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ENDOCRINE SYSTEM

Network of glands and organs that produce and release hormones via blood circulation

Growth Hormones

• Somatotropin

• A peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals.

GH agonists

Examples:

• Somatotropin

• Somatrem (Somatomedin C, IGF1)

• Mecasermin

• Somatropin

1. Achondroplasia

2. Growth failure due to IGF1 deficiency: Laron syndrome

Achondroplasia

Most common “dwarfism” in children

Mecasermin

Growth failure due to IGF1 deficiency: Laron Syndrome. Tx is ?

GH antagonists

Examples:

• Somatostatin - Growth Hormone Inhibiting Hormone (GHIH)

• Pegvisomant

• Octreoride & Lanreotide

Octreotide

Used in:

• Gigantism (Acromegaly)

• Pancreatic tumor (insulinoma - B cells & glucagonoma - a cells)

• Carcinoid tumor

MOA:

• It decreases the secretion of hormones

Pegvisomant

Pegylated (increased DOA); Used in acromegaly

HPA axis (Hypothalamic–Pituitary–Adrenal axis)

• Hypothalamus → secretes CRH (Corticotropin-Releasing Hormone)

• Anterior pituitary → releases ACTH (Adrenocorticotropic Hormone) in response to CRH

• Adrenal cortex → stimulated by ACTH to produce corticosteroids (mainly cortisol)

• Positive feedback - switch on

• Negative feedback - switch off

Adrenal Steroids

• Mineralocorticoids

• Glucocorticoids

• Adrenal androgen

Mineralocorticoids

Glomerulosa; salt

• Aldosterone - most common

• Fludrocortisone ⭐

Glucocorticoids

Fasciculata; sugar

• Low potency: Cortisone, Hydrocortisone (cortisol)

• Medium potency: Prednisone, Methylprednisolone, Triamcinolone

• High potency: Dexamethasone, Betamethasone

Adrenal androgen

Reticularis; sex

• DHEA (Dehydroepiandrosterone)

Corticosteroids Antagonists

• Receptor blockers

  • Spironolactone

  • Mifepristone

• Synthesis inhibitors

  • Metyrapone

  • Ketoconazole, Fluconazole (ANTI-FUNGAL) ⭐

Salt Retaining Property

• Highest salt retention: Aldosterone

• No salt retention: Dexamethasone, Betamethasone

Aldosterone

Highest salt retention

Conn’s disease

Hyperaldosteronism (↑ Aldosterone)

• ↑ Na, H2O

• ↓ K+ = ↑ HCO³- = Metabolic alkalosis

• SE: Gynecomastia - alt: Eplerenone

Dexamethasone, Betamethasone, Triamcinolone

No salt retention

Betamethasone, Dexamethasone

Hasten fetal lung maturation in premature babies - Acute respiratory distress syndrome (ARDS) ⭐

Spironolactone

Drug for Conn’s Disease (hyperaldosteronism)

Cushing Syndrome

Hypercortisolism = ↑ cortisol = ↑ sugar

Drugs for Cushing Syndrome (Hypercortisolism)

1. Endogenous Cushing Syndrome

• Due to adrenal adenoma, pituitary tumor

• Tx: Surgery (During surgery, stress dose using Hydrocortisone to prevent adrenal crisis)

2. Exogenous Cushing Syndrome

• Chronic or prolonged use of steroids causing HPA axis suppression

• Management: gradual dose reduction

• If inoperable:

  • (-) steroid synthesis: Ketoconazole, Metyrapone

  • (-) steroid receptor: Mifepristone (to control hyperglycemia)

Endogenous Cushing Syndrome

• Due to adrenal adenoma, pituitary tumor

• Tx: Surgery (During surgery, stress dose using Hydrocortisone to prevent adrenal crisis)

Exogenous Cushing Syndrome

• Chronic or prolonged use of steroids causing HPA axis suppression

• Management: gradual dose reduction (dose tapering)

• NO abrupt withdrawal → adrenal crisis

True

• Cushing syndrome - If inoperable:

  • (-) steroid synthesis: Ketoconazole, Metyrapone

  • (-) steroid receptor: Mifepristone (to control hyperglycemia)

Addison’s Disease (Adrenal insufficiency)

• Destruction of adrenal gland (low cortisol, aldosterone, and adrenal androgen)

• Mx: HRT - Hormone Replacement Therapy

  • Hydrocortisone - preferred agent

Addisonian Crisis (Acute adrenal crisis)

• Chronic use and suddenly stopped

• Low cortisol and androgen, normal aldosterone

• Mx: Do not abruptly stop!

Hypothalamic–Pituitary–Gonadal (HPG) axis

• Hypothalamus → secretes GnRH (Gonadotropin-Releasing Hormone) in a pulsatile manner

• Anterior Pituitary → responds to GnRH by releasing LH (Luteinizing Hormone) and FSH (Follicle-Stimulating Hormone)

• Ovary →

  • FSH → stimulates follicle growth and estrogen production

  • LH → triggers ovulation and formation of corpus luteum (which produces progesterone and estrogen)

Hypothalamic–Pituitary–Gonadal (HPG) axis

• Hypothalamus → secretes GnRH (pulsatile)

• Anterior Pituitary → releases LH and FSH in response to GnRH

• Testis →

  • LH → stimulates Leydig cells → produce testosterone

  • FSH → stimulates Sertoli cells → support spermatogenesis and produce inhibin

LH only

• Human Chorionic Gonadotropin (HCG)

  • Detect pregnancy

  • Detect prostate cancer

• Lutropin

FSH only

• Follitropin (a/B)

• Urofollitropin

LH and FSH

Menotropin

Pulsatile

Physiological GnRH

• Pattern → transient, rapid bursts of GnRH (~60–90 min)

• Effect on pituitary → stimulates LH and FSH secretion

• Outcome → normal reproductive function (ovulation in females, spermatogenesis in males)

Non-Pulsatile

Continuous GnRH

• Pattern → sustained, non-transient GnRH release

• Effect on pituitary → desensitization → ↓ LH and FSH

• Suppression of sex hormones (used in breast cancer, prostate cancer, endometriosis)

GnRH Agonists

suffix: -relin, leuprolide

1. Pulsatile: treatment of infertility

2. Nonpulsatile: treatment of prostate cancer, breast cancer, endometriosis

GnRH Antagonists

• Binds GnRH receptors on the pituitary → blocks GnRH action

• Effect on pituitary → rapid suppression of LH and FSH

• Outcome → ↓ gonadal sex hormones (testosterone in males, estrogen/progesterone in females)

GnRH Antagonists

suffix: -relix

1. Treatment of precocious puberty, endometriosis

2. Treatment of:

• Women: Breast cancer

• Men: Prostate cancer

Estrogens and Progestins

Estradiol

Most potent; pre menopausal estrogen

Estriol

Pregnancy estrogen

Estrone

Postmenopausal estrogen

Premarin

Pregnant mare’s urine

True

• Aromatase Inhibitors (AIs): Work by stopping estrogen from being produced in the first place by inhibiting the aromatase enzyme.

• Selective Estrogen Receptor Modulators (SERMs): Work by blocking the estrogen receptor on cancer cells, preventing estrogen from binding and stimulating growth.

Estrogens

• Major natural estrogen: Estradiol

• Rationale for synthetics:

  • Increase oral bioavailability, half-life, and feedback inhibition of FSH and LH

Estrogens

Estrogen increases cancer risk

• Endometrial cancer (unless progestins are added)

  • Risk factor: Endometrial hyperplasia

  • Prevention: Estrogen + Progestin

• Diethylstilbestrol (DES) during breastfeeding → vaginal cancer

Endometriosis

• Growth of endometrial tissue outside the uterus (e.g., ovaries, fallopian tubes, pelvic cavity)

• Pathophysiology →

  • Ectopic endometrial tissue responds to hormonal cycles → proliferates and bleeds

  • Causes inflammation, scarring, and adhesions

First-line drugs for endometriosis

1. Combined OCPs (+ NSAID)

2. Progestins (Medroxyprogesterone acetate - Depo-provera®) ⭐

• Others: Danazol, GnRH agonists (-relin), GnRH antagonists (-relix)

