bluuebunny/crossref_metadata_2025 huggingface dataset:
5164 Long COVID patients with menstrual symptoms: a retrospective study in Japan
Authors: Otsuka Fumio , Sakurada Yasue , Matsuda Yui , Hasegawa Toru , Otsuka Yuki , Nakano Yasuhiro , Tokumasu Kazuki , Yamamoto Koichiro , Sunada Naruhiko , Honda Hiroyuki , Hagiya Hideharu , Ueda Keigo
Published: October 2024

Disclosure: F. Otsuka: None. Y. Sakurada: None. Y. Matsuda: None. T. Hasegawa: None. Y. Otsuka: None. Y. Nakano: None. K. Tokumasu: None. K. Yamamoto: None. N. Sunada: None. H. Honda: None. H. Hagiya: None. K. Ueda: None.

It has been recognized that about one third of patients may suffer from prolonged illness after surviving from the acute phase of COVID-19. Various symptoms of the prolonged illness have been evaluated by many institutions including WHO. However, the mechanisms of the prolonged symptoms have yet to be elucidated. Long COVID is a complicated illness that develops after SARS-CoV-2 infection, independent of the severity of COVID-19. Long COVID is defined as symptoms that occur within 3 months after the initial infection and persist for at least 2 months. The major symptoms of long COVID include general fatigue, post-exertional malaise, headache, insomnia, dyspnea, cognitive dysfunction, low-grade fever, and muscle pain. Proposed pathophysiological mechanisms of long COVID include pathogen persistence and viral reactivation, immune dysregulation and autoimmunity, neurological abnormalities, tissue damage due to hypoperfusion and/or microclots, autonomic and endocrine dysfunctions, and dysregulation of microbiomes. In the present study, we aimed to elucidate the impact of long COVID on female reproductive health. In this retrospective study, medical records of patients who visited our long COVID clinic and clinical trends of their menstrual symptoms were evaluated. In our study, of 349 female patients who visited our clinic between Feb 2021 and Mar 2023, 223 patients with long COVID (18-50 years) were included. It was revealed that 44 females (19.7%) had menstrual symptoms associated with long COVID. The patients with menstrual symptoms were significantly older than those without menstrual symptoms (42.5 vs. 38 years). The percentage of patients with menstrual symptoms was higher during the Omicron phase (24%) than during the Preceding (13%) and Delta (12%) phases. Cycle irregularity (63.6%) was the most frequent menstrual symptom, followed by severe pain (25%), heavy bleeding (20.5%), perimenopausal symptoms (18.2%), and premenstrual syndrome (15.9%). Fatigue and depression were the most frequent complications with menstrual complaints. Scores indicating fatigue and QOL were significantly worse in long COVID patients with menstrual symptoms. Endocrine examinations showed significantly increased cortisol levels in patients with menstrual complaints although plasma adrenocorticotropin levels were not altered. Hence, long COVID has an impact on women’s reproductive and mental health.

Presentation: 6/1/2024
7132 Delayed Clinical Response To Unilateral Adrenalectomy In A Patient With Inconsistent Non-clearly Lateralized Primary Aldosteronism
Authors: Beland S , St-Jean M
Published: October 2024

Disclosure: S. Beland: None. M. St-Jean: None.

Unilateral adrenalectomy (UA) is the preferred treatment for patients with lateralized primary aldosteronism (PA). While treatment with mineralocorticoid receptor antagonists is preferred for non-lateralized PA, evidence suggests that UA may be associated with clinical and biochemical responses in some patients. We present the case of a 53-year-old woman with resistant hypertension who was referred to our clinic in September 2022 for the management of PA. Her medical history included non-ischemic cardiomyopathy, dyslipidemia, and transient ischemic attack. At referral, antihypertensives included telmisartan, indapamide, and amlodipine. Her aldosterone renin ratio was 138 pmol*L/ng*L, and an oral salt loading suppression test showed a 24h urinary aldosterone of 32 pmol/day. An abdominal CT scan did not show any adrenal nodule. Adrenal vein sampling was conducted, and two different basal Lateralization Ratio (LR) were obtained despite similar cortisol levels. Basal LR at -5 min was 12 but dropped to 1.3 at 0 min. The LR following 250 mcg of IV cosyntropin was around 1. Contralateral suppression (Aopp/Ap) was 6.5. Due to the inconsistent basal LRs and the non-suppressed contralateral suppression, non-lateralized PA was considered, and spironolactone was prescribed. By August 2023, despite optimizing her medication consisting of 6 antihypertensive drugs and achieving plasma renin values of 54 ng/L, the patient’s blood pressures remained above 140/90 mmHg. Considering the patient’s resistant hypertension and known cardiomyopathy, we decided to proceed with UA, which was performed in October 2023. In the immediate post-op period, spironolactone dosage was decreased by 50%, and terazosin was discontinued. Surprisingly, plasma aldosterone on post-op day 1 was <70pmol/L. Nevertheless, two weeks following surgery, the patient’s blood pressure remained around 150/100 mmHg. Shortly after the two-week follow-up, the patient presented with new onset stuttering, paresthesia, and hypotension with systolic reaching 60 mmHg. Brain MRI and CT scans showed no evidence of stroke, suggesting that her symptoms could be attributed to cerebral hypoperfusion secondary to changes in blood pressure. Her antihypertensive regimen was reviewed accordingly, and close clinical follow-ups were conducted. As of November 2023, the patient’s blood pressure has remained under 120/80, and all antihypertensive medications, except bisoprolol, were discontinued. Notably, one-month post-UA, plasma aldosterone and renin levels were 160 and 185 pmol/L, respectively. This case thus supports the potential benefit of UA in some patients with non-clearly lateralized PA, especially those resistant to treatment, and emphasizes the need to conduct close post-op monitoring. Finally, this case also highlights the need to obtain both basal and post-ACTH values during AVS.

Presentation: 6/1/2024
7407 Normosmic Idiopathic Hypogonadotropic Hypogonadism in Women: A Case Report and Comprehensive Review
Authors: Bustamante E G , Sulehri M , Patoli I , Karunakaran A
Published: October 2024

Disclosure: E.G. Bustamante: None. M. Sulehri: None. I. Patoli: None. A. Karunakaran: None.

Introduction: IHH is a rare genetic disorder affecting gonadotropic-releasing hormone (GnRH) production and/or action, resulting in diminished sex steroid levels. Characterized by the absence of spontaneous pubertal development. In women, it manifests with normal adrenarche but absent thelarche and menarche. Our case highlight a late diagnosis of IHH in a 34-year-old woman with primary amenorrhea. Case report:A 34 year old lady with a history of primary amenorrhea sought evaluation. At age 16, she underwent assessment for short stature and primary amenorrhea, denying anosmia, headache, visual disturbances. Evaluation revealed bone age concordant with chronological age and normal MRI Brain. Pelvic ultrasound (US) showed small premenarchal uterus and ovaries. She initiated oral contraceptive pills (OCP) and experienced regular menses. Seeking fertility assistance at age 24, a normal Hysterosalpingogram was followed by successful delivery of twins after ovarian stimulation. Post-delivery menses did not resume and OCP was not restarted. Family history revealed a sister with irregular periods requiring OCP.Subsequently workup at age 30 showed Estradiol 22 pg/ml, FSH/LH 4.1/2.3 mUI/mL; normal PRL, TFT, DHEAS, 17OHP. Repeat Pelvic US showed normal uterus, endometrial stripe normal at 0.24 cm and non-visualized ovaries. PCOS testing negative for hyperandrogenism. Progesterone challenge resulted in no withdrawal bleeding. Brain MRI demonstrated a 2.2 x 1.3 mm hypoenhancing ovoid mass in the pars Intermedia of the pituitary gland suggestive of pituitary microadenoma. Pituitary axis hormonal testing was normal. Karyotype revealed 46 XX (normal female). Genetic evaluation identified a pathogenic variant (p.R35C) in GNRH1 gene. Her final diagnosis: nIHH. Discussion HH is diagnosed in 5% of all women with primary amenorrhea and is divided into 2 major categories: Kallmann syndrome and nIHH. The majority of known causes of HH can be attributed to mutations in KAL1, FGFR1, or GNRHR. The p.R35C variant has been associated with autosomal dominant nIHH. Diagnosis involves clinical suspicious, low LH/FSH and sex steroid levels, normal hypothalamic–pituitary imaging, and exclusion of differentials.Treatment goal for female focus on regular breast and uterine development, as well as the capability to conceive. Use of hormonal replacement therapy and/or gonadotropins or pulsatile GnRH for ovarian stimulation are essential. ConclusionWhile IHH predominantly affects men, limited literature explores its manifestation in women and its impact on fertility. The identification of a GNRH1-related nIHH variant highlights the role of genetic testing in specific HH diagnoses. Failure to diagnose in adolescence may compromise women overall well-being

Presentation: 6/1/2024
6447 Delayed Presentation Of Primary Hyperaldosteronism In The Setting Of An Adrenal Incidentaloma
Authors: Devineni S K , Gilden J L
Published: October 2024

Disclosure: S.K. Devineni: None. J.L. Gilden: None.

Background: Current guidelines for biochemical monitoring in the setting of an adrenal incidentaloma suggest annual laboratory testing up to 4 years. If there is no progression in size and phenotype of adrenal mass, no further workup is generally recommended after 4 years. However, we present a case of delayed primary hyperaldosteronism development nearly 10 years after an adrenal lesion was diagnosed. CASE: A 71-year-old Filipino male was referred to the Endocrinology clinic for evaluation of an incidental finding of an adrenal mass in 2010. Initial imaging showed a right adrenal nodule measuring 1.1 cm with washout and Hounsfield units consistent with a benign adenoma. Biochemical laboratory testing was normal at that time. Family history is relevant for a biological brother who had an unknown type of adrenal tumor that was removed in middle age. Pertinent medical history included essential hypertension, well controlled at that time on dual antihypertensive therapy. Surveillance imaging and laboratory testing were continued annually per guidelines for the next 4 years and were normal. In 2016, nearly 6 years after initial diagnosis of adrenal lesion, patient’s blood pressure worsened thus his PCP added a third antihypertensive medication. At that time, repeat hormonal testing and imaging to rule out secondary hypertension etiologies were normal. Blood pressure remained stable but again started to rise in 2020, thus a fourth antihypertensive medication was added to his regimen. Biochemical evaluation now showed serum aldosterone-to-renin ratio (ARR) increased from normal level (less than 30) to 48, with up-trending aldosterone levels. Patient’s serum ARR continued to rise over the course of the following year (now 11 years from initial diagnosis of adrenal lesion) with levels increasing to 100, up to a peak level of 142. CT adrenal imaging showed bilaterally nodular adrenal glands with an unchanged 1.1 cm right adrenal nodule with absolute washout of 74.8% as well as a new right adrenal lesion measuring 2.0 cm with absolute washout of 65.8%. Due to these imaging findings, decision was made to substitute spironolactone therapy for one of his four antihypertensive medications. Patient remains biochemically and clinically stable and is awaiting adrenal venous sampling for determination of hormonal activity of adrenal lesions. CONCLUSION: We present a rare clinical scenario where an adrenal incidentaloma may be hormonally active nearly a decade after initial diagnosis with a delayed presentation of primary hyperaldosteronism. We hope this case sheds light on considerations for extended surveillance and monitoring of adrenal incidentalomas in the setting of worsening hypertension.

Presentation: 6/2/2024
8474 SOX11 mutations cause hypogonadotropic hypogonadism through both hypothalamic and pituitary level deficits
Authors: Sun Bang , Stockman Sara , Stamou Maria , Plummer Lacey , Salnikov Kathryn , Kotan Damla , Topaloglu Kemal , Seminara Stephanie Beth , Balasubramanian Ravikumar
Published: October 2024

Disclosure: B. Sun: None. S. Stockman: None. M. Stamou: None. L. Plummer: None. K. Salnikov: None. D. Kotan: None. K. Topaloglu: None. S.B. Seminara: None. R. Balasubramanian: None.

Purpose: Human SOX11 mutations cause Coffin-Siris Syndrome (CSS) which is clinically characterized by aplasia or hypoplasia of the distal phalanx/nail of the fifth digit, developmental delay, cognitive impairment, and distinctive facial features. Recent studies show hypogonadotropic hypogonadism (HH) occurs in ∼20% of patients with SOX11 mutations. The genotypic-phenotypic spectrum of SOX11 mutations in patients presenting with Idiopathic Hypogonadotropic Hypogonadism (IHH) is unknown. Methods: Exome sequencing data from 1810 unrelated IHH probands (anosmic and normosmic forms) were reviewed for SOX11 rare sequence variants (RSVs) [minor allele frequency <0.1%]. Rare variant association analysis (RVAS) and domain-based enrichment for SOX11 RSVs was performed between the IHH and gnomAD population cohort. RSVs predicted as pathogenic/likely pathogenic by ACMG criteria were deemed as pathogenic RSVs and detailed phenotypic analysis was undertaken for these variants. Results: A total of 4 pathogenic SOX11 RSVs were identified in 5 IHH cases. RVAS analysis showed that SOX11 inactivating RSVs (frameshift/non-sense) across the entire protein was enriched in the IHH cohort (2 RSVs in 3 IHH cases (p.S303X [de-novo]; p p.S345Afs*13); p<0.0001) while SOX11 missense RSVs was enriched only within the SOX11-HMG domain (2 RSVs in 2 IHH cases (p.G84D [de-novo]; p.P114S; p=0.003). Phenotypic review of individuals with pathogenic SOX11-RSVs revealed a spectrum of endocrine defects including: anosmic and normosmic forms of IHH, growth-hormone (GH) deficiency, neuroimaging defects (pituitary microadenoma and hypothalamic mass), and hypothyroidism. Additionally, we also identified a pathogenic SOX11 HMG domain RSV in a patient with functional HH (p.R100Q). CSS-associated features were present in almost all individuals with pathogenic SOX11 RSVs. Conclusions: This study validates SOX11 mutations as causal for IHH and reiterates the critical importance of the SOX11-HMG domain in disease pathogenesis. The spectrum of endocrine abnormalities in SOX11-related human disorders includes IHH, functional HH, GH deficiency, pituitary lesions, and hypothyroidism. The association of congenital anosmic and normosmic forms of IHH, functional HH, and anatomic abnormalities of the pituitary gland suggest that the pathogenesis of HH in SOX11-disorder may stem from both hypothalamic and pituitary level deficits.

Presentation: 6/1/2024
12271 Differential Impacts Of Body Composition Indices On Cortisol Response And Hpa Axis Activity
Authors: Gonsalves Stephen G , Ross Alex , Steele Michael E , Saligan Leorey N
Published: October 2024

Disclosure: S.G. Gonsalves: None. A. Ross: None. M.E. Steele: None. L.N. Saligan: None.

