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Controllo ormonale della follicologenesi Filippo Maria Ubaldi M.D. M.Sc.

www.generaroma.it. CLINICA VALLE GIULIA, Roma. Controllo ormonale della follicologenesi Filippo Maria Ubaldi M.D. M.Sc. Master in Medicina della Riproduzione 29-30 Maggio 2013. www.generaroma.it. Primordial germ cells migration. Primordial germ cells originate from the entoderm of

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Controllo ormonale della follicologenesi Filippo Maria Ubaldi M.D. M.Sc.

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  1. www.generaroma.it CLINICA VALLE GIULIA, Roma Controllo ormonale della follicologenesi Filippo Maria Ubaldi M.D. M.Sc. Master in Medicina della Riproduzione 29-30 Maggio 2013

  2. www.generaroma.it Primordial germ cells migration • Primordial germ cells originate from the entoderm of the yolk sac around the III week of gestation. • At VI week of gestation the number of the oogonia is about 1000. There is not yet meiotic activity

  3. www.generaroma.it Ovary • At VIII week of gestation the meiotic divisions lead to 600.000 oogonia and three activities are present: mithosis, meiosis and atresia. At XX week of gesta- tion the number of germ cells is 3-6 million • At birth 1-2 million of germ cells are present and at puberty there are left only 300.000 – 400.000 of whom only 400-500 will ovulate

  4. www.generaroma.it Ovarian cortical tissue Age 10-year-old 20-year-old 30-year-old

  5. www.generaroma.it Folliculogenesis Primary follicle Antral follicle Primordialfollicle Preovulatory follicle Preantral follicle Corpus luteum

  6. www.generaroma.it Sviluppo follicolare • Diverse classi follicolari definite in base al numero di • cellule della granulosa osservate: 1)follicoli primordiali: 30-60 mm costituiti da un ovoci- ta in diplotene circondato da un singolo strato di cellule non cubiche (pregranulosa) 2)follicoli primari: >60 mm costituiti da un ovocita pri- mario circondato da un singolo strato di cellule cubiche della granulosa 3) follicoli secondari: 120 mm costituiti da un ovocita primario circondato da diversi strati di cellule della granulosa

  7. Threshold Window FSH Menses RecruitmentSelectionDominance Atresia FOLLICULOGENESIS Ovulazione 50% Atresia VIII 77% 20mm 58% 6 60x10 cg 24% 35% 15% 24% VII 15mm 6 VI 90x10 cg 7mm 6 19x10 cg V 2mm 5 37x10 cg IV LH E2 FSH III 0,9mm 4 II 75x10 cg 0,4mm I 4 0,05mm 0,12mm 0,4mm 15x10 cg M 2 3 1 strato cg 6x10 cg 5x10 cg Primario Preantrale Antrale precoce FSH dipendente FSH LH dipendente Primordiale Crescita tonica Maturazione Reclutamento Selezione 10 gg >150 gg 120 gg 65 gg 10 gg

  8. www.generaroma.it FSH dependent follicular growth Threshold Window FSH Menses VIII Recruitment Selection Dominance PREOVULATORY 20mm 6 60x10 VII Atresia DOMINANT 15mm 6 VI 90x10 cg 7mm 6 19x10 cg V SELECTED 2mm 5 37x10 cg Atresia Atresia IV LH E2 FSH M Late dominance Early dominance Selection Recruitment LATE EARLY MID LATE LUTEAL FOLLICULAR FOLLICULAR FOLLICULAR

  9. www.generaroma.it Primordial Primary Secondary ? ? ? VIII 20mm 6 60x10 cg VII 15mm • Oocyte growth • Granulosa cell proliferation • Theca formation 6 VI 90x10 cg 7mm 6 19x10 cg V 2mm 5 37x10 cg IV LH E2 FSH III 0,9mm 4 II 75x10 cg 0,4mm I 4 0,05mm 0,12mm 0,4mm 15x10 cg M 2 3 1 strato cg 6x10 cg 5x10 cg Primario Preantrale Antrale precoce FSH dipendente FSH LH dipendente Primordiale Crescita tonica Maturazione Reclutamento selezione 10 gg >150 gg 120 gg 65 gg 10 gg

  10. www.generaroma.it Antral formation Early antral (200-300 µm diam) Preantral (<200 µm diam) VIII 20mm 6 60x10 cg FSH VII 15mm 6 VI 90x10 cg 7mm 6 19x10 cg V 2mm 5 37x10 cg IV LH E2 FSH • Granulosa cell proliferation • Follicular fluid formation • Oocyte growth • Thecal cell proliferation • LH receptor expression M FSH dependent FSH LH dependent Maturation 10 gg 10 gg

  11. www.generaroma.it Antral growth Graffian (terziary) (500-700 µm diam) VIII Early antral (200-300 µm diam) 20mm 6 60x10 cg VII FSH 15mm 6 VI 90x10 cg 7mm 6 19x10 cg V 2mm LH 5 37x10 cg IV LH E2 FSH • Granulosa cell proliferation • Follicular fluid formation • Oocyte growth • Thecal cell proliferation M FSH dpendent FSH LH dependent Maturation 10 gg 10 gg

  12. 13 www.generaroma.it FSH Theca cells Androgens ► estradiol A Androgens transferred to granulosa cells A A A A E E E E E E The ‘two-cell, two-gonadotrophin’ theory A Granulosa cells Oocyte maturation Cholesterols ►androgens Follicular growth Estradiol LH-activity Levy 2000; Hillier 1994; Kobayashi 1990; Fevold JCEM,1941

