Endocrinology

• The role of endocrine system is to maintain whole body homeostasis.

Mechanisms for cell-to-cell signaling via hormone molecules

NeurotransmittersEndocrineNeuroendocrineParacrineAutocrineCytokine

Cyclical variations in hormone release

-Seasonal changes-Diurnal cycle-Changes with development and aging- changes with sleep

RECEPTORSSerum hormone concentration are typically extremely low. Therefore, a receptor must have high affinity, as well as specificity for its cognate hormone.

Negative and positive feedback

Down regulation

When a hormone is present in excess, the number of active receptors generally decreases.

Internalization

Desensitization

Β-arrestins inactivate the receptor and promote endocytic removal of the receptor from the plasma membrane.

Up regulation

In the presence of a deficiency of the chemical messenger, there is increase in the number of active receptors.

Transport of the hormones in the circulation

Hormone binding proteins

The concentration of bound hormone (HP), free hormone (H), and plasma transport protein (P) are in equilibrium.If free hormone levels drop, hormone will be released from the transport proteins.

[H] x [P] [HP]

OR

K= [H] x [P]/[HP]

Hormone Protein bounding:

-Prolong the circulating half lives of hormones-Prevent from crossing the cell membrane -Prevent kidney excretion -Acts as reservoir of hormone-Buffer acute changes in hormone secretion

Hormones are cleared from the plasma in several ways, including:

1) metabolic destruction by the tissue

2) Binding with the tissue

3) Excretion by the liver into the bile

4) Excretion by the kidney into the urine

Metabolic clearance rate

Number of milliliters of plasma cleared of the hormone per minute

Or

Rate of disappearance of hormone from the plasma ---------------------------------------------------------------------

Concentration of hormone in the each milliliters of plasma

Hypothalamus- Pituitary Peripheral Gland Axis

MRI of the head shows that the proximity of hypothalamus and pituitary gland and their connection by neurohypophysial stalk

Diagram of pituitary gland

Several different cell types of anterior pituitary

1- Somatotropes Growth Hormone (GH)

2- Corticotropes Adrenocorticotropin (ACTH)

3- Thyrotropes Thyroid Stimulating Hormone (TSH)

4- Gonadotropes Luteining Hormone (LH) & Follicle Stimulating Hormone (FSH)

5- Lactotorpes Prolactin (PRL)

The relationships among various hypothalamic centers and their inputs from various other areas of the brain and their outputs to the posterior and anterior pituitary gland.

Hypothalamic- hypophysial portal system

Anatomical and functional relationships between the hypothalamus, the pituitary gland, and their blood supply.

Arrows indicate the direction of movement of hormone molecules.

Hypothalamic releasing and inhibitory hormones

1- Growth Hormone- Releasing Hormone (GHRH)

2- Growth Hormone Inhibitory Hormone (GHIH) or Somatostatin

3- Thyrotropin Releasing Hormone (TRH)

4- Corticotropin Releasing Hormone (CRH)

5- Gonadotropin- Releasing Hormone (GnRH)

6- Prolactin Inhibitory Hormone (PIH) (Dopamin)

GH

GH

TSH

ACTH

LH & FSH

PRL

Negative feedback loops regulating hormone secretion in a typical hypothalamus-pituitary-peripheral gland axis.

X, Peripheral gland hormoneXTH, Pituitary tropic hormoneXRH, Hypothalamic releasing hormoneXIH, Hypothalamic inhibiting hormone

The Corticotropes (POMC cells)

ACTH is a 39 amino acid peptide that is synthesis as a part of a larger prohormone, proopiomelanocortin (POMC).

ACTH

ACTH circulates as an unbound hormone and has a short half-life of about 10 minutes.

It binds to the melanocortin 2 receptor (MC2R) on cells in the adrenal cortex.

ACTH acutely increases cortisol and adrenal androgen production

increases the expression of steroidogenic enzyme genes, and in the long term, promotes the growth and survival of two zones in the adrenal cortex

At supraphysiological levels, ACTH causes darkening of light-colored skin (e.g., Cushing's disease).Normally, keratinocytes express the POMC gene but process it to α-MSH instead of ACTH.

Keratinocytes secrete α-MSH in response to ultraviolet light, and α-MSH acts as a paracrine factor on neighboring melanocytes to darken the skin.

α-MSH binds to the MC1R on melanocytes. However, at high levels, ACTH can also cross-react with the MC1R receptor on skin melanocytes. Thus, darkening of skin is one indicator of excessive ACTH levels.

