Dydrogesterone use in early pregnancy

Fadi Ghazi Mirza, Ameet Patki, Claire Pexman-Fieth

Abstract


Successful oocyte implantation and a favorable pregnancy outcome rely on optimal progesterone levels. Therefore, progesterone deficiencies associated with infertility and miscarriage have commonly been treated with progestogens that mimic the activity of progesterone. Among those is dydrogesterone, an oral retrosteroid with a structure closely related to that of progesterone yet with a greater bioavailability and higher selectivity for the progesterone receptor.

Dydrogesterone has been marketed since the 1960s and has been extensively used worldwide for the treatment of threatened miscarriage and recurrent miscarriage, as well as for luteal phase support in the setting of infertility. Additionally, dydrogesterone is approved for hormone replacement therapy, as well as pregnancy and non-pregnancy-related conditions where there is a progesterone deficiency.

This review describes the efficacy of dydrogesterone for the treatment of threatened and recurrent miscarriage, and infertility due to luteal phase insufficiency. Data from clinical trials evaluating dydrogesterone in assisted reproductive technology are also discussed.

Prospective clinical trials, systematic reviews and meta-analyses have demonstrated that dydrogesterone significantly improves pregnancy outcomes in women with threatened miscarriage or with a history of miscarriage. Although this is not yet a registered indication, dydrogesterone was as effective as vaginal micronized progesterone for luteal phase support in the setting of assisted reproductive technology. The safety and tolerability of dydrogesterone treatment in pregnant women are also briefly addressed and the data support a wellestablished and favorable risk-benefit profile.

According to recent systematic reviews and meta-analyses, dydrogesterone appears to be superior to vaginal micronized progesterone for the treatment of threatened miscarriage and with a history of miscarriage. Given its effectiveness as well as its well-established and favorable risk-benefit profile, wider potential benefits of dydrogesterone therapy (currently being investigated in phase III studies for insufficiency of the luteal phase in assisted reproductive technology) are highly anticipated.


Keywords


assisted reproductive technology; dydrogesterone; luteal phase support; pregnancy; progestogen; threatened miscarriage; recurrent miscarriage

References


“First trimester endocrinology: consequences for diagnosis and treatment of pregnancy failure.” Gynecol Endocrinol 18 (2004): 51–7.

Szekeres-Bartho, J., Barakonyi, A., Par, G., et al. “Progesterone as an immunomodulatory molecule.” Int Immunopharmacol 1 (2001): 1037–48.

Schindler, A.E. “Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium.” Maturitas 65 (2009): 3–11.

Blacker, C.M., Ginsburg, K.A., Leach, R.E., et al. “Unexplained infertility: evaluation of the luteal phase; results of the National Center for Infertility Research at Michigan.” Fertil Steril 67 (1997): 437–42.

Baird, D.D., Wilcox, A.J., Weinberg, C.R., et al. “Preimplantation hormonal differences between the conception and non-conception menstrual cycles of 32 normal women.” Hum Reprod 12 (1997): 2607–13.

Csapo, A.I., Pulkkinen, M.O., Ruttner, B., et al. “The significance of the human corpus luteum in pregnancy maintenance. I. Preliminary studies.” Am J Obstet Gynecol 112 (1972): 1061–7.

Couzinet, B., Le Strat, N., Ulmann, A., et al. “Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone).” N Engl J Med 315 (1986): 1565–70.

Spitz, I.M., Bardin, C.W. “Clinical pharmacology of RU 486 – an antiprogestin and antiglucocorticoid.” Contraception 48 (1993): 403–44.

de Lignieres, B. “Oral micronized progesterone.” Clin Ther 21 (1999): 41–60.

Di Renzo, G.C., Mattei, A., Gojnic, M., Gerli, S. “Progesterone and pregnancy.” Curr Opin Obstet Gynecol 17 (2005): 598–600.

