The clinical spectrum of 3b-hydroxysteroid dehydrogenase (3b-HSD) deficiency (def) congenital adrenal hyperplasia (CAH) ranges from the severe form manifesting ambiguous genitalia, salt-wasting, and hypogonadism to the less severe form manifesting premature pubarche (PP), pubertal onset hirsutism and menstrual disorder. Three hypotheses are advanced in this proposal: 1) Hormonal diagnosis (Dx) for the mild late-onset variant of 3b-HSD def, mild or severe, may reveal hormonal criteria which differ from the past published criteria for diagnosing the late-onset disorder; 2) Study of adrenal (Ad) 3b-HSD activity in carriers for 3b-HSD def may support or exclude the existence of an Ad 3b-HSD isoenzyme; and 3) The hormonal features of mildly decreased Ad 3b-HSD activity, leading to late-onset disorder in the past, may be associated with the insulin resistance of polycystic ovary syndrome (PCOS). We propose 5 specific aims: 1) the hormonal criteria via genotypic proof for mild to severe 3b-HSD def by a) analysis of the type II 3b-HSD gene encoding Ad and gonadal 3b-HSD in patients with various clinical/hormonal spectra of decreased Ad 3b-HSD activity; b) characterizing the mutant gene function in vitro, and c) correlating the genotype to hormonal/clinical phenotype of mild and severe variants of 3b-HSD def; 2) Ad 3b-HSD activity in the carriers of 3b-HSD def by a) identifying hormonal profiles in family members of patients with the 3b-HSD gene mutations b) comparing Ad hormonal profiles in carriers to the genotype; 3) prenatal diagnosis of 3b-HSD CAH in fetuses at risk by a) type II 3b-HSD gene analysis from amniotic and the proband's cells, b) hormonal analysis of amniotic fluid, c) fetal outcome verification; 4) association between the hormonal marker of mildly decreased Ad 3b-HSD activity and the insulin resistance of PCOS by examining A0 insulin sensitivity (SI) in the patients and control subjects, b) comparing SI to the Ad/ovarian components of androgen secretion; 5) long term outcome by periodic examinations of growth, maturation of H-P-O axis sensitivity and Ad 3b-HSD activity hormonally in girls with PP and the hormonal marker of mildly decreased Ad 3b-HSD activity. The proposed study will help to define the hormonal criteria essential to accurately diagnose patients with variants of 3b-HSD def CAH, examine the potential existence of an Ad 3b-HSD isoenzyme, verify accuracy of prenatal Dx of 3b-HSD def, and determine whether the hormonal features of mildly decreased Ad 3b-HSD activity are associated with insulin resistance and are a marker of PCOS from childhood to adulthood.
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