bluuebunny/crossref_metadata_2025 huggingface dataset:
8679 Case: The Sexual, Physical and Psychological Effects of Post-Finasteride Syndrome
Authors: Lonergan Eibhlin Marie , Maher Sean Martin , Yaseen Ibrahim , O'Shea Donal Brendan
Published: October 2024

Disclosure: E.M. Lonergan: None. S.M. Maher: None. I. Yaseen: None. D.B. O'Shea: None.

Post-finasteride syndrome (PFS) is an increasingly recognised disorder with a myriad of physical and neuropsychiatric symptoms persisting for greater than three months in a small proportion of patients treated with Finasteride. We present the case of a 45-year-old male who was taking oral Finasteride for hair loss. He first presented to endocrinology services having stopped Finasteride after twenty years reporting new onset reduced libido, penile shrinkage, fatigue, new food intolerances and agitated depression which was the predominant symptom in this case. He described the emergence of gynaecomastia, which was evident on examination, as well as muscle atrophy. Biochemistry was unremarkable including testosterone 24.6 nmol/L (8.6-29.0), oestradiol 100 pmol/L (50 – 159), LH 7.1 IU/L (1.7-8.6), FSH 16.8 IU/L (1.5-12.4), urinary free cortisol 177 nmol/24h (12-486) and urinary steroid profile. The patient was offered a trial of IM testosterone for 3 months followed by a course of hCG which he declined after discussing with patients online via a PFS patient forum citing anecdotal pseudo immune downregulation in this cohort. GLP-1 receptor agonist therapy was considered as a second-line treatment option. The patient expressed a preference for hydrocortisone treatment after conducting online research which has not been commenced due to a lack of evidence. The inhibition of 5-alpha-reductase in Finasteride-treated patients has been documented to cause reversible sexual dysfunction. However, with increasing case reports of PFS, it was included in the list of Rare and Genetic Diseases of the NIH in 2015. The syndrome encompasses symptoms and signs seen in our case, as well as erectile dysfunction, decreased ejaculatory volume, infertility, Peyronie’s disease, testicular pain, dry skin, memory problems and insomnia. Suicidal ideation was included in the product label as per FDA mandate in 2022. The literature is largely inconclusive regarding the underlying aetiology, duration, and severity of the disorder. A large retrospective study revealed 0.8% of patients developed sexual dysfunction with persistence in 33% of these cases after drug suspension, the main independent risk factor being drug treatment for longer than 7 months. Neuropsychiatric symptoms are likely related to the presence of 5-alpha-reductase isoforms in the brain with resulting alterations in CSF and plasma neuroactive steroid levels and metabolites. Evidence-based treatment options for PFS are limited. PFS is a rare but debilitating syndrome to which a subset of patients appears to be predisposed, but of which the pathophysiology is poorly understood. Further studies in this regard, as well as an exploration of effective treatment options are required.

Presentation: 6/1/2024
12456 Changes In High-sensitivity Cardiac Troponin I After 12 Months Of Gender Affirming Hormone Therapy
Authors: Cheung A S , Bretherton I , Perera S , Singh L , Chiang C Y
Published: October 2024

Disclosure: A.S. Cheung: None. I. Bretherton: None. S. Perera: None. L. Singh: None. C.Y. Chiang: None.

Background: Due to differences in cardiac size and physiology between cisgender men and women, sex-specific reference cut-offs are recommended for Abbott high-sensitivity cardiac troponin I (hsTnI) to improve diagnostic accuracy of acute coronary syndrome. There are no prospective studies which examine the impact of gender affirming hormone therapy on hsTnI. We aimed to prospectively evaluate the change in hsTnI in transgender men and women newly commencing gender affirming hormone therapy (GAHT) compared to cisgender men and cisgender women over 12 months. Methods: Transgender men (TM) and transgender women (TW) aged >18 years newly commencing GAHT were recruited from outpatient endocrine clinics. Cisgender men (CM) and cisgender women (CW) were recruited from local community advertisements. Fasting serum collected at baseline and 12 months was frozen at - 80 degrees with batch analysis on the Abbott ARCHITECT i2000 hsTnI assay. One-way ANOVA analysis was performed on age, baseline hsTnI, repeat hsTnI, and change in hsTnI over 12 months between the 4 groups. Chi-square was used to analyze categorical status of detectable hsTnI using a Limit of Quantitation of < 2 ng/L. Data are presented as mean (standard deviation). P value < 0.05 is defined as significant. Results: Baseline samples were available for 263 participants, and 103 had paired baseline and repeat hsTnI samples. The mean age of participants was 31 years ± 12.4 and none had renal impairment. The TM group was younger (n=58, 25.7 ± 6.2 years old, p < 0.005) compared to the other 3 groups (TW n=56, 33.8 ± 15.7 years, CM n=70, 32.7 ± 13.8 years, CF n=79, 31.2 ± 10.7 years). At baseline, CM (2.1 ± 2.4 ng/L) had comparable hsTnI to TW (1.8 ± 2.1, p = 0.9), but higher hsTnI compared to CF (0.8 ±1.1, p < 0.001) and TM (1.1 ± 1.8, p = 0.03). At 12 months follow-up, CM (2.5 ± 2.8ng/L) had higher hsTnI compared to TW (0.9 ± 0.9, p = 0.004), CF (0.6 ±0.6, p < 0.001) and TM (0.9 ± 0.5, p = 0.002). There was a significant decrease in hsTnI after 12 months in TW (-1.4 ± 2.2) compared with CM (0.6 ± 1.9, p = 0.013). Detectable baseline hsTnI became undetectable (<2ng/L) in 73% (8/11) of TW compared to 13% (1/8) CM subjects (p = 0.03). Conclusions: After 12 months of GAHT, hsTnI in transgender women reduced and became comparable to cisgender women and transgender men. Our data supports the use of the cisgender female hsTnI reference cut-off in transgender women and transgender men. Data suggests a possible reduction in cardiac muscle mass or improvement in cardiac physiology occurs after 12 months of GAHT in transgender women.

