Endocrine 3

The Calcium Cycle

• Calcium (Ca++) Regulation

  • Dietary intake of calcium

  • Absorption occurs in the gut with the help of Vitamin D and Parathyroid Hormone (PTH)

    • If not absorbed, Ca++ passes through the GI and is excreted through the feces

  • If absorbed, calcium enters the plasma and has 2 pathways

    • Calcitonin deposits the calcium to various body systems including bone and other tissues

      • Can then be reabsorbed by PTH back into the plasma

    • Excretion occurs through urine, or is reabsorbed by PTH (after being filtered by the kidneys

Parathyroid Hormone (PTH)

• Overview

  • Secreted from parathyroid chief cells embedded in the thyroid gland surface

  • There are 4 parathyroid glands located on the back of the thyroid gland

  • Removal of these glands leads to severe plasma calcium drop, resulting in tetanic convulsions or death

• Structure of PTH

  • Composed of 84 amino acids (mature form); the first 34 (N-terminal) are crucial for activity

    • It is these 34 amino acids that bind to the parathyroid hormone receptor and stimulate it

  • Synthesized from preproparathyroid hormone (since it is a peptide hormone) containing an N-terminal sequence (which undergoes cleavage) that guides it through the secretory system to produce PTH

  • Very short half-life of 3-18 minutes

Functions of PTH

• Main Functions

  1. Increase Plasma Calcium Levels:

     • Stimulates bone resorption to release Ca++ into body fluids

     • Enhances reabsorption of Ca++ in the kidney (proximal convoluted tubule)

     • Stimulates the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (active version) in the kidney

       • 25-hydroxyvitamin D3 undergoes 1 hydroxylation event on the B ring, creating the major circulating form of vitamin D, which then undergoes hydroxylation of the A ring, creating the active form

     • Together with vitamin D, facilitates Ca++ absorption from the gut

  2. Regulation:

     • Controlled directly by blood calcium levels

     • Calcium sensor on the parathyroids

  3. Mechanism of Action:

     • Binds to target cell receptors to exert physiological effects

Control of PTH Secretion

• Low Calcium Levels

  • Low plasma Ca++ levels trigger the parathyroid glands to increase PTH production, leading to increase in resorption and decrease in Ca++ urine concentration

• High Calcium Levels

  • High plasma Ca++ results in decreased PTH production, leading to reduced reabsorption and increased urinary excretion of calcium

Problems with Parathyroid Function

1. Hypoparathyroidism

• Low levels of PTH in circulation

• Causes hypocalcemia (low plasma calcium) leading to increased neuromuscular excitability, tetany, muscle spasms, and potentially death from asphyxiation

• Symptoms include less active vitamin D production

• Treatment: administration of 1,25-dihydroxyvitamin D and calcium

2. Hyperparathyroidism

• Excess PTH production, often caused by adenoma (benign growth of tissue)

• Symptoms include high plasma calcium, increased bone and kidney calcium resorption, leading to kidney stones and cardiac arrhythmias

• Treatment involves removal of affected parathyroids and replacement therapy

  • PTH is a peptide, meaning it is injectable, and less preferential

  • Instead, the active from of vitamin D is given

Vitamin D

• Sources and Synthesis

  • Limited dietary sources like cod liver oil and fatty fish; synthesized from cholesterol metabolites

  • Synthesized through:

    1. UVB light (300 nm) converting 7-dehydrocholesterol in skin

       • If the sun is low enough in the sky (<45°) and the light path through the ozone layer is longer, no UVB reaches the surface

    2. Hydroxylation in the liver (25-hydroxylation)

    3. Hydroxylation in kidney and peripheral tissues (1-hydroxylation) leading to 1,25-dihydroxyvitamin D3

• Physiological Functions

  1. Main function: Increase intestinal calcium absorption

  2. Regulates immune functions, provides infection protection, and has anticancer properties

• Regulation of Synthesis

  • Increased in low calcium conditions, decreased when calcium levels are high

  • Vitamin D deficiency in northern countries due to lack of UVB can cause rickets in children and osteomalacia (soft bone, not enough mineralized calcium) in adults

Problems Related to Vitamin D

• Hereditary Vitamin D-resistant Rickets

  • Due to inactivating mutation in vitamin D receptor

    • These individuals are bald

  • Also caused by an inability to form the active type of vitamin D

    • These individuals have hair

  • Shortened clavicles because the bones are not strong enough to support the weight of the individual

