bluuebunny/crossref_metadata_2025 huggingface dataset:
6777 Exploring the comorbidity in males with 45,X/46,XY mosaicism unveils a pattern mirroring that of Turner syndrome
Authors: Stochholm K , Gravholt C H , Berglund A
Published: October 2024

Disclosure: K. Stochholm: None. C.H. Gravholt: None. A. Berglund: None.

Background: Males with 45,X/46,XY mosaicism are rare with an apparent prevalence of 6 per 100,000 newborn males. Knowledge about associated health outcomes are limited. Females with 45,X/46,XY fall under the Turner syndrome diagnosis but males do not. Aim: To investigate the comorbidity pattern in a national cohort of males with 45,X/46,XY. Methods: Morbidity were investigated using Cox regression analysis on administratively longitudinally collected registry data regarding hospital diagnoses, prescribed medication, and surgery codes. Data were retrieved for all males diagnosed with 45,X/46,XY from 1960 to 2018 (n=135) and for 13,500 age-matched males from the general population, who served as comparator. Results: 45,X/46,XY was associated an increased overall risk of receiving a hospital diagnosis (HR: 1.6, CI: 1.3-1.9), being prescribed medication (HR: 1.2, CI: 1.03-1.5), and undergoing a surgical procedure (HR: 1.8, CI: 1.4-2.1). Dividing hospital diagnoses into 18 chapters according to the International Classification of Diseases (ICD-10), 45,X/46,XY had a significantly increased risk of diagnoses in all but three chapters. Among diagnoses with a significantly increased risk were gonadal dysfunction (HR=63.7, CI: 34.8-116.9), short stature (HR=24.7, CI: 10.0-60.6), pubertal disorders (HR=25.8, CI:7.2-92.6), type 1 (HR=4.1, CI: 1.8-9.4) and type 2 diabetes mellitus (HR=3.4, CI: 1.7-6.6), thyroid disorders (HR=3.8, CI: 1.4-10.4), obesity (HR=4.4, CI: 2.3-8.2), osteoporosis and osteopenia (HR=5.4, CI: 2.4-12.3), hearing loss (HR=2.2, CI: 1.3-3.8), otitis media (HR=1.6, CI: 1.3-1.9), ischemic heart disease (HR=2.4, CI: 1.3-4.4), hypertension (HR=2.3, CI: 1.4-3.9), inflammatory bowel disease (HR=2.5, CI: 1.2-5.4), cryptorchidism (HR=11.9, CI: 7.8-17.8), hypospadias (25.9, CI: 14.0-47.8), testis cancer (HR=6.4, CI: 2.0-20.6), infertility (HR=23.5, CI: 16.0-34.4), gynecomastia (HR=4.6, CI: 1.7-12.5), horse shoe kidney (HR=177,8, CI: 16.1-1968.8), coarctation of the aortae (HR=66.0, CI: 11.0-394.9), and bicuspid aortic valve (HR=53.4, CI: 12.7-223.7). Conclusion: Males with 45,X/46,XY mosaicism exhibit heightened morbidity, evidenced by a notable surge in hospital diagnoses, prescribed medications, and surgical interventions. This increased morbidity is linked to a broad spectrum of diseases, showcasing a comorbidity pattern reminiscent of Turner syndrome. This study emphasizes the need for systematic follow-up in individuals with 45,X/46,XY mosaicism, highlighting the imperative for proactive healthcare management in this population.

Presentation: 6/1/2024
12440 Exploring The Potential Protective Role Of The Bacterial-derived Metabolite Indole-3-propionic Acid Against Obesogenic Insults In Placenta Cell Lines
Authors: Ernst J , Conlon L , Gupta R , Kang L , Heard-Lipsmeyer M E
Published: October 2024

Disclosure: J. Ernst: None. L. Conlon: None. R. Gupta: None. L. Kang: None. M.E. Heard-Lipsmeyer: None.

Obesity during pregnancy is associated with detrimental changes in placental function that lead to the development of complications such as gestational diabetes and preeclampsia as well as altered metabolism in the offspring. With the incidence of obesity reaching epidemic levels world-wide, it is imperative to find mechanisms to mitigate these risks during pregnancy. The gut-microbiome is a diverse system that regulates numerous body functions through the secretion of specific metabolites. Gut dysbiosis has recently emerged as one mechanism that contributes to placental dysfunction and clear associations between obesity and gut dysbiosis are evident. Indole-3-propionic acid (IPA) is a gut microbiome-derived metabolite that has anti-inflammatory, anti-oxidative stress and glucose regulatory functions, all of which are dysregulated in obesity. Previous studies have found diminished levels of IPA in serum of women with overweight/obesity. However, it remains unknown what the physiological functions of IPA are in the placenta and if it could have potential protective effects against perturbations caused by obesity. The objective of this study is to determine what physiological role IPA plays in the placenta and if IPA can protect against obesogenic insults that contribute to placental pathology. For this study, we developed an in vitro model of obesity where two human placental cell lines, BeWo (choriocarcinoma) and HTR8 (normal immortalized trophoblasts) were cultured in media conditioned by mature human adipocytes (ACM). RNA sequencing (RNAseq) analysis was used to determine acute effects of IPA treatment after 24 hours in the presence and absence of ACM. We further examined the influence of IPA on insulin signaling with physiological and hyperinsulinemia levels of insulin at 24 and 72 hours utilizing QPCR and western blot analyses. RNAseq analysis revealed treatment with physiological levels of IPA induced changes in genes associated with normal placental function, autophagy and inflammatory mediated processes and other pathways. Our RNAseq analysis offers initial insight into the molecular mechanisms of IPA in placental cells. Future analyses will investigate the potential role of insulin signaling, glucose homeostasis and oxidative stress. Collectively, this study highlights the importance of a healthy gut microbiome and potentially serves as a window of opportunity to mitigate the onset or severity of pregnancy-related disorders such as gestational diabetes by enhancing the gut microbiome prior to pregnancy.

Presentation: 6/1/2024
6693 Hypopituitarism in Pregnancy
Authors: Mcheik Nora A , Howarth Hannah , Banka Ajaz
Published: October 2024

Disclosure: N.A. Mcheik: None. H. Howarth: None.

Background: Hypopituitarism in pregnancy requires careful management to ensure both maternal and fetal well-being. Disruptions of the pituitary gland in pregnancy can be due to adenomas, pituitary infarction, autoimmune disease, trauma, etc. Complications of hypopituitarism in pregnancy stem from inadequate production of thyroid stimulating hormone, growth hormone, gonadotropins and cortisol. Hormone replacement therapy will be necessary in such cases. For instance, patients in late pregnancy may require an increased dose of hydrocortisone due to the rise of corticosteroid-binding globulin. Patients may need increased doses of glucocorticoid therapy during labor given the major surgical stress. Antenatal care should include close follow up with endocrinologists and obstetricians and regular assessment of maternal hormone levels and fetal growth. Case: We present a case of a 37-year-old female G3P0020 at 24 weeks who presented with complaint of constant headache for 6 days. Associated with photophobia, intermittent blurry vision, nausea, and vomiting. She was admitted and given 1 g Magnesium bolus as well as Robaxin and Tylenol for headache without relief. Given persistence of symptoms and non-focal neurologic exam, MRI brain was completed that showed an enlarged pituitary gland with blood products. MRI pituitary showed an approximately 1.3 x 1.2 x 1.8 cm hemorrhagic lesion on the right side of pituitary gland with fluid level, most in keeping with hemorrhagic pituitary apoplexy. Thyroid function studies were consistent with central hypothyroidism with a low TSH 0.05, low Ft4 0.5, and normal Ft3 2.4. Luteinizing hormone was 0.1 mIU/mL (<1.5 normal in pregnancy), follicle stimulating hormone was <0.5 mIU/mL (<0.1 normal in pregnancy), estradiol >5000 pg/mL (1278-7192 normal in pregnancy), and prolactin 254 ng/mL (80-400 normal in pregnancy). IGF-1 was normal at 148 ng/ml. Morning cortisol was low at 1.8 ug/dL and ACTH was 9 pg/mL (low normal). Cortrosyn stimulation test at 60 minutes was normal at 17.7 ug/dL, however, given clinical improvement on steroids, the clinical picture is consistent with central hypoadrenalism. For treatment, she was started on IV hydrocortisone 50 mg every 8 hours and oral levothyroxine 100 mcg daily. The patient was discharged home on oral hydrocortisone 20 mg daily in the morning and 10 mg daily in the afternoon with close follow up. Conclusion: Ultimately, the management of hypopituitarism in pregnancy requires a personalized approach to hormone replacement and obstetric care and this is done through multidisciplinary care involving endocrinologists and obstetricians to optimize outcomes for both the mother and the baby.

Presentation: 6/1/2024
8796 Increased Sertoli Cell Proliferation in FSTL3 Deleted Mouse Testis
Authors: Ballesteros Randy , Mukherjee Abir
Published: October 2024

Disclosure: R. Ballesteros: None. A. Mukherjee: None.

Activin, a TGFβ ligand, plays key roles in Sertoli cell proliferation. Follistatin like 3 (FSTL3) is a glycoprotein inhibitor of activin expressed strongly in the testis. We have shown that FSTL3 deletion (FSTL3 KO) in mice increases testicular size, likely caused by increased spermatogenesis supported by the increased Sertoli cell numbers seen in FSTL3 KO mouse testes. It is not clear, however, whether there is increased proliferation of Sertoli cells postnatally. We, therefore, investigated Sertoli cell proliferation, and molecular pathways that might be activated upon FSTL3 deletion that lead to increased Sertoli cell proliferation in mice. Paired testes weight comparison indicates that there is significant increase in testicular mass in FSTL3 KO between 28d and 56d coinciding with the onset of continued spermatogenesis. Immunofluorescence studies using PCNA as marker for proliferation and SOX9 to identify Sertoli cells, however, found no significant differences between proliferation of Sertoli cells in WT and FSTL3 KO. BrdU injection of mice followed by immunofluorescence labelling of proliferating Sertoli cells also showed no difference between the two genotypes by immunofluorescence. We then proceeded to assess whether there is an alteration of differentiation in FSTL3 KO testes to test the possibility that instead of proliferation there is an increased differentiation of a pre-Sertoli like cell in FSTL3 KO mice using WT1 and SOX9 as markers for early or late Sertoli cells. This experiment revealed that there was no difference between the ratio of WT1 and SOX9 expression in the two genotypes. Flow cytometric analyses using testicular dispersates from mice using Sox9 and Ki67 antibodies to identify proliferating Sertoli cells, however, revealed an approximately two-fold increase in proliferating Sertoli cells in FSTL3 KO compared to WT at 7d. At 56d there were very few proliferating Sertoli cells in either genotype and there was no difference in this number in FSTL3 deleted mice compared to WT. mRNA sequence analysis showed that approximately 1000 genes are differentially regulated between WT and FSTL3 KO at 3d. Gene ontology and pathway analysis revealed that a constellation of meiosis related genes and activin signalling pathway, among others, are enriched in FSTL3 KO testis at this stage. Data presented here demonstrates that FSTL3 deletion induces activin receptor signalling pathway, genes crucial for meiosis and therefore the spermatogenic process, and Sertoli cell proliferation. This opens the possibility that the early arrest of Sertoli cell proliferation seen in mammals including mice and humans might be circumvented by inactivating FSTL3. This could then lead to a therapeutic angle in male infertility that are based on paucity of Sertoli cells. It will be important to address why FSTL3 deletion induces Sertoli cell proliferation only postnatally but not post pubertally.

