Overview of Endocrinology

Introduction

Endocrinology: the study of the endocrine system, one type of cell-to-cell signal transduction

glandular secretory cell secretes a hormone that diffuses into bloodstream Þ travels to other parts of body

hormone then diffuses out of the bloodstream and binds extracellular or intracellular receptor on target cell

binding to receptor causes changes in the target cell which represent the effect of the hormone

Compare with other cell-to-cell signal transduction systems:

(1) Neuronal – synaptic transmission

(2) Neuroendocrine – as in posterior pituitary, see below

(3) Paracrine – between adjacent cells

(4) Autocrine – within the same cell

Five major glands of the endocrine system

(1) Endocrine Pancreas – mediates carbohydrate metabolism via 2 hormones secreted from cells in Islets of Langerhans

Insulin:

Ý glucose transport in peripheral cells (especially adipose tissue and skeletal muscle)

ß lipolysis and proteolysis (restricting fuel sources)

ß hepatic glucose production: glycogenolysis and gluconeogenesis

ß hepatic ketogenesis

Glucagon (mirror image of insulin) Ý hepatic gluconeogenesis and glycogenolysis; Ý hepatic ketogenesis; Ý lipolysis

(2) Thyroid Gland – bi-lobed structure in the neck above the suprasternal notch

consists of spheres of thyroid cells called "follicles" which are composed of colloid (made up of thyroglobulin) and bordered by follicular cells

Thyroid Hormone – made from thyroglobulin – two forms: T₄ = Thyroxine; T₃ = Tri-iodothyronine

T₃ (3 iodine atoms) is more potent than T₄ (4 iodine atoms), but both have the same action

Primary Action: Ý metabolic rate – more O₂ and CO₂ is produced due to Ý cellular chemical reactions

Secondary Effects: Ý heat production; Ý cell activity; Ý cell turnover; Ý b -adrenergic receptor expression

follicular cells take up thyroglobulin, convert it to T₄ or T₃, and secrete it into the bloodstream

(3) Adrenal Gland – sit above kidneys in the retroperitoneum – consist of an outer cortex and an inner medulla

Adrenal Cortex – consists of three zones, in order from superficial to deep:

(a) Zona Glomerulosa – produces aldosterone, which enhances renal reabsorption of salt and H₂O, and excretion of potassium and acid

(b) Zona Fasciculata – produces cortisol, which primarily Ý fuels in blood (glucose, amino and fatty acids)

(c) Zona Reticularis – makes adrenal androgens and estrogen (this will be covered in repro committee)

Adrenal Medulla – produces two catecholamines – epinephrine (80%) and norepinephrine (20%); these hormones mediate the "fight or flight" reflex

(4) Parathyroid Gland – controls Ca⁺⁺ levels in the blood; secreted from 4 glands located on the thyroid gland in the neck

parathyroid hormone (PTH) increases Ca⁺⁺ in 3 ways:

(1) Ý bone resorption – increases serum Ca⁺⁺ and PO₄^2-

(2) Ý renal Ca⁺⁺ reabsorption – also Ý renal PO₄^2- excretion (ß serum PO₄^2- levels)

(3) Ý activation of Vitamin D – active vitamin D (1,25-dihydroxy vit.D) Ý absorption of Ca⁺⁺ and PO₄^2- from gut

inactive vitamin D comes from diet or is synthesized in skin from 7-dehydroxycholesterol + UV light
activation occurs by means of two hydroxylation events: in the liver (at C-25) and kidney cortex (at C-1)

(5) Pituitary Gland – connected to hypothalamus by a stalk – anterior and posterior parts have very different functions

Anterior Pituitary (adenohypophysis; pars distalis) – ball of discrete cell types that secrete different hormones

Thyroid stimulating Hormone (TSH) – stimulates production of thyroid hormone (T₃ and T₄)

Adrenocorticotrophic Hormone (ACTH) – stimulates adrenal production of cortisol

Leutinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) – regulate ovary and testis function

Growth Hormone (GH) – regulates growth during childhood and adolescence

Prolactin – stimulates synthesis of breast milk in lactating women

Posterior Pituitary (neurohypophysis; pars nervosa) – terminal axons of hypothalamic neurons (store 2 horm)

Anti-diuretic Hormone (ADH, vasopressin) – stimulates kidneys to reabsorb more H₂O

Oxytocin: stimulates uterine contractions during delivery and the milk let down reflex to initiate breast feeding
both are made in the neuronal cell bodies (in the hypothalamus) and released during action potential

Three Classes of Hormones

(1) Polypeptide Hormone – interact with cell surface receptors – usu. G-protein, occasionally receptor tyr kinase (insulin)

