Hormones – Comprehensive Study Notes

Definition of Hormones

Hormones are organic compounds secreted by specialized endocrine cells directly into the bloodstream. They exert effects either on nearby tissues or at distant sites.

Human Endocrine System Overview

• Principal glands: hypothalamus, pituitary, thyroid, parathyroids, adrenal cortex, adrenal medulla, pancreas (islets), gonads, kidney, gastrointestinal (GIT) tract and adipose tissue (leptin).
• Endocrine outputs coordinate metabolism, growth, homeostasis, behaviour, reproduction and stress responses.

General Functions of Hormones

Regulation of metabolism of carbohydrates, lipids and proteins.
Stimulation of tissue growth and differentiation.
Maintenance of internal milieu (homeostasis).
Modulation of behaviour (fear, depression, sexual drive).
Control of reproductive events (gametogenesis, pregnancy, lactation).

Chemical Classification of Hormones

Polypeptides/oligo-peptides: oxytocin, ADH, ACTH, glucagon, PTH.
Proteins & glycoproteins: insulin, GH, TSH, LH, FSH, prolactin.
Steroids: cortisol, aldosterone, estrogens, progesterone, androgens, calcitriol.
Amino-acid derivatives: $T3,\;T4,$ epinephrine, norepinephrine, serotonin.

Mechanistic (Receptor) Classification

• Group I – intracellular receptors (lipophilic): steroids, thyroid hormones, calcitriol.
• Group II – plasma-membrane receptors (hydrophilic): peptides, catecholamines.
– Second messenger cAMP (ACTH, glucagon, TSH, LH, FSH, PTH, etc.)
– Second messenger cGMP (only ANF).
– Second messenger $\text{Ca}^{2+}$ / phosphatidylinositides (TRH, angiotensin II, ADH, α-adrenergic catecholamines, acetylcholine muscarinic).
– Unknown/kinase cascades (insulin, GH, prolactin, NGF, IGF-1, EGF, PDGF).

Signal Transduction Highlights

• cAMP path: hormone→Gs→adenylate cyclase→ $ATP\to cAMP$ →PKA→protein phosphorylation; degraded by phosphodiesterase.
• cGMP: ANF binds guanylate cyclase → $GTP\to cGMP$ →PKG.
• $Ca^{2+}$ /IP₃/DAG: hormone→Gq→PLC→IP₃ releases $Ca^{2+}$ (calmodulin), DAG activates PKC.
• Tyrosine-kinase-linked receptors (TKRs): insulin autophosphorylates β-subunit →IRS→PI3K/PKB cascade, GLUT4 translocation, gene regulation.
• JAK/STAT: GH, prolactin, cytokines bind; JAK phosphorylates STATs →nuclear transcription.
• Protein tyrosine phosphatases modulate MAPK, cell cycle.
• NF-κB pathway triggered by cytokines, ROS; glucocorticoids inhibit.

Posterior Pituitary Hormones

Antidiuretic Hormone (ADH / Vasopressin)

– Synthesized as pre-pro-hormone in supraoptic & paraventricular nuclei, stored in posterior pituitary.
– Secreted in response to ↑ plasma osmolality (≥ $285\,\text{mOsm/kg}$ ) or hypovolemia; inhibited by ethanol.
– Acts on distal convoluted tubule & collecting duct via V2 receptors (cAMP) → aquaporin-2 insertion → water reabsorption.
– Deficiency: Diabetes insipidus (central vs. nephrogenic).
– Excess: SIADH → hyponatremia, cerebral edema.

Oxytocin

– Released by nipple stimulation or cervical stretch; augmented by estrogens, inhibited by progesterone.
– Produces uterine contractions (labour induction) and milk ejection via myoepithelial contraction.

Hypothalamic Releasing / Inhibiting Hormones

Hormone	Pituitary Target	Peripheral Effect
CRH	ACTH	Cortisol secretion
TRH	TSH	$T<em>3,T</em>4$ synthesis
GnRH	FSH, LH	Gonadal steroids & gametes
GHRH	GH ↑	Somatomedin C (IGF-1)
Somatostatin	GH ↓, TSH ↓	—
Dopamine (PRIH)	PRL ↓	—

Feedback: peripheral hormones suppress both pituitary and hypothalamus.

Anterior Pituitary Hormones

Protein family: GH, prolactin, placental lactogen.
Glycoproteins (α+β): TSH, LH, FSH, hCG (placenta).
POMC derivatives: ACTH, MSH, β-LPH, β-endorphin.

Growth Hormone (GH)

• 191-aa single chain, $M_w\approx23\,\text{kDa}$ .
• Via IGF-1 promotes longitudinal bone growth; enhances protein synthesis, lipolysis, ketogenesis and opposes insulin (diabetogenic).
• Excess pre-epiphyseal closure → gigantism; post-closure → acromegaly.
• Deficiency in childhood → pituitary dwarfism.

