessment CMS conducted an extensive literature search on gender reassignment related surgical procedures and on facets of gender dysphoria that provide context for this analysis. The latter includes medical and environmental conditions. CMS identified numerous publications related to gender reassignment surgery. A large number of these were case reports, case series with or without descriptive statistics, or studies with population sizes too small to conduct standard parametric statistical analyses. Others addressed issues of surgical technique. CMS identified and described 36 publications on gender reassignment surgery that included health outcomes. Because the various investigators at a site sometimes conducted serial studies on ever-enlarging cohort populations, studied sub-populations, studied different outcomes, or used different tools to study the same outcomes, not all study populations were unique. To reduce bias from over-lapping populations, only the latest or most germane publication(s) were described. Subsumed publications were delineated. Of these 36 publications, two publications used different assessment tools on the same population, and, so for the purposes of evaluation, were classified as one study (Udeze et al., 2008; Megeri and Khoosal, 2007). A total of 33 studies were reviewed (See Figure 1). Appendices C, D, and F include more detail of each study. The publications covered a time span from 1979 to 2015. Over half of the studies were published after 2005. Figure 1. Studies of Gender Reassignment Surgery (GRS) ANOVA=Analysis of Variance Normative=Psychometric Tests with known normative for large populations Figure 1 Legend: The studies in Figure 1 are categorized into three groups. The first group, depicted by the colored boxes (red, blue, and green), had explicit controls. There was a single randomized study. The remainder in the first group were observational studies. These were subdivided into longitudinal studies and cross-sectional studies. The second group, depicted by black boxes (starting with the surgery only population box) consisted of surgical series. The third group, depicted by black boxes (starting with mixed population), was composed of patients whose treatment could involve a variety of therapeutic interventions, but who were not stratified by that treatment. When looking at the totality of studies, the 33 studies could be characterized by the following research design groups: a. Observational, mixed population of surgical and non-surgical patients without stratification Asscheman H, Giltay EJ, Megens JA, de Ronde WP, van Trotsenburg MA, Gooren LJ. A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol. 2011 Apr;164(4):635-42. Epub 2011 Jan 25. Asscheman et al. conducted a retrospective, non-blinded, observational study of mortality using a longitudinal design to assess a mixed population treated with hormones, as well as, reassignment surgery in comparison to a population-based cohort. The study was not designed to assess the specific impact of gender reassignment surgery on clinical outcomes. The investigators assessed mortality in patients who (a) were from a single-center, unspecified, Dutch university specialty clinic, (b) had initiated cross-sex hormone treatment prior to July 1, 1997, and (c) had been followed (with or without continued hormone treatment) by the clinic for at least one year or had expired during the first year of treatment. The National Civil Record Registry (Gemeentelijke Basis Administratie) was used to identify/confirm deaths of clinic patients. Information on the types or hormones used was extracted from clinic records, and information on the causation of death was extracted from medical records or obtained from family physicians. Mortality data for the general population were obtained through the Central Bureau of Statistics of the Netherlands (Centraal Bureau voor Statistiek). Mortality data from Acquired Immune Deficiency Syndrome (AIDS) and substance abuse were extracted from selected Statistics Netherlands reports. The gender of the general Dutch population comparator group was the natal sex of the respective gender dysphoric patient groups. A total of 1,331 patients who met the hormone treatment requirements were identified (365 female-to-male [27.4%]; 966 male- to-female [72.6%]; ratio 1:2.6). Of these, 1,177 (88.4%) underwent reassignment surgery (343 [94.0% of female-to-male entrants]; 834 [86.3% of male-to-female entrants]; ratio difference 1:2.4 with a p-value p<0.0001). Later calculations did not distinguish between those with hormone therapy alone versus those with hormone therapy plus reassignment