Wylie C. Hembree

Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to formulate practice guidelines for endocrine treatment of transsexual persons. EVIDENCE This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence, which was low or very low. CONSENSUS PROCESS Committees and members of The Endocrine Society, European Society of Endocrinology, European Society for Paediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and World Professional Association for Transgender Health commented on preliminary drafts of these guidelines. CONCLUSIONS Transsexual persons seeking to develop the physical characteristics of the desired gender require a safe, effective hormone regimen that will 1) suppress endogenous hormone secretion determined by the persons genetic/biologic sex and 2) maintain sex hormone levels within the normal range for the persons desired gender. A mental health professional (MHP) must recommend endocrine treatment and participate in ongoing care throughout the endocrine transition and decision for surgical sex reassignment. The endocrinologist must confirm the diagnostic criteria the MHP used to make these recommendations. Because a diagnosis of transsexualism in a prepubertal child cannot be made with certainty, we do not recommend endocrine treatment of prepubertal children. We recommend treating transsexual adolescents (Tanner stage 2) by suppressing puberty with GnRH analogues until age 16 years old, after which cross-sex hormones may be given. We suggest suppressing endogenous sex hormones, maintaining physiologic levels of gender-appropriate sex hormones and monitoring for known risks in adult transsexual persons.

Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline

Objective: To update the “Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2009. Participants: The participants include an Endocrine Society‐appointed task force of nine experts, a methodologist, and a medical writer. Evidence: This evidence‐based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: Group meetings, conference calls, and e‐mail communications enabled consensus. Endocrine Society committees, members and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. Conclusion: Gender affirmation is multidisciplinary treatment in which endocrinologists play an important role. Gender‐dysphoric/gender‐incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender. They require a safe and effective hormone regimen that will (1) suppress endogenous sex hormone secretion determined by the persons genetic/gonadal sex and (2) maintain sex hormone levels within the normal range for the persons affirmed gender. Hormone treatment is not recommended for prepubertal gender‐dysphoric/gender‐incongruent persons. Those clinicians who recommend gender‐affirming endocrine treatments—appropriately trained diagnosing clinicians (required), a mental health provider for adolescents (required) and mental health professional for adults (recommended)—should be knowledgeable about the diagnostic criteria and criteria for gender‐affirming treatment, have sufficient training and experience in assessing psychopathology, and be willing to participate in the ongoing care throughout the endocrine transition. We recommend treating gender‐dysphoric/gender‐incongruent adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with gonadotropin‐releasing hormone agonists. Clinicians may add gender‐affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age. For the care of peripubertal youths and older adolescents, we recommend that an expert multidisciplinary team comprised of medical professionals and mental health professionals manage this treatment. The treating physician must confirm the criteria for treatment used by the referring mental health practitioner and collaborate with them in decisions about gender‐affirming surgery in older adolescents. For adult gender‐dysphoric/gender‐incongruent persons, the treating clinicians (collectively) should have expertise in transgender‐specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient. We suggest maintaining physiologic levels of gender‐appropriate hormones and monitoring for known risks and complications. When high doses of sex steroids are required to suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor both transgender males (female to male) and transgender females (male to female) for reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians should persistently monitor adverse effects of sex steroids. For gender‐affirming surgeries in adults, the treating physician must collaborate with and confirm the criteria for treatment used by the referring physician. Clinicians should avoid harming individuals (via hormone treatment) who have conditions other than gender dysphoria/gender incongruence and who may not benefit from the physical changes associated with this treatment.

Barriers to healthcare for transgender individuals.

Purpose of reviewTransgender persons suffer significant health disparities and may require medical intervention as part of their care. The purpose of this manuscript is to briefly review the literature characterizing barriers to healthcare for transgender individuals and to propose research priorities to understand mechanisms of those barriers and interventions to overcome them. Recent findingsCurrent research emphasizes sexual minorities’ self-report of barriers, rather than using direct methods. The biggest barrier to healthcare reported by transgender individuals is lack of access because of lack of providers who are sufficiently knowledgeable on the topic. Other barriers include: financial barriers, discrimination, lack of cultural competence by providers, health systems barriers, and socioeconomic barriers. SummaryNational research priorities should include rigorous determination of the capacity of the US healthcare system to provide adequate care for transgender individuals. Studies should determine knowledge and biases of the medical workforce across the spectrum of medical training with regard to transgender medical care; adequacy of sufficient providers for the care required, larger social structural barriers, and status of a framework to pay for appropriate care. As well, studies should propose and validate potential solutions to address identified gaps.

Priorities for transgender medical and healthcare research.

Purpose of reviewTransgender individuals experience unique health disparities but are the subject of little focused health research. This manuscript reviews current literature on transgender medical and mental health outcomes and proposes research priorities to address knowledge gaps. Recent findingsPublished research in transgender healthcare consists primarily of case reports, retrospective and cross-sectional studies, involving largely European settings. Challenges to US-based transgender health research include a diverse population where no single center has sufficient patient base to conduct clinical research with statistical rigor. Treatment regimens are heterogeneous and warrant study for best practices. Current research suggests increased mortality and depression in transgender individuals not receiving optimal care, and possibly a modest increase in cardiovascular risk related to hormone therapy. Current evidence does not support concerns for hormone-related malignancy risk. SummaryThe priorities for transgender medical outcomes research should be to determine health disparities and comorbid health conditions over the life span, along with the effects of mental health, medical, and surgical interventions on morbidity and mortality. Specific outcomes of interest based on frequency in the literature, potential severity of outcome, and patient-centered interest, include affective disorders, cardiovascular disease, malignancies, fertility, and time dose-related responses of specific interventions.

