Sex Hormones Research Articles

Androgen Deficiency, Associations and Survival of Men With Stage 4 and 5 Chronic Kidney Disease: A Cohort Study.

Anaemia is a key cause of morbidity in chronic kidney disease (CKD). Androgen deficiency (AD) in males can contribute to anaemia of all causes, including in CKD. We sought to examine the prevalence of AD in men with CKD, the extent to which it contributed to anaemia and whether it was independently associated with long-term survival. This cross-sectional observational study was conducted among males aged 18 years and over with CKD stages 4 and 5. The study analysed morning blood samples with regard to their full blood count, urea and electrolytes, albumin, lipids, testosterone (T) and sex hormone binding globulin, with calculation of free testosterone by mass action equation. Mortality data were obtained 15 years later for survival analysis. Among 322 patients with a mean age of 63 years, the overall prevalence of AD was 68.9%. There was a statistically significant negative correlation between erythropoiesis stimulating agent (ESA) dose and testosterone concentrations (Pearson correlation -0.193, p = 0.05). There was a positive correlation between haemoglobin (Hb) and free testosterone level among patients not on ESA therapy (Pearson correlation 0.331, p < 0.001). Kaplan-Meier plots showed p < 0.001 on log-rank analysis, indicating that AD was significantly associated with worse survival. However, in Cox regression analysis, free testosterone was not associated with survival (95% CI for free testosterone 0.997-1.000). AD is highly prevalent among this population, and increases further with older age and more severe CKD warranting haemodialysis. Association of lower Hb and higher ESA dose with lower T concentration might be causative, which has important pharmaco-economic as well as clinical implications. Lower survival in men with low T, more likely reflects overall poor health rather than causation. A properly constituted randomised controlled study evaluating the effect of native T replacement is warranted in men with CKD and AD.

8768 Initiation of Exogenous Sex Hormones in a Pediatric Gender Clinic

Abstract Disclosure: C.M. Roberts: None. M.M. Knoll: None. G. Robertson: None. A. Egan: None. C. Moser: None. Introduction: The demographics of patients seeking care for gender dysphoria have changed significantly since care was started in 1987. The criteria for prescribing sex hormones have also evolved to allow a greater range of patients to receive gender-affirming hormones. We examined factors associated with prescription of gender-affirming hormones to patients presenting for gender-affirming care our clinic. Methods: Secondary analysis of sex hormone initiation as a minor among 14-17-year-old adolescents diagnosed with gender dysphoria, seen in the pediatric gender clinic between 2/19/2018 and 7/20/2022. We extracted demographic variables, appointment dates, and sex hormone prescription data from our electronic medical record. We collected patient reports of gender identity and suicidal behavior, and parent and adolescent reports of general adolescent well-being, months of gender dysphoria and social transition, and parental support for the adolescent’s gender identity from electronic clinic surveys. Results: We identified 273 adolescent-parent dyads with complete data. Most of our sample were assigned female at birth (74.4%), transgender male (59.3%), and white (83.5%) adolescents who lived in urban (86.4%) and lower-middle-income (64.5%) areas. The average age was 15.9+/-1.1 years. A minority of adolescents reported recent suicidal ideation 60/273 (22%), and prior suicide attempts 20/273 (7%). Parents reported a shorter duration of gender dysphoria (-16.7 months (95%CI: -22.0, -11.5)) and social transition (-4.7: -6.5, -3.0), and higher levels of parental support than adolescents. Approximately half, 146/273 (53.5%), of adolescents started sex hormones. The average age at initiation was 16.5 years +/- 0.9. Age at presentation, length of gender dysphoria or social transition, and the presence of suicidal ideation or attempts were not associated with initiation of sex hormones. Assigned males (OR:1.82:95%CI 1.04, 3.19), adolescents with higher parent-reported parental support for the adolescent’s identity (1.03:1.01, 1.04), and adolescents with private insurance rather than Medicaid (Blue Cross- 5.39:2.73, 10.64) were more likely to start sex hormones as a minor. Conclusion: Published criteria for the initiation of sex hormones among adolescents with gender dysphoria, including age, persistence of dysphoria, and the presence of suicidality, did not predict the prescription of sex hormones to minors in our clinic. Parent-reported support for the adolescent’s gender identity played a small role in predicting the prescription of hormones, but male sex assigned at birth and having private health insurance played larger roles. Further exploration of these findings is needed to ensure equity in the treatment of gender dysphoria. Presentation: 6/3/2024

