bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth Hormone Deficiency: Extending the Phenotypic Spectrum of SALL4-Related Disorders
Authors: Kodytková Aneta , Amaratunga Shenali Anne , Zemková Daniela , Maratová Klára , Koloušková Stanislava , Lebl Jan
Published: May 2021

Background: The SALL4 gene encodes sal-like protein 4, a transcription factor with eight zinc finger motifs that is essential for the development of the epiblast and primitive endoderm. In association with TBX5 (T-box), SALL4 is responsible for the establishment and morphogenesis of the thumb. Pathogenic SALL4 variants have been reported to cause Duane-radial ray syndrome (also known as Okihiro syndrome), acro-renal-ocular syndrome and Holt-Oram syndrome. Hereby, we report on a family with radial hypoplasia and kidney dystopia in members of 4 consecutive generations, and short stature due to growth hormone deficiency (GHD) in the proband. Clinical Case: The male proband was born from the 3rd normal pregnancy at 39th week of gestation. He has no biological siblings. He was born small for gestational age (birth weight 2550 g, length 47 cm - both < 2SD) and had bilateral asymmetrical radial ray malformation consisting of radial hypoplasia, ulnar flexure and bilateral aplasia of the thumb, and pelvic dystopia of his right kidney. He had no cardiac malformations, clubfoot, ocular coloboma or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 ug/l (-1.0 SD), and peak GH in two stimulation tests was 6.2 ug/l. Other pituitary hormones were normal. His mother’s and father’s heights are 152.3 cm (-2.4 SD), and 177.8 cm (-0.4 SD), respectively. His father has malformation of the forearm that is milder than that of the son. The paternal grandfather is affected as well, with a radial defect with missing opposition of the thumb and height 164 cm (-2.3 SD). The family reports that the phenotype of radial dysplasia was apparent in the paternal grandfather’s mother as well. Due to the suggestive monogenic dominant transmission of the developmental abnormality, we carried out whole exome sequencing that revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. The proband was started with regular GH therapy at age 6.5 years and experienced catch-up growth as expected in GHD. By the age 11 years, his height stabilized at about the 25th percentile in accordance to the mid-parent height with a target height of 171.5 +/- 8.5 cm. Puberty started spontaneously at the age 12.5 years. Conclusion: This is the first case demonstrating a patient with a congenital upper limb defect based on a pathogenic variant of the SALL4 gene where an isolated growth hormone deficiency (GHD) was detected and has been successfully treated with growth hormone. Acknowledgements: Genetic testing was funded by AZV grant NV18-07-00283.
Primary Amenorrhea and Hyperandrogenism: Presenting Features of a Growth Hormone Producing Pituitary Adenoma in a Female Adolescent
Authors: Verma Arushi , Manea Anamaria , Koci Timothy M , Eckert Kathryn Lynn
Published: May 2021

Background: The combination of obesity, metabolic syndrome, hyperandrogenism and amenorrhea can be a common presentation of conditions such as polycystic ovarian syndrome. Growth hormone (GH) secreting pituitary adenomas are rare in children, but can present with a similar picture. Clinical Case: A 15-year 4-month old female was evaluated for primary amenorrhea and metabolic syndrome. Her weight was +2.96 SD, height +3.0 SD (mid-parental height 44th percentile, -0.1 SD) and BMI +2.53 SD, all >99th percentile. Weight and BMI were >99th percentile (weight +3.0 SD, BMI +2.4 SD) since 11 years of age and height was >99th percentile (+ 2.7 SD) since 8 years of age. Physical exam was remarkable for acanthosis, deepened voice, no hirsutism, Tanner III breasts and Tanner IV pubic hair. Laboratory evaluation was notable for prolactin (PRL) 147.8 ng/dL (2.6-18.0), LH <0.02 mIU/mL, FSH <0.09 mIU/mL, estradiol 23 pg/mL, total testosterone 81 ng/dL (<41), androstenedione 673 ng/mL (43-180), DHEA-S 627 mcg/dL (42-162), dyslipidemia and normal 17 hydroxy-progesterone and thyroid function tests. Bone age was 16 years. Brain MRI showed a 15x7mm pituitary macroadenoma without suprasellar invasion. Pituitary evaluation revealed IGF-1 619 ng/mL (192-568), IGF-BP3 5.15 mg/L (2.64-6.43) and adrenal insufficiency. Treatment with cabergoline 0.5 mg/week and maintenance hydrocortisone were initiated. An OGTT demonstrated baseline GH 4.9 ng/mL (0-6) and nadir 3.62 ng/mL (normal <1) consistent with GH excess. Surgery for the pituitary adenoma was recommended but unfortunately postponed. Four months later, her BP was elevated, she had clinical signs of diabetes insipidus (DI), PRL was 43.2 ng/dL and she failed a repeat GH suppression test. Follow-up MRI showed pituitary mass enlargement (17x9mm). Patient underwent total trans-sphenoidal tumor resection. Pathology confirmed a sparsely granulated (SG) GH adenoma immunoreactive for GH, PRL and estrogen receptor. Post-operative OGTT showed adequate GH suppression, normal prolactin levels, persistent testosterone elevation and DI. Conclusions: Hyperprolactinemia, hyperandrogenism and metabolic syndrome could be the presenting features of pituitary GH adenomas even in the absence of acromegalic features. Specifically, SG pituitary adenomas are frequently seen in young adults, are larger, more invasive and less likely to respond to medical treatment. Timely diagnosis and surgical treatment of GH adenomas is essential to prevent the high morbidity and mortality.
Symptomatic Rebound Hypercalcemia After Denosumab Discontinuation in a Pediatric Patient With Cherubism
Authors: Marpuri Ian , Cheung Clement C , Moke Diana J , Ryabets-Lienhard Anna
Published: May 2021

Background: Pediatric bone diseases due to osteoclast overactivity have limited therapeutic options. Denosumab, a human monoclonal antibody against RANK-ligand, has been used in the treatment of these conditions despite limited pediatric safety data. Rebound hypercalcemia after denosumab cessation is a rare and potentially serious complication in children with an unpredictable course (1). We present the first report of a child with cherubism who experienced acute symptomatic hypercalcemia five months after denosumab cessation.