Aim: The continued interest in the influence of muscle mass and fat distribution on stress stems from its implications on preventative healthcare. Fat mass index (FMI) and fat-free mass index (FFMI) were proposed as valuable indicators of body composition beyond body mass index (BMI). This study investigated correlations of FMI and FFMI with inflammatory stress markers, hypothesizing that these body composition indices identify inflammatory stress markers more distinctly than BMI. Methods: Skeletal muscle mass was assessed by Dual-Energy X-ray Absorptiometry, HPA axis response through an adrenocorticotropic hormone (ACTH) stimulation test, and markers of inflammation and stress response (e.g., dehydroepiandrosterone, DHEA) from peripheral blood of 104 healthy individuals aged 18-71 years, 52% female, with a mean BMI of 26.3 (+4.83). Perceived stress and fatigue were captured using patient-reported outcome questionnaires before the HPA procedure. Results: ACTH correlated with FFMI at baseline (ρ=0.299, p=0.009) and 60 minutes (ρ=0.254, p=0.041). Cortisol correlated with FFMI at 15 (ρ=–0.248, p≤0.025), 30 (ρ=–0.284, p≤0.010), and 60 minutes (ρ=–0.364, p≤0.001), and with BMI at 15 (ρ=–0.228, p=0.041). FMI and BMI did not correlate with ACTH and FMI with cortisol at any timepoint. With repeated measures ANOVA, FFMI at 50th percentile had large effect on cortisol (p=0.005, partial eta=0.094) at each timepoint, higher for the under lean than those with higher FFMI, compared to BMI at the same percentile (p=0.037, partial eta=0.054). None of the indices reached significance with ACTH. FMI correlated with Erythrocyte Sedimentation Rate (ESR) (ρ=0.521), C-reactive protein (CRP, ρ=0.493, both at p≤0.001), DHEA (ρ=0.252, p=0.030), and epinephrine (ρ=–0.246, p=0.045). FFMI was not correlated with ESR and CRP. BMI correlated only with albumin (ρ = –0.412, p ≤ 0.001 and CRP (ρ=0.342, p≤0.003). Discussion: The higher correlations of inflammatory stress markers with FMI and FFMI, as compared to BMI, supports our study hypothesis. These results hint that these body composition indices may detect subtle stress-related inflammatory changes than BMI. Future research should clarify underlying mechanisms driving these associations and explore the impact of targeted interventions on these indices and subsequent changes to inflammation and stress.

Presentation: 6/1/2024
6626 Fertility considerations in Klinefelter Syndrome complicated by hypogonadotrophic hypogonadism
Authors: Govinna Mauli , Sarlos Stella , Allan Carolyn A , Giri Rinky
Published: October 2024

Disclosure: M. Govinna: None. S. Sarlos: None. C.A. Allan: None. R. Giri: None.

Background: Klinefelter syndrome (KS) remains underdiagnosed with less than 50% of men ever diagnosed and >90% of diagnoses only occurring when fertility is sought. MicroTESE (microscopic testicular sperm extraction) is now successful in 47-69% [1]. Optimal timing of the procedure is uncertain. Case: A 14-year-old male student with a history of renal stones (normal genitourinary tract anatomy) and anxiety presented with a six-day history of new onset headaches and transient visual blurring. MRI scan showed a 2.1cm pituitary lesion with local mass effect and minimal compression of the optic chiasm. Pre-operative pituitary panel: FSH 29.8 IU/L (1.2 - 5.2 IU/L); LH 8.8 IU/L (2.0 - 8.0 IU/L); testosterone 10.9 nmol/L (0.7 - 17.6 nmol/L). Remainder of anterior pituitary function was normal; no AVP deficiency. On examination, Tanner stage P4 G4, testicular volumes 5-6ml (right) and 6-8ml (left) (expected range 15-20ml). Height 175cm (75th centile) and weight 60.1kg (63rd centile). Transsphenoidal resection (TSS) of the pituitary lesion was performed. Intraoperative appearances were suggestive of craniopharyngioma adherent to the pituitary stalk, with stalk transection to achieve complete resection. Post-operatively AVP-deficiency, hypocortisolism and secondary hypothyroidism required replacement therapy. Histopathology was subsequently consistent with Rathke’s cleft cyst. Karyotype testing confirmed 47 XXY genotype (Klinefelter syndrome). Post-TSS FSH and LH levels were 0.7IU/L (1.2 - 5.2 IU/L) and 0.3 IU/L (2.0 - 8.0 IU/L); with testosterone <0.1 nmol/L (0.7 - 17.6 nmol/L), consistent with hypogonadotrophic hypogonadism superimposed on a background of primary hypogonadism. Testosterone replacement therapy was commenced following discussion regarding potential future fertility options. Discussion: This diagnosis of KS highlights the importance of thorough assessment of pubertal development and testicular examination. Small testes with hypergonadotrophic hypogonadism in the context of pituitary pathology should trigger further assessment. Fertility preservation procedures in prepubertal and adolescent boys with KS remain controversial [2]. This patient represents a unique scenario whereby he is LH and FSH deficient post TSS. Whilst prior treatment with hCG does not increase sperm retrieval in non-mosaic KS [3] there may be a role for gonadotrophin therapy prior to undertaking microTESE in our patient. To date, there are no reported cases. References: 1. Sá R et al. Genes 2023, 14, 647. 2. Pook CJ et al. Front Reprod Health. 2021 Aug 3;3:629179.3. Guo F et al. Fertil Steril. 2020 Nov;114(5):997-1005.

