Physiology of Menstruation


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Physiology Of Menstruation
By: Nur Afiqah Binti Jasmi (11-2013-031) & Luqman Hakim Bin Mohd Jais (11-2013-170)
Dokter Pembimbing: Dr. Harianto Wijaya Sp.OG

Published in: Health & Medicine, Technology

Physiology of Menstruation

  1. 1. Physiology OfPhysiology Of MenstruationMenstruation Disusun Oleh: Nur Afiqah Binti Jasmi 11-2013-031 Luqman Hakim Bin Mohd Jais 11-2013-170 Dokter Pembimbing: dr Harianto Wijaya Sp.OG Kepaniteraan Klinik Ilmu Obstetri & Ginekologi RSUD Tarakan Fakultas Kedokteran Ukrida
  2. 2. MENSTRUAL CYCLE • Menstrual Cycle: 28 ± 7 days . Varied • Menstrual flow:4 ± 2 days • Hypothalamus- Pituitary-Ovary Axis • Hormone Communication
  3. 3. HYPOTHALAMUS Hypothalamus ----------------------------------------------> Circulating Hormones Hypothalamus ------------------------------> Pituitary Hypothalamus ------>Hypothalamus Long Feedback Loop Short Feedback Loop Ultrashort Feedback Loop
  4. 4. REPRODUCTIVE FUNCTIONS OF THE HYPOTHALAMUS Gonadotropin-Releasing Hormone • Decapeptide • From arcuate nucleus • Half life : 2-4 minutes • Gonadotropin-releasing hormone (GnRH) -> controlling factor for gonadotropin secretion. • Kiss1 gene -> Kisspeptins -> GPR54 (receptor) -> Signaling GnRH & GAP secretion
  5. 5. Neuronal BodyNeuronal Body Pre-pro-GnRHPre-pro-GnRH GnRH decapeptide GAP GnRH decapeptide GAP Portal VesselPortal Vessel ProteolyticProteolytic Nerve terminalNerve terminal GnRH geneGnRH gene
  6. 6. GnRH Pulsatile Secretion Continuous Exposure Downregulation GnRH receptor decrease Intermittent Exposure Upregulation Autoprime GnRH receptor increase
  7. 7. Follicular Phase Luteal PhaseMid Follicular
  8. 8. Endogenous Opioids and Effects on GnRH Opioid Endorphin ↑ Inhibit GnRH releases Ovarian Sex Streoids Endorphin Peak: Luteal Phase Nadir: Menses
  9. 9. PITUITARY Gonadotrophs are specialized cell types of the anterior pituitary that synthesize and secrete LH and FSH Gonadotrophs contain cell-surface GnRH receptors that mediate the action of GnRH.
  10. 10. Gonadotropin-Releasing Hormone Receptor • Hypothalamic GnRH -> Pituitary -> GnRH type I receptor -> activation of Gq/11. • PKC-, Ca2+-, and tyrosine kinase–dependent pathways. • Type 2 receptors: Inhuman Primates
  11. 11. Identical α subunit Gonadotropins Location of β-subunit gene Size of β-subunit Half-life in serum FSH Chromosome 117aa[*] 3-4h[†] 11p13 LH Chromosome 121aa 20 min[#] 19q13.3 hCG Chromosome 145aa 24h 19q13.3
  12. 12. Regulation of Circulating Levels of FSH & LH Pituitary Gonad Hormones Carbohydrates Residue Subunit α > β Inhibin Activin Follistatin Autocrine/ Paracrine Mechanism Sialic Acid hCG > FSH > LH slower clearance
  13. 13. OVARY Adult OvaryAdult Ovary Length: 2-5cm Width: 1.5-3cm Thickness: 0.5-1.5cm Weight: 5-10g Length: 2-5cm Width: 1.5-3cm Thickness: 0.5-1.5cm Weight: 5-10g Cortex: germinal epithelium, follicle Medulla: tissue, contractile cells, interstitial cells Hilum : blood vessel, lymp, erves Cortex: germinal epithelium, follicle Medulla: tissue, contractile cells, interstitial cells Hilum : blood vessel, lymp, erves
  14. 14. Ovaries Functions Production of oocytes Production of steroid and Peptide Hormones Embryolo gy of Ovary Endoder m of yolk sac Coelemic Epithelial cells Mesench ymal Cells Primordia l Germs Cells Granulos a Cells Ovarian Stroma
  15. 15. Primordial Cells Oogonia Primary Ooocyte Primordial Follicle Atretic 3rd week of gestation: Yolk Sac 6th week of gestation: Migration into the gonadal ridge -> generate the primary sex cords . Mitosis at Gonad 12th week of gestation Meiosis Surrounded by single layer of flattened granulosa cells
  16. 16. The number of oocytes in the ovary before and after birth and through Menopause.
  17. 17. Meiotic Division during Oocyte Maturation
  18. 18. Ovarian Follicular Development
  19. 19. Functional anatomy and developmental changes in the adult ovary during a ovarian cycle.
