Mechanism of action of pituitary and hypothalamic hormones

Hormonal regulation begins with the process of synthesis and secretion of hormones in the endocrine glands. They are functionally interconnected and represent a single whole. The process of hormone biosynthesis, carried out in specialized cells, occurs spontaneously and is fixed genetically. Genetic control of the biosynthesis of most protein-peptide hormones, in particular adenohypophysotropic hormones, is most often carried out directly in the polysomes of precursor hormones or at the level of formation of mRNA of the hormone itself, while the biosynthesis of hypothalamic hormones is carried out by forming mRNA of protein enzymes that regulate various stages of hormone formation, i.e., extraribosomal synthesis occurs. The formation of the primary structure of protein-peptide hormones is the result of direct translation of nucleotide sequences of the corresponding mRNA synthesized in the active sites of the genome of hormone-producing cells. The structure of most protein hormones or their precursors is formed in polysomes according to the general scheme of protein biosynthesis. It should be noted that the ability to synthesize and translate mRNA of this hormone or its precursors is specific to the nuclear apparatus and polysomes of a certain cell type. Thus, STH is synthesized in small eosinophils of the adenohypophysis, prolactin - in large eosinophilic, and gonadotropins - in special basophilic cells. The biosynthesis of TRH and LH-RH in hypothalamic cells occurs somewhat differently. These peptides are formed not in polysomes on the mRNA matrix, but in the soluble part of the cytoplasm under the influence of the corresponding synthetase systems.

Direct translation of genetic material in cases of secretion of most polypeptide hormones often leads to the formation of low-active precursors - polypeptide preprohormones (prehormones). Biosynthesis of a polypeptide hormone consists of two different stages: ribosomal synthesis of an inactive precursor on the mRNA matrix and post-translational formation of an active hormone. The first stage necessarily occurs in the cells of the adenohypophysis, while the second can also occur outside of it.

Post-translational activation of hormonal precursors is possible in two ways: by multi-stage enzymatic degradation of molecules of translated large-molecular precursors with a decrease in the size of the molecule of the activated hormone and by non-enzymatic association of pro-hormonal subunits with an increase in the size of the molecule of the activated hormone.

In the first case, post-translational activation is characteristic of AKTU, beta-lipotropin, and in the second - for glycoprotein hormones, in particular gonadotropins and TSH.

The sequential activation of protein-peptide hormones has a direct biological meaning. Firstly, it limits hormonal effects at the site of formation; secondly, it provides optimal conditions for the manifestation of polyfunctional regulatory effects with minimal use of genetic and building material, and also facilitates cellular transport of hormones.

The secretion of hormones occurs, as a rule, spontaneously, and not continuously and uniformly, but impulsively, in separate discrete portions. This is apparently due to the cyclic nature of the processes of biosynthesis, intracellular deposition and transport of hormones. Under physiological norm conditions, the secretory process must provide a certain basal level of hormones in the circulating fluids. This process, like biosynthesis, is under the control of specific factors. The secretion of pituitary hormones is primarily determined by the corresponding releasing hormones of the hypothalamus and the level of circulating hormones in the blood. The formation of hypothalamic releasing hormones themselves depends on the influence of neurotransmitters of adrenergic or cholinergic nature, as well as the concentration of hormones of the target glands in the blood.

Biosynthesis and secretion are closely interrelated. The chemical nature of the hormone and the features of its secretion mechanisms determine the degree of conjugation of these processes. Thus, this indicator is maximum in the case of secretion of steroid hormones, which diffuse relatively freely through cell membranes. The magnitude of conjugation of biosynthesis and secretion of protein-peptide hormones and catecholamines is minimal. These hormones are released from cellular secretory granules. An intermediate position in this indicator is occupied by thyroid hormones, which are secreted by releasing them from a protein-bound form.

Thus, it should be emphasized that the synthesis and secretion of hormones of the pituitary gland and hypothalamus are carried out to a certain extent separately.

