United States

Backround:Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with asymmetric short stature (e.g. Kniest dysplasia, spondyloepiphyseal dysplasia). Less is known about nonsyndromic collagenopathies - data about their frequency and subtle phenotypic signs are sparse, the information about their response to growth hormone (GH) treatment is lacking completely.?Aim:To evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response.?Methods:Out of 522 individuals treated in our center with GH from the indication of primary GH deficiency (GHD) or small for gestational age short stature (SGA-SS), 87 children with FSS fulfilled the inclusion criteria (pre-treatment height ≤-2 SD in both patient/their shorter parent, signed written informed consent) and were enrolled to the study. Next-generation sequencing was performed to search for variants in COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 and COL11A2 genes. The results were evaluated using ACMG guidelines. The phenotype of children with (likely) pathogenic variants was described including the short-term GH treatment response (growth velocity and body-height SDS increase over three years of treatment). For statistical evaluation, parametric tests were used, p-values &lt;0.05 were considered significant.?Results:A (likely) pathogenic variant in one of the collagen genes was found in 10/87 (11.5%) children. Their age was 12.5 years (median, range 6-17 years), their pre-treatment height was -3.1 SD (-2.4 to -4.3 SD). Their birth length (median -2.8 SD; range -0.7 to -4.1 SD) was more severely affected than birth weight (median -2.1 SD; range -1.0 to -2.7 SD). Eight children were treated with GH from SGA-SS indication, the remaining 2 were classified as mild GHD (maximal stimulated GH concentration 8.0 and 9.7 ug/l, normal brain MRI and examination of other pituitary hormones). Detailed anthropometric examination described mild asymmetry with shorter limbs and mild bone dysplasia signs (scoliosis, more pronounced lumbar lordosis, genua valga, limited elbow extension) in 2/10 and 4/10 affected children, respectively. Growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after one year of treatment (p&lt;0.001, paired-sample T-test), height improved from a median of -3.1 SD to -2.2 SD after three years of therapy (p=0.001, ANOVA repeated measures analysis of variants).?Conclusion:Nonsyndromic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.?Supported by the Ministry of Health, Czech Republic, grant number NV18- 07-00283 and by the research project of the Grant Agency of Charles University of Prague, GAUK 976718. ?? 

ENDO 2021

Familial Short Stature - a Novel Phenotype of Growth Plate Collagenopathies

ENDO is the leading meeting for endocrinology research and clinical care worldwide. 

Backround:Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with asymmetric short stature (e.g. Kniest dysplasia, spondyloepiphyseal dysplasia). Less is known about nonsyndromic collagenopathies - data about their frequency and subtle phenotypic signs are sparse, the information about their response to growth hormone (GH) treatment is lacking completely.?Aim:To evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response.?Methods:Out of 522 individuals treated in our center with GH from the indication of primary GH deficiency (GHD) or small for gestational age short stature (SGA-SS), 87 children with FSS fulfilled the inclusion criteria (pre-treatment height ≤-2 SD in both patient/their shorter parent, signed written informed consent) and were enrolled to the study. Next-generation sequencing was performed to search for variants in COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 and COL11A2 genes. The results were evaluated using ACMG guidelines. The phenotype of children with (likely) pathogenic variants was described including the short-term GH treatment response (growth velocity and body-height SDS increase over three years of treatment). For statistical evaluation, parametric tests were used, p-values <0.05 were considered significant.?Results:A (likely) pathogenic variant in one of the collagen genes was found in 10/87 (11.5%) children. Their age was 12.5 years (median, range 6-17 years), their pre-treatment height was -3.1 SD (-2.4 to -4.3 SD). Their birth length (median -2.8 SD; range -0.7 to -4.1 SD) was more severely affected than birth weight (median -2.1 SD; range -1.0 to -2.7 SD). Eight children were treated with GH from SGA-SS indication, the remaining 2 were classified as mild GHD (maximal stimulated GH concentration 8.0 and 9.7 ug/l, normal brain MRI and examination of other pituitary hormones). Detailed anthropometric examination described mild asymmetry with shorter limbs and mild bone dysplasia signs (scoliosis, more pronounced lumbar lordosis, genua valga, limited elbow extension) in 2/10 and 4/10 affected children, respectively. Growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after one year of treatment (p<0.001, paired-sample T-test), height improved from a median of -3.1 SD to -2.2 SD after three years of therapy (p=0.001, ANOVA repeated measures analysis of variants).?Conclusion:Nonsyndromic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.?Supported by the Ministry of Health, Czech Republic, grant number NV18- 07-00283 and by the research project of the Grant Agency of Charles University of Prague, GAUK 976718. ?? 

