bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of Norepinephrine Neurons in the NTS (A2 population) is Sufficient to Suppress Pulsatile LH Secretion in Female Mice
Authors: McCosh Richard B , Kreisman Michael J , Tian Katherine , Thomas Steven A , Breen Kellie M
Published: May 2021

The overarching goal of this work is to identify neural pathways underlying inhibition of pulsatile luteinizing hormone (LH) secretion during stress. Stress-induced suppression of LH secretion is mediated, at least in part, by suppression of arcuate kisspeptin (ARCKiss1) neurons. The mechanisms by which acute stress suppresses ARCKiss1 cell activity are largely unknown; however, several lines of evidence support the hypothesis that A2 neurons (norepinephrine [NE] neurons in the nucleus of the solitary tract [NTS] of the brainstem) are involved. First, A2 cells are activated during several reactive stress paradigms. Second, NE administered into the paraventricular nucleus, which is innervated by A2 neurons, suppressed pulsatile LH secretion. Finally, ablation of brainstem NE neurons restored estrous cyclicity following chronic glucoprivation (chronic metabolic stress model). The present study employed chemogenetics to test the hypothesis that A2 neurons are sufficient to suppress pulsatile LH secretion in ovariectomized female dopamine beta-hydroxylase (DBH) Cre positive and negative (wild type) mice. Mice received bilateral injections of either a Cre-dependent stimulatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) virus (AAV1-DIO-hM3Dq-mCherry) or a control virus (AAV1-DIO-mCherry) into the NTS. Mice were randomly assigned to receive either clozapine N-oxide (CNO, specific DREADD agonist; 1mg/kg, i.p.) or saline and blood samples were collected at 6-min intervals for 60 min before and 90 min after injection. Two weeks later, mice received the alternate treatment in a cross-over design (n= 5-10/grp). During the pre-injection period, all mice had clear LH pulses (mean: 6.0 ± 0.2 ng/mL, pulses/60 min: 3.4 ± 1.5). In DBH Cre- (wild type) mice with hM3D virus and DBH Cre+ with mCherry virus (both control groups), neither CNO nor saline altered mean LH or LH pulse frequency. However, DBH Cre+ mice with hM3D virus had a 54% reduction in mean LH (p < 0.05) and 59% reduction in pulse frequency (p < 0.05) following CNO; neither LH metric was altered in response to saline. To assess transduction efficiency, fixed neural tissue was collected. In tissue analyzed thus far, DBH Cre+ mice have mCherry labeling in ~70% of DBH-immunoreactive neurons in the NTS and >90% of mCherry neurons contained DBH immunoreactivity. Three DBH Cre+ mice with hM3D virus mice had no LH response to CNO and may represent missed viral injections, which will be determined when tissue is analyzed. These data demonstrate that activation of A2 neurons is sufficient to impair pulsatile LH secretion in female mice. Moreover, these data support the broad hypothesis that the A2 population of neurons is critical for modulating neuroendocrine function during stress and raises the possibility that A2 neurons directly or indirectly influence ARCKiss1 cell activity.
An Unusual Case of Transient Diabetes Insipidus After Prolonged Vasopressin Infusion
Authors: Chang Albert , Arudkumaran Dharscika , Umadat Deviani , Cocks Eschler Deirdre A
Published: May 2021

Background: Vasopressin is a hormone produced in the hypothalamus and secreted by the posterior pituitary. Underproduction or resistance to vasopressin can lead to diabetes insipidus (DI) resulting in the imbalance of fluid status and serum sodium levels. Synthetic vasopressin is a common second line agent used in the critical care setting for its vasopressor effects with an added clinical benefit by increasing cerebral perfusion pressure. There have been reported cases of transient DI after discontinuation of vasopressin in neurosurgical patients, however only few cases have been reported in septic shock patients without neurological involvement. We present a case of transient DI during treatment for septic shock after attempts to wean off vasopressin infusion. Presentation: A 41-year-old female with history of type 2 diabetes mellitus, quadriplegia following a motor vehicle accident at age 11 was admitted to the surgical intensive care unit for urosepsis after placement of right ureteral stent. The patient was started on broad spectrum intravenous (IV) antibiotics and vasopressors norepinephrine and vasopressin. After 8 days of vasopressin treatment, with each effort to wean IV vasopressin, the patient was noted to have significant polyuria with urine output reaching as much as 800 mL/hr and increase in her serum sodium to a maximum of 148 mmol/L (n 145 mmol/L). During episodes of excessive diuresis, urine sodium reached 87 mmol/L, urine osmolality was 72 mOsm/kg (50-1400 mOsm/kg), and serum osmolality was 288 mOsm/kg (n 300 mOsm/kg). The patient received three doses of 1 microgram of desmopressin 24 hours apart while weaning off vasopressin. This helped slow excessive diuresis while also maintaining normal serum sodium levels. Urine output decreased to approximately 150 mL/hr after each administration of desmopressin. The serum sodium levels eventually stabilized between 135-140 mmol/L and urine output held steady around 200 cc/hr. The patient did not require additional desmopressin and was hemodynamically stable off all vasopressors. Discussion: The pathophysiology behind transient diabetes insipidus following vasopressin infusion is still unclear. It is known that in septic shock, there is depletion of vasopressin stores which suggests central DI. Yet, pharmacologic doses of vasopressin are speculated to downregulate V2 receptors in the renal distal convoluted tubules and collecting ducts which suggests nephrogenic DI. Our patient responded to desmopressin which indicates that she at least had a central component of DI. There is no consensus on the duration of vasopressin required to precipitate transient DI, but vasopressin infusion was administered for at least 24 hours in other cases prior to onset. We present a rare case of transient diabetes insipidus after prolonged vasopressin infusion that clinicians should be aware of in the critical care setting.
Idiopathic Hypophysitis
Authors: Amjed Hafsa , Sadiq Sobia
Published: May 2021

