Endocrine Introduction

Cell activities are coordinated by the interplay of several types of chemical messenger systems:

Neurotransmitters

- released by axon terminals of neurons into the synaptic junctions

- act locally to control nerve cell functions.

Neuroendocrine hormones

- secreted by neurons into the circulating blood

- influence the function of cells at another location in the body.

Endocrine hormones

- released by glands or specialized cells into the circulating blood

- influence the function of cells at another location in the body.

Paracrines

-secreted by cells into the ECF

- affect neighboring cells of a different type.

Autocrines

- secreted by cells into the extracellular fluid

- affect the function of the same cells that produced them.

There are 3 general classes of hormones

1- Proteins and polypeptides:

- anterior and posterior pituitary gland - pancreas (insulin and glucagon)- parathyroid gland (parathyroid hormone)

2- Steroids:- adrenal cortex (cortisol and aldosterone) - ovaries (estrogen and progesterone)- testes (testosterone)- placenta (estrogen and progesterone)

3- Derivatives of the amino acid tyrosine:

- thyroid (thyroxine and triiodothyronine)

- adrenal medullae (epinephrine and norepinephrine)

Chemical Structure and Synthesis of Hormones

Polypeptide and Protein Hormones

Are Stored in Secretory Vesicles Until Needed.

• Most of the hormones in the body are polypeptides and proteins.

• These hormones vary in size [3 to 200 amino acids (a.a.)]

•In general,polypeptides with 100 a.a. proteins.

with 100 a.a. peptides.

Protein and peptide hormones

Synthesis and release

•synthesized on the rough endoplasmic reticulum.

• usually synthesized first as

preprohormones (larger proteins - not biologically active)

Then cleaved to form smaller prohormones.

• Golgi apparatus for packaging into secretory vesicles:

- enzymes cleave the prohormones to produce smaller, biologically active hormones and inactive fragments.

- The vesicles are stored, until needed.

•Secretion of the hormones (as well as the inactive fragments) by exocytosis.

The stimulus for exocytosis could be

• increase in cytplamsmic calcium (Ca++) concentration caused by depolarization of the plasma membrane.

•stimulation of an cell surface receptor causes

(cAMP) activation of protein kinases secretion of the hormone.

*The peptide hormones are water soluble so enter the circulatory system easily.

Steroid Hormones

Are Usually Synthesized from Cholesterol and Are Not Stored.

•chemical structure is similar cholesterol, and are generally synthesized from it. • They are lipid soluble.

•they simply diffuse across the cell membrane and enter the blood.

Mechanisms of Action of Hormones

Hormone Receptors and Their Activation

Locations for the hormone receptors are generally the following:

1] In or on the surface of the cell membrane.

They are specific mostly for the protein, peptide, and catecholamine hormones.

2]In the cytoplasm.

for the different steroid hormones.

3]In the nucleus.

for the thyroid hormones.

Protein hormone

Steroid hormone

The Number and Sensitivity of Hormone Receptors Are Regulated.

The number of receptors in a target cell usually does not remain constant.

The receptor proteins • inactivated or destroyed during (down-regulation) • reactivated or new ones manufactured (up-regulation )

Intracellular Signaling After Hormone Receptor Activation

The first step is forming a hormone-receptor complex.

Ion Channel-Linked Receptors. e.g caticholamines.

•opening or closing a channel for one or more ions.

G Protein-Linked Hormone Receptors.

hormones activate receptors that indirectly regulate the activity of target proteins (e.g., enzymes or ion channels) by coupling with GTP-binding proteins (G proteins).

Enzyme-Linked Hormone Receptors.

• Some receptors, when activated, function directly as enzymes or are closely associated with enzymes that they activate.

Second Messenger Mechanisms for Mediating Intracellular Hormonal Functions

• hormones stimulate formation of the second messenger e.g. cAMP- Ca ions inside the cell membrane.

• The Second Messenger causes subsequent intracellular effects of the hormone.

•cAMP and Ca ions are examples of Second Messenger .

