Human Physiology Course

Endocrine System Principles of hormonal regulation

Assoc. Prof. Mária Pallayová, MD, PhD [email protected]

Department of Human Physiology, PJ Safarik University FOM April 6-7, 2020 (9th week – Summer Semester 2019/2020) Chemical messenger systems

Types of chemical messenger systems:

Neurotransmitters

Endocrine hormones

Neuroendocrine hormones

Paracrines

Autocrines

Cytokines Neurotransmitters are released by axon terminals of neurons into the synaptic junctions act locally to control nerve cell functions. Endocrine hormones are released by glands or specialized cells into the circulating blood influence the function of target cells at another location in the body. Neuroendocrine hormones are secreted by neurons into the circulating blood influence the function of target cells at another location in the body. Paracrines are secreted by cells into the extracellular fluid affect neighboring target cells of a different type. Autocrines are secreted by cells into the extracellular fluid affect the function of the same cells that produced them. Cytokines are peptides secreted by cells into the extracelular fluid can function as autocrines, paracrines, or endocrine hormones. e.g., the interleukins and other lymphokines secreted by helper cells and act on other cells of the immune system. adipokines= cytokine hormones (e.g., leptin) produced by adipocytes. Hormonal vs. Humoral

????? Hormonal vs. Humoral

hormonal = endocrine humoral = endocrine + autocrine + paracrine The Endocrine Sytem

the endocrine signaling communication and coordination system. relies on hormones, chemical substances that are released into the bloodstream, to deliver messages to cells of the body. Hormones and Functions

Hormones are produced by: – endocrine glands – endocrine tissues (the brain, heart, kidney, adipose tissue, and GI tract). Endocrine cells may be: – diffusely located, e.g. in the stomach and intestines – found in clusters, e.g., the neurons of the hypothalamus. Endocrine Glands

Endocrine glands = ductless glands that empty their hormonal products directly into the blood. Anatomical loci of the principal endocrine glands and tissues of the body

Guyton and Hall Question

What is the largest endocrine tissue? Hormones signaling molecules involved in regulating a variety of processes.

The word “hormone” is derived from the Greek hormaein, which means to “excite” or to “stir up.”

Function: to regulate, integrate, and coordinate a variety of different physiological processes. Hormones Regulate and Coordinate Many Functions

The processes that hormones regulate fall into areas:

1) the digestion, utilization, and storage of nutrients; 2) growth and development; 3) ion and water balance; 4) reproductive function. Hormones and Functions

Thyroid hormone Parathyroids Thymus Adrenal glands Endocrine pancreas Ovaries, Testes Pineal Pituitary Hypothalamus-Pituitary Axis GIT, adipose tissue, brain, heart, kidney, ...

Guyton and Hall Essentials of Human Physiology Hormone receptors determine whether a cell will respond to a hormone are the molecular entities (usually a protein or glycoprotein) either outside or within a cell that recognize and bind a particular hormone. Only target cells that possess specific receptors for the hormone, will respond to that hormone. When a hormone binds to its receptor, biological effects characteristic of that hormone are initiated. the basis for specificity in cell-to-cell communication rests at the level of the receptor Feedback regulation an important part of endocrine function usually negative feedback a few positive feedback mechanisms simple first-order feedback loops more complex multilevel second- or third-order feedback loops Simple Feedback Loops

First-order feedback regulation is the simplest type and forms the basis for more complex modes of regulation.

E.g., an endocrine cell secretes a hormone that produces a specific biological effect in its target tissue. It also senses the magnitude of the effect produced by the hormone. As the biological response increases, the amount of hormone secreted by the endocrine cell is appropriately decreased. Negative feedback loop

Negative Feedback Prevents Overactivity of Hormone Systems. After a stimulus causes release of the hormone, conditions or products resulting from the action of the hormone tend to suppress its further release. E.g.: ft4 - TSH Feedback regulation of hormones can occur at all levels, including gene transcription and translation steps involved in the synthesis of hormones and steps involved in processing hormones or releasing stored hormones. Negative feedback loop

The controlled variable is sometimes not the secretory rate of the hormone itself but the degree of activity of the target tissue.

 only when the target tissue activity rises to an appropriate level will feedback signals to the endocrine gland become powerful enough to slow further secretion of the hormone. Positive feedback loop the surge of luteinizing hormone (LH) that occurs as a result of the stimulatory effect of estrogen on the anterior pituitary before ovulation

the secreted LH acts on the ovaries to stimulate additional secretion of estrogen, which in turn causes more secretion of LH

eventually, LH reaches an appropriate concentration and typical negative feedback control of hormone secretion is then exerted Complex Feedback Loops

More commonly, feedback regulation in the endocrine system is complex, involving second- or third-order feedback loops.

