Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN SIZE DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS SETTING METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTERESTS: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Plasma dehydroepiandrosterone-sulphate is related to personality and stress response.

OBJECTIVES: Dehydroepiandrosterone-sulphate (DHEAS) physiologic relevance remains controversial. However, several central nervous system and behavioural effects of DHEAS have been described. We explored the relation between DHEAS and both pituitary-adrenal axis reactivity and personality in human subjects. DESIGN: We studied 120 consecutive patients assisted at the out patient endocrine department of a public central hospital before medical treatment. Personality was evaluated with the Minnesota Multiphasic Personality Inventory (MMPI) and the pituitary-adrenal axis reactivity was assessed with the CRH test. RESULTS: Baseline DHEAS was inversely related to peak/basal cortisol (parcial r=-0.454, p<0.05) response to CRH infusion. DHEAS reactivity in the CRH test was directly related to the Deviant Behaviour triad (BD) (r=0.257, p<0.05) and type A personality (AP) (r=0.295, p<0.05). Basal ACTH was directly related to baseline DHEAS (r=0.366, p<0.001) and together with age and gender explained 34% of DHEAS variability. CONCLUSIONS: DHEAS may be a protective factor against an excessive cortisol response when people are under stress situations. Personality may be related to DHEAS reactivity.

Primary and Secondary Hypogonadism in Male Persons with Diabetes Mellitus.

AIMS: To characterize hypogonadism in male persons with diabetes mellitus. Patients and Methods. 184 consecutive male persons with diabetes were studied. Besides the usual care, total testosterone (TT), estradiol (E2), FSH, and LH were measured in the last appointment and in 40 patients, also in the next two appointments. Statistical analysis compared groups and explored factors for TT and LH levels. RESULTS: TT levels were stable and highly correlated (r > 0.750, p < 0.001) over a 6-12-month period. 20% of the patients presented secondary hypogonadism (SH) and 18% presented primary hypogonadism (PH). SH was inversely related to HbA1 (partial r (rp) = 0.229, p < 0.005), while PH was directly related to age (r = 0.356, p < 0.001). TT levels were reduced independently by metformin (364 ± 160 vs. 431 ± 242 ng/dL, t = 2.241, p < 0.05) and statins (359 ± 156 vs. 424 ± 230 ng/dl, t = 2.224, p < 0.05). TT levels were inversely related to microvascular disease (rp = -0.169, p < 0.05). Discussion. TT levels were stable over time and hypogonadism was common. SH, generally clinically, is related to the diabetic state, while PH, generally subclinically, is an age-dependent process unrelated to diabetes. Low TT levels were related to older age, poor metabolic control, metformin and statins use, and microvascular disease.

Plasma corticotropin releasing hormone during the feeling of induced emotions.

OBJECTIVES: Central neuropeptides modulate behaviour. Plasma levels of neuropeptides may reflect central levels due to specific brain-to-blood transport systems. We purposed to show the modulation of plasma corticotropin releasing hormone (CRH) levels in relation to induced emotions. DESIGN: Three groups were defined. For experimental groups A and B, an emotionally significant movie fragment was projected for 20 min, while no film projection occurred in group C. Peripheral venous blood samples were collected before, 10 and 60 min after the film or at 0 and 30 min for group C. Total CRH was measured in plasma. Personality was evaluated by the Minnesota Multiphasic Personality Inventory (MMPI). RESULTS: Plasma CRH levels did not change in the condition with no movie projection - group C - 346 + or - 198 vs. 327 + or - 143 pg/mL. Plasma CRH levels dramatically increased with the projection of a dramatic movie - group A - 394 + or - 147 vs. 791 + or - 636 vs. 803 + or - 771 pg/mL, p<0.05. Plasma CRH increased less markedly in the condition with the projection of a comic movie - group B - 364 + or - 138 vs. 486 + or - 260 vs. 483 + or - 228 pg/mL, p<0.05 for differences between samples 1 and 3. Baseline plasma CRH was significantly and independently related to the neurotic triad and psychotic dyad - partial r=0.328 and 0.267, respectively, p<0.05. CONCLUSIONS: We conclude that plasma CRH levels increase with experimental emotion induction and that baseline levels are significantly related to behavioural traits. Plasma levels of neuropeptides may reflect central levels and may be useful in clinical medicine and in the study of behavioural disorders.

Takotsubo Syndrome: A Pathway through the Pituitary Disease.

Takotsubo cardiomyopathy (TTC) is characterized by reversible left ventricular apical and/or midventricular hypokinesia with unknown etiology. The clinical presentation is similar to acute myocardial infarction in the absence of significant obstructive coronary artery disease. Various predisposing factors have been related to TTC, such as acute neurological illnesses, endocrine diseases, pain, and emotional stress. We present the first description of an association between TTC cardiomyopathy and panhypopituitarism. This case reinforces the connection between the hormonal and cardiovascular systems. Furthermore, it supports the importance of a comprehensive and integrated medical history in the approach of a patient with cardiac disease, towards clinical decision-making.

Mild Adrenal Steroidogenic Defects and ACTH-Dependent Aldosterone Secretion in High Blood Pressure: Preliminary Evidence.

Introduction. Adrenal glands play a major role in the control of blood pressure and mild defects of steroidogenesis and/or inappropriate control of mineralocorticoid production have been reported in high blood pressure (HBP). Patients and Methods. We used a specific protocol for the evaluation of 100 consecutive patients with inappropriate or recent onset HBP. Specific methods were used to confirm HBP and to diagnose secondary forms of HBP. In addition we tested adrenal steroidogenesis with the common cosyntropin test, modified to include the simultaneous measurement of renin and aldosterone besides 17-hydroxyprogesterone (17OHP) and 11-deoxycortisol (S). Results. Secondary forms of HBP were diagnosed in 32 patients, including 14 patients with primary hyperaldosteronism (PA) (14%) and 10 patients with pheochromocytoma (10%). Mild defects of the 21-hydroxylase (21OHD) and 11-hydroxylase (11OHD) enzymes were common (42%). ACTH-dependent aldosterone secretion was found in most patients (54%) and characteristically in those with mild defects of adrenal steroidogenesis (>60%), PA (>75%), and otherwise in patients with apparent essential HBP (EHBP) (32%). Discussion. Mild defects of adrenal steroidogenesis are common in patients with HBP, occurring in almost half of the patients. In those patients as well as in patients with apparent EHBP, aldosterone secretion is commonly dependent on ACTH.