Aug 2026· Journal of Clinical Endocrinology and Metabolism· 0 citations
Medicine
TL;DR
Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS, and the observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects.
Abstract
Background
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood.
Methods
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Findings
After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter.
Interpretation
Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects.
Funding
German Federal Ministry of Research and Education and Rhythm Pharmaceuticals.
The temporal decline of circulating miR-1-3p levels and the identification of PKC support a model in which miR-1-3p may contribute to functional maturation of the ZR through modulation of non-canonical intracellular signaling pathways.
Jani Liimatta, Emre Murat Altınkılıç, Therina du Toit et al.· Journal of Clinical Endocrin...· 0 citations
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) and male hypogonadism are increasingly prevalent, metabolically interrelated conditions. Testosterone (T) deficiency has been implicated in hepatic lipid dysregulation, insulin resistance, and visceral adiposity, whereas MASLD may impair the hypothalamic-pituitary-gonadal axis. We conducted a systematic review and meta-analysis to evaluate the bidirectional association between circulating T levels and MASLD in adult men.
METHODS
Following PRISMA guidelines, a literature search was performed from inception to July 31, 2025. Twenty-eight studies met the inclusion criteria (9 comparing hypogonadal vs. eugonadal men; 19 comparing MASLD vs. non-MASLD men). Random-effects models were used to pool effect sizes for dichotomous and continuous outcomes. Meta-regression analyses assessed the influence of age, anthropometric features, glycemic markers, liver enzymes, and hormonal parameters.
RESULTS
Hypogonadal men showed a significantly higher prevalence of MASLD than eugonadal men (p = 0.001) and exhibited higher fatty liver index scores (p < 0.001). Total T concentrations were significantly lower in men with MASLD than in controls (p = 0.014). Meta-regression analyses did not identify significant effects of study-level differences in age, body mass index, or biochemical variables on the observed associations. Sex hormone-binding globulin levels were also significantly reduced in MASLD (p < 0.001), with age emerging as the only significant modifier. No significant differences were observed for luteinizing hormone, estradiol, or fibrosis-4 index. Across studies evaluating MASLD severity, moderate-to-severe disease was associated with lower T levels, particularly in analyses based on imaging.
CONCLUSIONS
This meta-analysis supports a clinically relevant association between testosterone deficiency and MASLD, although evidence for the bidirectional nature of this relationship remains asymmetric but supports a clinically relevant endocrine-hepatic axis. T deficiency appears independently linked to MASLD onset and severity beyond the effects of age and adiposity. These findings underscore the need for reciprocal screening of liver health and gonadal status in at-risk men and highlight the importance of prospective studies and randomized trials to determine whether correcting T deficiency may modify MASLD progression.
G. Spaggiari, L. Valentina, C. Felicani et al.· Andrology· 0 citations
Abstract Objectives The melanocortin-4 receptor (MC4R) is a G protein–coupled receptor that regulates energy homeostasis. Pathogenic MC4R variants represent the most common cause of monogenic obesity and are frequently associated with increased linear growth. However, the mechanisms linking MC4R signaling to somatic growth remain incompletely understood. We report a child with severe growth hormone deficiency (GHD) carrying a heterozygous MC4R variant (c.496G>A; p.V166I), in whom recombinant human growth hormone (rhGH) therapy triggered an unexpectedly exaggerated clinical and biochemical response, suggesting a potential pharmacogenetic interaction between MC4R signaling and the GH/IGF-1 axis. Case presentation The male patient was first evaluated at 1 month of age due to micropenis and diagnosed with multiple pituitary hormone deficiencies. At 57 months of age, his height was 97.3 cm (−2.56 SDS) and annual growth velocity was 4.1 cm/year (<−2 SDS); rhGH (somatropin) therapy was initiated. Despite severe biochemically confirmed GHD, rhGH at 0.03 mg/kg/day triggered an exaggerated response: IGF-1 levels increased from −3.35 SDS to +8.00 SDS. Concurrently, his height velocity accelerated to 16 cm/year, and his bone age rapidly advanced by approximately 4 years over a 23-month period, culminating in mandibular prognathism. Conclusions The coexistence of severe GHD and an MC4R variant is rarely described, and such a pronounced response to rhGH has not previously been reported. These findings suggest that MC4R p.V166I may modulate peripheral GH/IGF-1 signaling and act as a pharmacogenetic modifier of GH responsiveness. Careful rhGH dose titration with close IGF-1 monitoring may be considered in patients carrying the MC4R p.V166I variant.
Ertuğrul Sancak, Muammer Büyükinan, Ahmet Fatih Yılmaz et al.· Journal of Pediatric Endocri...· 0 citations
BACKGROUND
A phase 2 trial of setmelanotide, a melanocortin-4 receptor agonist, showed substantial weight loss in patients with acquired hypothalamic obesity, but additional data are needed.
