Adrenal androgen excess in women: lack of a role for 17-hydroxylase and 17,20-lyase dysregulation.
Some investigators have suggested that "dysregulation" of cytochrome P450c17 alpha may result in the exaggerated secretion of ovarian androgens in hyperandrogenism. Although the majority of hyperandrogenic (HA) patients demonstrate an ovarian source for their androgens, approximately 50% also display adrenocortical hyperactivity and adrenal androgen excess. To determine whether 17-hydroxylase (17-OH) and/or 17,20-lyase dysregulation is responsible for the adrenocortical abnormalities noted in many HA patients, we studied 92 consecutive women with hirsutism and/or HA oligomenorrhea; 26 healthy eumenorrheic nonhirsute women served as controls. The basal levels of total and free testosterone (T), sex hormone-binding globulin, and dehydroepiandrosterone sulfate were measured, and pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione were measured 0 and 60 min after the acute iv administration of ACTH-(1-24). Controls and HA patients did not differ in mean age or body mass, but HA women had higher basal T, free T, dehydroepiandrosterone sulfate, androstenedione, and LH/FSH and lower sex hormone-binding globulin levels. The mean estimated basal 17-OH activity was higher among HA patients than in controls. Although 52 HA patients demonstrated solely an exaggerated basal delta 5-17-OH activity estimate, few HA patients had an exaggerated estimate for either basal delta 4-17-OH or ACTH-stimulated 17-OH activity. No HA patient demonstrated an exaggerated 17,20-lyase basal activity, whereas 14 demonstrated an exaggerated delta 4-17,20-lyase ACTH-stimulated activity only. There was no association between these estimates of 17-OH and 17,20-lyase activities and the circulating adrenal androgen levels in HA women. Importantly, none of the patients demonstrated an increase in the basal activities of both 17-OH and 17,20-lyase, and only 4 patients demonstrated an exaggerated ACTH-stimulated activity of both 17-OH and 17,20-lyase. In conclusion, the steroidogenic profile observed in this population of HA women before and after ACTH-(1-24) stimulation is not consistent with dysregulation of cytochrome P450c17 alpha and probably represents a generalized alteration of adrenocortical control or biosynthesis.
Azziz
R
R
Department of Obstetrics and Gynecology, University of Alabama, Birmingham 35233-7333.
Bradley
E L
EL
Potter
H D
HD
Boots
L R
LR
D000311:Adrenal Glands / Q000378:metabolism*; D000328:Adult; D000446:Aldehyde-Lyases / Q000502:physiology*; D000728:Androgens / Q000097:blood / Q000378:metabolism*; D003366:Cosyntropin / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D006801:Humans; D017588:Hyperandrogenism / Q000453:epidemiology / Q000378:metabolism; D015994:Incidence; D010446:Peptide Fragments / Q000494:pharmacology; D012016:Reference Values; D013254:Steroid 17-alpha-Hydroxylase / Q000502:physiology*
D000728:Androgens; D010446:Peptide Fragments; D003366:Cosyntropin; D003577:Cytochrome P-450 Enzyme System; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases