TITLE: Gender Reassignment Surgery: A Review of the Clinical Evidence and Guidelines

Transcription

1 TITLE: Gender Reassignment Surgery: A Review of the Clinical Evidence and Guidelines DATE: 23 July 2014 CONTEXT AND POLICY ISSUES Gender dysphoria, also known as Gender Identity Disorder (GID), is the distress resulting from the incongruence between gender identity and sex at birth, which is characterized by a strong and persistent cross-gender identification and a persistent discomfort with one's sex or sense of inappropriateness in the gender role of that sex, causing clinically significant distress or impairment in social, occupational, or other important areas of functioning (The World Professional Association for Transgender Health [WPATH]). 1,2 Estimating the prevalence of gender dysphoria is challenging due to cultural differences from one country to another and to the social stigma associated with this condition. 1 Therefore, instead of reporting the prevalence of gender dysphoria, the prevalence of male-to-female (MtF) transsexuals (range 1:11,900 to 1:45,000 and female-to-male (FtM) transsexuals (range 1:30,400 to 1:200,000) are usually reported. 1 Management of gender dysphoria consists of cross-sex hormone therapy (used as primary gender reassignment intervention or as an adjunct to surgery), gender reassignment surgery (GRS), and psychotherapy and mental health support. 3,4 Gender reassignment surgery is a set of procedures by which the physical appearance and function of primary sex characteristics such as the penis or vagina are surgically altered to resemble that of the opposite sex. 5 It is usually the last and the most considered step in the treatment process for gender dysphoria in many transsexuals who wish to live fully in the desired sex. Adult MtF individuals may receive vaginoplasty, labiaplasty, orchiectomy, breast augmentation and breast implants, while phalloplasty, urethral extension, scrotoplasty, metaiodoplasty and mastectomy are treatment options for FtMs. 3,4 Clinical effectiveness and safety of various treatment modalities for gender dysphoria have been reported in previous clinical trials. Administration of hormone therapy (HT) in MtF individuals was associated with increased cardiovascular events such as venous thrombosis and mortality. 6 For FtM individuals, the relationships between androgen replacement therapy and cardiovascular risk and insulin sensitivity remain unclear and conflicting findings were reported Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 across studies. Testosterone was reported to preserve bone mineral density. Effects of longterm testosterone administration on the ovaries and breasts remain unclear. 2 Gynecologic care is necessary for transsexual people of both sexes: for FtM individuals such care is needed for those who have not had genital surgery, and for MtF individuals, such care is needed after genital surgery. Cancer screening in this population is another challenge, especially for some cancers such as breast, cervical, ovarian, uterine and prostate. 1,7 There is a lack of large-scale prospective studies, therefore healthcare providers do not have enough evidence to choose the appropriate type and frequency of cancer screenings for this particular population. The purposes of this review are to identify the clinical evidence regarding the long-term patient outcomes following gender reassignment surgery, and to summarize the recommendations from evidence-based practice guidelines regarding the physical and mental health care of individuals who have undergone GRS. RESEARCH QUESTIONS 1. What is the clinical evidence regarding the long-term patient outcomes following gender reassignment surgery? 2. What are the evidence-based guidelines regarding the physical and mental health care of individuals who have undergone gender reassignment surgery? KEY FINDINGS The evidence from a systematic review comprised mostly of case series and case reports suggested that, following gender reassignment surgery, both female-to-male and male-tofemale GRS patients were satisfied with surgical outcomes and functioning. In one non-rct, treatment with GRS was associated with a higher risk of death and psychiatric hospitalizations compared to the general population. These findings must be interpreted with caution given the lower level of evidence. One clinical practice guideline suggested that cardiovascular risks and bone mineral density be evaluated regularly. Cancer screening for prostate and breast cancer were recommended. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2014, Issue 6), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2009 and June 23, Gender Reassignment Surgery 2

3 Selection Criteria and Methods One researcher screened the citations and abstracts from the literature search; selected articles according to the selection criteria outlined in Table 1, and examined the full-text publications for the final study inclusion for this report. Population Intervention Table 1: Selection Criteria Patients with gender dysphoria, including male-to-female and femaleto-male. Q1: Gender reassignment surgery Q2: Post-surgical care: Hormone replacement therapy Urogenital care Cardiovascular or osteoporosis screening Cancer screening Mental health support Comparator Outcomes No gender reassignment therapy or no comparator Q1: Clinical effectiveness (e.g. health-related quality of life and patient satisfaction), safety and harms (e.g. mortality, cardiovascular events and other adverse events) Q2: Optimal long-term and ongoing care (physical and mental health) requirements to maintain patient health and quality of life for individuals who have undergone gender reassignment surgery Study Designs Q1: Health technology assessments, systematic reviews, metaanalyses, randomized controlled trials, non-randomized controlled trials Q2: Evidence-based clinical practice guidelines Exclusion Criteria Articles were excluded if they did not meet the selection criteria in Table 1, if they were published prior to January 2009, if they were duplicate publications of the same study, or if they were referenced in a selected systematic review. Articles addressing surgical techniques or surgical complications were excluded. Articles were also excluded when data were presented for gender reassignment as a whole (hormonal therapy + surgery) as it was difficult to separate the impact of GRS from that of hormones. We focused on core surgeries (for example genital surgeries and mastectomy); therefore studies related to facial plastic procedures or laryngoplasty were excluded from this review. Studies were also excluded when they reported histological or laboratory results only. Gender Reassignment Surgery 3

4 Critical Appraisal of Individual Studies The quality of the included systematic reviews, clinical trials and practice guidelines was assessed using AMSTAR 8, Downs and Black checklist 9 and the AGREE II tool 10, respectively. Numeric scores were not calculated. Instead, the strengths and limitations of the studies are summarized. SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 525 citations. After screening titles and abstracts, 496 articles were excluded and 29 potentially relevant articles were selected for full-text review. Two relevant citations were identified from the grey literature. Of these 31 reports, 27 did not meet the inclusion criteria and were excluded, leaving a total of four relevant reports, one of which was a systematic review, 11 two non-rcts, 12,13 and one clinical practice guideline. 14 The study selection process is outlined in Appendix 1. No health technology assessments or randomized controlled trials were identified. Summary of Study Characteristics Characteristics of the included systematic review, clinical trials and clinical practice guideline are summarized below and details are provided in Appendix 2. Systematic review Sutcliffe and colleagues conducted a systematic review to examine the clinical evidence of core surgical procedures adopted in transgender individuals (Table A2.1). 11 English language literature was searched in multiple databases from 1980 to November Studies reporting an individual core surgical procedure in adult FtM and MtF individuals with any study design (except expert opinion and review articles) were included. The level of evidence was assessed using the National Health Services Centre for Reviews and Dissemination Group recommendations. A total of 38 published papers were identified for MtF transsexism in the review and all were case series or case reports. The number of patients ranged from 1 to 390 across studies. Forty-four publications were identified with respect to GRS in FtM individuals; all were case series or case reports but for one cohort study. The number of involved patients ranged from 1 to 209. Outcomes of interest in the systematic review were patient satisfaction, functional outcomes, surgery-related complications, and other adverse events. Non-randomized controlled trials Two retrospective non-rcts assessing the benefits and harms of GRS were identified (Table A2.2 in Appendix 2). 12,13 Adult patients from Sweden 12 and Switzerland 13, who had a diagnosis of gender dysphoria and had undergone GRS were enrolled. Long-term outcomes such as mortality, health-related quality of life and cardiovascular events were evaluated. In the two studies, the patients were compared with a general population. 12,13 Dhejne et al. (number of transsexual patients: 324) was a population-based matched cohort study. Kuhn et al. (number of transsexual patients: 55) was a case control study with 55 cases and 20 controls. In the Kuhn study, patients received adjunctive hormone therapy, and the average time since GRS to Gender Reassignment Surgery 4

