New perspectives on ovulation induction with letrozole in women with polycystic ovary syndrome


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Objective: To compare the efficacy and adverse event rates of letrozole in a stair-step and standard ovulation induction (OI) protocols in women with polycystic ovary syndrome (PCOS) and anovulatory infertility. Materials and methods: The study included 194 patients aged 28.7 (25;33), body mass index 21.5 (21;26) kg/m2. Of them, 106/194 (54.6%) women did not respond to the initial stimulation with 2.5 mg letrozole. They were divided into group 1 (n=52) and group 2 (n=54) undergoing stair-step protocol and standard protocol, respectively. During OI, the patients underwent ultrasound monitoring of ovarian and endometrial status. Furthermore, the clinical evaluation included estimated time of ovulation and ovulation and pregnancy rates. Results: The ovulation rates were equally high in both groups and was 92.3% on the stair-step protocol and 85.2% on the standard protocol (p=0.25). The time to ovulation was statistically significantly shorter in the stair-step protocol [33.9 (3.23) versus 59.5 (11.96) days; p<0.001]. The mean M echo was larger in the same group [0.2 (2.2) mm versus 9.3 (2.2) mm; p=0.01]. There was no statistical difference in pregnancy and live birth rates between the stair-step and standard protocols [17/52 (32.7%) versus 12/54 (22.2%); p=0.23 and 15/52 (28.8%) versus 11/54 (20.4%); p=0.31]. None of the patients developed ovarian hyperstimulation syndrome (OHSS). The incidence of multiple pregnancies in group 1 was 1/17 (5.9%) (p=0.31). Conclusion: The stair-step protocol with letrozole allows repeated stimulation without inducing a menstrual-like response and can be considered an effective treatment of anovulatory infertility in PCOS. It reduces the time to ovulation approximately twofold without increasing the risk of OHSS and multiple pregnancies, thus improving patients' quality of life.

Full Text

Restricted Access

About the authors

Galina E. Chernukha

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation

Email: c-galinai@yandex.ru
MD, Professor, Head of the Department of Gynecologic Endocrinology

Elena K. Kaprina

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation

Email: kaprina_elena@mail.ru
Postgraduate Student at the Department of Gynecologic Endocrinology

Alina A. Golovanova

ООО Medok LLC

Email: aleeshka@mail.ru
PhD, Obstetrician-Gynecologist, Medical Diagnostic Sonographer

