Pubertal Suppression in Early Puberty Followed by Testosterone Mildly Increases Final Height in Transmasculine Youth.

Context: Treatment for transmasculine youth (TMY) can involve testosterone treatment and is sometimes preceded by gonadotropin-releasing hormone agonist (GnRHa) treatment for puberty blockade. GnRHas can increase final height in birth-assigned females with central precocious puberty. Maximizing final adult height (FAH) is an important outcome for many TMY. Objective: Our objective was to determine how GnRHa treatment before testosterone impacts FAH. Methods: Retrospective cohort study at 5 US transgender health clinics. Participants were 32 TMY treated with GnRHas in early to midpuberty before testosterone (GnRHa + T group) and 62 late/postpubertal TMY treated with testosterone only (T-only group). Results: The difference between FAH minus midparental target height (MPTH) was +2.3 ± 5.7 cm and -2.2 ± 5.6 cm in the GnRHa + T and T-only groups, respectively (P < .01). In the GnRHa + T group, FAH was 1.8 ± 3.4 cm greater than predicted adult height (PAH) (P < .05) and FAH vs initial height (IH) z-score was 0.5 ± 1.2 vs 0.16 ± 1.0 (P < .05). After adjusting for patient characteristics, each additional month of GnRHa monotherapy increased FAH by 0.59 cm (95% CI 0.31, 0.9 cm), stage 3 breast development at start of GnRHa was associated with 6.5 cm lower FAH compared with stage 2 (95% CI -10.43, -2.55), and FAH was 7.95 cm greater in the GnRHa + T group than in T-only group (95% CI -10.85, -5.06). Conclusion: Treatment with GnRHa in TMY in early puberty before testosterone increases FAH compared with MPTH, PAH, IH, and TMY who only received testosterone in late/postpuberty. TMY considering GnRHas should be counseled that GnRHas may mildly increase their FAH if started early.

Exploring the Impact of Legislation Aiming to Ban Gender-Affirming Care on Pediatric Endocrine Providers: A Mixed-Methods Analysis.

Context: Access to gender-affirming medical care is associated with better mental health outcomes in transgender and gender diverse youth. In 2021 and 2022, legislation aiming to ban gender-affirming medical care for youth was proposed in 24 states. Objective: This study aimed to (1) assess the impact of this legislation on pediatric providers based on legislative status of their state of practice and (2) identify the themes of concerns reported by them. Methods: A mixed-methods study was conducted via an anonymous survey distributed to pediatric endocrinology providers. Survey responses were stratified based on US state of practice, with attention to whether legislation aiming to ban gender-affirming care had been considered. Data were analyzed both quantitatively and qualitatively. Results: Of 223 respondents, 125 (56.0%) were currently providing gender-affirming medical care. A total of 103 (45.7%) respondents practiced in a state where legislation aiming to ban gender-affirming care had been proposed and/or passed between January 2021 to June 2022. Practicing in legislation-affected states was associated with negative experiences for providers including (1) institutional pressure that would limit the ability to provide care, (2) threats to personal safety, (3) concerns about legal action being taken against them, (4) concerns about their career, and (5) institutional concerns about engagement with media. Major qualitative themes emerging for providers in legislation-affected states included safety concerns and the impact of laws on medical practice. Conclusion: This study suggests that legislation aiming to ban health care for transgender youth may decrease access to qualified providers in affected states.

A self-guided curriculum on endocrinology standard of care for gender diverse youth, including ethical considerations.

Objective: While the field of pediatric endocrinology, and the American Board of Pediatrics, continues expanding training to include gender-affirming care, many pediatric endocrinology fellowship programs do not have formal curriculum for this patient population. Members of the Pediatric Endocrine Society (PES) that have a special interest in transgender health designed a curriculum based on Endocrine Society practice guidelines to expand the knowledge of gender affirming care for medical trainees' and faculty. Methods: PES members designed a 5-part self-guided educational module series with embedded knowledge questions. Uniquely, medical ethical reflections were included within each module. Participants completed baseline demographic and baseline and follow-up knowledge surveys. Results: Most participants were pediatric endocrinology fellows and 44 % percent (n = 21) completed all study components, including the follow up knowledge survey. Knowledge question data analysis demonstrated knowledge gained in medical management of pubertal youth and surgical interventions. Conclusion: This is the first medical education curriculum in gender-affirming care created by pediatric endocrinologists grounded in the Endocrine Society practice guidelines. This study demonstrates medical knowledge gained in caring for gender diverse youth and is the first to incorporate ethical considerations for this patient population. While initially designed for pediatric endocrinology trainees and faculty, this curriculum may be of great utility for any provider interested in caring for gender diverse youth.

Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination.

CONTEXT: Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. OBJECTIVE: This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. METHODS: Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. RESULTS: Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. CONCLUSION: MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.

Hypothalamic Overexpression of Makorin Ring Finger Protein 3 Results in Delayed Puberty in Female Mice.

Makorin ring finger protein 3 (MKRN3) is an important neuroendocrine player in the control of pubertal timing and upstream inhibitor of gonadotropin-releasing hormone secretion. In mice, expression of Mkrn3 in the hypothalamic arcuate and anteroventral periventricular nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if the persistence of hypothalamic Mkrn3 expression peripubertally would result in delayed puberty. Female mice that received neonatal bilateral intracerebroventricular injections of a recombinant adeno-associated virus expressing Mkrn3 had delayed vaginal opening and first estrus compared with animals injected with control virus. Subsequent estrous cycles and fertility were normal. Interestingly, male mice treated similarly did not exhibit delayed puberty onset. Kiss1, Tac2, and Pdyn mRNA levels were increased in the mediobasal hypothalamus in females at postnatal day 28, whereas kisspeptin and neurokinin B protein levels in the arcuate nucleus were decreased, following Mkrn3 overexpression, compared to controls. Cumulatively, these data suggest that Mkrn3 may directly or indirectly target neuropeptides of Kiss1 neurons to degradation pathways. This mouse model suggests that MKRN3 may be a potential contributor to delayed onset of puberty, in addition to its well-established roles in central precocious puberty and the timing of menarche.

Providing Gender-Affirmative Care During the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic Era: Experiences and Perspectives from Pediatric Endocrinologists in the United States.

Transgender and gender diverse (TGD) youth are at risk of worsened health disparities during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Health care delivery by pediatric endocrinologists, including rapid implementation of telemedicine services, during the pandemic has not been documented. The Pediatric Endocrine Society's Transgender Health Special Interest Group met virtually to survey practice patterns during the SARS-CoV-2 pandemic. The majority of pediatric endocrinologists continued to provide most aspects of medical transition; however, we also identified several barriers to care. Overall, the survey results demonstrated that telemedicine can be utilized as an effective way to provide gender-affirming medical care to TGD youth.

Care for Transgender Young People.

Clinicians of all disciplines, including pediatric endocrinologists, are likely to encounter transgender and gender-diverse (TGD) young people in their practice regardless of whether they specialize in gender-affirming medical care. Because of this, it is important to be aware of the ways in which medical professionals can affirm these individuals. Although gender-affirming therapy should always include affirmation including proper use of names and pronouns, the transition journey will look different for each patient. The gender-affirming care of TGD young people may include both medical and nonmedical interventions (e.g., social transition). Therapies utilized for medical gender transition such as gonadotropin-releasing hormone agonists and/or gender-affirming hormones have implications for growth, bone health, cardiovascular health, and fertility, although these impacts are not yet completely understood. This review provides an overview of the care of transgender young people as well as a summary of what is known about the outcomes of these therapies. Clinicians should advise TGD young people and their families of the known and unknown risks and work together with patients to decide upon a treatment and follow-up regimen that aligns with their individual gender affirmation and health goals.

Growth, growth potential, and influences on adult height in the transgender and gender-diverse population.

The sexually dimorphic trait of height is one aspect of the experience of transgender and gender-diverse (TGD) individuals that may influence their gender dysphoria and satisfaction with their transition. In this article, we have reviewed the current knowledge of the factors that contribute to one's final adult height and how it might be affected in TGD youth who have not experienced their gonadal puberty in the setting of receiving gonadotropin-releasing hormone analog (GnRHa) and gender-affirming hormonal treatment. Additional research is needed to characterize the influence of growth and final adult height on the lived experience of TGD youth and adults and how to best assess their growth, predict their final adult height, and how medical transition can be potentially modified to help them meet their goals.

GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes.

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

The Peripubertal Decline in Makorin Ring Finger Protein 3 Expression is Independent of Leptin Action.

A critical body weight is necessary for pubertal development, an effect mediated in part by leptin. The potential regulation by leptin of Makorin Ring Finger Protein 3 (MKRN3), in which loss-of-function mutations are the most common genetic cause of central precocious puberty, has not been previously explored. In mice, expression of Mkrn3 in the hypothalamic arcuate nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if leptin contributes to the decrease in hypothalamic Mkrn3 mRNA levels observed in mice during pubertal development. We first used a leptin-deficient (ob/ob) mouse model. Mkrn3 mRNA levels in the mediobasal hypothalamus (MBH), which includes the arcuate nucleus, and in the preoptic area (POA), both showed a significant decrease with age from postnatal day (PND) 12 to PND30 in ob/ob mice in both males and females, similar to that observed in wild-type mice. To further explore the effects of leptin on Mkrn3 expression, we exposed prepubertal wild-type mice to high levels of leptin from age PND9-12, which did not result in any significant difference in Mkrn3 expression levels in either the MBH or POA. In summary, regulation of Mkrn3 expression by leptin was not observed in either the MBH or the POA, 2 hypothalamic sites important for pubertal maturation. These data suggest that the decline in Mkrn3 at the onset of puberty may occur independently of leptin and support our hypothesis that MKRN3 is a bona fide controller of puberty initiation.

Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay.

CONTEXT: The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis. OBJECTIVE: We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay. DESIGN, SETTING, AND PARTICIPANTS: We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty. INTERVENTION AND OUTCOME MEASURES: Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. RESULTS: All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. CONCLUSION: The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.

Induction and Maintenance of Amenorrhea in Transmasculine and Nonbinary Adolescents.

The treatment of persistent uterine bleeding in those patients who identify as transmasculine or nonbinary is often straightforward, but can be difficult in a subset of patients. This article reviews the physiology of the normal menstrual cycle and the hormonal influences on the endometrium, and then explores options for the treatment of persistent bleeding for people both already on testosterone and for those who are either not ready for or who do not desire testosterone.

Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty.

Context: Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3. Objective: To identify the genetic etiology of CPP in a large multigenerational family. Design: Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro. Setting: Endocrine clinic of an academic medical center. Patients: Patients with familial CPP were studied. Results: A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5' untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines. Conclusion: We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.

Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism.

BACKGROUND: Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). It can be inherited in an autosomal dominant manner or occur sporadically as a de novo mutation. Affected individuals display a wide phenotype from severe neonatal to mild subclinical hyperthyroidism. We describe a 6-month-old boy with a de novo mutation in the TSHR gene who presented with accelerated growth, enlarging head circumference, tremor and thyrotoxicosis. METHODS: Genomic DNA from the patient's and parents' peripheral blood leukocytes was extracted. Exons 9 and 10 of the TSHR gene were amplified by PCR and sequenced. RESULTS: Sequencing exon 10 of the TSHR gene revealed a novel heterozygous missense mutation substituting cytosine to adenine at nucleotide position 1534 in the patient's peripheral blood leukocytes. This leads to a substitution of leucine to methionine at amino acid position 512. The mutation was absent in the parents. In silico modeling by PolyPhen-2 and SIFT predicted the mutation to be deleterious. CONCLUSIONS: The p.Leu512Met mutation (c.1534C>A) of the TSHR gene has not been previously described in germline or somatic mutations. This case presentation highlights the possibility of mild thyrotoxicosis in affected individuals and contributes to the understanding of sporadic non-autoimmune primary hyperthyroidism.

Comparing breast cancer risk between lesbians and their heterosexual sisters.

