Steroid hormone

Steroid hormones are a type of steroid that function as hormones. They fall into two main classes: corticosteroids, typically produced in the adrenal cortex, and sex steroids, usually made in the gonads or placenta. Based on the receptors they bind to, there are five specific types: glucocorticoids and mineralocorticoids (both corticosteroids), plus androgens, estrogens, and progestogens (the sex steroids). Vitamin D derivatives form a sixth, closely related hormone system with similar receptors, sharing some traits of true steroids as receptor ligands. These hormones regulate metabolism, inflammation, immune responses, salt and water balance, sexual characteristic development, and the body’s ability to handle injury and illness. The term "steroid" covers both natural hormones and lab-made drugs that mimic their actions.

Natural steroid hormones are synthesized from cholesterol, mainly in the gonads and adrenal glands. Being lipids, they are fat-soluble and can cross cell membranes. Once inside, they bind to steroid hormone receptors—either nuclear or cytosolic, depending on the hormone—to trigger cellular changes. In the bloodstream, they travel attached to specific carrier proteins like sex hormone-binding globulin or corticosteroid-binding globulin. Further processing and breakdown occur in the liver, other peripheral tissues, and target tissues.

Many synthetic steroids and sterols have been created. Most are steroids, though some nonsteroidal molecules can also interact with steroid receptors due to similar shapes. Some synthetic versions are weaker or stronger than the natural hormones they activate. Examples include glucocorticoids like prednisone and dexamethasone, the mineralocorticoid fludrocortisone, the vitamin D analog dihydrotachysterol, androgens such as nandrolone, estrogens like ethinyl estradiol, and progestins including norethisterone. Some steroid antagonists exist, such as the androgen blocker cyproterone acetate and the progestin blockers mifepristone and gestrinone.

In the blood, steroid hormones are transported bound to carrier proteins—serum proteins like sex hormone-binding globulin, corticosteroid-binding globulin, and albumin—which increase their solubility in water. Most research suggests hormones affect cells only when unbound. To become active, they must detach from these proteins and either bind to extracellular receptors or passively cross the cell membrane to reach nuclear receptors, a concept called the free hormone hypothesis. One study found that steroid-carrier complexes can be taken into cells via endocytosis after binding to the membrane receptor megalin. Inside, they may go to the lysosome, where the carrier is broken down and the hormone is released into the cytoplasm, then following a genomic pathway. The role of endocytosis in this transport is still not well understood and is under investigation.

For steroid hormones to cross the lipid bilayer, they must overcome energetic barriers. Derived from cholesterol, they have hydrophilic functional groups at each end and a hydrophobic carbon backbone. When entering a membrane, free energy barriers arise as the functional groups move into the hydrophobic interior, but the hormone’s hydrophobic core finds it energetically favorable to enter. These barriers and wells reverse when exiting. At physiological conditions, steroid hormones easily enter and exit membranes, crossing at rates near 20 μm/s, depending on the hormone. Although it is energetically more favorable for them to stay in the membrane than in extracellular or intracellular fluid, they do leave once inside. This differs from cholesterol, which has a much larger negative Gibbs free energy well inside the membrane and does not leave, due to its aliphatic tail interacting very favorably with the lipid bilayer interior.

Steroid hormones affect target cells through multiple mechanisms, which fall into genomic or non-genomic pathways. Genomic pathways are slow, altering transcription levels of certain proteins; non-genomic pathways are much faster. In the first identified genomic pathway, free hormones pass through the cell membrane due to fat solubility. In the cytoplasm, the steroid may undergo enzyme-mediated changes like reduction, hydroxylation, or aromatization. Then it binds to a specific steroid receptor.