9208 Sex Hormones and Abdominal Muscle Area and Radiodensity in Men: A Multi-Ethnic Study of Atherosclerosis

Abstract Disclosure: A. Osmancevic: None. M. Allison: None. I. Miljkovic: None. C. Vella: None. P. Ouyang: None. P. Trimpou: None. B. Daka: None. Context: Information on the associations of testosterone, estradiol and sex hormone binding globulin (SHBG) levels with abdominal muscle volume and quality in men are unclear. Objective: To investigate the association between fasting serum sex hormones and CT-derived abdominal muscle area and radiodensity in adult men. Design: Cross sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. Participants: A community-based sample of 907 men aged 45-84 years; 878 men with complete data were included in the analysis. Main Outcome Measure(s): CT scans of the abdomen were interrogated for muscle characteristics. Multivariable linear regressions were used to test the associations. Results: After adjustment for age, race/ethnicity, visceral fat, CRP, lifestyle factors, comorbidities and medicine use, higher levels of both total testosterone and estradiol, but not SHBG, were associated with higher abdominal muscle area (B= 1.79, 95% CI 0.1 to 3.4, &amp; B=1.79, 95% CI 0.4 to 3.2, respectively). After the same adjustment, levels of total testosterone showed a significant positive association (B= 0.3, 95% CI 0.0 to 0.6), while a significant inverse relationship was observed for SHBG with abdominal muscle radiodensity (B=-0.34, 95% CI -0.6 to -0.1). Conclusion: Our results indicate significant associations between sex hormones and abdominal muscle characteristics in men from several different race/ethnic groups. These findings reveal novel insights into the previously unrecognized role that SHBG may play in skeletal muscle adipose tissue distribution. Presentation: 6/2/2024

7896 Sex Hormones and Abdominal Muscle Area and Radiodensity in Men: A Multi-Ethnic Study of Atherosclerosis

Abstract Disclosure: A. Osmancevic: None. M. Allison: None. I. Miljkovic: None. C. Vella: None. P. Ouyang: None. P. Trimpou: None. B. Daka: None. Context: Information on the associations of testosterone, estradiol and sex hormone binding globulin (SHBG) levels with abdominal muscle volume and quality in men are unclear. Objective: To investigate the association between fasting serum sex hormones and CT-derived abdominal muscle area and radiodensity in adult men. Design: Cross sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. Participants: A community-based sample of 907 men aged 45-84 years; 878 men with complete data were included in the analysis. Main Outcome Measure(s): CT scans of the abdomen were interrogated for muscle characteristics. Multivariable linear regressions were used to test the associations. Results: After adjustment for age, race/ethnicity, visceral fat, CRP, lifestyle factors, comorbidities and medicine use, higher levels of both total testosterone and estradiol, but not SHBG, were associated with higher abdominal muscle area (B= 1.79, 95% CI 0.1 to 3.4, &amp; B=1.79, 95% CI 0.4 to 3.2, respectively). After the same adjustment, levels of total testosterone showed a significant positive association (B= 0.3, 95% CI 0.0 to 0.6), while a significant inverse relationship was observed for SHBG with abdominal muscle radiodensity (B=-0.34, 95% CI -0.6 to -0.1). Conclusion: Our results indicate significant associations between sex hormones and abdominal muscle characteristics in men from several different race/ethnic groups. These findings reveal novel insights into the previously unrecognized role that SHBG may play in skeletal muscle adipose tissue distribution. Presentation: 6/2/2024

9208 Sex Hormones and Abdominal Muscle Area and Radiodensity in Men: A Multi-Ethnic Study of Atherosclerosis

Abstract Disclosure: A. Osmancevic: None. M. Allison: None. I. Miljkovic: None. C. Vella: None. P. Ouyang: None. P. Trimpou: None. B. Daka: None. Context: Information on the associations of testosterone, estradiol and sex hormone binding globulin (SHBG) levels with abdominal muscle volume and quality in men are unclear. Objective: To investigate the association between fasting serum sex hormones and CT-derived abdominal muscle area and radiodensity in adult men. Design: Cross sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. Participants: A community-based sample of 907 men aged 45-84 years; 878 men with complete data were included in the analysis. Main Outcome Measure(s): CT scans of the abdomen were interrogated for muscle characteristics. Multivariable linear regressions were used to test the associations. Results: After adjustment for age, race/ethnicity, visceral fat, CRP, lifestyle factors, comorbidities and medicine use, higher levels of both total testosterone and estradiol, but not SHBG, were associated with higher abdominal muscle area (B= 1.79, 95% CI 0.1 to 3.4, &amp; B=1.79, 95% CI 0.4 to 3.2, respectively). After the same adjustment, levels of total testosterone showed a significant positive association (B= 0.3, 95% CI 0.0 to 0.6), while a significant inverse relationship was observed for SHBG with abdominal muscle radiodensity (B=-0.34, 95% CI -0.6 to -0.1). Conclusion: Our results indicate significant associations between sex hormones and abdominal muscle characteristics in men from several different race/ethnic groups. These findings reveal novel insights into the previously unrecognized role that SHBG may play in skeletal muscle adipose tissue distribution. Presentation: 6/2/2024

8256 Early Life Stress and Pubertal Predictors of Youth Substance Use Initiation: Does Sex Moderate the Relationship Between ELS, Puberty, and Substance Use Initiation?