Anti-estrogens (SERMs)

• Clomiphene ⭐

  • Treatment of anovulatory infertility

  • A/E: multiple births

• Tamoxifen

  • Treatment of breast cancer in premenopausal women

  • A/E: Endometrial hyperplasia

  • If resistant to tamoxifen: Fulvestrant

• Raloxifene

  • Prevention and treatment of osteoporosis in postmenopausal women

Clomiphene

• Treatment of anovulatory infertility

  • Female infertility where a woman doesn't release an egg from her ovary during a menstrual cycle, which prevents pregnancy

• A/E: multiple births

Tamoxifen

• Treatment of breast cancer in premenopausal women

• A/E: Endometrial hyperplasia

• If resistant to tamoxifen: Fulvestrant (full antagonist)

• Partial agonist

Raloxifene

Prevention and treatment of osteoporosis in postmenopausal women

Aromatase inhibitors

1. Anastrozole

2. Letrozole

3. Exemestane

• Treatment of:

  • Anovulatory infertility

  • Breast cancer in postmenopausal women

Androgens

Androgens

• Major androgen: Testosterone

• Anabolic steroids: Oxandrolone, Fluoxymesterone

Anti-androgens

• GnRH analogs

  • Administered in continuous or non-pulsatile fashion

  • Use: Inoperable prostate cancer

• Androgen Receptor Blockers

  • Suffix: -tamide

  • Flutamide, Bicalutamide

  • Combined with GnRH analogs for prostate cancer

• 5α-reductase blockers

  • Suffix: -asteride

  • Reduce prostate volume and can retard progression of benign prostatic hyperplasia (BPH)

GnRH analogs

• Administered in continuous or non-pulsatile fashion

• Use: Inoperable prostate cancer

Androgen Receptor Blockers

• Suffix: -lutamide

• Flutamide, Bicalutamide

• Combined with GnRH analogs for prostate cancer

5α-reductase blockers

• Suffix: -steride

• The enzyme 5α-reductase converts testosterone into DHT.

  • DHT is a potent male sex hormone linked to prostate growth and hair loss.

  • By blocking this enzyme = reduced DHT levels in the body.

• Finasteride, Dutasteride

• Reduce prostate volume and can retard progression of benign prostatic hyperplasia (BPH)

• Decreased chances of male pattern baldness

Finasteride + Tamsulosin

• Finasteride works by reducing the size of the prostate, which relieves pressure on the urethra (the tube that empties the bladder).

• Tamsulosin works by relaxing muscles in the prostate and bladder, improving urine flow.

Thyroid Hormones

• Hypothalamus → secretes TRH (Thyrotropin-Releasing Hormone)

• Anterior Pituitary → responds to TRH by releasing TSH (Thyroid-Stimulating Hormone)

• Thyroid Gland → stimulated by TSH to produce:

  • T4 (Thyroxine) → mostly a prohormone

  • T3 (Triiodothyronine) → active form, converted from T4 in peripheral tissues

Thyroid Hormones

• Positive Feedback:

  • TSH stimulates thyroid gland → Enhances production of T3 and T4. This is a feed-forward stimulation (as long as the body needs thyroid hormones).

• Negative Feedback:

  • High levels of T3 and T4: Inhibit TRH release from hypothalamus Inhibit TSH release from pituitary → Prevents overproduction of thyroid hormones.

Hypothyroidism

• Most common: Hashimoto’s disease, thyroiditis

• Others: Cretinism, Myxedema

Hypothyroidism

• Hypothyroidism → Low T4, Low T3; High TSH

• Primary hypothyroidism

  • Most common

  • Cause → Underactive thyroid gland

• Secondary hypothyroidism

  • Cause → Thyroid hormone deficiency from pituitary gland dysfunction

• Tertiary hypothyroidism

  • Cause → Thyroid hormone deficiency from hypothalamic disorder

• Cretinism

  • Congenital hypothyroidism / Infantile hypothyroidism

• Myxedema

  • Adults with long-standing untreated hypothyroidism

  • Severe form → Medical emergency

Hypothyroidism

• DOC: Levothyroxine (L-thyroxine)

• Liothyronine (or T3)

