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Anti- Müllers hormoon : van foetaal tot volwassen leven

VVOG jaarcongres, Brussel 8 & 9 December 2010. Anti- Müllers hormoon : van foetaal tot volwassen leven. Jenny A. Visser Afd. Inwendige Geneeskunde Erasmus MC, Rotterdam Nederland. and. AMH action during sex differentiation. epididymis. testis. vas deferens. T. seminal vesicle.

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Anti- Müllers hormoon : van foetaal tot volwassen leven

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  1. VVOG jaarcongres, Brussel8 & 9 December 2010 Anti-Müllershormoon: van foetaal tot volwassenleven Jenny A. Visser Afd. Inwendige Geneeskunde Erasmus MC, Rotterdam Nederland

  2. and AMH action during sex differentiation epididymis testis vas deferens T seminal vesicle AMH bipotential gonad testis ovary Müllerian duct Wolffian duct ovary Fallopian tube uterus vagina

  3. Gonadal differentiation Undifferentiated Supporting cells Steroidogenic precursors Primordial germ cells Ovary Granulosa cells Theca cells Oocytes Testis Sertoli cells Leydig cells Prospermatogonia

  4. 100 80 60 AMH ng/ml 40 20 0 1-2 2-4 4-6 6-8 8-10 10-12 12-14 14-16 16-18 Age in years AMH levels during childhood Males Females Modified from Lee et al. (2003) Mol Cell Endo211:91-98

  5. Inverse expression pattern of AMH and AR Marmoset Perinatal Infantile (‘childhood’) Pubertal Adult 4 weeks 20 weeks 35 weeks 60 weeks 110 weeks Androgen receptor AMH Modified from Sharpe et al, Reproduction 2003, 125: 769-784

  6. AMH levels in disorders of sex development Rey et al, JCEM 1999, 84: 627-631

  7. Fernando Botero

  8. 100 80 60 AMH ng/ml 40 20 0 1-2 2-4 4-6 6-8 8-10 10-12 12-14 14-16 16-18 Age in years AMH levels during childhood Males Females Modified from Lee et al. (2003) Mol Cell Endo211:91-98

  9. AMH expression in the ovary (mouse)

  10. AMH expression in the ovary (human) primary, secondary small antral <1 mm large antral follicles: 6.1 and 2.5 mm Weenen et al. (2004) Mol Hum Reprod 10:77-83

  11. AMH expression in the ovary Initial recruitment Cyclic recruitment Selection for dominance FSH FSH AMH primordial follicle pool small preantral large preantral small antral large antral preovulatory

  12. 300 2000 * * * * 1500 200 1000 100 500 0 0 300 1200 * * * 1000 * 200 800 * 600 100 400 200 0 0 wt het ko Follicle numbers in AMH null mice primordial follicles non-atrectic follicles 4 months 13 months Durlinger et al (1999) Endocrinology140:5789–5796

  13. Large preantral Small preantral 60 1400 * * 1200 * 50 * *,# * 1000 40 * * 800 number of follicles number of follicles * 30 600 20 400 10 200 0 0 Proestrus Estrus Metestrus Diestrus 1 Diestrus 2 Proestrus Estrus Metestrus Diestrus 1 Diestrus 2 Large antral Small antral 14 60 12 50 *, # 10 40 8 number of follicles number of follicles 30 6 20 4 10 2 0 0 Proestrus Estrus Metestrus Diestrus 1 Diestrus 2 Proestrus Estrus Metestrus Diestrus 1 Diestrus 2 wt ko Enhanced and earlier cyclic recruitment of healthy growing follicles in AMH null mice # *: sig. diff. from wt #: sig.diff. from cycle day P<0.05 Visser et al (2007) Endocrinology148:2301–2308

  14. FSH AMH FSH T AMH Theca cell aromatase T E2 Granulosa cell AMH inhibits FSH sensitivity

  15. * * 250 250 200 200 150 150 E2 (pmol/L) E2 (pmol/L) 100 100 50 50 0 0 Ile/Ile Ile/Ser + Ser/Ser A/A A/G + G/G Estradiol levels in Dutch cohort Dutch women (n=32) mean age: 29.9 years, mean BMI: 22.2 kg/m2 Hormone levels on cycle day 3 AMH Ile49Ser AMHR2 -482 A>G * p < 0.05 Kevenaar et al (2007) Hum Reprod 22: 1547-1554

  16. AMH action in the ovary Initial recruitment Cyclic recruitment Selection for dominance FSH FSH AMH primordial follicle pool small preantral large preantral small antral large antral preovulatory

  17.  AMH as serum marker

  18. AMH and ovarian follicle development Ovulation 7.000.000 FSH sensitivity Growing follicles Apoptotic follicles Recruited follicles AMH production Primordial follicles 1.000.000 Initial recruitment Birth Puberty Menopause Fertile lifespan

  19. 30 20 Follicle number 10 0 0 2 4 6 AMH level (μg/L) AMH levels correlate with AFC r = 0.71, p < 0.001 de Vet et al. (2002) Fertil Steril 77:357-362

  20. AMH levels decline with aging 6 4 r = - 0.40, p = 0.01 AMH level (μg/L) 2 0 <25 25-30 30-35 35 Age (y) de Vet et al (2002) Fertil Steril 77:357-362

  21. Early decline in AMH levels with aging de Vet et al (2002) Fertil Steril 77:357-362

  22. 10 9 8 7 6 AMH (ng/ml) 5 4 3 2 1 0 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 AMH levels during the menstrual cycle 21 women; median age 25.5 yr menstrual cycle day Kevenaar, Visser unpublished results

  23. AMH in women • AMH levels correlate with AFC • AMH levels decline with age • AMH levels are cycle independent • Is AMH a marker for ovarian reserve?

  24. AMH expression in aging mice 4 months 8 months 12 months 16 months Kevenaar et al (2006) Endocrinology 147: 3228-3234

  25. 35 30 25 20 AMH level (ng/ml) 15 10 5 0 prim. foll 1:10 section grow. foll 1: 5 section Follicle numbers decline in aging mice 180 160 140 120 100 number of follicles 80 60 40 20 0 4 6 8 10 12 14 16 18 age (months) Kevenaar et al (2006) Endocrinology 147: 3228-3234

  26. Polycystic Ovary Syndrome Most common endocrine disorder in reproductive age women Prevalence 5-10% in general population Rotterdam Criteria 2003: • Polycystic ovaries • Oligo/amenorrhoea • Hyperandrogenism Other characteristics • Obesity (50%) • Insulin resistance (50%) Complex genetic trait

  27. 30 20 AMH (ng/ml) 10 0 N= 41 22 106 Controls Non-PCO PCO AMH serum levels are elevated in PCOS patients 25 20 15 AMH (ng/ml) 10 5 0 20 30 40 Age WHO2 Controls Laven et al (2004) JCEM 89: 318-323

  28. Summary AMH function • Mullerian duct regression • Leydig cell differentiation • FSH sensitivity • recruitment • FSH sensitivity serum AMH level as marker • ovarian reserve • (IVF outcome, POF, cancer treatment) • PCOS • presence testicular tissue • Sertoli cell function (before puberty)

  29. Acknowledgements Department of Internal Medicine Erasmus MC – Rotterdam The Netherlands Marlies Kevenaar Leonie van Houten Bas Karels Anke McLuskey Piet Kramer Frank H. de Jong Axel P.N. Themmen Jenny A. Visser Joop S.E. Laven, Rotterdam, The Netherlands André G. Uitterlinden, Rotterdam, The Netherlands Nigel Groome, Oxford, UK Manuela Simoni, Modena, Italy

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