BREAST CANCER AND CARDIOVASCULAR DISEASE RISKS RISK FOR BREAST CANCER WITH SYNTHETIC PROGESTINS
Many studies have assessed the risk for breast cancer with the use of a synthetic progestin for HRT. Despite significant variability in study design, synthetic progestins have been clearly associated with an increased risk for breast cancer. The Women’s Health Initiative (WHI), a large randomized clinical trial, demonstrated that a synthetic progestin, MPA, as a component of HRT significantly increased the risk for breast cancer (relative risk. This trial confirmed results from numerous other groups demonstrating that a synthetic progestin significantly increases breast cancer risk. In addition, higher doses of progestins, testosterone-derived synthetic progestins, and progestin-only regimens further increase the risk for breast cancer.
The Nurses’ Health Study, which followed 58 000 postmenopausal women for 16 years (725 000 person-years), found that, compared with women who never used hormones, use of unopposed postmenopausal estrogen from ages 50 to 60 years increased the risk for breast cancer to age 70 years by 23% (95% CI: 6–42). The addition of a synthetic progestin to the estrogen replacement resulted in a tripling of the risk for breast cancer (67% increased risk).
Ross et al compared the risk for breast cancer in 1897 women on combined estrogen and synthetic progestin with 1637 control patients who had never used HRT. Synthetic progestin use increased the risk for breast cancer by approximately 25% for each 5 years of use compared with estrogen alone.
In a meta-analysis of 61 studies, Lee et al found a consistently increased risk for breast cancer with synthetic HRT, with an average increase of 7.6% per year of use, and also found that higher doses of synthetic progestins conferred a significantly increased risk for breast cancer.
Ewertz et al examined the risk for breast cancer for approximately 80 000 women aged 40 to 67 years from 1989 to 2002. For women older than 50 years, current use of synthetic HRT increased the risk for breast cancer by 61% (95% CI: 1.38–1.88). Longer duration of use and the use of synthetic progestins derived from testosterone were associated with increased risk.
Newcomb et al studied the risk for breast cancer with synthetic HRT (80% used CEE and 86% used MPA) in more than 5000 postmenopausal women aged 50 to 79 years. They found a significant increase in breast cancer of 2% per year for the estrogen-only group and a 4% increase per year if a synthetic progestin was used in addition to the estrogen. Higher doses of progestin increased the risk for breast cancer, and use of a progestin-only preparation doubled the risk for breast cancer.
RISK FOR BREAST CANCER WITH BIOIDENTICAL PROGESTERONE Progesterone and synthetic progestins have generally indistinguishable effects on endometrial tissue. However, as discussed above, there is significant evidence that progesterone and synthetic progestins have differing effects on breast tissue proliferation. Thus, progesterone and synthetic progestins would be expected to carry different risks for breast cancer.
Although no randomized, controlled trials were identified that directly compared the risks for breast cancer between progesterone and synthetic progestins, large-scale observational trials58,59 and randomized placebo control primate trials16 do show significant differences. Furthermore, in contrast to the demonstrated increased risk for breast cancer with synthetic progestins,7,8,58,71–98 studies have consistently shown a decreased risk for breast cancer with progesterone.
Fournier et al reported an association between various forms of HRT and the incidence of breast cancer in more than 80 000 postmenopausal women who were followed for more than 8 postmenopausal years.59 Compared with women who had never used any HRT, women who used estrogen only (various preparations) had a non-significant increase of 1.29 times the risk for breast cancer (P = 0.73). If a synthetic progestin was used in combination with estrogen, the risk for breast cancer increased significantly to 1.69 times that for control subjects.
However, for women who used progesterone in combination with estrogen, the increased risk for breast cancer was eliminated with a significant reduction in breast cancer risk compared with synthetic progestin use . In a previous analysis of more than 50 000 postmenopausal women in the E3N-EPIC cohort, Fournier et al found that the risk for breast cancer was significantly increased if synthetic progestins were used (RR = 1.4), but was reduced if progesterone was used (RR = 0.9). There was a significant difference in the risk for breast cancer between the use of estrogens combined with synthetic progestins versus estrogens combined with.
Wood et al investigated whether the increased breast cancer risk with synthetic progestins was also seen when progesterone was used. Postmenopausal primates were given placebo, estradiol, estradiol and MPA, and estradiol and bioidentical progesterone, with each treatment for 2 months with a 1-month washout period. Ki67 expression is a biomarker for lobular and ductal epithelial proliferation in the postmenopausal breast and is an important prognostic indicator in human breast cancer.
Compared with placebo, significantly increased proliferation was found with the combination of estrogen and MPA in both lobular and ductal tissue, but was not seen with the combination of estrogen and progesterone. Intramammary gene expressions of the proliferation markers Ki67 and cyclin B1 were also higher after treatment with estrogen and MPA (4.9-fold increase, and 4.3-fold increase, respectively) but not with estrogen and progesterone.
Inoh et al investigated the protective effect of progesterone and tamoxifen on estrogen- and diethylstilbestrol-induced breast cancer in rats. The induction rate, multiplicity, and size of estrogen-induced mammary tumors were significantly reduced by simultaneous administration of either tamoxifen or progesterone.
Chang et al examined the effects of estrogen and progesterone on women prior to breast surgery in a double-blind, placebo-controlled study in which patients were given placebo, estrogen, transdermal progesterone, or estrogen and transdermal progesterone for 10 to 13 days before breast surgery. Estrogen increased cell proliferation rates by 230%, but progesterone decreased cell proliferation rates by 400%.
Progesterone, when given with estradiol, inhibited the estrogen-induced breast cell proliferation.22 Similarly, in a randomized, double-blind study, Foidart et al also showed that progesterone eliminated estrogen-induced breast cell proliferation. A prospective epidemiological study demonstrated a protective role for progesterone against breast cancer.
In this study, 1083 women who had been treated for infertility were followed for 13 to 33 years. The premenopausal risk for breast cancer was 5.4 times higher in women who had low progesterone levels compared with those with normal levels (95% CI: 1.1–49). The result was significant, despite the fact that the high progesterone group had significantly more risk factors for breast cancer than the low progesterone group, highlighting the importance of this parameter.
Moreover, there were 10 times as many deaths from cancer in the low progesterone group compared with those with normal progesterone levels. Women with low progesterone have significantly worse breast cancer survival rates than those with more optimal progesterone levels.
In a prospective study, luteal phase progesterone levels in 5963 women were measured and compared with subsequent risk for breast cancer. Progesterone was inversely associated with breast cancer risk for the highest versus lowest tertile. This trend became significant in women with regular menses, which allowed for more accurate timing of collection. Other case-control studies also found such a relationship.
Peck et al conducted a nested case-control study to examine third-trimester progesterone levels and maternal risk of breast cancer in women who were pregnant between 1959 and 1966. Cases were diagnosed with in situ or invasive breast cancer between 1969 and 1991. Controls were matched to cases by age at the time of index pregnancy using randomized recruitment.
Increasing progesterone levels were associated with a decreased risk of breast cancer. Relative to those with progesterone levels in the lowest quartile, those in the highest had a 50% reduction in the incidence of breast cancer The association was stronger for cancers diagnosed at or before age 50 years. Preeclampsia, with its associated increased progesterone levels, is also associated with a reduced risk for breast cancer.