Abstract Disclosure: A. Donovan: None. S. Assari: None. M. Shaheen: None. C. Grella: None. L. Richter: None. T.C. Friedman: None. Background: Early life stress (ELS) is a construct composed of children’s experiences of abuse, neglect, and conflict. Approximately 20% of adolescents in the United States have experienced ELS at some point, and these experiences influence adolescent and adult health behavior outcomes. Adults with a history of ELS display higher rates of substance use disorders (SUD) and report earlier initiation of substance use. Additionally, ELS has been associated with early puberty, which in turn is linked to earlier substance use initiation. Our study examines the roles of pubertal status, sex hormones (estradiol, testosterone, and DHEA) and ELS as predictors of the initiation of substance use among a nationally representative sample of male and female adolescents in NIDA’s Adolescent Brain Cognitive Development (ABCD) database. Methods: Baseline measures from the ABCD database release 5.0 were used to generate an ELS score (0-60), puberty assessed via parental report on the Pubertal Development Scale (PDS, 1-4), and sex hormones (estradiol, testosterone, and DHEA) were analyzed via salivary samples. The relationship between these scores and time to first use of alcohol, nicotine, and marijuana was determined via survival analysis utilizing a cox regression. Age was tested as a covariate in the interaction of ELS and time to first use of alcohol, nicotine, and marijuana. Data were analyzed overall and for biological boys and girls separately (N=11,866, 52%M 48%F. ages 9-11 at baseline). Results: We observed additive effects of PDS score, estradiol measure, age, and ELS on time to first use of any substance (alcohol, nicotine, or marijuana) and found age (Exp β= 1.029, p&amp;lt;0.001) and ELS (Exp β= 1.017, p&amp;lt;0.05) to be significant predictors of time to first use. After separating by sex, ELS was no longer a significant predictor for males (Exp β= 1.014, p=0.054), but remained a predictor for females (Exp β= 1.019, p&amp;lt;0.05) indicating the overall effect was driven by females. Additionally, salivary estradiol was a significant predictor of first use for females (Exp β= 1.208, p&amp;lt;0.05), while salivary DHEA and testosterone were not predictors for males or females. Conclusions: Our results indicate sex does moderate the relationship between ELS and substance use initiation within our population, with females showing increased risk of initiation with increases in estradiol. Further findings from our study will help to describe sex differences among the factors that increase the risk of substance use initiation among ELS-exposed youth and explore how these vary by substance. ABCD provides an unprecedented opportunity to explore the mechanisms behind complex effects of ELS by sex on risk factors for adolescent substance use initiation. Presentation: 6/1/2024

7820 Immune system adaptation during gender-affirming testosterone treatment

Abstract 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

7820 Immune system adaptation during gender-affirming testosterone treatment

Abstract 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

7428 Clinical and Radiological Characterization and Outcomes of Lipid-Poor Adrenal Masses- A Multi-Center Retrospective Study

Abstract Disclosure: V. Balderrama-Brondani: None. R. Al-ward: None. K. Kiseljak-Vassiliades: None. L.M. Fishbein: None. D.A. Kirelik: None. O. Hamidi: None. R. Pishdad: None. H.K. Ghayee: None. M. Sukkari: None. S.S. Bedrose: None. A.H. Hamrahian: None. M.A. Habra: None. Background: Lipid-poor adrenal masses (LPAMs) with pre-contrast radiodensity &amp;gt;10 Hounsfield Units (HU) on computed tomography (CT) represent ∼25% of adrenal tumors. There is limited data about the natural history of LPAMs; therefore, we evaluated a large series of patients with LPAMs to describe the radiological and clinical features and outcomes of these cases. Methods: We conducted a multi-center retrospective cohort study of patients with LPAMs with a baseline diameter of 10-39 mm and derived from 6 institution members of the American-Australian-Asian Adrenal Alliance (A5). We excluded suspected or proven adrenal metastasis, pheochromocytoma, sarcoma, lymphoma, myelolipoma, infiltrative lesions, and adrenal hemorrhage, as well as patients with personal/familial history of genetic predisposition to adrenal neoplasms. The data is presented in percentage and median (range). Results: A total of 242 adrenal masses from 218 patients were evaluated, but only 225 (93%) masses met the inclusion criteria and were analyzed. The age was 58 (23-92), and 61% were women. LPAMs were incidentally discovered in 155 (71.1%) cases, 32 (14.7%) cases were diagnosed due to hormonal overproduction, and 17 (7.8%) due to pain/mass effect. Forty-six (21.1%) patients were on surveillance for a history of extra adrenal malignancy. Masses were unilateral in 89.9% (left side, 57.1%), with size 21 (10-38) mm, with a pre-contrast density of 24 (11-136) HU. Absolute washout was reported in 107 LPAMs and was &amp;gt;60% in 73 (68.2%) cases. The follow-up time was 44.4 (0.9-241) months. Hormonal overproduction developed during the follow-up in 23 (10.5%) cases as follows: cortisol in 15 (6.9%), aldosterone in 4 (1.8%), and sex hormones in 3 (1.4%) cases. LPAM growth rate was 0.03 (-2.18-11.59) cm/year. Seventy-one masses (31.5%) underwent diagnostic procedures (surgery/biopsy) with adrenocortical adenoma (n=37; 52.1%) and adrenocortical carcinoma (ACC) (n=25; 35.2%) being the two most common diagnoses. The tumor growth rate of pathologically confirmed adenomas was 0.03 (-0.30-10.50) cm/year, and of ACC was 1.31 (0.03-11.59) cm/year. A total of 154 (68.4%) LPAMs remained under surveillance at the end of the study, with a follow-up time of 51.8 (6-241) months and a tumor growth rate of 0.02 (-2.18-1.36) cm/year. Forty-five (20.6%) LPAMs decreased by 2 mm (1-13) during the study period. Cases that proved to be ACC had the most significant tumor growth rate over the study (p&amp;lt;0.001). The median time between the initial discovery of LPAM and the surgical resection of ACC cases was 34 (6-128) months. Conclusion: Our study showed that LPAMs carry significant malignant potential, and close long-term follow-up is warranted when surgical resection is not pursued. Prospective studies are critically needed to validate our findings and to establish high-risk molecular, imaging, and biochemical features associated with malignancy. Presentation: 6/2/2024

