Journal of South Asian Federation of Obstetrics and Gynaecology

Register      Login

VOLUME 10 , ISSUE 4S2 ( October-December, 2018 ) > List of Articles

Original Article

Clomiphene Citrate versus Letrozole for Ovulation Induction in PCOS: A Comparative Study

Keywords : Clomiphene citrate, Follicle, Infertility, IVF, Letrozole, Pregnancy

Citation Information : Clomiphene Citrate versus Letrozole for Ovulation Induction in PCOS: A Comparative Study. J South Asian Feder Obs Gynae 2018; 10 (4S2):384-399.

DOI: 10.5005/jp-journals-10006-1631

License: CC BY-NC 4.0

Published Online: 01-06-2019

Copyright Statement:  Copyright © 2018; The Author(s).


Abstract

Polycystic ovary syndrome (PCOS) affects 20–33% of women of reproductive age and the leading cause of infertility. Treatment includes lifestyle modification, metformin, ovulation induction, surgery, in vitro fertilization. Clomiphene citrate is most commonly used for ovulation induction but is antiestrogenic. Clomiphene resistance occurs in 15–20% of patients. Letrozole, an aromatase inhibitor, inhibits aromatization thus conversion of androstenedione and testosterone to estrogen in the ovary. This releases the hypothalamic/pituitary axis from estrogenic negative feedback, follicle stimulating hormone secretion increases, stimulating ovarian follicular development. We compared clomiphene citrate vs letrozole for ovulation induction in the treatment of anovulatory infertility in women with the polycystic ovarian syndrome. Two hundred consecutive women were observed for a number of cycles required to achieve ovulation, follicular growth, endometrial thickness, dominant follicle size, pregnancy, multiple, and abortion rates. The groups were matched for age, parity, duration of married life, menstrual regularity and prior history of treatment for infertility. Clomiphene showed a significantly increased number of follicles. Monofollicular development and endometrial thickness were higher in the letrozole group. The difference in dominant follicle size, number of cycles to achieve pregnancy or difference in ovulation rate per cycle, number of pregnancies and pregnancy losses per cycle lacked statistical significance. Greater number of follicles in the clomiphene group did not result in increased pregnancy rate. A number of pregnancies were marginally higher but not statistically significant in the letrozole group. There were one quadruplet and one twin gestation in the clomiphene group with none in the letrozole group. This data was not sufficient for statistical analysis. There were no instances of ovarian hyperstimulation syndrome or congenital anomalies in either group.


