BclI polymorphism of the glucocorticoid receptor gene is associated with decreased bone mineral density in patients with endogenous hypercortisolism.

OBJECTIVE: The hypothalamic-pituitary-adrenal axis setpoint and the glucocorticoid sensitivity of various tissues are at least partially genetically determined. We investigated the impact of glucocorticoid receptor (GR) gene polymorphisms, including the BclI, N363S, ER22/23EK and A3669G variants on bone turnover and/or mineral density (BMD) in patients with endogenous glucocorticoid excess. DESIGN: Sixty patients including 35 patients with ACTH producing pituitary adenoma (CD) and 25 patients with adrenal Cushing's syndrome (ACS) as well as 129 healthy subjects were genotyped. Analysis of the GR gene polymorphisms were determined using allele specific PCR, PCR-RFLP and Taqman allelic discrimination assays. Hormonal evaluation, BMD and bone marker measurements were carried out. RESULTS: No significant differences were found in allelic frequencies of the four polymorphisms between patients with ACS, CD and healthy controls. Patients with endogenous hypercortisolism carrying the BclI polymorphism in a homozygous form had reduced BMD at femoral subregions compared to patients with the wild-type variant; femoral neck Z-score (-1.44 +/- 0.73 vs. -0.39 +/- 0.91; P < 0.05), trochanteric Z-score (-1.89 +/- 0.47 vs.-0.54 +/- 0.98; P < 0.05). Patients with homozygous BclI polymorphism had significantly higher beta-CrossLaps Z-scores compared to those with the heterozygous and wild-type variants (+4.42 +/- 2.37 vs. +0.79 +/- 1.67 and +0.11 +/- 1.47; P < 0.01). CONCLUSIONS: The BclI, N363S, ER22/23EK and A3669G polymorphisms of the GR gene probably do not modify the risk for the development of CD or ACS. Contrary to healthy subjects, however, the BclI polymorphism may modify the skeletal sensitivity to glucocorticoids in patients with endogenous glucocorticoid excess.

The protective effect of the ER22/23EK polymorphism against an excessive weight gain during pregnancy.

It has been shown that women who gained an excessive weight during pregnancy had an increase in long-term BMI compared with those without an excessive weight gain. Several studies have demonstrated that some polymorphisms of the glucocorticoid receptor (GR) gene may influence body composition and metabolic parameters. In the present study, we wanted to explore whether any association could exist between the BclI, N363S and ER22/23EK polymorphisms of the GR gene and the weight gain during pregnancy. We found that the allelic frequencies of the BclI, N363S and ER22/23EK polymorphisms in 300 women with uncomplicated pregnancies were similar to those measured in healthy Hungarian population. None of the three polymorphisms associated with body weight or BMI at the 1st trimester of pregnancy or before delivery. However, a significantly lower weight gain (p = 0.044) and consequently lower increase of BMI during pregnancy (p = 0.044) was observed in heterozygous carriers of the ER22/23EK polymorphism. These results support a protective role of the ER22/23EK polymorphism against an excessive weight gain and excessive increase of BMI during uncomplicated pregnancy.

Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene.

Endogenous and exogenous glucocorticoids influence fetal growth and development, and maternal administration of synthetic glucocorticoids may decrease the risk of perinatal morbidity including lung disease in preterm neonates. Because polymorphisms of the glucocorticoid receptor gene are known to influence the sensitivity to glucocorticoids, in the present study we examined whether any associations could exist among the BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene and gestational age, birth weight and/or perinatal morbidity of 125 preterm neonates born at 28-35 weeks' gestation with (n=57) or without maternal dexamethasone treatment (n=68). The prevalence of the three polymorphisms in the whole group of preterm infants was similar to that reported in healthy adult Hungarian population. However, we found that the BclI polymorphism significantly associated with higher birth weight adjusted for the gestational age (p=0.004, ANOVA analysis). None of the three polymorphisms showed an association with perinatal morbidities, including necrotizing enterocolitis, intraventricular hemorrhagia, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia and sepsis in the two groups of preterm neonates with and without maternal dexamethasone treatment. These results suggest that the BclI polymorphism of the glucocorticoid receptor gene may have an impact on gestational age-adjusted birth weight, but it does not influence perinatal morbidities of preterm neonates.

Expression of glucocorticoid receptor isoforms in human adrenocortical adenomas.

INTRODUCTION: Glucocorticoid receptor (GR) is expressed in the normal human adrenal gland, however, no study has been performed to evaluate the separate expression of alpha- and beta-isoforms (GRalpha and GRbeta) in normal human adrenals and in adrenocortical adenomas. EXPERIMENTAL: GRalpha and GRbeta mRNA expression was examined by quantitative real-time PCR in 31 adrenal tissues including 19 non-functioning adenomas (NFA), 6 cortisol-producing adenomas (CPA) and 6 normal adrenocortical tissues. In addition, the presence and cellular localization of GRalpha and GRbeta proteins in adrenal tissues were studied by immunohistochemistry. RESULTS: Compared to normal adrenocortical tissues, both GRalpha and GRbeta mRNAs were significantly increased in CPA but not in NFA. Using anti-GRalpha antibody a strong nuclear staining was observed in NFA and CPA, and a less remarkable immunoreactivity was detected in some nuclei of normal adrenocortical cells. GRbeta immunostaining was absent in normal adrenal tissues and NFA, while a strong cytoplasmic and nuclear immunoreaction was found in CPA. CONCLUSIONS: Altered expression of GRalpha and GRbeta in CPA raises their possible role in the pathophysiology of these adrenal tumors, although further studies are needed to elucidate the potential significance of these findings.

Maternal hyperandrogenism beginning from early pregnancy and progressing until delivery does not produce virilization of a female newborn.

A 33-year-old primagravida with a history of polycystic ovary syndrome was referred because of symptoms of moderate hyperandrogenism. Serum hormone levels, measured regularly from the 7th week of pregnancy until delivery, showed very high increases of testosterone, androstenedione and estradiol. Ultrasound showed no evidence of adrenal or ovarian masses. She delivered a female newborn with normal female external genitalia. Umbilical cord hormone levels were normal, except for a modest increase of serum testosterone. After delivery the androgen levels of the mother returned to normal and the symptoms of hyperandrogenism were also slightly improved.