Characteristics and clinical use of dydrogesterone – Expert Group Position Statement Experts recommendations
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Published:
Dec 31, 2023
Keywords:
dydrogesteron, progestogen, pregnancy, luteal phase support, hormone replacement therapy, menstrual disorders
Main Article Content
Abstract
Dydrogesterone was launched in 1961 and is currently available in more than 100 countries worldwide. It is characterized by good bioavailability and metabolic stability as well as the absence of estrogenic, androgenic and mineralocorticoid properties and preferable safety profile, making it a good alternative to other progestogens in many clinical cases. It is used in numerous gynecologic-obstetric indications, including menstrual and pregnancy disorders, and in menopausal hormonal therapy.
This paper presents the Expert Group’s position on the potential use of dydrogesterone in clinical practice. A narrative review of the literature base was conducted, focusing on the efficacy and safety of dydrogesterone in: abnormal uterine bleeding, painful menstruation, menstrual syndrome, secondary amenorrhea, treatment of threatened and habitual miscarriage, infertility associated with corpus luteum insufficiency, endometriosis, and hormonal menopausal therapy.
The identified scientific evidence confirms that the use of dydrogesterone in many clinical situations can be beneficial and the safety profile of the drug is very good. The important place of dydrogesterone in gynecologic-obstetric practice is undoubtedly justified, although further randomized studies are needed to unquestionably confirm the drug’s efficacy in all indications.
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Kwiatkowski, S., Sieroszewski, P., Kalinka, J., Paszkowski, T., Kuczyński, W., Jakimiuk, A., Skrzypulec-Plinta, V., Wender-Ożegowska, E., Pawelczyk, L., & Huras, H. (2023). Characteristics and clinical use of dydrogesterone – Expert Group Position Statement. Medycyna Faktow (J EBM), 16(4(61), 295-302. https://doi.org/10.24292/01.MF.0423.0X
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References
1. Queisser-Luft A. Dydrogesterone use during pregnancy: Overview of birth defects reported since 1977. Early Human Development. 2009; 85(6): 375-7.
2. Charakterystyka produktu leczniczego Duphaston (dydrogesteron).
3. Charakterystyka produktu leczniczego Femoston (Estradiol+dydrogesteron).
4. Charakterystyka produktu leczniczego Femoston mite (Estradiol+dydrogesteron).
5. Charakterystyka produktu leczniczego Femoston conti (Estradiol+dydrogesteron).
6. Charakterystyka produktu leczniczego Femoston mini (Estradiol+dydrogesteron).
7. Schindler AE. Differential effects of progestins: European Progestin Club. Maturitas. 2003; 46: 3-5.
8. Griesinger G, Tournaye H, Macklon N et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online. 2019; 38(2): 249-59.
9. Schindler AE. Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium. Maturitas. 2009; 65(suppl 1): S3-11.
10. Qing G, Hong Y, Feng X et al. Comparison of oral dydrogesterone and intramascular progesterone in the treatment of threatened abortion. Biomedica. 2015; 31(3): 223-7.
11. Foster RH, Balfour JA. Estradiol and dydrogesterone. A review of their combined use as hormone replacement therapy in postmenopausal women. Drugs Aging. 1997; 11(4): 309-32.
12. Rižner TL, Brožič P, Doucette C et al. Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids. 2011; 76(6): 607-15.
13. Griesinger G, Blockeel C, Tournaye H. Oral dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? Fertil Steril. 2018; 109(5): 756-62.
14. Tournaye H, Sukhikh GT, Kahler E et al. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017; 32(5): 1019-27.
15. Whitaker L, Critchley HOD. Abnormal uterine bleeding. Best Pract Res Clin Obstet Gynaecol. 2016; 34: 54-65.
16. Wang L, Guan H-Y, Xia H-X et al. Dydrogesterone treatment for menstrual-cycle regularization in abnormal uterine bleeding – ovulation dysfunction patients. World J Clin Cases. 2020; 8(15): 3259-66.
17. Trivedi N, Chauhan N, Vaidya V. Effectiveness and safety of dydrogesterone in regularization of menstrual cycle: a post-marketing study. Gynecol Endocrinol. 2016; 32(8): 667-71.
18. Guimarães I, Póvoa AM. Primary Dysmenorrhea: Assessment and Treatment. Rev Bras Ginecol Obstet. 2020; 42(8): 501-7.
19. Stute P. Dydrogesterone indications beyond menopausal hormone therapy: an evidence review and woman’s journey. Gynecol Endocrinol. 2021; 37(8): 683-8.
20. Taniguchi F, Ota I, Iba Y et al. The efficacy and safety of dydrogesterone for treatment of dysmenorrhea: An open-label multicenter clinical study. J Obstet Gynaecol Res. 2019; 45(1): 168-75.
21. Aydar CK, Coleman BD. Treatment of Primary Dysmenorrhea: A Double-Blind Study. JAMA. 1965; 192(11): 1003-5.
22. Gould CH. Dydrogesterone in teenage dysmenorrhoea. A multicentre trial in general practice. Practitioner. 1979; 222(1331): 718-23.
23. Tiranini L, Nappi RE. Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome. Fac Rev. 2022; 11: 11.
24. Khajehei M, Abdali K, Parsanezhad ME et al. Effect of treatment with dydrogesterone or calcium plus vitamin D on the severity of premenstrual syndrome. Int J Gynaecol Obstet. 2009; 105(2): 158-61.
25. Kerr GD, Day JB, Munday MR et al. Dydrogesterone in the treatment of the premenstrual syndrome. Practitioner. 1980; 224(1346): 852-5.
26. Panay N, Pritsch M, Alt J. Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study. Gynecol Endocrinol. 2007; 23(11): 611-8.
27. Hadaś K, Warenik-Szymankiewicz A, Halerz-Nowakowska B et al. [Repeated amenorrhea after body weight loss. Efficacy of treatment of estrogen and gestagen depending on the body mass index]. Ginekol Pol. 1999; 70(5): 383-8.
28. Battino S, Ben-Ami M, Geslevich Y et al. Factors associated with withdrawal bleeding after administration of oral dydrogesterone or medroxyprogesterone acetate in women with secondary amenorrhea. Gynecol Obstet Invest. 1996; 42(2): 113-6.
29. Katalinic A, Shulman LP, Strauss JF et al. A critical appraisal of safety data on dydrogesterone for the support of early pregnancy: a scoping review and meta-analysis. Reprod Biomed Online. 2022; 45(2): 365-73.
30. Walch K, Hefler L, Nagele F. Oral dydrogesterone treatment during the first trimester of pregnancy: the prevention of miscarriage study (PROMIS). A double-blind, prospectively randomized, placebo-controlled, parallel group trial. J Matern Fetal Neonatal Med. 2005; 18(4): 265-9.
31. Carp H. A systematic review of dydrogesterone for the treatment of recurrent miscarriage. Gynecol Endocrinol. 2015; 31(6): 422-30.
32. The ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J et al. (2023) ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023(1): hoad002.
33. Wahabi HA, Fayed AA, Esmaeil SA et al. Progestogen for treating threatened miscarriage. Cochrane Database Syst Rev. 2018(8): CD005943.
34. 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. 2007; 87(3): 613-8.
35. Das R, Rout RR, Tiwari RVC et al. Evaluation of per Vaginal Bleeding With Different Drugs in Successful Pregnancy in Patients With Recurrent Pregnancy Loss: An Original Research. J Pharm Bioallied Sci. 2022; 14(suppl 1): S193-5.
36. Ghosh S, Chattopadhyay R, Goswami S et al. Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study. J Obstet Gynaecol Res. 2014; 40(7): 1871-6.
37. Kale AR, Kale AA, Yelikar K. A Comparative, Randomized Control Trial in Patients of Per Vaginal Bleeding Comparing Efficacy of Oral Dydrogesterone Versus Vaginal Progesterone in Successful Pregnancy Outcome for Patients with Recurrent Pregnancy Loss. J Obstet Gynecol India. 2021; 71(6): 591-5.
38. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. Am J Reprod Immunol. 2005; 53(4): 166-71.
39. Ott J, Egarter C, Aguilera A. Dydrogesterone after 60 years: a glance at the safety profile. Gynecol Endocrinol. 2022; 38(4): 279-87.
40. van der Linden M, Buckingham K, Farquhar C et al. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015; (7): CD009154.
41. Balasch J, Vanrell JA, Márquez M et al. Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency. Fertil Steril. 1982; 37(6): 751-4.
42. Fatemi HM, Popovic-Todorovic B, Papanikolaou E et al. An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update. 2007; 13(6): 581-90.
43. Orazov MR, Radzinskiy VE, Nosenko EN et al. Combination therapeutic options in the treatment of the luteal phase deficiency. Gynecol Endocrinol. 2017; 33(suppl 1): 1-4.
44. Koninckx PR, Fernandes R, Ussia A et al. Pathogenesis Based Diagnosis and Treatment of Endometriosis. Front Endocrinol (Lausanne). 2021; 12: 745548.
45. Peng C, Huang Y, Zhou Y. Dydrogesterone in the treatment of endometriosis: evidence mapping and meta-analysis. Arch Gynecol Obstet. 2021; 304(1): 231-52.
46. Sun S, Zhang H, Zhong P et al. The Effect of Letrozole Combined with Dydrogesterone for Endometriosis in China: A Meta-Analysis. Biomed Res Int. 2021; 2021: 9946060.
47. Sukhikh GT, Adamyan LV, Dubrovina SOet al. Prolonged cyclical and continuous regimens of dydrogesterone are effective for reducing chronic pelvic pain in women with endometriosis: results of the ORCHIDEA study. Fertil Steril. 2021; 116(6): 1568-77.
48. de Carvalho BR. Dydrogesterone as an Option in the Medical Treatment of Endometriosis: A Brief Comment. Rev Bras Ginecol Obstet. 2022; 44(8): 802-3.
49. Stevenson JC, Durand G, Kahler E et al. Oral ultra-low dose continuous combined hormone replacement therapy with 0.5 mg 17β-oestradiol and 2.5 mg dydrogesterone for the treatment of vasomotor symptoms: results from a double-blind, controlled study. Maturitas. 2010; 67(3): 227-32.
50. Ren M, Ruan X, Gu L et al. Ultra-low-dose estradiol and dydrogesterone: a phase III study for vasomotor symptoms in China. Climacteric. 2022; 25(3): 286-92.
51. Nieto JJ, Cogswell D, Jesinger D et al. Lipid effects of hormone replacement therapy with sequential transdermal 17-beta-estradiol and oral dydrogesterone. Obstet Gynecol. 2000; 95(1): 111-4.
52. Kuba VM, Teixeira MA, Meirelles RMR et al. Dydrogesterone does not reverse the cardiovascular benefits of percutaneous estradiol. Climacteric. 2013; 16(1): 54-61.
53. Piróg M, Jach R, Kacalska-Janssen O. Differential effect of the ultra-low dose and standard estrogen plus dydrogesterone therapy on thrombin generation and fibrinolysis in postmenopausal women. Acta Obstet Gynecol Scand. 2017; 96(12): 1438-45.
54. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020; 371: m3873.
55. Fournier A, Mesrine S, Dossus L et al. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat. 2014; 145(2): 535-43.
56. Fournier A, Dossus L, Mesrine S et al. Risks of endometrial cancer associated with different hormone replacement therapies in the E3N cohort, 1992-2008. Am J Epidemiol. 2014; 180(5): 508-17.
2. Charakterystyka produktu leczniczego Duphaston (dydrogesteron).
3. Charakterystyka produktu leczniczego Femoston (Estradiol+dydrogesteron).
4. Charakterystyka produktu leczniczego Femoston mite (Estradiol+dydrogesteron).
5. Charakterystyka produktu leczniczego Femoston conti (Estradiol+dydrogesteron).
6. Charakterystyka produktu leczniczego Femoston mini (Estradiol+dydrogesteron).
7. Schindler AE. Differential effects of progestins: European Progestin Club. Maturitas. 2003; 46: 3-5.
8. Griesinger G, Tournaye H, Macklon N et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online. 2019; 38(2): 249-59.
9. Schindler AE. Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium. Maturitas. 2009; 65(suppl 1): S3-11.
10. Qing G, Hong Y, Feng X et al. Comparison of oral dydrogesterone and intramascular progesterone in the treatment of threatened abortion. Biomedica. 2015; 31(3): 223-7.
11. Foster RH, Balfour JA. Estradiol and dydrogesterone. A review of their combined use as hormone replacement therapy in postmenopausal women. Drugs Aging. 1997; 11(4): 309-32.
12. Rižner TL, Brožič P, Doucette C et al. Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids. 2011; 76(6): 607-15.
13. Griesinger G, Blockeel C, Tournaye H. Oral dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? Fertil Steril. 2018; 109(5): 756-62.
14. Tournaye H, Sukhikh GT, Kahler E et al. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017; 32(5): 1019-27.
15. Whitaker L, Critchley HOD. Abnormal uterine bleeding. Best Pract Res Clin Obstet Gynaecol. 2016; 34: 54-65.
16. Wang L, Guan H-Y, Xia H-X et al. Dydrogesterone treatment for menstrual-cycle regularization in abnormal uterine bleeding – ovulation dysfunction patients. World J Clin Cases. 2020; 8(15): 3259-66.
17. Trivedi N, Chauhan N, Vaidya V. Effectiveness and safety of dydrogesterone in regularization of menstrual cycle: a post-marketing study. Gynecol Endocrinol. 2016; 32(8): 667-71.
18. Guimarães I, Póvoa AM. Primary Dysmenorrhea: Assessment and Treatment. Rev Bras Ginecol Obstet. 2020; 42(8): 501-7.
19. Stute P. Dydrogesterone indications beyond menopausal hormone therapy: an evidence review and woman’s journey. Gynecol Endocrinol. 2021; 37(8): 683-8.
20. Taniguchi F, Ota I, Iba Y et al. The efficacy and safety of dydrogesterone for treatment of dysmenorrhea: An open-label multicenter clinical study. J Obstet Gynaecol Res. 2019; 45(1): 168-75.
21. Aydar CK, Coleman BD. Treatment of Primary Dysmenorrhea: A Double-Blind Study. JAMA. 1965; 192(11): 1003-5.
22. Gould CH. Dydrogesterone in teenage dysmenorrhoea. A multicentre trial in general practice. Practitioner. 1979; 222(1331): 718-23.
23. Tiranini L, Nappi RE. Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome. Fac Rev. 2022; 11: 11.
24. Khajehei M, Abdali K, Parsanezhad ME et al. Effect of treatment with dydrogesterone or calcium plus vitamin D on the severity of premenstrual syndrome. Int J Gynaecol Obstet. 2009; 105(2): 158-61.
25. Kerr GD, Day JB, Munday MR et al. Dydrogesterone in the treatment of the premenstrual syndrome. Practitioner. 1980; 224(1346): 852-5.
26. Panay N, Pritsch M, Alt J. Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study. Gynecol Endocrinol. 2007; 23(11): 611-8.
27. Hadaś K, Warenik-Szymankiewicz A, Halerz-Nowakowska B et al. [Repeated amenorrhea after body weight loss. Efficacy of treatment of estrogen and gestagen depending on the body mass index]. Ginekol Pol. 1999; 70(5): 383-8.
28. Battino S, Ben-Ami M, Geslevich Y et al. Factors associated with withdrawal bleeding after administration of oral dydrogesterone or medroxyprogesterone acetate in women with secondary amenorrhea. Gynecol Obstet Invest. 1996; 42(2): 113-6.
29. Katalinic A, Shulman LP, Strauss JF et al. A critical appraisal of safety data on dydrogesterone for the support of early pregnancy: a scoping review and meta-analysis. Reprod Biomed Online. 2022; 45(2): 365-73.
30. Walch K, Hefler L, Nagele F. Oral dydrogesterone treatment during the first trimester of pregnancy: the prevention of miscarriage study (PROMIS). A double-blind, prospectively randomized, placebo-controlled, parallel group trial. J Matern Fetal Neonatal Med. 2005; 18(4): 265-9.
31. Carp H. A systematic review of dydrogesterone for the treatment of recurrent miscarriage. Gynecol Endocrinol. 2015; 31(6): 422-30.
32. The ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J et al. (2023) ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023(1): hoad002.
33. Wahabi HA, Fayed AA, Esmaeil SA et al. Progestogen for treating threatened miscarriage. Cochrane Database Syst Rev. 2018(8): CD005943.
34. 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. 2007; 87(3): 613-8.
