Plasma 5alpha-androstane-3alpha,17betadiol, an endogenous steroid that positively modulates GABA(A) receptor function, and anxiety: a study in menopausal women

We tested the hypothesis that changes in endogenous neuroactive steroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors may be related to the menopause-associated mood alterations. The study sample consisted of twenty five drug-free menopausal women, 1-3 years since the onset of menopause, homogeneous for age and body mass index (BMI) and without personal history of psychiatric, metabolic or endocrine disorders. Depression and anxiety-related symptoms were assessed with the Zung Self-administered Depression Scale (ZSDS) and the Cornell's Dysthymia Rating Scale (CDRS). The cut-off value predicted by the ZSDS index defined two groups of women (asymptomatic [35.5+/-4.6, n=12] and symptomatic [60.8+/-7.9, n=13]), that were also significantly different according to the CDRS scores (10.6+/-3.4 and 31.5+/-12, respectively, P<0.05). Upon evaluation of the scores relative to the anxiety factor of the CDRS (items 11-15) the symptomatic, but not the asymptomatic, group showed a moderate level of anxiety. The plasma concentrations of several neuroactive steroids were measured, after extraction and HPLC purification, by radioimmunoassay with specific antisera. Only dehydroepiandrosterone and its metabolite 5alpha-androstane-3alpha,17betadiol (3alpha-ADIOL), a positive allosteric modulator of GABA(A) receptors, were significantly (P<0.05 and P<0.005) higher (+110% and +64%, respectively) in the asymptomatic group. A highly significant and negative correlation (r=-0.672, P=0.003) was found between the plasma 3alpha-ADIOL concentrations and the scores of the anxiety factor of the CDRS. These data suggest that endogenous 3alpha-ADIOL modulates the central GABAergic tone and that higher 3alpha-ADIOL concentrations could have a role in preventing the expression of anxiety in the asymptomatic women

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort

Background Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02–2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06–3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05–2·44; p=0·04) and Asp294His (2·15, 1·05–4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.</p

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

BACKGROUND: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. METHODS: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. FINDINGS: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1\ub754, 95% CI 1\ub702-2\ub733), including when analysis was restricted to patients aged 18 years or younger (1\ub780, 1\ub706-3\ub707). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1\ub760, 95% CI 1\ub705-2\ub744; p=0\ub704) and Asp294His (2\ub715, 1\ub705-4\ub740; p=0\ub704). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. INTERPRETATION: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies