The effect of serum prolactin on plasma adrenal androgens and the production and metabolic clearance rate of dehydroepiandrosterone sulfate in normal and hyperprolactinemic subjects

Hyperprolactinemic patients may have increases in plasma dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulfate (DHAS). We examined the effect of lowering serum PRL with bromocriptine or pituitary surgery on the serum concentrations of adrenal androgens and on the production rate (PR) and MCR of DHAS in eight hyperprolactinemic women (HP). We also examined the effect of bromocriptine therapy on adrenal androgens in five normal men. Serum DHAS was elevated in HP compared to normal women (mean ± SEM, 254 ± 28 vs. 182 ± 13 μg/dl; P < 0.04). Serum DHA and androstenedione (Δ⁴) in HP were not significantly different from normal. Serum PRL fell from 160 ± 16 to 37 ± 9 ng/ml during or after treatment. Mean 24-h serum DHAS fell from 198 ± 30 to 106 ± 17 μg/dl (P < 0.001) with treatment, without a change in the mean 24-h serum cortisol concentration (6.2 ± 0.4 vs. 6.6 ± 0.4 Mg/dl). Thus, the DHAS to cortisol (DHAS/F) ratio fell significantly (32± 5 to 17 ± 4; P < 0.001). This was also true of the DHAS/F ratio during ACTH stimulation (8 ± l t o 6 ± l ; P < 0.02). Similar changes were found in basal and ACTH-stimulated DHA/F ratios, whereas the basal and ACTH-stimulated A4/F ratios did not change significantly with treatment. Treatment lowered the PR of DHAS from 27 ± 5 to 17 ± 3 mg/24 h (P < 0.03) and increased the DHAS MCR from 16 ± 2 to 21 ± 3 liters/24 h (P < 0.01). Bromocriptine treatment of normal men lowered serum PRL from 15 ± 2 to less than 2.5 ng/ml. There were no significant changes in the basal and ACTH-stimulated serum DHAS/F, DHA/F, or Δ⁴F ratios or DHAS PR and MCR during bromocriptine therapy. The failure of bromocriptine to significantly alter these steroids in normal men suggests that bromocriptine was not directly responsible for the changes in HP treated with this drug. A mechanism for the increased PR of DHAS in HP was sought by examining the serum concentrations of the steroid biosynthetic intermediates relevant to DHAS production. Lowering serum PRL was associated with a decrease in basal and ACTH-stimulated 17-hydroxypregnenolone/17-hydroxyprogesterone and DHA/Δ⁴ ratios, suggesting an increase in 3β-hydroxysteroid dehydrogenase/Δ^{4, 5}-isomerase activity. However, increased gonadal secretion of the Δ⁴-steroids may have occurred with the fall in serum PRL. With treatment, both basal and ACTH-stimulated 17-hydroxypregnenolone/DHA and 17-hydroxyprogesterone/Δ⁴ ratios increased, suggesting a fall in 17, 20- desmolase activity. The basal DHA/DHAS ratio increased after treatment without a change in the ACTH-stimulated ratio, suggesting a fall in peripheral sulfokinase activity. We conclude that hyperprolactinemia is associated with an elevation of serum DHAS, which primarily reflects an increased DHAS PR. The mechanism of the increased DHAS PR may include increased 17, 20-desmolase activity, increased peripheral sulfokinase activity, and, possibly, decreased 3β-hydroxysteroid dehydrogenase/Δ^{4, 5}-isomerase activity.