Independent effects of testosterone, estradiol, and sex chromosomes on gene expression in immune cells of trans- and cisgender individuals.

The origins of sex differences in human disease are elusive, in part because of difficulties in separating the effects of sex hormones and sex chromosomes. To separate these variables, we examined gene expression in four groups of trans- or cisgender individuals: XX individuals treated with exogenous testosterone (n=21), XY treated with exogenous estradiol (n=13), untreated XX (n=20), and untreated XY (n=15). We performed single-cell RNA-sequencing of 358,426 peripheral blood mononuclear cells. Across the autosomes, 8 genes responded with a significant change in expression to testosterone, 34 to estradiol, and 32 to sex chromosome complement with no overlap between the groups. No sex-chromosomal genes responded significantly to testosterone or estradiol, but X-linked genes responded to sex chromosome complement in a remarkably stable manner across cell types. Through leveraging a four-state study design, we successfully separated the independent actions of testosterone, estradiol, and sex chromosome complement on genome-wide gene expression in humans.

Childhood Gender Diversity and Mental Health: Protocol for the Longitudinal, Observational Gender Journey Project.

BACKGROUND: Prepubertal transgender, nonbinary, and gender-diverse (TGD) children (ie, those asserting gender identity, expressing gender-role behavior outside of culturally defined norms for their sex registered at birth, or both) are presenting in greater numbers to pediatric gender clinics across the United States and abroad. A large subset of TGD children experiences gender dysphoria, that is, distress that arises from the incongruence between gender identity and sex registered at birth. A lack of consensus exists regarding care for prepubertal TGD children due, in part, to a dearth of empirical research on longitudinal developmental trajectories of gender identity, role behavior, and gender dysphoria (when present). OBJECTIVE: The objective of this National Institutes of Health-funded study is to provide evidence to inform clinical care for prepubertal TGD children by establishing a US longitudinal cohort (N=248) of prepubertal TGD children and their caregivers that is followed prospectively at 6-month intervals across 18 months. METHODS: At each timepoint, clinical and behavioral data are collected via web-based visit from child and caregiver reporters. Latent class analysis, among other methods, is used to identify subgroups and longitudinally characterize the gender identity and gender-role behavior of TGD children. These models will define longitudinal patterns of gender identity stability and characterize the relationship between TGD classes and mental and behavioral health outcomes, including the moderating role of social gender transition (when present), on these associations. RESULTS: Baseline data collection (N=248) is complete, and the identification of TGD subgroups based on gender identity and expression using latent class analysis is anticipated in 2024. The completion of all 4 waves of data collection is anticipated in July 2024, coinciding with the start of a no-cost study extension period. We anticipate longitudinal analyses to be completed by winter 2024. CONCLUSIONS: Through a longitudinal observational design, this research involving prepubertal TGD children and their caregivers aims to provide empirical knowledge on gender development in a US sample of TGD children, their mental health symptomology and functioning over time, and how family initiated social gender transition may predict or alleviate mental health symptoms or diagnoses. The research findings have promise for clinicians and families aiming to ensure the best developmental outcome for these children as they develop into adolescents. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55558.

Body image and psychosocial outcomes in youth and young adults with differences of sex development: a multi-method study.

OBJECTIVE: Differences of sex development (DSD) can affect the physical health, appearance, and psychosocial functioning of affected individuals, but little is known about how subjective appearance perceptions (body image) impact psychosocial outcomes. This study evaluated body image and its associations with psychosocial outcomes including quality of life, resilience, and psychosocial adjustment. METHODS: This cross-sectional, multi-method study assessed body image and psychosocial outcomes including quality of life, adjustment, and resilience in 97 youth and young adults with DSD (mean age = 17 ± 3.7 years; 56% assigned female in infancy) using psychometrically sound instruments. A subsample (n = 40) completed qualitative interviews. RESULTS: Quantitative results indicated that overall, participants were satisfied with their physical appearance, although less so with their primary sex characteristics. Body image dissatisfaction was associated with poorer psychosocial adjustment, quality of life, and resilience. Qualitatively, youth and young adults reported a variety of perceptions, both positive and negative, related to their body image and the impact of living with a DSD condition. Themes identified included appearance management; effects of DSD on body image; diagnostic factors and features; attitudes about diagnosis; and treatment. CONCLUSIONS: Body image is significantly associated with psychosocial outcomes in youth and young adults with DSD, with qualitative findings highlighting both positive and negative body image experiences. Results have implications for clinical care including screening for appearance concerns, normalization of appearance variations, and intervention development to better support healthy body image and psychosocial functioning in youth and young adults with DSD.

Trajectories of illness uncertainty among parents of children with atypical genital appearance due to differences of sex development.

OBJECTIVE: The present study aimed to identify distinct trajectories of parental illness uncertainty among parents of children born with atypical genital appearance due to a difference of sex development over the first year following diagnosis. It was hypothesized that four trajectory classes would emerge, including "low stable," "high stable," "decreasing," and "increasing" classes, and that select demographic, familial, and medical factors would predict these classes. METHODS: Participants included 56 mothers and 43 fathers of 57 children born with moderate to severe genital atypia. Participants were recruited from eleven specialty clinics across the U.S. Growth mixture modeling (GMM) approaches, controlling for parent dyad clustering, were conducted to examine classes of parental illness uncertainty ratings over time. RESULTS: A three-class GMM was identified as the best-fitting model. The three classes were interpreted as "moderate stable" (56.8%), "low stable" (33.0%), and "declining" (10.3%). Findings suggest possible diagnostic differences across trajectories. CONCLUSIONS: Findings highlight the nature of parents' perceptions of ambiguity and uncertainty about their child's diagnosis and treatment the year following their child's birth/diagnosis. Future research is needed to better understand how these trajectories might shift over the course of the child's development. Results support the development of tailored, evidence-based interventions to address coping with uncertainty among families raising a child with chronic health needs.

Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum.

Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (rg=0.585, P=8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (rg=0.403, P=2.16E-03). The evolutionary persistence of female infertility-risk alleles in EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near FSHB and ARL14EP colocalised with signals for anovulatory infertility, we found no rg between female infertility and reproductive hormones (P>0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in GPC2 were at higher risk of infertility (OR=2.63, P=1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.

Healthcare communication satisfaction and psychosocial outcomes in adolescents and young adults with differences of sex development.

OBJECTIVES: We examined: (1) healthcare communication satisfaction and psychosocial outcomes (resilience, QoL, and psychological adjustment) in adolescents and young adults (AYA) with differences of sex development (DSD), (2) differences in psychosocial outcomes between those who were highly satisfied and those who were less satisfied, and (3) group differences between adolescents (ages 12-17) and young adults (ages 18-26) regarding associations with healthcare communication and psychosocial outcomes. METHODS: AYA with DSD across four study sites reported on satisfaction with healthcare communication and psychosocial outcomes. Analyses included descriptive statistics (aim 1), independent samples t-tests (aim 2), and Pearson's correlations (aim 3). RESULTS: Participants reported high levels of satisfaction with healthcare communication. Higher healthcare communication satisfaction was associated with greater resilience (p = .01), better QoL (p = .02), and fewer internalizing problems (p = .04). For adolescents, higher healthcare communication satisfaction was associated with better psychosocial outcomes (p values ranging from.01-.04). No significant associations were found in the young adult group. CONCLUSIONS: Satisfaction with healthcare communication is related to positive psychosocial outcomes in adolescents with DSD. PRACTICE IMPLICATIONS: These data underscore the importance of optimizing communication with families, engaging AYA in early and ongoing discussions about their care, and including psychosocial providers in DSD care.

Laboratory Changes During Gender-Affirming Hormone Therapy in Transgender Adolescents.

OBJECTIVES: Guidelines for monitoring of medications frequently used in the gender-affirming care of transgender and gender-diverse (TGD) adolescents are based on studies in adults or other medical conditions. In this study, we aimed to investigate commonly screened laboratory measurements in TGD adolescents receiving gender-affirming hormone therapy (GAHT). METHODS: TGD adolescents were recruited from 4 study sites in the United States before beginning GAHT. Hemoglobin, hematocrit, hemoglobin A1c, alanine transaminase, aspartate aminotransferase, prolactin, and potassium were abstracted from the medical record at baseline and at 6, 12, and 24 months after starting GAHT. RESULTS: Two-hundred and ninety-three participants (68% designated female at birth) with no previous history of gonadotropin-releasing hormone analog use were included in the analysis. Hemoglobin and hematocrit decreased in adolescents prescribed estradiol (-1.4 mg/dL and -3.6%, respectively) and increased in adolescents prescribed testosterone (+1.0 mg/dL and +3.9%) by 6 months after GAHT initiation. Thirteen (6.5%) participants prescribed testosterone had hematocrit > 50% during GAHT. There were no differences in hemoglobin A1c, alanine transaminase, or aspartate aminotransferase. There was a small increase in prolactin after 6 months of estradiol therapy in transfeminine adolescents. Hyperkalemia in transfeminine adolescents taking spironolactone was infrequent and transient if present. CONCLUSIONS: Abnormal laboratory results are rare in TGD adolescents prescribed GAHT and, if present, occur within 6 months of GAHT initiation. Future guidelines may not require routine screening of these laboratory parameters beyond 6 months of GAHT in otherwise healthy TGD adolescents.

A framework for conducting time-varying genome-wide association studies: An application to body mass index across childhood in six multiethnic cohorts.

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS on each of the estimated phenotypes identified 28 genome-wide significant variants at 13 loci across the 12 estimated phenotypes, one of which was novel (in DAOA) and had not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover novel biological mechanisms influencing quantitative traits.

Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism.

CONTEXT: Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found. OBJECTIVE: To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. DESIGN: Case-control study. PARTICIPANTS: 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies. MAIN OUTCOME MEASURES: Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). RESULTS: The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.85, p = 1 × 10-16; for AAM, d = 0.67, p = 1 × 10-10). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, p = 0.003; AAM d = 0.10, p = 0.055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.04, p = 0.45; AAM d = -0.03, p = 0.86). CONCLUSIONS: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct.

Multi-stakeholder opinion statement on the care of individuals born with differences of sex development: common ground and opportunities for improvement.

BACKGROUND: In the last 15 years, the care provided for individuals born with differences of sex development (DSD) has evolved, with a strong emphasis on interdisciplinary approaches. However, these developments have not convinced some stakeholders to embrace the current model of care. This care model has also paid insufficient attention to socio-cultural differences and global inequalities. SUMMARY: This article is an opinion statement, resulting from in-depth discussions and reflection among clinicians, patients, and family support organizations based in the US and Europe, where we seek areas of common ground and try to identify opportunities to further develop resources. The product of these conversations is summarized in 10 panels. The corresponding sections provide additional discussion on some of the panel items. KEY MESSAGES: Participants identified areas of agreement and gained a deeper understanding of the reasons behind disagreements on certain matters and identified the necessary steps to foster future consensus. We offer preliminary recommendations for guiding clinical management and resource allocation. By promoting a broader consensus, we aim to enhance the quality of care and well-being for individuals of all ages who have a DSD.

Pediatric Features of Genetic Predisposition to Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) has historically been conceptualized as a disorder of the reproductive system in women. However, offspring of women with PCOS begin to show metabolic features of PCOS in childhood, suggestive of childhood manifestations. OBJECTIVE: To identify childhood manifestations of genetic risk for PCOS. METHODS: We calculated a PCOS polygenic risk score (PRS) for 12 350 girls and boys in 4 pediatric cohorts-ALSPAC (UK), COPSAC (Denmark), Project Viva (USA), and The HOLBÆK Study (Denmark). We tested for association of the PRS with PCOS-related phenotypes throughout childhood and with age at pubarche and age at peak height velocity and meta-analyzed effects across cohorts using fixed-effect models. RESULTS: Higher PRS for PCOS was associated with higher body mass index in midchildhood (0.05 kg/m2 increase per 1 SD of PRS, 95% CI 0.03, 0.07, P = 3 × 10-5) and higher risk of obesity in early childhood (OR 1.34, 95% CI 1.13, 1.59, P = .0009); both persisted through late adolescence (P all ≤.03). Higher PCOS PRS was associated with earlier age at pubarche (0.85-month decrease per 1 SD of PRS, 95% CI -1.44, -0.26, P = .005) and younger age at peak height velocity (0.64-month decrease per 1 SD of PRS, 95% CI -0.94, -0.33, P = 4 × 10-5). CONCLUSION: Genetic risk factors for PCOS are associated with alterations in metabolic, growth, and developmental traits in childhood. Thus, PCOS may not simply be a condition that affects women of reproductive age but, rather, a possible manifestation of an underlying condition that affects both sexes starting in early life.

Mental Health and Gender Affirmation of Black and Latine Transgender/Nonbinary Youth Compared to White Peers Prior to Hormone Initiation.