METHODS
We conducted a phase 3 trial in which participants were randomly assigned in a 2:1 ratio to receive setmelanotide (at a dose of 1.5 to 3.0 mg) or placebo administered subcutaneously once daily for 52 weeks after a dose-escalation period. Persons at least 4 years of age were potentially eligible for the trial if they had acquired hypothalamic obesity, which was defined by a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) that was at or above the 95th percentile for age and sex (for participants <18 years of age) or at least 30 (for participants ≥18 years of age) and a history of a hypothalamic tumor, lesion, or injury. The primary end point was the mean percent change in BMI from baseline to 52 weeks after the end of the dose-escalation period. Secondary end points included the mean change in the weekly average of the maximal daily hunger score (range, 0 to 10, with higher scores indicating more severe hunger), assessed in participants at least 12 years of age.
RESULTS
From April 26, 2023, to March 18, 2025, a total of 120 participants were assigned to receive setmelanotide (81 participants) or placebo (39 participants). The mean (±SD) age was 19.9±13.8 years (range, 4 to 66). Among participants 18 years of age or older, the mean BMI was 41.2±9.7; the mean BMI z score among those younger than 18 years of age was 3.61±1.66. The least-squares mean (LSM) change in BMI at 52 weeks was -16.5% (95% confidence interval [CI], -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001), and the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P = 0.009). Adverse events were reported in 100% of the participants in the setmelanotide group and in 90% of those in the placebo group, and serious adverse events were reported in 28% and 8%, respectively. The most common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache.
CONCLUSIONS
Setmelanotide led to significantly greater reductions in BMI and hunger than placebo at 52 weeks among participants 4 to 66 years of age with acquired hypothalamic obesity. (Funded by Rhythm Pharmaceuticals; TRANSCEND ClincialTrials.gov number, NCT05774756.).
J. Miller, H. vanSanten, Susan A Phillips et al.· New England Journal of Medic...· 4 citations· ⚡1
Male hypogonadism is associated with metabolic and cardiovascular comorbidities, and emerging evidence implicates testosterone deficiency in immune dysregulation that may elevate cancer risk. To review current evidence on the relationship between male hypogonadism, immune function, and cancer risk, focusing on mechanisms linking testosterone deficiency to immune suppression and oncologic outcomes. PubMed/MEDLINE, Google Scholar, and SciSpace were systematically searched (through April 2026) using predefined search strings. After removal of duplicates (n = 1535 records screened), 156 full-text articles were assessed for eligibility; 20 studies met predefined inclusion criteria (comprising 4 experimental studies, 4 prospective/RCT studies, 7 observational studies, and 5 reviews used as secondary literature) and were included in a narrative synthesis. Testosterone deficiency was consistently associated with elevated IL-6, TNF-α, IL-1β, and CRP, impaired neutrophil maturation, and reduced NK-cell cytotoxicity. Androgen deprivation augmented thymic output and anti-tumor T cell responses in prostate cancer models, yet promoted chronic inflammation in other contexts. Epidemiologically, low testosterone correlated with increased colorectal cancer risk and poorer survival in advanced malignancies; the prostate cancer relationship followed a paradoxical saturation model. The immunological consequences of hypogonadism are context-dependent. Testosterone deficiency drives pro-inflammatory signaling that may promote carcinogenesis, while androgen-mediated immunosuppression can paradoxically impair anti-tumor surveillance. No simple linear relationship exists between hypogonadism and cancer risk via immune suppression. Prospective studies are needed to guide clinical decisions on testosterone replacement therapy in hypogonadal men.
S. La Vignera, R. Condorelli· International Journal of Mol...· 0 citations
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by metabolic dysfunction, hyperandrogenism, and reproductive hormone imbalance. This meta-analysis aimed to evaluate the effects of ketone supplementation on anthropometric, metabolic, and hormonal parameters in patients with PCOS.
A systematic search of major electronic databases was conducted to identify clinical studies evaluating the impact of ketone supplementation on BMI, serum glucose, insulin, lipid profile, and reproductive hormones in women with PCOS. Pooled analyses were performed using inverse-variance (IV) random-effects models. Heterogeneity was assessed using I
2
statistics and χ
2
tests, while publication bias was evaluated using funnel plots.
A significant reduction in BMI was observed following ketone supplementation (IV − 13.08; 95% CI − 17.47 to − 8.69;
P
< .00001; I
2
= 0%), with symmetrical funnel plots indicating low publication bias. Serum glucose levels showed a marked decrease (IV − 10.83; 95% CI − 12.98 to − 8.68;
P
< .00001; I
2
= 93%), and insulin levels demonstrated a similarly significant reduction (IV − 11.87; 95% CI − 15.30 to − 8.44;
P
< .00001; I
2
= 93%). Cholesterol levels also decreased, although the change was not statistically significant (IV − 10.77; 95% CI − 26.84 to 5.30;
P
= .19; I
2
= 0%). Significant reductions were identified in LH levels (IV − 5.30;
P
< .00001) and androgen levels (IV − 6.93;
P
= .0001). In contrast, FSH and estrogen levels showed significant increases (both
P
< .00001).
Ketone supplementation appears to confer significant metabolic and endocrine benefits in women with PCOS, including reductions in BMI, glucose, insulin, LH, and androgens, along with increases in FSH and estrogen.
Sajjad Ahmed Khan, S. Kulsum, Anuj Subedi et al.· Medicine· 0 citations