Clinical pharmacology of selective estrogen receptor modulators (SERMs)

Selective estrogen receptor modulators (SERMs) are a group of drugs with heterogeneous structural chemical characteristics that are characterized as high-affinity ligands (in the subnanomolar concentration range) to estrogenic receptors (ERs) but have the peculiarity of triggering estrogen-agonist or estrogen-antagonist actions, depending on the tissue in which they act. From a pharmacological perspective, SERMs should be differentiated from pure antiestrogens, such as fulvestrant, which are molecules chemically related to estradiol and exclusively exhibit estrogenic antagonist activity. SERMs also should be differentiated from the so-called “gonadomimetic” drugs, such as tibolone, that act by means of nonselective binding to different types of sex steroid receptors.

The pharmacological development of these compounds has been closely connected, on one hand, to the vast experience that has been accumulated over decades in estrogen therapy (ET) and estrogen and progestin therapy (EPT) during menopause and, on the other hand, to the effects on nonbreast tissues of drugs traditionally classified as “antiestrogens”, tamoxifen being the principal example. ET and EPT have proven to be effective in the prevention and treatment of the signs and symptoms of early estrogen deficiency associated with perimenopause and accelerated bone mass loss occurring after ovarian function ceases. Numerous observational studies have demonstrated that postmenopausal women receiving long-term treatment with ET/EPT show a reduced risk of osteoporotic fractures, cardiovascular diseases, and even Alzheimer’s disease (Manson et al. 2001). However, the benefits suggested in the observational studies have not been confirmed in randomized, double-blind, placebo-controlled clinical trials, the design of which eliminates the significant selection bias presented in naturalistic studies. Recent clinical trials clearly have shown the lack of benefit from EPT or ET alone in primary and secondary prevention of ischaemic heart disease and cerebrovascular disease (Hulley et al. 1998; Writing Group for the Women’s Health Initiative Investigators 2002; Women’s Health Initiative Steering Committee 2004) and cast serious doubts on its safety in the deterioration of higher cognitive functions (Shumaker et al. 2004). Furthermore, treatment compliance tends to be very low because of the poor acceptance by many women regarding the return of menstrual bleeding or spotting and the fear of an increased risk of breast or uterine cancer. On the other hand, WHI trials suggest a positive effect of ET and EPT in reducing the risk for hip fracture and colorectal cancer, although the overall risk–benefit balance is not consistentwith the requirements for a viable intervention for primary prevention of chronic diseases (Writing Group for theWomen’sHealth Initiative Investigators 2002; Women’sHealth Initiative Steering Committee 2004).

Therefore, the primary objective for the pharmacological development of SERMs is to increase the benefit/risk ratio in comparison with ET and EPT in the prevention and treatment of several highly prevalent, chronic diseases in the postmenopausal period that are related to this physiological estrogen deficient state. As is often the case in medicine, the discovery of the pharmacological profile that gave grounds for hope in the development of this new drug class was the result of an unexpected paradox. Tamoxifen, a drug that was introduced over 35 years ago for hormone-dependent breast cancer treatment, has been considered an antiestrogen for decades because of its blocking action on the binding of endogenous estrogens to the estrogen receptor (ER) of neoplastic breast cells. However, several studies suggested that tamoxifen might have a protective action in bone tissue (estrogen agonist). For example, a study of postmenopausal women who previously had breast cancer but were clinically cancer free showed that tamoxifen increased lumbar spine bone mineral density compared to placebo (Love et al. 1992); that is, this study further suggested that tamoxifen was not purely antiestrogenic.

This drug class has an enormous potential in the primary and secondary prevention of several types of estrogen-dependent tumors, postmenopausal osteoporosis, and cardiovascular and neurodegenerative diseases.