Endocrinology Lecture Notes PDF

The Endocrine System The Endocrine System Control system Consists of cells secreting hormones  Hormones regulate: The metabolic functions of the body The rates of chemical reactions Transport of substances in the cells Growth Reproduction...

The Endocrine System The Endocrine System Control system Consists of cells secreting hormones  Hormones regulate: The metabolic functions of the body The rates of chemical reactions Transport of substances in the cells Growth Reproduction 3  Hormones blood target secreting cell cell (endocrine cell) –Classical Endocrine Definition: –Chemical signals packaged in granules or secretory vesicles –Secreted by a cell or group of cells –Transported by blood – Act on distant target tissues (receptors) –Activate physiological response at low concentrations (nanomolar to  Nature of a Hormone A chemical substance secreted into the internal body fluids by a cell or group of cells that exerts control on other cells of the body General hormones are secreted by the endocrine cells into the blood 5 Hormones  Where are these endocrine cells? Found in different organs Grouped to form endocrine gland (a gland is an organ that secretes) 8 Location of major endocrine glands 9 Hormone mode of action 10 Major classes of Hormones Proteins/peptides Insulin, glucagon, growth factors Amines (amino acid derivatives) Epinephrine, thyroxine Steroids (cholesterol derivatives) Aldosterone, cortisol, testosterone 12 Peptide/Protein hormones Amino acids are the building blocks of proteins Connected by peptide bonds to form polypeptide chains 13 Protein/peptide hormones 14 Where does the information for protein synthesis come from? 15 DNA molecule 16  RNA molecule Single strand (Similar to DNA) RNA nucleotide consists of nitrogenous base (adenine, uracil, cytosine or guanine) a ribose sugar a phosphate group Messenger RNA (mRNA): directs synthesis of protein Ribosomal RNA (rRNA): part of ribosome Transfer RNA (tRNA): brings amino acid to ribosome during protein synthesis 17  DNA strand transcriptio n Messenger RNA (mRNA) translation protein 18 19 20 22  Peptide hormone synthesis and secretion Nucleus Rough Golgi Secretory endoplasmic apparatus vesicles reticulum synthesis packaging storage secretion preprohormone prohormone hormone Hormone + “pro” prohormone hormone fragments 24  Protein/Peptide Hormones Synthesized as prehormones or preprohormones Contain a chain of amino acids called the “signal peptide” The signal peptide is cleaved off in the cisternae of the ER yielding either a prohormone or hormone The hormone or prohormone is than transported to the Golgi apparatus and packaged in membrane-bound vesicles Prohormones require farther cleavage to produce the final hormone which usually occurs in the Golgi of the membrane- bound vesicles When the prohormone is cleaved, the vesicles contain both hormone and “pro” fragments 26 Peptide hormone synthesis and secretion 27 Hormone Synthesis and Secretion Example: Insulin Produced as preproinsulin Cleaved to proinsulin in the ER Proinsulin is cleaved in the membrane-bound vesicles producing equal molar amounts of insulin and a “pro” fragment called connective peptide (C peptide) Both insulin and C peptide are released by the vesicles on stimulation 28  Peptide/protein Hormone Synthesis and Processing Prohormones Process to Active Hormone Plus Peptide Fragments The peptide chain of insulin’s prohormone folds back on itself with Proinsulin processes to Insulin the help of disulfide (S C-peptide —S) bonds. The prohormone cleaves to insulin and C-peptide. Clinicians can measure C-peptide concentrations in the blood of diabetic patients to monitor endogenous insulin production.  Clinical importance of “pro” fragments What might be the clinical importance of measuring C peptide in a person with type 1 diabetes mellitus? 