A genetic defect resulting in mild low-renin hypertension.

Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2) cause AME. Typical patients with AME have defective 11beta-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11-3H]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0-6% in typical patients with AME whereas the normal conversion is 90-95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C-->T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the Km (300 nM) over normal (54 nM). Because approximately 40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.

Dose-ranging study of indole-3-carbinol for breast cancer prevention.

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95% confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary.