INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.

Watson

INTRODUCTION TO ENDOCRINOLOGY

Learning Objectives At the end of this lecture you should be able to: 1. Explain how metabolism is regulated through both neural and endocrine mechanisms and that these pathways are highly integrated 2. Define and compare the terms endocrine, paracrine and autocrine 3. Define and outline modes of endocrine feedback 4. Define the 3 major classes of hormones. 5. List factors affecting hormone action 6. Describe the functional anatomy of the hypothalamic-pituitary unit including the 3 types of hypothalamic neurons and their functions. 7. Define the terms circadian, diurnal and ultradian. 8. Explain the generation and importance of episodic endocrine secretion. 9. Outline the 5 hypothalamic-anterior pituitary axes and 2 posterior pituitary axes.

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Introduction Metabolic control and homeostasis is maintained through both neural (electrochemical) and endocrine (chemical) mechanisms whereby the bodys sensory receptors (neuro-, mechano-, osmo-, baro- and chemo-receptors) detect changes in both the external and internal environments and initiate an appropriate response. The human neural and endocrine systems are highly integrated as elegantly demonstrated by the location of the master gland or pituitary within the sella turica at the base of the brain. Endocrine hormones are chemical messengers synthesized in specialized (endocrine) cells and then released into the circulation where they are available for uptake by and action on remote tissues. This is the classic definition of endocrine. However, one should be aware that many of these same endocrine hormones, and related cytokines and growth factors, can act in a paracrine (on a neighbouring cell or cells in a tissue) or even autocrine (on the same cell that produces it) fashion. The fundamental concept is that hormones are chemical mediators of metabolism.

Classes of Hormones Peptide and polypeptide hormones strings of amino acids (aa) small monomers e.g. thyrotropin releasing hormone (TRH); 3 aa large multimeric proteins containing several subunits e.g. thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and insulin (Ins). polypeptide hormones can have upwards of 200 residues larger protein hormones can be very complex in both primary and secondary structure and are often subject to post-translational modifications such as proteolytic processing and glycosylation, necessary to produce a functional hormone. water-soluble; may or may not be associated with carrier/binding proteins

Steroid hormones are derived from the metabolism of cholesterol through a series of enzymatic steps which take place in specific subcellular compartments. lipid-soluble serum carrier proteins (eg. CBG-Corticosteroid Binding Globulin; SHBG-Sex Hormone Binding Globulin) help to regulate steroid bioactivity--only free steroid is available to the cell. Amino acid derivatives as the name suggests, these hormones are derived from enzymatic modifications of an amino acid catecholamines are derived from the metabolism of phenylalanine and tyrosine to produce Ldopa, dopamine, norepinephrine and epinephrine all of which function as neurotransmitters of more interest to the endocrinologist are the thyroid hormones triiodothyronine (T3) and thyroxine (T4) which are produced from the biological iodination of tyrosine residues in thyroglobulin, which are then coupled and cleaved from the parent globulin.

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Regulation of Endocrine Secretion there are several schemas that are important in the regulation of hormone secretion from an endocrine gland. Most hormone secretion is controlled through negative feedback much like a thermostat

Negative Feedback
A _

Antagonistic Pairs
+ _ _ +
Compound X

Compound Y

+
e.g. TSH and T4 e.g. PTH and Ca++ e.g. Insulin, glucose and glucagon

Positive Feed Forward

rising levels of estrogen in the follicular phase of the menstrual cycle result in the preovulatory LH surge (green arrow) the red arrow indicates the negative feedback of estrogen on LH secretion

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Episodic Endocrine Secretion An important concept in hypothalamic and pituitary secretion is that of episodic secretion. That is, the factors and hormones are secreted in bursts or pulses according to rhythms generated in the hypothalamus and/or CNS. Rhythms may be: circadian diurnal ultradian -around 24 hr -exactly 24 hr (GHRH, CRH) -minutes or hrs (GnRH, LH)

Cortisol secretion is primarily diurnal with peak secretion upon waking:

Gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion are ultradian:

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Many hormones have a complex mixture of secretion pattern.

Human GH secretion is both diurnal and ultradian. There is a large peak during the middle of the sleep phase with smaller peaks throughout the day.

The suprachiasmatic nucleus (SCN) provides circadian timing to the hypothalamus the SCN has an intrinsic circadian pattern of secretion and neuronal activity achieved via coordinated expression of clock genes (the cryptochromes (Cry) and period (per) genes utilizes direct input from the retina (non-visual) light entrains or resets the pattern to correspond to day/night cycle

Pineal Gland (the third eye) produces melatonin during dark periods from metabolism of serotonin non-visual signals from retina to the SCN are relayed via the spinal cord to the pineal gland in response, melatonin is released and acts on the SCN to reset the clock

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

PVN

melatonin

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Factors Affecting Hormone Action: 1. Hormone production/release rates: regulation at level of gene protein translation/mRNA stability enzyme levels/activity secretion substrate/energy availability 2. Serum carrier proteins e.g. SHBG, CBG, IGFBP3 modulate: solubility stability metabolic clearance bioavailability 3. Converting/deactivating enzymes (in plasma and target cells): ACE-angiotensin converting enzyme ECE-endothelin converting enzyme COMT-catecholamine o-methyltransferase 4. Metabolic clearance: cellular uptake liver kidney 5. Hormone Receptors: Specificity of hormone action is achieved through receptor expression and available signaling pathway(s) Signal amplification- 1 hormone-receptor complex activates many second messenger molecules Compartmentalization of signalosomes- creation of distinct cytoplasmic domains

Hormone receptors can be broadly divided into 2 groups: 1. cell surface (membrane) receptorsfor water-soluble ligands and large ligands e.g. peptides, polypeptides, amino acid derivatives, ions 2. intracellular receptorsfor lipid-soluble ligands e.g. steroids, thyroid hormones

There are 4 types of cell surface receptors: 1. G protein-coupled receptors (GPCR) e.g. receptors for LH, GnRH, angiotensin, Ca++, light 2. Tyrosine kinase receptors (TKR) e.g. receptors for insulin, FGF, NGF

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

3. Tyrosine kinase-associated receptors (TKAR) e.g. receptors for GH, PRL, leptin 4. Receptor activated ion channels

Each receptor class and type will be discussed throughout the block where their actions are most relevant.

Water-soluble ligands:

Tyrosine kinase receptor

peptides polypeptides amino acid derivatives ions

Kinase

Tyrosine kinaseassociated receptor

Receptor-mediated ion channel

Lipid-soluble ligands:

steroids thyroid hormone Vit D

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

The Human Endocrine System Hormones are secreted from both discrete endocrine glands (e.g. the thyroid) and specialized cells within other tissues (e.g. hormone-secreting cells of the gut). The major endocrine glands include the hypothalamus, pituitary, thyroid, parathyroid, pancreas, adrenal and gonads. Hormones are also secreted by specialized cells in the heart, liver, gut and kidney. Fat cells produce a hormone called leptin. This lecture intends to provide a brief overview of the endocrine system. Detailed discussions of each system will be presented in other lectures.

The gut secretes its own series of hormones to regulate food intake and digestion (CCK, ghrelin, gastrin, secretin, NPY.) The heart secretes ANP, an important factor in regulating vascular tone and volume

The kidneys secrete EPO which increases erythrocyte formation The liver secretes angiotensinogen (angiotensin precursor), IGF-I and thrombopoietin ( platelets)

Fat produces many adipokines (e.g. leptin) Most cells produce locally-acting growth factors and cytokines

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Hypothalamus and Pituitary Introduction The hypothalamus is the primary region of integration between the central nervous and endocrine systems. Input from a vast array of neural, humoral and endocrine sources is processed, coordinated and then relayed into action: the secretion of factors which stimulate or inhibit anterior pituitary function; the release of neurohypophyseal hormones; as well as efferent output to the CNS. Together, the hypothalamus and pituitary are master regulators of human physiology.

Functional Anatomy The hypothalamus is a structure which surrounds or lines the 3rd ventricle of the brain immediately superior to the pituitary. The hypothalamus is connected to the pituitary gland by a narrow stalk composed of the unmyelinated axons of neurons which project from the paraventricular nucleus to terminate in the posterior pituitary. There is a network of blood vessels (or portal system) which traverse between the hypothalamus and anterior pituitary.

Functionally significant structures and nuclei in the hypothalamus include: preoptic nucleus (PON) paraventricular nucleus (PVN, occasionally PVH) periventriculur nucleus (PeVN) arcuate nucleus (AN) supra-optic nucleus (SON)

It is also important to note that certain CNS structures play a major role in homeostatic regulation and have significant afferent input to the hypothalamus. These include (but are not limited to): subfornical organ (SFO) organum vasculosum of lateral terminalis (OVLT) medial preoptic area (MeOP) nucleus of tractus solaris (NTS) medial amygdala (MeA) brainstem

10

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Hypothalamic neurons can be divided into three categories based on the type of output they use: magnocellular (terminate in posterior pituitary-secrete hormones into capillary bed) parvicellular (secrete release/inhibiting hypophyseotrophic factors into portal system) hypothalamic projection neuron (synapses with neuronal targets).

The figure below summarizes their location(s), major hormones and targets.

11

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Major Hypothalamic Factors Factor vasopressin (AVP) oxytocin (OXY) thyrotropin releasing hormone (TRH) gonadotropin-releasing hormone (GnRH) corticotrophin-releasing hormone (CRH) growth hormone-releasing hormone (GHRH) somatostatin (SRIF or SST) dopamine (DA)

Type peptide; 9aa peptide; 9aa peptide; 3aa peptide; 10aa peptide; 42aa peptide; 40 or 44 aa

Principle Action increase plasma volume and pressure uterine contraction; milk ejection stimulates release of TSH (and PRL) stimulates release of LH and FSH stimulates release of ACTH stimulates release of GH

peptide; 14aa (CNS) or 28aa inhibits release of GH (GI) bioactive amine inhibits release of PRL

Receptors for all of the hypothalamic hormones are 7-transmembrane G protein-coupled receptors (GPCR) linked to Gi or Gs and/or Gq proteins.

Hypothalamic-Pituitary-Adrenal Axis (HPA):

12

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Neural input: Processive/Stress

-lateral septum, hippocampus, prefrontal cortex inhibit corticotrophin releasing hormone (CRH) release -medial amygdala, Raphe nucleus stimulate CRH neurons

Physiological Stress -nucleus tractus solarus has receptors for cytokines, responds to oxidative and volume stress increase CRH -subfornical organ, organum vasculosum of lateral terminalis, medial preoptic area responds to osmotic challenge, imbalance in macromolecules increase CRH -these processes are often mediated by hypothalamic GABAergic and glutamatergic neurons Immune Stress -cytokine receptors in brainstem brainstem releases prostaglandins increase CRH release

CRH stimulates adrenocorticotrophic hormone (ACTH) release from adenohypophysis ACTH stimulates adrenal cortex increased glucocorticoid (cortisol) release Cortisol suppresses hypothalamus (CRH), pituitary (ACTH) and immune system (cytokines)

Propopiomelanocortin: is a 265 aa precursor to many hormones including ACTH arose early in evolution and still functional today excellent example of importance of post-translational processing N-terminal fragment -Lipoprotein

-MSH

ACTH

-MSH

ACTH

-Lipoprotein

-MSH

CLIP

-Lipoprotein

-Endorphin

13

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Hypothalamic-Pituitary-Thyroid Axis (HPT):

neural input

-autonomic, brainstem -arcuate nucleus

-decreased temperature increases TRH

-receptors for glucocorticoids and leptin (OB-R) sense energy state and adjust TRH accordingly (TRH neurons in PVN also have OB-R) (all of the above reset the TRH secretion set-point for endocrine feedback) TRH stimulates adenohypophyseal TSH secretion TSH stimulates thyroid production of T3/T4 T3/T4 inhibit both TRH and TSH secretion

