Disclosure: N. Chamorro-Pareja: None. K.E. Corey: Intercept. M.S. Haines: BioAge. C.C. Dobbie: None. J. Lin: None. M.L. Chicote: None. J.S. Husseini: None. M.A. Bredella: None. L.E. Dichtel: Perspectum Diagnostics, Lumos Pharma, Recordati, Novo Nordisk, Third Rock Ventures, Marea Therapeutics, Merida Biosciences, Flare Therapeutics. Background: Daily, subcutaneous growth hormone (GH) administration has been demonstrated to reduce hepatic steatosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). Ibutamoren is an investigational oral, small molecule GH secretagogue. We hypothesized that GH augmentation via ibutamoren would reduce intrahepatic lipid content (IHL) and improve body composition in a pilot study of individuals with MASLD. Methods: Thirteen adults with BMI ≥25 kg/m2 and MASLD without diabetes were enrolled in an open-label pilot study of daily oral ibutamoren 25 mg for 6 months (NCT05364684). The primary endpoint was absolute change in percent IHL by proton magnetic resonance spectroscopy. Secondary endpoints included absolute change in ALT, HbA1c and body composition by dual-energy x-ray absorptiometry. Data are reported as mean ± SD. The open-label pilot cohort was compared to a historical, prospective, placebo group studied under a similar protocol (NCT02217345). Results: Seven subjects completed the 6-month ibutamoren study (IBU) and were compared to 10 historical placebo controls (PBO) with similar mean weight change (IBU 1.7±2.8% vs PBO 2.9±1.9%, p=0.3). Baseline mean age (46±12 y), BMI (33±4 kg/m2), sex distribution (35% female) and IHL (17.1±13.8%) did not differ between IBU and PBO. IGF-1 Z-score was significantly augmented in IBU vs PBO, as expected (delta IGF-1 Z-score 0.9±0.5 vs -0.3±0.6, p<0.001). Three IBU subjects dropped out for treatment-emergent adverse events (n=2 hyperglycemia, n=1 brain fog). In an intent-to-treat analysis, there was no difference in absolute change in IHL in IBU vs PBO (3.9±6.7% vs 6.7±6.1%, p=0.4). Changes in serum ALT (8±18 IU/L vs 4±7 IU/L, p=0.6), appendicular lean mass (0.7±0.9 kg vs 1.0±0.6 kg, p=0.6) and visceral adipose tissue (-1.8±11.9 cm2 vs 5.3±13.0 cm2, p=0.3) did not differ in IBU vs PBO, respectively. HbA1c increased modestly within in the non-diabetic range in IBU vs PBO (5.3±0.2% to 5.7±0.4% vs 5.4±0.2% to 5.4±0.2%, p=0.008 for delta). In an as-treated secondary analysis excluding one IBU subject with suspected non-adherence to ibutamoren administration (based on lack of change in IGF-1 Z-score at 6 months), there was a beneficial effect on IHL in IBU vs PBO (1.5±2.3% vs 6.6±6.1%, p=0.03). All other findings were similar to the intent-to-treat analysis. Conclusion: In this pilot study, we demonstrated a possible beneficial signal of ibutamoren on IHL in an as-treated secondary analysis but were unable to demonstrate this effect in our primary analysis or an effect on body composition in either analysis. Future larger studies could investigate oral ibutamoren co-administered with weight loss medications such as GLP-1 receptor agonists, a combination which may offset the negative glycemic effect of ibutamoren while harnessing the potential for GH augmentation to further reduce liver fat and preserve muscle mass. Presentation: Saturday, July 12, 2025

