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FSH Isoforms : Any Impact on Individualized COH ?

FSH Isoforms : Any Impact on Individualized COH ?. Timur G ü rgan MD Dean and Professor Yeni Yüzyıl University Faculty of Medicine Dept. Of Obsterics and Gynecology Istanbul,Turkey. Is Dialogue Important ?. Dialogue in between couple and clinician

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FSH Isoforms : Any Impact on Individualized COH ?

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  1. FSH Isoforms : Any Impact on Individualized COH ? Timur Gürgan MD Dean and Professor Yeni Yüzyıl University Faculty of Medicine Dept. Of Obsterics and Gynecology Istanbul,Turkey

  2. Is Dialogue Important ? • Dialogue in between couple and clinician • Dialogue in between clinician and embyologist • Dialogue in between cumulus complex and oocyte • Dialogue in between oocyte and sperm • Dialogue in between embryo and endometrium • Dialogue in between fetus and mother • Dialogue in between mother and obstetrician SINGLE HEALTHY CHILD

  3. Structure of FSH FSH is a complex mix of molecules (isoforms) Four Asn-glycosylation sites: Alpha = Asn52 Asn78 Beta = Asn7 Asn24

  4. Oligosaccharide chains structure Sialic Acid Galactose N-Acetyl-Glucosamine Mannose áglycosylation = ásialic acid = áacidity

  5. Low sialic acid content High sialic acid content Basic Isoforms Acidic Isoforms - + Human FSH isoforms according to the point of isoelectricity (pI) pI 6 pI 5 pI 4 pI 3

  6. SummaryWhat are FSH isoforms? • FSH is a family of molecules carrying different amounts of sugars (glycosylation) • Due to their content in sialic acid, more glycosylated molecules are more acidic • Acidity is used in analytical tests • Natural FSH is a wide mix of the different molecules

  7. Oligosaccaride composition of industrial FSH products 0-sialic (%) 1-sialic (%) 2-sialic (%) 3-sialic (%) 4-sialic (%) Fostimon (IBSA) IBSA data on file 2 5 36 41 16 Bravelle (Ferring) Wolfenson 05 <5 2 57 36 <5 Puregon (Organon) De Leeuw 96 43 13 33 9 2 Gonal F (Serono) Driebergen 03 8 30 47 12 3

  8. Fostimon Gonal-F FSH isoforms according to Iso Electro Focusing From Lispi et al., RBMonline 2006

  9. SummaryPhysiological role of FSH isoforms

  10. Pattern of FSH glycosylation during the follicular cycle HG FSH LG FSH Imbalance for HG FSH during the recruitment phase, the opposite at time of ovulation

  11. Sensitive already at 1.5 mg/ml, ceiling already at 5 mg/ml Less acidic (scarce glycosylation) Unselective: All follicles are stimulated Acidic (high glycosylation) Sensitive only at 40 mg/ml, ceiling as high as 100 mg/ml Selective: Only “good” follicles are stimulated Antral follicular threshold for FSH glycoforms (Nayudu et al., RBMonline 2002) Selective recruitment with acidic isoforms

  12. Progressive increase of more biopotent, acidic forms with advancing age Compensative to the general ovarian resistance More precisely, reaction to the pathologic shortening of the early follicular phase Predominance of the very acidic forms in the recruitment phase i.e. luteal-follicular transition and early follicular phases Better selective for good quality follicles Longer (physiolocical) pre-antral phase SummaryNatural pattern of FSH isoform secretion Throughout the reproductive life In the follicular cycle FSH varies over time according to well defined patterns

  13. Company sponsored Multicentre Non-inferiority design to assess efficacy and tolerabiltiy Regulatory purposes EU study USA study Pivotal studies Aim: does Fostimon qualify as a suitable alternative to already existing drugs?