PURPOSE: To compare baseline mental health symptoms and gender affirmation between Black/Latine versus White transgender/nonbinary youth (BLTY vs. WTY) and examine relationships between gender affirmation and mental health symptoms, and whether associations differed by race/ethnicity subgroup. METHODS: Baseline data were analyzed from the gender-affirming hormone cohort of the Trans Youth Care United States Study-a 4-clinic site, observational study. Mental health symptoms assessed included depression, suicidality, and anxiety. Gender affirmation measures included the parental acceptance subscale from the perceived Parental Attitudes of Gender Expansiveness Scale-Youth Report; non-affirmation, internalized transphobia, and community connectedness subscales from the Gender Minority Stress and Resilience Measure-Adolescent; and self-reported living full time in affirmed gender. Fisher exact tests and independent sample t tests compared mental health symptoms and gender affirmation between subgroups. Logistic regression analyses evaluated associations between gender affirmation and mental health symptoms. Interaction analyses assessed differences in associations between subgroups. RESULTS: The sample (mean age 16 years, range 12-20 years) included 92 BLTY (35%) and 170 WTY (65%). Subgroups had comparable prevalence of depression and anxiety symptoms. WTY had higher prevalence of lifetime suicidality (73% vs. 59%; p = .02). There were no differences in gender affirmation. Among the whole sample, higher parental acceptance decreased odds of depression symptoms. Not living in affirmed gender increased odds of depression symptoms. Higher non-affirmation and internalized transphobia increased odds of depression and anxiety symptoms and suicidality. Associations did not vary by subgroup. DISCUSSION: BLTY and WTY had comparable mental health symptoms. For both subgroups, gender affirmation decreased odds of those symptoms.

Adverse Birth Experiences and Parent Adjustment Associated With Atypical Genital Appearance Due to Differences of Sex Development.

OBJECTIVE: Differences/disorders of sex development (DSDs) are rare, congenital conditions involving discordance between chromosomes, gonads, and phenotypic sex and are often diagnosed in infancy. A key subset of parents of children newly diagnosed with a DSD experience clinically elevated distress. The present study examines the relationship between perinatal factors (i.e., gestational age, delivery method) and trajectories of parental adjustment. METHODS: Parent participants (mothers = 37; fathers = 27) completed measures at baseline, 6- and 12-month follow-up. Multilevel linear regression controlled for clustering of the data at three levels (i.e., time point, parent, and family) and examined the relationship between perinatal factors and trajectories of depressive and anxious symptoms. Two-way interactions between perinatal factors and parent type were evaluated. RESULTS: Overall depressive and anxious symptoms decreased over time. There were significant interactions between gestational age and parent type for depressive and anxious symptoms, with younger gestational age having a stronger negative effect on mothers vs. fathers. There was a significant interaction between time and gestational age for depressive symptoms, with 36 weeks' gestational age demonstrating a higher overall trajectory of depressive symptoms across time compared to 38 and 40 weeks. Findings for the delivery method were not significant. CONCLUSIONS: Findings uniquely demonstrated younger gestational age was associated with increased depressive symptoms, particularly for mothers compared to fathers. Thus, a more premature birth may predispose parents of infants with DSD to distress. Psychosocial providers should contextualize early diagnosis-related discussions within stressful birth experiences when providing support.

Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.

CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

High Internalized Transphobia and Low Gender Identity Pride Are Associated With Depression Symptoms Among Transgender and Gender-Diverse Youth.

PURPOSE: Prior studies have identified a significant relationship between internalized transphobia and poor mental health among transgender and gender-diverse (TGD) adults; however, this relationship has not been extensively examined among youth. Further, little research has sought to explore protective factors, such as identity pride, and their influence on this relationship. We examined the association between internalized transphobia and depression and anxiety symptoms among TGD youth and explored the moderating role of gender identity pride on these associations. METHODS: Participants were 315 TGD youth ages 12-20 years (mean = 16; standard deviation = 1.89) seeking gender-affirming hormone treatment at one of four major pediatric hospitals across the United States. At the time of enrollment, participants were naïve to gender-affirming hormone treatment. Participants self-reported mental health, internalized transphobia, and identity pride. Multiple regression models were used with depression and anxiety symptoms as outcomes and age, designated sex at birth, and perceived parental support included as covariates. RESULTS: Greater internalized transphobia was associated with greater depressive symptoms, and gender identity pride moderated this relationship, such that greater gender identity pride was associated with fewer depressive symptoms. Greater internalized transphobia was significantly associated with greater anxiety symptoms; no moderation effect was observed for this relationship. DISCUSSION: Gender identity pride influenced mental health symptoms for youth experiencing internalized transphobia and represents a potential key protective factor. These results support efforts to further develop, test, and implement clinical inventions to bolster identity pride for TGD youth.

