Structure and Synthesis of Steroids

Steroids have a variety of uses in the human body, including, but not limited to: controlling meiosis, carbohydrate metabolism, fat storage, muscle growth, immune function and nerve cell membrane chemistry. Steroids can be separated into three main groups: gonadal compounds, glucocorticoids and mineralcorticoids. This distinction depends on the site of synthesis of the steroid. The gonadal variety are mainly synthesized in the gonads, as is suggested by the name, while the glucocorticoids (eg cortisol, cortisone) and mineralcorticoids (eg aldosterone) are synthesized in the adrenal cortex.

Steroids can also be divided into groups by function: androgens, estrogens, progestogens, anabolics, and catabolics. The two main types of steroids that we will consider are anabolics and androgens. Androgens exert some kind of masculinizing physical effect on the body, while anabolics promote growth. However, these distinctions are not completely exclusive. For example, testosterone is synthesized by the adrenal cortex as well as the testes, and has both anabolic and androgenic properties.

Steroids are fat-soluble hormones with a tetracyclic base structure. The base structure consists of four fused rings: three cyclohexane rings and one cyclopentane. The basic structural backbone can be seen below:
As you can see, each of the rings is designated by a letter. Rings A and D are the most commonly modified rings. The following diagram shows the numbering of the carbons in steroids, which will be useful later in this article. The two methyl groups on C10 and C13 are also designated with numbers, as they are present in most steroids.
Steroids are synthesized in the body from squalene, a complex linear aromatic molecule shown below:

Squalene is cyclized to form cholesterol. In the first few steps of this chemical pathway, squalene is converted to squalene epoxide, which has a different double-bond bond distribution that is necessary for the ring fusion to occur. In ten complex steps of cyclization and carbocation, squalene epoxide is converted to Lanosterol. This reaction is catalyzed by the enzyme cyclase. The lanosterol is then downgraded, with three methyl groups being removed, and cholesterol is formed. This process of the cyclization of squalene is considered to be one of the most fascinating and complex reactions in organic chemistry.

Steroids are all cholesterol derivatives. Cholesterol is hydroxylated and modified by the enzyme cytochrome P-450 (removing the 6-carbon side chain at position C21) into Pregnenolone. This is a hormone secreted in the uterus controlling ovum implantation, and is the precursor for the androgens, estrogens, and glucocorticoids.

At the cellular and molecular level, all of the steroids function in a very similar way. Because they are fat-soluble, they can easily diffuse across the cell membrane into the cytoplasm. Once in the cytoplasm, the steroids bind to receptors, which are composed of proteins. This forms what is known as a steroid-receptor complex. The complexes then undergo dimerization, where two complexes bind together to form a dimer. The dimer will then travel to the nucleus of the cell and bind to DNA, where it promotes gene transcription and translation, leading to the production of proteins (protein synthesis).

This process is shown in the diagram below. The effects of a steroid on gene expression and protein production are very complicated and difficult to understand. Often, the protein that is produced as a result of the dimer binding to the DNA is a regulatory protein, which is responsible for activating or suppressing other genes. This causes somewhat of a chain reaction. Also, the effect a steroid has on genes is determined by the type of cell in which it is present. For these reasons, the actual effects of steroids on gene expression will not be examined in this article.

Structure of Specific Steroids and Reactions They Undergo:
All molecules are actually 3-dimensional, but are represented in 2-D. The functional groups and side chains attached to the backbone are actually extending perpendicular to the flat backbone, not straight out, as is shown in the figures. The bold triangles show that the group is extending up from the backbone, while a series of dashes indicate it is extending down from the chain. When two groups are both extending in the same direction, they are said to be cis to each other. If they extend in opposite directions relative to the backbone, they are said to be trans. It should also be noted that all carbon atoms should have a total of four bonds. Where there are fewer than four bonds shown, assume hydrogen atoms are attached to make four.

