Drugs

, Volume 50, Issue 3, pp 480–494 | Cite as

Pharmacological Interventions for the Induction of Ovulation

  • John A. Collins
  • Edward G. Hughes
Practical Therapeutics

Summary

Ovulation induction is the most common medical intervention for the treatment of infertility. Clomifene is generally the first treatment choice for patients with amenorrhoea, unless there is profound hypothalamic deficiency. When Clomifene fails to induce ovulation, menotropins (human menopausal gonadotrophin) or gonadotrophin-releasing hormone (GnRH) are effective, most notably in WHO group 1. In this condition associated with low estrogen and gonadotrophin levels, the aggregate of reported pregnancy rates is 25% per cycle. In hyperprolactinaemic anovulation bromocriptine reduces prolactin levels and thereby restores normal cyclicity. In all of the above conditions, the pharmacological agent addresses a specific defect in an explicit manner.

WHO group 2 ovulatory disorders arise from hyperandrogenicity and other conditions that respond less predictably to gonadotrophin therapy. In women with WHO group 2 disorders, the aggregate of reported pregnancy rates is 8%. Ovulation induction is also used in ovulatory infertile women to generate multiple follicles and increase the likelihood of fertilisation. The aggregate of pregnancy rates in Clomifene trials was 7% per cycle, and 6% in gonadotrophin trials. Gonadotrophin therapy is more effective, however, in association with assisted reproduction techniques. The contrasting treatment success in discrete disorders (25% per cycle) and heterogeneous disorders such as WHO group 2 and persistent infertility (6 to 8% per cycle) underlines the need for research to discover specific causal mechanisms and identify explicit new pharmacological interventions.

