Endocrine Physiology

HORMONES

What is a hormone?

A chemical substance, formed in a tissue or organ and carried in the blood, that stimulates or inhibits the growth or function of one or more other tissues or organs

What is an endocrine pathway?

A hormone secreted into blood that acts on distant target cells

What is a paracrine pathway?

A hormone released from one cell that acts on neighboring cells

What is an autocrine pathway?

A hormone released that acts on the cell that secreted it

What is the fundamental mechanism of all hormone action?

Reversible, noncovalent binding to specific receptors on or in target cell

What are the three major classes of hormones?

1. Peptide hormones
   
2. Steroid hormones
   
3. Amine hormones

How are polypeptide hormones synthesized?

Peptide hormones are produced en masse during times of quiet and subsequently released into circulation in response to stimuli

Preprohormone produced from mRNA
↓ proteins cleaved
Prohormone↓ cleaved
Hormone (Golgi apparatus)
↓
Packaged into secretory granules for release

How are steroid hormones synthesized?

Steroid hormones are not stored in intracellular vesicles and must be synthesized on demand. They use the following general pathway:

Cholesterol
↓
Pregnenolone (mitochondria)
↓
Side chain modifications (in the endoplasmic reticulum)
↓
Various hormones

How are amino acid hormones synthesized?

Production is similar to peptide hormones in that they are synthesized and stored, but tend to be smaller, generally simpler, molecules

Tyrosine
↓ hydroxylation
↓ decarboxylation
Dopamine
↓ (many steps)
Various hormones

Where are polypeptide hormone receptors?

On the surface of target cell membranes

Where are steroid hormone receptors?

In the target cell cytoplasm

Where are amino acid hormone receptors?

These can be either on or inside the target cells. Two examples are:

Catecholamines: on target cell membrane

Thyroid hormones: in target cell cytoplasm

From Chap. 2, what is meant by “second messenger cascade”?

These are the systems that are used by receptors (of various types) that utilize intermediaries to cause intracellular changes

What are G-proteins?

A second messenger system; guanosine 5’-triphosphate (GTP)-binding proteins that couple hormone receptors on the cell surface to a secondary messenger system inside the cell

What type of intrinsic property do G-proteins have?

GTPase activity

What types of G-proteins are there?

Either stimulatory (G_s) or inhibitory (G_i)

What are G-proteins comprised of and what determines activity?

Three subunits: alpha, beta, and gamma. When the alpha subunit is bound to GTP, the G-protein is activated. It is inactivated when bound to GDP.

Describe, in words, the mechanism of the cyclic adenosine monophosphate (cAMP) second messenger system.

Hormone binds G-protein-coupled
receptor on membrane
↓
GDP replaced by GTP to activate G-protein
↓
Activation of adenylate cyclase
↓
↑[cAMP]_{intracellular}
↑protein kinase A phosphorylation of proteins
↓
Activation/inhibition of a metabolic process

Figure 7.1 cAMP pathway. Note that caffeine and theophylline both inhibit phosphodiesterase, thereby maintaining cAMP as active.

Describe, in words, the mechanism of the inositol triphosphate (IP₃) second messenger system.

Hormone binds G-protein-coupled receptor
↓
Activates phospholipase C
↓
Frees diacylglycerol (DAG) + IP₃ from membrane
↓
Ca²⁺ release from ER
↓
Activates protein kinase C
phosphorylation of proteins
↓
Activation/inhibition of a metabolic process

Figure 7.2 IP₃ pathway.

Describe, in words, the mechanism of the intracellular Ca²⁺-calmodulin second messenger system.

Hormone binds G-protein-coupled receptor
↓
Activates membrane Ca²⁺ channel and also releases Ca²⁺ from ER
↓
↑intracellular Ca²⁺
↓
↑ Ca²⁺ -calmodulin complex
↓
Regulation of other enzyme activities

Figure 7.3 Ca²⁺-calmodulin pathway.

Describe the mechanism of the steroid hormone activation.

