Physiology Endocrine

Calcitonin inhibits calcium absorption in the intestine.

The drug form of PTH is Teriparatide, which is a protein hormone consisting of 84 amino acids and is secreted from the chief cells of the parathyroid gland.

The main types of cell membrane receptors include:

• G-Protein Coupled Receptors (GPCRs)
• Receptor Tyrosine Kinase (e.g., Insulin)
• Cytokine Family Receptors (e.g., GH, Leptin, Erythropoietin)

In the inactive state, steroid hormone receptors are located in the cytoplasm and are bound to heat shock proteins. When a hormone binds to the receptor, it activates the complex, allowing it to enter the nucleus.

Examples of nuclear receptors include:

• Estrogen Receptor
• Retinoic Acid Receptor (RAR)
• Progesterone Receptor
• Thyroid Hormone Receptors

The mechanism of action of GPCRs involves the following steps:

1. Hormone binds to the receptor.
2. The α subunit of the G protein separates.
3. The receptor is activated.
4. Secondary messengers are triggered to enter the cell, leading to a cellular response.

Functions of second messengers include:

Leptin plays a crucial role in signaling energy status to the hypothalamus, which is essential for the onset of puberty. It influences the secretion of gonadotropin-releasing hormone (GnRH), thereby affecting the development of secondary sexual characteristics.

Prolactin is responsible for the initiation of milk secretion (lactogenesis) and the maintenance of lactation (galactopoiesis). It stimulates mammary gland development and milk production in response to suckling.

Negative feedback is a regulatory mechanism that helps maintain homeostasis in the endocrine system. It involves the inhibition of hormone release by the effects of the hormone itself or by the hormones produced by target glands, ensuring that hormone levels remain within a normal range.

ACTH stimulates the adrenal cortex to produce cortisol. In Addison's disease, there is an underproduction of cortisol, leading to increased levels of ACTH. This can result in symptoms such as hyperpigmentation due to the excess ACTH mimicking the action of melanocyte-stimulating hormone (MSH).

• Decreased insulin sensitivity
• Protein synthesis
• Sodium retention
• Lipolysis

The direct actions of GH mediated by the JAK-STAT pathway include:

1. Lipolysis
2. Bone growth: Conversion of prechondrocytes to chondrocytes.

The indirect actions of GH mediated by IGF-1 primarily involve:

• Bone Growth: All remaining actions at the level of bone.

In children, disorders associated with abnormal levels of GH include:

• ↑GH: Gigantism
• ↓GH: Dwarfism

Features of Acromegaly include:

• Bony overgrowth: Frontal bossing
• Increased hand and foot size
• Prognathism: Mandibular enlargement
• Increased heel pad thickness (due to soft tissue overgrowth)
• Carpal tunnel syndrome
• Sleep apnea (due to upper airway obstruction)
• Diabetes mellitus

Treatment options for Acromegaly include:

Surgical Treatment:

1. Trans-sphenoidal resection of microadenoma

Pharmacological Treatment:

1. Somatostatin analogues: Octreotide
2. GH receptor antagonist: Pegvisomant

Laron dwarfism, also known as GH insensitivity syndrome, is characterized by:

• Etiology: Defective receptors
• Hormone levels: Increased GH with decreased plasma levels of IGF-1
• Treatment: Mecasermin (recombinant form of IGF-1)

Recombinant Human Growth Hormone is used in:

• Treatment of dwarfism
• Treatment of muscle wasting in AIDS patients (increases lean body mass and muscle mass)
• Anti-aging treatment

• Proliferation of lobulo-alveolar epithelial cells in the breast leading to milk production.
• Acts as a negative regulator of reproductive functions by inhibiting GnRH, which in turn inhibits FSH and LH, resulting in lactational amenorrhea in females and decreased libido in females and spermatogenesis in males.

Factors increasing prolactin secretion include:

1. Marked increase during pregnancy and lactation
2. Sexual intercourse
3. Dopamine blockers
4. Exercise

Factors inhibiting prolactin secretion include:

1. Somatostatin
2. Dopamine agonists (like Bromocriptine)

The hypothalamus regulates prolactin secretion by releasing Thyrotrophin releasing hormone (TRH) which stimulates lactotrophs in the anterior pituitary to produce prolactin. Additionally, glucocorticoids and thyroid hormones inhibit prolactin secretion, as does the prolactin inhibiting factor (Dopamine).

