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PHYSIOLOGY OF FOLLICULOGENESIS

PHYSIOLOGY OF FOLLICULOGENESIS. Professor IOANNIS E. MESSINIS MD, PhD (Aberdeen, UK) Head of Department of Obs/Gynae University of Thessalia Larissa, Greece. OUTLINE. Untreated spontaneous (normal) menstrual cycles Ovarian stimulation. THE HUMAN OVARY. Growing follicle. Primordial

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PHYSIOLOGY OF FOLLICULOGENESIS

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  1. PHYSIOLOGY OF FOLLICULOGENESIS Professor IOANNIS E. MESSINIS MD, PhD (Aberdeen, UK) Head of Department of Obs/Gynae University of Thessalia Larissa, Greece

  2. OUTLINE • Untreated spontaneous (normal) menstrual cycles • Ovarian stimulation

  3. THE HUMAN OVARY Growing follicle Primordial follicle Mature Graafian follicle OVARY Corpus albicans Mature CL Oocyte (egg) Young CL

  4. STAGES OF FOLLICULOGENESIS CLASS 5 CLASS 6 CLASS 4 3-5 mm 6-10 mm 1-2 mm CLASS 3 CLASS 7 12-16 mm 0.9 HUMAN OVARY Early antral 0.2 18-20 mm CLASS 2 Pre-antral 0.1 CLASS 8 CLASS 1 Based on: Gougeon, 1986

  5. FACTORS INVOLVED IN HUMAN FOLLICULAR GROWTH INITIATION OF GROWTH (Not FSH) GONADOTROPHIN DEPENDENT (FSH, LH) TONIC GROWTH PHASE (FSH possibly important) 70 days 15 days 15 days CLASS 1 CLASS 5 CLASS 8 Primor- dial Cyclic recruitment selection Initial recruitment Based on: Gougeon, 1986; Hum. Reprod. 1, 81-87

  6. INTERCYCLE RISE OF FSH FOLLICULAR LUTEAL 6 LH IU/l FSH IU/l 4 2 8 6 4 2 -8 -6 -4 -2 1 3 5 7 DAYS Messinis et al., 1993; Clin. Endocrinol. 38, 159-163

  7. “CYCLIC RECRUITMENT’’ SELECTION Intercycle rise of FSH FSH Follicles 8 mm 10-12 mm 16 mm CLASS 5 CLASS 6 CLASS 7 DOMINANCE RECRUITMENT SELECTION

  8. FSH FSH R R Induction of FSHR cAMP cAMP aromatase R A E1 Chole- sterole LH A T T E2 (-) 5α-reductase 5α-reduced A Theca cell Granulosa cell TWO-CELL TWO-GONADOTROPHIN THEORY (Early follicular phase)

  9. PARACRINE/AUTOCRINE FACTORS • Inhibin, activin • Insulin-like growth factors (IGFs) and IGFBPs • Androgens • Estrogens • Others

  10. ROLE OF INHIBIN/ACTIVIN INHIBIN FSH LH (+) Gr Th E A (+) (-) ACTIVIN ACTIVIN Th: Theca cell Gr: Granulosa cell Based on a review by: Hillier, 2001

  11. FSH ΚΑΙ IGFs IGFs IGFs IGFBP-4 (-) IGFBP-4 PROTEASE (PAPP-A) Granulosa cell (+) E2, P4 and/or LH receptor R (+) (+) R FSH Based on reviews by: Εrickson & Shimasaki 2001; Spicer, 2004

  12. EFFECT OF ANDROGENS (small antral follicles) GRANULOSA CELL GRANULOSA CELL A A R FSH R FSH (+) (+) T DHT (+) R E E Harlow et al., 1986; Endocrinology 119, 1403-05 Weil et al., 1999; JCEM 84, 2951-56

  13. FACTORS FROM THE OOCYTE PREANTRAL FOLLICLES ANTRAL FOLLICLES GDF-9 (+) BMP-15 (GDF-9B) BMP-6 FGF-8 TGF-β2 (-) Granulosa cells Theca cells Reviews: Erickson & Shimasaki, 2000; Erickson & Shimasaki, 2001; Moore & Shimasaki, 2005 OOCYTE

  14. ATRESIARESCUE Androgenic milieu Estrogenic milieu LH FSH aromatase 5α-reductase FOLLICLE GROWTH

  15. SINGLE FOLLICLE SELECTION 15 FSH IU/L E2 pg/ml Intercycle rise 10 5 0 400 300 200 van Santbrink et al., 1995, Fertil. Steril. 100 0 M: menses D: Dominance M D LH peak

  16. FOLLICLE GROWTH IN THE NORMAL CYCLE (Ultrasound) 20 Follicle diameter (mm) 15 10 0 -5 -4 -3 -2 -1 0 +1 DAYS FROM LH SURGE ONSET Templeton, Messinis & Baird, 1986; Fertil. Steril. 46, 1113-1117 Mean values (n=11)