Clinical Case: An 11 year old male presented to our emergency department (ED) with 2 weeks of nausea, vomiting, abdominal pain, and bilateral leg pain. He was diagnosed with cherubism at age 3 years with progressive painless bilateral jaw swelling, teeth crowding, and proptosis. His bilateral maxilla and left mandible were debulked between ages 5-8 years due to tumors causing dyspnea. The resected tumors showed RANK-ligand expression. Thus, he started a 1-year course of denosumab 80 mg monthly subcutaneous injections for additional lesions not amenable to surgery with marked clinical and radiographic improvement. He had mild hypocalcemia during denosumab therapy, for which he received cholecalciferol 2000 IU and calcium citrate total 1500 mg per day. Calcium citrate was stopped with corrected serum calcium (Ca) 10.1 mg/dL (8.8-10.8 mg/dL) three months prior to ED visit. His presentation to ED five months after denosumab revealed marked hypercalcemia (corrected Ca 13.9 mg/dL), iPTH 5.4 pg/mL (7.5-53.5 pg/mL), 25-OH vitamin D 19 ng/mL (30-100 ng/mL), and hypercalciuria (urine Ca/creatinine ratio 0.58 mg/mg, normal <0.2 mg/mg) concerning for rebound hypercalcemia post-denosumab therapy. He received IV hyperhydration, furosemide, calcitonin, and IV pamidronate 0.5 mg/kg. At discharge, corrected Ca was 8.7 mg/dL. One week later he developed acute nausea and vomiting. Laboratory tests again showed hypercalcemia (Ca 13.3 mg/dL) and hypercalciuria. He received one dose of IV zoledronic acid at 0.025 mg/kg with resolution of hypercalcemia. He remains normocalcemic, normocalciuric, and asymptomatic two months after zoledronic acid treatment. Conclusion: This is the first case, to our knowledge, of a pediatric patient with cherubism with acute symptomatic hypercalcemia after denosumab treatment, reinforcing the need for frequent calcium monitoring months after cessation. Zoledronic acid is also shown to effectively treat rebound hypercalcemia after denosumab cessation. Larger studies are needed to further evaluate denosumab use and safety in pediatric bone diseases with osteoclast overactivity.

Reference: (1)Upfill-Brown A, Bukata S, Bernthal NM, Felsenfeld AL, Nelson SD, Singh A, Wesseling-Perry K, Eilber FC, Federman NC. Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases. JBMR Plus. 2019 Aug 22;3(10):e10210
Predicted Succinated Dehydrogenase Subunit Variant Pathogenicity: Why Are SDHB Variants “Bad”?
Authors: Gruber Lucinda , Maher L James
Published: May 2021

Variants in the 4 genes encoding subunits A-D of succinate dehydrogenase (SDH) are associated with paraganglioma and pheochromocytoma. Intuitively, loss-of-function variants affecting any of the subunits should equally diminish SDH function leading to succinate accumulation and tumorigenesis after loss of heterozygosity. However, variants in SDHB are associated with a higher prevalence of metastatic disease and a more aggressive clinical course. Evaluation of the SDH protein structure shows the fraction of amino acids in contact with other subunits or essential prosthetic groups to be: 13% (SDHA), 40% (SDHB), 28% (SDHC), and 28% (SDHD). We therefore hypothesized that SDHB missense variants are more penetrant because a larger fraction alter sensitive interfaces with other SDH subunits or essential molecular features (e.g. the three SDHB iron-sulfur clusters). We also wondered if truncating variants are more common for SDHB than other subunits. To test these hypotheses, we combined three databases (Genome Aggregation Database, ClinVar-NCBI-NIH, and Leiden Open Variant Database) and our institution’s data to create a pool of all known SDH variants. We categorized variants as truncating or missense and evaluated missense variants in the context of the SDH protein structure, scoring each variant in relation to important structures/interfaces and the severity of the amino acid change. This provided an ad hoc impact score for each variant, where a higher score predicts a more deleterious effect. We compared these scores to those obtained using the “Sorting Intolerant from Tolerant” (SIFT) tool that predicts impacts of amino acid changes based on evolutionary sequence conservation. SIFT scores of 0 to 0.05 predict deleterious effects. Both mean impact and SIFT scores could be weighted for the prevalence of each variant in the population. Our database included 2333 total SDH variants: SDHA (838, 36%), SDHB (703, 30%), SDHC (381, 16%), and SDHD (412, 18%). The fractions of truncating variants were 38%, 50%, 51%, and 53% for A-D subunits, respectively. When weighted for prevalence, these fractions were 0.39%, 6.8%, 8.2%, and 0.2%. The number of truncating variants per coding region length and the distribution of locations were similar between subunits. Ad hoc impact scores for A-D subunits were 3.08, 14.9, 9.93, and 11.0, respectively and, when weighted for prevalence, were 0.28, 3.25, 6.32, and 1.15. Mean SIFT scores for subunits A-D were: 0.185, 0.162, 0.238, and 0.410 respectively, and, when weighted for prevalence, were 0.58, 0.70, 0.22, and 0.018. Our results do not support the hypothesis SDHB variants predict a worse clinical outcome because average SDHB variants are, by chance, more biochemically severe. This suggests that SDHB loss may uniquely impact SDH biochemical function.
Associations of Size at Birth and Metabolic Syndrome Antecedents With Serum Spexin Levels in Prepubertal Children
Authors: Ozturk Onsal Fatma Duygu , Ucar Ahmet , Bulbul Ali , Yildirmak Zeynep Yildiz , Elitok Gizem Kara
Published: May 2021

