Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study.

BACKGROUND: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. METHODS: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. FINDINGS: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. INTERPRETATION: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.

High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort.

Context: Polycystic ovary syndrome (PCOS) etiology remains to be elucidated, but familial clustering and twin studies have shown a strong heritable component. Objective: The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods: This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were patients with PCOS diagnosed by the Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing, while 8 familial cases were studied by whole exome sequencing. Results: Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea, and 8 (15.1%) familial cases. DNA sequencing analysis identified 1 pathogenic variant in LMNA, 3 likely pathogenic variants in INSR, PIK3R1, and DLK1, and 6 variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15, and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants). Conclusion: Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.

Steroid Screening Tools Differentiating Nonclassical Congenital Adrenal Hyperplasia and Polycystic Ovary Syndrome.

PURPOSE: To analyze the performance of basal 17OH-progesterone (17OHP) levels versus the basal 17OHP/cortisol ratio in nonclassical congenital adrenal hyperplasia (NCAH) and polycystic ovary syndrome (PCOS) differential diagnosis. Basal 17OHP levels >10 ng/mL have been used to confirm NCAH diagnosis without the adrenocorticotropic hormone (ACTH) test; however, the optimal cutoff value is a matter of debate. METHODS: A cross-sectional study was performed at the endocrinology and gynecological endocrinology outpatient clinics of a tertiary hospital. A total of 361 patients with PCOS (age 25.0 ± 5.3 years) and 113 (age 19.0 ± 13.6 years) patients with NCAH were enrolled. Basal and ACTH-17OHP levels were measured by radioimmunoassay, and CYP21A2 molecular analysis was performed to confirm hormonal NCAH diagnosis. Receiver operating characteristic curve analysis compared basal 17OHP levels and the 17OHP/cortisol ratio between NCAH and PCOS patients. RESULTS: Basal 17OHP levels were higher in NCAH patients than in those with PCOS (8.85 [4.20-17.30] vs 1.00 [0.70-1.50] ng/mL; P < 0.0001), along with 17OHP/cortisol ratio (0.86 [0.47-1.5]) vs 0.12 [0.07-0.19]; P < 0.0001, respectively). Basal 17OHP levels and the 17OHP/cortisol ratio were strongly correlated in both groups (rho = 0.82; P < 0.0001). Areas under the curves for basal 17OHP levels (0.9528) and the 17OHP/cortisol ratio (0.9455) were not different to discriminate NCAH and PCOS (P > 0.05). Basal 17OHP level >5.4 ng/mL and 17OHP/cortisol ratio >2.90 had 100% specificity to identify NCAH. MAIN CONCLUSIONS: Basal 17OHP levels >5.4 ng/mL can be used to perform differential diagnoses between NCAH and PCOS, dismissing the ACTH test. The basal 17OHP/cortisol ratio was not superior to basal 17OHP levels in this scenario.

Long-term cardio-metabolic outcomes in patients with classical congenital adrenal hyperplasia: is the risk real?

PURPOSE OF REVIEW: Data on the long-term cardio-metabolic outcomes classical congenital adrenal hyperplasia (CAH) patients have been published with controversial results. Conventional treatment recommends hydrocortisone during childhood; and short and/or long-acting glucocorticoid during adulthood, associated or not with mineralocorticoid, in an attempt to simulate normal cortisol secretion and to normalize androgen excess. However, the balance between glucocorticoid over or undertreatment is very challenging, and patients frequently oscillate between hypercortisolism or hyperandrogenism. Considering these data, we reviewed the frequency of metabolic syndrome components and other cardiovascular risk factors in CAH. RECENT FINDINGS: Several studies reported increased prevalence obesity, abnormal body composition, increased homeostasis model assessment of insulin resistance and blood pressure levels in CAH patients. However, the evidence quality is still low, because most studies used different glucocorticoid regimes and had heterogeneous goals for hormonal control. SUMMARY: Despite the above-mentioned scenario of increased frequency of some cardiovascular surrogate markers in patients, most cohorts comprised young adults, and it is not known if patients will present high frequency of cardiovascular disease in the future. Prospective randomized studies comparing different glucocorticoid regimens should establish the real role of glucocorticoid and androgens on metabolic/cardiovascular profile.

Persistent Poor Metabolic Profile in Postmenopausal Women With Ovarian Hyperandrogenism After Testosterone Level Normalization.

CONTEXT: Data on prevalence of metabolic risk factors in hyperandrogenic postmenopausal women are limited. Also, the correlation between metabolic disorders and androgen excess in this scenario is poorly understood. OBJECTIVES: We aimed to assess the prevalence of obesity, hypertension, type 2 diabetes (T2D), and dyslipidemia (DLP) in postmenopausal women with hyperandrogenism of ovarian origin before and after surgical normalization of testosterone (T) levels, as well as the impact of androgen normalization on body mass index (BMI), glucose, and lipid metabolism. DESIGN: Retrospective study. SETTING: Tertiary health center. PARTICIPANTS: Twenty-four Brazilian women with postmenopausal hyperandrogenism who underwent bilateral oophorectomy between 2004 and 2014 and had histologically confirmed virilizing ovarian tumor (VOT) or ovarian hyperthecosis (OH) and T-level normalization after surgery were selected. MAIN OUTCOME MEASURES: FSH, LH, total and calculated free T, BMI, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) serum levels were accessed before (n = 24) and 24 months after (n = 19) bilateral oophorectomy. RESULTS: At baseline, the overall prevalence rates of obesity, T2D, DLP, and hypertension were 58.3%, 83.3%, 66.7%, and 87.5%, respectively. No significant difference in prevalence was found between patients with OH and VOTs. At follow-up, FSH, LH, and total and free T levels had returned to menopausal physiologic levels, but mean BMI and mean FPG, HbA1c, LDL-C, HDL-C, and TG levels did not differ from baseline. CONCLUSIONS: Postmenopausal hyperandrogenism is associated with adverse metabolic risk. Long-term normalization of testosterone levels did not improve BMI, glucose, or lipid metabolism.

Classic congenital adrenal hyperplasia and its impact on reproduction.

Women with classic congenital adrenal hyperplasia (CAH) can suffer from impaired fertility rates as a result of increased androgen secretion or impaired sex steroid production. In virilizing CAH forms, such as 21-hydroxylase and 11ß-hydroxylase deficiency, the low reported pregnancy rate is mainly secondary to a diminished desire to conceive. Optimal glucocorticoid and/or mineralocorticoid replacement, sufficient to normalize androgen and P levels in the follicular phase, allows natural conception in most cases. The remaining CAH forms exemplified by StAR, P450scc, P450-oxidoreductase, and 17α-hydroxylase/17-20 lyase deficiencies are associated with impaired sex steroid production. Several factors are involved in the true low fertility rate in this group: folliculogenesis arrest, uterine hypoplasia, and inadequate endometrial thickness related to aberrant androgen, estrogen, and P secretion. There are several reports of successful term pregnancies achieved through controlled ovarian hyperstimulation, followed by estrogen replacement and IVF. Progress in female genitalia reconstructive surgery, individualized hormonal therapies, psychosexual evaluation, and assisted reproductive technology have improved fertility and pregnancy outcomes in women with classic CAH. Finally, successful gestational management in CAH patients requires the close coordination of care between endocrinologists and obstetricians.

DLK1 Is a Novel Link Between Reproduction and Metabolism.

BACKGROUND: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. METHODS: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with those of 20 women with idiopathic CPP. RESULTS: We identified three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such as overweight/obesity, early-onset glucose intolerance/type 2 diabetes mellitus, and hyperlipidemia, were more prevalent in women with the DLK1 mutation than in the idiopathic CPP group. Notably, the human metabolic alterations were similar to the previously described dlk1-null mice phenotype. Two sisters who carried the p.Gly199Alafs*11 mutation also exhibited polycystic ovary syndrome and infertility. CONCLUSIONS: Loss-of-function mutations of DLK1 are a definitive cause of familial CPP. The high prevalence of metabolic alterations in adult women who experienced CPP due to DLK1 defects suggests that this antiadipogenic factor represents a link between reproduction and metabolism.

An update of genetic basis of PCOS pathogenesis.

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that affects 5-20% of reproductive age women. PCOS clinical symptoms include hirsutism, menstrual dysfunction, infertility, obesity and metabolic syndrome. There is a wide heterogeneity in clinical manifestations and metabolic complications. The pathogenesis of PCOS is not fully elucidated, but four aspects seem to contribute to the syndrome to different degrees: increased ovarian and/or adrenal androgen secretion, partial folliculogenesis arrest, insulin resistance and neuroendocrine axis dysfunction. A definitive etiology remains to be elucidated, but PCOS has a strong heritable component indicated by familial clustering and twin studies. Genome Wide Association Studies (GWAS) have identified several new risk loci and candidate genes for PCOS. Despite these findings, the association studies have explained less than 10% of heritability. Therefore, we could speculate that different phenotypes and subphenotypes are caused by rare private genetic variants. Modern genetic studies, such as whole exome and genome sequencing, will help to clarify the contribution of these rare genetic variants on different PCOS phenotypes. Arch Endocrinol Metab. 2018;62(3):352-61.

