Module 4: Endocrinology

Lecture 1: Endocrine Lecture

1. What the Endocrine System Is

• Endocrine system = hormone‑based control system.

• Hormones are cell signaling molecules secreted by endocrine cells → travel via blood → act on distant target cells that express specific receptors.

• Specificity comes from receptor expression, not hormone distribution.

→ specify = which means that cells can express the receptors (that’s correct) for a specific hormone to take effect

2. Modern View of Endocrinology

• Historically: focus on classic endocrine glands (pituitary, thyroid, adrenal).

• Now: many tissues are recognized as endocrine, e.g. GIT, heart, adipose tissue, bone.

• Endocrinology is now understood as cell‑to‑cell communication, not just “glands”.

3. Types of Cell Communication

Local (short range)

• Juxtracrine – direct contact (adhesion molecules, gap junctions).

• Autocrine – acts on same cell.

• Paracrine – acts on nearby cells.

How does juxtracrine differ from paracrine?

Juxtracrine requires direct physical contact between adjacent cells, while paracrine relies on the release of chemical signals into the extracellular space

Long‑distance

• Endocrine – hormones in blood.

• Nervous system – neurotransmitters.

• Neuroendocrine – neurons release hormones into blood.

4. Core Concepts in Cell Signalling

The lecture uses the “core concept inventory” diagram to emphasise:

1. Synthesis & release of messenger

2. Transport

3. Binding to receptor

4. Signal transduction

5. Cellular response

6. Termination of information transfer

These steps apply to all chemical messengers.

5. Chemical Classes of Messengers

Cell synthesizes and release a chemical messenger → and they are either stored in vesicle or escape via diffusion

Messenger molecules include:

• Peptides / polypeptides / proteins

• Steroids

• Amines (catecholamines, indoleamines)

• Lipids

• DNA, RNA, metabolites (modern expansion)

6. Storage & Secretion

Stored in vesicles → released by exocytosis

• Peptide hormones

• Catecholamines

Not stored → diffuse out immediately

• Steroid hormones

• Eicosanoids

Special case

• Thyroid hormones stored as thyroglobulin; released via carrier‑mediated diffusion.

7. Key Concept: Secretion = SUM of Stimuli

Hormone release is determined by net stimulatory vs inhibitory inputs, not a single trigger.

Example: Insulin secretion

Core concept: Transportation of chemical messenger

Transport depends on solubility:

Hydrophilic messenger (peptides, catecholamines)

• they dissolve easily in aqueous solution

• Travel freely in plasma

Sometimes they still bind to:

• Binding proteins → to protect them from being broken down too quickly

• Exosomes → tiny membrane vesicles that can carry signalling molecules

Hydrophobic messenger (steroids, thyroid hormones)

• Travel bound to plasma proteins

• if travelling on its own clump together or get stuck to membrane)

• So they must travel with carrier proteins, such as:

  • Binding proteins

  • Plasma proteins (e.g., albumin)

9. Plasma Hormone Levels = Balance of 4 Processes

1. Secretion

2. Activation (some hormones secreted inactive → require cleavage)

3. Binding to plasma proteins (lipophilic hormones)

4. Inactivation & excretion (liver metabolism, renal excretion)

Sensitivity of Target Cells

Sensitivity depends on:

• Number of receptors

• Receptor affinity

• Downstream signalling capacity

This determines how strongly a cell responds to a given hormone concentration.

11. Receptors & Signal Transduction

Hormones bind to receptors on or inside cells.

Receptor types mentioned

• GPCRs (oxytocin, GHRH, somatostatin, dopamine)

• Tyrosine kinase receptors (insulin, IGF‑1)

• Cytokine receptors (prolactin, GH, leptin, EPO)

• Steroid receptors (oestrogen)

12. Intracellular Responses

Signal transduction = signal relay and amplification

Hormone binding can cause:

1. Altered ion permeability (very fast)

2. Activation of enzymes/proteins (fast)

3. Gene expression changes (slow)

Second messengers (e.g., cAMP) allow rapid amplification.

13. Signal Amplification

Small hormone concentration → large cellular response.