technical paper

Introduction: The genetic basis of human growth regulation has only been partly elucidated thus far. Therefore, finding causative genes in patients with short stature help in understanding precise pathophysiological mechanisms, establishing genotype-phenotype relationships and optimizing treatment. In order to extend our knowledge about the genes involved in short stature, we studied a unique cohort of consanguineous families with children with short stature from Sulaymani in Kurdistan, Iraq. Patients and Methods: Fifty-five consanguineous families, with children shorter than -2.3SDS at the time of examination (median height -3.3SDS, range -2.3 to -15SDS), who were examined at the endocrine outpatient clinic of the Department of Pediatrics, Sulaymani University College of Medicine between January 2018 and February 2020, were included in the study. In families with more than one child with short stature, the shorter sibling was selected as the proband (median age 8 years, range 1 - 15 years). Three probands were subsequently excluded due to the diagnosis of Turner’s syndrome and Edward’s syndrome. Consent was obtained from all families and probands’ DNA was analyzed by Whole Exome Sequencing (WES) methods. The data were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Selected potentially pathogenic variants were confirmed using Sanger sequencing methods and evaluated by the American College of Medical Genetics (ACMG) standards and guidelines. Results: A monogenic cause of short stature, which explained the patient phenotype, was elucidated in 13 of 26 families who were analyzed thus far. Seven families had multiple affected children making a total of 22 patients with a positive genetic diagnosis. Pathogenic or likely pathogenic variants (according to the ACMG standards) were found in genes involved in the GH-IGF-1 axis (GHR), in the extracellular matrix of the growth plate (COL1A2, MMP13, LTBP3, and ADAMTS17), in the regulation of chondrocytes (NPR2 and CTSK), transporter coding genes (SLC34A3), and other genes (PTCH1, GALNS, DNACJ21, ZSWIM6, GNPTG). Among them, there are 9 novel variants and 10 homozygous variants including variants in genes causing syndromic short stature. Unexpectedly, we successfully identified three cases of autosomal dominant short stature (variants in genes NPR2, COL1A2, PTCH1) as well. The remaining probands from 26 families are still being analyzed. Conclusion: With the help of NGS methods, we have successfully elucidated the genetic cause of short stature in nearly 50% of patients who were analyzed thus far. These results further strength the concept that genes affecting the growth plate (chondrocytes and the extracellular matrix) play a crucial role in growth regulation. Acknowledgements: The study was co-funded by grants AZV 18-07-00283 and GAUK 340420.?? 

Growth Plate Genes Are Key Regulators of Growth: Lessons Learned From Children of Consanguineous Families From Kurdistan, Iraq