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

Long-term Effects of Gender Affirming Hormone Therapy (GAHT) on Lipid Profile 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
7407 Normosmic Idiopathic Hypogonadotropic Hypogonadism in Women: A Case Report and Comprehensive Review
Authors: Bustamante E G , Sulehri M , Patoli I , Karunakaran A
Published: October 2024

Disclosure: E.G. Bustamante: None. M. Sulehri: None. I. Patoli: None. A. Karunakaran: None.

Normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH) in Women: A Case Report and Literature ReviewIntroduction: IHH is a rare genetic disorder affecting gonadotropic-releasing hormone (GnRH) production and/or action, resulting in diminished sex steroid levels. Characterized by the absence of spontaneous pubertal development. In women, it manifests with normal adrenarche but absent thelarche and menarche. Our case highlight a late diagnosis of IHH in a 34-year-old woman with primary amenorrhea. Case report: A 34 year old lady with a history of primary amenorrhea sought evaluation. At age 16, she underwent assessment for short stature and primary amenorrhea, denying anosmia, headache, visual disturbances. Evaluation revealed bone age concordant with chronological age and normal MRI Brain. Pelvic ultrasound (US) showed small premenarchal uterus and ovaries. She initiated oral contraceptive pills (OCP) and experienced regular menses. Seeking fertility assistance at age 24, a normal Hysterosalpingogram was followed by successful delivery of twins after ovarian stimulation. Post-delivery menses did not resume and OCP was not restarted. Family history revealed a sister with irregular periods requiring OCP.Subsequently workup at age 30 showed Estradiol 22 pg/ml, FSH/LH 4.1/2.3 mUI/mL; normal PRL, TFT, DHEAS, 17OHP. Repeat Pelvic US showed normal uterus, endometrial stripe normal at 0.24 cm and non-visualized ovaries. PCOS testing negative for hyperandrogenism. Progesterone challenge resulted in no withdrawal bleeding. Brain MRI demonstrated a 2.2 x 1.3 mm hypoenhancing ovoid mass in the pars Intermedia of the pituitary gland suggestive of pituitary microadenoma. Pituitary axis hormonal testing was normal. Karyotype revealed 46 XX (normal female). Genetic evaluation identified a pathogenic variant (p.R35C) in GNRH1 gene. Her final diagnosis: nIHH. Discussion HH is diagnosed in 5% of all women with primary amenorrhea and is divided into 2 major categories: Kallmann syndrome and nIHH. The majority of known causes of HH can be attributed to mutations in KAL1, FGFR1, or GNRHR. The p.R35C variant has been associated with autosomal dominant nIHH. Diagnosis involves clinical suspicious, low LH/FSH and sex steroid levels, normal hypothalamic–pituitary imaging, and exclusion of differentials.Treatment goal for female focus on regular breast and uterine development, as well as the capability to conceive. Use of hormonal replacement therapy and/or gonadotropins or pulsatile GnRH for ovarian stimulation are essential. ConclusionWhile IHH predominantly affects men, limited literature explores its manifestation in women and its impact on fertility. The identification of a GNRH1-related nIHH variant highlights the role of genetic testing in specific HH diagnoses. Failure to diagnose in adolescence may compromise women overall well-being

Presentation: 6/1/2024
12540 Epigenetic Subtyping Of Adrenocortical Carcinoma In Archival Material And Implications For Disease Evolution
Authors: Mohan D , Lerario A M , Almeida M Q , Mendonca B B , Latronico A , Fragoso M C , Hammer G D
Published: October 2024

Disclosure: D. Mohan: None. A.M. Lerario: None. M.Q. Almeida: None. B.B. Mendonca: None. A. Latronico: None. M.C. Fragoso: None. G.D. Hammer: None.

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex, to date cured only by surgery. Pangenomic studies demonstrate that ACC is comprised of three molecular subtypes with distinct clinical outcomes. CIMP-high ACC, the most aggressive molecular subtype, is defined by abnormal epigenetic patterning including inappropriate DNA methylation. CIMP-high status of the primary tumor accounts for 30% of all ACC, but 70% of metastatic relapses. It remains unclear if ACC transitions molecular subtypes, e.g. acquires CIMP-high status, during metastatic dissemination. We and others have demonstrated that G0S2 methylation is a sensitive and specific single-locus biomarker capturing CIMP-high ACC. However, our prior studies utilized frozen tissues, often only available at specialized centers. Here, we measured G0S2 methylation in an expanded cohort of n=73 formalin-fixed paraffin-embedded (FFPE) primary, recurrent, and metastatic ACC samples. We show that G0S2 methylation status is stable in archival FFPE material, concordant with measurement in frozen specimen (Pearson r=0.94, n=28). We identify that, within individual patients, the G0S2 methylation status of the primary is often preserved in the metastasis or recurrence. These data suggest that ACC subtype switching is not required for metastatic evolution. In cases of advanced ACC with accessible lesions amenable to biopsy, epigenetic subtypes can be diagnosed prior to oncologic resection, enabling subtype-specific therapeutic interventions in the neoadjuvant setting.

