Sabine E. Hannema

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.

Early Medical Treatment of Children and Adolescents With Gender Dysphoria: An Empirical Ethical Study

PURPOSEnThe Endocrine Society and the World Professional Association for Transgender Health published guidelines for the treatment of adolescents with gender dysphoria (GD). The guidelines recommend the use of gonadotropin-releasing hormone agonists in adolescence to suppress puberty. However, in actual practice, no consensus exists whether to use these early medical interventions. The aim of this study was to explicate the considerations of proponents and opponents of puberty suppression in GD to move forward the ethical debate.nnnMETHODSnQualitative study (semi-structured interviews and open-ended questionnaires) to identify considerations of proponents and opponents of early treatment (pediatric endocrinologists, psychologists, psychiatrists, ethicists) of 17 treatment teams worldwide.nnnRESULTSnSeven themes give rise to different, and even opposing, views on treatment: (1) the (non-)availability of an explanatory model for GD; (2) the nature of GD (normal variation, social construct or [mental] illness); (3) the role of physiological puberty in developing gender identity; (4) the role of comorbidity; (5) possible physical or psychological effects of (refraining from) early medical interventions; (6) child competence and decision making authority; and (7) the role of social context how GD is perceived. Strikingly, the guidelines are debated both for being too liberal and for being too limiting. Nevertheless, many treatment teams using the guidelines are exploring the possibility of lowering the current age limits.nnnCONCLUSIONSnAs long as debate remains on these seven themes and only limited long-term data are available, there will be no consensus on treatment. Therefore, more systematic interdisciplinary and (worldwide) multicenter research is required.

Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents.

INTRODUCTIONnPuberty suppression using gonadotropin-releasing hormone agonists (GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric adolescents. Although GnRHas have long been used to treat precocious puberty, there are few data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal and liver function.nnnAIMnTo evaluate the efficacy and safety of GnRHa treatment to suppress puberty in gender dysphoric adolescents.nnnMETHODSnForty-nine male-to-female and 67 female-to-male gender dysphoric adolescents treated with triptorelin were included in the analysis.nnnMAIN OUTCOME MEASURESnPhysical examination, including assessment of Tanner stage, took place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6 months. Body composition was evaluated using dual energy x-ray absorptiometry.nnnRESULTSnGnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In one of four female-to-male subjects who presented at Tanner breast stage 2, breast development completely regressed. Gonadotropins and sex steroid levels were suppressed within 3 months. Treatment did not have to be adjusted because of insufficient suppression in any subject. No sustained abnormalities of liver enzymes or creatinine were encountered. Alkaline phosphatase decreased, probably related to a slower growth velocity, because height SD score decreased in boys and girls. Lean body mass percentage significantly decreased during the first year of treatment in girls and boys, whereas fat percentage significantly increased.nnnCONCLUSIONnTriptorelin effectively suppresses puberty in gender dysphoric adolescents. These data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is not necessary during treatment with triptorelin. Further studies should evaluate the extent to which changes in height SD score and body composition that occur during GnRHa treatment can be reversed during subsequent cross-sex hormone treatment.

Perceptions of Sex, Gender, and Puberty Suppression: A Qualitative Analysis of Transgender Youth

International guidelines recommend the use of Gonadotropin-Releasing Hormone (GnRH) agonists in adolescents with gender dysphoria (GD) to suppress puberty. Little is known about the way gender dysphoric adolescents themselves think about this early medical intervention. The purpose of the present study was (1) to explicate the considerations of gender dysphoric adolescents in the Netherlands concerning the use of puberty suppression; (2) to explore whether the considerations of gender dysphoric adolescents differ from those of professionals working in treatment teams, and if so in what sense. This was a qualitative study designed to identify considerations of gender dysphoric adolescents regarding early treatment. All 13 adolescents, except for one, were treated with puberty suppression; five adolescents were trans girls and eight were trans boys. Their ages ranged between 13 and 18xa0years, with an average age of 16xa0years and 11xa0months, and a median age of 17xa0years and 4xa0months. Subsequently, the considerations of the adolescents were compared with views of clinicians treating youth with GD. From the interviews with the gender dysphoric adolescents, three themes emerged: (1) the difficulty of determining what is an appropriate lower age limit for starting puberty suppression. Most adolescents found it difficult to define an appropriate age limit and saw it as a dilemma; (2) the lack of data on the long-term effects of puberty suppression. Most adolescents stated that the lack of long-term data did not and would not stop them from wanting puberty suppression; (3) the role of the social context, for which there were two subthemes: (a) increased media-attention, on television, and on the Internet; (b) an imposed stereotype. Some adolescents were positive about the role of the social context, but others raised doubts about it. Compared to clinicians, adolescents were often more cautious in their treatment views. It is important to give voice to gender dysphoric adolescents when discussing the use of puberty suppression in GD. Otherwise, professionals might act based on assumptions about adolescents’ opinions instead of their actual considerations. We encourage gathering more qualitative research data from gender dysphoric adolescents in other countries.

