Recent findings presented by Rowan T. Chlebowski, MD, PhD, from The Lundquist Institute in Torrance, California, at the 2024 annual meeting of the American Society of Clinical Oncology in Chicago, provide critical insights into the long-term effects of hormone therapy on ovarian cancer incidence and mortality. This re-analysis of the Women's Health Initiative (WHI) trials sheds new light on the impact of combined hormone therapy versus estrogen alone in postmenopausal women.
Study Overview
Dr. Chlebowski and his colleagues conducted a comprehensive analysis of data derived from two randomized, placebo-controlled trials within the WHI. Between 1993 and 1998, nearly 28,000 postmenopausal women aged 50-79 years without prior cancer were enrolled from 40 centers across the United States. The broader WHI effort encompassed a total cohort of 161,000 patients, including an observational study and two additional non-drug trials.
Hormone Therapy Trials
The two primary hormone therapy trials were designed to assess the effects of different hormone regimens:
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Combined Estrogen-Progestin Therapy: Involving 17,000 women with an intact uterus, participants were randomized to receive either combined equine estrogen plus medroxyprogesterone acetate or a placebo.
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Estrogen-Alone Therapy: Involving approximately 11,000 women with prior hysterectomy, participants were randomized to receive daily estrogen alone or a placebo.
Both trials were prematurely terminated. The estrogen-only trial was halted due to an elevated risk of stroke, while the combined therapy trial was stopped after findings indicated increased risks of breast cancer and cardiovascular events. The mean duration of hormone therapy exposure was 5.6 years for the combined therapy trial and 7.2 years for the estrogen-alone trial.
Key Findings at 20-Year Follow-Up
The latest re-analysis, focusing on a 20-year follow-up period, has unveiled significant findings regarding ovarian cancer incidence and mortality:
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Ovarian Cancer Incidence: Women who received estrogen alone exhibited a doubled incidence of ovarian cancer compared to those who received a placebo (hazard ratio = 2.04; 95% CI 1.14-3.65; P = .01). This significant difference was already apparent at the 12-year follow-up mark.
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Ovarian Cancer Mortality: Mortality due to ovarian cancer was also significantly higher in the estrogen-alone group.
These results underscore the critical role of progestin in mitigating the adverse effects of estrogen therapy. Specifically, the absence of progestin appears to markedly increase both the incidence and mortality of ovarian cancer among postmenopausal women.
Implications
The findings presented by Dr. Chlebowski and his team question the use of estrogen monotherapy in women without a uterus as estrogen therapy significantly increases the risk of ovarian cancer and associated mortality.
However, other studies indicate that progestins (like the MPA used in combination with estrogen within Chlebowski’s re-analysis) increase the risk of breast cancer, stroke, and DVTs. This may leave practitioners scratching their heads as to how to prescribe HRT.
While this cohort wasn’t offered an estradiol/progesterone combination, we may be able to extrapolate its efficacy based on studies showing progesterone's ability to decrease ovarian cancer cell lines as well as migration and invasion. Additionally, progesterone has demonstrated the ability to inhibit estrogen-driven growth in the uterus and protect the ovary from neoplastic transformation. While the debate of progestin vs. progesterone is likely to continue, the take home message here is that estrogen monotherapy in women without a uterus poses significant health risk.
These insights are vital for guiding clinical decisions regarding hormone therapy in postmenopausal women, emphasizing the need for a balanced approach that considers both the benefits and potential risks of hormone replacement strategies.
In light of these new findings, adopting proactive measures in hormone monitoring has become more crucial than ever. Salivary and urinary hormone testing, such as Doctor’s Data’s Comprehensive Hormone Profile (saliva) and the HuMap™ (Hormone and Urinary Metabolites Assessment Profile), provide non-invasive and accurate methods to assess hormone levels and ensure balanced therapy. These advanced tests offer critical insights into hormone fluctuations, facilitating personalized adjustments to therapy regimens and minimizing the risks associated with hormone replacement.
