bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Genetically Defined Male Counterpart of Polycystic Ovary Syndrome: Evidence for Ovarian-Independent Pathogenesis
Authors: Zhu Jia , Wittemans Laura Brigitte Leen , Lindgren Cecilia , Hirschhorn Joel N , Chan Yee-Ming 
Published: May 2021

Abstract
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 &lt;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.
Effect of Experimentally Induced Sleep Fragmentation and Hypoestrogenism on Fasting Nutrient Utilization in Pre-Menopausal Women
Authors: Grant Leilah K , Coborn Jamie E , Cohn Aviva , Abramson Mathena , Elguenaoui Elkhansaa , Russell Julia A , Wiley Aleta , Nathan Margo D , Scheer Frank A J L , Klerman Elizabeth B , Kaiser Ursula B , Rahman Shadab A , Joffe Hadine 
Published: May 2021

Abstract
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.
Euglycemic Diabetic Ketoacidosis in a Patient With Gestational Diabetes Mellitus and COVID-19 Infection
Authors: Karuppasamy Gowri , Saud Arwa Al , Abuhaliqa Wajeeha Mousa 
Published: May 2021

Abstract
Introduction: Diabetic ketoacidosis (DKA) is a life-threatening medical emergency requiring urgent treatment. Euglycemic DKA may occur in patients with both type 1 and type 2 Diabetes Mellitus (DM), as well as pregnancy. The absence of marked hyperglycemia can result in delayed diagnosis and treatment, resulting in potential adverse outcomes. Diabetes is a major comorbidity associated with severe hospital course and high fatality rate among patients with COVID-19 infection. We report our experience in a patient with gestational diabetes mellitus who developed euglycemic DKA and COVID-19 infection in her third trimester of pregnancy. Clinical Case: A 30-year-old lady at 29weeks gestation presented with two-day history of vomiting, diarrhea and abdominal pain. She reported good fetal movements. She had been diagnosed with Gestational Diabetes Mellitus (GDM) at 20 weeks gestational age, receiving treatment with multiple daily injections of insulin. 5 days earlier, she had tested positive for COVID-19 infection. She was asymptomatic; testing was performed as she had been in contact with a confirmed case. On examination she was afebrile and vitally stable, but dehydrated. Her initial laboratory investigations showed ketonemia with normal glucose level and normal anion gap. She was treated as a case of starvation ketosis and dehydration, with intravenous fluids and electrolyte replacement. However, 3 days later, the patient complained of worsening nausea and vomiting with dry cough and she developed hypotension. Chest X-ray showed bilateral mid and lower
zone pulmonary infiltrates. She was treated as COVID-19 pneumonia, received 2 units of COVID-19 convalescent plasma and broad-spectrum intravenous antibiotics. Repeated investigations showed worsening ketosis with high anion gap metabolic acidosis, consistent with a diagnosis of euglycemic DKA. Insulin infusion was initiated, isotonic saline with electrolyte replacement was also continued. She symptomatically improved over the next two days, with resolution of ketonemia and acidosis. The patient was discharged and she was well at her outpatient follow up visit. She underwent emergency Cesarean Section at 37 weeks gestational age, due to non-reassuring electronic fetal monitoring. She delivered a healthy female infant weighing 2445grams. Conclusion: Pregnancy is a high-risk period for DKA particularly when associated with other stressors that were identified in our patient – GDM, restricted calorie intake and COVID-19 infection. Diabetes is a risk factor for developing severe forms of COVID-19 and on the other hand, COVID-19 infection is associated with poor glycemic control and higher risk of hyperglycemic emergencies including ketoacidosis in diabetic patients. Prompt recognition of euglycemic DKA is critical in pregnancy, as this condition is associated with high fetal mortality rates.
Hypomagnesemia and Hypokalemia: The Possible Role of Vasopressinase in This Rare Presentation of Gestational Diabetes Insipidus
Authors: Okafor Anderson , Dhillon Vikramjit , George Joshua , Addepalli Aradhana 
Published: May 2021

