United States

Background: The prevalence of sarcopenic obesity (SO) is increasing worldwide, posing important challenges to public health and national health care system, especially during the COVID pandemic. In subjects with SO, it is essential to reduce body weight preserving lean mass, in order to avoid a worsening of muscle function. Lifestyle modification with adequate nutrition and proper physical activity is essential to counteract SO progression. In accordance with the Position Statement of the Italian Society of Endocrinology, Very Low Calorie Ketogenic Diet (VLCKD), a well established nutritional intervention in the context of obesity, has been promoted also for the treatment of SO (1). To date, the effects of physical training during VLCKD have not been studied. Aim: This pilot study aims to determine the efficacy of VLCKD combined with interval training, compared to a VLCKD alone, on weight-loss, body composition and physical performance in patient with SO. Materials and methods: Twenty-six patients with SO, aged between 50 and 70 years, who met the inclusion criteria, accepted to adhere to a VLCKD nutritional program (&lt; 800 Kcal/die) and gave informed consent, were enrolled in the study. Thirteen patients followed a structured VLCKD protocol (VLCKD group) and thirteen patients followed a structured VLCKD protocol combined with interval training (IT), two times a week (VLCKD+IT group). Data were collected at baseline (T0) and after 45 days (T45). Anthropometric indexes, body composition analysis by Bioelectrical Impedance Analysis (BIA), muscle strength measurement by Chair Stand Test and physical performance analysis by Short Physical Performance Battery were assessed at baseline and at the end of treatment. Results: At the end of the study, Body Mass Index, body weight and waist circumference were significantly reduced both in the VLCKD group and in the VLCKD+IT group. Moreover, significant improvement of muscle strength and physical performance was found in all groups. A significant reduction in hip circumference was observed only in the VLCKD+IT group. A multiple comparison of delta variations in the measured parameters between groups was performed. No differences were observed for the majority of parameters, with the exception of FFM and FM: interestingly, the individuals fed with VLCKD combined with IT preserved their FFM (p &lt;0.0001) and reduced their FM (p = 0.0006) to a greater extent than in the VLCKD group. Conclusions: Our pilot study showed that VLCKD was effective in terms of body weight reduction, particularly of FM; moreover, we conclude that the combination of VLCKD and interval training determines a better preservation of FFM. References: 1. Caprio, M. et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J Endocrinol Invest 2019, 42, 1365-1386, doi: 10.1007/s40618-019-01061-2.

ENDO 2022

Very Low Calorie Ketogenic Diet combined with interval training for preserving muscle mass during weight loss in sarcopenic obesity: a pilot study

**Program**
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This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

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Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Background: The prevalence of sarcopenic obesity (SO) is increasing worldwide, posing important challenges to public health and national health care system, especially during the COVID pandemic. In subjects with SO, it is essential to reduce body weight preserving lean mass, in order to avoid a worsening of muscle function. Lifestyle modification with adequate nutrition and proper physical activity is essential to counteract SO progression. In accordance with the Position Statement of the Italian Society of Endocrinology, Very Low Calorie Ketogenic Diet (VLCKD), a well established nutritional intervention in the context of obesity, has been promoted also for the treatment of SO (1). To date, the effects of physical training during VLCKD have not been studied. Aim: This pilot study aims to determine the efficacy of VLCKD combined with interval training, compared to a VLCKD alone, on weight-loss, body composition and physical performance in patient with SO. Materials and methods: Twenty-six patients with SO, aged between 50 and 70 years, who met the inclusion criteria, accepted to adhere to a VLCKD nutritional program (< 800 Kcal/die) and gave informed consent, were enrolled in the study. Thirteen patients followed a structured VLCKD protocol (VLCKD group) and thirteen patients followed a structured VLCKD protocol combined with interval training (IT), two times a week (VLCKD+IT group). Data were collected at baseline (T0) and after 45 days (T45). Anthropometric indexes, body composition analysis by Bioelectrical Impedance Analysis (BIA), muscle strength measurement by Chair Stand Test and physical performance analysis by Short Physical Performance Battery were assessed at baseline and at the end of treatment. Results: At the end of the study, Body Mass Index, body weight and waist circumference were significantly reduced both in the VLCKD group and in the VLCKD+IT group. Moreover, significant improvement of muscle strength and physical performance was found in all groups. A significant reduction in hip circumference was observed only in the VLCKD+IT group. A multiple comparison of delta variations in the measured parameters between groups was performed. No differences were observed for the majority of parameters, with the exception of FFM and FM: interestingly, the individuals fed with VLCKD combined with IT preserved their FFM (p <0.0001) and reduced their FM (p = 0.0006) to a greater extent than in the VLCKD group. Conclusions: Our pilot study showed that VLCKD was effective in terms of body weight reduction, particularly of FM; moreover, we conclude that the combination of VLCKD and interval training determines a better preservation of FFM. References: 1. Caprio, M. et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J Endocrinol Invest 2019, 42, 1365-1386, doi: 10.1007/s40618-019-01061-2.

technical paper

Background: Prader-Willi syndrome (PWS), a rare genetic neurobehavioral-metabolic condition, is characterized by hyperphagia, accumulation of excess fat, hypotonia, and behavioral/psychological complications.  There are no currently approved medications to treat hyperphagia in patients with PWS; DCCR is under development as a treatment for PWS.
Objectives and methods: The objective was to evaluate long-term safety of DCCR in individuals with PWS. 125 participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with oral daily DCCR in multi-center studies conducted at 29 sites in the US and the UK: a 13-week, Phase 3, double-blind, placebo-controlled study (DESTINY PWS) and its long-term, open-label extension study (to 52 weeks and beyond). Enrolled participants had hyperphagia assessed by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). The target DCCR dose was ≥3.3 mg/kg (optimal dose 4.2 - 5.8 mg/kg). 103 patients received DCCR for 52 weeks and 54 patients received DCCR for at least 78 weeks.
Results: Overall, DCCR was well tolerated with the majority of adverse events (AEs), (77.6%) having grade 1 or 2 severity. Treatment-emergent adverse events (TEAEs) occurred in 98.4% of participants.  Drug related TEAEs occurred in 80.0% of participants. Twenty participants experienced serious adverse events (SAEs), for which only two participants were considered drug related (one patient with peripheral/pulmonary edema and another with fluid retention). There were no Suspected Unexpected Serious Adverse Reactions (SUSARs) or SAEs leading to death.  The most common TEAEs were hypertrichosis (61.6%), peripheral edema (34.4%), and hyperglycemia (22.4%).  TEAEs infrequently resulted in discontinuation of study drug (7.2% of participants).  These results are consistent with the observed safety profile of DCCR from prior studies.
Consistent with the expected AE of hyperglycemia, fasting glucose rose through Week 26 (mean change from baseline ± SD mmol/L = 0.35±0.81) and returned nearly to baseline by 15 months of treatment (0.11±0.61).  HbA1c followed a similar pattern, increasing at 26 weeks (mean change from baseline ± SD % = 0.19±0.50) and returning nearly to baseline by 15 months (0.03±0.38).  In participants experiencing hyperglycemia, the AE resolved with continued treatment in about half of cases.  Four participants experienced recurrent hyperglycemia.  About 90% of cases of peripheral edema resolved while treatment continued, requiring infrequent dose adjustment (7%) or the need for diuretic treatment (3%). Most cases of hypertrichosis (>80%) were mild and only in one instance led to discontinuation.  About 35% of cases of hypertrichosis were resolved/resolving at Week 52.
Conclusions: DCCR was well tolerated beyond 52 weeks of administration. The most common treatment-emergent adverse events were expected based on prior studies of DCCR. These included hypertrichosis, peripheral edema and hyperglycemia, which were typically mild and resolved without treatment in most cases.