The raw materials required for thyroid hormone synthesis are:

• Tyrosine: Derived from thyroglobulin (Tg).
• Iodine: Present as iodide in the diet.

The Sodium Iodide Symporter (NIS) is located at the basolateral end of follicular cells and functions in iodide trapping through 2º active transport. It is also found in other locations such as the salivary gland, mammary gland, and placenta.

The wolf-Chaikoff effect is the phenomenon where excess iodide, through the sodium-iodide symporter (NIS), inhibits the organification of iodide, leading to decreased synthesis of thyroid hormones T3 and T4. Clinically, it is used in the treatment of patients with hyperthyroidism by administering Lugol's iodine prior to thyroid surgery.

Mutations in the iodide-chloride antiporter/pendrin can lead to:

• Goiter: Enlargement of the thyroid gland due to impaired iodide transport.
• Sensorineural hearing loss: A condition associated with Pendred syndrome, which is characterized by both thyroid dysfunction and hearing impairment.

Thyroid Peroxidase (TPO) is an enzyme that catalyzes the oxidation of iodide to iodine, which is essential for the synthesis of thyroid hormones T3 and T4. It plays a crucial role in the organification of iodide, which is necessary for the production of these hormones.

Thyroid hormones T3 and T4 are predominantly bound to binding proteins in the blood, with 99% of them being bound and only 1% free, which is responsible for their biological actions. The main binding proteins include:

• Thyroid Binding Globulin (TBG): Has the highest affinity for T3 and T4.
• Albumin: Binds a smaller fraction of thyroid hormones.
• Pre Albumin/Transthyretin: Binds T3, T4, and vitamin A.

T3 and T4 enter target cells through transporters such as monocarboxylate transporter (MCT) and organic anion transporting polypeptide (OATP). Once inside the cell, they bind to nuclear receptors in the nucleus, where they regulate gene expression and influence metabolic processes.

Thyroid hormones have a chronotropic and inotropic effect on the heart by increasing the number of β-adrenergic receptors, mediated by norepinephrine.

Thyroid hormones stimulate lipolysis in adipose tissue (catabolic effect) and increase proteolysis in muscle (catabolic effect).

Thyroid hormones promote brain growth through increased myelination in the CNS and support normal growth and skeletal development in bones.

T₃ prevents the accumulation of GAGS, while hypothyroidism leads to their accumulation, resulting in myxedema and puffiness of the face.

Congenital hypothyroidism can lead to mental retardation (most common reversible cause) and stunted growth.

T₃ increases metabolism and oxygen consumption, leading to hypoxia and a right shift of the oxygen dissociation curve, which stimulates respiration and increases respiratory rate.

T4 deiodinase catalyzes the conversion of T4 (thyroxine) to T3 (triiodothyronine) and contains the amino acid selenocystine.

T3 stimulates uncoupling protein I (UCPI), leading to heat dissipation and thermogenic action, which increases heat production in the body.

Hyperthyroidism results in increased heat generation and heat intolerance, while hypothyroidism leads to no heat generation and cold intolerance.

• Insulin is a large protein hormone composed of si amino acids.
• It was the first protein to be completely sequenced by Sanger.
• Insulin is produced using recombinant DNA technology.
• Zinc stabilizes the structure of insulin.
• Mutations in Hepatocyte Nuclear Factor (HNF) can lead to Maturity Onset Diabetes of the Young (MODY).

1. Glucose enters the beta cells via GLUT-2.
2. Increased glucose leads to ATP accumulation, causing the ATP-sensitive K+ channels to close.
3. This closure causes depolarization of the cell membrane, opening voltage-sensitive Ca2+ channels (VSCC).
4. Calcium influx triggers exocytosis of insulin, amylin, and C peptide from secretory granules.

• Heart
• Skeletal muscle (upregulates GLUT-4 to decrease serum glucose)
• Adipose tissue

Note: Exercise activates the AMP-activated kinase pathway, which also increases GLUT-4 independently of insulin, benefiting diabetics.

