HKCOG Guidelines Number 1 April 2003 Guidelines for use of gonadotrophins- revised published by The Hong Kong College of Obstetricians and Gynaecologists - A Foundation College of Hong Kong Academy of Medicine Number 1 1 INTRODUCTION This guideline addresses the clinical use of gonadotrophins in induction of ovulation and ovarian stimulation with or without assisted reproduction technology. 2 USE OF GONADOTROPHINS 2.1 Ovulation induction Gonadotrophin therapy is indicated in patients with hypogonadotrophic hypogonadism and with normogonadotrophic anovulation who failed to ovulate on clomiphene citrate (CC). Other infertility factors should be assessed before embarking on this therapy, which is associated with risks. The male partner should have semen analysis performed while the female partner should have a test of tubal patency. ˇ@ Gonadotrophin treatment is very effective in inducing ovulation and the results depend on the indication and the regimen employed1. The 6-month cumulative pregnancy rate in patients without polycystic ovary syndrome (PCOS) is around 90% with an abortion rate of 25% whereas the corresponding rate in PCOS is only 50-60% with an abortion rate of 30-40%. 2.2 Ovarian stimulation Many ˇ§unexplainedˇ¨ infertile women with normal ovulatory cycles are now receiving gonadotrophin therapy to induce development of multiple ovarian follicles in an effort to try to improve the chances of conception in any given cycle. This can be usedUsed in conjunction with natural intercourse or artificial insemination2-4. Ovarian stimulation is being used in the majority of assisted reproduction methods in order to improve the success rate by increasing the number of oocytes and thus the number of embryos to be replaced. 3 CONCERNS WITH GONADOTROPHIN 3.1 Multiple pregnancy Both ovulation induction and ovarian stimulation may result in unpredictable numbers of follicles and hence oocytes. Patients with polycystic ovaries may be particularly at risk. Multiple pregnancy occurs in approximately 15-20% of cases following gonadotrophin induced ovulations. Measures should be taken to avoid these multiple pregnancies whenever possible because of the increased likelihood of pre-term deliveries and the higher perinatal morbidity and mortality associated with delivery of small pre-term infants5. During ovulation induction, a lower starting dose of gonadotrophin is preferred and careful monitoring by ultrasound examination provides good assessment of ovarian response in terms of the number of developing follicles. It has been recommend that cycles with more than two follicles >16 mm in size should be cancelled in order to reduce the risk of multiple pregnancies and the starting dose of the drug should be reduced in the next cycle6. The number of intermediate-sized follicles will also have to be taken into consideration. When hCG is withheld because of the risk of OHSS and/or multiple pregnancy, the couple should be warned of such risk and to avoid sexual intercourse or to use contraception. Other options such as converting ovulation induction cycles to IVF treatment with replacement of two embryos only and aspirating supernumerary follicles can also help to reduce the risk of multiple pregnancies. When multiple pregnancies occur in spite of these measures, selective fetal reduction may be considered. However, selective fetal reduction is not without complications and it should never be considered a substitute for careful monitoring. The risk of multiple pregnancy during IVF treatment depends on the number of embryos replaced7-8. 3.2 Ovarian hyperstimulation syndrome (OHSS) OHSS is a serious and potentially life-threatening complication of ovulation induction and ovarian stimulation, usually arising from excessive ovarian stimulation. Before offering gonadotrophin therapy, every patient should be properly counselled about the risk of OHSS associated with the method used and educated on the presenting symptoms. Patients at risk of the syndrome are identified and different measures can be taken to prevent the syndrome or reduce the risk. Ovulation induction cycles with excessive response can also be converted to IVF treatment, in which the aspiration of follicles may have a protective effect against OHSS. Administration of intravenous albumin at the time of oocyte retrieval may be of benefit in prevention of severe OHSS in high-risk cases9. Clear guidelines on the management should be available10. 3.3 Ovarian cancer Recently, there has been increasing concern about a possible link between drugs given for ovulation induction or ovarian stimulation and development of ovarian cancer11-12. Infertility is an independent risk factor of ovarian cancer, separate from any effects of nulliparity, which in itself doubles the risk of ovarian cancer. Patients receiving gonadotrophin therapy should be informed that we are aware of this particular concern but the available evidence does not lead to the conclusion of a firm link between fertility drugs and ovarian cancer13. It also seems prudent that gonadotrophins are given at the lowest effective doses and limited to the least number of cycles. 