Long-Term Safety of Diazoxide Choline Extended-Release (DCCR) Tablets in Patients with Prader-Willi Syndrome

The need for personalized medicine in obesity is pressing, but we are currently unable to predict individual responses to weight loss (WL) medications. The melanocortin (MC) system consisting of proopiomelanocortin (POMC) and agouti related protein (AgRP) neurons and brain MC-Rs plays a critical role in regulating energy homeostasis and is targeted by lorcaserin (LOR), a 5HT2cR agonist previously FDA approved for WL. We therefore investigated the short and long-term effects of LOR on the MC system as assessed by cerebrospinal fluid (CSF) neuropeptide measurements and other parameters in order to identify potential biomarkers to predict WL response.
Methods: In phase-1 of our two-phase study, thirty subjects with obesity were randomized to receive placebo or LOR for 7-days and were then crossed over to 7-days of LOR or placebo after a 3-week washout period. Subjects then continued to phase-2 and were treated with LOR for 6-months. The study was terminated early as LOR was withdrawn from the market and only 19 subjects completed 6M. Anthropometrics, plasma and CSF were collected and test meals were administered after both placebo and LOR during phase-1 and at the end of phase-2. POMC prohormone and the POMC-derived peptide, β-endorphin (β-EP), were measured in CSF by in house ELISA and RIA. The MC-R antagonist, AgRP, was measured by ELISA in CSF and plasma as both may reflect brain AgRP.
Results: During phase-1 there was a decline in CSF POMC (p=0.001) and an increase in CSF β-EP (p=0.0017) resulting in an increase in the ratio of β-EP /POMC (processed peptide/prohormone) (p<0.0001) after 7-days of LOR vs placebo. Serum insulin and HOMA-IR also decreased despite no WL during phase-1 (p<0.005).
After 6M of LOR, average WL was 6.9 %, with 11/19 subjects achieving >5% and 7/19 >10% WL. Leptin, insulin and HOMA-IR declined. CSF POMC remained lower and β-EP and β-EP/POMC remained higher after 6M vs 7-day placebo (baseline), whereas AgRP increased only at 6M. Anthropometrics and caloric intake during test meals were not significantly different between LOR and placebo in phase-1 and did not predict WL at 6M. Phase-1 changes in POMC or β-EP did not predict WL. However, baseline CSF POMC and POMC/AgRP ratio correlated negatively with WL and were significantly lower in subjects with >10% WL. A CSF POMC cutoff of < 220 fmol/ml at baseline was found to predict 10% WL at 6M (p=0.045 Fisher).
Conclusion: In this study we show that the melanocortin system is impacted after 1 week of LOR. Furthermore lower melanocortin activity at baseline predicted a better weight loss response to drug treatment. Assessment of melanocortin activity could thus provide a way to personalize the pharmacotherapy of obesity with possible future alternative selective 5HT2cR agonists.

Defining Predictors of Weight Loss Response to Lorcaserin

BACKGROUND:
Combined estrogen and progestin hormonal contraceptives (CHCs, including combined oral contraceptives, hormonal patches, or vaginal rings) expose women to supraphysiologic levels of reproductive hormones, which in turn suppress endogenous estrogen and progesterone. Sustained elevations of synthetic estrogen/progestin or suppression of endogenous hormones in CHC users may lead to altered dietary intake and/or patterns of physical activity (PA). Previously, we reported that CHC use was associated with higher energy intake (EI) and weight regain over 1 year after weight loss in women with overweight and obesity enrolled in a behavioral weight loss program, suggesting a potential impact of CHCs on energy balance in the weight reduced state. The aim of this secondary data analysis was to compare dietary intake and PA in weight-stable women with overweight or obesity using CHCs to non-CHC users.
METHODS:
Pre-menopausal women with overweight or obesity (n=269, age 18-55 years, BMI 27-45kg/m2) enrolled in 3 different interventional weight loss trials were categorized as CHC users (CHC, n=48) or non-CHC controls (CON, n=221). Fat mass (FM) and lean mass (LM) were measured with DXA. Self-reported dietary energy and macronutrient intake was obtained from either 3-day (n=178) or 7-day (n=91) written diet diaries and analyzed using Nutrition Data System for Research (NDSR) software. Healthy eating index (HEI) scores for diet quality were calculated in a subset (CHC=17, CON=84) of participants using variables available in NDSR output files. Additionally, average daily step counts were measured over 1 week in a subset (CHC=27, CON=143) of participants using the activPAL device.
RESULTS:
Age was lower in CHC users (mean±SD; CHC 35.39.0 vs. CON 39.47.6 years, p<0.01), but race and ethnicity did not differ between the two groups. After controlling for age, there were no significant differences between groups in baseline BMI (mean±SEM; CHC 34.30.7 vs. CON 34.80.3 kg/m2), weight (93.62.4 vs. 94.21.1 kg), %FM (43.30.6 vs. 42.70.3 %), or %LM (54.30.6 vs. 54.70.3 %). There were no significant differences between groups in EI (mean±SEM; CHC 1763.778.1 vs. CON 1768.836.7 kcal); proportions of fat (36.70.9 vs. 36.90.4 %), carbohydrate (43.91.1 vs. 44.30.5 %), and protein intake (17.70.6 vs. 17.30.3 %); or HEI scores (58.32.9 vs. 56.81.3). There was a trend for lower daily step count in CHC users (mean±SEM; CHC 5978460 vs. CON 6913197 steps/day, p=0.07).
CONCLUSION:
Daily steps tended to be lower in CHC users compared to controls, while differences in self-reported dietary intake were not observed. Future studies that are done in larger samples over a greater range of BMI and with more detailed measures of PA timed to the menstrual cycle are needed to explore the extent to which CHC use may impact energy balance in women.