BACKGROUND:Physician parents experience challenges during their transition to parenthood and their return to work. We expanded a Parental Wellness Programme (PWP) to Department of Medicine faculty physicians and evaluated its impact on physician well-being. The programme supported new physician parents through peer mentorship and financial resources. METHODS:Through internal marketing, expectant and new parent faculty were encouraged to self-enrol and were supported until 12 months following the child's birth (up to an 18-month period). Participants enrolled between October 2021 and September 2022. The programme included a US$500 feeding/lactation reimbursement and pairing with a parental wellness advocate (PWA), a physician with parenting experience. Anonymised participant surveys were voluntary and conducted at programme entry, and at 6 months and 12 months following the child's birth to assess return-to-work experience, lactation, burnout and programme impact. A final feedback survey was sent after all participants completed the programme. RESULTS:The programme supported 67 participants (82% women). 53 participants responded to the baseline survey, of whom 85% were junior faculty/early career. At baseline, 85% of respondents planned to breastfeed; 88% at 12 months (n=25) reported breastfeeding. Participants indicated a desire for connection, support and resources at baseline; follow-up surveys confirmed that the programme provided these supports. By 12 months, 76% received individualised PWA support, 88% used the feeding/lactation reimbursement and 92% self-reported improved well-being on return to work. All respondents indicated they would recommend the programme to colleagues. Participant comments highlighted challenges with parental leave coverage, and time and space for lactation. CONCLUSIONS:We demonstrated the scalability of a novel PWP that successfully supported early career and junior faculty during a difficult transition period. Feedback indicated ongoing system-based challenges and a need for institutional culture change.

Background: Clinical guidelines emphasise identifying patients at risk of chronic liver disease progression. To avoid biopsy drawbacks, noninvasive imaging tests (NITs) have become part of standard-of-care. We assessed the real-world clinical profile, referral trends, and use of magnetic resonance imaging (MRI)-based tests, multiparametric MRI (mpMRI) and magnetic resonance elastography (MRE), as part of chronic liver disease management. Methods: Patients referred for abdominal imaging as part of standard-of-care were eligible for inclusion irrespective of liver aetiology or referral pathway. Liver fibrosis was assessed using MRE and disease severity using mpMRI (disease activity [iron-corrected T1, cT1], liver fat content [LFC] and iron). T-tests were used for group comparisons; Kaplan-Meier analyses for disease progression and area under the receiver operating characteristic (AUC) for diagnostic accuracy. Results: Over 18 months, 256 patients (53 years, 51% female, 48% with BMI > 30 kg/m(2)) were referred for liver imaging. The majority (66%) had steatotic liver disease (SLD). Of those with low MRE (73%) and low FIB-4 (42%), 36% had elevated cT1 (> 875 ms). Those with MRE > 5 kPa had cT1 > 875 ms. During follow-up, those with low MRE (< 3.14 kPa) but elevated cT1 (> 800 ms) had significant disease worsening (HR: 3.1, p = 0.0035) compared to all others. In the SLD group, cT1 (AUC: 0.71) outperformed LFC (AUC: 0.64) and MRE (AUC: 0.53) in predicting disease progression. Conclusion: Regardless of aetiology, patients with low fibrosis risk (MRE) but high disease activity (cT1) face a three-times higher risk of progression. Integrating both biomarkers into standard care, especially for SLD, can guide management adjustments.

Adult growth hormone deficiency (AGHD) is a rare disease with both physiological and psychological effects for untreated patients. AGHD symptoms can improve over time with GH treatment. Here we have analyzed the long-term effectiveness and safety of short-acting GH replacement therapy (GHRT) in treatment na & iuml;ve and nonna & iuml;ve patients with AGHD using real-world data from the NordiNet (R) International Outcome Study and American Norditropin (R) Studies: Web Enabled Research Program. Outcomes were compared between 3 age groups, comprised of patients aged 18 to 29 years, 30 to 39 years, and 40 to 59 years. The safety outcome was the incidence of nonserious and serious adverse reactions and serious adverse events by age group. Efficacy outcomes included mean GH exposure by age group alone, by sex and age group, or based on estrogen usage in female patients; IGF-I SD score (SDS) levels by sex and age group; mean glycated hemoglobin by sex and age group; and mean non-high-density lipoprotein cholesterol by sex and age group. The incidence rates of adverse events and reactions did not statistically differ between the 3 groups. Mean IGF-I SDS levels reached a normal range (-2 to 2) in >= 80% of patients from all groups in the effectiveness analysis set by year 2. Together with previous reports of older patients, these results support the real-world safety and efficacy of short-acting GHRT among all ages of patients with AGHD.