Chakravarty, B.N., Shirazee, H.H., Dam, P., et al. “Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.” J Steroid Biochem Mol Biol 97 (2005): 416–20.

Stanczyk, F.Z., Hapgood, J.P., Winer, S., Mishell, D.R. Jr. “Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.” Endocr Rev 34 (2013): 171–208.

Kanova, N., Bicikova, M. “Hyperandrogenic states in pregnancy.” Physiol Res 60 (2011): 243–52.

Rizner, T.L., Brozic, P., Doucette, C., et al. “Selectivity and potency of the retroprogesterone dydrogesterone in vitro.” Steroids 76 (2011): 607–15.

Wang, M.H., Baskin, L.S. “Endocrine disruptors, genital development, and hypospadias.” J Androl 29 (2008): 499–505.

Coppola, P.T., Coppola, M. “Vaginal bleeding in the first 20 weeks of pregnancy.” Emerg Med Clin North Am 21 (2003): 667–77.

Everett, C. “Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice.” BMJ 315 (1997): 32–4.

Qureshi, N.S. “Treatment options for threatened miscarriage.” Maturitas 65 (2009): 35–41.

Weiss, J.L., Malone, F.D., Vidaver, J., et al. “Threatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study.“ Am J Obstet Gynecol 190 (2004): 745–50.

Verma, S.K., Premi, H.K., Gupta, T.V., et al. “Perinatal outcome of pregnancies complicated by threatened abortion.” J Indian Med Assoc 92 (1994): 364–5.

Arck, P.C., Rucke, M., Rose, M., et al. “Early risk factors for miscarriage: a prospective cohort study in pregnant women.” Reprod Biomed Online 17 (2008): 101–13.

Aleman, A., Althabe, F., Belizan, J., Bergel, E. “Bed rest during pregnancy for preventing miscarriage.” Cochrane Database Syst Rev 2 (2005): CD003576.

Devaseelan, P., Fogarty, P.P., Regan, L. “Human chorionic gonadotrophin for threatened miscarriage.” Cochrane Database Syst Rev 5 (2010): CD007422.

Wahabi, H.A., Fayed, A.A., Esmaeil, S.A., Al Zeidan, R.A. “Progestogen for treating threatened miscarriage.” Cochrane Database Syst Rev 12 (2011): CD005943.

Pandian, R.U. “Dydrogesterone in threatened miscarriage: a Malaysian experience.” Maturitas 65 (2009): 47–50.

Omar, M.H., Mashita, M.K., Lim, P.S., Jamil, M.A. “Dydrogesterone in threatened abortion: pregnancy outcome.” J Steroid Biochem Mol Biol 97 (2005): 421–5.

El-Zibdeh, M.Y., Yousef, L.T. “Dydrogesterone support in threatened miscarriage.” Maturitas 65 (2009): 43–6.

Ehrenskjold, M.L., Bondo, B., Weile, F. “Treatment of threatened abortion with dydrogesterone.” 129 Ugeskr Laeger (1967): 1678–9.

Misto, A. “Experiences with 6-dehydro-retroprogesterone in the treatment of placental insufficiency.” Ann Obstet Ginecol Med Perinat 89 (1967): 102–12.

Czajkowski, K., Sienko, J., Mogilinski, M., et al. “Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone.” Fertil Steril 87 (2007): 613–8.

Carp, H. “A systematic review of dydrogesterone for the treatment of threatened miscarriage.” Gynecol Endocrinol 28 (2012): 983–90.

Vincze, E., Molnar, G.B., Foldesi, I., Pal, A. “Treatment possibilities for threatened abortion using progesterone and progesterone-type drugs.” Magyar Noorvosok Lapja 69 (2006): 281–4.

National Institute for Health and Care Excellence (NICE). “Ectopic pregnancy and miscarriage. Diagnosis and initial management in early pregnancy of ectopic pregnancy and miscarriage (2012 Dec).” Available from: [https://www.nice.org. uk/guidance/cg154/resources/guidance-ectopic-pregnancyand- miscarriage-pdf], last accessed Aug 24, 2015.

