Clinical pharmacology of selective estrogen receptor modulators (SERMs)

Abstract

Selective estrogen receptor modulators (SERMs) are a group of drugs withheterogeneous structural chemical characteristics that are characterized ashigh-affinity ligands (in the subnanomolar concentration range) to estrogenicreceptors (ERs) but have the peculiarity of triggering estrogen-agonistor estrogen-antagonist actions, depending on the tissue in which they act.From a pharmacological perspective, SERMs should be differentiated frompure antiestrogens, such as fulvestrant (Chap. 6), which are molecules chemicallyrelated 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 differenttypes of sex steroid receptors.The pharmacological development of these compounds has been closelyconnected, on one hand, to the vast experience that has been accumulated overdecades in estrogen therapy (ET) and estrogen and progestin therapy (EPT)during menopause and, on the other hand, to the effects on nonbreast tissuesof drugs traditionally classified as "antiestrogens", tamoxifen being the principalexample. ET and EPT have proven to be effective in the prevention andtreatment of the signs and symptoms of early estrogen deficiency associatedwith perimenopause and accelerated bone mass loss occurring after ovarianfunction ceases. Numerous observational studies have demonstrated thatpostmenopausal women receiving long-term treatment with ET/EPT showa reduced risk of osteoporotic fractures, cardiovascular diseases, and evenAlzheimer's disease (Manson et al. 2001). However, the benefits suggested inthe observational studies have not been confirmed in randomized, doubleblind,placebo-controlled clinical trials, the design of which eliminates thesignificant selection bias presented in naturalistic studies. Recent clinical trialsclearly have shown the lack of benefit from EPT or ET alone in primary andsecondary prevention of ischaemic heart disease and cerebrovascular disease(Hulley et al. 1998; Writing Group for the Women's Health Initiative Investigators2002; Women's Health Initiative Steering Committee 2004) and castserious doubts on its safety in the deterioration of higher cognitive functions(Shumaker et al. 2004). Furthermore, treatment compliance tends to be verylow because of the poor acceptance by many women regarding the return ofmenstrual bleeding or spotting and the fear of an increased risk of breast oruterine cancer. On the other hand, WHI trials suggest a positive effect of ETand EPT in reducing the risk for hip fracture and colorectal cancer, althoughthe overall risk-benefit balance is not consistentwith the requirements for a viableintervention for primary prevention of chronic diseases (Writing Groupfor theWomen'sHealth Initiative Investigators 2002;Women'sHealth InitiativeSteering Committee 2004).Therefore, the primary objective for the pharmacological development ofSERMs is to increase the benefit/risk ratio in comparison with ET and EPTin the prevention and treatment of several highly prevalent, chronic diseasesin the postmenopausal period that are related to this physiological estrogendeficient state. As is often the case in medicine, the discovery of the pharmacologicalprofile that gave grounds for hope in the development of thisnew drug class was the result of an unexpected paradox. Tamoxifen, a drugthat was introduced over 35 years ago for hormone-dependent breast cancertreatment, has been considered an antiestrogen for decades because ofits blocking action on the binding of endogenous estrogens to the estrogenreceptor (ER) of neoplastic breast cells. However, several studies suggestedthat tamoxifen might have a protective action in bone tissue (estrogen agonist).For example, a study of postmenopausal women who previously hadbreast cancer but were clinically cancer free showed that tamoxifen increasedlumbar 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 secondaryprevention of several types of estrogen-dependent tumors, postmenopausalosteoporosis, and cardiovascular and neurodegenerative diseases.In this chapter, a general review of SERMs will be given, highlightingsome of the latest advances in the development of new SERMs and problemsencountered during the clinical development of some of them. Detailson the efficacy, safety, and clinical use of SERMs in which more clinical experiencehas been accumulated will be discussed in greater depth in otherchapters. © Springer-Verlag Berlin Heidelberg 2006.