25 September 2017: 

The saga of the Women's Health Initiative (WHI) seems to have come to a turning point with a declaration that should vibrate now throughout the whole world. A new release of data from the WHI study has concluded that 'Among postmenopausal women, hormone therapy with CEE [conjugated equine estrogen] plus MPA [medroxyprogesterone acetate] for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years' [1]. Amazing as it is, the safety concerns that were attributed in the past to menopausal hormone therapy (MHT) need to be re-considered and to be put in their right perspective. It is not necessary to present again the main features of the CEE + MPA and the CEE-alone randomized studies.

The main issues discussed by the WHI investigators included the following:

• The present report is based on mortality follow-up through December 2014 and includes 7489 deaths (1088 occurred during the intervention phase and 6401 occurred post-intervention; 4083 additional deaths had occurred since the last report). For the CEE + MPA trial, the median post-intervention follow-up was 12.5 years and the cumulative follow-up was 18 years; for the CEE-alone trial, the median post-intervention follow-up was 10.8 years and the cumulative follow-up was 18 years.
• During the intervention phase, all-cause mortality in the pooled cohort was 4.0% with hormone therapy vs. 4.0% with placebo. Compared with placebo, women randomized to receive CEE + MPA had a hazard ratio (HR) of 0.97 (95% confidence interval (CI) 0.82–1.16) and women randomized to receive CEE alone had a HR of 1.04 (95% CI 0.89–1.22). During the post-intervention period, the HR for all-cause mortality was 1.04 (95% CI 0.97–1.10) for CEE + MPA and 0.92 (95% CI 0.85–0.99) for CEE alone.
• The HRs for all-cause mortality tended to differ by age during the intervention and cumulative follow-up phases. Comparison of women aged 50–59 years with those aged 70–79 years showed that the risk was significantly lower for the younger age group, as ratios of nominal HRs for all-cause mortality in the pooled cohort were 0.61 (95% CI 0.43–0.87) during the intervention phase and 0.87 (95% CI 0.76–1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Although younger women tended to have lower HRs than older women for mortality due to cardiovascular disease (CVD), cancer, and other (non-CVD, non-cancer) causes during the intervention phases of the two trials, only the latter outcome in the CEE-alone trial showed a statistically significant trend with age (p for trend by age = 0.002). During cumulative follow-up, trends in cause-specific mortality across age groups were not statistically significantly different.

In the Discussion section, the investigators had several important comments as well. They claimed that no other randomized clinical trial of hormone therapy has been large enough to assess a potentially modifying effect of age on all-cause mortality. They noted that observational studies, which primarily include women who initiate hormone therapy in early menopause, have generally demonstrated lower mortality among women using hormone therapy compared with non-users. HRs in most large cohort studies have ranged from 0.40 to 0.80. Regarding cause-specific mortality, the most marked risk reductions reported in observational studies have been for coronary or CVD deaths. Total cancer mortality did not differ significantly between intervention and placebo groups in either trial despite the increased incidence of breast cancer with CEE + MPA. However, a significant reduction in breast cancer was seen with CEE. Divergent findings for CEE alone and CEE + MPA for breast cancer point to an adverse effect of progestin on the breast epithelium, but progestins have been linked to favorable effects on the endometrium, and a decreased risk of endometrial cancer became apparent with long-term follow-up of the CEE + MPA trial. Last, but not least, it was mentioned that only one dose, formulation and route of administration in each trial were assessed; thus, results cannot necessarily be generalized to other hormone preparations.

This study report seems well balanced in its bottom-line messages. Still, we have to remember that the current long-term data refer to mortality, not to morbidity, and include an intervention phase of 5.6 years (for CEE + MPA) and 7.2 years (for CEE alone) and a post-intervention phase that reached a total cumulative period of up to 18 years. To note, fewer than 4% of women reported personal use of hormone therapy post-trial. The increased risk for thromboembolism during MHT and the potential adverse cardiovascular events in older women should not be overlooked. Still, for healthy women until the age of 60–65 years, the collected data point at a good safety profile and at a favorable risk–benefit ratio when MHT is prescribed to healthy, symptomatic women.

