bluuebunny/crossref_metadata_2025 huggingface dataset:
7117 Cushings Conundrum: Taming The Hormone Hurricane
Authors: Syed Shakera , Poloju Alekya , Krueger Abigail , Swe Khine , Kaeding Sylwia , Shariff Julia , O’connor Clare
Published: October 2024

Disclosure: S. Syed: None. A. Poloju: None. A. Krueger: None. C. O'connor: None.

Ectopic ACTH syndrome is a rare disease that presents with severe hypercortisolism that can be challenging to treat. This case reviews a patient with high- grade metastatic neuroendocrine tumor causing ectopic ACTH-related Cushing's syndrome and describes navigating these treatment challenges with an evidence-based and patient centered strategy to try to optimize care.Clinical case: This 32-year-old male, with a history of metastatic pancreatic neuroendocrine tumor and liver metastases, initially presented with dyspnea, hyperglycemia, and metabolic derangements. Agitated, with a systolic blood pressure of 190mm Hg, he exhibited notable hypokalemia (2.5mmol/L), hyperglycemia (508mg/dL), and elevated beta-hydroxybutyrate (3.60mmol/L). Random cortisol was 85.9ug/dL and ACTH 472pg/ml. Urgent cortisol control prompted etomidate infusion, lowering cortisol to 27ug/dL in 24 hours. Ketoconazole was initiated but discontinued later due to rising liver enzymes, Metyrapone and spironolactone were initiated and etomidate infusion titrated off. Hemorrhagic shock, DKA, and mental status changes complicated his course.Interventional radiology-guided hepatic artery embolization was performed. Post-procedure cortisol levels improved, metyrapone and spironolactone were stopped. Dexamethasone was initiated given concern for relative adrenal insufficiency during this time and was later switched to hydrocortisone, and eventually discontinued with normalizing cortisol levels. Octreotide and later lanreotide maintained stability for a year. He was readmitted with uncontrolled diabetes, hypertension, and vertebral compression fractures, requiring rapid control with etomidate infusion again. Metyrapone was reintroduced, facilitating etomidate tapering. Spironolactone was re-initiated. Bilateral adrenalectomy was discussed as definitive treatment for the ectopic ACTH syndrome (neuroendocrine cancer was deemed incurable, however he was considered elevated risk for surgery given other co-morbidities. Even with normalization of cortisol, he intermittently refused cares/medications. Conclusion: Managing ACTH-producing neuroendocrine tumors necessitates a multidisciplinary approach. In severe Cushing’s syndrome, etomidate infusion quickly normalizes cortisol but requires intensive care due to sedation risks. Ketoconazole and levoketoconazole carry a hepatotoxicity risk. Metyrapone and mitotane are alternatives but supply challenges exist. Osilodrostat, studied for short-term use, has limited data in ectopic ACTH syndromes. Bilateral adrenalectomy is an option if surgical risks are acceptable. Patient history influences therapeutic decisions, highlighting the need for a patient-centered approach.

Presentation: 6/3/2024
8314 Masculinizing Hormone Therapy and Gynecological Neoplasm: a Single Institution Cohort
Authors: Korpaisarn Sira , Ngaothepphurktharam Teerit , Tingthanatikul Yada
Published: October 2024

Disclosure: S. Korpaisarn: None. T. Ngaothepphurktharam: None. Y. Tingthanatikul: None.

Background: Gynecological neoplasm/malignancy is one of the concerned areas among transgender men on masculinizing hormone therapy (MHT). Long-term MHT and gynecological neoplasm/malignancy remain unclear. Methods: A retrospective cohort chart review was done on all transgender men (TM) who underwent hysterectomy with or without oophorectomy between January 2014 and October 2022. Intraoperative findings and pathological results of genital organs, including the cervix, endometrium, myometrium, and fallopian tubes, were extracted. The pathological results were classified as benign, precancerous, and malignant. Descriptive statistical analysis was used to demonstrate the prevalence of gynecological neoplasm and malignancy. Results: A total of 30 TM underwent hysterectomy with oophorectomy. Twenty-eight (93%) had bilateral oophorectomy, and 7% had unilateral oophorectomy due to gynecological conditions. The mean age when TM underwent surgery was 32.1 ± 5.1 years, and the mean age of gender-affirming hormone initiation was 28.7± 5.1 years. The median duration of MHT before gynecological surgery was 32 months (IQR 22-59). Most TM (73%) used testosterone enanthate, 17% testosterone undecanoate, and 2 transgender men did not start MHT before genital surgery. All TM who used GHT became amenorrheic before surgery. The median preoperative testosterone level was 561.5 ng/dL (IQR 776-1189). Intraoperative findings revealed that most TM (86.7%) had unremarkable uterus size, and 13% showed enlarged uterus size. In the latter, all were from myoma uteri. Most intraoperative findings of ovaries showed 93% unremarkable. One TM had intraoperative polycystic ovarian morphology, and one showed a unilateral ovarian cyst. Cervical pathological reports showed unremarkable results in 67%. Five TM (17%) had chronic cervical inflammation. There was 1 TM (3%) who showed low-grade squamous intraepithelial lesion (LSIL) with squamous metaplasia. Regarding endometrial pathology, the mean endometrial thickness was 0.13 ± 0.08 cm. Most endometrial reports (66%) were in a proliferative phase, 27% were in an atrophic or inactive endometrium, and 7% were in the secretory phase. Regarding pathological reports of ovaries, 80% had cystic ovaries. None of the TM showed precancerous or malignant conditions of endometrium, ovaries, and fallopian tubes. PAP smear was available in 27 TM; all were negative for intraepithelial lesions or malignancy. Conclusion: Among a cohort of TM who received MHT for 32 months, there is no evidence of precancerous or malignant pathology of the endometrium, ovaries, and fallopian tubes. Most of them had thin endometrium with cystic ovaries. One TM showed LSIL with squamous metaplasia of the cervix. Healthcare providers should follow local gynecological cancer screening guidelines developed for cisgender women in their clinical practice.

Presentation: 6/2/2024
8786 Novel TGFbeta Ligand Regulated Genes in WT and FSTL3 KO Testis Identified by ChIP-Seq Analysis: Implications for Signalling Cross-talk
Authors: Ballesteros Randy , Mukherjee Abir
Published: October 2024

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

Folistatin Like 3 (FSTL3) is a known antagonist of activin and myostatin action that when deleted from the mouse genome displayed a set of phenotypic changes that are directly linked to glucose metabolism and reproductive function. Although our previous work showed that β-cell hyperplasia, increased pancreatic islet number and size and reduced visceral fat seen in FSTL3 knockout mice (FSTL3 KO) could be explained by enhanced activin and myostatin action, the molecular bases of the changes in the reproductive function seen in this mouse model remain elusive. In contrast to testicular degeneration produced by INHBA (activin A) transgenic overexpression in mice, deletion of FSTL3 results in increased testicular size, with increased Sertoli cell numbers and early meiotic entry of the first spermatogenic wave. This suggests a possibility that the phenotype in FSTL3 deleted mice might involve alteration of additional transcripts other than those induced by activin alone in the testis. To identify transcripts induced in FSTL3 deleted testis as a consequence of induced TGFβ ligand action we performed sequencing of Smad4 Chromatin immunoprecipitation (ChIP-Seq) from postnatal (3d) and post-pubertal (56d) whole testis. Our results show high activity of Smad4 signalling during postnatal stages compared to post-pubertal stages in both genotypes (Fstl3-KO vs wild-type). Interestingly, postnatal testis from FSTL3 KO contains significantly less activity from Smad4 signalling (69 peaks) compared to wild type (775 peaks). By contrast, on the whole, Smad4 signalling in post-pubertal stages is less active with 34 peaks in wild-type and 29 peaks in Fstl3-KO of which 8 genes are SMAD activated in both genotypes. To identify whether SMAD-dependent signalling produces significant differences in RNA expression, we then used the list of genes that generated peaks in the Smad4-ChIP-Seq experiment to filter our RNA-Seq data generated in a parallel experiment followed by differential gene expression analysis of GO terms by GSEA in postnatal testis from both genotypes. We found that Smad4-interacting genes in posnatal FSTL3 KO testis generate enrichment of 13 pathways including the androgen receptor signalling pathway. Taken together so far, our findings reveal a novel catalogue of SMAD-regulated genes in the testis, identifies a set of genes specifically upregulated in the testis in a SMAD-dependent manner upon FSTL3 deletion and also identify possible cross-talk between TGFβ and 13 other signalling pathways. Currently we are further analysing our data to identify whether there are SMAD regulated genes and pathways common in postnatal and postpubertal testes. We are also undertaking experiments to investigate expression pattern in FSTL3 KO testis to identify which pathways might specifically affect Sertoli cell proliferation and activity.

