Hormones and Actions

Hormones and Actions

• Hormones are chemicals that transmit signals from one cell to another

Learning Objectives

• Understand the biomedical importance of hormones, pituitary, steroid, thyroid hormones

Intracellular Communication

• Intracellular signals provided via nervous and endocrine systems
• The nervous system uses "fixed communication"
• The endocrine system uses "mobile communication"

Biomedical Importance of Hormones

• Hormones classified as "messenger molecules"
• Hormones circulate through the blood
• Hormones act on adjacent cells (paracrine) or on the cell they are synthesized in (autocrine)
• Target cells must have receptors to respond to hormones
• Approximately 50 hormones exist in the human body, which contains 200 types of differentiated cells and trillions of cell targets
• Hormones are present in low concentrations, ranging from 10-5 to 10-9 mol/L.

Basic Categories of Hormones

• Amino acid-based hormones are modified amino acids (or amines), peptides, and proteins
• Steroid hormones are lipid molecules derived from cholesterol

Hormone Groups I and II

• Group I hormones include steroids, iodothyronines, calcitriol, and retinoids
  • These hormones are lipophilic, use transport proteins, and have a long plasma half-life
  • Intracellular receptors and receptor-hormone complexes mediate their actions
• Group II hormones include polypeptides, proteins, glycoproteins and cholamines
  • They are hydrophilic, don't use transport proteins, and have a short plasma half-life
  • Plasma membrane receptors mediate their actions, using cAMP, cGMP, Ca2+, phosphoinositols, and kinase cascades as mediators

Example of Hormone Action

• Epinephrine binds to a receptor and activates adenylyl cyclase to produce cAMP
• cAMP activates cAMP-dependent protein kinase A
  • This then activates glycogen phosphorylase b kinase, which in turn activates glycogen phosphorylase b
  • Causes the breakdown of glycogen into glucose-1-phosphate for extra energy

Nuclear Receptor Hormones

• Steroid, retinoid, vitamin D, and thyroid hormones are nonpolar
  • They pass through the plasma membrane to the nucleus and bind to receptor in nucleus
• Receptor-hormone complex binds to DNA and acts as a transcription factor, increasing or decreasing target gene expression
  • The process takes hours to days

Hormone Classification by Mechanism of Action

• Group I hormones bind to intracellular receptors
  • Includes androgens, calcitriol, estrogens, glucocorticoids, mineralocorticoids, progestins, retinoic acid, and thyroid hormones (T3 and T4)
• Group II hormones bind to cell surface receptors
  • The second messenger is cAMP:
    • Includes a2-adrenergic catecholamines, B-adrenergic catecholamines, adrenocorticotropic hormone, antidiuretic hormone, calcitonin, chorionic gonadotropin, corticotropin-releasing hormone, follicle-stimulating hormone, glucagon, lipotropin, luteinizing hormone, melanocyte-stimulating hormone, parathyroid hormone, somatostatin and thyroid-stimulating hormone
  • The second messenger is cGMP
    • Includes atrial natriuretic factor and nitric oxide
  • The second messenger is calcium or phosphatidylinositols, or both:
    • Includes acetylcholine (muscarinic), al-adrenergic catecholamines, angiotensin II, antidiuretic hormone (vasopressin), cholecystokinin, gastrin, gonadotropin-releasing hormone, oxytocin, platelet-derived growth factor, substance P, and thyrotropin-releasing hormone
  • The second messenger is a kinase or phosphatase cascade:
    • Includes chorionic somatomammotropin, epidermal growth factor, erythropoietin, fibroblast growth factor, growth hormone, insulin, insulin-like growth factors I and II, nerve growth factor, platelet-derived growth factor, and prolactin

Mechanisms of Hormone Release

• Humoral: In response to changing levels of ions or nutrients in the blood
• Neural: Hormones are released via nerve stimulation
• Hormonal: Hormone release from stimulation received from other hormones

Endocrine Organs

• Purely endocrine organs:
  • Pituitary, pineal, thyroid, parathyroid, and adrenal glands (cortex and medulla)
• Endocrine cells exist in other organs:
  • Pancreas, thymus, gonads, and hypothalamus

Hormone Study Focus

• Three hormone types to know in detail are the Hypothalamic and Pituitary, Steroid, and Thyroid Hormones

Hypothalamic and Pituitary Hormones

• The hypothalamus produces two types of endocrine factors
  • Hypothalamic neuropeptides
  • Hypothalamic releasing factors

Pituitary Glands

• The anterior pituitary (adenohypophysis) receives releasing factors from the hypothalamus through blood vessels
  • Produces long peptide hormones called tropins
  • Activates second targets such as the adrenal cortex, thyroid, and ovaries/testes
• The posterior pituitary (neurohypophysis) contains the end of axons from the hypothalamus
  • Stores short peptide hormones made in the hypothalamus, like vasopressin (ADH) and oxytocin

Hypothalamic Neuropeptides

• These are the neurohormones anti-diuretic hormone (ADH, vasopressin) and oxytocin
• Precursors of ADH and oxytocin are long polypeptides synthesized in the hypothalamus
• These are cleaved into active molecules, then transported to the posterior pituitary for storage
• Release into the bloodstream occurs via exocytosis