Some Hormones use the Adenylyl Cyclase-cAMP Second Messenger System

Adrenocorticotropic hormone (ACTH)

Glucagon

Parathyroid hormone

Thyroid – stimulating hormone ( TSH )

Vasopressin ( V2 receptor , epithelial cells)

The Cell Membrane Phospholipid Second Messenger System

Growth hormone – releasing hormone ( GHRH )

Oxytocin

Thyroid – releasing hormone ( TRH )

Vasopressin ( V1 receptor, vascular smooth muscle )

Pituitary glandAnterior Pituitary = adenohypophysis

hypothalamus

Hypothalamo- hypophyseal portal circulation

Hypothalamo- hypophyseal portal circulation

Pituitary glandPosterior Pituitary = neurohypophysis

Hypothalamo- hypophyseal neural tractHypothalamo- hypophyseal neural tract

ADH ( anti-diuretic hormone) = Vasopressin

• Synthesis: by the supraoptic nucleus {in the hypothalamus}.

• Storage & Release: by posterior pituitary.

Control:

Nerve impulses, originating in the hypothalamus stim. release of ADH stored in the nerve endings in post. Pit.

2 main stimuli

osmotic pressure of ECF osmotic pressure of ECF

•e.g. dehydration. •stim. of osmoreceptors (ant. hypothalamus)

• very sensetive (can sense 1% change )

•Thirst center is stim. by more rise in osmotic pressure

blood volume blood volume

• e.g. blood loss- dehydration.

• stim. Of volume receptors (veins)

baroreceptors (arteries)

Other factors affecting the release of ADH:

factors ( ); - pain & stress. - drugs (morphine - barbiturates - nicotine)

factors ( ); - alcohol.

Actions of ADH :

1- water reabsorption by the kidney

mechanism; increasing the permeability of distal tubules and collecting ducts. by stim. V2 receptors.

So urine becomes more concentrated ( specific gravity) & less in amount.

2- In high doses, generalized vasoconstriction & blood pressure.

by stim. V1 receptors.

In cases of acute blood loss

ADH(vasopressin) release VC. & B.P.

Oxytocin

• Synthesized by paraventricular nucleus in the hypothalamus.

• Stored & released by posterior pituitary.Actions:

1- Milk ejection from lactating breasts (Not synthesis).

by ++ contraction of myoepithelial cell surrounding mammary glands.

2- Uterine contractions during labour.

Factors Increasing release

Factors decreasing release

- stim. of nipple (suckling).

- Visual & auditory stim. from baby.

- Uterine distension and cervical stretch.

-Psychological & emotional factors e.g. fear.

-Alcohol.

Control of Oxytocin secretion:

Prolactin (mammotrophin) (lactogenic hormone)

-Secreted in a pulstile manner by the anterior pituitary.

Control:

1- continuously inhibited by hypothalamic prolactin inhibitory hormone (PIH), though to be dopamine.

release of prolactin is by abolishing the release of PIH.

2- PRH (prolactin releasing hormone is stimulated by suckling (nipple stimulation)

3- Exercise and sleep.

4- TRH & TSH.

5- Negative feedback on the hypothalamus.

6- Drugs

Actions of prolactin:Highest level is found at term.

1- During pregnancy:- Growth of mammary glands.

(no milk production due to the inhbitory effect of placental hormones)

-2- After delivery

PRL initiates and maintains milk production. (suckling stim. PRL release).

3- PRL decreases the sensitivity of ovaries to gonadotrophins leading to suppresion of menstrual cycle.

-Ocurrs in 50% of lactating women.- physiological birth control.

4- PRL acts on the limbic system producing the characteristic maternal and nursing behavior.

Hormones of the Anterior pituitary (Adenohypophysis)

TSH = Thyroid stimulating hormone. [glycoprotein]

Actions:

1- growth & development of the thyroid gland.

2- iodine trapping & concentration.

3- synthesis & release of thyroid hormones.

Control of TSH secretion:

1- TRH (Thyrotropin-releasing hormone), secreted by the hypothalamus.

TRH is controlled by the level of thyroid hormones (T3,T4), through a negative feedback mechanism.

2- circadian rhythm; TSH level is maximum at midnight,

// minimum at 11 a.m.