  20. 20. Steroidogenesis Across the Life Span Childhood • 8 weeks' gestation: Ovary →estrogen • 2nd trimester: Gonadotropin ↑ • The fetal hypothalamic-pituitary axis continues to mature -> sensitive to estrogen and progesterone -> fetal gonadotropins fall to low levels prior to birth. • Newborn: ↑ gonadotropins • Childhood: The hypothalamic-pituitary axis increased sensitivity to negative feedback →↓FSH LH • ↑ FSH:LH ratio : premenarchal girl and postmenopausal woman.        
  21. 21. Puberty • LH secretion ↑. Difference Day & Night • LH > FSH levels: Reproductive Years     • ↑ LH & FSH → ↑estrogen : growth spurt, maturation of the female internal and external genitalia, and development of a female habitus • Activation of the pituitary-adrenal axis → adrenal androgen production→axillary and pubic hair (adrenache or pubarche). Postmenopause • Few follicles → ↓estrogen & inhibin → ↑LH and FSH → androstenedione → estrone but inadequate to protect against bone loss.
  22. 22. Variations in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during different life stages in the female.
  23. 23. E & P Receptor Estrogen Progesteron + ligand
  24. 24. FOLLICULAR PHASE • 10–14 day • A series of sequential actions of hormones and autocrine/paracrine peptides on the follicle • Follicle destined to ovulate goes through a period of initial growth from a primordial follicle through the stages of the preantral, antral, and preovulatory follicle.
  25. 25. Primordial Follicle Primordial follicle in the cortical stroma. A layer of flattened follicular epithelial cells surrounds the oocyte with its large nucleus and prominent nucleolus. The ooplasm is not stained
  26. 26. • The granulosa cells become cuboidal and increase in number to form a pseudostratified layer. • The decline in luteal phase estrogen, progesterone, and inhibin-A production by the now-fading corpus luteum from the previous cycle • The increase in FSH that stimulates this follicular growth. • Hormone-mediated effects can be transmitted throughout the follicle. • Oocyte begins secretion of an acellular coat known as the zona pellucida.     
  27. 27. PreAntral Follicle • The stroma differentiates into the theca interna, which is adjacent to the basal lamina, and the theca externa, which abuts the surrounding stroma • Oocyte enlarges and is surrounded by a membrane, the zona pellucida • Granulosa cells -> estrogens> androgens or progestins
  28. 28. Ovary—Secondary Follicle or Preantral Follicle 1 Follicular epithelium 2 Zona pellucida 3 Basal membrane 4 Theca folliculi
  29. 29. Ovary—Secondary Follicle or Preantral Follicle 1 Beginnings of a follicular antrum 2 Theca folliculi interna 3 Theca folliculi externa 4 Cortical stroma 5 Primordial follicle
  30. 30. • Specific receptors for FSH are not detected on granulosa cells until the preantral stage, needed for androgen aromatase • The administration of FSH will raise and lower the concentration of its own receptor on granulosa cells (up- and down-regulation)
  31. 31. Two-Cell Theory of Ovarian Steroidogenesis
  32. 32. Antral Follicle ( Tertiary Follicle) • Follicular fluid begins to collect between the granulosa cells→ antrum. • Rapid increase in follicular size • The granulosa cells surrounding the oocyte are now designated the cumulus oophorus
  33. 33. • 1 Antrum folliculi • 2 Cumulus oophorus with oocyte • 3 Theca folliculi
  34. 34. LH Pulse Frequency: • Early follicular phase —90 minutes. • Late follicular phase —60–70 minutes. • Early luteal phase —100 minutes. • Late luteal phase —200 minutes. LH Pulse Amplitude: • Early follicular phase —6.5 IU/L. • Midfollicular phase —5.0 IU/L. • Late follicular phase —7.2 IU/L. • Early luteal phase —15.0 IU/L. • Midluteal phase —12.2 IU/L. • Late luteal phase —8.0 IU/L.
  35. 35. Gonad Peptide Hormone • Inhibin: Inhibitor of FSH secretion. • Activin: Stimulates FSH release • Follistatin : binding activin: Suppresses FSH activity
  36. 36. INHIBIN 2 Forms of Inhibin: • Inhibin A: Alpha-BetaA ( Corpus Luteum-Luteal Phase) • Inhibin B: Alpha-BetaB ( Granulosa Cells-Follicular Phase )  Inhibin: block the synthesis and secretion of FSH, reduce the number of GnRH receptors present, promotes intracellular degradation of gonadotropins.  FSH - Inhibin — a reciprocal relationship  Inhibin B: rises slowly but steadily, in a pulsatile fashion (60–70 min periodicity) reaching peak levels in the early and midfollicular phases, a nadir in the midluteal phase.  Inhibin A: suppression of FSH to nadir levels during the luteal phase
  37. 37. ACTIVIN • Activin : • Prior to ovulation: supress Progesteron production • Stimulate FSH release and GnRH receptor number. • Circulating levels of activin increase in the late luteal phase to peak at menses 3 Forms of Activin: •      Activin A: BetaA-BetaA •      Activin AB: BetaA-BetaB •      Activin B: BetaB-BetaB
  38. 38. Follistatin • Follistatin playing a role by inhibiting activin and enhancing inhibin activity.