Surgical approach of atypical genitalia according to adult patients with Differences of Sexual Development. Introduction: Differences of sexual development (DSD) define congenital diseases in which there is an atypical development of chromosomal, gonadal or anatomical sex, and may present varying degrees to genital atypia. There has been a discussion about the ideal time for surgical approach of atypical genitalia. S, because some non-governmental entities argue that the surgical approach should be delayed until adulthood after the patient's consent. Objective/methodology: To analyze the perspectives of adult DSD patients followed at a reference center in São Paulo on the surgical approach to correct atypical genitalia, through a semi-directed interview. Results: Thirty-seven adult patients with atypical genitalia were interviewed. Patients’ mean age was 36 years. 70% of them had atypical genitalia diagnosed at birth. The patients’ median age at the genitoplasty approach was 5 years (1 to 35 years). The median time interval between the beginning of the follow-up at the referral center and the surgical procedure was 1.9 years. When asked about the ideal period/age for genitoplasty, 72.2% considered the childhood, 16.7% cited when they’re teenagers, 8.3% in adulthood and 2.8% did n’t know. The discomfort reported by the patients related to atypical genitalia decreased after the surgical approach: from 3.8 to 2.9 p < 0.01 (on a scale of 1 “without discomfort’ to 4 “extreme discomfort”). Insecurity about the appearance of genitalia and functionality during sexual intercourse influences negatively affective relationships. Four (10.8%) patients presented gender dysphoria, all of them with 46 ,XY DSD, three with partial gonadal dysgenesis (all approached surgically before being admitted to our referral service) and one with 5-alpha-reductase 2 deficiency. Conclusion: Most 46 ,XY DSD patients considered childhood the ideal time to correct their atypical genitalia. An early follow-up in a reference center and an adequate evaluation by a multidisciplinary may influence the positive results associated to the surgical approach of the atypical genitalia in childhood and the low prevalence of gender dysphoria in adulthood.?? 

Self-Reported Feelings of Adult Patients With Differences of Sex Development (DSD) Regarding Genital Surgical Procedures

Gnas Heterozygous Inactiviation Affects Calcitonin Receptor Bioactivity in a Mouse Model of Albright Hereditary Osteodystrophy based upon Parental Inheritance

Introduction: In the United States, non-Hispanic white (NHW) children are disproportionately over-represented relative to children of racial and ethnic minorities in pediatric growth hormone (GH) treatment registries. This study sought to determine if this racial inequity is due to differences in GH stimulation testing and/or GH prescribing patterns in children referred for endocrine evaluation of short stature.?Methods: Retrospective chart review was performed including children aged 2-16 years, with height z-score ≤ -1.5, and of NHW, non-Hispanic black (NHB) or Hispanic race/ethnicity, referred for endocrine growth evaluation between January 1, 2012 and December 31, 2019. Age, sex, anthropometry, GH stimulation test results and GH treatment data were extracted. Comparisons between NHB, NHW and Hispanic children were performed using analysis of variance, chi-squared tests, Mann Whitney U and logistic regression tests.?Results: This study included 7,425 patients (5,905 NHW, 800 NHB, and 720 Hispanic). GH stimulation testing was performed in 992, and 576 were prescribed GH. NHW children were 1.4 (95% CI 1.04 - 1.8) times more likely than NHB children and 1.7 (95% CI 1.2 - 2.2) times more likely than Hispanic children to undergo GH stimulation testing. NHB children treated with GH had: 1) lower median peak GH concentration when compared with NHW (p=0.02) and Hispanic (p=0.08) children (NHB 4.7 [1.2, 8.3] ng/ml, NHW 7.2 [4.9, 9.7] ng/ml, Hispanic 7.1 [4.3, 11.9] ng/ml); 2) lower median height z-scores than NHW (p=0.01) but not Hispanic children (p=0.5); and 3) a greater height deficit from mid-parental height when compared with NHW (p=0.01) and Hispanic (p=0.002) children?Discussion: Racial and ethnic disparities are present in the evaluation and treatment of children with disordered growth. This likely results from both over-investigation of NHW children as well as under-investigation and under-treatment of children from minority communities. The evaluation and treatment of children with short stature should be determined by clinical concern alone, but this is unfortunately not current practice.?? 