Presentation: 6/2/2024
9242 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.

AbstractPurpose: 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
8607 Gender Affirming Hormone Therapy: Influence of Brain Network Connectivity Changes on Affect
Authors: Andreano J , Lopez A , Misra M
Published: October 2024

Disclosure: J. Andreano: None. A. Lopez: None. M. Misra: None.

Background: Previous research indicates that acute gonadal treatments and fluctuations in ovarian hormone levels over the course of the menstrual cycle can alter patterns of communication between brain regions, as well as producing significant changes in self-reported affect. Recent research from our laboratory indicates changes in both brain connectivity and affect with gender affirming hormone therapy (GAHT). However, the relationship between these changes with GAHT are not well understood. Additionally, it is difficult to separate influences of GAHT and transgender identity in understanding differences in connectvity and affect from cisgender controls. A better understanding of the influence of GAHT on intrinsic network connectivity could point the way towards improved GAHT treatment regimens that minimize affective side effects. Objective: To assess relationships between changes in brain network connectivity and affective changes following GAHT, identifying regions in which changes of connectivity are associated with changes in self-reported affect, and to examine differences in brain network connectivity between transgender participants and cisgender controls. Methods: 14 transgender individuals receiving GAHT (estradiol n =7, testosterone n = 7)) were scanned using functional magnetic imaging (fMRI) at rest at two timepoints: baseline, prior to treatment, and 6 months into GAHT. Additionally, 20 cisgender controls (10 male, 10 female) were scanned once each. The time course of neural activity was computed for each voxel in the brain, then tested for correlation with each other voxel to develop a whole-brain connectome for each participant. Maps of average connectivity to two seeds known to associate with two major networks in the brain (posterior cingulate cortex for Default Mode Network, and anterior insula for Salience Network) were then generated for each participant. Within transgender participants, these maps were then compared between the baseline and 6 month timepoints. Additionally, baseline scans were also compared to scans from cisgender controls corresponding to biological sex. Results: Within-subjects analyses of transgender participants showed diverse associations between changes in seed-based connectivity and changes in self-reported anxiety and depression following GAHT in both the default mode and salience networks. Between subjects comparisons showed significantly higher connectivity within the salience network in trans men relative to cis women, as well as greater inter-network connectivity in this group. In contrast, cis men showed greater connectivity within both default mode and salience networks relative to trans women. Conclusions: Changes in affect following GAHT appear related to GAHT-induced changes in network connectivity; these influences appear independent of differences between cis and transgender individuals.

Presentation: 6/2/2024
8723 Glucose Metabolism Disturbances in Non-Classic Adrenal Hyperplasia (NCAH)
Authors: Domagała Bartosz , Gamrat Aleksandra , Skalniak Anna , Przybylik-Mazurek(†) Elwira , Trofimiuk-Muldner Malgorzata , Hubalewska-Dydejczyk Alicja
Published: October 2024

Disclosure: B. Domagała: None. A. Gamrat: None. A. Skalniak: None. E. Przybylik-Mazurek(†): None. M. Trofimiuk-Muldner: None. A. Hubalewska-Dydejczyk: None.