Presentation: 6/1/2024
8417 Knowledge Of PCOS and Its Complications In A Population Of Hispanic Women
Authors: Rivera-Rodriguez Y G , Rios B Diaz , Casas Loyola C M , Rodriguez B Marin , Reyes P A Alicea , Romaguera J , Gonzalez-Rodriguez L A
Published: October 2024

Disclosure: Y.G. Rivera-Rodriguez: None. B. Diaz Rios: None. C.M. Casas Loyola: None. B. Marin Rodriguez: None. P.A. Alicea Reyes: None. J. Romaguera: None. L.A. Gonzalez-Rodriguez: Research Investigator; Self; Eli Lilly & Company.

Purpose: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting women across their lifespan, with metabolic complications that are often overlooked. Studies have revealed an inadequate understanding of PCOS, its complications, and management. There is also limited information about this condition in Hispanic women. The purpose of this study is to assess the knowledge about PCOS and its complications among a sample of Hispanic women living in Puerto Rico. Methods: This is a descriptive cross-sectional study of Hispanic women aged 21-45 years recruited from the General Endocrinology and Gynecology Clinics at the UPR-RCM Clinics. A self-administered questionnaire assessing their knowledge about PCOS, and its complications was given. Patients were classified according to PCOS diagnosis. Results were compared between the groups. Results: A total of 47 women were included in this study. Approximately 45% of participants had a diagnosis of PCOS. Most participants agreed that PCOS involves a set of symptoms associated with hormonal imbalances (94%) and irregular menses (91%). Only 40% of participants considered PCOS a chronic condition without a cure and only 34% acknowledge weight loss as one of the treatments of this condition. Two-thirds of participants didn’t know that PCOS can be diagnosed with blood tests. When assessing their knowledge about complications related to PCOS, we found that only 36% associated PCOS with an increased risk of cardiovascular disease, 56% with obesity and 62% with abnormal blood glucose levels. When comparing the knowledge about their condition in patients with a diagnosis of PCOS, we found increased knowledge about signs and symptoms such as hirsutism, hair loss and weight gain when compared to controls. However, when assessing their knowledge about complications related to PCOS, neither group recognized PCOS as a chronic condition, or associated PCOS with cardiovascular, metabolic complications and/or increased risk of cancer. Conclusion: Our study suggests that there is a lack of general knowledge about PCOS and its long-term complications among a sample of Hispanic women in reproductive years. Most importantly, our data showed that even patients with a diagnosis of PCOS do not understand their condition or comprehend the associated complications. Our study emphasizes the need to develop educational tools and strategies to improve the general population knowledge about this condition and raise awareness about preventable complications and the importance of early treatment.

Presentation: 6/3/2024
6450 Leydig Cell Tumor: A Rare Cause of Post-menopausal Hyperandrogenism
Authors: Nakdali Rama , Athimulam Shobana
Published: October 2024

Disclosure: R. Nakdali: None. S. Athimulam: None.

Introduction: Ovarian steroid cell tumors are a rare subtype of sex-cord stromal tumors. Leydig cell tumors is a subtype of sex-stromal tumors that is found in < 1% of all ovarian tumors. They are typically benign, unilateral, and secrete androgens which causes virilization. Below we present the case of a postmenopausal woman who presented with signs of virilization and was diagnosed with an ovarian Leydig cell tumor. Case: A 62-year-old postmenopausal woman, with a history of partial hysterectomy with right oophorectomy presented to Endocrinology clinic for evaluation of thyroid nodules. However, clinically she had signs of virilization noted by the provider on examination. She reported progressive androgenic alopecia, cystic acne, oily skin, hoarseness of voice and hirsutism, with increase hair growth over upper lip, chin and jaw line requiring daily shaving. She denied taking any supplements. She reported embarrassment of these physical changes and prior providers had attributed this to aging, therefore not prompting further testing. This caused significant emotional distress to the patient, leading to isolation. Biochemical testing confirmed elevated bioavailable testosterone (193.1 ng/dL) and total testosterone levels (579 ng/dL), with no evidence of hypercortisolemia. Magnetic resonance imaging (MRI) revealed a heterogenous soft tissue mass (2.9 x 2.1 x 2.1 cm) in the left ovary. She underwent a left salpingo-oophorectomy and pathology confirmed a well-differentiated 2.4 cm Leydig cell tumor. Post-operatively, she reported improvement in facial and body hirsutism, reduced shaving frequency decrease in androgenic hair loss, with noticeable hair growth in her frontal scalp, and her skin became less oily with reduced acne. Post-operative labs confirmed cure of hyperandrogenism (Bioavailable testosterone < 2.6 ng/dL; Total testosterone: < 10ng/dL; and Free androgen index < 0.5%). She has been referred to genetics for evaluation. Discussion: Post-menopausal hyperandrogenism poses a diagnostic challenge as it can be mistaken for hormonal imbalances seen with aging. Often times, patients do not report symptoms due to embarrassment unless specifically addressed by provider. Initial testing consists of total and free testosterone and dehydroepiandrosterone sulfate (DHEAS) levels to assess the source of hyperandrogenism. Ruling out hypercortisolemia and assessment for ingestion of testosterone or DHEA supplements is vital. Pelvic ultrasound or cross-sectional imaging (CT or MRI) of abdomen and pelvis can identify structural abnormalities in the ovaries or adrenal glands. Prompt evaluation and management can alleviate significant distress to the patient. Leydig cell tumors represent a rare but important consideration in the differential diagnosis of postmenopausal hyperandrogenism, such as in our patient.