Background: Spexin is a novel peptide implicated in food intake and obesity. The primary aim of this study was to analyze whether serum spexin levels, along with total leptin and active ghrelin levels were different in prepubertal children born small for gestational age(SGA) and appropriate for gestational(AGA). Secondary aims were to analyze whether serum spexin, leptin and active ghrelin levels correlated with metabolic syndrome(MS)antecedents according to the Dietary and lifestyle-induced health effects in children and infants (IDEFICS)study. Subjects and Methods: We conducted a cross-sectional study on prepubertal37SGA- (median:5.6yr)and50prepubertalAGA-born children(median:5.9yr). Anthropometric data, homeostasis model assessment of insulin resistance(HOMAIR),plasma lipids, serum spexin, total leptin and active ghrelin levels were analyzed. Associations of serum spexin levels with MS antecedents according to the IDEFICS study were investigated. Results: Children bornSGA had higher body mass index and waist circumference than AGA-born peers(p <0.05). Serum total leptin levels were higher in SGA-born children than in AGA-born peers (p<0.05). Plasma active ghrelin and spexin levels were not different between the subgroups(p>0.05). Children bornSGA had higher MS risk scores than AGA-born peers(p <0.05). Small for gestational age- born children had higher plasma glucose,insulin and HOMA-IR than AGA-born peers(p<0.05). In children born SGA, the number of subjects with excess adiposity (NSGA=18(43.9%)andNAGA=7(14%),p=0.016)and insulin resistance(NSGA=14(34%) andNAGA=6(12%),p=0.035)was higher than in AGA-born peers. There was no significant difference in frequency of dyslipidemia between the subgroups(p=0.19). The frequency of children with more than one MS antecedent was higher in SGA-born children than in AGA-born peers(Chi-Square p <0.01). Metabolic syndrome risk score according to IDEFICS was higher in SGA born children than in AGA-born peers(2.2±1.8vs1.1±1.8;p=0.008). Serum spexin levels were lower in children with MS antecedents than those without MS antecedents in both AGA -and SGA-born children[Serum spexin levels in AGA-born children with and without MS antecedents: 48,5pg/mL(25-75%IQR:19.8-93.8pg/mL)and143pg/mL(25-75%IQR:104-211pg/mL),p<0.001;respectively, serum spexin levels inSGAborn children with and without MS antecedents: 31,0pg/mL(25-75%IQR:16.5-47.0 pg/mL) and79.5pg/mL(25-75% IQR:49.5-274.8pg/mL),p=0,0016;respectively]. In the whole study group, the most important factor associated with excess adiposity was history of being born SGA(OddsRatio=91.3[95%CI:2.2-374;p=0.017]

Conclusions: Serum spexin levels were not different inSGA- and AGA-born children. Serum spexin levels were reduced in children with MS antecedents independent of size at birth.
Combined Oral Contraceptive Treatment Does Not Alter the Gut Microbiome or Serum Metabolomic Profile in Obese Girls with Polycystic Ovary Syndrome
Authors: Jobira Beza , Frank Daniel N , Silveira Lori J , Garcia-Reyes Yesenia , Robertson Charles E , Ir Diana , Alexander Keisha L , D’Alessandro Angelo , Nadeau Kristen , Cree-Green Melanie
Published: May 2021

Title: Combined Oral Contraceptive Treatment Does Not Alter the Gut Microbiome or Serum Metabolomic Profile in Obese Girls with Polycystic Ovary Syndrome

Background: The gut microbiome is altered in obese adolescents with polycystic ovary syndrome (PCOS), and is associated with free testosterone, metabolic markers and insulin resistance. Combined oral contraceptives (OCP) are a primary treatment for PCOS and lower testosterone, but it was unknown if they changed the gut microbiome in obese adolescents with PCOS.

Objective: Assess the gut microbiome profile, targeted serum metabolomics, hormonal and metabolic measures in adolescents with PCOS and obesity with and without OCP treatment.

