Steroid hormones

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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.

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).


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.

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

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.


Sex hormones are integral signalling modulators of the mammalian immune system and play definitive role in the genesis of autoimmunity: lymphocyte maturation, activation, and synthesis of antibodies and cytokines (Ackerman 2006).

The action of progesterone, a hormone regulating female reproduction, is mediated through binding to progesterone receptor (PR), which belongs to the family of ligand-activated nuclear transcription activators. The progesterone receptor exists in two isoforms: PRA and PRB, which both bind progesterone with identical affinity. Upon activation progesterone binds to its receptor, and resulting conformational changes lead the complex to the progesterone-responsive element in the DNA of the promoter of the target gene. Additionally, there are evidences that rapid effects of progesterone on spermatozoa, hepatocytes and on some specific brain areas are not mediated by PR but by binding sites in the membranes or on the membranes of these cells (Lösell et al 2003). This is so-called nongenomic action and it requires a shorter time frame to occur. Furthermore, several progesterone metabolites, which are unable to bind to the PR, are capable of inducing biological effects mediated by other receptors located in the membranes of cells. In the human uterus, the major action of progesterone seems to be mediated mainly by so-called “classic” receptors.

Mechanism of GR action (Herold et al 2006)
Mechanism of GR action (Herold et al 2006)

Glucocorticoids (GCs) are a class of steroid hormones, which regulate a variety of essential biological functions. They exert anti-inflammatory and immunosuppressive activity, induce lymphocyte apoptosis. Endogenous GCs also exert a wide range of immunomodulatory activities, including the control of T cell homeostasis. Glucocorticoids switch-off expression of multiple inflammatory genes encoding cytokines, chemokines, adhesion molecules, receptors and proteins that are activated in inflammatory processes. Additionally, they stimulate synthesis of anti-inflammatory proteins (Barnes 2006). Glucocorticoids exert their effects by binding to a ubiquitously expressed glucocorticoid receptor (GR) that is localized to the cytoplasm of target cells. GR is a modular transcription factor in which specific domains play selective roles. Unliganded GR is bound in cytoplasm to chaperones, such as heat shock protein 90 and FK-binding protein, which play a protecting role. The glucocorticoids target genes possess glucocorticoid responsive elements (GREs). A single gene encodes glucocorticoid receptor. There are two isoforms α and ß (GRα and GRß) that are products of the same gene and comprise of eight common and ninth different exons. GRα binds to glucocorticoid-responsive elements of DNA, whereas GRß has no ligand binding activity. GRß has very low expression in comparison to GRα and was implicated in steroid resistance in asthma (Leung et al 1997).

Gene List

Steroid hormone synthesis

Short name

Chrom. Loc.

steroid hormone synthesis in testis, prostate, liver

 

 

cytochrome P450, family 11, subfamily A, polypeptide 1

CYP11A1

15q23-q24

Cytochrome P450, family 17, subfamily A, polypeptide 1

CYP17A1

10q24.3

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2

HSD3B2

01p13.1

hydroxysteroid (17-beta) dehydrogenase 3

HSD17B3

09q22

cytochrome P450, family 3, subfamily A, polypeptide 4

CYP3A4

07q21.1

cytochrome P450, family 19, subfamily A, polypeptide 1

CYP19A1

15q21.1

cytochrome P450, family 1, subfamily B, polypeptide 1

CYP1B1

02p21

cytochrome P450, family 1, subfamily A, polypeptide 1

CYP1A1

15q22-q24

steroid-5-alpha-reductase, alpha polypeptide 2

SRD5A2

02p23

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1

HSD3B1

01p13.1

steroid biosynthesis in the adrenal cortex

 

 

cytochrome P450, family 11, subfamily A, polypeptide 1

CYP11A1

15q23-q24

Cytochrome P450, family 17, subfamily A, polypeptide 1

CYP17A1

10q24.3

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1

HSD3B1

01p13.1

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2

HSD3B2

01p13.1

cytochrome P450, family 21, subfamily A, polypeptide 2

CYP21A2

06p21.3

cytochrome P450, family 11, subfamily B, polypeptide 1

CYP11B1

08q21

cytochrome P450, family 11, subfamily B, polypeptide 2

CYP11B2

08q21-q22

17ß-Hydroxysteroid dehydrogenase

 

 

hydroxysteroid (17-beta) dehydrogenase 1

HSD17B1

17q11-q21

hydroxysteroid (17-beta) dehydrogenase 3

HSD17B3

09q22

hydroxysteroid (17-beta) dehydrogenase 7

HSD17B7

01q23

3ß-Hydroxysteroid dehydrogenase

 

 

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1

HSD3B1

01p13.1

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2

HSD3B2

01p13.1

Cytochrom P450 enzymes involved in steroid hormone synthesis

 

 

cytochrome P450, family 11, subfamily A, polypeptide 1

CYP11A1

15q23-q24

cytochrome P450, family 11, subfamily B, polypeptide 1

CYP11B1

08q21

cytochrome P450, family 11, subfamily B, polypeptide 2

CYP11B2

08q21-q22

Cytochrome P450, family 17, subfamily A, polypeptide 1

CYP17A1

10q24.3

cytochrome P450, family 19, subfamily A, polypeptide 1

CYP19A1

15q21.1

cytochrome P450, family 21, subfamily A, polypeptide 2

CYP21A2

06p21.3

 

 

 

Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)

NR3C1

05q31

steroidogenic acute regulator

STAR

08p11.2

steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)

SRD5A1

05p15

aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III)

AKR1C2

10p15-p14

aldo-keto reductase family 1, member D1 (delta 4-3-ketosteroid-5-beta-reductase)

AKR1D1

07q32-q33

aldo-keto reductase family 1, member C4 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehydrogenase 4)

AKR1C4

10p15-p14

steroid sulfatase (microsomal), arylsulfatase C, isozyme S

STS

0Xp22.32

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7

HSD3B7

16p12-p11.2

hydroxysteroid (11-beta) dehydrogenase 1

HSD11B1

01q32-q41

hydroxysteroid (11-beta) dehydrogenase 2

HSD11B2

16q22

hydroxysteroid (17-beta) dehydrogenase 2

HSD17B2

16q24.1-q24.2

hydroxysteroid (17-beta) dehydrogenase 4

HSD17B4

05q21

3-hydroxysteroid epimerase

HSD17B6

12q13

hydroxysteroid (17-beta) dehydrogenase 8

HSD17B8

06p21.3

hydroxysteroid (17-beta) dehydrogenase 12

HSD17B12

11p11.2

sterol-C4-methyl oxidase-like

SC4MOL

04q32-q34

sterol-C5-desaturase (ERG3 delta-5-desaturase homolog, fungal)-like

SC5DL

11q23.3

Steroid receptors

 

 

Sex hormones receptors

 

 

androgen receptor

AR

Xq11.2-q12

estrogen receptor 1

ESR1

06q25.1

estrogen receptor 2 (ER beta)

ESR2

14q23.2

estrogen-related receptor alpha

ESRRA

11q13

Estrogen-related receptor beta

ESRRB

14q24.3

estrogen-related receptor beta like 1

ESRRBL1

03q13.12-q13.13

estrogen-related receptor gamma

ESRRG

01q41

estrogen-related receptor alpha pseudogene

ESRRAP

13q12.1

progesterone receptor membrane component 1

PGRMC1

0Xq22-q24

progesterone receptor membrane component 2

PGRMC2

04q26

Unactive progesterone receptor, 23 kD

TEBP

12q13.3

Progesterone receptor

PGR

11q22-q23

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