  14. Pivotal studies EU Study: Antoine JMet al. ASRM 2006 - Poster presentation USA study: Baker VL et al. Fertility & Sterility 2009

  15. Pivotal studies, Conclusions In good prognosis patients with a fixed starting dose of gonadotrophin, the authors found no difference between hFSH and rFSH with respect to: • Mean number of oocytes retrieved • Clinical pregnancy rate • Live birth rate • Safety and tolerability The results from the pivotal studies showed totally overlapping results

  16. Pre-antral phase Priming the oocyte for a correct reproductive function • Stimulation with a HG FSH should result in a more selective recruitment and in a slower (physiological) antral phase • A proper pre-antral phase is mandatory for good quality oocytes • DNA imprinting • Genetic synthesis • Proteic synthesis

  17. Investigational questions • Does the pattern of activation of the oocyte genoma really vary according to the (FSH) stimulation regimen? • Are cumulus cells as well sensitive to alternative stimulation types? A new study for a new approach: “Effect of FSH stimulation Regimens on The Pattern of mRNA expression in human Cumulus Cells” Benkhalifa M, Menezo Y, Demirol A, Gurgan T

  18. Least acidic (Puregon) vs Sequential (Fostimon + Puregon) vs Acidic (Fostimon) Day 6 triggering Stimulation Standard long Down regulation Fostimon Puregon Fostimon or Puregon hCG, 10’000 IU 225 IU In this study we investigate the effect on the whole transcriptome of cumulus cells following follicular stimulation with regimens differing in their FSH isoforms composition

  19. Cluster Analysis Analysisper cluster shows modification in mRNAs expression in CC, according to the differenttreatments Itgives a too global response , to be handledwithcare But all FSH are not givingthesameresponse !

  20. By analysing transcriptome profile of cumulus cells from three protocols,we concluded that there are 147 genes involved in the stimulation processes

  21. Green colour means down regulated Red colour means upregulated

  22. Biological processes Involved processes: • mRNA transcription • Protein targeting and localization • Endocytosis • Intracellular signaling cascade • Nucleoside, nucleotide and nucleic acid metabolism • mRNA transcription regulation • Ion transport • Whenwewantedtoanalysebiologicalprocessesdeeplyweobservedinvolvedprocesseswereprimarlyforcellcyclesqualityandcellcyclecommunication (oocyte &CC) No significant variations in biological process

  23. Biological Processes Even if the pathways are not significantlyaffected , Fostimon & PuregonisratherdownregulatingwhereasPuregononlyisupregulating

  24. Molecular Function Involved process : Deacetylase Homeobox transcription factor Acting binding cytoskeletal protein G-Protein Reductase Oxidoreductase Molecular pathways involved the pathways of mRNA transcription,metabolic pathways and antiappoptotic processes to reduce ROS No significant variations in molecular function

  25. Molecular Function Acidicisoformsisratherdownregulatingwhereaslowacidicisoformsisupregulating

  26. Conclusions I • FSH isoforms are likely to play an important phisiological role • The available FSH drug products differ each other in terms of isoform • Clinical data available so far showed interesting outcomes from the sequential use of differently glycosylated FSHs

  27. Conclusion II • Different CHO (controlled hyperstimulation) treatmentsinducedifferentresponses in CC biochemicalpathways • Our data on cumulustranscriptomeprofilingshowedthatthegroup of genesinvolved in thebiologicalfunctionandmolecularprocess can be expresseddifferently on relationwiththeused FSH glycoformsMorestudiesneedto be done ( mainlyproteomics) toeluciatethecontinueddialoguebetweentheoocytesanditssomaticenvironmenttoreachits final maturationandcompetency at ovulation.

  28. Investigational AddressesWhy to use different FSH isoforms ? • To improve the recruitment process • To improve the quality of the oocytes/embryos • To increase the efficiency • Reproductive ageing … • PCOS … • Male indications …

  29. Y.Menezo M. Benkhalifa Shili Ons Jilani Nej MontJean Debbie Unilabs, Paris, Geneve ATL R&D. Reproductive Biology & Genetics Laboratory. Paris France A.Demirol , T.Gurgan & theembryologyTeam Women’sHealthClinic. IVF & Genetics Centre. Ankara. Turkey

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