Introduction: Hypophysitis is a heterogeneous condition that leads to inflammation of the sella / suprasellar region, potentially resulting in hormonal deficiencies or mass effects. Prevalence of hypophysitis ranges from 0.2% to 0.88%. Annual incidence of hypophysitis is 1 case per 9 million individuals. We present an interesting case of idiopathic hypophysitis. Clinical Case: A 52-year-old female was evaluated for secondary hypothyroidism. Patient complained of excess fatigue, weight gain, headaches, polyuria with nocturia and vision changes. She was seen by ophthalmology for formal visual field testing revealing right superior quadrantanopia. Labs significant for TSH 4 uIU/mL (ref range 0.27-4.2uIU/mL), FT4 0.72ng/dL (ref range 0.93-1.7 ng/dL), Anti TPO ab negative, AM cortisol 8.9UG/dL, ACTH 18pg/mL, IGF1 127ng/mL, prolactin 7ng/mL, FSH 102MIU/mL, LH 41 MIU/mL. MRI sella revealed homogenous enhancement of the pituitary with convex superior margin - 0.8*1*0.9cm concerning for hyperplasia. Due to the concern for hypophysitis, an extensive inflammatory workup was pursued which was negative. She was started on thyroid hormone replacement and DDAVP. An empiric trial of high dose steroids failed to provide any relief. During workup, patient complained of transient right sided face and arm tingling, diagnosed with TIA and started on aspirin. Due to worsening headaches, a pituitary biopsy was pursued. Pathology significant for glandular tissue ruling out inflammatory, neoplastic, and infectious etiologies. Neurology diagnosed the patient with hemicrania continua. Patient is currently maintained on thyroid hormone replacement and DDAVP with close follow-up. Discussion: The incidence of hypophysitis has recently increased due to increased awareness and also due to the use of medications like ICI. Primary hypophysitis is mostly due to autoimmune etiology. Secondary hypophysitis could result from infections, neoplastic conditions or an adverse effect of medications. Clinical presentations ranges from being asymptomatic to having features of hypopituitarism. Usually presents with mass effect, visual symptoms due to the upward expansion of the pituitary gland impinging the dura mater and optic chiasm. This is followed by symptoms of hormone deficiency, central DI and hyperprolactinemia. Central AI has been reported in 20%-75%, central hypogonadism in 15%-60%, central hypothyroidism in 25%-58%, GH deficiency in 5%-41%, and prolactin deficiency in 13%-25%. Typical MRI findings include, homogeneous pituitary contrast enhancement, pituitary stalk thickening and loss of posterior pituitary bright spot, ‘figure of 8’ appearance, ‘dural tail’. Treatment consists of surgery, anti-inflammatory medications, and radiotherapy. Glucocorticoid treatment is the cornerstone for medical management; however, the overall recurrence rate is high.
Pleurihormonal Pituitary Adenomas Presenting as Acromegaly
Authors: Schwehr Megan , Endo Mayumi
Published: May 2021

Background: Pleurihormonal pituitary adenomas represent 10-15% of all functioning pituitary adenomas1. One of the rarest combinations is ACTH-GH co-secretion with concomitant acromegaly and Cushing’s disease. Clinical Case: 30-year-old female with type 2 diabetes (A1c 11.4%) developed rapidly progressive peripheral neuropathy. Labs revealed a transaminitis. Hepatic ultrasound revealed fatty infiltration of the liver consistent with steatosis. Patient endorsed life-long “chicken legs”, buffalo hump, and easy bruising. She continued to have worsening paresthesias and stated her teeth were “more translucent”. At an endocrinology visit peripheral muscle wasting, atraumatic bruising at the ankles and toes,and striae on the abdomen, shoulders, breasts, and armpits were noted. She had also noted teeth separation and thinning over time and worsening diffuse joint aches. Lab results showed elevated cortisol value of 8.4 mcg/dl after 1 mg dexamethasone suppression test. 24-hour urine cortisol was elevated (87 ug/24 hrs, nl < 45 ug/24 hrs), confirming the diagnosis of Cushing’s syndrome. ACTH was inappropriately normal (56 pg/mL, nl 7.2 – 63 pg/mL), suggesting ACTH dependency. IGF-1 was elevated twice (328 ng/dL and 391 ng/dL, nl <303 ng/dL), and a GH suppression test was abnormal (GH 1.14 ng/mL at 90 minutes) confirming the diagnosis of acromegaly. Brain MRI revealed a cystic pituitary microadenoma (0.5 x 0.5 x 0.6 cm), and the patient underwent surgical resection via transnasal transsphenoidal pituitary surgery with total tumor removal. Immunostaining was positive for only synaptophysin and ACTH. Postoperative diagnosis of Cushing’s disease was made, with formal diagnosis of acromegaly pending improvement in follow-up IGF-1 levels. Literature reviews have revealed very few cases of pleurihormonal pituitary adenomas presenting with concomitant Cushing’s Syndrome and acromegaly. Roca et. al examined 17 studies which described 20 patients with this condition; only 4 presented with symptoms of both acromegaly and Cushing’s disease. In many cases previously reported, the clinical presentation of Cushing’s syndrome was subtle, often with subclinical Cushing’s syndrome, while patients had florid symptoms of acromegaly.1. Conclusion: This Cushing’s predominant case of a GH-ACTH co-secreting tumor is an incredibly rare presentation for this pleurihormonal pituitary adenoma, which is already a rare diagnosis.

References: 1.Roca E, Mattogno PP, Porcelli T, Poliani L, Belotti F, Schreiber A, Maffezzoni F, Fontanella MM, Doglietto F. Plurihormonal ACTH-GH Pituitary Adenoma: Case Report and Systematic Literature Review. World Neurosurg. 2018 Jun;114:e158-e164. PMID: 29501516.
Specificity for the Epiphyseal Round Cell Layer is Significantly Associated With Height GWAS​
Authors: Renthal Nora Edwards , Nakka Priyanka , Baronas John , Kronenberg Henry M , Hirschhorn Joel N
Published: May 2021

Human height is a model polygenic trait with thousands of height-related SNPs identified in GWAS to date. An important determinant of height is the proliferation and hypertrophy of growth plate chondrocytes during childhood long bone elongation. Connecting the expression of specific genes that affect skeletal biology to associated variants in GWAS remains a difficult challenge. To connect the genetics of height and growth plate gene expression, we studied the relationship between gene expression in the murine growth plate and common-variant associations from GWAS of height. To obtain gene expression data from the growth plate, we dissected three layers of murine tibial growth plates, extracted RNA from each layer, and measured expression using the Affymetrix GeneChip 430 3.0. For each gene, we derived a specificity score for each growth plate layer, and SNP-level p-values from a published GWAS of height (N~700000) were combined into gene-level p-values using MAGMA. We then used MAGMA to test for association between specificity of expression for each growth plate layer and the GWAS gene level p-values for height. We found that specificity for the round cell layer is significantly associated with height GWAS p-values (p = 8.5x10-9). This association remains when we condition on each of the other cell layers and on membership in a set of genes from OMIM that cause skeletal growth disorders (3.3x10-8 < p < 4.1x10-6). We replicated this result in a RNA-seq dataset of maturing chondrocytes sampled at three time points during development in vitro (days 3, 5, and 10): we found that z-scores for expression in the earliest two days of development are significantly associated with gene-level p-values from height GWAS (pDay3 = 1.2x10-21 and pDay5 = 2.0x10-20) and that this association remains after conditioning on the other timepoints and on the OMIM gene set (3.1x10-20 < pDay3 < 8.3x10-5; 3.7x10-19 < pDay5 < 0.002). We then performed pathway analysis of genes that are both highly specific to the round layer and highly significant in GWAS using Enrichr. Together, our results suggest that genes expressed in early chondrocyte development (the round cell layer) are particularly relevant to the contribution of growth plate-expressed genes to height. This conclusion both sheds light on the regulation of human skeletal growth and also helps prioritize relevant genes implicated from the height GWAS in skeletal biology.
Racial/Ethnic Disparities in the Investigation and Treatment of Pediatric Growth Hormone Deficiency
Authors: Hawkes Colin Patrick , Gunturi Hareesh , Dauber Andrew Nahum , Hirschhorn Joel N , Grimberg Adda
Published: May 2021

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.
Pituitary Macroprolactinoma Apoplexy in a Prepubertal Girl
Authors: Ribeiro Sabliny Carreiro , Dall agnese Angélica Cristina , Mota Laís Marques , Geremia Cesar , Bressiani Marina , Hertz Michele Teixeira , Marchesan Lucas Bandeira , Coutinho Márcia Khaled
Published: May 2021

Background: Prolactinomas are rare in children, with an incidence of 1: 10.000.000 cases, representing less than 2% of all intracranial tumors in this age group (1). Indeed, only a few cases are reported in prepubertal children.

Clinical Case: Eight-year old female prepubertal child, previously healthy, presented a progressive loss of the visual acuity in the last 5 months and was admitted to the emergency department with an intensive headache associated with nauseas, started 48 hours before the admission. At the physical examination, the patient was eutrophic, with an infantile genitalia and no breast development or galactorrhea. No focal neurologic deficits were detected and presented normal pupils reflex and preserved extrinsic eye movements. The Campimetry evidenced bitemporal heteronymous hemianopsia and the nuclear magnetic resonance of the central nervous system identified a suprasellar and intrasellar expansive lesion measuring 3.2 x 2.6 x 2.3 cm, with bleeding signs and compression of the optic chiasm. The hormonal evaluation showed: free T4 0.55 ng/dL (normal value: 0.93-1.70ng/dL), total T4 4.8ng/dL (5.1-14.1ng/dL), TSH 4.06µUI/mL (0.6-5.4µUI/mL), morning serum cortisol 1.80mcg/dL (6.2-2mcg/dL), ACTH 7.0pg/mL (<46pg/mL), prolactin 3.376ng/mL (4.8-23.3ng/mL). The patient initially started glucocorticoid replacement, subsequently levothyroxine and cabergoline. A diagnosis of macroprolactinoma with pituitary apoplexy and optic nerve compression was performed and confirmed by the Immunohistochemical after the transsphenoidal resection. No history of any neoplasms were reported by family members and calcium abnormalities were excluded in the child. A significant improvement of the visual field was suddenly observed and the prolactin substantially decreased to 35ng/mL within 30 days after the intervention. CONCLUSION: We report a rare case of macroprolactinoma in a prepubertal girl associated with pituitary apoplexy. Complete assessment and prompt intervention were essential to recover the visual field and to prevent major sequelae.

Reference: (1) Yang, A., Cho, S. Y., Park, H., Kim, M. S., Kong, D.S., Shin, H.J., & Jin, D.K. (2020). Clinical, Hormonal, and Neuroradiological Characteristics and Therapeutic Outcomes of Prolactinomas in Children and Adolescents at a Single Center. Frontiers in Endocrinology. 2020; 11:527.
Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia in the United Kingdom - Nationwide Multicentre Assessment
Authors: Lawrence Neil Richard , Bacila Irina-Alexandra , Mahdi Sundus , Albi Sabah , Cheetham Tim D , Crowne Elizabeth C , Das Urmi , Dawson Jeremy , Dattani Mehul Tulsidas , Davies Justin , Gevers Eveline , Krone Ruth , Kyriakou Andreas , Patel Leena , Randell Tabitha , Ryan Fiona , Keevil Brian George , Ahmed Syed Faisal , Krone Nils Peter
Published: May 2021

Introduction: Impaired Quality of Life (QoL) in Congenital Adrenal Hyperplasia (CAH) has been demonstrated in adults, but research in children has yielded variable results. We investigated the impact of CAH on QoL of children and adolescents alongside clinical health outcomes (biometric and biochemical profiles). Method: We collected data from 14 tertiary UK centres to explore current health status of 8-18 year olds with CAH. QoL was assessed by using three different questionnaires; strengths and difficulties questionnaire (SDQ), Paediatric Quality of life (PedsQL) and Self-image profile (SIP), the former two completed by both patients and their parents. Height, weight and blood pressure were converted to age and sex adjusted z-scores. Serum markers included 17OH-progesterone (17OHP), androstenedione (D4), testosterone (T) and 11-ketotestosterone (11KT). Statistical Analysis: Statistical analysis comprised of principal component analysis (PCA) followed by multivariate analysis of variance (MANOVA), and post hoc regression. Results: Of the 107 CAH patients included in the study, median age 12.4 years (IQR 10.0-15.1), 55% were female and 104 completed at least 1 questionnaire. Adequate data for PCA was available from 73/107. Three Principal Components (PCs) with observed eigenvalues > 1 explained 71% of the total variance in the observed variables. PC1 reflected ‘disease control’ comprising 17OHP, D4, T and 11KT. PC2 reflected ‘biometrics’ comprising age, and height and weight z-score. PC3 reflected ‘blood pressure’, comprising systolic and diastolic z-score. PC1 correlated with outcomes in the parent and patient SDQ as well as parent PedsQL. PC2 and PC3 did not correlate with QoL. Regression analysis revealed higher scores (indicating lower QoL) in the SDQ domain of emotional problems and PedsQL domain of emotional health in patients where biomarkers suggested good control or overtreatment. Post hoc regression analysis revealed a rise in Androstenedione of 10nmol/L equated to an improved SDQ emotional problems score of 0.5 points and an improved PedsQL emotional health score of 3 points. Conclusion: The study found an interrelation between QoL and biomarkers of disease control in CAH. There were more emotional problems with higher levels of androgen suppression. Biochemical control within normal ranges did not predict emotional problems. However, unexpectedly, patients with very high levels of androgens were highlighted as reporting fewer problems with their emotional QoL. Further research into QoL in CAH and optimal levels of biochemical control will further understanding.
Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long Term Follow up Study on Prevalence, Determinants, and the Effect of Years of Exposure
Authors: Madsen Milou Cecilia , van Dijk Dennis , Wiepjes Chantal , Conemans Elfi , Thijs Abel , Den Heijer Martin
Published: May 2021

