Elevated plasma 19-hydroxyandrostenedione levels in Cushing's disease: stimulation with ACTH and inhibition with metyrapone.
OBJECTIVE
The regulation of 19-hydroxyandrostenedione secretion has been suggested to be under the control of both the ACTH-adrenal axis and renin-angiotensin system. We undertook the present study to evaluate the effect of the chronic excess of ACTH, or the short-term excess of ACTH due to metyrapone, on 19-hydroxyandrostenedione secretion in patients with Cushing's disease.


METHODS
We measured plasma 19-hydroxyandrostenedione levels simultaneously with plasma delta 4-androstenedione, corticosterone, 11-deoxycorticosterone, aldosterone and cortisol levels after HPLC separation in 13 patients with Cushing's disease under basal conditions and during a dexamethasone suppression test or metyrapone test. Seven patients with Cushing's syndrome due to adrenal adenoma were used for comparison.


RESULTS
The basal levels of 19-hydroxyandrostenedione in Cushing's disease were elevated (mean +/- SD; 323 +/- 193 pmol/l, n = 13), while those in Cushing's syndrome due to adrenal adenoma were low (92 +/- 24 pmol/l, n = 7), compared to those in normal subjects (117 +/- 33 pmol/l, n = 54). The basal levels of delta 4-androstenedione were mildly elevated in Cushing's disease (9.0 +/- 6.5 vs 3.6 +/- 2.6 nmol/l of normal subjects) but not in Cushing's syndrome due to adrenal adenoma (3.1 +/- 3.0 nmol/l). In the overnight 8 mg dexamethasone suppression test in Cushing's disease (n = 12), plasma levels of 19-hydroxyandrostenedione and delta 4-androstenedione decreased from 277 +/- 172 to 156 +/- 99 pmol/l and from 9.2 +/- 6.8 to 4.7 +/- 3.4 nmol/l, respectively, whereas the overnight 1 mg dexamethasone suppression test did not induce significant changes. Metyrapone administration in Cushing's disease (n = 9) increased plasma delta 4-androstenedione level from 9.5 +/- 6.7 to 47.2 +/- 28.1 nmol/l, but decreased plasma 19-hydroxyandrostenedione level from 301 +/- 196 to 196 +/- 105 pmol/l.


CONCLUSIONS
These data indicate that plasma levels of 19-hydroxyandrostenedione in patients with Cushing's disease are elevated due to chronic ACTH excess, and that metyrapone can inhibit 19-hydroxylation in humans.
Third Department of Internal Medicine, Gifu University School of Medicine, Japan.
T
T
Mune
H
H
Morita
K
K
Yasuda
M
M
Murayama
N
N
Yamakita
K
K
Miura
D000305:Adrenal Cortex Hormones / Q000097:blood; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000328:Adult; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000097:blood; D001794:Blood Pressure / Q000502:physiology; D003480:Cushing Syndrome / Q000097:blood*; D003864:Depression, Chemical; D003907:Dexamethasone; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008797:Metyrapone; D008875:Middle Aged
D000305:Adrenal Cortex Hormones; D000735:Androstenedione; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; C011482:19-hydroxy-4-androstene-3,17-dione; D006854:Hydrocortisone; D008797:Metyrapone