Long-Term WHI Study Finds No Overall Link Between Menopausal Hormone Therapy and Liver Cancer

What's new

New findings from a long-term follow-up of the Women's Health Initiative (WHI) randomized trials provide insights into the potential link between menopausal hormone therapy (MHT) and primary liver cancer. This study, which tracked participants for nearly 24 years, aimed to clarify whether MHT influences the risk of developing or dying from liver cancer. Previous observational studies on this topic have yielded inconsistent results, making a randomized controlled trial's long-term data particularly valuable. The current analysis, involving over 27,000 postmenopausal women, found no overall statistically significant association between either estrogen-alone or estrogen-plus-progestin therapy and the incidence or mortality of liver cancer [1].

However, the research did identify some intriguing patterns within specific subgroups. For instance, women aged 50-59 years at the start of the trial who received combined estrogen-plus-progestin therapy showed a higher incidence of liver cancers compared to their placebo counterparts. Similarly, women with a history of oral contraceptive use who took combined MHT also exhibited an increased risk. These subgroup findings, while not definitive, suggest areas for future research into how MHT might interact with other factors to influence liver cancer risk [1].

The science behind it

The Women's Health Initiative (WHI) comprised two large, randomized, double-blind, placebo-controlled trials designed to evaluate MHT in postmenopausal women. The first trial involved 16,608 women with an intact uterus, randomized to receive either conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) or a placebo. The second trial included 10,739 women who had undergone a hysterectomy, randomized to receive CEE alone or a placebo [1].

Participants were aged 50-79 years at enrollment and were followed for an extended period, averaging nearly 24 years. During this time, 74 incident cases of primary liver cancer were identified across both study arms. Researchers used hazard ratios (HR) and 95% confidence intervals (CI) to assess the relative risk of liver cancer in the MHT groups compared to placebo. For CEE-alone therapy, the hazard ratio for liver cancer incidence was 0.75 (95% CI, 0.34-1.63), indicating no significant difference from placebo. For CEE plus MPA therapy, the hazard ratio was 1.63 (95% CI, 0.91-2.92), also not reaching statistical significance for the overall group [1].

Regarding liver cancer mortality, CEE plus MPA therapy showed a hazard ratio of 1.18 (95% CI, 0.67-2.07), again without a statistically significant overall effect. The subgroup analyses, however, highlighted specific populations where the risk appeared elevated. For women aged 50-59 years, CEE plus MPA was associated with 10 liver cancers compared to 0 in the placebo group (P-trend 0.01). Among women with prior oral contraceptive use, CEE plus MPA showed a hazard ratio of 4.30 (95% CI, 1.46-12.72; P-interaction 0.01). These findings suggest that while MHT may not broadly impact liver cancer risk, individual characteristics could modify its effects [1].

What it means in practice

For most postmenopausal women considering or currently using menopausal hormone therapy, these long-term findings offer reassurance that MHT does not appear to significantly increase the overall risk of primary liver cancer. This information can be a valuable addition to the comprehensive discussion between patients and their healthcare providers when weighing the benefits and risks of MHT for managing menopausal symptoms or preventing certain chronic diseases [1].

However, the study's subgroup findings underscore the importance of personalized medicine. Women who are younger (aged 50-59) when initiating combined estrogen-plus-progestin therapy, or those with a history of oral contraceptive use, might warrant a more detailed discussion regarding their individual risk profile for liver cancer. While these subgroup observations are not conclusive and require further investigation, they highlight that the effects of MHT may not be uniform across all individuals [1].

Healthcare providers should continue to consider a woman's full medical history, including age, prior hormone exposure, and other risk factors for liver disease, when counseling on MHT. The decision to use MHT should always be individualized, taking into account a woman's specific symptoms, health goals, and potential risks, including those that might be suggested by these subgroup analyses [1].

Caveats

While the WHI trials are robust due to their randomized, placebo-controlled design and extensive follow-up, several caveats should be considered. The number of liver cancer cases observed (74 over nearly 24 years) was relatively small, which can limit the statistical power to detect subtle effects or significant differences, especially in subgroup analyses. The subgroup findings, while statistically notable, are exploratory and should be interpreted with caution, as they may be due to chance or unmeasured confounding factors. They generate hypotheses for future research rather than providing definitive conclusions for clinical practice [1].

Furthermore, the MHT formulations used in the WHI (conjugated equine estrogen and medroxyprogesterone acetate) are specific. The results may not be generalizable to other types, doses, or routes of administration of menopausal hormone therapy, which are widely available today. The study population was primarily healthy postmenopausal women, and the findings might not apply to women with pre-existing liver conditions or other significant health issues [1].

Finally, the study focused on primary liver cancer. It did not assess the impact of MHT on metastatic liver cancer or other liver diseases. Continued research, particularly studies designed to specifically investigate the observed subgroup effects and different MHT formulations, will be crucial to fully understand the complex relationship between menopausal hormone therapy and liver health [1].

Source: [1] https://www.nature.com/articles/s41416-026-03621-9