1_Introduction to Endocrinology (PART A)

Hormones

• Chemical messenger systems of the body interact with one another to maintain homeostasis.

• It can be protein, cholesterol, steroid based, rarely carbohydrates

• Released by glands or specialized cells into the circulating blood towards the target cell

• Exert their effect on a cell that is away from its origin

• Ex. Growth ___ (from Ant. Pituitary Gland causes growth in most parts of body); Thyroxine (from Thyroid Gland increases rate of many chemical reactions)

protein, cholesterol, steroid based, rarely carbohydrates

Hormones can be

Growth Hormone

from Ant. Pituitary Gland causes growth in most parts of body

Ant. Pituitary Gland

Growth hormone is from ___causes growth in most parts of body

Thyroxine

from Thyroid Gland increases rate of many chemical reactions

Thyroid Gland

Thyroxine is from ____ increases rate of many chemical reactions

Autocrine

• A cell targets itself

• Secreted by a cell into the extracellular fluid

• Influences the action of the same cells that produced them

Paracrine

A cell targets a nearby cell

Endocrine

A cell targets a distant cell through the bloodstream

Signaling across gap junctions

A cell targets a cell connected by gap junction

Regulatory hormones

are released into the hypophyseal portal system for delivery to the anterior lobe of the pituitary gland

H-P-O axis

Three levels of endocrine control and function:

Hypothalamus

Levels of Endocrine Control:

• The highest level of control

• Releases hormones which affect the second level control

Pituitary gland (2nd level control)

Levels of Endocrine Control:

• Located at the Sella turcica

• Has an anterior and posterior lobe

• Affects the 3rd level control

End organs (3rd level)

Levels of Endocrine Control:

• kidneys, gonads, thyroid, muscle, adrenal gland, etc.

Sella Turcica

Location of Pituitary gland

R.R.R.C.R

(Regulation of electrolyte, Regulation of Calcium and Phosphate balance, Regulation of metabolism, Coordination of the hemodynamic metabolic counter-regulatory responses to stress, Regulation of reproduction and behavior, development, growth and senescence)

Functions of the Endocrine System:

Regulation of electrolyte

Functions of the Endocrine System:

• (mainly sodium) and water balance and control of blood volume and pressure (Aldosterone and ADH)

Regulation of Calcium and Phosphate balance

Functions of the Endocrine System:

• to preserve extracellular fluid concentrations required for a cell membrane integrity and intracellular signaling (PTH)

• for bones

Regulation of metabolism

Functions of the Endocrine System:

• energy balance and control of fuel mobilization, utilization, and storage to ensure that cellular metabolic demands are met (Insulin and Glucagon)

Coordination of the hemodynamic metabolic counter

Functions of the Endocrine System:

• regulatory responses to stress (Cathecholamines, Glucocorticoids)

Regulation of reproduction and behavior, development, growth and senescence

Functions of the Endocrine System:

• (Estrogen, Progesterone and Testosterone)

T. P. S.

(Tyrosine, Proteinaceous, Steroids)

Chemical Nature of Hormones:

Tyrosine (Amine)

Chemical Nature of Hormones:

• Tyrosine-based hormones

• Receptors are located inside the cell

• Thyroid hormone (T3 and T4)

Proteinaceous (Peptide)

Chemical Nature of Hormones:

• Protein-based hormones are the most common hormones.

• An example would be insulin.

• Act on receptors within the cellular membrane that are signaling pathways to produce hormone

Steroids

Chemical Nature of Hormones:

• Differ in structure because of the molecule of origin

• Made up of carbon rings

• Based on cholesterol backbones (cyclopentanoperhydrophenanthrene ring)

• Cholesterol problems will lead to cholesterol-based problems as well

  • Not all cholesterol forms are bad

  • Around 80% of cholesterol in the body is endogenous

carbon rings

Steroids are made up of ___

cholesterol backbones (cyclopentanoperhydrophenanthrene ring)

Steroids are based on ____

N. P. C

Feedback Mechanisms:

Negative Feedback

Feedback Mechanisms:

• Response reduces or shuts off the original stimulus, maintains stability

• If pituitary gland is producing excess ACTH→ influence adrenal gland -> send signal to hypothalamus -> hypothalamus will decrease stimulus of corticosterol -> decrease ACTH

• high A = organ A will produce hormone A = low A

Positive Feedback

Feedback Mechanisms:

• response amplifies the original stimulus; drives a process to completion

• Ovulation: increase in LH -> regulate receptors in egg cells -> more sensitive to gonadotrophins -> ovulate

• high A = organ B will produce hormone B = high B = organ A will produce hormone A = low A

Cyclical Feedback

Feedback Mechanisms:

• On repeat

• Menstrual cycle

• Ovulation cycle

• Cortisol – high in the morning and almost none in the evening (like a diurnal pattern

Cortisol

high in the morning and almost none in the evening (like a diurnal pattern)

cyclic pattern of activation

The number of receptors in the target cell does not remain constant; they are in a ____(production of new ones or incorporation of the receptor to cell membrane) and deactivation (destruction or desensitization)

deactivation

The number of receptors in the target cell does not remain constant; they are in a cyclic pattern of activation (production of new ones or incorporation of the receptor to cell membrane) and ____ (destruction or desensitization)

Sequestration

Mechanisms of Downregulation:

• The receptor is sequestered temporarily by the cell to prevent binding of the ligand; enclosed in a vesicle.

