ResearchPad - reproduction https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Infertility influencers: an analysis of information and influence in the fertility webspace]]> https://www.researchpad.co/article/elastic_article_11587 To examine fertility-related social media accounts and influencers on two social media platforms.MethodsThe search function of Twitter (TW) and Instagram (IG) was used to generate a list of accounts with the terms: fertility, infertility, ttc, egg freezing, ivf, endometriosis, and reproductive. Accounts not in English, in private, with no posts in > 1 year, or with content unrelated to search terms were excluded. Accounts were assessed for author type; REI board certification (REI-BC); influencer (INF) status (> 10 K followers on IG; verified check mark on TW); account demographics; and content in last 5 posts. Statistical analysis included unpaired t tests, a classification and regression tree (CART) analysis, and stepwise multiple logistic regression.ResultsSeven hundred ten accounts were identified and 537 (278 TW, 259 IG) were included. Account types included societies, clinics, physicians, patients, groups, and “other.” Instagram content (1290 posts reviewed) was primarily personal stories (31.7%) or inspiration/support (23.7%). Twitter content (1390 posts reviewed) was mostly promotion (28.2%) and research/education (20.2%). Thirty-nine accounts (12.5%) were influencers. Fertility influencers were most often awareness/support accounts (59.8% TW, 25.0% IG), patients (12.8% TW, 25% IG), or other (17.9% TW, 21.0% IG). Only 7.7% TW and 7.1% IG INFs were board-certified REI physicians. The best predictor for classification as an influencer was high activity (> 50 posts/month TW, > 10 posts/month IG).ConclusionAs patients increasingly utilize social media to obtain and engage with health information, it is critical to understand the fertility-related SM landscape. This understanding may help to successfully enhance relationships with patients and ensure dissemination of accurate information. ]]> <![CDATA[SUN-001 Identification of Dehydroepiandrosterone-s (DHEA-s) Elevation Due to Performance Enhancing Supplements]]> https://www.researchpad.co/article/elastic_article_8816 Background: Recreational athletes and individuals in certain occupations may utilize supplements with the goal of enhancing their physical performance and strength. These individuals may be reluctant to provide their supplement use history due to the stigma associated with performance enhancing drugs. We report a case of supplement use causing elevated dehydroepiandrosterone sulfate (DHEA-S) levels in a young woman presenting with alopecia. Clinical Case: A 29-year-old Caucasian woman presented for evaluation of progressive alopecia spanning 7 years. She was initially managed by dermatology with topical ketoconazole and clobetasol creams followed by intra-lesional triamcinolone injections. Despite treatment, she had minimal improvement. She reported menarche at age 15 with normal regular monthly menstrual cycles and normal breast development. She has no significant medical history. Physical exam was unremarkable other than localized alopecia and athletic build. She denied any medication use. Routine laboratory screening showed a DHEA-S of 624 ug/dL (ref. 35-430) with repeat DHEA-S at 602.2 ug/dL. Complete blood count, metabolic panel, thyroid function test, total/free testosterone, estradiol, 17-hydroxprogesterone, urinary 17-ketosteroids, prolactin, and iron panel were all within normal limits. Anabolic abuse screen was negative. Adrenal imaging was normal. After discussion on elevated DHEA-S results, patient revealed that she was taking a supplement that contained enobosarm (Ostarine). She was instructed to discontinue the supplement and repeat her labs but she was lost to follow up. Discussion: Developed in 1997, enobosarm is a selective androgen receptor modulator (SARMs) that is increasingly used as a performance-enhancing drug. SARMs have tissue specific androgenic receptor effect and patients on SARMs can present with a completely normal hypothalamic-pituitary gonadal axis without biochemical evidence of hyperandrogenism; which was the case in our patient. Conventional anabolic drug abuse screens do not detect SARMs. There have been multiple studies that have evaluated different performance enhancing supplements and nearly 25% of tested products contained compounds that were not correctly labeled. It is therefore uncertain what may have raised this patient’s DHEA-S levels, but the authors theorize the supplement may have contained exogenous DHEA rather than a direct effect of enobosarm. Unfortunately, there is paucity of data or literature on the effect of SARMs on androgen hormone synthesis and DHEA-S levels. A PubMed search for SARMs and DHEA-S levels led to zero returns. It is important for clinicians to recognize and identify the possibility of SARM or supplement use in order to guide diagnostic and management decisions. Further investigation is needed to understand the impact of SARMs on laboratory data and its long term effects.

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<![CDATA[MON-001 Peripartum Sertraline (Zoloft®) Increases Pup Mortality Immediately Postpartum]]> https://www.researchpad.co/article/elastic_article_8805 Peripartum and postpartum depression can be detrimental to both the mother and the developing child. Use of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), is common during the peripartal period and SSRIs have been the leading prescribed antidepressant to treat maternal depression. One of the most commonly prescribed SSRIs is sertraline (Zoloft®) because of the limited fetal teratogenic effects observed, unlike maternal paroxetine (Paxil®) usage which can manifest in fetal cardiovascular defects. Fluoxetine (Prozac®), like sertraline, has previously been shown to have limited teratogenic effects, however, we have shown treatment with fluoxetine for the entire period of pregnancy and lactation in mice compromises pup bones at weaning resulting in decreased long bone length and head circumference. Furthermore, maternal fluoxetine usage results in a sustained reduction in maternal bone mineral density post weaning, which may lead to long-term osteopenia, putting the mother at risk for bone-related disorders later in life. We hypothesized sertraline, like fluoxetine, will compromise maternal bone postpartum and fetal bone development at weaning. Treatment with sertraline in C57BL/6 dams throughout pregnancy and lactation reduced litter size (5.4 pups/dam) and increased pup mortality during the first 24 hours postpartum (20% dead pups/litter) compared to controls (6.8 pups/dam, 5% dead pups/litter, respectively; P < 0.018). Maternal calcium transporters (Orai1 and Serca2) were downregulated in the mammary gland in sertraline-treated dams on day 21 of lactation (P < 0.0032). Together, our data suggests in utero pharmacological exposure to sertraline may induce a failure to thrive in the pups and alters calcium metabolism in the dam. SSRI exposure during pregnancy and lactation may adversely affect the developing neonate(s) as well as have lasting impacts on the mother.

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<![CDATA[SUN-LB1 Atypical Presentation Of Myocardial Infarction In A Young Patient With Polycystic Ovarian Syndrome]]> https://www.researchpad.co/article/elastic_article_8787 Background: Polycystic ovarian syndrome (PCOS) is a very common and complex endocrine problem in women of childbearing age, with a prevalence of 4 to 12% globally. Myocardial infarction (MI) is the leading cause of death in women worldwide. PCOS increases the risk of MI because of chronic inflammation, endothelial dysfunction, impaired pulse wave velocity and its association with metabolic syndrome, and hormonal imbalance.

Clinical Case: A 36-year-old female with a history of PCOS, hirsutism, severe acne on spironolactone, presented to ER with a chief complaint of lower back pain for 10 days that started after lifting a 60-pounds printer. The pain was attributed to musculoskeletal type, one dose of ketorolac intramuscularly was given and she was discharged on cyclobenzaprine. The next morning, she presented with worsening back pain and new-onset vomiting. Physical exam was normal except for BMI 34.6kg/m2; vitals were stable. Lab work showed elevated troponin of 1.43 which rose to 10.6 ng/ml (normal 0.00-0.034), cholesterol 125 mg/dL (less than 200), HDL 33 mg/dL (normal 40-59), LDL 164 mg/dL (normal 100-129). Electrocardiogram showed sinus tachycardia with Q wave changes in leads III and V1 to V3. Echocardiogram showed hypokinesia of left ventricular wall in the mid to apical anterior septum. Computed tomography (CT) scan of the thoracic spine was negative for abscess or fracture. CT of abdomen and pelvis as well as CT angiography chest were negative. Urine drug screening was also negative.

As her presentation was attributed to MI, patient was started on heparin drip, aspirin, atorvastatin, and metoprolol. She underwent cardiac catheterization that showed 99% ostial left anterior descending artery stenosis; a drug-eluting stent was successfully placed. After intervention her back pain resolved. She was discharged on dual antiplatelet therapy (aspirin and Prasugrel) along with atorvastatin, metoprolol and nitroglycerin.

Conclusion: This case suggests an association of PCOS with MI. A meta-analysis has shown a two-fold increase in risk of coronary artery disease in patients with PCOS (1). Future studies are need to examine opportunities for cardiovascular disease risk reduction in PCOS patients.

Reference:1. de Groot PCM, Dekkers OM, Romijn JA, Dieben SWM, Helmerhorst FM. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Human Reproduction Update 2011. 17 495-500.

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<![CDATA[OR20-03 Transcriptional Changes in Lipid Metabolism of Adipocytes Derived from Subcutaneous Abdominal Adipose Stem Cells of Normal-Weight Polycystic Ovary Syndrome Women]]> https://www.researchpad.co/article/elastic_article_8683 Normal-weight polycystic ovary syndrome (PCOS) women exhibit increased adipose insulin resistance in vivo (1) accompanying enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with greater lipid accumulation per cell in vitro (2). To determine whether this phenomenon is associated with abnormal adipogenic gene transcription during ASC differentiation into adipocytes, SC abdominal ASCs isolated from three non-Hispanic Caucasian normal-weight PCOS women and three age- and BMI-matched controls were cultured in adipogenic differentiation medium for 3–12 days. After RNA isolation, gene expression levels were determined by RNA sequencing at days 3, 7, and 12. Differentially expressed genes were filtered for significance (padj<0.05) and fold change (>2-fold); upstream regulator genes and gene ontology (GO) functions were determined using Ingenuity Pathway Analysis. Gene set enrichment analysis (GSEA) also was used to identify enriched cellular processes (3). Differentially expressed genes in PCOS vs. control cells were either upregulated (466, 768 and 441 genes on days 3, 7 and 12, respectively) or downregulated (742, 974 and 605 genes on days 3, 7 and 12, respectively) over time, with critical genes governing adipocyte cell differentiation in PCOS cells increased 2–6 fold at days 3, 7 and 12 (PPARγ, CEBPα, ADIPOQ, AGPAT2, FABP4, LPL, PLIN1). The predicted upstream regulator genes TGFβ1 (an adipogenic inhibitor) and TNF (a pro-inflammatory adipokine) were significantly reduced in PCOS relative to control cells at all time points. The GO functions lipid oxidation and free fatty acid (FFA) beta-oxidation were enriched amongst upregulated genes in PCOS cells across all time points, while acylglycerol synthesis was increased at days 7 and 12 alone (z>2, p<0.05, all GO functions). In parallel, GSEA showed in PCOS cells significantly increased transcripts related to oxidative phosphorylation, peroxisome activity and adipogenesis at all time points (p<0.05). Thus, adipocytes derived from SC abdominal ASCs of normal-weight PCOS women exhibit early activation of adipogenic genes, potentially underlying their exaggerated lipid accumulation in vitro, as previously described (2). These PCOS-related changes in gene expression involve an increase in both oxidative phosphorylation and FFA beta oxidation, which could disrupt the balance between energy production and lipid storage, particularly when caloric intake exceeds energy utilization. References: (1) Dumesic DA, et al JCEM 2019;104(6):2171–83; (2) Leung KL, et al. JES 2019;3:Supplement 1, SUN-107 (3) Subhramanian A, et al. PNAS 2005;102:43

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<![CDATA[MON-003 Uterine Contractility in Pregnancies Complicated by Obesity: The Effects of Adipokines on the in Vitro Functional Contractility of Isolated Uterine Samples]]> https://www.researchpad.co/article/elastic_article_8674 Objectives: The onset of parturition in pregnant women with obesity is frequently delayed. Without induction, these women are nearly twice as likely as normal-weight to have prolonged pregnancy (≥41 weeks gestation) which is concerning because of associated two-fold increased risk of third-trimester stillbirth. Data from vascular studies have shown that different adipokines have different effects on smooth muscle contractility; either as relaxants or constrictors. However, only few studies have investigated their role in uterine contractility, a relationship that we sought to investigate. Materials and Methods: Total of 22 pregnant women scheduled for term cesarean delivery (CD) were recruited. Strips from the first two participants were used to identify dose response effects for each adipokine, and 20 participants’ data were included in the final analysis. Study groups consisted of normal-weight (N=10) and women with obesity (N=10). Myometrial strips were obtained from the hysterotomy incision at the time of the CD. Muscle strips were mounted within experimental recording baths. Both spontaneous and oxytocin induced contractions were recorded by a custom-build data acquisition software. Adipokines of interest included adiponectin, TNFα, resistin, and omentin. Adipokines were added to the muscle baths after muscle equilibration was achieved. Contractions outcomes of interest included forces, durations, and frequencies. Data comparisons were conducted using Wilcoxon Rank-Sum tests; medians and ranges are presented. Results: Forces of contractions in normal-weight participants were double those studied from participants with obesity (13.9 [9.3-34.3] vs. 8.9 [4.8-23.6], p=0.05). There were no statistically significant differences between contractility outcomes of interest after adding adiponectin, TNFα, and resistin to the muscle baths within and between the study groups. In participants with obesity, compared to baseline, omentin significantly reduced the force of spontaneous induced contractions (p=0.002) and prolonged the period between contractions (p=0.01). Importantly, that effect was not seen in normal-weight participants or in oxytocin induced contractions. Omentin also significantly reduced the forces of spontaneous induced contractions (2.9 [2.2-4.6] vs. 14.4 [4.8-33.6]; p=0.01) and prolonged the period (790.6 [753.0-832.0] vs. 611.4 [128.3-702.7]; p=0.04) in participants with obesity compared to normal-weight participants. Differences were no longer observed after adding oxytocin. Conclusion: In vitro, uterine contractions were reduced in muscle samples prepared from pregnant women with obesity compared to normal-weight counterparts. Omentin may have a role in reduced uterine contractility in pregnant women with obesity and that effect may be corrected by oxytocin administration.

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<![CDATA[SUN-009 Variable Presentation of Two Patients with Gestational Trophoblastic Disease and Hyperthyroidism]]> https://www.researchpad.co/article/elastic_article_8664 Background: Gestational trophoblastic disease (GTD) represents a group of tumours caused by abnormal proliferation of trophoblastic cells, including molar pregnancy. Elevated β-hCG levels are an established marker for the presence of the disease and useful for monitoring. Due to the shared structural homology of β-hCG and TSH, hyperthyroidism can occur.

Clinical Cases: We present two patients with GTD associated with hyperthyroidisim. Case 1, a 20 year old female (G1P0) presented to the emergency department complaining of vaginal bleeding associated with abdominal pain. She was estimated to be 13 weeks. Laboratory evaluation were β-hCG 648 324 IU/L, TSH 0.06 (0.35 - 4.94 mIU/L, free T4 23.2 (9.0 - 19.0 pmol/L, Hb 8.0 (11.6 - 16.4 g/dL). Ultrasound revealed molar pregnancy. She underwent uterine evacuation, thereafter complicated with thyroid storm (Burch Wartofsky score = 45). Post- operative vitals were BP 192/112, pulse rate 120 bpm and temperature 360C. She was managed in high care on labetolol, carbimazole, lugol’s iodine and hydrocortisone.

She was subsequently referred to Medical Oncology for further management. Histology sample obtained in theatre confirmed complete molar pregnancy.

Her staging CT scan indicated the presence of small lung nodules, suggesting metastatic disease. The patient’s FIGO/WHO score was III: 2. At the time of preparing this study, she had already received 7 weeks of methotrexate intramuscularly and still had detectable β-hCG levels.

Case 2 was a 31 year old female presented similarly. This was her second pregnancy (G2P1), 12 weeks by dates. Her vitals were BP 141/74, pulse rate 110 bpm and temperature 36oC. The Ultrasound revealed larger for gestational age uterus with cystic structures in utero. Her quantitative β-hCG was significantly elevated (> 1 500 000 IU/L) she was thyrotoxic [TSH (<0.1 (0.34 - 4.94 mIU/L) free T4 (47.2 (9.0 - 19.0 pmol/L)], however did not develop thyroid storm (Burch Wartofsky score = 20). This patient also underwent uterine evacuation and did well post operatively. She was treated for her thyrotoxicosis with carbimazole, propranolol and thiamine. Further management was by Medical Oncology. Histological examination was in keeping with a partial mole.

Her staging CT scan showed no metastasis, and had a FIGO/WHO score of 1: 4 due to her pre-treatment hCG of >1.5 million IU/L. She received 7 cycles of intramuscular methotrexate from which she achieved and maintained suppressed β-hCG levels (<1 IU/L).

Conclusions: This study has demonstrated that the β-hCG levels may not always correlate with disease severity and prognosis.

When comparing the two patients Case 1 had lower levels of β-hCG and of free T4 than Case 2, however was clinically more unwell, developed thyroid storm and had metastatic disease. Case 2 had hCG levels almost double those of Case 1, wsa stable and her levels decreased much quicker reaching undetectable levels

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<![CDATA[MON-028 Chronic Resveratrol Exposure Improves Glucose Homeostasis and Cardiac Function in a Rat Model of Polycystic Ovarian Syndrome]]> https://www.researchpad.co/article/elastic_article_8660 Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy in women of reproductive age, with a prevalence of 5-8%. Long-term complications seen in PCOS include cardiovascular disease and type 2 Diabetes Mellitus. Current therapies do not completely address the cardiometabolic perturbations seen in women with PCOS. Resveratrol (RSV), a natural polyphenol, is shown to have beneficial cardio-metabolic effects in various pathological conditions including that on insulin sensitivity, cardiovascular function. In-vitro studies suggest it’s beneficial effects on ovarian function as well. Therefore, we hypothesized that chronic exposure to RSV would improve both cardiovascular and metabolic phenotypes in PCOS. To test this hypothesis we used an established rat model of PCOS that develops metabolic derangement and irregular cycles. A 7.5 mg (90-day release) dihydrotestosterone (DHT) pellet providing a daily dose of 83 mcg was implanted in 5-week-old female rats. Studies were also conducted on littermate matched controls (C) with no DHT implant. A subgroup of the control and DHT treated rats (n=6 per group) received a 0.84 g/kg dose of resveratrol (RSV) in their chow starting at age 5 weeks. At 8 weeks, animals were weighed weekly (n=6 per group). Oral glucose tolerance test (OGTT n=6 per group) and cardiac echocardiogram (C n=12, C+RSV n=6, DHT n=10, DHT+RSV n=6) were conducted at 16-weeks of age. Body weight increased significantly in DHT treated rats compared to C between 8 and 16 weeks (40 vs 22 grams, p <0.001). RSV treatment did not mitigate the effects of DHT on body weight (34 vs 40 grams, p>0.5). There was significantly higher glucose excursion at 30 minutes post glucose load in both DHT (148± 7.4 mg/dl) and DHT+RSV (139± 7.4 mg/dl) compared to C group (121± 13 mg/dl, p<0.001, p=0.03 respectively). However, by 60 and 90 minutes only DHT group had a significantly higher glucose excursion compared to both DHT+RSV and C groups (131± 4.1,124± 5.7,110 ± 5.9 mg/dl, p=0.015,p=0.21 respectively); 90min (118±5.8,110±4.7,96±4.2 mg/dl, p<0.01,p=0.09 respectively). By 120 minutes, no significant difference in glucose levels existed between groups. Cardiac echocardiogram showed significantly lower mitral valve E/A ratio (and increased MV isovolumic relaxation time (IVRT) in DHT group compared to C. RSV treatment reversed these changes. In conclusion, RSV improved glucose homeostasis and diastolic dysfunction in the DHT induced rodent model of PCOS and may serve as a novel treatment option targeting the cardiometabolic derangement seen in PCOS. Further studies elucidating the mechanisms underlying the beneficial effects of RSV on cardio-metabolic phenotype in this PCOS rodent model is warranted.

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<![CDATA[SAT-016 Analytical Performance and Clinical Value of AMH Testing]]> https://www.researchpad.co/article/elastic_article_8628 The clinical uses for of anti-Mullerian hormone (AMH) measurements have risen dramatically over the past 5 years. This increase has been driven by the release of fully automated immunoassay systems with European and FDA approval of AMH measurements for assessing ovarian reserve in women presenting at fertility clinics. Most recently the MenoCheck® AMH method was cleared by FDA as an aid in determining menopausal status in women over the age of 40. Arguably much, of the increased use of AMH measurements is due more to greater test availability for infertility than to strong data supporting its clinical utility. Furthermore, few clinicians realize that the current methods for measuring AMH utilize antibodies with difference specificities, non-commutable calibrator materials, and significantly difference analytical performance characteristics.

This presentation will summarize the analytical validation of MenoCheck® AMH methodology and results of the assessment of clinical value. This method is calibrated with recombinant human AMH in a non-covalent complex associated with the cleaved N-terminal portion of the AMH prohormone protein (the major circulating form of AMH) and demonstrates commutability with native human AMH. Validation studies conformed with published Clinical Laboratory Standards Institute guidelines. Values generated by the method were not commutable to other widely available methods based on method comparison studies using control materials or unadulterated serum from normally cycling women. Clinical value assessment was possible only because of a limit of quantitation enabling measurement of AMH in the majority of perimenopausal women. SWAN study specimens carefully annotated with relevant clinical information, including date of their final menstrual period, were available from women sampled and examined during their menopausal transition. The impact of method-specific differences among the various assay systems and their implications for intended clinical use of AMH testing will be discussed. Clinicians and translational investigators must consider these technical specifications when ordering and interpreting results from AMH testing.

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<![CDATA[MON-LB004 Understanding the Influence of Endometrial Cancer Risk Factors Using Human Primary Endometrial Organoids]]> https://www.researchpad.co/article/elastic_article_8616 It is unclear how endometrial cancer risk factors such as obesity, high serum testosterone, and high serum levels of the endocrine-disrupting compound bisphenol-A (BPA) influence hormone action to promote carcinogenesis. We hypothesized that obesity, high testosterone, and BPA exposure alters the protective progesterone response in the benign endometrium. Primary human benign endometrial organoids, consisting of both epithelial and stromal cells, were exposed to each of these risk factors in vitro in the presence of cyclic levels of estradiol, progesterone, and testosterone for 14 days. Progesterone response genes HSD17B2, IGFBP1, PAEP, and PRL were measured by real-time qPCR and IHC. First, to simulate obesity, endometrial organoids were cocultured with increasing numbers of human adipocyte spheroids during the hormone treatment. Real-time qPCR analysis revealed dysregulation of expression of HSD17B2 and IGFBP1 by approximately 20% when cocultured with 30 adipocyte spheroids. In addition, PRL protein levels were significantly lower in the stroma of the endometrial organoids. Second, increasing concentrations of BPA and 3nM testosterone individually or in combination were added to endometrial organoids together with the 14-day menstrual cycle hormones. Treatment with 0.6 ng/mL of BPA decreased expression of HSD17B2, IGFBP1, and PAEP by 50% to 80%. However, this effect was not seen in the context of high testosterone, indicating that there may be crosstalk between these two risk factors. In summary, this study demonstrated that adipocytes, BPA exposure, and high testosterone directly alter progesterone action in benign endometrial organoids, suggesting a diminution of the protective effects of progesterone and an increased risk of endometrial cancer.

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<![CDATA[SAT-010 Non-Classic POR Deficiency as a Cause of Menstrual Disorders &amp; Infertility]]> https://www.researchpad.co/article/elastic_article_8615 P450 oxidoreductase deficiency (PORD) is an autosomal recessive disease caused by bi-allelic mutations of the POR gene. It is responsible for decreased activity of several P450 enzymes including CYP21A2, CYP17A1 and CYP19A1 that are involved in adrenal and/or gonadal steroidogenesis. PORD is typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. Adult-onset PORD has been very seldom reported and little is known about the optimal way to investigate and treat such patients. In this series, we report five women aged 19-38 years, who were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profile by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. In Vitro Fertilization (IVF) followed by frozen embryo transfer under glucocorticoid suppression therapy was performed in two patients. All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum progesterone (P) and 17-OHP levels, which further increased after ACTH administration. Despite excessive P, 17OH-P and 21-deoxycortisol rises after ACTH stimulation suggesting non-classic 21-hydroxylase deficiency, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. Pelvic imaging revealed bilateral ovarian macrocysts in all women. All patients were found to harbor rare bi-allelic POR mutations classified as pathogenic according to American College of Medical Genetics standards. IVF was performed in two women after retrieval of a normal oocyte number despite very low E2 levels during controlled ovarian hyperstimulation. Frozen embryo transfer under glucorticoid suppression therapy led to successful pregnancies. These observations suggest that diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21-hydroxylase deficiency is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation.

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<![CDATA[MON-022 Dissecting the Interplay Between Diet and PCOS Pathology on Gut Microbiota in a PCOS Mouse Model]]> https://www.researchpad.co/article/elastic_article_8543 The gut microbiome has been implicated in the development of metabolic disorders such as obesity and type-2 diabetes, and more recently polycystic ovary syndrome (PCOS). PCOS is a heterogeneous disorder with reproductive, endocrine and metabolic irregularities, and clinical and animal studies have reported that PCOS causes a decrease in microbial diversity and composition. Diet is an important regulator of the gut microbiome, and a recent study identified that alterations in macronutrient balance impact gut microbial communities which correlate with different metabolic health outcomes (1). We have identified that macronutrient balance impacts the development of PCOS traits. Therefore, to investigate the interplay between macronutrient balance and a PCOS environment on the gut microbiome, we analyzed the intestinal microbiome from fecal pellets of control and DHT-induced PCOS mice exposed to 10 different diets that varied systematically in protein (P), carbohydrate (C) and fat (F) content. The amount of dietary P, C and F consumed significantly altered alpha and beta diversity of the gut microbiota of pooled control and PCOS mice (P<0.0001). Alpha diversity between control and PCOS mice on the same diet did not differ significantly, and hence was only affected by diet composition. However, beta diversity was significantly altered between control and PCOS mice (P<0.05). We performed DESeq2 analysis and identified an operational taxonomic unit (OTU) within Bacteroides (OTU3) to be the most differentially abundant OTU between control and PCOS mice, with a significant decrease in PCOS mice compared to controls (control: 7.88 and PCOS: 5.38; fold change = 1.464; P<0.0001). The consensus sequence of Bacteroides OTU3 was found to share 99.2% similarity to Bacteroides acidifaciens. B. acidifaciens is associated with obesity with elevated levels reported to prevent the onset of obesity (2). Thus, we then investigated the influence of P, C and F on the relative abundance of Bacteroides OTU3 and revealed an association with C consumption, with increasing levels of C leading to increased levels of Bacteroides OTU3 (Carb: r= 0.22, p=0.0028, q=0.015). These findings demonstrate that diet exerts a stronger influence over the gut microbiome than PCOS pathology. However, the hyperandrogenic PCOS environment does lead to changes in gut microbiota beta diversity, with a specific decrease in an obesity-associated (2) Bacteroides species in PCOS mice that is also responsive to levels of C consumption. Reference: (1) Holmes et al., Cell Metabolism. 2017; 25(1): 140-151. (2) Yang et al., Mucosal Immunology. 2017, 10 (1), 104-116.

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<![CDATA[SUN-007 Elevated Levothyroxine Requirements Post-Partum as Initial Presentation of Placenta Accreta]]> https://www.researchpad.co/article/elastic_article_8540 Introduction: It is well known that estrogen plays an important role in thyroid regulation. We report an unusual case of post-partum placenta accreta causing pathologic estrogen secretion leading to increased levothyroxine (LT4) requirements and inability to lactate.

Case: A 36-year-old woman with history of Hashimoto’s hypothyroidism presented post-partum day 11 after a normal vaginal delivery with inability to produce breast milk and mildly elevated TSH levels. Prior to her pregnancy, she required an equivalent dose of 142 mcg of LT4 supplementation daily, which increased appropriately to 171 mcg during pregnancy. After delivery, LT4 was decreased to 150mcg in anticipation of normalization of levothyroxine requirements to pre-pregnancy level. However, she had difficulty lactating and was found to have elevated prolactin, estradiol, and TSH levels. The following day, she presented to her obstetrician for persistent vaginal bleeding and was found to have placenta accreta requiring dilation and curettage (D&C). Her LT4 requirements eventually dropped to 125 mcg with decreasing beta-HCG and estrogen levels after successful D&C treatment. She was also then able to produce sufficient breast milk for lactation.

Discussion: This case highlights the effect of estrogen on LT4 requirements during physiologic pregnancy and postpartum with placenta accreta. It is expected that hypothyroid patients have approximately 25-50% increased thyroid replacement requirements during pregnancy, which normalizes soon after delivery.1 Estrogen increases thyroxine-binding globulin and lowers circulating free thyroxine2,, which causes higher thyroid replacement requirements. Estrogen is also known to inhibit lactation. Our patient demonstrates that this holds true even in a pathologically high estrogen state from placenta accreta. Our case uniquely demonstrates a temporal association between estrogen levels and LT4 requirements in the post-partum hypothyroid patient. Patients with inappropriately high TSH levels after delivery should prompt investigation into pathologic causes of elevated estrogen-states, as levothyroxine requirements are expected to normalize immediately post-partum.

References:

1. Bungard TJ, Hurlburt M. Management of hypothyroidism during pregnancy. CMAJ. 2007;176(8):1077-8.

2. Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004 Jul 15;351(3):241-9.

