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

Abstract

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.

Figure 1. Estrogen synthesis in the ovary and brain

(a) Folliculogenesis. A primordial follicle consists of an oocyte and a layer of granulosa cells at the beginning of folliculogenesis. Thecal cells form a layer surrounding the granulosa cells when the follicle is activated. At end of folliculogenesis, thecal cells luteinize to form the corpus luteum after ovulation. (b) Cell-specific estrogen synthesis in the ovary. Production of estrogens starts with the synthesis of pregnenolone from cholesterol, catalyzed by the cytochrome P450 side chain cleavage enzyme (P450scc). Pregnenolone is then converted to progesterone by 3-beta-hydroxysteroid dehydrogenase (3β-HSD) in both thecal and granusola cells. Progesterone is converted to androgens via cytochrome P450 17α-hydroxylase (P45017α) and 17-beta-hydroxysteroid dehydrogenase (17β-HSD) in thecal cells during the follicular phase. The conversion of E2 is catalyzed by aromatase (P450Arom) in granulosa cells. (c) Cell-specific estrogen synthesis in the brain. Neurons and astrocytes express all enzymes required for estrogen synthesis to produce brain estrogen. (d) Microglial cells and oligodendrocytes are not able to produce estrogen. Dotted line indicates weak enzymatic activity converting testosterone to estrone in the brain.

Figure 1. Estrogen synthesis in the ovary and brain

(a) Folliculogenesis. A primordial follicle consists of an oocyte and a layer of granulosa cells at the beginning of folliculogenesis. Thecal cells form a layer surrounding the granulosa cells when the follicle is activated. At end of folliculogenesis, thecal cells luteinize to form the corpus luteum after ovulation. (b) Cell-specific estrogen synthesis in the ovary. Production of estrogens starts with the synthesis of pregnenolone from cholesterol, catalyzed by the cytochrome P450 side chain cleavage enzyme (P450scc). Pregnenolone is then converted to progesterone by 3-beta-hydroxysteroid dehydrogenase (3β-HSD) in both thecal and granusola cells. Progesterone is converted to androgens via cytochrome P450 17α-hydroxylase (P45017α) and 17-beta-hydroxysteroid dehydrogenase (17β-HSD) in thecal cells during the follicular phase. The conversion of E2 is catalyzed by aromatase (P450Arom) in granulosa cells. (c) Cell-specific estrogen synthesis in the brain. Neurons and astrocytes express all enzymes required for estrogen synthesis to produce brain estrogen. (d) Microglial cells and oligodendrocytes are not able to produce estrogen. Dotted line indicates weak enzymatic activity converting testosterone to estrone in the brain.

Figure 2. Schematic representation of the human CYP19 gene reveals the alternative splicing and tissue specific promoters

The regulatory region (~93 kb) contains 10 tissue-specific promoters and initial exons that differ in both location and size. These are alternatively spliced onto a common site just upstream of the ATG codon in exon II. The untranslated Exon I of mRNA species may be viewed as a signature of the tissue-specific promoter. Different promoters are named according to the 5'-UTR of their corresponding mature mRNA species. The coding region (~30 kb) spans exon II–X and is identical in all tissues and encodes the aromatase protein.

Figure 3. Schematic diagram of the two human ERs, ERα and ERβ

Both receptors consist of six functional domains, including the domain A/B at the N-terminal for protein–protein interactions and transcriptional activation of target-gene expression, the domain C for DNA-binding domain (DBD), domain D for the nuclear translocation signal, and domain E/F at the C-terminal for ligand-binding domain (LBD) and the ligand-dependent activation function AF-2. The percentage homology between the two receptors is indicated.

Figure 4. Signaling pathway mediated by E2 and ERs

There are 4 estrogen and estrogen receptor signaling pathways. Pathway 1: The nuclear-initiated estrogen signaling mediated through classical ERs leads to the transcriptional changes in estrogen-responsive genes with or without EREs. Pathway 2: The membrane initiated estrogen signaling leads to diverse cytoplasmic effects, including the regulation of membrane-based ion channels, regulation of second messenger systems, and modification of transcription factors or other membrane receptors. Pathway 3: Estrogen can also exert antioxidant effects in an ER-independent manner. Pathway 4: Ligand-independent genomic actions. Growth factors (GF) activate protein-kinase cascades, leading to phosphorylation (P) and activation of nuclear ERs at EREs.

Figure 5. Estrogen prevents the accumulation of Aβ

Estrogen can reduce Aβ production by favoring the non-amyloidogenic pathway of APP processing through activation of the MAPK/ERK or PKC pathways, while simultaneously promoting Aβ clearance in several ways, such as stimulating microglial phagocytosis and degradation as well as regulating levels of major enzymes involved in Aβ degradation.