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Hormones of the Reproductive System

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1. The Hypothalamic-Pituitary-Gonadal (HPG) Axis

• Medical Physiology, p. 1594

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2. Hypothalamic Hormone

Gonadotropin-Releasing Hormone (GnRH)

• Follicular phase: frequent, small-amplitude pulses
• Late follicular phase: increased frequency and amplitude
• Luteal phase: slower frequency, higher amplitude, progressively declining

• Berek & Novak's Gynecology, pp. 270-271

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3. Anterior Pituitary Gonadotropins

Follicle-Stimulating Hormone (FSH)

• Recruits a cohort of ovarian follicles at the start of each cycle
• Drives estradiol synthesis by granulosa cells (via the two-cell, two-gonadotropin model)
• Stimulates inhibin B production

• Acts on Sertoli cells to produce androgen-binding protein (ABP), aromatase, growth factors, and inhibin
• Supports spermatogenesis
• Increases LH receptor numbers on Leydig cells (via growth factors), amplifying testosterone production

Luteinizing Hormone (LH)

• Stimulates androgen (androstenedione) synthesis in theca cells
• Triggers ovulation (the midcycle LH surge, 24-36 hours before ovulation)
• Stimulates progesterone production in luteinized granulosa cells before and after ovulation
• Maintains the corpus luteum

• Stimulates Leydig cells to produce testosterone

• Medical Physiology, p. 1598

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4. Gonadal Hormones - Female

Estrogens (principally 17β-Estradiol, E2)

Progesterone

• Costanzo Physiology, pp. 1380-1396

Inhibin and Activin (Ovarian Peptides)

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5. Gonadal Hormones - Male

Testosterone

• Smith and Tanagho's General Urology, p. 752

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6. Hormonal Pattern of the Menstrual Cycle

• FSH rises (corpus luteum demise removes inhibin A/progesterone feedback)
• Follicles recruited; estradiol rises progressively
• Rising estradiol causes negative feedback on FSH (FSH begins to fall)
• Late follicular: estradiol burst switches to positive feedback → LH surge (and smaller FSH surge)
• Ovulation triggered 24-36 hours after LH surge

• Corpus luteum forms; secretes estradiol, progesterone, and inhibin A
• Progesterone converts endometrium from proliferative → secretory
• High progesterone + estrogen + inhibin A suppress FSH and LH
• If no fertilization: corpus luteum degenerates → hormone levels fall → menstruation
• Berek & Novak's Gynecology, pp. 359-374

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7. Hormones of the Posterior Pituitary (Relevant to Reproduction)

Oxytocin

• Released by the posterior pituitary
• Stimulates uterine contractions during labor
• Drives milk ejection (let-down reflex) during breastfeeding
• Levels increase progressively near term and are amplified by estrogen (which upregulates oxytocin receptors in the myometrium)

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8. Placental Hormones (Pregnancy)

Human Chorionic Gonadotropin (hCG)

Human Placental Lactogen (hPL / Chorionic Somatomammotropin)

• Promotes mammary gland preparation for lactation
• Antagonizes insulin → raises maternal blood glucose (ensures fetal glucose supply)

Placental Progesterone

• After 5-6 weeks, the placenta takes over progesterone synthesis independently
• Inhibits uterine contractions, maintains decidua, promotes mammary differentiation

Placental Estrogens

• The predominant form at term is estriol (E3), synthesized from fetal DHEAS via the fetoplacental unit
• Promotes growth of the uterus and mammary glands
• Color Atlas of Human Anatomy - Internal Organs, pp. 610-611

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Quick Reference Summary Table

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Neuromuscular Junction (NMJ)

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1. Structure of the NMJ

Presynaptic Terminal (Motor Nerve Ending)

• As the myelinated motor axon approaches the muscle, it loses its myelin sheath and divides into several terminal boutons
• Each bouton sits in a depression on the muscle surface
• The terminal is rich in:
  • Mitochondria (energy supply for ACh synthesis)
  • Synaptic vesicles (each containing ~5,000 molecules of acetylcholine)
  • Active zones - specialized docking sites where vesicles align for release
  • Voltage-gated Ca²⁺ channels adjacent to the active zones
  • SNARE proteins: synaptobrevin (VAMP), synaptophysin, synaptotagmin (Ca²⁺ sensor), synapsin