Disclosure: M.S. Haines: BioAge. L.E. Dichtel: Perspectum, Lumos Pharma, Recordati, Novo Nordisk, Third Rock Ventures, Merida Biosciences, Marea Therapeutics, Flare Therapeutics. C. Dobbie: None. S. Wasserman: None. A. Bader: None. M. Mirgorodsky: None. C.V. Anekwe: None. G. Curtis: None. W.P. Dutton: None. G. O'Brien: None. F.C. Stanford: Eli Lilly & Company, Novo Nordisk, Amgen Inc, Pfizer, Inc., AstraZeneca, Doximity, GoodRx, Sweetch, Clearmind Medicine, Apnimed, LifeForce, Mellicell, Currax, Vida Health, Ilant Health, Empros Pharma, Dox Health, Calibrate. K.K. Miller: Amgen Inc, Bristol-Myers Squibb, General Electric, Boston Scientific, Becton Dickinson. Loss of muscle mass is a consequence of weight loss in adults with obesity and may have unintended consequences on metabolic and bone health because muscle is responsible for most post-prandial glucose disposal and is a critical determinant of bone mineral density (BMD). About 40% of the weight lost secondary to semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is lean mass. However, predictors of muscle loss in this population are unknown, as are the effects of muscle loss on glucose and bone homeostasis. This observational prospective study aimed to identify risk factors for, and factors that protect against, loss of muscle mass due to weight loss with semaglutide, and to investigate whether muscle loss impacts glucose and bone homeostasis. We studied 39 adults with obesity and prescribed either semaglutide (n=22) or a diet and lifestyle intervention for weight loss [Healthy Habits for Life (HHL)] (n=17) for 3 months. The primary outcome was change in lean mass by DXA. Mean age [46 ± 13 y (SD)], BMI (37.7 ± 5.0 kg/m2), HbA1c (5.4 ± 0.3%), % female (72%, n=28) and race (77% White, n=30) were similar between groups. Mean weight loss was 6.7 ± 2.9 vs. 2.5 ± 3.2% in the semaglutide vs. HHL groups (p=0.002). Among those who lost weight, 47.5 ± 25.9% of the weight loss was lean mass in the semaglutide vs. 34.8 ± 41.6% in the HHL group (p=0.19). Change in lean mass was more strongly correlated with change in weight in the HHL (R=0.93, p<0.0001) vs. semaglutide (R=0.55, p=0.01) group (intervention arm * change in lean mass interaction, p=0.03). Lower protein intake at 3 months in the semaglutide group (R=0.52, p=0.02) and older age in the HHL group (R= -0.53, p=0.03) were associated with a greater decrease in lean mass. After adjusting for change in weight, older age (p=0.046), female sex (p=0.02), and lower protein intake at 3 months (p=0.03) were associated with a greater decrease in lean mass in the semaglutide, but not the HHL, group. In the same adjusted model, a greater decrease in lean mass was associated with less improvement in HbA1c in the semaglutide group (p=0.03) only. The bone resorption marker C-terminal telopeptide (CTX) (15 ± 29%, p=0.03) and total body BMD (1.9 ± 1.5%, p<0.0001) increased in the semaglutide, but not HHL, group. The bone formation marker procollagen type 1 N-terminal propeptide (P1NP) did not change in either group. In conclusion, older age and female sex may be associated with greater muscle loss, while higher protein intake may be relatively protective against muscle loss, in adults with obesity prescribed semaglutide. Greater muscle loss was independently associated with less improvement in glucose homeostasis with semaglutide. Therefore, maintaining muscle mass with weight loss in individuals with obesity on semaglutide may be essential to mitigate insulin resistance and frailty. The association between semaglutide and bone metabolism warrants further investigation. Presentation: Saturday, July 12, 2025

