GYN 7

• Neuroendocrine mechanisms


  The basic factors in the reproductive cycle

  
• Transducer concept


  The specialized neural cells of the hypothalamus function as the final common pathway to guide the appropriate anterior pituitary hormonal response

  
• Hypothalamus


  • Plays an important role in the neuroendocrine regulation
  • Has three well-defined areas: supraoptic area, tuberal region, and mamillary region
  • Contains both a tonic and a cyclic center resulting in changes in gonadotropin releasing hormone (GnRH) production

  
• Cortical centers


  Have neural connection with the hypothalamus

  
• Hypothalamus


  Has numerous output connections to pituitary gland and other areas of the central nervous system (CNS) like amygdala, hippocampus, thalamus, and pons

  
• Ovarian and menstrual cycle


  Are affected by various emotional and environmental factors through the connections between the hypothalamus and other CNS areas

  
• Hypothalamo-pituitary portal system


  The system of vessels connecting the hypothalamus to the anterior lobe of the pituitary (adenohypophysis)

  
• Supraoptic and paraventricular nuclei

  Directly connect the hypothalamus to the posterior lobe of the pituitary (neurohypophysis)

  
• Hypothalamus


  Produces a series of specific releasing and inhibiting hormones which have an effect on the production of the specific pituitary hormones

  
• Gonadotropin-releasing hormone (GnRH)


  • Also named as luteinizing hormone-releasing hormone (LHRH)
  • A decapeptide concerned with the release, synthesis and storage of both the gonadotropins (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)) from the anterior pituitary

  
• GnRH

  • Secreted by the arcuate nucleus of the hypothalamus in a pulsatile fashion
  • Has a very short half-life (2-4 minutes) due to cleavage of amino acid bonds
  • Stimulates anterior pituitary for synthesis, storage and secretion of gonadotropins
  • Receptor sensitivity decreases with continuous exposure (downregulation) and increases with intermittent exposure (upregulation)

  
• GnRH gene is located on the short arm of chromosome 8
• Several forms of GnRH decapeptides have been identified, with the principal one being GnRH-2 which differs from GnRH by 3 amino acids

  
• GnRH axons terminate within the capillary plexus in the median eminence where GnRH is released, and the hypophyseal portal vessels descend along the pituitary stalk to terminate in another capillary plexus within the anterior lobe of pituitary
• Kisspeptin (Kiss 1)


  Thought to be involved in the mechanisms of pulsatile release of GnRH
• Estradiol


  Decreases GnRH pulse amplitude
• Progesterone


  Decreases GnRH pulse frequency
• Prolactin inhibitory factor (PIF)

  Dopamine is the physiological inhibitor of prolactin secretion from the anterior pituitary

  
• Thyrotropin-releasing hormone (TRH)


  A tripeptide that stimulates the release of not only thyrotropin but also prolactin from the pituitary

  
• Corticotropin-releasing hormone (CRH)


  A tetradecapeptide

  
• Other secretions of the hypothalamus include growth hormone-releasing hormone (GHRH) and melanocytic releasing factor

  
• Ways the neurohormonal control of GnRH secretion is modulated

  • Neurotransmitters and neuromodulators
  • Peptides
  • Ultrashort feedback loop
  • Short feedback loop
  • Long feedback loop

  
• Neurotransmitters and neuromodulators


  • Catecholamines (dopamine, norepinephrine, serotonin) affect the frequency of GnRH pulse
  • Endogenous opioids (endorphins, enkephalins, dynorphins) inhibit GnRH release
  • Prostaglandin E increases GnRH release

  
• Activin, inhibin, follistatin


  • Peptides produced by GnRH from pituitary cells and granulosa cells of the ovary
  • Activin stimulates, follistatin inhibits, and inhibin blocks GnRH receptors

  
• Ultrashort feedback loop


  Autoregulation of the releasing hormone of the hypothalamus on its own synthesis

  
• Short feedback loop


  Relates to the secretion of GnRH by the interplay between neurotransmitters and pituitary gonadotropins (FSH and LH)

  
• Long feedback loop


  The secretion of the hypothalamus (GnRH) and pituitary (FSH, LH) are influenced by the sex steroids

  
• Nature of GnRH secretion

  • Tonic, cyclic, and pulsatile
  • Tonic center is controlled by negative feedback of sex steroids
  • Cyclic center is stimulated by positive feedback of preovulatory estradiol
  • Pulsatile release is regulated by neurotransmitters and neuromodulators

  
• GnRH pulse secretion


  • Rapid in follicular phase (about 1 pulse/hour), lower in luteal phase (about 1 pulse every 2-3 hours)
  • Amplitude is low in follicular phase, high in luteal phase
• GnRH action on anterior pituitary

  • Stimulates the synthesis and release of both LH and FSH from the same gonadotroph cells
  • Involved in maintaining the synthesis of gonadotropins
  • Lower GnRH pulse frequencies favor FSH secretion, higher frequencies favor LH secretion (self-priming)

  
• Estrogen


  Preferentially induces more LH than FSH release
• Physiological control mechanism of gonadotropin release

  • Two pools of gonadotropins: primary pool readily releasable, secondary reserve pool
  • GnRH makes the reserve pool more readily released by subsequent exposure
• Mechanism of action of GnRH on pituitary cell

  1. GnRH binds to specific receptors on gonadotroph cell membrane

  2. Activates adenyl cyclase, increasing cAMP

  3. cAMP-receptor protein complex activates protein kinase C

  4. Intracellular free Ca++ concentration increases

  5. Protein kinase C causes phosphorylation and activation of specific enzymes

  6. Ca++, protein kinase C and cAMP stimulate release of stored FSH and LH and their biosynthesis

  
• Continuous infusion of GnRH inhibits gonadotropin secretion due to receptor saturation and desensitization (downregulation)

  
• Anterior pituitary


  • Consists of chromophobes (parent cells) and chromophils (larger cells that stain easily)
  • Chromophils include acidophils (produce growth hormone and prolactin) and basophils (produce gonadotropins, thyrotropin, and corticotropin)
• Follicle-stimulating hormone (FSH)


  • One of the two gonadotropic hormones secreted from the anterior pituitary
  • A water-soluble glycoprotein with two subunits, with the hormone specificity determined by the difference in the β subunit

  
• Functions of FSH


  • Predominantly morphogenic, related to growth and maturation of Graafian follicle
  • Acts on granulosa cells
  • Involved in maturation of oocyte, ovulation and steroidogenesis

  
• Morphological effects of FSH


  • Rescues follicles from apoptosis
  • Stimulates formation of follicular vesicles (antral follicle)
  • Stimulates proliferation of granulosa cells
  • Helps full maturation of the Graafian follicle
• Biochemical effects of FSH

  • Synthesizes its own receptors in the granulosa
• FSH


  The function of FSH is predominantly morphogenic, related to the growth and maturation of the Graafian follicle. It acts primarily on the granulosa cells. In conjunction with LH, it is also involved in maturation of oocyte, ovulation and steroidogenesis.