T3/T4

ACTH = Adrenocortictrophic hormone (corticotrophin).

Actions:

1- Important for healthy growth of the adrenal cortex.

2- increases the lipid & free cholesterol content in the adrenal cortex.

3- stimulates the synthesis & release of cortisol & other glucocorticoids by the adrenal cortex.

4- stimulates insulin secretion & mobilization of free fatty acids (FFAs) from adipose tissue.

5- high ACTH level causes skin pigmentation due to the melanocyte-stimulating action.

Control of ACTH secretion:

1- CRH (Corticotrophin releasing hormone) released from the hypothamus.

CRH is under control of adrenal hormones by a negative feedback mechanism.

2- Circadian rhythm; -- ACTH is high in the morning & low in the evening.

-- related to sleep, reversed on night duty workers.

3- Emotional stress. 4- hypoglycemia.

Gonadotrophic hormones:

FSH = follicle stimulating hormone & LH = luteinizing hormone.

Actions : In females

1- FSH stim. growth & maturation of ovarian follicles during the first half of menstrual cycle.

2- FSH &LH stim. ovulation at mid cycle.

3- LH maintains the corpus luteum during the second half of menstrual cycle.

In males

1- FSH is responsible for growth & development of seminiferous tubules, and stim. spermatogenesis.

2- LH is required for full development and function.

FSH/LH Control:

At puberty

1- stim. By GnRH (gonadotrophin-releasing hormone) secreted by hypothalmaus.

2- Sex hormone in females (estrogen - progesterone) & in males (testosterone - inhibin) exert a negative feedback on gonadotrophic hormones.

Growth hormone (GH) (somatotrophin)• In childhood & adolescence regulates growth and metabolism.

•In adults regulates energy metabolism.

Actions:

I- Its effect on growth is mediated through somatomedian C, which is secreted by the liver.

• Growth stops with

the closure of the epiphysis.

[somatomedians are also known as

Insulin-like growth factor]

II- Metabolic effects of GH

1- protein metabolism

transport of a.a. into cells & stim. protein synthesis (anabolic effect)

2- carbohydrate metabolism [Hyperglycaemia]

inhibit peripheral utilization of glucose by muscle and adipose tissues.

(insulin antagonist)

• increase glucose output by the liver = stim. gluconeogensis (diabetogeic effect)

3-Fat metabolism [Hyperlipidemia]

mobilizes FFAs from adipose tissue stores.

increases oxidation of FFAs by the muscles.

Control of GH secretion

under dual control from the hypothalamus;

GHRH (growth hormone releasing hormone)

GHIH ( // inhibiting // ) = somatostatain.

[ ] Increase GH [ ] Decrease GH

1- hypoglycaemia & fasting

2- FFa, proteins

3- sleep

4- Testosterone, estrogen

1- hyperglycaemia

2- FFa

3- GH and somatomedins (negative feedback)

4- Aging and obesity.

Other factors affecting GH release

Abnormalities of GH secretion

Dwarfism.

• Usually results from generalized deficiency of anterior pituitary secretion (panhypopituitarism) during childhood.

•In general, body parts develop in appropriate proportion to one another, but the rate of development is decreased.

• panhypopituitary dwarfism does not pass through puberty.

• However, only growth hormone is deficient; these persons do mature sexually and occasionally reproduce.

# If decreased production in adulthood metabolic effects only

Gigantism.

• the acidophilic, growth hormone-producing cells of the anterior pituitary gland become excessively active.

• All body tissues grow rapidly, including the bones.

• If the condition occurs before adolescence, height increases so that the person becomes a giant-up to 8 feet tall.

Acromegaly.

acidophilic tumor occurs after adolescence (after closure of the epiphyses of long bones) i.e. the person cannot grow taller, but the bones can become thicker and the soft tissues can continue to grow.

1- Enlargement is marked in the bones of • hands and feet • membranous bones (cranium, nose, bosses on the forehead, supraorbital ridges, lower jawbone, and vertebrae, because their growth)

Consequently, the lower jaw protrudes forward, sometimes as much as half an inch.

2- tissue organs (tongue, the liver, and the kidneys) become greatly enlarged.