Example from lecture:

Epinephrine (10⁻¹⁰ M) → cAMP (10⁻⁶ M) → massive enzyme activation.

14. Summary of Key Principles

• Hormones are chemical messengers for long‑distance communication.

• Only free hormone is biologically active.

• Hormone levels reflect secretion vs metabolism/excretion.

• Some hormones require activation after secretion.

• Target cell response depends on receptor presence + sensitivity.

• Signal transduction pathways determine speed and type of response.

• Endocrinology is fundamentally cell‑to‑cell communication.

Lecture 2: Physiological response to hormones depends on

Physiological Response Depends On Two Major Factors

1. Concentration of free, biologically active hormone

Determined by:

• Secretion from endocrine gland

• Activation (some hormones secreted inactive → require cleavage)

• Binding to plasma proteins (lipophilic hormones)

• Metabolism & inactivation (mainly liver)

• Excretion (mainly kidney)

Only free hormone can bind receptors and produce effects.

2. Sensitivity of target cells

• Receptor number

• Receptor affinity

• Integrity of intracellular signalling pathways

2. Hormone Insensitivity (Hormone Resistance)

Cells show reduced physiological response despite normal or high hormone levels.

Example: Type II diabetes (insulin resistance)

Three levels where insensitivity can occur

1. Molecular recognition (ligand binding)

• ↓ receptor expression

• Receptor mutations → poor binding

2. Activation of receptor

• Receptor cannot undergo conformational change

• GPCR polymorphisms: G protein-coupled receptor polymorphisms is variations in the genetic sequences of genes that code for GPCRs (rare but possible)

3. Intracellular signaling defects

Definitions: when a cell fails to properly process or transmit chemical messages from its surface to its internal machinery

• ↓ signaling components

• ↑ inhibitors (e.g., inflammation → inhibitory molecules block insulin signaling)

3. Endocrine Diseases: Too Little vs Too Much Hormone Activity

Too little hormone activity

• Hyposecretion

• Increased clearance (rapid removal)

• Tissue insensitivity (common)

• Increased plasma protein binding (rare)

Too much hormone activity

• Hypersecretion

• Reduced clearance (e.g., kidney failure → hormone accumulation)

• Reduced plasma protein binding (malnutrition → ↑ free hormone)

• Excessive tissue response (rare)

Plasma protein binding: the attachment of chemicals to plasma proteins in the blood

4. Hypothalamus (Part 1) — Structure & Function

• Neural tissue + endocrine gland

• Contains:

  • Nuclei (clusters of neuronal cell bodies)

  • Nerve tracts (axons)

Inputs

• Neural (cortex, limbic system)

• Humoral (blood‑borne signals: hormones, metabolites, glucose)

Outputs

• Neural (autonomic nervous system)

• Hormonal (neurohormones)

5. Hypothalamic Roles

Behavioural regulation

• Feeding

• Reproductive behaviours

• Rage

Driven by higher brain centres (cortex, limbic system).

Vegetative (homeostatic) regulation

Automatic, subconscious:

• Temperature

• Hunger/satiety

• Water balance

• Stress

• Growth

• Reproduction

Hypothalamus integrates multiple signals → compares to set‑point → generates coordinated

Lecture 3: Pituitary gland

1. Posterior Pituitary Gland

Releases two neurohormones made in the hypothalamus:

1. Vasopressin (AVP / ADH)

• Peptide hormone produced in the hypothalamus and released by the pituitary gland. Its two primary functions are regulating the amount of water in the body and constricting blood vessels, which helps control blood pressure

• 9‑aa peptide

• Actions:

  • ↓ water excretion (anti‑diuretic) and keeps water in body (reabsorbing)

  • Vasoconstriction

• Regulated by:

  • ECF osmolality (osmoreceptors)

  • Blood volume (stretch receptors)

2. Oxytocin (OT)

• a powerful hormone and neuropeptide produced in the hypothalamus and released by the posterior pituitary gland. Known as the "love hormone" or "bonding hormone," it plays a vital role in social connection, reproduction, and childbirth

• 9‑aa peptide (differs from AVP by 2 residues)

• Synthesised in:

  • Paraventricular nucleus (PVN)

  • Supraoptic nucleus (SON)

• Axons project to posterior pituitary → release OT into blood.

2. Oxytocin — Actions

Smooth muscle contraction during:

• Parturition (uterine myometrium) - child birth

• Milk ejection (myoepithelial cells)

Stimulated by

• Cervical stretch (baby in birth canal)

• Suckling

• Positive emotional inputs

• Inhibited by fear/anxiety

Both are positive feedback loops.

Other roles

• CNS neurotransmitter

• Bonding, trust, social behaviour

• Sexual function (orgasm)

3. Milk Ejection Reflex Sequence:

1. Suckling → sensory input to hypothalamus

2. ↑ firing of OT neurons

3. OT released from posterior pituitary

4. OT → myoepithelial contraction → milk ejection

Emotional state modulates reflex.

4. Oxytocin Signal Transduction

• OT receptor = GPCR (Gq)

• Activates PLC → PIP₂ → IP₃ + DAG

• IP₃ → Ca²⁺ release from ER

• Ca²⁺ → myosin phosphorylation → contraction

5. Anterior Pituitary Gland

Contains 5 endocrine cell types:

Two functional groups

1. Tropic/trophic hormones (act on other endocrine glands)

   • ACTH, TSH, LH, FSH

2. Direct‑acting hormones

   • GH, PRL

→ these two are the focus of the other lectures

6. Hypothalamic Control of Anterior Pituitary

• the glandular front lobe of the pituitary gland, a pea-sized organ at the base of the brai. Often called the body’s "master gland," it produces and secretes crucial hormones that regulate fundamental processes like growth, metabolism, reproduction, and stress responses.

• Small‑bodied neurons release releasing hormones into median eminence

• Travel via hypophyseal portal system

• Act on anterior pituitary cells

Releasing hormones

• GHRH

• TRH

• CRH

• GnRH

• Somatostatin (inhibits GH)

• Dopamine (inhibits prolactin)

7. Pituitary Stalk Section Experiment

If the hypothalamus is disconnected:

RF = Releasing Factor → A hypothalamic hormone that stimulates pituitary secretion.

RIF = Releasing Inhibitory Factor → A hypothalamic hormone that inhibits pituitary secretion.

Shows primary regulation by hypothalamic releasing factors.

1. Prolactin

• RF? → None (no releasing factor)

• RIF? → Dopamine

  • Dopamine = Prolactin Inhibitory Factor (PIF)

• Effect when stalk cut: Prolactin ↑ (loss of inhibition)

2. Growth Hormone (GH)

• RF: GHRH = Growth Hormone–Releasing Hormone

• RIF: Somatostatin (also called GHIH = Growth Hormone–Inhibiting Hormone)

• Effect when stalk cut: GH ↓ (no GHRH)

3. Thyroid-Stimulating Hormone (TSH)

• RF: TRH = Thyrotropin-Releasing Hormone

• RIF: Somatostatin (also inhibits TSH)

• Effect when stalk cut: TSH ↓

4. Adrenocorticotropic Hormone (ACTH)

• RF: CRH = Corticotropin-Releasing Hormone

• RIF: None

• Effect when stalk cut: ACTH ↓

5. LH & FSH

• RF: GnRH = Gonadotropin-Releasing Hormone

• RIF: None

• Effect when stalk cut: LH/FSH ↓

8. Growth Hormone (GH)

Structure

• 191‑aa single‑chain polypeptide

• Produced by somatotrophs

Secretion pattern

• Pulsatile - does not release constantly but rather every few hours

• Peaks during slow‑wave sleep - largest GH surge of the entire day happens during deep sleep

• Abolished by sleep deprivation → Restored by daytime sleep

9. GH Regulation

Hypothalamic control

• GHRH (stimulates)

• Somatostatin (SS) (inhibits)

• Both released in pulses

GH secretion is controlled by alternating pulses of GHRH (stimulates) and somatostatin (inhibits). Their rhythmic release produces the characteristic pulsatile GH secretion pattern, with the largest GH pulse occurring during slow‑wave sleep.

