Chang, Alice Y.

Abstract STUDY QUESTION What is the fertility preservation (FP) utilization rate among transgender and gender diverse (TGD) patients at the Transgender and Intersex Specialty Care Clinic (TISCC) within the Mayo Clinic? SUMMARY ANSWER The rate of utilization of FP services by TGD patients at Mayo Clinic’s TISCC was determined to be 6.62%. WHAT IS KNOWN ALREADY TGD patients encounter several barriers when pursuing FP, which may contribute to a lower utilization rate of these services. These barriers include financial constraints and lack of insurance coverage, as well as societal and healthcare provider attitudes; TGD individuals face discrimination or lack of understanding, making it uncomfortable or difficult to discuss FP options. Additionally, there continues to be a lack of inclusive policies and support within healthcare systems that can further impede access to FP services for TGD individuals. STUDY DESIGN, SIZE, DURATION The study was executed in two phases. In the first phase, a retrospective cohort study was completed with TGD patients who provided electronic health record (EHR) research authorization from Mayo Clinic’s TISCC in Rochester, MN between 1 January 2015 and 30 July 2021. Search terms related to FP were used to determine the FP utilization rate among this patient population. In the second phase of the study, two sets of patients, (i) patients who were included in the cohort study in Phase 1, and (ii) members of JASMYN, a community organization specializing in care and wellness coordination for Lesbian, Gay, Bisexual, and Transgender (LGBT) teens and young adults in North Florida. Individuals were invited to participate in a qualitative interview exploring their cumulative healthcare experiences accessing gender-affirming care. Interviews were conducted from January 2023 to June 2023. Interviews examined participants’ perceptions of FP options, motivations for pursuing FP, and barriers to accessing both gender and fertility care. When applicable, participants also discussed their experiences pursuing FP and reflected on their satisfaction with their fertility and family planning decisions. PARTICIPANTS/MATERIALS, SETTING, METHODS In phase 1, a total of N = 1189 patients sought care from Mayo Clinic’s TISCC in Rochester, MN. Out of these patients, N = 589 patients provided research authorization and were included in the retrospective cohort study. The study team assessed whether FP terms were mentioned in each patient’s EHR, and whether patients scheduled and attended appointments with either the Department of Reproductive Endocrinology or the Department of Urology. FP search terms included sperm cryopreservation, sperm extraction, sperm aspiration, testicular tissue cryopreservation, oocyte cryopreservation, embryo cryopreservation, and ovarian tissue cryopreservation. In phase 2, N = 36 participants were interviewed, with N = 25 participants recruited from Mayo Clinic’s TISCC in Rochester, MN, and N = 11 participants recruited from JASMYN in Jacksonville, FL. Participants recruited from the Mayo Clinic participated in a video-call-based interview and those enrolled from JASMYN were interviewed in person. MAIN RESULTS AND THE ROLE OF CHANCE The study team observed a 6.62% utilization rate of FP services among N = 589 patients (median age: 28 years; age range: 8–78 years) included in the retrospective cohort study. N = 39 patients completed FP, with N = 14 receiving these services at other institutions before seeking care with the TISCC at Mayo Clinic. N = 25 patients pursued FP services within the Mayo Clinic. Patients with testes were more likely to complete FP via sperm cryopreservation when compared to the utilization of egg cryopreservation among patients with ovaries. Participants who completed an interview in Phase 2 (median age 27 years; age range: 22–80 years) reflected on their decision on whether to preserve their fertility and what factors influenced these decisions, and how their satisfaction with this decision has changed over their lifespan. The major themes reported here include the desire for biological children, planning gender care around fertility desires, conversations about FP options, physical and psychosocial barriers to pursuing FP, reflections on personal FP decisions, and reflections on having to make decisions about FP at a young age. LIMITATIONS, REASONS FOR CAUTION All participants who completed an interview have done so voluntarily; as such, there is a possibility of selection and recall bias. WIDER IMPLICATIONS OF THE FINDINGS Findings suggest that there is a need for more