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Polycystic ovary syndrome. A therapeutic challenge
Bayram, N.
Publication date
2004
Link to publication
Citation for published version (APA):
Bayram, N. (2004). Polycystic ovary syndrome. A therapeutic challenge.
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C H A P T E RR 4
Usingg an e l e c t r o c a u t e r y strategy or r e c o m b i n a n t
folliclee s t i m u l a t i n g h o r m o n e to induce o v u l a t i o n
inn polycystic ovary s y n d r o m e :
r a n d o m i s e dd c o n t r o l l e d trial
NerimanNeriman Bayram, Madelon van Wely, Eugenie M, Kaaijk, PatrickPatrick M.M. Bossuyt, Fulco van der Veen
Abstract t Objective e
Too compare the effectiveness of an electrocautery strategy with ovulation induction using recombinantt follicle stimulating hormone in patients with polycystic ovary syndrome.
D e s i g n n
Randomisedd controlled trial.
Setting g
Secondaryy and tertiary hospitals in the Netherlands.
Participants s
1688 patients with clomiphene citrate resistant polycystic ovary syndrome: 83 were allocatedd electrocautery and 85 were allocated recombinant follicle stimulating hormone.
Intervention n
Laparoscopicc electrocautery of the ovaries followed by clomiphene citrate and recombinantt follicle stimulating hormone if anovulation persisted, or induction of ovulationn with recombinant follicle stimulating hormone.
Mainn outcome measure
Ongoingg pregnancy within 12 months.
Results s
Thee cumulative rate of ongoing pregnancy after recombinant follicle stimulating hormonee was 67%. With only electrocautery it was 34%, which increased to 49% after clomiphenee citrate was given. Subsequent recombinant follicle stimulating hormone increasedd the rate to 67% at 12 months (rate ratio 1.01, 95% confidence interval 0.81 to 1.24).. No complications occurred from electrocautery with or without clomiphene citrate.. Patients allocated to electrocautery had a significantly lower risk of multiple pregnancyy (0.11, 0.01 to 0.88).
Conclusion n
Thee ongoing pregnancy rate from ovulation induction with laparoscopic electrocautery followedd by clomiphene citrate and recombinant follicle stimulating hormone if anovulationn persisted, or recombinant follicle stimulating hormone, seems equivalent to ovulationn induction with recombinant follicle stimulating hormone, but the former proceduree carries a lower risk of multiple pregnancy.
Introduction n
Polycysticc ovary syndrome is characterised by oligomenorrhoea or amenorrhoea, infertility,, hirsutism, acne, and bilaterally enlarged, cystic ovaries ( Franks, 1995; Balen andd Michelmore, 2002). The syndrome affects 4-9% of women of childbearing age (Homburg,, 2002). Infertility due to chronic anovulation is the most common reason for womenn seeking counselling or treatment. The drug of first choice for inducing ovulation iss clomiphene citrate, taken orally, although 20% of women given clomiphene citrate fail too ovulate (Imani et al., 1998).
Ovulationn induction with gonadotrophins is well established in patients resistant to clomiphenee citrate, but extensive monitoring is necessary because of the high sensitivity off polycystic ovaries to exogenous gonadotrophins, with the risk of multiple follicle developmentt leading to termination of the cycle, ovarian hyperstimulation syndrome, or multiplee pregnancy (Jacobs and Agrawal, 1998). To reduce these complications, various dosee regimens have been used (Homburg and Howies, 1999). A chronic low dose step-up regimenn is probably the most efficient and safest treatment at present (Chnstin-Maitre et al.,, 2003).
Recently,, laparoscopic electrocautery of the ovaries has been introduced as an alternative treatmentt for patients with clomiphene citrate resistant polycystic ovary syndrome. This involvess a single procedure, which has minimal morbidity, which can lead to consecutive ovulationss with minimal risks of multiple pregnancy (Donesky and Adashi, 1995). Patientss may also respond to clomiphene citrate after this treatment (Gjonnaess, 1984; Greenblattt and Casper, 1987). Disadvantages are the need for surgery under general anaesthesia,, the unknown long term effects on ovarian function, and possible adhesion formation. .