Somatotroph signalling (two method)

GHRH → GPCR → ↑ cAMP → ↑ Ca²⁺ → GH release

SS → GPCR → ↓ cAMP → inhibition

1. GHRH Pathway stimulates the release of GH

• GHRH binds its receptor on somatotrophs

• Receptor is Gs‑protein coupled

• Activates adenylyl cyclase

• ↑ cAMP

• Activates PKA

• PKA opens voltage‑gated Ca²⁺ channels

• ↑ intracellular Ca²⁺

• Ca²⁺ triggers exocytosis of GH‑containing vesicles

2. Somatostatin (ss) pathway inhibts the GH

• SS binds its Gi‑coupled receptor

• Inhibits adenylyl cyclase

• ↓ cAMP

• ↓ PKA activity

• Ca²⁺ channels stay closed

• No Ca²⁺ influx → no GH release

Feedback

• GH exerts short‑loop negative feedback on hypothalamus.

10. GH Actions

GH promotes growth, builds muscle/protein, burns fat, and increases blood glucose.

Growth by

• ↑ cell number & size

• ↑ bone length & thickness

Metabolic

• Distinct from growth effects

• (Details covered in later lectures)

11. GH Receptor Signalling (JAK‑STAT Pathway)

straight chain of events from GH binding → gene transcription.

1. GH binds GH receptor

2. Receptor conformational change - changes shape so inside can activate signaling

3. JAK2 activation

4. JAK2 phosphorylates receptor

5. STATs dock - STAT proteins attach to these phosphorylated sites.

6. STATs phosphorylated - JAK2 phosphorylates the STATs.

7. STAT dimers form

8. STATs enter nucleus - The STAT dimers move into the nucleus.

9. Gene transcription (e.g., IGF‑1 in liver) - They turn on GH‑responsive genes — most importantly IGF‑1 in the liver.

Lecture 4: Growth Hormone (GH), IGF‑1 & Growth Regulation

1. GH: Structure, Source & Secretion Pattern

Structure & Production

• GH is a polypeptide hormone synthesized and secreted by somatotrophs in the anterior pituitary.

• Transcript: “growth hormone is polypeptides… synthesised and secreted by the somatotroph cells in the anterior pituitary gland”

Hypothalamic Control

• GHRH (43 aa peptide) → stimulates GH.

• Somatostatin (14 & 28 aa forms) → inhibits GH.

• Both act via GPCRs on somatotrophs:

  • GHRH receptor → Gs → ↑cAMP → PKA → Ca²⁺ influx → GH exocytosis.Transcript: “GS stimulates adenylyl cyclase… cyclic AMP activates PKA… opening of calcium channels… exocytosis of growth hormone”

  • Somatostatin receptor → Gi → ↓cAMP → inhibition of GH release.

Pulsatile Secretion

• GHRH is released pulsatilely → each pulse produces a GH pulse.

• Interpulse interval dominated by somatostatin.Transcript: “A pulse of GHRH gives you a pulse of GH… in the interpulse interval… somatostatin being dominant”

Lifespan Changes

• High GH in neonates → maintained in childhood → peaks at puberty → declines in adulthood.

• Adults retain mainly one large nocturnal pulse.

2. GH Feedback Regulation

Short‑loop Negative Feedback

• GH feeds back to hypothalamus:

  • ↑GH → ↑somatostatin, ↓GHRH.Transcript: “High levels of growth hormone… switch on somatostatin, switch off GHRH”

Long‑loop Negative Feedback

• IGF‑1 (from liver + other tissues) inhibits GH secretion at pituitary & hypothalamus.

Integrated Hypothalamic Inputs

• Metabolic: high amino acids, low fatty acids, hypoglycaemia.

• Neural: exercise, slow‑wave sleep, stress, malnutrition.

• Hormonal: sex steroids (pubertal rise).

3. GH Receptor & Signalling (JAK‑STAT Pathway)

Receptor Type

• GH receptor = Class I cytokine receptor (shared with prolactin, EPO, ILs).