Introduction: There is data reporting an increased risk of cardiovascular and metabolic complications in patients with NCAH. This is frequently attributed to glucocorticoid (over)use or misdosing. It seems that long-term exposure to increased androgens concentrations may also itself lead to diminished insulin sensitivity and increased risk of prediabetes and diabetes. Aim: The study aimed to assess the link between NCAH diagnosis and glucose metabolism disturbances. Material and methods: The study included 327 subjects (315 females and twelve males, median age 25 years) referred for a cosyntropin stimulation test due to the suspected NCAH. Serum 17-OH-progesterone (17-OHP) was assessed with an ELISA assay. The diagnosis of NCAH was confirmed if the initial or stimulated 17-OHP concentration exceeded 10.0 ng/mL. None of the tested subjects was treated with glucocorticoids. A history of preexisting prediabetes or diabetes was recorded. Anthropometric measurements were obtained to calculate body mass index (BMI). Fasting glucose was measured in each subject. Mann-Whitney U and Yates’ χ2 tests were used in statistical analyses, with p<0.05 as the cut-off value of statistical significance. Results: 62 patients (60 females, two males; median age 26 years) were diagnosed with NCAH; the rest of the tested subjects were considered the control group. Preexisting type 2 diabetes was recorded in ten subjects in the entire study group (6 of them were diagnosed with NCAH). There was no significant difference in the fasting glucose levels (p=0.08) and BMI (p=0.32) between subjects with and without NCAH diagnosis (median fasting glucose: 4.96 mmol/L and 4.86 mmol/L, respectively; median BMI: 23.82 kg/m2 and 23.26 kg/m2, respectively). Diabetes was significantly more frequent in patients with NCAH diagnosis (p = 0.004; power: 0.74). The median 17-OHP was higher in patients with diabetes compared to those without it at both 30 (12.25 ng/mL vs 3.25 ng/mL; p=0.003) and 60 minutes (14.93 ng/mL vs 3.95 ng/mL; p=0.046) after stimulation. Conclusions: NCAH seems to be linked to increased diabetes risk, even in glucocorticoid-naïve patients. It seems advisable to screen NCAH patients for glucose metabolism disorders.

Presentation: 6/1/2024
12554 Human Sex Determination: SRY Length Regulates Its Cellular Stability And Hence The Robustness Of Testis Differentiation
Authors: Weiss M A
Published: October 2024

Disclosure: M.A. Weiss: None.

SRY length regulates its cellular stability and hence the robustness of testis determinationYen-Shan Chen[1], Ella Thomson2, Emanuele Pelosi[1], & Michael A. Weiss[1]*[1]Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA2Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia*Correspondence: Michael A. Weiss (weissma@iu.edu) Abstract: 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
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.

Immune system adaptation during gender-affirming testosterone treatment 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
8046 Milk Provision as a Potential Intervention to Improve Iodine Status in a Pregnant Cohort in Northern Ireland (NI), UK: A Randomised Controlled Trial
Authors: Kayes L R , Mullan K R , Woodside J V
Published: October 2024

Disclosure: L.R. Kayes: None. K.R. Mullan: None. J.V. Woodside: None.

Iodine deficiency is the leading cause of reversible mental retardation worldwide. During pregnancy there is ∼50% increase in iodine requirement for foetal neurodevelopment. The most recently studied cohorts of pregnant women across Ireland and UK consistently demonstrated mild iodine deficiency (target median urinary iodine concentration (mUIC) ≥150 µg/L). A recent study in NI has shown that women of child-bearing age provided with three litres of cow’s milk per week had improved iodine status. We wished to explore whether a similar milk intervention might improve iodine status during pregnancy. Pregnant women were recruited at their first antenatal appointment, and all were provided with the British Dietetic Association’s iodine food fact sheet. Participants were randomised to either milk intervention, (four litres/week milk delivered weekly free of charge), or no milk delivery (control group). Patients were stratified based on use of an iodine-containing multivitamin prior to randomisation. Urine was collected at recruitment, after 12-week intervention period, in the third trimester and 6-12 weeks postnatally along with an infant urine sample when possible. A total of 55 urine samples were collected from infants. A total of 118 women were recruited. Participants had a mean age of 32 years, (range 21 - 45) with a mean BMI of 27.5 kg/m2. Mean gestational age was 12 weeks (IQR 12-13 weeks). The mUIC in the whole group women was 53.2 µg/L in the first trimester. In the control group the mUIC at the first study visit (n=59) was 93.4 µg/L (22% achieving iodine sufficiency); at the second visit (n=38), the mUIC was 158.7 µg/L with 34% achieving sufficiency. In the milk group the mUIC at the first study visit (n=59) was 82.0 µg/L with 10% achieving sufficiency (no statistical significance between groups, p=0.08); at the second visit (n=43), mUIC was 154.7 µg/L with 37% achieving sufficiency (no statistical difference between groups p=0.78). The mean change in UIC between the first and second trimesters was 44.5 and 88.1 µg/L in the control and milk arms respectively (p=0.27). In this cohort, 71.4% of women reported taking an iodine-containing multivitamin in the first trimester of pregnancy with no difference between group randomised to milk intervention (p=0.95). In the infants, mUIC was 124.1 µg/L with no statistically difference in the proportion reaching iodine sufficiency according to maternal randomisation (p=0.64) or maternal use of an iodine-containing multivitamin (p=0.95). In this cohort, there was no significant improvement in mUIC in those receiving a milk intervention.