structured conversations around FP when TGD patients seek medical and surgical gender-affirming care. Accessibility, including financial barriers and limited insurance coverage, continues to limit the utilization of FP services among TGD patients. Increased affordability through insurance coverage may additionally improve FP utilization. STUDY FUNDING/COMPETING INTEREST(S) This project was funded by the Mayo Clinic Department of Obstetrics and Gynecology and the Mayo Clinic Center for Clinical and Translational Science (CCaTS), grant number UL1TR002377. This project was also supported by Clinical and Translational Science Award (CTSA) Grant Number TL1TR002380 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Felicity Enders reports grants from the National Institutes of Health and the Agency for Healthcare Research and Quality paid to her institution; speakers’ fees for lectures or presentations from Mount Sinai, University of Washington, University of Minnesota, University of Rochester, Cincinnati University, the National Institutes of Health, Duke University, Wake Forest University, the Patient Centered Outcomes Research Institute, Johns Hopkins University; travel support from the Association for Clinical and Translational Science and Cold Spring Harbor Laboratory; and an unpaid leadership role on the Board of Directors of the Association for Clinical and Translational Science. All other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Abstract Background Polycystic ovary syndrome (PCOS) affects 10% to 13% of individuals assigned female at birth (AFAB), although a greater prevalence is reported in transgender/gender diverse individuals (TGD) (23.8-38.8%). Testosterone therapy (TT) in TGD individuals is linked to worsening cardiovascular risk factors (CVRFs). Whether TT induces more adverse cardiometabolic changes in TGD with PCOS than TGD without PCOS remains uncertain. Objective To compare the effects of TT on CVRF in TGD with and without PCOS. Methods We retrospectively reviewed 373 records to identify 62 TGD with PCOS (withestablished guideline criteria) and 132 age-matched TGD without PCOS. Data included longitudinal anthropometric measurements, hormone and metabolic parameters, and CVRF before and after TT. Group comparison of PCOS vs without PCOS before and after TT was conducted via independent t-tests, Mann–Whitney-U, and Chi-square. Results At baseline, TGD with PCOS had significantly greater body mass index (BMI), obesity prevalence, and, after controlling for BMI, baseline metformin use. There were no significant differences between TGD with and without PCOS when comparing intra-participant changes after TT. Controlling for BMI, TGD with PCOS on TT exhibited significantly greater hyperlipidemia prevalence, alanine transaminase (ALT) levels, and bioavailable testosterone concentrations than TGD without PCOS on TT. Conclusion Greater baseline cardiometabolic risk was largely BMI-related in TGD with PCOS compared to TGD without PCOS. Only hyperlipidemia and elevated ALT were more prevalent during TT after adjusting for BMI. These findings support cardiometabolic monitoring during TT in all TGD individuals without significant increased risk with PCOS history.

Abstract Disclosure: S. Thota-Kammili: None. J.A. McNeil: None. S.J. Peres: None. M.A. Edgar: None. J.P. Reynolds: None. J. Eleazer: None. A.Y. Chang: None. Introduction: 45,X/46,X,psrY mosaicism has been reported in the context of prenatal diagnosis with few reports on the developmental phenotype through adulthood. The 45,X/46,XY karyotype is well-studied and linked to ambiguous genitalia, dysgenetic gonads, and increased gonadal tumor risk. Less is known about 45,X/46,X,psrY mosaicism, characterized by partial Y chromosome retention. Phenotypic variability with a broad spectrum of phenotypes including Turner syndrome features, delayed puberty, hypogonadism and infertility depends on the extent and functionality of preserved Y chromosome material. We present a case of 45,X/46,X,idic(Y)(q11.21) mosaicism in an individual assigned male at birth, with a nonbinary intersex gender identity who received gender affirming feminizing hormone therapy (GAHT) before orchiectomy. Clinical Case: This is a case of a 36 y.o. patient who was found to have 45,X/46,X +mar chromosomal abnormality prenatally and initially diagnosed with Turner’s syndrome. At birth, patient had male genitalia, descended testes, and only slight hypospadias. Subsequent Y-DNA studies determined the unknown marker to be the sex determining region of the Y chromosome. Early evaluations showed appropriate responses to LHRH