Update on menopause: An expert’s insight on pivotal studies

The risks associated with ET and with EPT differed significantly. Current ET users had a 30% increased risk for breast cancer (95% CI, 1.21-1.40) while current EPT users had a 100% increased risk (95% CI, 1.88-2.12). However, vaginal or other local EPT formulations did not increase the risk (RR 0.67, 95% CI, 0.30-1.49). No significant differences in risk were found between specific types or doses of EPT or between continuous combined and continuous cyclic regimens.

COMMENT
Limitations of observational studies

This extremely large observational study found levels of breast cancer risk associated with ET and EPT similar to those reported by the WHI and as predicted in 1997 by the Collaborative Group on Hormonal Factors in Breast Cancer study.¹ The Million Women Study implicates an expanded number of ET and EPT products and routes of administration.

Acting as devil’s advocate, I will point out that this is an observational study with large potential for error. The major weakness is that it is a snapshot of hormone therapy use taken at the time of the women’s entry into the study, which was at the time of their 3-year mammogram. No further information was gleaned from the women regarding subsequent changes in hormone therapy use, such as whether they terminated use or changed the dose or route.

Also, the patient-provided data at entry showed a 96% agreement with the actual prescription written by the physician. The 4% variance, although it seems small, is of some concern given the narrow difference in relative risks and the large number of study participants. This is a weakness of any observational study; even if the prescription is filled, evidence that it was actually taken is inadequate.

Finally, the authors report that current use of hormone therapy at baseline increased the risk of breast cancer, although the relative risk was not as large as for disease incidence. They were not able to come up with reliable estimates of mortality attributable to breast cancer.

“Million Women” can be accepted only as an observational confirmation of a small increase in absolute risk of breast cancer.

In conclusion, the Million Women Study can be accepted only as an observational study providing confirmation of a small increase in the absolute risk for breast cancer in women on hormone therapy.

Further implications. The suggestion that these results apply to products beyond those tested in the WHI is in agreement with the NAMS Advisory Panel’s 2003 statement on Postmenopausal Hormone Therapy, which supports the view that although it is not possible to make general conclusions about all members of the estrogen and progestogen families, an improved benefit-risk profile of other EPT agents cannot be assumed.

1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350:1047-1059.

Transdermal estrogen/progestogen had no effect on risk of venous thromboembolism in postmenopausal women.

ESTHER STUDYOral and transdermal EPT have different effects on risk of thromboembolism

Scarabin PY, Oger E, Plu-Bureau G, for the EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428–432.

• LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED STUDY
  

Investigators enrolled 155 women aged 45 to 70 years who had been diagnosed with VTE, defined as either pulmonary embolism or deep vein thrombosis, and 381 matched controls. In women with VTE, 21% were using oral EPT and 19% were using transdermal EPT. In controls, 7% and 24% were using oral or transdermal EPT, respectively. An adjusted analysis showed that, compared with nonuse, current use of oral EPT significantly increased the VTE risk (adjusted odds ratio, [OR] 3.5; 95% CI, 1.8-6.8); transdermal EPT did not increase the VTE risk (OR, 0.9; 95% CI, 0.5-1.6). A between-group comparison showed that current oral EPT users had a significantly increased VTE risk (OR, 4.0; 95% CI, 1.9-8.3) over transdermal EPT users.

COMMENT
More studies needed but unlikely

A prime consideration for nonoral EPT for postmenopausal women is avoidance of the first-pass hepatic effect of oral medications, thereby reducing potential for the adverse effects associated with oral therapies. This study demonstrates a difference between oral and transdermal therapy, but the number of patients is small and, while promising, it is probably not a final answer to the problem.