Tissue selective estrogen complex combinations with bazedoxifene/conjugated estrogens as a model

Abstract

The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator (SERM) with one or more estrogens. Different TSECs are associated with distinct gene expression profiles in mammary gland and endometrial tissue according to the individual SERM and estrogen components. Few TSECs have been evaluated outside the laboratory. In preclinical trials, bazedoxifene (BZA) was distinct from other SERMs, with a neutral effect on mammary gland and endometrial tissue, and an antagonist effect on these tissues when combined with conjugated estrogens (CE). The only TSEC in an advanced stage of clinical development pairs BZA with CE. In large, randomized clinical trials, two doses, BZA 20 mg/CE 0.45 and 0.625 mg, reduced menopausal symptoms and prevented bone loss in postmenopausal women with a favorable safety profile on the breast, endometrium, and ovary, and with cardiovascular and venous thrombosis events similar to placebo. Improvements were seen in sleep, health-related quality of life, and treatment satisfaction. Compared with traditional, progestogen-containing hormone therapy, BZA/CE had higher rates of amenorrhea and reduced breast pain, with changes in breast density from baseline similar to placebo. Future TSECs identified in preclinical studies need to be tested in rigorous phase-3 clinical trials for effectiveness, safety and tolerability.

Key words::

• TISSUE SELECTIVE ESTROGEN COMPLEX
• TSEC
• BAZEDOXIFENE
• CONJUGATED ESTROGENS
• BZA/CE
• MENOPAUSE
• MENOPAUSAL SYMPTOMS
• SAFETY

ACKNOWLEDGEMENTS

Medical writing support was provided by Katie McClendon, PhD, at MedErgy and was funded by Pfizer. The authors meet authorship criteria set forth by the International Committee of Medical Journal Editors (ICMJE), established the direction for the manuscript, reviewed all pertinent articles and data, had full control over content and structure of the article, were actively involved in all stages of manuscript development, and gave final approval.

Conflict of interest In the past 12 months, J. V. Pinkerton has served as a consultant (fees to the University of Virginia) for Pfizer, Noven Pharmaceuticals, Shionogi and DepoMed; has received grants/research support (fees to the University of Virginia) from Bionovo and Endoceutics; and received travel funds from Pfizer, Noven Pharmaceuticals, Shionogi and DepoMed. B. Komm and S. Mirkin are full-time employees of Pfizer.