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Hormone-nuclear receptor interactions in health and disease. Glucocorticoid resistance
1Pediatric Endocrinology Section, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892.
Abstract:
Familial glucocorticoid resistance results from the partial inability of glucocorticoids to exert their effects on their target tissues throughout the organism. The condition is associated with compensatory elevations of circulating ACTH and cortisol, with the former causing excess abnormal secretion of steroids with mineralocorticoid and androgen activity. The manifestations of glucocorticoid resistance vary from asymptomatic to chronic fatigue, to varying degrees of hypertension and/or hypokalaemic alkalosis and hyperandrogenism. The latter can be manifest in women as acne, hirsutism, menstrual irregularity, oligoanovulation and infertility, in men as infertility, and in children as precocious puberty. Different molecular defects of the highly conserved glucocorticoid receptor gene, altering its concentration and functional characteristics, appear to cause the syndrome of familial glucocorticoid resistance. Depending on the molecular defect, this syndrome is transmitted by an autosomal dominant or recessive trait. There are recent suggestions that non-generalized forms of glucocorticoid resistance may exist, resulting in autoimmune-inflammatory phenomena or psychiatric manifestations.
Insights
Familial glucocorticoid resistance is a genetic condition where the body cannot fully respond to glucocorticoids. This leads to hormonal imbalances and varied symptoms, including fatigue and hyperandrogenism.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Familial glucocorticoid resistance (FGR) is a rare endocrine disorder.
- It stems from the body's partial inability to respond to glucocorticoids.
- This resistance leads to compensatory hormonal changes, including elevated ACTH and cortisol.
Purpose of the Study:
- To describe the clinical and molecular characteristics of familial glucocorticoid resistance.
- To outline the diverse manifestations and genetic basis of the syndrome.
- To explore potential non-generalized forms of glucocorticoid resistance.
Main Methods:
- Review of clinical case studies and genetic analyses.
- Examination of molecular defects in the glucocorticoid receptor gene.
- Analysis of hormonal profiles and clinical presentations.
Main Results:
- FGR presents with variable symptoms, from asymptomatic cases to fatigue, hypertension, hypokalemic alkalosis, and hyperandrogenism.
- Hyperandrogenism manifestations include acne, hirsutism, menstrual irregularities, and infertility in women; infertility in men; and precocious puberty in children.
- Molecular defects in the glucocorticoid receptor gene cause FGR, inherited in autosomal dominant or recessive patterns.
Conclusions:
- Familial glucocorticoid resistance is caused by genetic defects in the glucocorticoid receptor.
- The syndrome exhibits a wide spectrum of clinical manifestations and inheritance patterns.
- Emerging evidence suggests potential non-generalized forms of glucocorticoid resistance impacting autoimmune and psychiatric conditions.