Keywords

Adis International Limited Infertility Endometriosis Pregnancy Rate Bromocriptine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mosher WD, Pratt WE Fecundity and infertility in the United States: incidence and trends. Fertil Steril 1991; 56: 192–3PubMedGoogle Scholar
  2. 2.
    Collins JA, Burrows EA, Willan A. Infertile couples and their treatment in Canadian academic infertility clinics. In: Royal Commission on New Reproductive Technologies, editors. Treatment of infertility: current practices and psychosocial implications. Ottawa: Ministry of Supply and Services Canada, 1993: 313–40Google Scholar
  3. 3.
    Kliger BE. Evaluation, therapy, and outcome in 493 infertile couples. Fertil Steril 1984; 41: 40–6PubMedGoogle Scholar
  4. 4.
    Collins JA, Rand CA, Wilson EH, et al. The better prognosis in secondary infertility is associated with a higher proportion of ovulation disorders. Fertil Steril 1986; 45: 611–6PubMedGoogle Scholar
  5. 5.
    Hull MGR, Glazener CMA, Kelly NJ, et al. Population study of causes, treatment, and outcome of infertility. BMJ 1985; 291: 1693–7PubMedCrossRefGoogle Scholar
  6. 6.
    Verkauf BS. The incidence and outcome of single-factor, multifactorial, and unexplained infertility. Am J Obstet Gynecol 1983; 147: 175–81PubMedGoogle Scholar
  7. 7.
    Harrison RF. Pregnancy successes in the infertile couple. Int J Fertil 1980; 25: 81–7PubMedGoogle Scholar
  8. 8.
    Thomas AK, Forrest MS. Infertility: a review of 291 infertile couples over eight years. Fertil Steril 1980; 34: 106–11PubMedGoogle Scholar
  9. 9.
    Newton J, Craig S, Joyce D. The changing pattern of a comprehensive infertility clinic. J Biosoc Sci 1974; 6: 477–82PubMedCrossRefGoogle Scholar
  10. 10.
    Raymont A, Arronet GH, Arrata WSM. Review of 500 cases of infertility. Int J Fertil 1969; 14: 141–53PubMedGoogle Scholar
  11. 11.
    Lamb E, Cruz A. Data collection and analysis in an infertility practice. Fertil Steril 1972; 23: 310–9PubMedGoogle Scholar
  12. 12.
    Dor J, Homburg R, Rabau E. An evaluation of etiologic factors and therapy in 665 infertile couples. Fertil Steril 1977; 28: 718–22PubMedGoogle Scholar
  13. 13.
    Sorensen SS. Infertility factors: their relative importance and share in an unselected material of infertility patients. Acta Obstet Gynecol Scand 1980; 59: 513–20PubMedCrossRefGoogle Scholar
  14. 14.
    Southam AL, Buxton CL. Factors influencing reproductive potential. Fertil Steril 1957; 8: 25–35PubMedGoogle Scholar
  15. 15.
    Sloan W. Infertility in Northern Ireland: a retrospect of nine years in a fertility clinic. j Obstet Gynaecol Br Commonw 1964; 71: 404–17PubMedCrossRefGoogle Scholar
  16. 16.
    Home H. Therapeutic results in infertility: a new standard reporting system and an analysis of 200 infertile couples. Obstet Gynecol 1957; 10: 202–6Google Scholar
  17. 17.
    Turner V, Davis C, Carter. Correlation of estimated prognosis with some findings and results in 750 sterile couples. Am J Obstet Gynecol 1955; 70: 1189–98PubMedGoogle Scholar
  18. 18.
    Frank R. A clinical study of 240 infertile couples. Am J Obstet Gynecol 1950; 60: 645–54PubMedGoogle Scholar
  19. 19.
    West CP, Templeton AA, Lees MM. The diagnostic classification and prognosis of 400 infertile couples. Infertility 1982; 5: 127–44Google Scholar
  20. 20.
    Johansson C-J. Clinical studies on sterile couples with special reference to the diagnosis, etiology and prognosis of infertility. Acta Obstet Gynecol Scand 1957; 36 Suppl. 5: 1–168CrossRefGoogle Scholar
  21. 21.
    Belsey MA, Ware H. Epidemiological, social and psychosocial aspects of infertility. In: Insler V, Lunenfeld B, editors. Infertility: male and female. New York: Churchill Livingstone, 1986: 631–47Google Scholar
  22. 22.
    Wysowski DE. Use of fertility drugs in the United States, 1973 through 1991. Fertil Steril 1993; 60: 1096–8PubMedGoogle Scholar
  23. 23.
    Hughes E, Fedorkow DM, Collins JA. Aquantititative overview of controlled trials in endometriosis-associated infertility. Fertil Steril 1993; 59: 5: 963–70PubMedGoogle Scholar
  24. 24.
    Filicori M. Gonadotrophin-releasing hormone agonists: a guide to use and selection. Drugs 1994; 48: 41–58PubMedCrossRefGoogle Scholar
  25. 25.
    Soliman S, Daya S, Collins JA, et al. The role of luteal phase support in infertility treatment: a meta-analysis of randomized trials. Fertil Steril 1994; 61: 6: 1068–76PubMedGoogle Scholar