The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Progesterone support of the luteal phase and in the first trimester. 13 A.D. Jul. Available from: [http://www.ranzcog. edu.au/doc/progesterone-support-of-the-luteal-phase-andearlypregnancy. html], last accessed Aug 24, 2015.

Schindler, A.E., Carp, H., Druckmann, R., et al. “European Progestin Club Guidelines for prevention and treatment of threatened or recurrent (habitual) miscarriage with progestogens.” Gynecol Endocrinol 31 (2015): 447–9.

Arab, H., Alsofayan, H., Alharbi, A., et al. “The Saudi Obstetrics and Gynecological Society (SOGS) National Guidelines for the Prevention and Treatment of Miscarriage.” Saudi J Obstet Gynecol 15 (2014): 40–64.

Practice Committee of Amrican Society for Reproductive Medicine. “Definitions of infertility and recurrent pregnancy loss: a committee opinion.” Fertil Steril 99 (2013): 63.

Royal College of Obstetricians and Gynaecologists. The Investigation and Treatment of Couples with Recurrent Firsttrimester and Second-trimester Miscarriage. Green-top Guideline No. 17. 2011 Apr. Available from: [https://www.rcog. org.uk/globalassets/documents/guidelines/gtg_17.pdf], last accessed Aug 24, 2015.

Garrido-Gimenez, C., Alijotas-Reig, J. “Recurrent miscarriage: causes, evaluation and management.” Postgrad Med J 91 (2015): 151–62.

Jauniaux, E., Farquharson, R.G., Christiansen, O.B., Exalto, N. “Evidencebased guidelines for the investigation and medical treatment of recurrent miscarriage.” Hum Reprod 21 (2006): 2216–22.

El-Zibdeh, M.Y. “Dydrogesterone in the reduction of recurrent spontaneous abortion.” J Steroid Biochem Mol Biol 97 (2005): 431–4.

MacDonald, R.R., Goulden, R., Oakey, R.E. “Cervical mucus, vaginal cytology and steroid excretion in recurrent abortion.” Obstet Gynecol 40 (1972): 394–402.

Kumar, A., Begum, N., Prasad, S., et al. “Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial.” Fertil Steril 102 (2014): 1357–63.

Ghosh, S., Chattopadhyay, R., Goswami, S., et al. “Assessment of subendometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study.” J Obstet Gynaecol Res 40 (2014): 1871–6.

Carp, H. “A systematic review of dydrogesterone for the treatment of recurrent miscarriage.” Gynecol Endocrinol 31 (2015): 422–30.

Freedman, R.S., Berry, A. “Progesterone deficiency in preganancy.” S Afr J Obstet Gynaecol 46 (1970): 72–6.

Haas, D.M., Ramsey, P.S. “Progestogen for preventing miscarriage.” Cochrane Database Syst Rev 10 (2013): CD003511.

El-Mashad, A.I., Mohamed, M.A., Farag, M.A., et al. “Role of uterine artery Doppler velocimetry indices and plasma adrenomedullin level in women with unexplained recurrent pregnancy loss.” J Obstet Gynaecol Res 37 (2011): 51–7.

Coomarasamy, A., Williams, H., Truchanowicz, E., et al. “A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.” N Engl J Med 373 (2015): 2141–8.

Abbott B.V. Duphaston 10mg Film-Coated Tablets Summary of Product Characteristics; 2012.

Bulletti, C., de Ziegler, D., Flamigni, C., et al. “Targeted drug delivery in gynaecology: the first uterine pass effect.” Hum Reprod 12 (1997): 1073–9.

Choi, T.Y., Lee, H.M., Park, W.K., et al. “Spontaneous abortion and recurrent miscarriage: a comparison of cytogenetic diagnosis in 250 cases.” Obstet Gynecol Sci 57 (2014): 518–25.