Abstract Disclosure: R. Boutin: None. M. Haines: None. R. Shahid: None. C. Mark: None. C. Gill: None. M. Bredella: None. K.K. Miller: Other; Self; Pfizer, Inc. L.E. Dichtel: Consulting Fee; Self; Lumos Pharma. Grant Recipient; Self; Lumos Pharma, Perspectum Ltd. Research Investigator; Self; Recordati, Novo Nordisk. Stock Owner; Self; Marea Therapeutics. Other; Self; Third Rock Ventures. Objective: Growth hormone (GH) stimulates osteoblast differentiation, while insulin-like growth factor-1 (IGF-1) stimulates osteoblast proliferation and bone formation. Retrospective studies have demonstrated a 2-to-3-fold increased fracture risk in adults with GH deficiency (GHD) due to organic hypothalamic or pituitary disease, particularly at vertebral sites. Adults with overweight/obesity produce relatively less GH than lean individuals, and serum IGF-1 levels are associated positively with BMD in adults with obesity. Yet, no published studies have examined the relationship between degree of GHD across these groups and vertebral strength, an understudied measure of bone quality in part because HR-pQCT cannot image this skeletal site. We hypothesized that there would be an inverse association between degree of GHD and vertebral strength, independent of age and BMI. Methods: Cross-sectional study of 134 estrogen-replete (with regular menses or taking estrogen) women: 16 with GHD secondary to hypopituitarism (HP, severe GHD), 91 with obesity (OB) without a hypothalamic/pituitary disorder (relative GHD), and 37 lean controls (LC) without a hypothalamic/pituitary disorder (normal GH production). Peak-stimulated GH was assessed by GHRH-arginine testing. CT imaging at the L4 vertebra was performed to determine vertebral cross-sectional area and total integrated volumetric bone mineral density (Int.vBMD), from which estimates of vertebral strength were calculated. Results: Mean age [44±9 (mean±SD) (HP) vs. 35±7 (OB) vs. 30±7 (LC) y, p<0.005] and BMI [30±6 (HP) vs. 34±6 (OB) vs. 22±2 (LC) kg/m2, p<0.004] differed between all groups. As expected, peak-stimulated GH was highest in LC (28.3 ± 9.5 ng/mL) followed by OB (12.4 ± 8.9 ng/mL) and HP (2.4 ± 1.7 ng/mL), p<0.0001. IGF-1 Z-scores were higher in LC (0.0 ± 0.6) and OB (0.0 ± 0.7) vs. HP (-1.4 ± 0.7), p<0.0001. Int.vBMD and vertebral strength were higher in LC and OB vs. HP [Int.vBMD (g/cm3) LC 0.21±0.04 and OB 0.21±0.04 vs. HP 0.16±0.03, and vertebral strength (N) LC 4540±850 and 4743±91 vs. HP 3542±651, both p<0.0001], which remained significant when adjusted for age and BMI (p≤0.01). Peak-stimulated GH and IGF-1 Z-scores were positively associated with vertebral strength (GH R=0.33, p=0.003 and IGF-1 Z-score R=0.41, p<0.0001) and Int.vBMD (GH R=0.46, p<0.0001 and IGF-1 Z-score R=0.40, p<0.0001), which remained significant when adjusted for age and BMI. Among the subset of patients without organic pituitary disease (LC and OB only), IGF-1 Z-scores remained positively associated with vertebral strength (R=0.24, p<0.03) and Int.vBMD (R=0.22, p<0.05). Conclusions: These findings suggest that severe GHD is associated with impaired vertebral volumetric bone density and strength. Moreover, the relative GHD of obesity may contribute to lower vertebral bone density and strength in otherwise healthy adults with overweight/obesity. Presentation: 6/3/2024

ImportanceAspirin may reduce severity of metabolic dysfunction–associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown.ObjectiveTo test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD.Design, Setting, and ParticipantsThis 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023.InterventionsParticipants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months.Main Outcomes and MeasuresThe primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified.ResultsAmong 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was −6.6% with aspirin vs 3.6% with placebo (difference, −10.2% [95% CI, −27.7% to −2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (−8.8 vs 30.0 percentage points; mean difference, −38.8 percentage points [95% CI, −66.7 to −10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (−2.7% vs 0.9%; mean difference, −3.7% [95% CI, −6.1% to −1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (−11.7 vs 15.7 percentage points; mean difference, −27.3 percentage points [95% CI, −45.2 to −9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn.Conclusions and RelevanceIn this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT04031729

