Physiological Mechanisms Hormonal Control Dr Smita Bhatia BP-5, II floor, Shalimar Bagh (West) Delhi 110088 Contact: 27483738 Email: [email protected] 1 Learning objectives Chemical nature of hormones Transport of hormones Mechanism of hormone action Hormone interactions Control of hormone secretion Clearance of hormones Major endocrine glands, their secretions and disorders Hypothalamic-hypophyseal axis Thyroid gland Parathyroid glands Adrenal glands Pancreatic islets Gonads and placenta Thymus Pineal gland Other endocrine tissues In addition to other homeostatic mechanisms of the body, one of the two major regulatory systems of the body is the endocrine system (the other being the nervous system). This system comprises the endocrine glands that release their secretions, called hormones, into the blood stream which transports it to the various target organs on which these hormones act to activate, inhibit or, modify certain functions. Hormones are released into the blood stream rather than directly reaching the target organs because these glands have no ducts (ductless glands) to convey their secretions (also because there could be many target organs for a single hormone so it would not be possible to take these secretions to each and every organ by means of ducts). Why do hormones act on certain specific organs and not on others? This is due to the presence of receptors in/on the target cell. These receptors are protein, or glycoprotein molecules, which can bind to the hormone. The location of receptors differs within a cell for different types of hormones. These receptors may be present: • On the cell: For the protein peptide and catecholamine hormones. • In the cytoplasm of the cell: Steroid hormones (since these hormones can readily enter a cell). • In the cell nucleus: Thyroid hormones (as these hormones can readily enter the cell because of their lipid soluble nature) where they directly affect the genes. A specific change occurs after the hormone binds to the receptor (see mechanism of hormone action). The number of receptors on the cell surface is regulated by the concentration of the circulating hormone. If the concentration is very high the number of receptors decreases so 2 that the cell becomes less sensitive to the hormone. This is known as down-regulation. If the concentration of the hormone becomes low, the number of receptors increases to increase the sensitivity of the cell to the hormone. This is known as up-regulation. Differences between the two major regulatory systems of the body—the endocrine and the nervous system Nervous system Endocrine system • Neurotransmitters are released which • Hormones are released which can be act locally carried anywhere in the body • Act on muscle cells, gland cells and • Act on a variety of cells other neurons • Effect of hormones may take seconds • Effect of neurotransmitters occurs to hours to days to occur within a short span of time (msec) • Effect may last for a long time (seconds • Effect lasts for a short time (msec) to days) Functions of hormones • Help to regulate the chemical composition and volume of the various components of the body, e.g. plasma, interstitial fluid. • Help regulate the metabolism and energy balance. • Help regulate the contraction of smooth and cardiac muscle fibres. • Help regulate glandular secretion and some immune system activities. • Control growth and development. • Regulate the functioning of the reproductive system. • Help establish circadian rhythms. • Help regulate the interaction between the environment and the body. Chemical nature of hormones Hormones are of different types: Protein or peptide hormones. These are made up of amino acids. They are water soluble. Peptides are made up of 3 to 49 amino acids. e g. oxytocin and insulin. Protein hormones are made up of 50 to 200 amino acids e.g., thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH). These are produced as biologically inactive precursor molecules (pre-prohormones) by the rough endoplasmic reticulum of the gland cell. These pre- prohormones are then cleaved into prohormones which are also biologically inactive. Prohormones are then packaged into vesicles as hormones by the Golgi body. These vesicles 3 are stored in the cytoplasm near the plasma membrane from where they are secreted by exocytosis on an appropriate stimulus. Steroid hormones. These hormones are derived from cholesterol e.g., testosterone, cortisol, progesterone. They are lipid soluble. These are not stored in the cytoplasm but are synthesized from cholesterol when needed and are secreted directly by passing through the plasma membrane as they are lipid soluble. Biogenic amines. They are derived from amino acids. They are of different types: • Thyroid hormones and catecholamines. Thyroxine (T4) and triiodothyronine (T3) are secreted by the thyroid gland. Catecholamines include epinephrine and non-epinephrine secreted by the adrenal medulla and dopamine secreted by the hypothalamus and other brain cells. They are all derivatives of the amino acid tyrosine. Thyroxine is synthesized in the thyroid follicles where they are stored with thyroglobulin (a glycoprotein). When needed, thyroxin is released from the thyroglobulin into the blood where it combines with the thyroxin-binding globulin. Catecholamines are stored in the vesicles in the cytoplasm which are released by exocytosis when needed. Catecholamines are water soluble while thyroid hormones are lipid soluble because they are iodinated. • Histamine secreted by the mast cells is derived from amino acid histidine. • Serotonin (or 5-hydroxytrptamine, 5-HT) and melatonin. Both are derived from the amino acid tryptophan. Serotonin is secreted by certain brain cells and melatonin is secreted by the pineal gland. • Eicosanoids. These are different types of hormones derived from the fatty acid arachidonic acid containing 20 carbon atoms. Eicosanoids include prostaglandins (like PGF2α), prostacyclins and leukotrienes. These are water-soluble. • Nitric oxide. Though it is a gas, it is produced as a hormone as well as a neurotransmitter. It is lipid soluble. Transport of hormones The secretion, transport and mechanism of action of these hormones depends on their polar or non-polar nature i.e., whether they are water soluble or lipid soluble. The water-soluble hormones do not need any carrier molecules in the plasma, where they can circulate freely in the aqueous medium. But lipid-soluble hormones cannot be transported as free molecules in the aqueous plasma and are transported by carrier proteins. In addition to transporting these hormones these carrier proteins also, • Prevent filtration of small lipid hormones through the glomerulus in the kidneys thus increasing their half-life. • Provide a readily available stock of these hormones circulating in the blood. 4 Mechanism of hormone action Sequence of events of the action of a lipid molecule Lipid soluble hormones Lipid hormone is released from the blood into the Lipid-soluble hormones bind to interstitial space the receptors present inside the target cells because these It crosses the plasma membrane of the cell and binds to hormones can cross the plasma specific receptors inside the cell membrane. The hormone-receptor complex turns certain specific genes on or off. Synthesis of certain specific mRNA (and hence specific 5 Water soluble hormones Since these hormone molecules cannot enter the cell they bind to receptors on the surface of the target cell and trigger the formation of another molecule within the cell. Here, the hormone molecule is known as the first messenger molecule and the molecule formed within the cell due to its binding is known as the second messenger. Sequence of events of the action of a water molecule (Figure 1) Water-soluble molecule binds to the receptor (it is a transmembrane protein) on the surface of the molecule Hormone-receptor complex activates a membrane bound (bound to the inner side of the plasma membrane) protein—the G-protein (which binds to a GTP molecule and releases a GDP molecule) G- protein activates enzyme adenylate cyclase Adenylate cyclase catalyses the conversion of ATP into cyclic AMP (cAMP). (This cAMP is the second messenger) cAMP activates a protein kinase Protein kinase phosphorylates other cellular proteins On phosphorylation some cellular proteins get activated while some other get inhibited Some physiological processes are stimulated or inhibited (depending upon whether the protein regulating this process has been activated or inhibited) After some time an enzyme phosphodiesterase breaks down the second messenger to stop this sequence of events till another hormone molecule binds to the receptors to trigger this again. Fig 1: Mechanism of G-protein mediated action of water soluble hormones 6 Different protein kinases exist in different cells or within the same cell, while one type of protein kinase may stimulate an activity by phosphorylating a protein another protein kinase may inhibit another activity by phosphorylating another protein. In addition to cAMP, other second messengers include cGMP (cyclic guanosyl monophosphate), inositol phosphate (IP3) and diacyl glycerol (DAG). Nitric oxide which causes vasodilation by stimulating the relaxation of smooth muscle fibres in blood vessels acts by stimulating the formation of cGMP (the secondary messenger) which stimulates the transport of Ca2+ into storage areas of the smooth muscle fibre from the cytosol. When cytosol Ca2+ ion concentration decreases it results in the relaxation of