Presentation: 6/1/2024
9172 Contrasting Bone Profiles In Pcos Are Related To Bmi: A Systematic Review And Meta-analysis
Authors: Premaor Melissa Orlandin , Risseti Graziela , Piovezan Julia , Comim Fabio Vasconcellos
Published: October 2024

Disclosure: M.O. Premaor: None. G. Risseti: None. J. Piovezan: None. F.V. Comim: None.

Polycystic ovary syndrome (PCOS) is a complex and multifaceted disorder that may affect bone health. Controversial results have emerged regarding whether PCOS is protective or increases the risk of bone frailty. We conducted a systematic review and meta-analysis of published research on bone mineral density (BMD), bone markers, and the risk of fractures in individuals with PCOS. We searched MEDLINE, Embase, and conference s and preprints. Studies were eligible if the PCOS was defined according to the NIH criteria, the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group criteria, AE-PCOS society criteria, or ICD codes. The endpoints studied included fractures, bone mineral density (BMD), and bone markers. The study protocol is available at PROSPERO (CRD42016049664). From the 3322 studies identified in the databases, 111 had their full texts evaluated, and 31 studies met the inclusion criteria for qualitative analysis. Overall, cross-sectional studies included 1822 individuals with PCOS and 1374 controls, while cohort studies incorporated 30305 women with PCOS and 101907 controls. No differences were observed between individuals with PCOS and the control group in the pooled analysis for the whole group. Nevertheless, contrasting profiles emerged after stratification using a BMI cutoff of 27 kg/m2. Women with PCOS and a mean BMI <27 kg/m2 exhibited lower spine BMD (MD -0.060; 95% CI, -0.110 and -0.011) and total hip BMD (MD -0.042; 95% CI, -0.068 and -0.017), and increased bone resorption marker (CTX) levels (SMD 0.38; 95%CI 0.03 and 0.72). Conversely, women with PCOS and a mean >27 kg/m2 exhibited increased spine BMD (MD 0.029; CI 95%, 0.009 to 0.048) and total hip BMD (MD 0.036; CI 95%, 0.010 to 0.063), with no significant changes in bone resorption markers. Due to the limited number of longitudinal studies available, it was not possible to determine the risk of bone fractures in both groups. In conclusion, the findings of this systematic review show a negative impact of PCOS on bone health in women with a BMI <27 kg/m2, suggesting that increased surveillance and research for bone disease may be necessary for this particular group.

Presentation: 6/3/2024
7770 Damage of Ovarian Vasculature by Chemotherapies induces Ovarian Dysfunction in Mice
Authors: So W , Dong R , Luan Y , Abazarikia A , Kim S Y
Published: October 2024

Disclosure: W. So: None. R. Dong: None. Y. Luan: None. A. Abazarikia: None. S. Kim: None.

