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Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).

OR YEARS, THERE HAS BEEN CONcern about possible associations of gynecologic malignancies with postmenopausal hormone therapy. The development of endometrial hyperplasia and endometrial cancer with unopposed estrogen is well recognized. To reduce or avoid this complication, progestin has been added, 1-3 although results from randomized trials are extremely limited. These concerns have created a need for reasonable monitoring guidelines to follow-up women who experience vaginal bleeding while taking estrogen plus progestin. The Women's Health Initiative (WHI) trial of estrogen plus progestin provides the first opportunity to examine possible associations of gynecologic malignancies with continuous combined postmenopausal hormone therapy in a large, randomized, double-blind, placebo-controlled setting. The trial was stopped early at the recommendation of the independent data and safety monitoring board on the basis of an increased risk of breast cancer supported by a summary measure of effects indicating risks exceeded

A B S T R A C T PurposeGermline mutations in BRCA genes are associated with breast and ovarian cancer susceptibility. Because infertility is associated with breast and ovarian cancer risks, we hypothesized that the mutations in the BRCA gene may be associated with low response to fertility treatments. MethodsWe performed ovarian stimulation in 126 women with breast cancer by using letrozole and gonadotropins for the purpose of fertility preservation by embryo or oocyte cryopreservation. As surrogates of ovarian reserve, the oocyte yield and the incidence of low response were compared with ovarian stimulation according to BRCA mutation status. ResultsOf the 82 women who met the inclusion criteria, 47 women (57%) had undergone BRCA testing, and 14 had a mutation in BRCA genes, of which two were of clinically undetermined significance. In BRCA mutation-positive patients, low ovarian response rate was significantly higher compared with BRCA mutation-negative patients (33.3 v 3.3%; P ϭ .014) and with BRCA-untested women (2.9%; P ϭ .012). All BRCA mutation-positive low responders had BRCA1 mutations, but low response was not encountered in women who were only BRCA2 mutation positive. Compared with controls, BRCA1 mutation-but not BRCA2 mutation-positive women produced lower numbers of eggs (7.4 [95% CI, 3.1 to 17.7] v 12.4 [95% CI, 10.8 to 14.2]; P ϭ .025) and had as many as 38.3 times the odds ratio of low response (95% CI, 4.1 to 353.4; P ϭ .001). ConclusionBRCA1 mutations are associated with occult primary ovarian insufficiency. This finding may, at least in part, explain the link between infertility and breast/ovarian cancer risks.

Observational research on postmenopausal hormone therapy suggests a 40-50% reduction in coronary heart disease incidence among women using these preparations. In contrast, the Women's Health Initiative clinical trial of estrogen plus progestin found an elevated incidence over a 5.6-year intervention period through July 7, 2002. Toward explaining this discrepancy, the authors analyzed data from this trial, which included 16,608 postmenopausal women aged 50-79 years, and corresponding data from 53,054 women in the Women's Health Initiative observational study, 33% of whom were estrogen-plus-progestin users at baseline. Estrogen-plus-progestin hazard ratio estimates for coronary heart disease, stroke, and venous thromboembolism in the observational study were 39-48% lower than those in the clinical trial following age adjustment. However, hazard ratios tended to decrease with increasing time from initiation of estrogen-plus-progestin use, and observational study hazard ratio estimates are heavily weighted by longer-term use while clinical trial hazard ratio estimates reflect shorter-term use. Following control for time from estrogen-plus-progestin initiation and confounding, hazard ratio estimates were rather similar for the two cohorts, although there was evidence of some remaining difference for stroke. These analyses have implications for both the design and the analysis of observational studies.

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