Presentation: 6/1/2024
8384 Reproductive Cancer Risk in Patients Treated with Denosumab Compared with Alendronate: A Population-based Cohort Study
Authors: Yahyavi Sam Kafai , Selmer Christian , Torp-Pedersen Christian , Juul Anders , Jensen Martin Blomberg
Published: October 2024

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

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

Presentation: 6/3/2024
12673 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
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.

AbstractPurpose: 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
7895 The accumulation of p63 in oocyte of primordial follicle is essential for triggering apoptosis following cisplatin treatment
Authors: Abazarikia A , So W , Kim S Y
Published: October 2024

Disclosure: A. Abazarikia: None. W. So: None. S. Kim: None.

Background: Women are born with a finite supply of primary oocytes housed in the ovaries, commonly known as the ovarian reserve, which represents their reproductive lifespan. The ovary serves as a crucial organ for production of oocytes and endocrine hormones, including 17β-estradiol and progesterone. However, chemotherapy inevitably leads to the depletion of the ovarian reserve, resulting in primary ovarian insufficiency (POI), which manifests as endocrine dysfunction and infertility. Within the oocytes of primordial follicles, the p63 protein is highly expressed as an inactive, dimeric form, playing a pivotal role in responding to DNA damage, thereby determining the fate of the oocytes. It is well-established that p63 undergoes activation through hyperphosphorylation and a conformational shift to a tetrameric structure. This activation subsequently triggers apoptosis by inducing the expression of proapoptotic genes. Hypothesis: Different chemotherapeutic agents may exhibit distinct mechanisms in the theregulation of p63 in oocytes. Methods: Postnatal day 5 CD-1 mice were utilized in the experimental groups, comprising control (Ctr), CDDP (cisplatin), CHX (cycloheximide), and PYR-41 (a Ubiquitin-Activating Enzyme E1 Inhibitor). We assessed the number of ovarian primordial follicles, the expression of p63, DNA double-strand breaks (DSBs), and apoptosis through immunoblotting and immunofluorescence assays. Additionally, p63 conformation was examined using Native PAGE Gel. Statistical differences were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's post-hoc test, with significance defined as a p-value less than 0.05. Results: Treatment with CDDP significantly increased p63 levels in oocytes (p<0.05). The combined administration of PYR-41 with CDDP induced a further substantial increase in p63 levels (p<0.001) compared to CDDP treatment alone. Conversely, p63 expression was significantly decreased (p<0.01) with CHX treatment, falling below the levels observed in the CDDP group. Notably, CHX appeared to protect ovarian follicles from the adverse effects of CDDP, as evidenced by the decreased levels of ɣH2AX, cleaved PARP, and PUMA, which is a known target gene of p63 in oocytes. Conclusion: Therefore, our findings strongly indicate that the accumulation of p63 represents the initial step in oocytes preceding CDDP-induced oocyte death, which is subsequently followed by hyperphosphorylation, tetramerization, and degradation of p63. Significance: Comprehending the mechanism behind cisplatin-induced oocyte death will contribute to the development of effective adjuvant therapies aimed at preserving ovarian reserve in young female cancer survivors undergoing CDDP treatment.

Presentation: 6/2/2024
8610 The Role of Adenylyl Cyclase 2 Gene-Dosage Changes in Congenital Male Genitourinary Anomalies
Authors: Lamb D J , O’Neill M A
Published: October 2024

Disclosure: D.J. Lamb: Advisory Board Member; Self; Ro Health, Inc. Stock Owner; Self; Fellow Health, Inc. M.A. O'Neill: None.