8359 Increased hepatic SGK1 activity promotes metabolic dysfunction-associated fatty liver disease in a sex-dependent manner

Abstract Disclosure: A. Vastola-Mascolo: None. G. Hernández: None. D. Alvarez de la Rosa: None. The serum and glucocorticoid-induced kinase 1 (SGK1) is a Ser/Thr kinase with key roles in fluid and electrolyte homeostasis, blood pressure regulation and energy metabolism. Its expression is controlled by steroid hormones such as glucocorticoids, mineralocorticoids and estrogen, in addition to other stimuli such as glucose. SGK1 activation mainly depends on the PI3 kinase pathway, implicating it in insulin signaling. Previous work from our laboratory demonstrated that a systemic increase in SGK1 activity exacerbates diet-induced development of metabolic syndrome in mouse, characterized by obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. In addition, a high-fat diet rapidly led to the development of hepatic steatosis. We now test the hypothesis that at least part of the effects of increased systemic SGK1 activity promoting the development of metabolic syndrome are due to alterations in liver glucose or lipid handling. To that end we developed a mouse strain with hepatocyte-specific transgenic SKG1 expression and challenged it with high-fat or high-fat/high-sucrose diets. Our results show sex differences in the development of obesity, with a marked increase in body weight in female, but not male transgenic animals. Glucose homeostasis was normal in both sexes. Increased obesity in females correlated with increased lipid accumulation in the liver. However, liver fibrosis, inflammation and dyslipidemia were more marked in male animals, further suggesting an interaction between SGK1 and sex steroid hormone signaling. Our results demonstrate a key role of SGK1 in liver lipid metabolism and suggest a crosstalk between this signaling pathway and sex hormones, which determine a more negative outcome in male animals. Presentation: 6/1/2024