Steroid hormone crosses cell membrane (readily soluble in lipid bilayer)
↓
Binds to cytoplasmic receptor
↓
Hormone-receptor complex enters nucleus
↓
Exposes DNA-binding domain on receptor
↓
Complex interacts with DNA to initiate or upregulate transcription
↓
Protein is then synthesized which activates physiologic pathways

What are the two principles of hormone receptor reregulation?

1. Down-regulation: ↓ number or affinity of receptor for a hormone
   
2. Up-regulation: ↑ number or affinity of a receptor for a hormone

Generally speaking, why does reregulation occur?

It occurs in response to over- or understimulation. An overstimulated receptor will be down regulated to limit activation and vice versa.

What are the two principles of regulation of hormone secretion?

1. Negative feedback (most common)
   
2. Positive feedback (rare)

What is negative feedback?

A hormone’s actions directly or indirectly inhibit its own secretion—a self-terminating cycle

What is positive feedback?

A hormone’s actions directly or indirectly promote its own secretion—a self-perpetuating cycle. These cycles are far rarer than negative feedback cycles.

HYPOTHALAMUS AND PITUITARY GLAND

Name the hormones of the:

Anterior pituitary

Thyroid stimulating hormone (TSH)

Luteinizing hormone (LH)

Follicle stimulating hormone (FSH)

Growth hormone (GH)

Prolactin (PRL)

Adrenocorticotropic hormone (ACTH)

Posterior pituitary

Oxytocin

Antidiuretic hormone (ADH)

The following hormones are released from the hypothalamus, name the corresponding pituitary hormones and their respective functions:

Thyrotropin-releasing hormone (TRH)

↑ TSH, PRL secretion; encourages thyroid synthesis and secretion, as well as prolactin secretion

Gonadotropin-releasing hormone (GnRH)

↑ LH, FSH secretion; important regulatory elements of the sex hormones

Corticotropin-releasing hormone (CRH)

↑ ACTH secretion (and α-[MSH], β-endorphin); stimulates the adrenal cortex to release cortisol

Growth hormone-releasing hormone (GHRH)

↑ GH secretion; a complex hormone that influences catabolism throughout the body.

Somatostatin (SS)

↓ release of GH, TSH (among others); a counterregulatory hormone

Prolactin inhibitory factor (PIF)

↓ release of prolactin; another regulatory hormone

Name the anatomic connection between the hypothalamus and the following:

Anterior pituitary

Hypothalamic-hypophysial portal system

Posterior pituitary

Hypothalamic tract

What is unique about the posterior lobe?

It is a collection of nerve axons whose cell bodies are located within the hypothalamus

What is the hypothalamic-hypophysial portal system?

Capillaries that carry blood from the hypothalamus to the anterior pituitary and from the anterior pituitary back to the hypothalamus

What is meant by retrograde blood flow in the hypophysial portal system?

Blood flow traveling from the pituitary back to the hypothalamus

What is the significance of the retrograde blood flow?

Feedback to the hypothalamus

How are the anterior pituitary hormones categorized?

GH-related hormones

Glycoprotein hormones

Corticotropin-related hormones

What is unique about the homology of the following?

GH-related hormones

GH is a polypeptide and is homologous with PRL and HPL

Glycoprotein hormones

All contain α- and β-subunits—α-subunits are similar; hormonal activity comes from β-subunits

Corticotropin related hormones

All are from the same precursor, proopiomelanocortin (POMC)

Describe the POMC protein.

It is a long protein that can be variably cleaved into different proteins, depending on the stage of development and the needs of the organism

Figure 7.4 POMC processing. The portion of POMC that is cleaved determines the metabolic activity.

Name the actions of the anterior pituitary hormones.

TSH

↑ T₃ and T₄ production (see thyroid section)

LH

↑ estrogen, androgen production

FSH

↑ oocyte and sperm maturation (see Chap. 8)

GH

↓ general growth

↑ glucose uptake into cells → diabetogenic

↑ protein synthesis

↑ lipolysis

↑ IGF production in liver

PRL

↑ milk production

↑ breast development

Inhibition of ovulation and spermatogenesis via ↓ GnRH

ACTH

↑ glucocorticoid production (see adrenal section)

What hormone is downstream to GH that is imperative in growth and development?