Patientss who fail to ovulate after electrocautery of the ovaries and clomiphene citrate can stilll be treated with gonadotrophins, before proceeding to the costly and burdensome proceduree of in vitro fertilisation and embryo transfer. Whether gonadotrophins or electrocauteryy should be the first treatment of choice in patients with clomiphene citrate resistantt polycystic ovary syndrome is still debatable. The three comparative studies that havee been published in this area have methodological flaws that weaken the conclusions (Abdell et al., 1990; Vicino et al., 2000; Farquhar et al., 2002).
Wee conducted a randomised controlled trial to compare the effectiveness of an electrocauteryy strategy against ovulation induction with recombinant follicle stimulating hormonee in women who had clomiphene citrate resistant polycystic ovary syndrome.
Methods s
Ourr trial took place between February 1998 and October 2001 in 29 Dutch hospitals. Womenn were invited to participate if they had chronic anovulation (World Health Organizationn type II) and polycystic ovaries, diagnosed by transvaginal ultrasonography (WHO,, 1993; Adams et al., 1985; van Santbrink et al., 1997). They had also to be resistantt to clomiphene citrate-that is, show persistent anovulation after taking 150 mg clomiphenee citrate daily for five days. Primary exclusion criteria were other causes of infertility,, including severe male factor subfertility, and age over 40 years.
andd chromopertubation. Secondary exclusion criteria identified during the procedure weree tubal obstruction, extensive adhesions of the ovaries or fallopian tubes, and endometriosiss stages III or IV according to the classification of the American Fertility Societyy (AFS, 1985).In absence of any of these, patients were randomised by computer generatedd block randomisation during laparoscopy, stratified for centre. They were allocatedd either laparoscopic electrocautery of the ovaries followed by clomiphene citrate andd recombinant follicle stimulating hormone if anovulation persisted, or ovulation inductionn with recombinant follicle stimulating hormone.
Electrocauteryy strategy
Thee ovaries of women allocated electrocautery were cauterised with an Erbotom ICC 350 Unitt (Erbe BV; Zaltbommel, The Netherlands) immediately after randomisation. A bipolarr insulated needle electrode (length 345 mm, shaft diameter 5 mm) was pressed at rightt angles to the surface of a follicle, and the needle (length 15 mm, diameter 0.9 mm) wass inserted into the follicle and surrounding tissue. Each ovary was randomly punctured 5-100 times, depending on its size.
Iff patients ovulated in six subsequent cycles, no further treatment was given. They then completedd the study according to protocol. If anovulation persisted for eight weeks after electrocauteryy or the patient became anovulatory again, treatment was started with 50 mg clomiphenee citrate. If ovulation occurred, this dose was maintained for a maximum of six ovulatoryy cycles. If no ovulation occurred the dose was increased to a maximum of 150 mg.. Patients then completed the study according to protocol after six subsequent ovulations.. If they remained anovulatory, treatment with recombinant follicle stimulating hormonee was started.
Recombinantt follicle stimulating hormone
Patientss allocated recombinant follicle stimulating hormone received 10 mg medroxyprogesteronee for 10 days after randomisation to induce a withdrawal bleed. Ovulationn induction was started on cycle day 3 by subcutaneous injection of 75 IU recombinantt follicle stimulating hormone (follitropin alpha, Gonal-F; Serono Benelux, Thee Netherlands) daily according to the chronic low dose step up regimen (Hamilton-Fairleyy et al, 1991). If the diameter of the follicles remained < 10 mm, the dose was increasedd by half an ampoule (37.5 IU) on each of cycle days 16 and 23. If no follicle developmentt (diameter > 10 mm) was seen by cycle day 30, the cycle was terminated becausee of poor response. Cycles were also terminated to prevent hyperstimulation or multiplee pregnancy when there were more than six follicles with a diameter of 14 mm or greaterr or more than three follicles with a diameter of 16 mm or greater (NVOG, 2004). Iff one follicle at least 18 mm in diameter and up to two follicles more than 15 mm diameterr were present then ovulation was induced with 10 000 IU of human chorionic gonadotrophinn (Pregnyl; NV Organon, Oss, The Netherlands) subcutaneously or intramuscularly.. Patients were treated until six subsequent cycles were achieved within 12 months.. Follicle development was monitored in both treatment arms by transvaginal ultrasonographyy at weekly intervals, or more frequently if indicated by follicle growth.
