Martin Bidlingmaier

Apelin, a hormone secreted by the posterior pituitary, antagonises arginine vasopressin in salt and water homoeostasis. Administration of apelin analogues increased urine output in hyponatremic rodent models, but corresponding human data are lacking. We therefore investigated intravenous [Pyr¹]apelin-13 in healthy participants with artificially induced syndrome of inappropriate antidiuresis. In this double-blind, randomised, placebo-controlled crossover study, 15 healthy adults (7 female; mean age, 28 years [SD, 8]) attended three study visits. Hyponatremia was induced using desmopressin, water loading, and hypotonic saline. Participants subsequently received high-dose [Pyr¹]apelin-13 (1800 nmol), low-dose [Pyr¹]apelin-13 (180 nmol), or placebo as a 3-hour infusion. The primary endpoint was cumulative urine output from infusion initiation until 1 hour after its completion. Neither apelin dose produced a clinically relevant difference in urine output compared with placebo. ClinicalTrials.gov: NCT06277336. Funded by the Swiss National Science Foundation. Registration number: NCT06277336 .

Long-acting growth hormone (LAGH) preparations have moved from development to routine clinical use over the past decade. Several products are now approved for paediatric growth hormone deficiency (GHD), selected non-GHD short-stature indications, and, in some regions, for adult GHD. The Growth Hormone Research Society convened an international workshop in October 2025 to reappraise the evidence base and refine clinical recommendations. Currently, data are available for up to 7 years of LAGH treatment in over 8000 individuals. This remains substantially shorter and smaller than for daily GH. Across preparations, short- to mid-term efficacy appears comparable to daily somatropin, provided dosing is individualized and monitored appropriately. Approvals and pivotal trials include both treatment initiation and switching from daily GH, depending on product and regional label. No new major safety signals have been identified in trials and real-world reports, although data on BMI trajectories require further evaluation. Injection-site reactions remain the most frequent adverse event and vary by formulation. Anti-drug antibodies have been observed, yet evidence suggests they have limited clinical impact. Effects on glucose metabolism resemble those of daily therapy, but metabolically, high-risk groups are under-represented in studies. Among cancer survivors, data on tumour recurrence and second neoplasms with LAGH are not yet available. Recommendations and practice points emphasized careful patient selection and counselling, product-specific dosing, and insulin-like growth factor-I (IGF-I) monitoring. Urgent knowledge gaps include transition care, long-term efficacy, adherence, and safety in cancer survivors. Well-resourced registries are essential for addressing these gaps and supporting safe, effective, and patient-centred use of LAGH.

Objective: Women with classic congenital adrenal hyperplasia (CAH) suffer from reduced fecundity and fertility. This study aimed to assess fertility outcomes following treatment with modified-release hydrocortisone (MRHC), which more closely replicates the physiological circadian cortisol rhythm. Methods: In this prospective case series, 8 women with classic CAH and either menstrual irregularities or an unfulfilled desire to have children despite conventional glucocorticoid (GC) therapy for a median duration of 4 years, including assisted reproduction, were switched to MRHC. Hormonal parameters, including morning serum progesterone, 17-hydroxyprogesterone (17OHP), androstenedione, testosterone, and daily salivary 17OHP profiles, were assessed before and after the switch. Clinical outcomes included menstrual cycle regularity and pregnancy. Results: Descriptive analysis of morning serum samples indicate lower median concentrations of progesterone (0.9 vs 2.1 ng/mL [2.9 vs 6.7 nmol/L]), 17OHP (49.0 vs 131.5 ng/dL [1.5 vs 4.0 nmol/L]), androstenedione (76.0 vs 261.0 ng/dL [2.7 vs 9.1 nmol/L]), and testosterone (27.0 vs 63.0 ng/dL [0.9 vs 2.2 nmol/L]) after switching to MRHC with a lower median hydrocortisone dose equivalent (HDE) (30.0 vs 32.5 mg/day). Salivary 17OHP profiles showed a trend toward lower median area under the curve (AUC) (183.9 vs 676.5 pgxt(n)/mL) and lower concentrations across all time points. Regular menstrual cycles were restored in all patients. All 5 women seeking pregnancy conceived within a median of 9.8 months. Two unintended pregnancies occurred. Outcomes included 6 healthy live births and 1 early miscarriage. Conclusion: Modified-release hydrocortisone improved hormonal control and was associated with restoration of menstrual cyclicity and high rates of spontaneous conception with a lower HDE. Circadian optimization of GC therapy by MRHC may represent a paradigm shift in fertility management in females with CAH.

Context: Patients with endogenous Cushing syndrome (CS) exhibit reduced muscle strength compared with healthy individuals and frequently experience a further postoperative decline despite remission. Objective: To evaluate the histological and immunohistochemical patterns underlying myopathy in patients with active and remitted CS. Patients and methods: We included nine patients with active CS and eight patients with CS in remission, prospectively enrolled at XXX Hospital. Patients in remission had curative tumor surgery and biochemical remission for ≥24 months. Biopsies of the vastus lateralis muscle were obtained surgically and analyzed by histology, immunohistochemistry, and electron microscopy. IGF-1 concentrations were determined by IDS-iSYS analyzer. Results: In active CS, the mean cross-sectional area of type II muscle fibers was reduced. Nicotinamide-adenine-dinucleotide staining revealed mild moth-eaten fiber patterns in four patients, accompanied by ultrastructural pathologies on electron microscopy, including increased subsarcolemmal mitochondrial aggregates that were also present in remitted CS. In active CS circulating absolute IGF-1 concentrations positively (rs=0.8, p=0.014) and age inversely (rs= -0.77, p=0.021) correlated with mean cross-sectional area of type II muscle fibers. In remission from CS, type II fiber atrophy was not present in most patients. No substantial associations were found between the severity of glucocorticoid-excess and histological alterations during active or remitted disease. Conclusion: Active CS is characterized by type II fiber atrophy and is associated with circulating IGF-1 and age. In remission type II fiber atrophy was not present, whereas mitochondrial ultrastructural alterations could be observed. These findings indicate sustained muscle alterations and highlight the need for mechanistic studies to guide targeted therapies.

Purpose: Sleep disturbances are common in endogenous Cushing’s syndrome (CS), impair quality of life, and often persist despite remission. We evaluated the diagnostic value of actigraphy in suspected CS, characterised sleep and rest-activity patterns during remission, and examined associations between late-night salivary cortisol (LNSC) and objective sleep measures. Methods: Exploratory prospective single-centre cohort study at LMU Hospital Munich with two cohorts: (1) individuals evaluated for suspected CS and (2) patients in remission, stratified by recovered versus persistent adrenal insufficiency. Participants wore an ActTrust2 actigraph for 21 days, provided daily LNSC samples, and completed the Munich Chronotype Questionnaire. Results: Cohort 1 included 16 patients with confirmed CS and 13 with exclusion of CS. Actigraphy detected comparable sleep efficiency, fragmentation and circadian rest-activity rhythms in both groups, without distinct alterations attributable to active CS, except for a significantly earlier chronotype (p=0.022). Cohort 2 comprised 23 patients in remission (13 with persistent, 10 with recovered adrenal insufficiency) and showed similar sleep characteristics across subgroups. LNSC revealed high inter- and intraindividual variability without consistent associations with actigraphy-derived sleep parameters. Statistically significant effects were confined to patients with persistent adrenal insufficiency, in whom higher LNSC (likely reflecting non-physiological replacement therapy) was associated with earlier bedtime, longer time in bed, prolonged sleep-onset latency, and reduced sleep efficiency. Conclusion: Apart from chronotype, actigraphy showed limited discriminatory value between clinical groups. LNSC was highly variable and showed no consistent associations with sleep parameters, underscoring the need for improved biomarkers and monitoring strategies in CS.

