bluuebunny/crossref_metadata_2025_split huggingface dataset:
THU632 Musculoskeletal Composition And Function In Polycystic Ovary Syndrome: Early Evidence From A Prospective Study
Authors: Kazemi Maryam , Michalak Julia , Xavier Isabella B , Parry Stephen A , Lujan Marla E 
Published: October 2023

Abstract
Disclosure: M. Kazemi: None. J. Michalak: None. I.B. Xavier: None. S.A. Parry: None. M.E. Lujan: None.
Current evidence on the body composition of women with polycystic ovary syndrome (PCOS) is primarily focused on fat accumulation and impaired fat function. The relevance of PCOS to non-fat (skeletal muscle, bone) components of body composition remains unknown, despite the clinical and prognostic value for musculoskeletal function and healthy aging. We recently showed a link between PCOS and the loss of skeletal muscle mass and bone concurrent with fat infiltration. While our observations reflect an aberrant musculoskeletal composition in PCOS, any impact on function is unknown. The objective of the current study was to test the hypothesis that musculoskeletal function and composition are poorer in PCOS vs. controls without PCOS. This work represented early evidence from a prospective case-control study (N=25, age 18-35y; BMI 18.2-41.5 kg/m2). Cases were defined as those with PCOS (NIH criteria; n=12). Controls were those without PCOS (n=13). Musculoskeletal composition traits (bone mineral density [BMD], lean body mass [LBM]) were evaluated by dual-energy X-ray absorptiometry. Furthermore, musculoskeletal function traits (maximum and average isometric strength of the hand and forearm muscles in 3 trials) were evaluated with a hydraulic dynamometer. Associations between PCOS status and traits were evaluated using generalized linear regression models. All p-values were BMI adjusted. Analyses of the musculoskeletal composition traits revealed comparable BMD between PCOS cases and controls (mean [SD]: 1.13 [0.03] vs. 1.11 [0.02] g/cm2; P=0.30). In contrast, PCOS cases showed an association with lower LBM vs. controls (40.98 [26.71] vs. 43.86 [24.10] kg; P&lt;0.001). Regarding musculoskeletal function, PCOS cases showed an association with lower maximum (29.10 [1.89] vs. 34.46 [1.88] kg; P=0.007) and average (27.33 [1.84] vs. 32.35 [1.88] kg; P=0.008) isometric strength of the dominant hand vs. controls. Similarly, PCOS cases showed an association with lower maximum (28.10 [2.15] vs. 32.25 [1.69] kg; P&lt;0.001) and average (26.93 [2.04] vs. 30.42 [1.61] kg; P&lt;0.001) isometric strength of the non-dominant hand vs. controls. Quantitative musculoskeletal traits, including lower LBM and hand grip strength differ in PCOS vs. controls. These findings reflect poorer skeletal muscle mass, physical fitness, and overall health status in PCOS. If confirmed by longitudinal studies, these observations may translate to a greater risk for musculoskeletal derangements in later life stages. Potential mechanisms underlying these aberrations are being investigated and will likely reveal environmental and biological pathways (assuming interactive) beyond obesity per se. Future studies should also delineate causal pathways of PCOS to musculoskeletal aberrations.
Presentation: Thursday, June 15, 2023
THU635 Metabolic Characteristics Among Polycystic Ovary Syndrome-Phenotypes In A Sample Of Hispanic Patients
Authors: Gonzalez-Rodriguez Loida Alejandra , Arroyo Isabel C , Diaz-Rios Beatriz , González-Sepúlveda Lorena , Casas-Loyola Cristina M , Bermúdez-Santos Jadailine , Pérez-Cardona Cynthia , Romaguera Josefina , Azziz Ricardo 
Published: October 2023

Abstract
Disclosure: L.A. Gonzalez-Rodriguez: Research Investigator; Self; Eli Lilly & Company. I.C. Arroyo: None. B. Diaz-Rios: None. L. González-Sepúlveda: None. C.M. Casas-Loyola: None. J. Bermúdez-Santos: None. C. Pérez-Cardona: None. J. Romaguera: None. R. Azziz, MD, MBA, MPH: Advisory Board Member; Self; Arora Forge. Consulting Fee; Self; Rani Therapeutics, Spruce Biosciences, Fortress Biotech, Core Access Surgical Technologies. Grant Recipient; Self; Ferring Pharmaceuticals. Stock Owner; Self; Martin Imaging.
PURPOSE: Polycystic Ovary Syndrome (PCOS), a common endocrinopathy affecting women in their reproductive years, is associated with an increased risk for cardiometabolic comorbidities. Even though PCOS is a common condition, there is often a delay in diagnosis and treatment due to several proposed diagnostic criteria. Due to the complexity of this syndrome and different clinical manifestations, it has been recommended to identify their 4 phenotypes. This study aimed to compare the clinical and metabolic characteristics among PCOS-phenotypes in a sample of Hispanic patients. METHODS: This is a cross-sectional study of females between 21-45 years of age with confirmed PCOS using the Rotterdam criteria. Patients were classified according to phenotypes: A, hyperandrogenism (HA), oligoovulation/menstrual dysfunction (OA/MD), and polycystic ovarian morphology (PCOM); B, HA + OA/MD; C, HA + PCOM; D, OA/MD + PCOM. Metabolic Syndrome (MetS) was diagnosed using ATP III criteria. Metabolic characteristics were compared between groups. RESULTS: Sixty-three patients with PCOS were evaluated with phenotypes A (60%), B (21%), C (5%), and D (14%). Only 26 patients (41%) had a previous diagnosis of PCOS. The prevalence of MetS in this sample was 52.4%. Among the phenotypes, phenotype B had the higher prevalence of MetS (61.5%) followed by phenotype D (55.6%) and phenotype A (52.6%). Significant differences in obesity, waist, and hip circumference were found, with phenotype-C having lower parameters (p ≤ 0.05). A tendency for lower BMI, waist-to-hip-ratio, HOMA-IR, and hs-CRP levels was also observed in phenotype-C. CONCLUSION: Our study found a high prevalence of MetS in this sample of patients with PCOS; phenotypes affected by menstrual dysregulation having a higher prevalence. Less than half of patients with PCOS were previously diagnosed despite multiple medical evaluations for symptoms, which emphasizes the importance of an early diagnosis to avoid cardiometabolic complications.
Presentation: Thursday, June 15, 2023
THU636 Prevalence Of Metabolic Syndrome In A Sample Of Hispanic Patients With Polycystic Ovary Syndrome
Authors: Arroyo Isabel C , Gonzalez-Rodriguez Loida , Rios Beatriz Diaz , Rivera-Rodriguez Yanni , Garcia-Irizarry Adriana , Cabrera-Martinez Hilary , Gonzalez-sepulveda Lorena , Perez-Cardona Cynthia , Romaguera Josefina , Azziz Ricardo 
Published: October 2023

Abstract
Disclosure: I.C. Arroyo: None. L. Gonzalez-Rodriguez: None. B. Diaz Rios: None. Y. Rivera-Rodriguez: None. A. Garcia-Irizarry: None. H. Cabrera-Martinez: None. L. Gonzalez-sepulveda: None. C. Perez-Cardona: None. J. Romaguera: None. R. Azziz, MD, MBA, MPH: Advisory Board Member; Self; Arora Forge. Consulting Fee; Self; Rani Therapeutics, Spruce Biosciences, Fortress Biotech, Core Access Surgical Technologies. Grant Recipient; Self; Ferring Pharmaceuticals. Stock Owner; Self; Martin Imaging.
PURPOSE: Polycystic ovary syndrome (PCOS) is an endocrinopathy affecting women of reproductive age. It confers an increased risk of comorbidities such as metabolic syndrome (MetS), cardiovascular (CV) disease, diabetes mellitus, and cancer. There is limited information about how this association impacts Hispanic women, a high-risk group for cardiometabolic disease. This study aimed to evaluate the association between PCOS and MetS in a sample of Hispanic patients. METHODS: This is a cross-sectional study of female patients between 21-45 years of age who underwent evaluation for PCOS and MetS. Patients underwent clinical, laboratory, and imaging studies. PCOS was diagnosed using the Rotterdam criteria and MetS was diagnosed using ATP III criteria. Prevalence of MetS and associated variables were compared between groups. RESULTS: Seventy-eight patients were included in this study (63 patients with PCOS+ and 15 patients with PCOS-). Mean age was 31 ± 6 years. PCOS+ patients were younger. MetS were observed in 52.4% of patients PCOS+ vs 40% of patients PCOS- (p&gt;0.05). No significant differences were found in BMI, waist circumference, blood pressures, triglycerides, HDL, fasting glucose levels, insulin levels, and A1c among groups (p&gt;0.05). A higher prevalence of elevated hs-CRP was observed in patients with PCOS+ (60.3%) vs PCOS- (42.9%). CONCLUSION: Our study found a prevalence of 52.4% of MetS in a sample of patients with PCOS+. Previous studies have shown a 41% prevalence of MetS among Puerto Rican women and 44% prevalence in women with PCOS. PCOS is associated with an increased risk of CV disease, cancer, and diabetes, the leading causes of death in PR. Strategies to decrease this prevalence and avoid its complications in our population are imperative.
Presentation: Thursday, June 15, 2023
OR03-01 Functional Rescue Of Trafficking-Defective Mutant Follicle-Stimulating Hormone Receptors (FSHR) Leading To Premature Ovarian Failure With The Pharmacoperone CAN1405
Authors: Ulloa-Aguirre Alfredo , Zariñán Teresa , Gutiérrez-Sagal Rubén , Nataraja Selvaraj , Yu Henry N , Jardón-Valadez Eduardo 
Published: October 2023

Abstract
Disclosure: A. Ulloa-Aguirre: None. T. Zariñán: None. R. Gutiérrez-Sagal: None. S. Nataraja: None. H.N. Yu: None. E. Jardón-Valadez: None.
Inactivating mutations in the follicle-stimulating hormone (FSH) receptor (FSHR) cause premature ovarian failure. Approximately 30% of mutant FSHRs (mutFSHR) are misfolded proteins unable to route to the plasma membrane (PM). We herein tested the effect of a small molecule FSHR ago-allosteric modulator (CAN1405) on the functional rescue of several inactivating mutFSHR. Wild-type (WT) and mutFSHRs A189V, A191I and D224V (at the ectodomain), and four FSHRs with mutations in the serpentine region (SR) of the receptor (D408Y, A419I, I423T, and P519T) were expressed in HEK-293 cells and stimulated with recombinant FSH in the presence of vehicle or CAN1405. Changes in plasma membrane expression and function provoked by CAN1405 exposure were analyzed by immunoblotting and by activation of the cAMP-sensitive pSOMLuc reporter plasmid and ERK1/2 phosphoryation, respectively. Molecular interactions between FSHR and CAN1405, were predicted in silico by computational docking. Exposure of WT and mutFSHR-expressing cells to CAN1405 increased the ratio of mature (PM-expressed) to immature (intracellular) FSHR forms (m/i ratio) of all SR mutant FSHRs (from 0.5 to 3.0) as disclosed by immunoblotting. Similar results were observed when activation of the cAMP-sensitive pSOMLuc reporter and ERK1/2 phosphorylation were examined in FSH-stimulated cells. PM expression of FSHR WT and the activation-defective mutFSHR I423T, but not the FSHRs with mutations in the ectodomain, were also increased by CAN1405. Interesting, in the presence of CAN1405, signaling of the mutFSHR I423T was marginal in terms of activation of the pSOMLuc reporter but not of pERK1/2, suggesting that binding of CAN1405 to the mutFSHR changed the conformation of the receptor allowing functional selectivity on FSH-stimulated signaling. CAN1405 was located in a binding pocket at interhelical upper half of the FSHR. Side chains of residues Y530, A450, T449 S453, L415, H615, M585, V612, I588, and K608 were detected in close interaction with the CAN1045 and the FSHR-CAN1405 complex was likely stabilized by hydrophobic interactions. It is concluded that the small molecule CAN1405 with ago-allosteric properties is an effective pharmacological chaperone that corrects trafﬁcking of SR misfolded mutFSHRs and also increases WT FSHR expression and function. These data demonstrate that allosteric modulators of the FSHR may serve as an effective therapeutic approach for the treatment of infertility in women bearing the WT FSHR or in heterozygous carriers of mutations at the transmembrane domain of this receptor.