E.g., multiple levels of feedback regulation may be involved in regulating hormone production by various endocrine glands under the control of the anterior pituitary. A complex, multilevel feedback loop

The hypothalamic-pituitary- target gland axis

Solid lines indicate stimulatory effects; dashed lines indicate inhibitory, negative- feedback effects.

Lippincott Signal Amplification is an important characteristic of the endocrine system

Blood concentrations of hormones are exceedingly low, generally, 10-9 to 10-12 mol/L.

Therefore, for hormones to be effective regulators of biological processes, amplification must be part of the overall mechanism of hormone action. Signal Amplification

Amplification generally results from the activation of a series of enzymatic steps involved in hormone action.

At each step, many times more signal molecules are generated than were present at the prior step, leading to a cascade of increasing numbers of signal molecules.

The self-multiplying nature of the hormone action pathways provides the molecular basis for amplification in the endocrine system. Chemical structure of hormones

Amino Acid-Derived Hormones - the simplest hormones in terms of structure, consist of one or two modified amino acids

Protein and Polypeptide Hormones

Steroid Hormones - derived from cholesterol

Eicosanoids - lipids synthesized from FA chains of phospholipids found in plasma membrane („local hormones“) Amino acid-derived hormones derived from one or two amino acids are small in size and often hydrophilic are formed by conversion from a commonly occurring amino acid (epinephrine and thyroxine are derived from tyrosine) the synthesis of amino acid-derived hormones can be influenced by a variety of environmental/pharmacological agents Polypeptide Hormones are quite diverse in size and complexity may be as small as the tripeptide thyrotropin-releasing hormone (TRH) or as large as human chorionic gonadotropin (hCG), which is a glycoprotein composed of separate alpha and beta subunits

Polypeptide and Protein Hormones Are Stored in Secretory Vesicles Until Needed. a number of families of hormones can be grouped into families based on homology with regard to amino acid sequence and structure Examples of Peptide Hormone Families

Glycoprotein Family Secretin Family . Luteinizing hormone (LH) . Secretin . Follicle-stimulating hormone (FSH) . Vasoactive intestinal peptide (VIP) . Thyroid-stimulating hormone (TSH) . Glucagon . Human chorionic gonadotropin (hCG) . Gastric inhibitory peptide (GIP)

Growth Hormone Family Insulin Family . Growth hormone (GH) . Insulin . Insulin-like growth factor I . Prolactin (PRL) . Insulin-like growth factor II . Human placental lactogen (hPL) . Relaxin Steroid Hormones lipid-soluble, hydrophobic molecules usually synthesized from cholesterol and are not stored. large stores of cholesterol esters in cytoplasm vacuoles can be rapidly mobilized for steroid synthesis after a stimulus.

Much of the cholesterol in steroid-producing cells comes from the plasma, but there is also de novo synthesis of cholesterol in steroid- producing cells.

Because the steroids are highly lipid soluble, once they are synthesized, they simply diffuse across the cell membrane and enter the interstitial fluid and then the blood. Steroid Hormones

They can be classified into six categories, based on their primary biological activity. 1) Cortisol (a glucocorticoid) 2) Aldosterone (a mineralocorticoid) 3) Testosterone (an androgen) 4) Estradiol (an estrogen) 5) Progesterone (a progestin) 6) 1,25 (OH)2 Cholecalciferol (a calciferol) 1) Glucocorticoids

Glucocorticoids (e.g., cortisol) are primarily produced in cells of the adrenal cortex.

Glucocorticoids regulate processes involved in glucose, protein, and lipid homeostasis.

Glucocorticoids generally produce effects that are catabolic in nature. 2) Mineralocorticoids

Mineralocorticoids (e.g., aldosterone) are produced in cells of the outermost portion of the adrenal cortex.

Aldosterone is primarily involved in regulating Na and K balance by the kidneys and is the principal mineralocorticoid in the body. 3) Androgens

Androgens, such as testosterone, are produced by the gonads (by the Leydig cells in testes in men and by the ovaries in women).

Physiologically significant amounts can be synthesized by the adrenal cortex in both sexes as well. 4) Estrogens

The primary female sex hormone is estradiol, a member of the estrogen family.

Estradiol is produced by the ovaries and placenta.