PURPOSE: The purpose of this study was to explore the similarities and differences between lesbians and their heterosexual sisters in the established risks for developing breast cancer. METHODS: The design for this study was a matched (lesbian with heterosexual sister) cross-sectional, mail-back, anonymous survey. We distributed the surveys throughout the state of California to English-speaking women who identified themselves as lesbians, age 40 and older, and their sisters. Using the modified Gail Breast Cancer Risk model as well as other well-established factors associated with the development of breast cancer, we compared the breast cancer risk potential for 324 sister pairs (N = 648). Data were analyzed using paired t-tests, analysis of covariance (ANCOVA), McNemar's chi(2), or the Bowker statistic, as appropriate for the level of data. MAIN FINDINGS: The lesbians had significantly higher 5-year (p <.0001) and lifetime (p =.001) risk for developing breast cancer. The reasons for lesbians' predicted rate of breast cancer were most likely their higher scores on all pregnancy-related variables and the relatively high number of breast biopsies they reported. The lesbians had used birth control pills less (p <. 0001), had significantly fewer pregnancies (p <.0001), children (p <.0001), abortions (p <.0001), and miscarriages (p <.0001) as well as significantly more breast biopsies (p =.02) than did their heterosexual sisters. CONCLUSIONS: A lesbian who comes out to her clinician is relying on the clinician to be informed and be open to discuss her life. When a lesbian has a lump or a suspicious mammogram, she needs her clinician to advocate for her within the health care system because she is at higher risk for having cancer than a heterosexual woman.

Cardiovascular disease risk in lesbian women.

Lesbians may be a higher risk subpopulation of women for cardiovascular disease due to the prevalence of risk factors and attitudes about weight. In a survey of 648 women, we compared various cardiovascular risk factors between 324 lesbians age 40 and older residing in California and their heterosexual sisters closest in age. Compared with their sisters, the lesbians had a significantly higher body mass index, waist circumference, and waist-to-hip ratio (WHR). The lesbians were also more likely to have ever smoked, but were as likely as their sisters to be current smokers. They were significantly less likely to have eaten red meat in the past year, but did not differ significantly from their sisters on the other nutritional variables. They were more likely, however, to report a history of weight cycling. With regard to exercise, the lesbians were significantly more likely to exercise at least weekly. Yet the two groups did not differ in the number of times per week exercised, the length of the exercise session, nor the exercise vigor. This is the first study to report waist circumference measurements and WHR for lesbians. Our findings suggest that lesbians, as a group, may have greater abdominal/visceral adiposity and, thus, a metabolic profile placing them at higher risk for cardiovascular disease. Future studies of cardiovascular risk in lesbians should measure low-density lipoprotein, C-reactive protein, and identifiers of the metabolic syndrome, namely blood pressure, triglyceride and high-density lipoprotein levels, and fasting glucose. Interventions designed to reduce abdominal/visceral adiposity in lesbians should also be examined in future studies.

Improving cancer screening among lesbians over 50: results of a pilot study.

PURPOSE/OBJECTIVES: To explore the impact of two one-hour lesbian-specific educational interventions by a lesbian physician on the cancer screening behaviors of lesbians. DESIGN: A pilot pre- and post-test intervention study. SETTING: Two lesbian, gay, bisexual, and transgendered senior organizations in the San Francisco Bay Area (one urban, one suburban). SAMPLE: 36 participants aged 50-81 (meanX = 60.2, SD = 6.48). The majority were Caucasian (86%), single (61%), living in urban areas (67%), employed (56%), and educated beyond high school (meanX = 15.47 years, SD = 2.90, range 9-21). Eleven percent (n = 4) did not have any health insurance and were not on Medicaid or Medicare. METHODS: A lesbian physician led a one-hour, didactic, lesbian- specific educational program on cancer screening, including a review of current research findings with regard to lesbians' risk for cancer and 45 minutes of information on recommended cancer screening, followed by a 15-minute question-and-answer period. Participants completed a pre- and postintervention survey. FINDINGS: Follow-up data were available for 22 women. Of the six women (27%) who had not focused their attention on breast screening behaviors for two years or more, one-third had obtained mammograms and half began performing monthly breast self-examinations. Of the four women (18%) who had not undergone a pelvic examination for three years or more, one obtained a pelvic examination. The women reported no changes in colorectal cancer screening behaviors. CONCLUSIONS: Some of these difficult-to-reach women changed their behavior in a very short period of time, supporting the need for a larger study to confirm these findings. IMPLICATIONS FOR NURSING: A need exists to develop appropriate interventions for the underserved population of lesbians older than 50.