Presentation: 6/2/2024
8125 Long-term Effects of Gender Affirming Hormone Therapy (GAHT) on Lipid Profile
Authors: Le Guillaume , Pinkson Sheila , Trejo Jonathan , Tripathy Devjit
Published: October 2024

Disclosure: G. Le: None. S. Pinkson: None. J. Trejo: None. D. Tripathy: None.

There is differential effect of long-term Estrogen and Testosterone therapy on lipid profile. While oral estradiol therapy in post-menopausal women has been associated with increased serum triglyceride and HDL, testosterone therapy in hypogonadal men decreases total cholesterol, LDL and HDL cholesterol. However, the long-term effects of Estrogen and Testosterone on lipid profile in transgender patients are not clear. We conducted a retrospective study to analyze the long-term effects of GAHT in transgender men and women followed in Endocrinology Clinic at Veterans Affairs Hospital. 36 transgender men (age 38 ± 2 years, on IM Testosterone cypionate) and 54 transgender women (age 46 ± 2 years, 36 on E2 tablet, 12 on patch, 6 on IM) were followed for 46 ± 5 months and 61 ± 5 months, respectively. Total cholesterol, triglyceride, HDL, LDL cholesterol, systolic and diastolic blood pressures, and BMI were compared before and after initiation of therapy. As expected, following GAHT, total testosterone was higher (546 ± 48 vs. 35 ± 9 ng/dL, P<0.001) in transgender men; in transgender women, serum E2 was higher (110 ± 9 vs. 26 ± 2 pg/dL, P<0.001) and total testosterone was suppressed (444 ± 29 ng/dL vs. 66 ± 13 ng/dL). In transgender men, after a follow-up period of approximately 4 years, there were no significant changes in lipid profile (total cholesterol 178 ± 8 vs. 175 ± 8 mg/dL, triglyceride 121 ± 4 vs 134 ± 12 mg/dL, HDL 47 ± 2 vs. 44 ± 2 mg/dL, LDL 107 ± 7 vs. 106 ± 8 mg/dL, all p=NS). Similarly in transgender women, no difference in lipid profile (total cholesterol 170 ± 5 vs. 175 ± 4 mg/dL, triglyceride 118 ± 7 vs 140 ± 9 mg/dL, HDL 49 ± 2 vs. 53 ± 3 mg/dL, LDL 99 ± 4 vs. 97 ± 4 mg/dL, all p=NS) was observed after 5 years of GAHT. There were no differences in lipid profile regardless of E2 tablet, patch or IM therapy. In transgender men, there was an increase in diastolic blood pressure (72 ± 3 vs. 76 ± 2 mmHg, P<0.05) while in transgender women there was decrease in systolic blood pressure (124 ± 2 vs. 118 ± 2 mmHg, p<0.005), and slight increase in BMI (28 ± 0.9 vs. 30 ± 1 kg.m2, P<0.005). In conclusion, long-term testosterone therapy in transgender men and estrogen therapy in transgender women was not associated with worsening lipid profile. Estrogen therapy was associated with lower BP in transgender women and testosterone therapy led to higher BP in transgender men.

Presentation: 6/2/2024
12468 Loss Of Enterococcus And Faecalibacterium Associate With Polycystic Ovary Syndrome And Hirsutism In A Sample Of Hispanic Patients
Authors: Gonzalez-Rodriguez Loida Alejandra , Loyola Cristina Marie Casas , Martinez-Hernandez Carolina I , Penna Laurianne El Musa , Romaguera Josefina , Godoy-Vitorino Filipa
Published: October 2024

Disclosure: L.A. Gonzalez-Rodriguez: Research Investigator; Self; Eli Lilly & Company. C.M. Casas Loyola: None. C.I. Martinez-Hernandez: None. L. El Musa Penna: None. J. Romaguera: None. F. Godoy-Vitorino: None.