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

OBJECTIVEnIncreased 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.nnnMETHODSnCases were developed based on these recently revised guidelines for gender-dysphoric and gender-nonconforming persons.nnnRESULTSnSix 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.nnnCONCLUSIONnEndocrinologists 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.nnnABBREVIATIONSnBMI = body mass index GnRH = gonadotropin-releasing hormone HDL = high-density lipoprotein LDL = low-density lipoprotein.

Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis

BACKGROUNDnComplete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8-22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure.nnnOBJECTIVE AND HYPOTHESESnTo establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy.nnnMETHODnData were collected from the Cambridge DSD database on patients with CAIS (nxa0=xa0225; age range 3-88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry.nnnRESULTSnEvaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range: 18 days-68 years). Pubertal status was: prepuberty, nxa0=xa062; postpuberty, nxa0=xa068. Thirteen cases were aged >20xa0years at gonadectomy. The pattern of histology is summarised in the Summary table.nnnDISCUSSIONnIn this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres.nnnCONCLUSIONnThe results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.

Clinical and Molecular Characteristics May Alter Treatment Strategies of Thyroid Malignancies in DICER1-syndrome

ContextnDICER1 syndrome is a rare autosomal-dominantly inherited disorder that predisposes to a variety of cancerous and noncancerous tumors of mostly pediatric and adolescent onset, including differentiated thyroid carcinoma (DTC). DTC has been hypothesized to arise secondarily to the increased prevalence of thyroid hyperplastic nodules in syndromic patients.nnnObjectivenTo determine somatic alterations in DICER1-associated DTC and to study patient outcomes.nnnDesignnRetrospective series.nnnSettingnTertiary referral centers.nnnPatientsnTen patients with germline pathogenic DICER1 variants and early-onset DTC.nnnMethodsnSomatic DICER1 mutation analysis, extensive somatic DNA variant and gene fusion analyses were performed on all tumors.nnnResultsnMedian age at DTC diagnosis was 13.5 years and there was no recurrent or metastatic disease (median follow-up, 8 years). All thyroid specimens showed diffuse nodular hyperplasia with at least one focus suspicious of DTC but without infiltrative growth, extrathyroidal extension, vascular invasion, or lymph node metastasis. Most of the individual nodules (benign and malignant) sampled from the 10 tumors harbored distinct DICER1 RNase IIIb hotspot mutations, indicating a polyclonal composition of each tumor. Furthermore, nine of 10 DICER1-related DTCs lacked well-known oncogenic driver DNA variants and gene rearrangements.nnnConclusionnOn the basis of our clinical, histological, and molecular data, we consider that most DICER1-related DTCs form a low-risk subgroup. These tumors may arise within one of multiple benign monoclonal nodules; thus, hemi-thyroidectomy or, more likely, total thyroidectomy may often be required. However, radioiodine treatment may be unnecessary given the patients ages and the tumors low propensity for metastases.

The efficacy and safety of pubertal induction using 17beta-estradiol in transgirls.

ContextnPuberty suppression using gonadotropin-releasing hormone agonists, followed by induction of the desired sex characteristics using sex steroids, has been recommended by the current guidelines as the treatment of choice for gender dysphoric adolescents, although little evidence is available.nnnAimnTo evaluate the efficacy and safety of estrogen treatment for pubertal induction in transgirls (female-identifying adolescents assigned male at birth).nnnMethodsnTwenty-eight adolescents treated with oral estrogen for ≥1 year were included. The Tanner stage, anthropometry, laboratory parameters, bone age, and body composition were evaluated.nnnResultsnBreast development started within 3 months in 83% of adolescents, and after 3 years, 86% had Tanner breast stage 4 to 5. The hip circumference increased and the waist/hip ratio decreased. The median serum estradiol was 100 pmol/L (range, 24 to 380) at the standard adult dose of 2 mg of 17β-estradiol. The adult height standard deviation score was +1.9 (for females). The body mass index standard deviation score, lean body mass percentage, fat percentage, and blood pressure did not change. No abnormalities of creatinine or liver enzymes were detected, and the hematocrit and hemoglobin A1c did not change. One individual developed hyperprolactinemia during high-dose ethinylestradiol treatment to limit growth.nnnConclusionsnPubertal induction using estradiol is effective; however, an adult dose of 2 mg does not always result in appropriate serum estradiol levels. Monitoring renal function, liver enzymes, hematocrit, and hemoglobin A1c during pubertal induction with estradiol is not necessary. Further studies are needed to establish effective and safe methods to limit growth.

A bone overgrowth disorder due to a gain-of-function mutation in the kinase homology domain of guanylyl cyclase B, the receptor for CNP

A bone overgrowth disorder due to a gain-offunction mutation in the kinase homology domain of guanylyl cyclase B, the receptor for CNP Michaela Kuhn, Thomas Premsler, Ruey-Bing Yang, Thomas D Mueller, Birgit Gasner, Heike Oberwinkler, Sabine E Hannema, Hermine A van Duyvenvoorde, Ferdinand Roelfsema, Gijs WE Santen, Timothy Prickett, Sarina G Kant, Annemieke JMH Verkerk, Andre G Uitterlinden, Eric Espiner, Claudia AL Ruivenkamp, Wilma Oostdijk, Alberto M Pereira, Monique Losekoot, Jan M Wit