Abstract
Background: Gestational diabetes insipidus (GDI) is a rare but recognized complication of pregnancy. We are reporting the case of a 33-year-old patient who presented in her 3rd trimester with GDI, severe asymptomatic hypokalemia & hypomagnesemia. This presentation of GDI has not been reported yet to our knowledge.
Clinical Case: A 33-year-old G2P1 patient who presented to the hospital due to the discovery of new onset severe asymptomatic hypokalemia on routine labs. Further evaluation revealed K of 2.8 mEq/L, Mg of 1.4 mg/dL & Na of 142mEq/L. She endorsed polyuria & polydipsia and a 24-hour urine collection of 9.35L confirmed diabetes insipidus. Labs also revealed a serum osmolality of 286mOsm/kg & urine K of 15mEq/L. Her urine osmolality was inappropriately low at 138mOsm/kg. She received K & Mg supplementation. In pregnant patients suspected of having GDI who have normal serum Na, water restriction test can be done for further evaluation. It must performed with close monitoring because dehydration can lead to uteroplacental insufficiency. Given her history of previous fetal demise & report of headaches with attempts of water restriction, we opted not to do the test. She was given subcutaneous 1 mcg of desmopressin overnight with her thirst & polyuria improving only briefly. Due to her suboptimal response, we began her on 10 mcg of intranasal spray of desmopressin once in the evening. Her symptoms resolved on this regimen after a few days of observation. Her Mg & eventually K levels reached and remained at normal levels after repletion. The rest of her pregnancy went on without complications and she delivered a healthy male infant via scheduled cesarean section at 36 weeks gestation. She discontinued intranasal desmopressin after 2 weeks and has remained asymptomatic. Labs at follow up 4 weeks later remained normal. It is known that vasopressinase which is made by placental trophoblasts during pregnancy degrade endogenous ADH1. We are hypothesizing that since ADH has been shown to be effective in conserving magnesium in rats by stimulating its uptake in the distal convoluted tubule cells2, a similar mechanism could be present in humans. We believe that the loss of endogenous ADH, leads to the depletion of Mg and consequently hypokalemia in susceptible patients.
Conclusion: To our knowledge this is the first case presenting the possible role of vasopressinase in the development of hypomagnesemia & hypokalemia in a patient with GDI.
Reference: 1. Gordge MP, Williams DJ, Huggett NJ, Payne NN, and Neild GH. Loss of biological activity of arginine vasopressin during its degradation by vasopressinase from pregnancy serum. Clinical Endocrinology, vol. 42, no. 1, pp. 51- 58, 1995. 2. Dai LJ, Bapty B, Ritchie G, Quamme GA. Glucagon and arginine vasopressin stimulate Mg2+ uptake in mouse distal convoluted tubule cells. Am J Physiol. 1998 Feb;274(2):F328-35. doi: 10.1152/ajprenal.1998.274.2.F328. PMID: 9486227.
Lack of Hirsutism in an XX Woman With History of Hyperandrogenism and Oligomenorrhea: Two Coexisting Disorders or Novel Syndrome of Androgen Insensitivity?
Authors: Ueda Masako , Amorosa Louis F 
Published: May 2021

Abstract
Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women, and its etiologies have not been clearly elucidated. Non-classical congenital adrenal hyperplasia (NC-CAH) with mild to moderate enzyme deficiency of 21-hydroxylase due to bi-allelic mutations in its gene (CYP21A2) is a cause of secondary PCOS that should always be considered. Common clinical features of NC-CAH include menstrual irregularities, hirsutism, acne, advanced bone age with accelerated linear growth, and short stature, associated with hyperandrogenism. Androgen insensitivity syndrome (AIS) is another cause of hyperandrogenism due to lack of response to androgen typically in genetic male (XY) presenting with female physical characteristics, most commonly due to a mutation in the androgen receptor (AR) gene on the X chromosome. Here, we present a 61 years old woman, with a diagnosis of PCOS based on oligomenorrhea and high testosterone ~90 pg/mL at age 18, meeting both NIH and Rotterdam PCOS diagnostic criteria. She took oral contraceptive pills only for one year, despite continued menstrual irregularities. After age 42, her menstrual cycles became and remained regular without further intervention until menopause at age 51, while her testosterone levels fluctuated between 80 and 250 pg/mL. After menopause, her testosterone levels drastically increased to &gt;350 pg/mL. The patient has been recommended, but reluctant to undergo oophorectomy for enlarged non-cystic ovaries. Other potentially related clinical features include the presence of a pituitary adenoma, and a thyroid nodule. She has no notable adrenal mass or myelolipoma. Patient is lean and well-fit, at 5’11” and 151 lb. The most puzzling feature has been a lack of virilization and hirsutism. During laboratory evaluation, high 17-hydroxyprogesterone was identified, and NC-CAH became a potential etiology of PCOS, but this did not explain the lack of apparent virilization. The finding of unimpressive levels of DHEA implied that this pathway probably was unlikely the major cause of high testosterone. Investigation for hyperandrogenism focusing on AIS revealed normal female karyotype XX, and no identifiable mutations or abnormal copy number in AR. The findings thus far have provided no unifying diagnosis for her clinical features, especially for androgen insensitivity, and additional studies are being performed. Assessment of other genes recently reported to be associated with AIS is being performed as well as genetic confirmation of NC-CAH by analyzing CYP21A2. Steroid 5-alpha reductase 2 (SRD5A2), whose mutations and polymorphism interestingly are associated with AIS and PCOS, respectively, and nuclear receptor subfamily 5, group A, member 1 (NR5A1) is another gene associated with AIS. It remains to be determined whether she has AIS as a coexisting disorder with NC-CAH or a novel syndrome with a feature of androgen insensitivity.
Ovarian Hyperthecosis: Hyperandrogenism in a Post-Menopausal Woman
Authors: Fayad Christine , Champion Amber , Izuora Kenneth E 
Published: May 2021