Presentation: 6/1/2024
12485 Evaluating B7-H3-CAR T Cell Therapy In Preclinical Models Of Pediatric Adrenocortical Tumors
Authors: Modolo Pinto Emilia , Epperly Rebecca , Santiago Teresa , Sheppard Heather , Clay Michael , Morton Christopher , Nguyen Phuong , Zhou Yinmei , Woolard Mary A , O’Reilly Carla , Justice Julie , Akers Walter , Johnson Melissa , Cheng Cheng , Zambetti Gerard , Davidoff Andrew M , Ribeiro Raul , DeRenzo Christopher
Published: October 2024

Disclosure: E.M. Pinto: None. R. Epperly: None. T. Santiago: None. H. Sheppard: None. M. Clay: None. C. Morton: None. P. Nguyen: None. Y. Zhou: None. M.A. Woolard: None. C. O'Reilly: None. J. Justice: None. W. Akers: None. M. Johnson: None. C. Cheng: None. G. Zambetti: None. A.M. Davidoff: None. R. Ribeiro: None. C. DeRenzo: None.

Over the past decade, significant progress has been achieved in understanding the underlying molecular mechanisms driving adrenocortical tumorigenesis, with the identification of several genetic and molecular drivers of this disease. However, a lack of preclinical models has hindered the discovery of new therapeutic treatment modalities, particularly in the pediatric population. In this study we describe the development of three patient-derived xenograft models for pediatric adrenocortical tumors (SJ-ACC3, SJ-ACC4, and SJACT030812_X1), which recapitulate the molecular features and heterogeneity of these rare tumors. All three models were derived from aggressive tumors, harboring TP53 and ATRX variants. We evaluated the efficacy of various chemotherapeutic agents in two models. SJ-ACC3 tumors exhibited sensitivity to cisplatin and topotecan, while SJ-ACC4 demonstrated limited response to all evaluated drugs including cisplatin, doxorubicin, and etoposide. Consistent with adult adrenocortical tumors, we found that most primary pediatric adrenocortical tumors express the tumor associated antigen B7-H3 (CD276), regardless of their molecular subtype. Notably, B7-H3 was highly expressed in two of our models, SJ-ACC4 and SJACT030812_X1, with limited expression in SJ-ACC3. Critically, we demonstrated that B7-H3 CAR T cells exhibited significant antitumor activity in both B7-H3-positive models, clearing tumors in most mice. These findings suggested that CAR T cells therapy targeting B7-H3 might be a promising therapeutic strategy for pediatric patients with high-risk adrenocortical tumors.

Presentation: 6/3/2024
7131 The Morbidity Pattern in Females with 45,X/46,XY Mosaicism
Authors: Stochholm K , Gravholt C H , Berglund A
Published: October 2024

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

Background: Turner syndrome (TS) includes females with 45,X/46,XY mosaicism, a rare variant with a prevalence of 2.1 per 100,000 newborn females. Specific knowledge about their associated health outcomes is limited. Aim: To investigate the morbidity pattern in a national cohort of females with 45,X/46,XY. Methods: Data were retrieved for all females diagnosed with 45,X/46,XY from 1960 to 2018 (n=46) and for 4,377 age-matched females from the general population. Morbidity were investigated using Cox regression analysis on registry data regarding hospital diagnoses, redeemed medication, and surgery codes. Results: 45,X/46,XY was associated an increased overall risk of a hospital diagnosis (Hazard ratio (HR): 1.6, confidence interval (CI): 1.2-2.1). The risk of undergoing surgery was significantly increased before the age of 40 years (HR: 1.6, CI: 1.0-2.5), but not in total (HR: 1.2, CI: 0.8-1.7). The HR of redeeming medication was similar to comparators, HR: 1.2, CI: 0.86-1.66. Dividing hospital diagnoses into 18 chapters according to the International Classification of Diseases, 45,X/46,XY had a significantly increased risk of diagnoses due to endocrine disorders (HR=3.6, CI: 2.3-5.8), disorders of the ear (HR=7.1, CI: 4.5-11.3), disorders of the circulation (HR=2.8, CI: 1.7-4.9), and due to congenital malformations (HR=25.1, CI: 17.5-35.8). Among specific diagnoses with a significantly increased risk were gonadal dysfunction, valve diseases, hypertensive diseases, diseases of arteries and aneurisms. Surgery due to disorders of the heart and greater vessels were significantly increased in total (HR=9.3 CI: 2.2-40.4), as were surgery on the aortic valve (HR=36.9, CI: 3.3-409.2), and on female genitalia (HR=2.1, CI: 1.3-3.4), whereas obstetric surgery was significantly decreased (HR 0.2, CI: 0.0-0.7). In females with 45,X/45,XY, there were no registrations related to gonadoblastoma as neither ovarian surgery nor registrations on cancer of the ovary were present. The HR of redeeming a prescription was significantly decreased in the categories of dermatologicals (HR=0.6, CI: 0.4-0.9), musculoskeletal (HR=0.6, CI: 0.4-0.9), antiparasitics (HR=0.5, CI: 0.2-0.8), and in respiratory system (HR=0.6 CI: 0.4-0.9), and significantly increased in systemic hormones (HR=2.2, CI: 1.4-3.7) and in sex hormones (HR=2.9, CI: 2.0-4.1). Conclusion: 45,X/46,XY in females is associated with an increased morbidity with a skewed pattern, as indicated by an overall increased risk of hospital diagnoses, but a unaffected usage of prescribed medication. Surgical procedures were affected with a pattern as in others with Turner syndrome, with a surprisingly absent registration of procedures linked to gonadoblastoma. This study is most likely curtailed by the limited number of females diagnosed with 45,X/46,XY, however the imperative for systematic follow-up is underlined.