Racial/Ethnic Disparities in the Investigation and Treatment of Pediatric Growth Hormone Deficiency

Prader-Willi syndrome (PWS) is a complex genetic disorder associated with multiple neuroendocrine abnormalities including significantly decreased hypothalamic oxytocin levels, resulting in symptoms of severe hyperphagia (an unrelenting false sense of starvation) and multiple severe neuropsychiatric and behavioral issues. CARE-PWS, a multi-center, randomized, double-blind, placebo-controlled phase 3 study, has evaluated the efficacy, safety, and tolerability of intranasal carbetocin, a selective oxytocin receptor agonist, in participants with PWS.?Eligible participants aged 7 through 18 with genetically confirmed PWS were randomized in equal proportions to three treatment arms for the 8-week placebo-controlled period of the study: carbetocin 9.6 mg, carbetocin 3.2 mg, or a matching placebo, administered by nasal spray three times a day with meals. The primary endpoint assessed changes from baseline to week 8 in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores for the carbetocin 9.6 mg arm vs placebo, and the first secondary endpoint assessed changes from baseline to week 8 in HQ-CT or CY-BOCS scores for the carbetocin 3.2 mg arm vs placebo. Additional secondary endpoints included changes from baseline to week 8 in PWS Anxiety and Distress Questionnaire (PADQ) scores, and Clinical Global Impression of Change (CGI-C) scores evaluating the overall change in severity of PWS symptoms at week 8.?Due to COVID-19, enrollment was closed early with 119 evaluable participants for the primary analysis. In the carbetocin 9.6 mg arm, trends toward numerically greater improvements in HQ-CT and CGI-C scores relative to placebo were observed but did not reach statistical significance; however, the carbetocin 3.2 mg arm demonstrated a significant improvement in HQ-CT scores (LS mean improvement vs placebo -3.14 points, p=0.016). In the 3.2 mg arm, additional consistent evidence of improvements versus placebo was seen in multiple secondary endpoints, including CGI-C (p=0.027) and PADQ (p=0.027). Numeric trends toward improvement in CY-BOCS scores were observed in each dose arm, but did not reach statistical significance versus placebo. During the subsequent long-term follow-up period of the study, both carbetocin arms have experienced continued numeric improvements from baseline across multiple endpoints. Intranasal carbetocin was generally well-tolerated; the most frequently reported adverse event was flushing, which was generally mild and transient.?In conclusion, results of the CARE-PWS study support that intranasal carbetocin appears to be safe and well tolerated, and reduces hyperphagia and anxiety and distress behaviors in PWS.?? 

Topline Results of the CARE-PWS Phase 3 Study: Intranasal Carbetocin Improves Hyperphagia and Anxiety and Distress Symptoms in Prader-Willi Syndrome (PWS)

The timing of puberty in females is highly sensitive to metabolic cues and energy reserves. Epidemiologic studies indicate a relationship between increased body mass index and earlier puberty in girls. In contrast, a significant delay in puberty and menarche is seen in girls who have diminished body fat. Multiple peripheral hormones are responsible for transmitting metabolic information to hypothalamic kisspeptin and GnRH neurons. Sufficient levels of leptin, an adipose tissue hormone with a permissive/stimulatory effect on the metabolic control of reproduction, are required for puberty onset, reproductive function and fertility. Loss-of-function mutations in the Delta-like homolog 1 (DLK1) gene have been described in girls with central precocious puberty (CPP) and increased body fat, suggesting a link between metabolism and reproduction. DLK1 is a paternally expressed gene located on human chromosome 14q32.2 in a locus associated with Temple syndrome (TS). Dlk1 knockout mice display pre- and postnatal growth retardation, a phenotype that overlaps with TS. We have shown that Dlk1 deficient female mice achieved puberty at the same age as wild type mice, despite a considerably lower body weight (BW) (“relative precocious puberty”). To date, the mechanisms of action of Dlk1 in determining pubertal onset remain unknown. In this study, we used a Dlk1 deficient mouse model to explore the influence of Dlk1 in the regulation of reproductive axis, particularly its effects on leptin and/or kisspeptin, a major excitatory factor of the reproductive axis. By RT-qPCR and Western blot, we confirmed that both Dlk1 mRNA and protein were undetectable in the mediobasal hypothalamus (MBH) of Dlk+/p- (which inherited the mutant allele from their father), but it was present in Dlk+/+ mice. White adipose tissue (WAT) and blood were collected from Dlk+/p- and Dlk+/+ female mice at postnatal day (PND) 26, and MBH tissue was obtained from both groups at PND 15, 26 and 60. Quantification of total WAT showed no significant difference between Dlk1+/p-and Dlk1+/+ mice (p=0.8) at PND26, even after correction for total BW (p=0.29). Hypothalamic mRNA levels of Kiss1 and Socs3, a downstream mediator of leptin signaling, were measured by RT-qPCR. Kiss1 mRNA levels were significantly reduced in the MBH of Dlk1+/p- mice at PND15 and PND60, but no significant difference was found at PND 26. Socs3 expression was significantly lower in Dlk1+/p- mice (p=0.04) as a result of the reduced circulating levels of leptin (ELISA) observed in these mice at PDN26 (p=0.01). Our findings suggest that the absence of Dlk1 may attenuate the metabolic effects of low body weight and low leptin levels on puberty onset and that, as seen in humans, DLK1 is an important link between body weight and pubertal development. Finally, Dlk1 deficiency leads to activation of the reproductive axis despite lower levels of kisspeptin.?? 