Background: Erythrocytosis is a known side effect of testosterone therapy in hypogonadal men and can increase the risk of thromboembolic events. Erythrocytosis is also seen in trans men (birth-assigned female, male gender identity) receiving testosterone therapy. Currently there are no clinical guidelines for the management of this problem in trans men. Specific aims: 1. To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone. 2. To study the association between duration of testosterone treatment and hematocrit levels. Methods: A 20 year follow-up study in adult trans men who started testosterone, and had monitoring of hematocrit levels at our center (n=1073). Results: Erythrocytosis (defined as hematocrit levels of >0.50 l/l twice) occurred in 11% of trans men. Multilevel analyses showed former or current smoking (OR 2.2, 95%CI 1.6-3.3), testosterone administration as long-acting intramuscular injection (OR 2.9, 95% CI 1.7-5.0), a higher age at initiation of hormone therapy (up to OR 5.9, 95% CI 2.8-12.3) for people above 40 compared to <18), higher BMI (>30 g/m2 compared to 18.5-25 kg/m2) (OR 3.7, 95% CI 2.2-6.2) and a medical history for chronic pulmonary diseases, sleep apnea or polycythemia vera (OR 2.5, 95% CI 1.4-4.4) as determinants that increased the risk of high hematocrit levels. In the first year of testosterone therapy hematocrit levels increased most: from 0.39 l/l at baseline to 0.45 l/l after 1 year. Although there was only a slight continuation of this increase in the following 20 years (0.45 at 1 year and 0.46 at 20 years), the probability of developing erythrocytosis still increased (10% after 1 year, 38% after 20 years). Conclusion: Erythrocytosis frequently occurs in trans men using testosterone. The biggest increase in hematocrit was seen in the first year, but also after the first years there is a substantial number of people that present with hematocrit >0.50. Because smoking, obesity and use of injection as dosage form are associated with a higher risk for erythrocytosis, a reasonable first step in the care for transmen with erythrocytosis while on testosterone is to advise them to quit smoking and to switch to a transdermal administration type and if BMI is high, to lose weight.
A Simple Algorithm is Created for Identifying Intermenstrual Intervals Containing an Oscillatory LH Pattern That Associates With Vasomotor Symptoms Using Daily Urinary LH Excretion in the Study of Women’s Health Across the Nation (SWAN)
Authors: Lasley Bill L , McConnell Daniel S , Crawford Sybil
Published: May 2021

Background: A specific and unique pattern of luteinizing hormone (LH) excretion has been associated with vasomotor symptoms (VMS) in early menopausal women. Described as “oscillations” of LH excretion, this pattern is consistent with secretory “surges” of LH followed by pituitary “fatigue”. This pattern has not been observed in non-VMS intermenstrual intervals and supports the concept that a breakdown in the hypothalamic-pituitary ovarian axis feed-back loops leads to extreme and cyclic variations in gonadotropin hormone releasing hormone (GnRH) secretion that stimulates collateral nerves to alter core body temperature. Regardless of the precise mechanism, the pattern of LH secretion, as transduced in daily urine as oscillations, provides the basis for the development and validation of a VMS algorithm. Objective: The purpose of this study was to create a simple algorithm to identify intermenstrual intervals exhibiting oscillatory LH, to facilitate investigations into its associations with VMS and other symptoms during the menopausal transition (MT). Methods: As part of the Study of Women’s Health Across the Nation (SWAN), participants in the Daily Hormone Substudy (DHS) were asked to provide daily urine samples - from which LH, E1c, and PdG were measured - and complete a daily symptoms diary for one menstrual cycle (up to 50 days). Analyses included 144 participants whose first DHS collection did not meet the Kassam criterion for evidence of luteal activity; of these, 61 were assessed by an expert as having oscillatory LH and 83 as non-oscillatory LH. Proposed algorithm-based classifications regarding oscillatory LH included number of days with LH at least 50% of the collection maximum LH (number of large-LH days) and number of days with LH no more than twice the collection minimum LH (number of small-LH days). Agreement of these 2 criteria with rater-assigned oscillatory LH was assessed using nonparametric t-tests and binomial logistic regression. Associations of these with VMS frequency were assessed using Spearman correlations. Results: The number of large-LH days was strongly associated with oscillatory LH: median (interquartile range) = 13 (7,22) for oscillatory collections versus 4 (2, 11) for non-oscillatory collections (p<.0001) but number of small-LH days was unrelated (p=.98). Percentage of collection days with VMS was significantly correlated with number of large-LH days (Spearman r=.37, p<.0001) but not with number of small-LH days (Spearman r=.03, p>.05); adjustment for total collection length had negligible impact. Conclusion: A simple algorithm using urinary LH profiles can be used to identify intermenstrual collections that likely contain intervals of VMS.
Adiposity Alters Follicle Dynamics in Women of Reproductive Age With Regular Menstrual Cycles
Authors: Oldfield Alexis , Jarrett Brittany Y , Carter Faith , Brink Heidi Vanden , Lujan Marla Elaine
Published: May 2021