The gonadal axis in men with schizophrenia

The typical onset of schizophrenia during late adolescence and early adulthood has stimulated interest in the potential contribution of hypothalamo-pituitary-gonadal (HPG) axis abnormalities to this disorder. Previous investigations of reproductive hormone function in men with schizophrenia suggest diminished activity of the HPG axis. These studies have been hampered, however, by methodologic limitations. We have attempted to address these limitations by rigorous determination of gonadotropin and gonadal hormone levels, and attention to demographic and diagnostic variables. In contrast to prior studies, our results indicate that schizophrenic patients do not show statistically significant differences from healthy volunteers with respect to luteinizing hormone pulsatility, response to gonadotropin-releasing hormone challenge, and testosterone secretion. Due to the small number of subjects, however, these findings must be regarded as preliminary and warrant further study.

Male Contraception and Family Planning: A Social and Historical Review

Men have historically been ignored by family planners. The technologic and societal reasons for this lack of involvement of men in the family planning process are examined. Even the structure of medical education and the organization of medical institutions of biomedical research did not foster interest in male reproduction. Males worldwide do take responsibility for contraception and they are showing greater interest in it all the time a fact illustrated by the rising number of vasectomies performed annually. Despite the need for and interest in new research in the field of male contraception funding so far has been low. There is a clear need for greater support for development of an improved male contraceptive. Feminists are demanding that men share responsibility in this area.

Marihuana’s Effects on Human Gonadal Function

Regulation of gonadal function in the human male begins in utero by the time a pregnancy can first be detected. Biochemical and morphological observations support the concept that the Y-bearing primitive germ cells are responsible for initiating the sequence of developmental events by which these gonocytes are enveloped by the Sertoli cells within seminiferous tubules. Thereafter, they are bathed by periodic surges of testosterone production by the peritubular Leydig cells. The dependence of this reproductive unit on hypothalamic-pituitary function becomes apparent during the perinatal period and is sustained until senescence.

Management of juvenile gender dysphoria.

Purpose of reviewTo describe the treatment of gender dysphoria in adolescents. Recent findingsCareful study and evaluation of children with persistent severe gender dysphoria has led to the recommendation that puberty be suppressed at Tanner Stage II. If the dysphoria persists until age 16, treatment with sex steroids of the appropriate gender may begin at age 16 and be followed by gender-appropriate surgery. SummaryProtocols and results of treatment of early adolescents have demonstrated that the harmful effects of persistent gender dysphoria can be prevented. Pubertal suppression in early puberty not only prevents the severe distress, but also allows healthy adolescent development living in the appropriate gender.

ENDOCRINE TREATMENT OF GENDER-DYSPHORIC/GENDER-INCONGRUENT PERSONS: AN ENDOCRINE SOCIETY* CLINICAL PRACTICE GUIDELINE

Wylie C. Hembree, Peggy T. Cohen-Kettenis, Louis Gooren, Sabine E. Hannema, Walter J. Meyer, M. Hassan Murad, Stephen M. Rosenthal, Joshua D. Safer, Vin Tangpricha, and Guy G. T’Sjoen New York Presbyterian Hospital, Columbia University Medical Center, New York, New York 10032 (Retired); VU University Medical Center, 1007 MB Amsterdam, Netherlands (Retired); VU University Medical Center, 1007 MB Amsterdam, Netherlands (Retired); Leiden University Medical Center, 2300 RC Leiden, Netherlands; University of Texas Medical Branch, Galveston, Texas 77555; Mayo Clinic EvidenceBased Practice Center, Rochester, Minnesota 55905; University of California San Francisco, Benioff Children’s Hospital, San Francisco, California 94143; Boston University School of Medicine, Boston, Massachusetts 02118; Emory University School of Medicine and the Atlanta VA Medical Center, Atlanta, Georgia 30322; and Ghent University Hospital, 9000 Ghent, Belgium

2017 AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/ENDOCRINE SOCIETY UPDATE ON TRANSGENDER MEDICINE: CASE DISCUSSIONS

OBJECTIVE Increased numbers of transgender and gender-nonconforming people are presenting to physicians in the United States and abroad due to increased public recognition and acceptance and increased access to healthcare facilities. However, there are still gaps in medical knowledge among endocrinologists and other health care professionals. The purpose of these cases is to present several common clinical vignettes of transgender people presenting in an office setting that illustrate some of the key recommendations of the Endocrine Societys revised Endocrine Treatment of Gender Dysphoria/Gender Incongruent Persons guidelines, cosponsored by the American Association of Clinical Endocrinologists. METHODS Cases were developed based on these recently revised guidelines for gender-dysphoric and gender-nonconforming persons. RESULTS Six cases are presented that illustrate the diagnosis, treatment, and long-term management of trans-gender children and adults based on the revised guidelines for the endocrine care of gender-dysphoric and gender-nonconforming persons. Several key teaching points are presented from the presentation of these cases. CONCLUSION Endocrinologists should be familiar with the revised guidelines for gender-dysphoric and gender-nonconforming persons. Important aspects of care are the diagnosis of gender dysphoria, the timing of treatment with gender-affirming hormones, and the long-term monitoring for potential adverse outcomes. Long-term health outcome studies are needed to further help guide care in this unique population. ABBREVIATIONS BMI = body mass index GnRH = gonadotropin-releasing hormone HDL = high-density lipoprotein LDL = low-density lipoprotein.