Part I: The Chemistry

Ever wonder what’s going on with all of that testosterone running around in your bloodstream? I do! I’m infinitely curious about how things work, especially when it comes to biology. The beauty of life absolutely fascinates me. To borrow a phrase from a friend, I like to watch the atoms dance. The whole thing is quite beautiful and magical.

Human bodies are infinitely complex systems, and the interactions are amazing to watch. We are only beginning to understand how things really work, and we’re constantly learning new and interesting things about ourselves. I predict that it will take us hundreds of years to really get our heads around all of the things that are going on in our bodies; it’s the height of hubris to assume that we understand it now.

So now that I’ve told you that we don’t know anything, let’s try to understand something about androgens.

“Hormones” are molecules that exert their primary effects in the body by some form of binding to another molecule called a “receptor.” These molecules fit together something like a key and lock, and when the two molecules are in the locked position, this assemblage is called a “complex.”

A “steroid” is an organic molecule with the multi-ring structure of cholesterol. “Steroid hormones,” then, are obviously hormones with a steroid structure. All steroid hormones are “lipids.” Lipids are organic molecules that are insoluble in water but soluble in other lipids. By definition, then, cholesterol is both a lipid and a steroid.

Here are the fun terms. An “androgen” is a substance that stimulates the androgen receptor. Androgens usually exert some kind of physiological effect that is considered to be masculinizing: things like increasing muscle mass, decreasing body fat, increasing strength, increasing growth in facial and body hair, and promoting male pattern baldness. There is more than a single kind of androgen. Testosterone is an androgen. So is DHT. So are nandrolone, trenbolone and oxymetholone. I use the term “androgen” to refer to all of these substances; when I’m talking about a particular substance, I’ll use that substance’s particular common or chemical name.

An “anabolic” substance is any substance that promotes physical growth. Therefore, strictly speaking, estrogens (also steroid hormones) are anabolic, since they increase the deposition of body fat. Androgens are anabolic, too, in that they promote muscle growth. So you can’t just say “anabolic steroid” when you’re talking about androgens specifically. There’s misunderstanding #1 taken care of! The term I like to use when talking about testosterone and its close relatives is “anabolic/androgenic steroid,” or AAS. (We have to have an acronym for everything, right?)

“Handy Guide to Modern Science: 1. If it’s green or it wiggles, it’s biology. 2. If it stinks, it’s chemistry. 3. If it doesn’t work, it’s physics.”
“Chemistry […] is an art, it’s music, it’s a style of thinking. Orbitals are for mathematicians, chemistry is for people who like to cook!” — Alexander Shulgin

Do you remember chemistry as a boring subject that you were forced to take in school? I do. I liked the idea of making things in the lab that would explode or change colours or whatever my frosh mind expected them to do, but oh my Gawd, the textbook stuff was sooooooooo boring. I kept this disdain for chemistry for years, until I started getting interested in hormones and figured out that chemistry could be related to biology. And see, that was a good thing, because I was always interested in biology. Anyway, I don’t know if I can make chemistry interesting for you, but I’m going to try!

(Note: Everything that I’m going to say here is true for our purposes. However, as anybody with real knowledge of chemistry or physics will tell you, at a subatomic level things are far more complex than they will appear to be after reading this article. My advice–and don’t you want to hear my advice?–is to not worry about it. We’re not talking about quantum mechanics. If we were, I’d be writing stories about cats and people with crazy German names.)

Let’s explore chemistry in the context of organic chemistry, just because organic chemistry is the branch that will help explain steroids and their biochemical actions. Organic chemistry is the branch of chemistry that deals with carbon compounds. If you’ve ever seen the episode of Star Trek in which Spock communes with a rock creature, you know that all life on earth is carbon-based. This means that carbon is the atomic substance upon which we’re built. Cool, huh?