Collectively, congenital genitourinary (GU) birth defects are the most common birth defects in males, yet relatively little is known about their cause. In part, this reflects the current clinical perspective that, because most of these birth defects can be surgically repaired, there is nothing to be gained by understanding the cause. Yet our studies show that seemingly simple birth defects like hypospadias or cryptorchidism, may be associated with other more significant underappreciated defects, such as those affecting the kidney, heart, eyes or behavior. We tested the hypothesis that chromosome microdeletions and microduplications (called copy number variations, CNVs) result in gene-dosage changes that are important regulators of GU development and when haploinsufficient or duplicated normal genitourinary development is impacted causing birth defects of the upper and/or lower genitourinary tract. We successfully used this strategy to identify 15 different previously unrecognized genes that when microduplicated or microdeleted result in conditions such as cryptorchidism, hypospadias, disorders of sexual differentiation (DSD) and other anomalies. Remarkably, gene-dosage changes affected major signaling pathways and post-translational modifications in novel, previously unrecognized ways. Herein, we focused on defining the role of a candidate gene commonly microdeleted or microduplicated in patients with cryptorchidism, hypospadias and/or micropenis. Locus mapping allowed identification of adenylate cyclase 2 (ADCY2) as a candidate gene at the 5p15.31 Cri-du-Chat region in patients with male genital tract anomalies. ADCY2 CNVs were more common in non-syndromic patients with micropenis, cryptorchidism, and/or hypospadias (1.6%) than the general population (0.07%; p< 0.001). Whole exome sequence studies revealed a range of phenotypic anomalies in patients with damaging and potentially damaging ADCY2 variants in addition to the male GU anomalies, including congenital anomalies of the kidney and urinary tract. It is our hypothesis that ADCY2 duplications result in a de-sensitization of the LH receptor diminishing testosterone biosynthesis in the testis, whereas deletions diminish LH receptor signaling. ADCY2 CNVs were assessed in 100 men with spermatogenic failure who were born with cryptorchidism. The ADCY2 CNV frequency was the same as in our cohort of boys with GU anomalies, but as adults they also have hypergonadotropic hypogonadism, which we predicted if ADCY2 over-expression was impacting adult Leydig cell steroidogenesis through partial desensitization of the LH receptor. These studies identified an unrecognized cause of GU anomalies. In the future, such knowledge may lead to improved diagnosis and therapeutic approaches to ameliorate these common birth defects.

Presentation: 6/2/2024
8622 The Severity of Vasomotor Symptoms Is Associated With Metabolic Dysfunction Associated Liver Disease (Masld) in Peri- AndPostmenopausal Women
Authors: Armeni E , Augoulea A , Karagkouni I , Avgousti I , Charamanta M , Stergiotis S , Lambrinoudaki I
Published: October 2024

Disclosure: E. Armeni: None. A. Augoulea: None. I. Karagkouni: None. I. Avgousti: None. M. Charamanta: None. S. Stergiotis: None. I. Lambrinoudaki: None.