Abstract
Introduction: Ovarian Hyperthecosis (OH) is a disorder characterized by severe hyperandrogenism and insulin resistance. It is a rare cause of hyperandrogenism primarily among postmenopausal women. We present a case report about a patient with adrenal incidentalomas and later found to have ovarian hyperthecosis during her evaluation.
Case Description: 62-year-old post-menopausal female was referred to the Endocrinology clinic for evaluation of adrenal incidentalomas which were discovered on imaging work-up for hematuria. MRI Abdomen and Pelvis revealed a 17mm right and 14mm left sided adrenal nodules, with signal dropout suggesting benign adenomas. Patient stated she had menopause at age 39 years old, one child, and multiple miscarriages during her reproductive years. Examination revealed BMI of 31.1 kg/m2, moderate hirsutism, and skin tags near the neck. There was no evidence of hyperpigmentation or abdominal striae. Patient had phenotype suggestive of insulin resistance-without diagnosis of diabetes.
Results: Laboratory workup revealed normal levels of 24-hour metanephrines, cortisol, renin, aldosterone, and DHEA-S suggesting that the adrenal adenomas were not hyperfunctioning. Further workup revealed: Total Testosterone: 220 [2 - 45 ng/dL]; Free Testosterone 23.8 [0.1 - 6.4 pg/mL]; DHEA-S 43 [12 - 133 mcg/dL]. Prolactin 6.3 [Postmenopausal 2.0-20.0 ng/mL]. A1c 5.4 [&lt;5.7%]. Serum FSH, LH, PRL, and IGF-1 were within normal reference ranges. The patient, with adrenal adenomas, elevated testosterone, and a normal DHEA-S suggested a non-adrenal source. Patient was evaluated by OB/GYN with finding of normal postmenopausal ovaries on transvaginal ultrasonography. Based on a high suspicion for OH, patient underwent hysterectomy with bilateral salpingo-oophorectomy which confirmed pathological diagnosis of Bilateral OH. On follow-up 2 months post-op, Total/Free Testosterone had normalized 36 [2 - 45 ng/dL] and 3 [0.1 - 6.4 pg/mL] respectively).
Conclusion: In women presenting with elevated testosterone (&gt;150 ng/dL) and clinical features of hyperandrogenism, proper laboratory and imaging evaluation is imperative to determine the source of excess androgen production. Untreated, OH is associated with increased mortality from type 2 diabetes, cardiovascular disease, and endometrial carcinoma. The diagnosis of OH can be confirmed only by histologic examination of the ovaries. Often, ovarian imaging is negative, therefore, surgical intervention is recommended. Hence, clinicians should rely on the clinical assessment in making management decisions in patients with OH.
Primary Hyperparathyroidism in Pregnancy - Two Case Reports
Authors: Mehta Anku , Galliford Thomas , Tauni Rahat , Chan Yik Lam 
Published: May 2021

Abstract
Introduction: Primary hyperparathyroidism in pregnancy is rare, with a reported incidence of 1%. The physiological changes of pregnancy can mask its diagnosis. Primary hyperparathyroidism is characterized by the overproduction of parathyroid hormone (PTH) and results in hypercalcemia and a raised or inappropriately normal PTH.
Maternal and fetal/neonatal complications are estimated to occur in 67 and 80% of untreated cases respectively. Maternal complications include nephrolithiasis, pancreatitis, hyperemesis gravidarum, pre-eclampsia and hypercalcemic crises. Fetal complications include intrauterine growth restriction; preterm delivery and an increased risk of miscarriage.
Case reports
Case 1: An 18-year old woman presented in her first pregnancy with a known history of MEN type 1. She was diagnosed at the age of 17 following an appendectomy. She has a strong family history and subsequent genetic test confirmed the diagnosis of MEN1. Pre-pregnancy parathyroid sestamibi scan showed bilateral parathyroid adenoma. MRI pituitary was in keeping with a pituitary microadenoma. She had a corrected calcium ranged between 2.7-3.3mmol/L and an inappropriately raised PTH of 24.1pg/ml. She underwent elective parathyroidectomy at 15 week gestation. Post operatively she remained normocalcaemic. She subsequently developed gestational diabetes and was induced at 34 + 3 weeks due to multiple episodes of hypoglycaemia, reduced fetal movement and suspected placental insufficiency. She had a good fetal outcome.
Case 2: A 29-year-old woman in her first pregnancy presented with recurrent episodes of renal colic and imaging confirmed significant bilateral renal calculi. A diagnosis of primary hyperparathyroidism was made with adjusted calcium of 2.94 mmol/L (2.20-2.60) and inappropriately unsuppressed parathyroid hormone of 20.1pg/ml (1.6-6.9), along with ultrasound parathyroid. She was managed with fluid rehydration initially and parathyroidectomy was performed at 12 weeks due to persistently elevated serum calcium. Her genetic screening for MEN (multiple endocrine Neoplasia) was negative. Fetal growth was closely monitored and the rest of her pregnancy was uncomplicated. She had an assisted vaginal delivery at term with good fetal outcome.
Learning Points: 1. The physiological changes of pregnancy can mask its diagnosis; hence a high index of suspicion is needed to diagnose primary hyperparathyroidism in pregnancy.2. Management with rehydration forms the cornerstone in mild cases and Parathyroidectomy is the definitive treatment and recommended in second trimester.
3. Ultrasound is the only recommended imaging modality in pregnancy.4. Primary hyperparathyroidism can be genetically determined in 10% of cases. Genetic testing enables patients to be screened for the development of other syndrome-related diseases e.g. neuroendocrine tumours in MEN1.
Comparative Transcriptional Analysis of Patient Responders Versus Non-Responders to Glucocorticoid Treatment for Bronchopulmonary Dysplasia
Authors: Shi Victoria J , Burale Suban , Lewis Tamorah , Silswal Neerupma , Monaghan-Nichols Paula 
Published: May 2021

Abstract
Bronchopulmonary Dysplasia (BPD) is a common heterogeneous lung disease that can result from preterm birth at less than 28-weeks gestation, prenatal and postnatal inflammatory insults, ventilator associated lung injury, and oxygen-related injury. Synthetic glucocorticoids (sGCs) are commonly used pre- and postnatally to treat inflammation and improve lung physiology. Clinical responses to sGC therapy for BPD vary in patients. We hypothesize that genetic background differences in transcriptional response to sGC therapy dictate the efficacy in infants with BPD. Identifying pathways and genes that mediate these differences will allow prospective determination of which infants would respond to sGC treatment.
26 preterm infants that received sGC treatment for BPD were identified. Respiratory Severity Score (RSS), an indication of BPD severity, was measured at diagnosis, 4 days, and 7 days post-sGC treatment. Patients were stratified into Responders versus Non-Responders by improvement in respiratory function after treatment. Changes in RSS were used to discriminate Responders (R &gt;3 decrease in RSS) to treatment from Non-Responders (NR &lt;3 decrease). 13 Responders and 13 Non-Responders were selected. They included 7 females and 19 males with an average gestational age of 24.3 weeks, and were 46% Caucasian, 31% African American, 19% Hispanic, and 4% other. 100µL of blood was collected before and after seven days of a dexamethasone treatment course.
To examine differences in transcription response between Responders (n = 13) and Non-Responders (n= 13), RNA was isolated and analyzed using the Clariom S Human Transcriptome Affymetrix array. 21,500 expressed genes were profiled. Results: were imported into the Transcriptome Analysis Console (TAC) software, and genes with a significant difference (fold change &gt;1.48 or &lt; -1.48 and p-value &lt;0.05) in Responders and Non-Responders were identified. Of those, 133 genes were upregulated and 74 downregulated. Ingenuity Pathway Analysis (IPA) was used to identify signaling pathways and disease processes that were uniquely altered in Responders versus Non-Responders. Non-Responders showed significant activation of neuroinflammatory signaling pathways, degranulation pathways, and lymphocyte activation disease pathways. Target genes in the top dysregulated pathways were evaluated using quantitative Polymerase Chain Reaction (qPCR). Expression changes in Matrix Metalloproteinase-25, Interleukin-12 Receptor beta, and Microsomal Glutathione Transferase-1, key mediators of inflammation, were validated in independent studies using qPCR. While response to systemic glucocorticoids in neonates with BPD is variable, these studies identified pathways that are altered in Responders versus Non-Responders and are a step towards developing pre-screening tools to stratify infants for response to sGC BPD therapy.