Obesity increases a woman’s likelihood of experiencing adverse reproductive health outcomes, including menstrual cycle irregularity, anovulation, and luteal phase dysfunction. Despite a heightened risk of reproductive dysfunction some women with obesity display ovulatory cyclicity. The degree to which adiposity affects menstrual cycle characteristics in this population is limited to endocrine assessments; evidence supports decreased luteinizing hormone pulse amplitude and reduced luteal phase progesterone. However, these endocrine disruptions have not been linked to alterations in follicular events. The objectives of the present analysis were to evaluate longitudinal changes in follicle size populations and growth kinetics of selectable follicles (6-9mm) and identify endocrine abnormalities associated with obesity in regular cycles. 14 non-obese women (BMI <30 kg/m2) and 15 obese women (BMI≥ 30 kg/m2) with regular cycles were evaluated by serial ovarian transvaginal ultrasonography and venipuncture every-other-day for one complete inter-ovulatory interval (IOI). The number and diameters of all follicles ≥2 mm at each visit were documented offline using the grid method. Growth profiles of individual follicles which grew to >7mm were assessed using the Identity Method. Diagnostic, morphologic, and endocrine features were compared across groups using parametric and non-parametric t-tests (i.e. cross-sectional features) and mixed models (i.e. longitudinal features). Non-obese and obese women with regular cycles showed similar IOI, follicular phase, and luteal phase lengths. The mean number of recruitment events, maximum dominant follicle diameter, and the growth rates of ovulatory follicles over time did not differ between groups, despite confirmation of compromised mean luteal progesterone production (8.23 ng/mL vs. 14.75 ng/mL, p=0.047) and decreased mean luteal FSH levels in women with obesity (2.33 mIU/mL vs. 5.83 mIU/mL, p=0.040). Over the IOI women with obesity showed an increased proportion of 2-5 mm follicles (β=5.3%; p<0.05) and a decreased proportion of 6-9mm follicles (β=-5.0%; p=0.05) versus non-obese women consistent with fewer follicles transitioning from the 2-5 mm pool to the selectable stage. This is the first comparison of follicle dynamics between non-obese and obese women with regular ovulatory cycles. These data suggest that a smaller pool of selectable follicles is present in women with obesity and may result in suboptimal follicle development luteal function. Future studies are needed to understand the impact of altered follicle populations and luteal hormone dynamics on endometrial receptivity and fertility/fecundity.
Anti-Mullerian Hormone Protein-Altering Variants Are Associated With Hypertriglyceridemia in the General Population
Authors: Chang Sydney , Copperman Alan , Dunaif Andrea Elizabeth
Published: May 2021

We found 17 rare PCOS-specific functional protein-altering variants (PAVs) or mutations in the gene, AMH, that decrease the biologic activity of the encoded protein, anti-Müllerian hormone (AMH), in the heterozygous state. Approximately 3% of European ancestry PCOS cases in our cohort of ~700 were affected. Our preliminary studies found evidence for a metabolic phenotype in both PCOS as well as their male first-degree relatives who were heterozygous carriers of these AMH PAVs. We performed this study to test the hypothesis that AMH mutations are associated with metabolic abnormalities in the general population. The Mount Sinai BioMe Biobank is an electronic health record (EHR)-linked biobank, containing anonymized whole exome sequences from 30,813 participants of diverse ancestries. We interrogated the sequence data to identify individuals with PCOS-related AMH PAVs. IRB-approval was obtained to review the linked EHR. Outcomes were the presence of obesity (BMI ≥ 30 kg/m2), type 2 diabetes (hemoglobin A1C ≥ 6.5%), prediabetes (hemoglobin A1C 5.7% - 6.4%), elevated cholesterol (total cholesterol ≥ 200 mg/dL), hypertriglyceridemia (TG ≥ 150 mg/dL), and hypertension (≥2 blood pressure values ≥140/90, or administration of antihypertensive medications). Control subjects were obtained from the National Health and Nutrition Examination Survey using propensity score matching (for sex, age, and BMI) with a 1:4 case:control ratio. A total of 292 individuals with AMH PAVs were identified, resulting in a combined 0.95% prevalence of AMH PAVs in an unselected population (1.07% in Europeans, 0.28% in African Americans, 0.54% in Hispanics, and 0.07% in Asians). After adjusting for age, BMI, and race/ethnicity, there was a statistically significant increased prevalence of hypertriglyceridemia in both women (OR 7.29, 95% CI 3.77-14.00) and men (OR 10.15, 95% CI 4.68-22.00) with AMH

PAVs compared to sex-, age- and BMI-matched controls. There was also a statistically significant increased prevalence of elevated cholesterol in men with AMH PAVs compared to controls (OR 2.48, 95% CI 1.15-5.34). There were no significant differences between individuals with AMH PAVs and matched controls with respect to the other outcomes. These findings suggest that decreased bioactivity of AMH is causally related to dyslipidemia in the general population. TG levels are elevated in both sexes, whereas increases in cholesterol are only seen in men. The mechanisms by which decreases in AMH bioactivity alter circulating lipid levels are of considerable interest since AMH has no known metabolic actions. It is possible that the putative metabolic effects of AMH are mediated by increases in circulating testosterone (T) levels that in turn alter lipid metabolism. Since T levels are not commonly available in EHR, future studies will be needed to investigate this hypothesis as well as to explore metabolic actions of AMH.
Involvement of BMP-15 in Glucocorticoid Actions on Ovarian Steroidogenesis by Rat Granulosa Cells
Authors: Kashino Chiaki , Hasegawa Toru , Nakano Yasuhiro , Iwata Nahoko , Yamamoto Koichiro , Kamada Yasuhiko , Masuyama Hisashi , Otsuka Fumio
Published: May 2021