Psychosocial Functioning in Transgender Youth after 2 Years of Hormones.

BACKGROUND: Limited prospective outcome data exist regarding transgender and nonbinary youth receiving gender-affirming hormones (GAH; testosterone or estradiol). METHODS: We characterized the longitudinal course of psychosocial functioning during the 2 years after GAH initiation in a prospective cohort of transgender and nonbinary youth in the United States. Participants were enrolled in a four-site prospective, observational study of physical and psychosocial outcomes. Participants completed the Transgender Congruence Scale, the Beck Depression Inventory-II, the Revised Children's Manifest Anxiety Scale (Second Edition), and the Positive Affect and Life Satisfaction measures from the NIH (National Institutes of Health) Toolbox Emotion Battery at baseline and at 6, 12, 18, and 24 months after GAH initiation. We used latent growth curve modeling to examine individual trajectories of appearance congruence, depression, anxiety, positive affect, and life satisfaction over a period of 2 years. We also examined how initial levels of and rates of change in appearance congruence correlated with those of each psychosocial outcome. RESULTS: A total of 315 transgender and nonbinary participants 12 to 20 years of age (mean [±SD], 16±1.9) were enrolled in the study. A total of 190 participants (60.3%) were transmasculine (i.e., persons designated female at birth who identify along the masculine spectrum), 185 (58.7%) were non-Latinx or non-Latine White, and 25 (7.9%) had received previous pubertal suppression treatment. During the study period, appearance congruence, positive affect, and life satisfaction increased, and depression and anxiety symptoms decreased. Increases in appearance congruence were associated with concurrent increases in positive affect and life satisfaction and decreases in depression and anxiety symptoms. The most common adverse event was suicidal ideation (in 11 participants [3.5%]); death by suicide occurred in 2 participants. CONCLUSIONS: In this 2-year study involving transgender and nonbinary youth, GAH improved appearance congruence and psychosocial functioning. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).

Approaches to Identify Factors Associated with Pubertal Timing in Self-Limited Delayed Puberty.

INTRODUCTION: Children with self-limited delayed puberty (DP) (constitutional delay) enter puberty after variable waiting times, and the factors associated with their eventual pubertal timing are not well understood. METHODS: We conducted a retrospective study of 99 girls and 228 boys with self-limited DP at an academic medical center between 2000 and 2015. To define features and potential subtypes of self-limited DP, we performed group-based trajectory modeling on childhood growth and latent-variable factor analysis on clinical characteristics. We then conducted time-to-event analyses to identify associations with pubertal timing. RESULTS: We identified two distinct growth trajectories in individuals with self-limited DP: one with stable and the other with declining height percentiles. Latent-variable factor analysis identified five factors underlying clinical variation that appear to correspond to genetic height potential, body mass index, childhood growth, parental pubertal delay, and medical issues (attention-deficit/hyperactivity disorder and inhaled glucocorticoid use). We observed correlations between pubertal timing and bone age (p = 0.01), childhood height (p = 0.004), and midparental target height (p < 0.001), but not with parental pubertal delay or with testosterone treatment in boys. CONCLUSIONS: By illustrating the heterogeneity within self-limited DP and identifying factors underlying this heterogeneity, our study suggests that there may be multiple causes of self-limited DP. However, our ability to determine when puberty will eventually occur remains limited. Dissecting self-limited DP into its component subtypes may inform future studies of the mechanisms contributing to pubertal delay as well as studies of the short- and long-term outcomes of self-limited DP.

Exploring Factors Associated with Decisions about Feminizing Genitoplasty in Differences of Sex Development.