You might recall from high school biology the chant of “CHON.” That was an acronym that stood for “carbon, hydrogen, oxygen and nitrogen.” These four elements are fundamental to the way life works. If we were missing any of the four of them, life would either not exist or it would take a completely different form.

A bond is a concept that describes two or more atoms having an electrical relationship with one another. It’s a unit of chemical attraction. (I’ll refrain from making jokes about sex. You can thank me later.)

To be stable (i.e., electrically neutral), carbon atoms require four bonds. Nitrogen must have three, oxygen two, and hydrogen one. Electrons, which are negatively charged particles, fly around the nucleus of atoms in “electron shells.” Atomic nuclei are composed of protons (positively charged particles) and neutrons (particles with effectively no electrical charge). The first electron shell of any atom has, at most, two electrons. The second shell has, at most, eight electrons. And so on. An atom with the same number of electrons and protons is, for all purposes, electrically neutral. An atom with a mismatched number of electrons and protons has a significant electrical charge, and is called an “ion.”

Electron shells are filled from the inside shells outwards. The outermost electron shell of an atom is called a “valence shell.” For some atoms–including carbon, hydrogen, nitrogen and oxygen–to be stable, their valence shells need to be completely filled with electrons. This is an inherent trait of some atoms (“noble gases” helium, argon, krypton, radon, xenon, and neon), but since carbon, hydrogen, nitrogen and oxygen do not have their valence shells filled, this is accomplished by bonding with other atoms to form “molecules.”

Let’s talk about two different kinds of bonding. An ionic bond is a bond in which the electron density in the valence shell is primarily on one of the atoms. A covalent bond is a bond in which electrons are shared fairly equally in the valence shells of all bonded atoms. An example of an ionic bond would be the bond between sodium and chlorine in sodium chloride (more commonly known as “table salt”). An example of a covalent bond would be the bond between two hydrogen atoms.

Hydrogen is the simplest element we know of. It has a single proton and a single electron. It requires a single bond to be stable. Since the first electron shell of an atom can hold a maximum of two electrons, this means that hydrogen has to share only one electron with another atom to be stable.

Oxygen has eight electrons. Two electrons fill the first (inner) shell and six are in the second (and outer) shell. As the second shell will contain a maximum of eight electrons, oxygen requires two bonds to be stable.

Nitrogen has seven electrons: two in the inner shell and five in the other shell. It therefore requires three bonds to be stable. (Nitrogen can have four bonds, but we’re going to ignore that. La la la la, I’m not listening….)

Carbon, our main organic “building block,” has six electrons. Because it only has four electrons in the outer shell, it requires four bonds to reach the number of 8. This makes carbon stable and happy.

Now that we know about this bonding stuff, let’s move on to molecules.

Molecules are chemical structures containing two or more atoms. The simplest organic molecule is methane, made up of one carbon atom (requiring four bonds) and four hydrogen atoms (requiring one bond each). The chemical formula for methane is CH4. Methane stinks. Literally.

Ooh, hey, speaking of methane, let’s talk a bit about naming organic compounds.

Benzene
Fig. 1 Benzene
Propane
Fig. 2 Propane
Cyclopropane
Fig. 3 Cyclopropane

A hydrocarbon molecule is a molecule composed predominantly of–get this!–hydrogen and carbon. Complex hydrocarbons tend to form more complex patterns: rings, chains, etc. You can see some examples, like benzene [Figure 1] (a.k.a. phenyl hydride; that ring structure is called a “phenyl ring”), propane [Figure 2], cyclopropane [Figure 3] and even cholesterol [Figure 4]. See the lines in those pictures? At the junction of each line is a carbon atom that has two hydrogens attached. If three lines meet, it’s a carbon atom with one hydrogen attached. And if four lines meet, the carbon atom has no hydrogens. The number of lines connecting any two carbon atoms tells you how many bonds there are between those two atoms. Look at benzene again. See how they alternate between single and double bonds? That’s what I mean.

Cholesterol
Fig. 3 Cholesterol
Phenylamine
Fig. 4 Phenylamine
Testosterone
Fig. 5 Testosterone

While we’re reviewing pictures, let’s explain “functional groups.” Take a look again at cholesterol. See the OH- in the bottom left-hand corner? That’s an oxygen and a hydrogen, and as a group it’s called “hydroxyl.” Next take a look at phenylamine [Figure 4], which is benzene with an -NH2 attached. That “-NH2,” as a group is called an “amine.” Other relevant groups are keto (O=, or a double-bonded oxygen, which you can see in the lower left of the testosterone molecule [Figure 5]) and methyl (H3C-). Functional groups are very important to the naming of organic compounds, not to mention to their actions and structure.

It is important to note that, in any organic molecule, the carbons are numbered. There are rules for the numberings of each class of organic molecules, specified by the International Union of Pure and Applied Chemistry. There are fairly standard rules, but for more complex molecules you have to be familiar with the base compound in order to draw it or know what it looks like. We tend to use shorthand and designate variations from the shorthand. Testosterone is more properly called 17beta-Hydroxyandrost-4-en-3-one, but really, who wants to say that? And nandrolone is more properly called “19-nortestosterone,” or even better, 17beta-Hydroxyestra-4-en-3-one. I don’t know about you, but I think I like “nandrolone.”

Molecules are always named by starting with the most similarly named molecule.

Anyway! Let’s give a handful of basic nomenclature rules.

  • Methyl (H3C-) groups are designated by the suffix… “-methyl.” That one’s pretty easy.
  • Hydroxyl (-OH) groups are designated by the prefix “hydroxy-” or the suffix “-ol.” Molecules with hydroxyl groups are called “alcohols.”
  • Amine (-NH3) groups are designated by the suffix “-amine,” and are called (not surprisingly) “amines.”
  • Keto (O=) groups are designated by the prefixes “keto-” or “oxo-,” or the suffix “-one.” Molecules with keto groups are called “ketones.”
  • Single bonds between carbon atoms are named with the suffix “-ane.” Double bonds are named with the suffix “-ene,” and triple bonds are named with the suffix “-yne” or “-ine.”
  • If a molecule is visualized as flat and lying down, functional groups that stick upwards are named with the prefix “ß” (“beta”). If they stick downwards then they are named with the prefix “a” (“alpha”).
  • If a molecule replaces a methyl group with a single hydrogen atom, this is designated by the prefix “nor-.”
  • If a molecule’s carbons are in a ring structure, like in benzene, this compound is named with the prefix “cyclo-“.

All androgens are based on the name “-andro-.” All progestins are based on the name “-pregn-.” All estrogens are based on the name “-estr-.” (As an aside, androgens without a methyl group at carbon 19 can either be named “-estr-” or “19-noranstrost-.” They’re typically named with the -andro- root if their effects are predominantly at the androgen receptor, and -estr- if their effects are predominantly at estrogen receptors.

That’s all we’re going to cover here, because that’s all we’ll need to discuss anabolic/androgenic steroids. If you’re a real nerd (like me) and you want to know more about organic nomenclature, visit links like Purdue’s cyclic nomenclature page or the page at Chemguide.

Genetics

Now that we know a bit more about chemistry, let’s look at the biochemistry of AAS. In order to do that, we need to review some very fundamental concepts of genetics.

DNA Strand
Fig 6. DNA Strand
Deoxyribose
Fig 7. Deoxyribose
Adenine
Fig 8. Adenine
Guanine
Fig 9. Guanine
Cytosine
Fig 10. Cytosine
Thymine
Fig 11. Thymine
Ribose
Fig. 12 Ribose
Uracil
Fig. 13 Uracil

Structurally, DNA (deoxyribonuclieic acid) is a long pair of strands in a twisted helical ladder formation. If you conceptualize DNA as a ladder that has been twisted along its length [Figure 6], the sides of the ladder are made of a sugar called “deoxyribose” [Figure 7] and the “rungs” are pairs of four molecules called “nucleotides” or “bases.” In all life on earth, these nucleotides are adenine [Figure 8], guanine [Figure 9], cytosine [Figure 10] and thymine [Figure 11]. Pretty simple? To make things even simpler, adenine only binds with thymine, and guanine only binds with cytosine, to form wht are referred to as “base pairs.” It’s amazing that such a simple code can result in such complex life, isn’t it? (That’s a hypothetical question. Don’t worry. It’s not on the quiz.)

Each three base pairs forms a “triplet.” Each triplet is the code for a single amino acid; the amino acid is specified by the type and order of the base pairs within the triplet. An amino acid is the building block of “peptides,” which are strings of amino acids. Any peptide that is a string of larger than about 50 amino acids is called a “protein.” Proteins have TONS of uses in the body. It can be pretty accurately stated that proteins are the fundamental building block of human life. Incidentally,

“Genes” are sections of DNA triplets that code for a certain biochemical action — usually the production of proteins. The type and order of the bases in a gene determine the protein that will be made.

Every cell in your body has DNA. Messenger RNA (mRNA) is a molecule that’s similar to half of the DNA ladder, but with a few notable differences. mRNA’s triplets are called “codons.” Its ladder sides are the sugar “ribose” [Figure 12] instead of deoxyribose, and thymine is replaced by uracil [Figure 13]. It is supposed that the purpose of this replacement is to give the body a way to identify and destroy mRNA without destroying DNA as well. mRNA codes a gene from within the DNA strand and travels to the part of the cell that handles protein synthesis. mRNA, then, can be seen as truly a messenger who delivers orders, while DNA can be seen as the mistress (or master, I don’t discriminate) giving those orders. mRNA delivers these orders for protein production to “ribosomes,” which are structures inside cells that produce proteins.

If we do the math, we can see that there are sixty-four possible amino acids that can be coded for in each three-pair codon. However, several of these combinations produce the same amino acid. There are only 20 naturally occuring amino acids. Redundancy is a good thing.

What Do AAS do?

Remember this?

“Hormones” are molecules that exert their primary effects in the body by some form of binding to another molecule called a “receptor.” These molecules fit together something like a key and lock, and when the two molecules are in the locked position, this assemblage is called a “complex.”

Well, androgen receptors are very complex proteins that act by promoting gene transcription when activated. (And yes, this is one reason that androgens are called anabolic.) Receptors are produced by one gene. So there’s an androgen receptor gene in your DNA. Cool, innit?

Steroid receptors are in the cytosol of cells, not on the cell membranes. Remember this, because it’s a common mistake to assume that all receptors are on the cell membranes.

When a hormone binds with a receptor, the resultant structure is called a “complex.” That’s not the end of things in the world of steroid hormones, though. Each steroid/receptor complex binds with another steroid/receptor complex to form a “dimer.” (The process, in case you care, is called “dimerization.”) This dimer travels to the nucleus of the cell, binds with DNA, and promotes protein synthesis by promoting gene transcription through production of mRNA.

Any substance that promotes a receptor’s action is called an “agonist.” Any substance that blocks a receptor’s action (by, for example, blocking the binding of the hormone to the receptor, or inhibiting the dimerization of the steroid/receptor complex, or whatever) is called an “antagonist.”

No matter what you’ve heard, there is only one kind of androgen receptor. There are a few different kinds of estrogen receptors. Maybe that’s where the confusion comes from. I dunno.

To summarize, the primary anabolic action of androgens is in their promotion of gene transcription. There are other actions as well–including increased fluid retention in muscles and improved recovery time–that may or may not relate to the actions of androgens at the androgen receptor. Androgens do have effects that are not mediated by the androgen receptor.

Stay tuned next time when we discuss in greater depth the biochemical nitty-gritty of androgens and the resultant physiological effects.