Insulin Stimulates Androgen Accumulation in Incubations of Ovarian Stroma Obtained from Women with Hyperandrogenism*

Abstract

The effects of insulin and insulin-like growth factors (IGFs) on ovarian androgen production were examined in ovarian stroma obtained from four women with hyperandrogenism and three women without hyperandrogenism. In incubations of stroma obtained from all four hyperandrogenic patients, insulin alone (500 ng/ml) significantly stimulated androstenedione and testosterone release. LH alone (25 ng/ml) significantly stimulated androstenedione release in incubations of stroma obtained from three of the four hyperandrogenic patients and testosterone release in incubations of stroma obtained from one of the four hyperandrogenic patients. In stromal incubations from three of the four hyperandrogenic patients, insulin alone (500 ng/ml) resulted in a significantly greater release of androstenedione and testosterone than did LH alone (25 ng/ml). Dihydrotestosterone was released in measurable quantities in incubations of stromal tissue obtained from three of the four hyperandrogenic women. In all three instances in which dihydrotestosterone was detectable, insulin alone (500 ng/ml), but not LH alone (25 ng/ml), significantly stimulated dihydrostestosterone release. Incubations of stroma obtained from three nonhyperandrogenic, normally cycling women demonstrated low levels of androstenedione release and negligible testosterone and dihydrotestosterone release. Insulin alone (500 ng/ml) and LH alone (25 ng/ml) produced no significant increase in androstenedione release. Insulin (500 ng/ml) plus LH (25 ng/ml) significantly stimulated androstenedione accumulation in stroma obtained from two of the nonhyperandrogenic women. One insulin dose-response experiment was performed using stromal tissue obtained from a hyperandrogenic woman. In this experiment, insulin, at a dose of 50 ng/ml, was as effective as insulin at a dose of 500 ng/ml in stimulating androstenedione and testosterone release. In addition to insulin, IGF-I/somatomedin C (50 ng/ml) stimulated androstenedione and testosterone release. Relaxin (1 microgram/ml) and multiplication-stimulating activity (50 ng/ml) did not stimulate androstenedione and testosterone release. These studies suggest that human ovarian stroma may be a target tissue for insulin and IGF-I, and that hyperinsulinemia may be an important factor contributing to ovarian hyperandrogenism.

Body Shape and Size and Insulin Resistance as Early Clinical Predictors of Hyperandrogenic Anovulation in Ethnic Minority Adolescent Girls

“…(24)(25)(26)(27) Obesity begets insulin resistance, the associated hyperinsulinemia suppresses hepatic production of SHBG, and in turn free plasma testosterone becomes elevated. (28)(29)(30) Women with PCOS have insulin resistance that is more severe than can be accounted for by obesity alone (25,31,32) and this leads to even greater reductions in SHBG and higher androgens. In turn insulin may drive androgen secretion in PCOS, thus causing a feed-forward mechanism promoting hyperandrogenemia.…”

Testosterone, SHBG and cardiovascular health in postmenopausal women

“…Insulin inhibits hepatic SHBG production in vitro. 99 Simultaneously, insulin stimulates ovarian testosterone production 100 and luteinizing hormone release from pituitary cells. 101 Furthermore, suppression of insulin levels by metformin therapy reduces androgen levels in polycystic ovary syndrome women.…”

Does Early Physical Maturity Influence Breast Cancer Risk?

“…While physiological insulin levels synergise with FSH in their action on granulosa cells (49), high levels of insulin amplify the action of LH in stimulating androgen synthesis in adult ovarian stroma (50). The concomitant aromatisation of the excess androgen to oestrogen in the granulosa cells is likely to increase oestrogen production also (51) so that both androgen and oestrogen levels are modified.…”