Insulin Augmentation of 17α-Hydroxylase Activity Is Mediated by Phosphatidyl Inositol 3-Kinase But Not Extracellular Signal-Regulated Kinase-1/2 in Human Ovarian Theca Cells

Abstract

Polycystic ovary syndrome, characterized by hyperandrogenism and chronic anovulation, is frequently associated with insulin resistance. Ample evidence implicates a role for insulin in the genesis of ovarian hyperandrogenism. The objective of this study was to begin to define the intracellular signaling pathway(s) that mediates insulin regulation of 17alpha-hydroxylase activity in human ovarian theca cells. Third-passage theca cells, isolated from the ovaries of regularly cycling premenopausal women, were used. Insulin alone had no effect on 17alpha-hydroxylase activity or CYP17 mRNA expression but required costimulation with forskolin. At the insulin concentration used (10 ng/ml), a neutralizing antibody to the insulin receptor (but not an antibody to the type I IGF receptor) blocked the insulin stimulation of 17alpha-hydroxylase activity, demonstrating that the effects were mediated by the insulin receptor. Insulin stimulated both phosphatidylinositol-3-kinase (PI3-kinase) and extracellular signal-regulated kinase-1/2 (MAPK) pathways. Specific inhibition of MAPK kinase (MEK) with PD98059 or I0126 did not decrease the 17alpha-hydroxylase activity stimulated by forskolin or forskolin plus insulin. In contrast, the PI3-kinase inhibitor LY294002 completely blocked insulin-stimulated 17alpha-hydroxylase activity. Our data demonstrate that insulin stimulates PI3-kinase and extracellular signal-regulated kinase-1/2 activities in human theca cells, but only PI3-kinase mediates the insulin augmentation of forskolin-stimulated 17alpha-hydroxylase activity.

High prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus despite different hormonal profiles

“…The mean Ferriman-Gallwey score in obese girls with hirsutism was 10.6 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The prevalence of T2DM or obesity in first-degree family members of the obese girls with hirsutism was not significantly different from that found in the obese girls without hirsutism (T2DM: 25.7 vs 15%; P!0.19 and obesity: 45.7 vs 41.7%; P!0.7).…”

“…Although the prevalence of hirsutism in the European Caucasian girls with T1DM was lower than that of the T1DM girls of other ethnic origins, this difference was not statistically significant (13 vs 28%; PZ0.11). The mean Ferriman-Gallwey score in the girls with T1DM and hirsutism was 13.4 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The prevalence of T2DM and obesity in first-degree family members of the girls with T1DM and hirsutism was higher, but not statistically significant, than that of the girls with T1DM and without hirsutism (T2DM: 33 vs 11.7%; PO0.05 and obesity: 20 vs 6%; P!0.1).…”

“…In women with T1DM, the aetiology of their hyperandrogenism is unclear, and it has been proposed that their hyperandrogenism is due to non-physiological insulin replacement therapy (4,5). Indeed, the results of several laboratory and clinical studies have found that insulin can also influence the production of ovarian and adrenal androgens (6,7,8,9,10,11).…”

Insulin and hyperandrogenism in women with polycystic ovary syndrome

“…3). On the other hand, specific inhibition of MEK/ERK, another component of the MAPK insulin pathway, increases P450c17 activity [105]. Increased expression of P450c17 after inhibition of MEK/ERK was also found in human adrenal cells [107].…”

“…Insulin acts through its own receptor in the-cal [94,103] or fasciculata [104] cells. Specific blockade of PI-3K in normal human thecal cells markedly inhibits the combined insulin and LH stimulation of P450c17 activity [105]. It was also suggested that insulin may stimulate P450c17 activity through some players of the MAPK pathway such as MKK3/p38 and MKK4/JNK (see for review: [106] and Fig.…”