Background: Chemotherapy demonstrates efficacy to destroying cancer cells; however, it can inadvertently impact normal healthy cells, leading to irreversible side effects, particularly affecting the ovaries in female patients. Female cancer survivors encounter endocrine dysfunction and infertility due to ovarian damage caused by gonadotoxic cancer therapies. The ovary, a vital organ responsible for producing oocytes and endocrine hormones, faces significant challenges following such treatment. A study with premenopausal breast cancer patients reported a significant reduction in ovarian blood flow and volume immediately following chemotherapy. The preservation of ovarian function depends on the ovarian vasculature in supporting the development and maintenance of ovarian follicles. Despite its importance, the relationship between ovarian vasculature and follicle following chemotherapy has not been studied. Results: To investigate the direct impacts of chemotherapy, ovaries from postnatal 5 CD-1 mice were subjected to testing with three chemotherapeutic agents: cisplatin (CDDP), cyclophosphamide (CPA), and doxorubicin (DOXO). The expression of CD31/PECAM-1 (platelet endothelial adhesion molecule) exhibited a significant decrase after 96 hours of culture with 4-HC, an active metabolite of CPA. This reduction implies that ovarian vasculature was also compromised when chemotherapy eliminated immature follicles. In order to evaluate the influence of vascular endothelial growth factor (VEGF) in safeguarding both vasculature and ovarian follicles, ovaries were co-cultured with VEGF165 or VEGF165b in combination with chemotherapy. Interestingly, pre-treatment with VEGF165 before 4-HC led to an increased expression of CD31 in the cortex area, while VEGF165b further diminished CD31 expression compared to treatment with 4-HC alone. Additionally, adolescent CD-1 mice were intraperitoneally injected with CDDP, CPA, or DOXO, and ovaries were harvested one week after injection. Ovaries treated with chemotherapeutic agents exhibited a reduction in ovary weight and decreased CD31 expression compared to control mice. Conclusions: We propose that these chemotherapeutic agents not only induced the loss of ovarian follicles but also affected ovarian vasculature in mice. This suggests a potential decrease in folliculogenesis within the ovary, coupled with the depletion of ovarian reserve, as the delivery of nutrients and oxygen to growing ovarian follicles may be compromised. VEGF165 may play a beneficial role in maintaining ovarian function by safeguarding ovarian vasculature following chemotherapy. Understanding these intricate dynamics is essential for developing strategies to mitigate the negative impact of cancer therapies on reproductive health in female cancer survivors, particularly in preserving endocrine function and reproductive lifespan.

Presentation: 6/2/2024
8228 Effect of Long-Term Testosterone Therapy on Cardiovascular Safety among Adult Male Patients with Testosterone Deficiency
Authors: Lin Y , Gupta S , Shi L , Fonseca V A
Published: October 2024

Disclosure: Y. Lin: None. S. Gupta: None. L. Shi: None. V.A. Fonseca: None.

Background: As testosterone therapy (TTh) prescriptions are increasing rapidly, the cardiovascular (CV) safety of TTh remains controversial among observational studies and clinical trials. Our objective is to determine the CV safety of long-term TTh in adult men with testosterone deficiency (TD) in a real-world setting. Method: This is a multi-center retrospective study comparing testosterone-treated men with untreated men diagnosed with TD. A total of 2,683 men (18+ years) with confirmed TD diagnosis and continuous enrollment were extracted from the REACHnet electronic health records data from 1/1/2013-7/1/2022. The TD was confirmed by at least 2 TD diagnoses (ICD-9/10 codes 253, 257.1, 257.2, 257.8, 257.9, E23, E29.1, E29.8, E29.9) and with the serum testosterone level less than 350 ng/dl before the first recorded TD diagnosis. We further excluded patients with a malignancy history prior to the first TD diagnosis date. Propensity score matching (PSM) by 1:1 ratio based on age, race, Charles Comorbidity Index, and serum testosterone level was conducted among men with TD. The treated group of 928 patients who were compared to the untreated group of 928 patients who opted against taking TTh. The intent to treat analysis using Kaplan-Meier curves and Cox regressions was used to examine CV risk for major adverse cardiovascular events (MACE), defined as a composite outcome of myocardial infarction, stroke, and cardiovascular death. Results: The treatment and control cohorts with 928 patients each had a median follow-up of 3 years. After PSM, only body mass index, diastolic blood pressure, hyperlipidemia, hypertension, depression, and anxiety were statistically significant between treatment and control cohorts. The log-rank test for the cumulative MACE incidence was comparable (p-value>0.05). There were no statistically significant associations between TTh use and increased CV risk in the univariate Cox regression (Hazard Ratio (HR) [95% CI]: 1.01 [0.75-1.36]) and Cox regressions adjusted by the pre-existing MACE (HR [95% CI]: 0.98 [0.72-1.32]) and other baseline covariates (HR [95% CI]: 0.93 [0.68-1.26]). Conclusion: TTh use among adult males with TD was not found to be associated with increased CV risk in real-world clinical practice. Further studies are needed for TTH use in a high-risk population with cardiovascular risk factors.