surgery. The mean age at the time of hormone initiation in female-to-male and male-to-female patients was 26.1±7.6 (range 16–56) years and 31.4±11.4 (range 16–76) years respectively, although the male-to-female subjects were relatively older (p<0.001). The mean duration of hormone therapy in female-to-male and male-to-female patients was 18.8±6.3 and 19.4±7.7 years respectively. There were a total of 134 deaths in the clinic population using hormone therapy with or without surgical reassignment. Of these patients, 12 (3.3%) of the 365 female-to-male patients and 122 (12.6%) of the 966 male-to-female patients died. All-cause mortality for this mixed population was 51% higher and statistically significant (Standardized Mortality Ratio [SMR] 95% confidence interval [CI]) 1.47-1.55) for males-to-females when compared to males in the general Dutch population. The increase in all-cause mortality (12%) for females-to-males when compared to females in the general Dutch population was not statistically significant (95% CI 0.87-1.42). Ischemic heart disease was a major disparate contributor to excess mortality in male-to-female patients but only in older patients (n=18, SMR 1.64 [95% CI 1.43-1.87]), mean age [range]: 59.7 [42-79] years. Current use of a particular type of estrogen, ethinyl estradiol, was found to contribute to death from myocardial infarction or stroke (Adjusted Hazard Ratio 3.12 [95% CI 1.28-7.63], p=0.01). There was a small, but statistically significant increase in lung cancer that was thought to possibly be related to higher rates of smoking in this cohort. Other contributors to the mortality difference between male-to-female patients and the Dutch population at large were completed suicide (n=17, SMR 5.70 [95% CI 4.93-6.54]), AIDS (n=16, SMR 30.20 [95% CI 26.0-34.7]), and illicit drug use (n=5, SMR 13.20 [95% CI 9.70-17.6]). An additional major contributor was “unknown cause” (n=21, SMR 4.00 [95% CI 3.52-4.51]). Of the 17 male-to-female hormone treated patients who committed suicide, 13 (76.5%) had received prior psychiatric treatment and six (35.3%) had not undergone reassignment surgery because of concerns about mental health stability. Overall mortality, and specifically breast cancer and cardiovascular disease, were not increased in the hormone-treated female-to-male patients. Asscheman et al. reported an elevated SMR for illicit drug use (n=1, SMR 25 [6.00-32.5]). This was the cause of one of the 12 deaths in the cohort. This study subsumes earlier publications on mortality (Asscheman et al. 1989 [n=425]; Van Kesteren et al. 1997 [n=816]). Gómez-Gil E, Zubiaurre-Elorza L, Esteva I, Guillamon A, Godás T, Cruz Almaraz M, Halperin I, Salamero M. Hormone- treated transsexuals report less social distress, anxiety and depression. Psychoneuroendocrinology. 2012 May;37(5):662-70. Epub 2011 Sep 19. Gómez-Gil et al. conducted a prospective, non-blinded observational study using a cross-sectional design and non-specific psychiatric distress tools in Spain. The investigators assessed anxiety and depression in patients with gender dysphoria who attended a single-center specialty clinic with comprehensive endocrine, psychological, psychiatric, and surgical care. The clinic employed World Professional Association for Transgender Health (WPATH) guidelines. Patients were required to have met diagnostic criteria during evaluations by 2 experts. Investigators used the Hospital Anxiety and Depression Scale (HADS) and the Social Anxiety and Distress Scale (SADS) instruments. The SADS total score ranges from 0 to 28, with higher scores indicative of more anxiety. English language normative values are 9.1±8.0. HAD-anxiety and HAD-depression total score ranges from 0 to 21, with higher scores indicative of more pathology. Scores less than 8 are normal. ANOVA was used to explore effects of hormone and surgical treatment. Of the 200 consecutively selected patients recruited, 187 (93.5% of recruited) were included in the final study population. Of the final study population, 74 (39.6%) were female-to-male patients; 113 (60.4%) were male-to-female patients (ratio 1:1.5); and 120 (64.2%) were using hormones. Of those using hormones, 36 (30.0%) were female-to-male; 84 (70.0%) were male-to-female (ratio 1:2.3). The mean age was 29.87±9.15 years (range 15-61). The current age of patients using hormones was 33.6±9.1 years (n=120) and older than the age of patients without hormone treatment (25.9±7.5) (p=0.001). The age at hormone initiation, however, was 24.6±8.1 years. Of those who had undergone reassignment surgery, 29 (36.7%) were female-to-male; 50 (63.3%) were male-to-female (ratio 