INTRODUCTION:

Steroid hormones are crucial substances for the proper function of the body. They mediate a wide variety of vital physiological functions ranging from anti-inflammatory agents to regulating events during pregnancy. They are synthesized and secreted into the bloodstream by endocrine glands such as the adrenal cortex and the gonads (ovary and testis). Steroid hormones are all characterized by the steroid nucleus which is composed of three six member rings and one five member ring, ingeniously labeled A, B, C, and D respectively. The steroid nucleus (Figure1) has the following Structure: and is known as cyclopentanophenanthrene^1-2.

Figure1: Steroid nucleus (cyclopentanophenanthrene)

This structure, which has six asymmetric cartoons, provides many possible stereo isomers, which one would expect since steroid hormones have an array of functions. Furthermore at C-17, there is a substituent which varies from hormone to hormone, depending on its function. In discussing steroid hormones one is compelled to discuss cholesterol since it is the precursor for steroid hormones, as well as, bile acids and provitamin D. Cholesterol is a sterol which is a natural product derived from the steroid nucleus. Besides being the building block for steroid hormones, cholesterol is also a component of the cell membrane. It is thought that the cholesterol present in the cell membrane is responsible for allowing steroid hormones to enter the cell, bind to the hormone receptor, and ultimately to a specific site on the chromatin, in turn activating the gene in question^1,3.

Steroid Nomenclature:

In humans, all steroid hormones are derived from cholesterol. Cholesterol is in turn synthesized de novo from acetate (~90%) or obtained from the diet (~10%). Cholesterol is mainly produced and stored in the liver, and is transported to the cells in the form of high density lipoprotein (HDL) and low density lipoprotein (LDL). In normal individuals, both the synthesis of cholesterol and its uptake into the target cells are tightly regulated. Figure 2 shows the structure of cholesterol. The carbons are numbered according to the convention used for steroid nomenclature. The rings are assigned letters from left to right for reference in discussion of the steroid backbone⁴.

Figure 2: Structure of Cholesterol

Cholesterol is a hydrophobic molecule; in fact, it is essentially insoluble in water. In the body, the majority of the cholesterol is associated with cell membranes, where it has an important role in maintaining membrane fluidity. During transport (in HDL and LDL) and storage (in intracellular lipid droplets), however, the 3 position hydroxyl is modified to increase the hydrophobicity of the molecule still further, by esterification with a fatty acid (Figure 3).

Figure 3: A cholesteryl ester

As we will see in greater detail in the next chapter, all steroid hormones are derived from cholesterol. The production of the hormones involves a number of precise modifications to the cholesterol structure, with different series of modifications occurring in different pathways. These modifications include attack at the 11, 16, 17, 18, 19, 20, and 21 positions, conversion of the 3-hydroxyl to a ketone, and isomerization of the 5-6 double bond to the 4-5 position (Figure 4). A number of additional modifications, not shown here, occur during conversion of the steroid hormones to inactive metabolites. Each set of alterations to the steroid backbone alters the affinity of the steroid for a given steroid receptor^4,5.

Figure 4: Locations of attacks on the cholesterol backbone during conversion to steroid hormones

In organic chemistry, sites of unsaturation (i.e. double bonds) are often referred to using the Greek letter ∆. Thus, steroids containing the 5-6 double bonds, such as cholesterol, are designated ∆5 steroids; those with 4-5 double bonds are called ∆4 steroids⁶.

Vitamin D3 and its metabolites are also derived from cholesterol. The numbering used for the metabolites of Vitamin D is the same as that used for all of the other cholesterol metabolites; however, some aspects of the nomenclature can be somewhat confusing because during the synthesis of Vitamin D₃ the 9-10 bond of the B-ring is cleaved and the A-ring is flipped around the 6-7 bond. The active derivative of Vitamin D₃, 1α, 25-dihydroxy-Vitamin D₃, is produced by successive hydroxylation at the 25 and 1 position.

Fig. 2-4 are representations of the steroid backbone that ignore most of the stereochemistry. Figure 5 shows cholesterol with a little more attention to the stereo chemical details. For our purposes, this representation contains more detail than we are usually going to need, but it does illustrate a few important points. The 3-hydroxyl, the 18- and 19-methyl groups and the side-chain attached to the 17-carbon all project above the plane of the fused ring system. Substituent located above the ring plane are denoted b. Substituent located below the ring plane (such as the hydrogen shown in Fig. 5 at the 3 and 17 positions) are denoted a. The difference between α and β is often the difference between an active and an inactive compound^5-7.