A Cross-Sectional Study Evaluating the Impact of Combined Hormonal Contraceptives on Components of Energy Balance in Pre-Menopausal Women with Overweight or Obesity

Background: The central hypothalamic melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Certain variants in genes upstream of MC4R, including those encoding the leptin receptor (LEPR), proopiomelanocortin (POMC), steroid receptor coactivator 1 (SRC1; also known as NCOA1), prohormone convertase (PC)1/3 (encoded by the gene PCSK1), and SH2B adaptor protein 1 (SH2B1) genes, lead to impaired MC4R pathway signaling and rare genetic diseases of obesity. While the deficiencies resulting from these genetic variants differ in some clinical features, they are all characterized by hyperphagia (pathologic insatiable hunger) and early-onset obesity during childhood. Setmelanotide, an MC4R agonist, reduced body weight and hyperphagia (assessed by hunger scores) after 3 months in patients with heterozygous POMC, including patients with the N221D variant in PCSK1; LEPR; SRC1; and SH2B1 (including a 220–kilobase pair distal deletion of chromosome 16p11.2) variants in an earlier Phase 2 trial. In the Phase 2 trial, 12 of 35 (34%) patients with heterozygous POMC, PCSK1, or LEPR variants; 9 of 30 patients (30%) with heterozygous SRC1 variants; and 13 of 35 (37%) patients with heterozygous SH2B1 variants achieved ≥5% weight loss after 3 months of setmelanotide treatment.Methods: EMANATE is a randomized, double-blind, placebo-controlled Phase 3 trial (NCT05093634) comprising 5 similar independent sub-studies based on genetic variants. For eligibility, patients must be 6-65 years old, have history of hyperphagia and childhood obesity, current obesity defined as BMI ≥30 kg/m² (in those ≥18 years old), and BMI ≥95th percentile (in those 6-17 years old). Patients must also have a heterozygous genetic variant in POMC or PCSK1; heterozygous genetic variant in LEPR; a homozygous, heterozygous, or compound heterozygous variant in SRC1 or SH2B1 (including a chromosomal deletion of 16p11.2 including SH2B1); or a heterozygous N221D variant in PCSK1. Patients with ≥2% weight loss in the prior 3 months, HbA1C >10%, clinically significant pulmonary, cardiac, or oncological disease, or history of significant liver or serious kidney disease are not eligible. Within each sub-study, patients will be randomized 1: 1 to receive daily subcutaneous injections of setmelanotide or placebo for 52 weeks. The primary outcome is the mean change in body weight in patients who receive setmelanotide compared with placebo. Safety will be assessed by frequency and severity of adverse events.
Current Status: EMANATE is currently underway and began enrolling patients in early 2022. The planned enrollment is 560 patients. If successful, this placebo-controlled Phase 3 trial will support setmelanotide treatment for improvements in body weight–related measures and hunger in an expanded population of patients living with rare genetic diseases of obesity.

