Targeting hormonal growth pathways has been an effective strategy in the management of various tumors such as breast, prostate, and endometrial cancers. Early approaches were directed at surgical ablation of the glands supplying these hormonal stimuli (i.e., ovariectomy for breast cancer and orchiectomy for prostate cancer), but over the pst 30 years a large number of medical agents have become available based on an increasing understanding of molecular endocrinology.
Medical endocrine strategies in breast cancer are designed to counteract the proliferative effects of estrogen in ER-positive breast cancer, either with drugs that compete with estrogen for ER and block its effect (i.e., antiestrogens), or strategies that induce estrogen deprivation and remove the proliferative signal [i.e., oophorectomy or gonadotropin-releasing hormone (GnRH) agonists in premenopausal women, and aromatase inhibitors in postmenopausal women]. Tamoxifen is a nonsteroidal estrogen receptor (ER) antagonist that inhibits breast cancer growth by competitive antagonism of ER, although its actions are complex as a result of partial estrogenic agonist effects, which in some tissues (i.e., bone) can be beneficial but which in others may be harmful, increasing the risk of uterine cancer and thromboembolism. Oral aromatase inhibitors prevent conversion of adrenal androgens (androstenedione and testosterone) into estradiol (EJ and estrone (E2) by the cytochrome P-450 enzyme aromatase. Alternative endocrine approaches are also being developed, including steroidal antiestrogens that selectively downregulate expression of ER.4
Normal prostate cells and tumor cells are sensitive to androgens, which are produced by two major sources: the testicles, which produce testosterone (95% of all androgens), and the adrenal glands, which produce dehydroandrosterone, dehy-droandrosterone sulfate, and androstenedione. Both are under the influence of luteinizing hormone (LH), which in turn is controlled by GnRH produced by the hypothalamus. Testosterone levels have a negative feedback effect on GnRH release from the hypothalamus. Targeted endocrine medical treatment of prostate cancers aims to decrease the activity of androgens on the AR, either with antiandrogens (i.e., nonsteroidal agents such as flutamide, biclutamide) that competitively block dihydrotestosterone (DHT) binding to AR, and subsequent activation of AR-regulated genes, or by suppression of LH secretion (i.e., using specific LH agonists that ultimately inhibit LH secretion, thus reducing androgen production).
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