Presentation: 6/1/2024
6951 European survey of diagnosis and management of the polycystic ovary syndrome: full report on the ESE PCOS Special Interest Group’s 2023 Questionnaire
Authors: Livadas S , Yildiz B O , Mastorakos G , Gambineri A , Pignatelli D L , Giorgino F , Andersen M , Obermayer-Pietsch B M , Macut D P
Published: October 2024

Disclosure: S. Livadas: None. B.O. Yildiz: None. G. Mastorakos: None. A. Gambineri: None. D.L. Pignatelli: None. F. Giorgino: None. M. Andersen: None. B.M. Obermayer-Pietsch: None. D.P. Macut: None.

Background: Although polycystic ovary syndrome (PCOS) constitutes a common endocrinopathy, there are several issues which confuse clinicians during everyday practice.Objective: To define the current status of knowledge of the full spectrum of PCOS among European endocrinologists. Methods: A detailed questionnaire comprising 41 items covering various aspects of diagnosis and management of women with PCOS was shared via web among members of European Society of Endocrinology. Results: 505 European endocrinologists (64% females), with a mean age of 47±11.6 years answered the questionnaire. Rotterdam criteria were used by 85% of endocrinologists. The most frequent age at referral was between 20-40 years (87.1%). A quarter of doctors have access to mass spectrometry for the evaluation of androgen levels. Extended metabolic profile was part of workup by the vast majority, but there was significant uncertainty regarding the diagnosis of chronic anovulation. Diabetes, gestational or type 2, was considered a major consequence for women with PCOS and screening is carried out regardless of BMI status. Lifestyle modification and metformin are considered a standard approach of all participants and oral contraceptives are a standard therapeutic modality, but there is significant discrepancy on the duration of treatment.Conclusions: Rotterdam diagnostic criteria are currently an established diagnostic approach within the European endocrine community. This updated survey showed an advance in using steroid profiling for diagnosis and strong position on recognizing PCOS as a metabolic condition with potential broader consequences. Therapeutic aspects are currently changed into the need for more lifestyle intervention involvement and the use of metabolic therapies either as monotherapy or in combination with standard hormonal compounds.

Presentation: 6/3/2024
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. References1. 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
5165 Cushing’s Disease And Primary Aldosteronism Confounded By A Non-functioning Solitary Adrenal Incidentaloma
Authors: Friedman Jared G , Huang Wenyu
Published: October 2024

Disclosure: J.G. Friedman: None. W. Huang: None.

Background: Adrenal incidentalomas are common, affecting ∼2% of the general population. The presence of adrenal incidentaloma necessitates biochemical testing for hypersecretion, however hypercortisolism and/or hyperaldosteronism may not necessarily originate from the nodule that prompted the initial workup. Clinical Case: A 53-year-old man with a history of obesity and hypertension was referred for workup of a 2.4 x 1.4 cm R adrenal nodule that was incidentally discovered on an abdominal CT to rule out pancreatitis. He was noted on examination to have some Cushingoid features. He was on three antihypertensives (amlodipine 10 mg, carvedilol 50 mg, and spironolactone 50 mg) with adequate blood pressure control and no hypokalemia. He denied spells nor exogenous steroid exposure. Initial testing for hypersecretion showed an elevated cortisol 8.7 ug/dL (<1.8) after 1 mg dexamethasone with adequate dexamethasone level, aldosterone concentration (PAC) 9 ng/dL (3-16), plasma renin activity (PRA) 0.7 ng/mL/h (0.25-5.82), potassium of 3.8 mmol/L (3.5-5.1), and normal plasma metanephrines. Further testing revealed elevated 24-hour urinary free cortisol 81.3 mcg/24h (4-50) and elevated late night salivary cortisol 0.10 and 0.13 mg/dL (<0.09). Baseline 8 AM ACTH was not suppressed 16.3 pg/mL (7.2-63.6). DDAVP stimulation resulted in an increase in cortisol and ACTH suggestive of Cushing’s disease, which was confirmed by inferior petrosal sinus sampling (IPSS). Pituitary MRI showed a 3.6 mm L-sided microadenoma. He underwent transsphenoidal resection with pathology consistent with an ACTH-staining pituitary adenoma. Immediate post-op cortisol nadir was 4.9 ug/dL. A few weeks after surgery, he underwent retesting for primary aldosteronism notable for PAC 14 ng/dL, PRA 0.58 ng/mL/h, and K 4.0 mmol/L. After oral salt loading, 24-hour urine aldosterone was 14.4 mcg/24h (<12) with urine sodium 247 mmol/L/24h (>200). He completed AVS which lateralized to the L adrenal gland despite a R adrenal nodule. He underwent L adrenalectomy with significant improvement in blood pressure which is now well-controlled on carvedilol monotherapy with normalization of PRA to 1.94 ng/ml/h. The R adrenal nodule remains stable in size and appearance on follow up imaging. Conclusion: The presence of an adrenal adenoma with concomitant biochemical evidence of hormonal excess cannot inherently be attributed to nodular autonomous function without further workup. Other hormonal assessment including ACTH level and localization studies are necessary prior to any surgical procedure to avoid missed diagnoses of Cushing’s disease and contralateral primary aldosteronism in the presence of a non-functioning adrenal nodule.

