Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised co
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《英国医生杂志》
1 Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Academic Medical Centre, PO Box 22700, 1100 DE, Amsterdam, Netherlands, 2 Clinical Epidemiology and Biostatistics, Academic Medical Centre
Correspondence to: N Bayram n.bayram@amc.uva.nl.
Abstract
Polycystic ovary syndrome is characterised by oligomenorrhoea or amenorrhoea, infertility, hirsutism, acne, and bilaterally enlarged, cystic ovaries.1 2 The syndrome affects 4-9% of women of childbearing age.3 Infertility due to chronic anovulation is the most common reason for women seeking counselling or treatment. The drug of first choice for inducing ovulation is clomiphene citrate, taken orally, although 20% of women given clomiphene citrate fail to ovulate.4
Ovulation induction with gonadotrophins is well established in patients resistant to clomiphene citrate, but extensive monitoring is necessary because of the high sensitivity of polycystic ovaries to exogenous gonadotrophins, with the risk of multiple follicle development leading to termination of the cycle, ovarian hyperstimulation syndrome, or multiple pregnancy.5 To reduce these complications, various dose regimens have been used.6 A chronic low dose step-up regimen is probably the most efficient and safest treatment at present.7
Recently, laparoscopic electrocautery of the ovaries has been introduced as an alternative treatment for patients with clomiphene citrate resistant polycystic ovary syndrome. This involves a single procedure, which has minimal morbidity, which can lead to consecutive ovulations with minimal risks of multiple pregnancy.8 Patients may also respond to clomiphene citrate after this treatment.9 10 Disadvantages are the need for surgery under general anaesthesia, the unknown long term effects on ovarian function, and possible adhesion formation.
Patients who fail to ovulate after electrocautery of the ovaries and clomiphene citrate can still be treated with gonadotrophins, before proceeding to the costly and burdensome procedure of in vitro fertilisation and embryo transfer. Whether gonadotrophins or electrocautery should be the first treatment of choice in patients with clomiphene citrate resistant polycystic ovary syndrome is still debatable. The three comparative studies that have been published in this area have methodological flaws that weaken the conclusions.11-13
We conducted a randomised controlled trial to compare the effectiveness of an electrocautery strategy against ovulation induction with recombinant follicle stimulating hormone in women who had clomiphene citrate resistant polycystic ovary syndrome.
Methods
A total of 213 consecutive patients were invited to participate in the study. Thirty six were initially excluded: 27 refused, five became pregnant while awaiting laparoscopy, one had a language barrier, and three were too obese to undergo general anaesthesia. Nine further patients were excluded during diagnostic laparoscopy; one with endometriosis stage IV, five with adhesions, two with tubal occlusion, and one because electrocautery was technically not feasible.
Overall, 168 patients were eligible for inclusion in our study, of whom 83 were allocated to the electrocautery strategy and 85 were allocated to recombinant follicle stimulating hormone (fig 1). Forty five patients allocated to electrocautery had persistent anovulation or recurrence of anovulatory cycles during follow up and received clomiphene citrate; 21 of these subsequently received recombinant follicle stimulating hormone, and two started recombinant follicle stimulating hormone directly after electrocautery. Table 1 lists the characteristics of the patients at baseline. The treatment groups did not differ.
Fig 1 Flow of participants through trial. *=patients who received recombinant follicle stimulating hormone after electrocautery
Table 1 Characteristics of women allocated to electrocautery strategy or ovulation induction with recombinant follicle stimulating hormone. Values are numbers (percentages) of women unless stated otherwise
Electrocautery versus recombinant follicle stimulating hormone
Figure 2 shows the cumulative ongoing pregnancy rates over time from electrocautery and from ovulation induction with recombinant follicle stimulating hormone. The ongoing pregnancy rate in both groups at 12 months was 67% (rate ratio 1.01, 95% confidence interval 0.81 to 1.24). Pregnancy rates in the two treatment arms over 12 months did not differ (log rank score 0.25, P = 0.62). Table 2 summarises the outcomes of pregnancy.
Fig 2 Cumulative ongoing pregnancy rate over time from electrocautery or ovulation induction with recombinant follicle stimulating hormone
Table 2 Pregnancy outcomes at 12 months in 83 women allocated to electrocautery strategy and 85 allocated to ovulation induction with recombinant follicle stimulating hormone. Values are numbers (percentages) of women
Electrocautery strategy
In the 83 patients allocated to the electrocautery strategy, 61% (228 of 375) of the cycles were ovulatory. After electrocautery only, 70% (127 of 182) of cycles were ovulatory. In the subgroup that subsequently received clomiphene citrate, 45% (69/152) of cycles were ovulatory, and in the subgroup that subsequently received recombinant follicle stimulating hormone, 78% (32 of 41) of cycles were ovulatory.