The Thyrotropes

Thyrotropes regulate thyroid function by secreting the hormone thyroid-stimulating hormone (TSH; also called thyrotropin)

TSH is a heterodimer glycoprotein composed of an α subunit, (89 amino acids), and a β subunit (112 amino acids).

Glycosylation of the subunits increases their stability in circulation and enhances the affinity and specificity of the hormones for their receptors.

The half-life of TSH is relatively long, ranging from tens of minutes to several hours.

The Gonadotropes The gonadotrope secretes FSH and LH (also called gonadotropins) and regulates the function of gonads in both sexes.

FSH is a heterodimer glycoprotein composed of an α subunit, (89 amino acids), and a β subunit (112 amino acids).

LH is a heterodimer glycoprotein composed of an α subunit, (89 amino acids), and a β subunit (115 amino acids).

FSH and LH are segregated into different secretory granules and are not cosecreted in equimolar amounts

Hypothalamus-pituitary-gonadal axis.

The somatotrope

The somatotrope produces growth hormone (GH or hGH also called somatotropin).

GH Half-life is 20 min.

Normal concentration of GH in plasma of an adult is between 1.6 and 3 ng/ml

Structure of human growth hormone (hGH). GH is a single polypeptide chain with two disulfide bridges.

Signal transduction via the JAK-STAT pathway.

Comparison of weight gain of a rat injected daily with GH with that of normal littermate.

GHPromotes increase sizes of the cells

Increases mitosis

Developments of the cells

Differentiate certain types of the cells

The effects of GH on growth, cartilage, and protein

metabolism depend on an interaction between GH and

Somatomedins, which are polypeptide growth factors

secreted by the liver and other tissue.

Insulin-Like Growth Factor I (IGF-I, Somatomedin C)

Insulin-Like Growth Factor II (IGF-II)

Biological action of GH (Somatotropic Hormone)

The IGFs

The IGFs are multifunctional hormones that regulate cellular proliferation, differentiation, and metabolism. These protein hormones resemble insulin in structure and function.

IGFs stimulate glucose and amino acid uptake and protein and DNA synthesis.

Essentially all circulating IGFs are transported in serum bound to insulin-like growth factor-binding proteins (IGFBPs).

Half-life of IGFs are about 20 hours.

Protein/peptide hormones are soluble in body fluids and with the notable exceptions of IGFs and GH, circulate in blood predominantly in an unbound form and therefore have short biological half- lives.

Role of GH in promoting protein deposition

1- Enhancement of amino acid transport through the cell membrane

2- Enhancement of RNA translation 3- Enhancement of DNA transcription (over more prolonged periods; 24 to 48 hrs)

4- Decrement of protein catabolism

Effect of GH on carbohydrate metabolism

decreased glucose uptake and use in skeletal muscle and adipose tissue. Induces of gluconeogenesis in liver.

GH antagonizes the action of insulin at the postreceptor level in skeletal muscle and adipose tissue (but not the liver).GH produces insulin insensitivity, it is considered a diabetogenic hormone.

When secreted in excess, GH can cause diabetes mellitus, and the insulin levels necessary to maintain normal metabolism increase. Excessive insulin secretion resulting from an excess of GH can cause damage to pancreatic beta cells.

The hyperglycemic effects of GH are mild and

slower than those of glucagon and epinephrine.

Effect of GH on fat

Releasing of fatty acids from adipose tissue and increasing fatty acids in the body fluid.

GH enhances the conversion of fatty acids to acetyl-CoA and subsequent utilization of this for energy.

Mobilization of fat by GH requires several hours to occur

Excessive amounts of GH causes fat mobilization from adipose tissue sometimes become so great that large quantities of aceto-acetic acid are formed by the liver and released into body fluids (ketosis).

This also frequently causes a fatty liver.

Biological action of GH (Somatotropic Hormone)

As long as the rate of mitotic activity in the zone of proliferation equals the rate of resorption in the zone of assification, the epiphyseal plate remains the same width and the bone continues to grow longer.

Endochondral Ossification

Chondrocytes randomly distributed throughout the matrix are mitotically active.

Chondrocytes rapidly proliferateing, form of rows of isogenous cells that parallel the direction of bone growth

Chondrocytes mature, hypertrophy, and accumulate glycogen in their cytoplasm

Hypertrophied chondrocytes die, and cartilage matrix becomes calcified

Osteoprogenitor cells invade the area and differentiated into osteoblasts. This followed by resorption of the calcified cartilage/calcified bone complex.