Abstract Disclosure: C.O. Sailer: None. A. Aulinas Maso: None. F. Galbiati: None. M. Muhammed: None. R. Boutin: None. J. Bourassa: None. C. Atila: None. J. Crowley: None. A. Dayno: None. H. Pearlstein: None. L. Nachtigall: None. K.K. Miller: None. N.A. Tritos: None. U.B. Kaiser: None. J.G. Verbalis: None. L. Dichtel: Consulting Fee; Self; Lumos Pharma. Research Investigator; Self; Pfizer, Inc., Spectrum Ltd, Novartis Pharmaceuticals. E.A. Lawson: Research Investigator; Self; Tonix Pharmaceuticals. Background: Arginine-vasopressin (AVP) deficiency (AVP-D), formerly known as central diabetes insipidus, is characterized by insufficient AVP secretion leading to polyuria/polydipsia and treated with desmopressin. AVP-D is most often acquired secondary to neurohypophyseal or hypothalamic damage, e.g., from tumor or surgical complication, and can be transient or chronic. While cases of spontaneous recovery from chronic AVP-D have been described, no study has compared clinical characteristics of those who recover to those who do not. Understanding these differences may elucidate mechanisms of AVP-D recovery and help identify individuals who are at risk of developing complications of overtreatment in the setting of recovery. Methods: In this retrospective case-control study (1:2 matched for sex and desmopressin treatment duration), we investigated clinical characteristics of adults with chronic AVP-D with (n=18) vs without (n=36) recovery, defined as discontinuation of desmopressin after at least 6 months of initial treatment without recurrence of sustained polyuria/polydipsia. Diagnosis of AVP-D was confirmed by chart review by board certified endocrinologists. Clinical characteristics were assessed at diagnosis of AVP-D, recovery from AVP-D, and most recent visit. Group comparisons were done using t-test or X2-test. Results: Most common etiologies of pituitary/hypothalamic disease were craniopharyngioma (35%), non-functioning pituitary adenoma (15%), and germinoma (15%). AVP-D mainly developed after surgery (63%) or was tumor-related (32%). At diagnosis, those who ultimately recovered from AVP-D (vs those who did not) were older (46 vs 33 years, p=0.007); had lower random sodium levels (144 vs 148 mmol/l, p=0.015); received lower desmopressin doses (100 vs 200 ug/d, p=0.012); and trended toward lower polydipsia (5.9 vs 9.5 L/d, p=0.09). At recovery, mean duration of AVP-D was 8.5±8.3 years. Initial signs of recovery were reduced desmopressin dose (67%), reduced nocturia frequency and/or volume (67%), reduced urine output frequency and/or volume (50%), reduced thirst perception (22%), and development of hyponatremia (17%). At most recent visit, those who recovered (vs those who did not) were less likely to have gonadotropin deficiency (56% vs 89%, p=0.015). Conclusion: We have identified clinical differences in a cohort of adults with chronic AVP-D who recovered compared to those who did not, supporting the notion that chronic AVP-D may not always be permanent and improving our understanding of disease course. Recovery from AVP-D seems to be more common than previously considered, and patients, especially those with milder initial AVP-D, should be monitored regularly and reassessed for continued replacement need to prevent complications such as hyponatremia. Presentation: 6/2/2024

AbstractMyostatin inhibition improves insulin sensitivity in preclinical and clinical models; however, studies investigating the relationship between serum myostatin levels and insulin sensitivity are discrepant. Sensitive and specific myostatin LC–MS/MS assays are now available to accurately assess serum myostatin level in vivo. We sought to determine whether higher serum myostatin levels are independently associated with lower insulin sensitivity in adults with overweight/obesity. Participants included 74 adults, 20–65 years old, BMI ≥25 kg/m2 without type 2 diabetes. Appendicular lean mass (ALM) was measured by dual‐energy x‐ray absorptiometry; visceral adipose tissue (VAT) was measured by computed tomography. Main outcome measures were serum myostatin levels (LC–MS/MS) and insulin sensitivity (Matsuda index). Mean age was 48 ± 12 years, and BMI was 33.1 ± 5.6 kg/m2 (mean ± SD). Men had higher mean serum myostatin levels versus women (8.3 ± 1.9 vs. 7.2 ± 1.9 ng/mL, p = 0.01) and higher serum myostatin levels were associated with higher ALM (R = 0.34, p = 0.003). Higher serum myostatin levels were associated with lower Matsuda index (R = −0.44, p = 0.0004), which remained significant after controlling for BMI, VAT, ALM, and sex. In conclusion, higher serum myostatin levels are independently associated with lower insulin sensitivity in adults with overweight/obesity and may be a marker of or play a mechanistic role in the development of insulin resistance.

