bluuebunny/crossref_metadata_2025 huggingface dataset:
OR15-03 Lower Hepatic Mitochondrial Respiration Relates To Dysmetabolism In Adolescents With Severe Obesity
Authors: Finn Erin , Fuller Kelly N Z , Knaub Leslie A , Reyes Yesenia Garcia , Derderian Sarkis C , Schoen Jonathan , Inge Thomas , Reusch Jane E , Nadeau Kristen , Cree Melanie
Published: October 2023

Disclosure: E. Finn: None. K.N. Fuller: None. L.A. Knaub: None. Y. Garcia Reyes: None. S.C. Derderian: None. J. Schoen: None. T. Inge: None. J.E. Reusch: Advisory Board Member; Self; Medtronic Diabetes. K. Nadeau: None. M. Cree: None.

Introduction: The severity of metabolic disease in youth with obesity is varied and determinants of disease progression are not known. Non-alcoholic fatty liver disease appears to be central to the development of cardiometabolic disease in youth with severe obesity. We tested the hypothesis that hepatic mitochondrial respiratory capacity would correlate with cardiometabolic measures in youth with severe obesity and a range of glycemia. Methods: Adolescents with severe obesity and a range of dysglycemia undergoing bariatric surgery were enrolled. Participants underwent anthropomorphic assessments, fasting labs, and a 4-hour mixed meal tolerance test (MMTT, 45 g carbs, 14 g protein, and 14 g fat) over 30 minutes followed by serial measures of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and free fatty acids. Liver biopsies obtained at time of vertical sleeve gastrectomy surgery were analyzed for mitochondrial respiration. Permeabilized liver tissue was assessed for mitochondrial oxygen consumption by respirometry (Oxygraph-2k, OROBOROS) under both pyruvate (carbohydrate) and palmitoyl-carnitine (lipids) substrate conditions. Results: Fifteen youth with severe obesity (female=60%, mean age 16.9 ± 1.5 years, mean BMI 47.4 ± 7.2 kg/m2) were enrolled. Lower hepatic carbohydrate-supported respiration relates to higher serum glucose concentrations throughout the 4-hr MMTT (P=< 0.001 to 0.05) as well as higher fasting serum triglycerides (p =<0.001-0.05). Lower liver lipid-supported respiration is associated with higher C-peptide levels (p =0.001-0.01) throughout MMTT, increased Matsuda Index (p =0.001-0.05), and higher fasting hepatic transaminases, alanine aminotransferase (p =0.006-0.04), aspartame aminotransferase (p =0.007-0.02), and gamma-glutamyl transferase (p =0.01-0.03). Insulin, GLP-1, and free fatty acids are not correlated with mitochondrial respiration. Conclusion: Consistent with findings in adults and animals, youth with severe obesity have lower hepatic mitochondrial respiration which correlates with markers of poorer cardiometabolic health including higher triglycerides, higher glucose concentraions, lower insulin sensitivity, higher insulin secretion (C-peptide), and higher liver transaminases. Based on these findings, dysregulated hepatic mitochondrial respiration should be further explored as a possible contributor to the development of early liver disease and glucose dysregulation.

Presentation: Friday, June 16, 2023
OR15-05 Maternal Obesogenic Diet Exposure Leads To Transgenerational Worsening Of Offspring NAFLD In Male Mice
Authors: Hinrichs Holly , Ballentine Samuel J , Thompson Michael D
Published: October 2023

Disclosure: H. Hinrichs: None. S.J. Ballentine: None. M.D. Thompson: None.

Background: The Developmental Origins of Health and Disease (DOHaD) hypothesis states that development of chronic disease is impacted by early life or in utero exposures. Recent studies have found that exposure to maternal obesity/obesogenic diet increases the susceptibility of offspring to non-alcoholic fatty liver disease (NAFLD). We have shown that maternal obesogenic diet exposure (MODE) in mice leads to worse NAFLD progression to fibrosis in first generation offspring with associated changes in the microbiome. Evidence indicates that some developmentally programmed phenotypes are passed transgenerationally or to the third generation of offspring. The goal of the current study was to evaluate if MODE-induced programming of worse NAFLD progression is passed transgenerationally. Methods: F0 Female mice were fed chow (CON) or high fat-fructose-cholesterol (HFFC) diet for 6 weeks and bred with lean males. F1 and F2 females were fed chow diet and mated with chow-fed males to yield an F3 generation where only the F0 female was fed HFFC diet. F3 male offspring were weaned to HFFC diet for 7 weeks to induce progressive NAFLD. Liver was collected for histopathologic analysis. NAFLD activity scoring (NAS) was performed by a pathologist blinded to group. Results: F3 HFFC offspring had decreased liver weight and liver weight/body weight ratio compared to F3 CON offspring. F3 HFFC offspring had increased hepatic free fatty acids, but no difference in hepatic triglycerides and cholesterol. Mac-2 and CD45 staining was increased in F3 HFFC offspring. Sirius red staining for collagen was also increased in F3 HFFC offspring. NAS scoring confirmed histologic finding showing an increased frequency of higher inflammation and total NAS scores in F3 HFFC offspring. Fibrosis scores were also higher in F3 HFFC offspring. Conclusions: MODE leads to transgenerational transmission of worse NAFLD progression in male offspring. This suggests a role for an epigenetic mechanism involved in developmental programming of NAFLD. Future studies will focus on the mechanisms of this transgenerational event.

Presentation: Friday, June 16, 2023
THU256 Prevalence And Risk Factors Associated With Diabetes Mellitus Among Middle Aged Women In Southern Brazil: A Population Based Study
Authors: Oppermann Karen , Spritzer Poli Mara
Published: October 2023

Disclosure: K. Oppermann: None. P.M. Spritzer: None.

