Observational, interventional and experimental studies demonstrated that even moderate alcohol consumption and acute alcohol administration affect the endocrine profile in women of reproductive age, by elevating, and suppressing, estrogens and progesterone levels, respectively; the mechanisms underlying these endocrine effects are still to be completely elucidated; nevertheless, proposed mechanisms include a decreased rate of hepatic estradiol oxidation and an increased aromatization of testosterone to estradiol, a decreased rate of hepatic conversion of pregnenolone to progesterone and reduced uptake of cholesterol, and a dose-dependent and time-dependent decrease in LH/human chorionic gonadotropin (hCG) receptors in granulosa cells, therefore involving both ovarian and extra-ovarian actions of alcohol [
157]. Opposite endocrine effects were reported in alcohol abusers, which displayed reduced estrogens and increased progesterone levels compared to non-alcohol abusers. A major role in estrogens-related and progestins-related endocrine derangement induced by alcohol has to be ascribed to the liver, in particular in the case of chronic alcohol consumption, with changes in steroid hormones occurring before liver damage has appeared; nevertheless, in cases of alcoholism determining severe liver damage, disentangle a selected effect of alcohol on estrogens and progestins metabolism from the general effects of liver disease is quite puzzling, therefore dampening the results presented by studies on alcoholism [
158]. An observational prospective cohort study attempted to address the relationship between alcohol consumption and estradiol levels, by trying to minimize intra-individual variability and circadian hormone variations by repeating hormone measurement twice, at a one-year interval, within the same phase and on the same day of the menstrual cycle, and at the same hour of the day, by also accounting for other confounders [
159]. The results of the study demonstrated that women who consumed alcohol had significantly higher serum levels of total estradiol, compared with abstainers, when estradiol levels were analysed as average of two measurements over a year [
159]; moreover, when stratifying women according to alcohol intake categories, estradiol serum levels were found to be higher in the higher-intake categories, suggesting a dose-dependent effect, although differences in estradiol levels among different strata did not reach statistical significance [
159]. Observational studies specifically addressing the impact of alcoholism on estrogens and progesterone levels attained inconsistent findings. In particular, two prospective studies conducted in alcohol abusers
vs. non-alcohol abusers found no significantly different levels of estradiol and estrone, although opposite trends, specifically, higher [
160], or lower [
161] levels were reported, in alcohol abusers
vs. non-alcohol abusers; the same studies highlighted that alcoholism did not significantly change progesterone levels, although progesterone levels tended to be higher in the follicular phase of the menstrual cycle [
160], and lower in the mid-cycle [
160] and luteal phase of the menstrual cycle [
160,
161], in alcohol abusers. Conversely, a different case-control study demonstrated that estradiol levels were significantly reduced, and progesterone levels were significantly increased, in alcohol abusers, as compared to non-alcohol abusers [
158]. Discrepancies among studies in alcohol abusers might be accounted by differences in the definition of alcoholism, in the amount of alcohol consumed, and in the age of participants. Moreover, none of these studies took into consideration the circadian variations of hormones levels. Lastly, although these studies were performed in alcohol abusers in absence of overt liver damage, a contribution of liver dysfunction on the observed endocrine derangements can’t be completely disregarded. An interventional study on healthy women subjected to acute administration of ethanol solution (0.695 g/kg), prepared with 40% beverage ethanol (vodka), and administered during the follicular phase of the menstrual cycle over a 19 minutes interval, demonstrated that acute administration of alcohol significantly increased plasma estradiol levels within minutes from alcohol administration [
162]; these findings were in line with previous reports from similar studies performed during the mid-luteal phase of the menstrual cycle [
163], but were in contrast with a previous study on pregnant women with alcohol abuse reporting reduced estradiol levels [
164], therefore suggesting a dose-dependent, biphasic, effect of alcohol intake on estrogens, or, again, a contribution of liver dysfunction to decreased estradiol levels in alcohol abusers. The mechanisms beneath the acute response to moderate alcohol ingestion have not been fully addressed in humans, nevertheless, the rapidity of estradiol surge potentially rules out the hypothesis of an effect of alcohol on aromatase activity and testosterone aromatization to estradiol, which has only been demonstrated in a long-term chronic setting of alcohol ingestion, in men [
165] and male animal models [
166], and indirectly postulated in experimental in vitro studies on human granulosa cells [
167]; more likely, a role for the decrease in the liver NAD
+/NADH ratio caused by increased ethanol hepatic metabolism might be hypothesized, indeed, in these conditions, hepatic estradiol to estrone oxidation is less favored, and might determine estradiol accumulation [
157,
162]. Consistently, a different interventional study on healthy women subjected to acute administration of ethanol solution (0.4g/kg), prepared as 8% ethanol in lingonberry juice, demonstrated that intake of alcohol significantly increased and decreased plasma testosterone and androstenedione levels, respectively, reflecting a reduced liver oxidation of androgens [