Presentation: 6/1/2024
7828 First Trimester Serum 11-Deoxycorticosterone Predicts Extreme Premature Childbirth
Authors: Ronde Salminen Emma K , Schoenmakers Sam , van Zelst Bertrand D , van den Berg Sjoerd A A
Published: October 2024

Disclosure: E.K. Ronde Salminen: None. S. Schoenmakers: None. B.D. van Zelst: None. S.A. van den Berg: None.

First Trimester Serum 11-Deoxycorticosterone Predicts Extreme Premature Childbirth Background: Preterm birth is the leading cause of perinatal mortality and morbidity worldwide. Unfortunately, the prediction of preterm birth remains challenging, causing unnecessary hospital admittance and overexposure to medication. Studies have shown that metabolites of progesterone can influence uterine contractility[1] and serum levels of 11-deoxycorticosterone have been shown to correlate with an increased risk of preterm birth before 32 weeks of gestation2. The aim of this prospective study was to determine whether first trimester measurement of the progesterone metabolites 11-deoxycorticosterone (11-DOC) and 16-alpha hydroxyprogesterone (16-OHP) could be used as a predictive marker for preterm birth. Methods and results: A cohort of 386 pregnant women were included at 12 weeks of gestation between 2014-2016. Their obstetric histories and comorbidities were noted and their plasma was frozen. Of these women, n=26 delivered prior to 32 weeks of gestation and n=286 delivered at term. 11-DOC and 16-OHP were determined using LC-MS/MS. Mann-Whitney U test was used to statistically analyze differences between the groups. There was a highly significant difference in the level of 11-DOC between women delivering prior to 32 weeks of gestation in comparison to women delivering after 37 weeks of gestation (p=0.007). 16-OHP levels tended to be different between the two groups, but this did not reach statistical significance (p=0.062). No difference was found in the ratio 16-alpha hydroxyprogesterone/11-deoxycorticosterone between the two groups (p=0.916). Conclusion: Plasma levels of progesterone metabolites collected late in the first trimester of pregnancy predicts preterm birth prior to 32 weeks of pregnancy. References: 1.Patil AS, Swamy GK, Murtha AP et al, Progesterone metabolites produced by cytochrome P450 3A modulate uterine contractility in a murine model, Reprod Sci, 2015 Dec 22(12):1577-1586 2.Patil AS, Gaikwad NW, Grotegut CA et al, Alterations in endogenous progesterone metabolism associated with spontaneous very preterm delivery, Hum Reprod Open, 2020 Apr 6;2020(2):hoaa007

Presentation: 6/1/2024
7830 Gender-Affirming Hormone Therapy Improves Levels of Depression in Transgender Individuals Within the First Year of Treatment
Authors: Godar Cassandra M , De La Torre Sebastian C , Shakir Mohamed K M , Hoang Thanh D
Published: October 2024

Disclosure: C.M. Godar: None. S.C. De La Torre: None. M.K. Shakir: None. T.D. Hoang: None.

Introduction: High rates of depression and suicidality are known threats to the health of transgender individuals in the United States. Epidemiologic studies report depression rates as high as 69% of the transgender population. Nearly 40% of the trans population has a history of suicide attempt, which is 8 times that of the general US population. Initiation of gender-affirming hormone therapy (GAHT) is a life-saving intervention that improves gender dysphoria and the overall health status of patients who choose this therapy. In this study we apply a validated metric, the Beck Depression Inventory (BDI), to demonstrate the mental health benefits of GAHT in transgender people. Methods: A prospective study of 31 transgender patients was approved by IRB at an academic medical center. 18 transgender females and 13 transgender males completed the BDI prior to initiation of GAHT and again after one year of GAHT use. The BDI is a 21-item self-reported questionnaire that is scored to identify levels of depression. Depression levels are stratified as normal (1-10 levels), mild mood disturbance (11-16 levels), borderline clinical depression (17-20 levels), moderate depression (21-30 levels), severe depression (31-40 levels), or extreme depression (>40 levels). Median scores for baseline and 12-month data were analyzed for total population and male and female subgroups. Results: In the total study population, an average BDI score of 11 at baseline (range 0-32) improved to average score of 8 after 1 year of GAHT (range 0-28). Average BDI for transgender females was at 10.5 at baseline and 7.4 at 1 year. Average BDI for transgender males was 10.7 at baseline and 7.7 at 1 year. Transgender females reported increased crying (question 10), and transgender males reported increased irritability (question 11) at 1 year. Both genders report increased satisfaction with life, interest in others, physical appearance, and sleep quality. Both genders report slight decrease of suicidal ideation (average BDI 0.9 decreased to 0.1 for question 9) though with no decrease in median BDI score. Discussion: Uninterrupted access to GAHT is critical to the well-being of transgender individuals. GAHT use improves depression by about 3 levels as demonstrated above and is one component of a holistic treatment approach to include behavioral health therapy, gender-affirming surgeries, and speech therapy to improve gender dysphoria and overall quality of life. Regular behavioral health follow-up is important to support at-risk patients through gender transition. BDI is a simple, open-access tool to screen for depression and expedite behavioral health treatment for this vulnerable population.