The main structural and functional element of the secretory process of protein-peptide hormones are secretory granules or vesicles. These are special morphological formations of ovoid shape of various sizes (100-600 nm), surrounded by a thin lipoprotein membrane. Secretory granules of hormone-producing cells arise from the Golgi complex. Its elements surround the prohormone or hormone, gradually forming granules that perform a number of interrelated functions in the system of processes that cause hormone secretion. They can be the site of activation of peptide prohormones. The second function performed by granules is the storage of hormones in the cell until the moment of action of a specific secretory stimulus. The membrane of the granules limits the release of hormones into the cytoplasm and protects hormones from the action of cytoplasmic enzymes that can inactivate them. Special substances and ions contained inside the granules have a certain significance in the deposition mechanisms. These include proteins, nucleotides, ions, the main purpose of which is to form non-covalent complexes with hormones and prevent their penetration through the membrane. Secretory granules have another very important quality - the ability to move to the periphery of the cell and transport the hormones deposited in them to the plasma membranes. The movement of granules is carried out inside the cells with the participation of cell organelles - microfilaments (their diameter is 5 nm), built of actin protein, and hollow microtubes (diameter 25 nm), consisting of a complex of contractile proteins tubulin and dynein. If it is necessary to block secretory processes, drugs that destroy microfilaments or dissociate microtubes (cytochalasin B, colchicine, vinblastine) are usually used. Intracellular transport of granules requires energy costs and the presence of calcium ions. The membranes of the granules and plasma membranes, with the participation of calcium, come into contact with each other, and the secret is released into the extracellular space through the "pores" formed in the cell membrane. This process is called exocytosis. The emptied granules are able in some cases to reconstruct and return to the cytoplasm.

The trigger point in the process of secretion of protein-peptide hormones is the increased formation of AMP (cAMP) and the increase in the intracellular concentration of calcium ions, which penetrate the plasma membrane and stimulate the transition of hormonal granules to the cell membrane. The processes described above are regulated both intracellularly and extracellularly. If the intracellular regulation and self-regulation of the hormone-producing function of the pituitary gland and hypothalamus cells are significantly limited, then the systemic control mechanisms ensure the functional activity of the pituitary gland and hypothalamus in accordance with the physiological state of the body. Violation of regulatory processes can lead to serious pathology of the functions of the glands and, consequently, the entire body.

Regulatory influences can be divided into stimulating and inhibiting. All regulatory processes are based on the principle of feedback. The leading place in the regulation of the hormonal functions of the pituitary gland belongs to the structures of the central nervous system, and primarily to the hypothalamus. Thus, the physiological mechanisms of control of the pituitary gland can be divided into neural and hormonal.

When considering the processes of regulation of the synthesis and secretion of pituitary hormones, it is necessary to first of all point out the hypothalamus with its ability to synthesize and secrete neurohormones - releasing hormones. As indicated, regulation of the adenohypophyseal hormones is carried out with the help of releasing hormones synthesized in certain nuclei of the hypothalamus. Small-celled elements of these hypothalamic structures have conducting pathways that contact the vessels of the primary capillary network, through which the releasing hormones enter, reaching the adenohypophyseal cells.

Considering the hypothalamus as a neuroendocrine center, i.e. as a place of transformation of a nerve impulse into a specific hormonal signal, the carrier of which are releasing hormones, scientists study the possibility of the influence of various mediator systems directly on the processes of synthesis and secretion of adenohypophysial hormones. Using improved methodological techniques, researchers have identified, for example, the role of dopamine in regulating the secretion of a number of tropic hormones of the adenohypophysis. In this case, dopamine acts not only as a neurotransmitter that regulates the function of the hypothalamus, but also as a releasing hormone participating in the regulation of the function of the adenohypophysis. Similar data have been obtained with respect to norepinephrine, participating in the control of ACTH secretion. The fact of dual control of the synthesis and secretion of adenohypophysiotropic hormones has now been established. The main point of application of various neurotransmitters in the system of regulation of hypothalamic releasing hormones are the hypothalamus structures in which they are synthesized. At present, the spectrum of physiologically active substances involved in the regulation of hypothalamic neurohormones is quite wide. These are classical neurotransmitters of adrenergic and cholinergic nature, a number of amino acids, substances with a morphine-like effect - endorphins and enkephalins. These substances are the main link between the central nervous system and the endocrine system, which ultimately ensures their unity in the body. The functional activity of hypothalamic neuroendocrine cells can be directly controlled by various parts of the brain using nerve impulses coming through various afferent pathways.