The prevalence of diabetes mellitus (DM) has been growing steeply. The early recognition of clinical characteristics related to DM may be determinant to reduce its prevalence in specific populations. The aim of this cross-sectional study, nested to the Passo Fundo cohort study, was to investigate the prevalence and the clinical factors associated with diabetes mellitus (DM) among middle-aged women. A total of 298 women were enrolled in which demographic, anthropometric characteristics, blood pressure (BP), use of hormone therapy (HT), physical activity (PA), smoking status, alcohol intake were obtained. Habitual PA was assessed by digital pedometer for 7 days, and participants were stratified into active and inactive (≥ 6,000 and < 6,000 steps/day, respectively). Mean age was 57.1±5.4 years, 78.7% women were postmenopausal, 8.3 % menopausal transition, 7.3% pre-menopause and 5.6% were classified as “hysterectomy” that is, those women who had previously undergone hysterectomy which menopause status could not be classified. The prevalence of DM was 17.1% (n= 51): pre-menopause 9.1%, menopausal transition 20.0%, post-menopause 18.4% and hysterectomized women, 5.9% (p=0.53). Women with DM were older (58.7 ±5.2 vs. 56.8 ± 5.4 years, p=0.022), worked fewer hours per week in the last month (p= 0.040), had lower age at menarche (12.6 ±1.8 vs. 13.2 ± 1.9 years, p=0.026), were more frequently inactive (83.7 vs. 64.7 %, p=0.010), had higher BMI (30.9 ± 6.3 vs. 28.4 ± 6.4 kg/m2, p=0.012), waist circumference (WC) (98.5 ± 13.2 vs. 90.3 ±13.3 cm) p<0.001), and higher visceral (218.5±85.2 vs. 164.9±71.6 p < 0.001) and total fat, (534.9 ±167.8 vs. 451.8±170.2 p=0.003) but not subcutaneous fat (315.5±117.3 vs. 286.9±118.7 p=0.140), and systolic blood pressure (SBP) (138.7 ± 17.3 vs. 130.2 ± 18.7 mmHg, p=0.003). The prevalence of current smoking was 19.5%, alcohol use was 32.5%, HT current use was 16.1% and it was not statistically different between women with and without DM. Women with DM presented higher prevalence of metabolic syndrome, 76.5% (n=39) vs. 34.8 % (n=86), p<0.001 as well as using statins more often (35.3% vs. 12.6%, p<0.001). A higher prevalence ratio of DM was associated with physical inactivity (PR 2.137; 95% CI 1.056-4.325; p<0.035). For each year of anticipated menarche, the risk of DM increases by 12% and for each mmHg there is an increase of 1.4% of DM diagnosis. Conclusion: The prevalence of DM among middle-aged women was 17.1%. Women with DM were older, have less working activity, earlier menarche, using statins more often and walk less. Also, they have higher BMI, waist circumference, visceral abdominal fat, and MS. Age, physical inactivity, early age at menarche, and systolic blood pressure were related independently to higher prevalence of DM in this unselected population of middle-aged women.

Presentation: Thursday, June 15, 2023
THU631 Steroyl-CoA Desaturase Is A Progesterone Receptor Target Gene In Uterine Leiomyoma
Authors: Komorowski Allison S , Zuberi Azna , Coon V John S , Anton Melania Lidia , Bulun Serdar Ekrem , Yin Ping
Published: October 2023

Disclosure: A.S. Komorowski: None. A. Zuberi: None. J.S. Coon V: None. M.L. Anton: None. S.E. Bulun: None. P. Yin: None.

Uterine leiomyomas (LM) are common benign neoplasms affecting approximately one in four reproductive-age women. LM can cause menorrhagia, dysmenorrhea, anemia, and infertility. Steroyl-CoA desaturase (SCD) is a delta-9 fatty acid desaturase which converts saturated fatty acids to monounsaturated fatty acids in a reaction that is critical to maintenance of fatty acid homeostasis. Prior work has demonstrated upregulation of SCD in multiple cancer types as part of lipid metabolic reprogramming, and SCD has been identified as a potential drug target for cancer and non-alcoholic steatohepatitis. Growth of LM tumors is progesterone-dependent, and we found that progesterone receptor (PR)-binding sites were enriched in the SCD gene locus. Normalized RNA-seq count demonstrated that knockdown of PR decreased SCD expression in LM cells. Further experiments with knockdown of PR in LM cells demonstrated decreased SCD expression on both quantitative real-time PCR and Western blot. Treatment of LM cells with progesterone for 6 hours lead to mild upregulation of SCD expression. In summary, steroyl-CoA desaturase, an enzyme involved in lipid homeostasis, is upregulated by progesterone and may represent a novel target for treatment of uterine LM.

Presentation: Thursday, June 15, 2023
THU637 The Effects Of Polyphenol On Insulin Resistance And Hormonal Parameters On Women With Polycystic Ovary Syndrome: A Systematic Review And Meta-analysis Of Randomized Controlled Trials
Authors: Almeida Balieiro Caroline Cristine , Hespanhol Larissa C , Araújo Freitas Marcos Aurélio , de Oliveira Lilia Maria Lima
Published: October 2023

Disclosure: C.A. Balieiro: None. L.C. Hespanhol: None. M. Araújo Freitas: None. L. Lima de Oliveira: None.