1:1.7). The number of patients not on hormones and who had undergone at least one gender-related surgical procedure (genital or non-genital) was small (n=2). The number of female-to-male patients on hormones who had undergone such surgery (mastectomy, hysterectomy, and/or phalloplasty) was 28 (77.8%). The number of male-to-female patients on hormones who had undergone such surgery (mammoplasty, facial feminization, buttock feminization, vaginoplasty, orchiectomy, and/or vocal feminization (thyroid chondroplasty) was 49 (58.3%). Analysis of the data revealed that although the mean scores HAD-Anxiety, HAD-Depression, and SADS were statistically lower (better) in those on hormone therapy than in those not on hormone therapy, the mean scores for HAD-Depression and SADS were in the normal range for gender dysphoric patients not using hormones. The HAD-Anxiety score was 9 in transsexuals without hormone treatment and 6.4 in transsexuals with hormone treatment. The mean scores for HAD-Anxiety, HAD- Depression, and SADS were in the normal range for gender dysphoric patients using hormones. ANOVA revealed that results did not differ by whether the patient had undergone a gender related surgical procedure or not. Gómez-Gil E, Zubiaurre-Elorza L, de Antonio I, Guillamon A, Salamero M. Determinants of quality of life in Spanish transsexuals attending a gender unit before genital sex reassignment surgery. Qual Life Res. 2014 Mar;23(2):669-76. Epub 2013 Aug 13. Gómez-Gil et al. conducted a prospective, non-blinded observational study using a non-specific quality of life tool. There were no formal controls for this mixed population ± non-genital reassignment surgery undergoing various stages of treatment. The investigators assessed quality of life in the context of culture in patients with gender dysphoria who were from a single-center (Barcelona, Spain), specialty and gender identity clinic. The clinic used WPATH guidelines. Patients were required to have met diagnostic criteria during evaluations by both a psychologist and psychiatrist. Patients could have undergone non-genital surgeries, but not genital reassignment surgeries (e.g., orchiectomy, vaginoplasty, or phalloplasty). The Spanish version of the World Health Organization Quality of Life-Abbreviated version of the WHOQOL-100 (WHOQOL- BREF) was used to evaluate quality of life, which has 4 domains (environmental, physical, psychological, and social) and 2 general questions. Family dynamics were assessed with the Spanish version of the Family Adaptability, Partnership Growth, Affection, and Resolve (APGAR) test. Regression analysis was used to explore effects of surgical treatment. All consecutive patients presenting at the clinic (277) were recruited and, 260 (93.9%) agreed to participate. Of this number, 59 of these were excluded for incomplete questionnaires, 8 were excluded for prior genital reassignment surgery, and 193 were included in the study (the mean age of this group was 31.2±9.9 years (range 16-67). Of these, 74 (38.3%) were female-to-male patients; 119 (61.7%) were male-to-female patients (ratio1:1.6). Of these, 120 (62.2%) were on hormone therapy; 29 (39.2%) of female-to-male patients had undergone at least 1 non-genital, surgical procedure (hysterectomy n=19 (25.7%); mastectomy n=29 (39.2%)); 51 (42.9%) of male-to-female patients had undergone at least one non-genital surgical procedure with mammoplasty augmentation being the most common procedure, n=47 (39.5%), followed by facial feminization, n=11 (9.2%), buttocks feminization, n=9 (7.6%), and vocal feminization (thyroid chondroplasty), n=2 (1.7%). WHOQOL-BREF domain scores for gender dysphoric patients with and without non-genital surgery were: “Environmental” 58.81±14.89 (range 12.50-96.88), “Physical” 63.51±17.79 (range 14.29-100), “Psychological” 56.09+16.27 (range 16.67- 56.09), “Social” 60.35±21.88 (range 8.33-100), and “Global QOL and Health” 55.44+27.18 (range 0-100 with higher score representing better QOL). The mean APGAR family score was 7.23±2.86 (range 0-10 with a score of 7 or greater indicative of family functionality). Regression analysis, which was used to assess the relative importance of various factors to WHOQOL-BREF domains and general questions, revealed that family support was an important element for all four domains and the general health and quality- of-life questions. Hormone therapy was an important element for the general questions and for all of the domains except “Environmental.” Having undergone non-genital reassignment surgery, age, educational levels, and partnership status, did not impact domain and general question results related to quality of life. Hepp U, Kraemer B, Schnyder U, Miller N, Delsignore A. Psychiatric comorbidity in gender identity disorder. J Psychosom Res. 2005 Mar;58(3):259-61. Hepp et al. conducted a single-site (Zurich, Switzerland) prospective, non-blinded, observational study using a cross-sectional design. There was some acquisition of retrospective data. The investigators assessed current and lifetime psychiatry co-morbidity using structured interviews for diagnosis of Axis 1 disorders (clinical syndromes) and Axis 2 disorders (developmental or personality disorders) and HADS for dimensional evaluation of anxiety and depression. Statistical description of the cohort and intra-group comparisons was performed. Continuous variables were compared using t-tests and ANOVA. A total of 31 patients with gender dysphoria participated in the study: 11 (35.5%) female-to-male; 20 (64.5%) male-to-female (ratio 1:1.8). The overall mean age was 32.2±10.3 years. Of the participants, seven had undergone reassignment surgery, 10 pre- surgical patients had been prescribed hormone therapy, and 14 pre-surgical patients had not been prescribed hormone therapy. Forty five and one half percent of female-to-male and 20% of male-to-female patients did not carry a lifetime diagnosis of an Axis 1 condition. Sixty three and six tenths percent of female-to-male and 60% of male-to-female patients did not carry a current diagnosis of an Axis 1 condition. Lifetime diagnosis of substance abuse and mood disorder were more common in male-to-female patients (50% and 55% respectively) than female-to-male patients (36.4% and 27.3% respectively). Current diagnosis of substance abuse and mood disorder were present in male-to-female patients (15% and 20% respectively) and absent in female-to-male patients. One or more personality disorders were identified 41.9%, but whether this was a current or lifetime condition was not specified. Of the patients, five (16.1%) had a Cluster A personality disorder (paranoid-schizoid), seven (22.6%) had a Cluster B personality disorder (borderline, anti-social, histrionic, narcissistic), six (19.4%) had a Cluster C personality disorder (avoidant, dependent, obsessive-compulsive), and two (6.5%) were not otherwise classified. HADS scores were missing for at least one person. The HADS test revealed non-pathologic results for depression (female-to-male: 6.64±5.03; male-to-female: 6.58±4.21) and borderline results for anxiety (female-to-male: 7.09±5.11; male-to-female: 7.74±6.13, where a result of 7-10 = possible disorder). There were no differences by natal gender. The investigators reported a trend for less anxiety and depression as measured by HADS in the patients who had undergone surgery. Johansson A, Sundbom E, Höjerback T, Bodlund O. A five-year follow-up study of Swedish adults with gender identity disorder. Arch Sex Behav. 2010 Dec;39(6):1429-37. Epub 2009 Oct 9. Johansson et al. conducted a two center (Lund and Umeå, Sweden) non-blinded, observational study using a semi-cross-sectional design (albeit over an extended time interval) using a self-designed tool and Axis V assessment. The study was prospective except for the acquisition of baseline Axis V data. There were no formal controls in this mixed population with and without surgery. The investigators assessed satisfaction with the reassignment process, employment, partnership, sexual function, mental health, and global satisfaction in gender-reassigned persons from two disparate geographic regions. Surgical candidates were required to have met National Board of Health and Welfare criteria including initial and periodic psychiatric assessment, ≥1 year of real-life experience in preferred gender, and ≥1 year of subsequent hormone treatment. In addition, participants were required to have been approved for reassignment five or more years prior and/or to have completed surgical reassignment (e.g., sterilization, genital surgery) two or more years prior. The investigators employed semi-structured interviews covering a self-designed list of 55 pre-formulated questions with a three or five point ordinal scale. Clinician assessment of Global Assessment of Functioning (GAF; Axis V) was also conducted and compared to initial finding during the study. Changes or differences considered to be biologically significant were not pre- specified except for GAF, which pre-specified a difference to mean change ≥5 points. Statistical corrections for multiple comparisons were not included. There was no stratification by treatment. Of the pool of 60 eligible patients, 42 (70.0% of eligible) (17 [40.5 %] female-to-male; 25 [59.5%] male-to-female; ratio 1:1.5) were available for follow-up. Of these, 32 (53.3% of eligible) (14 [43.8%] female-to-male; 18 [56.2%] male-to-female [ratio 1:1.3]) had completed genital gender reassignment surgery (not including one post mastectomy), five were still in the process of completing surgery, and five (one female-to-male; four male- to-female; ratio 1:4) had discontinued the surgical process prior to castration and genital surgery. The age (ranges) of the patients at entry into the program, reassignment surgery, and follow-up were 27.8 (18-46), 31.4 (22- 49), and 38.9 (28-53) years in the female-to-male group respectively and 37.3 (21-60), 38.2 (22-57), and 46.0 (25.0-69.0) years in the male- to-female group respectively. The differences in age by cohort group were statistically significant. Of participants, 88.2% of all enrolled female-to-male versus 44.0% of all enrolled female-to-male patients had cross-gender identification in childhood (versus during or after puberty) (p<0.01). Although 95.2% of all enrolled patients self-reported improvement in GAF, in contrast, clinicians determined GAF improved in 61.9% of patients. Clinicians observed improvement in 47% of female-to-male patients and 72% of male-to- female patients. A ≥5 point improvement in the GAF score was present in 18 (42.9%). Of note, three of the five patients who were in the process of reassignment and five of the five who had discontinued the process were rated by clinicians as having improved. Of all enrolled 95.2% (with and without surgery) reported satisfaction with the reassignment process. Of these 42 patients, 33 (79%) identified themselves by their preferred gender and nine (21%) identified themselves as transgender. None of these nine (eight male-to-female) had completed reassignment surgery because of ambivalence secondary to lack of acceptance by others and dissatisfaction with their appearance. Of the patients who underwent genital surgery (n=32) and mastectomy only (n=one), 22 (66.7%) were satisfied while four (three female-to-male) were dissatisfied with the surgical treatment. Regarding relationships after surgery, 16 (38.1%) (41.2% of female- to-male; 36.0% of male-to-female patients) were reported to have a partner. Yet more than that number commented on partner relationships: (a) 62.2 % of the 37 who answered (50.0% of female- to- male; 69.6% of male-to-female patients) reported improved partner relationships (five [11.9%] declined to answer.); (b) 70.0% of the 40 who answered (75.0% of female-to-male; 66.7% of male-to-female patients) reported an improved sex life. Investigators observed that reported post-operative satisfaction with sex life was statistically more likely in those with early rather than late cross-gender identification. In addition 55.4% self-reported improved general health; 16.1% reported impaired general health; 11.9% were currently being treated with anti-depressants or tranquilizers. This study subsumes earlier work by Bodlund et al. (1994, 1996). The nationwide mortality studies by Dhejne et al. (2011) may include all or part of this patient population. Leinung M, Urizar M, Patel N, Sood S. Endocrine treatment of transsexual persons: extensive personal experience. Endocr Pract. 2013 Jul-Aug;19(4):644-50. (United States study) Leinung et al. conducted a single-center (Albany, New York) a partially prospective, non-blinded, observational study using a cross-sectional design and descriptive statistics. There were no formal controls. The investigators assessed employment, substance abuse, psychiatric disease, mood disorders, Human Immunodeficiency Virus (HIV) status in patients who had met WPATH guidelines for therapy, and who had initiated cross-sex hormone treatment. A total of 242 patients treated for gender identity disorder in the clinic from 1992 through 2009 inclusive were identified. The number of those presenting for therapy almost tripled over time. Of these patients, 50 (20.7%) were female-to-male; 192 (79.3%) male-to-female (ratio 1:3.8). The age of female-to-male and male-to-female patients with gender dysphoria at the time of clinic presentation was 29.0 and 38.0 years respectively. The female-to-male and male-to-female patients with gender dysphoria at the time of hormone initiation were young: 27.5 and 35.5 years old respectively (p<0.5). Of the male-to-female cohort, 19 (7.8%) had received hormone therapy in the absence of physician supervision; Of the patient population, 91 (37.6%) had undergone gender-reassignment surgery (32 female-to-male [64.0% of all female-to- male; 35.2% of all surgical patients]; 59 male-to-female [30.7% of all male-to-female; 64.8% of