and ACTH, and developmental milestones were met without major health or behavioral concerns aside from a delay in puberty. The patient experienced early gender incongruence and faced questioning for gender expression. Delayed puberty led to testosterone therapy, worsening distress. Parents did not share the medical history with the patient until adulthood, when they notified them about the potential for infertility. During infertility evaluation, semen analysis revealed azoospermia. Testosterone therapy was re-attempted for hypogonadism but resulted in increased distress and patient began GAHT. Patient sought a second opinion on previous diagnosis of differences of sexual development (DSD). Chromosomal analysis revealed the 45,X/46,X,idic(Y)(q11.21) mosaicism, with duplication of Yp and deletion of the Yq. Pt was referred to urology for bilateral orchiectomy to reduce gonadal tumor risk and gender dysphoria. Pathology revealed atrophic seminiferous tubules with complete absence of spermatogenesis which were populated by Sertoli cells only and surrounded by thickened basal lamina. Leydig cells were markedly depleted. These changes are seen in transgender patients treated with estrogen prior to orchiectomy. Conclusion: Our case expands the phenotypic characterization of 45,X/46,X,idic(Y)(q11.21) mosaicism by detailing clinical features and previously unreported testicular pathology. This patient had minimal developmental concerns, and testicular pathology reflected changes associated with GAHT, highlighting the variability in phenotypic expression of 45,X/45,X,psrY mosaicism. Presentation: Sunday, July 13, 2025

Abstract Disclosure: A.M. Gonzalez Gil: None. E.F. Elli: None. R.J. Singh: None. S. Peres: None. A.Y. Chang: None. Background: Treatment of hypercortisolism in primary bilateral macronodular adrenal hyperplasia (PBMAH) with mild autonomous cortisol secretion (MACS) can be challenging. Medical treatment is useful for therapeutic purposes and as a bridge for adrenalectomy. We present the case of a patient who benefited from mifepristone but developed hyperestrogenism. Clinical Case: A 64-year-old man with prediabetes, hypertension, and cardiovascular disease had incidentally discovered bilateral nodular adrenal enlargement on CT scan following coronary artery bypass surgery. A few months later, he reported increasing fatigue, brain fog, weight gain, and worsening blood pressure. Physical exam showed no features of hypercortisolism. Work-up revealed baseline AM cortisol 17.3 mcg/dL [reference range (RR) 4.8-20], ACTH 10 pg/mL (RR 7.2-63) and DHEA-S 55 mcg/dL (RR 12-227); two abnormal AM cortisols after 1 mg overnight dexamethasone (5.4 and 6.9 mcg/dL; cut-off <1.8), and a normal 24-hour urine free cortisol (23 mcg/24h, RR 3.5-45). 24-hour urine metanephrines and aldosterone/renin ratio were normal. A 2-hour 75 g oral glucose tolerance test was diagnostic for type 2 diabetes mellitus (2-hour glucose 214 mg/dL). Baseline total testosterone (TT) was 366 ng/dL (RR 264-916) with normal follicle stimulating hormone (FSH) and luteinizing hormone (LH)concentrations. After a diagnosis of MACS, adrenal vein sampling showed bilateral excess cortisol secretion (lateralization ratio 1.09). Medical management versus right adrenalectomy based on nodule burden were offered, and he started mifepristone. With initial symptom improvement, his dose was increased from 300 mg to 300 mg alternating with 600 mg daily. When he developed increased blood pressure and hypokalemia, eplerenone was added. After 6 months of mifepristone and 5 months eplerenone 50 mg daily, he developed tender gynecomastia with elevated estradiol (106 pg/mL, RR ≤39), low TT (112 ng/dL) and undetectable FSH and LH. As expected with mifepristone, 17-hydroxyprogesterone was high (933 ng/dL, RR 51-190), but androstenedione and DHEA-S were normal. Reduction in mifepristone and eplerenone decreased estradiol levels (56 pg/mL) but gonadotrophins remained undetectable and TT decreased to 72 ng/dL. Despite discontinuation of eplerenone for 1 month, estradiol again increased (91 pg/mL), TT remained low (77 ng/dL), and mastalgia persisted. A decision to stop mifepristone and proceed with right adrenalectomy was made. Conclusion: This is a previously unreported incident of symptomatic estradiol-induced secondary hypogonadism on mifepristone therapy. Hyperestrogenism with gynecomastia and secondary hypogonadism with mifepristone suggests that some individuals may convert cortisol precursors to estradiol. Presentation: Saturday, July 12, 2025