Posterior Pituitary Hormones

• One such hormone is Anti-Diuretic Hormone (ADH)
• ADH is also called vasopressin
  • It prevents diuresis by stimulating the kidneys to reclaim water from urine, raising blood pressure
  • ADH deficiency causes diabetes insipidus, characterized by excretion of large volumes of dilute urine
• Another posterior pituitary hormone is Oxytocin
  • It earned its name because it stimulates birth
  • Oxytocin acts on an estrogen-primed uterus
  • Pitocin, a synthetic derivative of oxytocin, induces labor
  • Important effect on mammary glands, stimulates neurogenic reflex, stimulates production of oxytocin, and ejects milk

Hypothalamic Releasing Factors

• Pituitary secretes 9 hormones
  • Anterior pituitary and posterior pituitary
• Pituitary secretes these nine hormones:
  • TSH, ACTH, FSH, LH, GH, PRL, MSH, ADH (vasopressin), Oxytocin
  • TSH, ACTH, FSH, and LH are the tropic hormones, which regulate the function of other hormones

What those letter stand for...

• TSH: thyroid-stimulating hormone
• ACTH: adrenocorticotropic hormone
• FSH: follicle-stimulating hormone
• LH: luteinizing hormone
• GH: growth hormone
• PRL: prolactin
• MSH: melanocyte-stimulating hormone
• ADH: antidiuretic hormone
• Oxytocin

Hypothalamus controls Anterior Pituitary releasing factors

• Releasing factors are secreted into capillaries and veins of the anterior pituitary like neurotransmitters
  • TRH turns on TSH
  • CRH turns on ACTH
  • GnRH (=LHRH) turns on FSH and LH
  • PRF turns on PRL
  • GHRH turns on GH
• Inhibiting hormones
  • PIF turns off PRL
  • GH inhibiting hormone turns off GH

Hormones of the Anterior Pituitary

• Anterior pituitary hormones are tropic; they stimulate secretion from target organs
• Secretions of all these hormones are regulated by hypothalamic releasing or inhibitory factors

Growth Hormone (GH)

• Also called somatotropin
• Effects: stimulate growth of soft tissues, bone and cartilage.
• Highest levels of GH are met during deep sleep
• Excess GH due to a GH secreting tumor leads to gigantism in children and acromegaly in adults
• Deficiency of GH in early childhood results in pituitary dwarfism

Functions of the four tropic pituitary hormones

• TSH stimulates the thyroid to produce thyroid hormone.
• ACTH stimulates the adrenal cortex to produce corticosteroids: Aldosterone and cortisol.
• FSH stimulates follicle growth and ovarian estrogen production and stimulates sperm production and the production of androgen-binding protein.
• LH: plays a role in ovulation and growth of the corpus luteum, stimulates the androgen secretion

Functions of the non-tropic pituitary hormones

• GH stimulates growth of skeletal epiphyseal plates and synthesis of protein.
• PRL stimulates mammary glands to make milk.
• MSH stimulates melanocytes and may increase mental alertness

From the Posterior Pituitary...

• ADH stimulates the kidneys to reclaim more water from the urine, raising blood pressure
• Oxytocin cause contraction of smooth muscle in reproductive tracts, initiating labor and ejection of milk from breasts

Putting it all together: Hypothalamus to Target Organ

• TRH (thyroid releasing hormone) turns on TSH
• CRH (corticotropin releasing hormone) turns on ACTH
• GnRH (gonadotropin releasing hormone) turns on FSH and LH
• PRF (prolactin releasing hormone) turns on PRL
• GHRH (growth hormone releasing) turns on GH
• TSH stimulates the thyroid to produce thyroid hormone
• ACTH stimulates the adrenal cortex to produce corticosteroids: Aldosterone and cortisol
• FSH stimulates follicle growth and ovarian estrogen production and stimulates sperm and androgen-binding protein
• LH has a function in ovulation and growth of the corpus luteum, and it stimulates androgen secretion by interstitial cells
• GH stimulates growth of skeletal epiphyseal plates, and is responsible for the synthesis of protein
• PRL stimulates mammary glands to make milk
• MSH stimulates melanocytes and may increase mental alertness
• ADH stimulates the kidneys to reclaim more water from the urine, which raises blood pressure
• Oxytocin prompts contraction of smooth muscle during labor and ejection of milk from breasts

Steroid Hormones

• Cholesterol is the precursor of all five classes of steroid hormones: glucocorticoids (cortisol), mineralocorticoids (aldosterone), androgens, estrogens, and progestins
• Glucocorticoids and mineralocorticoids are called corticosteroids
• These hormones all have four fused rings, and are synthesized in:
  • Adrenal cortex, ovaries and placenta, and testes
  • Transported by plasma protein

