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  • 1. Female Reproductive Endocrinology Chapter 18
  • 2.  
  • 3. Anatomy <ul><li>Vulva – external genitalia </li></ul><ul><li>Vagina </li></ul><ul><ul><li>Functions: </li></ul></ul><ul><ul><ul><li>Sperm, menstrual flow passage </li></ul></ul></ul><ul><ul><ul><li>Receptacle for penis </li></ul></ul></ul><ul><ul><ul><li>Birth canal </li></ul></ul></ul><ul><ul><li>Rugae </li></ul></ul><ul><ul><li>Acidic environment </li></ul></ul>
  • 4.  
  • 5. <ul><li>Uterus </li></ul><ul><ul><li>Functions: </li></ul></ul><ul><ul><ul><li>Sperm transport </li></ul></ul></ul><ul><ul><ul><li>Implantation fert’d ovum </li></ul></ul></ul><ul><ul><ul><li>Fetal dev’t </li></ul></ul></ul><ul><ul><ul><li>Labor </li></ul></ul></ul><ul><ul><ul><li>Menstruation </li></ul></ul></ul><ul><ul><li>Cervix secretes mucus </li></ul></ul>
  • 6. <ul><li>Uterus – cont’d </li></ul><ul><ul><li>Three histological layers </li></ul></ul><ul><ul><ul><li>Perimetrium – outside </li></ul></ul></ul><ul><ul><ul><li>Myometrium – sev muscle layers + connective tissue </li></ul></ul></ul><ul><ul><ul><ul><li>Forms bulk of uterine wall </li></ul></ul></ul></ul><ul><ul><ul><li>Endometrium – closest to uterine cavity </li></ul></ul></ul><ul><ul><ul><ul><li>Covered w/ epithelium </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Vascular w/ tubular glands </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Further divided  3 layers </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Innermost shed w/ menstruation </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Outermost  new inner layer during cycle </li></ul></ul></ul></ul></ul>
  • 7. <ul><li>Oviducts </li></ul><ul><ul><li>Transport </li></ul></ul><ul><ul><ul><li>Peristalsis </li></ul></ul></ul><ul><ul><ul><li>Cilia </li></ul></ul></ul><ul><ul><li>Isthmus, ampulla, infundibulum </li></ul></ul><ul><ul><li>Not static tube </li></ul></ul><ul><li>Ovaries = gonads </li></ul><ul><ul><li>Inner medulla, outer cortex </li></ul></ul><ul><ul><li>Gametogenesis, hormonogenesis </li></ul></ul>
  • 8.  
  • 9. Ovaries <ul><li>Prepubertal </li></ul><ul><ul><li>Anatomy </li></ul></ul><ul><ul><ul><li>Smooth outer germinal epithelium </li></ul></ul></ul><ul><ul><ul><li>Connective tissue </li></ul></ul></ul><ul><ul><ul><li>Cortex w/ ovarian follicles in stroma </li></ul></ul></ul><ul><ul><li>Low quantities of sex steroid </li></ul></ul><ul><ul><ul><li>Feedback inhibition of gonadotropins </li></ul></ul></ul><ul><li>Puberty  gonadotropins  sex steroids </li></ul><ul><ul><li>LH  PKA  StAR  P450scc in partic cells </li></ul></ul><ul><ul><li>FSH  E2 secr’n in partic cells </li></ul></ul>
  • 10. Ovarian Cycle <ul><li>Controls, controlled by hormones </li></ul><ul><li>Coupled to uterine cycle </li></ul><ul><li>Related to maturation ovarian follicles </li></ul><ul><ul><li>Gonadotropin dependent </li></ul></ul><ul><li>Two phases </li></ul><ul><ul><li>Follicular </li></ul></ul><ul><ul><li>Luteal </li></ul></ul>
  • 11. Follicular Phase <ul><li>Variable length </li></ul><ul><li>Maturing follicles secrete </li></ul><ul><ul><li>17  -estradiol </li></ul></ul><ul><ul><li>Inhibin </li></ul></ul><ul><li>Absence functional CL </li></ul><ul><ul><li>Plasma progesterone low </li></ul></ul><ul><li>FSH elevated @ beginning, diminishes </li></ul><ul><ul><li>High FSH impt to follicle selection, early maturation </li></ul></ul>
  • 12. <ul><li>As follicle dev’s, more E2, inhibin  </li></ul><ul><ul><li>Decr’d FSH (neg feedback) </li></ul></ul><ul><ul><li>Decr’d LH </li></ul></ul><ul><ul><li>Upregulation ant pit GnRH receptors </li></ul></ul><ul><li>E2 peaks @ midcycle  FSH/LH surge </li></ul><ul><li>Now new ability some ovarian cells to produce sex steroids (progesterone) </li></ul><ul><li>Now ovum released from mature follicle </li></ul>
  • 13.  
