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THE ENDOCRINE ASPECTS OF FOLLICULOGENESIS

THE ENDOCRINE ASPECTS OF FOLLICULOGENESIS. Professor IOANNIS E. MESSINIS MD, PhD (Aberdeen, UK) Head of Department of Obs/Gynae University of Thessalia Larissa, GREECE. 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.

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THE ENDOCRINE ASPECTS OF FOLLICULOGENESIS

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

  2. 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

  3. 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

  4. INITIAL RECRUITMENT • IGF-1, EGF, TGF-α, TGF-β, GDNF, KGF, KITL, HGF, PDGF, LIF, BMP-4 • Anti-mullerian hormone (AMH or MIS) • Others (WT1, pRb, myc etc)

  5. ANTI-MULLERIAN HORMONE (AMH) AND FOLLICULOGENESIS IN MICE FSH FSH (-) (-) AMH AMH (+) (+) (-) Primordial Primary Pre-antral Antral Visser & Themmen, 2005 Mol. Cell. Endocrinol. 234, 81-86

  6. FOLLICULOGENESIS (TGF-β family) BMP-2,-5,-6 (+) AMH (-) Inhibin Activin BMP-4 (+) BMP-7 (+) TGF-β Oocyte Granulosa Theca GDF-9 (+) BMP-15 (+) BMP-6 (+) ΑΜΗ (-) Inhibin Activin BMP-2,-5,-6 (+) Knight & Glister, 2006 Reproduction, 132, 191-206

  7. 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

  8. DIFFERENTIATION OF GRANULOSA CELLS Oocyte morphogens FSH receptor High mitotic index IGF-1 HAS2 Cox-2 FSH receptor Cumulus oophorus Periantral FSH receptor LH receptor P450arom Kit ligand u-PA Membrana Erickson & Shimasaki, 2000, TEM, 11, 193-198

  9. 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

  10. 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

  11. “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

  12. 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)

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

  14. 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

  15. 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

  16. ROLE OF IGF-1 HDL/LDL THECA CELL R _ + R C EGF/TGFα + R IGF-1 P450ssc + Pr + + + 3β-HSD R ΤGFβ cAMP PKA _ P P45017α R LH AC GS A + ATP + A cAMP PKA P450arom R E1 FSH AC GS 17βHSD + E2 ATP E2 IGF-1 + GRANULOSA CELL

  17. ROLE OF IGF-2 Androstenedione Testosterone IGF-2 THECA CELL R LH R IGF-2 R FSH GRANULOSA CELL E1, E2 R IGF-2 IGF-2

  18. 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

  19. EFFECT OF ANDROGENS VIA OOCYTE FACTORS 14000 ** DO+IGF1 * 3H-thymidine Incorporation (cpm) GDF9+IGF1 7000 ** * * IGF1 0 C 0 5 50 500 IGF1 DHT (nM) 14000 ** DO+IGF1 3H-thymidine Incorporation (cpm) ** GDF9+IGF1 ** 7000 ** ** IGF1 * 0 Hickey et al., 2005 Biol. Reprod. 73, 825-32 C 0 10 100 1000 IGF1 T (nM) Porcine GC

  20. EFFECT OF ESTROGENS (rat antral follicles) GRANULOSA CELL GRANULOSA CELL R FSH arom R arom FSH (+) R E Adashi and Hsueh 1982 J. Biol. Chem. 257, 6077-83

  21. LEPTIN AND REPRODUCTION HYPOTHALAMUS GnRH + FAT TISSUE PITUITARY + LEPTIN FSH LH ? + OVARY ? Leptin Based on: Messinis & Milingos, 1999 Hum. Reprod. Update 5, 52-63 E2 P4

  22. EFFECT OF LEPTIN (human luteinized granulosa cells) 360000 270000 E2 pmol/l 180000 90000 0 GH IGF-1 GH+L1ng GH+L10ng IGF-1+L1ng GH+L100ng IGF-1+L10ng IGF-1+L100ng Karamouti et al., 2008 Fertil. Steril. 90, 1444-50

