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On October 19th Menopause Live issued the following commentary:

Serum estradiol in women taking oral estrogen therapy

Summary

Sriprasert et al have reported the findings of an unplanned post hoc analysis of serum estradiol levels in 275 women who were randomised 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 a 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 first line for smokers to minimise the risk of VTE [3].

So, do the findings from this study inform how to prescribe estrogen to minimise side effects and maximise 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

The authors of the original article “Factors Associated with Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy” by Sriprasert I, Kono N, Karim R, Hodis HN, Stanczyk FZ, Shoupe D, and Mack WJ (Obstet Gynecol. 2020;136(4):675-684″ responded with a rebuttal as follows:

We appreciate the comments on our work and would like to address these comments as follows:

  • Comment: “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.”
    Response: In our study, we found that BMI, alcohol use and smoking are associated with serum E2 levels among postmenopausal women using oral E2 therapy, and concluded that clinicians prescribing oral E2 should take into consideration these modifiable lifestyle factors for the most appropriate treatment dose. This recommendation is consistent with a personalized approach that has been proposed for the treatment of postmenopausal women. The basis for this approach is that each person’s individual biologic profile can be used to guide the choice of therapy. Factors that contribute to this biologic profile include age, BMI, time since menopause, symptom severity, vascular health, breast cancer risk profile, genetic characteristics, and biomarker levels (Manson et al., 2013). Using these factors it is possible to determine a woman’s individual risk stratification that can predict their likelihood of having favorable treatment outcomes and propensity for adverse effects and can therefore help the clinician make the best choice of formulation, dose, and route of administration (Lobo et al., 2016). A variety of circulating biochemical markers, including sex steroid hormones, have been proposed to assist with risk stratification for HT decision-making (Manson et al., 2013). In our study, we measured only serum levels of E2, but a limitation in the study, which we acknowledged, is that E1 and free E2 should have been measured as well. Nevertheless, E2 has been shown to be an important biomarker. We have previously reported that the effect of HT on atherosclerosis progression among postmenopausal women is related to achieved serum E2 levels (Karim et al., 2008; Sriprasert et al., 2019). We found that higher E2 levels were associated with decreased atherosclerosis progression in early postmenopausal women but increased atherosclerosis progression in late postmenopausal women. Although we still have limited data on the association between E2 levels to prevent the clinical cardiovascular outcome, E2 levels have been reported in association with hot flashes and bone mineral density in postmenopausal women. In the Kronos Early Estrogen Prevention Study (KEEPS), higher E2 levels were related to lower intensity of hot flashes (Santoro et al., 2017), and in the Ultra-Low-dose Transdermal Estrogen Assessment (ULTRA) trial, higher E2 levels were related to higher bone mineral density compared with lower E2 levels (Ettinger et al., 2004). In our study, we do not make any generalized clinical recommendations based on serum E2 levels. Post hoc analysis of data from our ELITE study allowed us to evaluate possible correlates of serum E2 that included demographics, clinical characteristics, medication use, and biomarkers of liver and kidney metabolic function in postmenopausal women treated with oral E2. We identified BMI, alcohol use, and smoking as statistically significant correlates of E2 levels. Based on these findings, we concluded that clinicians should consider these modifiable lifestyle factors for the most appropriate oral E2 dose for each individual woman. This does not mean that the lowest oral E2 dose cannot be used initially and be titrated according to symptoms. Also, we are aware that our findings cannot be extrapolated to parenteral estrogen therapy. Our study involved oral E2 therapy, which is used by millions of women throughout the world.
  • Comment: “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 (Gartoulla et al., 2015). 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 (Baber et al., 2016). Similarly, nonoral MHT is the first-line for smokers to minimize the risk of VTE (Baber et al., 2016).”
    Response: We agree that adipose tissue is an important source of E2 in postmenopausal women. Consistent with this, our results showed higher E2 concentrations in oral HT users with higher BMI, indicating that women with higher BMI might do just as well with a lower dose of HT for atherosclerosis benefit. We also agree that nonoral menopausal HT should be considered first line for obese women. Nevertheless, many obese women continue to use oral HT.
  • Comment: “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.”
    Response: We are well aware of the complexity of estrogen biosynthesis and metabolism, which is subject to large individual variation (Vesper et al., 2014), and that serum E2 levels may not reflect overall tissue exposure to estrogen (Stanczyk et al., 2015). Nevertheless, the importance of E2 testing in patient care is well recognized. It provides information not only about patients’ responses in postmenopausal women using HT, but also responses to treatments in women using aromatase inhibitors and GnRH agonists to treat certain cancers. In addition, E2 testing is used for differential diagnosis of amenorrhea, for assessment of fertility, and for monitoring of follicle stimulation therapy. In addition to E2 variability in the biosynthesis and metabolism of E2 associated with an individual’s unique biologic profile, high inaccuracy and low reproducibility in E2 measurements, especially at low levels found in postmenopausal women, can also contribute to the variability in a woman’s E2 level. To reduce the variability in E2 testing and to improve patient care, standardization of E2 measurements is being carried out by the Centers for Disease Control in its Hormone Standardization Program using a LC-MS/MS assay.
  • Comment: “The conclusion about alcohol use and serum estradiol being based on 11 women who reported consuming more than 2 standard drinks per day.”
    Response: We agree that our finding regarding increased E2 levels with alcohol consumption is not new and is based on a relatively small sample size, which we acknowledge in the Discussion. Nevertheless, the strength of our study is that the randomized clinical trial data provided prospective repeated measurements of E2 levels from each study participant over a prolonged time. This allowed a more accurate determination of biologic factors associated with E2 levels among postmenopausal women taking oral E2 therapy, with good compliance, resulting in findings consistent with the cumulated literature.
  • Comment: “No mention of timing of each blood draw to the prior dose of estradiol.”
    Response: We agree that time of blood draw should have been included in the manuscript. Generally, participants were instructed to take the medication at night and a fasting blood draw was collected in the morning at the baseline and follow up visits. Estradiol was measured in serum from these samples. There was significant within-subject variability in E2 levels across follow-up visits (p=0.01). We statistically accounted for this within-subject variability in the mixed effects linear model by including a random participant-level intercept to model variability around population-level means.
  • Comment: “No mention of the adjustment of serum estradiol for single baseline value.”
    Response: Baseline serum estradiol levels used in the analysis were the average over 2 measurements in the samples obtained at the screening and randomization visits.

Frank Z. Stanczyk
Professor of Research Departments of Obstetrics and Gynecology,
Director, Reproductive Endocrine Research Laboratory,
University of Southern California, Keck School of Medicine, Los Angeles, California

References

  1. Baber RJ, Panay N, Fenton ATIWG. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19:109-150.
    https://pubmed.ncbi.nlm.nih.gov/26872610/
  2. Ettinger B, Ensrud KE, Wallace R, Johnson KC, Cummings SR, Yankov V, Vittinghoff E, Grady D. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol. 2004;104:443-51.
    https://pubmed.ncbi.nlm.nih.gov/15339752/
  3. 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;22:694-701.
    https://pubmed.ncbi.nlm.nih.gov/30358730/
  4. Karim R, Hodis HN, Stanczyk FZ, Lobo RA, Mack WJ. Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. J Clin Endocrinol Metab. 2008;93:131-8.
    https://pubmed.ncbi.nlm.nih.gov/17925335/
  5. Lobo RA, Pickar JH, Stevenson JC, Mack WJ, Hodis HN. Back to the future: Hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis. 2016;254:282-290.
    https://pubmed.ncbi.nlm.nih.gov/27745704/
  6. Manson JE. The role of personalized medicine in identifying appropriate candidates for menopausal estrogen therapy. Metabolism. 2013;62 Suppl 1:S15-9.
    https://pubmed.ncbi.nlm.nih.gov/23018143/
  7. Santoro N, Allshouse A, Neal-Perry G, Pal L, Lobo RA, Naftolin F, Black DM, Brinton EA, Budoff MJ, Cedars MI, Dowling NM, Dunn M, Gleason CE, Hodis HN, Isaac B, Magnani M, Manson JE, Miller VM, Taylor HS, Wharton W, Wolff E, Zepeda V, Harman SM. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 2017;24:238-246.
    https://pubmed.ncbi.nlm.nih.gov/27779568/
  8. Sriprasert I, Hodis HN, Karim R, Stanczyk FZ, Shoupe D, Henderson VW, Mack WJ. Differential effect of plasma estradiol on subclinical atherosclerosis progression in Early vs Late Postmenopause. J Clin Endocrinol Metab. 2019;104:293-300.
    https://pubmed.ncbi.nlm.nih.gov/30272234/
  9. Stanczyk FZ, Mathews BW, Sherman ME. Relationships of sex steroid hormone levels in benign and cancerous breast tissue and blood: A critical appraisal of current science. Steroids. 2015;99:91-102.
    https://pubmed.ncbi.nlm.nih.gov/25554581/
  10. Vesper HW, Botelho JC, Vidal ML, Rahmani Y, Thienpont LM, Caudill SP. High variability in serum estradiol measurements in men and women. Steroids. 2014;82:7-13.
    https://pubmed.ncbi.nlm.nih.gov/24407040/
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