Hormones: Intracellular Communication

Intracellular Communication

• The nervous and endocrine systems both facilitate intracellular communication.
• The nervous system provides "fixed" communication, whereas the endocrine system provides "mobile" communication.

Biomedical Importance of Hormones

• Hormones function as "messenger molecules".
• Hormones circulate through the bloodstream.
• Hormones can influence adjacent cells through paracrine actions.
• Hormones can also affect the same cell that produced them through autocrine actions.
• Target cells possess receptors that enable them to respond to specific hormones.
• Roughly 50 known hormones influence about 200 types of differentiated cells in the human body.
• Hormones typically present at low concentrations, ranging from 10⁻⁵ to 10⁻⁹ mol/L.

Basic Hormone Categories

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

Hormone classification based on solubility, transport, receptor location, and mediators

• Group I hormones include steroids, iodothyronines, calcitriol, and retinoids.
• Group II hormones include polypeptides, proteins, glycoproteins, and cholamines.
• Group I hormones are lipophilic, while Group II hormones are hydrophilic
• Group I hormones use transport proteins, but Group II do not.
• Group I hormones have a longer plasma half-life (hours to days) than Group II hormones (minutes).
• The receptor for Group I hormones is intracellular, while for Group II it is on the plasma membrane.
• Group I hormones use a receptor-hormone complex as a mediator.
• Group II hormones use cAMP, cGMP, Ca2⁺, metabolites of complex phosphoinositols and kinase cascades as mediators.

Example of Epinephrine activating cAMP

• Epinephrine binding to a receptor activates adenylyl cyclase, yielding cAMP.
• cAMP then activates cAMP-dependent protein kinase A.
• Protein kinase A activates glycogen phosphorylase b kinase.
• Glycogen phosphorylase b kinase activates glycogen phosphorylase b.
• Glycogen phosphorylase b helps break down glycogen to glucose-1-phosphate, providing extra energy.

Nuclear Receptor Hormones

• Steroid, retinoid, vitamin D, and thyroid hormones pass through the plasma membrane to the nucleus due to their nonpolar nature.
• These hormones bind to a receptor inside the nucleus.
• The receptor-hormone complex interacts with DNA, functioning as a transcription factor.
• These hormones increase or decrease the expression of genes,
• This process takes hours to days.

Mechanisms of Hormone Release

• Humoral release involves changes in blood levels of ions or nutrients.
• Neural release involves stimulation by nerves.
• Hormonal release involves stimulation received from other hormones.

Endocrine Organs

• Purely endocrine organs include the pituitary, pineal, thyroid, parathyroid and adrenal glands.
• The adrenal glands consist of two parts which are the cortex and the medulla
• Endocrine cells are also present in the pancreas, thymus, gonads, and hypothalamus.

Hypothalamic and Pituitary Hormones

• The hypothalamus produces hypothalamic neuropeptides and hypothalamic releasing factors related to endocrine function.

Posterior Pituitary

• The posterior pituitary (neurohypophysis) contains nerve axons originating from the hypothalamus.
• The posterior pituitary stores short peptide hormones (vasopressin/ADH and oxytocin) produced in the hypothalamus.

Anterior Pituitary

• The anterior pituitary (adenohypophysis) receives releasing factors from the hypothalamus through blood vessels.
• It produces long peptide hormones (tropins) that then activate adrenal cortex, thyroid, ovaries/testes.

Hypothalamic Neuropeptides

• Hypothalamic neuropeptides include anti-diuretic hormone (ADH, vasopressin) and oxytocin.
• The precursors for ADH and oxytocin are long polypeptide molecules.
• They are synthesized in the hypothalamus.
• Synthesized polypeptides get cleaved into active hormone molecules.
• Active hormone molecules are transported to the posterior pituitary for storage and released into the bloodstream via exocytosis.

Anti-Diuretic Hormone (ADH)

• ADH is also known as vasopressin and prevents diuresis.
• It prompts the kidneys to retain more water from urine, raising blood pressure.
• ADH deficiency results in diabetes insipidus, marked by excretion of large amounts of dilute urine.

Oxytocin

• Oxytocin's name means "to stimulate birth".
• Oxytocin affects the mammary glands; suckling generates a neurogenic reflex, stimulating oxytocin production and milk ejection.
• It acts on an estrogen-primed uterus.
• Pitocin, a synthetic oxytocin, induces labor.

Hypothalamic Releasing Factors and Pituitary Control

• The pituitary secretes 9 hormones.
• Of these, TSH, ACTH, FSH, and LH are tropic, regulating other hormones.
• Posterior pituitary hormones are ADH (vasopressin) and oxytocin.
• Anterior pituitary hormones are TSH, ACTH, FSH, LH, GH, PRL, and MSH.
• The hypothalamus uses releasing factors to control pituitary function.

Anterior Pituitary Hormones Actions

• TSH stimulates the thyroid to produce thyroid hormone.
• ACTH stimulates the adrenal cortex to release aldosterone and cortisol.
• FSH stimulates follicle growth and ovarian estrogen production and stimulates sperm production and androgen-binding protein.
• LH mediates ovulation, growth of the corpus luteum, and stimulates androgen production in testes.
• GH helps growth of skeletal epiphyseal plates and synthesizes protein.
• PRL stimulates mammary glands to produce milk.
• MSH stimulates melanocytes which may increase mental alertness.