Mechanism

1. GH binds two receptor arms → conformational change.

2. Activates JAK2 (autophosphorylation).Transcript: “conformational change results in activation of JAK2… autophosphorylates”

3. JAK2 phosphorylates tyrosine residues on receptor.

4. STATs (mainly STAT5) dock and are phosphorylated.

5. STAT dimers translocate to nucleus → bind STAT response elements → gene transcription (e.g., IGF‑1 in hepatocytes).

6. Amplification occurs via multiple STAT molecules (not shown in simple diagrams).

Other Pathways

• GH can also activate MAPK in some tissues.

4. IGF‑1: Structure, Receptors & Actions

Structure

• IGF‑1 is structurally similar to insulin (shared homology in B and A domains).

Receptor

• IGF‑1 receptor = tyrosine kinase receptor (autophosphorylates).

• Signals via:

  • PI3K–AKT pathway → survival, protein synthesis.

  • MAPK pathway → proliferation.

Actions

• Hypertrophy (↑cell size)

• Hyperplasia (↑cell number)

• ↑Cell survival

5. Somatomedin Hypothesis (Classic vs Modern)

Classic (1950s)

• GH does not directly stimulate growth.

• GH → liver → IGF‑1 → systemic growth.

Modern Understanding

• GH has direct effects on many tissues (GH receptors are widespread).

• IGF‑1 comes from:

  • Liver (endocrine)

  • Local tissues (paracrine) e.g., bone, muscle.

• Local IGF‑1 can spill into circulation.

• Both GH + IGF‑1 are required for normal growth.

Evidence

• Knockout of IGF‑1 in muscle → 30% drop in circulating IGF‑1, showing non‑liver contribution.Transcript: “knocked out IGF1 in muscle… mice had a 30% decline in circulating IGF‑1”

6. GH & IGF‑1 in Bone Growth

Epiphyseal Plate Zones

• Proliferation zone: GH + IGF‑1 stimulate chondrocyte division.

• Hypertrophy zone: mainly IGF‑1 increases chondrocyte size.

• Osteoblasts replace cartilage with bone → elongation.

Growth Plate Closure

• Occurs after puberty due to oestrogen (in both sexes).

• After closure:

  • GH/IGF‑1 cannot increase bone length.

  • Can still increase bone thickness (acromegaly).

7. GH Metabolic Actions (Direct via GH‑R)

Muscle

• ↑Amino acid uptake

• ↓Glucose uptake

• ↓Protein breakdown

• ↑Muscle mass

Adipose Tissue

• ↓Glucose uptake

• ↑Lipolysis → ↓fat stores

Liver

• ↑Protein synthesis

• ↑Gluconeogenesis

• ↑Blood glucose

Overall

• GH is anti‑insulin for glucose & fat metabolism but anabolic for protein.

8. Growth Patterns Across Life

Two Major Postnatal Growth Spurts

1. Infancy: birth → 24–36 months

2. Puberty:

   • Girls: 8–13 years

   • Boys: 10–15 years

IGF‑1 Peaks at Puberty

• Peak IGF‑1 levels correspond to peak height velocity.

Determinants of Stature

• GH allows achievement of genetic potential.

• Nutrition is a major modulator.

9. GH Disorders

GH Deficiency

• Children: pituitary dwarfism

  • Short stature (~1.2 m), normal proportions, poor muscle development, ↑subcutaneous fat.

  • Recombinant GH restores near‑normal growth if treated before puberty.

• Adults: minimal symptoms.

GH Excess

• Children: gigantism (very tall, proportional growth).

• Adults: acromegaly

  • Enlarged hands, feet, jaw; thickened soft tissues; deep voice.

  • Treatment: somatostatin analogues or surgery.

10. Hormonal Interactions Required for Normal Growth

• Thyroid hormones

• Sex steroids (T, E)

• Insulin

• Glucocorticoids (excess inhibits growth)

Lecture 5: Growth hormone GH

1. GH Structure, Source & Secretion Pattern

• GH = polypeptide hormone secreted by somatotrophs in anterior pituitary. Transcript: “growth hormone is polypeptides… synthesised and secreted by the somatotroph cells”

• Circulates unbound (water‑soluble).

• GH receptors are widely expressed → GH has direct actions on many tissues.