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<![CDATA[SAT-029 AMH Is Higher Across the Menstrual Cycle in Early Post-Menarchal Girls Than in Ovulatory Women]]> https://www.researchpad.co/article/elastic_article_8531 Ovaries of young girls contain healthy and degenerating follicles from the primordial to antral stage, suggesting coordination of growth and atresia. At age 6 yrs, antral follicle (AF) number and size increase; by late puberty, AF count is higher than at any other life stage. The discovery of AMH, a biomarker of AFs, has facilitated the study of the immature ovary. AMH, a granulosa cell product of pre-antral and small AFs, inhibits primordial follicle growth and AF selection. As a marker of AF count, AMH should be highest during puberty, yet cross-sectional studies suggest that AMH peaks in the mid-20’s. In the current studies we compared AMH levels in early post-menarchal girls and regularly cycling adults. The rich phenotypic data available for this adolescent cohort (Sun 2019) was used to investigate further the relationship between AMH, LH, FSH, and sex steroids, and the propensity for anovulatory cycles (ANOV) in girls. 23 healthy girls (12.8–17.6 yrs;1.7±0.2 yrs post-menarche; 56% overweight/obese [OB]) underwent hormone measurements and pelvic ultrasounds during 2 consecutive menstrual cycles. Cycles were classified as ovulatory (OV) based on an LH and E2 peak and P4 >1.65 ng/mL (Sun 2019). AMH was measured in a random subset of samples (5x/subject) with the Ansh ultrasensitive ELISA. Maximum average ovarian volume (VOL) was calculated in the absence of a dominant follicle. Hormones were compared with data from 32 historic adult controls (18–34 yrs; 44% OB) with regular cycles (Lambert-Messerlian 2016). In adults, AMH was measured during the follicular and luteal phase of an OV (5x/subject) using the Ansh assay. AMH was compared among groups using a mixed model. AMH (in adults), LH (in both) and androgens (in girls) were natural log-transformed (ln) before analysis. 11 girls had 2 OV, 5 girls had 1 OV, and 5 girls had no OV; 2 could not be classified due to loss to follow-up. Girls had higher AMH than women (5.2 ± 0.3 vs. 3.3 ± 0.4 ng/mL; p<0.01) and girls with more OV tended to have lower AMH than those with ANOV (2 OV 4.5 ± 0.2, 1 OV 5.7 ± 1.1, 0 OV 6.8 ± 1.1 ng/mL; p=0.1). In girls, AMH correlated with ln_LH (r=0.4, p=0.02), ln_a’dione (r=0.4, p=0.04), ln_testosterone (r=0.5, p=0.02) and VOL (r=0.6, p=0.01) but not with FSH, E2, or BMI. In women, AMH correlated with E2 (r=-0.4, p=0.03) and not with ln_LH or BMI. Within-person variability in AMH was similar in girls and adults (CV 18%). During the early post-menarchal years, AMH levels exceed those of adults with OV, particularly among girls with ANOV, and correlate with LH and androgens. The finding of higher AMH in adolescents is consistent with previous studies demonstrating a peak in AF count during this stage of development. Investigation into how the normal ovary matures and is pruned of excess AFs, either by increased recruitment and growth or by atresia, may provide insights into the pathogenesis of PCOS, wherein follicles are arrested at the pre-antral and antral stage.

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<![CDATA[SUN-005 Hirsutism Due to Bilateral Leydig Cell Tumors]]> https://www.researchpad.co/article/elastic_article_7200 Severe hyperandrogenism in post-menopausal women is rare. It may be caused by either benign or malignant neoplasms of the adrenal or ovary. We report a rare case of a post-menopausal woman with hirsutism associated with virilization due to Leydig cell tumors (LCT) of both ovaries. Case report 61 yo female presented for evaluation of hirsutism. She had also been experiencing increased facial hair growth, deepening of voice, clitoromegaly, alopecia, and acne. Physical examination: normal vital signs. Patient had signs of virilization, including coarse hair along her upper lip, chin, lower abdomen and inner thigh with Ferriman-Gallwey score of 8, acne, and clitoromegaly. She had no signs of acanthosis nigricans or Cushing syndrome. Base line labs: Hemoglobin 16.2 gm/dL (ref 12.0 to 15.5), total testosterone 803 ng/dL (ref 3–41), free testosterone 20.2 pg/mL (ref 0.0–4.2), estradiol 77 pg/mL (<6.0−54.7), estrone 148 pg/mL (ref 7–40), FSH 11.5 mIU/mL (ref 25.8 - 134.8), LH 6.90 mIU/mL (ref 7.7 - 58.5), androstenedione 28 ng/dL (ref 17–99), DHEAS 99.9 mcg/dL (ref 19–205), dehydroepiandrosterone 512 ng/dL (ref 31–701), inhibin A 2.3 pg/mL (ref <5), inhibin B <7.0 pg/mL (ref 00-16.9), 17-alpha hydroxyprogesterone 187 ng/dl (ref <51). Her other serum markers such as anti -Mullerian hormone, alpha-fetoprotein, and hCG were normal. A CT scan of adrenals: normal. Similarly a transvaginal US did not show any ovarian pathology, however MRI of the pelvis showed homogeneous ovarian enhancement bilaterally and based on this information a diagnosis of ovarian hyperthecosis was considered and patient underwent laparoscopic bilateral oophorectomy. Pathology confirmed: LCT in both ovaries. Laboratory values performed 3 months later showed the following values: hemoglobin 14.2 gm/dL, total testosterone 13 ng/dL, free testosterone 1.4 pg/mL, LH 124 mIU/mL, FSH 99mIU/mL, estradiol <5.0 pg/mL. In 6 months she had significant improvement in hirsutism and virilization. Discussion Hyperandrogenism, especially serum testosterone in the male range with rapidly progressive hirsutism or virilization signs in a female indicates tumor etiology. Androgen-secreting ovarian tumors are usually small and often embedded in the ovary. Transvaginal US is useful in the diagnosis of ovarian tumors. However, in our case, transvaginal US failed while MRI scan showed bilaterally enlarged ovaries and with this information patient underwent bilateral oophorectomy. Although 5 cases of bilateral LCT are reported in the literature, LCT is unilateral 95% of the time, the pathogenesis of Leydig cell proliferation and LCT is unclear. In conclusion, androgen secreting tumors should be considered in women (especially in post-menopausal state) with hyperandrogenism and hirsutism. In fact, diffuse stromal Leydig cell hyperplasia and small Leydig cell tumors may be missed on imaging and in some cases only pathology can confirm the result.

