Effects of Aromatase Inhibitor on Reproductive Hormone Profiles and Ovulation Induction

방향화효소억제제의 생식호르몬 분비와 배란유도에 대한 효과

  • Kim, Sook-Hyun (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Kim, Jeong-Ah (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Park, Joon-Cheol (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Bae, Jin-Gon (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Shin, So-Jin (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Kwon, Sang-Hoon (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Cho, Chi-Heum (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Yoon, Sung-Do (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Cha, Soon-Do (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Kim, Jong-In (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University) ;
  • Rhee, Jeong-Ho (Department of Obstetrics and Gynecology, School of Medicine, Keimyung University)
  • 김숙현 (계명대학교 의과대학 산부인과학교실) ;
  • 김정아 (계명대학교 의과대학 산부인과학교실) ;
  • 박준철 (계명대학교 의과대학 산부인과학교실) ;
  • 배진곤 (계명대학교 의과대학 산부인과학교실) ;
  • 신소진 (계명대학교 의과대학 산부인과학교실) ;
  • 권상훈 (계명대학교 의과대학 산부인과학교실) ;
  • 조치흠 (계명대학교 의과대학 산부인과학교실) ;
  • 윤성도 (계명대학교 의과대학 산부인과학교실) ;
  • 차순도 (계명대학교 의과대학 산부인과학교실) ;
  • 김종인 (계명대학교 의과대학 산부인과학교실) ;
  • 이정호 (계명대학교 의과대학 산부인과학교실)
  • Published : 2008.06.30

Abstract

Objective: To investigate the effects of aromatase inhibitor on reproductive hormone profiles and evaluate it's ovulation inducing capability in anovulatory infertile women. Methods: We quantified the blood levels of reproductive hormones from 30 healthy normal cycling women in natural cycle (control) and letrozole medicated cycle (study). LH, FSH, estradiol, testosterone, DHEA-S were quantified on third, 11th, 21th day in both cycles, and on 21th day, progesterone was added. Sixth anovulatory infertile women received either letrozole or clomiphene citrate for ovulation induction (n=30 in each groups). We compared the clinical parameters such as ovulation rate, pregnancy rate, the day of LH surge, number of follicles and endometrial thickness, cervical mucus amount, spinnbarkeit, mean diameter of follicles on the day of LH surge. Results: Letrozole had no effect on the LH, FSH, estradiol, DHEA-S secretion but there were significant increase in testosterone level on day 11 and progesterone level on day 21 in letrozole medicated cycle compared than control cycle ($0.40{\pm}0.16$ vs $0.28{\pm}0.11\;ng/ml$, p=0.002, $18.18{\pm}13.07$ vs $8.38{\pm}7.64\;ng/ml$, p=0.001, respectively). In comparison between letrozole and clomiphene groups, there were no significant difference in ovulation rate, pregnancy rate, number of mature follicle, mean diameter of follicles, but showed earlier LH surge, thicker endometrium, more cervical mucus, and higher spinnbarkeit in letrozole group ($12.12{\pm}2.46$ vs $14.52{\pm}3.18$ days, p=0.006, $10.48{\pm}1.23$ vs $8.52{\pm}0.93\;mm$, p=0.000, $2.04{\pm}0.61$ vs $1.57{\pm}0.59$, p=0.012, $6.00{\pm}1.12$ vs $4.95{\pm}1.61\;cm$, p=0.003, respectively). Conclusion: Letrozole may augment folliculogenesis and improve the endometrial condition for implantation in normal cycling women. Ovulation efficacy of letrozole in anovulatory women was comparable to clomiphene citrate and letrozole may be more physiological in ovulation induction.

목 적: 방향화효소억제제가 생식호르몬 분비 양상에 미치는 영향과 무배란 여성에서의 배란유도 효과를 평가하기 위함. 연구방법: 정상 월경주기를 가진 여성 30명을 대상으로 letrozole을 투여하지 않은 주기 (대조군)와 투여한 주기 (연구군)에서 생식호르몬 혈중치를 측정하였다. 각 월경주기 3, 11, 21일에 LH, FSH, $E_2$, testosterone, DHEA-S의 혈중치를 측정하였고 각 주기 21일에는 progesterone 측정이 추가되었다. 불임의 원인이 무배란으로 진단된 환자 60명에게 크로미펜과 letrozole을 투여한 후 (각 치료 군, 30명) 배란율, 임신율, LH 분비폭발 시점, 성장 난포 수, 자궁내막 두께, 자궁경관 점액의 양과 견사성, LH 분비폭발 시점의 난포 직경 등을 측정하여 두 군 간의 임상 효과를 비교하였다. 결 과: Letrozole은 LH, FSH, $E_2$, DHEA-S 분비에는 영향을 미치지 않았으나 letrozole 투여 주기 11일째의 testosterone과 21일째의 progesterone 혈중치는 대조군에 비해 유의한 상승을 보였다 ($0.40{\pm}0.16$ vs $0.28{\pm}0.11\;ng/ml$, p=0.002, $18.18{\pm}13.07$ vs $8.38{\pm}7.64\;ng/ml$, p=0.001). Letrozole과 크로미펜 군 간의 배란유도 효과에 대한비교에서 배란율, 임신율, 성장 난포 수, 배란 전 난포 직경에서는 두 군 간에 유의한 차이가 없었으나 크로미펜 군과 비교할 때 letrozole 군에서 조기에 LH 분비폭발이 발생했고 ($12.12{\pm}2.46$일 vs $14.52{\pm}3.18$, p=0.006), LH 분비폭발 시점에서의 자궁내막 두께가 두꺼웠으며 ($10.48{\pm}1.23$ vs $8.52{\pm}0.93\;mm$, p=0.000), 자궁경관 점액 양이 많았고 견사성이 높았다 ($2.04{\pm}0.61$ vs $1.57{\pm}0.59$, p=0.012, $6.00{\pm}1.12$ vs $4.95{\pm}1.61\;cm$, p=0.003). 결 론: Letrozole은 정상 월경주기를 가진 여성에서 난포 성장을 촉진하고 자궁내막을 호전시키며 무배란 여성에서는 크로미펜에 필적하는 배란유도 효과가 있으며 더욱 생리적인 배란유도가 이루어질 것으로 사료된다.

Keywords

References

  1. Greenblatt RB, Barfield WE, Jugck EC, Ray AW. Induction of ovulation with MRL/41: preliminary report. JAMA 1961; 178: 101-4 https://doi.org/10.1001/jama.1961.03040410001001
  2. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996; 2: 408-506
  3. 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
  4. 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: 633-9
  5. Dickey RP, Olar TT, Taylor SN, Curole DN, Harrigill K. Relationship of biochemical pregnancy to preovulatory endometrial thickness and pattern in ovulation induction patients. Hum Reprod 1993; 8: 327-30 https://doi.org/10.1093/oxfordjournals.humrep.a138045
  6. Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil Steril 2006; 85: 277-84 https://doi.org/10.1016/j.fertnstert.2005.05.078
  7. Mitwally MFM, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002; 77: 776-80 https://doi.org/10.1016/S0015-0282(01)03280-0
  8. Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, Bondy CA. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab 1998; 83: 2479-89 https://doi.org/10.1210/jc.83.7.2479
  9. Adashi E. Intraovarian regulation: the proposed role of insulinlike growth factors. Ann NY Acad Sci 1993; 687: 10-2 https://doi.org/10.1111/j.1749-6632.1993.tb43847.x
  10. Giudice LC. Insulin-like growth factors and ovarian follicular development. Endocr Rev 1992; 13: 641-69
  11. Yen SSC, Laughlin GA, Morales AJ. Interface between extraand intra-ovarian factors in polycystic ovary syndrome (PCOS). Ann NY Acad Sci 1993; 687: 98-111 https://doi.org/10.1111/j.1749-6632.1993.tb43858.x
  12. Cortínez A, De Carvalho I, vantman D, Gabler F, Iñiguez G, Vega M. Hormone profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril 2005; 83: 110-5 https://doi.org/10.1016/j.fertnstert.2004.05.099
  13. Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002; 78: 280-5 https://doi.org/10.1016/S0015-0282(02)03241-7
  14. Mitwally MFM, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fetil Steril 2001; 75: 305-9 https://doi.org/10.1016/S0015-0282(00)01705-2
  15. Bayar U , Basaran M, Kiran S, Coskun A, Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial. Fertil Steril 2006; 86: 1447-51 https://doi.org/10.1016/j.fertnstert.2006.04.026
  16. Begum MR, Quadir E, Begum A, Begum RA, Begum M. Role of aromatase inhibitor in ovulation induction in patients with poor response to clomiphene citrate. J Obstet Gynaecol Res 2006; 32: 502-6 https://doi.org/10.1111/j.1447-0756.2006.00434.x
  17. Garcia-Velasco JA, Moreno L, Pacheco A, Guillén A, Duque L, Requena A, Pellicer A. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in lower responder patients: a pilot study. Fertil Steril 2005; 84: 82-7 https://doi.org/10.1016/j.fertnstert.2005.01.117
  18. Mitwally MFM, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility. Hum Reprod 2003; 18: 1588-97 https://doi.org/10.1093/humrep/deg311
  19. Mitwally MFM, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002; 77: 776-80 https://doi.org/10.1016/S0015-0282(01)03280-0
  20. Barroso G, Menocal G, Felix H, Rojas-Ruiz JC, Arslan M, Oehninger S. Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphene citrate as adjuvants to recombinant follicle-stimulating hormone in controlled ovarian hyperstimulation: a prospective, randomized, blinded clinical trial. Fertil Steril 2006; 86: 1428-31 https://doi.org/10.1016/j.fertnstert.2006.03.044
  21. Bedaiwy MA, Forman R, Mousa NA, Al Inany HG, Casper RF. Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation. Hum Reprod 2006; 21: 2838-44 https://doi.org/10.1093/humrep/del273
  22. Mitwally MFM, Casper RF. Single-dose administration of an aromatase inhibitor for ovarian stimulation. Fertil Steril 2005; 83: 229-31 https://doi.org/10.1016/j.fertnstert.2004.07.952
  23. Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005; 84(Suppl), S95
  24. Tulandi T, Al-Fadhli R, Kabli N, Martin J, Forman R, Hitkari J, Librach C, Greenblatt E, Casper R. Congenital malformations among 911 newborns conceived following letrozole or clomiphene citrate for infertility treatment. Fertil Steril 2006; 85: 1761-5 https://doi.org/10.1016/j.fertnstert.2006.03.014