7131 The Morbidity Pattern in Females with 45,X/46,XY Mosaicism

Abstract Disclosure: K. Stochholm: None. C.H. Gravholt: None. A. Berglund: None. Background: Turner syndrome (TS) includes females with 45,X/46,XY mosaicism, a rare variant with a prevalence of 2.1 per 100,000 newborn females. Specific knowledge about their associated health outcomes is limited. Aim: To investigate the morbidity pattern in a national cohort of females with 45,X/46,XY. Methods: Data were retrieved for all females diagnosed with 45,X/46,XY from 1960 to 2018 (n=46) and for 4,377 age-matched females from the general population. Morbidity were investigated using Cox regression analysis on registry data regarding hospital diagnoses, redeemed medication, and surgery codes. Results: 45,X/46,XY was associated an increased overall risk of a hospital diagnosis (Hazard ratio (HR): 1.6, confidence interval (CI): 1.2-2.1). The risk of undergoing surgery was significantly increased before the age of 40 years (HR: 1.6, CI: 1.0-2.5), but not in total (HR: 1.2, CI: 0.8-1.7). The HR of redeeming medication was similar to comparators, HR: 1.2, CI: 0.86-1.66. Dividing hospital diagnoses into 18 chapters according to the International Classification of Diseases, 45,X/46,XY had a significantly increased risk of diagnoses due to endocrine disorders (HR=3.6, CI: 2.3-5.8), disorders of the ear (HR=7.1, CI: 4.5-11.3), disorders of the circulation (HR=2.8, CI: 1.7-4.9), and due to congenital malformations (HR=25.1, CI: 17.5-35.8). Among specific diagnoses with a significantly increased risk were gonadal dysfunction, valve diseases, hypertensive diseases, diseases of arteries and aneurisms. Surgery due to disorders of the heart and greater vessels were significantly increased in total (HR=9.3 CI: 2.2-40.4), as were surgery on the aortic valve (HR=36.9, CI: 3.3-409.2), and on female genitalia (HR=2.1, CI: 1.3-3.4), whereas obstetric surgery was significantly decreased (HR 0.2, CI: 0.0-0.7). In females with 45,X/45,XY, there were no registrations related to gonadoblastoma as neither ovarian surgery nor registrations on cancer of the ovary were present. The HR of redeeming a prescription was significantly decreased in the categories of dermatologicals (HR=0.6, CI: 0.4-0.9), musculoskeletal (HR=0.6, CI: 0.4-0.9), antiparasitics (HR=0.5, CI: 0.2-0.8), and in respiratory system (HR=0.6 CI: 0.4-0.9), and significantly increased in systemic hormones (HR=2.2, CI: 1.4-3.7) and in sex hormones (HR=2.9, CI: 2.0-4.1). Conclusion: 45,X/46,XY in females is associated with an increased morbidity with a skewed pattern, as indicated by an overall increased risk of hospital diagnoses, but a unaffected usage of prescribed medication. Surgical procedures were affected with a pattern as in others with Turner syndrome, with a surprisingly absent registration of procedures linked to gonadoblastoma. This study is most likely curtailed by the limited number of females diagnosed with 45,X/46,XY, however the imperative for systematic follow-up is underlined. Presentation: 6/1/2024

9294 Clinical and Radiological Characterization And Outcomes of Lipid-Poor Adrenal Masses- A Multi-Center Retrospective Study

Abstract Disclosure: V. Balderrama-Brondani: None. R. Al-ward: None. K. Kiseljak-Vassiliades: None. L.M. Fishbein: None. D.A. Kirelik: None. O. Hamidi: None. R. Pishdad: None. H.K. Ghayee: None. M. Sukkari: None. S.S. Bedrose: None. A.H. Hamrahian: None. M.A. Habra: None. Background: Lipid-poor adrenal masses (LPAMs) with pre-contrast radiodensity &amp;gt;10 Hounsfield Units (HU) on computed tomography (CT) represent ∼25% of adrenal tumors. There is limited data about the natural history of LPAMs; therefore, we evaluated a large series of patients with LPAMs to describe the radiological and clinical features and outcomes of these cases. Methods: We conducted a multi-center retrospective cohort study of patients with LPAMs with a baseline diameter of 10-39 mm and derived from 6 institution members of the American-Australian-Asian Adrenal Alliance (A5). We excluded suspected or proven adrenal metastasis, pheochromocytoma, sarcoma, lymphoma, myelolipoma, infiltrative lesions, and adrenal hemorrhage, as well as patients with personal/familial history of genetic predisposition to adrenal neoplasms. The data is presented in percentage and median (range). Results: A total of 242 adrenal masses from 218 patients were evaluated, but only 225 (93%) masses met the inclusion criteria and were analyzed. The age was 58 (23-92), and 61% were women. LPAMs were incidentally discovered in 155 (71.1%) cases, 32 (14.7%) cases were diagnosed due to hormonal overproduction, and 17 (7.8%) due to pain/mass effect. Forty-six (21.1%) patients were on surveillance for a history of extra adrenal malignancy. Masses were unilateral in 89.9% (left side, 57.1%), with size 21 (10-38) mm, with a pre-contrast density of 24 (11-136) HU. Absolute washout was reported in 107 LPAMs and was &amp;gt;60% in 73 (68.2%) cases. The follow-up time was 44.4 (0.9-241) months. Hormonal overproduction developed during the follow-up in 23 (10.5%) cases as follows: cortisol in 15 (6.9%), aldosterone in 4 (1.8%), and sex hormones in 3 (1.4%) cases. LPAM growth rate was 0.03 (-2.18-11.59) cm/year. Seventy-one masses (31.5%) underwent diagnostic procedures (surgery/biopsy) with adrenocortical adenoma (n=37; 52.1%) and adrenocortical carcinoma (ACC) (n=25; 35.2%) being the two most common diagnoses. The tumor growth rate of pathologically confirmed adenomas was 0.03 (-0.30-10.50) cm/year, and of ACC was 1.31 (0.03-11.59) cm/year. A total of 154 (68.4%) LPAMs remained under surveillance at the end of the study, with a follow-up time of 51.8 (6-241) months and a tumor growth rate of 0.02 (-2.18-1.36) cm/year. Forty-five (20.6%) LPAMs decreased by 2 mm (1-13) during the study period. Cases that proved to be ACC had the most significant tumor growth rate over the study (p&amp;lt;0.001). The median time between the initial discovery of LPAM and the surgical resection of ACC cases was 34 (6-128) months. Conclusion: Our study showed that LPAMs carry significant malignant potential, and close long-term follow-up is warranted when surgical resection is not pursued. Prospective studies are critically needed to validate our findings and to establish high-risk molecular, imaging, and biochemical features associated with malignancy. Presentation: 6/2/2024

Exploring the protective effect of silver Croton tiglium nano-extract against azoxymethane induced toxicity in female reproductive organs in rats

Reproductive toxicity from food and environmental contaminants has greatly affected human life. Plants are a fundamental source of bioactive components for relieving the harmful effects of pollutants. Hydrazine metabolites pose health threats when they enter the food chain. Croton tiglium (C. tiglium) exhibits anti-inflammatory and anti-tumor properties. Silver nanoparticles enhance the chemical stability of C. tiglium. Reproductive toxicity of Azoxymethane (AOM) and anticancer effects of silver C. tiglium were evaluated. Thirty-six adult female rats were divided into six groups (n = 6) and treated with AOM with or without silver C. tiglium nano-extract as pre- and post-treatment. Sexual hormones and proteins were assessed under silver C. tiglium nano-extract and AOM. Histopathologically, AOM caused metaplastic myometrial endometriotic cysts and endometrial metaplasia. Silver C. tiglium in pre- and post-treated rats mitigated the carcinogenic effects of AOM. Immunohistochemically, AOM carcinogenicity was evident through moderate detection of the CK-7 tumor marker in the ovaries and uterus of the AOM-, simultaneous-, and post-treated groups. C. tiglium ameliorated this, with CK-7 slightly expressed in the pre-treated group. Furthermore, C. tiglium alleviated the negative impact on FSH, LH, and 17-β estradiol hormones. In conclusion, Silver C. tiglium nano-extract successfully prevented tumors in the ovaries and uterus of AOM-treated rats.

8053 A Ligand-Based Differentiation Protocol for Human Induced Pluripotent Stem Cells Recapitulates Granulosa Cell Development and Induces Steroidogenic Pathway Genes

Abstract Disclosure: H. Kubo: None. M.M. Laronda: None. Sex determination is a developmental process that defines the gonad as a testis or ovary, and influences sex hormone production. While key signaling events are well conserved across mammals, there can be differences between species. Therefore, there is a need to develop a human model to fully understand this critical process in humans. We have developed a ligand-based differentiation protocol for human induced pluripotent stem cells (hiPSCs) to generate granulosa-like cells (GLCs). Additionally, hiPSC-derived GLCs could become the foundation for a cell-based hormone replacement therapy that recapitulates cyclicity, physiologic levels of hormones, and production of peptide hormones that are not included in currently available hormone replacement therapies. We aim to gain further understanding of the key factors and culture conditions necessary for functional GLCs that produce ovarian hormones, which includes maintained expression of FOXL2. We used our monolayer differentiation protocol that includes WNT-agonist CHIR99021 treatment for 2 days, followed by a combination treatment of BMP4, FST, and DKK1-inhibitor Gallocyanine for 3 days. We have tested our protocol on three different hiPSC lines: IISH2i-BM9s, STiPS-A3, and STiPS-A6. Expression of pluripotency marker POU5F1 is reduced during differentiation, while expression of the intermediate mesoderm markers PAX2, LHX1, and WT1 and bipotential gonad marker GATA4 peak at day 2. Peak expression of the bipotential gonad marker NR5A1 occurred at day 2 in the STiPS-A6 cells, but at day 5 in IISH2i-BM9 and STiPS-A3 cells. Interestingly, FOXL2 expression peaks at day 2 in all three lines and drops by day 5. In the IISH2i-BM9s, FOXL2 protein peaks at day 2 by Jess Western while there is the highest percentage of FOXL2-positive cells at day 5 by immunofluorescence. In murine granulosa cells, FOXL2 maintenance depends on NR5A2. NR5A2 expression drops in the GLCs, which suggests that NR5A2 loss may be preventing FOXL2 maintenance. Additionally, as FOXL2 is required for expression of aromatase and HSD17B1, we are using this model to interrogate NR5A2 upstream of FOXL2 and control hormone production. CYP19A1 and HSD17B1 along with AMH are induced during this differentiation protocol, suggesting these GLCs can be steroidogenic and produce peptide hormones. Additionally, scRNA-seq analysis of the GLCs is underway to identify types of granulosa cells produced by this protocol. Future directions include optimizing GLC culture conditions to generate hormones and to test if NR5A2 inhibitors alter FOXL2 expression. Put together, the data suggests that cells differentiated with our protocol show promise as a human model of ovarian development and a foundation for a personalized cell-based hormone replacement therapy. This work is supported by the NIH/NICHD R01HD104683 (MML), HuBMAP U01HD110336 (MML), and Gesualdo Family Research Scholar (MML). Presentation: 6/2/2024

