Alcohol, Smoking Alter Estradiol Levels in Hormone Therapy

Tara Haelle

November 25, 2019

CHICAGO — A variety of lifestyle factors, particularly smoking and alcohol use, affect serum estradiol levels in women receiving hormone therapy, new data suggest.

"Healthcare providers prescribing hormone therapy need to consider these modifiable lifestyle factors" because they might affect the appropriate treatment dose for each individual woman, said Intira Sriprasert, MD, a doctoral student at the University of Southern California Keck School of Medicine in Los Angeles.

"The variety of dosing options for estradiol therapy is key to maximizing the treatment of menopause symptoms," she told Medscape Medical News.

Guidelines from the North American Menopause Society (NAMS) and good clinical practice recommend "using the lowest effective dose of estradiol to achieve efficacy of the agent with the goal of minimizing side effects," Sriprasert said. "And low compliance requires individualization of estradiol for each woman, according to her symptoms and responsiveness to therapy."

But few data exist on the relation between estradiol dose and serum estradiol levels, effectiveness, adverse effects, and compliance, she added.

So Sriprasert and her colleagues analyzed data from two randomized, controlled, double-blind studies — the multicenter REPLENISH trial and the single-center ELITE trial — to identify the determinants of estradiol levels in healthy women using hormone therapy. Findings from both were presented as posters at the NAMS 2019 Annual Meeting.

They found that estradiol dose and serum levels in women taking hormone therapy were independently associated with changes in metabolic measures, and that serum estradiol levels from hormone therapy were associated with the progression of atherosclerosis.

To achieve serum estradiol levels desirable for the prevention of atherosclerosis, "factors that affect serum estradiol levels, such as BMI, smoking, and alcohol, should be considered in individual women," said Sriprasert.


For the REPENISH study, funded by TherapeuticsMD, the researchers analyzed data from 5881 study visits made by 1173 women, 40 to 65 years of age. Average age in the study cohort was 54 years, average time since the onset of menopause was 5.2 years, and all women had a uterus.

Participants had been randomly assigned to receive one of four combinations of 17β-estradiol plus progesterone —1 mg plus 100 mg, 0.5 mg plus 100 mg, 0.5 mg plus 50 mg, or 0.25 mg plus 50 mg — or placebo. Women with adherence rates below 80% were excluded from the analysis.

Serum estradiol levels were measured in each woman at 3, 6, 9, and 12 months. Average levels were 6.15 pg/mL at baseline and 27.71 pg/mL during the trial.

The researchers looked for correlations with the following baseline factors: age, years since menopause, weight, body mass index (BMI), creatinine, creatinine clearance, aspartate aminotransferase (AST), alanine aminotransferase (ALT), current smoking status, current alcohol use, and the use of dyslipidemia, antihypertensive, anticonvulsant, diabetic, and antifungal medications.

Multivariate analysis that controlled for estradiol dose and baseline serum estradiol levels showed that current smoking (= .01) and time since menopause (< .0001) predicted lower serum levels during the trial, and that current alcohol use (= .002) predicted higher levels.

Serum estradiol levels were highest among postmenopausal women who currently use alcohol but do not smoke, and lowest among those who currently smoke but do not use alcohol," Sriprasert and her team report.

In addition to serum estradiol levels, other factors might enhance or limit the effect of hormone therapy on metabolic measures, they conclude.


For the ELITE study, funded by National Institute on Aging, National Institute of Health, Sriprasert and her colleagues looked at demographic and clinical characteristics, medication use, and laboratory values related to kidney and liver metabolic function to identify possible correlates in the 256 study participants.

The average age of the 118 study participants in early menopause (less than 6 years since menopause) was 55 years, and average time since menopause was 3.6 years. The average age of the 138 in late menopause (at least 10 years since menopause) was 64 years, and average time since menopause was 16.0 years.

Half the women were randomly assigned to receive oral 17β-estradiol 1 mg daily and half to placebo. Again, women with adherence rates below 80% were excluded from the analysis.

Serum estradiol levels in the women were measured every 6 months over a median 4.8 years of follow-up.

Average estradiol levels were 10.8 pg/mL at baseline and 54.2 pg/mL during the trial. Median levels were 9.0 pg/mL and 46.5 pg/mL, respectively.

On multivariate analysis, adjusted for baseline estradiol levels, there were significant associations between higher serum estradiol levels and increased BMI (< .0001), higher creatinine, lower ALT (= .03), surgical menopause (= .02), and dose-dependent alcohol use (P = .0001). And there were significant associations between lower serum estradiol levels and current and past smoking (= .0005) and use of antifungal drugs (= .008). These associations did not vary much between early- and late-menopausal women.

"As certain lifestyle factors are modifiable, healthcare providers need to advise that postmenopausal women control their weight and refrain from smoking and alcohol use, with the goal of obtaining the appropriate effective dose of estradiol therapy," said Sriprasert.

Differences in the two study populations could account for some of the different associations identified, she pointed out.

Differences in Study Populations

"In ELITE, many women were surgically menopausal and did not take progesterone; when they did use progesterone, it was vaginal, not oral," said Lisa Larkin, MD, founder and chief executive officer of Ms. Medicine. "All women in REPLENISH had a uterus and received oral progesterone with estradiol."

Other differences included the younger age of study participants and the lower dosages of estradiol in REPLENISH. "All of these differences may explain that lack of association in REPLENISH with BMI, blood pressure medication use, and antifungal use," she told Medscape Medical News

Larkin said she was surprised to see age as a predictor of estradiol levels in REPLENISH, but not smoking and alcohol use.

Our hypothesis anticipated involvement with smoking and alcohol, said Sriprasert. "Oral estradiol therapy undergoes first-pass metabolism by the liver before entering the systemic circulation. Since smoking and alcohol are well-known factors that affect liver metabolism, it was not surprising that smoking and alcohol intake were significantly associated with serum estradiol levels in postmenopausal women on oral estradiol therapy."

It would be interesting to find out what else the REPLENISH data could reveal, like whether serum estradiol levels correlate with metabolic effects, such as lipids and breast density, said Larkin.

North American Menopause Society (NAMS) 2019 Annual Meeting.

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