Practice Committee of the American Society for Reproductive Medicine. “Current clinical irrelevance of luteal phase deficiency: a committee opinion.” Fertil Steril 103 (2015): 27–32.

Balasch, J., Vanrell, J.A., Marquez, M., et al. “Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency.” Fertil Steril 37 (1982): 751–4.

Gidley-Baird, A.A., O’Neill, C., Sinosich, M.J., et al. “Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/ estrogen ratios in humans and mice.” Fertil Steril 45 (1986): 69–74.

van der Linden, M., Buckingham, K., Farquhar, C., et al. “Luteal phase support for assisted reproduction cycles.” Cochrane Database Syst Rev 7 (2015): CD009154.

Kupferminc, M.J., Lessing, J.B., Amit, A., et al. “A prospective randomized trial of human chorionic gonadotrophin or dydrogesterone support following in-vitro fertilization and embryo transfer.” Hum Reprod 5 (1990): 271–3.

Patki, A., Pawar, V.C. “Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone.” Gynecol Endocrinol 23 (2007): 68–72.

Ganesh, A., Chakravorty, N., Mukherjee, R., et al. “Comparison of oral dydrogestrone with progesterone gel and micronized progesterone for luteal support in 1,373 women undergoing in vitro fertilization: a randomized clinical study.” Fertil Steril 95 (2011): 1961–5.

Salehpour, S., Tamimi, M., Saharkhiz, N. “Comparison of oral dydrogesterone with suppository vaginal progesterone for lutealphase support in in vitro fertilization (IVF): a randomized clinical trial.” Iran J Reprod Med 11 (2013): 913–8.

Tomic, V., Tomic, J., Klaic, D.Z., et al. “Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial.” Eur J Obstet Gynecol Reprod Biol 186 (2015): 49–53.

van der Linden, M., Buckingham, K., Farquhar, C., et al. “Luteal phase support for assisted reproduction cycles.” Cochrane Database Syst Rev 10 (2011): CD009154.

Podzolkova, N., Tatarchuk, T., Doshchanova, A., et al. “Dydrogesterone treatment for menstrual-cycle regularization in routine clinical practice: a multicenter observational study.” Gynecol Endocrinol 2015, DOI: 10.3109/09513590.2015.1115832

Queisser-Luft, A. “Dydrogesterone use during pregnancy: overview of birth defects reported since 1977.” Early Hum Dev 85 (2009): 375–7.

Medicines and Healthcare products Regulatory Agency (MHRA). MHRA UK Public Assessment Report. Efficacy of progestogens in the maintenance of early pregnancy in women with threatened miscarriage or recurrent miscarriage (Feb 2008). Available from: [http://www.mhra.gov.uk/home/groups/s-par/documents/ websiteresources/con079333.pdf], last accessed Aug 24, 2015.


GOST Style Citations


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2. Szekeres-Bartho, J., Barakonyi, A., Par, G., et al. “Progesterone as an immunomodulatory molecule.” Int Immunopharmacol 1 (2001): 1037–48.

3. Schindler, A.E. “Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium.” Maturitas 65 (2009): 3–11.

4. Blacker, C.M., Ginsburg, K.A., Leach, R.E., et al. “Unexplained infertility: evaluation of the luteal phase; results of the National Center for Infertility Research at Michigan.” Fertil Steril 67 (1997): 437–42.

5. Baird, D.D., Wilcox, A.J., Weinberg, C.R., et al. “Preimplantation hormonal differences between the conception and non-conception menstrual cycles of 32 normal women.” Hum Reprod 12 (1997): 2607–13.

6. Csapo, A.I., Pulkkinen, M.O., Ruttner, B., et al. “The significance of the human corpus luteum in pregnancy maintenance. I. Preliminary studies.” Am J Obstet Gynecol 112 (1972): 1061–7.

