Physiology of the Pituitary and Hypothalamus Notes

Anatomical and Functional Organization of the Hypothalamic-Pituitary Axis (HPA)

• General Organization:

  • The endocrine system primarily revolves around the anterior pituitary gland.

  • Hypothalamus: Produces hypophysiotropic hormones in neurons. These are released into a capillary bed and travel down the portal hypophysial (PH) vessels to the anterior lobe.

  • Anterior Pituitary (Lobe): Contains endocrine epithelial cells that respond to hypophysiotropic hormones by releasing tropic hormones into the general circulation.

  • Posterior Pituitary (Lobe): Also known as the neurohypophysis. It is an extension of the hypothalamus, not technically part of the HPA feedback loop in the same way the anterior system is.

  • Infundibulum: The stalk connecting the hypothalamus to the pituitary.

• Functional Divisions:

  • Paraventricular (PVN) & Supraoptic (SON) Nuclei: Contain magnocellular neurons that synthesize hormones (ADH and Oxytocin) transported down axons to the posterior lobe.

  • Portal Hypophysial Vessels: The anterior pituitary is the most richly vascularized human tissue, facilitating the delivery of hypothalamic hormones and the export of pituitary hormones.

Hypophysiotropic and Tropic Hormones of the HPA

• Hypothalamic Hormones (Hypophysiotropic):

  • GHRH (Growth Hormone Releasing Hormone): Stimulates GH.

  • SSTN/GHIH (Somatostatin/Growth Hormone Inhibiting Hormone): Inhibits GH.

  • TRH (Thyrotropin Releasing Hormone): Stimulates TSH.

  • CRH (Corticotropin Releasing Hormone): Stimulates ACTH.

  • GnRH (Gonadotropin Releasing Hormone): Stimulates FSH and LH.

  • PIH (Prolactin Inhibiting Hormone/Dopamine): Inhibits Prolactin.

• Anterior Pituitary Hormones (Tropic):

  • ACTH (Adrenocorticotropic Hormone): Targets the adrenal cortex to release cortisol.

  • TSH (Thyroid Stimulating Hormone): Targets the thyroid gland to release thyroid hormone.

  • FSH (Follicle Stimulating Hormone) & LH (Luteinizing Hormone): Known as gonadotropins; target the gonads (testes/ovaries) to release androgens and estrogens.

  • GH (Growth Hormone): Targets the liver to produce IGF-1 and has direct metabolic effects.

  • Prolactin: Targets the breast for milk production.

Posterior Pituitary: ADH and Oxytocin

• Anatomy and Histology:

  • Consists of axon terminals of magnocellular neurons.

  • Pituicytes: Astrocyte-like cells that provide structural support to the axon terminals.

  • Herring Bodies: Swollen axon terminals where hormones are stored before release into capillary beds.

• Hormone Synthesis and Processing:

  • Synthesized as a $164$ amino acid preprohormone in the neuron soma.

  • Components of Preprohormone:

    • Signal peptide.

    • Hormone (ADH or Oxytocin).

    • Neurophysins: Neurophysin 2 (for ADH) and Neurophysin 1 (for Oxytocin). They have no known function outside the pituitary.

    • Copeptin: Part of the ADH preprohormone; proposed as a more reliable proxy for ADH measurement.

  • Structure:

    • ADH (Arginine Vasopressin/AVP): $Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH_2$.

    • Oxytocin: $Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH_2$.

• Antidiuretic Hormone (ADH) Regulation and Receptors:

  • V1a Receptor: Coupled to G̑_q; found in arterial vascular smooth muscle. Stimulates contraction and increases blood pressure by decreasing vascular volume.

  • V1b Receptor (V3): Coupled to G̑_q; found in anterior pituitary corticotrophs. Stimulates ACTH secretion during stress.

  • V2 Receptor: Coupled to G̑_s; found in renal Principal cells of the distal convoluted tubule (DCT) and collecting ducts. Stimulates water conservation.

• ADH Secretion Stimuli:

  • Plasma Osmolality: Major endocrine response. Linear increase in ADH starting at ~$280\,mOsm/kg$. Tracked by osmoreceptors.

  • Blood Volume/Pressure: Detected by baroreceptors. Secretion increases exponentially when blood volume depletion exceeds $10\%$. This is primarily a stress response to severe depletion.

• Aquaporin 2 Mechanism:

  • ADH binds to G̑_s-coupled V2 receptors.

  • Increases Aquaporin 2 transcription and transport to the apical membrane for water reabsorption.

Hypothalamic Integration and Nuclei

• Integration Functions: Coordinates drive-related behaviors, energy, time, stress, sleep/wake cycles, temperature, and water balance.

• Key Nuclei and Secretions:

  • Supraoptic (SON): ADH, Oxytocin.

  • Paraventricular (PVN): ADH, Oxytocin, TRH, CRH, SSTN.

  • Suprachiasmatic (SCN): Circadian rhythms and Pineal gland regulation.

  • Arcuate (ARC): GHRH, GnRH, PIH, SSTN. Appetite control center (POMC and Agouti-related transcript).

  • Ventromedial (VMN): GHRH, SSTN. Satiety center.

  • Lateral Hypothalamic Area (LHA): Hunger center.

  • Anterior Hypothalamic Area (AHA): Thermoregulation (cooling) and thirst.

  • Posterior Hypothalamic Nucleus (PHN): Thermoregulation (heating).

Feedback Mechanisms and Endocrine Disease

• Loop Types:

  • Long-loop: Peripheral hormone feeds back to the hypothalamus and anterior pituitary.

  • Short-loop: Pituitary hormone feeds back to the hypothalamus.

  • Ultra-short-loop: Hormone feeds back on the cell that secreted it.

• Primary vs. Secondary Disease:

  • Primary Disease: Defect in the peripheral endocrine gland (e.g., adrenal tumor). Result: $\uparrow$ Peripheral Hormone (PH), $\downarrow$ Trophic Hormone (TH), $\downarrow$ Hypophysotropic Hormone (HH).

  • Secondary Disease: Defect in the anterior pituitary (e.g., pituitary tumor). Result: $\uparrow$ PH, $\uparrow$ TH, $\downarrow$ HH.

  • Tertiary Disease: Defect in the hypothalamus.

  • Symptom Note: The peripheral hormone excess causes the symptoms. Peripheral glands (e.g., both adrenals) will often be hypertrophied in secondary disease because tumors are resistant to negative feedback.

Anterior Pituitary Histology and Cell Types

• Embryology: Intermediate lobe is vestigial in humans but can secrete MSH in other species.

• Cell Distribution:

  • Somatotrophs (~50%): Secrete GH (Acidophils).

  • Lactotrophs (~15%): Secrete prolactin (Acidophils).

  • Corticotrophs (~20%): Secrete ACTH (Basophils).

  • Thyrotrophs (~5%): Secrete TSH (Basophils).

  • Gonadotrophs: Secrete LH and FSH (Basophils). Dispersed; most secrete both, some only LH, none only FSH.

  • Chromophobes: Non-hormone secreting follicles (Follicular-Stellate cells); may be stem cells or paracrine modulators.

Anterior Pituitary Hormone Structure

• ACTH/POMC Family: Small peptides like ACTH ($39$ amino acids).

• GH/Prolactin Family: Related proteins.

• Glycoprotein Family (TSH, LH, FSH, hCG):

  • Consist of two subunits.

  • $\alpha$ subunit: Common to all four.

  • $\beta$ subunit: Unique; provides receptor specificity.

  • hCG: From placenta; 1st sign of pregnancy; binds to the same receptor as LH.

Pro-opiomelanocortin (POMC) Processing

• Tissue Specificity:

  • Corticotrophs: Contain Prohormone Convertase 1/3 (PC1/3). Process POMC into ACTH and $\beta$-lipotropin.

  • Other tissues (Arcuate, Melanocytes): Contain PC1/3 and PC2. Process POMC into $\alpha$-MSH, $\gamma$-MSH, and $\beta$-endorphin.

• Melanocortins and Receptors:

  • MSH (Melanocyte Stimulating Hormone): Regulates skin/hair pigmentation and appetite.