Presentation: Thursday, June 15, 2023
OR04-01 Single Nucleus RNA Sequencing Reveals Diet Induced Obesity And SGLT2 Inhibitor Therapy Modulate the Testes Transcriptome In Male Mice
Authors: Ozturk Berkcan , Efthymiou Vissarion , Ali Waqar , Ferraz-Bannitz Rafael , Erika Pacheco , Navarrete Valerie , Dreyfuss Jonathan M , Pan Hui , Patti Mary-Elizabeth 
Published: October 2023

Abstract
Disclosure: B. Ozturk: None. V. Efthymiou: None. W. Ali: None. R. Ferraz-Bannitz: None. P. Erika: None. V. Navarrete: None. J.M. Dreyfuss: None. H. Pan: None. M. Patti: Consulting Fee; Self; AstraZeneca, MBX-Biosciences, Hanmi Pharmaceutical. Other; Self; DSMB: Fractyl Health, Inc.
Paternal environmental exposures during postnatal life can influence health of their offsprings, modulating risk of metabolic disease. We have previously shown that pharmacologic interventions to improve the health of fathers may also reduce metabolic disease risk of offsprings. To identify potential mechanisms responsible for paternally-mediated intergenerational metabolic disease risk, we analyzed the transcriptome in testes using single-nucleus RNA sequencing. C57BL/6J male mice, age 8 weeks, were treated with low fat (10% fat) or high fat diet (HFD, 60% fat) diet to induce obesity and hyperglycemia; after 4 weeks, HFD-fed mice were randomized to continued HFD or HFD containing the SGLT2 inhibitor canagliflozin (250 mg/ kg/ day) (CANA). After 20 weeks, we dissected testes for single nucleus RNA sequencing (LFD, HFD, CANA n=3,4,4 respectively). Unsupervised clustering revealed 35 distinct clusters. We employed supervised cell-calling and identified 13 distinct canonical testis-residing cell types and 2 novel subtypes. The magnitude of differential expression between groups was most pronounced in Leydig cells, pachytene-stage cells, and round spermatids, suggesting that the transcriptome of particular cell types in testis is more robustly affected in response to obesity. Ontology analysis of differentially expressed genes (DEG) in those 3 cell types (FDR≤0.1 for input genes and p≤0.05 for enrichment analysis) revealed that downregulated genes in HFD as compared to LFD were enriched in cytoskeletal element organization, posttransciptional and posttranslational modifications respectively. Importantly, upregulated genes in CANA compared to HFD were also enriched in similar ontology terms. In addition, ontology analysis of DEGs in CANA compared to HFD showed enrichment in mitochondrial oxidative phosphorylation in Leydig cells and round spermatids which suggests unique transcriptomic changes driven by canagliflozin in these cell types. Thus, diet-induced obesity has striking effects to remodel the testicular transcriptome, with substantial reversal by SGLT2i. Transcriptomic differences induced by high fat diet and reversed by SGLT2i may reveal molecular mechanisms that mediate the reduction in risk of metabolic disease to offspring.