Introduction: Reproductive aging and ovarian senescence are associated with accelerated accumulation of cardiometabolic risk factors, but also progressively increasing risk for cardiovascular disease (CVD). Metabolic-dysfunction-associated steatotic liver disease (MASLD) is linked with a higher risk for CVD. The prevalence of MASLD with regards to reproductive aging, and the possible link with vasomotor symptoms has not been evaluated yet Methods: For the purpose of this cross-sectional study, we evaluated 106 peri- and postmenopausal women, retrieved from the outpatient Menopause clinic of the Second Department of Obstetrics and Gynecology, University of Athens, Aretaieio Hospital, Athens, Greece. The extent of steatotic liver disease (SLD) was estimated as values of the fatty liver index; using the known cut-off ≥ 60 for higher risk for SLD. MASLD was defined as the presence of ≥1 of the following risk factors in a woman with hepatic steatosis: 1) body mass index (BMI) ≥25 kg/m2 or waist circumference ≥85 cm; 2) fasting glucose ≥100 mg/dL or type 2 diabetes or hypoglycemic treatment; 3) blood pressure ≥130/85 mmHg or antihypertensive treatment; 4) triglycerides ≥150 mg/ dL or related treatment; and 5) high-density lipoprotein cholesterol ≤40 mg/dL or lipid-lowering treatment. The severity of vasomotor symptoms (VMS) was assessed using the Greene Climacteric Scale. Results: Moderate-to-severe VMS were evident in 42 women of our sample while 64 women had no-to-mild severity of VMS. Logistic regression analysis showed that moderate-to-severe VSM, as opposed to no-to-mild symptoms, were associated with MASLD (MASLD rates, moderate-to-severe VSM vs no-to-mild: 26.2% vs 12.5%, p-value=0.072; OR = 3.022, p-value =.041). This association became even stronger when we restricted the sample to early postmenopausal women (up to 5 years after the final menstrual period, N=57, VMS no-to-mild vs moderate-to-severe, 3.6% vs 24.1%, p-value = 0.025; OR=9.333, p-value=0.045). The models were adjusted for age, physical exercise, alcohol intake, current smoking, history of menstrual irregularity, and HRT use. Conclusion: The results of this study indicate that the severity of vasomotor symptoms is associated with the diagnosis of MASLD in midlife women, irrespective of the use of HRT. These observations underscore the importance of cardiovascular risk assessment in women with bothersome vasomotor symptoms.

Presentation: 6/3/2024
12465 Unraveling The Enigma: A Multifaceted Presentation Of Hormonal Dysregulation In A 37-year-old Woman
Authors: Rizvi Syeda Yumna , Jones Krister J , Ahmad Nazish
Published: October 2024

Disclosure: S.Y. Rizvi: None. N. Ahmad: None.

Title: Unraveling the Enigma: A Multifaceted Presentation of Hormonal Dysregulation in a 37-Year-Old Woman Background: Leydig cell tumors (LCTs) are rare gonadal tumors, arising from the interstitial cells of the testis or, less commonly, the ovary, 0.1%. These tumors are known for their potential to produce androgens, leading to virilization symptoms such as hirsutism. While LCTs are typically benign, they can occasionally exhibit malignant features. Accurate diagnosis and appropriate management are crucial to prevent complications and ensure favorable outcomes. Clinical Case: A 37-year-old, G3P3A0 woman, presented to our endocrinology clinic for a follow-up visit following the removal of a malignant thyroid nodule. During the visit, her endocrinologist noted elevated testosterone levels and worsening hirsutism. She reported mild abdominal pressure but denied other symptoms. She also complained of pain in the lower abdomen, although physical examination findings were limited due to type II obesity. Diagnostic investigations revealed a history of imaging studies, including CT scans and pelvic ultrasounds, demonstrating various findings such as a fibroid uterus, ovarian abnormalities, and a heterogeneous mass in the left adnexa. Laboratory evaluations over time showed fluctuations in androgen levels, with notable values including DHEA-sulfate (137.5 ug/dL), total testosterone (309.6 NG/dL), and free testosterone (12.85 NG/dL). Tumor markers, including CA 19-9= 16 U/mL, CA 125= 23.3 U/mL, CEA = 1.7 NG/mL, and HCG, were unremarkable. Gynae/Oncology was consulted, and she underwent surgical exploration with laparoscopic left oophorectomy. It revealed a Leydig cell tumor without overt malignant features, as confirmed by histopathological examination and immunohistochemical analysis. Her testosterone improved since oophorectomy. Patient undergoes frequent post-op follow up of her testosterone, free+total lc/MS to monitor for hyperandrogenism. Conclusion: This case highlights the importance of considering Leydig cell tumors in the differential diagnosis of hirsutism, particularly in the presence of elevated androgen levels. Multidisciplinary collaboration involving endocrinologists, gynecologists, oncologists, radiologists, and pathologists is essential for accurate diagnosis and optimal management. Surgical resection remains the cornerstone of treatment for Leydig cell tumors, with careful histopathological evaluation necessary to assess for potential malignancy. Long-term follow-up is warranted to monitor for recurrence or metastasis, although the prognosis for benign Leydig cell tumors is generally favorable. Patients with large body habitus may present challenges in physical examination, necessitating reliance on imaging and laboratory studies for diagnostic evaluation. Keywords: hirsutism, testosterone, ovary

Presentation: 6/2/2024