4 GONDADOTROPHIN PREPARATIONS Hypogonadotropic hypogonadal women who have very low serum LH concentrations should be given a gonadotrophin preparation containing both FSH and LH because of the fundamental role of LH in ovarian steroidogenesis. When recombinant FSH is offered to these women, follicular development is satisfactory but serum oestradiol concentration remains low and the endometrial lining is thin. Both urinary gonadotrophin and recombinant FSH are equally effective for inducing ovulation in women with CC-resistant PCOS 14. A meta-analysis15 of randomized trials on IVF cycles demonstrated that the use of urinary or recombinant FSH was associated with a significantly higher clinical pregnancy rate than human menopausal gonadotrophin. A more recent meta-analysis16 by the same group further indicated that recombinant FSH was superior to urinary FSH in terms of the pregnancy rate. However, it is still controversial whether recombinant FSH results in a higher pregnancy rate than urinary gonadotrophins when use of different regimens of pituitary desensitization are also taken into consideration17. In addition to the effectiveness, there are differences in safety (including the theoretical risk of transmitting Creutzfeldt-Jakob disease through contaminated urine extracts and allergic reaction) and cost between urinary and recombinant preparations18. 5 ADJUVANT THERAPY 5.1 Gondotrophin-releasing hormone (GnRH) agonists The use of GnRH agonist prior to gonadotrophin administration will lower the tonic high LH levels in the follicular phase of PCOS patients and prevent the occurrence of premature LH surges or premature luteinisation. This may reduce the associated high abortion rate. A recent meta-analysis19 of three randomised trials shows that there is no clear advantage in the routine use of GnRH agonist in conjunction with gonadotrohphin for ovulation induction in patients with CC-resistant PCOS. Moreover, the use of GnRH agonist will further increase the cost of gonadotrophin treatment because of the GnRH agonist and the increased amount of gonadotrophins used after using GnRH agonist. Therefore, routine administration of GnRH agonist with gonadotrophin is not indicated in ovulation induction. It may be more appropriate to use GnRH agonist in women who show evidence of premature luteininisation in previous gonadotrophin treatment cycles. On the other hand, the routine use of GnRH agonist in assisted reproduction cycles significantly reduced cancellation rates, increased the number of oocytes recovered, and improved pregnancy rates20. 5.2 Gonadotrophin-releasing hormone (GnRH) antagonist GnRH antagonists immediately suppress the secretion of gonadotrophins from the pituitary gland after administration. Many clinical studies have confirmed the efficacy of the GnRH antagonists in the prevention of premature LH surges during ovarian stimulation in assisted reproduction cycles and their safety, whether they were given as multiple daily doses or as a single dose. Compared with the use of GnRH agonist in the long protocol, GnRH antagonist is associated with shorter duration and lower dosage of gonadotrophin but a significantly lower pregnancy rate (Odd ratio 0.79; 95% confidence interval 0.63ˇV0.99)21. 5.3 Insulin sensitising agents Insulin resistance and compensatory hyperinsulinemia play significant role in the causation of anovulation in women with PCOS. Therefore, insulin sensitizing agents such as metformin have been widely used for ovulation induction when there is no response to CC in patients with PCOS22. Some studies23,24 could not demonstrate improved ovulation rate after taking metformin, with or without CC. Treatment with metformin during gonadotrophin therapy for ovulation induction alone or IVF treatment may allow a reduced rate of hyperstimulation and reduce the risk of multiple pregnancy22. 6 RECOMMENDATIONS 6.1 Selection of patients Treatment with gonadotrophins should be restricted to appropriately investigated couples with a diagnosis in whom such treatment has been shown to be beneficial in view of its costs and risks. Results in relation to patientsˇ¦ age and diagnosis should be considered. 6.2 Welfare of the child In accordance with Code of Practice on Reproductive Technology and Embryo Research25, the welfare of any resulting child from the treatment and of other existing children must be considered when offering all types of assisted conception. 6.3 Counselling Prior to treatment couples must be made aware of the problem of multiple pregnancy and the potential risks this carries during the antenatal, intrapartum and neonatal period as well as subsequently. The risk of OHSS and its symptoms during development need to be highlighted. The putative risk of developing ovarian cancer after gonadotrophin therapy should be informed. 6.4 Treatment centre Stimulation of ovarian function with gonadotrophins should be restricted to specialist practice with access to intensive monitoring by plasma or serum estradiol and pelvic ultrasound6. Careful monitoring is especially important to allow adjustment of dosage and to avoid OHSS. Such specialist practice centres should also have trained gynaecologists with specialist knowledge and facilities to monitor and treat patients with OHSS should it develop. 6.5 Gonadotrophin preparation As it is still controversial whether recombinant FSH results in a higher pregnancy rate than urinary gonadotrophins, additional factors should be considered when choosing a gonadotrophin preparation, including the safety, cost, patient acceptability and drug availability. REFERENCES: 1. Hull MGR. Infertility treatment: relative effectiveness of conventional and assisted conception methods. Hum Reprod 1992; 7: 785-96. 2. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod 1997; 12: 1865-72. 3. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, Hill JA, Mastroianni L, Buster JE, Nakajima ST, Vogel DL, Canfield RE: Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999; 340: 177-83. 4. Cohlen BJ, Vandekerckhove P, te Velde ER, Habbema JD. Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for subfertility in men. Cochrane Database Syst Rev 2000; 2: CD000360. 5. The ESHRE Capri Workshop Group. Multiple gestation pregnancy. Hum Reprod 2000; 15: 1856-64. 6. RCOG Evidence-based clinical guidelines No. 3 The management of infertility in secondary care, 1998. 7. Templeton A. & Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med, 1998; 339: 573-7. 8. Schieve LA, Peterson HB, Meikle SF, Jeng G, Danel I, Burnett NM, Wilcox LS. Live-birth rates and multiple-birth risk using in vitro fertilization. JAMA, 1999; 282: 1832-8. 9. Aboulghar M, Evers J.H, Al-Inany H. Intra-venous albumin for preventing severe ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2002; 2: CD001302. 10. RCOG Green-Top Guidelines No. 5 Management and prevention of ovarian hyperstimulation syndrome (OHSS), 1995. 11. Whittemore AS, Harris R, Itnyre J, Collaborative Ovarian Cancer Group. (1992) Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies II. Invasive epithelial ovarian cancers in white women. Am J Epidemio 1992; 136: 1184-203. 12. Rossing RA, Daling JR, Weiss NS, Moore DE, Self SG (1994) Ovarian tumours in a cohort of infertile women. N Engl J Med 1994; 331: 771-6. 13. Nugent D, Salha O, Balen AH, Rutherford AJ Ovarian neoplasia and subfertility treatment. Br J Obstet Gynaecol 1998; 105: 584-91. 14. Bayram N, van Wely M, van Der Veen F. Recombinant FSH versus urinary gonadotrophins or recombinant FSH for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev 2001; 2: CD002121. 15. Daya S, Gunby J, Hughes EG, Collins JA, Sagle MA. Follicle-stimulating hormone versus human menopausal gonadotrophin for in vitro fertilization cycles: a meta-analysis. Fertil Steril 1995; 64: 347-54. 16. Daya S. Updated meta-analysis of recombinant follicle-stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction. Fertil Steril 2002; 77:711-4. 17. Agrawal R, Holmes J, Jacobs HS. Follicle-stimulating hormone or human menopausal gonadotrophin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis. Fertil Steril 2000; 73: 338-43. 18. Norbert G, Vietzke M, Vidali A. Bye-bye urinary gonadotrophins? Recombinant FSH: a real progress in ovulation induction and IVF? Hum Reprod 2003; 18: 476-482. 19. Hughes E, Collins J, Vandekerckhove P. Gonadotrophin-releasing hormone analogue as an adjunct to gonadotrophin therapy for clomiphene-resistant polycystic ovarian syndrome. Cochrane Database Syst Rev, 2002; 2: CD000097. 20. Hughes EG, Federkow DM, Daya S, Sagle M, De Koppel P, Collins J. The routine use of gonadotropin releasing hormone agonists prior to in-vitro fertilization and gamete intrafallopian transfer: A meta-analysis of randomized controlled trials. Fertil Steril 1992; 58: 888-96. 21. Al-Inany H, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev. 2001; 4: CD001750. 22. Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz DJ. Straegies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002; 77: 209-15. 23. Ng EHY, Wat WMS, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene resistant polycystic ovaries: A randomized, double-blinded placebo-controlled trial. Hum Reprod 2001; 16: 1625-31. 24. Sturrock NDC, Lannon B, Fay TN. Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice. Br J Clin Pharmacol 2002; 53: 469-73. 25. The Council on Human Reproductive Technology. Code of Practice on Reproductive Technology and Embryo Research can be viewed at the web site of the Health, Welfare and Food Bureau (http//www.info.gov.hk/hwfb/). ACKNOWLEDGEMENT: This guideline supersedes the previous guidelines published in May 1997. It was produced by the Working Group on Reproductive Technology, membership of which include Dr. Ernest HY Ng (Chairman), Dr. LP Cheung, Professor PC Ho, Dr Milton Leong, and Dr Lawrence CH Tang. It was endorsed by the Council of the Hong Kong College of Obstetricians and Gynaecologists. This guideline was produced by The Hong Kong College of Obstetricians and Gynaecologists as an educational aid and reference for obstetricians and gynaecologists practising in Hong Kong. The guideline does not define a standard of care, nor is it intended to dictate an exclusive course of management. It presents recognised clinical methods and techniques for consideration by practitioners for incorporation into their practice. It is acknowledged that clinical management may vary and must always be responsive to the need of individual patients, resources, and limitations unique to the institution or type of practice. Particular attention is drawn to areas of clinical uncertainty where further research may be indicated. First version published May 1997. HKCOG GUIDELINES NUMBER 1 (revised April 2003)