Selective modulation of postmenopausal women: cutting the Gordian knot of hormone replacement therapy with breast carcinoma.

BACKGROUND Hormone replacement therapy (HRT) has proven and presumable benefits for women desiring postmenopausal health preservation. Among HRT-associated risks, the fear of breast carcinoma intimidates women and physicians contemplating hormonal treatment and limits long-term compliance. Identifying effective alternative medications that are not associated with breast carcinoma or that even may prevent its development would be a major advance. METHODS This article discusses the clinical perspective of HRT and selective estrogen receptor modulators (SERMs) in light of the molecular and cellular mechanisms of estrogen and progesterone action on the breast. Emphasis is placed on the potential of selective receptor modulation as the future of postmenopausal treatment. RESULTS Current epidemiologic evidence suggests that HRT is associated with a small but substantial increase in the risk of breast carcinoma, and combined estrogen-progesterone regimens further increase this hazard. Ample biologic data support this clinical association and propose multiple molecular mechanisms for the effects of estrogen and progesterone on breast cells. SERMs are a novel class of drugs that demonstrate estrogen agonistic and antagonistic actions in a tissue specific manner. SERMs act by binding the estrogen receptor and selectively modulating its effect on gene transcription at target tissues. CONCLUSIONS SERMs offer an alternative to HRT that can successfully circumvent the intimidating side-effect of breast carcinoma. Further insight into the molecular mechanisms of SERM action may enable the development of agents with improved target-tissue selectivity. Identifying selective modulators with unique pharmacologic properties would facilitate the creation of individualized treatment for the postmenopausal woman according to her particular predisposition for menopause-related morbidities and her overall clinical profile. Cancer 2003;97:12–20. © 2003 American Cancer Society. DOI 10.1002/cncr.11049