The first steroid we will look at is testosterone, an androgenic steroid produced mainly in the gonads, and to a smaller extent, in the adrenal cortex. Testosterone has one of the simpler structures of all the steroid molecules:
The only differences between Testosterone and Pregnenolone is that in testosterone, the 2-carbonylethyl group attached to the C17 has been replaced by a hydroxyl group, and the Hydroxyl on C3 has been replaced by a carbonyl (double-bonded oxygen). It should be noted that the 4-ring backbone of testosterone, and all other steroids, is not flat. Instead, all the rings are slightly contorted to minimize interactions between atoms and to achieve the ideal bond angle of 109.5°. Because of this contortion, the molecule is not planar. That is, it does not lie in one linear plane. If you were to view a steroid molecule from the side, you would not see all the atoms in a straight line, like a sheet of paper. Instead, some of the rings might be v-shaped, while others are shaped similar to a chair. A more complex view of Testosterone, which shows this contortion, can be seen below.
The two previous diagrams are the structures for basic testosterone. However, sometimes other side-chains of atoms can be added, forming such compounds as Testosterone cypionate, Testosterone enanthate, and Testosterone propionate. These side chains are known as esters, are usually composed of C, H and O, and control the rate at which the steroid is released into the bloodstream. Larger esters are released into the bloodstream more slowly, as the ester decreases the solubility of the steroid in water, and increases its fat solubility. When a steroid has an ester attached, the steroid is rendered inactive, because the ester prevents it from binding to a receptor. In order for the steroid to become active again, the enzyme esterase must detach the ester and restore the hydrogen to form the hydroxyl group attached to C17. Once the molecule is converted back to testosterone, it is able to bind to a receptor and is an active steroid. Esters are usually attached at C17, though they are sometimes found at C3. Testosterone cypionate is shown below:
In testosterone cypionate, the hydrogen from the hydroxyl group on C17 has been removed and replaced with an 8-carbon side chain containing one cyclopentane ring and one carbonyl (=O) group. This is one of the larger esters of testosterone. In order of size, from smallest molecular weight to largest, the esters of testosterone are: acetate, propionate, phenylpropionate, isocaproate, caproate, enanthate, cypionate, decanoate, undecylenate, undecanoate, laurate. The largest of these esters, laurate, contains 12 carbon atoms, 24 hydrogen atoms, and 2 oxygen atoms. These esters can be attached to other steroids as well, and are not limited to testosterone.

Testosterone is easily converted in the body into Dihydrotestosterone (DHT). This reaction is carried out by the enzyme 5-alpha reductase (5-AR). During this reaction, the double bond between C4 and C5 is reduced to a single bond, and two new hydrogen atoms are added, one each to C4 and C5.

The hydrogen attached to the C5 is trans to the methyl groups while the H attached to the C4 can be either cis or trans, as there is already one H bonded to that carbon. 5-AR does not convert all steroids to DHT. As with most enzymes, there has to be an exact fit between the enzyme and the substrate, in this case, the steroid. The analogy of a lock and key is sometimes used to describe the specificity of enzymes.

The next steroid we will examine is Nandrolone (Deca):
As you can see, Nandrolone differs from Testosterone in only one aspect- the methyl (CH3) group has been removed from C10 and replaced by a hydrogen (not shown). Because the structure is so similar to that of Testosterone, it can also be altered by the 5-AR enzyme. In this case, the resulting molecule is known as Dihydronandrolone, and is very similar in structure to DHT. A good determinant of whether or not a steroid will be converted by 5-AR is the shape of the A ring. In Testosterone and Nandrolone, the double bond gives the ring a somewhat flat structure. However, if the double bond is not present, the molecule is not as flat and the ring assumes the chair conformation, in which it is slightly twisted. This prevents the molecule from fitting into the active site of 5-AR, and prevents reduction. A good example of this is 5-Andriodiol, which has no double bond in the A ring. Also note that the double-bonded oxygen on C3 has been replaced with a hydroxyl group.

Another conversion that some steroids can undergo is aromatization. This is the conversion of an androgen into an estrogen, and is catalyzed by the enzyme aromatase. It is known as aromatization because the A ring is converted into an aromatic ring, meaning it has alternating double bonds and is completely flat. Aromatic rings are also very dense in electrons because of the many double bonds. When Testosterone is aromatized, it is converted into Estradiol, which is shown below:
If you compare this to testosterone, you will notice that the methyl group on C10 has been removed and the oxygen on C3 has been reduced to a hydroxyl (-OH) group. These two changes reduce the number of bonds on all the carbons, so aromatization occurs, and alternating double bonds form. In order for aromatase to function and aromatize a steroid, the steroid must have a methyl group attached to the C10. This is another example of the lock and key model. For this reason, Nandrolone does not aromatize and is not converted to an estrogen. It does not have the methyl group.

Another factor that will influence whether or not a steroid is aromatized is the structure of the A ring. If the A ring is altered enough, aromatase cannot function and aromatization cannot occur. One example of an altered A-ring is Oxandrolone (Anavar), in which the 2C is replaced with an oxygen. Note that the methyl group on C10 is still present, yet no aromatization will occur.

One other notable example of this A ring alteration is Stanozolol. In this molecule, a whole new ring has been attached to the A ring. This fifth ring prevents Stanozolol from being aromatized in any way.

Yet another important conversion steroids may undergo is 17-alpha alkylation. In this process, a methyl group (CH3) is added to C17. This methyl group is trans to the other methyl groups. One notable characteristic of these steroids is that they make the steroid much more difficult for the liver to degrade and process into waste products and these steroids usually have a longer half life than their non-alkylated counterparts. This is because the methyl prevents the steroid from fitting into the active site on the various liver enzymes that process steroids. One example of a 17 alpha alkylated steroid is Oxandrolone, shown above. Note the CH3 on C17. Most oral steroids are 17a-alkylated steroids, and are thus more liver toxic than many Injectable steroids, which are usually esterified.

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Jan Nichols

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