Prolactin (PRL)

• 199-aa, $M_w\approx23\,\text{kDa}$ .
• With estrogen/progesterone initiates & maintains lactation.
• Hyperprolactinemia → galactorrhoea, infertility.

TSH

Stimulates iodide uptake, thyroglobulin iodination → $T3,T4$ synthesis.

Gonadotropins

• FSH: ovarian follicle maturation, spermatogenesis.
• LH: ovulation, corpus luteum progesterone, Leydig testosterone.
• hCG (placenta) mimics LH → progesterone support of early pregnancy, fetal testicular testosterone; used for pregnancy tests.

ACTH / POMC Tree

ACTH (39 aa) triggers adrenal cortical steroidogenesis (cholesterol → pregnenolone).
MSH disperses melanin.
β-LPH yields β-endorphin & enkephalins → analgesia (18–30 × morphine).

Adrenal Cortex Hormones

• Layers: zona glomerulosa (aldosterone), fasciculata (cortisol), reticularis (androgens).
• Rate-limiting step: cholesterol → pregnenolone via P-450scc (mitochondrial, needs $NADPH$ and $O_2$ ).

Glucocorticoids (C21)

– 92 % bound to transcortin; half-life hours.
– Metabolic: ↑ gluconeogenesis, glycogenesis, lipolysis, protein catabolism.
– Immunologic: anti-inflammatory, immunosuppressive.
– Stress response, BP maintenance.
– Excess → Cushing syndrome (truncal obesity, hyperglycemia, hypertension, hyperpigmentation via ACTH).
– Deficiency → Addison disease (hypoglycemia, hypotension, weight loss).

Mineralocorticoids (C21)

– Aldosterone acts on DCT via MR (intracellular) to reabsorb $Na^+$ /& $H2O$ , excrete $K^+$ / $H^+$ / $NH4^+$ .
– Stimuli: angiotensin II, hyperkalemia.
– Hyperaldosteronism (Conn): hypertension, hypokalemic alkalosis.

Adrenal Androgens (C19)

– DHEA, androstenedione; minor in males, significant in females (pubic hair).

Adrenal Medulla Catecholamines

Tyrosine → DOPA → dopamine → norepinephrine → epinephrine (PNMT).
Metabolized by MAO & COMT → $\text{VMA},\;\text{HVA}$ .
Physiology: “fight-or-flight” – ↑ cardiac output, BP, bronchodilation, glycogenolysis, lipolysis.

Gonadal Steroid Hormones

Androgens (Testosterone → DHT via 5α-reductase)

• Leydig synthesis (LH).
• Actions: male differentiation, spermatogenesis (with FSH-induced ABP), secondary sex traits, anabolic protein synthesis, behavioural aggression.
• Hypogonadism → obesity, muscle wasting.

Estrogens (Estradiol E₂ > Estrone E₁ > Estriol E₃)

• Follicles/corpus luteum, placenta (E₃). Bound to TEBG.
• Functions: growth of uterus, vagina, mammary ducts; secondary female traits; up-regulate progesterone receptors; maintain menstrual cycle.

Progesterone (Corpus luteum, later placenta)

• Prepares endometrium for implantation, maintains pregnancy (uterine quiescence), develops secretory mammary tissue, antagonizes estrogen in some tissues.

Thyroid Hormones

• Follicular synthesis from tyrosyl residues in thyroglobulin, iodinated to MIT/DIT → $T3,T4$ ; peripheral deiodination $T4\to T3$ (active) or rT3 (inactive).

Metabolic/Systemic Effects

– ↑ basal metabolic rate (BMR) via $Na^+/K^+$ -ATPase, O₂ consumption, heat (thermogenesis).
– Carbohydrate: ↑ gut absorption, glycolysis, gluconeogenesis, insulin secretion.
– Lipid: lipolysis, FFA oxidation, cholesterol clearance.
– Protein: normal levels → synthesis; excess → catabolism.
– CVS: ↑ heart rate, CO; Resp: ↑ ventilation; CNS & skeletal growth.

Disorders

Hypothyroidism (iodine deficiency, Hashimoto) → cretinism (infant), myxedema (adult). Hyperthyroidism (Graves, toxic adenoma) → weight loss, heat intolerance, exophthalmos.
Diagnosis: free $T_4$ , $TSH$ (elevated in hypo, suppressed in hyper), auto-antibodies.