Structure – protein consisting of 3-250 amino acids

Synthesis – prohormone formed by transcription and translation in RER

N-terminal signal sequence causes transportation to Golgi – modification by glycosylation, cleavage, etc.
mature hormone is packaged into secretory granules and released when necessary

Secretion – by exocytosis (involves reorganization of microtubules and microfilaments) followed by diffusion into capillaries

exocytosis commonly occurs as a result of Ý cAMP, Ca⁺⁺, and/or phosphatidylinositol signals

secretion from golgi vesicles can lead to low level of prohormone in circulation

Transport – free unbound state, since peptide hormones are water-soluble

unbound state leads to high metabolic clearance and short half-life

this is appropriate for insulin, which regulates sudden and rapid fluctuations in glucose level

Metabolism – generally cleared by non-specific proteases, especially in the kidney and liver

breakdown products generally are metabolically inactive; also minor urinary excretion of peptide hormone

(2) Steroid Hormones – diffuse into cell and activate transcription factors that directly affect gene transcription

Structure – based on cholesterol, often with significant modifications (e.g., cholesterol is broken open by UV light in Vit D)

Synthesis – stepwise reactions involving cholesterol as substrate (hydroxylase, oxidoreductase, isomerase, sulfatase, etc.)

Note: Vit D looks different because it is actually formed by breaking one of the rings of cholesterol

Secretion – diffuse into circulation as they are made, since they are lipid soluble – steroid hormones are never stored

Transport – bound to protein – since steroid hormones are lipid-soluble, this greatly increases solubility in blood

bound state leads to low metabolic clearance and long half-life

this is appropriate for cortisol, which makes gross adjustments in the levels of glucose, amino acids and fatty acids

Metabolism – hydroxylated then conjugated with glucuronic acid and excreted in the urine

metabolism does not always inactivate, but can also change activity (e.g., testosterone Þ estradiol)

(3) Amine Hormones – all structurally based upon tyrosine, but other characteristics are more diverse – two examples:

(a) Thyroid Hormone – similar to steroid hormones, with intracellular receptors

Structure – two tyrosines added together and several iodine atoms added at various locations

Synthesis – occurs in cytoplasm of follicular cell – includes organification (addition of iodine to tyrosine rings)

iodide from blood is actively pumped into cells (iodide trapping), is oxidized to iodine and rapidly added to tyrosine rings (organification)

two tyrosine residues are coupled by folding into thyroglobulin which is excreted and stored in the colloid

Secretion – upon stimulation to secrete, follicular cells bring thyroglobulin back into the cell by pinocytosis

lysosomal degradation yields mature T₃ and T₄ which then diffuses into circulation

Transport – highly protein bound (99.9%) so low clearance and long half-life (very slow fluctuations)

Metabolism – deiodination – initial metabolism of T₄ to T₃ actually Ý potency

(b) Catecholamines (epinephrine, norepinephrine) – similar to peptide hormones, with cell surface receptors

Structure – modified and hydoxylated tyrosine

Synthesis – series of reactions in cytoplasm and secretory granules (hydroxylation, decarboxylation and methylation)

Secretion – exocytosis of secretory granules (like peptide hormones)

Transport – free unbound state (like peptide hormones)

Metabolism – methylation and oxidation with renal excretion of the products – several pathways

pheochromocytoma (catecholamine-secreting tumors) also metabolize the catecholamines they produce, so urinary analysis of this tumor must involve measurements of metabolites/degradation products

Regulation of Hormone Secretion

Hormone regulation occurs primarily by negative feedback (like a thermostat): Ý Hormone Þ Ý Substrate Þ ß Hormone

such loops exist for TSH/thyroid hormone; glucagon/glucose; PTH/Ca⁺⁺; ACTH/cortisol; aldosterone/K⁺

Neural stimuli from brain in response to time of –Day –Month –Life, Sleep, light, pain, sex, stress, nausea…

e.g., neural stimuli cause release of CRF from hypothalamus Þ Ý ACTH Þ Ý cortisol

Measurement of Hormone – the Radioimmune Assay

The Radioimmune Assay is based upon competition of radiolabelled ("tracer") and native hormone for a binding protein.

the ratio of bound to free tracer hormone will be inversely proportional to the concentration of unlabelled hormone, since the unlabelled hormone will displace a certain amount of the tracer

a standard curve can be produced from fixed amount of tracer hormone and various amounts of unlabelled hormone, and this can be used to measure conc. of hormone in blood or urine

The Dose-Response Curve – an analogy to Pharmacology

A shift to the right (Þ ) means ß in hormone sensitivity; caused by:

ß in # of receptors; ß in affinity of receptor for hormone;

Ý hormone degradation; Ý in competitive antagonist for receptor

A decrease in maximum responsiveness can be caused by:

ß # of target cells; ß in receptor # (if max respon. requires saturation)

ß in target enzyme or substrate; Ý in non-competitive antagonist