  23. GHRELIN AND REPRODUCTION HYPOTHALAMUS GnRH - ? STOMACH PITUITARY -? GHRELIN FSH LH - ? Based on: Messini et al., 2009; Hum. Reprod. Martini et al., 2006; Endocrinology Viani et al., 2008 JCEM OVARY E2 P4

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

  25. 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

  26. 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 Mean values (n=11) Templeton, Messinis & Baird, 1986; Fertil. Steril. 46, 1113-1117

  27. GROWTH OF THE DOMINANT FOLLICLE MIDCYCLE INTERCYCLE FSH LH dependence Intrafollicular regulators 10-12 16 18-20 mm CLASS 5 CLASS 6 CLASS 7 CLASS 8 Messinis 2008; In: Infertility and Assisted Reproduction; Rizk et al., (eds), Cambridge UP

  28. GRANULOSA CELLS IGFs Inhibin/activin Estrogens TGF-β FGF TNF-α IL-1β THECA CELLS BMP-4 BMP-7 TGFα HGF FGF CRH KGF (FGF-7) INTRAFOLLICULAR REGULATORS • GDF-9 • BMP-15 • BMP-6 • ΤΝF-α OOCYTE

  29. ROLE OF THECA-DERIVED BMPs FSH LH 18-20 mm Follicles FSH LH P4 - StAR BMP-4, -7 Th Gr Based on: Tajima, 2007 RBMOnline 15, 591-609 P450 + arom A A E2

  30. LH DEPENDENCE 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)

  31. EXPRESSION LEVEL OF FSHR AND LHR IN IVM-GCs 6  5 FSHR  4 LHR Relative expression 3 2 1 0 C A A+HCG A+FSH A+HCG + FSH Human unluteinized granulosa cells Lindeberg et al., 2007 Hum. Reprod. 22, 401-6

  32. DOMINANT FOLLICLE Gonadotrophin dependence 2 FSHR R²=69.5 P<0.01 DF gene expression relative to reference (log2 transformed) ESR2 1 R²=57.5 P<0.01 0 -1 R²=63.7, P<0.01 -2 LHCGR -3 1 2 3 4 5 6 Days after wave emergence Mihm et al., 2006 Biol. Reprod. 74, 1051-9 (modified) In cattle

  33. 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. 

  34. FSH OR LH? Cetrorelix 3 mg sc E2 LH FSH Follicle diameter 17 mm 0 24 hours Based on: Leroy et al., 1994; Fertil. Steril. 62, 461-7

  35. FSH OR LH? (Follicle growth rate) 20 FD mm 18 16 14 12 10 Spontaneous cycles 8 GnRH antagonist + FSH (from FD 14 mm) 6 4 Spontaneous cycles 2 0 -6 -5 -4 -3 -2 -1 0 DAYS RELATIVE TO HCG

  36. HYPOGONADOTROPHIC HYPOGONADISM 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

  37. 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

  38. 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

  39. FSH CYCLE LUTEAL PHASE FOLLICULAR PHASE LUTEAL PHASE FSH LH • FSH leads the follicles to the pre-ovulatory stage • LH is required for the production of steroids

  40. LH RECEPTORS • FSH is unable to stimulate development of mice early antral follicles to the preovulatory stage in the absence of LHR Pakarainen et al., 2005 Mol. Endocrinol. 19, 2591-2602

  41. DUAL ACTION OF LH ON THECA CELLS AND ‘LH ceiling’ concept LH FSH Luteinization of theca and granulosa cells Steroidogenesis (androstendione) Based on a review by: Tajima, 2007 RBMOnline 15, 591-07

  42. CONCLUSIONS - 1 • Both FSH and LH are important for the final stages of follicle maturation • The action of FSH predominates in the first half and that of LH in the second half of the follicular phase

  43. CONCLUSIONS - 2 • Different intrafollicular regulators are important for the selection and the growth of the dominant follicle • Under pharmacological interventions, FSH is capable to initiate and sustain the growth of the dominant follicle, while LH is required for steroids production

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