Nine cycles were terminated because of poor response (five cycles), risk of ovarian hyperstimulation syndrome (two), risk of multiple pregnancy (one), and other (one). The mean duration of stimulation was 18.2 (SD 7.3) days and for use of recombinant follicle stimulating hormone was 2057 (1556) IU.
Of the 56 (67%) ongoing pregnancies in the electrocautery group, one resulted in quintuplets in a patient also given recombinant follicle stimulating hormone, and successful embryo reduction led to the live birth of twins. Neither electrocautery alone nor subsequent treatment with clomiphene citrate resulted in multiple pregnancy.
Recombinant follicle stimulating hormone
Of the 85 patients allocated recombinant follicle stimulating hormone, 69% (188 of 272) of the cycles were ovulatory. Reasons for termination of the 80 cycles were poor response (34 cycles), risk of ovarian hyperstimulation syndrome (24), risk of multiple pregnancy (13), and other (9). For each patient the mean duration of stimulation was 18.6 (6.8 SD) days and for use of recombinant follicle stimulating hormone was 1957 (975 SD) IU.
Of the 57 ongoing pregnancies in the women allocated recombinant follicle stimulating hormone, eight were twin pregnancies and one was a triplet pregnancy. Neonatal death occurred in one of the twin pregnancies at 26 weeks' gestation. The triplet pregnancy ended with premature delivery at 22 weeks.
Safety
No patient had perioperative complications or ovarian hyperstimulation syndrome. Ovulation induction with recombinant follicle stimulating hormone resulted in significantly more multiple pregnancies than with the electrocautery strategy (rate ratio 0.11, 0.01 to 0.88).
Discussion
Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333: 853-61.
Balen A, Michelmore K. What is polycystic ovary syndrome? Hum Reprod 2002;17: 2219-27.
Homburg R. What is polycystic ovarian syndrome? Hum Reprod 2002;17: 2495-9.
Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1998;83: 2361-5.
Jacobs HS, Agrawal R. Complications of ovarian stimulation. Baillierès Clin Obstet Gynaecol 1998;12: 565-79.
Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update 1999;5: 493-9.
Christin-Maitre S, Hugues JN on behalf of the Recombinant FSH Study Group. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod 2003;18: 1626-31.
Donesky BW, Adashi EY. Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. Fertil Steril 1995;63: 439-63.
Gjonnaess H. Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope. Fertil Steril 1984;41: 20-5.
Greenblatt E, Casper RF. Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet Gynecol 1987;156: 279-85.
Abdel Gadir A, Mowafi RS, Alnaser HM, Alrashid AH, Alonezi OM, Shaw RW, 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 1990;33: 585-92.
Vicino M, Loverro G, Bettocchi S, Simonetti S, Mei L, Selvaggi L. Predictive value of serum androstenedione basal levels on the choice of gonadotropin or laparoscopic ovarian electrocautery as ovulation induction in clomiphene citrate-resistant patients with polycystic ovary syndrome. Gynecol Endocrinol 2000;14: 42-9.
Farquhar CM, Williamson K, Gudex G, Johnson NP, Garland J, Sadler L. A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome. Fertil Steril 2002;78: 404-11.
WHO manual for the standardized investigation and diagnosis of the infertile couple. Cambridge: Cambridge University Press, 1993.
Adams J, Franks S, Polson DW, Mason HD, Abdulwahid N, Tucker M, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 1985;ii: 1375-9.
Van Santbrink EJ, Hop WC, Fauser BC. Classification of normogonadotropic infertility: polycystic ovaries diagnosed by ultrasound versus endocrine characteristics of polycystic ovary syndrome. Fertil Steril 1997;67: 452-8.
Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 1985;43: 351-2.
Hamilton-Fairley D, Kiddy D, Watson H, Sagle M, Franks S. Low-dose gonadotrophin therapy for induction of ovulation in 100 women with polycystic ovary syndrome. Hum Reprod 1991;6: 1095-9.
Dutch Society for Obstetrics and Gynaecology. www.nvog.nl
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. In: Cochrane Library, issue 3. Oxford: Update Software, 2001.
Kaaijk EM, Beek JF, van der Veen F. Laparoscopic surgery of chronic hyperandrogenic anovulation. Lasers Surg Med 1995;16: 292-302.
Vegetti W, Ragni G, Baroni E, Testa G, Marsico S, Riccaboni A, et al. Laparoscopic ovarian drilling versus low-dose pure FSH in anovulatory clomiphene-resistant patients with polycystic ovary syndrome: randomized prospective study. Hum Reprod 1998;13: S120.
Lazovic G, Milacic D, Terzic M, Spremovic S, Mitijasevic S. Medicaments or surgical therapy of PCOS. Fertil Steril 1998;70: S472.
