Endocrine PhysiologyDale Buchanan Hales, PhDDepartment of Physiology & Biophysics

Arnold A Berthold (1803-1861) In one of the first endocrine experiments ever recorded, Professor Arnold A. Berthold of Gottingen did a series of tests on roosters in 1849 while he was curator of the local zoo.

Ablation and replacementBethold found that a rooster's comb is an androgen-dependent structure. Following castration, the comb atrophies, aggressive male behavior disappears, and interest in the hens is lost.Importantly, Berthold also found that these castration-induced changes could be reversed by administration of a crude testicular extract (or prevented by transplantation of the testes).

Claude Bernard(1813-1878)Claude Bernard stated that the endocrine system regulates the internal milieu of an animal. The internal secretions were liberated by one part of the body, traveled via the bloodstream to distant targets cells. Circa 1854Bernard's charge was to demonstrate that medicine, in order to progress, must be founded on experimental physiology.

Endocrine system maintains homeostasisThe concept that hormones acting on distant target cells to maintain the stability of the internal milieu was a major advance in physiological understanding. The secretion of the hormone was evoked by a change in the milieu and the resulting action on the target cell restored the milieu to normal. The desired return to the status quo results in the maintenance of homeostasis

Charles Edouard Brown-Squard (1817-1894) Brown-Sequard further piqued mainstream scientific interest in the chemical contents of the testes with his famous auto-experimentation. On June 1, 1889, before the Socite de Biologic in Paris, Brown-Sequard reported that he had increased his physical strength, mental abilities and appetite by self-injection with an extract derived from the testicles of dogs and guinea pigsAlthough never substantiated, this claim prompted researchers around the world to pursue the new field of organotherapy

Ernest Henry Starling (1866-1927)Besides "his" law of the heart, Starling discovered the functional significance of serum proteins. In 1902 along with Bayliss he demonstrated that secretin stimulates pancreatic secretion. In 1924 along with E. B. Vernay he demonstrated the reabsorption of water by the tubules of the kidney.He was the first to use the term hormone

Jim Ferguson1947-2002Famous cardiovascular physiologistTruly understood Starlings LawDisputed that the main purpose of the cardiovascular system was to deliver hormones.

Sensing and signalingEndocrine glands synthesize and store hormones. These glands have a sensing and signaling system which regulate the duration and magnitude of hormone release via feedback from the target cell.

Endocrine vs. Nervous SystemMajor communication systems in the bodyIntegrate stimuli and responses to changes in external and internal environmentBoth are crucial to coordinated functions of highly differentiated cells, tissues and organsUnlike the nervous system, the endocrine system is anatomically discontinuous.

Nervous system

The nervous system exerts point-to-point control through nerves, similar to sending messages by conventional telephone. Nervous control is electrical in nature and fast.

Hormones travel via the bloodstream to target cellsThe endocrine system broadcasts its hormonal messages to essentially all cells by secretion into blood and extracellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

A cell is a target because is has a specific receptor for the hormoneMost hormones circulate in blood, coming into contact with essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.

Principal functions of the endocrine systemMaintenance of the internal environment in the body (maintaining the optimum biochemical environment).Integration and regulation of growth and development.Control, maintenance and instigation of sexual reproduction, including gametogenesis, coitus, fertilization, fetal growth and development and nourishment of the newborn.

Types of cell-to-cell signalingClassic endocrine hormones travel via bloodstream to target cells; neurohormones are released via synapses and travel via the bloostream; paracrine hormones act on adjacent cells and autocrine hormones are released and act on the cell that secreted them. Also, intracrine hormones act within the cell that produces them.

Response vs. distance traveled

Endocrine action: the hormone is distributed in blood and binds to distant target cells. Paracrine action: the hormone acts locally by diffusing from its source to target cells in the neighborhood. Autocrine action: the hormone acts on the same cell that produced it.