STUDY QUESTION: Does late-night, modified-release hydrocortisone (MR-HC) improve biochemical control and restore menstrual regularity in women with non-classic congenital adrenal hyperplasia (NCCAH)? SUMMARY ANSWER: Once-daily MR-HC substantially improved biochemical androgen control and rapidly restored menstrual cyclicity in women with NCCAH, including those with longstanding irregular cycles. WHAT IS KNOWN ALREADY: While pregnancy rates in women with NCCAH are generally comparable to those of the general population, time to conception is often prolonged and assisted reproductive techniques are frequently required. Optimizing adrenal androgen suppression through the superior pharmacokinetic profile of MR-HC may shorten this interval and reduce the need for fertility interventions. So far, MR-HC has not been tested in NCCAH. STUDY DESIGN, SIZE, DURATION: Prospective observational cohort study conducted between September 2021 and November 2025 at a tertiary referral center and European Reference Network (Endo-ERN) hub for congenital adrenal hyperplasia. Thirty women with NCCAH were enrolled and followed for a median of 22.5 months (interquartile range [IQR] 8.25–36.75), with up to five study visits. Only women with at least 3 months of follow-up were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cohort comprised 30 women with NCCAH. At initiation of MR-HC, 20 women transitioned from conventional glucocorticoid therapy, and 10 were treatment-naïve. Sixteen women had an active desire to conceive, while 15 presented with irregular menstrual cycles or secondary amenorrhea at baseline. MAIN RESULTS AND THE ROLE OF CHANCE: Among 14 evaluable women, ovulatory function, defined as return of regular menstrual cycles or conception, was restored in 13 (92.6%) of women within 6 months of MR-HC initiation. One woman with concomitant hypothalamic hypogonadism remained amenorrhoeic and commenced hormone replacement therapy. Cycle normalization occurred at a median MR-HC dose of 10 mg (IQR 10–15 mg), with all but one woman receiving a single bedtime dose. Among 16 women seeking pregnancy, ten conceived within a median of 2.65 months (IQR 2.0–12.4) compared to 8 months (IRQ 1.0-24.0) in a historic cohort of NCCAH women before the approval of MR-HC (not significant). Among those seeking pregnancy, 10 women had been attempting to conceive unsuccessfully for a median of 28.5 months (IQR 12–46) before. Six women did not become pregnant during follow-up (13.5 months; IQR 6.25–23). The hydrocortisone equivalent dose (HCeq) at the time of conception was significantly lower under MR-HC (10.0 mg (IQR 10–12.5) vs. 16.9 mg (IQR 15–25), P = 0.02) in the historic cohort. Transition to MR-HC led to marked reductions in early-morning salivary 17-hydroxyprogesterone and serum testosterone, independent of prior glucocorticoid (GC) exposure. Metabolic effects were minimal: body weight decreased slightly, glycated hemoglobin (HbA1c) rose transiently, predominantly in treatment-naïve women, before returning to baseline. Blood pressure, fasting glucose, and lipid profiles remained stable. LIMITATIONS, REASONS FOR CAUTION: While the rapid normalization of, in part, long-standing menstrual irregularities was striking, the absence of a control group does not allow causal inferences, and the single-center design within a specialized tertiary setting may limit generalizability. WIDER IMPLICATIONS OF THE FINDINGS: A single nightly dose of MR-HC appears sufficient to achieve hormonal control and subsequent menstrual-cycle restoration in most women with NCCAH and may improve time to conception. These findings support MR-HC as a promising therapeutic option in the management of NCCAH. FUNDING: This work was supported by the Deutsche Forschungsgemeinschaft (Heisenberg Professorship 325768017, project 314061271 TRR205 to NR and FBCRC-1665 -515637292 to NR and UK). LT was supported by the LMU Munich funding scheme (FöFoLe) and by the IFCAH (International Fund Congenital Adrenal Hyperplasia) grant 2023. HN was supported by the Clinician Scientist Program RISE, supported by the Eva Luise und Horst Köhler Stiftung & Else Kröner-Fresenius-Stiftung (2019_KollegSE.03 to HN). DISCLOSURES: N.R. was Principal Investigator and consulted for Neurocrine Biosciences and Diurnal Ltd. L.T., M.K. A. und H.F.N. were Sub-Investigators for Neurocrine Biosciences and Diurnal Ltd. TRIAL REGISTRATION NUMBER: N/A