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age. It is characterized by symptoms such as irregular menstrual periods, excess androgen levels and polycystic ovaries. Women with PCOS often display insulin resistance independent of fat and have been associated with an increased risk of diabetes mellitus, cardiovascular disease, and mood disorders. The gut microbiota, the community of microbes living in the human gastrointestinal tract, plays a crucial role in human health and has been implicated in various diseases, including metabolic and inflammatory conditions. We aimed to characterize the gut microbiota in a sample of Hispanic women living in Puerto Rico (n=50). Of these 38 had confirmed PCOS as per Rotterdam criteria and 12 were controls. A stool sample was collected for genomic DNA extractions followed by amplification and sequencing of 16S rRNA genes (V4 region) with Illumina MiSEQ. Data analyses were performed with standard pipelines with variables sample group (PCOS vs Controls), insulin resistance assessed using HOMA-IR and hirsutism status according to modified-Ferriman Gallwey (mFG) score and controlled for age and other clinical variables. Despite there were no changes in alpha or beta diversity among the microbiota of these groups, composition was significantly different. Women with PCOS had significantly lower levels of Enterococcus species as well as Hungatella, taxa that are part of a physiologically normal gut flora. Enterococcus species contribute to the balance of the microbial community and play roles in the metabolism and immune function and are very resilient. Hungatella species are a known source of catabolic enzymes that degrade glycosaminoglycans which are important in tissue repair. These dominant taxa in controls was substituted by other taxa in PCOS. Women with prominent hirsutism had significantly lower levels of Faecalibacterium while those with insulin resistance had increased levels of Clostridium. We found that higher levels Clostridium, and lower levels of protective anti-inflammatory taxa such as Faecalibacterium or Enterococci, which are important for gut health and metabolic regulation, are linked to this metabolic disturbance. Even though this is a preliminary report, it opens potential therapeutic strategies, such as the use probiotics, and dietary modifications to modulate the gut microbiome and improve PCOS outcomes.

Presentation: 6/1/2024
8235 Mutations in EMX2, a Homeodomain Transcription Factor, Cause Idiopathic Hypogonadotropic Hypogonadism
Authors: Stamou Maria , Tompkin Miranda , Bow Hannah , Brand Harrison , Plummer Lacey , Talkowski Michael , Shen Yipin , Wu Doris , Balasubramanian Ravikumar , Wray Susan , Seminara Stephanie Beth
Published: October 2024

Disclosure: M. Stamou: None. M. Tompkin: None. H. Bow: None. H. Brand: None. L. Plummer: None. M. Talkowski: None. Y. Shen: None. D. Wu: None. R. Balasubramanian: None. S. Wray: None. S.B. Seminara: None.

The genetic etiology of infertility remains largely unknown. To identify novel human infertility genes, we applied a de novo rare variant analysis in 142 parent-proband trios with idiopathic hypogonadotropic hypogonadism (IHH), a Mendelian disease caused by Gonadotropin Releasing Hormone (GnRH) deficiency. The discovery pipeline identified 43 rare de novo copy number variants (CNVs-deletions) spanning 263 genes and 213 rare de novo single nucleotide variants (SNVs) in 191 genes. Four genes were found to be affected by both rare de novo CNVs and SNVs among unrelated sporadic IHH probands. A rare variant association testing for protein truncating variants (PTVs) in the IHH cohort (N=1,394) compared to gnomAD controls (N=125,784) revealed that 3/4 genes demonstrated enrichment for PTVs in the IHH cohort compared to controls: the 2 known for IHH genes (ANOS1 and FGFR1) and one novel candidate gene, EMX2. IHH probands with de novo EMX2 variants demonstrated developmental delay and hearing loss. Common EMX2 variants were linked to delayed puberty/infertility, hearing loss and Parkinson’s disease in a phenome-wide association study of the Massachusetts General Brigham Biobank (N=65,253). Emx2 lineage tracing was conducted on Emx2Cre/+; RosatdT/+ and Emx2Cre/-; RosatdT/+ mouse embryos at embryonic day(E) 13.5. The tdT reporter was co-expressed in neuroendocrine GnRH (nGnRH) cells as they migrated from the olfactory pit to the nasal forebrain junction. WT and KO embryos from Emx2+/- matings were immunostained for GnRH across E12.5, E13.5, E14.5 and E16. The total number of nGnRH cells was greater in the Emx2 KO mice compared to WT littermates. However, by E16.5, fewer nGnRH cells were detected in the forebrain of Emx2 KO, compared to WT (WT= 496±28, KO=384±147, p=0.0125). Thus, failure of nGnRH neurons to enter the forebrain could contribute to the IHH pathogenesis. In conclusion, by utilizing a de novo variant analysis and a mouse model, EMX2 was uncovered as a novel gene for human infertility.

Presentation: 6/1/2024
6420 Organokines and Liver Enzymes in Adolescent Girls with Polycystic Ovary Syndrome During Randomized Treatments
Authors: Garcia-Beltran C , Peyrou M , de Zegher F E , López-Bermejo A , Villarroya F , Ibanez L
Published: October 2024

Disclosure: C. Garcia-Beltran: None. M. Peyrou: None. F.E. de Zegher: None. A. López-Bermejo: None. F. Villarroya: None. L. Ibanez: None.

Introduction: Polycystic ovary syndrome (PCOS) is often related to metabolic associated fatty liver disease (MAFLD). MAFLD has been associated with altered hepatic function and systemic dysmetabolism and with abnormal circulating levels of signaling molecules, so-called organokines. Here, we assessed the effects of two randomized treatments on a set of organokines in adolescent girls with PCOS and without obesity, and report the associations with circulating biomarkers of liver damage which were assessed longitudinally in the aforementioned studies as safety markers. Materials and Methods: Liver enzymes [aspartate aminotransferase (AST), alanine amino transferase (ALT) and gamma-glutamyl transferase (GGT)] were assessed as safety markers in previous randomized pilot studies comparing the effects of an oral contraceptive (OC) to those of a low-dose combination of spironolactone-pioglitazone-metformin (spiomet) for 1 yr. As a post-hoc endpoint, the organokines fibroblast growth factor-21 (FGF21), diazepam-binding protein-1 (DBI) and meteorin-like protein (METRNL), were assessed by ELISA after 6 months on OC (N=26) or spiomet (N= 28). Auxological, endocrine-metabolic, body composition (by DXA) and abdominal fat partitioning (by MRI) were also evaluated. Healthy age-matched adolescent girls (N=17) served as controls. Results: Circulating ALT and GGT levels raised during OC treatment and returned to baseline concentrations in the post-treatment phase; in contrast, spiomet treatment elicited no detectable changes in ALT and GGT concentrations. In relation to organokines after 6 mo on treatment, (1) FGF21 levels were significantly higher in PCOS adolescents than in control girls; (2) DBI levels were lower in OC-treated girls as compared to controls and spiomet-treated girls; (3) no differences were observed in METRNL concentrations between PCOS girls and controls. Serum ALT and GGT levels directly correlated with circulating METRNL levels only in OC-treated girls (R=0.449; P=0.036 and R=0.552; P=0.004, respectively). Conclusion: The on-treatment increase in ALT and GGT levels occurring only in OC-treated girls associates with circulating METRNL levels suggesting an enhanced METRNL synthesis as a reaction to the hepatic changes elicited by OC treatment. Trial registration numbers: ISRCTN29234515 (https://doi.org/10.1186/ISRCTN29234515) and ISRCTN11062950 (https://doi.org/10.1186/ISRCTN11062950)

Presentation: 6/2/2024
8354 Ovarian Hyperthecosis: an Uncommon Cause of Hyperandrogenism in a Postmenopausal Woman
Authors: de Griné Severino Mariana , Silva Francisca Pinho , Lopes Marta Vaz , Doutel Delfim , Nunes Carla , Alexandre Maria Inês , Bugalho Maria Joao
Published: October 2024

Disclosure: M.D. Severino: None. F.P. Silva: None. M.V. Lopes: None. C. Nunes: None. M.I. Alexandre: None. M.J. Bugalho: None.

Introduction: Severe hirsutism in postmenopausal women demands a careful clinical evaluation to exclude a malignant cause, such as adrenal or ovarian androgen-secreting tumors. Ovarian hyperthecosis is an uncommon and benign cause of hyperandrogenism and, consequently, hirsutism. It is caused by persistent testosterone synthesis due to proliferation of ovarian stromal cells and nests of luteinized theca cells. It occurs more often in postmenopausal women, as aromatization of testosterone to estradiol decreases due to the loss of granulosa cells. It is also frequently associated with obesity and insulin resistance. Clinical case: We present the case of a 61-year-old woman, with a history of hypertension and dyslipidemia, referred to Endocrinology Clinic due to a year long history of hirsutism, most severe on her face, chest, and abdomen. She also mentioned slight clitoromegaly. She had no other virilization symptoms such as acne, male-pattern alopecia, voice deepening or mammary atrophy. Her menarche occurred at the age of 14 and she had regular menses until menopause, at the age of 51. She had a BMI of 32 kg/m2 and an uncharacteristic phenotype. At observation, she had a mild hirsutism (Ferriman-Gallwey score of 9). This contrasted with the biochemical findings of severe androgenism - total testosterone of 366 ng/dL (reference values [RV] for women between 5-48) with free testosterone 7.8 pg/mL and SHBG 74 nmol/L (RV 32-128), resulting in a Free Androgen Index of 17,16 (RV <6.6). DHEAS, androstenedione, 17-hydroxyprogesterone and prolactin were normal, and gonadotropins were in the menopausal range. Blood tests also showed hyperinsulinemia and pre-diabetes with HbA1c 6,2%. She denied exposure to steroids in the form of new medication, supplements, or creams/gels (including second-hand exposure through her partner) and she had no exposure to other drugs with androgenic effect. Abdominal and pelvic CT scan, as well as transvaginal ultrasound, showed no adrenal or ovarian lesions. An ovarian cause was deemed the most likely and laparoscopic diagnostic bilateral salpingo-oophorectomy was performed. Gross pathology revealed ovaries of regular size, while histology showed bilateral ovarian stromal hyperthecosis. Testosterone levels returned to normal one month after surgery (14,2 ng/dL). Conclusion: Benign, ovarian causes of hyperandrogenism are uncommon in postmenopausal women, requiring a high index of suspicion. The diagnosis is difficult, and laparoscopic bilateral salpingo-oophorectomy is essential as both a diagnostic and therapeutic tool.

Presentation: 6/2/2024
7789 PCOS and probiotics - a randomized controlled trial with a comparison to metformin
Authors: Obermayer-Pietsch B M , Valentin B , Luegger B , Regina R , Haudum C W , Tandl V
Published: October 2024

Disclosure: B.M. Obermayer-Pietsch: None. B. Valentin: None. B. Luegger: None. R. Regina: None. C.W. Haudum: None. V. Tandl: None.