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<![CDATA[SAT-002 Does the Age of Women Influence the Evaluation of Ovarian Reserve Through the Determination of Antimullerian Hormone and Follicle Count?]]> https://www.researchpad.co/article/elastic_article_7189 INTRODUCTION: Oocyte number and quality are known to decline with age. However, fertility varies significantly even among women of the same age. Given that maternal age has been delayed in recent years, an ovarian biomarker that could reflect follicular activity with precision and accuracy is needed in reproductive medicine.

In recent years, two key methods, the concentration of serum antimüllerian hormone (AMH), which reflects the number of small antral follicles and is predictive of ovarian response, and antral follicle count (AFC) performed by ultrasonography, have emerged as preferred methods for assessing ovarian reserve.

AIM: To assess the influence of women’s age in the association between AMH serum level and antral follicle count by ultrasonography in the evaluation of ovarian reserve

SUBJECTS AND METHODS: 49 women between 25 and 45 years old who attended our laboratory with request for AMH and transvaginal ultrasound in early follicular phase were included in the study. In all of them serum AMH was tested using an electrochemiluminescence immunoassay (ECLIA) on a Roche Diagnostic Cobas e801 analyzer. Transvaginal ultrasonography follicle count was performed in both ovaries by Philips affinity 70 on first days of the menstrual cycle. Statistical analysis was performed through SPSS 23 software.

RESULTS: Median and ranges of the variables are the following: AMH: 0.78 (<0.03-9.98) ng/ml and AFC: 6 (1.0-60.0) follicles. AMH and AFC were negatively associated with age (r: -0.302, p< 0.01; r: -0.267 p<0.01, respectively). AMH showed a positive correlation with AFC (r=0.567,p<0.01). We then divided the study population in two subgroups, according to age: Group 1, women <40 years old(n=28) and Group 2, women ≥40 years old (n=21).Considering AMH= 1ng/ml and AFC = 7, the cut-off value used routinely in our institution, we calculated the Kappa coefficient in each group to test the degree of agreement between these two variables, with the following results: Group 1, Kappa= 0.4510, CI 95% [0.1566 – 0.7453], p= 0.0088; Group 2, Kappa= -0.0370, CI 95% [-0.4371 – 0.3630], p=ns.

CONCLUSION: despite the positive correlation found between AMH levels and AFC in the whole group, Kappa values show that in women younger than 40 years serum AMH>1 ng/ml is a good predictor of AFC >7, but this agreement is lost in women above this age, with the cut-off values used in this study. These results must be confirmed with a larger group of women.

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<![CDATA[MON-018 Fertility Rates in Rats Characterized by Increased Hypothalamic CRH Secretion]]> https://www.researchpad.co/article/elastic_article_7035 Certain strains of rats are characterized by hyperactive Hypothalamic-Pituitary-Adrenal axis responses to stress, increased hypothalamic Corticotropin-Releasing Hormone (CRH) production and decreased fertility rates. Activation of the HPA-axis and CRH secretion has been associated with suppression of the Hypothalamic-Pituitary-Ovarian axis primarily as a result of glucocorticoids. Here we examined the hypothesis that Fischer rats have decreased fertility rates because of hypothalamic CRH hypersecretion. Antalarmin, a CRH receptor type 1 antagonist, is known to suppress adrenocorticotropin hormone secretion and other CRH receptor type 1-mediated responses. Adult female Fischer rats were injected with antalarmin or placebo, twice a day, for 16 days. Mating was evidenced by the presence of spermatozoa in the vaginal smear performed every morning. After 16 days, 20% of rats (20%) treated with placebo became pregnant and 55% rats treated with antalarmin became pregnant. We have previously reported that administration of antalarmin after the first day of pregnancy does not affect blastocyst implantation in Fischer rats. Our data suggest that antalarmin improves fertility rates in Fischer rats by antagonizing the direct antireproductive role of hypothalamic CRH.

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<![CDATA[SAT-006 A New Concept for the Endocrinology of Pre-Eclampsia: The Role of Spiral Steroids]]> https://www.researchpad.co/article/elastic_article_6920 Background: In 1987, Graves observed that during the 3rd trimester, some patients with pre-eclampsia had high levels of unknown materials that could be detected with assays for digoxin (DLM). In 2018, we characterized a new candidate for the DLM, Ionotropin. It is a phosphocholine (PC) ester of a novel steroid with 23 carbon atoms. As Ionotropin shares structural features (a) with spironolactone (both have spiral lactones in the E-ring) and (b) with digoxin (E-ring lactone and 3α-5β configuration), we have proposed that Ionotropin may function as a potassium (K+) sparing diuretic. This suggestion is supported by the observations that [1] patients who cannot make Ionotropin (7-dehydrosterol reductase deficiency) are K+ wasting and [2] breast cyst fluids with high K+ levels also have high Ionotropin levels.

Hypothesis: During the 3rd trimester, fetal requirements for K+ reach a maximum, fetal blood pressure increases and aldosterone signaling is blocked. This blockage leads to fetal sodium (Na+) wasting and is essential for formation of amniotic fluid. These events are consistent with a normal role for an unknown endogenous K+ sparing hormone and would be the basis for a modest elevation of maternal DLM during the 3rd trimester. Our hypothesis is that if any of the functions were inadequate, then the fetal-placental unit would synthesize excess PC-spiral steroids; the woman would exhibit symptoms of K+ sparing hormone excess (hypertension and proteinuria) and would be diagnosed with pre-eclampsia.

Experimental Results: We have just reported a pilot study associating elevated PC esters of spiral steroids in women with pre-eclampsia. In brief, 12 of 19 women had elevated levels of at least one of the PC steroids (Z-score > 2) when compared to the levels in 20 pregnant women matched for gestational age and fetal sex. There are two basic mechanisms for this dichotomy: (a) there may be episodic secretion with of a DLM with a short half-life or (b) there may be two different underlying biochemical causes. In prior studies, there has been no indication of episodic secretion of DLM similar to that observed with glucocorticoids, Ionotropin or other PC spiral steroids.