Introduction: Polycystic ovary syndrome (PCOS) is an endocrinopathy with a high prevalence in women of reproductive age. This syndrome is characterized by ovarian cysts, anovulation, infertility, skin disorders, increased Body Mass Index (BMI), insulin resistance, and altered hormone levels. The most commonly affected hormones include testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and insulin. Different treatments have been tested to increase insulin sensitivity and hormone regulation, and recently polyphenols have emerged as a promising option for these women. We aimed to perform a systematic review and meta-analysis of randomized clinical trials (RCTs) comparing polyphenols to placebo in women with PCOS. Methods: The PubMed, Cochrane, and Embase databases were searched for RCTs comparing polyphenols to placebo. Data were extracted from published reports, and quality assessment was performed according to PRISMA guidelines. Endpoints included were: changes in levels of serum insulin, changes in BMI, LH, and testosterone levels. We used a random-effects model to calculate the Mean Difference (MD), Standardized Mean Difference (SMD), and 95% confidence interval (CI). Heterogeneity was examined with the Cochrane Q test and I² statistics: p values inferior to 0.05 and I² > 25% were considered significant for heterogeneity. Results: A total of 15 studies involving 916 patients were included. Of all participants, 445 (49%) received polyphenols. Polyphenols resulted in a significant decrease in serum insulin level (MD -2.49 [-3.72, -1.25] 95% CI; p < 0.0001, I² = 64%), in comparison to placebo. In addition, BMI levels were significantly reduced in patients treated with polyphenols when compared to placebo (MD -0.12 [-0.18, -0.06] 95% CI; p = 0.0002, I² = 0%). There was a reduction in LH levels in the intervention group, when compared with the baseline levels to the final levels (MD -0.87 [-1.54, 0.20] 95% CI; p = 0.01, I² = 46%). The decrease in testosterone levels was not significantly different when comparing polyphenols and placebo (SMD -0.14 [-0.53, 0.25] 95% CI; p = 0.48, I² = 73%). Conclusion: This meta-analysis provided evidence of the effectiveness of polyphenols in reducing serum insulin, LH and BMI in women with polycystic ovary syndrome compared to placebo. There was no statistically significant difference in the reduction of testosterone levels between polyphenols and placebo. This study represents the most current evidence on this promising treatment.

Presentation: Thursday, June 15, 2023
THU640 Clustering Of Genetic Loci Identifies 4 Distinct Polycystic Ovarian Syndrome Physiologic Pathways
Authors: Stamou Maria , Smith Kirk T , Kim Hyunkyung , Balasubramanian Ravikumar , Gray Kathryn , Udler Miriam
Published: October 2023

Disclosure: M. Stamou: None. K.T. Smith: None. H. Kim: None. R. Balasubramanian: None. K. Gray: None. M. Udler: Other; Self; Dr. Udler receives royalties from UpToDate, Inc and is part of an unpaid research collaboration with AstraZeneca, Inc.

Introduction: Genome-wide association studies (GWAS) have implicated severe genetic loci with polycystic ovarian syndrome (PCOS), with disease pathogenesis remaining largely unknown. Methods: To group PCOS GWAS loci into genetic clusters driven by disease physiology we performed a cluster analysis for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N=62,252). Associations with clinical outcomes (type 2 diabetes/T2D, coronary artery disease/CAD and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N=898,130, CARDIOGRAM/UKBB, N=547,261) and individual-level pPS in MGBB.Results: Four PCOS genetic clusters were identified with top loci indicated as following: (i) Cluster 1, obesity (FTO); (ii) Cluster 2, hormonal changes (FSHB); (iii) Cluster 3, inflammatory markers (ATXN2/SH2B3); (iv) Cluster 4, insulin resistance/liver enzymes (MAF, SLC38A11). Cluster pPS’s were associated with distinct clinical traits in MGBB females: Cluster 1 with increased body mass index (BMI; p=6.63x10-29); Cluster 2 with increased age of menarche (p= p=1.5x10-4); Cluster 3 with decreased mean platelet volume (MPV; p= p=3.07 x10-6); and Cluster 4 with increased ALP & ALT (p=0.007 & 0.02). Cluster 1 pPS was associated with increased T2D (OR 1.067; p=7.31x10-50) in GWAS, with replication in MGBB all participants (OR 1.088, p=7.63x10-7) and females only (OR 1.107, 9.59x10-5).Conclusions: Distinct genetic clusters in PCOS individuals may underlie the clinical heterogeneity of the disease.

Presentation: Thursday, June 15, 2023
THU646 Postmenopausal Hyperandrogenism Secondary To Ovarian Leydig Cell Tumor
Authors: Batch Jennifer Tania , Gandhi Gunjan Yogendra
Published: October 2023

Disclosure: J.T. Batch: None. G.Y. Gandhi: None.