  • 14. Luteal Phase <ul><li>Invariant 14 + 2 d length </li></ul><ul><li>CL begins, develops, dies </li></ul><ul><li>CL secretes progesterone (also E2, inhibin) as matures </li></ul><ul><ul><li>Progesterone  postov decr LH, FSH (neg feedback) </li></ul></ul><ul><ul><li>Midluteal peak over week </li></ul></ul><ul><ul><li>E2 minimally elevated </li></ul></ul>
  • 15. <ul><li>Hormone secretion diminishes as CL declines </li></ul><ul><ul><li>If no fertilization </li></ul></ul><ul><ul><li>Get sharp decline in plasma progesterone </li></ul></ul><ul><li>Now less neg feedback due to progesterone </li></ul><ul><ul><li> FSH/LH again secreted </li></ul></ul><ul><ul><li>FSH influences new follicle selection, early maturation </li></ul></ul>
  • 16.  
  • 17. Gametogenesis <ul><li>Ovarian follicles named by maturation stage </li></ul><ul><li>Primordial </li></ul><ul><ul><li>Primary oocyte </li></ul></ul><ul><ul><li>Squamous epithelium; single layer </li></ul></ul><ul><ul><ul><li>Dev’s  granulosa cells </li></ul></ul></ul><ul><ul><li>Growth & remodeling </li></ul></ul><ul><ul><li>40  ; oocyte 15-25  </li></ul></ul><ul><ul><li>Quiescent </li></ul></ul>
  • 18.  
  • 19. <ul><li>Primary follicle </li></ul><ul><ul><li>Oocyte enlarges (80-100 m) </li></ul></ul><ul><ul><li>Follicle epithelium </li></ul></ul><ul><ul><ul><li>Simple cuboidal </li></ul></ul></ul><ul><ul><ul><li>“ Granulosa cells” </li></ul></ul></ul><ul><ul><ul><li>Express FSH receptors </li></ul></ul></ul><ul><ul><li>FSH response  organize, stratify granulosa cell layers </li></ul></ul><ul><ul><li>Zona pellucida (glycoprotein layer) deposits </li></ul></ul><ul><ul><li>Stroma begins to organize as theca </li></ul></ul>
  • 20. <ul><li>Secondary=preantral follicle </li></ul><ul><ul><li>Granulosa proliferates, stratifies </li></ul></ul><ul><ul><ul><li>Signaled by oocyte growth factors </li></ul></ul></ul><ul><ul><ul><ul><li>Growth Differentiation Factor 9 (GDF-9) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Bone Morphological Protein 15 (BMP-15) </li></ul></ul></ul></ul><ul><ul><ul><li>Mitosis and/or pattern of arrangement stim’d </li></ul></ul></ul><ul><ul><ul><ul><li>Simple cuboidal  stratified, pseudostratified columnar </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Diff layers have diff morphology, function </li></ul></ul></ul></ul><ul><ul><li>Granulosa cells produce activin </li></ul></ul><ul><ul><ul><li>Stim’s FSH receptor synth </li></ul></ul></ul><ul><ul><li>Granulosa cells become sensitive to FSH </li></ul></ul><ul><ul><ul><li>Impt to selection </li></ul></ul></ul><ul><ul><ul><li>Impt to differentiation </li></ul></ul></ul><ul><ul><ul><li>Impt to maturation </li></ul></ul></ul>
  • 21. Figure 9. The early differentiation of the granulosa cells during preantral folliculogenesis involves the expression of FSH receptors. Animal studies support the concept that this process involves an activin autocrine/paracrine mechanism. (Erickson GF: Dissociation of Endocrine and Gametogenic Ovarian Function. In Lobo, R. (ed.): Perimenopause. Serono Symposia, Springer-Verlaag, 1997. Reproduced with permission from Springer-Verlag, New York.)
