Naltrexone effects on insulin sensitivity and insulin secretion in hyperandrogenic women^*

Abstract

A total of 12 women (24.2 +/- 1.6 years old, BMI 36.7 +/- 1.5 Kg/m2) with hyperandrogenism (HA) and with normal glucose tolerance test were studied to evaluate the involvement of endogenous opioids in the pathophysiology of insulin secretion and insulin sensitivity in HA by administering naltrexone, an oral opioid receptor antagonist. Six patients received naltrexone orally (75 mg daily) and another six received placebo for 12 weeks (double-blind study). Before and after therapy a frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed. The insulin sensitivity index (SI) was determined by Bergman's program. SHBG, DHEAS, testosterone, free androgen index (FAI) and plasma concentrations of IGF-I and IGFBP-1 were determined in 3 basal samples, before and after therapy. Treatment with naltrexone in hyperandrogenic patients resulted in a decrease in fasting insulin concentrations of 40% and C-peptide concentrations of 50% (p < 0.05). Insulin and C-peptide from the FSIVGTT displayed a similar pattern with a fall in the area under the curve under naltrexone treatment of 34% for insulin and 35% for C-peptide. Insulin sensitivity did not change under naltrexone (1.26 +/- 0.19 vs 1.32 +/- 0.32 10(-4) x min(-1)/(uU/ml)) or placebo (0.95 +/- 0.19 vs 1.12 +/- 0.28 10(-4) x min(-1)/(uU/ml)) administration. However, glucose effectiveness increased significantly with naltrexone (2.231 +/- 0.002 vs 3.354 +/- 0.006 x 10(-2) min(-1)). Glucose (fasting and area under the curve) was not modified significantly after naltrexone administration. Baseline hormone levels were similar in the two groups, and they did not change after long-term treatment with naltrexone or placebo. In conclusion, these results support the hypothesis of elevated opioid tonus and increased insulin secretion as a possible mechanism of hyperinsulinism in a group of hyperandrogenic women of ovarian origin. This alteration could act as an additional factor in the pathogenesis of insulin resistance found in an important proportion of these patients.

Impact of the opioid system on the reproductive axis

“…Endogenous opioids stimulate pancreatic cell insulin secretion, likely via paracrine and autocrine mechanisms. b-Endorphin-containing cells have been identified in areas surrounding the pancreatic b-cells, and opioids have been shown to stimulate insulin secretion (52,54). It is therefore tempting to speculate that locally elevated opioid activity stimulates insulin secretion from the pancreas.…”

Metformin, naltrexone, or the combination of prednisolone and antiandrogenic oral contraceptives as first-line therapy in hyperinsulinemic women with polycystic ovary syndrome

“…Such an effect has not been observed in women with hypothalamic amenorrhea, but has been described in some (15) but not all women suffering from PCOS (2,4). These discrepant findings may reflect the presence of diverse mechanisms of regulation of the hypothalamic-pituitary-adrenal axis in women with PCOS.…”

“…Subjects were randomized to receive a 3-month course of [1] metformin (M), [2] naltrexone (N), or [3] a combination of prednisolone and an antiandrogenic oral contraceptive (OC/Pr) for the first month. Therapies 1 and 3 are widely used.…”

“…Therapies 1 and 3 are widely used. In contrast, although N has been demonstrated to normalize insulin levels in women with PCOS (2)(3)(4), as recently reviewed (5), its effects on ovarian function have not been extensively studied.…”

Opiate receptor blockade on human granulosa cells inhibits VEGF release

“…Prompted by the evidence for an intrafollicular opioid system in mammals (Dell'Aquila et al, 2002;Hamada et al, 1995;Kaminski et al, 2000Kaminski et al, , 2004Slomczynska et al, 1997), and supported by data from previous clinical trials on the administration of opioid antagonists in the context of gynaecological endocrinology (Hadžiomerović-Pekić et al, 2010;Leyendecker et al, 1993;Sir-Petermann et al, 1998), we set out to elucidate the presence of opioid receptors in human granulosa cells and to test the effects of exogenous opiates on granulosa cell VEGF production. This study is the necessary first step to elucidate the role of endogenous opioids in human granulosa cells as a component of the follicular microenvironment.…”