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Abnormalities of 21-Hydroxylase Gene Ratio and Adrenal Steroidogenesis in Hyperandrogenic Women with an Exaggerated 17-Hydroxyprogesterone Response to Acute Adrenal Stimulation^*

Departments of Obstetrics and Gynecology, and Microbiology The University of Alabama Birmingham, Birmingham, Alabama 35294
Dept. of Gynecology and Obstetrics The Johns Hopkins Hospital Baltimore, Maryland 21205

Address requests for reprints to: Ricardo Azziz, M.D., Department of Ob/Gyn, UAB Medical Center, Birmingham, Alabama 35294.

One to 2% of hyperandrogenic women demonstrate a 17-hydroxyprogesterone (17-HP) level greater than 36.3 nmol/L (1200 ng/dL) after acute ACTH–(l–24) adrenal stimulation, consistent with 21–hydroxylase (21-OH) deficient lateonset adrenal hyperplasia (LOAH). The following study was undertaken to endocrinologically and genetically define hyperandrogenic patients with an exaggerated 17-HP response to ACTH stimulation, and which do not represent LOAH. Of 265 consecutive patients suffering from hirsutism and/or hyperandrogenic oligomenorrhea, 23 (8.7%) demonstrated a 17-HP level 30 min post stimulation greater than 9.6 nmol/L or 316 ng/dL (the upper 95th percentile in 41 eumenorrheic nonhirsute healthy control women). Seven patients or five separate families (1.8% of total) demonstrated poststimulation 17-HP levels consistent with LOAH. Of the remaining 16 patients, the net increment in 17-HP (17-HP_0–30) was within normal limits in seven (2.6%) and these women were assumed to have a normal 17-HP adrenocortical response superimposed on an elevated basal level of nonadrenal (e.g. ovarian) origin. In the remaining nine hyperandrogenic patients (3.4%) various abnormalities of adrenal response were noted in all but one patient, consistent with adrenal hyper-responsiveness. One patient demonstrated an 11-deoxycortisol poststimulation level greater than 3-fold the upper 95th percentile of normal, consistent with 11-hydroxylase LOAH and was excluded from further study. Six of these women were available for further genetic characterization, all Caucasian and unrelated. Three were heterozygotes for HLA–B14, three for B40, and one for B35 antigen, HLA-types associated with the inheritance of 21-OH deficiencies. Although, normally there are two 21-OH genes (a pseudogene and a functional gene) present in a 1:1 ratio, we have previously reported a high frequency of 21-OH gene ratio abnormalities in LOAH. All but one of our patients demonstrated an abnormal 21-OH gene ratio. In conclusion, 3.4% of our hyperandrogenic population demonstrated an exaggerated 17-HP increment after ACTH stimulation, not consistent with LOAH or increased extraadrenal 17-HP production. The increased prevalence of HLA alleles known to be linked to inherited defects of 21-OH function and the increased frequency in 21-OH gene ratio abnormalities suggest that a majority of these individuals may be carriers for these genetic disorders. However, the adrenocortical abnormalities noted were more consistent with a generalized hyperreactivity of the adrenal to ACTH stimulation, than a specific enzyme deficiency, implying that carrier status for 21-OH deficiency may be incidental to the hyperandrogenism.

^* Supported in part by Grant DK–32767 from the National Institute of Diabetes, and Digestive and Kidney Diseases, NIH.

Received February 28, 1991.

This article has been cited by other articles:

				E. S. Knochenhauer, C. Cortet-Rudelli, R. D. Cunnigham, B. A. Conway-Myers, D. Dewailly, and R. Azziz Carriers of 21-Hydroxylase Deficiency Are Not at Increased Risk for Hyperandrogenism J. Clin. Endocrinol. Metab., February 1, 1997; 82(2): 479 - 485. [Abstract] [Full Text] [PDF]