Hormones of the Pituitary Gland

Anterior Pituitary Hormones (Adenohypophysis)

Overview of Cell Types and Secretory Products

Cell Type	Hormone Produced	Structure	Target Organ
Somatotropes	Growth Hormone (GH)	191-aa single-chain peptide	Liver, Bone, Adipose
Lactotropes	Prolactin (PRL)	199-aa single-chain peptide	Mammary Glands
Thyrotropes	Thyroid-Stimulating Hormone (TSH)	Glycoprotein heterodimer ($\alpha ,\beta$)	Thyroid Gland
Corticotropes	Adrenocorticotropic Hormone (ACTH)	39-aa single-chain peptide	Adrenal Cortex
Gonadotropes	Luteinizing Hormone (LH)	Glycoprotein heterodimer ($\alpha ,\beta$)	Gonads (Leydig/Theca cells)
Gonadotropes	Follicle-Stimulating Hormone (FSH)	Glycoprotein heterodimer ($\alpha ,\beta$)	Gonads (Sertoli/Granulosa cells)

• Differentiation of somatotropes, lactotropes, and thyrotropes dependent on POU1F1 (Pit1) transcription factor.
• Gonadotrope differentiation heavily dependent on Prop1 and Nr5a1 (SF1).

Growth Hormone (GH)

Molecular Structure

• 191-amino acid, single-chain, nonglycosylated polypeptide.
• Molecular weight 22-kDa (75%–90% of total pituitary GH).
• Alternative splicing produces 20-kDa variant (<10%).
• Encoded by GH1 gene on chromosome 17q22-24.

Secretion and Regulation

• Secretion highly pulsatile; peak secretion during first slow-wave sleep.
• Regulated by alternating secretion of hypothalamic hormones.
• Peaks occur when Growth Hormone-Releasing Hormone (GHRH) peaks coincide with somatostatin troughs.

Regulator	Effect on GH	Mechanism / Origin
GHRH	Stimulates	Hypothalamic peptide; binds G-protein-coupled receptor; increases cAMP.
Somatostatin (SRIF)	Inhibits	Hypothalamic 14-aa peptide; decreases adenylate cyclase and intracellular calcium.
Ghrelin	Stimulates	Gastric peptide; activates GH Secretagogue Receptor (GHS-R).
IGF-1	Inhibits	Long-loop negative feedback.
GH	Inhibits	Short-loop negative feedback via periventricular somatostatin neurons.

• Physiologic stimulators: Exercise, physical stress, trauma, fasting, hypoglycemia, puberty.
• Physiologic inhibitors: Hyperglycemia, hypothyroidism, free fatty acids, glucocorticoids, obesity.

Receptor and Mechanism of Action

• Binds Growth Hormone Receptor (GHR), a 620-aa class 1 hematopoietic cytokine receptor.
• Extracellular domain cleaved to form circulating GH-binding protein (GHBP).
• Requires receptor dimerization.
• Activates receptor-associated Janus kinase 2 (JAK2).
• Phosphorylation initiates Signal Transducer and Activator of Transcription (STAT) 5b pathway.
• STAT5b translocates to nucleus to alter gene transcription.

Biological Effects

• Stimulates hepatic synthesis of Insulin-like Growth Factor 1 (IGF-1).
• Direct anabolic effects: Increases linear growth, bone thickness, soft tissue growth, protein synthesis.
• Direct metabolic effects: Stimulates lipolysis, decreases insulin sensitivity, elevates blood glucose.

Prolactin (PRL)

Molecular Structure

• 199-amino acid single-chain peptide.
• Structurally homologous to GH and placental lactogen.

Secretion and Regulation

• Constitutively secreted unless actively inhibited.
• Primary inhibitor: Hypothalamic dopamine.
• Primary stimulators: Thyrotropin-Releasing Hormone (TRH), estrogen, suckling/nipple stimulation.
• Disruptions to pituitary stalk elevate PRL levels by removing dopaminergic inhibition.

Biological Effects

• Prepares breast tissue for lactation.
• Initiates and maintains postpartum milk production.
• Modulates gonadal steroidogenesis (low concentrations upregulate LH receptors; high concentrations inhibit steroid biosynthesis).