Pulsatile secretion

• GHRH pulses → GH pulses. Transcript: “A pulse of GHRH gives you a pulse of GH”

• Somatostatin dominates interpulse intervals → suppresses GH.

• Pulsatility changes across lifespan: high in neonates, stable in childhood, peak at puberty, decline in adulthood.

2. Hypothalamic Regulation of GH

Releasing factor

• GHRH (43 aa)

  • Receptor = Gs‑coupled GPCR

  • ↑Adenylyl cyclase → ↑cAMP → ↑PKA → Ca²⁺ influx → GH exocytosis

Inhibitory factor

• Somatostatin (14 & 28 aa forms)

  • Receptor = Gi‑coupled GPCR

  • ↓cAMP → ↓Ca²⁺ influx → ↓GH secretion

Convergence

• GHRH and somatostatin converge on cAMP levels inside somatotrophs. Transcript: “this… is what we call convergence… levels of cyclic AMP determine secretion”

3. GH Feedback Regulation

Short‑loop negative feedback

• GH → hypothalamus:

  • ↑Somatostatin

  • ↓GHRH Transcript: “High levels of GH… switch on somatostatin, switch off GHRH”

Long‑loop negative feedback

• IGF‑1 (liver + other tissues) inhibits GH at pituitary & hypothalamus.

Other regulators

• Metabolic: high AA, low FAs, hypoglycaemia

• Neural: exercise, slow‑wave sleep, malnutrition

• Hormonal: sex steroids (pubertal rise)

4. GH Receptor & JAK‑STAT Signalling

GH receptor = Class I cytokine receptor (shared with PRL, EPO, ILs).

Mechanism

1. GH binds two receptor arms → conformational change

2. Activates JAK2 (autophosphorylation)

3. JAK2 phosphorylates receptor tyrosines

4. STATs (mainly STAT5) dock and are phosphorylated

5. STAT dimers → nucleus → bind STAT response elements

6. ↑Transcription of growth‑related genes (e.g., IGF‑1 in hepatocytes) Transcript: “one of the key targets… regulate IGF‑1”

Amplification

• Many STATs activated → large transcriptional response.

Other pathways

• GH can also activate MAPK in some cells.

5. IGF‑1: Structure, Receptor & Actions

• IGF‑1 = polypeptide structurally similar to insulin (shared homology in B & A domains).

• Receptor = tyrosine kinase receptor (autophosphorylates).

• Signalling:

  • PI3K–AKT → survival, protein synthesis

  • MAPK → proliferation

Actions

• Hypertrophy (↑cell size)

• Hyperplasia (↑cell number)

• ↑Cell survival

6. Somatomedin Hypothesis (Classic → Modern)

Classic (1950s)

• GH does not directly stimulate growth.

• GH → liver → IGF‑1 → systemic growth.

Modern understanding

• GH has direct effects on many tissues (GH‑R widely expressed).

• IGF‑1 comes from:

  • Liver (endocrine)

  • Local tissues (paracrine) e.g., bone, muscle

• Local IGF‑1 can spill into circulation.

Key evidence

• Muscle‑specific IGF‑1 knockout → 30% drop in circulating IGF‑1. Transcript: “those mice had a 30% decline in circulating IGF‑1”

Conclusion

• Growth = combined actions of GH + IGF‑1 (endocrine + paracrine).

7. GH in Bone Growth

Epiphyseal plate

• Proliferation zone: GH + IGF‑1 stimulate chondrocyte division

• Hypertrophy zone: IGF‑1 increases chondrocyte size

• Osteoblasts replace cartilage → bone elongation

Growth plate closure

• Occurs after puberty due to oestrogen.

• After closure: GH/IGF‑1 cannot increase bone length → only thickness.

8. GH Metabolic Actions (Direct via GH‑R)

Muscle

• ↑AA uptake

• ↓Glucose uptake

• ↓Protein breakdown

• ↑Muscle mass

Adipose

• ↓Glucose uptake

• ↑Lipolysis → ↓fat stores

Liver

• ↑Protein synthesis

• ↑Gluconeogenesis

• ↑Blood glucose

Overall: GH is anti‑insulin for glucose/fat metabolism but anabolic for protein.