  26. 26.
    Insler V. Gonadotrophin therapy: new trends and insights. Int J Fertil 1988; 33: 85–97PubMedGoogle Scholar
  27. 27.
    Mantel N, Haenszel W Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719–48PubMedGoogle Scholar
  28. 28.
    Breslow NE, Day NE. Volume 1: the analysis of case-control studies. In: Davis W, editor. Statistical methods in cancer research. Lyon: International Agency for Research on Cancer, 1980: 136–57Google Scholar
  29. 29.
    Fluker MR, Urman B, Mackinnon M, et al. Exogenous gonadotrophin therapy in World Health Organization Groups I and II ovulatory disorders. Obstet Gynecol 1994; 83: 189–96PubMedGoogle Scholar
  30. 30.
    Scialli AR. The reproductive toxicity of ovulation induction. Fertil Steril 1986; 45: 315–22PubMedGoogle Scholar
  31. 31.
    Borenstein R, Shoham Z, Yemini M, et al. Tamoxifen treatment in women with failure of clomiphene citrate therapy. Aust NZ J Obstet Gynaecol 1989; 29: 173–5CrossRefGoogle Scholar
  32. 32.
    Suginami H, Kitagawa H, Nakahashi N, et al. A clomiphene citrate and tamoxifen citrate combination therapy: a novel therapy for ovulation induction. Fertil Steril 1993; 59(5): 976–9PubMedGoogle Scholar
  33. 33.
    Gysier M, March CM, Mishell DR, et al. A decade’s experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 1982; 37: 161–7Google Scholar
  34. 34.
    Connaughton JF, Garcia CR, Wallach Induction of ovulation with cisclomiphene and a placebo. Obstet Gynecol 1974; 43: 697–701PubMedGoogle Scholar
  35. 35.
    Cudmore DW, Tupper WRC. Induction of ovulation with clomiphene citrate. Fertil Steril 1966; 17: 363–73PubMedGoogle Scholar
  36. 36.
    Garcia CR, Freeman EW, Rickels K, et al. Behavioral and emotional factors and treatment responses in a study of anovulatory infertile women. Fertil Steril 1985; 44: 478–83PubMedGoogle Scholar
  37. 37.
    Johnson JE, Cohen MR, Goldferb AF, et al. The efficacy of clomiphene citrate for induction of ovulation. Int J Fertil 1966; 11: 265–70PubMedGoogle Scholar
  38. 38.
    Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 261Google Scholar
  39. 39.
    Correy JF, Newman NM, Collins JA, et al. Use of prescription drags in the first trimester and congenital malformations. Aust NZ J Obstet Gynaecol 1991; 31: 340–4CrossRefGoogle Scholar
  40. 40.
    Randall JM, Templeton A. Cervical mucus score and in vitro sperm mucus interaction in spontaneous and clomiphene citrate cycles. Fertil Steril 1991; 56: 465–8PubMedGoogle Scholar
  41. 41.
    Whittemore AS, Harris R, Itnyre J, et al. Characteristics relating to ovarian cancer risk: collaborative analysis 12 US case-control studies: II. Invasive epithelial cancers in white women. Am J Epidemiol 1992; 136: 1184–203PubMedGoogle Scholar
  42. 42.
    Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumours in a cohort of infertile women. N Engl J Med 1994; 331: 771–6PubMedCrossRefGoogle Scholar
  43. 43.
    Jones KP, Ravnikar VA, Schiff I. Results of human menopausal gonadotropin therapy at the Boston Hospital for Women (1979–1981). Int J Fertil 1987; 32: 131–4PubMedGoogle Scholar
  44. 44.
    March C. Improved pregnancy rate with monitoring of gonadotropin therapy by three modalities. Am J Obstet Gynecol 1987; 156: 1473–9PubMedGoogle Scholar
  45. 45.
    Caspi E, Levin S, Bukovsky I, et al. Induction of pregnancy with human gonadotropins after clomiphene failure in menstruating ovulatory infertility patients. Israel J Med Sci 1974; 10: 249–55Google Scholar
  46. 46.
    Ellis JD, Williamson JG. Factors influencing the pregnancy and complication rates with human gonadotrophin therapy. Br J Obstet Gynaecol 1975; 82: 52–7PubMedCrossRefGoogle Scholar
  47. 47.
    Lunenfeld Serr DM, Mashiach S, et al. Therapy with gonadotrophins: where are we today? Analysis of 2890 menotropin treatment cycles in 914 patients. In: Insler V, Bettendorf G, editors. Advances in diagnosis and treatment of infertility. New York: Elsevier North-Holland, 1981: 27–31Google Scholar
  48. 48.
    Lipitz S, Seidman DS, Alcalay M, et al. The effect of fertility drugs and in vitro methods on the outcome of 106 triplet pregnancies. Fertil Steril 1993; 60: 1031–4PubMedGoogle Scholar
  49. 49.
    Devroey P, Ubaldi F, Smitz J, et al. Recombinant follicle stimulating hormone. Assisted Reprod Rev 1994; 4: 2–9Google Scholar
  50. 50.