• L-thyroxine (or T4)

Hyperthyroidism

• Most common: Grave's disease

• Others: Plummer's disease, thyrotoxicosis, thyroid storm

Hyperthyroidism

• Hyperthyroidism → ↑ T4, ↑ T3; Low TSH

• Primary hyperthyroidism

  • Most common

  • Cause → Overactive thyroid gland

• Secondary hyperthyroidism

  • Cause → Overproduction of TSH

• Tertiary hyperthyroidism

  • Cause → Overproduction of TRH

• Grave's Disease

  • Most common cause of hyperthyroidism

• Plummer's Disease

  • Toxic multinodular goiter

• Thyroid Storm

  • Rare but life-threatening complication of untreated hyperthyroidism

• Thyrotoxicosis

  • Elevated levels of thyroid hormone in the body, regardless of cause

Hyperthyroidism

• DOC: Methimazole (preferred)

  • S/E: Aplsia cutis - CI to pregnancy in first trimester

• If pregnant: Propylthiouracil (PTU) (lower risk of birth defects)

• A/E: Liver damage, agranulocytosis (PTU is 2x riskier)

• Symptom controller: Beta-blockers (propranolol)

Hyperthyroidism

• Thiamides

• Iodides

• Beta blockers (propranolol)

Prolactin

• Milk production

• Prolactin-inhibiting hormone: Dopamine

• Hyperprolactinemia

  • Causes: Infertility

  • Acromegaly: ↑ GH, ↑ Prolactin

  • Treatment: + Octreotide

    1. Bromocriptine

    2. Cabergoline

Dopamine

Prolactin-inhibiting hormone

Hyperprolactinemia

• Causes: Infertility

• Acromegaly

• Treatment: + Octreotide

  1. Bromocriptine

  2. Cabergoline

Vasopressin

AKA Antidiuretic hormone (ADH)

• V1 = Blood vessels = Vasoconstriction

• V2 = Kidneys = Anti-diuresis

Vasopressin Agonist

• Indication:

  • Central Diabetes Insipidus = ↓ ADH (polyuria - increased urination)

• Nonselective (V1, V2):

  • Vasopressin

• Selective:

  • Desmopressin - selective in D2 (DOC FOR Central Diabetes Insipidus) - synthetic ADH/Vasopressin

Desmopressin

Selective in D2 ⭐

• DOC FOR Central Diabetes Insipidus

• Synthetic ADH/Vasopressin

Nephrogenic Diabetes Insipidus

Kidneys unresponsive to ADH → polyuria, polydipsia

Treatment:

• Amiloride

  • Blocks lithium entry in collecting ducts

  • Reduces polyuria

• Thiazides (HCTZ)

  • Paradoxical effect: normally a diuretic but reduces urine output

  • Mechanism:

    • Causes mild extracellular volume depletion

    • ↑ Proximal tubule water reabsorption

    • Less water reaches collecting duct → ↓ urine volume

Vasopressin Antagonist

• Indication:

  • ↑ ADH, SIADH (Syndrome of Inappropriate Antidiuretic Hormone)

  • Fluid retention, Hyponatremia

• Nonselective (V1, V2):

  • Conivaptan

• Selective V2:

  • Tolvaptan (preferred)

• Additional info: Demeclocycline is also used for SIADH

Desmopressin

Used in:

• Hemophilia A

  • ↓ Clotting Factor VIII → impaired coagulation → prolonged bleeding

  • X-linked recessive

  • Related to vWF → CF VIII normally stabilized by vWF

• Von Willebrand Disease

  • ↓ von Willebrand Factor → impaired platelet adhesion and ↓ CF VIII

  • Symptoms → Mucocutaneous bleeding

  • Overlaps with Hemophilia A → low CF VIII contributes to bleeding

• Nocturnal Enuresis

  • In children with bleeding disorders (Hemophilia A or vWD) → urinary tract bleeding may worsen enuresis

  • Definition → involuntary urination at night (≥5 years old)

Oxytocin

Milk ejection

Oxytocin agonist

• For labor

• Synthetic oxytocin (Pitocin®)

Oxytocin Antagonist

• Labor suppressant (for premature labor)

• -siban (atosiban)

Diabetes Mellitus

Group of common endocrine diseases characterized by sustained high blood sugar levels.

