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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
Carbunaru, Goldy; Prasad, Pallavi; Scoccia, Bert et al. (2004) The hormonal phenotype of Nonclassic 3 beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab 89:783-94
Pang, Songya; Carbunaru, Goldy; Haider, Anzar et al. (2003) Carriers for type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency can only be identified by HSD3B2 genotype study and not by hormone test. Clin Endocrinol (Oxf) 58:323-31
Pang, Songya; Wang, Weihua; Rich, Barry et al. (2002) A novel nonstop mutation in the stop codon and a novel missense mutation in the type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing, respectively, nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab 87:2556-63
Lutfallah, Chantal; Wang, Weihua; Mason, J Ian et al. (2002) Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 87:2611-22
Pang, S (2001) Congenital adrenal hyperplasia owing to 3 beta-hydroxysteroid dehydrogenase deficiency. Endocrinol Metab Clin North Am 30:81-99, vi-vii
Zhang, L; Mason, J I; Naiki, Y et al. (2000) Characterization of two novel homozygous missense mutations involving codon 6 and 259 of type II 3beta-hydroxysteroid dehydrogenase (3betaHSD) gene causing, respectively, nonsalt-wasting and salt-wasting 3betaHSD deficiency disorder. J Clin Endocrinol Metab 85:1678-85