Steroid hormones

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[[Category:Sterols (ST)]] [[Category:Lipid signalling]]
[[Category:Sterols (ST)]] [[Category:Lipid signalling]]

Revision as of 10:38, 2 November 2006

Cholesterol serves as a precursor steroid hormones that are synthesized in steroidogenic cells of the adrenals, gonads, placenta and brain and are essential for normal reproductive function and body homeostasis. In brain, steroid hormones regulate neuronal survival and differentiation, myelination, neurogenesis, plasticity and repair after injury (Sierra, 2004). There are several classes of steroid hormones and steroid hormone receptors. In the kidney mineralocorticoids mediate water and salt metabolism and regulate blood pressure. Glucocorticoids regulate stress and immune responses. Sex steroids: progestins, estrogens and androgens are involved in sex differentiation and reproduction. Steroidogenic cells do not store significant quantities of steroid hormones; hence steroid secretion is directly related to steroid synthesis. Steroid synthesis is regulated both acutely and chronically.

Steroid hormone biosynthesis in the adrenal cortex (Lisurek and Bernhardt 2004)
Steroid hormone biosynthesis in the adrenal cortex (Lisurek and Bernhardt 2004)

The first, rate-limiting and hormonally regulated step in the biosynthesis of all steroid hormones is the conversion of cholesterol to pregnenolone (Fig. 44) within the inner mitochondrial membrane by cytochrome P450scc (CYP11A1). The P450scc-linked monooxygenase system is located on the matrix side of the inner mitochondrial membrane. Various pathways regulate the level of P450scc and the amount of P450scc mRNA is correlated with steroid hormone production (DiBlasio et al. 1987). P450scc can function only within mitochondria (Black et al. 1994). The transfer of cholesterol to P450scc requires hormonal activation of cholesterol mobilization to the mitochondria. Transport of cholesterol from the outer to the inner mitochondrial membrane is the rate-limiting step in steroidogenesis, and the steroidogenic acute regulatory protein (StAR) has been demonstrated to mediate this process in steroidogenic cells (Stocco, 2001). Delivery of cholesterol to P450scc requires de novo synthesis of the protein (Kim et al. 2004). StAR was identified as a 30 kDa phosphoprotein associated with mitochondria (Kruger et al.1983) and it has been soon discovered that mutations in the StAR gene leads to congenital lipoid adrenal hyperplasia, a disease that is characterised by almost complete lack of steroid hormone synthesis (Lin et al 1995). The peripheral benzodiazepine receptor (PBR), located in the outer mitochondrial membranes, is another protein that allows cholesterol to cross the mitochondrial membrane in steroidogenesis (Lavaque et al. 2006). PBR is closely associated to StAR and it has been suggested it may function as a channel for cholesterol in steroid hormones synthesis (Papadopoulos 2004).

Steroid hormone synthesis & metabolism in testis, prostate and liver (Platz and Giovannucci 2004)
Steroid hormone synthesis & metabolism in testis, prostate and liver (Platz and Giovannucci 2004)