Discussion: There are two basic types of K+ sparing diuretics. Type A: Spironolactone functions by regulating the NaK-ATPase. Type B: Triamterene functions by blocking synthesis of epithelial Na+ channels. Thus, Type A would have high levels of spiral steroids and Type B would have low levels of spiral steroids. Type A patients would be expected to have higher risk of long-term consequences when compared to the Type B patients.

Conclusion: The recognition of the division of pre-eclampsia into two separate diseases might be the key observation for developing Type-specific diagnosis and therapy. For example, a Type A patient might benefit from a low salt diet but that diet would not be expected to benefit a patient with Type B disease.

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<![CDATA[A value‐based healthcare approach: Health‐related quality of life and psychosocial functioning in women with Turner syndrome]]> https://www.researchpad.co/article/elastic_article_6782 As part of the value‐based healthcare programme in our hospital, a set of patient‐reported outcome measures was developed together with patients and implemented in the dedicated Turner Syndrome (TS) outpatient clinic. This study aims to investigate different aspects of health‐related quality of life (HR‐QoL) and psychosocial functioning in women with TS in order to establish new possible targets for therapy.Design/ParticipantsA comprehensive set of questionnaires (EQ‐5D, PSS‐10, CIS‐20, Ferti‐QoL, FSFI) was developed and used to capture different aspects of HR‐QoL and psychosocial functioning in a large cohort of adult women with Turner syndrome. All consecutive women, ≥18 years, who visited the outpatient clinic of our tertiary centre were eligible for inclusion.ResultsOf the eligible 201 women who were invited to participate, 177 women (age 34 ± 12 years, mean ± SD) completed at least one of the validated questionnaires (88%). Women with TS reported a lower health‐related quality of life (EQ‐5D: 0.857 vs 0.892, P = .003), perceived more stress (PSS‐10:14.7 vs 13.3; P = .012) and experienced increased fatigue (CIS‐20: P < .001) compared to the general Dutch population. A relationship between noncardiac comorbidities (eg diabetes, orthopaedic complaints) and HR‐QoL was found (R = .508).ConclusionsWe showed that TS women suffer from impaired HR‐QoL, more perceived stress and increased fatigue compared to healthy controls. A relationship between noncardiac comorbidities and HR‐QoL was found. Especially perceived stress and increased fatigue can be considered targets for improvement of HR‐QoL in TS women. ]]> <![CDATA[SAT-023 Osteosarcopenia in Reproductive-Aged Women with Polycystic Ovary Syndrome: A Multicenter Case-Control Study]]> https://www.researchpad.co/article/elastic_article_6560 Osteosarcopenia is defined by the loss of skeletal muscle and bone mass and/or function usually associated with aging. Osteosarcopenia shares common risk factors and pathophysiological mechanisms with polycystic ovary syndrome (PCOS), including obesity and endocrine aberrations. Relationship between osteosarcopenia and PCOS has biological plausibility yet remains unclear. We hypothesized (1) reproductive-aged women with PCOS would exhibit early signs of osteosarcopenia evidenced by decreased appendicular skeletal muscle index (appendicular skeletal muscle mass/weight (kg) × 100 = SMI%), and bone mineral density (BMD); and (2) SMI% and BMD are aggravated by endocrine disruptions in PCOS. The SMI% and BMD of 203 women (18 – 48 y) were compared across 4 groups: (1) PCOS (hyperandrogenism and oligoamenorrhea), (2) hyperandrogenism and eumenorrhea (HA), (3) normoandrogenic oligoamenorrhea (OA), and (4) Controls. Associations between endocrine measures and SMI% and BMD were evaluated by partial correlations and all comparisons were adjusted for age and obesity. Women with PCOS exhibited reduced total SMI% (mean [95% confidence interval]; 26.2% [25.1 – 27.3] vs. 28.8% [27.7 – 29.8]), lower-extremity SMI% (LESMI%; 57.6% [56.7 – 60.0] vs. 62.5% [60.3 – 64.6]), and total BMD (1.11 [1.08 – 1.14] vs. 1.17 [1.14 – 1.20] g/cm2) compared to Controls. Women with PCOS also had decreased upper (0.72 [0.70 – 0.74] vs. 0.73 [0.71 – 0.76] g/cm2) and lower (1.13 [1.10 – 1.16] vs. 1.15 [1.12–1.18] g/cm2) limb BMD compared to the HA group. Insulin sensitivity evidenced by Matsuda index was declined in PCOS group compared to Controls, yet was positively associated with SMI% in all groups (All: P ≤ 0.05). The OA group exhibited exaggerated insulin-like-growth-factor-1 (IGF-1) compared to Controls (P = 0.01) that had negative associations with LESMI% (r = -0.90; P < 0.01). Only Controls showed positive associations between IGF-1 and upper (r = 0.84) and lower (r = 0.72) limb BMD (All: P < 0.01). Unlike PCOS group, estradiol (r = 0.64) and the ratio of luteinizing hormone to follicle-stimulating hormone (r = 0.54) were positively associated with BMD (All: P < 0.05) in OA group. Also, unlike PCOS group, IGF binding protein-2 (IGFBP-2) was positively associated with muscle or bone mass in other groups. Specifically, IGFBP2 was associated with SMI% in Controls (r = 0.45) and HA (r = 0.67), with LESMI% in OA (r = 0.91), and with upper limb BMD (r = 0.98) in HA groups (All: P < 0.05). Reproductive-aged women with PCOS exhibited early signs of osteosarcopenia likely owing to their unique metabolic and endocrine alterations. Perturbations in insulin signaling and function may drive muscle and bone loss in PCOS. Understanding the biological mechanisms and management strategies that may delay or prevent the development of osteosarcopenia is recommended to improve the musculoskeletal health and associated long-term comorbidities of PCOS.

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