14

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Hypothalamic-Pituitary-Growth Axis:

Neural Input

Raphe nucleus (5HT) and basal forebrain (ACh) inhibit SRIF release (positive effect on growth hormone-releasing hormone (GHRH)) brainstem can stimulate either SRIF or GHRH NPY neurons in arcuate nucleus integrate systemic growth hormone (GH), leptin (from adipose tissue) and ghrelin (from stomach) signals regulate periventricular SRIF neurons (indirect GHRH regulation) SRIF nuclei with GH and SRIF receptors inhibit GHRH release (short-loop feedback) neurons in arcuate nucleus secrete galanin or dopamine stimulate GHRH

SRIF inhibits both GHRH and GH release GHRH stimulates adenohypophyseal GH release GH stimulates fat metabolism and liver IGF-I synthesis

15

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

IGF-I provides negative feedback control of GH at anterior pituitary Ghrelin (growth hormone secretagogue or GHS) produced by stomach provides positive feedback to both pituitary and hypothalamus Leptin from adipose tissue stimulates GH release and inhibits SRIF through NPY neurons. (Generally, leptin acts at the hypothalamus to inhibit feeding behaviour and increase metabolism through a complex interaction with specific neurons) FFA from fat metabolism inhibits pituitary GH release

Prolactin:

dopaminergic (DA) neurons in the arcuate nucleus are the primary endocrine regulators (inhibitory) of adenohypophyseal PRL release neural Inputs Raphe nucleus (5-HT) stimulates PRF neurons in paraventricular nucleus Basal forebrain and hypothalamic glutaminergic neurons inhibit DA neuron Mammilary nuclei and hypothalamic opioid neurons stimulate DA neuron peripheral NS suckling or nipple stimulation stimulates PRF neurons and inhibits DA neurons

16

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Prolactin Releasing Factor (PRF) may be TRH, VIP, Oxytocin or an unknown factor stimulates PRL release PRL negatively regulates its own secretion inhibits anterior pituitary and stimulates DA neurons PRL stimulates milk production in the breast

Hypothalamic-Pituitary-Gonadal Axis (HPG):

This topic will be more extensively covered in the puberty/abnormal puberty lectures. Neural input is from: brainstem, limbic system, and other hypothalamic nuclei Negative regulators: GABA, endogenous opiates Positive regulators: glutamate, norepinephrine

17

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

The Neurohypophysis: Magnocellular Neurons The neurohypohysis consists of the magnocelluar hypothalamic neurons which synthesize vasopressin (AVP) and oxytocin (OXY) and their termini within the posterior pituitary. Secretion of these two hormones occurs into the capillary bed of the posterior pituitary.

Arginine Vasopressin (AVP): responsible for pressure-volume regulation release controlled by neural input from arterial and cardiac volume receptors, and by osmotic receptors in the OVLT (organum vasculosum of the lateral terminalis) Osmolality dopamine (-)

Brain

Neurohypophysis (posterior pituitary)

ADH

Blood volume ( BP)

H20 reabsorption Na+ retention activation of renninangiotensin system aldosterone secretion

18

INTRODUCTION TO ENDOCRINOLOGY Dr. P.H.Watson

Oxytocin (OXY): initiates uterine contraction, milk ejection, role in maternal behaviour (?) secretion stimulated by stretch (uterus) and suckling (breast) Central secretion of oxytocin has putative roles in: feeding behaviour and satiety gastric acid secretion BP, temp and heart rate regulation stimulation of glucagon secretion gonadotropin secretion stress responses tubule contraction and sperm transfer in testis

Brain
(+)

(+)

Neurohypophysis (posterior pituitary)

(+)

OXY

(+)

(+)

Vaginal/cervical stimulation

Suckling

Uterine contraction

Milk let-down

A good example of neural control of hormone secretion.

19