In the adult testis, estrogen is synthesized by Leydig cells and the germ cells, producing a relatively high concentration in rete testis fluid. Estrogen receptors are present in the testis, efferent ductules and epididymis. 5) Progestins

Progestins, such as progesterone, are involved in maintenance of pregnancy.

Progestins are produced by the ovaries and placenta.

Testicular progesterone has been regarded as a by-product of steroidogenesis, which is not converted into testosterone. With aging, the testicular progesterone/androgen ratio increases and absolute progesterone concentrations can reach high levels. 6) Calciferols

The calciferols, such as 1,25-dihydroxycholecalciferol, are involved in the regulation of calcium homeostasis.

1,25-dihydroxycholecalciferol is the hormonally active form of vitamin D and is formed by a sequence of reactions occurring in skin, liver, and kidneys. Synthesis of Hormones

Steroid hormones are synthesized and secreted on demand. Polypeptide hormones are typically stored prior to secretion. Polypeptide hormones are synthesized with a pre- or signal peptide at their amino terminal end that directs the growing peptide chain into the cisternae of the rough ER. Most polypeptide hormones are synthesized as part of an even larger precursor or preprohormone. The prepeptide is cleaved off upon entry of the preprohormone into the rough ER, to form the prohormone. As the prohormone is processed through the Golgi apparatus and packaged into secretory vesicles, it is proteolytically cleaved at one or more sites to yield active hormone. Synthesis and secretion of peptide hormones:

 The stimulus for hormone secretion often involves changes in IC Ca or cAMP. Transport of Hormones

Most amino acid-derived and polypeptide hormones dissolve readily in the plasma, and thus no special mechanisms are required for their transport. Steroid and thyroid hormones are relatively insoluble in plasma ( most of them are bound to plasma proteins).

The principal binding proteins involved in specific and nonspecific transport of steroid and thyroid hormones are synthesized and secreted by the liver, and their production is influenced by changes in various nutritional and endocrine factors. Circulating Transport Proteins

Lippincott The relationship between hormone secretion, carrier protein binding, and hormone degradation determines the amount of free hormone available for receptor binding and the production of biological effects. Measurement of Hormone Concentrations

an important tool in endocrinology

 Bioassay

 Radioimmunoassay (RIA)

 The enzyme-linked immunosorbent assay (ELISA) MECHANISMS OF HORMONE ACTION

Hormones are one mechanism by which cells communicate with one another.

Fidelity of communication in the endocrine system depends on each hormone’s ability to interact with a specific receptor in its target tissues.

This interaction results in the activation (or inhibition) of a series of specific events in cells that results in precise biological responses characteristic of that hormone. MECHANISMS OF HORMONE ACTION

The binding of a hormone to its receptor with subsequent activation of the receptor is the first step in hormone action.

Abnormal interactions of hormones with their receptors are involved in the pathogenesis of a number of endocrine disease states. MECHANISMS OF HORMONE ACTION

The locations for the different types of hormone receptors:

1) In or on the surface of the cell membrane. The membrane receptors are specific mostly for the protein, peptide, and catecholamine hormones.

2) In the cell cytoplasm. The primary receptors for the different steroid hormones are found mainly in the cytoplasm.

3) In the cell nucleus. The receptors for the thyroid hormones are found in the nucleus. Intracellular Signaling After Hormone Receptor Activation

a hormone affects its target tissues by first forming the hormone-receptor complex

– this alters the function of the receptor itself,

– the activated receptor initiates the hormonal effects Intracellular Signaling After Hormone Receptor Activation

Examples of the different types of interactions:

Ion Channel–Linked Receptors

G Protein–Linked Hormone Receptors

Enzyme-Linked Hormone Receptors

Intracellular Hormone Receptors and Activation of Genes Ion Channel–Linked Receptors

• e.g. neurotransmitters (acetylcholine, norepinephrine)  combine with receptors in the postsynaptic membrane, opening or closing a channel for one or more ions (Na, K, Ca, etc.)

• most hormones do this indirectly by coupling with G- protein-linked or enzyme-linked receptors G Protein–Linked Hormone Receptors heterotrimeric GTP-binding proteins when the hormone binds to the EC part of the receptor, activation of the G protein induces IC signals that – open or close membrane ion channels or – change the activity of an enzyme in the cytoplasm of the cell some hormones are coupled to inhibitory G proteins, some to stimulatory G proteins  a hormone can either decrease or increase the activity of IC enzymes Enzyme-Linked Hormone Receptors e.g. leptine receptor proteins that pass through the membrane only once and when activated, function directly as enzymes Second Messenger Mechanisms for Mediating IC Hormonal Functions