Endochondral Ossification

Effects of GH on bone

Stimulates protein deposition by chondrocytes

Increases of chondrocyte proliferation

Increases on endochondreal bone formation

Increased deposition of protein by osteogenic cells

Stimulates osteoblasts

Somatomedins have the potent effect on increasing all aspects of bone growth

Regulation of GH secretion.

GHRH (44 amino acids) releases from ventromedial nucleus of hypothalamus

Hypothalamic ghrelin stimulate GH secretion.

Estrogen, androgen, and thyroid hormone enhances GH and IGF-1 secretion.

Factors That Stimulate or Inhibit Secretion of Growth Hormone

Stimulate Growth Hormone Secretion

Inhibit Growth Hormone Secretion

Decreased blood glucose Increased blood glucose

Decreased blood free fatty acids Increased blood free fatty acids

Starvation of fasting, protein deficiency Aging

Trauma, stress, excitement Obesity

Exercise Somatostatin (Growth hormone- inhibitory hormone)

Testosterone, estrogen Growth hormone (exogenous)

Deep sleep Somatomedins (insulin- like growth factor)

Growth hormone- releasing hormone, and ghrelin

Effect of extreme protein deficiency on the plasma concentration of GH in the disease Kwashirkor.

GH secretion is pulsatile.

GH secretion prominent diurnal rhythmus, with peak secretion occurring in the early morning just before awaking.

Lifetime pattern of GH secretion.

5 to 20 years 6 ng/ml20 to 40 years 3 ng/ml40 to 70 years 1.6 ng/ml

Possible role of decreased GH secretion in causing changes associated with aging

5 to 20 years 6 ng/ml20 to 40 years 3 ng/ml40 to 70 years 1.6 ng/ml

Panhypopiuitarism

Decreased secretion of all the anterior pituitary hormones.

It can be congenital or may be occurs during life.

Most instances of dwarfism result from Panhypopiuitarism.

They don’t pass puberty.

The general effects of adult Panhypopiuitarism are:

1- hypothyroidism2- depressed production of glucocorticoids3- suppressed secretion of gonadotropic hormones

Abnormalities of growth hormone secretion

1- Dwarfism

1-1- Laron Dwarfs: are resistant to GH because of a genetic defect in expression of the GH receptor such that the response to GH is impaired

1-2-African Pygmy: have normal serum GH levels but they don’t exhibit the normal rise in IGF

2- Gigantism

3- Acromegaly

Gigantism

Acromegalic patient

Prolactin (PRL)

198 amino acids

JAK/STAT signaling

Half-life 20 min

TRH , and “prolactin releasing factor or PRF” stimulate prolactin release

Prolactin (PRL)

Prolactin causes milk secretion from the breast.

Its effects on the breast involves increased production of casein and lactalbumin.

Prolactin inhibits the effects of gonadotropins.

Prolactin supresses reproductive function in the nursing mother.

Prolactin receptors are present on leydig cells and PRL increases the number of LH receptors and synergizes with LH to stimulate androgen production.

Prolactin act as fetal growth hormone.

PRL releases in response to stress.

Surgery, fear, stimuli causing arousal, sleep, and exercise are all effective stimuli.

Somatostatin and TSH also inhibits PRL secretion.

Posterior Lobe

Neurohypophysis is composed mainly of glial-like cells called pituicyte.

This cells have supporting role for large number of terminal nerve fibers.

Hypothalamic control of the posterior pituitary.

ADH + neurophysin IIOCT+ neurophysin I

Herring body

Synthesis, processing, and transport of ADH.

ADH and oxytocin are nanopeptides.

Neurophysins are carrier protein.

Neurophysisn II stimulate prolactin secretion.

Pathways involved in regulating secretion of ADH

Osmoreceptors in supraoptic nucleus or in the organum vasculosum (antroventral wall of the third ventricle).

Action of ADH via the V2 receptor on the principle cell of the late distal tubule and collecting duct.

ADH increases the permeability of the terminal portion of the inner medullary collecting duct to urea.

ADH stimulates reabsorption of NaCl by the thick ascending limb of Henle’s loop and by the distal tubule and cortical segment of the collecting duct.

Osmotic and hemodynamic control of secretion of ADH.

Oxytocin

Oxytocin causes contraction of the myoepithelial cells that line the ductus of the breast.

Oxytocin causes contraction of the smooth muscle of the uterus.The sensivity of the uterine musculature to oxytocin is enhanced by estrogrn and inhibited by preogesteron.

Oxytocin may also act on the non pregnant uterus to facilitate sperm transport.

Oxytocin causes increased contraction of the smooth muscle of the vas deferences, propelling sperm toward the urethra.