Antiestrogen and Antiprogestin Active Principles

Selective estrogen receptor modulators (SERMs) (A). Estrogen receptors belong to the group of transcription-regulating receptors (p.64). The female gonadal hormone estradiol is an agonist at these receptors. Several drugs are available that can produce estrogen-antagonistic effects. Interestingly, these are associated with estrogen-agonistic effects in certain tissues. A tentative explanation derives from the idea that each ligand induces a specific conformation of the estrogen receptor. The ligand–estrogen receptor complexes combine with co-activators or repressors at specified gene sequences. The pattern of co-regulators differs from tissue to tissue, allowing each SERM to generate a tissue-specific activity. It is of therapeutic significance that the patterns of estrogenic and antiestrogenic effects differ in a sub- stance-specific manner among the drugs of this class.

It is useful to compare the activity profile of a SERM with that of estradiol, particularly in relation to effects seen postmenopausally. During chronic administration of estradiol, the risk of endometrial cancer rises; co-ad- ministration of a progestin prevents this effect. Breast cancers occur more frequently, likewise thromboembolic diseases. Estradiol effectively alleviates climacteric hot flashes and sweating. After chronic treatment it reduces the incidence of osteoporotic bone fractures by preventing the loss of an estro- gen-dependent portion of bone mass. Nonetheless, estrogens can no longer be recommended for this purpose because of the unfavorable benefit–risk constellation (p.330).

Clomifene is a stilbene derivative used orally for the therapy of female infertility. Owing to its antagonistic action at estrogen receptors in the adenohypophysis, feedback inhibition by estradiol of gonadotropin secretion is suppressed. The resulting increase in release of FSH induces augmented maturation of oocyte follicles. For instance, clomi-

fene can be used for the treatment of luteal phase defects associated with disturbances of follicular maturation or the treatment of polycystic ovary syndrome. Since its use is confined to a few selected days during the ovarian cycle, chronic effects need not be considered.

Tamoxifen is a stilbene derivative that is used in metastasizing breast cancer to block the estrogenic stimulus for tumor cell growth. As a mixed estrogenic antagonist/ partial agonist, tamoxifen promotes rather than ameliorates climacteric complaints; at the same time it displays agonistic features that are of concern as a potential risk factor when use of the drug for the prophylaxis of breast cancer is being considered.

Raloxifene is approved for use in the treatment and prophylaxis of osteoporosis. As shown in the table opposite, it has other beneficial as well as adverse effects.

The estrogen receptor antagonist fulvestrant is devoid of agonist activities and, given as a monthly injection may be used to delay progression of breast cancer. It causes downregulation and degradation of the estrogen receptor protein.

Progestin receptor antagonist (B). Approximately one week after conception, the embryo implants itself into the endometrium in the form of the blastocyst. By secreting human chorionic gonadotropin (HCG, mainly LH), the trophoblast maintains the corpus luteum and secretion of progesterone and thereby prevents menstrual bleeding. Mifepristone is an antagonist at progestin receptors and prevents maintenance of the endometrium during early pregnancy. Consequently, it acts as an abortifacient in early pregnancy. Its use has provoked medical debates (comparison of adverse reactions to mifepristone vs. surgical intervention) and aroused ethical-ideological conflicts.

Aromatase Inhibitors

Aromatase inhibitors constitute an additional antiestrogenic principle that is based upon inhibition of estrogen formation. They are used chiefly in the therapy of advanced breast cancer when the tumor has become insensitive to estrogen and the patient has completed menopause. However, one agent in this class (anastrozole) was recently licensed for use in early breast cancer.

Aromatase. The enzyme converts androgens such as testosterone and androstenedione into the estrogens estradiol and estrone.This reaction involves cleavage of the methyl group at C10 and aromatization of ring A. Aromatase is a cytochrome P450-containing enzyme (isozyme CYP19). During the female reproductive phase, the major portion of circulating estrogens originates from the ovaries, where estradiol is synthesized in the granulosa cells of the maturing tertiary follicles. Theca cells surrounding the granulosa cells supply androgen precursors. FSH stimulates formation of estrogens by inducing the synthesis of aromatase in granulosa cells. An isoform of the enzyme 17β-hydroxyste- roid dehydrogenase (17β-HSD 1) catalyzes the conversion of androstenedione to testosterone and of estrone to estradiol. After menopause, ovarian function ceases. However, estrogens do not disappear completely from the blood because they continue to enter the circulation from certain other tissues, in particular the subcutaneous adipose tissue, which produces estrone. In hormonedependent breast cancers, tumor growth is thereby promoted. In addition, breast cancer cells themselves may be capable of producing estrogens via aromatase.

Aromatase inhibitors serve to eliminate extraovarian synthesis of estrogens in breast cancer patients. This can be achieved effectively only in postmenopause because, as an FSH-dependent enzyme, ovarian aromatase is subject to feedback regulation of female

gonadal hormones. A drop in blood estradiol concentration would lead to increased release of FSH with a compensatory increase in synthesis of aromatase and estrogens.

Two groups of inhibitors can be distinguished on the basis of chemical structure and mechanism of action. Steroidal inhibitors (formestane, exemestane) attach to the androgen binding site on the enzyme and in the form of intermediary products give rise to an irreversible inhibition of the enzyme.

Nonsteroidal inhibitors (anastrozole, letrozole) attach to a different binding site of the enzyme; via their triazole ring they interact reversibly with the heme iron of cytochrome P450.

Among the adverse effects, climacteric-like complaints predominate, reflecting the decline in estrogen levels. Unlike the SERMs, tamoxifen, which is used for the same indication, aromatase inhibitors do not promote endometrial growth and do not increase the risk of thromboembolic complications.