DM Type 1

• Cause: No insulin due to pancreatic β-cell destruction

• Also known as: IDDM (Insulin-Dependent Diabetes Mellitus)

• DOC (treatment) → Insulin

DM Type 2

• Cause: Not enough insulin or insulin does not work properly

• Also known as: NIDDM (Non-Insulin Dependent Diabetes Mellitus)

• 1st-line treatment: Metformin and oral hypoglycemic drugs

• Insulin → Used as adjunct if needed

Gestational DM

• Cause: Affects pregnant women, usually disappears after delivery

• DOC (treatment) → Insulin (the only FDA approved for pregnancy)

Insulin

Insulin stimulates glycogenesis

• Mechanism:

  • ↑ Glucose uptake into liver and muscle

  • Activates glycogen synthase → converts glucose-1-phosphate to glycogen

  • Inhibits glycogenolysis (breakdown of glycogen)

• Key effect

  • Stores excess glucose as glycogen → lowers blood glucose levels

Insulin

• Storage

  • Promotes glycogen storage in liver and muscle

• Uptake

  • Increases glucose uptake in muscle and adipose tissue via GLUT4 transporters

• Utilization

  • Stimulates glycolysis → glucose converted to pyruvate → ATP production

• Energy

  • Enhances fatty acid and protein synthesis

• Key effect

  • Lowers blood glucose by facilitating cellular glucose utilization and storage

Diabetes Mellitus

• Hyperglycemia (High blood sugar)

  • ↓ Insulin (Type 1) or ↓ insulin effectiveness (Type 2) → impaired glycogenesis → less glucose stored as glycogen

  • ↓ Glucose uptake → impaired glycolysis → cells have less energy

  • More glucose in the blood

• Clinical effects

  • Polyphagia → increased hunger because cells are energy-deprived

  • Polyuria → excess glucose filtered by kidneys → osmotic diuresis

  • Polydipsia → excessive thirst due to fluid loss from polyuria

Secretagogues, Sensitizers

Problem: Absent or insufficient insulin

Solution: ?

True

Problem: High blood glucose

Solution:

• Decrease glucose absorption

• Decrease glucose reabsorption

• Decrease cravings (carbohydrates)

Secretagogues

• Augment insulin secretion = ↑ storage and uptake of glucose

• S/E: hypoglycemia, weight gain (because of enhanced glycogenesis)

• Insulin, Sulfonylureas

Insulin

Types:

• Ultra-rapid: Afrezza®

• Rapid: Glulisine, Aspart, Lispro

• Short: Regular, Semilente

• Intermediate: NPH or Isophane, Lente

• Long: Ultralente, Glargine, Detemir

• Ultra-long: Degludec, Icodec

Insulin

• Most common route: Subcutaneous ⭐

• Use: DM type 1 & Gestational (DOC), DM Type 2 (Adjunct)

Hexamer

Storage form of insulin

Monomer

Active form of insulin

Glargine

Peakless insulin

Regular Insulin

The only IV route insulin

• Preferred agent for Diabetic Ketoacidosis (DKA)

Lente (Intermediate)

Insulin Zinc Suspension

Amorphous Insulin Zinc Suspension

• Type: Short-acting

• Also called: Semi-lente

• Onset/Action:

  • Faster absorption

  • Controls postprandial blood glucose

Crystalline Insulin Zinc Suspension

• Type: Long-acting

• Also called: Ultralente

• Onset/Action:

  • Slow, extended absorption

  • Provides basal insulin control over 24 hours

Sulfonylureas

• MOA

  • Close ATP-sensitive K⁺ channels on pancreatic β-cells

  • Membrane depolarization → triggers opening of voltage-gated Ca²⁺ channels

  • ↑ Intracellular Ca²⁺ → stimulates insulin secretion

• 1st gen: -amides

  • Chlorpropamide, Tolbutamide, Acetohexamide

  • No selectivity

• 2nd gen: Gly, Gli

  • Glibenclamide (Glyburide) Glimepiride, Glipizide, Gliclazide