, Volume 66, Issue 2, pp 191-221
Date: 17 Sep 2012

Emerging Selective Estrogen Receptor Modulators

Abstract

Menopause, regardless of age at onset, is associated with a marked increase in coronary heart disease (CHD) risk. On the basis of epidemiological studies that demonstrated mainly positive effects of postmenopausal hormone therapy on CHD as well as on risk markers of CHD, it has been suggested that CHD could be prevented in postmenopausal women with long-term hormone therapy. However, since the publications of the Heart and Estrogen/progestin Replacement Study and the Women’s Health Initiative trial, prescription of hormone therapy for the prevention of CHD has become controversial.

Major efforts have been made to identify alternatives for hormone therapy. Compounds suggested have included selective estrogen receptor modulators (SERMs), which represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favourable estrogenic effects on the bone and cardiovascular system from unfavourable stimulatory effects on the breast and endometrium. Two SERMs presently on the market are tamoxifen and raloxifene. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. These trials found fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo.

Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures, is safe for the endometrium and holds high promise for the prevention of breast cancer. The effect of raloxifene on CHD is still uncertain. On the basis of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, raloxifene may offer some protection to women with CHD or to those who are at high risk of CHD. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway.

Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339. The aim is to find a compound with the ideal profile, that is, alleviation of climacteric symptoms and prevention of osteoporotic fractures, but without an adverse effect on the breast and endometrium, and no negative effect or even a beneficial effect on the cardiovascular system and the brain. Currently, limited data are available with regard to these next-generation SERMs and CHD. Nevertheless, some of these novel agents provide arguments for continuing the search for an ideal SERM.