  39. 39. Selection Of Dominant Follicle • The successful conversion to an estrogen dominant follicle marks the “selection” of a follicle destined to ovulate -> One Single Follicle Succeed -> Dominant Follicle -> Estrogen • estrogen - FSH interaction (+ for maturing follicle) • estrogen - pitutary interaction (- feedback) -> FSH ↓ Other cells entered Apoptosis -> TNF -> inhibit FSH stimulation , estradiol secretion
  40. 40. PreOvulatory / Graafian Follicle • Fluid-filled antrum that is composed of plasma with granulosa-cell secretion • The oocyte remains connected to the follicle by cumulus oophorus • Estrogens - LH (+ feedback) -> Luteinization of the granulosa cells -> Progesterone & Prostaglandin -> Initiation of ovulation • Plasminogen -> Proteolytic enzymes, plasmin
  41. 41. • Ovulation will occur in the single mature, Graafian follicle 10 to 12 hours after the LH peak or 34 to 36 hours after the initial rise in midcycle LH. • Inhibin, Activin and follistatin, insulinlike growth factor (ILGF)-1, epidermal growth factor (EGF)/transforming growth factor (TGF)-α, TGF-β1, β-fibroblast growth factor (FGF), interleukin-1, tissue necrosis factor-α, OMI, and renin–angiotensin
  42. 42. Ovary—Graafian Follicle Human follicles reach a diameter of 20–25mm 1 Antrum folliculi 2 Cumulus oophorus 3 Granulosa epithelial cells 4 Theca folliculi 5 Radial corona cells
  43. 43. OVULATION • Oocyte-cumulus is released from the follicle • Toward the end of the follicular phase, estradiol levels increase dramatically • Estradiol - Pituitary (+ Feedback) • Estradiol concentrations of 200 pg/mL for 50 hours →initiate a gonadotropin surge • The mean duration of the LH surge is 48 hours • Ovulation occurrs approximately 36 to 40 hours after the onset of the LH surge
  44. 44. • Gn surge -> Plasminogen activity ↑ • Plasmin and collagenase-> follicular wall thinning • Prostaglandin-> Ovary muscle contraction • Extrusion of the oocyte only lasts a few minutes
  45. 45. LUTEAL PHASE • The remaining -> corpus luteum • granulosa / theca cells proliferate + hypertrophy -> granulosa-lutein cells / smaller theca-lutein cells • Basement membrane degenerates + vascularize -> Capillary invasion • Progesterone Dominant -> 40 mg of progesterone per day • Inhibin A -> low FSH level
  46. 46. Corpus Luteum 1 Granulosa lutein cells 2 Theca lutein cells 3 Connective tissue of the theca folliculi
  47. 47. LUTEOLYSIS • Luteal regression • Blood supply diminishes • E & P secretion drop • Luteal cells apoptosis -> fibrotic -> corpus albicans
  48. 48. The Luteal-Follicular Transition • Estradiol, progesterone, inhibin -> nadir • E & P decrease -> increasing GnRH pusatile • Inhibin A decrease + increasing GnRH pulsatile -> FSH > LH
  49. 49. UTERUS • Decidua functionalis -intermediate zone (stratum spongiosum) -superficial compact zone (stratum compactum). • Decidua basalis is the deepest region of the endometrium
  50. 50. Proliferative Phase • Early proliferative phase, the endometrium is relatively thin (1–2 mm). • Initially straight, narrow, and short endometrial glands → longer structures. • These proliferating glands have multiple mitotic cells • Low columnar pattern → pseudostratified pattern before ovulation.
  51. 51. Proliferative Phase • Proliferative phase: straight to slightly coiled, tubular glands are lined by pseudostratified columnar epithelium with scattered mitoses.
  52. 52. Secretory Phase Early secretory phase: • 48-72 hours after ovulation: Progesteron↑ • coiled glands lined by simple columnar epithelium • glycogen containing vacuoles • Apocrine secretion • Stroma edema
  53. 53. • Late secretory phase: • serrated, dilated glands with intraluminal secretion are lined by short columnar cells. • 2 days before menses: PMN infilitration→endome trial stroma collapse
  54. 54. • Decidua functionalis breakdown→menses • Sex steroids withdrawal: spiral artery vascular spasm →endometrial ischemia. • Lysosomes breakdown →proteolytic enzymes →promote local tissue destruction. • Prostaglandin F2α → potent vasoconstrictor→ arteriolar vasospasm and endometrial ischemia. PGF2α also produces myometrial contractions Menstrual Phase
  55. 55. Effects of Ovarian Steroids on Endometrium Striking thickening of endometrial tissue. Stroma & epithelial proliferate rapidly. inhibit or reverse proliferative action of estrogen. Differentiation of epthelial & stroma.