Estradiol surge behind cravings for alcohol?

old and new data reviewed

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Back in the mid-1990’s I worked with the research teams at the Alcohol and Drug Abuse Research Center (ADARC), McLean Hospital in Belmont MA. Some of our projects looked at the gonadal steroid hormonal basis of addiction and metabolism of abused substances.

https://www.invitra.com/en/phases-of-the-menstrual-cycle/

Pathways of estrogen metabolism:

Pathways of oestrogen metabolism. The A-ring hydroxylated compounds are converted to the methoxy compounds by catechol O-methyltransferases. The structures of estetrol and ethinylestradiol are shown, as is the steroid ring labelling and atom numbering system. J Steroid Biochem Mol Biol. 2013 Sep;137:27–49. doi: 10.1016/j.jsbmb.2012.12.014

The reaction catalysed by 17β-HSD1, of estrone reduced to estradiol [a more potent form], is a random order bi–bi mechanism:

The proposed random order bi–bi mechanism of 17β-HSD1. The mechanism believed to be preferred is shown in bold. E – enzyme, E1 – estrone, E2 – estradiol.

It utilizes reducing equivalents as cofactors in the reaction.

Alcohol metabolism shifts estrone to estradiol

One area of our focus was on the metabolism of alcohol in different estrogen states. We studied post menopausal women who were dosed with hormone replacement therapies.

Objective: To determine if moderate alcohol drinking increases circulating estradiol levels in postmenopausal women who are taking estrogen replacement. Design: Randomized, double-blind, placebo-controlled crossover study of the effects of alcohol ingestion on plasma estradiol and estrone. Setting: Inpatient Clinical Research Center. Participants: Twelve healthy postmenopausal women receiving oral estrogen (estradiol, 1 mg/day) and progestin (medroxyprogesterone acetate) replacement therapy were compared with 12 postmenopausal women who were not using estrogen replacement therapy (ERT). Intervention: Each group drank alcohol (0.7 g/kg) and an isoenergetic (isocaloric) placebo (randomized sequence) on consecutive days. Women who were taking ERT were studied during the estrogen-only portion of their replacement cycle, and estrogen was administered each evening at 2100 hours. Main outcome measure: The impact of alcohol ingestion on plasma estradiol and estrone levels. Results: Alcohol ingestion lead to a 3-fold increase in circulating estradiol in women on ERT; however, alcohol did not change estradiol significantly in control women who were not on ERT. In women using ERT, estradiol levels increased from 297 to 973 pmol/L (81 to 265 pg/mL) within 50 minutes (P<.001) during the ascending limb of the blood alcohol curve and remained significantly above baseline for 5 hours (P<.001). No significant increase in circulating estrone was detected in either group. However, estrone levels decreased after alcohol and placebo in women on ERT (P<.05). Blood alcohol levels did not differ significantly in women who used ERT and those who did not. Peak blood alcohol levels of 21 mmol/L were attained in each of the 2 groups within 50 to 60 minutes after drinking began. Changes in estradiol were significantly correlated with changes in blood alcohol levels on both the ascending (P<.001) and descending (P<.001) limb of the blood alcohol curve. Conclusions: Acute alcohol ingestion may lead to significant and sustained elevations in circulating estradiol to levels 300% higher than those targeted in clinical use of ERT.

Previous ADARC research had shown similar results in post menopausal women who were using transdermal estradiol patches for replacement.

Rapid Neuronal Actions of Estradiol

In a previous newsletter I described research showing immediate rapid effects of estradiol on neuronal excitabililty:

In Mice, Estrogen surge triggers binge drinking via immediate actions on BNST neurons

Now a new study delved further into the interaction of estrogen dynamics with alcohol ingestion behavior in female mice.

Representative images of vaginal epithelial cells across the estrous cycle. b Ovarian aromatase (AROM) protein expression in female mice categorized as proestrus compared to metestrus status females (N’s = metestrus 7, proestrus 7). c Plasma E2 concentrations in proestrus and metestrus status females (N’s = metestrus 4, proestrus 4; each N represents a pooled sample from five mice). d Whole-brain E2 concentrations in proestrus and metestrus status females (N’s = metestrus 10, proestrus 9). e Drinking in the Dark (DID) binge drinking paradigm. f Average 2-h consumption of EtOH across cycles of DID (N’s = 27 F, 7 M; Biorender license: RP27GVXCTW). g First EtOH access (N’s = high E2 8, low E2 9, M 11). h Average 2-h consumption of sucrose across cycles of DID (N’s = 15 F, 15 M; Biorender license: DD27GVXH5F). i First sucrose access consumption (N’s = high E2 6, low E2 7, M 7). j % Time spent in the center of the open field (OF; N’s = high E2 6, low E2 13, M 10). k Distance traveled in the OF (N’s = high E2 6, low E2 13, M 10). l % Time on the light side of the light:dark box (LDB; N’s = high E2 7, low E2 12, M 10). m % Time in open arms of the elevated plus maze (EPM; N’s = high E2 7, low E2 11, M 10). n Distance traveled in the EPM (N’s = high E2 7, low E2 11, M 10). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, ^&P < 0.10 for unpaired t-tests, mixed effects analysis main effects, one way ANOVA main effects of group, and post hoc t-tests paired t-tests with H-S corrections between high and low E2 days in f and post hoc unpaired t-tests with H-S corrections for other panels, as indicated. - LJ Zallar, et al.

Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen occurred via rapid signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking. Thus, this study demonstrates a rapid, nongenomic signaling mechanism for ovarian-derived estrogen in the brain controlling behavior in gonadally intact females. -LJ Zallar, et al

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So high blood levels of estradiol increase craving for alcohol. Drinking alcohol causes an immediate surge in estradiol, which then further excites brain neuro circuits (BNST) involved in craving. Hence, a positive feed forward cycle commences.

[note: in pregnancy, estrogen levels are very high but progesterone is even more so, and may be a counterbalancing effect. Also, high levels of hCG induce a vague nausea, thus, helping to avoid alcohol intoxication.

In males, circulating androgens are converted to estrogens via the aromatase enzyme, especially in the brain. ]

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REFERENCES

MP Thomas, BV Potter BV. The structural biology of oestrogen metabolism. Epub 2013 Jan 4. J Steroid Biochem Mol Biol. 2013 Sep;137:27–49. doi: 10.1016/j.jsbmb.2012.12.014

ES Ginsburg, et al. Effects of alcohol ingestion on estrogens in postmenopausal women. JAMA. 1996 Dec 4;276(21):1747-51. doi: 10.1001/jama.1996.03540210055034.

ES Ginsburg, et al. The effects of ethanol on the clearance of estradiol in postmenopausal women. Fertil Steril. 1995 Jun;63(6):1227-30

LJ Zallar, et al. Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice. Nat Commun 15, 10725 (2024). https://doi.org/10.1038/s41467-024-54737-6