Glucocorticoid receptor (GR) are known to be expressed in the ovary and glucocorticoids are shown to exert direct effects on granulosa cell functions. In the clinical setting, menstrual abnormality, amenorrhea and hypermenorrhea can be shown in patients with glucocorticoid excess. On the other hand, glucocorticoids can also be used for the treatment of PCOS with hyperandrogenism. However, the effects of glucocorticoids on the reproductive system have not been fully elucidated. In the present study, we investigated the influence of glucocorticoids on follicular steroidogenesis using primary culture of rat granulosa cells, by focusing on the ovarian bone morphogenetic proteins (BMPs) acting as a luteinizing inhibitor. Granulosa cells isolated from female immature rats were treated with follicle-stimulating hormone (FSH) in the presence of dexamethasone (Dex) in serum-free conditions. After treatment with Dex for 48 h, the changes of estradiol (E2) and progesterone (P4) production and cAMP synthesis induced by FSH treatments were measured by ELISA. Total RNAs of granulosa cells treated with FSH, Dex and BMPs were extracted and mRNA levels of steroidogenetic factors and enzymes, BMP receptors and Id-1 were quantified by real-time RT-PCR. Phosphorylation of Smad1/5/9 induced by BMPs was evaluated by Western blotting using cell lysates in the presence or absence of Dex. As a result, it was revealed that Dex treatment decreased FSH-induced E2 production by granulosa cells. In accordance with the steroid results, Dex suppressed FSH-induced P450arom mRNA expression as well as FSH-induced cAMP synthesis by granulosa cells. By contrast, Dex treatment augmented FSH-induced P4 production by granulosa cells in a concentration-dependent manner. Dex treatment was found to enhance basal and FSH-induced mRNA levels of P4-synthetic enzymes including P450scc and 3βHSD. Of note, Dex treatment activated the BMP target gene Id-1 transcription and Smad1/5/9 phosphorylation, in particular, induced by BMP-15 among various BMP ligands including BMP-2, -4, -6, -7, -9 and -15. It was also revealed that Dex treatment increased mRNA levels of ALK-6, a type-I receptor for BMP-15, and that BMP-15 treatment in turn upregulated GR mRNA levels expressed by granulosa cells. Given that BMP-15 acts as an inhibitor for P4 production by suppressing FSH-receptor actions, it was suggested that glucocorticoid is functionally linked to the enhancement of endogenous BMP-15, leading to the negative feedback toward the P4 overproduction induced by FSH and Dex in granulosa cells. Collectively, it was revealed that glucocorticoids elicit differential effects on the ovarian steroidogenesis of E2 and P4, in which GR and BMP-15 actions are mutually enhanced in granulosa cells.
Pre-Eclampsia Strikes: Could It Be Related This Gland?
Authors: Lofters Jason , Flemming Nia , Gayle Latoya , Simmonds Ro-Kaye , Adedoyin Oluwafeyi , Brijmohan Sharmela , Fein Deborah
Published: May 2021

Introduction: Primary hyperparathyroidism (PHPT) is rarely diagnosed in pregnancy and if left untreated has the potential to lead to serious maternal and neonatal complications. We describe a case of PHPT with associated complicated pre-eclampsia. Clinical Case29-year-old primigravida admitted at 33 + 6 weeks with fatigue, 10lbs weight gain and elevated BP. Labs revealed potassium 2.9 (3.5-5.2mmol/L), corrected serum calcium (Ca)11.62 (8.4-10.2mg/dL), ionized calcium 1.69 (1.15-1.33mmol/L), PTH 163.9 (15-65pg/mL) and vitamin D 24.6 (30-100ng/mL). Other labs were normal. Urine studies showed 315mg/24h proteinuria and urine calcium of 129.5 mg/24hrs (100-300mg/24hrs). She was started on magnesium sulphate along with labetalol for BP control, given betamethasone for stimulation of fetal lung maturity as well as potassium repletion. Hypercalcemia (HCa) was initially managed with fluids and Lasix intravenously. At 34 + 2 weeks she developed SOB, orthopnea, headaches with new 9lbs weight gain over 5 days and sustained BP elevation. Urgent C-section was done for pre-eclampsia with severe features. Post-operatively, she suffered from postpartum hemorrhage, managed with transfusion of packed red cells and transient placement of a Bakri balloon. Her HCa worsened with Ca 12.56 and cinacalcet was started after delivery. This coincided with gradual improvement of her BP and Ca to 10.8. She declined additional work-up and was discharged in stable condition. Clinical LessonPHPT often goes undiagnosed in pregnancy, with symptoms of fatigue and constipation mimicking common complaints of pregnancy. Studies have also suggested that up to 25% of patients with PHPT during pregnancy present with hypertension and pre-eclampsia and that there is an association between preeclampsia and the presence of parathyroid adenomas. The pathophysiology is unclear but is thought to be due to endothelial dysfunction triggered by hypercalcemia as well as abnormal placentation. No clear guidelines exist for the management of PHPT during pregnancy, with observation and rehydration being the preferred initial options. The use of cinacalcet as well as curative surgical parathyroidectomy when Ca levels persist >11 in the second trimester have also been described. Our patient presented similarly, with severe pre-eclampsia needing urgent C-section, further complicated by persistent severe HCa. Early diagnosis of PHPT, along with treatment including cinacalcet improved her Ca. It is therefore important that PHPT be considered in patients presenting like ours, progressing to severe pre-eclampsia as early reduction of serum calcium may reduce morbidity and mortality. ReferencesMcCarthy, A., Howarth, S., Khoo, S., Hale, J., Oddy, S., Halsall, D., ... & Samyraju, M. (2019). Management of primary hyperparathyroidism in pregnancy: a case series. Endocrinology, diabetes & metabolism case reports, 2019(1).
Muscle Strength in Transgender Women After Long-Term Hormone Therapy: A Cross-Sectional Study
Authors: Alvares Leonardo A M , Santos Marcelo R , Souza Francis Ribeiro , Santos Lívia Marcela , Ramos Henrique A , Mendonca Berenice Bilharinho , Alves Maria-Janieire N Nunes , Costa Elaine Maria Frade , Domenice Sorahia
Published: May 2021

