Studies in three families (A, B, and C) revealed five patients with congenital adrenal hyperplasia (CAH) due to partial and combined 21- and 11 beta-hydroxylase deficiency. One patient (A-11 1), a 23-yr-old severely virilized chromosomal female, was reared as a male, and two females (B-11 2 and C-1) complained only of hirsutism, acne, and menstrual abnormalities. Patients A-11 2 and B-11 8 (17 1/2 and 10 yr old) were asymptomatic and detected by finding an HLA genotype identical to that of their respectively affected brother and sister. Three patients (A-11 1, A-11 2, and C-1) had moderate hypertension. In spite of the wide range of clinical manifestations, all individuals had elevated androgen levels, while cortisol secretion was severely impaired only in A-11 2. 21-Hydroxylase deficiency was diagnosed on the basis of markedly increased plasma and urinary levels of 17-hydroxyprogesterone (17-OHP) and 21-deoxycortisol and their respective urinary metabolites pregnanetriol and pregnanetriolone. PRA was elevated in three patients, while urinary aldosterone was normal or increased. 11 beta-Hydroxylase deficiency was diagnosed on the basis of increased 11-deoxycortisol and deoxycorticosterone in plasma and tetrahydro-11-deoxycortisol and deoxycorticosterone in urine, particularly after ACTH administration. In contrast to classical 11 beta-hydroxylase deficiency CAH, urinary 18-hydroxycorticosterone and 18-hydroxy-11-deoxycorticosterone were normal or elevated. The nature and mechanism of a combined enzymatic defect are unknown. The coincidental presence in a single individual of the mutant genes for both 21- and 11 beta-hydroxylase deficiency CAH is very unlikely to occur. Two alternative hypotheses may explain our findings. One is the existence of a genetically inherited abnormal (or aberrant) 11 beta-hydroxylase, whose affinity for its normal substrate is changed for an abnormal one (17-OHP). As a result, 11 beta-hydroxylation of 11-deoxycortisol is deficient while 17-OHP 11 beta-hydroxylation is markedly enhanced. Thus, both 11-deoxycortisol and 21-deoxycortisol as well as their urinary metabolites accumulate. The ability for 18-hydroxylation, however, remains normal. In this case, 21-hydroxylase is not deficient, yet 21-deoxycortisol cannot be further hydroxylated to cortisol, since this steroid is not a suitable substrate for the enzyme. Such a disorder may represent a new allelic variant of 11 beta-hydroxylase deficiency CAH, which, similar to 21-hydroxylase deficiency, is completely linked to the HLA complex.(ABSTRACT TRUNCATED AT 400 WORDS)
Clinical follow-up studies of women with breast cystic disease indicate an increased risk of subsequent development of breast cancer, but the absolute risk marker has not yet been identified. It has been shown that bombesin/gastrin-releasing peptide can stimulate the proliferation of breast cancer cells in culture. In order to address the question of whether biological measurements might identify women with benign breast disease (BBD) at particular risk for breast cancer, analyses of bombesin and dehydroepiandrosterone sulfate (DHEAS) levels in tumor tissue from patients with breast cancer and BBD were carried out.The groups of patients comprised 13 women with breast cancer (mean age 52.3 years), 12 women with fibroadenoma (mean age 47.5 years), 6 with microcystic breast disease (mean age 43.5 years) and 6 with gross cystic breast disease (mean age 47.2 years). Malignant and benign tumor tissues were collected after mastectomy or tumorectomy. Bombesin and DHEA-S levels was measured by RIA after homogenization and extraction of tissues. Bombesin concentrations were higher in women with breast cancer (83.67\m=+-\21.07 ng/g) than in other groups, except women with gross cystic disease (79.6\m=+-\10.9ng/g).In contrast, tissue concentrations of DHEAS in women with breast cancer (130.5\m=+-\34.5\g=m\g/g) were lower with comparison to the others, except women with fibroadenoma (177.7\m=+-\84.9\g=m\g/g). Bombesin and DHEAS tissue concentrations showed significant negative correlation only in women with fibroadenoma. All values are means\m=+-\S.D.The significantly higher bombesin levels in tissues from women with breast cancer and in breast benign gross cystic disease (high risk of cancer) suggests the possible role of bombesin in the malignant process. Further studies are necessary to confirm these initial results.
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