Methods: Adolescent girls with PCOS and obesity with and without PCOS were recruited from a tertiary referral hospital and underwent stool and fasting blood collection, an oral glucose tolerance test and MRI for hepatic fat fraction. Fecal bacterial were profiled by high throughput 16S rRNA gene sequencing and fasting serum metabolomics performed with mass spectroscopy. Groups were compared with t-tests and correlations performed. Results: Twenty-nine obese adolescents with PCOS [Untreated N=21, 16±1.2 years, BMI%ile 36.5± 3.0; OCP N=8, 15.5±0.9, BMI%ile 32.5±3.9] participated. OCP therapy had lower free testosterone and higher SHBG (p<0.001). Platelets were significantly higher (p=0.01), along with a trend in elevated CRP (p=0.09) in the OCP group. There was no difference in measures of fasting glucose, insulin or lipids. Measures of insulin resistance including HOMA-IR and Matsuda were also similar. Principle components analysis of the serum metabolome was not different between the groups. Girls treated with OCP had similar stool microbiome α-diversity measures of bacterial evenness (p=0.28), bacterial diversity (p=0.15), and global microbial composition (β-diversity, p=0.56). Further, the percent relative abundance (%RA) of the Firmicutes: Bacteroidetes ratio was similar, as well as the %RA at the phyla, family and genus level. Bacterial α-diversity was negatively associated with serum bile acids and branched chain amino acids. A higher %RA of family Ruminococcaceae was significantly associated with serum conjugated bile acids and HOMA-IR.

Conclusion: Despite changes in free testosterone and SHBG, adolescent girls with PCOS treated with OCP had similar clinical and gut microbiome profile compared to the untreated PCOS group. The significant association between bacterial α-diversity, Ruminococcaceae, clinical markers and bile acids suggests a potential role of the gut microbiome in the pathogenesis of metabolic syndrome and PCOS.
Relationship Between Iodine Status and Thyroid Function in Preschool Children: From the Environmental and Development of Children (EDC) Study
Authors: Lee Yun Jeong , Heo You Joung , Choe Yunsoo , Park Sang Hee , Lim Youn-Hee , Kim Bung-Nyun , Kim Johanna Inhyang , Hong Yun-Chul , Cho Sun Wook , Park Young Joo , Shin Choong Ho , Lee Young Ah
Published: May 2021

Background: We investigated iodine status and its association with thyroid function among preschool children residing in iodine-sufficient area. Methods: From the Environment and Development of Children study, 477 children were evaluated for thyroid function and urine iodine concentration (UIC) at age 6 during 2015-2017. After excluding children born with multiple birth and with congenital hypothyroidism or Hashimoto thyroiditis, 439 (231 boys) were included. Subclinical hypothyroidism (SCH) was defined as thyroid stimulating hormone (TSH) levels between 4.9-10 μIU/mL with normal free T4 levels. Iodine status was evaluated by UIC and children were categorized into 4 groups: iodine deficient (UIC < 100 μg/L), adequate (UIC, 100-299 μg/L), mild excessive (UIC, 300-999 μg/L), severe excessive (UIC ≥ 1000 μg/L). Results: Goiter was palpated in 64 (14.6%) with female predominance (26.0% vs. 4.3%, P < 0.001). Serum level of free T4 and T3 was 1.2 ± 0.1 ng/dL and 148.1 ± 18.5 ng/dL, respectively. The median TSH level was 2.3 (0.53-8.59) μIU/mL and the prevalence of SCH was 4.3% without sex-difference. The median UIC level was 606.2 (19.9-16409.7) μg/L, higher in boys (684 vs. 545 μg/L, P = 0.021) than in girls. Iodine was deficient in 19 (4.3%), adequate in 96 (21.9%), mild excessive in 170 (38.7%), and severe excessive in 145 (35.1%). After excluding 19 iodine deficient children, the relationship between iodine status and thyroid function was evaluated by multiple regression analysis after adjusting for age, sex, birth weight, gestational age, body mass index Z-score, and family history. As iodine status increased from adequate, mild excessive to severe excessive group, T3 levels decreased, and TSH levels increased with marginal significance (P for trend < 0.1 for T3 and TSH). When stratified by sex, similar association was found in only girls (P for trend = 0.043 for T3, and 0.062 for TSH) but not in boys, and mild excessive group showed lower free T4 levels (β = -0.05, P = 0.013) and severe excessive group had lower T3 levels (β = -7.04, P = 0.035) than iodine adequate group in only girls, but not in boys. Conclusion: Iodine was deficient in 4.3%, adequate in 21.9%, and excessive in 73.8% among preschool children residing in South Korea. As iodine status increased from adequate to excessive group, TSH levels increased with decreasing free T4 and T3 levels in girls.
Risk of Complications in Children With Adrenal Insufficiency and Covid-19
Authors: Raisingani Manish Gope
Published: May 2021

Background: Adrenal insufficiency may put a person at higher risk with infections due to a lack of normal stress response by the body. Limited data has been available in pediatric adrenal insufficiency with Covid-19 Methods: We used TriNetX, with a large COVID-19 database, collecting real-time electronic medical records data. We compared children (0-18 years) who were diagnosed with Covid-19 with and without Adrenal insufficiency. This database collected information from 54 health care organizations Results: Mortality rate in children with Covid-19 and Adrenal insufficiency was 2.246% (19/846). Mortality rate in children with Covid-19 without adrenal insufficiency was 0.097 % (244/252211). Relative risk of mortality for children with Covid-19 and Adrenal insufficiency was 23.2 with a p value of < 0.0001. Endotracheal intubation rate in children with Covid-19 and Adrenal insufficiency was 1.418% (12/846). Endotracheal intubation rate in children with Covid-19 without Adrenal insufficiency was 0.065% (165/252211). Relative risk of endotracheal intubation for children with Covid-19 and Adrenal insufficiency was 21.68 with a p value of < 0.0001. Sepsis rate in children with Covid-19 and Adrenal insufficiency was 6.974% (59/846). Sepsis rate in children with Covid-19 without Adrenal insufficiency was 0.274% (691/252211). Relative risk of sepsis for children with Covid-19 and Adrenal insufficiency was 25.45 with a p value of < 0.00001. Conclusion: Mortality rate, endotracheal and sepsis showed increased association in children with Adrenal insufficiency and Covid-19 versus children with Covid-19 and no Adrenal insufficiency. Further studies with larger sample size are needed to study complication rates of Covid-19 and Adrenal insufficiency.
The Relationship of Early Adiposity Rebound With Accelerated Bone Age and Breast Development in Girls: A Prospective Cohort Study
Authors: Jung Hae Woon , Lee Yun Jeong , Lim Youn-Hee , Kim Johanna Inhyang , Kim Bung-Nyun , Hong Yun-Chul , Shin Choong Ho , Lee Young Ah
Published: May 2021

Introduction: Adiposity rebound (AR) refers to the increase in body mass index (BMI) that follows the BMI nadir in childhood. Earlier AR increases the likelihood of being overweight/obese and may lead to early pubertal advancement, especially in girls. We aimed to evaluate the longitudinal changes in anthropometrics, bone age (BA), and breast development in relation to AR timing in girls. Methods: This study included girls (n = 349) of the Environment and Development of Children (EDC) cohort, a prospective cohort of healthy children started in 2012 with biennial visits to study the effects of environmental exposures on physical and neurobehavioral development. The BMI trajectories of girls with 3 or more measurements between 2 and 8 years of age (n = 242) were visually inspected to determine AR timing. After excluding preterm and multiple births, 204 girls were included and categorized according to the age at AR: group 1 (<3.9 years; n = 34, 17%), group 2 (3.9-5.9 years; n = 55, 27%) and group 3 (≥6 years; n = 115, 56%). AR groups were compared for differences in anthropometric measures, BA progression, and breast development. The relationships between AR and outcomes were analyzed with adjustment for age, gestational age, birthweight, physical activity and diet. Results: At age 2, there were no differences in anthropometric measures. By age 4, group 1 showed higher mean BMI z-scores (0.87) than groups 2 (-0.19) and 3 (-0.45) (P <0.001). The differences in BMI z-scores were significant between all 3 groups at 6 and 8-years (P <0.001, for all). Height differences became significant at 8-years (P = 0.010), with greater mean height z-score in group 1 (0.80) compared to group 3 (0.30). BA progression differed significantly between groups 1, 2 and 3 at 6-years (BA 6.87 vs. 6.44 vs. 6.36 years respectively; P < 0.001) and at 8-years (BA 9.65 vs. 8.82 vs. 8.60 respectively; P < 0.001). The inverse relationship between AR timing and BA remained significant after adjusting for covariates at 6 years (B = -0.222, P = 0.040) and 8 years (B = -0.468, P <0.001). Breast development occurred in 49 girls (24%) by age 8 with increased occurrence in the earlier AR groups: group 1 (n = 16, 47%), group 2 (n = 17, 31%), and group 3 (n = 16, 14%) (P for trend <0.001). When compared to group 3, the earlier AR groups had significantly increased risk of breast development at age 8 (OR 5.1, 95%CI 2.1-12.4 for group 1 and OR 2.4, 95%CI 1.1-5.4 for group 2, P <0.001 for both), after adjusting for covariates (P <0.05, for both). Conclusions: Girls who had earlier AR showed greater BA progression starting at 6 years and continuing at 8 years along with greater height at 8 years. These girls are at risk for early breast development after adjustment for covariates. AR timing may be a predictor for BA progression and onset of breast development in girls.
Self-Reported Feelings of Adult Patients With Differences of Sex Development (DSD) Regarding Genital Surgical Procedures
Authors: Lousada Lia Mesquita , Domenice Sorahia , Frade Costa Elaine Maria , Bachega Tania A , Batista Rafael Loch , Mendonca Berenice Bilharinho
Published: May 2021

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.
Effect of One Month Exposure to Components of Reprometabolic Syndrome on Physical Activity & Body Composition in Lean Women
Authors: Yabroudi Dana Fatal , Kuhn Katherine , Fought Angela J , Bradford Andrew P , Schauer Irene Elizabeth , Kohrt Wendy M , Santoro Nanette F , Pretzel Shannon M
Published: May 2021

Background: Subfertility in obese women is associated with chronic pituitary suppression, reduced sensitivity to GnRH and decreased sex steroid production. We have found evidence for a combined effect of hyperinsulinemia and high circulating fatty acids to acutely (4h infusion) suppress pituitary gonadotropin secretion and are currently investigating the effects of one-month exposure to a eucaloric high-fat diet (HFD) on gonadotropin levels in lean women. The aim of this study is to examine the effect of the one-month HFD on physical activity and body composition.

Methods: 12 normal weight (BMI < 25 kg/m2), normally cycling female participants of reproductive age were given a one-month eucaloric HFD, from the onset of menses in one cycle through the next, with 48% calories from fat. A Fitbit was provided to monitor changes in daily activity and sleep throughout the study. Measurement of gonadotropin pulsatility and reproductive hormones were done using frequent blood sampling and daily urine excretion, respectively. These measurements were obtained for a total of 4 menstrual cycles: 1 pre-diet cycle, the HFD cycle, and 2 post-diet cycles. DEXA body composition was measured at baseline and at the end of the 2nd post diet cycle. Pre and post diet comparisons were done using linear mixed model testing and reported as estimated means ± standard error.