9224 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p&amp;lt;0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p&amp;lt;0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

5116 Postmenopausal Hyperandrogenism due to Rare Ovarian Tumor

Abstract Disclosure: M. Salim: None. S. Dasaraju: None. Y. Lee: None. S. Afzal: None. B.K. Erickson: None. M.A. Khalifa: None. L.A. Burmeister: None. Background: Hyperandrogenism in postmenopausal women may arise from either ovarian or adrenal source and can pose challenging diagnostic dilemma. Clinical Case: A 66-year-old multigravida, post-menopausal woman presented with a 3-month history of worsening alopecia. Her past medical history included diabetes mellitus type 2 and breast cancer. Menarche was at age 12. There was no history of infertility. Menopause was in her 40’s. She had been shaving her upper lip and chin hair every 3 days for the past 10 years. Scalp hair loss had accelerated in the last 3 months, with loss of the bangs. Physical exam was significant for body mass index 34, deep voice, and clitoromegaly. Laboratory tests showed testosterone 160 ng/dL, (8-60 ng/dL), free testosterone 3.37 ng/dL (0.06-0.38 ng/dL), androstenedione 2.196 ng/mL (0.13-0.82 ng/mL), sex hormone binding globulin (SHBG) 31 nmol/L (30-135 nmol/L), dehydroepiandrosterone-sulfate (DHEAS) 86 ug/dL (13-130 ug/dL), 17-hydroxy progesterone 96 ng/dL (&amp;lt;51 ng/dL), inhibin A 1.1 pg/mL (&amp;lt;6.9 pg/mL), inhibin B &amp;lt;10 pg/mL (&amp;lt;16 pg/mL), adrenocorticotropic hormone 38 pg/mL (&amp;lt;47 pg/mL), and cortisol 12.2 ug/dL (4-22 ug/dL). Response to 1 mg overnight dexamethasone suppression test demonstrated persistently elevated testosterone (160 ng/dL), and incomplete suppression of androstenedione (0.827 ng/mL) and cortisol (2.4 ug/dL). Computerized tomography (CT) scan showed a left adrenal nodule (12 mm, 5 Hounsfield units, stable compared to imaging 2 years prior) and unremarkable appearance of the ovaries. Pelvic ultrasound did not show ovarian tumor on the right and left ovary was not seen. Adrenal and ovarian vein sampling suggested the ovaries as the source of the testosterone. Given the ovarian vein sampling results, a multidisciplinary discussion between endocrinology and gynecologic oncology concluded that bilateral salpingo-oophorectomy (BSO) was the next best step for diagnosis and management. Laparoscopic BSO was performed. Intraoperatively, the ovaries appeared grossly normal with the exception of dilated ovarian veins. Histopathology showed bilateral Leydig cell tumors (left: 1.5 cm; right: 2.0 cm) and a 0.7 cm left ovarian Brenner tumor. At 1-year postoperative follow-up, alopecia had resolved. Laboratory evaluation showed normalization of the testosterone (23 ng/dL), free testosterone (0.47 ng/dL). Androstenedione (1.023 ng/mL) was lower than before surgery but higher than reference range. Conclusion: The presented rare case of postmenopausal virilization is even more unique due to the synchronous presence of 2 rare ovarian tumors, both capable of causing hyperandrogenism, including bilateral ovarian Leydig cell tumor, Brenner tumor and adrenal incidentaloma. Despite normal appearing ovaries on imaging studies, BSO was ultimately necessary for diagnosis and management. Presentation: 6/3/2024

7838 Improvement of Cognition and Memory Scores in Transgender Individuals Within One Year of Initiating Gender-Affirming Hormone Therapy

Abstract Disclosure: C.M. Godar: None. S.C. De La Torre: None. O. Bonsu: None. M.K. Shakir: None. T.D. Hoang: None. Introduction: The use of gender-affirming hormone therapy (GAHT) in transgender individuals is known to provide many beneficial health effects to reduce gender dysphoria, reduce depressive symptoms, and increase overall quality of life. Cognitive function and memory ability are known to be influenced by sex hormone levels in studies of hormone replacement therapy in post-menopausal women, but studies of GAHT’s effects on cognition and memory in transgender patients have been scarcely reported. We discuss a study of cognitive testing in transgender individuals before and after 12 months of gender-affirming feminizing or masculinizing hormone therapy using a validated cognitive assessment tool. Methods: A prospective study of 32 transgender patients aged 18-45 years was approved by IRB at an academic medical center. The Wechsler Memory Scale 4th edition (WMS®-IV, Pearson) was administered to 19 transgender females and 13 transgender males prior to initiation of GAHT and again after one year of GAHT use. Mean scores were analyzed and reported for five categories of cognitive and memory function: auditory memory (AMI), visual memory (VMI), visual working memory (VWMI), immediate memory (IMI), and delayed memory (DMI). Mean scores for baseline and 12-month data were analyzed for total population and male and female subgroups. Results: Baseline mean WMS-IV values for the total study population were: AMI 105 points, VMI 78 points, VWMI 107 points, IMI 88 points, DMI 91 points. Mean values after 12 months of GAHT were: AMI 120 points, VMI 81 points, VWMI 110 points, IMI 99 points, DMI 102 points. Mean percent change from baseline to 12 months was as follows: AMI 13.4%, VMI 8.9%, VWMI 2.6%, IMI 12.8%, DMI 13%. Similar patterns were noted for both gender subgroups. Discussion: It is well-known that transgender individuals are subject to higher rates of depression, anxiety, and suicidality compared to the general population. Decreased cognitive function and memory are known effects of untreated depression. Our study demonstrated that treatment of gender dysphoria with GAHT provided a tangible cognitive and memory benefit. The long-term impact of GAHT on cognition and memory is not known and deserves additional study. Limitations of this study included the absence of a cis-gender control group and inability to stratify data based on age, which may provide additional significance. Presentation: 6/2/2024