  • 22. <ul><li>Secondary follicle – cont’d </li></ul><ul><ul><li>Granulosa cells connected by gap junctions </li></ul></ul><ul><ul><ul><li>Synchronization </li></ul></ul></ul><ul><ul><ul><li>Nutrient transfer </li></ul></ul></ul><ul><ul><li>Basement membr dev’s </li></ul></ul><ul><ul><li>When 6 layers granulosa </li></ul></ul><ul><ul><ul><li>Definitive theca layer </li></ul></ul></ul><ul><ul><ul><li>Angiogenesis  blood supply to theca </li></ul></ul></ul>
  • 23. <ul><li>Secondary follicle (cont’d) </li></ul><ul><ul><li>Final 2 o follicle 100-200  </li></ul></ul><ul><ul><ul><li>Fully grown oocyte w/ zp </li></ul></ul></ul><ul><ul><ul><li>Approx 9 layers granulosa </li></ul></ul></ul><ul><ul><ul><li>Basal lamina </li></ul></ul></ul><ul><ul><ul><li>Theca interna w/ capillary net </li></ul></ul></ul><ul><ul><ul><li>Theca externa </li></ul></ul></ul>
  • 24. Granulosa cells
  • 25. Thecal cells
  • 26. <ul><li>Tertiary=antral follicle </li></ul><ul><ul><li>Chamber </li></ul></ul><ul><ul><li>Follicular fluid contains hormones </li></ul></ul><ul><ul><ul><li>Blood-derived </li></ul></ul></ul><ul><ul><ul><li>From oocyte </li></ul></ul></ul><ul><ul><ul><li>From granulosa cells </li></ul></ul></ul><ul><ul><li>Cavitation signalled by follicle cells </li></ul></ul><ul><ul><li>Corona radiata = granulosa cells anchored to zp </li></ul></ul><ul><ul><li>Theca fully developed </li></ul></ul>
  • 27. <ul><li>Tertiary follicle – cont’d </li></ul><ul><ul><li>Theca interna = steroid producing (androstenedione) </li></ul></ul><ul><ul><ul><li>Extensive sER, cytoplasmic lipid droplets, tubular mitoch cristae </li></ul></ul></ul><ul><ul><ul><li>Receptors for LH, insulin </li></ul></ul></ul><ul><ul><ul><li>Richly vascularized </li></ul></ul></ul><ul><ul><li>Theca externa </li></ul></ul><ul><ul><ul><li>Smooth muscle cells </li></ul></ul></ul><ul><ul><ul><li>Autonomic neurons </li></ul></ul></ul>
  • 28. Figure 12. Photomicrograph of an early tertiary follicle 0.4 mm in diameter at the cavitation or early antrum stage. zona pellucida (ZP); granulosa cells (GC); basal lamina (BL); theca interna (TI); theca externa (TE); granulosa mitosis (arrowheads). (Bloom W, Fawcett DW In A Textbook of Histology. Philadelphia, WB Saunders Company, Philadelphia 1975. With permission from Arnold.)
  • 29. <ul><li>Preovulatory=Graafian follicle </li></ul><ul><ul><li>Now single, dominant follicle </li></ul></ul><ul><ul><li>Overall size varies; deter’d by amt follicular fluid </li></ul></ul><ul><ul><li>Cumulus oophorus = oocyte + corona radiata </li></ul></ul><ul><ul><ul><li>Will be expelled @ ovulation </li></ul></ul></ul><ul><ul><li>Hyaluronic acid accumulates </li></ul></ul><ul><ul><ul><li>Break attachment corona radiata and granulosa </li></ul></ul></ul><ul><ul><li>LH surge induces completion 1 st meiotic division  2 o oocyte </li></ul></ul><ul><ul><ul><li>2 nd meiotic division @ fert’n </li></ul></ul></ul>
  • 30.  