Insulin-like growth factor (IGF)

Name the actions of GH that are mediated through IGF.

↑ protein synthesis in bone, muscle, and organs → ↑ linear growth, ↑ lean body mass, and ↑ organ size

When during a lifetime is GH release greatest?

During the “growth spurt” of puberty

During a 24-hour period, when is GH the highest?

Around midnight

What factors ↓ GH secretion?

1. GHRH
   
2. Sleep
   
3. Stress
   
4. Exercise
   
5. Starvation
   
6. Hypoglycemia

What factors ↓ GH secretion?

1. GH and IGF (negative feedback)
   
2. Obesity
   
3. Hyperglycemia
   
4. Somatostatins

Diagram the GH feedback loop.

Figure 7.5 GH feedback loop.

In children, what do we call the clinical condition wherein excess GH is released?

Gigantism. The epiphyseal plates are open and children experience linear growth in excess of expected. In adults this leads to acromegaly.

What factors ↑ prolactin secretion?

Breast-feeding (most important stimulus)

Stress

TRH

Dopamine antagonists

What factors ↓ prolactin secretion?

Dopamine (PIF)- tonic inhibition prolactin (negative feedback)

Dopamine agonists (e.g., bromocriptine)

SS

Diagram prolactin secretion and negative feedback.

Figure 7.6 Prolactin secretion. Prolactin also inhibits GnRH which discourages the gonadal hormones and thereby pregnancy.

Name the actions of the posterior pituitary hormones.

Oxytocin

↑ contraction of myoepithelial cells in breasts (↑ milk ejection)

↑ contraction of uterus

ADH

↑ H₂O permeability of the distal tubule and collecting duct

Constricts vascular smooth muscle

What type of hormones are oxytocin and ADH?

Polypeptide hormones

Where is ADH synthesized?

Supraoptic nuclei of the hypothalamus

Where are oxytocin and ADH stored and released?

Posterior pituitary

How are oxytocin and ADH synthesized and secreted?

Precursor protein
↓
Cleaved and packaged into secretory
granules with neurophysins
(carrier proteins)
↓
Transported by axoplasmic flow to posterior pituitary

What is the ADH receptor used in the kidney and in vascular tissue? What is its second messenger system?

Renal effect: V₂ receptor → cAMP

Smooth muscle effect: V₁ receptor → IP₃

What factors ↑ ADH secretion? (See also Chap. 5)

High serum osmolarity (directly)

Volume depletion (indirectly)

Pain (minor)

Nausea (minor)

Hypoglycemia (minor)

Nicotine (minor)

Opiates (minor)

What factors ↓ ADH secretion? (See also Chap. 5)

Low serum osmolarity

Atrial natriuretic peptide (ANP)

α-Agonists

Ethanol

How does the hypothalamus sense osmolarity changes of serum?

Specialized vessels in the region lack the standard blood-brain barrier, perivascular cells swell or shrink according to the tonicity of serum. This provides information via specialized mechanoreceptors

Where is oxytocin synthesized?

Paraventricular nuclei of the hypothalamus

What factors regulate oxytocin secretion?

Breast-feeding

Sight or sound of infant

Dilation of cervix

What effect does lithium have on the body’s response to ADH?

Decreases the response through nephrogenic resistance

ADRENAL GLAND

What are the three zones of the adrenal cortex (from outer to inner zones) and what do they produce?

Zona Glomerulosa—Mineralocorticoids

Zona Fasciculata—Glucocorticoids

Zona Reticularis—Androgens

*Remember: “GFR” makes “salt, sugar, sex”

What are the special cells of the adrenal medulla called?

Chromaffin cells

What are the embryological origins of chromaffin cells?

Neural crest cells

What is the product of the adrenal medulla?

Catecholamines: epinephrine (Epi), norepinephrine (NE)

What controls the release of catecholamines from the medulla?

Discussed at length in Chap. 2, but recall that the chromaffin cells, derived from neural crest cells, are simply modified postganglionic sympathetic neurons, so release of catecholamines is a consequence of CNS sympathetic discharge.

From what are the adrenocortical (steroid) hormones derived?