Synthesis of Steroid Hormones

• Synthesis starts with shortening the hydrocarbon chain of cholesterol
• Synthesis of 21-carbon pregnenolone is the rate limiting step
  • Catalyzed by cholesterol side chain cleavage enzyme (P450), a cytochrome P450 and mixed function oxidase
• Requires O2 and NADPH
• Pregnenolone is the parent compound for all steroid hormones
• It is converted to progesterone, which is further modified to produce other steroid hormones, through hydroxylation reactions in the ER and mitochondria
• Enzyme defects effects and results into Congenital Adrenal Hyperplasias

Adrenal Cortical Steroid Hormones

• Steroid hormones are secreted on demand
• Glucocorticoids, mineralocorticoids, and androgens are made in different areas of the adrenal cortex

Cortisol

• Synthesis in the adrenal cortex is controlled by the Hypothalamus
• In response to severe stress, hypothalamus produces corticotropin releasing hormone (CRH), and subsequently ACTH, which are called “stress hormones"
• The stress hormone then stimulates the adrenal gland to produce glucocorticoids
• Cortisol allows the body to respond to stress via increased gluconeogenesis as well as inflammatory and immune responses
• As cortisol levels rise, release of CRH and ACTH is inhibited

Aldosterone

• Aldosterone production is stimulated by a decrease in the plasma of Na+/K+ ratio and by angiotensin II
• Its primary action is on kidney tubules, where aldosterone stimulates Na and H2O uptake

Androgens

• The adrenal cortex produces androgens
  • While the adrenal androgens are weak, they are converted to testosterone or estrogen in the peripheral tissue

Secretion of Steroid Hormones from Gonads

• Testes and ovaries synthesize the hormones needed for for sexual differentiation and reproduction
• Gonadotropin-releasing hormone (GRH) stimulates the hypothalamus to release glycoproteins such as luteinizing hormones (LH) and follicle-stimulating hormones (FSH)
• Testes are stimulated by the LHs to produce testosterone, and the ovaries are stimulated to produce the estrogens and progesterone by the same LH

Gonadotropins

• They are LH (Luteinizing hormone) and FSH (Follicle stimulating hormone) from the pituitary gland
  • Effects: FSH and LH secreted under GnRH effect. Puberty will not start unless Hypothalamus starts pulsating secretion of LHRH
  • FSH causes growth in ovarian follicles in females/ Spermatogenesis (sertoli cells) in males
  • Testosterone in males; progesterone in females increased- influence of LH
  • FSH rises during menstrual cycle follicular phase: peak day 14 (ovulation); FSH + LH fall during post ovulation phase.

Metabolism of Steroid Hormones

• Steroid hormones are converted to inactive metabolic products in the liver
• They become water soluble through hydroxyl and/or uranic acid/sulfate groups
  • 20-30% of their metabolites are secreted into the bile for fecal excrement
  • The rest goes into the kidney and are peed out since they are water soluble.

Thyroid Harmones

• Thyroid gland creates:
  • Thyroxine (T4): Principle hormone, energy and protein metabolism
  • Triiodothyronine (T3): energy and protein metabolism
  • Calcitonin: Regulates calcium metabolism. Works with parathyroid hormone and vitamin D
• Thyroid can control rate body burns calories, control heartbeat rate, body temp, adjust fat food going through digestive track, muscle strength, control process of how dying cells are quickly replaced

Thyroid Hormone Feedback Mechanism

• The pituitary gland and the thyroid gland work together

Synthesis of Thyroid Harmones

• Iodide is the oxidized by the thyroid cell to make iodine
• Second step stimulated by TSH
• Drug inhibitions such as such as thiourea, thiouracil and methimazole
• Thyroglobulin (Tgb) is iodinated.
• Tgb contains- 115 tyrosine residues and 35 residues can be iodinated.

Additional Harmone Info

• Mono-iodo tyrosine (MIT) and di-iodo tyrosine (DIT) are produced
• When two DIT molecules: 1 molecule of tetra-iodo thyronine (T4) is created
• If we want Tri-iodo thyronine (T3): must be by deiodination of T4
• Most made thyroid gald =T4=99%

Further Considerations

• Thyroid gland= only the endocrine to store large amount of hormones.
• Thyroglobulin- taken intro cell via pinocytosis is needed.
• The T4– liberated via the hydrolysis action (specific proteases)
• The T3- created via de-iodination at 5' section. This happens inside thyroid/surrounding tissues T4 has shorter half life= about 1-7-days/ while T3 is only days
• T3 is biologically more acitve so T4 is the prohormone

Thyroid Stimulating Hormone (TSH) (Thyrotropin)

The TSH allows for secretion more thyroid horomes and stimualtes all synthetic production steps

• High TSH=primary hypothyroidism, lack of feedback contro,. Normal between .05 to 5 mcrounits ml Increased serum= hypothyroidism (3-10 normal, Hashimoto's thyroiditis, ectopic:Tumors (lungs, breast, and thyroid hormone resistance
• Lower Level: primary hyperthyroidism, secondary cause: pituitary origin tertiary: caused by the hypothalamus; subclinical

Multiple Choice Answers

• B) Hormonal stimuli
• D) TSH
• D) half life
• A) Testosterone
• D) Prolactin