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Controllo ormonale della follicologenesi Filippo Maria Ubaldi M.D. M.Sc. CLINICA VALLE GIULIA, Roma www.generaroma.it Master in Medicina della Riproduzione.

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Presentation on theme: "Controllo ormonale della follicologenesi Filippo Maria Ubaldi M.D. M.Sc. CLINICA VALLE GIULIA, Roma www.generaroma.it Master in Medicina della Riproduzione."— Presentation transcript:

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

2 Primordial germ cells migration www.generaroma.it 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 Ovary www.generaroma.it 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 Ovarian cortical tissue www.generaroma.it 10-year-old20-year-old30-year-old Age

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

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

8 FSH LH E2E2E2E2 Preantrale Antrale precoce FSH dipendente FSH LH dipendente Reclutamento Selezione 10 gg Maturazione Crescita tonica 65 gg 0,4mm 5x10 cg 3 I 0,4mm 15x10 cg 4 II III IV 0,9mm 75x10 cg 4 2mm 2mm 37x10 cg 5 V 7mm 6 19x10 cg VI VII VIII 15mm 90x10 cg 6 20mm 60x10 cg 6 24% 35% 15%24% 58% 77% 50% Atresia Ovulazione FOLLICULOGENESIS Menses Threshold Recruitment Selection Dominance Window Window Atresia FSH M Primordiale Primario 120 gg >150 gg 0,12mm 6x10 cg 2 1 strato cg 0,05mm

9 FSH dependent follicular growth www.generaroma.it Recruitment Selection SELECTED LATE EARLY MID LATE LATE EARLY MID LATE LUTEAL FOLLICULAR FOLLICULAR FOLLICULAR Mense s Threshold Recruitment Selection Dominance Window Window Atresia FSH DOMINANT Early dominance Atresia PREOVULATORY Late dominance Atresia FSH LH E2E2E2E2 IV 2mm 2mm 37x10 cg 5 V 7mm 6 19x10 cg VI VII VIII 15mm 90x10 cg 6 20mm 6 M 60x10

10 www.generaroma.it FSH LH E2E2E2E2 Primordiale PrimarioPreantrale Antrale precoce FSH dipendente FSH LH dipendente Reclutamento selezione 10 gg Maturazione Crescita tonica 65 gg 120 gg >150 gg 0,12mm 6x10 cg 2 1 strato cg 0,4mm 5x10 cg 3 I 0,4mm 15x10 cg 4 II III IV 0,05mm 0,9mm 75x10 cg 4 2mm 2mm 37x10 cg 5 V 7mm 6 19x10 cg VI VII VIII 15mm 90x10 cg 6 20mm 60x10 cg 6 M PrimordialPrimarySecondary Oocyte growth Oocyte growth Granulosa cell proliferation Granulosa cell proliferation Theca formation Theca formation ? ? ?

11 www.generaroma.it FSH LH E2E2E2E2 FSH dependent FSH LH dependent 10 gg Maturation 2mm 2mm 37x10 cg 5 V 7mm 6 19x10 cg VI VII VIII 15mm 90x10 cg 6 20mm 60x10 cg 6 M IV FSH Granulosa cell proliferation Follicular fluid formation Oocyte growth Thecal cell proliferation LH receptor expression Antral formation Preantral (<200 µm diam) Early antral (200-300 µm diam)

12 www.generaroma.it FSH LH E2E2E2E2 FSH dpendent FSH LH dependent 10 gg Maturation 2mm 2mm 37x10 cg 5 V 7mm 6 19x10 cg VI VII VIII 15mm 90x10 cg 6 20mm 60x10 cg 6 M IV FSH Antral growth Graffian (terziary) (500-700 µm diam) Granulosa cell proliferation Follicular fluid formation Oocyte growth Thecal cell proliferation Early antral (200-300 µm diam) LH

13 www.generaroma.it 13 The two-cell, two-gonadotrophin theory Theca cells Cholesterolsandrogens Granulosa cells Androgens transferred to granulosa cells A A A A A A Androgens estradiolFSH Oocyte maturation Follicular growth E E E E E E Estradiol Levy 2000; Hillier 1994; Kobayashi 1990; Fevold JCEM,1941 LH-activity

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

15 www.generaroma.it What is the importance of LH as an ovarian regulator? Role of LH 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

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

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

18 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 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 LH CEILING LH THRESHOLD LH WINDOW

19 Role of LH in follicular development LH CEILING LH THRESHOLD LH WINDOW 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)

20 Serum LH threshold www.generaroma.it 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

21 Serum LH threshold www.generaroma.it LH <0.07 IU/L - <0.5 IU/L: impaired reproductive outcome (Fleming 2000; Esposito 2001; Humaiden 2002) LH <1.0 IU/L: serum and follicular E2 and T (Fleming 1996) 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) No threshold: (Balash 2001; Cabrera; Bjercke 2005)

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

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

24 Valle Giulia Clinic, Rome, Italy 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 Early folliculogenesis: implication for human reproductive life span and ovarian failure 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

25 Valle Giulia Clinic, Rome, Italy 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 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) 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) 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 Animals heterozygous for null mutations in these genes have higher ovulation rates than wild-type contemporaries, while homozygotics display ovarian failure Primordial to primary follicle transition: regulation of ovulation rate regulation of ovulation rate

26 Valle Giulia Clinic, Rome, Italy Follicular antral growth: OSFs regulate the two cells / two gonadotropins model of steroidogenesis OSFs Regulation of steroidogenesis Intriguingly, because inhibin acts primarily on the pituitary, the oocyte may indirectly regulate secretion of key endocrine hormones such as FSH Regulate the granulosa cell activin- Regulate the granulosa cell activin- follistatin-inhibin system follistatin-inhibin system Modulate FSH-induced P and E2 synthesis Modulate FSH-induced P and E2 synthesis by mural and cumulus granulosa cells by mural and cumulus granulosa cells Modulate GCs AMH secretion Modulate GCs AMH secretion LHR mRNA and aromatase mRNA in CCs LHR mRNA and aromatase mRNA in CCs 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 Once again oocyte secreted factors regulate the two cells function coordinating follicu- lar growth, including the process of follicle selection, steroidogenesis and maturation


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