7. Couzinet, B., Le Strat, N., Ulmann, A., et al. “Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone).” N Engl J Med 315 (1986): 1565–70.

8. Spitz, I.M., Bardin, C.W. “Clinical pharmacology of RU 486 – an antiprogestin and antiglucocorticoid.” Contraception 48 (1993): 403–44.

9. de Lignieres, B. “Oral micronized progesterone.” Clin Ther 21 (1999): 41–60.

10. Di Renzo, G.C., Mattei, A., Gojnic, M., Gerli, S. “Progesterone and pregnancy.” Curr Opin Obstet Gynecol 17 (2005): 598–600.

11. Chakravarty, B.N., Shirazee, H.H., Dam, P., et al. “Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.” J Steroid Biochem Mol Biol 97 (2005): 416–20.

12. Stanczyk, F.Z., Hapgood, J.P., Winer, S., Mishell, D.R. Jr. “Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.” Endocr Rev 34 (2013): 171–208.

13. Kanova, N., Bicikova, M. “Hyperandrogenic states in pregnancy.” Physiol Res 60 (2011): 243–52.

14. Rizner, T.L., Brozic, P., Doucette, C., et al. “Selectivity and potency of the retroprogesterone dydrogesterone in vitro.” Steroids 76 (2011): 607–15.

15. Wang, M.H., Baskin, L.S. “Endocrine disruptors, genital development, and hypospadias.” J Androl 29 (2008): 499–505.

16. Coppola, P.T., Coppola, M. “Vaginal bleeding in the first 20 weeks of pregnancy.” Emerg Med Clin North Am 21 (2003): 667–77.

17. Everett, C. “Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice.” BMJ 315 (1997): 32–4.

18. Qureshi, N.S. “Treatment options for threatened miscarriage.” Maturitas 65 (2009): 35–41.

19. Weiss, J.L., Malone, F.D., Vidaver, J., et al. “Threatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study.“ Am J Obstet Gynecol 190 (2004): 745–50.

20. Verma, S.K., Premi, H.K., Gupta, T.V., et al. “Perinatal outcome of pregnancies complicated by threatened abortion.” J Indian Med Assoc 92 (1994): 364–5.

21. Arck, P.C., Rucke, M., Rose, M., et al. “Early risk factors for miscarriage: a prospective cohort study in pregnant women.” Reprod Biomed Online 17 (2008): 101–13.

22. Aleman, A., Althabe, F., Belizan, J., Bergel, E. “Bed rest during pregnancy for preventing miscarriage.” Cochrane Database Syst Rev 2 (2005): CD003576.

23. Devaseelan, P., Fogarty, P.P., Regan, L. “Human chorionic gonadotrophin for threatened miscarriage.” Cochrane Database Syst Rev 5 (2010): CD007422.

24. Wahabi, H.A., Fayed, A.A., Esmaeil, S.A., Al Zeidan, R.A. “Progestogen for treating threatened miscarriage.” Cochrane Database Syst Rev 12 (2011): CD005943.

25. Pandian, R.U. “Dydrogesterone in threatened miscarriage: a Malaysian experience.” Maturitas 65 (2009): 47–50.

26. Omar, M.H., Mashita, M.K., Lim, P.S., Jamil, M.A. “Dydrogesterone in threatened abortion: pregnancy outcome.” J Steroid Biochem Mol Biol 97 (2005): 421–5.

27. El-Zibdeh, M.Y., Yousef, L.T. “Dydrogesterone support in threatened miscarriage.” Maturitas 65 (2009): 43–6.

28. Ehrenskjold, M.L., Bondo, B., Weile, F. “Treatment of threatened abortion with dydrogesterone.” 129 Ugeskr Laeger (1967): 1678–9.

29. Misto, A. “Experiences with 6-dehydro-retroprogesterone in the treatment of placental insufficiency.” Ann Obstet Ginecol Med Perinat 89 (1967): 102–12.

