Endocrine System and Hormones

• Endocrine physiology involves hormones and the scope of the endocrine system
• The topics covered include properties and synthesis of steroid, protein and amide hormones.

Hormones

• Chemicals produced in specific cells.
• They are transported via blood or interstitial fluid.
• Hormones activate signaling in specific target tissues.
• They regulate physiology.
• There are over 100 recognized hormones.
• ~40 of these hormones will be covered.
• The covered hormones will mostly consist of the "classic" hormones.
• The principles that will be covered are universal.
• Hormones regulate activities of various body systems, making them appropriate.
• They maintain homeostasis, the stable condition of the body.

Endocrine System Function

• Input: including endocrine tissue and hormones
• Target tissue: including receptor, signal, and response
• Feedback

Homeostatic Processes Regulated by Hormones

• Blood glucose and metabolism is regulated by insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic peptide, growth hormone, IGF1, cortisol, epinephrine, thyroid hormone, and sex steroids (Topics 5, 6, 8, 10, 11 & 12).
• Maintenance of physiological energy stores includes leptin, insulin and ghrelin (Topics 7 & 8).
• Blood calcium is regulated by parathyroid hormone, calcitriol, and calcitonin (cortisol and sex steroids) – Topic 14.
• Osmolarity in the ECF, and Na+, K+ and water balance is regulated by antidiuretic hormone, and aldosterone- Topic 13.

Hormones Promoting Long-Term Non-Homeostatic Processes

• Growth and physical development are regulated by growth hormone, insulin-like growth factor 1, somatostatin, growth hormone releasing hormone, insulin, thyroid hormone, TSH, TRH, testosterone, and estrogens (Topics 9 & 15).
• Sexual development and reproduction are regulated by estrogens, testosterone, progesterone, gonadotropin releasing hormone, inhibin, antimüllerian hormone, and the gonadotropins (Topic 16).
• Lactation is regulated by prolactin, prolactin inhibiting hormone, and oxytocin (Topic 17).

Pathophysiology in Endocrine Systems

• Endocrine tissues can have Hormone hypersecretion caused by tumors and abuse.
• Endocrine tissues can have Hormone hyposecretion caused by Autoimmune attack, Infection, Injury and Genetic defects.
• Target tissue can suffer from resistance.

Hormone Communication

• Endocrine signaling (most common), involves hormones secreted into the blood stream.
• Neuroendocrine signaling.
• Paracrine signaling (rare), involves hormones traveling through interstitial fluid (autocrine).

Hormone Sources

• Endocrine glands (classic)
• Endocrine tissues
• Endocrine tissues not traditionally considered glands include neurons, placenta, adipose tissue.

Hormone Chemical Classes

• Proteins: peptides (small), glycoproteins (large, glycosylated, >1 subunit).
• Steroids
• Amides can be similar to proteins or steroids.

Hormone Properties

• The properties of hormones can be explained by their chemical properties.
• Properties include: Origin, Synthesis mechanism, Transport from the cell and to the blood stream, Half-life, Presence of a binding protein, Receptor type, Signaling mechanism, Time for action & Regulation.
• Determine if a hormone is a protein or steroid to understand its function.

Steroid Hormones

• Steroid hormones are derived from cholesterol and are hydrophobic.
• Steroid Properties:
• Stepwise synthesis
• Diffuses from cells
• Transported bound to a protein
• Lasts long
• Diffuses into cells
• Bind to transcription factors and regulate gene expression

Important Steroid Hormones

• Adrenal produced hormones include Aldosterone, Cortisol and DHEA.
• Gonadal derived hormones include Progesterone, Estradiol (E₂) and Testosterone.
• Calcitriol which relies on Skin → Liver → Kidney, has a different synthesis pathway.
• Androgens.

Steroid Synthesis

• Synthesized in a common pathway by specialized enzyme
• Cholesterol precursor:
  • Major source is low density lipoproteins
  • Minor source is de novo synthesis
• Cytochromes P450 (CYP):
  • Mono-oxygenases of hydrophobic organic molecules
  • Iron-containing protein
  • NAD(P)H binding protein
  • 57 genes in humans
  • Localized to Inner mitochondrial membranes & Outside of endoplasmic reticulum
  • Other functions may include Hydrophobic metabolism and Drug metabolism

Steroid Synthesis cont.

