The modulation of estrogen-induced apoptosis as an interpretation of the women’s health initiative trials

Abstract

The Women’s Health Initiative (WHI) consisted of two placebo controlled trials: one in women with a uterus, using conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and the second trial in women without a uterus used CEE alone. The study population average age was approximately 63 years. Although the predicted rise in breast cancer occurred in the MPA plus CEE trial, the CEE alone trial, had a sustained decrease in breast cancer incidence. A unifying theory is presented that explains the decrease in breast cancer based on the new biology of estrogen-induced apoptosis in long-term estrogen deprived nascent breast cancer cells. Glucocorticoids block estrogen-induced apoptosis and MPA has glucocorticoid activity. This is why MPA increases breast cancer when used with CEE as menopausal hormone replacement. A safer menopausal hormone therapy can now be designed with a more selective synthetic progestin such as norethindrone acetate.

KEYWORDS:

• conjugated equine estrogen
• medroxyprogesterone acetate
• menopausal hormone therapy
• estrogen-induced apoptosis
• breast cancer
• glucocorticoid activity
• inflammatory response
• estrogen deprivation

Financial & competing interests disclosure

The authors were supported by the NIH MD Anderson Cancer Center Support Grant (CA016672). VC Jordan has an endowed Dallas/Ft. Worth Chair for Cancer Research from the MD Anderson Cancer Center and Susan G. Komen Grant SAC1000BC as PI. B. Abderrahman is a Postdoctoral Fellow for the MD Anderson Cancer Center. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The Women’s Health Initiative (WHI) estrogen alone menopausal hormone replacement trial demonstrated a consistent decrease in the incidence of breast cancer in women recruited, on average, over 60 years of age.

• The WHI estrogen plus medroxyprogesterone acetate (MPA) combination menopausal hormone therapy trial, demonstrated a consistent increase in the incidence of breast cancer in women recruited, on average, over 60 years of age.

• The Million Women’s Study proves important complimentary data that is women starting estrogen alone replacement therapy ≥5 years post-menopause had no increase in breast cancer, but there is a 40% increase in relative risk if estrogen is started immediately at menopause. MPA plus estrogen increases relative risk for breast cancer whenever it is given relative t menopause.

• Clinical experience with the treatment of breast cancer in post-menopausal women demonstrates that estrogen therapy is only effective in causing a 30% response rate if initiated ≥5 years post-menopause.

• Estrogen deprivation of Estrogen Receptor (ER) positive breast cancer cells under laboratory conditions requires the evolution of cell populations over 5 years. This change in acquired resistance over years to antihormone therapies eventually exposes cellular vulnerability to estrogen-induced apoptosis.

• Glucocorticoids such as dexamethasone inhibit estrogen-induced apoptosis under laboratory conditions.

• The synthetic progestin MPA is used in the majority of menopausal hormone therapy preparations to prevent endometrial cancer from unopposed estrogen therapy for post-menopausal women. However, MPA is not a pure progestin but has associated glucocorticoid activity.

• Laboratory data demonstrate that prolonged treatment of estrogen deprived ER-positive breast cancer cells with MPA plus estrogen blunts estrogen-induced apoptosis resulting in the regrowth of breast cancer cell populations.

• It is suggested that the fact that MPA plus estrogen increases the incidence of breast cancer whereas estrogen alone decreases breast cancer incidence in the WHI studies then the glucocorticoid activity of MPA prevents the beneficial effect of estrogen to induce apoptosis in occult estrogen-deprived breast cancer cells. New approaches to combination menopausal hormone therapy must be sought.