5 outcome measurements was 15 years. The status of hormone therapy in the Dhejne study was unknown. Clinical practice guidelines In 2009, the Endocrine Society in the United States issued clinical practice guidelines to assist endocrinologists in disease management for gender dysphoria, especially endocrine treatment. 14 The guideline was developed using the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group. 15 The recommendations were classified into one of two grades (strong or weak) and the quality of the evidence into one of four categories (high, moderate, low, or very low). 15 It indicated that the best available research evidence and evidence from systematic reviews were employed in generating recommendations; however, specific information about the literature search for this guideline was not provided in details. It is unclear which databases were searched (Table A2.3 in Appendix 2). Summary of Critical Appraisal The strengths and limitations of the included studies are summarized in Appendix 3. Systematic review The quality of the Sutcliffe review was assessed using AMSTAR. 8 The methods of study selection and data extraction were reported. The literature search was limited to English language publications. Any study designs were eligible except for expert opinions and review articles; however, almost all included studies were case series and case reports. The level of evidence was rated as III or IV (refers to retrospective cohort study, case-control study, metaanalysis of level 3 studies or case series ). Data extraction and quality assessment of the included studies were primarily conducted by one author and then verified by the second author. Patients demographic characteristics and medical characteristics of the included studies were not reported. The instruments used in each study to measure patient satisfaction and functional outcomes were not specified; in addition, it was unclear at what time points these outcomes were evaluated and for how long the patients were followed. Publication bias was not assessed in this review. Non-randomized controlled trials The quality of these studies was compromised due to the nature of the study design. Both studies clearly stated the objectives. The patient inclusion/exclusion criteria in the individual studies were not explicitly described. In both studies, the study population was compared with the general population or healthy controls that did not have GRS. Patient s baseline demographic characteristics and medical characteristics were inadequately reported, thus it is difficult to assess the comparability between the treatment group and the controls. Potential confounders were adjusted for in data analysis in one study, 12 but not in the other. In the Dhejne study, patients were selected from the entire population, while in the Kuhn study, a power or sample size calculation was not conducted. These limitations make it difficult to draw conclusions regarding the effectiveness of GRS. Clinical practice guidelines The AGREE II instrument for guideline quality 10 was used as a general guide with particular attention paid to guideline scope (including specific patient population and intended users) and aspects of clinical practice guidelines methodology such as scope, extent and reporting of the Gender Reassignment Surgery 5

6 literature search, types of included evidence, grading of evidence and recommendations, and funding and conflict-of-interest. One major limitation to this guideline was the fact that the methodology was not adequately described and as such it was unclear if all the relevant databases were searched, although it indicated that the recommendation formulation was based on best available research evidence including systematic reviews. See Table A3.3 in Appendix 3 for the strengths and limitations of this practice guideline. Summary of Findings The overall findings are summarized below and detailed findings from the individual clinical studies are provided in Appendix 4. What is the clinical evidence regarding the long-term patient outcomes following gender reassignment surgery? Systematic review In total, 82 case series or case reports concerning the clinical effectiveness of GRS were identified from a comprehensive literature search in the Sutcliffe review, 38 for the MtF individuals and 44 for the FtM individuals. Effectiveness In the MtF patient group, satisfactory cosmetic appearance and functional results (for example sexual and urinary functions) were reported in studies of clitoroplasty, vaginoplasty and neovagina construction. No studies were found for labiaplasty, orchidectomy and penectomy. In the FtM patient group, satisfactory cosmetic appearance and function results were reported in patients who had undergone hysterectomy, mastectomy, metoidioplasty, phalloplasty and scrotoplasty. No studies were found for salpingo-oophorectomy, urethroplasty and vaginectomy. The results from the included studies were briefly described in the systematic review, without providing sufficient details. Safety In one study of MtF individuals, major complications (tissue necrosis, rectal lesion and severe wound infections) occurred during, immediately and after surgery in nine of the 66 patients (14%). In studies of FtM individuals who underwent phalloplasty, serious surgery complications, such as vesicovginal, urethrovaginal fistulas and urinary incontinence, were reported. Long-term harms or complications of GRS were not reported in the systematic review. Non-randomized controlled trials Effectiveness Health-related quality of life was assessed in one study. 13 A validated tool - the King s Health Questionnaire was employed. A change of at least five points is considered significant. In this study, compared to the control group, patients who had undergone GRS reported statistically Gender Reassignment Surgery 6

