Low Dose of Gonadotropin with Letrozole Versus High Dose of Gonadotropin in Patients with Poor Ovarian Response Undergoing Ivf: A Randomised, Single-Blind, Prospective Trial

Year 2020, Volume: 51 Issue: 4, 221 - 225, 15.12.2020

Harika Yumru Çeliksoy Ercan Baştu Burçin Karamustafaoğlu Balcı Cenk Yaşa Özlem Dural Faruk Buyru

https://doi.org/10.16948/zktipb.775168

Abstract

Objective : The ideal controlled ovarian stimulation protocol for patients with poor ovarian response (POR) is not clear yet, and is the subject of many studies. Aromatase inhibitors have been introduced as a new treatment modality in controlled ovarian stimulation as they were found to elevate follicular sensitivity to gonadotropins(Gn). The aim of this study was to evaluate whether it is possible to reduce the required Gn dose by adding letrozole to the treatment without compromising success.
Material and Methods: Patients who underwent in vitro fertilization treatment between 2014 and 2015 in our department and who were classified as poor responder patients according to Bologna criteria were recruited and randomized. In the first group, 33 patients were treated with 150 IU Gn in combination with letrozole 5 mg /day for the first five days of the stimulation. In the second group, 27 patients were treated with 300 IU Gn.
Results: Amoung the groups there were no statistically significant difference in duration of ovulation stimulation, duration of antagonist use, number of retrieved oocytes, number of transferred embryos, implantation, cycle cancelation, chemical, clinical and ongoing pregnancy rates (all p>0.05). Gn use was significantly higher in 300 IU Gn alone group compared to 150 IU Gn in combination with letrozole group (1354 ± 468 IU versus 2555 ± 725 IU, p<0.05).
Conclusion: The addition of letrozole yields comparable pregnancy outcomes with significantly low doses of Gn, so may be regarded as an effective adjuvant agent in POR patients.

Keywords

gonadotropin, letrozole, poor ovarian response

Poor Responder Hasta Grubunda Yüksek Doz Gonadotropine Karşı Letrozol ile Düşük Doz Gonadotropinin Karşılaştırılması: Randomize, Tek Kör, Prospektif Çalışma

Abstract

Amaç: Kontrollü over stimülasyonuna zayıf cevap veren hastalar için ideal protokol henüz net değildir ve birçok çalışmanın konusudur. Aromataz inhibitörleri ile foliküllerde gonadotropin(Gn) duyarlılığının arttığı tespit edilmiştir. Bu çalışmanın amacı, başarıdan ödün vermeden tedaviye letrozol ekleyerek gerekli olan Gn dozunu azaltmanın mümkün olup olmadığını değerlendirmektir.
Gereç ve Yöntem: Kliniğimizde 2014-2015 yılları arasında infertilite tedavisi gören ve Bologna kriterlerine göre zayıf cevap veren hasta olarak sınıflandırılan hastalar randomize edildi. Birinci hasta grubuna (n=33), stimülasyonun ilk beş günü için 5 mg/gün letrozol ile birlikte 150 IU/gün Gn uygulandı. İkinci gruba (n=27) ise sadece 300 IU/gün Gn uygulandı.
Bulgular: Gruplar arasında ovulasyon stimülasyonu süresi, antagonist kullanım süresi, elde edilen oosit sayısı, transfer edilen embriyo sayısı, implantasyon, siklus iptali, kimyasal, klinik ve devam eden gebelik oranlarında istatistiksel olarak anlamlı bir fark yoktu (p> 0.05). Ancak Gn kullanımı, sadece 300 IU Gn grubunda, letrozol grubu ile birlikte 150 IU Gn'e kıyasla daha yüksekti (1354 ± 468 IU, 2555 ± 725 IU, p <0.05).
Sonuç: Letrozol sayesinde önemli ölçüde düşük Gn dozları ile karşılaştırılabilir gebelik sonuçları elde edilmiştir, bu nedenle POR hastalarında etkili bir adjuvan ajan olarak kabul edilebilir.

