The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: Basic and clinical insights

Abstract

Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrogen receptors (ERs) and exert agonist or antagonist effects on ERs in a tissue-specific manner. Tamoxifen, a first generation SERM, is used for treatment of ER positive breast cancer. Raloxifene, a second generation SERM, was used to prevent postmenopausal osteoporosis. The third-generation SERM bazedoxifene (BZA) effectively prevents osteoporosis while preventing estrogenic stimulation of breast and uterus. Notably, BZA combined with conjugated estrogens (CE) is a new menopausal treatment. The menopausal state predisposes to metabolic syndrome and type 2 diabetes, and therefore the effects of SERMs on metabolic homeostasis are gaining attention. Here, we summarize knowledge of SERMs’ impacts on metabolic, homeostasis, obesity and diabetes in rodent models and postmenopausal women.

Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance

“…The most consistently reported adverse metabolic effect of breast cancer endocrine therapy is an elevated risk of type 2 diabetes [6][7][8]18 . Therefore, we evaluated fasting insulin, glucose, and calculated HOMA-IR, an estimation of insulin resistance, as early markers that could predict diabetes.…”

“…Conflicting metabolic consequences of endocrine therapy have been reported in preclinical models. A number of metabolic studies employed supra-physiological doses of TAM to induce the expression of Cre-ER transgenes (reviewed in 18 ). High-dose TAM over a short period of time leads to weight loss in mice, but this is not representative of the physiological response in breast cancer survivors [19][20][21][22] .…”

Tamoxifen treatment causes early hepatic insulin resistance

“…Tamoxifen decreases food intake, body weight and (at least in the short-term) fat mass in rodents. Despite lowering body weight in obese women, tamoxifen may increase the incidence of diabetes [2]. This potential side effect has been attributed to decreased β-cell survival and proliferation, but also hepatic steatosis in rodents [3].…”

Chronic Oral Administration of Tenebrio molitor Extract Exhibits Inhibitory Effect on Glucocorticoid Receptor Overexpression in the Hippocampus of Ovariectomy‐Induced Estrogen Deficient Mice

“…Menopause is presented as systemic estrogen deficiency in females. It can lead to secondary systemic metabolic disorders such as osteoporosis, obesity, and type 2 diabetes (Nicodemus, Folsom, & Iowa Women's Health, ; Russo et al., ; Xu, Lovre, & Mauvais‐Jarvis, ). It has been reported that chronic estrogen deficient condition has pivotally negative effects on brain functions such as enhanced oxidative stress, memory impairment, amyloidogenesis, and hyperactivation of NF‐ĸB activation (Anukulthanakorn et al., ; Connell et al., ; Riedel, Thompson, & Brinton, ; Topcuoglu et al., ; Xiao, Cao, Marshall, & Hu, ; Yun et al., ; Zhao, Woody, & Chhibber, ).…”