Major Hypothalamic Releasing Factors

• Thyrotropin-releasing hormone (TRH) stimulates TSH and prolactin (PRL) secretion and acts as a neuromodulator.
• Gonadotropin-releasing hormone (GnRH) releases LH and FSH, and induces spermatogenesis, ovulation, and testosterone production.
• Growth hormone-releasing hormone (GHRH) stimulates growth hormone secretion.
• Corticotropin-releasing factor (CRF) releases ACTH and is inhibited by cortisol.
• Somatostatin inhibits the secretion of growth hormone, thyroid-stimulating hormone and pancreatic hormones.
• Prolactin-inhibiting factor (PIF) inhibits prolactin release

Hypothalamic Control of the Anterior Pituitary

• TRH turns "on" TSH; CRH turns "on" ACTH; GnRH (LHRH) activates FSH and LH; PRF turns "on" prolactin (PRL); and GHRH stimulates growth hormone (GH).
• Prolactin inhibitory factor (PIF) turns "off" prolactin (PRL), and growth hormone inhibiting hormone inhibits growth hormone (GH).

Growth Hormone (GH)

• GH is also known as somatotropin.
• GH stimulates overall tissue growth, including soft tissues, cartilage, and bone.
• GH levels peak during deep sleep.
• Excess GH secretion from tumors leads to gigantism in children and acromegaly in adults.
• Insufficient GH secretion in childhood results in pituitary dwarfism.

Steroid Hormones

• Cholesterol is a precursor for all five classes of steroid hormones: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestins.
• Glucocorticoids and mineralocorticoids are collectively known as corticosteroids.
• All steroid hormones have 4 fused rings.
• Steroid hormones need special transport as they are lipophilic.

Steroid Hormone Synthesis

• The adrenal cortex synthesizes cortisol, aldosterone and androgens
• The ovaries and placenta synthesize estrogens and progestins
• The testes synthesize testosterone
• The synthesis involves shortening the hydrocarbon chain of cholesterol and begins with the synthesis of pregnenolone.
• The synthesis of 21-carbon pregnenolone is a rate-limiting step and requires O₂ and NADPH.
• The reaction is catalyzed by cholesterol side chain cleavage enzyme (P450).

Pregnenolone

• Pregnenolone is the parent compound for all steroid hormones.
• It is converted to progesterone which is further modified to the other steroid hormones by hydroxylation reaction in the ER and mitochondria
• Defects in enzymes can cause numerous undesirable effects.
• These defects are known as Congenital Adrenal Hyperplasia.

Adrenal cortex synthesizes androgens production

• Although adrenal androgens themselves are weak.
• They are can be converted into more active androgen testosterone and into an estrogen, the estradiol, in peripheral tissue.

Gonad steroid secretion

• The testes and ovaries produce hormones required for both sexual differentiation and reproduction.
• Gonadotropin-releasing hormone (GRH) stimulates the hypothalamus to release LH and FSH.
• LH stimulates the testes to produce testosterone, and the ovaries to produce estrogens and progesterone.
• LH and FSH are secreted under the effect of gonadotropin releasing hormone (GnRH).
• FSH promotes growth of ovarian follicles in females and spermatogenesis (Sertoli cells) in males.
• Testosterone level in males and progesterone level in females, are increased under the influence of LH.
• FSH secretion increases during the follicular phase of the menstrual cycle, reaches its peak about the 14th day and starts falling when ovulation occurs.

Metabolism of Steroid Hormones

• Steroid hormones are converted in the liver to excretable, inactive molecules.
• They are converted via addition of hydroxyl & uranic acid/sulfate groups to water soluble products.
• Between 20-30% of metabolites are secreted into the bile and excreted in the feces.
• The rest are released in the blood, and these are filtered by the kidney and released through the urine.

Thyroid Hormones

• Thyroid hormones are made by the thryoid gland.
• The types are:
  • Thyroxine (T4) that is the principle hormone and that increases energy and protein metabolism rate.
  • Triiodothyronine (T3) increases energy and protein metabolism rate.
  • Calcitonin regulates calcium metabolism and works with parathyroid hormone and vitamin D.
• Thyroid hormones control body metabolism, heart rate, body temperature, digestion,muscle strength and dying cell replacement.

Thyroid Hormone Synthesis

• Thyroids hormones are synthesized when the iodide is taken up by the thyroid cell and oxidized to active iodine.
  • This step is stimulated by TSH.
• Anti-thyroid drugs such as thiourea, thiouracil, and methimazole inhibit the process
• Then thyroglobulin (Tgb) is iodinated.
• There are 115 tyrosine residues in Tgb, about 35 of which can be iodinated.
• Mono-iodo tyrosine (MIT) and di-iodo tyrosine (DIT) are produced.
• When two DIT molecules couple, one molecule of tetra-iodo thyronine (T4) is formed
• Under normal conditions, 99% of the hormone produced by the thyroid gland is T4
  • Tri-iodo thyronine (T3) is formed by de-iodination of T4.

Thyroid Glandular Specifics

• The thyroid is the only endocrine gland to store appreciable amounts of the hormone
• Thyroid hormones in the thyroid cell are produced by these steps:
  • T4 is released by hydrolysis by speific peroteases
  • thyroglobulin is taken into the cell via pinocytosis
  • T3 is produced by de-iodination at 5' position
• T4 has a half-life from 4-7 days whilst T3 has the half life of about 1 day.
• T3 is biologically more active and T4 is a prohormone which is deiodinated to T3.

Thyroid Stimulating Hormone (TSH)

• TSH increases the secretion of thyroid hormones.
• Normal TSH level is 0.5-5 microunits per ml.
• High TSH levels lead to hypothyroidism, lack of feedback, Hashimoto's thyroiditis, and ectopic TSH secretion by tumors.
• Decreased TSH levels lead to hyperthyroidism and hypo/hyperthyroidism.