Major hormones and systemsTop down organization of endocrine system.Hypothalamus produces releasing factors that stimulate production of anterior pituitary hormone which act on peripheral endocrine gland to stimulate release of third hormoneSpecific examples to followPosterior pituitary hormones are synthesized in neuronal cell bodies in the hypothalamus and are released via synapses in posterior pituitary. Oxytocin and antidiuretic hormone (ADH)

Types of hormonesHormones are categorized into four structural groups, with members of each group having many properties in common: Peptides and proteins Amino acid derivatives Steroids Fatty acid derivatives - Eicosanoids

Range from 3 amino acids to hundreds of amino acids in size. Often produced as larger molecular weight precursors that are proteolytically cleaved to the active form of the hormone. Peptide/protein hormones are water soluble.Comprise the largest number of hormones perhaps in thousands

Peptide/protein hormones

Peptide/protein hormonesAre encoded by a specific gene which is transcribed into mRNA and translated into a protein precursor called a preprohormonePreprohormones are often post-translationally modified in the ER to contain carbohydrates (glycosylation)Preprohormones contain signal peptides (hydrophobic amino acids) which targets them to the golgi where signal sequence is removed to form prohormoneProhormone is processed into active hormone and packaged into secretory vessicles

Peptide/protein hormonesSecretory vesicles move to plasma membrane where they await a signal. Then they are exocytosed and secreted into blood stream In some cases the prohormone is secreted and converted in the extracellular fluid into the active hormone: an example is angiotensin is secreted by liver and converted into active form by enzymes secreted by kidney and lung

Peptide/protein hormone synthesis

Amine hormonesThere are two groups of hormones derived from the amino acid tyrosineThyroid hormones and Catecholamines

Thyroid HormoneThyroid hormones are basically a "double" tyrosine with the critical incorporation of 3 or 4 iodine atoms. Thyroid hormone is produced by the thyroid gland and is lipid solubleThyroid hormones are produced by modification of a tyrosine residue contained in thyroglobulin, post-translationally modified to bind iodine, then proteolytically cleaved and released as T4 and T3. T3 and T4 then bind to thyroxin binding globulin for transport in the blood

Thyroid hormones

Catecholamine hormonesCatecholamines are both neurohormones and neurotransmitters. These include epinephrine, and norepinephrine Epinephrine and norepinephrine are produced by the adrenal medulla both are water solubleSecreted like peptide hormones

Synthesis of catecholamines

Amine HormonesTwo other amino acids are used for synthesis of hormones: Tryptophan is the precursor to serotonin and the pineal hormone melatonin Glutamic acid is converted to histamine

All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it.All steroid hormones are lipid soluble Steroid hormones

Types of steroid hormonesGlucocorticoids; cortisol is the major representative in most mammals Mineralocorticoids; aldosterone being most prominent Androgens such as testosterone Estrogens, including estradiol and estrone Progestogens (also known a progestins) such as progesterone

Steroid hormonesAre not packaged, but synthesized and immediately releasedAre all derived from the same parent compound: CholesterolEnzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ERSteroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells

Steroid hormonesSteroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins. Corticosteroid binding globulin carries cortisolSex steroid binding globulin carries testosterone and estradiolIn some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain

Steroids can be transformed to active steroid in target cell

Steroidogenic Enzymes

Steroid hormone synthesisAll steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates. The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR)

Steroid hormone synthesisThe cholesterol precursor comes from cholesterol synthesized within the cell from acetate, from cholesterol ester stores in intracellular lipid droplets or from uptake of cholesterol-containing low density lipoproteins. Lipoproteins taken up from plasma are most important when steroidogenic cells are chronically stimulated.

cholesterolExtracellular lipoproteinCholesterol poolLHATPcAMPPKA+PregnenoloneProgesteroneAndrostenedioneTESTOSTERONE3bHSDP450c1717bHSDacetate

1,25-dihydroxy Vitamin D3 is also derived from cholesterol and is lipid solubleNot really a vitamin as it can be synthesized de novoActs as a true hormone 1,25-Dihydroxy Vitamin D3

Fatty Acid Derivatives - EicosanoidsArachadonic acid is the most abundant precursor for these hormones. Stores of arachadonic acid are present in membrane lipids and released through the action of various lipases. The specific eicosanoids synthesized by a cell are dictated by the battery of processing enzymes expressed in that cell. These hormones are rapidly inactivated by being metabolized, and are typically active for only a few seconds.