Thyroid-Stimulating Hormone (TSH)

Molecular Structure

• Heterodimeric glycoprotein.
• $\alpha$-subunit (89-aa): Identical sequence to FSH, LH, and human chorionic gonadotropin (hCG).
• $\beta$-subunit (112-aa): Confers biological specificity.

Secretion and Regulation

• Stimulated by hypothalamic TRH.
• Inhibited by dopamine, somatostatin, and glucocorticoids.
• Strict negative feedback exerted by circulating Triiodothyronine (T3) and Thyroxine (T4).

Receptor and Mechanism of Action

• Binds TSH receptor (G-protein-coupled receptor) on thyroid follicular cells.
• Activates adenylate cyclase $\to$ increases intracellular cAMP.
• Stimulates all steps of thyroid hormone biosynthesis (iodide trapping, iodotyrosine synthesis, thyroglobulin synthesis).
• Induces hypertrophy and hyperplasia of thyroid gland.

Adrenocorticotropic Hormone (ACTH)

Molecular Structure

• 39-amino acid single-chain peptide.
• Derived via proteolytic cleavage from 241-aa precursor proopiomelanocortin (POMC).
• Bioactivity resides in first 20–24 amino acids.

Secretion and Regulation

• Regulated primarily by Corticotropin-Releasing Hormone (CRH) synthesized in paraventricular nucleus.
• Arginine Vasopressin (AVP) co-secreted with CRH; synergistically augments ACTH release.
• Secreted in pulsatile, diurnal pattern; peak levels upon waking, nadir 1-2 hours after sleep onset.
• Stimulated by physical stress, trauma, hypoglycemia, inflammatory cytokines (IL-1, IL-2, IL-6, TNF-$\alpha$).
• Negative feedback inhibition by cortisol (acts on hypothalamus and pituitary).

Receptor and Mechanism of Action

• Binds Melanocortin 2 Receptor (MC2R), a G-protein-coupled receptor located exclusively in adrenal cortex.
• Receptor trafficking dependent on MC2R Accessory Protein (MRAP).
• Activates adenylate cyclase $\to$ increases cAMP $\to$ activates Protein Kinase A (PKA).

Biological Effects

• Acute Phase (Minutes): Increases cholesterol esterase activity, upregulates Steroidogenic Acute Regulatory (StAR) protein, facilitates free cholesterol transport into mitochondria.
• Chronic Phase (Hours/Days): Increases transcription of genes encoding steroidogenic enzymes (e.g., P450scc) and LDL receptors.
• Stimulates cortisol synthesis in zona fasciculata and androgen synthesis in zona reticularis.
• Regulates fetal adrenal growth; stimulates production of local growth factors (IGF-2, FGF2, EGF).

Gonadotropins: Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH)

Molecular Structure

• Glycoproteins sharing identical $\alpha$-subunit.
• Distinct $\beta$-subunits confer receptor specificity (115 amino acids long).
• Molecular heterogeneity exists due to varying degrees of glycosylation, sialylation, and sulfonation, altering in vivo bioactivity and half-life.
• LH half-life shorter (~20 minutes initial phase) than FSH.

Secretion and Regulation

• Synthesized by common gonadotrope cells.
• Secretion strictly controlled by pulsatile Gonadotropin-Releasing Hormone (GnRH).
• Differential secretion modulated by GnRH pulse frequency: High frequency favors LH $\beta$-subunit expression; low frequency favors FSH $\beta$-subunit expression.
• Continuous/non-pulsatile GnRH exposure downregulates receptors and suppresses gonadotropin release.

Feedback Regulation

Target Hormone	Feedback Mechanism	Modulator
LH	Negative Feedback	Testosterone (males), Estrogen/Progesterone (females).
LH	Positive Feedback	Preovulatory peak sustained estradiol ($\ge$ 36 hours) triggers midcycle LH surge.
FSH	Negative Feedback	Inhibin B (Sertoli cells/Granulosa cells), Estrogen.
FSH	Positive Feedback	Activin (homodimers of inhibin $\beta$-subunit) stimulates FSH release.

Biological Effects in Males

• LH: Binds receptors on Leydig cells. Stimulates adenylate cyclase/cAMP/PKA cascade. Upregulates P450scc to convert cholesterol to pregnenolone, driving testosterone synthesis.
• FSH: Binds receptors on Sertoli cells. Stimulates gametogenesis, seminiferous tubule maturation, and secretion of Inhibin B and Anti-Müllerian Hormone (AMH).

