Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital.

Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.)

Context: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. Design and Participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C). Conclusions: Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain.

Context: Idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH) or anosmia (Kallmann syndrome) is associated with defects in the production or action of GnRH. Accordingly, most IHH patients respond to physiological pulsatile GnRH replacement by normalizing serum LH, FSH, and testosterone (T) levels and achieving gametogenesis; some patients, however, show atypical responses. Interestingly, several IHH-associated genes are expressed in multiple compartments of the hypothalamic-pituitary-gonadal axis. Objective: The aim of the study was to investigate whether the clinical, biochemical, or genetic characteristics of IHH men with atypical responses to GnRH indicate alternative or additional defects in the hypothalamic-pituitary-gonadal axis. Subjects: We studied 90 IHH men undergoing long-term pulsatile GnRH treatment over 30 yr. Design and Setting: We conducted a retrospective study of response to GnRH at a Clinical Research Center. Interventions: Physiological regimens of pulsatile sc GnRH were administered for at least 12 months. Dose-response studies using iv GnRH pulses assessed the pituitary LH response. Main Outcome Measures: We measured serum T, LH, FSH, and inhibin B levels, sperm in ejaculate, and determined the sequence of IHH-associated genes. Results: Twenty-six percent of subjects displayed atypical responses to GnRH: 1) 10 remained hypogonadotropic and hypogonadal, demonstrating pituitary and testicular defects; 2) eight achieved spermatogenesis and normal T but only with hypergonadotropism, indicating impaired testicular responsiveness to gonadotropins; and 3) five remained azoospermic despite achieving adult testicular volumes and normal hormonal profiles, suggesting primary defects in spermatogenesis. Mutations were identified only in KAL1 across groups. Conclusion: In addition to hypothalamic GnRH deficiency, IHH men can have primary pituitary and/or testicular defects, which are unmasked by GnRH replacement.

Artificial pancreas (AP) systems have shown an improvement in glucose control and a reduced risk of nocturnal hypoglycemia under controlled conditions but remain to be evaluated under daily-life conditions. To assess the feasibility, safety, and efficacy of the MD-Logic AP in controlling nocturnal glucose levels in the patient's home. Two-arm study, each covering four consecutive nights comparing the MD-Logic AP ('closed-loop' arm) with sensor-augmented pump therapy ('control' arm). Fifteen patients (mean age 19 ± 10.4 yr, A1c 7.5 ± 0.5% or 58 ± 5.9 mmol/mol, diabetes duration 9.9 ± 8.2 yr) were randomly assigned either to 'Group A' (first 'closed-loop', then 'control' arm) or to 'Group B' (vice versa). Investigators were masked to treatment intervention. Primary endpoints were the time spent with glucose levels below 70 mg/dL and the percentage of nights in which the mean overnight glucose levels were within 90-140 mg/dL. Endpoint analyses were based on unmodified sensor glucose readings of the four study nights. Time of glucose levels spent below 70 mg/dL was significantly shorter on the closed-loop nights than on control nights, median and interquartile range 3.8 (0, 11.6) and 48.7 (0.6, 67.9) min, respectively; p = 0.0034. The percentage of individual nights in which mean overnight glucose level was within 90-140 mg/dL was 67 (33, 88), and 50 (25, 75), under closed-loop and control nights, respectively, with no statistical difference. Secondary endpoint analyses demonstrated significant improvements in hypoglycemia parameters. No serious adverse events were reported. This interim analysis demonstrates the feasibility, safety, and efficiency of the MD-Logic AP system in home use, and demonstrates an improvement over sensor-augmented pump therapy. (ClinicalTrials.gov identifier NCT01726829).

Objective: Thyroid dyshormonogenesis is a genetically heterogeneous group of inherited disorders in the enzymatic cascade of thyroid hormone synthesis that result in congenital hypothyroidism (CH). Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis. The aim of this study was to identify TPO gene defects in a cohort of patients with thyroid dyshormonogenesis from Slovenia, Bosnia, and Slovakia. Design and methods: Forty-three patients with permanent CH and orthoptic thyroid glands from 39 unrelated families participated in the study. Mutational analysis of the TPO gene and part of its promoter consisted of single-stranded conformation polymorphism analysis, sequencing, and restriction fragment length polymorphism (RFLP) analysis. Results: TPO gene mutations were identified in 46% of participants. Seven different mutations were identified, four mutations of these being novel, namely 613C > T (R175X), 1519_1539del (A477_N483del), 2089G > A (G667S), and 2669G > A (G860R). Only a single allele mutation was identified in 65% of the TPO mutation carriers. Conclusions: The results showed a higher prevalence of TPO gene mutations in thyroid dyshormonogenesis when compared with published studies. The high percentage of single allele mutations implied possible intronic or regulatory TPO gene mutations or monoallelic expression.