Exploring the effects of estrogen deficiency and aging on organismal homeostasis during menopause

Abstract

Sex hormone signaling declines during aging, from early midlife through menopause, as a consequence of reduced circulating estrogens and decreased receptiveness to these hormones in target tissues. Estrogens preserve energy homeostasis and promote metabolic health via coordinated and simultaneous effects throughout the brain and body. Age-associated loss of estrogen production during menopause has been implicated in a higher risk for metabolic diseases and increased mortality. However, it remains unclear whether age-associated changes in homeostasis are dependent on reduced estrogen signaling during menopause. Although menopausal hormone therapies containing estrogens can alleviate symptoms, concerns about the risks involved have contributed to a broad decline in the use of these approaches. Non-hormonal therapies have emerged that target tissues or pathways with varying levels of selectivity, reducing risk. We summarize here the broad effects of estrogen loss on homeostasis during menopause, current and emerging therapies and opportunities for understanding homeostatic disruptions associated with menopause.

Figure 1:

Overview of estrogen signalling and physiological effects. 17-Beta Estradiol (17βE2) is the predominant circulating estrogen produced by the ovary following the release of FSH and LH from the anterior pituitary. a) 17βE2 binds to classical estrogen receptors, translocates to the nucelus and binds to estrogen response elements (EREs) which increases gene transcription influencing metabolism, anti-inflammatory pathways and mitochondrial activation by the nuclear initiated pathway. b) 17βE2 binding to membrane bound G protein coupled receptors initiate calcium signalling, cAMP, PKA and eNOS pathways. c) Estrogen signalling plays a role in energy balance, thermoregulation, bone and muscle growth and is essential for reproductive behaviours. d) reduced circulating estrogens post menopause increases the risk for cardiovascular disease (CVD), metabolic dysfunction, thermodysregulatinon, osteoporosis, neurological disorders, bone degeneration and sleep loss.