  • 31. Ovulation <ul><li>Induced by LH surge </li></ul><ul><li>Rupture </li></ul><ul><ul><li>Follicle wall </li></ul></ul><ul><ul><li>Follicle cell layers </li></ul></ul><ul><li> Corona radiata w/ oocyte expelled into peritoneal cavity </li></ul>
  • 32.  
  • 33. Luteinization <ul><li>Initiated by LH surge </li></ul><ul><li>CL forms from </li></ul><ul><ul><li>Graunulosa lutein </li></ul></ul><ul><ul><li>Theca lutein </li></ul></ul><ul><ul><li>Assoc’d microvasculature </li></ul></ul><ul><li>Defined life span </li></ul><ul><ul><li>If no fertilization, involution & apoptosis 14 d after form’n </li></ul></ul>
  • 34. <ul><li>Contributes to next developing cohort of follicles </li></ul><ul><ul><li>CL degeneration  decr’d E2, inhibin A </li></ul></ul><ul><ul><li> incr’d FSH </li></ul></ul><ul><ul><li> incr’d FSH in follic fluid of Graafian follicle </li></ul></ul><ul><ul><li> dominant follicle selection, maturation </li></ul></ul>
  • 35. Atresia <ul><li>Remaining 99.9% follicles </li></ul><ul><li>Apoptosis of oocyte, granulosa cells </li></ul><ul><ul><li>Ligand signalling pathways  cell death </li></ul></ul><ul><li>FSH=survival factor </li></ul><ul><ul><li>Prevents apoptosis </li></ul></ul>
  • 36. Ovarian Steroidogenesis <ul><li>Maturing follicles and CL </li></ul><ul><li>Maturing follicles – 2 adjacent impt pop’ns </li></ul><ul><ul><li>Granulosa cells </li></ul></ul><ul><ul><li>Theca interna cells </li></ul></ul><ul><li>CL – impt cells der’d from follicle after ov’n </li></ul><ul><ul><li>Granulosa lutein </li></ul></ul><ul><ul><li>Theca lutein </li></ul></ul>
  • 37. <ul><li>Sex steroids </li></ul><ul><ul><li>Prior to ov’n (from maturing follicle): E2 </li></ul></ul><ul><ul><li>After ov’n (from CL): progesterone + E2 </li></ul></ul><ul><li>Book notes progesterone=distinctive female hormone </li></ul><ul><ul><li>CL and placenta only </li></ul></ul><ul><li>Cell pop’ns coordinate in prod’n sex steroids </li></ul>
  • 38.  
  • 39. <ul><li>Theca (interna & externa) express P450scc </li></ul><ul><ul><li>Cholesterol  pregnenolone </li></ul></ul><ul><ul><li>Sensitive to LH </li></ul></ul><ul><ul><ul><li> cAMP  PKA  StAR  PBR  P450scc activity in inner mitoch membr </li></ul></ul></ul><ul><ul><li>Pregnenolone  androgen pathway </li></ul></ul><ul><ul><ul><li>Uses P450c17 </li></ul></ul></ul><ul><ul><li>Preovulatory LH surge  </li></ul></ul><ul><ul><ul><li>Ovulation </li></ul></ul></ul><ul><ul><ul><li>Luteinization theca interna, granulosa </li></ul></ul></ul><ul><ul><ul><li>Development CL </li></ul></ul></ul>
  • 40. <ul><li>Theca interna express aromatase (androgens  estrogens) </li></ul><ul><ul><li>BUT once ovulation occurs, expression ceases </li></ul></ul><ul><ul><li>So decr’d secr’n estrogens from CL </li></ul></ul>
  • 41. <ul><li>Granulosa cells lack P450scc, P450c17 </li></ul><ul><ul><li>No cholesterol  pregnenolone </li></ul></ul><ul><ul><li>No further androgen synth </li></ul></ul><ul><ul><li>Rely on theca cell androgens </li></ul></ul><ul><ul><li>Insensitive to LH signal for androgen prod’n </li></ul></ul><ul><ul><ul><li>EXCEPT when advanced follicle dev’d </li></ul></ul></ul><ul><ul><ul><ul><li>Just prior to ov’n </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Small numbers LH receptors expressed </li></ul></ul></ul></ul><ul><ul><ul><ul><li>LH stim’s steroidogenesis in these cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Impt to luteinization </li></ul></ul></ul></ul>
  • 42. <ul><li>Granulosa cells – cont’d </li></ul><ul><ul><li>BUT sensitive to FSH </li></ul></ul><ul><ul><ul><li>FSH stim’n  </li></ul></ul></ul><ul><ul><ul><ul><li>Proliferation granulosa cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Secretion inhibin B </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Expression aromatase through cAMP, PKA act’n </li></ul></ul></ul></ul><ul><li>Granulosa cells express aromatase </li></ul><ul><ul><li>Androgens  estrogens </li></ul></ul><ul><ul><li>Most impt source of E2 </li></ul></ul>
  • 43.  