An update of genetic basis of PCOS pathogenesis

ABSTRACT Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that affects 5-20% of reproductive age women. PCOS clinical symptoms include hirsutism, menstrual dysfunction, infertility, obesity and metabolic syndrome. There is a wide heterogeneity in clinical manifestations and metabolic complications. The pathogenesis of PCOS is not fully elucidated, but four aspects seem to contribute to the syndrome to different degrees: increased ovarian and/or adrenal androgen secretion, partial folliculogenesis arrest, insulin resistance and neuroendocrine axis dysfunction. A definitive etiology remains to be elucidated, but PCOS has a strong heritable component indicated by familial clustering and twin studies. Genome Wide Association Studies (GWAS) have identified several new risk loci and candidate genes for PCOS. Despite these findings, the association studies have explained less than 10% of heritability. Therefore, we could speculate that different phenotypes and subphenotypes are caused by rare private genetic variants. Modern genetic studies, such as whole exome and genome sequencing, will help to clarify the contribution of these rare genetic variants on different PCOS phenotypes. Arch Endocrinol Metab. 2018;62(3):352-61

An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles.

OBJECTIVES: Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism. METHODS: Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing. RESULTS: The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH. CONCLUSION: These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.

An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles

OBJECTIVES: Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism. METHODS: Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing. RESULTS: The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH. CONCLUSION: These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency.

P450 oxidoreductase deficiency (PORD) is a variant of congenital adrenal hyperplasia that is caused by POR gene mutations. The POR gene encodes a flavor protein that transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 type II (including 21-hydroxylase, 17α-hydroxylase 17,20 lyase and aromatase), which is fundamental for their enzymatic activity. POR mutations cause variable impairments in steroidogenic enzyme activities that result in wide phenotypic variability ranging from 46,XX or 46,XY disorders of sexual differentiation, glucocorticoid deficiency, with or without skeletal malformations similar to Antley-Bixler syndrome to asymptomatic newborns diagnosed during neonatal screening test. Little is known about the PORD long-term evolution. We described a 46,XX patient with mild atypical genitalia associated with severe bone malformation, who was diagnosed after 13 years due to sexual infantilism. She developed large ovarian cysts and late onset adrenal insufficiency during follow-up, both of each regressed after hormone replacement therapies. We also described a late surgical approach for the correction of facial hypoplasia in a POR patient.

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

SUMMARY P450 oxidoreductase deficiency (PORD) is a variant of congenital adrenal hyperplasia that is caused by POR gene mutations. The POR gene encodes a flavor protein that transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 type II (including 21-hydroxylase, 17α-hydroxylase 17,20 lyase and aromatase), which is fundamental for their enzymatic activity. POR mutations cause variable impairments in steroidogenic enzyme activities that result in wide phenotypic variability ranging from 46,XX or 46,XY disorders of sexual differentiation, glucocorticoid deficiency, with or without skeletal malformations similar to Antley-Bixler syndrome to asymptomatic newborns diagnosed during neonatal screening test. Little is known about the PORD long-term evolution. We described a 46,XX patient with mild atypical genitalia associated with severe bone malformation, who was diagnosed after 13 years due to sexual infantilism. She developed large ovarian cysts and late onset adrenal insufficiency during follow-up, both of each regressed after hormone replacement therapies. We also described a late surgical approach for the correction of facial hypoplasia in a POR patient.

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction.

BACKGROUND: Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. OBJECTIVE: To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients. METHODS: DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3-7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). RESULTS: Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3ng/mL was the best cutoff to identify NC-patients carrying severe mutations. CONCLUSIONS: We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease's severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

A Single Nucleotide Variant in the Promoter Region of 17ß-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency.

BACKGROUND: In 21-hydroxylase deficiency (21-OHD), there is an influence of genotype on the severity of external genitalia virilization. However, females carrying mutations predicting a similar impairment of enzymatic activity present a wide variability of genital phenotypes. In such cases, interindividual variability in genes related to the sex steroid hormone pathway could play a role. OBJECTIVE: To evaluate the influence of POR, HSD17B5 and SRD5A2 variants on the severity of external genitalia virilization in 21-OHD females. DESIGN AND PATIENTS: Prader stages were evaluated in 178 females with 21-OHD from a multicenter study. The 21-OHD genotypes were divided into two groups according to their severity: severe and moderate. The influences of the POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants on the degree of external genitalia virilization were analyzed. RESULTS: The POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants were found in 25, 33, 17, 1, and 31% of the alleles, respectively. In uni- and multilinear regression, HSD17B5 c.-210A>C has a significant influence on the degree of external genitalia virilization. This variant was also identified with a higher frequency in the most severely virilized females. CONCLUSION: We demonstrated that a variant in the promoter region of HSD17B5 related to fetal androgen synthesis influences the genital phenotype in 21-OHD females.

