Sex differences in acute hormonal and subjective response to naltrexone: The impact of menstrual cycle phase

Abstract

Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n = 46 women) participated in two morning sessions in which they received 50 mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n = 23) or luteal phase of the MC. Serum cortisol, prolactin, and luteinizing hormone (LH), salivary cortisol, and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women.

Acute responses to opioidergic blockade as a biomarker of hedonic eating among obese women enrolled in a mindfulness-based weight loss intervention trial

“…These factors may impinge on associations between naltrexone-induced nausea and hedonic eating behavior, and deserve further attention. In addition, the naltrexone-induced cortisol increases and nausea were not highly correlated, as found in earlier studies (e.g., Daubenmier et al, 2014; Roche and King, 2015). Opioidergic systems governing subjective responses such as nausea may be separate from hypothalamic opioid tone.…”

“…Opioidergic systems governing subjective responses such as nausea may be separate from hypothalamic opioid tone. Indeed, the gastrointestinal tract is home to several endogenous opioidergic actions, and direct action on this opioidergic system could contribute to naltrexone-induced nausea (Holzer, 2009; Roche & King, 2015). …”

“…Due to a non-normal and skewed distribution of cortisol responses, we analyzed simple effects using Wilcoxon sum rank tests. Second, recent evidence suggests that naltrexone-induced cortisol responses can vary across menstrual cycle phase (e.g., luteal and follicular phases) and hormone use (e.g., oral contraceptives; Roche & King, 2015; Roche, King, Cohoon, & Lovallo, 2013). Therefore, we first used repeated measures ANOVA to determine whether time (1 PM, 3 PM, and 4 PM) and day (placebo vs. naltrexone) interacted with self-reported menstrual phase (follicular vs. luteal), menopausal status (pre-menopausal vs. menopausal), and hormone use (i.e., oral contraceptives) to predict cortisol levels.…”

Cortisol Stress Response in Men and Women Modulated Differentially by the Mu-Opioid Receptor Gene Polymorphism OPRM1 A118G

“…Women show variations in cortisol stress reactivity as a function of the menstrual cycle (Kudielka et al, 2009) and use of hormonal contraceptives (Kirschbaum et al, 1999;Roche et al, 2013). Similarly, cortisol response to naltrexone is larger during the luteal phase of the menstrual cycle relative to the follicular phase (Roche and King, 2015). We have reported that women as a group have large cortisol responses to 50 mg naltrexone relative to men (Lovallo et al, 2012), suggesting a greater degree of mu-opioid receptor restraint over the endogenous activity of the HPA in women that attenuates stress reactivity and is unmasked by opioid antagonism.…”

Sustained opioid antagonism modulates striatal sensitivity to baby schema in opioid use disorder

“…Excluding polysubstance use could have yielded a more homogeneous sample but would not be representative of the clinical OUD population (Wang et al, 2015). Finally, the between-subject variability in the menstrual cycle phase across scan sessions in this outpatient study could obscure the possible reproductive hormone-related effects (Carroll, Lynch, Roth, Morgan, & Cosgrove, 2004; Roche & King, 2015; Sprengelmeyer et al, 2009). Controlling for the menstrual cycle phase in a patient population may require a more structured environment than an outpatient setting could offer.…”