7 significant lower scores (less impairment) in the General Health and Role Limitation, but higher scores (greater impairment) in Physical Limitation and Personal Limitation. The between-group differences were all greater than 5-point. In the same study, patient satisfaction was evaluated 15 years after GRS, using a 10-point VAS. Higher VAS scores indicated greater patient satisfaction. The VAS scores were 4.49 ± 0.1(mean ± standard error of the mean) with transsexuals versus 7.35 ± 0.26 with controls, p= Safety Mortality and psychiatric hospitalization were examined in the study by Dhejne et al. The authors found that treatment with GRS was associated with a higher risk of mortality, especially for death by suicide. GRS was associated with higher psychiatric-related hospitalizations. What are the evidence-based guidelines regarding the physical and mental health care of individuals who have undergone gender reassignment surgery? Clinical practice guideline The CPG was reviewed for recommendations on long-term care requirements to maintain patient health and quality of life (Table 2). Table 2: Summary of Recommendations in CPG Related to Long-Term Care Requirements in Patients Undergoing Gender Reassignment Surgery Organization, Year Recommendations The Endocrine Society Regular clinical and laboratory monitoring every 3 months during the first year and then once or twice yearly. (weak recommendation; low quality evidence, page 3133) Monitor prolactin levels in MtF persons treated with estrogens. (weak recommendation; low quality evidence, page 3133) Evaluate cardiovascular risk factors in transsexual persons treated with hormones. (weak recommendation; low quality evidence, page 3133) Obtain bone mineral density measurements if risk factors for osteoporosis exist, specifically in those who stop hormone therapy after gonadectomy. (weak recommendation; moderate quality evidence, page 3133) For MtF persons who have no known increased risk of breast cancer, breast screening guidelines recommended for biological women should be followed (weak recommendation; low quality evidence, page 3133) For MtF persons treated with estrogens, follow screening guidelines for prostatic disease and prostate cancer recommended for biological men (weak recommendation; very low quality evidence, page 3133) The physician responsible for endocrine treatment medically clear transsexual individuals for sex reassignment surgery and collaborate with the surgeon regarding hormone use during and after surgery (strong recommendation; very low quality evidence, page 3133) Limitations Clinical evidence for benefits and harms of GRS in patient with gender dysphoria was limited. Studies included in the one systematic review in our review were all case series and case reports. Other clinical trials identified from the literature were non-randomized, retrospective studies. Gender Reassignment Surgery 7

8 The included studies did not report whether the patients were given hormonal therapies after the surgery. During the long-term follow up, the effectiveness or safety of GRS can be confounded by concomitant hormonal therapy. The study results should be interpreted with caution. The two non-rcts used the general population as controls. Although one non-rct matched patients based on age and birth/reassigned gender, it is uncertain if this group was comparable with the study population in terms of patient demographic characteristics and medical conditions not related to GID, as these individuals may not face the same societal and personal selfesteem issues as the patients with gender dysphoria. Only one non-rct considered health-related quality of life. The questionnaire used for quality of life assessment has been validated in other populations (incontinent patients), but not in transsexual patients. It is unclear if it can detect the clinically important difference in this population. Power or sample size calculation was not conducted or described in one non-rct, which would have an impact on validity of the study results and interpretation. None of the included studies were conducted in a Canadian setting. Considering the quantity and quality of the available evidence, generalizability of the study results to Canadian patients is uncertain. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING In total, one systematic review, two non-randomized controlled studies and one clinical practice guideline for patients diagnosed with gender dysphoria have been examined in the current report. The number of transsexual patients in the included clinical trials ranged from 55 to 324 whereas the case series or case reports included in the systematic review ranged from one patient to 390 patients. There were no head to head clinical trials comparing GRS regimen with no GRS regimen. There are uncertainties around data interpretation given the lower level of evidence. Evidence from the systematic review suggested that following gender reassignment surgery, both femaleto-male and male-to-female were satisfied with the surgical outcomes and functioning. Conflicting results were reported for health-related quality of life 15 years after the surgery in one non-rct. Treatment with GRS was associated with higher risk of mortality in another non- RCT. One clinical practice guideline suggested that cardiovascular risks and bone mineral density be evaluated regularly. Cancer screening was also recommended. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Gender Reassignment Surgery 8