Setmelanotide in Patients With Heterozygous POMC, LEPR, SRC1, or SH2B1 Obesity: Design of EMANATE – A Placebo-Controlled Phase 3 Trial

Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Monogenic obesity disorders, including CLD, have been reported to be prevalent among children with severe obesity in a consanguineous Pakistani population. Targeted therapy is available in the form of recombinant human leptin (metreleptin). We previously reported baseline characteristics of the first cases of CLD identified in the United States, sisters of Pakistani origin with a family history of consanguinity. This report provides follow-up after 18 months of metreleptin therapy in an observational research protocol.

Clinical Case: Two sisters ages 18 yrs (A; BMI 45.2 kg/m2) and 20 yrs (B; 45.0 kg/m2) were referred for evaluation of obesity. Both had hyperphagia and excessive weight gain by age 3 months. They had been treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years and was treated with metformin and liraglutide with suboptimal glycemic control (HbA1C 9.3%). At the time of their initial evaluation, serum leptin levels were undetectable. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. Treatment was initiated with metreleptin 5 mg daily SC in Sister A and 3.75 mg SC daily, increasing to 5 mg daily at Week 8 in Sister B. Both remained on therapy throughout the 18 month observational trial without serious adverse effects or clinical evidence of neutralizing antibodies. At study end, both had substantial weight loss (Sister A: 45.3 kg or 32.8% of initial weight, Sister B: 39.1 kg or 33.1% of initial weight). Clinically significant improvements in related parameters were observed, including percent body fat (Sister A: -13%, Sister B: -18%), HOMA2-IR (A: -83% , B: -80% ), ALT (A: -90%, B: -91%), triglycerides (A: -47%, B: -26%), hsCRP (A: -80%, B: -84%), FGF-21 (A: -81%, B: -67%), and adiponectin (A: +42%, B: +37%). In both sisters, hepatic steatosis improved and bone mineral density increased (A: +0.7 SD, B: +0.6 SD). At study end, Sister A's HbA1C was 5.4% off medication. Spontaneous regular menses resumed after 3 months of therapy in Sister A and four months in Sister B. Improvements were observed in mood, self-esteem, physical function, energy, quality of life, dietary disinhibition, and perceived hunger, measured by validated questionnaires.

Conclusion: Metrelepin produced significant improvements in weight, metabolic profiles, hepatic steatosis, reproductive function, mood and quality of life in our patients. Given the efficacy of metreleptin therapy, screening for CLD should be undertaken for any patient presenting with hyperphagia and early onset of obesity.

Congenital Leptin Deficiency: Metabolic, Reproductive, and Psychological Impacts of Therapy