168]. These results corroborate the implication of hepatic steroids metabolism as the mechanisms driving the alcohol-induced increase in estrogens levels; on the other hand, the excess of testosterone might also represent a stimulus to push hepatic aromatase activity toward increased estradiol production, nevertheless, this mechanism has not been validated in interventional or experimental in vivo studies so far. A different interventional study performed across six consecutive menstrual cycles evaluated the effects of moderate alcohol consumption on pooled plasma and urinary estrogens levels, at different time-points within the menstrual cycle, in the attempt to detect differential changes in estrogens levels, according to different phases of the menstrual cycle [
169]. Alcohol consumption was set as 30 g of ethanol
per day, for three consecutive menstrual cycles, with ethanol withdrawal for the last three cycles. The hormonal assessment showed significantly increased plasma levels of estrone and estradiol, and urinary levels of estradiol during the periovulatory phase, whereas, in the luteal phase, a significant increase in urinary levels of estrone, estradiol and estriol were found [
169]. These results further strengthen the evidence of a link between alcohol consumption and increased estrogens levels. Moreover, in the specific experimental setting, the lack of changes in the excretion of estrogens catabolites pinpoints to increased estrogens production, rather than variations in estrogens clearance [
169]. Conversely, an observational prospective cohort study across a single monitored menstrual cycle, failed to find any association between self-reported alcohol consumption and pooled plasma estrogens levels, in any of the menstrual cycle phases [
170]; nevertheless, the pattern of alcohol intake was not accounted for, in this study, in which the median weekly alcohol intake was 51 g [
170], therefore, discrepancies between the two studies might be due to different experimental settings. Lastly, the alcohol-induced increase in estrogens levels has been also shown in post-menopausal women, and has been shown to enhance the effects of estrogen replacement therapy and to maintain estrogens levels, after medication removal [
157]. Interventional human studies suggested that alcohol ingestion might have adverse effects on progesterone production. A study on women subjected to acute administration of ethanol solution (0.34-1.02 g/kg), demonstrated that intake of alcohol significantly decreased progesterone levels, although no dose-dependent effects were detected [
171]. Moreover, two different studies found that alcohol ingestion significantly inhibited progesterone raise during the early follicular phase of the menstrual cycle in women receiving naltrexone [
172], and during the luteal phase of the menstrual cycle in women receiving hCG [
173]. The hypothesized mechanism driving the observed alcohol-induced progesterone suppression implies a reduced rate of hepatic conversion of pregnenolone to progesterone, an enzymatic process which might be adversely affected by the decreased liver NAD
+/NADH ratio caused by increased ethanol hepatic metabolism [
172]. Experimental in vitro studies on human luteinized granulosa cells confirmed the stimulatory effect of alcohol on estradiol production. In particular, treatment with ethanol at different concentrations induced a dose-dependent increase in basal estradiol secretion by reaching a significant increase at 20 mM [
154]; nevertheless, ethanol concentrations above 20 mM did not further increase estradiol secretion by granulosa cells, therefore supporting the hypothesized biphasic action of ethanol observed in vivo. Increased aromatase activity has been indirectly proposed as the driving mechanisms of increased basal estradiol production, since ethanol treatment was shown to significantly increase estradiol levels, in the presence of androstenedione excess [
167]. Moreover, at a low concentration of 5 mM, ethanol significantly enhanced FSH-induced estradiol secretion, but this effect was not observed at higher concentrations of ethanol [
154]; conversely, ethanol dose-dependently and significantly decreased LH-induced estradiol secretion [
154]. The same in vitro study on human luteinized granulosa cells highlighted comparable effects of ethanol treatment on progesterone secretion; in particular, a weak although significant increase in basal progesterone secretion, an inconsistent effect on FSH-induced progesterone secretion, and a significant decrease in LH-induced progesterone secretion [
154]. Further in vitro experiments showed that ethanol treatment induced a significant dose-dependent and time-dependent decrease in LH/hCG receptors in granulosa cells, therefore explaining the observed effects of ethanol on LH-induced estradiol and progesterone secretion [
154]. These experimental results suggest that ethanol might exert direct and indirect effects on ovarian steroidogenesis by potentially acting at two different levels, namely, increased aromatization of androgens, and decreased LH/hCG receptors expression, therefore stimulating basal estrogens secretion while simultaneously reducing the ovarian response to LH stimulation on estradiol and progesterone synthesis. These results might also address the inhibitory effect of alcohol ingestion on naltrexone-stimulated and hCG-stimulated progesterone production observed in clinical studies. Lastly, an in vitro study on human cytotrophoblast cells isolated from normal-term placenta demonstrated that ethanol treatment dose-dependently decreased progesterone secretion, by possibly blocking the trafficking of cholesterol within cytotrophoblast cells organelles [
174]; nevertheless, the exact mechanisms beneath this action are still unclear, and need further investigation.
In conclusion, alcohol consumption has been associated to derangements of the endocrine function, mediated by both ovarian and extra-ovarian actions, although mechanisms underlying the endocrine effects are still to be completely elucidated, in particular in moderate drinkers, displaying higher estrogens and lower progesterone levels, whereas a more complex and opposite profile occurs in alcohol abusers, with a prominent role of non-specific interference of chronic alcoholism, and therefore general liver dysfunction in such endocrine picture.