Biological Effects in Females

• LH: Binds receptors on Theca cells. Stimulates androgen (androstenedione) biosynthesis. Induces ovulation and luteinization of preovulatory follicle.
• FSH: Binds receptors on Granulosa cells. Upregulates aromatase activity to convert theca-derived androgens into estradiol. Stimulates follicular maturation and inhibin secretion.

Posterior Pituitary Hormones (Neurohypophysis)

Anatomy and Synthesis

• Posterior pituitary acts as storage/release site; does not synthesize hormones.
• Hormones synthesized in magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus.
• Transported down pituitary stalk via axonal transport.
• Co-synthesized and transported with specific carrier proteins: Neurophysin I (for oxytocin) and Neurophysin II (for vasopressin).

Arginine Vasopressin (AVP) / Antidiuretic Hormone (ADH)

Molecular Structure

• Nonapeptide (9-amino acids).
• Differs from oxytocin by only two amino acids.
• Derived from precursor protein containing AVP, neurophysin II, and copeptin (stable biomarker).
• Extremely short plasma half-life (5–10 minutes).

Regulation of Secretion

• Osmotic Regulation (Primary): Mediated by osmoreceptors located outside the blood-brain barrier in circumventricular organs (Organum Vasculosum of the Lamina Terminalis [OVLT] and Subfornical Organ [SFO]).
  • Secretion threshold begins at plasma osmolality ~283 mOsm/kg.
  • Linear increase in AVP secretion up to maximum at ~320 mOsm/kg.
• Non-Osmotic Regulation (Volume/Pressure): Mediated by baroreceptors in aortic arch and carotid sinus; signals relayed via vagus and glossopharyngeal nerves to nucleus tractus solitarius.
  • Hypovolemia and hypotension stimulate massive AVP release, overriding osmotic inhibition.
• Other Stimulators: Angiotensin II, nausea, hypoglycemia, pain, physical stress.
• Inhibitors: Atrial Natriuretic Peptide (ANP), cold exposure, ethanol.

Receptors and Mechanisms of Action

Receptor	Location	Second Messenger	Physiological Action
V1 (V1a)	Vascular smooth muscle, Hepatocytes, Platelets	Phospholipase C (IP3/Ca2+)	Vasoconstriction, Glycogenolysis, Platelet aggregation.
V2	Renal collecting duct, Thick ascending limb	Adenylate cyclase (cAMP)	Aquaporin-2 insertion $\to$ Free water reabsorption.
V3 (V1b)	Anterior pituitary corticotropes	Phospholipase C (IP3/Ca2+)	Stimulates ACTH secretion in synergy with CRH.

Oxytocin

Molecular Structure and Synthesis

• Nonapeptide (9-amino acids).
• Co-synthesized with Neurophysin I.

Biological Effects

• Exerts potent smooth muscle contractile activity.
• Binds specific G-protein-coupled receptors.
• Mediates uterine contractions during parturition.
• Stimulates myoepithelial cell contraction in the breast, mediating milk ejection (let-down reflex) during lactation.

Hypothalamic Regulation and the Portal System

• Anterior pituitary relies exclusively on delivery of hypothalamic regulatory peptides via the hypophyseal portal venous system.
• Peptides are synthesized in hypothalamic nuclei, secreted into the primary capillary plexus at the median eminence, and travel down portal veins to the anterior lobe.
• Key Releasing Hormones:
  • GHRH (Growth Hormone-Releasing Hormone): Stimulates GH.
  • TRH (Thyrotropin-Releasing Hormone): Stimulates TSH and PRL.
  • CRH (Corticotropin-Releasing Hormone): Stimulates ACTH.
  • GnRH (Gonadotropin-Releasing Hormone): Stimulates FSH and LH.
• Key Inhibiting Hormones:
  • Somatostatin (GHIH): Inhibits GH and TSH.
  • Dopamine: Tonically inhibits PRL.

(Note: The integration of upstream hypothalamic signals dictates the ultimate secretory output of the anterior pituitary gland, whereas the posterior pituitary functions as a direct neural extension of the hypothalamus.)