- The document provides information about several genetic polymorphisms related to the hypothalamic-pituitary-gonadal axis, including the LH receptor, FSH receptor, and GnRH1. - It discusses two common polymorphisms in the FSH receptor gene - the N680S variation is associated with higher FSH levels and altered ovarian response to FSH stimulation. - The LH receptor gene contains a common insertion/deletion polymorphism of two amino acids (LQ) in the signal peptide. Studies found the LQ variant is associated with decreased disease-free survival in breast cancer patients.

2. Consulting, research funding and lecture fees from: Schering Plough (Organon), P & G, Ferring, Grunenthal, Besins Health Int, HRA Pharma,Wyeth, Pfizer, Ferring, Preglem SA, Pierre Fabre.- Consulting: HAS, AFSSAPS, WHO, EMEA

3. 1- Nouveautés dans la physiopathologie du SOPK

4. Lean Obese 200 Insulin 100 30 60 90 30 60 90 120 Minutes Morphology Syndrome Endocrinology Ultrasound Metabolic 1935 1963 1980 1988 1990 Balen, HRU 2003 Yen, JCEM 80 LH FSH Lobo, JCEM 83 AD DHEA Stein Leventhal Axelrod & Goldzieher, 1963 (187 references, 1079 cases Dunaif, JCEM 83 0 C PCO HPD T ng/ml DHEAS 1

5. PCOS 1- Excessovarianandrogen production 2- Insulinresistance and highinsulinlevels

6. Vendola KA JCI 12:2622 1998

7. S Franks International J of Obesity, 2008, 32: 1035- 41.

8. JCR: LA- cp rodent model ObR defect: malfunction of the leptin R Endocrinology 2009

9. FIG. 1. A-C, Ovarian sections from the JCR:LA-cp rats CTRL cp/cp ctrl cp/cp cp/cp cp/cp Shi, D. et al. Endocrinology 2009;150:4425-4436 Copyright ©2009 The Endocrine Society

15. 2- Prédictions de réussite des traitements d’infertilité

16. FIG. 1. Live birth prediction chart for method of ovulation induction using clinical measures Rausch, M. E. et al. J Clin Endocrinol Metab 2009;94:3458-3466 Copyright ©2009 The Endocrine Society

17. FSH and LH receptor polymorphisms Polymorphisms are gene DNA variants that exist in the normal population at a frequency of 1% or more Mainly in the form of so-called single nucleotidepolymorphisms (SNPs).

18. Bouligand J et al NEJM, 2009

19. Polymorphisms: GnRH1 A polymorphism in the first exon of GnRH 1has been described, constituting an aminoacid variation at codon 16 (Trp16Ser). Results are contradictory in terms of Estrogenexposure.

20. - NH 2 - COOH insLLKLLLLLQ -> ** LeuGlu Val144Phe Cys133Arg Phe194Val Deletion of: Asn291Ser Exon 8 -> * Exon 10 -> Cys343Ser * Glu354Lys Asn312Ser Trp491Stp Ala593Pro Leu368Pro Leu608/Val609 D Ile542Leu Ala373Val insT->fs Cys581Arg Ser616Tyr Asp578Tyr /Glu/Gly/His Ile625Lys Met398Thr Ile374Thr Thr577Ile Ile575Leu Leu457Arg Thr392Ile Cys545Stp Ala572Val Asp564Gly Met571Ile Ala568Val Arg554Stp APN Themmen Cys543Arg

21. LHR polymorphisms 282 SNPshave been identified Most are located in large introns, which account for more than 95% of the LHR gene The most frequent polymorphisms is the absence or presence of a 2 aminoacid insertion at positon 18 in exon 1, And 2 variable aminoacids in postions 291 and 312: 291 NS, and 312 SN in exon 10.

22. LH receptor polymorphisms LQ (Leu-Gln) insertion at pos 18 in signal peptide N291S - glycosylation site N312S - near glycosylation site others silent (no AA change)

23. Human LH receptor LQ (signal peptide) N291S N312S APN Themmen

24. LH receptor LQ variant and breast cancer 751 breast cancer cases median 130 months follow-up LQ not a risk allele disease free survival

25. Disease Free Survival 100 75 Disease free survival (%) 50 25 Logrank P=.003 0 180 months -LQ +LQ APN Themmen

26. Disease Free Survival 100 premenopausal 75 Disease free survival (%) 50 25 Logrank P=.009 0 180 months -LQ +LQ

27. Disease Free Survival 100 postmenopausal 75 Disease free survival (%) 50 25 Logrank P=.12 0 180 months -LQ +LQ

28. Disease Free Survival 100 BMI >27.5 75 Disease free survival (%) 50 25 Logrank P=.02 0 180 months -LQ +LQ

29. Disease Free Survival 100 BMI 27.5 75 Disease free survival (%) 50 25 Logrank P=.03 0 180 months -LQ +LQ

30. Functional studies LQ variant: EC 50 250000 225000 insLQ-LHR 200000 delLQ-LHR 175000 150000 [RLU/bgal] 125000 0.4 0.4 P=0.0154 ) ) 100000 ßgal ßgal 0.3 0.3 75000 0.2 0.2 log EC50 (RLU/ log EC50 (RLU/ 50000 0.1 0.1 25000 0 0.0 0.0 0.01 0.1 1 10 100 1000 LHR +LQ LHR +LQ LHR - LQ LHR - LQ [hCG (ng/ml)]

31. Functionalstudies LQ variant: B max P = 0.0006 4.0 3.5 3.0 2.5 Bmax (fmol/RL) 2.0 1.5 1.0 0.5 0.0 +LQ -LQ

32. Polymorphisms: LHR In addition, Exon 10 of LHR contains 2 coding SNPs that cause a change in amino acids: Asn 291Ser and Ser312Asn). Asn312 has been associated with increased rik of BC (piersma 2007) suggesting a more active LHR; Similarly, a lower frequency of the Asn312 allele has been described in infertile men with impaired spermatogenesis (Simoni 2008).

33. FSHR polymorphisms The FSHR harbours more than 900 SNPsarranged in two major linkage disequilibrium blocks.

35. Polymorphisms: FSHR (p.N680S) Simoni et al 1999 Perz Mayorga 2000 Sudo 2002 De Castro 2003, 2004 Laven 2003 Behre 2005 Falconer 2005 Jun 2006 Loutradis 2006 De Koning 2006, Yang 2006

37. Polymorphisms: FSHR A well known combination of two polymorphisms has been described in exon 10 of the FSHR gene As coding SNPs at codon position 307 and 680 (Simoni 1999). The minor allele at position 680 (Ser 680) is associated with significantly higher levels of FSH, and altered ovarian response to FSH: N680S or N/N vs S/S (Perez Mayorga 2000)

38. Polymorphisms: FSHR Ser/Asn 680 Higher frequency of Ser 680 has been reported in anovulatorysubjects (Laven 2003). However, although the FSHR is less responsive, this polymorphismdoes not modify the response to exogenous FSH.

39. N680S

42. Polymorphisms: PCOS: The most striking association was observed with FSHR

43. Polymorphisms: Ser 680 in PCOS This variant did not constitue a risk allelle for PCOS, And no association was found with the number of antral follicules or with AMH levels. FSH levels were increased in carriers but also LH levels.

44. Polymorphisms: PCOS The contributions of these polymorphisms to the phenotype of PCOS is small and may only be relevant in conjunction with other genetic variants that contribute to minor phenotypical variation (Simoni 2008).

45. 3- traitement des Bouffées de chaleur ???

46. Randomised, double blind study comparing efficacy and tolerance of venlafaxine vs medroxyprogesterone acetate vs cyproterone acetate for vasomotor hot flushes in men on GnRH-analogs for prostate cancer. Jacques Irani1, Laurent Salomon2, Rostand Oba3, Philippe Bouchard4 , Nicolas Mottet5

48. VLF = venlafaxine LP - CYP = cyproterone acetate - MPR = medroxyprogesterone acetate

50. Table 3 –Relative score changes according to the hot-flush diary: P-value adjusted by Bonferroni method of two-by-two comparison of treatment groups

53. 4- Quiz

55. Vous avez dit KiSS !Why Kiss or KiSS ?

58. KiSS