STUDY OBJECTIVE: Infants with genital development considered atypical for assigned female sex may undergo feminizing genitoplasty (clitoroplasty and/or vaginoplasty) in early life. We sought to identify factors associated with parent/caregiver decisions regarding genitoplasty for their children with genital virilization. DESIGN: Longitudinal, observational study SETTING: Twelve pediatric centers in the United States with multidisciplinary differences/disorders of sex development clinics, 2015-2020 PARTICIPANTS: Children under 2 years old with genital appearance atypical for female sex of rearing and their parents/caregivers INTERVENTIONS/OUTCOME MEASURES: Data on the child's diagnosis and anatomic characteristics before surgery were extracted from the medical record. Parents/caregivers completed questionnaires on psychosocial distress, experience of uncertainty, cosmetic appearance of their child's genitalia, and demographic characteristics. Urologists rated cosmetic appearance. For 58 patients from the study cohort with genital virilization being raised as girls or gender-neutral, we compared these data across 3 groups based on the child's subsequent surgical intervention: (i) no surgery (n = 5), (ii) vaginoplasty without clitoroplasty (V-only) (n = 15), and (iii) vaginoplasty and clitoroplasty (V+C) (n = 38). RESULTS: Fathers' and urologists' ratings of genital appearance were more favorable in the no-surgery group than in the V-only and V+C groups. Clitorophallic length was greater in the V+C group compared with the V-only group, with substantial overlap between groups. Mothers' depressive and anxious symptoms were lower in the no-surgery group compared with the V-only and V+C groups. CONCLUSIONS: Surgical decisions were associated with fathers' and urologists' ratings of genital appearance, the child's anatomic characteristics, and mothers' depressive and anxious symptoms. Further research on surgical decision-making is needed to inform counseling practices.

Surgical experiences in adolescents and young adults with differences of sex development: A qualitative examination.

BACKGROUND: Surgical intervention in youth with differences of sex development (DSD) is a controversial topic. Historically, evidence suggests that genital surgery in DSD is associated with mixed patient satisfaction. However, less is known about surgical outcomes under therapeutic advancements in the past several decades. OBJECTIVE: The purpose of the current study is to provide an updated and empirical qualitative examination of the surgical experiences and responses to care of adolescents and young adults (AYA) with DSD in order to fill this gap in the literature and inform patient care. METHODS: Qualitative interviews were conducted with 37 AYA (ages 12-26) with DSD. Interviews were transcribed, coded, and analyzed thematically. RESULTS: Three major themes were identified: 1) knowledge related to surgery; 2) surgical and medical experience; and 3) psychosocial factors related to surgery. Results demonstrated that most AYA were not involved in the decision to pursue surgery and were observed to have varying levels of knowledge regarding their surgeries. Most participants in the current study had received a DSD-related surgery and the majority described having positive surgical experiences and few regrets. Nonetheless, AYA described both medical and psychosocial challenges related to their surgeries and recoveries and offered feedback on ways to improve the surgical process. DISCUSSION: The current study provides a qualitative examination of the surgical experiences of 37 AYA with DSD. Findings highlight the importance of regular and ongoing communication with providers to improve knowledge related to surgery during the decision-making process as well as after surgical intervention. Results underscore the benefits of multidisciplinary teams and the value of patient handouts and decision aids in assisting AYA in the decision to pursue surgical intervention. Other specific recommendations for providers include increased patient privacy during genital exams, greater emphasis on psychoeducation and pain management strategies, and the use of behavioral health services to assist with challenges and social support. CONCLUSIONS: The decision to pursue surgical intervention in youth with DSD remains a complex and controversial issue, and more information regarding patients' perspectives on surgery is needed. The current study provides novel insights into patient experiences of surgical intervention and highlights the need for psychosocial support throughout the shared decision-making process.

Stigma, Intrusiveness, and Distress in Parents of Children with a Disorder/Difference of Sex Development.

OBJECTIVE: The impact of parent-reported stigma due to their child's disorder/difference of sex development (DSD) on parent psychosocial adjustment is poorly understood. In other pediatric populations, perceived interference of medical conditions into daily activities (i.e., illness intrusiveness ) mediates the relationship of stigma to adjustment. This study assessed relationships between parent-focused and child-focused stigma → illness intrusiveness → depressive and anxious symptoms . Exploratory analyses sought to identify patient characteristics associated with stigma. METHOD: Caregivers (59 women and 43 men) of 63 children diagnosed with a DSD up to age 4 years completed measures of demographics, parent-focused and child-focused stigma, illness intrusiveness, and depressive and anxious symptoms. RESULTS: Increased parent-focused and child-focused stigma were associated with increased illness intrusiveness, which, in turn, was associated with increased depressive and anxious symptoms for parents nested within dyads. Among children with DSD family histories, parents reported greater child-focused stigma. CONCLUSION: Parents who experience DSD-related stigma report greater interference of their child's DSD into their daily activities, which is associated with poorer psychosocial adjustment. Findings support developing clinical interventions related to parents' perceptions of stigma and illness intrusiveness to improve parent adjustment.