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.

Factors associated with parental COVID-19 vaccine attitudes and intentions among a national sample of United States adults ages 18-45.

PURPOSE: This study explored factors associated with parents' attitudes and intentions to seek information about the COVID-19 vaccine for their children (ages 0-18) and intentions to vaccinate their age-eligible children. DESIGN AND METHODS: As part of an anonymous online cross-sectional survey, parents' vaccine attitudes, COVID-19 vaccine intentions for their children, health literacy, health numeracy, and sociodemographic variables were assessed. Multivariable ordered logistic regression models identified factors associated with parents' COVID-19 vaccine intentions for their children. RESULTS: Parents/guardians (n = 963) were mostly White (82.3%), insured (88.0%), and college graduates (57.3%). Men reported higher intentions than women to seek information about the COVID-19 vaccine for their children (p = 0.003) and higher intentions to vaccinate their children (p = 0.049). Parental characteristics associated with increased intentions to have their children vaccinated included higher educational attainment (p < 0.001), more positive general vaccine attitudes (p < 0.001), preference for health information in a language other than English (p = 0.006), higher income (p = 0.048), having health insurance (p = 0.05), health literacy (p = 0.024), and health numeracy (p = 0.049). CONCLUSIONS: Multiple sociodemographic characteristics including male gender, higher health literacy and numeracy, and language preference are noteworthy factors associated with parental COVID-19 vaccine intentions that could inform the planning and implementation of educational interventions. PRACTICE IMPLICATIONS: Nurses are important sources of trusted information and play an important role in parent/family health education and in understanding myriad factors that may improve attitudes and enhance readiness toward vaccine uptake. Our findings emphasize the potential value of examining tailored/targeted COVID-19 vaccine education according to key influencing factors.

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.

Return of individual research results from genomic research: A systematic review of stakeholder perspectives.

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants.

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.

Views on genomic research result delivery methods and informed consent: a review.

There has been little discussion of the way genomic research results should be returned and how to obtain informed consent for this. We systematically searched the empirical literature, identifying 63 articles exploring stakeholder perspectives on processes for obtaining informed consent about return of results and/or result delivery. Participants, patients and members of the public generally felt they should choose which results are returned to them and how, ranging from direct (face-to-face, telephone) to indirect (letters, emails, web-based delivery) communication. Professionals identified inadequacies in result delivery processes in the research context. Our findings have important implications for ensuring participants are supported in deciding which results they wish to receive or, if no choice is offered, preparing them for potential research outcomes.

A serous borderline ovarian tumour in a transgender male adolescent.

Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.

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.

Topical Analgesic Improved or Maintained Ballistic Hip Flexion Range of Motion with Treated and Untreated Legs.

Increased stretch tolerance can contribute to improved range of motion (ROM). Since menthol-based topical analgesics (TopAnalg) suppress pain, they may increase stretch thresholds improving ROM. Other modalities such as transcutaneous electrical nerve stimulation and rolling have demonstrated decreased pain sensitivity in the contralateral limb. The purpose of this study was to investigate the effects of a TopAnalg on active and passive ROM of the treated and contralateral (untreated) leg. With a double blind, repeated measures design, 14 university students had a TopAnalg or a placebo gel applied to their hamstrings, rested for 20-min and then either performed static or dynamic stretching. Prior to gel application and after stretching, participants were tested for passive static, active and ballistic hip flexion ROM. Near significant greater ballistic hip flexion ROM for both legs (treated: p = 0.08; 3.6%; contralateral: p = 0.1; 1.6%) were observed with the TopAnalg. With dynamic stretching, ballistic hip flexion ROM of both limbs at post-test (p=0.01-0.007; 3.3-4.2%) and post-10 minutes (p = 0.06-0.01; 2.7-4.1%) decreased with the placebo, whereas there were no significant reductions with the TopAnalg. There was a near significant higher active hip flexion ROM (stretched leg: p = 0.05; 4.6%), and significantly higher ballistic hip flexion ROM (p = 0.04-0.05; 3.4-3.5%) with static versus dynamic stretching for both legs. In conclusion, TopAnalg can increase hip flexion ROM of the treated and contralateral limbs. Secondly, static stretching contributed to greater ballistic ROM in both the stretched and non-stretched contralateral limbs. Hence, TopAnalg may be used to enhance flexibility training with rehabilitation or highly trained athletes.