Results: Mean number of daily steps were (9,226 ± 1,140) pre diet, (9,132 ± 1,140) during the diet and (7,533 ± 1,140) post diet. Daily active calories were (1,982 ± 99) pre diet, (1,975 ± 99) during the diet and (1,856 ± 99) post diet. Means in the HFD cycle did not differ from the pre-diet cycle. Daily sleeping minutes pre diet were (443 ± 19), (451 ± 20) during the diet and (412 ± 19) post diet, with no statistical difference between the 3 time points. BMI did not differ between pre-diet (21.84 ± 0.52) and post-diet (21.77 ± 0.52). DEXA body composition measurements indicated a statistically significant decrease in total fat percentage, (32.26 ± 1.53) pre diet and (31.31 ± 1.53) post diet, which does not appear clinically significant as the difference of less than 1% falls within the anticipated measurement error of the method. Visceral fat volume (cm3) did not differ between pre diet (299.51 ± 27.76) and post diet (295.53 ± 27.76).

Conclusions: The complete cohort has not yet been fully recruited and analyzed. These preliminary findings indicate that women consuming a one-month, HFD maintain their usual level of physical activity and sleep patterns, and do not appear to sustain change in visceral fat. Further accrual of participants should clarify the small decrease in total body fat observed without a change in BMI.

Supported by HD087314 ROI to NS UL1TR002535 to the Colorado Clinical and Translational Sciences Institute.
Longitudinal Health Care for Girls and Women With Turner Syndrome
Authors: Ghosh Priyanka , Zeinab Zorkot , Witchel Selma Feldman , Snook Meredith , Yatsenko Svetlana
Published: May 2021

Background Turner Syndrome (TS) is the most common chromosomal abnormality seen in females and is often diagnosed in childhood. The transition of patients with TS from pediatric to adult providers is characterized by inconsistency. As such, limited data are available to assess long term health outcomes of women with TS.

Objectives: 1) To evaluate the long term health outcomes in women with TS followed at a single academic institution and 2) to establish clinical recommendations for evaluation, counseling, and planned transition of this population.

Methods: A retrospective pilot study was performed by examining medical records of women with TS who presented with short stature or delayed puberty and were diagnosed with TS on the basis of cytogenetic analysis. Patients with monosomy X, mosaic monosomy X, or X chromosome structural abnormalities consistent with TS or mosaic TS diagnosis were included. Medical records from an academic children’s hospital and an affiliated women’s hospital were reviewed.

Results: To date, 15 females aged 26-32 years were identified. Electronic records were available for 12/15 with age at diagnosis ranging from in utero to 15 years of age. Those with pediatric information available had documentation addressing use of growth hormone and pubertal hormone replacement therapies. Of the 12 patients, 11 had cardiac imaging performed; only one had an MRI. Consistent planned transition to adult health care providers was not evident. Of the 12 patients, 3 had consultation with a Reproductive Endocrinology and Infertility specialist; 3 had a diagnosis of anxiety or depression; 3 had a DEXA scan done (1 had osteopenia); 5 had dyslipidemia; and 2 developed insulin resistance.

Conclusions: This pilot study confirms heterogeneity in practice patterns and variable interactions of women with TS with the healthcare system, especially as patients enter adulthood. Although some women were referred to subspecialists, our initial data uncover patient uncertainty about healthcare and transition recommendations. Our preliminary data indicate the need for early patient education in a collaborative, multi-disciplinary fashion. We plan to validate and extend our initial findings by reviewing additional medical records. Ultimately, we plan for expanded education, consistent surveillance recommendations, and planned transition of patients with TS from pediatrics to adult caregivers.
Obese Women Exhibit Reduced Inhibin B and Estradiol SecretionFollowing Pulsatile Intravenous FSH Administration
Authors: Luu Thanh Ha , Kuhn Katherine , Bradford Andrew P , Johnson Rachel , Carlson Nichole , Kumar T Rajendra , Polotsky Alex Joel
Published: May 2021

Introduction: Maternal obesity is an independent risk factor for reduced reproductive fitness. Decreased secretion of FSH in women with obesity is well documented but poorly understood. Furthermore, obese women secrete less protein and steroid hormones from their ovaries. In mice, prior studies have demonstrated that pulsatile release of FSH enhances ovarian function and fertility.

Hypothesis: We hypothesize that insufficient FSH pulsatility, as seen in women with obesity, results in inadequate folliculogenesis and reduced ovarian steroid production. We attempt to correct pulsatile FSH secretion in obese women by administering exogenous FSH to compensate for the suppressed circulating ovarian hormones. Our primary outcome is the change in peak inhibin B between pre- and post-treatment. We present results from our interim analysis.

Methods: Reproductive aged, regularly menstruating, normal weight (NW) (BMI 18.5-24.9) and obese (OB) (BMI >30) women were recruited for a 26hr study during the early follicular phase. Frequent blood sampling (q10min) for 10h was performed to obtain baseline hormone levels. At 10h, 3 mg of cetrorelix, a gonadotropin hormone antagonist, was given followed by a secondary dose (0.25mg) 6h later. At this time, hourly IV recombinant (r)FSH (30IU) was initiated and frequent blood sampling continued for 10h. LH, FSH, estradiol (E2) were measured by immunoassay (Advia Centaur XP, Siemens). Inhibin B was measured using an ELISA kit (Ansh labs). Differences between groups were modeled by linear regression, adjusted for age and cycle day (continuous). The relationship between change in peak inhibin B and change in peak E2 was estimated in a linear regression.

Results: A total of 36 participants (19 NW and 17 OB) were included in our interim analysis. There were no differences in age, cycle day of study, race, and waist/hip ratio. Inhibin B and E2 rises following the intervention were statistically significant within each group. Peak Inhibin B and E2 levels following intervention were lower in obese women compared to normal weight (133.4 vs 202.5 pg/mL and 85.8 vs 126.4 pg/mL, respectively). The difference in pre and post peak inhibin B levels trended lower in the obese group (-40.1 (95%CI: -86.2, 6.1, p=0.087). No difference was seen in maximal E2 response. There was no relationship between inhibin B and E2 response [0.08 (95%CI -0.26, 0.42), p=0.634].

Conclusions: These early results suggest obese women may have a lower response to pulsatile rFSH as compared to normal weight counterparts even with intravenous administration. We speculate this may be due to decreased uptake of rFSH in obese patients or a sign of ovarian dysfunction in obese women. Additional subjects are recruited to detect these differences.
Serum Concentrations of GDF9 and BMP15 Across the Menstrual Cycle
Authors: Riepsamen Angelique Helena , Donoghoe Mark W , Baerwald Angela , Pankhurst Michael W , Lien Shelly , Chong Yih Harng , Robertson David Mark , Ledger William L , Gilchrist Robert B
Published: May 2021

Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are TGF-β proteins that regulate key processes throughout folliculogenesis and are determinants of mammalian fecundity (1). They are uniquely produced predominantly by the oocyte and have potential clinical application as markers of oocyte quality and quantity (2). However, no studies have been conducted to assess whether serum concentrations alter across the different phases of the menstrual cycle, and thus if assessment should be confined to specific cycle stages. The aim of this study was to measure serum concentrations of these proteins during the menstrual cycle in women at different stages of reproductive life. Serum was collected every 1-3 days throughout the menstrual cycle from 41 healthy ovulatory women from three cohorts: menses to late luteal phase (21-29 years of age; n=16; University of Otago) and across one interovulatory interval (18-35 years of age; n=10; and 45-50 years of age; n=15; University of Saskatchewan), with simultaneous ultrasound scans confirming ovulation. Serum concentrations of GDF9, BMP15, estradiol, FSH, LH, progesterone, inhibin A and B and AMH were measured. GDF9 and BMP15 were detectable in 54% and 73% of women and varied 236- and 52-fold between women, respectively. To detect changes, mean concentrations and variances across the cycle were statistically modelled using a generalized additive model of location, shape and scale (GAMLSS). Across the menstrual cycle, there were minimal changes in serum GDF9 or BMP15 within a woman for all cohorts, with no significant differences detected in modelled mean concentrations. However, modelled variances were highest in the luteal phases of all women for BMP15 immediately following ovulation, regardless of age, suggesting a possible underlying cyclic pattern. These results suggest that serum BMP15 and GDF9 are not overtly affected by menstrual cycle dynamics but may be more stable in the follicular phase. Larger studies with more frequent sampling should establish if BMP15 and presumably GDF9 demonstrate clinically relevant cyclic variation.

References: (1) Gilchrist RB et al., HRU 2008; 14:159-77. (2) Riepsamen AH et al., Endocrinol 2019; 160:2298-313.
Assessment of Depression Among Adolescent Indian Girls With PCOS
Authors: Talwar Vipan , Talwar Gourav
Published: May 2021

Background: Prevalence of PCOS is increasing among Indian women due to growing changes in environment and lifestyle and also due to awareness of symptoms and willingness to seek medical help. Six out of ten females diagnosed with PCOS are teenage girls. Studies have shown that the women with PCOS often suffer from psychiatric comorbidities including depression but the data regarding the prevalence of depression in adolescent Indian girls with PCOS are scarce. Aim: To find out the prevalence of depression and its associations among adolescent Indian girls with PCOS. Methods: This was a cross sectional, case-control study conducted in the Endocrinology department of a speciality hospital of North India. We evaluated 160 newly diagnosed adolescent PCOS girls aged between 13-19 years, diagnosed by Revised Rotterdam criteria. Control group included 80 healthy, age matched, non-PCOS girls. Detailed history, Anthropometric measurements and standard hormonal evaluation were done. Depression was assessed by administering Patient Health Questionnaire-Adolescents (PHQ-A), a self-administered questionnaire based on DSM IV criteria. PHQ-A score of >10 was considered as the threshold for significant depression. Statistical evaluation was done with SPSS and P value of <0.05 was significant. Results: Mean age of the patients was 16.3 +/- 3.2yrs. The frequencies of significant depression in PCOS and control groups were 36.5% and 11.9% respectively. PCOS adolescents having higher HOMA-IR value (p-0.03), higher hirsutism score (P-0.01) and higher BMI (p-<0.01) had a higher risk of significant depression. Menstrual irregularity, acne, dyslipidaemia, serum testosterone, 17-OHP, prolactin and serum TSH levels had no significant correlation with depression. Discussion: PCOS commonly prevails during adolescence, a phase when girls are more concerned about their physiology and physical health. Negative body image and chronic stress can lead to disturbed mental health. Our study by using a simple and patient friendly clinical tool the PHQ-A has found higher prevalence of depression (almost 3 times) in Indian adolescent PCOS girls as compared to controls and it significantly corelates with insulin resistance, hirsutism and obesity. PCOS puts tremendous burden, on both physical as well as mental health, especially in adolescents, due to its effects on physical appearance, self-esteem, fertility and also due to other long term metabolic complications associated with it. PCOS is an urgent health problem that needs careful assessment and appropriate treatment of its all aspects. Timely recognition of mental health issues in these girls can help with early interventions including referral to mental health specialists (if needful) and add to the wellbeing of these young girls. Conclusion: The initial evaluation of PCOS in adolescent girls should also include the assessment of mental health disorders.
Overnight Melatonin Concentration and Sleep Quality Are Associated With Clinical Features of Polycystic Ovary Syndrome
Authors: Evans Adam T , Brink Heidi Vanden , Lim Jessica S , Jarrett Brittany Y , Lujan Marla Elaine , Hoeger Kathleen M
Published: May 2021

