Principles of Hormonal Integration

Dr. M. Alzaharna (2014) Until now, we have considered individual endocrine glands, and some basic information about their physiological functions It is helpful for the student first to understand one hormone at a time or one gland at a time It must be recognized that life is considerably more complex, and that endocrinological solutions to physiological problems require integration of a large variety of simultaneous events By integration we mean the coordination of reactions to separate physiological demands into a balanced overall response or group of responses 2

Dr. M. Alzaharna (2014) Integration of Hormonal Signals at the Cellular Level Augmentation, antagonism, and synergy Integration takes place at the level of individual cells as well as the whole body Individual cells must respond to the barrage of signals that reach them simultaneously Most cells express receptors for multiple hormones and other signaling molecules and are simultaneously bombarded with: – excitatory, – inhibitory, – or a conflicting mixture of excitatory and inhibitory hormonal stimuli 3

Dr. M. Alzaharna (2014) Integration of Hormonal Signals at the Cellular Level Each hormone independently excites its receptors and initiates a cascade of transduction mechanisms The immediate consequences of which contribute in determining the nature and magnitude of cellular responses Therefore, target cells must integrate the various inputs at both receptor and postreceptor levels and resolve them into productive responses 4

Dr. M. Alzaharna (2014) Hypothetical Example- Integration at the cellular level Hormone B signals by stimulating production of the second messenger cAMP Its ability to increase cAMP concentrations is diminished by the hormones A and C whose actions lower cAMP concentrations: – by speeding its destruction (hormone A) – and by diminishing its rate of production (hormone C) At the same time hormone C may initiate other responses through activation of the DAG/IP3 second messenger system 5 AC: adenylyl cyclase PLC: phospholipase C PDE: phosphodiesterase

Dr. M. Alzaharna (2014) Hypothetical Example- Integration at the cellular level The combined actions of the three hormones determines the concentration of cAMP The net response of the cell is determined by the relative intensity of stimulation by hormones A, B, and C It will vary with the physiological circumstances that affect the degree to which each of these hormones is secreted At times the action of hormone B will prevail; at other times it will be overwhelmed by the combined actions of hormones A and C, or by the dominant actions of either hormone A or hormone C 6

Dr. M. Alzaharna (2014) One hormone may also influence responses to other hormones by regulating expression of key components of transduction or signaling pathways For example, responses to epinephrine depend on the availability of: – its receptors (adrenergic receptors), – G-proteins, – and downstream mediators Thyroid hormones increase expression of adrenergic receptors in some tissues, and cortisol appears to increase expression of adrenergic receptors, as well as Gα s, and other components of G-protein signaling Consequently, – in states of thyroid or adrenal insufficiency, responses to epinephrine are blunted or deficient, – and conversely, after a period of increased secretion of thyroxine or cortisol, responses to epinephrine may be exaggerated 7

Dr. M. Alzaharna (2014) Interactions Between Hormones Interactions between hormones that occur downstream from the receptors may be seen in the final expression of the cellular response 8 Interaction of A & B hormonesResponse A + B hormones act through independent signaling pathways to achieve a response = Sum of A + B (Augmentation) A + B hormones compete for some shared component of their signaling pathways < sum of A & B (Antagonism) A & B hormones act through separate but complementary pathways, they may enhance each other’s actions > sum of A & B (Synergism)

Dr. M. Alzaharna (2014) Interactions Between Hormones Synergistic effects of human growth hormone (hGH) and the synthetic glucocorticoid dexamethasone (DEX) on lipolysis as measured by the increase in glycerol release Both hGH and Dex were somewhat effective when added individually But when added together the overall tissue response was greater than the sum of the responses produced by each hormone alone 9

Dr. M. Alzaharna (2014) Permissiveness A hormone acts permissively when its presence is necessary for, or permits, a response to occur, even though the hormone itself does not initiate the response In this case, two hormones acting together may produce an effect that neither can produce alone 10

Dr. M. Alzaharna (2014) Maintaining Signal Fidelity There are more hormones than there are signaling pathways, and virtually no signaling pathway is used exclusively by any one hormone Cells preserve the integrity of the actions of each hormone even when their transduction pathways appear to share common components The precise mechanisms that assure signal fidelity are not always understood Most hormones do not simply activate a linear series of reactions, but rather signal through multiple parallel intracellular pathways The particular combination of signaling pathways that are activated may determine the final outcome 11

Dr. M. Alzaharna (2014) Sensitivity and Capacity Sensitivity describes the ability of a cell or organ to recognize and respond to a signal in proportion to the intensity of that signal Because it is difficult to measure small responses with precision, the threshold is seldom used in describing sensitivity Instead, sensitivity usually is described in terms of: – the concentration of hormone needed to produce a half- maximal response, which is sometimes abbreviated as EC 50 The capacity to respond, the maximum response that a tissue or organ is capable of achieving – depends upon the number of target cells and their competence Hormones regulate both the sensitivity and the capacity of target tissues to respond either to themselves or to other hormones 12

Dr. M. Alzaharna (2014) Sensitivity When sensitivity is increased, a lower concentration of hormone is needed to achieve a half maximal response When sensitivity is decreased, a higher concentration of hormone is needed to evoke the same response Sensitivity can be changed by: – upregulation or downregulation of receptors more common – The affinity of the receptor for its hormone This may be increased or decreased by covalent modifications such as phosphorylation or dephosphorylation 13 Normal T3 decreases the sensitivity of the thyrotropes of the pituitary to TRH Prolactin and growth hormone may upregulate their own receptors

Dr. M. Alzaharna (2014) Capacity The maximum response may be increased (Curve A) or decreased (Curve C), But the sensitivity (i.e., the concentration of hormone needed to produce the half-maximal response) remains unchanged at 1 ng/ml At the tissue, organ, or whole body level, the response to a hormone is the aggregate of the contributions of all the stimulated cells, so that the magnitude of the response is determined both by: – the number of responsive cells – and their competence 14 Normal

Dr. M. Alzaharna (2014) Capacity For example, ACTH produces a dose-related increase in blood cortisol concentration in normal individuals However, immediately after removal of one adrenal gland, changes in the concentration of cortisol in response to ACTH administration would be only half as large as seen when both glands are present Therefore, a much higher dose of ACTH will be needed to achieve the same change as was produced preoperatively With time however, as the adrenal cortical cells upregulate ACTH receptors and increase their enzymatic capacity for steroidogenesis, the concentration of ACTH needed to achieve a particular rate of cortisol secretion will decline 15

Dr. M. Alzaharna (2014) Hormonal Integration at the Whole Body Level 1- Redundancy The body has more than one way to achieve a given end For example, conversion of liver glycogen to blood glucose can be signaled by at least two hormones: – glucagon from the alpha cells of the pancreas – and epinephrine from the adrenal medulla Both of these hormones increase cAMP production in the liver, and thereby activate the enzyme, glycogen phosphorylase, which catalyzes glycogenolysis 16

Dr. M. Alzaharna (2014) Hormonal Integration at the Whole Body Level 2- Reinforcement In accomplishing any end, most hormones act at several locales either within a single cell, or in different tissues or organs to produce separate but mutually reinforcing responses For example, the way ACTH acts on the fasciculata cells of the adrenal cortex to promote the production of cortisol – Increases uptake of cholesterol, which serves as a substrate for hormone synthesis – Activates the esterase enzyme needed for mobilization of cholesterol from storage droplets – Increases the synthesis and activity of the StAR (steroid acute regulatory) protein needed for delivery of cholesterol to the intramitochondrial enzyme that converts it to pregnenolone – Increases adrenal blood flow, which facilitates the delivery not only of the cholesterol precursor to the adrenal cortex, but also the newly synthesized hormone to the rest of the body 17

Dr. M. Alzaharna (2014) Each of these effects contribute to the end of providing the body with cortisol But collectively, they make possible an extremely broader range of response in a shorter time frame A good example of this is the action of glucocorticoid hormones to promote gluconeogenesis 18

Dr. M. Alzaharna (2014) Push–pull Mechanisms Many critical processes are under dual control by agents that act antagonistically either to stimulate or to inhibit Such dual control allows for more precise regulation through negative feedback than would be possible with a single control system Epinephrine and norepinephrine released from the adrenal medulla and sympathetic nerve endings override both negative feedback systems by: – inhibiting insulin secretion – and stimulating glucagon secretion 19 In emergency situations or during exercise Hepatic production of glucose, which is increased by glucagon and inhibited by insulin