Keywords

gonadotropin, letrozol, zayıf over yanıtı

References

• 1. Garcia JE, Jones GS, Acosta AA, Wright G. HMG/hCG follicular maturation for oocytes aspiration: phase II, 1981. Fertil Steril 1983;39:174–179.
• 2. Keay SD, Liversedge NH, Mathur RS, Jenkins JM. Assisted conception following poor ovarian response to gonadotropin stimulation. Br J Obstet Gynaecol 1997;104:521–7.
• 3. Karande V, Gleicher N. A rational approach to the management of low responders in in- vitro fertilization: opinion. Hum Reprod 1999;14:1744–8.
• 4. A.P. Ferraretti, A. La Marca, B.C.J.M. Fauser, B.Tarlatzis, G.Nargund and L. Gianaroli on behalf of the ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization:the Bologna criteria. Human Reprod 2011; 26:1616–1624.
• 5. van-Hooff MH, Alberda AT, Huisman GJ, Zeilmaker GH and Leerentveld RA. Doubling the human menopausal gonadotropin dose in the course of an in-vitro fertilization treatment cycle in low responders: a randomized study. Hum. Reprod 1993;8:369–373.
• 6. Rombauts L, Suikkari AM, MacLachlan V, Trounson AO and Healy DL. Recruitment of follicles by recombinant human follicle-stimulating hormone commencing in the luteal phase of the ovarian cycle. Fertil Steril 1998; 69:665–669.
• 7. Land JA, Yarmolinskaya MI, Dumoulin JC and Evers JL. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome. Fertil Steril 1996;65:961–965.
• 8. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response:a preliminary report. Hum Reprod 2004;19:2031–5.
• 9. Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, et al. 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;84:82–7.
• 10. Mitwally M, Casper R. Aromatase inhibition improves ovarian response to follicle stimulation hormone in poor responders’. Fertil Steril 2002;77:776–80.
• 11. Weil S, Vendola K, Zhoe J, Bondy CA. Androgen and folliclestimulating hormone interaction in primate ovarian follicle development. J Clin Endocrinol Metab 1998;84:2951–6.
• 12. Adashi E. Intraovarian regulation: the proposed role of insulin-like growth factors. Ann NY Acad Sci 1993;687:10–2.
• 13. Miller PB, Parnell BA, Bushnell G, Tallman N, Forstein DA, et al. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum. Reprod 2012;27:881–8. 
 14. Kamath MS1, Maheshwari A, Bhattacharya S, Lor KY, Gibreel A. Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database Syst Rev 2017 Nov 2;11:CD008528. doi: 10.1002/14651858.CD008528.pub3.
• 15. Bechtejew TN, Nadai MN, Nastri CO, Martins WP. Clomiphene citrate and letrozole to reduce follicle-stimulating hormone consumption during ovarian stimulation: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017 Sep;50(3):315-323. doi: 10.1002/uog.17442. Epub 2017 Aug 10.
• 16. Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotropin dose required for controlled ovarian stimulation in women with unexplained infertility. Hum Reprod 2003;18:1588.
• 17. Suzuki T, Sasano H, Kimura N, Tamura M, Fukaya T, Yajima A, et al. Immunohistochemical distribution of progesterone, androgen and oestrogen receptors in the human ovary during the menstrual cycle: relationship to expression of steroidogenic enzymes. Hum Reprod 1994;9:1589–95.
• 18. Fábregues F, Peñarrubia J, Creus M, Manau D, Casals G,et al. Transdermal testosterone may improve ovarian response to gonadotropins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod 2009 Feb;24(2):349-59.
• 19. Lossl K, Yding Anderson C, Loft A, Freiesleben NLC, BangsbØll S. Nyboe Anderson A. Short term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial. Hum Reprod 2008;23:1820– 9.
• 20. Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intraovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update 2004;10:107–17.
• 21. Ozmen B. Sönmezer M. Atabekoglu CS, Olmus H. Use of aromatase inhibitors in poor- responder patients receiving GnRH antagonist protocols. Reprod Biomed Online 2009;19(4):478-85.
• 22. Hofmann G, Toner J, Muasher S, Jones G. High-dose follicle stimulating hormone (FSH) ovarian stimulation in low responder patients for in vitro fertilization. J In Vitro Fert Embryo Transf 1993;6:285.
• 23. Harrison RF, Jacob S, Spillane H, Mallon E, Hennelly B. A prospective randomized clinical trial of differing starter doses of recombinant follicle-stimulating hormone (follitropin-beta) for fi rst time in vitro fertilization and intracytoplasmic sperm injection treatment cycles. Fertil Steril 2001;75:23.
• 24. Klinkert ER, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotropins in IVF treatment: a randomized controlled trial. Hum Reprod 2005;20:611.
• 25. Kyung-Hee Lee, Chung-Hoon Kim, Hye-Jin Suk, You-Jeong Lee, Su-Kyung Kwon, et al. The effect of aromatase inhibitor letrozole incorporated in gonadotropin-releasing hormone antagonist multiple dose protocol in poor responders undergoing in vitro fertilization. Obstet Gynecol Sci 2014;57(3):216-222.
• 26. Lazer T, Dar S, Shlush E, Al Kudmani BS, Quach K,et al. Comparison of IVF Outcomes between Minimal Stimulation and High-Dose Stimulation for Patients with Poor Ovarian Reserve. Int J Reprod Med 2014;2014:581451.