PDF Share
  1. Balen AH, Conway GS, et al. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod 1995;10:2107-2111
  2. Polson DW, Adams J, et al. Polycystic ovaries–a common finding in normal women. Lancet 1988;1:870-872.
  3. Farquhar CM, Birdsall M, et al. The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Aust N Z J Obstet Gynaecol 1994;34:67-72.
  4. Michelmore KF, Balen AH, et al. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol Oxf 1999;51:779-786.
  5. Franks S. Polycystic ovary syndrome. New England Journal of Medicine 1995;333:853-861.
  6. Sperling L, Heimer W. Androgen biology as a basis for the diagnosis and treatment of androgenic disorders in women. Int J Am Acad Dermatol 1993;28:669-681.
  7. Nelson VL, Legro RS, et al. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol 1999;13:946-957.
  8. Gilling–Smith C, Willis DS, et al. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab 1994;79:1158-1165
  9. Gilling–Smith C, Story H, et al. Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovarian syndrome. Clin Endocrinol 1997;47:93-99
  10. Conway GS, Clark PM, et al. Hyperinsulinemia in the polycystic ovary syndrome confirmed with a specific immunoradiometric assay for insulin. Clinical Endocrinology [Oxford] 1993;38:219-222.
  11. Schwartz R. Acanthosis nigricans. J Am Acad Dermatol 1994; 31:1-19.
  12. Burghen GA, Givens JR, et al. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980; 50:113-116.
  13. Coulam CB, Annegers JF, et al. Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol 1983;61:403-407.
  14. Azziz R. The Rotterdam 2003 Criteria for defining PCOS. Can or how to define syndrome. J Clin Endocrinol Metab First Published January 2003;17:2006.
  15. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop Group, Revised consensus or diagnostic criteria and long term health risks related to polycystic ovary syndrome, 2003.
  16. Fulghesu AM, Ciampelli M, et al. A new ultrasound criteria for the diagnosis of polycystic ovary syndrome: the ovarian stroma total area ratio. Fertil Steril 2001;76:326-331.
  17. Burton J, Shuster S. The relationship between seborrhea and acne vulgaris. British journal of Dermatol 1971;84:600-602.
  18. Simpson N, Barth J. Hair patterns: hirsuties and androgenic alopecia. In R Dawber (ed): Diseases of the hair and scalp. Oxford: Blackwell Science 1997; 67-122.
  19. Dunaif A, Hoffman A, et al. Clinical, biochemical and ovarian morphologic features in women with acanthosis nigricans and masculinization. Obstetrics and gynaecology 1985;66;545-552.
  20. Morin–Papunen LC, et al. Endocrine and metabolic effects of metformin vs. ethinyl estradiol-cyproterone acetate in obese women with polycystic ovarian syndrome: randomized study. J Clin Endo and Metab 2000;85(9):3161-3168.
  21. Pasquali R, Gambineri A, et al. Effect of long term treatment with metformin added to hypocaloric diet on body composition, fat distribution and androgen and insulin levels in abdominally obese with and without polycystic ovary syndrome. J of Clin Endo and Metab 2000;85(8):2767-2774
  22. Tasdemir S, Ficicioglu C, et al. The effect of metformin treatment to ovarian response in cases with PCOS. Arch Gynaecol Obstet 2003;23.
  23. Barbieri R L. Metformin for the treatment of polycystic ovary syndrome. Obstet Gynaecol 2003;101(4)785-793.
  24. Greenbhatt RB. Chemical induction of ovulation. Fertil Steril 1961;12:402.
  25. Gjonaess H. Polycystic ovarian syndrome treated by ovarian electrocautery through laparoscopy. Fertil Steril 1984;41:20-25.
  26. Abdel Gadir A, Mowafi RS, et al. Ovarian electrocautery versus human menopausal gonadotrophins and pure follicle stimulating hormone therapy in the treatment of patients with polycystic ovarian disease. Clin Endocrinol [Oxf.] 1990;33:585-592.
  27. Lessing JB, Amit A, et al. Avoidance of cancellation of potential hyperstimulation cycle by conversion to in vitro fertilization- embryo transfer. Fertil Steril 1991;56(1):75-78.
  28. Kyei-Mensah A, Maconochie N, et al. Transvaginal three dimensional ultrasound: reproducibility of ovarian and endometrial volume measurements. Fertil Steril 1996;5:718-722
  29. Levene MI, Wild J, et al. Higher multiple births and the modern management of infertility in Britain. Br J Obstet Gynaecol 1992; 99:607-613
  30. Botting BJ, Macfarlane AJ, et al. [eds.] Three, four and more: a study of triplet and higher order births. HMSIO, London 1990.
  31. Sammour A, Biljan MM, et al. Prospective randomized trial comparing the effects of letrozole and clomiphene citrate on follicular development, endometrial thickness and pregnancy rate in patients undergoing superovulation prior to intrauterine insemination. Fertil Steril 2001;76(suppl-1):S110.
