Review
Estrogen synthesis and signaling pathways during aging: from periphery to brain

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Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissues such as liver, heart, muscle, bone and brain, and tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. In this article we review tissue and cell-specific estrogen synthesis and estrogen receptor signaling in three parts: (i) synthesis and metabolism, (ii) the distribution of estrogen receptors and signaling, and (iii) estrogen functions and related disorders, including cardiovascular diseases, osteoporosis, Alzheimer's disease (AD), and Parkinson disease (PD). This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases.

Section snippets

Estrogen synthesis

In premenopausal women, estrogens are produced from cholesterol primarily in the ovaries, corpus luteum, and placenta, although small but significant amounts can be produced by nongonad organs such as the liver, heart, skin, and brain. Three major forms of physiological estrogens are present in females: estrone (E1), estradiol (E2, or 17β-estradiol), and estriol (E3). E2 is the major product of the entire biosynthesis process and is the most potent estrogen during the premenopausal period. E1

Tissue-specific ERs and signaling

Estrogen signaling is primarily mediated through ERs, including nuclear receptors ERα and ERβ, and membrane receptors such as GPR30 and ER-X [31]. Although both types of ERs transduce estrogen signals into a large variety of physiological responses in various organs, the biological events mediated by nuclear ERs occur slowly over hours or even days, whereas the intracellular signaling cascades triggered by cell-membrane ERs respond much faster, even within seconds. In combination with the

Estrogen signaling pathways

Although most estrogen-mediated signaling pathways are ER-dependent, ER-independent mechanisms exist. There are two different ER-dependent mechanisms, classified as ‘genomic’ and ‘nongenomic’ based on whether the end result is transcriptional regulation. Despite these traditional classifications, recent studies implicate some ‘nongenomic’ pathways in gene transcription. In addition to being either genomic or nongenomic, ER-dependent pathways can initiate either in the nucleus or at the plasma

Estrogen and ERs in age-related diseases

Because age-related changes in estrogen production and estrogen receptor expression can differ based on cell or tissue types, it is important to understand the tissue-specific roles in the context of age-related diseases. Reduced endogenous estrogen levels increases the risk of bone fracture, cardiovascular disease, and AD in postmenopausal women. Although estrogen therapy is osteoprotective [80], whether estrogen therapy can protect against heart disease or AD remains controversial [81]. It is

Concluding remarks

Although the roles of estrogens in gonadal organs are well understood, recent studies have begun to demonstrate that localized estrogen production plays tissue-specific roles, with or without dependency on circulating estrogen. The cell- and tissue-specific actions of estrogen and ERs are directly involved various age-related diseases. Nevertheless, it remains unclear how the local synthesis of estrogens and their respective receptor functions are controlled in normal aging. We believe that

Acknowledgments

This work was supported by the Alzheimer's Association (grant IIRG-07-59510), the American Health Assistance Foundation (G2006-118), and the National Institutes of Health (R01AG032441-01 and R01AG025888). We also thank Alex Bishop, Jon Reed, and Balaji Jothishankar for editing and proofreading.

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