Abstract Background Medical chaperones are authorized individuals present during physical examinations involving the genitals, breasts/chest, or anal areas. The use of medical chaperones may provide an opportunity to improve transgender and gender diverse (TGD) patients’ experiences with sensitive examinations. Aim To examine TGD adult patients’ preferences and comfort for having a medical chaperone and whether TGD-specific characteristics, social anxiety symptoms, and feelings of medical mistrust are associated with preference for having a medical chaperone present during a sensitive physical examination. Methods This study used a cross-sectional survey that randomly sampled adult patients from a gender clinic in the Midwest region of the U.S. A total of 420 surveys were mailed. Sixty-two surveys were returned undeliverable, 358 reached recipients; 151 were returned (42.1% response rate). The survey included items related to demographics, gender-related anatomical dysphoria, social anxiety symptoms, feelings of medical mistrust, and preference and comfort towards medical chaperones. Results Among 149 respondents, 74 (49.7%) reported comfort for the idea of having a medical chaperone present during a sensitive physical examination, 50 (33.6%) reported neutral comfort, and 25 (16.8%) reported discomfort. Among 147 respondents, 89 (60.5%) endorsed a preference for a female medical chaperone. We found no associations between gender-related anatomical dysphoria or social anxiety symptoms and comfort for having a medical chaperone, or the gender preference for a medical chaperone. Medical mistrust was associated with lower comfort with having a medical chaperone present during a sensitive physical examination. Clinical Implications Routinely offering medical chaperones, especially female chaperones, is like to be generally acceptable to most TGD patients. These findings may inform clinic policies on providing medical chaperones during sensitive examinations. Strengths and Limitations This study is the first to examine TGD preferences for medical chaperones. Findings are limited by a single site, homogeneous sample, cross-sectional design, and reliance on hypothetical rather than observed examinations. Conclusion TGD adults report comfort with the concept of having a medical chaperone during sensitive examinations and most would prefer the chaperone to be female. Preference for having a medical chaperone present during a sensitive physical exam is not likely influenced by gender dysphoria or social anxiety.

Abstract J.A. McNeil: None. J. Herndon: None. A.Y. Chang: None. C.J. Davidge-Pitts: None. O. Hamidi: None. Background: Testosterone therapy (TT) in individuals assigned female at birth (AFAB) is linked to an atherogenic lipid profile, including lower HDL cholesterol, elevated triglycerides, and LDL cholesterol. Polycystic ovary syndrome (PCOS), characterized by androgen excess, affects 16-20% of cisgender individuals AFAB. Recent data suggests a greater PCOS prevalence in transmasculine transgender/gender diverse (TGD) individuals at 23.8% to 38.8%. Whether TT in AFAB individuals with history of PCOS triggers more adverse metabolic changes than in TGD individuals without PCOS remains uncertain. While cohort studies haven't indicated increased cardiovascular (CV) risk with TT, it's unclear if specific subgroups, such as those with PCOS, develop more CV risk factors. Objective: To compare the effects of TT on CV risk factors in TGD individuals with a history of PCOS vs. TGD without PCOS. Methods: We retrospectively reviewed 454 records in a multispecialty TGD clinic to identify 62 with PCOS, and 132 controls without PCOS (1:2 case-control ratio) matched on age. Data included longitudinal vital signs, metabolic profiles, and details on psychiatric and medical conditions. PCOS diagnosis was validated using Rotterdam criteria. Exclusions comprised individuals under 14, those on puberty-suppressing gonadotropin-releasing hormone analogues, or already undergoing TT at the initial visit. Results: Among 454 subjects, 62 (13.7%) were diagnosed with PCOS. At baseline, PCOS was associated with significantly higher BMI (p < 0.01), SBP (p = 0.01), prevalence of obesity (p < 0.01), obstructive sleep apnea (OSA, p < 0.01), and type 2 diabetes mellitus (p = 0.01). History of PCOS was associated with greater metformin use (p < 0.001), CV disease history (p = 0.003), and transaminitis (p = 0.03). After weight adjustment, only baseline metformin use differed significantly between PCOS and controls. 