Asymptomatic left ventricular dysfunction in patients with type 2 diabetes free of cardiovascular disease and its relationship with clinical characteristics: The DIACAR cohort study.

AIMS: To assess the prevalence, type and clinical factors associated with left ventricular (LV) dysfunction in patients with type 2 diabetes mellitus (T2DM) by performing a comprehensive echocardiographic Doppler assessment including speckle tracking. METHODS: Two hundred T2DM patients without overt cardiovascular disease were prospectively enrolled in a single-centre cohort study between 2018 and 2019. RESULTS: Left ventricular mass was increased in 24 patients (12%) and relative wall thickness (h/r) was increased in 46 patients (23%). Left atrial (LA) enlargement was observed in 27 patients (13.6%) and global longitudinal strain (GLS) was reduced in 38 patients (20.3%). In univariate analysis, LV hypertrophy (LVH) or increased h/r were associated with age, renal function, hypertension and B-type natriuretic peptide (BNP) plasma level. LA dilation was associated with age, history of hypertension, diabetes duration and complications, insulin treatment, BNP level and renal function. GLS was associated with body mass index (BMI) and, in a borderline manner, with diabetes duration. In multivariate analysis, hypertension was associated with LVH and with h/r and a borderline relationship was observed for female gender (LVH), age and insulin treatment (h/r). Age, hypertension and, in a borderline manner, insulin treatment were associated with LA dilation. BMI and shorter diabetes duration were associated with reduced GLS. CONCLUSION: A high prevalence of asymptomatic cardiac dysfunction/structural abnormalities was observed in patients with T2DM without overt cardiac disease and was associated with either age, diabetes duration or treatment and with comorbidities including hypertension and obesity. Whether these preclinical abnormalities are associated with poor outcomes warrants further study.

NR5A1 (SF-1) mutations are not a major cause of primary ovarian insufficiency.

CONTEXT: Primary ovarian insufficiency (POI) is a disorder affecting approximately 1% of women under the age of 40 years. NR5A1 (SF-1) mutations have been recently reported in association with POI. OBJECTIVE: Our objective was to evaluate the frequency and functional impact of NR5A1 variants in POI. PATIENTS AND METHODS: One hundred eighty patients diagnosed with idiopathic POI were screened for NR5A1 mutations and functional analysis was performed for the identified variants. The DNA-binding capacity of the variants was evaluated by means of EMSA, while their transcriptional activity was assessed using luciferase reporter assays. RESULTS: Sequencing the NR5A1 gene revealed 4 missense variants in 3 patients. These patients were aged 20, 25, and 33 years at diagnosis and presented with secondary amenorrhea. None of them presented a syndromic form, although 2 had a familial history of POI. The functional analysis carried out for these missense variants showed no significant difference in DNA binding capacity or in transcriptional activity compared to wild-type NR5A1. CONCLUSIONS: Our study in a large cohort of patients with POI showed the prevalence of NR5A1 mutations to be low (1.6%, upper 95% confidence interval 3.5%). Moreover, no functional impact was observed. Overall, in contrast with the initial report, our results exclude NR5A1 mutations as a major genetic cause of POI.

Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.

CONTEXT: TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. OBJECTIVE: To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations. RESULTS: From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio. CONCLUSION: The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.