• Kidney Failure

  • Leads to reduced levels of active vitamin D, causing deficient bone mineralization and conditions such as rickets and osteomalacia

Calcitonin

• Overview

  • 32 amino acid peptide hormone produced in C-cells of the thyroid gland

  • Lowers plasma calcium by promoting blood to bone transfer, enhancing urinary calcium excretion

  • Levels rise with plasma Ca++ increase, and decrease when plasma Ca++ drops

  • Less critical compared to PTH and active vitamin D

Adrenal Glands

• Location: Adjacent to the upper surface of the kidneys

  • Medulla in the middle

  • Cortex on the outside

• Structure:

  • Cortex contains epithelial cells and is derived from the mesoderm

  • Medulla contain chromaffin cells and is derived from the neural crest

• Comparison of Cortex and Medulla

  • Cortex: Produces steroid hormones (glucocorticoids (cortisol, corticosterone) and mineralocorticoids (aldosterone)) and low levels of sex hormones (progestin)

  • Medulla: Produce catecholamines (epinephrine, norepinephrine) and peptide hormones (enkephalins, dynorphins, and atrial natriuretic peptides)

Hormones Produced by Adrenal Cortex

• Adrenal Cortex Layers:

  1. Zona Glomerulosa: Produces mainly mineralocorticoids (aldosterone)

     • Has the enzymes necessary for the biosynthesis of mineralocorticoids and lacks the enzymes necessary for the production of glucocorticoids

  2. Zona Fasciculata: Produces glucocorticoids (cortisol)

  3. Zona Reticularis: Produces glucocorticoids, progestins, andrognes, and estrogens

• Steroid Hormones

  • In the case of steroid hormones, it is a gene encoding for the enzyme, not the hormone itself

    • Steroid hormones regulate the transcription of hormone/receptor-specific target genes

  • In the absence of the ligand, the steroid hormone receptors are in the cytoplasm

    • Binding the hormone indices a translocation into the nucleus

• Regulation of Synthesis

  • Controlled by adrenocorticotropin (ACTH), affecting mineralocorticoid synthesis through 18-hydroxylase action

Action and Effects of Adrenal Hormones

• Aldosterone

  • Involved in sodium metabolism and increases its reabsorption in the kidney

  • Must be done in an electrochemically neutral way

    • Sodium is taken up with chloride ions

    • Sodium in, potassium or proton out

• Glucocorticoids

  • Effects:

    1. Salt retention (less effective than aldosterone)

    2. Alters protein and carbohydrate metabolism, leading to increased blood glucose

       • Induce protein breakdown

       • Can induce adrenal diabetes

    3. Enhances lipid metabolism leading to elevated lipids

       • Increase lipid breakdown enzymes in adipose tissue

    4. Anti-inflammatory and immunosuppressive properties

       • Glucocorticoids repress the changes in metabolism of immune cells

    5. Leads to osteoporosis through protein loss in the bone matrix (due to prolonged exposure of high glucocorticoids levels)

Feedback Control of Hormonal Secretions

• ACTH and Negative Feedback Mechanism

  • The hypothalamus releases corticotropin releasing hormone (CRH)

  • This triggers the pituitary to release adrenocorticotropic hormone (ACTH)

  • ACTH stimulates the adrenal cortex to secrete glucocorticoid and cortisol

  • The increased plasma concentration serves as a negative feedback loop on the release of CRH and ACTH

  • Conditions with enzyme deficiencies (ex. lack of 11b-hydroxylase that is necessary for cortisol production) break the negative feedback loop, causing ACTH levels to go unchecked

    • Increased ACTH with no cortisol production causes the cortex to compensate by growing, resulting in congenital adrenal hyperplasia

    • Treatment - administration of cortisol

• Mechanism of ACTH Action

  • Binds to specific receptors on zona fasciculata and zona reticularis, stimulating steroidogenesis through cyclic AMP production

  • Diurnal rhythm observed in ACTH and plasma cortisol: Increases from 12:00 am to 8:00 am, then decreases

    • The levels fluctuate according to the negative feedback loop, but there is a delay

Stress Responses

• Psychological and physical stress raises CRH, ACTH, and cortisol synthesis and release

  • Stress can provide energy through tissue protein breakdown

  • Prolonged stress leads to adverse effects like insulin resistance (leading to increased blood glucose/diabetes mellitus), immune suppression, and loss of bone integrity