    Giudice E, Crisci C, Eshkol A, et al. Composition of commercial gonadotrophin preparations extracted from human postmenopausal urine: characterization of non-gonadotrophin proteins. Hum Reprod 1994; 9: 2291–9PubMedGoogle Scholar
  51. 51.
    Bachus KE, Hughes CL, Haney AF, et al. The luteal phase in polycystic ovary syndrome during ovulation induction with human menopausal gonadotropin with and without leuprolide acetate. Fertil Steril 1990; 54: 27–31PubMedGoogle Scholar
  52. 52.
    Dodson WC, Hughes C, Whitesides D, et al. The effect of leuprolide acetate on ovulation induction with human menopausal gonadotropins in polycystic ovary syndrome. J Clin Endocrinol Metab 1987; 65: 95–100PubMedCrossRefGoogle Scholar
  53. 53.
    Homburg R, Eshel A, Kilborn J, et al. Combined luteinizing hormone releasing hormone analogue and exogenous gonadotropins for the treatment of infertility associated with polycystic ovaries. Hum Reprod 1990; 5: 32–5PubMedGoogle Scholar
  54. 54.
    van Weissenbruch MM, Schoemaker HC, Drexhage HA, et al. Pharmaco-dynamics of human menopausal gonadotrophin (HMG) and follicle-stimulating hormone (FSH): the importance of the FSH concentration in initiating follicular growth in polycystic ovary-like disease. Hum Reprod 1993; 8: 813–21PubMedGoogle Scholar
  55. 55.
    Buvat J, Buvat-Herbaut M, Marcolin G, et al. Purified folliclestimulating hormone in polycystic ovary syndrome: slow administration is safer and more effective. Fertil Steril 1989; 52: 553–9PubMedGoogle Scholar
  56. 56.
    Dale PO, Tanbo T, Lunde O, et al. Ovulation induction with low-dose follicle-stimulating hormone in women with the polycystic ovary syndrome. Acta Obstet Gynecol Scand 1993; 72: 43–6PubMedCrossRefGoogle Scholar
  57. 57.
    Kim J-H, Richards CJ, Seibel MM. Proper selection of patients for intermediate-dose pure follicle stimulating hormone. J Reprod Med 1994; 39: 1–5PubMedGoogle Scholar
  58. 58.
    Strowitzki T, Seehaus D, Korell M, et al. Low-dose follicle stimulating hormone for ovulation induction in polycystic ovary syndrome. J Reprod Med 1994; 39: 499–503PubMedGoogle Scholar
  59. 59.
    Larsen T, Larsen JF, Schioler V, et al. Comparison of urinary human follicle-stimulating hormone and human menopausal gonadotropin for ovarian stimulation in polycystic ovary syndrome. Fertil Steril 1990; 53: 426–431PubMedGoogle Scholar
  60. 60.
    McFaul PB, Traub AI, Thompson W. Treatment of clomiphene citrate-resistant polycystic ovarian syndrome with pure follicle-stimulating hormone or human menopausal gonadotropin. Fertil Steril 1990; 53: 792–7PubMedGoogle Scholar
  61. 61.
    Seibel MM, McArdle C, Smith D, et al. Ovulation induction in polycystic ovary syndrome with urinary follicle-stimulating hormone or human menopausal gonadotropin. Fertil Steril 1985; 43: 703–8PubMedGoogle Scholar
  62. 62.
    Sagle MA, Hamilton-Fairley D, Kiddy DS, et al. A comparative, randomized study of low-dose human menopausal gonadotropin and follicle-stimulating hormone in women with polycystic ovarian syndrome. Fertil Steril 1991; 55: 56–60PubMedGoogle Scholar
  63. 63.
    Filicori M, Flamigni C, Meriggiola MC, et al. Ovulation induction with pulsatile gonadotropin-releasing hormone: technical modalities and clinical perspectives. Fertil Steril 1991; 56: 1–13PubMedGoogle Scholar
  64. 64.
    Martin KA, Hall JE, Adams JM, et al. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab 1993; 77: 125–9PubMedCrossRefGoogle Scholar
  65. 65.
    Filicori M, Flamigni C, Deliai P, et al. Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles. J Clin Endocrinol Metab 1994; 79: 1215–20PubMedCrossRefGoogle Scholar
  66. 66.
    Tang LCH, Sung ML, Ma HK. Hyperprolactinaemic amenorrhoea in Hong Kong. Aust NZ J Obstet Gynaecol 1983; 23: 165–9CrossRefGoogle Scholar
  67. 67.
    Al-Suleiman SA, Najashi S, Rahman J, et al. Outcome of treatment with bromocriptine in patients with hyperprolactinaemia. Aust NZ J Obstet Gynaecol 1989; 29: 176–9CrossRefGoogle Scholar
  68. 68.
    Webster J, Piscitelli G, Polli A, et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994; 331: 904–9PubMedCrossRefGoogle Scholar
  69. 69.
    Bergh T, Nillius SJ, Enoksson P, et al. Bromocriptine-induced pregnancies in women with large prolactinomas. Clin Endocrinol 1982; 17: 625–31CrossRefGoogle Scholar
  70. 70.
    Harrison RF, O’Moore RR, McSweeney J. Idiopathic Infertility: A trial of bromocriptine versus placebo. Jlr Med Assoc 1979; 72: 11: 479–82Google Scholar
