Involvement of Ovarian Steroids in the Opioid-Mediated Reduction of Insulin Secretion in Hyperinsulinemic Patients with Polycystic Ovary Syndrome

Abstract

To evaluate the possible involvement of ovarian steroids on the opioid-mediated disorders of insulin in patients affected by polycystic ovary syndrome (PCOS), we studied 40 PCOS women. All patients underwent an oral glucose tolerance test (OGTT; 75 g) and basal hormone assay; based on the insulin response to OGTT, 26 women were classified as hyperinsulinemic and continued the study protocol.Patients were randomly divided into three groups characterized by different treatments: group A (nine patients) was treated with GnRH analog (one ampule every 28 days for 2 months), group B (eight patients) was treated with naltrexone (an oral opioid antagonist, 50 mg/day, orally) for 8 weeks, and group C (nine patients) was treated with GnRH analog plus naltrexone for 2 months. After continuation of treatment, all patients repeated the basal study in a second hospitalization.Naltrexone treatment significantly reduced the insulin response to OGTT, whereas GnRH analogue administration did not significantly change the insulin secretion after the glucose load. The GnRH analog/ naltrexone cotreatment was not able to influence the insulin secretory pattern; in fact, the insulin area under the curve was superimposable before and after therapy. These data could lead to the hypothesis that the opioidergic regulation of insulin secretion requires a normal steroidogenic pattern, thus suggesting that ovarian steroids modulate opioid activity also at peripheric districts. (J Clin Endocrinol Metab 83: [1742][1743][1744][1745] 1998) T HE PATHOGENESIS of polycystic ovary syndrome (PCOS) is still controversal. Inappropriate gonadotropin secretion, elevated serum androgen concentrations, hyperinsulinism, and insulin resistance are the common features (1, 2).Many studies have found a relationship between hyperinsulinism and elevated circulating androgen levels in PCOS (2-4), suggesting that insulin may cooperate with LH in inducing chronic hyperandrogenemia in PCOS patients. Previously, we showed that despite a marked and prolonged decrease in androgen ovarian production obtained by GnRH agonist, insulin secretion in response to an oral glucose tolerance test (OGTT) did not change in PCOS patients, thus indicating that androgens do not cause hyperinsulinism (5).Our recent data demonstrated that treatment with naltrexone (a long acting opioid antagonist) is able to reduce the LH response to GnRH stimulus in PCOS patients (6).Moreover, increasing evidence indicates that endogenous opiates are involved not only in the mechanism of gonadotropin release, but also in the regulation of many other compartments such as pancreatic islet function and thus in the pathogenesis of hyperinsulinemia and insulin resistance in subjects suffering from PCOS (7). Both acute (naloxone) and chronic (naltrexone) inhibition of opioidergic system significantly decreased the insulinemic response to an OGTT in a group of hyperinsulinemic PCOS patients without any change of plasma androgen levels (8, 9).Several in vivo and in vitro studies suggested that the ef...

Beta endorphin in serum and follicular fluid of PCOS- and non-PCOS women

“…In bovine oocyte maturation, an inhibitory effect of beta endorphin has been demonstrated, but only in the absence of sex hormones [25]. This is consistent with the known effects of beta endorphin in the human pancreas and hypothalamus, where the presence of sex hormones is pivotal for stimulating insulin/glucagon release and inhibition of GnRH pulsatility, respectively [5, 26]. …”

“…The role of endogenous opioids, especially the POMC-derivate beta endorphin, in PCOS has been a research topic for some time [3–5], but has not been extensively studied.…”

“…Beta endorphin has been shown to modulate pancreatic insulin and glucagon release [14]. Interestingly, the presence of sex steroids seems to be critical for beta endorphin action in the human pancreas [5]. …”

Role of Opioid Antagonists in the Treatment of Women with Glucoregulation Abnormalities

“…Some investigators even postulated that the opioidergic impairment in PCOS patients could be caused by a functional state secondary to ovarian acyclicity. In the attempt to evaluate this aspect, we studied the effects of naltrexone on gluco-insulinemic metabolism in different hormonal environments [68]. By the long-term administration of a GnRH analog (GnRH-A), we obtained a marked and prolonged decrement in androgens and gonadotrophins levels in a group of PCOS patients.…”