Davidge‐Pitts, Caroline

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

OBJECTIVE In this study, the authors aimed to establish a supervised machine learning (ML) model based on multiple tree-based algorithms to predict long-term biochemical outcomes and intervention-free survival (IFS) after endonasal transsphenoidal surgery (ETS) in patients with Cushing’s disease (CD). METHODS The medical records of patients who underwent ETS for CD between 2013 and 2023 were reviewed. Data were collected on the patient’s baseline characteristics, intervention details, histopathology, surgical outcomes, and postoperative endocrine functions. The study’s primary outcome was IFS, and the therapeutic outcomes were labeled as "under control" or "treatment failure," depending on whether additional therapeutic interventions after primary ETS were required. The decision tree and random forest classifiers were trained and tested to predict long-term IFS based on unseen data, using an 80/20 cohort split. RESULTS Data from 150 patients, with a median follow-up period of 56 months, were extracted. In the cohort, 42 (28%) patients required additional intervention for persistent or recurrent CD. Consequently, the IFS rates following ETS alone were 83% at 3 years and 78% at 5 years. Multivariable Cox proportional hazards analysis demonstrated that a smaller tumor diameter that could be detected by MRI (hazard ratio 0.95, 95% CI 0.90–0.99; p = 0.047) was significantly associated with greater IFS. However, the lack of tumor detection on MRI was a poor predictor. The ML-based model using a decision tree model displayed 91% accuracy (95% CI 0.70–0.94, sensitivity 87.0%, specificity 89.0%) in predicting IFS in the unseen test dataset. Random forest analysis revealed that tumor size (mean minimal depth 1.67), Knosp grade (1.75), patient age (1.80), and BMI (1.99) were the four most significant predictors of long-term IFS. CONCLUSIONS The ML algorithm could predict long-term postoperative endocrinological remission in CD with high accuracy, indicating that prognosis may vary not only with previously reported factors such as tumor size, Knosp grade, gross-total resection, and patient age but also with BMI. The decision tree flowchart could potentially stratify patients with CD before ETS, allowing for the selection of personalized treatment options and thereby assisting in determining treatment plans for these patients. This ML model may lead to a deeper understanding of the complex mechanisms of CD by uncovering patterns embedded within the data.

AbstractBackgroundTransgender and gender‐diverse (TGD) patients experience challenges and disparities when seeking health care across a multitude of settings. Studies have demonstrated that TGD individuals experience bias when interacting with health care providers, including pharmacists in the community and hospital settings. Without proper training, pharmacists are less likely to be prepared to provide equitable and optimal patient care to TGD patients. This quality improvement initiative aimed to identify gaps in pharmacist knowledge and comfort with regard to TGD health care.MethodsA 29‐item reflective questionnaire was designed to collect information on pharmacist training and experiences in caring for TGD patients. The survey was distributed via email to all 490 pharmacists within a single health system and responses were collected from October 23, 2023 to November 3, 2023.ResultsA total of 116 pharmacists completed the survey, for a response rate of 24%. Although 77% of respondents reported caring for a TGD patient, only 21% reported receiving any formal education or training on TGD health care. While 83% of respondents agreed that formal education on TGD health care is important, and 90% indicated that education on gender‐affirming therapy is important, a majority of pharmacists disagreed that they were comfortable with making recommendations and providing counseling on gender‐affirming therapy. A majority of pharmacists were interested in formal education and engaging in departmental initiatives to improve TGD care.ConclusionsThere was a gap in confidence and education in caring for TGD patients among pharmacists practicing in a single academic institution. Pharmacists reported that more education is warranted to bridge current gaps in pharmacist comfort and TGD health care.

Abstract Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim–Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely positioned to achieve early diagnosis by recognizing the varied nonendocrine features of these disorders. This article provides an overview of the endocrine manifestations of histiocytic disorders and presents a simplified algorithm to guide the diagnostic workup in cases presenting with “idiopathic” AVP-D or APD. Such cases should be evaluated for histiocytic neoplasms with additional imaging studies and biopsies of suspected disease sites. If no disease site beyond the pituitary is identified, the risks and benefits of a pituitary stalk lesion biopsy must be carefully considered. While treatments of histiocytic neoplasms are highly efficacious, endocrinopathies are considered permanent and require long-term hormone replacement. It remains unclear whether early diagnosis and novel targeted therapies can reverse these endocrine disorders. Therefore, the role of the endocrinologist role is critical in the diagnosis and management of these rare diseases.