Calcium-Regulating Hormones

Parathyroid Hormone (PTH)

– 84-aa; biological activity first 1–34 aa.
– Secreted when $[Ca^{2+}]{plasma}$ falls; restores by (i) renal 1-α-hydroxylase → calcitriol, (ii) bone resorption, (iii) renal $Ca^{2+}$ reabsorption, $PO4^{3-}$ excretion.
– Hypoparathyroidism → hypocalcemic tetany; hyperparathyroidism (primary, secondary renal, tertiary) → bone demineralization, stones.

Calcitriol (1,25-diOH-Vit D₃)

$7\text{-dehydrocholesterol} \xrightarrow{UV} D_3 \xrightarrow[Liver]{25\text{-hydroxylase}} 25\text{-OH D} \xrightarrow[Kidney]{1\alpha\text{-hydroxylase}} 1,25\text{-diOH D}$
– Stimulated by PTH & low $Ca^{2+}$ .
– Increases intestinal calbindin, renal & bone $Ca^{2+}$ mobilisation; supports bone mineralization (osteocalcin).

Calcitonin (32-aa) & Katacalcin (21-aa)

– Parafollicular C-cells; lowers plasma $Ca^{2+}$ by inhibiting osteoclasts, promoting deposition. Katacalcin similar potency.

Pancreatic Islet Hormones

Gastrointestinal Peptide Hormones

• Gastrin (G cells): ↑ gastric HCl, pepsinogen, mucosal growth, ileocecal relaxation.
• Cholecystokinin (CCK, I cells): ↑ pancreatic enzyme output, bile flow, gall-bladder contraction.
• Secretin (S cells): ↑ pancreatic & biliary $HCO_3^-$ , water; potentiates CCK; insulinotropic.
• GIP (K cells): inhibits gastric acid, potentiates insulin (“incretin”); stimulates lipogenesis.
• VIP: smooth-muscle relaxation, vasodilation, cardiac inotropy, glycogenolysis.
• Motilin: interdigestive migrating motor complex, pancreatic endocrine secretion.
• Enteroglucagon (L cells): slows gut motility when fats/glucose present.
• Enkephalins, Substance P, Bombesin (GRP), Neurotensin: neurotransmission, vasodilation, pain, gastrin release, smooth muscle effects.

Kidney Hormones

• Renin: $\to$ angiotensin II → vasoconstriction & aldosterone.
• Erythropoietin (EPO) & erythrogenin: stimulate erythropoiesis.
• Calcitriol & $24,25\text{-diOH D}$ : calcium metabolism.
• Vasodilatory renomedullary prostaglandins/lipids; kinins.

Prostaglandins & Related Lipid Mediators

(see lipid notes) – local regulators of vascular tone, platelet aggregation, inflammation.

Leptin – Adipose-Derived Energy Hormone

• 167-aa, 16 kDa protein encoded by $OB(Lep)$ gene (chromosome 7).
• Circulates proportionally to fat mass.
• Acts on hypothalamus to suppress appetite, increase energy expenditure, sympathetic output →↑ BP, HR; modulates immunity (T-cell maturation), fertility, bone mass.
• Obesity often shows leptin resistance (high plasma leptin yet no satiety).

Integrated Endocrine Control & Stress Hormones

Sensory inputs → hypothalamic releasing hormones → pituitary → peripheral glands/organs → target tissues, completing feedback loops. In stress, cortisol, catecholamines, glucagon dominate (“anti-metabolic” catabolic hormones) whereas insulin, GH, sex steroids restore anabolic state.

Key Numerical / Formula References

Plasma osmolality triggering ADH ≈ 270!\text{–}!285\,\text{mOsm·kg}^{-1}.
Daily insulin need ≈ 50 units ≈ half pancreatic store.
GH molecule $M_w = 23{,}000$ Da, PRL similar.
Conversion ratios: $T4 \to T3 \ (\approx80\%)$ in liver & peripheral tissues.
ACTH derived from 285-aa POMC; ACTH itself 39 aa.

Ethical & Clinical Implications

• Hormone therapies (insulin, glucocorticoids, thyroxine) require precision to prevent resistance or adverse metabolic shift.
• Endocrine disruptors (goitrogens, xenobiotics) may provoke hypo- or hyper-function.
• Gene mutations in receptors (e.g., TKRs, TSHR) or signalling proteins (Gsα) underlie many pathologies (e.g., nephrogenic DI, familial precocious puberty).
• Endogenous opioids (endorphins, enkephalins) highlight biochemical basis of addiction and pain management.

Summary Connections

The endocrine system constitutes an intricate network in which chemical nature (lipid vs. peptide), receptor localization, second-messenger design and feedback architecture dictate hormone potency, half-life and pathophysiological outcomes. Understanding these paradigms allows prediction of drug targets, diagnostic test selection (e.g., free $T_4$ , plasma ACTH, PTH), and integrated management of metabolic, growth and reproductive disorders.