  71. 71.
    McBain JC, Pepperell RJ. Use of bromocriptine in unexplained infertility. Clin Reprod Fertil 1982; 1: 145–50PubMedGoogle Scholar
  72. 72.
    Wright CS, Steele SJ, Jacobs HS. Value of bromocriptine in unexplained primary infertility: a double-blind controlled trial. BMJ 1979; 1: 1037–9PubMedCrossRefGoogle Scholar
  73. 73.
    Liu JH, Durfee R, Yen SSC. Induction of multiple ovulation by pulsatile administration of gonadotropin-releasing hormone. Fertil Steril 1983; 40: 18–25PubMedGoogle Scholar
  74. 74.
    Shaw RW, Ndukwe G, Imoedemhe D, et al. Stimulation of multiple follicular growth for in vitro fertilization by administration of pulsatile lueinizing hormone-releasing hormone during the luteal phase. Fertil Steril 1986; 46: 135–7PubMedGoogle Scholar
  75. 75.
    Deaton JL, Gibson M, Blackmer KM, et al. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990; 54: 1083–8PubMedGoogle Scholar
  76. 76.
    Fisch P, Casper RF, Brown SE, et al. Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertil Steril 1989; 51: 828–33PubMedGoogle Scholar
  77. 77.
    Glazener CMA, Coulson C, Lambert PA, et al. Clomiphene treatment for women with unexplained infertility: placebocontrolled study of hormonal responses and conception rates. Gynecol Endocrinol 1990; 4: 75–83PubMedCrossRefGoogle Scholar
  78. 78.
    Harrison RF, O’Moore RR. The use of clomiphene citrate with and without human chorionic gonadotropin. Ir Med J 1983; 76: 273–4PubMedGoogle Scholar
  79. 79.
    Arici A, Byrd W, Bradshaw et al. Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles. Fertil Steril 1994; 61: 314–8PubMedGoogle Scholar
  80. 80.
    Crosignani PG, Walters DE, Soliani A. The ESHRE multicentre trial on the treatment of unexplained infertility: a preliminary report. Hum Reprod 1991; 6: 953–8PubMedGoogle Scholar
  81. 81.
    Evans JH, Wells C, Gregory L, et al. A comparison of intrauterine insemination, intraperitoneal insemination, and natural intercourse in superovulated women. Fertil Steril 1991; 56: 1183–7PubMedGoogle Scholar
  82. 82.
    Ho P-C, Poon IML, Chan SYW, et al. Intrauterine insemination is not useful in oligoasthenospermia. Fertil Steril 1989; 51: 682–4PubMedGoogle Scholar
  83. 83.
    Ho PC, So WK, Chan YF, et al. Intrauterine insemination after ovarian stimulation as a treatment for subfertility because of subnormal semen: a prospective randomized controlled trial. Fertil Steril 1992; 58: 995–9PubMedGoogle Scholar
  84. 84.
    Karlstrom PO, Bergh T, Lundkvist O. Aprospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertil Steril 1993; 59: 554–9PubMedGoogle Scholar
  85. 85.
    Kirby CA, Flaherty SP, Godfrey BM, et al. A prospective trial of intrauterine insemination of motile spermatozoa versus timed intercourse. Fertil Steril 1991; 56: 102–7PubMedGoogle Scholar
  86. 86.
    Martinez AR, Bernardus RE, Voorhorst FJ, et al. Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: a prospective, randomized, controlled study. Fertil Steril 1990; 53: 847–53PubMedGoogle Scholar
  87. 87.
    Martinez AR, Bernardus RE, Voorhorst FJ, et al. Pregnancy rates after timed intercourse or intrauterine insemination after human menopausal gonadotropin stimulation of normal ovulatory cycles: a controlled study. Fertil Steril 1991; 55: 258–65PubMedGoogle Scholar
  88. 88.
    Nulsen JC, Walsh S, Dumez S, et al. A randomized and longitudinal study of human menopausal gonadotropin with intrauterine insemination in the treatment of infertility. Obstet Gynecol 1993; 82: 780–6PubMedGoogle Scholar
  89. 89.
    De Velde ER, van Kooy RJ, Waterreus JJH. Intrauterine insemination of washed husband’s spermatozoa: a controlled study. Fertil Steril 1989; 51: 182–5Google Scholar
  90. 90.
    Zikopoulos K, West CP, Thong PW, et al. Homologous intrauterine insemination has no advantage over timed natural intercourse when used in combination with ovulation induction for the treatment of unexplained infertility. Hum Reprod 1993; 8: 563–7PubMedGoogle Scholar
  91. 91.
    Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273: 408–12PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • John A. Collins
    • 1
    • 2
  • Edward G. Hughes
    • 1
  1. 1.Department of Obstetrics and Gynecology, Faculty of Health SciencesMcMaster UniversityHamiltonCanada
  2. 2.Department of Clinical Epidemiology and BiostatisticsMcMaster UniversityHamiltonCanada

Personalised recommendations