The Multiple Roles of Estrogens and the Enzyme Aromatase

doi:10.1016/S0079-6123(08)81012-6

Progress in Brain Research

Volume 181, 2010, Pages 209-232

https://doi.org/10.1016/S0079-6123(08)81012-6 Get rights and content

Abstract

Aromatase is the enzyme that catalyzes the last step of estrogen biosynthesis. It is expressed in many tissues such as the gonads, brain and adipose tissue. The regulation of the level and activity of aromatase determines the levels of estrogens that have endocrine, paracrine and autocrine effects on tissues. Estrogens play many roles in the body, regulating reproduction, metabolism and behavior. In the brain, cell survival and the activity of neurons are affected by estrogens and hence aromatase.

Section snippets

Aromatase

Aromatase cytochrome P450 is the enzyme that catalyzes the last step of estrogen biosynthesis (Fig. 1), that is, the rate-limiting irreversible aromatization of androgens to estrogens. Although actions of estrogens (uterine and vaginal tissue changes during menstrual cycles in guinea pigs) were first described in 1917 (Stockard and Papanicolaou, 1917) and the responsible steroids estrone and 17β-estradiol were purified from urine of pregnant women in the next decades (Allen and Doisy, 1983), it

Aromatization

Aromatase belongs to the cytochrome P450 superfamily and thus it is a haem-binding protein (see review by Conley and Hinshelwood, 2001). It is localized at microsomal organelles of estrogen-producing cells. It has a high substrate (androgens) specificity that is conferred by the hydrophobic and polar residues lining the androstenedione cleft, which complements the steroid backbone. To catalyze the conversion of androgens to estrogens, aromatase forms a complex with NADPH-cytochrome P450

Peripheral tissues

Aromatase expression in pre-menopausal women is found in granulosa cells (the major site of expression) and the corpus luteum of the ovary (McNatty et al., 1976). It is also detected in human testicular Leydig and Sertoli cells (Brodie and Inkster, 1993), the epididymis (Carpino et al., 2004), germ cells (Lambard et al., 2004), syncytotrophoblasts of the placenta (Kilgore et al., 1992) and numerous foetal tissues (Price et al., 1992, Toda et al., 1994). Extragonadal tissues expressing aromatase

Cyp19 (aromatase) gene expression regulation

Aromatase is encoded by the Cyp19 gene. More than one copy of the Cyp19 gene has been isolated in fish (gonadal cyp19a1 and brain cyp19a2; Kazeto et al., 2001) and boar (cyp19a1, cyp19a2, cyp19a3; Corbin et al., 2009). It had been hypothesized that multiple isoforms of aromatase may exist in the human body (Osawa et al., 1987). However, from restriction mapping and genomic Southern analyses, Means et al. (1989) demonstrated that there is no evidence for more than one isoform of aromatase

Regulation of aromatase activity

The activity of aromatase activity has been shown to be regulated by phosphorylation. The first evidence came from the quail preoptic–hypothalamic homogenate – 15 minute preincubation with 1 mM ATP and 5 mM MgCl₂ (a limiting factor for kinases) reduced the aromatase activity significantly down to 16.9% of that of controls (Balthazart, Baillien, & Ball, 2001c). Incidently, the inhibition by ATP/Mg²⁺ could be blocked by 10 μM staurosporine (a general serine/threonine kinase inhibitor) or 10 μM

Multiple roles of aromatase

The multiple roles of aromatase were uncovered by studying models of aromatase deficiency – both human and mice.

Physiological effects of estrogen

Estrogen is considered to be the female steroid also because of its traditional role in the female reproductive system. But today, estrogen is implicated in a far wider range of actions including metabolic regulation, and neurological and behavioral effects in both male and female.

Effects of aromatase in the brain

In the 1970s, it was first demonstrated that estrogens could be produced in the brain by the local aromatization of testosterone (Naftolin et al., 1975). Research in this area has been gaining momentum and evidence is mounting to show that locally synthesized estrogens from pregnenolone (Hojo et al., 2004) could modulate neuronal functions in addition to their neuroprotective effects.