Introduction: Hirsutism is typically the initial presentation of virilization, including male pattern balding, deepening of the voice, and clitoromegaly. Postmenopausal hyperandrogenism can originate from adrenal or ovarian causes. This report describes marked hirsutism and scalp hair loss in a patient, leading to significant negative psychological and social impacts. Case Report: A 73-year-old female presented to the clinic complaining of scalp hair loss and increased facial hair in the upper lip and chin. She has hypertension (treated with amlodipine, losartan, metoprolol tartrate, and hydrochlorothiazide), dyslipidemia (treated with omega-3 fatty acids), hypothyroidism (treated with levothyroxine), and transvaginal hysterectomy without oophorectomy in 1994 for menorrhagia (no hormonal replacement therapy after surgery). The patient reported regular menstrual periods before the hysterectomy but developed menorrhagia during her early 50s. For the past five years, she noted bitemporal scalp hair loss that progressed significantly and created recession of the hairline and thinning of hair in her crown area. She developed dark pigmented hair on her upper lip and chin area, lower abdomen, and chest. Due to the significant impact of these physical changes, she became socially withdrawn and admitted to only leaving home to attend doctors’ appointments. She denied using supplements or physical contact with anyone using topical testosterone. She denied enlargement of her clitoris. She did note a deepening of her voice, although she is a chronic smoker. A hormonal work-up revealed a significantly high total testosterone of 511 ng/dL (normal range 2-45 ng/dL). DHEA-sulfate was normal at 62 mcg/dL (4-157 mcg/dL), and 17-hydroxyprogesterone was not significantly high at 192 ng/dL. MRI abdominal and pelvis with and without contrast revealed a 1.8 cm avidly enhancing left ovarian nodule. The patient underwent bilateral salpingo-oophorectomy. Pathology showed tumor cells with eosinophilic cytoplasm, central nucleus, and prominent nucleolus, consistent with a Leydig cell tumor measuring 1 cm and was confined to the left ovary. Four weeks after surgery, a repeat hormonal work-up revealed a normal total testosterone level of 23 ng/dL (normal range 2-45 ng/dL). Discussion: Hyperandrogenism with rapidly progressing hirsutism indicates a tumoral etiology. Leydig cell ovarian tumors are uncommon neoplasms arising from the gonadal stroma, accounting for <0.1% of all primary ovarian tumors. The diagnosis is based mainly on clinical and laboratory data since imaging studies may not show the small androgen-producing lesion. Bilateral oophorectomy should be recommended in postmenopausal women when an ovarian source is suspected. Most ovarian virilizing tumors are benign, and bilateral salpingo-oophorectomy results in a cure.

Presentation: Thursday, June 15, 2023
OR04-04 Sexually Dimorphic Impact Of Gestational Hyperandrogenism On Offspring Growth Trajectory
Authors: Topaktas Eylem , Ghnenis Adel B G , Ciarelli Joseph Norman , Domke Stephanie , Padmanabhan Vasantha , Kalla Vyas Arpita
Published: October 2023

Disclosure: E. Topaktas: None. A.B. Ghnenis: None. J.N. Ciarelli: None. S. Domke: None. V. Padmanabhan: None. A.K. Vyas: None.

Gestational hyperandrogenism, as seen in polycystic ovary syndrome, adversely programs birth weight and small for gestational babies. In our established sheep model of PCOS phenotype, gestational testosterone (T) excess from days 30-90 of gestation (sexually dimorphic window where male fetuses naturally are exposed to elevated T) had no effect on fetal weight in early and mid-gestation (day 65 and 90; term 147 days) but manifested in intrauterine growth restriction (IUGR) on day 140 gestation followed by catch up growth in the early postnatal period in female lambs. The impact of T excess on IUGR and postnatal catch up seen in female may not be seen in the male due the elevated T it is naturally exposed to. We hypothesized that gestational T excess will have sexually dimorphic impact on late gestational fetal weights, a period of maximal fetal growth and the postnatal growth trajectory. Pregnant ewes were injected with T propionate (T), or oil-vehicle (CON), 100 mg I.M. twice weekly from gestational day 30 to 90 to obtain CON female (CF), T females (TF), CON males (CM), and T males (TM) fetuses on day 120 of gestation(GD120). In a the follow up study, lambs were delivered and weekly weights from CF, TF, CM, and TM were obtained till early adulthood. GD120 data and neonatal cytokine profile was analyzed by 2-way ANOVA and Cohen D (d) analysis while the postnatal growth data was subjected to mixed model ANOVA. T fetuses at GD120 weighed less then CON (P<0.05); prenatal T excess reduced body weight (BW in kg) in both sexes compared to CON (CM 3.38±0.15 vs.TM 2.68±0.14, p=0.001; CF 3.27±0.21 vs.TF 2.72±0.11, p=0.03). There was a large magnitude increase in IL4 (d=0.92) and moderate in IL6 (d=0.78), IL1α (d=0.74), TNFα (d=0.77) and MIPβ (d=0.74) in TF compared to CF. TF also has large magnitude increase in MIPβ (d=0.97) and moderate magnitude increase in IL36RA (d=0.78), IL6 (d=0.70) compared to TM. TM has large magnitude increase in MIPβ (d=0.99) and IL6 (d=0.80) compared to CM. In contrast, during postnatal life, a significant age x treatment interaction (p =0.029) in average weight gain over time was evident. Growth was significantly higher in CM, TM and TF than CF and did not differ between CM and TM. Presence of IUGR in both sexes in late gestation, as opposed to catchup growth in the postnatal period only in TF not TM could have implication in sex-specific impact on the cardiometabolic function in the lambs. Supported by NIH R01HL139639.

Presentation: Thursday, June 15, 2023
FRI375 Validation Of A Novel Mouse Placenta Explant Protocol For Screening Of Drugs Modulating Circadian Rhythms
Authors: Lee Jessica Sora , Hoffmann Hanne Mette
Published: October 2023

Disclosure: J.S. Lee: None. H.M. Hoffmann: None.

Introduction Pre-eclampsia is one of the leading causes of maternal, fetal, and neonatal morbidity and mortality, complicating about 4% of pregnancies. Recent work has identified PERIOD3 (PER3), a gene regulating 24-hour circadian rhythms, to be downregulated in the preeclamptic placenta. The role of circadian rhythms in the placenta largely remains unknown. Our goal is to establish an organotypic placental preparation to allow screening of drugs that regulate circadian rhythms. These studies are a first step towards understanding how circadian rhythm changes are caused in the placenta and will be the basis for future studies to understand how circadian rhythm disruption in the placenta cause pregnancy complications, such as preeclampsia.

Methods We established a novel organotypic placenta preparation allowing to study circadian rhythms in a LumiCycle using gestation day (GD) 14 and GD18 placental explants from the validated circadian reporter mouse Per2::Luciferase. Using H&E we validated the explants to be >80% enriched in either decidua (DC) which is strictly of maternal origin, labyrinth (LB) which is strictly of fetal origin, and the junctional zone (JZ) which consists of binucleated cells fused of maternal and fetal cells.

Results Through H&E staining, we validated by distinct morphology that the DC is enriched with neutrophils; the JZ contains spongiotrophoblasts and glycogen trophoblasts; whereas the LB has anucleated red blood cells. We next established a protocol to record Per2::Luciferase circadian rhythms for <6 days. We found that the Per2::Luciferase circadian rhythm shortens with increased gestational age, where the period in DC, LZ and LB in the GD14 placenta is ∼4h longer than in the GD18 placenta, showing an unexpected plasticity in circadian timekeeping in the placenta. Because PER3 is downregulated in the pre-eclamptic placenta, we asked if the explants would be useful for pharmacologically screenings. We applied PF670462 (1μM), which stabilizes PER1/2/3, or epidermal growth factor (EGF, 30ng/mL), a growth factor important in placental function and a PER2 enhancer. PF670462 lengthened Per2::Luciferase period in the DC and JZ, confirming the expected circadian rhythm stabilizing effect of PF670462. Surprisingly, EGF only modulated circadian rhythms in the GD14 placental, where EGF shortened Per2::Luciferase period in DC, and lengthen the period in the JZ and LB zones in the GD14 placenta. This data suggests EGF has gestational age and placenta zone specific effects.

Conclusion We validated a novel ex vivo placental preparation to study circadian rhythms at GD14 and GD18. We identified a placenta zone and gestation age specific effect of EGF, an effect future studies will further expand on. This model will be useful to complete pharmacological screenings of drugs that can restore circadian rhythms in the preeclamptic placenta.

Presentation: Friday, June 16, 2023
FRI384 Sterilization Of Female Dogs By A Neonatal Treatment Of Estrogen-Releasing Implants
Authors: Park Chan Jin , Lin Po-Ching , Zhou Sherry , Hess Rex A , Ko Chemyong
Published: October 2023

Disclosure: C. Park: None. P. Lin: None. S. Zhou: None. R.A. Hess: None. C. Ko: None.

Hypothalamic Kisspeptin neurons that control the GnRH neuron activity are known to be a core regulator of the reproductive axis. Loss of the Kisspeptin-1 gene in these neurons results in infertility. Recent reports showed that inhibition of Kisspeptin neuron development by daily injection of 17β-estradiol benzoate (EB, 0.5 mg/day), a long-lasting estrogen, to neonatal female rats for 10 days causes sterility. We aim to develop a single injection solution for achieving sterilization in female dogs by targeting developing Kisspeptin neurons. In this study, we tested a working hypothesis that, in female dogs, extended exposure to EB for 2 weeks after birth by slow-releasing implants will result in sterility. This hypothesis was proposed based on our proof-of-concept study in which neonatal treatment of female rats with implants that contained 0.3 mg EB decreased the number of Kisspeptin neurons, and made them infertile permanently. To test the hypothesis in dogs, pellets that contained 0.5 mg (n=3) or 1.0 mg EB (n=2) and were designed to release EB for 2-3 weeks were subcutaneously implanted in female beagle dogs on postnatal day 6 (PND6). Intact dogs (n=4) were used as controls. The indices for female fertility (estrous cyclicity, ovulation) were assessed by daily vulva examination (swelling, discharge) and monthly measurement of serum progesterone levels. In addition, when a dog exhibited signs of estrus, the dog was bred with fertility-proven male dogs. During the 3 years of the study period, control dogs showed a minimum of 3 reproductive cycles (estrus, ovulation), and successfully produced puppies each time. Treated dogs displayed dose-dependent fertility outcomes; none of the EB 1.0 mg-treated dogs exhibited estrus nor had elevated serum progesterone levels, while two dogs out of the three EB 0.5 mg-treated dogs remained infertile. The other dog of the EB 0.5 mg group showed estrus signs during the study period and produced a litter when bred with a proven male. In the second experiment, implants that contained 0.5 mg (n=2) or 1.0 mg EB (n=3) were injected into female puppies on PND1. They are currently 1-1.2 years of age, and none have shown estrus/ovulation signs so far. Our study demonstrates that neonatal treatment of EB by slow-releasing implants sterilizes female beagle dogs. During the study period, the complete blood cell count and serum chemistry of treated dogs were within the normal range. This study shows that the non-surgical solution using EB implants is a promising approach to replace the current practice of sterilizing pets with surgical methods. Supported by NSF SBIR grant (#2052603)

Presentation: Friday, June 16, 2023
FRI403 The Unintended Consequences Of Applying Topical Testosterone Directly To The Scrotum
Authors: Melendez-Rivera Juan Gabriel , Steven Scott James
Published: October 2023

Disclosure: J.G. Melendez-Rivera: None. S.J. Steven: None.

Background: Topical testosterone is commonly used to treat hypogonadism in men. A concern associated with its use is the unintentional transfer to partners and children by direct contact with the application site. While prior studies and case reports have demonstrated the effects of direct skin contact with traditional application sites including the axillary regions and the abdomen, scarce data is available regarding the effects of transfer from application to the scrotum. Clinical Case: A 44-year-old woman presented with gradually worsening hirsutism and deepening voice over the past two years along with sudden cessation of menses. Initial laboratory studies revealed elevated testosterone of 1,776 ng/dL [10-55 ng/dL], elevated free testosterone of 14.4 pg/mL [0-4.2 pg/mL], normal androstenedione of 80 ng/dL [41-262 ng/dL) and normal DHEA-S of 57.7 ug/dL [57.3-279.2 ug/dL]. Transvaginal ultrasound revealed no ovarian masses or hyperplasia and CT abdomen and pelvis with and without contrast revealed no adrenal masses or hyperplasia. Ovarian and adrenal vein sampling were unremarkable. Anabolic steroid panel demonstrated a significantly elevated testosterone-to-epitestosterone ratio of 83.5 [<4] confirming an exogenous source of testosterone. Although the woman initially reported that her husband was applying topical testosterone, she reported that he was “obsessive” about being sure to wash the area of application prior to intimacy. Further questioning revealed that her husband was actually applying high concentration topical testosterone directly to his scrotum with sexual intercourse occurring up to five times daily. Conclusion: This case illustrates the dangers of applying topical testosterone directly to the scrotum. Prior studies have demonstrated that it may result in higher levels of serum testosterone in a shorter period of time which makes it seem like an attractive option for men desiring rapid resolution of their hypogonadal symptoms. Despite these perceived benefits, it can be detrimental to the health of their female partners who may experience extraordinarily elevated testosterone levels as a result of direct intravaginal absorption of topical testosterone.