Menstrually related mood disorder (MRMD) is marked by severe affective symptoms in the late luteal phase of the menstrual cycle. We hypothesized that women with MRMD experience relative neuroactive steroid deficiency, specifically low allopregnanolone levels due to reduced conversion of progesterone, in association with the onset of affective symptoms in the late luteal phase. Nine subjects with MRMD and 14 healthy controls were studied. Daily Record of Severity of Problems was used to diagnose MRMD by DSM-5 criteria for premenstrual dysphoric disorder. Depression and anxiety symptom severity (16-Item Quick Inventory of Depressive Symptomatology Self Report, Generalized Anxiety Disorder 7-Item Scale) and levels of plasma neuroactive steroids by mass spectrometry were assessed at the mid-follicular, mid-luteal, and late luteal phases. Depression severity was greater in women with MRMD than healthy controls in the late luteal phase only, as expected. In the mid-follicular phase, the mean allopregnanolone level and allopregnanolone/progesterone ratio were higher in women with MRMD than healthy controls. There were no differences between groups in luteal phase allopregnanolone levels. Higher follicular phase allopregnanolone sulfate and allopregnanolone levels were associated with greater depression severity in the mid-luteal and late luteal phases and greater anxiety severity in the late luteal phase. Levels of allopregnanolone, which have antidepressant effects, were higher in the mid-follicular phase in women with MRMD compared to healthy controls. In MRMD, increased conversion of progesterone to allopregnanolone in the mid-follicular phase may be a compensatory response to luteal phase depression and anxiety, or increased allopregnanolone levels could paradoxically trigger depression and anxiety.

Abstract Disclosure: N. Chamorro-Pareja: None. M. Haines: None. L.E. Dichtel: Consulting Fee; Self; Lumos Pharma. Research Investigator; Self; Recordati, NovoNordisk, Perspectum Ltd, Lumos Pharma, Pfizer, Inc.. Stock Owner; Self; Marea Therapeutics. Other; Self; Third Rock Ventures. B.M. Biller: Consulting Fee; Self; Xeris Pharmaceuticals, Recordati Rare Diseases, Sparrow, Lundbeck. Background: Endogenous Cushing’s syndrome (CS) is a rare condition of excess cortisol secretion; the most common cause is a pituitary corticotroph tumor (Cushing’s disease [CD]). Medical treatment for CD is primarily used to control hypercortisolism in patients with persistent or recurrent disease after transsphenoidal surgery (TSS). Levoketoconazole (LKCZ), a steroidogenesis inhibitor, was FDA approved in January 2022 for CS treatment. This reports 3 cases of patients who were treated with LKCZ for recurrent CS. Clinical Cases: Case 1: 44-year-old (yo) male (M) with a history of CD with urinary free cortisol (UFC) >26x upper limit of normal (ULN) who was treated preoperatively with ketoconazole (KCZ) 1000 mg/day with UFC improved to 6x ULN. KCZ was discontinued at TSS, and he achieved remission post-operatively. He was lost to follow-up and re-presented after several years with worsening hypertension, muscle weakness, edema, and anxiety with UFC 28x ULN and a recurrent pituitary lesion on MRI. He declined repeat TSS and underwent radiation therapy (RT) and medical treatment. LKCZ was initiated at 150 mg twice daily (BID) and increased to 300 mg BID. At LKCZ 300 mg BID, he had a low UFC and mild nausea but an adequate serum morning cortisol (10.4 ug/dL, ref:6-18.4 ug/dL); LKCZ was reduced to 150 mg BID with resolution of symptoms (sxs) and normal UFC. Case 2: 56 yo M with a history of CD (UFC >3x ULN) who underwent 2 TSSs and RT over 10 years prior with eventual remission, but later recurred. Sxs included brain fog and mood disturbances. He achieved control with pasireotide but discontinued due to abnormal liver function tests. He was then treated with KCZ 400 mg/day but remained hypercortisolemic (LNSC 1.1x ULN) and was interested in trying a new medication, so was switched to LKCZ 150 mg BID with significant improvement of sxs and normalization of LNSC. Case 3: 54 yo F with presumed cyclic CD (negative whole-body and octreotide scans) with UFC 1.7x ULN and LNSC 3x ULN. TSS was performed with negative pathology; she had persistent hypercortisolemia and sxs including insomnia, fatigue, and mood disturbances. She was intolerant to and/or uncontrolled on 4 medications, including KCZ at 1000 mg/day that was discontinued due to a rash. She was started on LKCZ 150 mg BID and achieved normal LNSC and UFC after about 1 month. The drug was discontinued due to the development of a rash similar to that with KCZ. Conclusion: LKCZ is a new option for the treatment of CS in patients whose disease persists after TSS. These 3 patients had improvement of sxs and normalization of cortisol levels while on LKCZ, although one patient discontinued LKCZ due to a rash that was previously experienced with KCZ. The other two patients are being carefully monitored for liver function test elevation, QTc abnormalities and adrenal insufficiency with no issues to date. To our knowledge, this is the first case series of CS patients treated clinically with LKCZ. Presentation: 6/1/2024

