To the Editor:

We thank Dr. Chang and colleagues for their robust summary of hormonal and nonhormonal methods for managing menopausal symptoms.¹ In particular, their individualized symptom treatment algorithm has increased efficiency in our women’s health clinic.

However, we are puzzled by Table 2 (Estrogen-Only Hormone Therapies for Vasomotor Symptoms of Natural Menopause), which lacks a discussion or justification for listing sequential dosing of estrogen formulations (eg, Estrace is reportedly dosed as daily for 21 days, then 7 days off). This is a departure from traditional teaching on hormone therapy and a previous American Family Physician article that only discussed continuous therapy.² We could not find this dosing schedule in the references or in guidelines from the North American Menopause Society or the American College of Obstetricians and Gynecologists.^3,4

Sequential therapy is typically reserved for women who are pre- or perimenopausal and have an intact uterus. The combination regimen of 21 days on and 7 days off would cause withdrawal bleeding that may be undesirable in postmenopausal patients. A Cochrane review found that when continuous and interrupted regimens were compared, there were no statistically significant differences in the odds of developing endometrial hyperplasia or endometrial carcinoma, in adherence to therapy, or in withdrawal from therapy at 12, 24, and 36 months of treatment.⁵ In fact, the North American Menopause Society states that there may be an increased risk of endometrial cancer with sequential compared with continuous progesterone therapy.

For women without a uterus, interrupted dosing would not cause bleeding but would still cause the patient’s menopausal symptoms to return for 1 week every month. If the justification is to reduce the risks of estrogen therapy outside of the uterus, it is worth noting that estrogen causes a twofold increase in venous thromboembolism when using conjugated equine estrogens vs estradiol, but it generally carries only a small increased risk of breast and ovarian cancer and gall-bladder disease; there is no increased risk of lung cancer or coronary heart disease.⁶

Again, we thank the authors for equipping readers with the knowledge about hormonal and nonhormonal methods for managing menopausal symptoms to have efficient risk vs benefit discussions with our patients, but the confusing exclusion of standard continuous hormone replacement requires further explanation.

Editor’s Note: The online version of Table 2 has been corrected, per Dr. Chang’s Reply.

The authors thank Dr. Saramati J. Krishna for her help with the preparation of this letter.

In Reply:

I am grateful to Drs. Taher and Thompson for raising this concern about the dosing of oral estrogen for vasomotor symptoms of menopause. I have suggested corrections and clarification to the information in Table 2, specifically citing the daily (continuous) dosing regimens recommended by the American College of Obstetricians and Gynecologists and the Endocrine Society guidelines.^1,2 An in-depth review of varied dosing regimens was beyond the scope of the original article, but such instruction would be beneficial, particularly for clinicians inexperienced with menopausal hormone therapy.³

The cyclic dosing options for oral estrogen formulations were moved to the footnote in Table 2 and provide additional guidance for more nuanced treatment of women in the early stages of menopausal transition, especially those who may still experience infrequent or irregular menses.^2,3 Women with an intact uterus should still receive a progestin for the final 10 to 14 days of a 28- to 30-day cycle, regardless of whether estrogen therapy is continuous or cyclic.² I feel it is worth noting that when I cross-referenced common point-of-care drug dosing guides, several were found to recommend cyclic administration without explaining its nuanced use for women in early menopause.^3–7 For example, on January 2, 2025, a search for Estrace (estradiol) and Menest (esterified estrogen) in two different digital drug references found that dosing instructions primarily recommended cyclic administration (specifically 3 weeks on and 1 week off) or listed it as an option to consider for treating vasomotor symptoms of menopause.^3–7 This discrepancy between clinical guidelines and pharmaceutical references for menopausal hormone therapy is worth highlighting as a potential source of confusion for clinicians. I believe it calls attention to the need for better alignment between pharmaceutical and clinical references.

I appreciate this opportunity for dialogue that exposes what I feel to be an important discrepancy between what may be traditionally taught about hormone therapy and what clinicians may find when using point-of-care drug references. Ultimately, individualized, patient-centered, shared decision-making should guide attempts to use the lowest effective dosing strategies and minimize adverse effects.^2,3,8