35. Das R, Rout RR, Tiwari RVC et al. Evaluation of per Vaginal Bleeding With Different Drugs in Successful Pregnancy in Patients With Recurrent Pregnancy Loss: An Original Research. J Pharm Bioallied Sci. 2022; 14(suppl 1): S193-5.
36. Ghosh S, Chattopadhyay R, Goswami S et al. Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study. J Obstet Gynaecol Res. 2014; 40(7): 1871-6.
37. Kale AR, Kale AA, Yelikar K. A Comparative, Randomized Control Trial in Patients of Per Vaginal Bleeding Comparing Efficacy of Oral Dydrogesterone Versus Vaginal Progesterone in Successful Pregnancy Outcome for Patients with Recurrent Pregnancy Loss. J Obstet Gynecol India. 2021; 71(6): 591-5.
38. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. Am J Reprod Immunol. 2005; 53(4): 166-71.
39. Ott J, Egarter C, Aguilera A. Dydrogesterone after 60 years: a glance at the safety profile. Gynecol Endocrinol. 2022; 38(4): 279-87.
40. van der Linden M, Buckingham K, Farquhar C et al. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015; (7): CD009154.
41. Balasch J, Vanrell JA, Márquez M et al. Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency. Fertil Steril. 1982; 37(6): 751-4.
42. Fatemi HM, Popovic-Todorovic B, Papanikolaou E et al. An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update. 2007; 13(6): 581-90.
43. Orazov MR, Radzinskiy VE, Nosenko EN et al. Combination therapeutic options in the treatment of the luteal phase deficiency. Gynecol Endocrinol. 2017; 33(suppl 1): 1-4.
44. Koninckx PR, Fernandes R, Ussia A et al. Pathogenesis Based Diagnosis and Treatment of Endometriosis. Front Endocrinol (Lausanne). 2021; 12: 745548.
45. Peng C, Huang Y, Zhou Y. Dydrogesterone in the treatment of endometriosis: evidence mapping and meta-analysis. Arch Gynecol Obstet. 2021; 304(1): 231-52.
46. Sun S, Zhang H, Zhong P et al. The Effect of Letrozole Combined with Dydrogesterone for Endometriosis in China: A Meta-Analysis. Biomed Res Int. 2021; 2021: 9946060.
47. Sukhikh GT, Adamyan LV, Dubrovina SOet al. Prolonged cyclical and continuous regimens of dydrogesterone are effective for reducing chronic pelvic pain in women with endometriosis: results of the ORCHIDEA study. Fertil Steril. 2021; 116(6): 1568-77.
48. de Carvalho BR. Dydrogesterone as an Option in the Medical Treatment of Endometriosis: A Brief Comment. Rev Bras Ginecol Obstet. 2022; 44(8): 802-3.
49. Stevenson JC, Durand G, Kahler E et al. Oral ultra-low dose continuous combined hormone replacement therapy with 0.5 mg 17β-oestradiol and 2.5 mg dydrogesterone for the treatment of vasomotor symptoms: results from a double-blind, controlled study. Maturitas. 2010; 67(3): 227-32.
50. Ren M, Ruan X, Gu L et al. Ultra-low-dose estradiol and dydrogesterone: a phase III study for vasomotor symptoms in China. Climacteric. 2022; 25(3): 286-92.
51. Nieto JJ, Cogswell D, Jesinger D et al. Lipid effects of hormone replacement therapy with sequential transdermal 17-beta-estradiol and oral dydrogesterone. Obstet Gynecol. 2000; 95(1): 111-4.
52. Kuba VM, Teixeira MA, Meirelles RMR et al. Dydrogesterone does not reverse the cardiovascular benefits of percutaneous estradiol. Climacteric. 2013; 16(1): 54-61.
53. Piróg M, Jach R, Kacalska-Janssen O. Differential effect of the ultra-low dose and standard estrogen plus dydrogesterone therapy on thrombin generation and fibrinolysis in postmenopausal women. Acta Obstet Gynecol Scand. 2017; 96(12): 1438-45.
54. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020; 371: m3873.
55. Fournier A, Mesrine S, Dossus L et al. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat. 2014; 145(2): 535-43.
56. Fournier A, Dossus L, Mesrine S et al. Risks of endometrial cancer associated with different hormone replacement therapies in the E3N cohort, 1992-2008. Am J Epidemiol. 2014; 180(5): 508-17.