Pubertal Onset Occurs in Female Mice Lacking Paternally Expressed Dlk1 Despite Lower Leptin and Kisspeptin Levels

Background and aim: Polycystic ovary syndrome (PCOS) is associated with obesity, and white adipose tissue (WAT) and brown adipose tissue (BAT) dysregulation. However, the molecular mechanisms that mediate WAT and BAT derangements in PCOS are poorly understood. Subcutaneous (SC) WAT (SC-WAT) can transition to a beige/brite adipose tissue phenotype (browning) under altered thermogenic conditions. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in androgen-mediated browning and beiging derangements in both SC-WAT and BAT. Methods: Three week-old miR-21 knockout (miR21KO) or wild type (WT) female mice were treated with dihydrotestosterone (DHT, 8 mg/silastic tube) or vehicle for 90 days (n=12/grp). Body composition was measured by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), and carbon dioxide production (VCO2) were measured by indirect calorimetry. Glucose homeostasis was measured by oral glucose tolerance test (OGTT). HOMA-IR index was calculated from fasting serum glucose and insulin levels. Gene expression for browning (UCP1, Cox7a1, Elov3, Dio2 and Cidea) and beiging (Hspb7 and Txb1) markers was quantified by RT-qPCR in SC-WAT and BAT. Results: DHT increased body weight (25.07 ± 0.52 vs 21.79 ± 0.47 g, p<0.05) and fat mass (4.60 ± 0.46 vs 1.98 ± 0.12 g, p<0.05), impaired OGTT (186.10 ± 5.99 vs 250.70 ± 14.76 mg.min/dL, p<0.05), and did not significantly change EE, VO2 or VCO2 in WT mice. All browning markers were downregulated by DHT in SC-WAT; however, only iodothyronine deiodinase 2 (Dio2) downregulation reached significance in both SC-WAT and BAT (by 53 and 40%, respectively) compared with the vehicle-treated mice. Beiging markers were significantly upregulated in SC-WAT and did not change in BAT. DHT-treated miR21KO mice showed attenuated DHT-mediated increase in body weight (23.84 ± 0.99 vs 25.07 ± 0.52 g, p<0.05) compared with WT mice. MiR-21 ablation did not modify DHT-mediated increase in fat mass or OGTT but worsened insulin resistance as calculated by the HOMA-IR index. Additionally, DHT-treated miR21KO mice showed a trend to reduced EE, VO2 and VCO2 values compared with DHT-treated WT. Gene expression analysis showed an exacerbation in DHT-mediated reduction in browning markers expression in the SC-WAT. Additionally, the induction in the adaptive beiging response was abolished in SC-WAT. Conclusion and significance: These findings suggest that adipose tissue miR-21 may have a protective role in PCOS and ameliorate the DHT-mediated decrease in energy expenditure. Adipose tissue-specific modulation of miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements. (Supported by NIH grants NIGMS P20GM121334 to LLYC and DGR, NIDDK R21DK113500 to DGR, NIGMS P20GM104357 and NHLBI P01HL51971)?? 