Polycystic ovary syndrome (PCOS) has a complex association not only with gonadal hormones, but also with insulin resistance and the gut – showing a decreased alpha diversity of the microbiome in PCOS women. Based on our previous investigations, we conducted a randomized controlled trial (RCT) using probiotics (OMNi-BiOTiC®, Institut Allergosan) and placebo daily, compared to a metformin group over 6 months. In this RCT, we included 112 women with PCOS, defined by Rotterdam criteria. Clinical and biochemical characterisation covered medical history with cycle abnormalities, Ferriman–Gallwey (FG) Score and anthropometric data. Hormonal profiles included gonadal hormones with a focus on androgens and AMH. Oral glucose tolerance tests (oGTT) with parallel insulin/c-peptide determinations and stool sampling for microbiome determination at every visit were done. Study participants were randomized 2:1 for probiotics/placebo or metformin (Glucophage®, Merck) and further 1:1 between probiotics and placebo for 6 months followed by a voluntary 6 months period on probiotics only. NGS for microbiome profiles was carried out. 93 PCOS women completed the study, 19 drop-outs for various reasons including 6 pregnancies were recorded (5 in the probiotic/placebo group, 1 in the metformin group). Participants were 27±5 years old, obesity with a BMI >30 was found in 35% of them. Initial cycle duration ranged from 22 to 200 days, 18% had amenorrhoea. Hirsutism was present with a mean FG score of 12,7±7,71. Mean levels (±standard deviation, reference range, no units depicted) for total testosterone were 0,38±0,15 (0,14-0,77), SHBG 54,1±29,0 (19–117), free testosterone 3,2±3,1 (0,45-2,19) and AMH 8,9±4,8 (0,17-7,37). Initial oGTTs showed insulin resistance prevalent in 43%, with an overall reduction to 36% at visit 2. Weight loss over 6 months was documented in 37%, cycle abnormalities decreased overall to 14%. Group comparisons and microbiome characterisation are ongoing. No serious adverse reactions related to the study medication were recorded. All intervention products were well tolerated in our PCOS study cohort. Based on the intended cycle normalisation, 6 pregnancies were recorded. Metabolic changes were seen both in the probiotic/placebo and in the metformin groups, with fewer changes in the placebo group despite nutritional counselling. Microbiome changes were recorded in both intervention groups.

Presentation: 6/3/2024
9221 Reproductive Cancer Risk in Patients Treated with Denosumab Compared with Alendronate: A Population-based Cohort Study
Authors: Yahyavi Sam Kafai , Selmer Christian , Torp-Pedersen Christian , Juul Anders , Jensen Martin Blomberg
Published: October 2024

Disclosure: S.K. Yahyavi: Research Investigator; Self; Principal investigator (PI) on an RCT with denosumab. C. Selmer: None. C. Torp-Pedersen: None. A. Juul: None. M. Blomberg Jensen: Other; Self; Holds two patents on the use of RANKL inhibitors to treat male infertility.

Background and Objective: Antiresorptive treatment is used in millions of patients with osteoporosis and cancer but during the early studies of denosumab there was a slight increase in ovarian cancer incidence. The aim of this study is to determine the association between use of denosumab and risk of reproductive cancers compared with the use of alendronate in both men and women. Methods: Using a retrospective study design, we combined the Danish registries and identified a population of subjects > 50 years of age. We compared users of Denosumab that had been on alendronate treatment for at least 6 months with a matched population of patients that had been treated for at least 6 months with alendronate alone. Using the L-TMLE method we estimate the risk of reproductive cancers and the risk difference between the groups. Secondary analysis included comparisons with a healthy background population. Results: In the main analysis, a total of 18,162 subjects were included, with 6,054 denosumab users matched 1:2 with 12,108 alendronate users and followed for 3 years. 727 women and 183 men were diagnosed with a reproductive cancer during follow-up. Use of denosumab was not associated with higher risk of reproductive cancer. Compared to alendronate, women who received treatment with denosumab had a 0.06% (95% CI -0.12%; 0.26%) higher risk of a cancer diagnosis after 3 years of treatment. In a model fully adjusted for socioeconomic factors and comorbidities the risk was 0.01% (95% CI -0.35%; 0.37%) higher. The same results were found in men, and when comparing with a healthy background population and sensitivity analysis only using CKD measurements the results were confirmed. Conclusion: When comparing treatments of denosumab and alendronate, this study finds no increased risk of either cancers overall or specific reproductive cancers in men or women.

Presentation: 6/3/2024
8384 Reproductive Cancer Risk in Patients Treated with Denosumab Compared with Alendronate: A Population-based Cohort Study
Authors: Yahyavi Sam Kafai , Selmer Christian , Torp-Pedersen Christian , Juul Anders , Jensen Martin Blomberg
Published: October 2024

Disclosure: S.K. Yahyavi: Research Investigator; Self; Principal investigator (PI) on an RCT with denosumab. C. Selmer: None. C. Torp-Pedersen: None. A. Juul: None. M. Blomberg Jensen: Other; Self; Holds two patents on the use of RANKL inhibitors to treat male infertility.

Background and Objective: Antiresorptive treatment is used in millions of patients with osteoporosis and cancer but during the early studies of denosumab there was a slight increase in ovarian cancer incidence. The aim of this study is to determine the association between use of denosumab and risk of reproductive cancers compared with the use of alendronate in both men and women. Methods: Using a retrospective study design, we combined the Danish registries and identified a population of subjects > 50 years of age. We compared users of Denosumab that had been on alendronate treatment for at least 6 months with a matched population of patients that had been treated for at least 6 months with alendronate alone. Using the L-TMLE method we estimate the risk of reproductive cancers and the risk difference between the groups. Secondary analysis included comparisons with a healthy background population. Results: In the main analysis, a total of 18,162 subjects were included, with 6,054 denosumab users matched 1:2 with 12,108 alendronate users and followed for 3 years. 727 women and 183 men were diagnosed with a reproductive cancer during follow-up. Use of denosumab was not associated with higher risk of reproductive cancer. Compared to alendronate, women who received treatment with denosumab had a 0.06% (95% CI -0.12%; 0.26%) higher risk of a cancer diagnosis after 3 years of treatment. In a model fully adjusted for socioeconomic factors and comorbidities the risk was 0.01% (95% CI -0.35%; 0.37%) higher. The same results were found in men, and when comparing with a healthy background population and sensitivity analysis only using CKD measurements the results were confirmed. Conclusion: When comparing treatments of denosumab and alendronate, this study finds no increased risk of either cancers overall or specific reproductive cancers in men or women.