140 (72.2%) received TT, 50 (80.6%) with PCOS and 90 (68.2%) controls. After weight adjustment, notable baseline changes in ALT (p = 0.006), HDL (p < 0.001), LDL (p < 0.001), hypertension, and hypertriglyceridemia prevalence (p=0.001) were observed in the full cohort on TT. Compared to controls, PCOS patients on TT exhibited higher hypercholesterolemia prevalence (p = 0.03) and elevated bioavailable testosterone (p = 0.04) after weight correction. Conclusions: TGD Individuals with PCOS had significantly worse CV risk profile compared to controls before starting TT attributed to greater weight. Significant changes in ALT, LDL, HDL, and prevalence of hypertriglyceridemia were seen across the entire TGD cohort treated with TT, but only hypercholesterolemia prevalence remained significantly higher in TGD PCOS cases on TT when corrected for weight. PCOS history was not associated with greater changes in CV risk factors in TGD individuals starting TT. Sunday, June 2, 2024

Abstract Disclosure: A.L. McKenna: None. Y. Huang: None. L. Yang: None. N. Loo: None. C. Ritchie: None. A. Metcalfe: None. R. Nakhleh: None. M. Krishna: None. S. Thota-Kammili: None. J. Eleazer: None. A.Y. Chang: None. Hepatocellular adenomas (HCA) are uncommon, benign epithelial tumors of the liver. Risk factors include exogenous estrogen or androgen use, and genetic and metabolic syndromes. Management of HCA is delineated by sex assigned at birth; Observation is recommended in an HCA less than 5 cm in an individual assigned female at birth, while resection of an HCA in an individual assigned male at birth is recommended no matter the size due to risk of malignant transformation. What is not known is whether risk is different for individuals with gender incongruence on gender affirming hormone therapy (GAHT). There is limited data on the risk of HCA in this population. One case report of a transgender man who continued GAHT after diagnosis of an HCA though no follow-up information was available. We present follow-up on a transgender man assigned female at birth with multiple hemorrhagic HCA that was re-initiated on GAHT after stabilization of adenomas off GAHT. Unlike prior cases, the molecular profile showed ß-catenin negative, estrogen and androgen receptors positive. This is the first case report to our knowledge reporting detailed follow-up after restarting masculinizing GAHT after diagnosis of HCA. A 24-year-old transgender man presented to the emergency department with right upper quadrant pain. Initial labs were notable for ALT of 239 units per liter (U/L) and AST 165 U/L. Magnetic resonance imaging (MRI) of the abdomen and liver elastogram revealed multiple bilobar hepatic masses, the largest measuring 9.9 cm concerning for hemorrhagic HCA which was subsequently confirmed on liver biopsy. Immunostains were positive for estrogen and androgen receptors. The patient had no history of alcohol or illicit drug use, tattoos, or family history of liver disease. The patient had been treated with 100 mg of intramuscular testosterone cypionate weekly for the past six years for gender incongruence locally. No testosterone concentrations were available from prior to or during acute presentation. Discontinuation of hormone therapy was recommended along with conservative management with frequent MRI. Over the next 19 months, monitoring revealed improvement/resolution of the auto infarcting adenomas with the last MRI noting two stable HCA measuring 2.1 cm and 0.8 cm without new or enlarging liver lesions. Due to gender dysphoria off GAHT, reinitiation of hormone therapy with low dose AndroGel 1.62% topically was prescribed at 18 months after presentation. The patient has been monitored with labs monthly and plans to obtain MRI abdomen every three months. To date, the patient has tolerated reinitiation of therapy. This case demonstrates that patients on masculinizing GAHT who develop HCA can be conservatively managed and monitored based on pathology and that testosterone does not necessarily explain sex differences in the presentation/malignant transformation of HCA cisgender men as opposed to cisgender women. Presentation: 6/3/2024