Rapid actions (within seconds):

• Decrease in blood glucose via GLUT-4.
• Decrease in K+ levels (used in treatment of hyperkalemia with insulin + dextrose).

Long-term actions (in days):

• Major anabolic hormone promoting storage of nutrients.

1. PI3 Kinase pathway (PI3K):

   • Mediates growth-promoting and anabolic functions.
   • Upregulates GLUT-4.

2. MAP Kinase pathway (MAPK):

   • Also involved in growth promotion and metabolic actions.

Insulin is a hypoglycemic hormone; a decrease in blood glucose levels can lead to coma if levels drop below 30 mg/dl. It plays a crucial role in maintaining glucose homeostasis, especially after protein meals where insulin and glucagon levels increase.

Factors that increase insulin secretion include:

• High blood glucose
• Glucagon
• Amino acids like arginine and leucine
• Acetylcholine (Parasympathetic ANS)
• β receptor mediated (Sympathetic ANS)
• Gastrin, cholecystokinin, secretin
• Incretin hormones such as GLP-1 and GIP, which enhance insulin secretion more from oral glucose than from IV glucose.

Factors that decrease insulin secretion include:

• Epinephrine
• Somatostatin
• Toxins such as streptozocin and alloxan
• α adrenergic receptor mediated (Sympathetic ANS, dominant effect)

Ketogenesis is mediated by hyperglycemic/counter-regulatory hormones, which include:

• Cortisol
• Growth hormone
• Glucagon
• Epinephrine
• Thyroid hormones

The adrenal gland has different zones that secrete various hormones:

• Zona glomerulosa: Secretes mineralocorticoids (e.g., aldosterone)
• Zona fasciculata: Secretes glucocorticoids (e.g., cortisol)
• Zona reticularis: Secretes sex steroids
• Adrenal medulla: Secretes catecholamines (90% epinephrine, 10% norepinephrine)

The major source of testosterone is the testis.

The HPA axis regulates hormone synthesis through a feedback loop where the hypothalamus releases corticotropin-releasing hormone, stimulating the anterior pituitary to release adrenocorticotropic hormone, which in turn stimulates the adrenal cortex to produce cortisol, aldosterone, and adrenal sex steroids.

Aldosterone has a half-life of 20 minutes and is considered a life-saving steroid hormone due to its critical role in regulating sodium and potassium levels in the body.

The mineralocorticoid receptor (MR) is found in the kidneys, colon, hippocampus, salivary glands, and sweat glands.

Deficiencies of enzymes involved in adrenal hormone synthesis can lead to Congenital adrenal hyperplasia, a condition that affects hormone production and can have significant clinical implications.

Aldosterone primarily promotes the reabsorption of sodium (Na⁺) through epithelial sodium channels (ENaC) and facilitates the excretion of potassium (K⁺) via renal outer medullary potassium channels (ROMK).

Liddle's syndrome is characterized by a gain of function mutation of ENaC, leading to increased sodium reabsorption, which results in hypertension as a key manifestation.

Aldosterone escape refers to the phenomenon where an increase in extracellular fluid (ECF) does not lead to edema despite hyperaldosteronism, which results in increased sodium (Na⁺) levels.

Aldosterone facilitates the excretion of potassium (K⁺) through renal outer medullary potassium channels (ROMK), which helps regulate potassium levels in the body.

Atrial natriuretic peptide promotes natriuresis, which is the excretion of sodium in urine, counteracting the effects of aldosterone and preventing edema.

Hyperkalemia stimulates aldosterone release, while ACTH increases aldosterone levels transiently.

The clinical features of Conn's syndrome include:

1. Metabolic alkalosis due to H+ excretion.
2. Hypokalemia leading to muscle cramps, interstitial atony, and nephropathy.
3. Hypertension due to Na+ and H₂O retention, increasing extracellular fluid and blood pressure without edema.

Aldosterone escape refers to the phenomenon where there is Na+ and H₂O excretion despite increased aldosterone levels, due to:

• Pressure diuresis caused by increased blood pressure.
• Atrial natriuretic peptide promoting natriuresis. This results in no edema despite high aldosterone levels.