Introduction: Cisgender women (CW) are usually weaker than cisgender men (CM), but when the strength is expressed in relation to the body weight (BW) or fat free mass (FFM) it is observed that the difference disappears what suggests that the innate qualities of the muscle and its motor control mechanisms are similar in CW and CM. The effects of prior exposure to testosterone during puberty on the performance of transgender women (TW) undergoing physical effort are not well known. Objective: To evaluate muscular strength of TW in long-term gender affirming hormone therapy (GAHT). Methods: A cross-sectional study was carried out with 8 TW (average age of 34.0 yo, SD ±4.8), 8 CM and 8 CW matched by age and body mass index (BMI). All TW were non-gonadectomized subjects and were in estrogen plus cyproterone acetate therapy (average time of 15.6 years (SD ±8.7) of treatment). Mean total testosterone (ng/dL) levels of TW, CW and CM were 83.5, 20.5 and 480.5 at the time of the study, respectively. Hemoglobin levels of TW, CW and CM were 14,2 (range 13,5-14,9), 14,35 (range 12,8-14,7) and 15,35 (range 14,0-18,2), respectively BC was assessed by InBody 720. Handgrip strength tests were carried out using the Stoelting hand-held hydraulic dynamometer. Results: The mean maximum strength was 31,9 kg (SD±2.4) in TW, 29.2 kg (SD±4.4) in CW, and 47.5 (SD±8.6) in CM (TWvs.CW p=0.0743; TWxCM p<0.0018; CWvsCM p<0.001). Free fat mass (FFM) of TW was 55.56±6.88 kg, CW 38.98±4,09 kg, CM 64,98±6,29 kg (TWvsCW p<0,0001; TWvsCM p=0,024; CWvsCM p<0,0001). In the evaluation Median Strength/FFM, a mean of 0.54 was observed in the TW group, and 0.76 in the CW and CM (TWvsCW p=0.0157 and TWvsCM p=0.036, CWvsCM p>0.9999). Discussion: The expression of muscle strength/FFM is the same in CM and CW, which suggests that the innate quality of the muscles as well as their motor control is similar in these groups, as showed in many data in the literature. However, the analysis of this ratio in TW showed a significant lower rate than the other groups. Conclusion: After GAHT muscle strength of TW is equal of CW. There is a decrease in the functionality of the muscular unit in producing strength in this group of TWs since strength decreased disproportionately to muscle mass which leads us to believe that there are important functional changes in intracellular oxidation mechanism.
Anxiety and Fear During the Covid-19 Pandemic: A Web-Based Survey of Thyroid Cancer Survivors
Authors: Graves Claire E , Goyal Neha , Levin Anna , Nuno Miriam A , Kim Jina , Campbell Michael J , Shen Wen T , Gosnell Jessica Erin , Roman Sanziana , Sosa Julie Ann , Duh Quan-Yang , Suh Insoo
Published: May 2021

Background: The coronavirus (COVID-19) pandemic has led to rapid changes in our society and healthcare system. Cancer patients and survivors may be disproportionately affected by these changes, including decreased access to healthcare, increased infection risk, and economic challenges. We sought to determine the effects of the pandemic on thyroid cancer survivors’ quality of life. Methods: An anonymous web-based survey was administered in collaboration with ThyCa: Thyroid Cancer Survivors’ Association, consisting of questions about (1) demographics, (2) thyroid cancer clinical characteristics, (3) attitudes toward and impact of COVID-19, and (4) the Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item profile. The survey was linked on the ThyCa homepage. PROMIS measures were scored using item response theory models with a T-score metric relative to U.S. reference data via the HealthMeasures Scoring Service (https://www.healthmeasures.net). T-scores were analyzed using Mann-Whitney U, Wilcoxon signed-rank, Kruskal-Wallis, and Spearman’s rank correlation tests. Results: From 5/6/2020 - 10/8/2020, 505 participants accessed the survey, and all completed surveys by U.S.-based thyroid cancer survivors were analyzed (n=378, 75%). Mean age was 53 years, 89% were female, 90% were white, 74% had papillary thyroid cancer, 97% had surgery, and 70% received radioactive iodine. The vast majority agreed or strongly agreed (83%) that their lives were very different during COVID-19, as was the way they interacted with their doctors (79%). Less than half (43%) agreed or strongly agreed that they were satisfied with the amount of information from their doctor’s office regarding COVID-19 changes. Compared to previously-published PROMIS data for this population, T-scores were significantly higher in the domain of anxiety/fear (57.8 vs. 56.5, p<0.01) and lower for ability to participate in social roles and activities (46.2 vs. 48.1, p<0.01). Younger age was weakly correlated with greater anxiety/fear (Spearman’s rho=-0.38, p<0.01), and greater anxiety/fear was associated with pending treatment (p<0.01), lower cancer stage (p=0.01), and female sex (p=0.02). Conclusions: During the COVID-19 pandemic, thyroid cancer survivors reported increased anxiety/fear and decreased social participation. In our efforts to care for patients both physically and mentally as the pandemic continues, we must better understand their fears and concerns and improve communication about potential changes to their care.