Presentation: 6/1/2024
7975 TLR4 Signaling Modulates Reproductive and Metabolic Outcomes in a Mouse Model of Polycystic Ovary Syndrome
Authors: Wiggins Kiara Dominique , Del Mundo Zena , Ayala Angulo Julio A , Lopez Miranda , Garcia Christopher , Nguyen Christy , De La Torre Jamie-Jean , Saba Angelina , Trinh Davina , Nicholas Dequina
Published: October 2024

Disclosure: K.D. Wiggins: None. Z. Del Mundo: None. J.A. Ayala Angulo: None. M. Lopez: None. C. Garcia: None. C. Nguyen: None. J. De La Torre: None. A. Saba: None. D. Trinh: None. D. Nicholas: None.

Polycystic Ovarian Syndrome (PCOS), characterized by disruptions in both reproductive and metabolic functions, is associated with abnormal immune system activity and chronic inflammation. Although the precise mechanistic drivers of chronic inflammation in PCOS are not fully elucidated, elevated serum levels of lipopolysaccharide (LPS) have been observed. We propose that Toll-like receptor 4 (TLR4) signaling, influenced by dysregulated LPS levels, is a central driver of chronic inflammation affecting both reproductive and metabolic pathways. To investigate this hypothesis, we subcutaneously implanted a nonsteroidal aromatase inhibitor, Letrozole (LET), in pubertal TLR4 knockout mice (TLR4KO) and C57BL/6J (wild type) mice. Our five-week LET treatment revealed that TLR4KO mice successfully entered all phases of the estrous cycle, with normalized Luteinizing Hormone (LH) and increased Follicle Stimulating Hormone (FSH) levels. These findings highlight TLR4's role in shaping cycling patterns and regulating fundamental hormonal pathways vital for reproductive health. Despite the genetic manipulation of the inflammatory pathway leading to a reduction in overall body weight gain, it had no discernible impact on the overall body composition of fat and lean mass. Additionally, our study found that dysregulation of blood glucose levels over time was independent of reduced body weight. TLR4KO mice demonstrated inefficient glucose clearance compared to wild-type mice, hinting at potential increases in insulin resistance, imbalances in adipose tissue inflammation, or possible alterations in the gut microbiota. Our study underscores the significance of disrupting the pro-inflammatory TLR4 pathway in shaping the reproductive and metabolic phenotypes in Letrozole-induced PCOS. The investigation into TLR4 becomes pivotal for comprehending the role of chronic inflammation in PCOS development or progression, offering valuable insights into potential therapeutic targets.

Presentation: 6/2/2024
9360 Evaluating The More Accurate Indicator Of Kidney Function In Mild Autonomous Cortisol Secretion: EGFR Creatinine Versus EGFR Cystatin
Authors: Rahimi Leili , Saini Jasmine , Atkinson Elizabeth , Achenbach Sara J , Kattah Andrea , Bancos Irina
Published: October 2024

Disclosure: L. Rahimi: None. J. Saini: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None.

Introduction: Patients with mild autonomous cortisol secretion (MACS) have higher prevalence of cardiovascular comorbidities including chronic kidney disease. However, considering that patients with MACS may have relative skeletal muscle atrophy, it is unclear whether the creatine-based assessment of kidney function is accurate in this population. Objective: To characterize the differences in assessing estimated glomerular filtration rate using cystatin (eGFRcys) versus creatinine (eGFRcre) in patients with MACS versus referent subjects. Methods: Cross-sectional single-center study, 2019-2022. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST). For each patient, eGFRcre, eGFRcys and eGFRcre/eGFRcys ratio were measured and compared between the two groups. Body composition was measured by DXA scan. The Kruskal-Wallis test was used to compare measurements between groups. Result: A total of 37 patients with MACS (median age 59 years (interquartile range, IQR 47-67), 25 (68%) women) and 45 referent subjects (median age 57 years (IQR 51-66), 30 (67%) women) were included. The distribution of BMI, total body fat mass and total body lean mass were similar between the two groups. In the MACS cohort, the median cortisol following 1-mg DST was 3.0 ug/dL (IQR, 2.2-4.0). While assessment of kidney function with eGFRcre showed no differences between patients with MACS and referent subjects (median 85.1 vs 87.0 ml/min/1.73m2, P=0.431), kidney function using eGFRcys was lower in MACS (median 78.0 vs 89.3 ml/min/1.73m2 in referents, P<0.014), resulting also in a higher eGFRcre/eGFRcys ratio (median 1.07 vs 0.97 in MACS vs referents, P=0.053). After adjusting for age, sex, and BMI, a higher 1 mg DST cortisol level in the MACS cohort was associated with a higher eGFRcre/eGFRcys ratio (Spearman correlation coefficient of 0.35, P = 0.042). Lower eGFRcys was associated with higher fat mass (Spearman correlation of -0.26, P = 0.023), and a higher eGFRcre/eGFRcys ratio showed a trend towards lower lean mass (Spearman correlation of -0.20, P = 0.081). Conclusion: Creatinine-based eGFR assessment in patients with MACS underestimates the degree of kidney dysfunction, likely due to underlying skeletal muscle atrophy. eGFRcys is a more accurate indicator of kidney function in patients with hypercortisolism.