Fatty Acid Derivatives - Eicosanoids Eicosanoids are a large group of molecules derived from polyunsaturated fatty acids. The principal groups of hormones of this class are prostaglandins, prostacyclins, leukotrienes and thromboxanes.

Regulation of hormone secretionSensing and signaling: a biological need is sensed, the endocrine system sends out a signal to a target cell whose action addresses the biological need. Key features of this stimulus response system are: receipt of stimulus synthesis and secretion of hormone delivery of hormone to target cell evoking target cell response degradation of hormone

Control of Endocrine ActivityThe physiologic effects of hormones depend largely on their concentration in blood and extracellular fluid. Almost inevitably, disease results when hormone concentrations are either too high or too low, and precise control over circulating concentrations of hormones is therefore crucial.

Control of Endocrine ActivityThe concentration of hormone as seen by target cells is determined by three factors: Rate of productionRate of deliveryRate of degradation and elimination

Control of Endocrine Activity Rate of production: Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Such control is mediated by positive and negative feedback circuits, as described below in more detail.

Control of Endocrine ActivityRate of delivery: An example of this effect is blood flow to a target organ or group of target cells - high blood flow delivers more hormone than low blood flow.

Control of Endocrine ActivityRate of degradation and elimination: Hormones, like all biomolecules, have characteristic rates of decay, and are metabolized and excreted from the body through several routes. Shutting off secretion of a hormone that has a very short half-life causes circulating hormone concentration to plummet, but if a hormone's biological half-life is long, effective concentrations persist for some time after secretion ceases.

Feedback Control of Hormone ProductionFeedback loops are used extensively to regulate secretion of hormones in the hypothalamic-pituitary axis. An important example of a negative feedback loop is seen in control of thyroid hormone secretion

Inputs to endocrine cells

Neural controlNeural input to hypothalamus stimulates synthesis and secretion of releasing factors which stimulate pituitary hormone production and release

Chronotropic controlEndogenous neuronal rhythmicityDiurnal rhythms, circadian rhythms (growth hormone and cortisol), Sleep-wake cycle; seasonal rhythm

Episodic secretion of hormonesResponse-stimulus coupling enables the endocrine system to remain responsive to physiological demands Secretory episodes occur with different periodicity Pulses can be as frequent as every 5-10 minutes

The most prominent episodes of release occur with a frequency of about one hourreferred to as circhoral An episode of release longer than an hour, but less than 24 hours, the rhythm is referred to as ultradian If the periodicity is approximately 24 hours, the rhythm is referred to as circadian usually referred to as diurnal because the increase in secretory activity happens at a defined period of the day.

Episodic secretion of hormones

Circadian (chronotropic) control

Circadian Clock

Physiological importance of pulsatile hormone release Demonstrated by GnRH infusion If given once hourly, gonadotropin secretion and gonadal function are maintained normally A slower frequency wont maintain gonad function Faster, or continuous infusion inhibits gonadotropin secretion and blocks gonadal steroid production

Clinical correlateLong-acting GnRH analogs (such as leuproline) have been applied to the treatment of precocious puberty, to manipulate reproductive cycles (used in IVF), for the treatment of endometriosis, PCOS, uterine leiomyoma etc

Feedback controlNegative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretionPositive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation

Negative feedback effects of cortisol

Substrate-hormone controlGlucose and insulin: as glucose increases it stimulates the pancreas to secrete insulin

Feedback control of insulin by glucose concentrations