Presentation: Friday, June 16, 2023
FRI412 A Case of 46,XX Gonadal Dysgenesis With Mayer-Rokitansky-Küster-Hauser Syndrome And Primary Hypothyroidism
Authors: Al Allawi Sarah , Osman Radwa
Published: October 2023

Disclosure: S. Al Allawi: None. R. Osman: None.

Introduction: The association between Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome and gonadal dysgenesis is rarely reported in the literature. Coexistence of hypothyroidism with this condition is scarce and clinical correlation remains unclear. We describe a case of this rare clinical entity in conjunction with primary hypothyroidism.

Clinical case: A 27-year-old Female with a medical history of primary hypothyroidism was referred to our clinic for evaluation of primary amenorrhea. She was born with a female phenotype. Growth was appropriate, but puberty was delayed with self-reported late pubarche at age 19. She never had a menstrual cycle, and had received hormonal replacement therapy (HRT) for a few months but failed to trigger menarche. However due to financial constraints, treatment was not continued. She was diagnosed with hypothyroidism since birth, for which she is currently maintained on levothyroxine 225 mcg daily.

On physical exam, blood pressure was 126/72 mmHg, pulse rate 83 BPM, height 5’9”, BMI 34 kg/m2. No facial dysmorphisms or skeletal deformity were apparent. She had normal pubic and axillary hair distribution, breast budding consistent with Tanner Stage II. Genital examination revealed normal external genitalia and a blind vaginal pouch.

Hormonal workup revealed hypergonadotrophic hypogonadism with estradiol < 0.5 pg/mL and post-menopausal range follicle-stimulating hormone (FSH) 36.7 mIU/mL. Thyroid stimulating hormone (TSH) 2.19 uIU/ml (nl 0.45-4.5 uIU/mL) and anti-TPO antibodies 10 IU/mL (nl 0-34 IU/mL). Prior thyroid ultrasound reported a small thyroid gland. Fluorescence in situ hybridization (FISH) analysis revealed 46XX karyotype. Abdominal and pelvic ultrasound showed normal kidneys with a non-visualized uterus and ovaries. Pelvic MRI confirmed the absence of both and showed a blind end vaginal pouch, leading to the conclusion of the coexistence of gonadal dysgenesis with MRKH. She was then placed on transdermal estradioltherapy.

Conclusion: The association between gonadal dysgenesis (the most common cause of primary amenorrhea) and MRKH syndrome (the second most common cause) is infrequent. HRT remains the only therapeutic option. It aims to trigger the development of secondary sexual characteristics and prevent osteoporosis by allowing appropriate bone mineral accrual. Unfortunately, infertility remains the most significant consequential issue; hence the availability of good caring and psychological counseling should not be underestimated.

The co-existence of likely non-immune primary hypothyroidism is even less frequent. To our knowledge, our case is the second reported case of this trilogy. Given the paucity of data, the association of this condition with primary hypothyroidism cannot be well established and can be coincidental. More studies are needed to determine if this condition has a higher prevalence of hypothyroidism.

Presentation: Friday, June 16, 2023
FRI413 Hormonal Menstural Suppression For Menstrual Obstruction: A Retrospective Review Of Patients With Complex Obstructed Uterovaginal Anomalies Who Underwent Surgical Management In A Tertiary Referral Centre
Authors: Learner Hazel Isabella , Creighton Sarah M , Clarke Sophie A
Published: October 2023

Disclosure: H.I. Learner: None. S.M. Creighton: None. S.A. Clarke: None.

Aims: To describe the use of hormonal menstrual suppression in patients undergoing surgery for complex utero-vaginal anomalies with menstrual obstruction.

Background: Obstructed menstruation can present with painful primary amenorrhea or progressive dysmenorrhea due to unilateral obstructing duplication utero-vaginal anomalies. Menstrual suppression is essential to relieve pain during investigation and surgical planning. The off licence use of progestogens, hormonal contraception and GNRH analogues is common but there is little literature describing their best use in this context.

Methods: This was a retrospective case series review of patients undergoing surgical management of complex menstrual obstruction in a tertiary referral centre between 2016-2022. Data collected on age, diagnosis, symptoms, duration of symptoms, surgery, the type of endometrial suppression used and associated side effects.Patients with partial obstruction were excluded.

Results: Eighty-four patients were identified from the surgical database. The median age at time of surgery was 16 years (range 11-36). Unilateral obstruction was managed in 53/84 and complete obstruction in 31/84. Diagnoses included obstructed hemi-vagina (32/84), unicornuate uterus with functional uterine remnant (19/84), transverse vaginal septum (15/84), cervical/vaginal agenesis (9/84), and Mullerian agenesis with functional uterine remnant (5/84). Symptom duration information was available in 74/84 with a median of 10 months(0-252 months). Changes to endometrial suppression treatment were required in most patients, with 50/84 (40%) remaining on their original prescription. The average number of treatment regimes was 2 (0-7). Menstrual suppression at time of surgery was Norethisterone 35/84 (42%), Continuous combined oral contraceptive pill18/84 (21%), Medroxyprogesterone 11/84 (13%), GNRH 10/84 (12%), Desogestrel 6/84 (7%), and Depo-Provera 4/84 (5%). Tibolone was used as add-back in five patients on GNRHa for more than 6 months duration of use (4/5) or hypoestrogenic side-effects (1/5) .

Conclusion Menstrual suppression for pain relief is an essential component in management for complex uterovaginal anomalies. Suppression should be started at initial presentation but there is limited guidance for clinicians as to what and how to prescribe. Our study has demonstrated that this can lead to chaotic prescribing, unnecessary pain and multiple treatment changes.

Presentation: Friday, June 16, 2023
FRI431 Erythrocytosis Associated With Oral Testosterone Replacement
Authors: Engel Ashley A , Sarvaideo Jenna Lynne
Published: October 2023

Disclosure: A.A. Engel: None. J.L. Sarvaideo: None.

Background: A growing prevalence in male hypogonadism has led to increased interest in the most common adverse event, erythrocytosis. Defined by hematocrit (HCT) > 49-51%, the incidence varies depending on the testosterone formulation.3 The formulations with the lowest risk of erythrocytosis are intranasal testosterone (0-2%) and oral testosterone (0.03%).3 A phase 3 clinical trial of testosterone undecanoate (Jatenzo) reported 4.8% patients experienced an increase in hematocrit, although not severe enough to warrant therapy discontinuation.2 We present a case of erythrocytosis with oral testosterone undecanoate that prompted a change in therapy. Clinical Case: Our patient is a 55-year-old male with secondary hypogonadism potentially related to obesity (BMI 37 kg/m²). AM total testosterone (TT) 151 (348-1197 ng/dL), free testosterone 4.6 pg/mL (6.8-21.5 pg/mL) and LH 3.8 mIU/mL. Labs confirmed. Secondary work-up negative. HCT 43.6% prior to any therapy. Patient treated with injectable testosterone. Despite decreasing to testosterone cypionate 80 mg weekly his HCT increased to 52.7% with a TT of 544 ng/dL. He was switched to oral testosterone undecanoate 237 mg twice daily given presumably lower risk of erythrocytosis. However, HCT increased to 55.1% and TT to 1542 ng/dL. Patient donated blood and oral testosterone dose decreased to 158 mg twice daily with starting HCT 48.9%, but this increased to 53.7%. TT 522 ng/dL. Therapy stopped with improvement of HCT to 45.8%-48.9%, TT 192 ng/dL, and SHBG 20 g/dL. Erythropoietin remained normal. Patient does not smoke cigarettes nor has OSA. Conclusion: We present a case of oral testosterone undecanoate complicated by persistent erythrocytosis despite dose reduction. Testing for contributing etiology was unrevealing. Oral testosterone replacement is considered the formulation least likely to cause erythrocytosis. Certain patient characteristics like OSA, advanced age, obesity, type II diabetes mellitus and an elevated HCT > 50% can predict the likelihood of erythrocytosis although its specific etiology is unclear.3 Proposed mechanisms include elevation in dihydrotestosterone, erythropoietin stimulation, suppression of hepcidin and relation to androgen receptor CAG repeat length.1 Providers should be aware of the possibility of erythrocytosis on oral testosterone. Further research is needed to determine predictive characteristics for erythrocytosis and etiology.

Reference: 1. Aghazadeh, M, et al. Elevated dihydrotestosterone is associated with testosterone induced erythrocytosis. J Urol. 2015; 194(1): 160-165. 2. Swerdloff, S, et al. A new oral testosterone undecanoate formulation restores testosterone to normal concentrations in hypogonadal men. J Clin Endocrinol Metab. 2020; 105)8): 1-17. 3. White, J, et al. Testosterone therapy and secondary erythrocytosis. IJIR: Your Sexual Medicine Journal. 2022; 34: 693-697.

Presentation: Friday, June 16, 2023
FRI442 Ongoing Clomiphene Treatment For Men With Hypogonadotropic Hypogonadism
Authors: Smith Stephen Ross
Published: October 2023

Disclosure: S.R. Smith: None.

Context: Male hypogonadism is becoming recognized with increasing frequency. Testosterone products remain the only approved medical therapy, although highly problematic in men with hypogonadotropic hypogonadism because of inconvenient routes of administration, high cost, and unavoidable suppression of the hypothalamic-pituitary-gonadal axis. There is a need for effective and safe alternative medication.

Objective: The purpose of this study was to evaluate the use of clomiphene long term in men with hypogonadotropic hypogonadism.

Methods: Thirty-one men with non-congenital hypogonadotropic hypogonadism were treated with clomiphene citrate on an ongoing basis for up to 20 years. Seven patients were treated for > 12 years; 20 patients were treated for > 4 years. Initial age range was from 23 to 74 years, with a mean of 52. Serum testosterone and LH levels were monitored periodically. Clomiphene dose was adjusted at each office visit as required to achieve and maintain normal testosterone levels and improvement in hypogonadal symptoms in each individual patient. Patients were monitored for adverse effects. Data generated were analyzed retrospectively with Microsoft Excel statistical programs.