Cohen J, Jones HW Jr. How to avoid multiple pregnancies in assistive reproductive technologies. Semin Reprod Med 2001;19: 269-78.(Neriman Bayram, specialis)
Correspondence to: N Bayram n.bayram@amc.uva.nl.
Abstract
Polycystic ovary syndrome is characterised by oligomenorrhoea or amenorrhoea, infertility, hirsutism, acne, and bilaterally enlarged, cystic ovaries.1 2 The syndrome affects 4-9% of women of childbearing age.3 Infertility due to chronic anovulation is the most common reason for women seeking counselling or treatment. The drug of first choice for inducing ovulation is clomiphene citrate, taken orally, although 20% of women given clomiphene citrate fail to ovulate.4
Ovulation induction with gonadotrophins is well established in patients resistant to clomiphene citrate, but extensive monitoring is necessary because of the high sensitivity of polycystic ovaries to exogenous gonadotrophins, with the risk of multiple follicle development leading to termination of the cycle, ovarian hyperstimulation syndrome, or multiple pregnancy.5 To reduce these complications, various dose regimens have been used.6 A chronic low dose step-up regimen is probably the most efficient and safest treatment at present.7
Recently, laparoscopic electrocautery of the ovaries has been introduced as an alternative treatment for patients with clomiphene citrate resistant polycystic ovary syndrome. This involves a single procedure, which has minimal morbidity, which can lead to consecutive ovulations with minimal risks of multiple pregnancy.8 Patients may also respond to clomiphene citrate after this treatment.9 10 Disadvantages are the need for surgery under general anaesthesia, the unknown long term effects on ovarian function, and possible adhesion formation.
Patients who fail to ovulate after electrocautery of the ovaries and clomiphene citrate can still be treated with gonadotrophins, before proceeding to the costly and burdensome procedure of in vitro fertilisation and embryo transfer. Whether gonadotrophins or electrocautery should be the first treatment of choice in patients with clomiphene citrate resistant polycystic ovary syndrome is still debatable. The three comparative studies that have been published in this area have methodological flaws that weaken the conclusions.11-13
We conducted a randomised controlled trial to compare the effectiveness of an electrocautery strategy against ovulation induction with recombinant follicle stimulating hormone in women who had clomiphene citrate resistant polycystic ovary syndrome.
Methods
A total of 213 consecutive patients were invited to participate in the study. Thirty six were initially excluded: 27 refused, five became pregnant while awaiting laparoscopy, one had a language barrier, and three were too obese to undergo general anaesthesia. Nine further patients were excluded during diagnostic laparoscopy; one with endometriosis stage IV, five with adhesions, two with tubal occlusion, and one because electrocautery was technically not feasible.
Overall, 168 patients were eligible for inclusion in our study, of whom 83 were allocated to the electrocautery strategy and 85 were allocated to recombinant follicle stimulating hormone (fig 1). Forty five patients allocated to electrocautery had persistent anovulation or recurrence of anovulatory cycles during follow up and received clomiphene citrate; 21 of these subsequently received recombinant follicle stimulating hormone, and two started recombinant follicle stimulating hormone directly after electrocautery. Table 1 lists the characteristics of the patients at baseline. The treatment groups did not differ.
Fig 1 Flow of participants through trial. *=patients who received recombinant follicle stimulating hormone after electrocautery
Table 1 Characteristics of women allocated to electrocautery strategy or ovulation induction with recombinant follicle stimulating hormone. Values are numbers (percentages) of women unless stated otherwise
Electrocautery versus recombinant follicle stimulating hormone
Figure 2 shows the cumulative ongoing pregnancy rates over time from electrocautery and from ovulation induction with recombinant follicle stimulating hormone. The ongoing pregnancy rate in both groups at 12 months was 67% (rate ratio 1.01, 95% confidence interval 0.81 to 1.24). Pregnancy rates in the two treatment arms over 12 months did not differ (log rank score 0.25, P = 0.62). Table 2 summarises the outcomes of pregnancy.
Fig 2 Cumulative ongoing pregnancy rate over time from electrocautery or ovulation induction with recombinant follicle stimulating hormone
Table 2 Pregnancy outcomes at 12 months in 83 women allocated to electrocautery strategy and 85 allocated to ovulation induction with recombinant follicle stimulating hormone. Values are numbers (percentages) of women
Electrocautery strategy
In the 83 patients allocated to the electrocautery strategy, 61% (228 of 375) of the cycles were ovulatory. After electrocautery only, 70% (127 of 182) of cycles were ovulatory. In the subgroup that subsequently received clomiphene citrate, 45% (69/152) of cycles were ovulatory, and in the subgroup that subsequently received recombinant follicle stimulating hormone, 78% (32 of 41) of cycles were ovulatory.
