Clinical Opinion: The Biologic and Pharmacologic Principles for Age-Adjusted Long-term Estrogen Therapy

Morris Notelovitz, MD, PhD, MB BCh, FACOG, FRCOG

In This Article

Global Index and Individualizing ET

The global index is a recently introduced statistical evaluation of population RCTs. Its validation and its applicability to individualized clinical care have not been established. The primary outcome of the estrogen-alone WHI study was CHD incidence, and invasive breast cancer was the primary safety outcome.[16] The results for women aged 50 to 59 years (the candidates most likely to be treated with ET in everyday clinical practice) showed a CHD protective effect (HR 0.56 [0.30-1.03]) and a reduction in breast cancer incidence (HR 0.72 [0.43-1.41]). The colorectal cancer incidence was also reduced, but not hip fracture, although ET in older cohorts (who are at greater risk for hip fracture) was significantly decreased: 60 to 69 years (HR 0.33 [0.18-0.83]); 70 to 79 years (HR 0.62 [0.38-1.00]).[16] Despite this encouraging outcome, the study authors concluded that "[a]t present, these data demonstrate no overall benefit of CEE for chronic disease prevention in postmenopausal women and thus argue against its use in this setting." This decision was based on the global index of the total group and factored in the risks and benefits of ET, including the primary outcomes plus stroke, pulmonary embolism, colorectal cancer, and hip fracture. The excess risk for all monitored events in the global index was a nonsignificant 2 events per 10,000 person-years. Although there were 12 additional strokes per 10,000 person-years, there were the same number of strokes (19) in both the CEE- and placebo-treated 50- to 59-year-olds. The statement that ET "does not significantly affect the incidence of CHD (the primary outcome). . ."[16] after an average of 6.8 years of ET may be applicable to women in the older groups. Given the natural history of atherothrombotic disease, however, the women in the 50 to 59 year age range had not yet reached the chronologic age at which women typically experience myocardial infarction and related CHD events. Extension of the study for 5 or more years may have decided this issue.

In practice, an individualized global (index) evaluation is (or should be) performed on every patient before prescribing hormone or any other pharmacologic therapy. Thorough clinical evaluation of the total healthcare needs of every woman and an understanding of the underlying biology of a given condition are central to appropriate and individualized pharmacologic intervention. Results of clinical trials do provide guidance and direction. For example, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial[104] found women without prevalent fractures had a lower risk for future fractures and cardiovascular events but a greater risk for breast cancer than matched cohorts with a prevalent fracture on study entry. This result dovetails with the known biology and hormonal contribution to these diseases: higher endogenous E2 levels are associated with an increased risk of breast cancer but a lower risk of osteoporosis (and vice versa). It is appropriate to consider all relevant scientific data and to base clinical decisions on the evidence. However, this should also include validated biologic evidence, which is the foundation for the 3 basic sciences on which medical training and practice are founded: physiology, pathology, and pharmacology. The biologic heterogeneity in the pathogenesis of all conditions and diseases previously discussed is clear. The pharmacologic differences in available ETs are well documented. The resulting variables and reality of clinical practice confirm that individualized ET can only be achieved by personalized evaluation and pharmacologic intervention.


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