Tissue selective estrogen complex (TSEC): a review

Abstract

Objective:This review describes historical development of selective estrogen receptor modulators (SERMs) and their combination with estrogens, termed a tissue selective estrogen complex (TSEC), and considers the potential for future TSEC development.Methods:This narrative review is based on literature identified on PubMed and the TSEC research and development experience of the authors.Results:SERMs have estrogenic and antiestrogenic effects in various tissues; however, no single agent has achieved an optimal balance of agonist and antagonist effects for the treatment of menopausal symptoms. Clinically, a number of SERMs protect against osteoporosis and breast cancer but can exacerbate vasomotor symptoms. Estrogens alleviate menopausal hot flushes and genitourinary symptoms as well as reduce bone loss, but the addition of a progestogen to menopausal hormone therapy to protect against endometrial cancer increases vaginal bleeding risk, breast tenderness, and potentially breast cancer. The search for an effective menopausal therapy with better tolerability led to the investigation of TSECs. Clinical development of a TSEC consisting of conjugated estrogens/bazedoxifene increased understanding of the importance of a careful consideration of the combination's components and their respective doses to balance safety and efficacy. Bazedoxifene is an estrogen receptor agonist in bone but an antagonist/degrader in the endometrium, which has contributed to its success as a TSEC component. Other oral TSEC combinations studied thus far have not demonstrated similar endometrial safety.Conclusions:Choice of SERM, selection of doses, and clinical trial data evaluating safety and efficacy are key to ensuring safety and adequate therapeutic effect of TSECs for addressing menopausal symptoms.

Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study

“…Similar to findings reported for cynomolgus monkeys (18) we observed a reduction in benign breast tissue Ki-67 in women from cohort B who had measurable proliferation (1% or higher Ki-67 immunolabeling) at baseline. Reduction in systemic progesterone levels due to physiologic progression of menopause transition (45); and/or disruption of estrogen and progesterone receptor signaling by Duavee are potential explanations for the observed decreases in proliferation (8,15). Progesterone increases proliferation-associated gene expression by increasing transcription factors including STAT5a, PDK4, and RANKL (46,47).…”

“…Tissue selective estrogen complexes (TSEC) combine estrogen for menopause symptoms with a selective estrogen receptor modulator (SERM) to act as an estrogen antagonist in the uterus and breast (8). In preclinical studies, the estrogen antagonist properties of bazedoxifene (BZA) in the uterus were superior to other SERMs such as raloxifene and lasoxifene (8,9), and its growth inhibitory effects on ER þ breast cancer cell lines were at least equivalent to active tamoxifen metabolites or the estrogen receptor downregulator fulvestrant (9,10). Inhibition of cell growth appeared linked to blockade of estrogen upregulation of cyclin D1 (CCND1) gene expression as well as accelerated ER alpha protein degradation (10).…”

Az ösztrogének lehetséges szerepe a vastagbéldaganatok kialakulásában

“…Az ösztrogénreceptorokon keresztül ható és a különböző szövetekben eltérő, agonista vagy antagonista vegyületeket szelektív ER-modulátoroknak (selective estrogen receptor modulator [SERM]) nevezzük. Egy nagy esetszámú vizsgálat szerint a tamoxifen agonista hatást fejt ki ez endometrium ER-ain keresztül, ezért növelheti az endometriumcarcinoma kialakulásának kockázatát [36]. A bazedoxifen már az uterusban is antagonista hatással bír, és konjugált ösztrogénekkel kombinálva a menopauza vazomotoros tüneteinek enyhítésére alkalmazzák [37].…”

“…Mindezek alapján a bazedoxifen az IL11/GP130 gátló hatása révén új és hatékony terápiás lehetőség lehet a CRC kezelésében, még oxaliplatinrezisztencia esetén is [38]. A későbbiekben további SERM-vegyületeket is fejlesztettek, ezek eltérő szöveti hatását a 4. ábra foglalja össze [36].…”

“…Szelektív ösztrogénreceptor-modulátorok (SERM) különböző szövetekre gyakorolt agonista, illetve antagonista hatása Az ábra forrása: Pickar és mtsai [36] alapján, újraszerkesztve ÖSSZEFOGLALÓ KÖZLEMÉNY mérsékelheti az adenocarcinoma kialakulásának kockázatát. Az ER-ok a ligandumkötést követően transzkripciós szinten is befolyásolhatják számos emésztőrendszeri daganat kialakulását [45][46][47], és módosíthatják olyan szervekben is a sejtosztódást, amelyeket korábban nem tekintettek a hormonok célszerveinek.…”