Recently, another problem has arisen in neuroendocrinology - the study of the functional role of releasing hormones localized in other structures of the central nervous system, outside the hypothalamus and not directly related to the hormonal regulation of adenohypophyseal functions. It has been experimentally confirmed that they can be considered both as neurotransmitters and as neuromodulators of a number of systemic processes.

In the hypothalamus, releasing hormones are localized in certain areas or nuclei. For example, LH-RH is localized in the anterior and mediobasal hypothalamus, TRH in the middle hypothalamus, and CRH mainly in its posterior sections. This does not exclude the diffuse distribution of neurohormones in the gland.

The main function of the adenohypophyseal hormones is to activate a number of peripheral endocrine glands (adrenal cortex, thyroid gland, gonads). The pituitary tropic hormones - ACTH, TSH, LH and FSH, STH - cause specific responses. Thus, the first causes proliferation (hypertrophy and hyperplasia) of the fascicular zone of the adrenal cortex and increased synthesis of glucocorticoids in its cells; the second is the main regulator of morphogenesis of the follicular apparatus of the thyroid gland, various stages of synthesis and secretion of thyroid hormones; LH is the main stimulator of ovulation and formation of the corpus luteum in the ovaries, growth of interstitial cells in the testes, synthesis of estrogens, progestins and gonadal androgens; FSH accelerates the growth of ovarian follicles, sensitizes them to the action of LH, and also activates spermatogenesis; STH, acting as a stimulator on the secretion of somatomedins by the liver, determines the linear growth of the body and anabolic processes; LTH promotes the manifestation of the action of gonadotropins.

It should also be noted that the pituitary tropic hormones, acting as regulators of the functions of the peripheral endocrine glands, are often capable of exerting a direct effect. For example, ACTH as the main regulator of glucocorticoid synthesis produces a number of extra-adrenal effects, in particular lipolytic and melanocyte-stimulating.

Hormones of hypothalamic-pituitary origin, i.e. protein-peptide, disappear from the blood very quickly. Their half-life does not exceed 20 minutes and in most cases lasts 1-3 minutes. Protein-peptide hormones quickly accumulate in the liver, where they undergo intensive degradation and inactivation under the action of specific peptidases. This process can also be observed in other tissues, as well as in the blood. Metabolites of protein-peptide hormones are apparently excreted mainly in the form of free amino acids, their salts and small peptides. They are excreted primarily with urine and bile.

Hormones most often have a fairly pronounced tropism of physiological action. For example, ACTH acts on the cells of the adrenal cortex, adipose tissue, nervous tissue; gonadotropins - on the cells of the gonads, hypothalamus and a number of other structures, i.e. on organs, tissues, target cells. Hormones of the pituitary gland and hypothalamus have a wide range of physiological action on cells of different types and on various metabolic reactions in the same cells. The structures of the body, according to the degree of dependence of their functions on the action of certain hormones, are divided into hormone-dependent and hormone-sensitive. If the former are completely conditioned by the presence of hormones in the process of full differentiation and functioning, then hormone-sensitive cells clearly exhibit their phenotypic characteristics even without the corresponding hormone, the degree of manifestation of which is modulated by it in a different range and is determined by the presence of special receptors in the cell.

The interaction of hormones with the corresponding receptor proteins is reduced to non-covalent, reversible binding of hormonal and receptor molecules, resulting in the formation of specific protein-ligand complexes capable of including multiple hormonal effects in the cell. If the receptor protein is absent in it, then it is resistant to the action of physiological concentrations of the hormone. Receptors are necessary peripheral representatives of the corresponding endocrine function, determining the initial physiological sensitivity of the reacting cell to the hormone, i.e. the possibility and intensity of reception, conduction and implementation of hormonal synthesis in the cell.

The effectiveness of hormonal regulation of cellular metabolism is determined by both the amount of active hormone entering the target cell and the level of receptors in it.