Presentation: Thursday, June 15, 2023
OR09-02 Chemogenetic Manipulation Of Brainstem Noradrenergic Neurons Modulates The Activity Of The Kisspeptin GnRH Pulse Generator In Mice
Authors: Vas Szilvia , Ruiz-Cruz Miguel , Han Su Young , Hwa-Yeo Shel , Herbison Allan Edward 
Published: October 2023

Abstract
Disclosure: S. Vas: None. M. Ruiz-Cruz: None. S. Han: None. S. Hwa-Yeo: None. A.E. Herbison: None.
The kisspeptin neurons in the arcuate nucleus (ARNKISS) represent the GnRH pulse generator that drives pulsatile luteinizing hormone secretion. These neurons serve as a hub to integrate multiple cues, such as the negative feedback control from steroid hormones, as well as metabolic, and stress-related inputs. Brainstem noradrenergic (NA) neurons have long been implicated in the control of GnRH pulse generator frequency and fertility but the precise mechanisms through which they operate, and their roles remain unclear. Here we used intersectional Cre-lox and FLP-FRT recombination approaches to couple ARNKISS neuron GCaMP6 fiber photometry with the brainstem NA DREADD (Designer Receptor Exclusively Activated by Designer Drug) modulation to investigate the role that NA may play in controlling ARNKISS pulse generator activity. Kiss1-Cre,GCaMP6s mice were crossed with a mouse line in which FLP recombinase is expressed selectively in dopamine β-hydroxylase (NA) neurons. Adult female mice were injected bilaterally with a FLP-dependent retrograde viral vector (AAVrg-hSyn-fDIO-hM3D(Gq)-mCherry-WPREpA) into the mid-caudal ARN to express excitatory (hM3Dq) DREADD receptors selectively in brainstem NA neurons that project to the ARN. An optical fiber was then implanted to detect the calcium-dependent population activity of KISSARN neurons. Histology revealed m-Cherry/DREADD expression in small sub-populations of tyrosine-hydroxylase neurons located in the brainstem A1, A2 and A6, confirming direct innervation from these regions to the ARN. Selective activation of these NA neurons with 1.5 and 3 mg/kg CNO (s.c.) in diestrous-stage mice, dose-dependently inhibited the frequency of the pulse generator synchronization episodes by 48-76% over 4 hours. These observations demonstrate that, when activated, brainstem NA neurons exert an inhibitory influence on the kisspeptin GnRH pulse generator in intact female mice. The new data may help to dissect how key components of the stress-responsive circuitry impact the central regulation of fertility.
Presentation: Friday, June 16, 2023
OR09-03 Loss of Inhibin Negative Feedback In The Pituitary Leads To Enhanced Ovulation But Pregnancy Failure In Mice
Authors: (Claire) Lin Yeu-Farn , Brule Emilie , Cowan Mitra , Boehm Ulrich , Bernard Daniel J 
Published: October 2023

Abstract
Disclosure: Y. Lin: None. E. Brule: None. M. Cowan: None. U. Boehm: None. D.J. Bernard: None.
Loss of inhibin negative feedback in the pituitary leads to enhanced ovulation but pregnancy failure in mice
Follicle-stimulating hormone (FSH) is an essential regulator of gonadal function, particularly in females. Inhibins are TGFβ family ligands made in the gonads that suppress FSH synthesis. Inhibins require a co-receptor, betaglycan or TGFBR3L, to mediate their actions in pituitary gonadotrope cells. Female mice with a gonadotrope-specific knockout of betaglycan or global deletion of Tgfbr3l exhibit increased ovarian follicle development, numbers of ovulated eggs, and litter sizes compared to controls. Females with both co-receptors knocked out (hereafter dKO) show dramatic increases in FSH levels, numbers of antral follicles and corpora lutea, serum progesterone levels, and ovarian aromatase expression. They ovulate 3-4 times as many eggs in natural cycles compared to control females. dKO females can become pregnant and show an increased number of implanted embryos at 7.5 days post coitum (7.5 dpc). Nevertheless, dKO females do not give birth to live offspring. By 10.5 dpc, the weight of the fetoplacental unit is decreased in dKO females, and many embryos display morphological abnormalities. By 14.5 dpc, most embryos in dKO females are either dead or resorbing. Wild-type surrogates give birth to live young following transplantation of embryos from control or dKO females. Conversely, control but not dKO females carry wild-type embryos to term. These data suggest that the maternal environment in dKO mice cannot support full-term pregnancies. Based on the hormonal profile of the cycling females, we suspected a deleterious effect of elevated estrogens. Consistent with this idea, treatment with the aromatase inhibitor anastrozole increased fetal survival in some dKO mice, suggesting a role for estrogens in embryo death. We are currently more thoroughly characterizing the maternal hormonal environment throughout gestation and investigating placental structure/function to gain more insight into the precise nature of the pregnancy failure. Our results will show how loss of inhibin action in the pituitary impede embryo survival and whether pregnancy loss is linked to increases in FSH.