Introduction
Changes in the expression of microRNA facilitate in the formation of various tumors. MEN1 is a rare disease caused by mutations in MEN1 gene encoding the menin protein and characterize by the occurrence of parathyroid, pituitary, gastroenteropancreatic and other tumors. If a patient with the MEN1 phenotype carry no mutations in the MEN1 gene, the condition considers a phenocopy of syndrome (phMEN1). We hypothesize that the pathogenic link among the above sporadic tumors might be represented by molecular pathways involving the MEN1 gene and epigenetic regulations — particularly microRNAs.
Materials & methods
Single-center, case-control study: assessment of plasma microRNA expression in patients with phMEN1, acromegaly (AM), primary hyperparathyroidism (PHPT) and healthy controls. Morning plasma samples were collected from fasting patients and age- and sex-matched controls and stored at –80°C. Total RNA isolation: miRNeasy Mini Kit with QIAcube. The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer. Circulating miRNA sequencing was done on Illumina NextSeq 500 (Illumina). Subsequent data processing was performed using the DESeq2 bioinformatics algorithm.
Results
We enrolled 36 consecutive patients (12 patients in each group) with phMEN1, AM, PHPT, along with 12 age and gender matched controls. Median age of phMEN1 group — 59 [52; 60.5]; AM — 59 [52; 63]; PHPT — 60.5 [54; 62.5]; control — 59 [51.5; 62.5]. The groups did not differ in age (p=0.88) and gender – in all groups were 11 women and 1 man (p=1.00).
We divided all assessed microRNAs into 3 groups based on the significance of the results; the first group consisted of samples with the highest levels of detected microRNAs (>50), the second group — moderate (10–50), the third group — the lowest (<10).
The microRNA expression pattern was almost the same between AM and phMEN1 groups (15 microRNAs upregulated, 10 — downregulated), we found slightly decreased hsa-miR-4301 (padj=0.038); it is interesting that phMEN group when compared to PHPT and control groups showed decline in hsa-miR-4301 too. PHPT and control groups had also quite similar expression profile (4 microRNAs upregulated, 19 — downregulated).
607 microRNA were differently expressed in groups phMEN1 and PHPT (473 upregulated microRNAs, 134 — downregulated). We found increased expression of some microRNAs that interferes with menin: hsa-miR-24-1-5p (padj=0.0008), hsa-miR-24-3p (padj=0.034), hsa-miR-26a-5p (padj=0.0005), hsa-miR-421 (padj=0.018), hsa-miR-762 (padj=0.027). In addition, we found decreased microRNAs with oncogene potential: miR-3182 (padj=0.007), hsa-miR-875-5p (padj<0.001), hsa-miR-6749-5p (padj<0.001).
173 microRNA differed in phMEN1 and control groups (11 microRNAs upregulated, 162 — downregulated). We detected several decreased microRNAs in phMEN1 that participate in tumor genesis: hsa-miR-625-3p (padj<0.005), hsa-miR-3168 (padj=0,028), hsa-miR-302b-3p (padj<0.001).
Conclusion
We found microRNAs, which could potentially become biomarkers in phMEN1 diagnosis. The results need to be validated using different measurement method with larger sample size. Likewise further assessment of plasma microRNA expression in genetically confirmed MEN1 patients is needed.

Plasma MicroRNA Expression in Phenocopy of Multiple Endocrine Neoplasia Type 1 Compared to Patients with Acromegaly and Primary Hyperparathyroidism: Potential Biomarkers of Multiple Endocrine Tumor Growth

Background: Differential diagnosis of hyponatremia is challenging, particularly for thiazide associated hyponatremia (TAH), as patients might have either volume depletion in need for fluid substitution or syndrome of inappropriate antidiuresis (SIAD)-like presentation requiring fluid restriction. Urine indices are of little utility, because they are influenced by thiazide therapy. Apparent strong ion difference (aSID) describes the relation between sodium, potassium and chloride in serum and is used in evaluation of acid-base disorders according to Stewart model. aSID could help in the differential diagnosis of TAH because a value >40 identifies patients with contraction alkalosis due to relative hypochloremia, and hypochloremic alkalosis is a well-known possible adverse effect of thiazide diuretics.
Material and Methods: This was a post-hoc analysis of prospectively collected data of hospitalized patients with hypotonic hyponatremia <125 mmol/l. TAH patients were divided according to treatment response in patients needing intravenous fluid substitution or fluid restriction. Treatment response was defined as a sodium increase of at least 4 mmol/l/die or >130 mmol/l based on chart review. aSID at baseline was calculated with the formula serum sodium plus potassium minus chloride and a value >40 was used to identify volume-depleted TAH patients. Descriptive analysis was carried out to find differences between volume-depleted and SIAD-like TAH patients, and patients with SIAD without thiazide use. Logistic regression and ROC curves were computed to investigate the role of aSID>40 for differential diagnosis of hyponatremia in TAH patients, in addition to known factors for identifying SIAD patients as body mass index (BMI) and fractioned uric acid excretion (FUA) with the previous described cut-off of 12%.
Results: Out of 303 hyponatremia patients, 131 (43.2%) had a TAH and 75 (24.8%) SIAD without thiazide use. Among TAH patients, 81 (61.8%) were successfully treated with fluid substitution and 31 (23.7%) with fluid restriction. 19 patients (14.5%) were excluded as they received no treatment, or needed to switch treatment during hospitalization. No differences in baseline characteristics were seen between patients with SIAD and SIAD-like TAH patients, except for BMI, lower in SIAD patients (mean(SD) 23.5(5.1) vs 27.0(5.7) kg/m2, p=0.003). A higher BMI and a FUA<12% had a sensitivity of 84% with a specificity of 60% in identifying volume-depleted TAH patients. Adding aSID>40 improved the specificity to 74% maintaining a sensitivity to 82%.
Conclusion: In hospitalized patients with TAH, calculation of aSID may help differentiating patients with volume depletion in need of fluid substitution from SIAD-like manifestation requiring fluid restriction.

Role of Apparent Strong Ion Difference in the Differential Diagnosis of Thiazide Associated Hyponatremia

Background: Aneurysms of the internal carotid arteries are a rare cause of pituitary dysfunction1. While there are reports of primary amenorrhea in females due to ectatic internal carotid arteries2, hypogonadism in a male due to "kissing internal carotid arteries" causing compression of the pituitary gland has not previously been reported.
Clinical Case: A 27-year-old male with history of Crohn's disease, obesity, depression and sleep apnea on CPAP presented to endocrinology clinic for evaluation of low testosterone levels diagnosed 9 months prior to his initial visit. At the time of initial evaluation patient was using intramuscular testosterone cypionate 120mg weekly with total testosterone of 2.43 ng/mL (2.50-9.50 ng/mL). Testosterone replacement therapy was discontinued at that time to assess the hypothalamic-pituitary-gonadal (HPG) axis. After 9 months without testosterone treatment, repeat labs demonstrated total testosterone 0.91 ng/mL, bioavailable testosterone 0.69 ng/mL (1.10-4.0 ng/mL), SHBG 8 nmol/L (10-89 nmol/L), LH 3.1 mIU/mL (2-12 mIU/mL), FSH 2.7 mIU/mL (1.5-10 mIU/mL), estradiol 23 pg/mL (6-44 pg/mL), IGF-1 193 ng/mL (85-310 ng/mL), prolactin 10 ng/mL (3-23 ng/mL), TSH 1.03 mIU/L (0.3-5.5 mIU/L), FT4 1.15 ng/dL (0.76-1.70 ng/dL), 8 AM cortisol 13.5 ug/dL (5.3-22.5 ug/dL) and ACTH 37 pg/mL (5-52 pg/mL). Semen analysis was also performed which was unremarkable. Pituitary MRI revealed symmetric ectatic cavernous portions of the internal carotid arteries compressing and distorting the normal anatomy of the anterior pituitary gland consistent with "kissing carotid arteries." MRA was performed which did not demonstrate aneurysm or malformation of the cavernous internal carotid arteries. Patient was started on subcutaneous semaglutide 0.25mg weekly which was titrated to 1mg weekly for treatment of obesity. Testosterone replacement therapy was not re-initiated given future fertility goals and normal semen analysis.
Conclusion: To our knowledge, this is the first reported case of kissing internal carotid arteries causing isolated hypogonadotropic hypogonadism in a male patient.
References
1) Heshmati HM, Fatourechi V, Dagam SA, Piepgras DG. Hypopituitarism caused by intrasellar aneurysms. Mayo Clin Proc. 2001 Aug;76(8): 789-93. doi: 10.1016/S0025-6196(11)63222-9. PMID: 11499817
2) Sahin M, Dilli A, Karbek B, Unsal IO, Gungunes A, Colak N, Uçan B, Cakal E, Ozbek M, Delibasi T. Unusual cause of primary amenorrhea due to kissing internal carotid arteries. Pituitary. 2012 Jun;15(2): 258-9. doi: 10.1007/s11102-012-0393-9. PMID: 22492265.

Kissing carotid arteries: An unusual cause of male hypogonadotropic hypogonadism.