Figure 5: Stereochemical projection of cholesterol

The names we will use for the biologically relevant steroids imply the correct stereochemistry unless specifically noted otherwise (e.g. in order to be cholesterol the steroid must have a 3β-hydroxyl and the branched 8-carbon side-chain at the 17β position). However, there is a chemical nomenclature for each steroid that uniquely denotes the structure for that compound. This nomenclature is based on describing the modifications to one of four possible backbones (Figure 6).

Figure 6: The basic backbone structures of the physiological steroids

All physiological steroids are derivatives of one of these four backbone structures. The differences among these basic structures are relatively minor. The differences between cholestane (which has 27 carbons), pregnane (which has 21 carbons), and androstane (which has 19 carbons) are limited to the length of the side-chain at the 17β position. Estrane differs from androstane in that it lacks the 19 methyl group. To generate the names of the actual compounds, it is simply necessary to decide which backbone is correct, and then make a note of the modifications. For example the chemical name of cholesterol is 5-cholestene-3b-ol^6-8. In other words it is a C27 steroid (cholestane) with a 5-6 double bond (5-cholestene), and a 3β-hydroxyl (3β-ol). This same nomenclature is used for all physiological steroids. Further examples of this nomenclature are given in Table I.

Table 1: Steroid Nomenclature Examples

Backbone	Trivial Name	Chemical Name
Cholestane	Cholesterol	5-cholestene-3β-ol
Pregnane	Cortisol Aldosterone Progesterone	4-pregnene-11β,17α,21-triol-3,20-dione 4-pregnene-11β,21-diol-3,18,20-trione 4-pregnene-3,20-dione
Androstane	Pregnenolone Androstenedione Testosterone DHEA	5-pregnene-3β-ol-20-one 4-androstene-3,17-dione 4-androstene-17β-ol-3-one 5-androstene-3β-ol-17-one
Estrane	Dihydrotestosterone Estradiol Estrone Estrone	androstane-17β-ol-3-one 1,3,5(10)-estratrien-3,17β-diol 1,3,5(10)-estratrien-3-ol-17-one 1,3,5(10)-estratrien-3,16α,17β-triol

The major classes of Steroid Hormones:

In human endocrine physiology, there are three major classes of steroid hormones: glucocorticoids, mineralocorticoids, and the sex steroids^6,7,9. The following discussion is intended only to point out a few of the structural differences among these types; the functions of some of these steroids (glucocorticoids and mineralocorticoids) are discussed in more detail in later chapters.

1) Glucocorticoids⁷: Steroid hormones that affect energy metabolism (among a large variety of other actions). The primary glucocorticoid in humans is cortisol (Figure 7). Cortisol is a 21-carbon steroid, a pregnane. The modifications shown in Figure 7 are all required for activity. For example, conversion of the 11β-hydroxyl to a ketone yields cortisone, an inactive metabolite of cortisol. The steroid that lacks the 17α-hydroxyl, corticosterone, has 70% lower glucocorticoid activity in humans, although it is the major glucocorticoid in rats.

Figure 7: The structures of the primary human glucocorticoid steroid hormone, cortisol (4-pregnene-11β,17α,21-triol-3,20-dione), and of the primary human mineralocorticoid, aldosterone (4-pregnene-11β,21-diol-3,18,20-trione)

2) Mineralocorticoids⁸: Steroid hormones that affect electrolyte balance. The primary human mineralocorticoid, aldosterone, is also shown in Figure 7. Note that it is structurally very similar to cortisol, except that it lacks the 17a-hydroxyl group, and has an aldehyde at the 18-methyl. The 18-aldehyde is critical for mineralocorticoid activity; the sole difference between corticosterone and aldosterone is the 18-aldehyde, but aldosterone has 200 times higher mineralocorticoid activity than corticosterone.

3) Sex steroids⁹: Steroid hormones that affect sexual development and reproductive functioning. There are three types of sex steroids in humans: progestins, androgens, and estrogens. Representative structures of these hormones are shown in Figure 8. The human progestin is progesterone, which is a 21-carbon (pregnane) 3-keto ∆4 steroid like cortisol and aldosterone. In addition to its hormonal function, progesterone is also a precursor to the other hormonal steroids, and therefore it has fewer modifications from the basic steroid backbone.