9 REFERENCES 1. Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, De Cuypere G, Feldman J, et al. Standards of care for the health of transsexual, transgender, and gender-nonconforming people, version 7. International Journal of Transgenderism [Internet] [cited 2014 Jul 15];13: Available from: 2. Meriggiola MC, Berra M. Safety of hormonal treatment in transgenders. Curr Opin Endocrinol Diabetes Obes Dec;20(6): Maycock LB, Kennedy HP. Breast care in the transgender individual. J Midwifery Womens Health [Internet] Jan [cited 2014 Jul 7];59(1): Available from: 4. Byne W, Bradley SJ, Coleman E, Eyler AE, Green R, Menvielle EJ, et al. Report of the American Psychiatric Association Task Force on Treatment of Gender Identity Disorder. Arch Sex Behav Aug;41(4): Ainsworth TA, Spiegel JH. Quality of life of individuals with and without facial feminization surgery or gender reassignment surgery. Qual Life Res Sep;19(7): Gooren LJ, Wierckx K, Giltay EJ. Cardiovascular disease in transsexual persons treated with cross-sex hormones: reversal of the traditional sex difference in cardiovascular disease pattern. Eur J Endocrinol Jun;170(6): Meriggiola MC, Jannini EA, Lenzi A, Maggi M, Manieri C. Endocrine treatment of transsexual persons: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. Eur J Endocrinol [Internet] May [cited 2014 Jul 3];162(5): Available from: 8. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2014 Jul 21];7:10. Available from: 9. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet] Jun [cited 2014 Jul 21];52(6): Available from: Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare. CMAJ [Internet] Dec [cited 2014 Jul 21];182(18):E839-E842. Available from: Sutcliffe PA, Dixon S, Akehurst RL, Wilkinson A, Shippam A, White S, et al. Evaluation of surgical procedures for sex reassignment: a systematic review. J Plast Reconstr Aesthet Surg Mar;62(3): Gender Reassignment Surgery 9

10 12. Dhejne C, Lichtenstein P, Boman M, Johansson AL, Langstrom N, Landen M. Long-term follow-up of transsexual persons undergoing sex reassignment surgery: cohort study in Sweden. PLoS ONE [Internet] [cited 2014 Jul 3];6(2):e Available from: Kuhn A, Bodmer C, Stadlmayr W, Kuhn P, Mueller MD, Birkhauser M. Quality of life 15 years after sex reassignment surgery for transsexualism. Fertil Steril Nov;92(5): Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer WJ, III, Spack NP, et al. Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab Sep;94(9): Swiglo BA, Murad MH, Schunemann HJ, Kunz R, Vigersky RA, Guyatt GH, et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab Mar;93(3): Gender Reassignment Surgery 10

11 APPENDIX 1: Selection of Included Studies 525 citations identified from electronic literature search and screened 496 citations excluded 29 potentially relevant articles retrieved for scrutiny (full text, if available) 2 potentially relevant reports retrieved from other sources (grey literature, hand search) 31 potentially relevant reports 27 reports excluded: -irrelevant population (2) -irrelevant intervention (17) -irrelevant outcomes (4) -study design (4) 4 reports included in review Gender Reassignment Surgery 11

12 APPENDIX 2: SUMMARY OF STUDY CHARACTERISTICS Table A2.1: Characteristics of Included Systematic Review First Author, Publication Year, Country Study Design Population Interventions Comparator Outcomes Sutcliffe SR 2014, UK 11 Included any study design Number of patients ranged from 1 to 390 Literature search Patients diagnosed with gender dysphoria who had undergone GRS For FtM: Hysterectomy Mastectomy Metoidioplasty Phalloplasty Salpingo-oophorectomy Scrotoplasty/placement of testicular prostheses Urethroplasty Vaginectomy For MtF: Clitoroplasty Labiaplasty Orchidectomy Penectomy Vaginoplasty Not stated FtM=female-to-male; GRS=gender reassignment surgery; MtF=male-to-female; SR=systematic review Patient satisfaction, function, surgical complication rates Gender Reassignment Surgery 12