30. Czajkowski, K., Sienko, J., Mogilinski, M., et al. “Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone.” Fertil Steril 87 (2007): 613–8.

31. Carp, H. “A systematic review of dydrogesterone for the treatment of threatened miscarriage.” Gynecol Endocrinol 28 (2012): 983–90.

32. Vincze, E., Molnar, G.B., Foldesi, I., Pal, A. “Treatment possibilities for threatened abortion using progesterone and progesterone-type drugs.” Magyar Noorvosok Lapja 69 (2006): 281–4.

33. National Institute for Health and Care Excellence (NICE). “Ectopic pregnancy and miscarriage. Diagnosis and initial management in early pregnancy of ectopic pregnancy and miscarriage (2012 Dec).” Available from: [https://www.nice.org. uk/guidance/cg154/resources/guidance-ectopic-pregnancyand- miscarriage-pdf], last accessed Aug 24, 2015.

34. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Progesterone support of the luteal phase and in the first trimester. 13 A.D. Jul. Available from: [http://www.ranzcog. edu.au/doc/progesterone-support-of-the-luteal-phase-andearlypregnancy. html], last accessed Aug 24, 2015.

35. Schindler, A.E., Carp, H., Druckmann, R., et al. “European Progestin Club Guidelines for prevention and treatment of threatened or recurrent (habitual) miscarriage with progestogens.” Gynecol Endocrinol 31 (2015): 447–9.

36. Arab, H., Alsofayan, H., Alharbi, A., et al. “The Saudi Obstetrics and Gynecological Society (SOGS) National Guidelines for the Prevention and Treatment of Miscarriage.” Saudi J Obstet Gynecol 15 (2014): 40–64.

37. Practice Committee of Amrican Society for Reproductive Medicine. “Definitions of infertility and recurrent pregnancy loss: a committee opinion.” Fertil Steril 99 (2013): 63.

38. Royal College of Obstetricians and Gynaecologists. The Investigation and Treatment of Couples with Recurrent Firsttrimester and Second-trimester Miscarriage. Green-top Guideline No. 17. 2011 Apr. Available from: [https://www.rcog. org.uk/globalassets/documents/guidelines/gtg_17.pdf], last accessed Aug 24, 2015.

39. Garrido-Gimenez, C., Alijotas-Reig, J. “Recurrent miscarriage: causes, evaluation and management.” Postgrad Med J 91 (2015): 151–62.

40. Jauniaux, E., Farquharson, R.G., Christiansen, O.B., Exalto, N. “Evidencebased guidelines for the investigation and medical treatment of recurrent miscarriage.” Hum Reprod 21 (2006): 2216–22.

41. El-Zibdeh, M.Y. “Dydrogesterone in the reduction of recurrent spontaneous abortion.” J Steroid Biochem Mol Biol 97 (2005): 431–4.

42. MacDonald, R.R., Goulden, R., Oakey, R.E. “Cervical mucus, vaginal cytology and steroid excretion in recurrent abortion.” Obstet Gynecol 40 (1972): 394–402.

43. Kumar, A., Begum, N., Prasad, S., et al. “Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial.” Fertil Steril 102 (2014): 1357–63.

44. Ghosh, S., Chattopadhyay, R., Goswami, S., et al. “Assessment of subendometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study.” J Obstet Gynaecol Res 40 (2014): 1871–6.

45. Carp, H. “A systematic review of dydrogesterone for the treatment of recurrent miscarriage.” Gynecol Endocrinol 31 (2015): 422–30.

46. Freedman, R.S., Berry, A. “Progesterone deficiency in preganancy.” S Afr J Obstet Gynaecol 46 (1970): 72–6.

47. Haas, D.M., Ramsey, P.S. “Progestogen for preventing miscarriage.” Cochrane Database Syst Rev 10 (2013): CD003511.

48. El-Mashad, A.I., Mohamed, M.A., Farag, M.A., et al. “Role of uterine artery Doppler velocimetry indices and plasma adrenomedullin level in women with unexplained recurrent pregnancy loss.” J Obstet Gynaecol Res 37 (2011): 51–7.

