Chronic ethanol drinking increases during the luteal menstrual cycle phase in rhesus monkeys: implication of progesterone and related neurosteroids

Abstract

Rationale: Sporadic reports of alcohol consumption being linked to menstrual cycle phase highlight the need to consider hormonally-characterized menstrual cycle phase in understanding the sex-specific effects of risk for alcohol drinking in women. Objectives:We investigated the association between menstrual cycle phase, characterized by circulating progesterone and menses, with accurate daily alcohol intakes in rhesus monkeys, and the contribution of progesterone derived neuroactive steroids to cycle-related alcohol drinking.Methods: Menses (daily) and progesterone (2-3x/week) were obtained in female monkeys (n=8, 5 ethanol, 3 control) for 12-18 months. Ethanol monkeys were then induced to drink ethanol (4% w/v; 3 months) and given 22 hrs/day access to ethanol and water for approximately one year. In selected cycles, a panel of neuroactive steroids were assayed during follicular and luteal phases from pre-ethanol and ethanol exposure.Results: There were minimal to no effects of ethanol on menstrual cycle length, progesterone levels, follicular or luteal phase length. The monkeys drank more ethanol during the luteal phase, compared to the follicular phase, and ethanol intake was highest in the late luteal phase when progesterone declines rapidly. Two neuroactive steroids were higher during the luteal phase versus the follicular phase, and several neuroactive steroids were higher in the pre-vs post-ethanol drinking menstrual cycles.

The Endocrine System and Alcohol Drinking in Females

“…In contrast to studies of rodents, a recent, longitudinal study of female rhesus monkeys with systematic and extensive hormonal monitoring of menstrual cycle phase across 15 months of active alcohol drinking determined that the monkeys drank more alcohol during the luteal versus the follicular phase and drank the most alcohol during the late luteal phase, when progesterone declines rapidly. 50 These results from a nonhuman, primate model of self-administration of alcohol were the first to show that typical menstrual cycle–related fluctuations in progesterone, especially during the late luteal phase, modulated alcohol drinking. Previous studies that used less accurate characterization of menstrual cycles and differing histories of alcohol intake revealed inconsistent effects of the menstrual cycle on alcohol drinking.…”

“…In a small cohort of females with AUD, a significant reduction in allopregnanolone, progesterone, and estradiol levels was detected upon detoxification, and levels recovered to baseline values after 4 months of abstinence. 90 In contrast, chronic alcohol drinking did not significantly alter serum allopregnanolone levels in female monkeys, 50 nor did withdrawal from chronic alcohol vapor exposure alter plasma allopregnanolone levels in female mice (DA Finn and JP Jensen, unpublished data, Feb 2019 and Nov 2019).…”

“…Previous studies that used less accurate characterization of menstrual cycles and differing histories of alcohol intake revealed inconsistent effects of the menstrual cycle on alcohol drinking. Therefore, Dozier and colleagues' method of extensive menstrual cycle characterization during periods of active drinking 50 likely was necessary to show the significant menstrual cycle-related fluctuation in alcohol drinking.…”

“…Fifteen months of active drinking also did not alter progesterone or estradiol levels in the female monkeys. 50 The method of chronic alcohol exposure and resulting blood alcohol concentrations, which are considerably higher for vapor exposure (e.g., 200 mg%) than for drinking models (e.g., 80 mg% to 100 mg%), may contribute to the differences among studies with regard to whether chronic alcohol exposure disrupted the estrous or menstrual cycle.…”

Discriminative Stimulus Effects and Metabolism of Ethanol in Rhesus Monkeys

“…The rate of EtOH elimination is within the range of reports in human subjects, providing face validity for future research on alcohol self‐administration in rhesus macaques. One limitation of the current experiment is the inclusion of only male subjects, as there are known differences between males and females in EtOH pharmacokinetics (Baraona et al., ; Green et al., ; Zorzano and Herrera, ) and sex‐specific effects in females related to different phases of the menstrual cycle (Dozier et al., ; Grant et al., ; Green et al., ). Future studies examining these variables in female rhesus macaques would allow for complete cross‐species and cross‐sex comparisons in translational alcohol research.…”