Synaptic Cleft

• The gap (~20-50 nm wide) between the nerve terminal and the motor endplate
• Filled with a proteoglycan matrix
• Contains acetylcholinesterase (AChE), anchored to the basement membrane - the enzyme that rapidly degrades ACh

Postsynaptic Membrane (Motor Endplate)

• The thickened region of the muscle sarcolemma opposite the nerve terminal
• Forms deep junctional folds that greatly increase surface area
• Concentrated at the tops of the junctional folds: nicotinic cholinergic receptors (N_M type)
• At the bottoms of the folds: voltage-gated Na⁺ channels (important for action potential propagation)
• The AChR is anchored to the membrane by rapsyn (43 kDa protein, 1:1 ratio with AChR)

• Ganong's Review of Medical Physiology, p. 141

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2. Acetylcholine - Synthesis, Storage, and Release

• ACh is synthesized in the axon terminal cytoplasm from choline + acetyl-CoA via the enzyme choline acetyltransferase (ChAT)
• Acetyl-CoA is produced in mitochondria
• Choline is actively transported into the terminal from the synaptic cleft (recycled after ACh hydrolysis) - this choline reuptake is the rate-limiting step

• Newly synthesized ACh is transported into synaptic vesicles
• Each vesicle holds ~5,000 ACh molecules along with ATP
• A single nerve impulse releases approximately 200 quanta (~1,000,000 molecules of ACh total)

• ACh is released in discrete packets called quanta (one quantum = one vesicle's worth)
• Even at rest, individual vesicles occasionally fuse spontaneously with the membrane, producing small spontaneous depolarizations called miniature endplate potentials (MEPPs)
• MEPPs are the physiological signature of quantal release
• Miller's Anesthesia, p. 1158-1160

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3. Step-by-Step Transmission

• Ganong's Review of Medical Physiology, pp. 141-142

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4. The Nicotinic ACh Receptor (nAChR)

• Pentameric protein complex (~250 kDa): 2α₁ + β₁ + δ + ε subunits (mature/junctional type)
• Fetal/immature/extrajunctional receptor: 2α₁ + β₁ + δ + γ subunits (γ replaces ε)
• Neuronal α7 receptor: 5 × α7 subunits (found at autonomic ganglia and presynaptically)
• ACh binding sites are on each α-subunit (at cysteine residues 192-193)
• The five subunits form a barrel/cylinder arrangement around a central ion pore
• When both α-sites are occupied by ACh, the channel opens → Na⁺ in, K⁺ out → EPP

• Mature (junctional): clustered at endplate, shorter channel open time
• Fetal (extrajunctional): present throughout muscle membrane in denervated/immature muscle; longer open time, more sensitive to depolarizing blockers (e.g., succinylcholine)
• Miller's Anesthesia, pp. 1170-1171

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5. Safety Margin of Transmission

• Far more ACh molecules are released per impulse than needed to trigger an EPP above threshold
• Far more AChRs are available than are actually occupied during normal transmission
• Only a small fraction of vesicles and receptors are used with each nerve impulse

• Miller's Anesthesia, p. 1158

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6. Vesicle Recycling

• Guyton & Hall Textbook of Medical Physiology, p. 574

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7. Pharmacological Targets at the NMJ

• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 3496

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8. Diseases of the Neuromuscular Junction

• Robbins & Kumar Basic Pathology, p. 755

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Quick Summary

Hypothalamus (motor cortex/spinal cord)
         ↓  Action potential
Motor neuron axon (myelinated)
         ↓  Arrives at terminal bouton
Ca²⁺ entry via VGCC
         ↓  SNARE-mediated
ACh exocytosis (quantal, ~200 quanta/impulse)
         ↓  Diffuses across synaptic cleft (~200 μsec)
Binds N_M nicotinic AChR (tops of junctional folds)
         ↓  Ion channel opens (Na⁺ in, K⁺ out)
Endplate Potential (EPP)
         ↓  Local current spreads
Muscle fiber action potential (voltage-gated Na⁺ channels)
         ↓
Excitation-contraction coupling → Contraction
ACh hydrolyzed by AChE → choline recycled