  • 44. <ul><li>Granulosa lutein cells express P450scc </li></ul><ul><ul><li>So can produce pregnenolone </li></ul></ul><ul><li>BUT granulosa lutein cells lack P450c17 </li></ul><ul><ul><li>No androgen synth from pregnenolone </li></ul></ul><ul><ul><ul><li>Rely on theca lutein cells for androgens </li></ul></ul></ul><ul><ul><li>BUT progesterone synth from pregnenolone </li></ul></ul><ul><ul><li>Insensitive to LH signal to produce androgens </li></ul></ul><ul><ul><ul><li>BUT small numbers LH receptors expressed in advanced follicle </li></ul></ul></ul><ul><ul><ul><li>LH  secr’n progesterone, secr’n inhibin A </li></ul></ul></ul>
  • 45. <ul><li>Granulosa lutein cells express aromatase </li></ul><ul><ul><li>Androgens  estrogens </li></ul></ul><ul><ul><li>Activated with LH </li></ul></ul><ul><li>If pregnancy, interrelationships balanced also with placental cells </li></ul>
  • 46.  
  • 47. Endometrial (Uterine) Cycle <ul><li>Coupled to ovarian cycle </li></ul><ul><ul><li>Gametogenesis </li></ul></ul><ul><ul><li>Hormonogenesis </li></ul></ul><ul><li>Three phases </li></ul>
  • 48. <ul><li>Menstruation – during follicular phase </li></ul><ul><ul><li>With demise of CL </li></ul></ul><ul><ul><li>Plasma progesterone decr’d </li></ul></ul><ul><ul><li>Uterine endometrium shed </li></ul></ul><ul><ul><ul><li>Leaves basal portion of endometrial glands </li></ul></ul></ul><ul><ul><li>2-7 d (4 d avg) </li></ul></ul><ul><ul><li>30 mL blood loss avg </li></ul></ul>
  • 49. <ul><li>Proliferative – during follicular phase </li></ul><ul><ul><li>E2 dependent regeneration, growth of endometrium </li></ul></ul><ul><ul><li>E2 receptor binding @ remaining basal stratum  stromal, epithelial cell growth </li></ul></ul><ul><li>Secretory – during luteal phase </li></ul><ul><ul><li>Progesterone-dependent maturation of endometrium </li></ul></ul><ul><ul><li>Requires E2 prep’n endometrium </li></ul></ul><ul><ul><li>Now suitable for blastocyst implantation </li></ul></ul>
  • 50.  
  • 51.  
  • 52.  
  • 53.  
  • 54. Vaginal Cycle <ul><li>After puberty </li></ul><ul><li>In response to estrogens </li></ul><ul><ul><li>Changes w/ menstrual cycle </li></ul></ul><ul><li>Early follicular phase </li></ul><ul><ul><li>Epithelium rounded basal cells </li></ul></ul><ul><li>Late follicular phase – maximum growth </li></ul><ul><ul><li>Basal cells covered w/ flattened cells </li></ul></ul><ul><ul><li>Outermost cells keratinized </li></ul></ul><ul><li>End luteal </li></ul><ul><ul><li>Epith invaded w/ leukocytes, dead cells degen’d </li></ul></ul>

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