Presentation: Friday, June 16, 2023
FRI381 Melanocortin 4 Receptor Signaling In Sim-1 Neurons Permits Sexual Receptivity In Female Mice
Authors: Harberson Mitchell Thomas , Semple Erin , Hill Jennifer W 
Published: October 2023

Abstract
Disclosure: M.T. Harberson: None. E. Semple: None. J.W. Hill: None.
Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear. In this study, female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) paired with males were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice). Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects. These results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits.
Presentation: Friday, June 16, 2023
FRI383 Androgen Receptor Signaling Regulates Follicular Growth And Steroidogenesis In The Ovary In Interaction With Gonadotropins During Mini-puberty In Mice
Authors: Devillers Marie , François Charlotte M , Chester Mélanie , Corre Raphael , Cluzet Victoria , Giton Frank , Cohen-Tannoudji Joelle , Guigon Celine J 
Published: October 2023

Abstract
Disclosure: M. Devillers: None. C.M. François: None. M. Chester: None. R. Corre: None. V. Cluzet: None. F. Giton: None. J. Cohen-Tannoudji: None. C.J. Guigon: None.
Introduction: In females, androgens contribute to ovarian diseases such as polycystic ovary syndrome (PCOS), but their action is also crucial for ovarian physiology, i.e., follicular growth and estradiol (E2) synthesis during reproductive life, in interaction with the gonadotropins LH and FSH. However, it is unclear whether androgens already play a role in the ovary at mini-puberty, a phase of postnatal development with active follicular growth and high E2 levels. Hypothesis/question: Given their role in the adult ovary, we hypothesized that androgens may regulate early ovarian function at mini-puberty. Therefore, we analyzed their potential actions on the ovary and their possible interaction with gonadotropins during this period. Methods: We used the mouse as an experimental model to measure the intra-ovarian content and serum levels of testosterone by gas chromatography-mass spectrometry (GC-MS) at different prepubertal ages, including mini-puberty. We performed molecular-based studies (immunohistochemistry, RT-qPCR), morphometric studies and pharmacological approaches in vivo and in cultured ovaries. Main results: We found that mini-pubertal ovaries produce significant amounts of testosterone and display androgen receptor (AR) expression in growing follicles, both under the control of LH. By blocking AR signaling with flutamide either in vivo or in ovarian cultures, we found that this pathway may participate in the regulation of prepubertal E2 synthesis and follicular growth, possibly by regulating the expression of a number of key intra-ovarian regulators, including FSH receptor (Fshr), the aromatase enzyme converting androgens into estrogens (Cyp19a1) and the cell cycle inhibitor p27KIP1 (Cdkn1b). We further showed that AR may stimulate FSH-mediated regulation of Cyp19a1 through its action on Fshr mRNA abundance. Conclusion: This work supports the idea that AR signaling is already activated in mini-pubertal ovaries to regulate E2 synthesis and follicular growth, in interaction with LH and FSH signaling. This early physiological action of androgens may contribute to the implementation of early ovarian function with possible impacts on reproductive function.
Presentation: Friday, June 16, 2023