The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome.

Abstract

Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO. Eight patients with PCO and seven matched controls received ovine corticotropin-releasing hormone (oCRH; 0.1 micrograms/kg) iv before and after hypoestrogenism was induced by leuprolide acetate (LA; 1 mg, sc, each day). In patients with PCO, a third oCRH test was repeated after transdermal estradiol (E2; 0.1 mg) had been applied for a week, during which time LA was continued. At baseline, patients with PCO had increased responses of 11 beta-hydroxyandrostenedione and dehydroepiandrosterone (P < 0.03 and P < 0.02) and increased delta maximal ratios of androstenedione (A4)/ACTH and dehydroepiandrosterone/ACTH (P < 0.01) after oCRH treatment. After LA administration to patients with PCO, these ratios were significantly suppressed (P < 0.01) and returned to baseline after E2 was added. There were no changes in controls. Steroid ratio responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal E2 administration. There was a significant positive correlation between changes in E2 levels and delta maximum change in the ratios of A4/17-OHP after oCRH treatment, signifying 17,20-desmolase activity (r = 0.58, P < 0.02). In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome.

New insights into steroidogenesis in normo- and hyperandrogenic polycystic ovary syndrome patients

“…In the current study, normo-and hyperandrogenic PCOS patients demonstrated equal ratios of progesterones (17-OHP4/17-OHPE p = 0.837), suggesting equal 3β-HSDII activity in these groups for the conversion of 17-OHPE to 17-OHP4. Equivalent 3β-HSDII activity was previously reported for the comparison between healthy women and PCOS patients (13). Using DHEAS as a surrogate for DHEA, the higher A/DHEAS ratio in hyperandrogenic patients found in the current study suggests higher 3β-HSDII activity specifically for the conversion of DHEA to A.…”

“…The increase in 17,20 lyase activity was also seen in PCOS patients, even after diagnostic standardization, and it was attributed to the phosphorylation of Ser/Thr residues, cytochrome b5, and cytochrome c allosteric actions (22)(23)(24). In fact, P450c17α dysregulation has been attributed to the modulatory effects of cytochrome b5, insulin, and estradiol (13,23). In the current study, estradiol levels were not increased in the hyperandrogenic group, and this finding does not support previous observations indicating that estrogen may increase 17,20 lyase activity in the conversion of 17-OHP4 to A in PCOS patients (13,14).…”

“…Both decreases in 17-hydroxylase activity with increases in 17,20 lyase (18) and increases in 17-hydroxylase in relation to 17,20 lyase (12) activity have been detected in PCOS patients, even after the adoption of the new exclusion criteria. An early study demonstrated that in PCOS patients, estrogen may activate 17,20 lyase for the conversion of 17-OHP4 into A without affecting the conversion of 17-OHPE into DHEA (13). The increase in 17,20 lyase activity was also seen in PCOS patients, even after diagnostic standardization, and it was attributed to the phosphorylation of Ser/Thr residues, cytochrome b5, and cytochrome c allosteric actions (22)(23)(24).…”

“…In fact, P450c17α dysregulation has been attributed to the modulatory effects of cytochrome b5, insulin, and estradiol (13,23). In the current study, estradiol levels were not increased in the hyperandrogenic group, and this finding does not support previous observations indicating that estrogen may increase 17,20 lyase activity in the conversion of 17-OHP4 to A in PCOS patients (13,14). Although hyperandrogenic patients presented higher baseline insulin levels, reports of the role of insulin in P450c17α enzyme activity have been inconsistent (13,23,25).…”

“…Currently, few studies have investigated the activity of corticosteroidogenic enzymes in this syndrome (13), and these studies have not compared their results to those obtained in studies performed prior to the introduction of the NIH/Rotterdam diagnostic criteria. Considering the current exclusion criteria, differences in steroidogenic enzyme activities may exist between PCOS patients for whom diagnosis was performed before (11) or after the (14) NIH/ Rotterdam consensus.…”