Modulatory effect of BclI GR gene polymorphisms on the obesity phenotype in Brazilian patients with Cushing's disease

OBJECTIVES: Patients with Cushing's disease exhibit wide phenotypic variability in the severity of obesity, diabetes and hypertension. In the general population, several glucocorticoid receptor genes (NR3C1) and HSD11B1 polymorphisms are associated with altered glucocorticoid sensitivity and/or metabolism, resulting in an increased or reduced risk of an adverse metabolic profile. Our aim was to analyze the association of NR3C1 and HSD11B1 gene variants with the severity of some clinical and hormonal features of Cushing's disease. METHODS: Sixty-four patients presenting with Cushing's disease were diagnosed based on adrenocorticotrophic hormone levels, high-dose dexamethasone suppression tests and/or inferior petrosal sinus sampling and magnetic resonance imaging. The A3669G, ER22/23EK, N363S BclI-NR3C1 and HSD11B1-rs12086634 variants were screened. RESULTS: The BclI, HSD11B1-rs12086634 and A3669G variants were found in 36%, 19.5% and 14% of alleles, respectively. The N363S and ER22/23EK polymorphisms were identified in heterozygosis once in only two patients (1.5% of alleles). There were no differences in the weight gain or prevalence of diabetes and hypertension in the patients carrying the abovementioned alleles compared to the wild-type carriers. Interestingly, the mean body mass index (BMI) of the BclI carriers was significantly higher than the non-carriers (34.4±7 kg/m2 vs. 29.6±4.7 kg/m2, respectively). None of the polymorphisms were associated with the basal adrenocorticotrophic hormone, FU levels or F level after dexamethasone suppression testing. CONCLUSION: Although Cushing's disease results from increased glucocorticoid secretion, we observed that interindividual variability in the peripheral glucocorticoid sensitivity, mediated by the glucocorticoid receptor, could modulate the obesity phenotype

Molecular Bases of Congenital Adrenal Hyperplasia

Congenital adrenal hiperplasia (CAH) is a recessive autossomic disease caused by inherited defects in cortisol biosynthesis. The manifestations are caused both by the deficient synthesis of cortisol, and sometimes of aldosterone, and by accumulation of the precursor steroids. The objective of this review is to present the molecular mechanisms of the main enzymatic defects involved in the etiopathogenesis of CAH. Deficiency of 21-hydroxylase (21OH) accounts for more than 95% of all cases of CAH. The human genome contains two CYP genes: one active, CYP21, and a pseudogene, CYP21P. Both are highly homologous (98%), facilitating recombination events during meiosis, leading to duplication and/or deletion or conversion of these genes. Additionally, point mutations have also been described. Deficiency of 11beta-hydroxylase (11betaOH) is caused by mutations in the CYP11B1 gene, and accounts for 5% of all cases. Some mutations are recurrent, and mainly located on exons 6-8, which is considered a hot-spot area in CYP11B1 gene. Deficiency of 17alpha-hydroxylase (17OH) is caused by mutations in the CYP17 gene, producing a truncated or impaired protein. These mutations have been described in patients with combined deficiencies of 17OH and 17,20-lyase or with isolated 17,20-lyase. Finally, CAH caused by 3beta-HSD deficiency is the consequence of mutations in the gene HSD3B2 that encodes 3beta-HSD type II. In the classical form of the disease nonsense mutations, insertion and deletions have been described, while in non classical forms, mutations result in diminished enzyme affinity and loss of enzyme activity.Hiperplasia adrenal congênita (HAC) é uma doença autossômica recessiva decorrente da alteração de enzimas que participam da síntese do cortisol. As manifestações podem ser causadas pela deficiência do cortisol e, em alguns casos, aldosterona e pelo acúmulo de precursores. O objetivo desta revisão é apresentar os mecanismos moleculares dos principais defeitos enzimáticos envolvidos na etiopatogênese da HAC. A deficiência da 21-hidroxilase (21OH) ocorre em 95% dos casos de HAC. Existem dois genes que codificam o P450c21: um ativo, CYP21, e um pseudogene CYP21P. Ambos são altamente homólogos (98%), o que favorece o emparelhamento desigual dos cromossomos homólogos durante a meiose, levando a duplicações e/ou deleções ou conversões desses genes. Adicionalmente, foram também descritas mutações de ponto, muitas delas presentes no pseudogene sugerindo microconversões. Mutações no gene CYP11B1 causam HAC por deficiência da 11beta-hidroxilase, forma esta que corresponde a 5% dos casos. Algumas mutações são recorrentes, situando-se principalmente entre os exons 6-8 que representaria uma área hot-spot no gene CYP11B1. A deficiência de 17-hidroxilase é causada por mutações no gene CYP17, que codificam uma proteína alterada, levando a deficiência total ou parcial de 17-hidroxilação e 17,20-liase ou deficiência isolada de 17,20-liase. Finalmente, deficiência de 3beta-HSD é causada por mutações no gene HSD3B2, que codifica a enzima 3beta-HSD tipo II e estas mutações têm sido associadas tanto com a forma clássica como com a forma não clássica da deficiência da 3beta-HSD

Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome

OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects. CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment

Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome

OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects. CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry

Objective: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). Design: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. Patients: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. Measurements: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). Results: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1–9.2) were taking a median 11.3 mg/m2/day (8.6–14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0–104.0). Median D4 under 12 years was 0 nmol/L (0–2.0) and above 12 years was 10.5 nmol/L (3.9–21.0). There were significant differences in biomarker values between centres (p 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2/day for every 1 point increase in weight standard deviation score. Discussion: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain