Once in the bloodstream, the anabolic steroid travels to all tissues in the body, where it enters the cells to reach its target. In order to get into a muscle cell for example, the steroid must leave the capillary and then enter the muscle cell. This means that the steroid must cross two different types of membranes, the capillary membrane and the muscle cell membrane. To cross the capillary membrane, the spaces between loosely packed endothelial cells and the presence of numerous pores or fenestra1, allow small molecules or charged molecules to squeeze through (Figure 3 and see Module 1). Non-polar molecules can diffuse through the endothelial cell membranes easily in addition to moving through the pores.
However the muscle cell membrane (like most cells in the body) does not have the small pores or spaces and therefore the steroid can only cross the membrane by diffusing across or in some cases by a carrier protein (transporter). Steroids cross the cell membrane principally by passive diffusion2, which is driven by the concentration gradient – this does not require energy. Passive diffusion depends on the physiochemical characteristics of the membrane and the drug3. The muscle cell membrane, like all cell membranes in the body, is a lipid bilayer (Figure 4). It consists of lipids arranged with their polar4 head groups facing the outside and inside of the cell. The chains of fatty acids face each other, forming the hydrophobic5 (water-fearing) or non-polar6 interior. Because anabolic steroids7 are very lipophilic8 (lipid-loving) and non-polar, they diffuse easily into the hydrophobic membrane interior. As they concentrate within the hydrophobic membrane interior, a new driving force is generated, pushing the steroid into the cytoplasmic side of the cell membrane.
Figure 4 Schematic view of a cell membrane. Lipids are arranged with polar head-groups facing the outside and inside of the cell, while the fatty acid chains form the non-polar (hydrophobic) membrane interior.
Once the anabolic steroid diffuses into the cytoplasm of the cell, it binds to the androgen receptor9 (Figure 5). [Receptors for other steroids are found in the nucleus instead of the cytoplasm.] The complex of steroid and receptor then crosses the nuclear membrane to enter the nucleus of the cell, where the steroid exerts its effects. Although the steroid is able to diffuse into the cell by passive diffusion, once bound to the steroid receptor, it is too large. Thus, the steroid-receptor complex diffuses through small pores in the nuclear membrane to enter the nucleus. The movement through the nuclear pores is enabled by a group of proteins lining the pores that act like gates, letting molecules in and out of the nucleus. Movement of large molecules through the nuclear pores is an example of facilitated diffusion10, which occurs in the direction of the concentration gradient. Therefore, no energy is required. In contrast, active transport11, which occurs against the concentration gradient, requires energy.
Once inside the nucleus, the steroid-receptor complex (in this case the testosterone-androgen receptor) binds to a specific location on the DNA to initiate transcription…the first step in protein synthesis. Go to the next section to learn how the androgenic and anabolic effects are produced.
Figure 5 Watch how testosterone (or anabolic-androgenic steroids) binds to the androgen receptor in the cytoplasm and the complex moves into the nucleus where it interacts with DNA to initiate protein synthesis.
1 small spaces or pores within endothelial cells that form the capillary membrane. These pores allow charged drugs or larger drugs to pass through the capillaries.
2 the movement of a solute in its uncharged form to cross a membrane along a concentration gradient. No energy is required.
3 a substance that affects the structure or function of a cell or organism.
4 a chemical property of a substance that indicates an uneven distribution of charge within the molecule. A polar substance or drug mixes well with water but not with organic solvents and lipids. Polar or charged compounds do not cross cell membranes (lipid) very easily.
5 “water-fearing”; a compound that is soluble in fat but not water. This is typical of compounds with chains of C atoms.
6 a chemical property of a substance that indicates an even distribution of charge within the molecule. A non-polar or non-charged compound mixes well with organic solvents and lipids but not with water.
7 synthetic versions of testosterone designed to promote muscle growth without producing androgenic effects. The better term is anabolic-androgenic steroid.
8 high lipid solubility. Lipophilic compounds dissolve readily in oil or organic solvent. They exist in an uncharged or non-polar form and cross biological membranes very easily.
9 a protein to which hormones, neurotransmitters and drugs bind. They are usually located on cell membranes and elicit a function once bound.
10 the movement of molecules across a membrane with the concentration gradient. No energy is required, but transport proteins can become saturated, limiting the diffusion process.
11 the movement of molecules against the concentration gradient with the help of a transport protein. Active transport requires energy in the form of ATP.