Conclusion

Estrogens play multiple roles in regulating physiological functions. Mounting evidence has been gathered to support that estrogens act in paracrine or autocrine manners in the brain to regulate neuronal survival and brain functions. This is possible due to the expression of aromatase in specific brain regions/nuclei and cell populations. Since aromatase expression levels are highly regulated at the genomic levels and the aromatase activity are regulated by phosphorylations, the levels of brain

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Many chemicals spilled in aquatic ecosystems can interfere with cognitive abilities and brain functions that control fitness-related behaviour. Hence, their harmful potential may be substantially underestimated. Triclocarban (TCC), one of the most common aquatic contaminants, is known to disrupt hormonal activity, but the consequences of this action on behaviour and its underlying cognitive mechanisms are unclear. We tried to fill this knowledge gap by analysing behaviour, cognitive abilities, and brain gene expression in zebrafish larvae exposed to TCC sublethal concentrations. TCC exposure substantially decreased exploratory behaviour and response to stimulation, while it increased sociability. Additionally, TCC reduced the cognitive performance of zebrafish in a habituation learning task. In the brain of TCC-exposed zebrafish, we found upregulation of c-fos, a gene involved in neural activity, and downregulation of bdnf, a gene that influences behavioural and cognitive traits such as activity, learning, and memory. Overall, our experiments highlight consistent effects of non-lethal TCC concentrations on behaviour, cognitive abilities, and brain functioning in a teleost fish, suggesting critical fitness consequences of these compounds in aquatic ecosystems as well as the potential to affect human health.
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Chapter 12 - The Multiple Roles of Estrogens and the Enzyme Aromatase

Abstract

Section snippets

Aromatase

Aromatization

Peripheral tissues

Cyp19 (aromatase) gene expression regulation

Regulation of aromatase activity

Multiple roles of aromatase

Physiological effects of estrogen

Effects of aromatase in the brain

Conclusion

Experimental Neurology

Hormones and Behavior

The Journal of Steroid Biochemistry and Molecular Biology

The Journal of Steroid Biochemistry and Molecular Biology

Trends in Neurosciences

The Journal of Steroid Biochemistry and Molecular Biology

Brain Research. Molecular Brain Research

Neurobiology of Aging

The Journal of Steroid Biochemistry and Molecular Biology

The Journal of Steroid Biochemistry and Molecular Biology

The Journal of Steroid Biochemistry and Molecular Biology

The Journal of Steroid Biochemistry and Molecular Biology

The Journal of Steroid Biochemistry and Molecular Biology

Atherosclerosis

Behavioural Brain Research

Brain Research

Neuroscience

Molecular and Cellular Endocrinology

Biochemical and Biophysical Research Communications

Molecular and Cellular Neuroscience

Mol Cellular Neurosci

Biological Psychiatry

Molecular and Cellular Neuroscience

Molecular and Cellular Neuroscience

Biochemical and Biophysical Research Communications

Biochemical and Biophysical Research Communications

Biochimica et Biophysica Acta

The Journal of Steroid Biochemistry and Molecular Biology

Bone

The Journal of Steroid Biochemistry and Molecular Biology

Experimental Neurology

Neurobiology of Aging

Biochemical and Biophysical Research Communications

Molecular and Cellular Endocrinology

Biochimica et Biophysica Acta

Bone

The Journal of Steroid Biochemistry and Molecular Biology

The American Journal of Pathology

Brain Research. Brain Research Reviews

Brain Research. Brain Research Reviews

International Immunopharmacology

Androgens regulate aromatase cytochrome P450 messenger ribonucleic acid in rat brain

Endocrinology

Neurotransmitter-mediated regulation of brain aromatase: Protein kinase C- and G-dependent induction

Journal of Neurochemistry

Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the akt/protein kinase B pathway

Journal of Neuroscience

Landmark article Sept 8, 1923. An ovarian hormone. Preliminary report on its localization, extraction and partial purification, and action in test animals. By Edgar Allen and Edward A. Doisy

JAMA

Localization of estrogen receptor beta-immunoreactivity in astrocytes of the adult rat brain

Glia

Brain aromatase is neuroprotective

Journal of Neurobiology

The aromatase knock-out mouse provides new evidence that estradiol is required during development in the female for the expression of sociosexual behaviors in adulthood

Journal of Neuroscience

Rapid and reversible inhibition of brain aromatase activity

Journal of Neuroendocrinology

Identification and developmental changes of aromatase and estrogen receptor expression in prepubertal and pubertal human adrenal tissues

Journal of Clinical Endocrinology and Metabolism