Influence of the A3669G Glucocorticoid Receptor Gene Polymorphism on the Metabolic Profile of Pediatric Patients with Congenital Adrenal Hyperplasia.

Background. Pediatric CAH patients have an increased risk of cardiovascular disease, and it remains unknown if genetic predisposition is a contributing factor. Glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of pediatric CAH patients. Methods. Forty-one patients (26SW/15SV) received glucocorticoid (GC) replacement therapy to achieve normal androgen levels. Obesity was defined by BMI ≥ 95th percentile. NR3C1 alleles were genotyped, and association analyses with phenotype were done with Chi-square, t-test, and multivariate and regression analysis. Results. Obesity was observed in 31.7% of patients and was not correlated with GC doses and treatment duration. Z-score BMI was positively correlated with blood pressure, triglycerides, LDL-c levels, and HOMA-IR. NR3C1 polymorphisms, BclI and A3669G, were found in 23.1% and 9.7% of alleles, respectively. A3669G carriers presented higher LDL-c levels compared to wild-type subjects. BclI-carriers and noncarriers did not differ. Conclusion. Our results suggest that A3669G-polymorphism could be involved with a susceptibility to adverse lipid profile in pediatric CAH patients. This study provides new insight into the GR screening during CAH treatment, which could help to identify the subgroup of at-risk patients who would most benefit from preventive therapeutic action.

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. .

Mineralocorticoid replacement during infancy for salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: The protocols for glucocorticoid replacement in children with salt wasting 21-hydroxylase deficiency are well established; however, the current recommendation for mineralocorticoid replacement is general and suggests individualized dose adjustments. This study aims to retrospectively review the 9-α-fludrocortisone dose regimen in salt wasting 21-hydroxylase deficient children who have been adequately treated during infancy. METHODS: Twenty-three salt wasting 21-hydroxylase deficient patients with good anthropometric and hormonal control were followed in our center since diagnosis. The assessments of cortisone acetate and 9-α-fludrocortisone doses, anthropometric parameters, and biochemical and hormonal levels were rigorously evaluated in pre-determined intervals from diagnosis to two years of age. RESULTS: The 9-α-fludrocortisone doses decreased over time during the first and second years of life; the median fludrocortisone doses were 200 µg at 0-6 months, 150 µg at 7-18 months and 125 µg at 19-24 months. The cortisone acetate dose per square meter was stable during follow-up (median = 16.8 mg/m²/day). The serum sodium, potassium and plasma rennin activity levels during treatment were normal, except in the first month of life, when periodic 9-α-fludrocortisone dose adjustments were made. CONCLUSIONS: The mineralocorticoid needs of salt wasting 21-hydroxylase deficient patients are greater during early infancy and progressively decrease during the first two years of life, which confirms that a partial aldosterone resistance exists during this time. Our study proposes a safety regiment for mineralocorticoid replacement during this critical developmental period.

Mineralocorticoid replacement during infancy for salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE: The protocols for glucocorticoid replacement in children with salt wasting 21-hydroxylase deficiency are well established; however, the current recommendation for mineralocorticoid replacement is general and suggests individualized dose adjustments. This study aims to retrospectively review the 9-∝-fludrocortisone dose regimen in salt wasting 21-hydroxylase deficient children who have been adequately treated during infancy. METHODS: Twenty-three salt wasting 21-hydroxylase deficient patients with good anthropometric and hormonal control were followed in our center since diagnosis. The assessments of cortisone acetate and 9-∝-fludrocortisone doses, anthropometric parameters, and biochemical and hormonal levels were rigorously evaluated in pre-determined intervals from diagnosis to two years of age. RESULTS: The 9-∝-fludrocortisone doses decreased over time during the first and second years of life; the median fludrocortisone doses were 200 µg at 0-6 months, 150 µg at 7-18 months and 125 µg at 19-24 months. The cortisone acetate dose per square meter was stable during follow-up (median = 16.8 mg/m²/day). The serum sodium, potassium and plasma rennin activity levels during treatment were normal, except in the first month of life, when periodic 9-∝-fludrocortisone dose adjustments were made. CONCLUSIONS: The mineralocorticoid needs of salt wasting 21-hydroxylase deficient patients are greater during early infancy and progressively decrease during the first two years of life, which confirms that a partial aldosterone resistance exists during this time. Our study proposes a safety regiment for mineralocorticoid replacement during this critical developmental period.