Newer data suggest the type of progestogen used affects risk
In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.9 A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.
Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.1 Similar findings were found in women aged 50 to 60 years.
The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.10
In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.11 By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.
In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.4,5
Both the Abenhaim cohort9 and the longterm outcomes of WHI RCT trial data11 found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.14 A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.15
Prescribing progesterone as part of combination menopausal hormone therapy: Practical considerations
Progesterone capsules, available in generic form in 100-mg and 200-mg doses, are formulated with peanut oil, and they should be taken at bedtime as progesterone can induce drowsiness.
When combined with standard-dose estrogen, including oral estradiol 1.0 mg, transdermal estradiol 0.05 mg, or oral conjugated equine estrogen 0.625 mg, the appropriate dose of progesterone is 100 mg if used continuously or 200 mg if used as cyclic therapy. With higher doses of estrogen, progesterone 200 mg should be taken continuously.
An oral formulation that combines estradiol 1 mg and progesterone 100 mg does not contain peanut oil and, accordingly, can be used safely by those with peanut allergies. This combination product is marketed under the name Bijuva (TherapeuticsMD, Boca Raton, Florida).1
Reference
1. Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2018;132:161-170. doi: 10.1097/AOG.0000000000002645. Erratum in: Obstet Gynecol. 2018;132:786.
Race considerations
The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.9 However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).1 When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.17 The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.
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