Objective: To evaluate outcomes after switching from conventional glucocorticoids (GCs) to modified-release hydrocortisone (MR-HC; Efmody) in adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency under real-life conditions. Design: Prospective, observational cohort study at a tertiary endocrine center. Methods: Sixty-two adults with classic CAH (25 male; 42 salt-wasting) were switched to MR-HC and followed up for at least 12 months and up to 4 visits or until termination of treatment (median 23.5 months; visit 4 not yet completed in 6/62). Outcomes included hormonal control, metabolic parameters, and menstrual patterns. Results: At baseline, 42/62 patients had androstenedione (A4) within the reference range, 13/62 showed elevated concentrations, and 7/62 had suppressed concentrations. At the last available visit, 11/13 of patients with elevated A4 normalized. Salivary 17-hydroxyprogesterone decreased significantly in the early morning (P = .025), 12 Pm (P = .036) and 4 Pm (P = .042). Median hydrocortisone-equivalent dose declined from 30 mg (IQR 25-37.5) to 25 mg (IQR 20-30) (P < .001). HOMA-IR improved (2.15-1.67; P = .023), while other metabolic parameters remained stable. Daytime blood systolic and diastolic pressure decreased by ∼5 mmHg (P = .007 and P = .003). Fludrocortisone was reduced in 12/41 (29.3%) salt-wasting patients. Among women with menstrual disturbances (12/42), 6/12 normalized and 1/12 conceived; among women with regular cycles, 3/12 developed irregular cycles or amenorrhea. The adrenal crisis rate was 5.0 per 100 patient-years. Conclusion: MR-HC enabled stable biochemical control with reduced GC exposure and was associated with improvements in insulin sensitivity, blood pressure, and menstrual regularity, supporting its role as a safe and physiological treatment option in adults with CAH.

Context: Cushing’s syndrome (CS) is associated with an unfavorable lipid profile. However, data on lipid alterations during early postoperative remission, a particularly cardiovascular vulnerable period, are lacking. Objective: Evaluation of lipid profiles during active CS and the early postoperative period. Patients and methods: In this single-center cohort study at LMU Hospital, Munich, we analyzed lipid profiles (total cholesterol, LDL, HDL, ApoA1, ApoB, lipoprotein (a), triglycerides, and non-esterified fatty acids) and metabolic markers in 26 patients with endogenous CS before surgery and 1, 3, 6, 12 and 24 months (n = 23) after curative surgery and compared them with 26 age-, BMI-, and sex-matched controls without hypercortisolism at baseline. Results: Paradoxically, most lipid parameters worsened postoperatively. One month following surgery, HDL (1 month postoperative 38 mg/dL [35-46] vs. active CS 49.5 mg/dL [45-61.3], P < .0001) and ApoA1 concentrations (1-month postoperative 160 mg/dL [147-168] vs. active CS 193 mg/dL [169-211], P < .0001) were significantly lower compared to preoperative levels. Similarly, 1-month following surgery triglycerides concentrations (1-month postoperative 185 mg/dL [154-218] vs. active CS 129 mg/dL [89.3-186] preoperatively, P < .0001) were higher. These changes remained evident until 6 months post-surgery. The triglyceride-glucose index increased during early remission and showed a positive correlation with inflammatory markers CRP and IL-6. Non-esterified fatty acids displayed 3 distinct postoperative trajectories depending on BMI at baseline. Conclusion: During the early remission phase following curative surgery for CS, we observed a further deterioration in lipid parameters. This can affect cardiovascular health and provide the basis for targeted therapy.

Background: The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity. Methods: We evaluated the ISPa in: (1) GHD subjects with homozygous GHRH-R c.57 + 1G→A mutation, (2) heterozygotes (HTZ), and (3) homozygous wild-type controls (HMZ). Parameters from the ISPa were measured at LMU Klinikum, Munich. Additional biochemical parameters were analyzed at the Federal University of Sergipe, Brazil. Results: As expected, GHD subjects had markedly low GH, IGF-I, IGF-II, free IGF-I, and IGFBP 3 (P < .001), while HTZ resembled HMZ subjects. STC2, PAPP-A, and PAPP-A-STC2 complex concentrations did not differ between groups. However, PAPP-A2 and intact IGFBP 4 were higher in the GHD subjects (P < .05 and P < .01). Notably, IGF-I and IGFBP 3 positively correlated with IGF-II, whereas intact IGFBP 4 and PAPP-A2 showed inverse correlations with IGF-I and IGF-II. Conclusion: Our findings suggest altered IGF-I bioavailability regulation via the ISPa in congenital lifetime GHD, leading to increased PAPP-A2 proteolytic activity, reduced PAPP-A enzymatic activity, and reduced sequestration of PAPP-A2 by STC2.