The tissue-selective estrogen complex (TSEC) is a strategy to harness the benefits of estrogens while limiting their negative consequences, by combining an estrogen with a selective estrogen receptor modulator (SERM). Carolyn Smith, MD, Baylor College of Medicine, Houston, Texas, USA, reviewed research with this new class of estrogen receptor (ER)-targeted therapy.

Estrogen research is uncovering new concepts about its effects in different target tissues, and in the process it is clarifying the benefits of hormone replacement therapy, which can delay or improve many of the symptoms or diseases associated with menopause. The discovery of a second ER expands the potential for estrogen action.

Because current concepts of estrogen action are extraordinarily complex, stated Dr. Smith, this translates clinically into a variety of actions, many of which are beneficial, in diverse tissues. Estrogen is a key hormone in maintaining skeletal integrity; improved cognition and protection against tooth loss and macular degeneration are also emerging as possible benefits of estrogen.

The United States Food and Drug Administration has approved one TSEC, comprising conjugated estrogens (CE; 0.45 mg) and bazedoxifene (BAZ; 20 mg), as a treatment for moderate-to-severe vasomotor symptoms (VMS) associated with menopause and for the prevention of postmenopausal (PM) osteoporosis in women with a uterus. The estrogenic component provides relief of hot flashes and prevents bone loss, whereas the antiestrogenic component inhibits action in breast and endometrial tissue.

Basic science research has shown differential regulation of ER–target gene expression in relation to the specific SERM that was combined with CE in the TSEC [Chang KCN et al. J Steroid Biochem Mol Biol 2010]. TSEC activates the transcriptional activity of ER–heteroligand dimers, in which 1 receptor is bound to an agonist (CE or estradiol), and the other receptor is bound to an antagonist (tamoxifen, raloxifene, or BAZ). This activation has been shown in multiple cell types and requires both receptors to bind to DNA. TSEC stimulation of messenger RNA expression was gene specific, and it has been shown that different subsets are regulated by different combinations of agonist and antagonist [Chang KCN et al. J Steroid Biochem Mol Biol 2010]. Expression of ERs in breast and endometrial cells was downregulated with BAZ [Wardell SE et al. Clin Cancer Res 2013]. A program of 5 randomized, double-blind, placebo- and active-controlled Phase 3 trials called the Selective Estrogens, Menopause, and Response to Therapy [SMART; Komm BS et al. Steroids 2014] trials evaluated the safety and efficacy of the CE–BAZ TSEC in PM women with a uterus (Table 1). Together, the trials showed that this TSEC relieved VMS and vulvar-vaginal atrophy (VVA) symptoms, increased bone mineral density, exerted minimal breast stimulation, and provided adequate endometrial protection.

The preclinical work and evidence from the SMART trials support the ability of TSECs to blend the desirable ER agonist activity of estrogens and the tissue-selective ER agonist and ER antagonist properties of a SERM, stated Dr. Smith.