  17. GROWTH OF THE DOMINANT FOLLICLE MIDCYCLE INTERCYCLE FSH 10-12 16 18-20 mm CLASS 5 CLASS 6 CLASS 7 CLASS 8

  18. ROLE OF LH LH FSH R R Induction of LHR cAMP cAMP aromatase R A E1 Chole- sterole LH A T T (-) E2 5α-reductase 5α-reduced A Theca cell Granulosa cell MID- TO LATE FOLLICULAR PHASE (Dominant follicle)

  19. NORMAL CYCLE LH SURGE LUTEAL PHASE FOLLICULAR PHASE Early Mid- Late LUTEAL PHASE FSH • FSH • Aromatase  • E2  • FSHR  • LHR  • GC prolif.  • LH • A  • FSH • Aromatase • E2 • FSHR • LHR • GC prolif.  • LH • A  • E2  • GC prolif. 

  20. OUTLINE • Untreated spontaneous (normal) menstrual cycles • Ovarian stimulation

  21. LESSONS FROMOVARIAN STIMULATION • Anovulation – ovulation induction • PCOS • Hypogonadotrophic-hypogonadism • IVF – superovulation induction • FSH • LH

  22. LESSONS FROMOVARIAN STIMULATION • Anovulation – ovulation induction • PCOS • Hypogonadotrophic-hypogonadism • IVF – superovulation induction • FSH • LH

  23. OVULATION INDUCTION (hypo-, hypo-) FSH (IU/L) Follicle diameter (mm) E2 (pmol/L) 20 Follicle 15 FSH E2 10 5 200 100 0 6 10 15 20 25 30 35 Days recFSH 75 IU Shoham et al., 1993 Fertil. Steril. 59, 738-42 7 14 21

  24. HYPOGONADOTROPHIC HYPOGONADISM (Use of rFSH with rLH) FSH LH E2 IU IU (pmol/l) Couzinet et al., 1988 225 225 2753 (HMG) (HMG) Kousta et al.,1996 150 225 780 El-Shawarby et al., 2004 50-75 75 3155 Based on a review by: Messinis, 2005 Hum. Reprod. 20, 2688-97

  25. HMG PROTOCOL FSH THRESHOLD 5 days 5 days 200+1/3=267 IU 150+1/3=200 IU 150 IU FSH dose (LH) (based on: Brown et al., 1969) E2 Class 5 10-12 mm 18 mm hCG Hypo-, hypo- women Based on : Messinis, 2005, Hum. Reprod. 20,2688-97

  26. WHO GROUP I (rFSH)A dose-finding study of rLH rLH dose HCG Mean E2 Conceptions OHSS (IU/day) (pmol/l) 0 (n=8) 1 65 0 0 25 (n=7) 1 195 0 0 75 (n=9) 5 1392 1 2 225 (n=10) 5 2441 2 3 Adapted from The European Recombinant Human LH Study Group, 1998

  27. Summary • In anovulatory women with : • normal LH levels only exogenous FSH is needed for follicle maturation • extremely low LH levels both exogenous FSH and LH are needed for normal follicle development

  28. LESSONS FROMOVARIAN STIMULATION • Anovulation – ovulation induction • Hypogonadotrophic-hypogonadism • Polycystic ovary syndrome (PCOS) • IVF – superovulation induction • FSH • LH

  29. A) SINGLE FOLLICLE SELECTION B) MULTIPLE FOLLICLE SELECTION FSH WINDOW

  30. INDUCTION OF MULTIPLE FOLLICLES FSH WINDOW (intercycle) MIDCYCLE

  31. INDUCTION OF MULTIPLE FOLLICLES Augmenting FSH rise Follicle selection FSH WINDOW (intercycle) MIDCYCLE

  32. AUGMENTING FSH WINDOW (Messinis et al., 1993; Clin. Endocrinol. 39, 45-50) 20 75 IU 225 IU 450 IU 16 12 FSH IU/L 8 4 0 400  300 E2 pmol/l 200 100 0 0 4 8 12 24 0 4 8 12 24 0 4 8 12 24 Cycle day 2 TIME (hours)

  33. MULTIPLE FOLLICULAR RECRUITMENT (Single follicle development) 24 FSH IU/l 12 0 Control (Sp. Cycles) 8 LH IU/l 4 FSH cycles (450 IU single injection) 0 800 E2 pmol/l 400 0 Cycle days Cycle days 2 3 4 5 6 7 8 Messinis et al., 1994 J. Reprod. Fert. 101, 689-695 FSH 450 IU

  34. AUGMENTING FSH WINDOW Based on: Schipper et al., 1998, JCEM 83, 1292-98 375 IU FSH * 12 * FSH IU/L 8 4 0 13 15 17 19 days Days 14-19 * 12 No of follicles 6 0 8-10 >10 Control cycle Follicle size (mm) FSH cycle

