Hormones are chemical messengers which interact with target cells by means of specific receptor molecules located either on the plasma membrane or within the target cell's cytoplasm. Although hormones are generally considered to be either proteins or steroids, a variety of molecules can be used by the body as  hormones.

 Peptide hormones are composed of amino acids arranged in one or more chains. Disulfide bonds provide interchain stability and maintain both tertiary and dimeric structure (eg. PRL, insulin). Many of the peptides are actually glycoproteins whose carbohydrate moities are of functional significance (FSH, LH, hCG). Often, families of peptide hormones can be recognized based upon a common similarity of structure between the various members (insulin, NGF, and relaxin are examples).
 In contrast to peptide hormones, steroids are lipid soluble compounds synthesized from cholesterol. All share a basic structure consisting of a 4-membered ring system. Several of the steroids are reproductively active and are produced by tissues of mesodermal origin (eg. gonadal and adrenal glands). Recent evidence also suggests that steroid synthesis may take place in the brain.

Catecholamines and prostaglandins are two classes of compounds with significant functions. Catecholamines include serotonin, dopamine, epinephrine, and norepinephrine. In particular, dopamine appears to be the prolactin-inhibiting hormone of the hypothalamus. Prostaglandins (of which there are many) are synthesized from fatty acid substrates such as arachadonic acid. These have important reproductive functions, including smooth muscle contraction.

 Many other chemical messengers may function within the endocrine system. Some of these include: (1) neuropeptides, (2) chalones, (3) pheromones, (4) peptide growth-stimulating factors, (5) ions, and (6) amino acids and glucose. Each year this list becomes longer as new hormonally active substances are reported.

 Three requirements must be satisfied in order for a peptide  hormone to exert an effect on a target cell: (1) receptors must exist on the plasma membrane, (2) a transducer system must be present for information transfer, and (3) there must be a cellular response mechanism.

Receptor Binding

 Receptors are integral membrane proteins which recognize and bind hormones. They then translate this binding into a biological activity such as synthesis and release of product. The loss or gain of membrane receptors by a cell may be determined by the binding of other hormones to their specific receptors on the same cell. For example, binding of FSH to ovarian follicular cells increases the content of LH receptors on those same cells. Also, a hormone may stimulate its own receptors on a target cell. Exposure of hepatocytes to PRL increases PRL receptors on cell membranes. Up regulation occurs when hormonal stimulation causes an increase in receptor content. Down regulation results when exposure to a hormone decreases membrane receptor content. Continuous exposure of lymphocytes to insulin results in the down regulation of insulin receptors on the lymphocytes.
 

Cooperativity and Spare Receptors

 When a hormone initially binds to its receptor, the binding event may affect the subsequent binding of hormone to the remaining receptors. If the initial binding event increases the affinity of other receptors for the hormone (sensitization), positive cooperativity has occurred. If binding desensitizes subsequent receptors for the hormone, we have negative cooperativity. For example, the Ka of insulin receptors decreases as more receptors bind the hormone. Usually a maximum biological response occurs when about 1-2% of available receptors are occupied. The remaining 98-99% are "spare" and may function to increase the sensitivity of the system to low levels of hormone.

Signal Transduction

 Binding of a hormone to its receptor initiates a series of events within the plasma membrane which result in activation of a cellular response mechanism. These events represent the transducer system and appear to involve a group of proteins known as guanyl nucleotide regulatory proteins (G-proteins). Presently, at least three G-proteins have been described and two of these have been characterized. Gs stimulates the adenylate cyclase system while Gi inhibits adenylate cyclase. Both of these are composed of 2 subunits (a,b) with the a-subunit responsible for the specific activity. A proposed sequence of events is shown below:

                                                                Hormone Binding
 
                                                                    stimulates

                                                  Gs                  or                   Gi

                                                              subunit dissociation

                                                  A-subunit                              A-subunit

                                                                     binds GTP

                                                  Activates                                 Inhibits
 

                                                                 Adenylate Cyclase

Signal Transduction

 Signal transduction results in the activation of mucleotide-cyclizing enzymes located on the inner surface of the cell membrane. The enzyme systems, C-AMP and C-GMP, are not bound to the hormone receptors. These are the well known Second Messengers, becauce they mimic the effect of the original hormone on cellular response.
 Signal transduction may also involve mono- and divalent cations such as calcium, as well as prostaglandins, and the G-proteins,

  Steroid hormones are lipid soluble compounds which can readily diffuse across the plasma membrane of all cells. They are easily extracted from tissues using ether or other organic solvents. Very little evidence has been reported to indicate any form of regulated passage across cell membranes as is true for the peptides. Thus, target cell response to steroid hormones depends on the presence of receptor proteins located within the cytoplasm of the cell.

 Steroid Entry into Target Cells

 The classic demonstration of steroid uptake by target tissues was performed in 1962 by Jensen and Jacobson. Spayed female rats were injected with 3H-estradiol and accumulation of the radioactive label in various organs was measured over time. Results of these experiments showed that reproductive tissues accumulated the labelled steroid against a concentration gradient.
 

Steroid-Receptor Binding

 Once steroid hormones enter a cell, they bind to specific receptor proteins located in the cytoplasm. Binding has been described as a 2-step, temperature dependent phenomenon. In the first step, the hormone enters the sytoplasm and binds to an 8s cytoplasmic receptor protein. If the temperature of the reaction is between 0-4oC, the steroid-receptor complex remains in the cytoplasm. At 37oC however, the receptor complex translocates to the nucleus and becomes bound to acceptor sites on chromatin. Translocation also involves an alteration in the receptor which changes from an 8s to a 5s form. Once bound to chromatin, the nuclear receptor complex initiates transcription followed by translation of m-RNA into new proteins.