• Steroid dehydrogenases/reductases are also part of the process
• Steroid synthesis starts with cholesterol mobilization & side chain cleavage.
• Cholesterol ester in lipid droplets are used.
• Cholesterol esterase
• StAR, Steroid acute regulatory protein
• Cytochrome P450scc, Side Chain Cleavage is involved.
• Key steps in steroid biosynthesis include StAR and P450scc, as well as internalization of cholesterol by the LDL receptor.

Later Stages of Steroid Synthesis

• Common pathways lead to multiple hormones
• Tissue specific pathways
• Steroid hormones require binding protein in aqueous ECF.
• Free hormone enters cells for signaling or metabolism (t₁/₂).

• 90% hormones can be bound in ECF.

• Binding Proteins:
  • Steroid binding globulin: low capacity /high affinity & Usually made in liver.
  • albumin: High capacity/low affinity & >10⁶ fold more abundant than SBG.

Protein Hormones

• Protein hormones are synthesized from amino acids.

• Translated from mRNA.

• Actively transported from cells.

• They are Soluble in the aqueous blood stream, and use Cell surface receptors.

• Two classes include:

  • Peptides are Usually smaller (3 to <100 amino acids) that have Short half-lives and their Synthesis requires extensive proteolytic processing.

• Glycoproteins include >100 amino acids that have Long half-lives and undergo Little proteolysis.

Peptide Hormone Synthesis

• Hormone gene is transcribed to mRNA.
• The mRNA is translated by membrane-bound ribosomes on the endoplasmic reticulum (ER); preprohormone.
• The signal sequence is cleaved by the signal peptide peptidase in the ER; prohormone.
• The prohormone is transported from the ER, through the trans-Golgi, and into dense core secretory granules (a.k.a. DCSG or exocytotic vesicles).
• The DCSG contain concentrated prohormone (can be >0.5 M and in crystal form), one or more of a class of secretory proteins called 'granins' that bind Ca²⁺ & ATP; low internal pH of 4-6.

Continued Peptide Hormone Synthesis

• This lower pH is required to activate the prohormone convertases (proteases) that produce the mature hormone
• Hormone is released into the blood (actually, extracellular fluid, ECF) via exocytosis.
• Requires a specific release signal; otherwise the hormone remains stored in the vesicle for up to 10 hours or so.

Examples of peptide hormone synthesis:

• Preprothyrotropin releasing hormone
• POMC- Made in anterior pituitary & other tissues:
  • Processed by proteases called prohormone convertases: PC1/3 and PC2
    • J-Peptide: Joining peptide; no known function.
    • β-LPH & γ-LPH involve lipid mobilization in animals, but probably not in humans.
    • CLIP: corticotropin-like intermediate peptide that has unknown function.
    • α & γ-MSH disperse melanocyte pigment granules; α-MSH is a key appetite suppressing neurotransmitter.
    • β endorphin is an opiate neurotransmitter to reduce pain in times of stress.
    • ACTH, made in specialized anterior pituitary cells called corticotrophs.
    • MSH, made in hypothalamus part called arcuate nucleus.

Glycoprotein Synthesis

• Involves Chaperone proteins for folding
• Glycosylation & subunit assembly
• Less proteolysis in the process

Peptide Hormone Stages

• Preprohormone:Newly translated and has a signal sequence attached, and it is inactive.
• Prohormone: Any hormone precursor that is Usually inactive applies to both protein and steroid precursors.
• Hormone: Finished protein or steroid that is Active

Amide Hormones

• These hormones combine aspects of steroids and proteins.
• They are not a major class.
• They are Derived from one of two amino acids including:
  • Tryptophan: produces melatonin, and.
  • Tyrosine: produces Thyroid hormones and Catecholamines like Dopamine (prolactin inhibiting hormone), Norepinephrine and Epinephrine.