Summary
Sriprasert et al. have reported the findings of an unplanned post hoc analysis of serum estradiol levels in 275 women who were randomized to oral micronized estradiol 1mg/day, with/without vaginal micronized progesterone, in the ELITE trial [1]. Although the initial treatment was with 1mg estradiol/day, dose reduction was permitted. Hence some women switched to either 0.5mg/0.25mg micronized estradiol daily during the study. The findings suggest that women with a higher BMI or women who consumed more than 2 standard alcoholic drinks/day had higher serum estradiol concentrations, whereas smoking was associated with lower serum estradiol. Although the authors point out that expert societies recommend against titrating estrogen therapy against serum estradiol concentrations, they also comment that serum estradiol is associated with treatment effects [1]. Hence, the authors recommend that these lifestyle variables need to be taken into account by clinicians when prescribing the dose of menopausal estrogen therapy.
Commentary
As the authors have discussed and fully referenced in their paper, previous studies have demonstrated higher BMI and alcohol consumption are associated with higher serum estradiol concentrations and smoking with lower estradiol concentrations in women taking oral estrogen therapy. The study has multiple study limitations, with significant ones including no mention of timing of each blood draw to the prior dose of estradiol, the adjustment of serum estradiol for single baseline value, and the conclusion about alcohol use and serum estradiol being based on 11 women who reported consuming more than 2 standard drinks per day. With regard to the latter, although there are plausible explanations as to why high alcohol consumption might influence serum estradiol through effects on hepatic metabolism, regular consumption of 3 or more standard drinks per day may be associated with nutritional deficits that complicate the picture. Nonetheless, this is not a new finding.
The controversial issue raised in this paper is the authors’ recommendation that clinicians take into account women’s BMI, alcohol use and smoking when considering the dose of estrogen therapy to prescribe. It is over-simplistic to base dosing and treatment effects on serum estradiol when we know that estrogen biosynthesis and action is complex and subject to vast individual variation. The variation resides not only in the conversion between estradiol, estrone and estrone sulphate in peripheral tissues but also in tissue sensitivity which is modulated by receptor sensitivity and receptor modulators (coactivators and corepressors). Thus, serum estradiol may not reflect overall tissue exposure to estrogen.
Women who are overweight or obese are more likely to experience moderate to severe vasomotor symptoms, despite fat tissue being a major source of estrone and estradiol biosynthesis in postmenopausal women [2]. It is also not uncommon, in my experience, for overweight/obese women to require a generous dose of estrogen replacement to alleviate their symptoms. Consequently, the dose should not be informed by BMI. Rather, BMI informs the best route of administration, and the dose should be that needed to alleviate symptoms. As higher BMI increases the risk of venous thromboembolic events (VTE), nonoral menopausal hormone therapy (MHT) should be considered first-line for obese women [3]. Similarly, nonoral MHT is the first-line for smokers to minimize the risk of VTE [3].
So, do the findings from this study inform how to prescribe estrogen to minimize side effects and maximize compliance? I suggest not, as 1) the findings cannot be extrapolated to nonoral estrogen therapy, which should be used for smokers and overweight/obese women, and 2) it is prudent to commence most women on low dose estrogen and titrate the dose according to symptoms as one can never predict who will experience complete symptoms relief with a low dose, or equally who will have side effects even with low dose therapy.
Susan R Davis MBBS, FRACP, PhD, FAHMS
Professor of Women’s Health and NHMRC Senior Principal Research Fellow
Director, Women’s Health Research Program
School of Public Health and Preventive Medicine,
Monash University, Melbourne, Australia
References
- Sriprasert I, Kono N, Karim R, et al. Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy. Obstet Gynecol. 2020;136(4):675-684.
https://pubmed.ncbi.nlm.nih.gov/32925623/ - Gartoulla P, Worsley R, Bell RJ, Davis SR. Moderate to severe vasomotor and sexual symptoms remain problematic for 60-65 year old women. Menopause. 2015;22(7):694-701.
https://pubmed.ncbi.nlm.nih.gov/30358730/ - Baber RJ, Panay N, Fenton ATIWG. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109-150.
https://pubmed.ncbi.nlm.nih.gov/26872610/
