bluuebunny/crossref_metadata_2025_split huggingface dataset:
7886 Impact of Withania somnifera (Ashwagandha) Supplement on Androgen Signalling Pathways
Authors: Barata I S , Yakubu J , Du Toit T , Pandey A V 
Published: October 2024

Abstract
Disclosure: I.S. Barata: None. J. Yakubu: None. T. Du Toit: None. A.V. Pandey: None.
Supplements derived from plant extracts are often used as alternatives to pharmaceutical drugs. These products are often perceived as safe despite the absence of scientific evidence regarding their efficacy and safety and are less strictly regulated than pharmaceutical products. Winter cherry (Withania somnifera, commonly known as ashwagandha) is used as a testosterone booster supplement in multiple countries. Withania somnifera extract was found to increase testosterone and androgen precursors in a small clinical study. However, there is a lack of data regarding effects of Withania somnifera on the steroidogenic pathways. Steroidogenesis impacts not only sexual differentiation, reproduction, and fertility but also other physiological processes, including hypertension and obesity. Moreover, the modulation of hormone signaling is an important target in hormone-responsive pathogenesis, and overproduction of androgens has been implicated in the pathogenesis of prostate cancer (PCa) and polycystic ovarian syndrome (PCOS). In humans, testosterone is mainly produced in the testes after conversion of pregnenolone to 17-hydroxypregnenolone (17-OHPreg) and dehydroepiandrosterone (DHEA, the precursor of androgens) by adrenal CYP17A1, which catalyzes both the 17-hydroxylation of steroids for cortisol production and the breakage of 17,20 bonds (17,20 lyase) in 17-OHPreg to produce DHEA. The intake of substances that may increase androgen levels by people with PCa or PCOS or with predisposition to these conditions may trigger pathogenesis or worsen prognosis by accelerating disease progression. We investigated the effects of Withania somnifera in modulating the adrenal steroidogenic pathway and the possible consequences on the pathogenesis of androgen-responsive conditions, specifically PCa. Adrenal cells were treated with the extract of Withania somnifera to characterize its effect on adrenal steroid profile and CYP17A1 hydroxylase and lyase activities. Prostate cancer proliferation was assessed by direct incubation of prostate cancer cells with extracts as well as with conditioned media from adrenal cells treated for 48h, to simulate natural steroidogenesis. The results suggest that adrenal steroid hormone biosynthesis can be altered by the intake of Withania somnifera extract and that this supplement may affect proliferation of PCa cells. Moreover, the reported testosterone booster effect of Withania somnifera supplementation does not appear to be through increased adrenal androgen production.
Presentation: 6/1/2024
7985 Insights into the Menopausal Transition: A Comparative Analysis of Hypothalamic Reproductive Aging in Women and a Mouse Model of Menopause
Authors: Bloom Jordana C B , Pereira Sidney Alcântara , Jimenez Encarnacion Torres , Page David C , Navarro Victor Manuel 
Published: October 2024

Abstract
Disclosure: J.C. Bloom: None. S.A. Pereira: None. E. Torres Jimenez: None. D.C. Page: None. V.M. Navarro: None.
Menopause onset is the major determinant of reproductive lifespan in women and is characterized by the decline in estrogen production from the ovary. While much of our current understanding of the menopause transition in humans comes from a series of observational longitudinal studies initiated in the 1980s and 1990s, the mechanisms by which reproductive aging impacts healthy brain aging remains a profoundly under-studied aspect of women’s health. The hypothalamus, a hub of homeostatic and temperature regulation, is highly sensitive to changes in sex steroid levels. Recently, activation of the neurokinin 3 receptor (NK3R) by neurokinin B (NKB) has been linked to the onset of vasomotor symptoms (VMS) during menopausal transition. NKB is secreted by hypothalamic Kisspeptin, NKB, Dynorphin (KNDy) neurons in response to decreasing estradiol levels. Here, we present a comparative study of the expression trajectories of the KNDy genes (KISS1, TAC3, PDYN, respectively) and NK3R (TACR3) in hypothalamic samples of humans across menopause and a mouse model of peri- and post-menopause (short- and long-term ovariectomy (OVX), respectively). RNA-sequencing data of human and mouse hypothalamic samples revealed a high correlation in the expression profile of the KNDy/NK3R genes between both species. Further investigation has revealed a highly conserved pool of genes in human and mouse hypothalami that correlate with TACR3 upon decline of circulating sex steroids. Thus, by examining conserved gene expression patterns across this critical reproductive period, we have been able to identify novel candidate targets involved in menopausal transition which may serve to better elucidate the biology of menopause-associated conditions affecting the brain, such as VMS and cognitive decline.
Presentation: 6/2/2024
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

Abstract
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

Abstract
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 &lt;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

Abstract
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

Abstract
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

Abstract
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 &lt;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&lt;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

Abstract
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