MicroRNA-21 Modulates White Adipose Tissue Browning and Altered Thermogenesis in a Mouse Model of Polycystic Ovary Syndrome

We identified a stop-gain mutation in eIF4ENIF1 in a family in which multiple women developed primary ovarian insufficiency (POI) at approximately age 30 years. We hypothesized that the same mutation in a mouse model would replicate POI. Methods: The Eif4enif1 C57/Bl6 transgenic mouse model contains a floxed exon 10-19 cassette and a conditional knock-in cassette containing exon 10 with the c.1286C>G stop-gain mutation causing familial POI and WT exons 11-19 (Eif4enif1WT/flx). The hybrid offspring of CMV-Cre mice with Eif4enif1WT/flx mice were designated Eif4enif1WT/Δ for simplicity. Follicles were counted in fixed H&E stained ovaries from mice age days 1-5 (primordial and primary follicles), day 10, day 22 (first wave of growing follicles from small preantral to small antral follicles), week 20 (peak fertility), then every 2 months from 10 months to 26 months (follicle exhaustion). Litter frequency, pup number and genotype were recorded. Serum FSH levels were measured by the University of Virginia Ligand Assay and Analysis Core. Results: The heterozygotes have no outward or internal phenotypic differences compared to WT (Eif4enif1WT/flx), with the exception of reproductive organs in females and males. A subset of female heterozygotes (Eif4enif1WT/Δ) had no litters for 20 weeks (2 of 18; 11%). In those with litters, the average length of time between litters was not different but the final litter was earlier (5.6±2.7 vs. 10.5±0.7 months; p=0.02). Heterozygous breeding pair (Eif4enif1WT/Δ x Eif4enif1WT/Δ) litter size was 60% of WT litter size (3.9±2.3 vs. 7.2±2.1 pups/litter; 0<0.001). The genotypes were 35% Eif4enif1WT/flx and 65% Eif4enif1WT/Δ, with no homozygotes. The number of follicles in ovaries from Eif4enif1WT/Δ mice was lower starting at the primordial (499±290 vs. 1445±381) and primary follicle stage (1069±346 vs. 1450±193) on day 10 (p<0.05). The preantral follicle number was lower starting on day 21 (213±86 vs. 522±227; p<0.01) and the antral follicle count was lower starting on week 20 (78±38 vs. 119±18; p<0.01). The FSH level in 12-month old mice during estrus was higher in a heterozygote compared to WT (25.0 vs. 12.1 ng/mL). Conclusions: Heterozygous Eif4enif1 stop-gain mutants have follicle loss documented by day 10, decreased pup number with no homozygotes, earlier end of reproductive function and elevated FSH levels. These mice replicate the POI phenotype in women. eIF4ENIF1 regulates protein translation by binding and storing eIF4E bound mRNA. Therefore, the unique mouse model provides a platform to study temporal and spatial regulation of protein translation across oocyte and embryo development in mammals. Further studies will determine whether follicle loss results from premature protein translation in oocytes.?? 

Heterozygous Eif4nif1 Stop Gain Mice Replicate the Primary Ovarian Insufficiency Phenotype