all surgical patients]; ratio 1:1.8). Psychiatric disease was more common in those who initiated hormone therapy at an older age (>32 years) 63.9% versus 48.9% at a younger age and by natal gender (48.0% of female-to-male; 58.3% male-to-female). Mood disorders were more common in those who initiated hormone therapy at an older age (>32 years) 52.1% versus 36.0% at a younger age and this finding did not differ by natal gender (40.0% of female-to-male; 44.8% male-to- female). The presence of mood disorders increased the time to reassignment surgery in male-to-female patients. Motmans J , Meier P, Ponnet K, T'Sjoen G. Female and male transgender quality of life: socioeconomic and medical differences. J Sex Med. 2012 Mar;9(3):743-50. Epub 2011 Dec 21. Motmans et al., conducted a prospective, non-blinded, observational study using a cross-sectional design and a non-specific quality of life tool. No concurrent controls were used in this study. Quality of life in this Dutch-speaking population was assessed using the Dutch version of a SF-36 (normative data was used). Participants included subjects who were living in accordance with the preferred gender and who were from a single Belgian university specialty clinic at Ghent. The Dutch version of the SF-36 questionnaire along with its normative data were used. Variables explored included employment, pension status, ability to work, being involved in a relationship. Also explored, was surgical reassignment surgery and the types of surgical interventions. Intragroup comparisons by transgender category were conducted, and the relationships between variables were assessed by analysis of variance (ANOVA) and correlations. The age of the entire cohort (n=140) was 39.89±10.21 years (female-to-male: 37.03±8.51; male-to-female: 42.26±10.39). Results of the analysis revealed that not all female-to-male patients underwent surgical reassignment surgery and, of those who did, not all underwent complete surgical reassignment. The numbers of female-to-male surgical interventions were: mastectomy 55, hysterectomy 55, metaoidplasty eight (with five of these later having phalloplasty), phalloplasty 40, and implantation of a prosthetic erectile device 20. The frequencies of various male-to-female surgical interventions were: vaginoplasty 48, breast augmentation 39, thyroid cartilage reduction 17, facial feminization 14, and hair transplantation three. The final number of subjects with SF-36 scores was 103 (49 [47.6%] female-to-male; 54 [52.4%] male-to-female; ratio 1:1.1). For this measure, the scores for the vitality and mental health domains for the final female-to-male cohort (n= 49 and not limited to those having undergone some element of reassignment surgery) were statistically lower: 60.61±18.16 versus 71.9±18.31 and 71.51±16.40 versus 79.3±16.4 respectively. Scores were not different from the normative data for Dutch women: vitality: 64.3±19.7 or mental health 73.7±18.2. None of the domains of the SF-36 for the final male-to-female cohort (n=54 and not limited to those having undergone some element of reassignment surgery) were statistically different from the normative data for Dutch women. Analysis of variance indicated that quality of life as measured by the SF-36 did not differ by whether female-to-male patients had undergone genital surgery (metaoidoplasty or phalloplasty) or not. Also, ANOVA indicated that quality of life as measured by the SF-36 did not differ by whether male-to-female patients had undergone either breast augmentation or genital surgery (vaginoplasty) or not. Whether there is overlap with the Ghent populations studied by Heylens et al. or Weyers et al. is unknown. Newfield E, Hart S, Dibble S, Kohler L. Female-to-male transgender quality of life. Qual Life Res. 2006 Nov;15(9):1447-57. Epub 2006 Jun 7. (United States study) Newfield et al. conducted a prospective, observational internet self-report survey of unknown blinding status using a cross- sectional design and a non-specific quality of life tool in a mixed population with and without hormone therapy and/or reassignment surgery. There were no formal controls. The investigators recruited natal female participants identifying as male using email, internet bulletin boards, and flyers/postcards distributed in the San Francisco Bay Area. Reduction of duplicate entries by the same participant was limited to the use of a unique user name and password. The investigators employed the Short-Form 36 (SF-36) Version 2 using U.S. normative data. They reported using both male and female normative data for the comparator SF-36 cohort. Data for the eight domains were expressed as