Background: Erdheim-Chester disease (ECD) manifests as multi-organ infiltration of clonal histiocytes with mutations primarily in the mitogen-activated protein kinase (MAPK) pathway. The revised classification of histiocytosis (2016) categorizes ECD with typical bilateral, symmetric osteosclerosis of the lower extremity long bones as classical (C) and as non-classical (NC) if otherwise. The clinical and biological significance of this classification is unclear. This study compared the clinical and genotypic findings of the 2 subtypes within a large cohort of ECD patients. Methods: We included patients seen at our institution since 1990 meeting the following criteria: A) had an ECD diagnosis based on the revised criteria by Haroche J, et al. (Blood 2020;135:1311-1318); B) completed whole-body imaging studies including long bones of the legs. Classification as C-ECD required symmetric osteosclerosis of the distal femur and/or proximal tibia/fibula. Results: A total of 145 patients were enrolled, comprising a male-to-female ratio of 2:1 (66.2% male). C-ECD was diagnosed in 77.2% of cases, and NC-ECD in 22.8%. The median age at diagnosis was similar with 58.5 years (range, 18-82) in C-ECD and 55 years (range, 20-81) in NC-ECD, (p=0.65). The most frequently affected systems included skeletal (81.4%), renal (60.0%), vascular (45.5%), cardiac (40.0%), central nervous (38.6%), sinus (37.2%), pulmonary (36.6%), and adrenal (32.4%). The numbers of organs involved were significantly higher in C-ECD compared to NC-ECD (median 5 vs 3, p<0.01). Higher rates of skeletal (100% vs. 18.2%, p<0.01), adrenal gland (37.5% vs. 15.2%, p=0.02), and sinus (44.6% vs. 12.1%, p<0.01) involvement were observed in C-ECD. Arginine vasopressin deficiency (AVP-D) was exclusively observed in C-ECD (20.7% vs. 0%, p<0.01). NC-ECD had a higher rate of cardiac involvement (69.7% vs. 31.3%, p<0.01). No significant differences were found in other systems. The overall median time between onset of the first symptoms/signs to diagnosis was 15 months with no significant difference between C-ECD and NC-ECD (17.5 vs. 12 months, p=0.18). The median time to diagnosis of ECD in patients with AVP-D was 38.5 months, compared to 12 months without AVP-D (p=0.09). Genetic testing was conducted in 86.2% of patients and B-Raf proto-oncogene (BRAF) alterations were identified in 59.2% of the tested cases. BRAFV600E was more prevalent in C-ECD (61.3% vs. 21.9%, p<0.01), whereas non-V600 mutations were more commonly found in NC-ECD (12.5% vs. 1.1%, p<0.01). There was no significant difference in the frequency of BRAF fusions. NC-ECD patients exhibited a higher rate of MAP2K1 mutations (25.0% vs. 5.4%, p<0.01). Other frequently mutated genes included KRAS (4.0%), NRAS (2.4%), and CSF1R (2.4%), although no significant difference was observed in their frequency between C-ECD and NC-ECD. Testicular involvement appeared to be more common in patients with MAP2K1 mutations (23.1% vs. 8%, p=0.08). Two patients with pathogenic CSF1R mutations both had central nervous system (CNS) involvement. Among C-ECD patients, BRAFV600E conferred a higher rate of CNS involvement (50.9% vs. 25%, p=0.01). No significant difference was observed in NC-ECD patients (71.4% vs 36%, p=0.09). Among NC-ECD cases, MAP2K1 mutations conferred a reduced risk of cardiac involvement (37.5% vs. 79.2%, p=0.03) and no such difference was observed in patients with C-ECD (40% vs 34.1%, p=0.79). The median numbers of organs involved in patients with BRAF, MAP2K1, and KRAS/NRAS mutations were 5, 3, and 3, respectively, with no significant difference. Conclusions: C-ECD affects more organs and more frequently involves bones, adrenal glands, and sinuses. AVP-D was exclusively observed in C-ECD. Conversely, NC-ECD showed a higher prevalence of cardiac involvement. BRAFV600E was more commonly identified in C-ECD, whereas non-V600 mutations and MAP2K1 mutations were more prevalent in NC-ECD. Among C-ECD patients, BRAFV600E was correlated with a greater likelihood of CNS involvement. Conversely, NC-ECD patients with MAP2K1 mutations had a reduced risk of cardiac involvement. This study highlights the distinct clinical and molecular features of C-ECD and NC-ECD, underscoring the importance of subclassifying ECD into classical and non-classical forms. Further studies are needed to explore differences in the clinical outcomes between the 2 forms.

Abstract Aims Gender-affirming hormone therapy (GAHT) is used by some transgender individuals (TG), who comprise 1.4% of US population. However, the effects of GAHT on electrocardiogram (ECG) remain unknown. The objective is to assess the effects of GAHT on ECG changes in TG. Methods and results Twelve-lead ECGs of TG on GAHT at the Mayo Clinic were inspected using a validated artificial intelligence (AI) algorithm. The algorithm assigns a patient’s ECG male pattern probability on a scale of 0 (female) to 1 (male). In the primary analysis, done separately for transgender women (TGW) and transgender men (TGM), 12-lead ECGs were used to estimate the male pattern probability before and after GAHT. In a subanalysis, only patients with both pre- and post-GAHT EGCs were included. Further, the autopopulated PR, QRS, and QTc intervals were compared before and after GAHT. Among TGW (n = 86), the probability (mean ± SD) of an ECG male pattern was 0.84 ± 0.25 in the pre-GAHT group, and it was lowered to 0.59 ± 0.36 in the post-GAHT group (n = 173, P < 7.8 × 10−10). Conversely, among TGM, male pattern probability was 0.16 ± 0.28 (n = 47) in the pre-GAHT group, and it was higher at 0.41 ± 0.38 in the post-GAHT group (n = 53, P < 2.4×10−4). The trend persisted in the subanalysis. Furthermore, both the PR (P = 5.68 × 10−4) and QTc intervals (P = 6.65×10−6) prolonged among TGW. Among TGM, the QTc interval shortened (P = 4.8 × 10−2). Conclusion Among TG, GAHT is associated with ECG changes trending towards gender congruence, as determined by the AI algorithm and ECG intervals. Prospective studies are warranted to understand GAHT effects on cardiac structure and function.