Presentation: 6/2/2024
12334 Harnessing Protective Diets: Phytoestrogens As A Strategy To Alleviate Estradiol-driven Progression And Symptomatology In Endometriosis
Authors: Strong A D , Andrisse S , Antani D
Published: October 2024

Disclosure: A.D. Strong: None. S. Andrisse: None. D. Antani: None.

Endometriosis (EMS) is a prevalent gynecological disorder affecting 10% of reproductive-age women with up to 50% experiencing infertility. It is characterized by the presence of endometrial-like tissue outside the uterus, leading to symptoms such as pelvic pain and infertility. While the exact cause of EMS remains elusive, hormonal dysregulation and the succeeding inflammation play a crucial role in its pathogenesis. Phytoestrogens (PEs) are a diverse group of plant-derived compounds that exhibit structural and functional similarities to endogenous estrogens and have emerged as potential therapeutic agents due to their ability to modulate hormonal signaling and inflammatory pathways. This integrative review aimed to provide a summation of the current evidence on the mechanisms of action and potential therapeutic applications of PEs in the context of EMS. PEs exhibit weak estrogenic activity and can interact with estrogen receptors (ERs), influencing hormonal and molecular pathways relevant to the pathology. These compounds have shown promise in regulating estrogen levels, inhibiting cell proliferation, and modulating insulin-like growth factor 1 signaling, all of which are critical in developing and progressing the disease state. Notably, curcumin and resveratrol have demonstrated anti-proliferative effects on endometrial cells by targeting key pathways involved in cell growth and angiogenesis. Curcumin has been shown to downregulate inflammatory factors like COX-2 and TNF-α while reducing vascular endothelial growth factor expression associated with angiogenesis. Similarly, resveratrol has been found to suppress inflammatory responses in endometrial stromal cells through the sirtuin 1 pathway. Studies indicate PEs can enhance antioxidant defenses and counteract reactive oxygen species levels implicated in endometriotic pain and disease progression. By restoring antioxidant balance and mitigating oxidative damage, PEs may offer therapeutic benefits in managing EMS symptoms. In conclusion, their multifaceted effects on estrogen signaling, inflammation, and oxidative stress highlight their potential as adjunctive or alternative treatments for symptomatic women with active disease. Plausible evidence supports that certain dietary components can reduce or exacerbate inflammation associated with EMS symptoms and progression. Foods that are rich in phytoestrogens include soy, fruits, vegetables, spinach, sprouts, beans, cabbages, and grain. Specifically, curcumin is a primary component in turmeric and resveratrol is found in high amounts in black and red grapes, red wine, berries, and nuts. While more research is still needed to fully understand the relationship between diet and endometriosis, utilizing therapeutic dietary interventions appears to be a promising self-management strategy for improving quality of life and symptom management.

Presentation: 6/3/2024
12554 Human Sex Determination: SRY Length Regulates Its Cellular Stability And Hence The Robustness Of Testis Differentiation
Authors: Chen Yen-Shan , Thomson Ella , Pelosi Emanuele , Weiss Michael A
Published: October 2024

Disclosure: M.A. Weiss: None.