6983 Pembrolizimab Induced Hypophysitis: Uncommon Side Effect Leading To Late Diagnosis

Abstract Disclosure: T. Chaudhary: None. O. Syed: None. A. Shridar: None. R. Kaur: None. O. Chaudhary: None. M.S. Zubair: None. Background: Pembrolizumab, an immune checkpoint inhibitor, has shown efficacy inducing remission in various malignancies. Associated immune-related adverse effects (irAEs) have been recorded but cases of concomitant hypophysitis and thyroiditis are rare. Clinical case: The patient is a 41-year-old male with a past medical history significant for metastatic melanoma of the left calf, status post sentinel lymph node biopsy and left inguinal lymph node dissection, treated with pembrolizumab for one year. He initially presented with a severe headache that was preceded by two months of fatigue and impaired concentration. CT and MRI head were both unremarkable while lab work was significant for cortisol 0.2 ug/dL and adrenocorticotropic hormone (ACTH) 1.1 pmol/L. A full hormone panel was ordered which showed normal insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Free testosterone was at the lower end of normal. Prolactin was elevated at 27.3 ng/mL. The thyroid function tests showed primary hypothyroidism with elevated thyroid stimulating hormone (TSH) at 109 uIU/mL, low T4 at 1.5 ug/dL, and low free T4 at 0.4 ng/dL. There were no signs or symptoms of posterior pituitary dysfunction. The patient was diagnosed with hypophysitis and started on hydrocortisone 20 mg once daily along with levothyroxine 175 mcg once daily. DEXA scan showed normal bone mineral density. Subsequently, the patient presented to our care and reported symptom improvement after taking the prescribed medication however he continued to develop fatigue by the end of the day. Therefore, hydrocortisone prescription was switched to 15 mg in the morning and 10 mg at noon. A repeat thyroid function panel, sex hormone binding globulin, and LH were ordered, to be followed up at the patient's next visit. The patient was also advised to wear a medical alert bracelet at all times moving forward. Conclusion: Due to non-specific symptoms at onset, hypophysitis can be undiagnosed or misdiagnosed therefore it is important to have a high clinical suspicion with patients on PD-1 inhibitors presenting with such symptoms. It is also imperative to order a full set of hormones as this patient had concomitant primary hypothyroidism. Presentation: 6/1/2024

6961 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p&amp;lt;0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p&amp;lt;0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

9284 Leveraging Inter-Individual Transcriptional Correlation Structure To Infer Discrete Signaling Mechanisms Across Metabolic Tissues

Abstract Disclosure: M. Zhou: None. I. Tamburini: None. C. Van: None. J. Molendijk: None. L.M. Velez: None. C. Nguyen: None. R. Yeo: None. C. Filho: None. A.L. Hevener: None. J. Justice: None. L.M. Sparks: None. E.E. Kershaw: None. D. Nicholas: None. M. Seldin: None. Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned those parallel strategies could be leveraged to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of genetic gene variation between individuals. Thus, genetics comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling by adopting a gene-centric approach. Here, we surveyed gene-gene genetic correlation structure for ∼6.1x10^12 gene pairs across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. where the variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments that recapitulate experimental observations. Further, similar analyses were applied to explore both local within-tissue signaling mechanisms (liver PCSK9) as well as genes encoding enzymes producing metabolites (adipose PNPLA2), where genetic inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference in tissue-specific variation in relationships with metabolic traits. Finally, we utilized this resource to suggest new functions for metabolic coordination between organs. For example, we prioritized key proteins for putative signaling between skeletal muscle and hippocampus, and further suggest colon as a central coordinator for systemic circadian clocks. We refer to this resource as Genetically-Derived Correlations Across Tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables the querying of any gene in any tissue to find genetic coregulation correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs. Presentation: 6/1/2024