MOLECULAR ABNORMALITIES OF THE 21-HYDROXYLASE GENE IN HYPERANDROGENICWOMEN WITH AN EXAGGERATED 17-HYDROXYPROGESTERONE RESPONSE TO SHORT-TERM ADRENAL STIMULATION

OBJECTIVE: bur purpose was to establish the incidence of point mutatio ns of the 21-hydroxylase gene (CYP21) in hyperandrogenic women with an d without a 17-hydroxyprogesterone response to corticotropin stimulati on above normal but below those levels associated with nonclassic adre nal hyperplasia. STUDY DESIGN: We studied 22 patients with hirsutism o r hyperandrogenic oligoovulation: eight with an exaggerated net increa se in 17-hydroxyprogesterone (i.e., change in 17-hydroxyprogesterone b etween 8.8 and 36 nmol/L) and 14 with a normal change in 17-hydroxypro gesterone. Large deletions of the 21-hydroxylase gene were evaluated b y laser densitometry. Point mutations were detected with the polymeras e chain reaction and dot blot hybridization analysis and included 30 L eu, intron-2 (G), 8 bp deletion exon-3, 172 Asn, 236-237-239 exon-6, 2 81 Leu, 318 stop, 339 His, 341 Trp, 356 Trp, and 453 Ser. RESULTS: Fou r patients with an increase in 17-hydroxyprogesterone carried a 281 Le u mutation, one patient had an intron-2 (G) mutation, and one had a co mplete deletion of CYP21. Only two of these patients demonstrated no o bvious abnormality of CYP21. In contrast, only one of the control pati ents demonstrated a CYP21 abnormality, a significant difference (p < 0 .001). CONCLUSIONS: These findings suggest that the majority of hypera ndrogenic women with an exaggerated 17-hydroxyprogesterone response to corticotropin stimulation are heterozygotes (carriers) for inherited defects of CYP21. Whether these mutations are incidental to the androg en excess or predispose to the development of this disorder remains to be determined.