30 Peptide Hormone Synthesis and Processing  Peptide hormone secretion: exocytosis Exit of substances (proteins) from the cell secretory Vesicles fuse with the plasma membrane Empty of their contents to the exterior of the cell Requirements Calcium Intact cytoskeleton (microtubules, 32  Peptide/Protein hormone circulation and metabolism Short half-life Half-life of a hormone: the amount of time required for half of the molecules to become inactivated or cleared from circulation. Short peptide (oxytocin) – 30 minutes Larger peptide (TSH) – 60 minutes Peptidase (proteolytic enzyme) Found in tissue fl uids or associated with cellular membranes Inactivates peptide hormones by splitting the molecule at specifi c peptide bonds Short half-life has limited clinical use 33 Transport of protein/peptide hormones Soluble in aqueous solvents Most circulate in the blood in the unbound form 34  Protein/peptide hormone administration Protein/peptides are digested (GIT) Administration by: Injection Sublingually or intranasally (through mucous membrane) 35  Questi on Why insulin (protein hormone) is administered by injection and not in a pill form? © 2013 Pearson Education, Inc.  Protein/peptide hormones: Synthesized as pre- or preprohormones Stored in membrane bound vesicles Are relatively polar Often circulate in blood unbound Cannot be administered orally Have cell membrane receptors 38 Steroid hormones 38 Steroid hormone structure 39  Steroid hormone synthesis cholesterol pregnenolone dehydroepiandrosterone progesterone 17-hydroxyprogesterone androstenedione corticosterone cortisol aldosterone 40  Steroid Hormones Cholesterol is the parent compound for all steroid hormones. Dihydro- testosterone DHEA  dehydroepiandrosterone (DHT) Adrenal Ovary cortex  intermediate compounds whose names have been aromatase omitted for simplicity. Testosterone Estradiol Andro- aromatase DHEA stenedione Estrone 21-hydroxylase Cortisol 21-hydroxylase Cholesterol Progesterone Corticosterone Aldosterone Each step is catalyzed by an enzyme, but only two enzymes are shown in this figure.  Hormones: Cholesterol-derived Steroid – Lipophilic and easily cross membranes – Synthesized on demand in parent cell smooth ER- diffuse out Bind carrier proteins in blood – Lengthens their half-life Cytoplasmic or nuclear receptors – Genomic effect to activate or repress genes for protein synthesis – Slower acting Cell membrane receptors – Nongenomic responses Administered orally (GI absorption ok) © 2013 Pearson Education, Inc.  Amine hormones Derived from the amino acid tyrosine Thyroid, Catecholamines 43  Amine Hormones made from Tyrosine Most amine hormones are derived from the amino acid tyrosine. Tyrosine is the parent amino acid for catecholamines and thyroid hormones. Catecholamines Thyroid hormones are made by modifying are synthesized from two the side groups of tyrosine. tyrosines and iodine (I) atoms. Dopamine Thyroxine (Tetraiodothyronine, T4) Norepinephrine Epinephrine Triiodothyronine (T3)  Amine hormones Thyroid hormones Are stored in the follicle Not soluble in blood and aqueous fluids: transported bound to plasma proteins Administered orally Act through intracellular receptors 44  Amine hormones Catecholamines Synthesized and stored within the endocrine cells in preformed vesicles Soluble in blood: transported in free form and bound to plasma proteins Could not be administered orally Act through cell surface receptors 46 Comparison of Peptide, Steroid, and Amino Acid-Derived Hormones  Hormone binding to plasma proteins Steroid and thyroid hormones Proteins in plasma Saturable binding Reversible binding bound [hormone] 47  Hormone binding to plasma proteins hormone + protein hormone-protein [H] + [P] [HP] *free hormone = biologically active 49 Hormone-Protein Binding Serves transport Provides a reservoir Buffers acute changes in hormone secretion Slows their clearance from plasma 50  Hormone action Hormone Receptor Effect 51 A 46, XY (man), phenotypic woman with complete androgen 52 Hormone response determinants? Number of receptors Receptor affi nity for hormone 53  Hormone receptors Large proteins (2,000-100,000/cell) Highly specific for a single hormone Lack of receptor ==> lack of response Receptor Location: Cell membrane Cytoplasm Nucleus 54 Hormone receptors and response Plasma hormone concentration low 10-12 - 10-9 M (molar = moles/liter) hormone receptors have high affi nity for the hormone Nuclear receptors present in small numbers Magnitude of response depends on receptor number 55  Hormone dose response Insulin dose-response curve. Effects of decreased insulin sensitivity or insulin responsiveness or both. 56  Spare receptors Cell surface receptors present in large number Maximum response can occur with only 15-25% of receptor binding Spare receptors The additional receptors, over and above the number necessary to produce a maximal response Presence of spare receptors: response is affected more by the receptor affi nity than the receptor number 57  Receptor number regulation Number of receptors in target cell can increase or decrease Upregulation (increased synthesis or decrease degradation) Downregulation (increased degradation or decreased synthesis) Increased hormone levels => reduce H receptor level Receptor synthesis Receptor internalization => endocytosis => PM R No * H: hormone; PM: plasma membrane; R: receptor; No: number 58  Endocytosis involved in receptor downregulation 59 Endocytosis 60 61 Endocrine Pathways In complex endocrine pathways, the hormones of the Control Pathway for Cortisol Secretion pathway serve as negative feedback signals. Cortisol is a steroid hormone secreted by the adrenal cortex. ACTH  corticotropin or adrenocorticotropic hormone; CRH  corticotropin-releasing hormone. Stimulus Hypothalamus Hypothalamus Short-loop negative feedback (IC1) CRH Trophic hormone (H1) Long-loop negative feedback Anterior Long-loop negative feedback pituitary Anterior pituitary (IC2) ACTH Trophic hormone (H2) Adrenal cortex Endocrine gland (IC3) Cortisol Hormone (H3) Target To target tissue tissue Target tissue Response Response Endocrine pathologies Hypersecret ion Hyposecreti on  Primary and secondary Primary Hypersecretion Due to Problem with Adrenal Cortex Secondary Hypersecretion Due to Pituitary Problem Secondary Hypersecretion Due to Hypothalamic Problem hypersecretion of cortisol Hypothalamus CRH HypothalamusCRH HYPERSECRETING TUMOR IN CRH HYPOTHALAMUS PATHOLOGY Anterior Anterior ACTH pituitary IN ACTH ACTH ANTERIOR pituitary PITUITARY PATHOLOGY IN Cortisol Adrenal Adrenal cortex ADRENAL cortex Cortisol Cortisol Negative CORTEX feedback fails Symptoms Symptoms Symptoms of excess of excess of excess CRH levels – low CRH levels – low CRH levels – high ACTH levels – low ACTH levels – high ACTH levels – high Cortisol levels – high Cortisol levels – high Cortisol levels – high  Hormone Interactions Synergism – Combined effect is greater than the sum of individual effects Permissiveness – Need second hormone to get full effect – TH and reproductive hormones are both needed for normal development of the reproductive system Antagonism – One substance opposes the action of another – Competitive inhibitors vs. functional antagonism – competition for the same receptor – Glucagon and growth hormone oppose insulin’s blood glucose lowering action, but each uses a © 2013 Pearson different mechanism Education, Inc.  Figure 7.12 Synergism 250 Glucagon  Epinephrine  Cortisol Blood glucose (mg/dL) 200 150 Glucagon  Epinephrine Epinephrine Glucagon 100 Cortisol 0 1 2 3 4 5 Time (hours)  Circadian Rhythm World: rhythmic place (sun rise and set, season changing) Nearly every organism must adapt to these rhythms to thrive Most organisms (humans), have internal mechanisms that track time Biological timekeepers that operate on a daily cycle are called circadian clocks and generate circadian rhythms The word circadian means "about a day." 68  Circadian Rhythm Circadian rhythms are generated endogenously (the rhythms persist in the absence of external time cues) Such mechanisms have many uses: Regulate daily activity patterns Trigger reproduction. 69  Hormonal rhythms Periodic or rhythmic secretion of hormones Period of rhythms: minutes – months Rhytmicity: important for normal endocrine function 70 Hormonal rhythms Changes in hormone secretion occur during the day 71  Hormonal rhythms Air travel, shift work and space travel are modem activities that profoundly disturb the body's inner biological or "circadian" clock, giving rise to several minor (and in some cases serious) health problems. Jet lag is a familiar disorder in which rapidly flying across several time zones disrupts the body's circadian rhythm. Its hallmarks are lightheadedness, diffi culty concentrating, fatigue and an inability to sleep well. 72 Study tips: Where is the hormone produced? What is the structure of the hormone? In what class it belongs? (peptide/protein, amine, steroid) How is the hormone produced? How is the hormone transported in the blood? What are the main target tissues of the hormone? What is the mechanism of action of the hormone? receptors ? What are the main effects of the hormone in the target tissues? What are the major pathologies associated with hypersecretion or hyposecretion of the hormone? The end 74