normative scoring. The Bonferroni correction was used to adjust for the risk of a Type 1 error with analyses using multiple comparisons. A total of 379 U.S. respondents classified themselves as males-or-females to males with or without therapeutic intervention. The mean age of the respondents who classified themselves as male or female-to-male was 32.6±10.8 years. Of these 89% were Caucasian, 3.6% Latino, 1.8% African American, 1.8% Asian, and 3.8% other. Of these, 254 (67.0%) reported prior or current testosterone use while 242 (63.8%) reported current testosterone use. In addition, 136 (36.7%) reported having had “top” surgery and 11 (2.9%) reported having “bottom” surgery. Complete SF-36 data were available for 376 U.S. respondents. For the complete, non-stratified U.S. cohort the Physical Summary Score (53.45±9.42) was statistically higher (better) than the natal gender unspecified SF-36 normative score (50±10) (p=<0.001), but was within one standard deviation of the normative mean. The Mental Summary Score (39.63±12.2) was statistically lower (worse) than the natal gender unspecified SF-36 normative score (50±10) (p<0.001), but was well within two standard deviations of the normative mean. Subcomponents of this score: Mental Health (42.12±10.2), Role Emotional (42.42±11.6), Social Functioning (43.14±10.9), and Vitality (46.22±9.9) were statistically lower (worse) than the SF-36 normative sub-scores, but well within one standard deviation of the normative sub- score means. Interpretive information for these small biologic differences in a proprietary assessment tool was not provided. Additional intragroup analyses were conducted, although the data were not stratified by type of therapeutic intervention (hormonal, as well as, surgical). Outcomes of hormone therapy were considered separately and dichotomously from reassignment surgery. The Mental Summary Score was statistically higher (better) in those who had “Ever Received Testosterone” (41.22±11.9) than those with “No Testosterone Usage” (36.08±12.6) (p=0.001). The Mental Summary Scores showed a trend towards statistical difference between those who “Ever Received Top Surgery” (41.21±11.6) and those without “Top Surgery” (38.01±12.5) (p=0.067). These differences were well within one standard deviation of the normative mean. Interpretive information for these small biologic differences in a proprietary assessment tool was not provided. b. Observational, surgical series, without concurrent controls Blanchard R, Steiner BW, Clemmensen LH. Gender dysphoria, gender reorientation, and the clinical management of transsexualism. J Consult Clin Psychol. 1985 Jun; 53(3):295-304. Blanchard et al. conducted a single-center (Ontario, Canada), prospective, non-blinded, cross-sectional study using a self-designed questionnaire and a non- specific psychological symptom assessment with normative data. The investigators assessed social adjustment and psychopathology in patients with gender dysphoria and who were at least one year post gender reassignment surgery. Reassignment surgery was defined as either vaginoplasty or mastectomy/construction of male chest contour with or without nipple transplants, but did not preclude additional procedures. Partner preference was determined using Blanchard’s Modified Androphilia-Gynephilia Index, and the nature and extent of any psychopathology was determined with the Symptom Check List 90-Revised (SCL-90R). Differences in test scores considered to be biologically significant were not pre-specified in the methods. Of the 294 patients (111 natal females and 183 natal males, ratio: 1:1.65) initially evaluated, 263 were diagnosed with gender dysphoria. Of these 79 patients participated in the study (38 female-to-male; 32 male-to-female with male partner preference; 9 male-to-female with female partner preference). The respective mean ages for these 3 groups were 32.6, 33.2, and 47.7 years with the last group being older statistically (p=0.01). Additional surgical procedures in female-to-male patients included: oophorectomy/hysterectomy (92.1%) and phalloplasty (7.9%). Additional surgical procedures in male-to-female patients with male partner preference included facial hair electrolysis 62.5% and breast implantation (53.1%). Additional procedures in male-to-female patients with female partner preference included facial hair electrolysis (100%) and breast implantation (33.3%). The time between reassignment surgery and questionnaire completion did not differ by group. Psychopathology as measured by the Global Severity Index of the SCL-90R was absent in all three patient groups. Interpretation did not differ b