Interestingly, similar issues were discussed recently, based on WHI statistics. The first study included 45,112 participants in the WHI observational study (average follow-up 5.5 years) [2]. Oral CEE < 0.625  mg/day  +  progestogen (P), oral CEE 0.625  mg/day  +  P, oral estradiol, and transdermal estradiol regimens were compared. Associations with time to first global index event (GIE) were sought; GIE was defined as coronary heart disease, breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death. Users of oral CEE < 0.625 mg/day  +  P had a lower risk of a GIE (adjusted HR 0.74, 95% CI 0.56–0.97) than users of oral CEE 0.625  mg/day  +  P. GIE risk in users of oral CEE 0.625  mg/day  +  P was greater with at least 5-year use (1.22, 95% CI 1.06–1.41) than with less than 5-year use. In women with prior hysterectomy, compared with women taking oral CEE 0.625  mg/day for less than 5 years, GIE risk was similar with oral CEE < 0.625  mg/day, oral estradiol, and transdermal estradiol, whether used for less than 5 years or for at least 5 years.

The second study evaluated the risks of vaginal estrogen use in the WHI observational study [3]. Among women with an intact uterus, the risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, and pulmonary embolism/deep vein thrombosis were not significantly different between users and non-users, whereas the risks of coronary heart disease, fracture, all-cause mortality, and GIE were lower in users than in non-users (GIE HR 0.68, 95% CI 0.55–0.86). Among hysterectomized women, the risks of each of the individual GIE components and of the overall GIE were not significantly different in users vs. non-users of vaginal estrogen.

Another large population study that evaluated the association between cancer and MHT in Sweden has just been published [4]. The cohort included 290,186 women aged 40 years or more having used systemic MHT during the study period (2005–2012), compared with the Swedish female background population. MHT ever-use (all MHT, estrogen-only MHT [E-MHT] and estrogen + progestin MHT [EP-MHT]) was based on the nationwide Prescribed Drug Registry. Cancer diagnoses were grouped into 16 different anatomical locations, for which standardized incidence ratios (SIRs) were calculated. The SIR of any cancer was 1.09 (95% CI 1.07–1.11) following MHT ever-use, 1.04 (95% CI 1.01–1.06) for E-MHT and 1.14 (95% CI 1.12–1.17) for EP-MHT. The highest SIR was found for EP-MHT among users aged 70 years or older (SIR = 1.33, 95% CI 1.26–1.40). The risk for invasive breast, endometrial or ovarian cancer combined was increased for any MHT (1.31, 95% CI 1.28–1.34). The risk of invasive breast cancer was increased following MHT and increased with age for EP-MHT users. The risk of gastrointestinal cancers combined was decreased (0.90, 95% CI 0.86–0.94), particularly the esophagus (0.81, 95% CI 0.64–1.00), liver (0.81, 95% CI 0.65–0.99) and colon (0.90, 95% CI 0.84–0.95). It was concluded that MHT, notably EP-MHT, was associated with a limited increase in overall cancer risk. The increased risk of cancers of the female reproductive organ was almost balanced by a decreased risk of gastrointestinal cancers.

New guidelines or recommendations on MHT should now include the updated WHI results, and efforts should be invested in bringing this news to the awareness of the health-care providers, the media and the population of postmenopausal women world-wide.

Amos Pines

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality. The Women’s Health Initiative randomized trials. JAMA 2017;318:927-38
   http://www.ncbi.nlm.nih.gov/pubmed/28898378
2. Crandall CJ, Hovey KM, Andrews C, et al. Comparison of clinical outcomes among users of oral and transdermal estrogen therapy in the Women's Health Initiative Observational Study. Menopause 2017 Jul 10. Epub ahead of print
   http://www.ncbi.nlm.nih.gov/pubmed/28697036
3. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study. Menopause 2017 Aug 14. Epub ahead of print
   http://www.ncbi.nlm.nih.gov/pubmed/28816933
4. Simin J, Tamimi R, Lagergren J, Adami HO, Brusselaers N. Menopausal hormone therapy and cancer risk: an overestimated risk? Eur J Cancer 2017;84:60-8
   http://www.ncbi.nlm.nih.gov/pubmed/28783542