  32. Stein IF, Leventhal ML. Amenorrhoea associated with PCOS. Am J Obst and Gynaecol 1935;29:181-191.
  33. Dahlgren E, Johannsen S, et al. Women with polycystic ovary disease wedge resected in 1956-1965: A long term follow up focusing on natural history and circulating hormones. Fertil Steril 1992;57:505-513.
  34. Donesky BW, Adashi EY. Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. Fertil Steril 1995;63:439-463
  35. Stein IF, Cohen MR, et al. Results of bilateral ovarian wedge resection in 47 cases of sterility. Am J Obst and Gynae 1948; 58:267-273.
  36. Chereau A. Memoire pour server a I’ Etude des Maladies des ovaries. Paris: Fortin. Masson and Cie, 1844.
  37. Dickey RP, Taylor SN, et al. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod 1996; 11:2623-2628.
  38. Hammond MG. Monitoring techniques for improved pregnancy rates during clomiphene ovulation induction. Fertil Steril 1984;42:499-508.
  39. Hammond M, Halme J, et al. Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation. Obstet Gynaecol 1983;62:196-202
  40. Adams J, Franks S, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet 1985;(2):1375-1378
  41. Badawy A, Aal IA, et al. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome? A prospective randomized trial. 14th World Congress On In Vitro Fertilization And Third World Congress On In Vitro Maturation, 2007.
  42. Randall JM, Templeton A. Cervical mucus score and in vitro sperm mucus interaction in spontaneous and clomiphene citrate cycles. Fertil Steril 1991;56:465-468.
  43. Gonen Y, Casoer RF. Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth. Hum Reprod 1990;5:670-674.
  44. Rossing MA, Daling JR, et al. Ovarian tumours in a cohort of infertile women. N Engl J Med 1994;331:771-776
  45. Mitwally MFM, Casper RF. Aromatase inhibition: a novel method of ovulation induction in women with polycystic ovarian syndrome. Report Technol 2000:10:244-247.
  46. Okman KT, Kucuk M, et al. Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium and hormone levels in the rat. Fertil Steril 2003; 80:1330-1332.
  47. Tulandi T, Martin J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761-1765.
  48. Mitwally MFM, Casper RF. The use of an aromatase inhibitor for induction of ovulation in cases of clomiphene failure [abstract]. In program and abstracts of the 16th Annual Meeting of the European Society for Human Reproduction and Embryology [ESHRE]. Bologna. Italy June 2000;15:71.
  49. Mitwally MFM, Casper RF. The aromatase inhibitor, letrozole, decreases FSH dose required for ovarian superovulation. In: Proceedings of the 46th Annual Meeting of the Canadian Fertility and Andrology Society, September 2000; New foundland, Canada.
  50. Mitwally MFM, Casper RF. Aromatase inhibition improves response to controlled ovarian hyperstimulation without the antioestrogenic effects of clomiphene citrate [abstract]. J Soc Gynecol Investi 2001:8:85A
  51. Mitwally MFM, Casper RF. Aromatase inhibition improves ovarian response to FSH a potential option for low responders during ovarian stimulation. Fertil Steril 2001;75:(4 Suppl 1):S8-S9.
  52. Mitwally MRM, Casper RF. Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305-309.
  53. Cortinez I, De Carvalho D, et al. Hormonal profile and endometrial morphology in letrozole controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril. 2005;83:110-115.
  54. Fischer SA, Reid RL, et al. A randomized double blind comparison of the effects of clomiphene citrate and the aromatize inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002;78:280-285.
  55. Kilic Okman T, Kucuk M, et al. Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium and hormone levels in the rat. Fertil Steril 2003;80:1330-1332.
  56. Al-Fouzan H, Al-Khadouri M, et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82:1561-1563.
  57. Bayar U, Tanriverdi HA, et al. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006;85:1045-1048.
  58. Bishai R, Arbour L, et al. Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous. Teratology 1999;60:143-145.
  59. Mitwally MFM, Biljan M, et al. Pregnancy outcome after the use of an aromatase inhibitor for ovulation stimulation. Am J Obstet Gynecol 2005;192:381-386.
  60. Nejad TE, Abediasl Z, et al. Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphene citrate gonadotropins in controlled ovarian hyperstimulation: a prospective, simply randomized, clinical trial. J Assist Reprod and Genet 2008;25(5):187-190.
  61. Bedaiwy M, Forman R, et al. Cost effectiveness of aromatase inhibitor cotreatment for controlled ovarian stimulation. Human Reprod 2006;21:2838-2344.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.