• Can also occur in the presynaptic neuron wherein the hormone is taken back in to prevent interaction with the receptor.

Inactivation of receptor

Mechanisms of Downregulation:

• Even if there is an excess of hormones in the body, there will be no response.

Inactivation of intracellular signaling molecules

Mechanisms of Downregulation:

• Normal response: Hormone can bind to receptor → activates signaling pathways

• If the signal is too weak or not enough to elicit a response, it will not activate the different signaling pathways.

• Significant in pharmacology which target the pathways to prevent propagation of cancer cells

Destruction of the receptors

Mechanisms of Downregulation:

• Lysosomes act on the internalized vesicle, releasing its enzymes to destroy the receptor.

• Autoimmune diseases (ex. Lupus) act like this wherein the body recognize its own cell as foreign, eliciting an immune response to destroy it

Production rate

Mechanisms of Downregulation:

• Decreased production of the receptor leads to small number of receptors that can bind with the hormone → decreased effect

• Same goes with the amount of hormone produced; less hormone concentration, lesser hormone that will bind to the receptor → less effect

I. I. S. D. P.

(Inactivation of receptor, Inactivation of intracellular signaling molecules, Sequestration, Destruction of the receptors, Production rate)

Mechanisms of Downregulation:

G. P.

(Greater availability of the receptor for interaction, Production rate)

Up-regulation of the receptors and intracellular signaling proteins increases the target tissue’s sensitivity to the hormone. It may be due to the ff:

target tissue’s sensitivity to the hormone

Up-regulation of the receptors and intracellular signaling proteins increases the ____

Greater availability of the receptor for interaction

Mechanism of Upregulation:

• The more receptors present that can interact with the hormone, the more responsive the cell is.

Production rate

Mechanism of Upregulation:

• Increased production of the receptor or intracellular signaling proteins → increased possibility (or time) to elicit the effect

D. G

(Direct Ion Channel-Linked Receptor, G Protein-linked Hormone Receptor)

Intracellular Signaling:

Direct Ion Channel-Linked Receptor

Intracellular Signaling:

• The easiest pathway; can be seen in neurotransmitters (like Ach and NE).

• Ligand bind with the receptor → conformational change → open or close an ion channel (usually for Na , K

• → ions enter or leave the cell → eliciting the effect on the cell

• E.g.: Opening of Ca2+ channels in the presynaptic neuron → Influx of Ca2+ → release of hormone into the synapse

• E.g.: Ach bind to muscular Ach receptor → Ca2+ → muscular contraction

G Protein-linked Hormone Receptor

Intracellular Signaling:

• G-protein coupled receptors are seven transmembrane proteins / serpentine receptors.

• The cytoplasmic tail part is coupled with G proteins (heterotrimeric guanosine triphosphate [GTP] – binding proteins) which have α, β, γ subunits and can be stimulatory (Gs) or inhibitory (Gi) which both lead to activation of a cascade of enzymes.

G-protein coupled receptors

are seven transmembrane proteins / serpentine receptors.

G proteins (heterotrimeric guanosine triphosphate [GTP]

The cytoplasmic tail part of G Protein-linked Hormone Receptor is coupled with ____– binding proteins) which have α, β, γ subunits and can be stimulatory (Gs) or inhibitory (Gi) which both lead to activation of a cascade of enzymes.

α, β, γ subunits

The cytoplasmic tail part of G Protein-linked Hormone Receptor is coupled with G proteins (heterotrimeric guanosine triphosphate [GTP]– binding proteins) which have ____and can be stimulatory (Gs) or inhibitory (Gi) which both lead to activation of a cascade of enzymes.

A.A.C.C.C.F.G.G.

• Adrenocorticotropic hormone (ACTH)

• Angiotensin II

• Calcitonin

• Catecholamines

• Corticotropin-releasing hormone

• Follicle-stimulating hormone

• Glucagon

• Growth hormone-releasing hormone

Hormones that use Adenylyl Cyclase - cAMP Second Messenger System:

Adrenocorticotopic hormone (ACTH)

Which hormone that uses Adenylyl Cyclase - cAMP Second Messenger System:

• induce T3/T4 production

Angiotensin II (epithelial cells)

Which hormone that uses Adenylyl Cyclase - cAMP Second Messenger System:

• increases GFR in kidney

A.C.G.G.P.O.T.V.

• Angiotensin II (vascular smooth muscle)

• Catecholamines (a receptors)

• Gonadotropin-releasing hormone (GnRH)

• Growth hormone-releasing hormone (GHRH)

• Parathyroid Hormone (PTH)

• Oxytocin

• Thyrotropin-releasing hormone (TRH)

• Vasopressin (V1 receptor, vascular smooth muscle)

Hormones that use the Phospholipase C Second Messenger System:

F.G.H.I.I.L.P.V

• Fibroblast Growth Factor

• Growth Hormone

• Hepatocyte Growth Factor

• Insulin

• Insulin-like Growth Factor

• Leptin

• Prolactin

• Vascular Endothelial Growth Factor

Other hormones that uses Receptor Tyrosine Kinase Signaling:

Posterior lobe of Pituitary Gland

Direct release of hormones from the hypothalamus (like sensory and osmoreceptor stimulation) will be connected to the ____

Anterior lobe of the Pituitary Gland

Indirect control through release of regulatory hormones (like CRH, TRH, GH-RH, PRH, PIH, GnRH) from the hypothalamus will be directed to ____