9. Growth Patterns

• Two major postnatal growth spurts:

  1. Infancy (0–2/3 years)

  2. Puberty (girls 8–13, boys 10–15)

• IGF‑1 peaks at puberty → peak height velocity.

10. GH Disorders

GH deficiency

• Children: pituitary dwarfism

  • Short stature (~1.2 m), normal proportions, poor muscle development, ↑subcutaneous fat

  • Recombinant GH restores near‑normal growth

• Adults: minimal symptoms

GH excess

• Children: gigantism

• Adults: acromegaly

  • Enlarged hands/feet/jaw, thickened soft tissues, deep voice

  • ↑CVD risk, ↑T2DM risk

  • Loss of IGF‑1 negative feedback

  • Treatment: surgery or somatostatin analogues (e.g., octreotide)

Lecture 6: Prolactin (PRL)

1. Structure, Synthesis & Secretion

• PRL = polypeptide hormone (199 aa).

• Produced by lactotrophs in anterior pituitary.

Regulation

• Inhibited by dopamine (PIF)

  • Dopamine from hypothalamic arcuate nucleus

  • Acts via D2 (Gi) receptors → ↓cAMP → ↓Ca²⁺ influx → ↓PRL secretion Transcript: “Dopamine… inhibits secretion, synthesis, lactotroph proliferation”

• Stimulated by PRF (identity unknown; TRH/VIP suggested but not physiologically dominant except in stress/lactation)

Spontaneous secretion

• Lactotrophs show intrinsic spontaneous activity:

  • ↑cAMP

  • Membrane depolarisation

  • Ca²⁺ influx

  • PRL exocytosis (Shown in Stojilkovic data)

2. Prolactin Signalling

• PRL receptor = Class I cytokine receptor (same family as GH‑R).

• Main pathway: JAK2–STAT5

  • STAT5 → nucleus → transcription of milk‑related genes

• STAT1/3 also activated in some contexts.

3. Prolactin Actions

Mammary gland

• Development

  • Puberty: oestrogen + GH

  • Pregnancy: PRL + oestrogen + progesterone → alveologenesis

• Lactation (lactopoiesis)

  • ↑Milk protein synthesis (β‑casein, WAP, α‑lactalbumin)

  • ↑Milk fat secretion

  • Regulates ion transport + tight junction integrity

  • ↑Lactose synthesis → major osmotic driver of milk volume

Milk ejection vs milk production

• Oxytocin → milk ejection (myoepithelial contraction)

• Prolactin → milk synthesis/secretion Slides: “Oxytocin = ejection; Prolactin = secretion”

Non‑reproductive roles

• Immune modulation

• Behavioural effects

4. Feedback Regulation

Short‑loop negative feedback

• PRL → hypothalamus → ↑dopamine → ↓PRL

• No long‑loop feedback (mammary gland does not produce a hormone).

Non‑lactating individuals

• High dopamine tone keeps PRL low. Slides: “Dopamine constantly suppresses PRL… main regulator is inhibitory factor”

Lactation

• Suckling → ↓dopamine + ↑PRF → ↑PRL

• PRL surge prepares milk for next feed (feed‑forward).

• Oestrogen during pregnancy ↑PRL mRNA.

5. Suckling Reflex

• Nipple mechanoreceptors → hypothalamus

  • ↓PIF (dopamine)

  • ↑PRF

  • ↑PRL (milk synthesis)

  • ↑Oxytocin (milk ejection)

6. Prolactin Disorders

Hyposecretion

• Failure to lactate

• Possible immune/metabolic effects

Hyperprolactinaemia

• Causes:

  • Prolactinoma (benign pituitary tumour)

  • Antipsychotics (dopamine antagonists)

• Effects:

  • Females: galactorrhoea, amenorrhoea

  • Males: gynecomastia, low libido

  • PRL inhibits HPG axis → ↓GnRH → ↓LH/FSH

• Treatment:

  • Dopamine agonists (e.g., bromocriptine, cabergoline)

  • Surgery (transsphenoidal)