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous condition that affects 6-10% of women of reproductive age. PCOS is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. Both ovarian-related and ovarian-independent factors have been implicated in the pathogenesis of PCOS, but it remains to be determined which are the inciting events and which are the secondary consequences. Studies of male relatives of women with PCOS have proposed a male counterpart of PCOS, which suggests that PCOS is not always a primary disorder of female reproduction, but rather can be, at least in part, a condition of cardiometabolic dysregulation and hyperandrogenism, with ovarian dysfunction as a secondary consequence.?Methods: To investigate a genetically defined male counterpart of PCOS, we optimized a polygenic risk score (PRS) algorithm for predicting PCOS based on 206,851 unrelated women of European ancestry in the UK Biobank, then used this algorithm to calculate PCOS PRS for 176,360 men in the UK Biobank. We used logistic regression to calculate odds ratios for dichotomous outcomes by comparing men with high and low PRS (testing a variety of percentile cutoffs) and ANCOVA to compare continuous outcomes across deciles of PRS. All analyses were adjusted for age, age2, assessment center, genotyping array, and the first 10 principal genetic components to account for ancestry.?Results: Men who carried a high PCOS PRS (top 20%) had a 17% increased risk of obesity defined as BMI ≥30 kg/m2 (OR 1.17, 95% confidence interval [CI] 1.14-1.20, p=1.3x10-30), 15% increased risk of type 2 diabetes mellitus (OR 1.15, 95% CI 1.09-1.20, p=5.3x10-8), 5% increased risk of coronary artery disease (OR 1.05, 95% CI 1.01-1.09, p=0.03), and 5% increased risk for androgenic alopecia (OR 1.05, 95% CI 1.01-1.08, p=0.01). BMI, hemoglobin A1c, triglycerides, and the free androgen index all increased across deciles of the PRS, while HDL and SHBG decreased across PRS deciles (p all <0.001). The relationship between the PCOS PRS and coronary artery disease, HDL, and triglycerides appeared to be mediated by BMI. In contrast, the associations between the PCOS PRS and type 2 diabetes mellitus and hemoglobin A1c remained significant after adjusting for BMI, suggesting independent mechanisms of pathogenesis.?Conclusions: By demonstrating associations between PCOS genetic risk factors and cardiometabolic dysfunction and androgenic conditions in men, we have shown that these genetic risk factors can act independently of ovarian function. Thus, at least in some cases, the reproductive dysfunction of PCOS in women may arise secondarily from disruption of biological pathways common to both men and women. Future dissection of these biological pathways will further inform efforts to identify pathological mechanisms underlying PCOS.?? 

A Genetically Defined Male Counterpart of Polycystic Ovary Syndrome: Evidence for Ovarian-Independent Pathogenesis

Effect of Experimentally Induced Sleep Fragmentation and Hypoestrogenism on Fasting Nutrient Utilization in Pre-Menopausal Women Background: Both sleep disturbance and menopause have independently been associated with weight gain in women. Possible mechanisms contributing to this weight gain may be changes in resting energy expenditure (REE) and/or nutrient utilization. Therefore, in the current study we aimed to examine the effects of experimentally induced sleep fragmentation and pharmacologic estradiol (E2) withdrawal on REE and nutrient utilization in the fasted state. Design: We studied pre-menopausal women during 5-night inpatient studies repeated in the mid-to-late follicular phase (high-E2; n=21) and following leuprolide-induced hypoestrogenism (low-E2; n=9 completed second visit). During each admission there were two nights of unfragmented sleep [8-h time in bed (TIB)] and three nights of fragmented sleep [9-h TIB]. Sleep was fragmented using an auditory stimulus delivered every 15 minutes that sustained wake for 2 minutes, producing 1 hour of wake after sleep onset. Study diets consisted of 3 meals and a snack each day and were iso-caloric across the two visits. REE and nutrient utilization were assessed in the fasted state via indirect calorimetry and compared between E2 states following unfragmented and fragmented sleep using linear mixed models. Results: Sleep fragmentation in the high-E2 state increased the respiratory quotient (RQ; +3%; p=0.03) with an accompanying increase in carbohydrate oxidation (+20%; p=0.02) and decrease in fat oxidation (-16%; p=0.03). The same effect was observed in response to E2-withdrawl during unfragmented sleep [increased RQ (+5%; p=0.01) and carbohydrate oxidation (+33%; p=0.01), and decreased fat oxidation (-26%; p=0.01)]. There was no additive effect of sleep fragmentation on nutrient utilization in the low-E2 state suggesting a possible ceiling (RQ and carbohydrate oxidation) and floor (fat oxidation) effect. There was no effect of sleep fragmentation or E2 state on REE. Conclusion: Both sleep fragmentation and hypoestrogenism were shown to alter fasting nutrient utilization, but not REE, in a manner that may contribute to weight gain in menopausal women. These findings are important for understanding weight gain during menopause, which is characterized by estrogen withdrawal and often accompanied by sleep disturbances.?? 

Familial Short Stature - a Novel Phenotype of Growth Plate Collagenopathies

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