  35. INDUCTION OF MULTIPLE FOLLICLES Augmenting and widening FSH window Follicle selection Follicle maturation FSH WINDOW (intercycle) MIDCYCLE

  36. MULTIPLE FOLLICULAR RECRUITMENT AND MATURATION 20 Lolis et al., 1995, Fertil. Steril. 63, 1272-7 FSH mIUml 18 12 FSH+150 IU 8 FSH+75 IU FSH+0 Control 4 0 800 E2 pg/ml 600 FSH+150 IU FSH+75 IU 400 FSH+0 Control 200 0 450 IU FSH IM • 3 4 5 6 7 8 9 10 • Cycle days

  37. NUMBER OF FOLLICLES AND SERUM E2 VALUES (mean) FOLLICLES CYCLES >10 mm >15 mm E2 (pg/ml) Control (n=13) 1.0 1.0 258 FSH+0 (n=13) 2.6 1.0 250 FSH+75 IU (n=12) 3.2 1.4 460 FSH+150 IU (n=10) 6.0* 2.7* 852* * P<0.001 Lolis et al., 1995

  38. THRESHOLDS OF FSH Threshold of recruitment-selection Threshold of growth-maturation FSH IU/L 12 IU/L 8 IU/L Foll. in order 3rd 2nd 1st FOLLICULAR PHASE

  39. INDUCTION OF MULTIPLE FOLLICLES Widening FSH window Follicle maturation FSH WINDOW (intercycle) MIDCYCLE

  40. WIDENING FSH WINDOW 6 recFSH 4 n=9 2 0 recFSH 75 IU/day 6 recFSH 4 Mean No. of follicles n=10 2 >15 mm 0 12-15 mm 6 recFSH 4 10-12 mm n=5 2 8-10 mm 0 3 5 7 9 HCG Hohmann et al., 2001 Hum. Reprod. 16, 846-54 HCG-1/2 Cycle days

  41. LESSONS FROMOVARIAN STIMULATION • Anovulation – ovulation induction • Hypogonadotrophic-hypogonadism • Polycystic ovary syndrome (PCOS) • IVF – superovulation induction • FSH • LH

  42. CAN LH ALONE INITIATE FOLLICLE GROWTH AND AFFECT THE OUTCOME? 7 days r-hLH treated* (n=49) No r-hLH (n=49) P-value 2-tailed t-test L1 (mm) 8.2 7.3 0.36 S1 (mm) 8.5 8.8 0.77 Embr. (2PN) 5.5 7.0 0.03 Ong. Preg. 37% 38% NS 0.007 Durnerin et al., 2008 Hum. Reprod. 23, 421-6 GnRH-ag * 300 IU/d IVF

  43. LESSONS FROMOVARIAN STIMULATION • Anovulation – ovulation induction • Hypogonadotrophic-hypogonadism • Polycystic ovary syndrome (PCOS) • IVF – superovulation induction • FSH • LH

  44. MULTIPLE FOLLICULAR DEVELOPMENT GnRH LH FSH (basal) Negative feedback E2 Inhibin (-) OVARY Messinis, 2006 Hum. Reprod. Update 12, 557-571

  45. SERUM LH VALUES IN CYCLES TREATED WITH FSH 20 uFSH FSH IU/l rFSH (Gonal-f) 10 0 7 Control LH IU/l rFSH/uFSH 0 10000 E2 pmol/l Messinis et al., 1998 Hum. Reprod. 13, 2415-20 1000 100 Cycle days2 3 4 5 6 7 8 9 10

  46. LH AND FSH VALUES DURING TREATMENT WITH rFSH LH IU/L FSH IU/L 8 20 6 15 4 10 2 5 0 0 1 6 8 10 1 6 8 10 Stimulation day Stimulation day Ganirelix Buserelin (LONG) Borm & Mannaerts, 2000 Hum. Reprod. 15, 1490-1498

  47. FSH vs FSH+LH Live birth rate Favours FSH Favours FSH+LH Kolibianakis et al., Hum Reprod Update. 2007, 13, 445-52

  48. LH IN FOLLICULAR MATURATION 15 FSH IU/L DAY 0 (FD: 14 mm) 10 5 DAY 1 0 DAY 2 (day of HCG) 4 LH IU/L 2 0 2000 E2 pg/ml 1000 Sullivan et al., 1999 JCEM 84, 228-232 FSH up to 14 mm GnRH agonist 0 S FSH LH-H LH-L

  49. FSH LH LH SPONTANEOUS CYCLE LH FSH LH (HCG) FSH CYCLE

  50. CONCLUSIONS (1) • Final follicle maturation is dependent on both gonadotrophins • The role of FSH and LH is different in the spontaneous and the FSH superovulated cycles • Each follicle has two thresholds (recruitment-selection and growth) • Manipulation of FSH thresholds can affect the final number of follicles

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