Abstract Disclosure: A.Y. Chang: None. D.Z. Erickson: None. W.F. Young: None. K. Grennan: None. J.C. Andrews: None. E. Kapoor: None. Background: While mild androgen excess is frequently encountered in endocrine practices, severe symptoms, rapid onset or markedly abnormal biochemical testing lead to further evaluation for rare ovarian androgen-producing tumors, ovarian hyperthecosis or androgen-secreting adrenal tumors. Combined ovarian and adrenal vein sampling (COAVS) might be necessary to identify the source of androgen hypersecretion and guide treatment. The utility of COAVS has been studied in limited case series, combining case reports and different centers. There is no consensus regarding the testosterone gradient that localizes the androgen source or the added value of COAVS when a pathologic source of androgen excess is suspected. The additional clinical benefit of adrenal vein sampling (AVS) when combined with ovarian vein sampling (OVS) has also not been examined. Objectives: We sought to determine: a) the optimal total testosterone (TT) gradient for identifying unilateral vs bilateral source of hyperandrogenism and b) the utility of AVS in addition to OVS. Methods: We performed a retrospective chart review of all adult women who had COAVS at Mayo Clinic, Rochester from 1996 to 2023. Pathologic sources of androgen excess were defined as ovarian hyperthecosis (OH) as well as ovarian and adrenal tumors. We calculated the ratio of dominant OV or AV divided by the nondominant OV or AV. Results: 22 COAVS procedures from 7 premenopausal and 15 postmenopausal women were included in the study: 12 (55%) women had adrenal abnormalities seen on computed cross sectional imaging and 5 (23%) had unilateral ovarian imaging abnormalities. Of the 22 participants in the case series, successful 4-vessel catheterization was completed in 20 (1 right ovarian vein could not be cannulated, and 1 had bilateral oophorectomy). Nine (41%) women had unilateral and 10 (45%) bilateral ovarian androgen hypersecretion. Eleven (50%) women had pathologic causes for elevated TT (5 ovarian tumors, 6 cases of OH), 5 lacked follow-up pathology and 5 had benign pathology. AVS did not diagnose an adrenal source of androgen hypersecretion. TT concentrations were significantly greater in patients with unilateral compared to those with bilateral ovarian androgen hypersecretion (median 262.5 ng/dL [245- 401.5 IQR] vs 104 ng/dL [82-190], P = 0.01). In addition, TT concentrations were higher in those women with a pathologic source of TT hypersecretion compared to those with benign ovaries (349 ng/dL [251-538] vs 115 ng/dL [93-195], P = 0.03). All cases of unilateral ovarian disease had a dominant OV gradient of TT ≥ 2.1 compared to the nondominant OV. Conclusion: In a series of successful COAVS in women with androgen hypersecretion, an ovarian side-to-side gradient of ≥ 2.1 diagnosed all sources of unilateral ovarian pathology. AVS did not diagnose any pathologic source of adrenal androgen excess in this patient cohort. Presentation: 6/3/2024

ABSTRACT The management of hepatic adenoma in transgender individuals undergoing gender-affirming hormone therapy remains unclear, especially whether treatment should be based on sex assigned at birth or therapy patient received. We presented a transgender man, female at birth, with hepatic adenomatosis with molecular profile differed from typical adenomas in cisgender males on testosterone. Discontinuing testosterone led to autoinfarction of the adenoma, allowing the avoidance of invasive treatments and resumption of gender-affirming hormone therapy. This case underscores the necessity for personalized care in the growing transgender population and challenges current consensus of treatment based on sex assigned at birth, emphasizing a tailored approach.

Insulin is a key regulator of amino acid metabolism. Many plasma amino acids, including lysine and its metabolite, α-aminoadipic acid (α-AA), a predictor for developing diabetes, are elevated in insulin resistance (IR). In 18 overweight women with IR and polycystic ovary syndrome compared with 12 lean control women, high physiological insulin during a euglycemic clamp failed to normalize many elevated amino acid metabolites, including branched-chain and aromatic amino acids, α-aminobutyric acid, and lysine, but normalized α-AA. To understand the underpinnings of differential responses of lysine and its metabolic product α-AA to high physiological insulin in IR compared with control participants, we developed a kinetic model using [α-15N1]-lysine and [13C1]-α-AA as tracers and measured the two tracers simultaneously in α-AA by innovative mass spectrometry. High insulin increased lysine conversion to α-AA in the IR and control groups but failed to normalize plasma lysine concentrations in IR due to a decrease in lysine metabolic clearance rate (MCR). In contrast, despite higher conversion rates of lysine to α-AA by high insulin, α-AA concentration decreased in IR because of the sustained greater MCR of α-AA. The abnormal amino acids and metabolites, even while on high physiological insulin, could potentially explain many functional derangements in IR. Article Highlights