Results: Improvement in hypogonadal symptoms occurred in nearly all patients. All 31 men experienced increases in serum testosterone and LH levels into the normal range, and statistical analysis showed these increases to be highly significant. Testosterone levels increased from 226 +/- 12 to 542 +/- 35 (mean +/- SEM) ng/dl through the period of treatment (P < .0001). LH levels increased from 3.6 +/- 0.4 to 10.0 +/- 1.6 mIU/ml (P < .0002). Clomiphene dose required to achieve and maintain appropriate responses was highly variable within the group of patients, ranging from 3.57 to 200 mg daily, with a mean dose of 54.4 mg daily. There was evidence of diminishing returns with dosage increases to > 100 mg daily. However, response to adjusted clomiphene dose, once established, was generally quite stable for each patient over extended periods of time, up to 20 years. No major adverse effects were encountered. Conclusions: Clomiphene is an effective and safe long-term treatment for men with non-congenital hypogonadotropic hypogonadism. It should be made available as an alternative to testosterone products for this group of men.

Presentation: Friday, June 16, 2023
FRI445 A Late Diagnosis Of Complete Androgen Insensitivity Syndrome
Authors: Muuse Janelle , Shah Rutu Jatin , Belany Paul A
Published: October 2023

Disclosure: J. Muuse: None. R.J. Shah: None. P.A. Belany: None.

Introduction: Complete Androgen Insensitivity Syndrome (CAIS) is a rare disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. Individuals with CAIS are born unambiguously female without any apparent abnormalities. They develop a short blind ending vaginal canal, with absence of Wolffian duct derived structures (vas deferens, seminal vesicles). Breast development advances regularly at puberty, while there is absent pubic and axillary hair, both due to peripheral conversion of testosterone to estrogen. Testes remain undescended in the abdominal cavity.

Case: A 28 year old female with a past medical history of bipolar disorder presented to her primary care physician’s office with a chief complaint of fatigue. Blood work revealed an elevated testosterone level of 686, at which time she was referred to endocrinology for further work up. On further history gathering, she endorsed a life long history of amenorrhea. She saw an OB-GYN at 19 years old and was told she had a short vaginal canal. A pelvic ultrasound revealed no uterus and one left ovary. She was not given a diagnosis other than congenital absence of a uterus. She was lost to follow up until 28 years of age when she sought medical help for her fatigue. Physical exam was pertinent for a tall female with no signs of hirsuitism. Additional blood work revealed normal LH, FSH, and DHEA-S. A chromosomal analysis revealed XY. She was referred to gynecology for further management and assessment for orchiectomy.

Discussion: This was an unusual case of CAIS, as this was diagnosed far past menarche. Most cases are diagnosed during puberty- which aids in an early approach towards the psychological and social well being of the individual as well as close follow up for evaluation of orchiectomy. Orchiectomy is recommended due to the increased risk of gonadal malignancy following puberty. The risk of developing malignancy increases with age, and has been reported to be between 15-22%. Thus it is important to identify this syndrome early in life to ensure this is addressed. It is followed by long term hormonal therapy with estrogen to maintain normal breast and bone development. This case highlights the importance of maintaining a high clinical suspicion of CAIS in females presenting with short vaginal canal and absence of a uterus in order to prevent malignancy and provide optimal psychological support to the individual.

Presentation: Friday, June 16, 2023
FRI451 Effect Of Estrogen Replacement On Various Metabolic Parameters In Turner’s Syndrome
Authors: Mishra Ipsita , Jena Sweekruti , Baliarsinha Anoj Kumar
Published: October 2023

Disclosure: I. Mishra: None. S. Jena: None. A.K. Baliarsinha: None.

Turner’s Syndrome is a rare genetic disorder caused by complete or partial X chromosome monosomy in a phenotypic female, and is associated with increased morbidity and mortality for cardiovascular diseases, impaired glucose tolerance, liver dysfunction and dyslipidemia. Estrogen therapy was initially focused on pubertal induction and preservation of bone health. Recent longitudinal studies have shown the beneficial effect of estrogen therapy on various metabolic parameters, liver dysfunction and insulin resistance in these patients.To study the effect of estrogen therapy on various metabolic parameters, a cohort of 24 adolescent girls with Turner’s Syndrome planned for hormonal replacement therapy were recruited. Baseline data of detailed history, clinical examination, biochemical evaluation including glycemic status, lipid profile, liver function test and fibroscan were collected. At 6 month follow-up of estrogen replacement, repeat biochemical evaluation and fibroscan were done.The data obtained was entered into Microsoft Excel Worksheet and analysed using Statistical Package for Social Sciences (SPSS, IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp.). The normal distribution of data was confirmed with Shapiro-Wilk's test and appropriate parametric tests were employed. Mean and standard deviation were computed for all continuous variables. At baseline visit and 6 month follow up, statistically

significant improvement, was found in fasting plasma glucose, post-prandial plasma glucose, fasting insulin, HOMA-IR, VLDL and total bilirubin with estrogen therapy. Maximum reduction (p <0.001) was seen in LDL, AST, ALT and fibroscan values .No improvement was seen in triglyceride, HDL, direct bilirubin and ALP levels. Estrogen has been shown to improve insulin sensitivity and suppress gluconeogenesis by transcription factor Foxo1(1). Hepatoprotective role of estrogen has been explained by anti-inflammatory effects and protection from oxidative stress, mainly mediated via β estrogen receptor(2). Beneficial effects of estrogen on lipid profile have been verified in several studies. We conclude that the benefits of estrogen therapy in Turner’s Syndrome are much beyond the limit of puberty induction and bone health and pleiotropic actions of estrogen still need to be elucidated with further studies.

Reference: (1) Yan et al; Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1. Diabetes 1 February 2019; 68 (2): 291–304. (2) Koulouri O et al. Liver dysfunction in Turner's syndrome: prevalence, natural history and effect of exogenous oestrogen. ClinEndocrinol (Oxf). 2008 Aug;69(2):306-10.

Presentation: Friday, June 16, 2023