The abundance of transcription factors (TFs) mediated by the rates of degradation are subjected to be a robust to an appropriate level. This regulation via the proteasome is largely controlled by the stability of individual proteins and then could determine the direction of a gene-regulatory network. Insight is obtained through studies of bistable genetic circuits mediated by initiating transcription factors. A model is provided by SRY, a Y-encoded TF that initiates testicular differentiation. Known functions in human SRY (204 residues) majorly cluster in its high mobility group (HMG) box whereas the functions of the N- and C-terminal non-box segments are not well characterized. Here, we have used cell-based and mouse transgenic studies to measure the transcriptional threshold of SRY regulating the balance between development and dysgenesis. Our findings demonstrate a threshold length in the C-terminal domain of human SRY that determines the protein’s proteosome-enforced half-life. In a pre-Sertoli cell model, truncation of SRY resulted in the reduction of intracellular concentration and twofold attenuation of the male-specific GRN. Expression of the 1-164 fragment of human SRY in CRISPR-Cas9-edited XX mice failed to drive male differentiation whereas the 1-200 of SRY initiated male GRN development. This study provides insight into the robustness of human SRY and illustrates a powerful strategy to link biochemical properties in cultured cells and in vivo developmental outcomes. Our study reveals a checkpoint in a key TF initiating a sex-specific GRN, functioning as an experimental “control knob” in development. Our approach probes molecular determinants of cell fate and so promises to extend structure-function studies of SRY to the flanking and relatively obscure non-box domains. This result implies the balance between robustness and evolvability in metazoan is a game of numbers of initial transcription factor in the networks.

Presentation: 6/1/2024
7667 Cushing’s Puzzle: Echinococcal Pituitary Cyst In A Rare Encounter
Authors: Sari Esra , Erenler Feyza
Published: October 2024

Disclosure: E. Sari: None. F. Erenler: None.

Introduction: Echinococcus is a rare parasitic infection endemic in the Mediterranean, Middle East, South America and Africa, which can cause cystic disease in several organs. Central nervous system involvement is known to comprise 1-2% of all cystic echinococcal disease. Hereby, we report a case of an opportunistic pituitary echinococcus infection in a patient with hypercortisolism due to adrenocortical adenoma with initial misdiagnosis of Cushing’s disease. Clinical Case: A 40-year-old South American female with poorly controlled T2DM on oral agents and hypertension presented to the ER with abdominal pain and subsequent CT of the abdomen with contrast showed a right adrenal mass measuring up to 2.8 cm. A follow up CT with adrenal protocol confirmed 3.3 cm right adrenal mass, 46 HU in precontrast images with >50% washout. Review of records revealed that a recent MRI brain with contrast was performed for headache evaluation and showed an incidental 5x7x4 mm lesion in the pituitary gland. Endocrinology evaluation revealed 24-hour urine volume 1800 mL, elevated free cortisol levels 277.6 mcg/24hr (RR: 4.0-50.0 mcg/24hr), creatinine of 0.67g/24hr (RR: 0.50-2.15g/24hr). 1 mg dexamethasone suppression test showed AM cortisol of 28.7 mcg/dL. ACTH was elevated at 67 pg/mL (RR: 6-50 pg/mL). FSH, LH, and GH were normal. Presumed diagnosis of ACTH-dependent hypercortisolism was made and she underwent bilateral inferior petrosal sinus sampling with confirmed successful cannulation but this was inconclusive due to low ACTH levels. Follow-up MRI of the pituitary gland showed T1 bright, T2 isointense circumscribed lesion measuring 7x6x3 mm at anterior pituitary gland with a thin rim of peripheral enhancement consistent with cystic features. She underwent transsphenoidal resection of the pituitary lesion and the pathology specimen showed parasites consistent with echinococcosis. Infectious disease was consulted, and the patient started on albendazole. Post-operative laboratory evaluation was notable for persistently elevated AM cortisol, 24-hour urine free cortisol levels, and low ACTH levels, confirming ACTH independent hypercortisolism. She underwent right adrenal nodule resection and pathology was consistent with adrenocortical adenoma. Post-adrenalectomy AM cortisol levels were < 2 mcg/dL, indicating the resolution of hypercortisolism along with substantiating the diagnosis of primary adrenocortical hyperfunction. Conclusion: To the best of our knowledge, this is the first case report of an opportunistic echinococcus infection presenting as a pituitary lesion in the setting of Cushing Syndrome. We would like to highlight the importance of recognizing opportunistic infections, including Echinococcus as a potential etiology in the setting of hypercortisolism, especially for patients from endemic regions.

Presentation: 6/2/2024
7820 Immune system adaptation during gender-affirming testosterone treatment
Authors: Lakshmikanth T , Consiglio C , Sardh F , Forlin R , Wang J , Tan Z , Barencilla H , Rodriguez L , Sugrue J , Noori P , Ivanchenko M , Piñero Páez L , Gonzalez L , Habimana Mugabo C , Johnsson A , Ryberg H , Hallgren Å , Pou C , Chen Y , Mikeš J , James A , Dahlqvist P M , Wahlberg Hughes J , Hagelin A , Holmberg M , Degerblad M , Isaksson M , Duffy D , Kampe O , Landegren N , Brodin P
Published: October 2024

