클로미펜에 얇은 자궁내막을 보이는 환자에서 성선자극호르몬 병합 과배란유도시 클로미펜과 레트로졸의 임상적 효용성

Clinical Efficacy of Clomiphene Citrate and Letrozole Combined with Gonadotropins for Superovulation in Patients with Clomiphene-Induced Thin Endometrium

  • 이은주 (연세대학교 의과대학 산부인과학교실) ;
  • 박현종 (연세대학교 의과대학 산부인과학교실) ;
  • 양효인 (연세대학교 의과대학 산부인과학교실) ;
  • 이경은 (연세대학교 의과대학 산부인과학교실) ;
  • 서석교 (연세대학교 의과대학 산부인과학교실) ;
  • 김혜연 (연세대학교 의과대학 산부인과학교실) ;
  • 조시현 (연세대학교 의과대학 산부인과학교실) ;
  • 최영식 (연세대학교 의과대학 산부인과학교실) ;
  • 이병석 (연세대학교 의과대학 산부인과학교실) ;
  • 박기현 (연세대학교 의과대학 산부인과학교실) ;
  • 조동제 (연세대학교 의과대학 산부인과학교실)
  • Lee, Eun-Joo (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Park, Hyun-Jong (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Yang, Hyo-In (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Lee, Kyung-Eun (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Seo, Seok-Kyo (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Kim, Hye-Yeon (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Cho, Si-Hyun (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Choi, Young-Sik (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Lee, Byung-Seok (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Park, Ki-Hyun (Department of Obstetrics and Gynecology, Yonsei University College of Medicine) ;
  • Cho, Dong-Jae (Department of Obstetrics and Gynecology, Yonsei University College of Medicine)
  • 발행 : 2009.06.30

초록

목 적: 클로미펜을 사용한 배란유도시 얇은 자궁내막을 보였던 환자들에서 성선자극호르몬에 클로미펜 또는 레트로졸을 병합 투여하는 과배란유도 방법의 임상적 효용성을 비교 분석하고자 하였다. 연구방법: 이전의 클로미펜을 사용한 배란유도 주기에서 8 mm 미만의 얇은 자궁내막을 보였던 불임 환자들에서 시행된 성선자극호르몬 병합 과배란유도/인공수정 51주기가 연구에 포함되었다. 월경주기 제3일째부터 5일 동안 클로미펜+성선자극호르몬 군은 일일 클로미펜 100 mg을 투여하였고 (n=26) 레트로졸+성선자극호르몬 군은 일일 레트로졸 2.5 mg 또는 5 mg을 투여하였다 (n=25). 양 군에서 월경주기 제5~7일째부터 우성난포의 크기가 18 mm 이상에 도달할 때까지 이틀에 한 번씩 성선자극호르몬은 75~150 IU를 투여하였다. 양 군에서 성선자극호르몬 총 사용량, 자궁내막의 두께, 자궁내막의 형태, hCG 투여일의 14 mm 이상 난포의 수, hCG 투여일, 임신율, 다태 임신율을 비교하였으며 통계 분석은 Mann-Whitney U test or Fisher's exact test 등을 이용하였다. 결 과: 연령, 불임기간, 이전 인공수정 횟수, 기저 혈중 LH, FSH, $E_2$ 농도, 불임의 원인 등의 임상적 특성은 양 군간 차이가 없었다. 성선자극호르몬 병합 과배란유도시 배란전 자궁내막의 두께는 이전의 클로미펜을 사용한 주기와 비교하여 유의하게 증가되었다. 성선자극호르몬 총 사용량, hCG 투여일, 자궁내막의 삼중선 비율, 임신율 및 다태 임신율은 유의한 차이가 없었다. 클로미펜+성선자극호르몬 군에 비하여 레트로졸+성선자극호르몬 군에서 14 mm 이상 난포의 개수는 유의하게 적었고 ($3.7{\pm}1.7$ vs. $2.8{\pm}1.7$, p=0.03). 배란 전 자궁내막 두께는 유의하게 두꺼웠다 ($7.7{\pm}1.5\;mm$ vs. $9.1{\pm}1.7\;mm$, p<0.05). 결 론: 배란유도를 위하여 클로미펜 사용시 얇은 자궁내막을 보였던 환자들에서 인공수정을 위한 과배란유도시클로미펜 또는 레트로졸을 성선자극호르몬과 병합하여 사용하는 방법은 클로미펜의 자궁내막에 대한 부정적인 효과를 피할 수 있는 것으로 사료된다. 적절한 자궁내막의 발달 및 적절한 난포의 성장 측면에서 성선자극호르몬에 레트로졸을 병합하는 과배란유도 방법이 클로미펜을 병합하는 방법에 비하여 더 유용할 수 있으나 추가적인 대규모 전향적 연구가 필요할 것으로 사료된다.

Objective: The aim of this study was to compare the clinical efficacy of clomiphene citrate (CC) and letrozole combined with gonadotropins for controlled ovarian stimulation (COS) in patients with CC-induced thin endometrium Methods: Fifty-one intrauterine insemination cycles performed in patients who previously had a thin endometrium (<8 mm) to ovulation induction using CC were included in this study. A CC 100 mg/day (CC+gonadotropin group, n=26) or letrozole 2.5 or 5 mg/day (letrozole+gonadotropin group, n=25) was administered on day 3~7 of the menstrual cycle, combined with gonadotropins at dose 75~150 IU every other day starting on day 5~7. We compared total dose of gonadotropin used, endometrial thickness, endometrial pattern, number of follicles ${\geq}14\;mm$ on hCG day, pregnancy rate and multiple pregnancy rate between the two groups, which were statistically analyzed using Mann-Whitney U test or Fisher's exact test, where appropriate. Results: There were no significant differences in clinical characteristics such as age, duration of infertility, number of previous IUI cycles, basal serum hormone levels and cause of infertility between the two groups. In both groups, the endometrium was significantly thicker than that of previous ovulation induction cycles using CC. No significant differences were found in the total dose of gonadotropin used, day of hCG administration, the rate of triple endometrium and pregnancy rate. The number of follicles ${\geq}14\;mm$ was significantly lower ($3.7{\pm}1.7$ vs. $2.8{\pm}1.7$, p=0.03) and the endometrium on hCG day was significantly thicker ($7.7{\pm}1.5$ vs. $9.1{\pm}1.7$, p=0.001) in letrozole+gonadotropin group compared to CC+gonadotropin group. Conclusion: The clomiphene citrate and letrozole combined with gonadotropins appear to avoid the undesirable effects on the endometrium frequently seen with CC for ovulation induction. However, in terms of adequate endometrial development or optimal follicular growth, letrozole may be more beneficial than CC for gonadotropin-combined COS in patients with CC-induced thin endometrium. Further prospective randomized controlled studies in a larger scale will be necessary to confirm our findings.

키워드

참고문헌

  1. Adashi EY. Ovulation induction: clomiphene citrate. In: Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive endocrinology, surgery and technology. Lippencott-Raven, Philadelphia, PA 1996; 1: 1181-206
  2. Deaton JL, Gibson M, Blackmer KM, Nakajima ST, Badger GJ, Brumsted JR. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990; 54: 1083-8
  3. Glazener CM, Coulson C, Lambert PA, Watt EM, Hinton RA, Kelly NG, et al. Clomiphene treatment for women with unexplained infertility: placebo-controlled study of hormonal responses and conception rates. Gynecol Endocrinol 1990; 4:75-83 https://doi.org/10.3109/09513599009012324
  4. Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998; 70: 207-13 https://doi.org/10.1016/S0015-0282(98)00177-0
  5. Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod 1996; 11: 2623-8
  6. Gorlitsky GA, Kase NG, Speroff L. Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol 1978; 51: 265-9 https://doi.org/10.1097/00006250-197803000-00002
  7. Garcia J, Jones GS, Wentz AC. The use of clomiphene citrate. Fertil Steril 1977; 28: 707-17
  8. Hammond MG. Monitoring techniques for improved pregnancy rates during clomiphene ovulation induction. Fertil Steril 1984;42: 499-509
  9. Gysler M, March CM, Mishell DR, Bailey EJ. A decades experience with an individualized clomiphene treatment regimen including its effects on the postcoital teat. Fertil Steril 1982; 37: 161-7 https://doi.org/10.1016/S0015-0282(16)46033-4
  10. Gonen Y, Casper RF. Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth. Hum Reprod 1990; 5: 670-4 https://doi.org/10.1093/oxfordjournals.humrep.a137165
  11. Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson ME. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 1989; 73: 187-90
  12. Opsahl MS, Robins ED, O'Connor DM, Scott RT, Fritz MA. Characteristics of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate treatment. Fertil Steril 1996; 66: 533-9 https://doi.org/10.1016/S0015-0282(16)58564-1
  13. Dickey RP, Olar TT, Taylor SN, Curole DN, Harrigill K. Relationship of biochemical pregnancy to pre-ovulatory endometrial thickness and pattern in patients undergoing ovulation induction. Hum Reprod 1993; 8: 327-30
  14. Casper RF. Letrozole: ovulation or superovulation? Fertil Steril 2003; 80: 1335-7 https://doi.org/10.1016/j.fertnstert.2003.05.004
  15. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation induction. Semin Reprod Med 2004; 22: 61-78 https://doi.org/10.1055/s-2004-823028
  16. Ivoson T, Smith I, Ahern J, Smithers D, Trunel P, Dowseh M. Phase I study of the oral nonsteroidal aromatase inhibiter COS 20267 in post menopausal patients with advanced breast cancer. Cancer Res 1993; 53: 266-70
  17. Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol 2005; 192: 381-6 https://doi.org/10.1016/j.ajog.2004.08.013
  18. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001; 75: 305-9 https://doi.org/10.1016/S0015-0282(00)01705-2
  19. 김혜옥, 양광문, 허 걸, 박찬우, 차선화, 김해숙 등. 클로미펜에 부적절한 반응을 보이는 다낭성난소증후군 환자에서 Aromatase Inhibitor의 유용성. 대한불임학회지 2005; 32: 27-32
  20. Eijkemans MJ, Polinder S, Mulders AG, Laven JS. Habbema JDF, Fauser BC. Individualized cost-effective conventional ovulation induction treatment in normogonadotrophic anovulatory infertility (WHO group 2). Hum Reprod 2005; 20: 2830-7 https://doi.org/10.1093/humrep/dei164
  21. Matorras R, Diaz T, Corcostegui B, Ramon O, Pijoan JI, Rodriguez-Escudero FJ. Ovarian stimulation in intrauterine insemination with donor sperm: a randomized study comparing clomiphene citrate in fixed protocol versus highly purified FSH. Hum Reprod 2002; 17: 2107-11 https://doi.org/10.1093/humrep/17.8.2107
  22. Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotropin dose required for controlled ovarian stimulation in women with unexplained infertility. Hum Reprod 2003; 18:1588-97 https://doi.org/10.1093/humrep/deg311
  23. Bedaiwy MA, Forman R, Mousa RA, Hesham G, Inany AI, Casper RF. Cost-effectiveness of aromatase inhibitor cotreatment for controlled ovarian stimulation. Hum Reprod 2006; 21: 2838-44 https://doi.org/10.1093/humrep/del273
  24. Jee BC, Ku SY, Suh CS, Kim KC, Lee WD, Kim SH. Use of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemination cycles: a pilot study. Fertil Steril 2006; 85: 1774-7 https://doi.org/10.1016/j.fertnstert.2006.02.070
  25. Casper RF, Mitwally MFM. Review: aromatase inhibitors for ovulation induction. J Clin Endocrinol Metabol 2006; 91: 760-71 https://doi.org/10.1210/jc.2005-1923
  26. Requena A, Herrero J, Landeras J, Navarro E, Neyro JL, Salvador C, et al. Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum Reprod Update 2008; 14: 571-82 https://doi.org/10.1093/humupd/dmn033
  27. Ensieh Sh, Tehrani N, Zhila A, Batool H, Rashidi, Elham Azimi. Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphen citrate gonadotropins in controlled ovarian hyperstimulation: a prospective, simply randomized, clinical trial. J Assist Reprod Genet 2008; 25: 187-90 https://doi.org/10.1007/s10815-008-9209-2
  28. Kolibianakis EM, Zikopoulos KA, Fatemi HM, Osmanagaoglu K, Evenpoel J, Van Steirteghem A, et al. Endometrial thickness cannot predict ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination. Reprod Biomed Online 2004; 8: 115-8 https://doi.org/10.1016/S1472-6483(10)60505-6
  29. Warrington C, Faraj R, Willett M. Endometrial thickness and outcome in sub-fertile women treated with clomiphene citrate. J Obstet Gynaecol 2008; 28: 626-8 https://doi.org/10.1080/01443610802355718
  30. Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responder. Fertil Steril 2002; 7: 776-80