Adenylyl Cyclase–cAMP Second Messenger System Adrenocorticotropic hormone (ACTH) Angiotensin II (epithelial cells) Calcitonin Catecholamines (β receptors) Corticotropin-releasing hormone (CRH) Follicle-stimulating hormone (FSH) Glucagon Human chorionic gonadotropin (HCG) Luteinizing hormone (LH) Parathyroid hormone (PTH) Secretin Somatostatin Thyroid-stimulating hormone (TSH) Vasopressin (V2 receptor, epithelial cells) Second Messenger Mechanisms for Mediating IC Hormonal Functions

Cell Membrane Phospholipid Second Messenger System Angiotensin II (vascular smooth muscle) Catecholamines (α receptors) Gonadotropin-releasing hormone (GnRH) Growth hormone–releasing hormone (GHRH) Oxytocin Thyrotropin releasing hormone (TRH) Vasopressin (V1 receptor, vascular smooth muscle)

Calcium-Calmodulin Second Messenger System • calmodulin-Ca  activation of myosin light chain kinase The cAMP and the cell membrane phospholipid second messenger systems

Guyton and Hall Hormones That Act Mainly on the Genetic Machinery of the Cell

Steroid Hormones Increase Protein Synthesis 1. The steroid hormone diffuses across the cell membrane and enters the cytoplasm of the cell, where it binds with a specific receptor protein. 2. The combined receptor protein–hormone then diffuses into or is transported into the nucleus. 3. The combination binds at specific points on the DNA strands in the chromosomes, which activates the transcription process of specific genes to form mRNA. 4. The mRNA diffuses into the cytoplasm, where it promotes the translation process at the ribosomes to form new proteins. Hormones That Act Mainly on the Genetic Machinery of the Cell (cont.)

Thyroid Hormones Increase Gene Transcription in the Cell Nucleus

1. They activate the genetic mechanisms for the formation of many types of intracellular proteins—probably 100 or more. Many of these are enzymes that promote enhanced intracellular metabolic activity in virtually all cells of the body.

2. Once bound to the intranuclear receptors, the thyroid hormones can continue to express their control functions for days or even weeks. Dose-response curves

Physiological or pathophysiological alterations in target tissue responses to hormones can take one of two general forms, as indicated by changes in their dose-response curves.

Changes in dose-response curves can serve to distinguish between a receptor abnormality and a postreceptor abnormality in hormone action, providing useful information regarding the underlying cause of a particular disease state. A normal dose-response curve of hormone activity A minimal threshold concentration must be present to produce the cellular response.

At higher hormone concentrations, a maximal response by the target cell is produced, and no greater response can be elicited by increasing the hormone concentration. The concentration of hormone required to produce a response half- way between the maximal and basal responses, the median effective dose or ED50, is a useful index of the sensitivity of the target cell for that particular hormone. Altered target tissue responses

A change in responsiveness is indicated by an increase or decrease in the maximal response of the target tissue and may be the result of one or more factors.

Altered responsiveness can be caused:

– by a change in the number of functional target cells in a tissue,

– by a change in the number of receptors per cell for the hormone in question,

– by a change in the specific rate-limiting postreceptor step in the hormone action pathway (if receptor function itself is not rate- limiting for hormone action) Altered target tissue responses

A change in sensitivity is reflected as a right or left shift in the dose- response curve and, thus, a change in the ED50; a right shift indicates decreased sensitivity and a left shift indicates increased sensitivity for that hormone. Changes in sensitivity reflect: (1) an alteration in receptor affinity (2) a change in receptor number (if submaximal concentrations of hormone are present) Dose response curves may also reflect combinations of changes in responsiveness and sensitivity in which there is both a right or left shift of the curve (a sensitivity change) and a change in maximal biological response to a lower or higher level (a change in responsiveness). Altered target tissue responses reflected by dose- response curves. A, Decreased target tissue responsiveness. B, Decreased target tissue sensitivity. Summary

Hormones are chemical substances, involved in cell-to-cell communication, that promote the maintenance of homeostasis. There are six classes of steroid hormones, based on their primary actions. Most polypeptide hormones are initially synthesized as preprohormones. Steroid hormones and thyroid hormones are generally transported in the bloodstream bound to carrier proteins, whereas most peptide and protein hormones are soluble in the plasma and are carried free in solution. Altered hormone-receptor interactions may lead to endocrine abnormalities. References

Guyton and Hall: Textbook of medical physiology, 12th ed., p. 881-894.

Patricia E. Moline: Endocrine Physiology, 3rd ed.

Lippincott: Medical Physiology

Essentials of Human Physiology