P450scc catalyses three reactions of 20-, 22-hydroxylation of cholesterol and scission of 20,22 carbon-carbon bond that result in formation of pregnenolone and isocaproaldehyde. Pregnenolone is a subject for P450c17 enzyme, that determines which class of steroids, will be produced and directs pregnenolone towards its final metabolic pathway. P450c17 resides in endoplasmic reticulum (Miller 2005). Pregnenolone undergoes 17α-hydroxylation by P450c17 to yield 17-OH pregnenolone and subsequently 17-OH pregnenolone is converted to dehydroepiandrosterone (DHEA) by the 17,20 lyase activity of P450c17 (Auchus 2004). As for other steroid hormones, the synthesis of sex steroids from cholesterol requires trafficking between mitochondria and smooth endoplasmic reticulum, which involves many enzymatic steps, where most of these steps use cytochrome P450 haem-containing enzymes. The enzymes modulating sex steroid metabolism and, consequently, the concentration of active steroids in peripheral tissues include steroid sulphatases, 3ß-hydroxysteroid dehydrogenases (3ß-HSDs), 3α-hydroxysteroid dehydrogenases (3α-HSDs), aromatase, 17ß-hydroxysteroid dehydrogenases (17HSDs) and 5α-reductases. There are two known isoforms of 3ß-HSD, type 1 being found in the placenta, skin, mammary gland, prostate and endometrium, and type 2 in the adrenals and gonads This particular enzyme is not a P450 enzyme but converts pregnenolone to progesterone and dehydroepiandrosterone (DHEA) to androstenedione. 17ß-HSDs are a relatively large family of steroidogenic enzymes of which types 1, 3, 5 and 7 catalyse a reductive reaction, generally converting biologically weaker steroids into more biologically active steroids. Types 2, 4, 6 and 8 are oxidative enzymes and convert more active steroids into less biologically active steroids. 17ß-HSD type 1 converts estrone to the more potent 17b-estradiol, whilst type 5 converts androstenedione to testosterone and DHEA to androstenediol. The latter can also catalyse 5a-ihydrotestosterone/androstanedione and androstenediol/androsterone interconversion. Sulphotransferases (mainly SULT1E1) and steroid sulphatase interconvert active estrone and DHEA into inactive estrogen and androgen sulphates. Although these enzymes are expressed in classical steroidogenic organs such as the gonads and adrenal gland, they are also expressed in a large number of other tissues, including brain, liver, reproductive tracts, and adipose tissue, skin and breast tissue. However peripheral tissues are not able to synthesise sex hormones de novo, a variety of tissues can convert relatively inactive circulating steroid precursors into biologically active steroids. Locally produced steroids exert their effects in an intracrine manner in the same cell where they were generated and without diffusion into circulation they regulate target genes (Vihko et al 2006). Estrogens are key regulators of growth, differentiation, and the physiological functions of a wide range of target tissues, including the male and female reproductive tracts, breast, and skeletal, nervous, cardiovascular, digestive and immune systems. The majority of these biological activities of estrogens are mediated through two genetically distinct receptors, ER alpha and ER beta, which belong to the nuclear hormone receptor superfamily and act as ligand-inducible transcription factors (Gustafsson 1999). Additionally, estrogen receptors have been identified as key mediators in breast cancer, osteoporosis and coronary heart disease (Knox et al 2006). In a classical mechanism of estrogen action, estrogens diffuse into the cell and binds with in the nucleus located estrogen receptor. The estrogen-ER complex binds to estrogen response element sequences through protein-protein interactions with activator protein 1 (AP1) or SP1 sites in the promoter region of estrogen-responsive genes, resulting in recruitment of coregulatory proteins to the promoter, increased or decreased mRNA levels and associated protein production, and finally a physiological response. This classical, or “genomic,” mechanism typically occurs over the course of hours. Additionally, estrogen can act more quickly (within seconds or minutes) via “nongenomic” mechanisms, resulting in cellular responses such as increased levels of Ca2+ or NO, and activation of kinases. The ER may be targeted to the plasma membrane by adaptor proteins such as caveolin-1 or Shc (Deroo et al 2006). The family of estrogen receptor-related receptors (ERR alpha, ERR beta, ERR gamma) is a subfamily of the orphan nuclear receptors, which is closely related to the estrogen receptor (ER) family. Research on ERRs has shown that the ERR family shares target genes, co-regulators and promoters with the ER family. ERRs bind and regulate transcription via estrogen response elements (EREs) and extended ERE half-sites termed ERR response elements (ERREs), but do not bind endogenous estrogens (Sun et al 2006). Androgens (testosterone), acting via the androgen receptor (AR) regulate male sexual development and body composition. The expression of androgen receptor (AR) is implicated in regulation of cellular events in advanced prostate cancer (Heinlein et al 2004). AR is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver and central nervous system (CNS), with the highest expression level observed in the prostate, adrenal gland, and epididymis. Androgen receptor belongs to the class I subgroup of the nuclear receptors superfamily. Upon binding with androgen, cytoplasmatically located androgen receptor translocates to the nucleus. Unbound to ligand, AR is maintained in an inactive, but highly responsive state by a large dynamic heterocomplex composed of heat shock proteins, co-chaperones, and tetratricopeptide repeat (TPR)-containing proteins (Prescott et al 2006). Androgen receptor (AR) and estrogen receptors (ER) act as homodimers and bind hormone-responsive elements (HRE) in the DNA of a target gene.

Intracellular action of sex hormones (Federman 2006)
Intracellular action of sex hormones (Federman 2006)
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