  13. www.generaroma.it Roleof LH What is the importance of LH as an ovarian regulator? Stimulates the enzyme adenylatecyclase synthesis of cAMP activates the enzyme pyruvatekinase and cholesterole transport to the mitochondria where is converted in pre- gnenolone, the rate-determining step in andro- gen biosynthesis Shoham, 1993

  14. www.generaroma.it Roleof LH What is the importance of LH as an ovarian regulator? • Tonic stimulation of thecal androgen production • Mainteins normal follicular oestradiol biosynthesis • Selection of the dominant follicle • Triggers ovulatory LH surge • Luteinisation of granulosa cells • Mainteins corpus luteum

  15. www.generaroma.it Role of LH ? • The optimal amount of LH • The drugs to be used

  16. OUCH ! Watch the ceiling, darling.... Over exposure to LH LH Ceiling(Hillier, 1994) Rec-FSH with GnRH antag. Rec- FSH with GnRH agon. LH deficiency: Hypo-Hypo & older patients OUCH ! Watch the bottom, darling.... Role of LH in follicular development HMG or CC/HMG (PCO Patient) Flare-up GnRHa Protocol LH Threshold

  17. Normal follicular growth and development Paracrine signaling activated by FSH and LH Adequate granulosa cell proliferation Full follicle and oocyte maturation Follicular growth-granulosa cell prolife. (FSH action) Induction of granulosa cell aromatase activity No paracrine signals between gran. and theca layers No androgen synthesis (no estrogens) No full oocyte maturation Role of LH in follicular development Suppression of granulosa cell proliferation Follicular atresia of non dominant follicles Premature luteinisation of pre-ovulatory foll. Oocyte development compromised LH CEILING LH WINDOW LH THRESHOLD

  18. The amount of LH activity actually necessary for normal follicle and oocyte development is unknown, but it is likely to be low, as <1% of follicular LH receptors need to be occupied to allow normal steroidogenesis (Chappel 1991) Role of LH in follicular development LH CEILING LH WINDOW LH THRESHOLD

  19. www.generaroma.it Serum LH “threshold” Serum LH levels remained below 1.0 IU/L in hypo-hypo patients who received 75-225 IU every day of rec-LH together with rec-FSH (The European Rec LH Study group, JCEM, 1998) ?Measurements of serum immunoreactive LH to identify patients with sufficient endo- genous LH to respond adequately to FSH

  20. www.generaroma.it Serum LH “threshold” • LH <0.5 IU/L: no. of oocytes, fertilization and embryo quality rates(Fleming 1998; Janssens 2000) • LH <0.5 IU/L: miscarriage rate(Westergaard 2000) • LH <1.0 IU/L: serum and follicular E2 and T (Fleming 1996) • LH <0.07 IU/L - <0.5 IU/L: impaired reproductive outcome(Fleming 2000; Esposito 2001; Humaiden 2002) • No threshold:(Balash 2001; Cabrera; Bjercke 2005)

  21. www.generaroma.it Role of exogenous LH Clincal results • Older poor responder patients • Some patients treated with FSH and GnRH-a • Some patients treated with FSH and GnRH-ant

  22. www.generaroma.it La crioconservazione nelle azoospermie La crioconservazione nelle azoospermie Master in Medicina della Riproduzione Thank you for your attention

  23. Valle Giulia Clinic, Rome, Italy Early folliculogenesis: implication for human reproductive life span and ovarian failure The first germ cells initiate meiosis at 11–12 weeks of gestation, with subsequent groups of cells entering meiosis over the course of the next several weeks. Oocytes progress through meiotic prophase, undergoing the complex events of synapsi and recombination, and then enter a protracted arrest phase in late prophase Around the time of arrest, oocytes become surrounded by somatic cells (pregranulosa cells), forming primordial follicles Genetic check-point control meccanism Demise of germinal cells Premature ovarian failure and/or accelerated onset of human age-related aneuploidy. The genetic quality of the oocyte meiotic prophase is critical during this developmental window for the formation of primordial follicle

  24. Valle Giulia Clinic, Rome, Italy Primordial to primary follicle transition: regulation of ovulation rate The pre-antral phase of folliculogenesis is characterized by zona pellucida formation, granulosa cell proliferation, which is at first slow, the recruitment of thecal cells to the follicular basal lamina and a dramatic increase in oocyte volume Pre-antral follicle growth is hormonal independent and its regulation predominantly involves direct interactions between granulosa cells and oocytes. The local production of growth factors (TGF-b superfamily) regulate this transition Genetic alteration in oocytes secreted factors OSFs governing this transition, in particular GDF-9 and BMP15, are critical for regulation of ovulation rate and result in high multifollicular rate or ovarian failure(McNatty et al. 2003) Animals heterozygous for null mutations in these genes have higher ovulation rates than wild-type contemporaries, while homozygotics display ovarian failure

  25. Follicular antral growth: OSFs regulate the two cells / two gonadotropins model of steroidogenesis Valle Giulia Clinic, Rome, Italy Follicle progression through the antral stage of development is a gonadotrophins depen- dent phase associated with intense proliferation of granulosa and theca cells, increased thecal vascularisation, further oocyte enlargement and increase in diameter and volume Onceagain oocyte secreted factors regulate the two cells function coordinating follicu- lar growth, including the process of follicle selection, steroidogenesis and maturation OSFs • Regulate the granulosa cell activin- follistatin-inhibin system • Modulate FSH-induced P and E2 synthesis by mural and cumulus granulosa cells • Modulate GCs AMH secretion • ↓ LHR mRNA and ↑aromatase mRNA in CCs Regulation of steroidogenesis Intriguingly, because inhibin acts primarily on the pituitary, the oocyte may indirectly regulate secretion of key endocrine hormones such as FSH

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