Cholesterol

Figure 7.7 Steroid hormone pathway.
’Remember, individual layers of cortex have the portion of the pathway necessary to produce their primary hormone.

Which zone of the adrenal gland is the only producer of aldosterone synthase?

The zona glomerulosa, that is why it is the only zone to produce aldosterone

What happens when there is an enzyme deficiency in the pathway?

Steroid intermediates will accumulate above the level of the missing enzyme, and will be shunted down an alternative pathway.

What is the most common enzyme deficiency?

21 β-Hydroxylase

What steroids will be produced in excess if there is a deficiency in:

21 β-Hydroxylase

Mineralocorticoid and glucocorticoid production is halted, and adrenal androgen production will be increased.

17α-Hydroxylase

Decreased glucocorticoid and androgen production, increased mineralocorticoid production

What is special about the enzymes of the steroid hormone pathway?

Most are members of the cytochrome P 450 system

What is the rate-limiting step in the synthetic pathway?

Cholesterol desmolase; the initial step in all steroid pathways.

How is this step regulated?

ACTH

Name the actions of ACTH.

1. ↑ activation of desmolase
   
2. preferential expression of enzymes leading to cortisol synthesis
   
3. ↑ cholesterol uptake into adrenal cortex
   
4. ↑ proliferation of zona fasciculata if ACTH elevation is prolonged

What factors ↑ ACTH secretion?

1. CRH
   
2. Circadian rhythm-peak in the early morning
   
3. Emotions/stress
   
4. Central nervous system (CNS) trauma

What factors ↓ ACTH secretion?

Cortisol (negative feedback)

Figure 7.8 CRH, ACTH, cortisol loop.

Clinically, what is the most important stimulus for cortisol secretion?

Stress and illness; through all of the mechanisms discussed below it is the predominate counter-regulatory hormone for acute inflammation.

Name the actions of cortisol.

↑ hepatic gluconeogenesis

↓ protein synthesis

↑ protein degradation

↓ bone formation

↓ insulin sensitivity

↓ immune/inflammatory response

↓ ACTH secretion (negative feedback)

Facilitate vasoconstrictive properties of arterioles to catecholamines via alpha-1 receptor up-regulation

How does cortisol suppress the immune/inflammatory response?

Induces the synthesis of lipocortin, which inhibits the formation of arachidonic acid

Inhibits IL-2 production

Inhibits the release of histamine and serotonin from mast cells and platelets

Name the primary actions of aldosterone.

↑ Na⁺ resorption in renal distal tubules and ↑ K⁺ and H⁺ excretion

What factors regulate aldosterone synthesis?

1. Renin-angiotensin II-aldosterone system
   
2. ↑ K⁺
   
3. Some tonic control by ACTH

Describe the renin-angiotensin-aldosterone pathway.

Decreased perfusion of the juxtaglomerular apparatus (JGA) in the kidney stimulates the release of renin. Renin cleaves the inactive peptide angiotensinogen to angiotensin I. The angiotensin converting enzyme (ACE) converts angiotensin I to the active peptide, angiotensin II, which acts as a potent vasoconstrictor and stimulates the release of aldosterone from the adrenal cortex. Aldosterone, in turn, stimulates the reabsorption of Na⁺ and water, increasing blood volume.

When is the renin-angiotensin II-aldosterone system activated?

1. ↓ blood volume
   
2. ↓ serum Na⁺

What cells monitor hyponatremia and hypovolemia to regulate renin release?

Hypovolemia is detected by arterial baroreceptors which communicate with the JGA via the nervous system. The macula densa of the distal tubule monitors sodium concentrations and communicates with the juxtaglomerular cells to release renin when that value falls.

Where is ACE found?

Lungs (major) and vasculature (minor)

What other systems are influenced by aldosterone?

Many, aldosterone works nearly everywhere sodium can be lost, so in addition to the vascular and renal systems, the GI tract and even sweat glands are affected.

How are all the above steroid hormones inactivated and excreted?

1. Catabolized by liver (majority)
   
2. Excreted through urine and bile/stool

From what precursor are the catecholamines derived?

Tyrosine

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