References

  1. Balen A.H., Morley L.C., Misso M., Franks S., Legro R.S., Wijeyaratne C.N. et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum. Reprod. Update. 2016; 22(6): 687-708. https://dx.doi.org/10.1093/humupd/dmw025.
  2. ESHRE Capri Workshop Group. Health and fertility in World Health Organization group 2 anovulatory women. Hum. Reprod. Update. 2012; 18(5): 586-99. https://dx.doi.org/10.1093/humupd/dms019.
  3. Teede H.J., Misso M.L., Costello M.F., Dokras A., Laven J., Moran L. et al.; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum. Reprod. 2018; 33(9): 1602-18. https://dx.doi.org/10.1093/humrep/dey256.
  4. Bozdag G., Mumusoglu S., Zengin D., Karabulut E., Yildiz B.O. The prevalence and phenotypic features of polycystic ovarysyndrome: a systematic review and meta-analysis. Hum. Reprod. 2016; 31(12): 2841-55. https://dx.doi.org/10.1093/humrep/dew218.
  5. Министерство здравоохранения Российской Федерации. Клинические рекомендации. Синдром поликистозных яичников. М.; 2021.
  6. Legro R.S., Brzyski R.G., Diamond M.P., Coutifaris C., Schlaff W.D., Casson P. et al.; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 2014; 371(2): 119-29. https://dx.doi.org/10.1056/NEJMoa1313517.
  7. Franik S., Kremer J.A., Nelen W.L., Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2014; 24(2): CD010287. https://dx.doi.org/10.1002/14651858.CD010287.pub2.
  8. Tulandi T., Martin J., Al-Fadhli R., Kabli N., Forman R., Hitkari J. et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil. Steril. 2006; 85(6): 1761 5. https://dx.doi.org/10.1016/j.fertnstert.2006.03.014
  9. Sharma S., Ghosh S., Singh S., Chakravarty A., Ganesh A., Rajani S., Chakravarty B.N. Congenital malformations among babies born following letrozole or lomiphene for infertility treatment. PLoS One. 2014; 9(10): e108219. https://dx.doi.org/10.1371/journal.pone.0108219.
  10. Tatsumi T., Jwa S.C., Kuwahara A., Irahara M., Kubota T., Saito H. No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology. Hum. Reprod. 2017; 32(1): 125-32. https://dx.doi.org/10.1093/humrep/dew280.
  11. Garcia-Velasco J.A., Moreno L., Pacheco A., Guillen A., Duque L., Requena A., Pellicer A. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: A pilot study. Fertil. Steril. 2005; 84(1): 82-7. https://dx.doi.org/10.1016/j.fertnstert.2005.01.117.
  12. Palomba S. Aromatase inhibitors for ovulation induction. J. Clin. Endocrinol. Metab. 2015; 100(5): 1742-7. https://dx.doi.org/10.1210/jc.2014-4235.
  13. Hurst B.S., Hickman J.M., Matthews M.L., Usadi R.S., Marshburn P.B. Novel clomiphene "stair-step" protocol reduces time to ovulation in women with polycystic ovarian syndrome. Am. J. Obstet. Gynecol. 2009; 200(5): 510.e1-4. https://dx.doi.org/10.1016/j.ajog.2008.10.031.
  14. Deveci C.D., Demir B., Sengul O., Dilbaz B., Goktolga U. Clomiphene citrate 'stair-step' protocol vs. traditional protocol in patients with polycystic ovary syndrome: a randomized controlled trial. Arch. Gynecol. Obstet. 2015; 291(1): 179-84. https://dx.doi.org/10.1007/s00404-014-3398-y.
  15. AbdelHamid A.M.S., Rateb A.M., Madkour W.A.I. Is clomiphene citrate stairstep protocol a good alternative to gonadotrophins in clomiphene-resistant PCO patients? Prospective study. J. Obstet. Gynaecol. Res. 2016; 42(5): 547-53. https://dx.doi.org/10.1111/jog.12940.
  16. Horowitz E., Levran D., Weissman A. Extension of the clomiphene citrate stairstep protocol to gonadotropin treatment in women with clomiphene resistant polycystic ovarian syndrome. Gynecol. Endocrinol. 2017; 33(10): 807-10. https://dx.doi.org/10.1080/09513590.2017.1320381.
  17. Agrawal K., Gainder S., Dhaliwal L.K., Suri V. Ovulation induction using clomiphene citrate using stair - step regimen versus traditional regimen in polycystic ovary syndrome women - A randomized control trial. J. Hum. Reprod. Sci. 2017; 10(4): 261-4. https://dx.doi.org/10.4103/jhrs.JHRS_15_17.
  18. Jones T., Ho J.R., Gualtieri M., Bruno-Gaston J., Chung K., Paulson R.J., Bendikson K.A. Clomiphene stair-step protocol for women with polycystic ovary syndrome. Obstet. Gynecol. 2018; 131(1): 91-5. https://dx.doi.org/10.1097/AOG.0000000000002418.
  19. Thomas S., Woo I., Ho J., Jones T., Paulson R., Chung K., Bendikson K. Ovulation rates in a stair-step protocol with Letrozole vs clomiphene citrate in patients with polycystic ovarian syndrome. Contracept. Reprod. Med. 2019; 4: 20. https://dx.doi.org/10.1186/s40834-019-0102-4.
  20. Sakar M.N., Oglak S.C. Comparison of the efficacy of letrozole stair-step protocol with clomiphene citrate stair-step protocol in the management of clomiphene citrate-resistant polycystic ovary syndrome patients. J. Obstet. Gynaecol. Res. 2021; 47(11): 3875-82. https://dx.doi.org/10.1111/jog.14936.
  21. The Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group. Revised 2003 consessus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. 2004; 19(1): 41-7. https://dx.doi.org/10.1093/humrep/deh098.
  22. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum. Reprod. 2008; 23(3): 462-77. https://dx.doi.org/10.1093/humrep/dem426.
  23. Морчиладзе А.З., Савина В.А., Ткаченко Н.Н., Ярмолинская М.И. Применение ингибитора ароматазы летрозола для индукции овуляции у женщин с синдромом поликистозных яичников. Журнал акушерства и женских болезней. 2011; 60(2): 52-7.
  24. Кузнецова И.В., Фернандес Д.О., Гаврилова Е.А., Ведзижева Э.Р. Восстановление фертильности у пациенток с нормогонадотропной овуляторной дисфункцией и ожирением. Эффективная фармокотерапия. 2021; 17(43): 14-9. https://dx.doi.org/10.33978/2307-3586-2021-17-43-14-19.
  25. Yin X., Ji Y., Chan C.L.W., Chan C.H.Y. The mental health of women with polycystic ovary syndrome: a systematic review and meta-analysis. Arch. Womens Ment. Health. 2021; 24(1): 11-27. https://dx.doi.org/10.1007/s00737-020-01043-x.
  26. Miller P.B., Parnell B.A., Bushnell G., Tallman N., Forstein D.A., Higdon H.L. 3rd, et al. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum. Reprod. 2012; 27(3): 881-8. https://dx.doi.org/10.1093/humrep/der452.
  27. Ganesh A., Chauhan N., Das S., Chakravarty B., Chaudhury K. Endometrial receptivity markers in infertile women stimulated with letrozole compared with clomiphene citrate and natural cycles. Syst. Biol. Reprod. Med. 2014; 60(2): 105-11. https://dx.doi.org/10.3109/19396368.2013.862316.
  28. Diamond M.P., Kruger M., Santoro N., Zhang H., Casson P., Schlaff W. et al. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet. Gynecol. 2012; 119(5): 902-8. https://dx.doi.org/10.1097/AOG.0b013e31824da35c.
  29. Farhi J., Orvieto R., Homburg R. Administration of clomiphene citrate in patients with polycystic ovary syndrome, without inducing withdrawal bleeding, achieves comparable treatment characteristics and outcome. Fertil. Steril. 2010; 93(6): 2077-9. https://dx.doi.org/10.1016/j.fertnstert.2009.08.019.
  30. Chatzakis C., Tsakmaki E., Psomiadou A., Charitakis N., Eleftheriades M., Dinas K. et al. Different pregnancy outcomes according to the polycystic ovary syndrome diagnostic criteria: a systematic review and meta-analysis of 79 studies. Fertil. Steril. 2022; 117(4): 854-81. https://dx.doi.org/10.1016/j.fertnstert.2021.12.027.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2022 Bionika Media