Presentation: 6/3/2024
9240 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study
Authors: Ogoniak Lynn , Sandmann Sarah , Varghese Julian , Busch Alexander S
Published: October 2024

Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None.

Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p <0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes.

Presentation: 6/2/2024
8429 Serotonin Receptor Antagonist Alleviates Vascular Defects Produced by Selective Serotonin Reuptake Inhibitor Treatment During Gestation
Authors: Agnew L P , Domingues R , Weichmann A , Hernandez L L
Published: October 2024

Disclosure: L.P. Agnew: None. R. Domingues: None. A. Weichmann: None. L.L. Hernandez: None.

Maternal mental health is critical for both mother and infant and often antidepressant therapy outweighs the potential risks of selective serotonin reuptake inhibitor (SSRI) treatment; however, SSRI use is associated with adverse neonatal outcomes. Preliminary work in our laboratory revealed placental apoptosis in pregnant dams treated with fluoxetine (FLX) and dams genetically deficient for the serotonin transporter gene. We hypothesize that SSRIs decrease placental blood flow, causing apoptosis and organ death via signaling through the serotonin 2A/2C receptors. Pregnant female C57BL6 mice were randomized to be treated daily, via I.P. injection, from E10-17.5 with saline (CON; n=6), 2 mg/kg FLX (n=5), or 2 mg/kg ketanserin plus 2 mg/kg FLX (n=5). On E17.5, using high-resolution ultrasound imaging, we identified the uterine artery, individual umbilical cords, and placental disc blood vessels. We calculated blood pressure, blood volume, blood flow rate, and heart rate in the uterine artery, umbilical cord, and placental disc. FLX (decreased blood volume in the uterine artery compared to ketanserin plus FLX (48.42 ± 18.26, 116.54 ± 45.25; p=0.0077), and decreased average (89.38 ± 31.50) and peak (130.36 ± 39.05) blood velocity in the uterine artery compared to ketanserin plus FLX average (162.76 ± 68.46; p=0.0322) and peak (236.77 ± 92.43; p=0.0242) blood velocity. FLX decreased average (0.04 + 0.02) and peak (0.07 ± 0.04) blood pressure in the uterine artery compared to ketanserin and FLX treated animals average (0.12 ± 0.10; p=0.0634) and peak (0.25 ± 0.19; p=0.0412) blood pressure. Ketanserin plus FLX (391 ± 38.29) decreased heart rate (BPM) in the placental disc compared to untreated controls (450.67 ± 26.08; p=0.0128). In the umbilical cord, ketanserin plus FLX (393 ± 28.25) decreased BPM compared to CON (450.17 ± 29.44; p=0.0078) and compared to FLX treatment alone (437.20 ± 17.28; p=0.0450). FLX treatment of dams during pregnancy reduces blood flow volume, heart rate, and blood flow velocity to the placenta via the uterine artery. The use of ketanserin, an inhibitor of serotonin receptor 2A/2C signaling, in combination with FLX, reduced the effects of FLX on the uterine artery. These data suggest that treatment with ketanserin could be utilized to alleviate the reproductive side effects of antidepressant usage for pregnant mothers while allowing the mother to remain on antidepressants. Future research should further investigate the effects of SSRI and ketanserin on blood flow to the fetus through the umbilical cord.

Presentation: 6/2/2024
9208 Sex Hormones and Abdominal Muscle Area and Radiodensity in Men: A Multi-Ethnic Study of Atherosclerosis
Authors: Osmancevic Amar , Allison Matthew , Miljkovic Iva , Vella Chantal , Ouyang Pamela , Trimpou Penelope , Daka Bledar
Published: October 2024

Disclosure: A. Osmancevic: None. M. Allison: None. I. Miljkovic: None. C. Vella: None. P. Ouyang: None. P. Trimpou: None. B. Daka: None.

Context: Information on the associations of testosterone, estradiol and sex hormone binding globulin (SHBG) levels with abdominal muscle volume and quality in men are unclear. Objective: To investigate the association between fasting serum sex hormones and CT-derived abdominal muscle area and radiodensity in adult men. Design: Cross sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. Participants: A community-based sample of 907 men aged 45-84 years; 878 men with complete data were included in the analysis. Main Outcome Measure(s): CT scans of the abdomen were interrogated for muscle characteristics. Multivariable linear regressions were used to test the associations. Results: After adjustment for age, race/ethnicity, visceral fat, CRP, lifestyle factors, comorbidities and medicine use, higher levels of both total testosterone and estradiol, but not SHBG, were associated with higher abdominal muscle area (B= 1.79, 95% CI 0.1 to 3.4, & B=1.79, 95% CI 0.4 to 3.2, respectively). After the same adjustment, levels of total testosterone showed a significant positive association (B= 0.3, 95% CI 0.0 to 0.6), while a significant inverse relationship was observed for SHBG with abdominal muscle radiodensity (B=-0.34, 95% CI -0.6 to -0.1). Conclusion: Our results indicate significant associations between sex hormones and abdominal muscle characteristics in men from several different race/ethnic groups. These findings reveal novel insights into the previously unrecognized role that SHBG may play in skeletal muscle adipose tissue distribution.

Presentation: 6/2/2024