Pulsed administration for physiological estrogen replacement in mice

Abstract

Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid.

Physiological levels of estradiol limit murine osteoarthritis progression

“…OVX mice subjected to an experimental model of OA were treated with a physiological dose of 17-estradiol (E2) in an early phase of the OA disease progression (Byers et al, 2012). E2 was administered in a pulsed fashion to resemble normal hormone fluctuations during the murine estrous cycle (Corciulo et al, 2021).…”

“…Female mice, eight weeks old, were employed in the study and all underwent ovariectomy (OVX) or sham surgery as previously described (Corciulo et al, 2021). Mice were allowed to recover from the OVX procedure for ten days before the surgery for destabilization of the medial meniscus (DMM).…”

“…Moreover, estradiol is a well-known regulator of bone and immune system homeostasis and also controls motor ability and pain sensitivity (Straub, 2007). Although epidemiological studies reported that post-menopausal women have a higher risk to develop OA compared to men, the association between the risk to develop OA and hormonal factors is not clear (de Klerk et al, 2009). The effect of ovariectomy (OVX) on experimental OA models consistently points towards deterioration of the articular cartilage, while the effect of estradiol replacement displays conflicting results (Roman-Blas et al, 2009).…”