Background: Patients with hypopituitarism can have a complete or partial deficiency of pituitary hormones. If not treated adequately, it can result in episodes of myxedema coma or adrenal crisis. Our patient was unique with findings of both myxedema coma and adrenal crisis together on initial presentation.
Clinical Case: A 35-year-old female with a medical history of Sheehan's Syndrome, transient diabetes insipidus and lyme carditis presented to the emergency department with dizziness, lethargy, and generalized weakness for 1 day. EMS found her blood glucose level to be 21. The patient was given oral glucose. In the ED, her blood glucose level was found to be 34. She confessed she had been noncompliant with her medications for a month. She had no other complaints or possible precipitating factors including illness/trauma/stress. On admission, she was found to be hypothermic to 91.3 deg F, bradycardic to 40-50s, and hypotensive (Systolic 80s-90s/diastolic 50s-60s). On physical examination, she was thin and lethargic but oriented. No gross focal neurological deficits were noted. In addition to the initial hypoglycemia, her laboratory findings were significant for a TSH level of 0.52, T3 level of <30, T4 level of <0.5, eosinophilia as well as normal sodium levels. The sepsis workup was negative. Her VBG showed mild respiratory acidosis. For the myxedema coma and adrenal crisis, she was initially given hydrocortisone 100 mg and levothyroxine 200mcg. Her hypoglycemia improved after administration of these medications and intravenous fluids of dextrose-normal saline. The endocrinology service was consulted, and the patient was admitted to the ICU for monitoring. The next day her hypothermia, hypotension resolved and her lethargy, weakness improved. Once she was stabilized in the ICU, she was transferred to the floors. For the myxedema coma, once stable, she was started on oral levothyroxine 100mcg in accordance with weight-based dosing (1.6 mcg/kg daily) on the following day. Her free T4 level improved from 0.48 to 0.56 to 0.72. Her T3 level improved from <30.0 to 42.7. For the adrenal crisis, after the initial dose of IV hydrocortisone 100mg, it was tapered down to IV hydrocortisone 50 mg, then switched to oral prednisone daily. Eosinophilia from admission was mild which resolved later. Additional management of her history of Sheehan's Syndrome, her levels of LH 0.5, FSH 1.2, Estradiol <5, and Prolactin 0.6 were all low, so was advised to follow up with hormone replacement therapy outpatient.
Conclusion: This is an interesting case presentation of myxedema coma and adrenal crisis in a patient with a history of Sheehan's Syndrome. It is important to consider the unique and similar presentations of both myxedema coma and adrenal crisis such as hypotension, bradycardia, hypothermia, hypoglycemia, and lethargy.

Unique Case of Combined Presentation of Myxedema Coma and Adrenal Crisis in a Patient With Hypopituitarism or Post Sheehan's Syndrome

The anterior pituitary controls growth, metabolism, reproduction and stress responses through the synthesis and secretion of specific hormones. Distinct cell lineages within the anterior pituitary generate specific hormones. Interestingly, the anterior pituitary exhibits a high level of adult cell plasticity that allows committed hormone-producing cells to alter their cell fate and produce different hormones to meet altered organismal demands. The molecular mechanisms underlying this adult cell plasticity have not been fully characterized. Our recent work has implicated the stem cell determinant and sequence-specific mRNA binding protein, Musashi, as a regulator of pituitary cell plasticity. The mechanisms by which Musashi controls pituitary cell plasticity are unknown. In this study, we have sought to identify the mRNA regulatory targets of Musashi in the adult mouse pituitary. Through the use of Musashi-RNA-immunoprecipitation we report a cohort of 1192 pituitary mRNAs that specifically interact with Musashi. mRNAs specific to each of the hormone-producing cell lineages were identified, as well as mRNAs specific to immature stem and progenitor cell lineages. The biological pathways encoded by the Musashi-enriched mRNAs include cell adhesion, cellular homeostasis, unfolded protein responses, protein trafficking, endocrine processes and female pregnancy. Functional analysis of validated mRNAs reveals both activating and inhibitory control of mRNA translation by Musashi. Together, our findings indicate a broad and complex role for Musashi in the post-transcriptional regulation of adult pituitary function.

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