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

The Breast and Breast Cancer

Fear of breast cancer is the primary reason why many menopausal women elect not to take hormone therapy. The common perception is that the disease is caused by estrogen despite contrary evidence. The single greatest risk factor for breast cancer is aging; the highest prevalence of this disease occurs at a time when systemic estrogen levels are the lowest.[84]

Although linked by a common histology, breast cancer is a varied and complex multifactorial disease. Estrogen does have an important role in its development, but there is much evidence to support the concept that exogenous estrogen (ie, ET) may serve as a promoter and not an initiator of breast cancer. Central to this issue is the genetic polymorphism of younger women (< 50 years) who may have gene mutations controlling breast cell cycle growth (mutated BRCA1, BRCA2, P53 genes) vs postmenopausal women (> 50 years) with a genetic predisposition to increased or aberrant breast tissue estrogen synthesis and metabolism.[85] Estrogen-associated breast cancer is more prevalent in women with a predominant ERalpha/ERbeta distribution.[86]

Women with breast cancer have higher tissue levels of estrogen. This has been correlated with increased enzymatic activity (aromatase, sulfatase, and 17beta OH dehydrogenase).[87] The synthesis of estrogen takes place in the stromal tissue of the breast. Estrogen-dependent growth factors are stimulated via paracrine signaling and induce specific pathways that effect cell cycle genes.[88] ERalpha and ERbeta are found in the ductal epithelium. ERalpha is co-localized with the progestin receptor (PR), of which there are 2 isoforms. PRB is the active receptor; PRA is either inactive or acts as an inhibitor of PRB. Approximately 10% to 20% of epithelial cells are ERalpha and PR positive and are distributed in both the intralobular duct and the peripheral alveoli.[88]

Estrogen-related breast cancer is preceded histologically by atypical epithelial hyperplasia.[89] The site for the transformation of normal to abnormal cell growth is the terminal duct lobuloalveolar unit (TDLU).[90] The degree of differentiation of the TDLUs determines the percentage of ERalpha and PR-positive cells.[88] The percentage of steroid receptor-positive cells decreases progressively as the lobules mature. Factors influencing this include the duration of premenopausal exposure to estrogen and pregnancy-induced differentiation and maturation of the ductal epithelium. Thus, women who have an early menarche and a late menopause are at increased risk of breast cancer; early and repeated pregnancy reduces the risk of breast cancer.[90]

In short, women who develop breast cancer while taking ET or HT are probably genetically programmed to modify physiologic pathways in response to hormonal therapy and/or environmental carcinogens.

Mammographic density reflects the breast's hormonal environment, the influence of background genetics regulating this environment, and the effect of various exogenous hormone therapies and other therapies.[91] Approximately 25% of HT users have dense breasts. Most of the increase in breast density occurs within the first year of treatment and diminishes within 3 weeks of stopping HT.[92] The literature on the association between ET/HT and breast density is extensive and has recently been reviewed.[93,94,95] Continuous combined HT preparations are more likely to cause an increase in density (20% to 35%) than in estrogen-alone treated women (10% to 20%), and oral ET more so than transdermal ET.[93] The type and dosage of estrogen and co-prescribed progestins are important.[94] Studies of free E1 and E2 in breast adipocytes obtained from postmenopausal women before and after treatment with CEE showed a greater amount of E1 and E2 in the adipocytes both before and after treatment. Pre- and post-ET adipocyte E2 concentrations were 13 pg/mL and 35 pg/mL; the respective estrone values were 209 pg/mL and 626 pg/mL.[96] Relatively low serum estradiol values (> 10 pmol/L [2.7 pg/mL]) are associated with almost a 7-fold higher rate of breast cancer than that of women with undetectable estradiol levels.[97]

The estrogen plus progestin arm of the WHI study confirmed that HT increased the risk of breast cancer (1.26 [1.00-1.59]),[98] a result that is consistent with most of the observational studies and meta-analyses comparing the risk of breast cancer and HT in users vs nonusers.[84,99] The risk of breast cancer increases with the duration of therapy.[84] A minority of women from the estrogen plus progestin arm of the WHI study were adversely affected: 35 vs 30 events annually of 10,000 women on HT and placebo, respectively.[98]

What predisposes the few extra women on relatively short-term ET to develop breast cancer? Apart from the individual's genetically determined biology (and occasional mutations of genes that result in extremely high aromatase activity, for example),[100] progestins may potentially increase the risk of breast cancer. Thus, the recent WHI estrogen-alone study reported a 23% lower rate of breast cancer in women treated with CEE vs placebo (26 vs 33 per 10,000 women-years). The HR of 0.77 narrowly missed statistical significance (P = .06).[16] The subject of progestin-additive therapy is beyond the scope of this review. However, studies in cynomolgus monkeys have shown that CEE and MPA[101] induce significant epithelial proliferation in the mammary glands of castrated monkeys, whereas a combination of EE and NETA does not.[102] This finding is consistent with the results of another simian study, which found that CEE treatment increased the total amount of PR and that the addition of MPA decreased repressor PRA but further increased the proliferating PRB levels. MPA-alone therapy had no effect on the amount of PRA or PRB.[103]

The biology of breast tissue and its oncogenic potential cannot be clinically evaluated and monitored. Given the variability of endogenous and exogenous estrogen metabolism, it is prudent to select a dose and route of ET that most closely replicates the age-matched hormonal milieu of the women being treated. Low-dose oral or transdermal E2 has a pharmacologic profile that most closely meets this objective. Mammographic density testing is a valuable surrogate measure of breast tissue estrogenicity.[91]


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