13 Table A2.2: Characteristics of Included Non-Randomized Controlled Trials First Author, Publication Year, Country Study design Patient characteristics, sample size Interventions Dhejne 2011, Sweden 12 Kuhn 2009, Switzerland 13 Population based cohort study MtF and FtM were compared with randomly selected, ageand birth or final sexmatched controls (10:1) Case control study MtF and FtM were compared with healthy female medical staff with at least 1 previous abdominal or pelvic operation Patients with GID who underwent GRS between 1973 and 2003, N=324 (FtM, n=133 and MtF, n=191) Transsexual patients who received HRT, N=55 (MtF=52 and FtM=3) Controls, N=20 All patients underwent GRS Information for HT was not available All patients in GRS group underwent the surgery Median of duration of follow-up after the surgery was 15 years Outcomes Mortality (average follow-up time for allcause mortality 11.4 years), psychiatric morbidity Adjustments made for psychiatric morbidity and immigrant status Healthrelated quality of life measured by KHQ Patient satisfaction measured with a VAS CV=cardiovascular; FtM=female-to-male; GD=Gender dysphoria; GID=Gender Identity Disorder; HT=hormone therapy; KHQ=The King s Health Questionnaire; MtF=male-to-female; RCT=randomized controlled trial; VAS=visual analogue scale Gender Reassignment Surgery 13

14 Table A2.3: Characteristics of Included Clinical Practice Guidelines Organization, year The Endocrine Society, Patient population covered by CPG; target audience for CPG Adults with Gender dysphoria; endocrinologists Literature search described Extent of included evidence Grading of evidence & recommendations NR NR Yes followed the GRADE approach (see text of Summary of Study Characteristics for details) Funding COI=conflict of interest; CPG=clinical practice guideline; NR=not reported; WPATH=the World Professional Association of Transgender Health European Society of Endocrinology, European Society for Pediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and WPATH Gender Reassignment Surgery 14

15 APPENDIX 3: SUMMARY OF STUDY STRENGTHS AND LIMITATIONS Table A3.1: Critical Appraisal of Included Systemic Review First Author, Strengths Publication Year, Country Sutcliffe 2009, UK 11 Objectives and inclusion/ exclusion criteria were stated Multiple databases were searched Interventions, and outcomes were described List of excluded studies was provided Limitations Lack of control arms, all studies were case series/case reports English language publications only Patient characteristics were not described Instruments used for outcome measures were not described Publication bias was not assessed Conflict of interest was not declared Table A3.2: Critical Appraisal of Included Non-Randomized Controlled Trials First Author, Strengths Limitations Publication Year, Country Dhejne 2011, Sweden 12 Kuhn 2009, Austria 13 Objectives were stated Outcomes were described P values provided Multiple national registers and randomly selected controls were used to increase the representativity of the study population Objectives were stated Interventions and outcomes were described P values were provided Conflict of interest was reported Inclusion/ exclusion criteria were not clearly stated Patient characteristics were not reported in details Number discontinued or lost to follow up was not reported No details for concomitant hormone therapy No justification of sample size selection Inclusion/ exclusion criteria were not stated Patient characteristics were not reported in details Sample size determination was not reported Generalizability of the study results was unclear Loss to follow up was not reported Insufficient data reporting (lack of data regarding concurrent hormone therapy, detailed patient characteristics, etc.) Gender Reassignment Surgery 15

16 Table A3.3: Strengths and Limitations of Included Clinical Practice Guidelines Organization, Year Strengths Limitations The Endocrine Society Clearly defined scope and target audience Used the GRADE system to develop recommendations Broad consultation and input Recommendations and levels of evidence provided GRADE=Grading of Recommendations Assessment, Development and Evaluation Detailed methodology for search of the evidence was not provided, although it indicated that best available research evidence was used in formulating recommendations Process for updating guideline was not provided Conflict of interest information was not reported Unclear if the guideline has been peerreviewed Gender Reassignment Surgery 16

17 APPENDIX 4: MAIN STUDY FINDINGS AND AUTHORS CONCLUSIONS First Author, Main Findings and Authors Conclusion Publication Year, Country HTA/Systematic review/meta-analysis Sutcliffe 2009, Main Findings: UK 11 FtM: Hysterectomy: 1 study, blood loss during surgery < ml. Mastectomy: 3 studies, patients satisfied with surgical outcomes; 2 areolar necroses occurred. Metoidioplasty: 2 studies, surgery was satisfactory; 1 severe haematoma occurred. Phalloplasty: 36 studies, good operative results (appropriate size, stiffness without vascular compromise, to void whilst standing, and psychological outcomes); serious complications (vesicovaginal, urethrovaginal fistulas, urinary incontinence, neourethra, stricture formation) were reported. Salpingo-oophorectomy: no studies. Scrotoplasty/placement of testicular prostheses: 2 studies; implant expulsion, rupture or dislocation were reported in small number of patients. Urethroplasty: no study. Vaginectomy: no study. MtF: Clitoroplasty: 3 studies; successful results in terms of function and cosmetic appearance; urine leakage and necrosis of the neoclitoris were reported in small number of patients. Labiaplasty: no study. Orchidectomy: no study. Penectomy: no study. Vaginoplasty: 32 studies, satisfactory cosmetic and functional results (capacity of orgasm and sexual intercourse) were reported in a large number of studies while 1 study reported poor functional outcomes; major complications included necrosis of distal urethra, glans, rectal lesion and severe wound infections. Authors Conclusion: The evidence concerning GRS in both MtF and FtM transsexism has several limitations: lack of controlled studies, data not collected prospectively, high loss to follow up, and lack of validated assessment measures. Some satisfactory outcomes were reported, but the magnitude of benefit and harm for individual surgical procedures cannot be estimated accurately using the current available evidence. Non-RCTs Dhejne 2011, Sweden 12 Main Findings: All-cause mortality (adjusted a hazard ratio compared to controls, 95% CI) 2.8 ( ) Death by suicide: 19.1 ( ) Death by CV disease: 2.5 ( ) Death by cancer: 2.5 ( ) Any psychiatric hospitalization: 2.8 ( ) Gender Reassignment Surgery 17

18 First Author, Publication Year, Country Kuhn 2009, Austria 13 Main Findings and Authors Conclusion Authors Conclusion: Persons with transsexualism after GRS, had higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. Main Findings: QOL measured with KHQ: In the 8 domains of KHQ, statistically significant between group differences were observed in 4 domains (see the following table). In the other 4 domains (emotions, sleep, incontinence, and symptom severity), the differences did not reach statistical significance. Outcomes b General health, mean±sem Role limitation, mean±sem Physical limitation, mean±sem Personal limitation, mean±sem Transsexuals N= ± ±2.3 P= ± ±1.7 P= ± ±1.9 P < ± ±0.4 P < Controls N=20 Patient satisfaction measured with VAS c : 4.49±0.1(mean±SEM) with transsexuals vs. 7.35±0.26 with controls, p= Authors Conclusion: After 15 years after the GRS, patient QOL was lower in the domains of general health and role limitation, and higher in the domains of physical and personal limitation. Patient general life satisfaction was significantly lower than the controls. a adjusted for premorbid differences in psychiatric morbidity and immigrant status; b scale of 0 to 100; a lower value denotes better HRQoL outcome; c scale of 0 1o 10; a lower value denotes less satisfaction. CI=confidence interval, FtM=female-to-male; GRS=gender reassignment surgery; MtF=male-to-female; KHQ=King s Health Questionnaire; QOL=quality of live; SEM=standard error of the mean; VAS=visual analog scale Gender Reassignment Surgery 18