Figure 8: The structures of the sex steroids: the progestin progesterone (4-pregnene- 3, 20-dione), the androgen testosterone (4-androstene-17β-ol-3-one), and the estrogen estradiol (1, 3, and 5(10)-estratriene-3,17β-diol)

Humans use several androgens; the structure shown is that of testosterone. Testosterone, like progesterone, aldosterone, and cortisol, is a ∆4 steroid. However, it lacks the 2-carbon side-chain attached to the 17 position, making it a 19-carbon steroid (androstane). The side-chain has been replaced by a 17β-hydroxyl. The stereochemistry at this position has important consequences for receptor binding: the 17-ketosteroid, androstenedione, has a much lower affinity for the receptor, and epitestosterone (17α-hydroxy-testosterone) is inactive¹⁰.

The estrogens are unique among the steroid hormones in that they have an aromatic A-ring (i.e. the phenol-like structure). This requires the loss of the 19-methyl; thus estrogens are 18-carbon (estrane) steroids. The nomenclature for estradiol, the most potent human estrogen is also shown in Figure 8. The aromatic ring has three double bonds (estratriene). By convention, the double bond positions are given using only the lower numbered carbon, with the assumption that the bond goes from there to the next higher numbered carbon. However, this is not the case for one of the double bonds in estradiol, which goes from the 5 to the 10 carbon, hence the “5(10)” in the name. As with testosterone, the 17-ketosteroid, estrone, has a much lower affinity for the receptor, and 17α-hydroxy-estradiol is inactive^9-10.

Steroid Hormone mechanism of action:

Steroids, like all hormones, act to transmit information. However, the information being transmitted is not contained within the actual hormone molecule; instead, the hormone acts as a signal to activate (or deactivate) cellular processes. The precise nature of these processes depends on the cell type¹¹.

A great deal has been learned about steroid hormone action recently as a result of improved techniques. All of the well characterized steroid hormone receptors are intracellular proteins. The following general description of steroid hormone action via these intracellular receptors is illustrated in Figure 9. The steroid hormone enters the cell, probably by passive diffusion, and binds the receptor. The binding of hormone triggers a hormone-dependent activation of the receptor (a conformational change, and possibly phosphorylation). The activated receptor interacts with DNA and with other nuclear proteins, resulting in a change in the rate of mRNA transcription. The mRNA is then translated into new proteins which either have direct effects or return to the nucleus to alter the rate of transcription of other genes; in combination, these changes yield the biological effects associated with the steroid hormone^11-13.

In Figure 9 the unoccupied receptor is shown as being located both in the cytoplasm and in the nucleus. Most of the available evidence suggests that the receptors are predominantly present within the nucleus in both the presence and absence of hormone. The older model, in which the binding of hormone was thought to result in a translocation of the receptor from the cytoplasm to the nucleus, is probably incorrect, at least for the majority of the receptor types. However, due to the conflicting data concerning this issue, I have presented both models in this drawing. The steroid hormone receptors are generally present in small quantities (a few hundred to a few thousand molecules per cell). They have high affinity for their ligands (dissociation constant usually less than 1 nanomolar). They function as ligand activated transcription factors, specifically activating a small number of genes (less than 50, and possibly less than 10 genes per cell).

Regulation / Control:

The production and secretion of steroid hormones are controlled by trophic hormones, which themselves are either proteins or peptides. For example, the target-organ steroid, cortisol, secreted by the adrenal is released by the action of the tropic peptide hormones work indirectly by stimulating other organs or, in this case, glands^14,15.

Studies have shown that dietary cholesterol (polyunsaturated fatty acids) suppresses synthesis of cholesterol: Two mechanisms exist. 1. Synthesis of enzymes is inhibited at transcription level. This makes sense since this conserves energy by stopping the production of synthesis at the start and not by going through useless processes that would waste energy. 2. Activity of the enzyme is modulated through a mechanism involving cyclic phosphorylation and dephosphorylation of the reductase protein (enzyme) itself. A level of steroid hormones present at any given time is regulated by its rate of synthesis, which is ultimately controlled by brain signals¹⁵.

Estrogene and testosterone are very useful steroid hormones; however, excessive amounts of both can have serious effects. For example; we are aware that estrogen regulates female characteristics just as testosterone does for males. However, estrogen is also a crucial risk factor in breast cancer. There is a component known as indole-3-carbinol (I3C) that regulates the production of the malignant estrogen by altering the process by which the body synthesizes this. I3C causes the body to produce the benign byproduct instead of the highly estrogenic and potentially carcinogenic one. I3C is found in cabbage and broccoli, so better eat your vegetables¹³.

Circulating testosterone is not beneficial and needs to be controlled; it can cause prostate cancer. This problem has been treated with a luteinizing hormone (LHRH) against it, however, this has not been proven completely effective since the adrenals also produce testosterone to a certain extent. Therefore, the concept of total androgen ablation or maximum androgen blocked has been created. This concept combines LHRH against an anti-androgen (such as glutamine) to suppress production of residual testosterone. This process works by antagonizing the androgen receptor in the hypothalamus, preventing it from binding to the androgen steroid hormone and producing stimulating production of testosterone¹⁴.

Other processes exist to inhibit production of certain steroid hormones. Inhibition of enzymes of androgen biosynthesis [e.g. Ketoconazole (a drug) suppresses synthesis of testosterone by inhibiting the enzyme, 17 (α- hydroxylase Lyase). 5 (α)-dihydrotesterone main androgen causing prostate cancer, its derived from testosterone by testosterone-5 (α)-reductase. Inhibitors (flutamide, cypoterone aceterte, or rilutamide are known as anti-androgens) of this enzyme could prove essential in treating this disease¹⁵.

FUNCTION / ROLE:

While all steroids contain the four-ring structure of the sterol nucleus and are remarkably similar in structure, they have enormous differences in their physiological effects. In vertebrates, steroid hormones function as genetic regulators, controlling the rate of synthesis of a particular protein. Steroid hormones are crucial for many enzymatic reactions; the glucocorticoids trigger a variety of cellular responses including the synthesis of second messengers such as cAMP in the short term and the modulation of protein synthesis in the long term. On the molecular level, the enzymatic reaction rates are controlled by phosphorylation and dephosphorylation by increasing the reaction cascades. The administration of estrogens (female sex hormone) such as B- estradiol causes chicken oviducts to increase their ovalbumin mRNA level from ~ 10 to ~ 50,000 molecules per cell. Similarly in insects, the steroid hormone ecdysone mediates several aspects of larval development^14,15.

Steroid hormones, which are non-polar molecules, simply pass through the plasma membranes of their target cell to the cytosol where they bind to their respective receptors. The steroid hormone penetrates the cell membrane and moves through the cytoplasm to the nucleus; it then couples with the receptor protein, forming a hormone receptor complex.

The steroid receptor complexes, in turn enter the nucleus where they bind to specific chromosomal enhancers so they can induce or repress, the transcription of their associated gene. The action of eukaryotic steroid receptors therefore appears to resemble that of transcriptional regulators such as E. coli complex^15,16.

For instance, different cell types may have the same receptor for a given steroid hormone and yet synthesize different proteins in response to the hormone. Only some genes are made available for activation by that steroid.

The following steroid hormones (glucocorticoids, mineralocorticoids, estrogens, androgens, progestines, and vitamin D) will be defined according to their origin and their major effects^{8, 9, 15, 16}.

Glucocorticoids: Glucocorticoids originate in the adrenal cortex and affect mainly metabolism in diverse ways; decrease inflammation and increase resistance to stress.

Mineralocorticoids: Mineralocorticoids originate in adrenal cortex and maintain salt and water balance.

Estrogens: Estrogens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (female sexual determination).

Androgens: Androgens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (male sexual determination).

Progestins: Progestin originate from both ovaries and placenta, and mediate menstrual cycle and maintain pregnancy.

Androgens and estrogens play a major role in the development of both sexes secondary characteristics. Androgens, or testosterone and androsterone give the male its sex characteristics during puberty and for promoting tissue and muscle growth. Estrogens, or estrone and estradiol are forms of testosterone synthesized in the ovaries, which control female secondary characteristics and regulation of the menstrual cycle. Another sex hormone is needed for preparing the uterus for implantation of the ovum, this hormone is progesterone.

Hormones are needed throughout the body for various functions, however, just as important as these functions are the regulation and control of these steroids.

CONCLUSION:

It discussing steroid hormones, one is required to talk about cholesterol; cholesterol is known as a sterol, which is a natural product from the steroid nucleus. Cholesterol is very important, as we learned, in the production of steroid hormones; in fact they are the precursor for bile acids (bile acids aid in fat digestion), steroid hormones, and provitamin D (When irradiated by sunlight it changes to vitamin D3.

Cholesterol, if we recall, is incorporated into the cell membrane by lipoproteins. There it plays a role in the regulation of membrane fluidity. It has been stated that cholesterol is probably responsible for permitting steroid hormones to enter the cell ¹⁶.

ACKNOWLEDGEMENTS:

Author has grateful to SRMS, CET Management for encouragement. Special thanks are due to Professor M.D. Kharya for his helpful comments.

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Received on 16.09.2014 Modified on 01.10.2014

Asian J. Research Chem. 7(11): November, 2014; Page 964-969