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Clomiphene citrate – End of an era?

Clomiphene citrate – End of an era?. Roy Homburg Fertility Symposium, Kfar HaMaccabiah, January 2005. Clomiphene citrate. Starting day “The starting day of treatment, whether on day 2-5 of the cycle, does not influence results” Wu & Winkel, 1989. Dose

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Clomiphene citrate – End of an era?

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  1. Clomiphene citrate –End of an era? Roy Homburg Fertility Symposium, Kfar HaMaccabiah, January 2005

  2. Clomiphene citrate

  3. Starting day “The starting day of treatment, whether on day 2-5 of the cycle, does not influence results” Wu & Winkel, 1989 Dose “…no apparent advantage in using a daily dose of >150mg which neither increases the ovulation rate nor follicular recruitment” Dickey et al, 1997 Clomiphene citrate

  4. Duration of treatment 6 ovulatory cycles recommended No pregnancies after 7 cycles (VUMC) 75% of pregnancies in first 3 cycles Gysler et al, 1982 Clomiphene citrate

  5. Response (ovulation) by dose-Metanalysis of 13 reports % Rostami-Hodjegan et al, 2004

  6. CC - Results • Pregnancy rate - 33% • Miscarriage rate - 25% • Multiple pregnancy rate - 12% Adashi 1979;Dickey 1996;Kousta 1997;Imani 1998; etc

  7. Response to clomiphene No response Ovulation - no pregnancy Ovulation & pregnancy 33%

  8. Failure to ovulate FAI BMI LH Insulin Amenorrhea Non-response to clomiphene

  9. Ovulation but no conception Anti-estrogen effects - cervical mucous - endometrium High LH Reasons for clomiphene failure

  10. CC ER ER ER ER E2 FSH Day 5 Clomiphene Citrate Treatment

  11. Anti-estrogen effect on endometrium • Endometrial thinning in 15-50% (Gonen &Casper, 1990;Dickey et al, 1993) • Causes ER downregulation and depletion. • Suppresses pinopode formation (Creus et al, 2003) • No pregnancies when endometrial thickness at midcycle < 7mm

  12. CC and endometrium • Doses of 50, 75, 100 or 150mg - No significant difference in endometrial thickness. Not dose dependent. • Endometrial suppression recurred in repeat cycles in the same woman. • No pregnancies when endometrial thickness < 8mm.

  13. ER ER ER ER E2 E2 FSH FSH Day 10 Day 5 Clomiphene Citrate Treatment CC CC ER ER ER ER

  14. Results of treatment with CC100 women No response 25 Ovulate 75 No conception 42 Conception 33 Miscarriage 8 Multiple pregs 3 Singleton live birth 22

  15. Induction of ovulation for PCOS- first-line treatment Clomiphene citrate Metformin Aromatase inhibitors FSH/HMG

  16. Metformin for induction of ovulation Alone – modest effect With clomiphene – beneficial (Lord et al, 2003) -- not beneficial (Dutch study, 2005)

  17. Dutch Study 20 centres N=280 PCOS CC + Metformin CC + placebo

  18. CC+metformin vs CC+placebo No difference – • Ovulations • Ongoing pregnancies • Miscarriages

  19. Replacements for CC • Metformin ?? • Aromatase inhibitors ? Rec-FSH !!

  20. CONVENTIONAL REGIMEN WITH GONADOTROPHINS 75 75 75 5 5 5 5 DAYS

  21. Results of conventional therapy14 series, 1966-1984, WHO I & II Hamilton-Fairley & Franks, 1990

  22. Low dose rec-FSH 100-150 IU 75-112.5 IU 50-75 IU 14 7 7 Days

  23. Low dose gonadotropinsSummary of resultsPatients - 841, Cycles 1556 Updated from Homburg & Howles, 1999

  24. Results of treatment with rec-FSH -100 women No response 15 Ovulate 85 No conception 40 Conception 45 Miscarriage 9 Multiple pregs 2 Singleton live birth 34

  25. Comparison of resultsCC vs rec-FSH – 100 women CC rec-FSH 22 Single live births 34 3 Twins 2 BUT……. Low dose rec-FSH has only been given to clomiphene failures!

  26. Projection / 100 women Starting with CC rec-FSH Singleton live births 22 57 Multiples 3 4

  27. Can rec-FSH replace CC? CC recFSH + Ease of administration + Cost = Monitoring = Treatment - pregnancy time + Chances for pregnancy + Single live birth +

  28. Should clomiphene citrate or low dose gonadotropin therapy be the first line treatment for anovulatory infertility WHO II? Randomized, prospective study and cost effectiveness analysis.

  29. COFFI Participants • R.Homburg, Amsterdam • A.Balen, Leeds • R.Ruez, Bogota • A.Martinez, Mendoza • T.d’Hooge, Leuven • M.Brincat, Malta • T.Childs, Oxford • R.Anderson, Edinburgh • M.Davis, London • R.Fleming, Glasgow • R.Rajkhowa, Dundee • J.Farhi, Ashdod

  30. CC or rec-FSH for first-line treatment? PCOS Randomization CC rec-FSH 3 cycles

  31. Induction of ovulation for PCOS- first-line treatment Clomiphene citrate Metformin Aromatase inhibitors FSH/HMG

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