Introduction: Women with polycystic ovary syndrome (PCOS) have an increased incidence of sleep disturbances compared to healthy women. Circulating melatonin (MEL) is elevated in women with PCOS, thought to reflect an increased daytime and blunted peak in overnight MEL, consistent with an altered circadian rhythm. Whether circadian disruptions coincide with sleep disturbances in women with PCOS or their symptom severity is unclear.

Objective: To determine whether altered MEL production coincides with reduced sleep quality in women with PCOS and to examine whether there is a relationship between MEL production, sleep disturbances and the diagnostic features of PCOS.

Methods: Women with PCOS (n=22) and controls (n=12) were recruited prospectively. PCOS was defined based on the 2018 International Guideline. Controls exhibited no more than 1 diagnostic feature of PCOS. Women underwent a reproductive history, clinical exam, and transvaginal ultrasound. Fasting blood samples were obtained to measure reproductive hormones. Urine samples were collected in the evening and upon awakening on 1-2 days and assayed for urinary 6-sulfatoxymelatonin as a proxy for daytime and overnight MEL production, respectively. The night:day (N:D) MEL ratio was determined to assess the rhythm of MEL production. Sleep quality and duration were assessed using the Pittsburgh Sleep Quality Index (PSQI) and via overnight wrist actigraphy. Differences between measures of urinary MEL and sleep quality were analyzed using two tailed t-tests. Associations between diagnostic features of PCOS and sleep-related measures were computed using Pearson partial correlations after adjusting for BMI.

Results: No differences were detected in overnight MEL, daytime MEL, or the N:D ratio in women with PCOS versus controls. PCOS group experienced reduced weekend sleep efficiency vs. controls (81.18% vs. 87.76% p<0.05), albeit no differences were detected in PSQI scores, sleep duration or total sleep efficiency determined via wrist actigraphy between groups. Longer menstrual cycle length correlated with poor sleep quality as defined by PSQI (rho=0.3662, p<0.05) and FNPO was positively associated with overnight MEL (rho=0.3586, p<0.05).

Conclusions: Day and night MEL production and sleep quality did not differ between women with PCOS and controls despite weekend sleep efficiency being reduced in women with PCOS. Diagnostic features of PCOS were associated with MEL production and sleep disturbances suggesting that women with a more severe clinical presentation of PCOS may be more likely to experience altered MEL production or sleep disturbances. Further studies with a larger sample size are needed to understand the link between degree of symptomology in PCOS, MEL production, and sleep disturbances.
The Association Between Clinical and Biochemical Hyperandrogenism in Women With Female Pattern Hair Loss
Authors: Odhaib Samih A , Mansour Abbas A , Al Hamdi Khalil I
Published: May 2021

Background: The exact association between clinical and biochemical hyperandrogenism (HA) is heterogeneous and cannot be ascertained, especially in normoandrogenic women. Aim: Evaluate any association between clinical HA phenotypes and biochemical parameters in premenopausal women with female pattern hair loss (FPHL). Methods: A cross-sectional observational study on 362 women with different degrees of FPHL, who were assessed for general characteristics, the degree of FPHL by Sinclair’s score, hirsutism by modified Ferriman-Gallwey (mFG) score. Evaluation for biochemical HA included total testosterone (TT), sex-hormone-binding globulin (SHBG), calculated free testosterone (FT), calculated bioavailable testosterone (BT), and dehydroepiandrosterone sulfate (DHEA-S). The variables of clinical HA which were used in this study are FPHL, hirsutism, and acne. We used the Free and Bioavailable Testosterone Calculator to calculate the FT and BT. Results: The enrolled young premenopausal women’s age range was (14-47 years). Around 78% of them were overweight or obese. Eighty-percent of women had a mild FPHL, with a median duration of three years where 2/3 of women had a duration < 3 years, and had no significant relationship to FPHL degree. About 73% of women had either a mild to moderate hirsutism, and around 16% had acne. The biochemical HA was confirmed in around 52% of women (n=188), who show high levels of calculated FT. The calculated BT is high in 78.5% of the enrolled women (n=284). The means of biochemical indicators for HA were in their reference ranges or slightly above, with no specific change pattern with the corresponding FPHL severity. None of these parameters had a significant relationship to the severity of FPHL. The duration of FPHL was not affected by any presumed variable of clinical or biochemical HA. Conclusions: FPHL severity is associated with other clinical HA signs like hirsutism and acne, but not to HA’s biochemical parameter. Other parameters, like SHBG, HOMA-IR, and BMI, had no significant relation to the severity of FPHL. Clinical implications: FPHL severity does not correlate with the magnitude of hyperandrogenism. The assessment of women with FPHL is primarily clinical. The biochemical picture assists the diagnostic process.