Presentation: 6/1/2024
7954 Vitamin D Deficiency Underlies Defective Endometrial Decidualization In Vivo and In Vitro
Authors: Yi MyeongJin , Wang Tianyuan , Jukic Anne Marie , DeMayo Francesco John
Published: October 2024

Disclosure: M. Yi: None. T. Wang: None. A. Jukic: None. F.J. DeMayo: None.

Several epidemiologic studies have reported associations between vitamin D and both menstrual cycles and fertility. Vitamin D signaling occurs most often through the interaction of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) with its cognate receptor, the transcription factor vitamin D receptor (VDR). This study aims to define the role of vitamin D and VDR on female reproduction and identify vitamin D-mediated signaling. In our studies, preliminary results demonstrate mice on a vitamin D-deficient diet showed a significantly impaired uterine decidualization reaction in response to exogenous hormones. To knockdown VDR expression, human endometrial stroma cells (THESCs) were transfected with either non-targeting control (siNT) or VDR siRNA (siVDR) for 48 h. And, to perform the in vitro decidualization, the cell culture media was replaced to differentiate the cells by treatment with 17β-estradiol (E), medroxyprogesterone acetate (P), and db-cAMP (C) for 72 h. At the 48 h exposure of EPC, the decidual media was replaced with containing 1,25(OH)2D3 or vehicle and cultured for 24 h additionally. Treatment of 1,25(OH)2D3 (ligand) and knockdown of VDR (receptor) in THESCs resulted in an increased expression of the decidualization markers, PRL and IGFBP1. Transcriptomic analysis was then conducted to identify the biological networks regulated by the ligand and receptor in THESCs. THESCs were transfected with either siNT or siVDR for 48 h, and the culture media was replaced with either treatment of 2 nM of 1,25(OH)2D3 or vehicle for an additional 24 h. Differentially expressed genes (DEGs) were affected by the ligand and receptor (N = 626 and 1499, respectively) based on a three-way ANOVA filtered with false discovery rate (FDR)-adjusted p-value<0.05 and fold-change (FC)≥|1.4|. Pathway analyses and predicted upstream regulators were analyzed by Ingenuity Pathways Analysis (IPA), and among the predicted upstream regulators of the DEGs, β-estradiol was predicted as an activator for both. Thus, to test the role of vitamin D in estrogen signaling, THESCs were treated with either EPC or PC for 72 h in total, and at the 48 h exposure, the decidual media was replaced with 1,25(OH)2D3 or vehicle and cultured for 24 h additionally. Removal of estrogen (PC) caused loss of the enhanced expression of decidual markers by 1,25(OH)2D3 that was observed in control EPC-treated cells. In conclusion, Vitamin D signaling modulates human and mouse uterine stromal cell differentiation by modulating the ability of estrogen to stimulate decidualization in endometrial stromal cells, a process critical to establishing pregnancy.

Presentation: 6/2/2024
8815 ANPEP regulates one-carbon metabolism in prostate cancer
Authors: El-Kenawi A , Putney R , Berglund A , Yamoah K
Published: October 2024

Disclosure: A. El-Kenawi: None. R. Putney: None. A. Berglund: None. K. Yamoah: None.

African American men (AAM) experience disproportionately higher rates of both prostate cancer (PCa) incidence and mortality compared to their European American counterparts (EAM). To investigate some of the biological factors which contribute to these disparities, we carried out an unbiased genomic expression analysis of PCa by ancestry using the matched GRID and VANDAAM cohorts. In this analysis, we discovered aminopeptidase N (ANPEP, APN, CD13), to be the most differentially expressed functional gene in both self-identified and ancestry derived AAM compared with EAM. Further computational analyses revealed that ANPEP correlates with signatures of cholesterol transport, estrogen and androgen receptor (AR) signaling. The functional role of ANPEP in regulating cholesterol metabolism and AR signaling remains unclear. Further computational analyses demonstrate that expression of ANPEP predominantly correlates with various amino acid transporters. In addition, comprehensive metabolomic characterization revealed that ANPEP-overexpressing cells exhibit altered level of one-carbon metabolism metabolites. The one-carbon metabolic pathway regulates amino acids homeostasis and epigenetic mechanisms. Metabolomics-based approach to assess the consumption of over 15 amino acids in patient-derived explants validate enrichment of one-carbon metabolism circuits in AAM. Thus, we further investigated whether ANPEP impact high methylation capacity by performing genome-wide methylation profiling in cells. We unraveled that ANPEP overexpression is associated with elevated methylation of DNA. Our future studies will assess whether ANPEP regulation of methylation capacity have an impact on AR binding to DNA.

Presentation: 6/3/2024