49. Coomarasamy, A., Williams, H., Truchanowicz, E., et al. “A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.” N Engl J Med 373 (2015): 2141–8.

50. Abbott B.V. Duphaston 10mg Film-Coated Tablets Summary of Product Characteristics; 2012.

51. Bulletti, C., de Ziegler, D., Flamigni, C., et al. “Targeted drug delivery in gynaecology: the first uterine pass effect.” Hum Reprod 12 (1997): 1073–9.

52. Choi, T.Y., Lee, H.M., Park, W.K., et al. “Spontaneous abortion and recurrent miscarriage: a comparison of cytogenetic diagnosis in 250 cases.” Obstet Gynecol Sci 57 (2014): 518–25.

53. Practice Committee of the American Society for Reproductive Medicine. “Current clinical irrelevance of luteal phase deficiency: a committee opinion.” Fertil Steril 103 (2015): 27–32.

54. Balasch, J., Vanrell, J.A., Marquez, M., et al. “Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency.” Fertil Steril 37 (1982): 751–4.

55. Gidley-Baird, A.A., O’Neill, C., Sinosich, M.J., et al. “Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/ estrogen ratios in humans and mice.” Fertil Steril 45 (1986): 69–74.

56. van der Linden, M., Buckingham, K., Farquhar, C., et al. “Luteal phase support for assisted reproduction cycles.” Cochrane Database Syst Rev 7 (2015): CD009154.

57. Kupferminc, M.J., Lessing, J.B., Amit, A., et al. “A prospective randomized trial of human chorionic gonadotrophin or dydrogesterone support following in-vitro fertilization and embryo transfer.” Hum Reprod 5 (1990): 271–3.

58. Patki, A., Pawar, V.C. “Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone.” Gynecol Endocrinol 23 (2007): 68–72.

59. Ganesh, A., Chakravorty, N., Mukherjee, R., et al. “Comparison of oral dydrogestrone with progesterone gel and micronized progesterone for luteal support in 1,373 women undergoing in vitro fertilization: a randomized clinical study.” Fertil Steril 95 (2011): 1961–5.

60. Salehpour, S., Tamimi, M., Saharkhiz, N. “Comparison of oral dydrogesterone with suppository vaginal progesterone for lutealphase support in in vitro fertilization (IVF): a randomized clinical trial.” Iran J Reprod Med 11 (2013): 913–8.

61. Tomic, V., Tomic, J., Klaic, D.Z., et al. “Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial.” Eur J Obstet Gynecol Reprod Biol 186 (2015): 49–53.

62. van der Linden, M., Buckingham, K., Farquhar, C., et al. “Luteal phase support for assisted reproduction cycles.” Cochrane Database Syst Rev 10 (2011): CD009154.

63. Podzolkova, N., Tatarchuk, T., Doshchanova, A., et al. “Dydrogesterone treatment for menstrual-cycle regularization in routine clinical practice: a multicenter observational study.” Gynecol Endocrinol 2015, DOI: 10.3109/09513590.2015.1115832

64. Queisser-Luft, A. “Dydrogesterone use during pregnancy: overview of birth defects reported since 1977.” Early Hum Dev 85 (2009): 375–7.

65. Medicines and Healthcare products Regulatory Agency (MHRA). MHRA UK Public Assessment Report. Efficacy of progestogens in the maintenance of early pregnancy in women with threatened miscarriage or recurrent miscarriage (Feb 2008). Available from: [http://www.mhra.gov.uk/home/groups/s-par/documents/ websiteresources/con079333.pdf], last accessed Aug 24, 2015.





DOI: http://dx.doi.org/10.18370/2309-4117.2016.30.46-55

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