Background Hypoparathyroidism (HypoPT) is characterized by parathyroid hormone (PTH) deficiency and hypocalcemia and is often caused by damage/removal of parathyroid glands during neck surgery. Conventional treatments with oral calcium and 1,25(OH) 2 vitamin D can lead to blood calcium fluctuations, hypercalciuria, and renal complications. PTH-replacement strategies can potentially restore reduced bone remodeling in HypoPT. Eneboparatide (AZP-3601/LA-PTH), a PTH1 receptor (PTH1R) agonist, induces prolonged calcemic responses and shows promise in clinical trials as a potential treatment for HypoPT, but its effects on bone are uncertain. Objectives Determine optimal doses of eneboparatide and PTH(1-34) for normalizing serum calcium in thyroparathyroidectomized (TPTX) rats and evaluate the effects on bone microarchitecture and bone turnover markers. Methods This dose-range analysis in TPTX rats compared effects of daily subcutaneous injections of eneboparatide or PTH(1-34) or continuous PTH(1-34) infusion on serum calcium, bone microarchitecture, and bone turnover markers. Male Sprague-Dawley TPTX rats (∼8 per group) were treated for 16 days with eneboparatide daily subcutaneous injection (1.0, 2.0, or 4.0 nmol/kg), PTH(1-34) continuous infusion (1.5, 2.0, or 3.0 nmol/kg daily), or PTH(1-34) daily subcutaneous injection (50 nmol/kg). Blood ionized calcium and serum total calcium were measured at various timepoints. On day 16 (24 hours after last injection), serum was analyzed for P1NP, CTX-1, and TRAP-5b and femur bone microarchitecture was analyzed using microcomputed tomography. Results Optimal doses for normalizing serum calcium were PTH(1-34) 50 nmol/kg daily subcutaneous injection, PTH(1-34) 3.0 nmol/kg daily continuous infusion, and eneboparatide 1.0 nmol/kg daily subcutaneous injection; higher eneboparatide doses (2.0 and 4.0 nmol/kg) caused hypercalcemia. At optimal doses, eneboparatide produced minimal changes in bone turnover markers and microarchitecture; PTH(1-34) daily subcutaneous injection showed anabolic effects on bone, and PTH(1-34) continuous infusion exerted catabolic effects. Conclusions Eneboparatide normalized serum calcium in TPTX rats without compromising bone microarchitecture, supporting potential therapeutic use for HypoPT.
Background Management of adrenal insufficiency (AI) can be challenging for patients, requiring daily hormone replacement and monitoring of symptoms to avoid life-threatening crises. In diabetes, another chronic endocrinopathy, the demands of disease management impact the wellbeing of the loved ones (LOs) living with the affected person. Research into LOs of persons with diabetes has helped identify unmet needs and areas of improvement to target future interventions. Similar research exploring LOs of individuals with AI is lacking. Objectives The objectives are to (1) examine the role of LOs of persons with AI in disease management, and (2) to explore the impacts of AI on the LOs. Methods We conducted an exploratory qualitative study using one-on-one semi-structured interviews with LOs of persons with AI. Recruitment was accomplished via criterion sampling at an academic endocrinology outpatient clinic with a goal of 15-20 participants. Interviews were transcribed and analyzed using thematic analysis. A sample of transcripts were independently coded by two researchers to create a codebook which was used to guide analysis of the remaining transcripts and develop initial themes. Themes were finalized in consultation with the broader team. Results Fifteen interviews were completed. We identified 5 overarching themes. (1) There is an imposition of roles and responsibilities on the LOs because of AI. (2) LOs are often required to bridge gaps in formal care without formal training. (3) LOs live with constant fear of adrenal crisis. (4) Even outside of acute incidents, there are noticeable impacts of the disease on day-to-day living. Finally, (5) the magnitude of impacts on the LO is linked to their perception of the patient’s ability to manage their condition independently. Conclusion Persons with AI often require support from LOs to effectively manage their condition. This is the first study seeking to understand the lived experience of LOs of individuals with AI. The themes we have identified depict previously undocumented morbidity resulting from AI. Furthermore, these themes demonstrate that care gaps exist and that future studies focusing on increasing education and support of LOs may benefit them and the persons with AI.
Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare but potentially life-threatening immune-related adverse event, most commonly associated with programmed cell death protein 1 (PD-1) inhibitors. It is characterized by abrupt and often irreversible β-cell failure, frequently presenting with diabetic ketoacidosis (DKA). Early recognition is challenging because symptoms may be nonspecific and islet autoantibodies may be absent. We report the case of a 62-year-old man with stage IV BRAF V600E-positive metastatic melanoma who developed polyuria, polydipsia, nausea, vomiting, and rapid weight loss approximately 10 days after his third pembrolizumab infusion. He presented with severe DKA, including a glucose level of 658 mg/dL, arterial pH of 7.02, bicarbonate of 6 mmol/L, anion gap of 32 mEq/L, and β-hydroxybutyrate of 7.2 mmol/L. C-peptide was undetectable (<0.1 ng/mL), while GAD65, IA-2, ZnT8, and islet cell antibodies were negative. Pancreatic enzymes and imaging were unremarkable, and no alternative cause of insulin deficiency was identified. He responded promptly to standard DKA management with intravenous fluids, insulin, and electrolyte replacement and was subsequently transitioned to lifelong basal-bolus insulin therapy. C-peptide remained undetectable at 6 months, while HbA1c improved from 8.9% to 6.8% and time in range reached 82%. Pembrolizumab was permanently discontinued following multidisciplinary assessment. ICI-associated diabetes requires early recognition, prompt DKA management, and lifelong insulin therapy. Future research should identify predictive genetic and immunologic biomarkers, optimize glucose and ketone surveillance, clarify mechanisms of β-cell destruction, and establish safe strategies for continuing or rechallenging immunotherapy.
Background/Objective Gestational diabetes mellitus (GDM) leads to changes in maternal blood pressure indices, resulting in preeclampsia as well as fetal abnormalities. This study aims to describe the relationship between blood pressure indices with some clinical and paraclinical characteristics in GDM without coexisting hypertension. Methods A cross-sectional study analyzing 371 women with GDM and no coexisting hypertension, diagnosed for the first time was conducted from 2015 to 2023. The preeclampsia risk factors examined in this study included insulin resistance, blood glucose levels, obesity, advanced maternal age (over 35 years), and primigravidity. Systolic and diastolic blood pressure (SBP and DBP) were measured at rest on at least two separate occasions. Results GDM with obesity had significantly higher SBP and DBP than the group without obesity (113.0 vs 107.7 mmHg for SBP and 70.0 vs 66.0 mmHg for DBP, all p < 0.001). The group diagnosed with GDM by fasting plasma glucose (FPG) criteria had significantly higher SBP than the group without increased FPG (111.9 vs 109.5 mmHg, p = 0.02). The group diagnosed with GDM by 2-hr post-oral glucose tolerance test criteria had significantly higher SBP and DBP than the group without increased values (111.1 vs 108.9 for SBP and 68.5 vs 66.8 for DBP, all p < 0.05). TyGBMI index (TyGBMI) was weakly associated with SBP (beta = 0.16, p < 0.001). Additionally, hemoglobin levels significantly contributed to the variance (beta = 0.12, p = 0.005). When tested separately, pre-pregnancy BMI remained a dominant factor (beta = 0.65, p < 0.001). Similar trends were observed for DBP, with TyGBMI showing a positive correlation (beta = 0.11, p < 0.001). Hemoglobin also remained an independent predictor (beta = 0.09, p = 0.012), while pre-pregnancy BMI maintained high significance (beta = 0.41, p < 0.001). Conclusion Our descriptive study highlights pre-pregnancy BMI and the TyGBMI index as significant metabolic correlates of blood pressure levels. Furthermore, the observed association with Hemoglobin suggest that hematological factors may also play a role in the hemodynamic profile of this population.
Immune checkpoint inhibitors, particularly programmed cell death protein 1 (PD-1) inhibitors, can cause endocrine immune-related adverse events, including hypophysitis and secondary adrenal insufficiency. Isolated adrenocorticotropic hormone (ACTH) deficiency is uncommon but may present as a life-threatening adrenal crisis. We report the case of a 65-year-old man with stage IV BRAF wild-type metastatic melanoma receiving pembrolizumab who presented with profound fatigue, nausea, vomiting, weight loss, orthostatic dizziness, and hypotension. Laboratory evaluation revealed severe hyponatremia, mild hyperkalemia, hypoglycemia, and acute kidney injury. Serum cortisol was 2.1 µg/dL with an inappropriately low ACTH concentration of <5 pg/mL. A conventional 250 µg cosyntropin (Synacthen) stimulation test demonstrated an inadequate cortisol response, while other pituitary axes remained preserved. Pituitary magnetic resonance imaging showed mild enlargement and stalk thickening, consistent with hypophysitis. Intravenous hydrocortisone and fluid resuscitation rapidly restored hemodynamic and metabolic stability. At 6 months, ACTH remained <5 pg/mL, with persistent isolated corticotroph deficiency. Pembrolizumab-associated isolated ACTH deficiency should be considered when patients develop unexplained constitutional symptoms, hypotension, hyponatremia, or hypoglycemia. Prompt cortisol and ACTH assessment and glucocorticoid treatment are essential to prevent morbidity and mortality.