The main functions of sex steroids include:

• Axillary hair growth
• Pubic hair growth
• Libido

Cortisol acts as a 'hyperglycemic hormone' by increasing gluconeogenesis, which raises blood glucose levels.

Cortisol has a catabolic effect in muscle, leading to proteolysis, while it has an anabolic effect in the liver, increasing the synthesis of plasma proteins.

Cortisol is lipolytic, meaning it promotes the breakdown of fats.

Cortisol acts as an anti-inflammatory agent, reducing inflammation and immune responses.

Cortisol decreases the blood levels of eosinophils and lymphocytes while increasing the levels of neutrophils, platelets, and red blood cells (RBCs).

Cortisol alters mood and behavior and increases appetite.

Cortisol increases the glomerular filtration rate and calcium excretion in the kidneys.

Cortisol increases bone resorption by enhancing the activity of osteoclasts, which can lead to bone loss.

Cortisol inhibits fibroblast proliferation and collagen formation, which can delay wound healing and cause purple striae on the skin.

Cortisol increases gastric acid secretion, which can lead to peptic ulcers.

Cortisol inhibits GnRH, leading to amenorrhea, loss of libido, and infertility.

Normal serum calcium levels range from 9 to 11 mg/dL.

Ionized calcium and protein-bound calcium each make up 50% of total calcium in the serum, with ionized calcium being the physiologically active form and protein-bound calcium being the inactive form.

In respiratory alkalosis, the decrease in H⁺ ions causes calcium to bind to albumin, increasing the bound form of calcium and decreasing the free form, which can lead to hypocalcemic tetany.

• Na⁺ channels are affected by calcium levels.
• A decrease in Ca²⁺ opens more Na⁺ channels, leading to:
  1. Increased depolarization
  2. Increased frequency of action potentials
  3. Resulting in hyperexcitability and hypocalcemic tetany.

1. Trousseau's sign: Eliciting carpopedal spasm by inflating a sphygmomanometer 20 mm Hg above SBP for 3 minutes.

2. Chvostek's sign: Facial muscle twitching upon tapping the facial nerve at the angle of the jaw.

• Site: Secreted by the parathyroid glands.
• Structure: Composed of 84 amino acids.
• Actions: PTH acts on bone by stimulating osteoblasts, which in turn activate RANK ligand, leading to osteoclast differentiation and bone resorption, releasing calcium and phosphate into the bloodstream.

• Teriparatide is a drug form of PTH.
• Continuous administration leads to bone resorption.
• Intermittent administration promotes bone formation.

PTH increases calcium reabsorption in the kidneys, specifically in the distal convoluted tubule (DCT) and proximal convoluted tubule (PCT). It also promotes phosphaturia through the Na+ PO4- cotransporter, leading to increased excretion of phosphate in urine.

PTH indirectly increases calcium absorption from the gastrointestinal tract by enhancing the synthesis of Vitamin D, which in turn promotes calcium absorption from the diet.

Calcium sensing receptors (CaSR) help regulate PTH secretion. A mutation in CaSR can lead to a condition where PTH is not suppressed, resulting in elevated levels of PTH and causing familial hypocalciuric hypercalcemia.

Calcitonin is produced by the parafollicular C cells of the thyroid gland. Its primary action is to lower blood calcium levels by inhibiting osteoclast activity, thus reducing bone resorption.

Bone markers are classified into two types:

1. Bone formation markers:

   • Osteocalcin
   • Alkaline phosphatase
   • Pro-peptides of type I collagen

2. Bone resorption markers:

   • TRAP (Tartrate resistant acid phosphatase)
   • MMP (matrix metalloproteinase)
   • Cathepsin K
   • NTX (N telopeptides of collagen crosslinks)
   • CTX (C telopeptides of collagen crosslinks)

Facilitating factors for calcium absorption include gastric acid and a protein-rich diet. Inhibiting factors include phytates and oxalates, which form insoluble complexes that hinder absorption.

PTH increases phosphate excretion by inhibiting the Sodium Phosphate cotransporter in the proximal convoluted tubule (PCT).