Nine cycles were terminated because of poor response (five cycles), risk of ovarian hyperstimulation syndrome (two), risk of multiple pregnancy (one), and other (one). The mean duration of stimulation was 18.2 (SD 7.3) days and for use of recombinant follicle stimulating hormone was 2057 (1556) IU.
Of the 56 (67%) ongoing pregnancies in the electrocautery group, one resulted in quintuplets in a patient also given recombinant follicle stimulating hormone, and successful embryo reduction led to the live birth of twins. Neither electrocautery alone nor subsequent treatment with clomiphene citrate resulted in multiple pregnancy.
Recombinant follicle stimulating hormone
Of the 85 patients allocated recombinant follicle stimulating hormone, 69% (188 of 272) of the cycles were ovulatory. Reasons for termination of the 80 cycles were poor response (34 cycles), risk of ovarian hyperstimulation syndrome (24), risk of multiple pregnancy (13), and other (9). For each patient the mean duration of stimulation was 18.6 (6.8 SD) days and for use of recombinant follicle stimulating hormone was 1957 (975 SD) IU.
Of the 57 ongoing pregnancies in the women allocated recombinant follicle stimulating hormone, eight were twin pregnancies and one was a triplet pregnancy. Neonatal death occurred in one of the twin pregnancies at 26 weeks' gestation. The triplet pregnancy ended with premature delivery at 22 weeks.
Safety
No patient had perioperative complications or ovarian hyperstimulation syndrome. Ovulation induction with recombinant follicle stimulating hormone resulted in significantly more multiple pregnancies than with the electrocautery strategy (rate ratio 0.11, 0.01 to 0.88).
Discussion
Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333: 853-61.
Balen A, Michelmore K. What is polycystic ovary syndrome? Hum Reprod 2002;17: 2219-27.
Homburg R. What is polycystic ovarian syndrome? Hum Reprod 2002;17: 2495-9.
Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1998;83: 2361-5.
Jacobs HS, Agrawal R. Complications of ovarian stimulation. Baillierès Clin Obstet Gynaecol 1998;12: 565-79.
Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update 1999;5: 493-9.
Christin-Maitre S, Hugues JN on behalf of the Recombinant FSH Study Group. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod 2003;18: 1626-31.
Donesky BW, Adashi EY. Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. Fertil Steril 1995;63: 439-63.
Gjonnaess H. Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope. Fertil Steril 1984;41: 20-5.
Greenblatt E, Casper RF. Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet Gynecol 1987;156: 279-85.
Abdel Gadir A, Mowafi RS, Alnaser HM, Alrashid AH, Alonezi OM, Shaw RW, 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 1990;33: 585-92.
Vicino M, Loverro G, Bettocchi S, Simonetti S, Mei L, Selvaggi L. Predictive value of serum androstenedione basal levels on the choice of gonadotropin or laparoscopic ovarian electrocautery as ovulation induction in clomiphene citrate-resistant patients with polycystic ovary syndrome. Gynecol Endocrinol 2000;14: 42-9.
Farquhar CM, Williamson K, Gudex G, Johnson NP, Garland J, Sadler L. A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome. Fertil Steril 2002;78: 404-11.
WHO manual for the standardized investigation and diagnosis of the infertile couple. Cambridge: Cambridge University Press, 1993.
Adams J, Franks S, Polson DW, Mason HD, Abdulwahid N, Tucker M, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 1985;ii: 1375-9.
Van Santbrink EJ, Hop WC, Fauser BC. Classification of normogonadotropic infertility: polycystic ovaries diagnosed by ultrasound versus endocrine characteristics of polycystic ovary syndrome. Fertil Steril 1997;67: 452-8.
Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 1985;43: 351-2.
Hamilton-Fairley D, Kiddy D, Watson H, Sagle M, Franks S. Low-dose gonadotrophin therapy for induction of ovulation in 100 women with polycystic ovary syndrome. Hum Reprod 1991;6: 1095-9.
Dutch Society for Obstetrics and Gynaecology. www.nvog.nl
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. In: Cochrane Library, issue 3. Oxford: Update Software, 2001.
Kaaijk EM, Beek JF, van der Veen F. Laparoscopic surgery of chronic hyperandrogenic anovulation. Lasers Surg Med 1995;16: 292-302.
Vegetti W, Ragni G, Baroni E, Testa G, Marsico S, Riccaboni A, et al. Laparoscopic ovarian drilling versus low-dose pure FSH in anovulatory clomiphene-resistant patients with polycystic ovary syndrome: randomized prospective study. Hum Reprod 1998;13: S120.
Lazovic G, Milacic D, Terzic M, Spremovic S, Mitijasevic S. Medicaments or surgical therapy of PCOS. Fertil Steril 1998;70: S472.
Cohen J, Jones HW Jr. How to avoid multiple pregnancies in assistive reproductive technologies. Semin Reprod Med 2001;19: 269-78.(Neriman Bayram, specialis)