  • MC1R: Skin pigmentation. Overexpressed ACTH (e.g., in Addison's) can bind MC1R and darken skin.

  • MC2R: Adrenal cortex; binds only ACTH.

  • MC4R (and MC3R): Hypothalamic appetite control.

Growth Hormone (GH) and Insulin-Like Growth Factor 1 (IGF-1)

• Growth Hormone (GH):

  • $191$ amino acid protein.

  • Signals via JAK/STAT pathway: Binding causes receptor dimerization $\rightarrow$ JAK2 autophosphorylation $\rightarrow$ phosphorylation of receptor tyrosines $\rightarrow$ STAT binding and dimerization $\rightarrow$ nucleus for transcription regulation.

  • Metabolic Effects: Counter-regulatory to insulin (Diabetogenic). Stimulates gluconeogenesis in the liver, lipolysis in adipose, and decreases skeletal muscle glucose uptake.

• IGF-1:

  • $68$ amino acid protein similar to insulin.

  • Major source is the liver (stimulated by GH).

  • Signals via Receptor Tyrosine Kinase (RTK) similar to insulin.

  • Half-life: Long ($t_{1/2}$) because it is bound to IGFBP3 and Acid-Labile Subunit (ALS).

  • Bone Growth: GH stimulates chondrocyte maturation; IGF-1 stimulates chondrocyte division in the epiphyseal plate.

• IGF-2:

  • Prominent in fetus and neonates; essential for placental growth.

  • IGF-2 receptor (mannose-6-phosphate receptor) lacks signaling and acts primarily as a clearance mechanism for IGF-2.

• GH Regulation:

  • GHRH: Stimulates transcription and release via G̑_s-PKA-cAMP pathway.

  • Somatostatin (SSTN): Inhibitory via G̑_i. cAMP has more influence on pulses than synthesis.

  • Temporal Control: Peaks at age 12; pulses increase with sleep (circadian).

  • Stimuli for GH: Amino acids (arginine), fasting/starvation, exercise, estrogens/androgens, ghrelin, thyroid hormone.

  • Inhibitors of GH: High blood glucose, high blood lipids, cortisol.

Lactation

• Prolactin:

  • Synthesized in lactotrophs; similar to GH.

  • Predominantly under inhibitory control by PIH (Dopamine).

  • Functions: Breast development during pregnancy, milk production (lactogenesis) after parturition.

  • Feedback: High prolactin inhibits GnRH, leading to lactational amenorrhea (reduced fertility).

• Regulation of Milk Production:

  • Requires loss of placenta (removal of estrogen/progesterone inhibition).

  • PIH (Dopamine): Binds D2 receptors (G̑_i) to inhibit adenylyl cyclase and PRL exocytosis.

• Oxytocin and the "Let Down" Reflex:

  • Posterior pituitary hormone; G̑_q signaling.

  • Stimulates contraction of myoepithelial cells in the breast for milk ejection.

  • Triggered by suckling (touch receptors) or higher brain centers (child's cry) in a positive feedback neuroendocrine reflex.

Melatonin and the Pineal Gland

• Synthesis Pathway:

  • Tryptophan $\xrightarrow{\text{Tryptophan hydroxylase}}$ 5-OH-L-Trp $\xrightarrow{\text{AAA decarboxylase}}$ Serotonin $\xrightarrow{\text{AANAT}}$ N-acetyl serotonin $\xrightarrow{\text{HIOMT}}$ Melatonin.

  • Arylalkylamine N-acetyl transferase (AANAT) is the rate-limiting step.

  • Cofactors: Tetrahydrobiopterin ($BH_4$) and Pyridoxine (Vitamin $B_6$).

• Regulation:

  • SCN inhibits the pathway in response to sunlight.

  • Norepinephrine (NE) activates $\beta_1$ receptors during darkness, increasing cAMP/PKA to stimulate synthesis.

• Receptors and Function:

  • MT1 & MT2: G̑_i coupled receptors.

  • MT3: Cytosolic; quinone reductase 2.

  • Roles: Used for jet lag and sleep disorders; minimal well-established physiological role in humans regarding puberty or intrinsic circadian regulation.