Abstract Disclosure: A. Kimball: None. J. Bourassa: None. M. Chicote: None. A.V. Gerweck: None. L.E. Dichtel: Other; Self; Dr. Dichtel is a Mass General Brigham (MGB) Innovation Fellow hosted by Third Rock Ventures. Financial interests were reviewed and are managed by MGH and MGB in accordance with their COI policies. K.K. Miller: None. Menstrually related mood disorder (MRMD), which includes premenstrual dysphoric disorder (PMDD) and subthreshold PMDD, is marked by severe psychiatric impairment in the late luteal phase of the menstrual cycle, but little is known about the mechanisms responsible. Allopregnanolone is a neuroactive metabolite of progesterone and a potent GABAA receptor allosteric activator with antidepressant and anxiolytic properties. We have shown that allopregnanolone levels increase, while the allopregnanolone/progesterone ratio decreases, from the follicular to luteal phase in healthy women. We hypothesized that allopregnanolone levels would decrease in association with the increase in depression severity experienced in the late luteal phase by women with MRMD. We studied 23 women with regular menses [MRMD (n=9) and healthy controls with no premenstrual symptoms or psychiatric history (HC) (n=14)] in the mid-follicular (cycle day 6-10), mid-luteal (5-9 days after LH surge), and late luteal (9-13 days after LH surge) phases. No subjects took gonadal steroids or psychotropic medications. The Daily Record of Severity of Problems was used to diagnosed PMDD (≥5 symptoms) and subthreshold PMDD (1-4 symptoms). Depression and anxiety symptom severity were assessed using the Quick Inventory of Depressive Symptomatology and Generalized Anxiety Disorder 7-item Scale, respectively. Fasting plasma hormone levels were measured by GC/MS. Data are presented as median(95% CI). Normal ranges were calculated as the 95% CI of HC. Median age [30(28,33) years] and BMI [23.8(22.9,29.0) kg/m2] were similar between groups. Depression severity was greater in MRMD vs HC [7(3,13) vs 2(1,4), p=0.005) in the late luteal phase only, as expected. In the follicular phase, the median allopregnanolone level was higher in MRMD vs HC [86(40,148) vs 29(24,73) pg/mL, p=0.05] and frankly elevated in 6 of 9 (67%) MRMD women. The median allopregnanolone/progesterone ratio in the follicular phase was higher in MRMD vs HC [0.8(0.4,2.2) vs 0.4 (0.3,0.8), p=0.03] and elevated in 4 of 9 (44%) MRMD women. There were no differences in neuroactive steroid levels between groups during the luteal phase. Higher allopregnanolone levels in the follicular phase were associated with greater depression severity in the mid-luteal (r=0.51, p=0.01) and late luteal (r=0.54, p=0.007) phase and greater anxiety severity in the late luteal phase (r=0.41, p=0.05). Conclusion: Contrary to our hypothesis, we found that levels of neuroactive steroids, which have antidepressant effects, were higher in the follicular phase in women with MRMD – who experience depression in the late luteal phase – compared with HC. This suggests that increased conversion of progesterone to allopregnanolone in the follicular phase, resulting in elevated allopregnanolone levels, may be a compensatory response to premenstrual depression and anxiety in some women with MRMD. Presentation Date: Friday, June 16, 2023

Physician parents encounter unique challenges in balancing new parenthood with work responsibilities, especially upon their return from parental leave. We designed a pilot program that incorporated 1:1 parental coaching to expectant and new physician parents and provided stipends for lactation support and help at home. Additional initiatives included launching a virtual new parent group during the COVID-19 pandemic and starting an emergency backup pump supplies program. There was positive feedback for our Parental Wellness Program (PWP), which was used to secure expanded funding. Pilot results showed that our program had a meaningful impact on parental wellness, morale, productivity, and lactation efforts.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide. There are limited biomarkers that can detect progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The purpose of our study was to utilize CT texture analysis to distinguish steatosis from NASH. Methods: 16 patients with NAFLD (38% male, median (interquartile range): age 57 (48-64) years, BMI 37.5 (35.0-46.8) kg/ m2) underwent liver biopsy and abdominal non-contrast CT. CT texture analysis was performed to quantify graylevel tissue summaries (e.g., entropy, kurtosis, skewness, and attenuation) using commercially available software (TexRad, Cambridge England). Logistic regression analyses were performed to quantify the association between steatosis/NASH status and CT texture. ROC curve analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of texture parameters to differentiate steatosis from NASH. Results: By histology, 6/16 (37%) of patients had simple steatosis and 10/16 (63%) had NASH. Patients with NASH had lower entropy (median, interquartile range (IQR): 4.3 (4.1, 4.8) vs. 5.0 (4.9, 5.2), P = 0.013) and lower mean value of positive pixels (MPP) (34.4 (21.8, 52.2) vs. 66.5 (57.0, 70.7), P = 0.009) than those with simple steatosis. Entropy values below 4.73 predict NASH with 100% (95%CI: 67-100%) specificity and 80% (50-100%) sensitivity, AUC: 0.88. MPP values below 54.0 predict NASH with 100% (67-100%) specificity and 100% (50-100%) sensitivity, AUC 0.90. Conclusion: Our study provides preliminary evidence that CT texture analysis may serve as a novel imaging biomarker for disease activity in NAFLD and the discrimination of steatosis and NASH.

Context Overweight and obesity are associated with relative growth hormone (GH) deficiency, which has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a progressive disease without effective treatments. Objective We hypothesized that GH administration would reduce hepatic steatosis in individuals with overweight/obesity and NAFLD. Methods In this 6-month randomized, double-blind, placebo-controlled trial of low-dose GH administration, 53 adults aged 18 to 65 years with BMI & GE;25 kg/m(2) and NAFLD without diabetes were randomized to daily subcutaneous GH or placebo, targeting insulin-like growth factor 1 (IGF-1) to the upper normal quartile. The primary endpoint was intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) assessed before treatment and at 6 months. Results Subjects were randomly assigned to a treatment group (27 GH; 26 placebo), with 41 completers (20 GH and 21 placebo) at 6 months. Reduction in absolute % IHL by 1H-MRS was significantly greater in the GH vs placebo group (mean & PLUSMN; SD: -5.2 & PLUSMN; 10.5% vs 3.8 & PLUSMN; 6.9%; P = .009), resulting in a net mean treatment effect of -8.9% (95% CI, -14.5 to -3.3%). All side effects were similar between groups, except for non-clinically significant lower extremity edema, which was more frequent in the GH vs placebo group (21% vs 0%, P = .02). There were no study discontinuations due to worsening of glycemic status, and there were no significant differences in change in glycemic measures or insulin resistance between the GH and placebo groups. Conclusion GH administration reduces hepatic steatosis in adults with overweight/obesity and NAFLD without worsening glycemic measures. The GH/IGF-1 axis may lead to future therapeutic targets for NAFLD.

Normal aging is linked to various endocrine gland changes, including changes in the adrenal glands. Aging is linked to alterations of the hypothalamic-pituitary-adrenal (HPA) axis, including an increase in cortisol levels, a disruption of the negative cortisol feedback, and attenuation of cortisol's diurnal pattern. In addition, secretion of aldosterone and adrenal androgens [dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)] from the adrenal cortex decreases with aging. In this review, we describe normal adrenal function, the adrenal response to stress and immunomodulation in aging individuals as well as the effects of adrenal aging on body composition, metabolic profile, bone health and cognition.

Chronic liver disease is a major public health burden worldwide. Despite various liver injury mechanisms, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis. We examined the association between clonal hematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 58,358 individuals from four prospective cohorts with whole exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent chronic liver disease (OR 2.70 CI 1.42, 5.16, p=0.002) and incident chronic liver disease (HR 2.01 CI 1.46, 2.79, p=0.001) from both alcoholic and nonalcoholic causes. Individuals with CHIP showed 75% greater odds of MRI detectable liver inflammation and fibrosis (5.9% versus 3.5%, p=0.007) compared to those without CHIP. To assess causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (OR 2.37 CI 1.57, 3.6, p<0.001). In a dietary model of nonalcoholic steatohepatitis (NASH), mice transplanted with Tet2-deficient hematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated via NLRP3 inflammasome and increased downstream inflammatory cytokine expression, including IL6. In summary, clonal hematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression via an aberrant inflammatory response.