Traditional endocrinology

The nature of endocrine regulation

Endocrine gland secretion is not a haphazard process; it is subject to precise, intricate control so that its effects may be integrated with those of the nervous system and the immune system. The simplest level of control over endocrine gland secretion resides at the endocrine gland itself. The signal for an endocrine gland to secrete more or less of its hormone is related to the concentration of some substance, either a hormone that influences the function of the gland (a tropic hormone), a biochemical product (e.g., glucose), or a biologically important element (e.g., calcium or potassium). Because each endocrine gland has a rich supply of blood, each gland is able to detect small changes in the concentrations of its regulating substances.

Some endocrine glands are controlled by a simple negative feedback mechanism. For example, negative feedback signaling mechanisms in the parathyroid glands (located in the neck) rely on the binding activity of calcium-sensitive receptors that are located on the surface of parathyroid cells. Decreased serum calcium concentrations result in decreased calcium receptor binding activity that stimulates the secretion of parathormone from the parathyroid glands. The increased serum concentration of parathormone stimulates bone resorption (breakdown) to release calcium into the blood and reabsorption of calcium in the kidney to retain calcium in the blood, thereby restoring serum calcium concentrations to normal levels. In contrast, increased serum calcium concentrations result in increased calcium receptor-binding activity and inhibition of parathormone secretion by the parathyroid glands. This allows serum calcium concentrations to decrease to normal levels. Therefore, in people with normal parathyroid glands, serum calcium concentrations are maintained within a very narrow range even in the presence of large changes in calcium intake or excessive losses of calcium from the body.

Control of the hormonal secretions of other endocrine glands is more complex, because the glands themselves are target organs of a regulatory system called the hypothalamic-pituitary-target gland axis. The major mechanisms in this regulatory system consist of complex interconnecting negative feedback loops that involve the hypothalamus (a structure located at the base of the brain and above the pituitary gland), the anterior pituitary gland, and the target gland. The hypothalamus produces specific neurohormones that stimulate the pituitary gland to secrete specific pituitary hormones that affect any of a number of target organs, including the adrenal cortex, the gonads (testes and ovaries), and the thyroid gland. Therefore, the hypothalamic-pituitary-target gland axis allows for both neural and hormonal input into hormone production by the target gland.

When stimulated by the appropriate pituitary hormone, the target gland secretes its hormone (target gland hormone) that then combines with receptors located on its target tissues. These receptors include receptors located on the pituitary cells that make the particular hormone that governs the target gland. Should the amount of target gland hormone in the blood increase, the hormone’s actions on its target organs increases. In the pituitary gland, the target gland hormone acts to decrease the secretion of the appropriate pituitary hormone, which results in less stimulation of the target gland and a decrease in the production of hormone by the target gland. Conversely, if hormone production by a target gland should decrease, the decrease in serum concentrations of the target gland hormone leads to an increase in secretion of the pituitary hormone in an attempt to restore target gland hormone production to normal. The effect of the target gland hormone on its target tissues is quantitative; that is, within limits, the greater (or lesser) the amount of target gland hormone bound to receptors in the target tissues, the greater (or lesser) the response of the target tissues.

In the hypothalamic-pituitary-target gland axis, a second negative feedback loop is superimposed on the first negative feedback loop. In this second loop, the target gland hormone binds to nerve cells in the hypothalamus, thereby inhibiting the secretion of specific hypothalamic-releasing hormones (neurohormones) that stimulate the secretion of pituitary hormones (an important element in the first negative feedback loop). The hypothalamic neurohormones are released within a set of veins that connects the hypothalamus to the pituitary gland (the hypophyseal-portal circulation), and therefore the neurohormones reach the pituitary gland in high concentrations. Target gland hormones effect the secretion of hypothalamic hormones in the same way that they effect the secretion of pituitary hormones, thereby reinforcing their effect on the production of the pituitary hormone.

The importance of the second negative feedback loop lies in the fact that the nerve cells of the hypothalamus receive impulses from other regions of the brain, including the cerebral cortex (the centre for higher mental functions, movement, perceptions, emotion, etc.), thus permitting the endocrine system to respond to physical and emotional stresses. This response mechanism involves the interruption of the primary feedback loop to allow the serum concentrations of hormones to be increased or decreased in response to environmental stresses that activate the nervous system. The end result of the two negative feedback loops is that, under ordinary circumstances, hormone production by target glands and the serum concentrations of target gland hormone are maintained within very narrow limits but that, under extraordinary circumstances, this tight control can be overridden by stimuli originating outside of the endocrine system.

There are important supplemental mechanisms that control endocrine function. When more than one cell type is found within a single endocrine gland, the hormones secreted by one cell type may exert a direct modulating effect upon the secretions of the other cell types. This form of control is known as paracrine control. Similarly, the secretions of one endocrine cell may alter the activity of the same cell, an activity known as autocrine control. Thus, endocrine cell activity may be modulated directly from within the endocrine gland itself, without the need for hormones to enter the bloodstream.

If the requirement that a hormone act at a site remote from the endocrine cells in which the hormone is produced is excluded from the defining characteristics of hormones, additional classes of biologically active materials can be considered as hormones. Neurotransmitters, a group of chemical compounds of variable composition, are secreted at all synapses (junctions between nerve cells over which nervous impulses must travel). They facilitate or inhibit the transmission of neural impulses and have given rise to the science of neuroendocrinology (the branch of medicine that studies the interaction of the nervous system and the endocrine system). A second group of biologically active substances is called prostaglandins. Prostaglandins are a complex group of fatty acid derivatives that are produced and secreted by many tissues. Prostaglandins mediate important biological effects in almost every organ system of the body.

Another group of substances, called growth factors, possess hormonelike activity. Growth factors are substances that stimulate the growth of specific tissues. They are distinct from pituitary growth hormone in that they were identified only after it was noted that target cells grown outside the organism in tissue culture could be stimulated to grow and reproduce by extracts of serum or tissue chemically distinct from growth hormone.

Still another area of hormonal activity that has come under intensive investigation is the effect of endocrine hormones on behaviour. While simple direct hormonal effects on human behaviour are difficult to document because of the complexities of human motivation, there are many convincing demonstrations of hormone-mediated behaviour in other life-forms. A special case is that of the pheromone, a substance generated by an organism that influences, by its odour, the behaviour of another organism of the same species. An often-quoted example is the musky scent of the females of many species, which provokes sexual excitation in the male. Such mechanisms have adaptive value for species survival.