Disclosure: T. Lakshmikanth: None. C. Consiglio: None. F. Sardh: None. R. Forlin: None. J. Wang: None. Z. Tan: None. H. Barencilla: None. L. Rodriguez: None. J. Sugrue: None. P. Noori: None. M. Ivanchenko: None. L. Piñero Páez: None. L. Gonzalez: None. C. Habimana Mugabo: None. A. Johnsson: None. H. Ryberg: None. Å. Hallgren: None. C. Pou: None. Y. Chen: None. J. Mikeš: None. A. James: None. P.M. Dahlqvist: None. J. Wahlberg Hughes: None. A. Hagelin: None. M. Holmberg: None. M. Degerblad: None. M. Isaksson: None. D. Duffy: None. O. Kampe: None. N. Landegren: None. P. Brodin: None.

Infectious, inflammatory and autoimmune conditions present differently in males and females. Following SARS-CoV-2 infection, male sex is associated with increased risk of death, while female sex is associated with increased risk of the postinfectious disorder, long COVID. Similar trends are seen in other infections. Female immune responses to vaccines are typically stronger, and adverse reactions are more frequent, like most autoimmune diseases. Immunological sex-differences stem from genetic, hormonal and behavioural factors but their relative importance is poorly understood. To understand the consequences of changing sex-hormones in vivo, we performed longitudinal, systems-level analyses in 22 adults, assigned female at birth, and undergoing gender-affirming testosterone treatment (trans-men). We find that sex hormones modulate a cross-regulation axis of type-I interferon (IFN-I) and TNFα in humans. This is mediated by a reduced frequency of plasmacytoid dendritic cells (pDC), and functional attenuation of IFN-I responses in both pDCs and monocytes. Conversely, testosterone potentiates monocyte responses to lipopolysaccharide (LPS) leading to increased TNFα, IL-6 and IL-15 production and downstream epigenetic opening of NFκB regulated genes and potentiation of IFNγ responses, primarily by NK cells. IFNγ in turn feeds back onto monocytes leading to upregulation of SLAMF7 and further enhanced TNFα responses by myeloid cells. These results are corroborated by sex-divergent responses in multiple public datasets and collectively illustrate the dynamic recalibration of human immune systems by sex hormones with implications for individuals undergoing gender-affirming hormone therapy, but also better understanding of divergent responses to infection, vaccines and self-antigens in cisgender individuals.

Presentation: 6/2/2024
7939 Impact of genetic background on chronic inflammation in a letrozole-induced mouse model of PCOS
Authors: Ujagar Naveena , De Robles Gabriela , Velez Leandro Martin , Seldin Marcus , Nicholas Dequina
Published: October 2024

Disclosure: N. Ujagar: None. G. De Robles: None. L.M. Velez: None. M. Seldin: None. D. Nicholas: None.

The etiology behind polycystic ovary syndrome (PCOS) is elusive due to the heterogeneity of its symptoms and varying severity in patients. There are a wide variety of factors associated with PCOS, like hyperinsulinemia, hyperandrogenism, endotoxemia and chronic inflammation that have been implicated as causal factors in the condition. However mechanisms of cause and effect are difficult to establish in human cohorts. Endotoxemia, observed in humans and mouse models of PCOS, is known to trigger chronic inflammation by activating immune cells. Although correlation of chronic inflammation with PCOS has been established, the type of inflammation in PCOS patients has not been defined, in part due to the genetic variance from person to person. Using a systems immunology approach to mimic human genetic diversity, combined with a letrozole-induced PCOS mouse model, we aim to distinguish the types of inflammation present in PCOS. We analyzed the immune cells from lymph nodes and spleens of 21 different strains of PCOS induced and control mice (130 mice in total), and found that based on genetic background the reproductive and metabolic phenotypes differed- similar to how PCOS presents clinically. We were able to categorize each letrozole-induced mouse strain into the sub-phenotypes of PCOS based on the current guidelines for diagnosing PCOS published in 2023 and extensive characterization of each strain. Splenocytes from these control and PCOS mice were activated in vitro to trigger T cell and myeloid cell cytokine secretion, which was measured via luminex. Clustering analysis of these multi-analyte cytokine measurements together with flow cytometry of the immune cells allowed us to identify T-helper 17 (Th17) cells as the prominent immune cell driving inflammation in letrozole-induce mouse model of PCOS independent of genetic background. This systems immunology approach has allowed us to define PCOS associated inflammation and will be the basis for integrating human inflammation in PCOS with mouse models that appropriately recapitulate disease. The discovery of Th17 cells as key inflammatory mediators provide targets for understanding the mechanisms linking chronic inflammation to reproductive and metabolic outcomes in PCOS, and will assist in future development of anti-inflammatory therapies.

Presentation: 6/2/2024
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

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

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