Statisticall analysis and study design
Thee primary end point was ongoing pregnancy within 12 months, defined as a viable pregnancyy of at least 12 weeks. Secondary end points were ovulation, miscarriage, ectopic
pregnancy,, multiple pregnancy, and live birth. The effectiveness of the electrocautery strategyy compared with recombinant follicle stimulating hormone was expressed as a relativee rate ratio for pregnancy, with corresponding 95% confidence intervals. We used thee log rank test to compare cumulative pregnancy rates over time.
Wee designed our study as a non-inferiority trial for pregnancy rates because of the anticipatedd benefits of electrocautery. The electrocautery strategy started with a single procedure,, leading to consecutive ovulations with minimal risks of multiple follicle growthh and multiple pregnancy, and was expected to have fewer adverse events. We thereforee considered the strategy sufficient to show a pregnancy rate within 12 months of noo lower than 5% of that achieved by ovulation induction with recombinant follicle stimulatingg hormone.
Assumingg an ongoing pregnancy rate within 12 months of 38% after treatment with gonadotrophins,, with an alpha of 5% and a beta of 20%, and a pregnancy rate of 52% withh the electrocautery strategy, we required 168 patients to exclude a difference of 5% or moree to the detriment of electrocautery of the ovaries (Bayram et al„ 2004; Kaaijk et al., 1995).. All outcomes were analysed on an intention to treat basis.
Results s
AA total of 213 consecutive patients were invited to participate in the study. Thirty six were initiallyy excluded: 27 refused, five became pregnant while awaiting laparoscopy, one had aa language barrier, and three were too obese to undergo general anaesthesia. Nine further patientss were excluded during diagnostic laparoscopy; one with endometriosis stage IV, fivee with adhesions, two with tubal occlusion, and one because electrocautery was technicallyy not feasible.
Overall,, 168 patients were eligible for inclusion in our study, of whom 83 were allocated too the electrocautery strategy and 85 were allocated to recombinant follicle stimulating hormonee (Figure 1). Forty five patients allocated to electrocautery had persistent anovulationn or recurrence of anovulatory cycles during follow up and received clomiphene citrate;; 21 of these subsequently received recombinant follicle stimulating hormone, and twoo started recombinant follicle stimulating hormone directly after electrocautery. Table 11 lists the characteristics of the patients at baseline. The treatment groups did not differ.
Electrocauteryy versus recombinant follicle stimulating hormone
Figuree 2 shows the cumulative ongoing pregnancy rates over time from electrocautery and fromm ovulation induction with recombinant follicle stimulating hormone. The ongoing pregnancyy rate in both groups at 12 months was 67% (rate ratio 1.01, 95% confidence intervall 0.81 to 1.24). Pregnancy rates in the two treatment arms over 12 months did not differr (log rank score 0.25, P = 0.62). Table 2 summarises the outcomes of pregnancy.
Electrocauteryy strategy
InIn the 83 patients allocated to the electrocautery strategy, 6 1 % (228 of 375) of the cycles weree ovulatory. After electrocautery only, 70% (127 of 182) of cycles were ovulatory. In thee subgroup that subsequently received clomiphene citrate, 45% (69/152) of cycles were ovulatory,, and in the subgroup that subsequently received recombinant follicle stimulatingg hormone, 78% (32 of 41) of cycles were ovulatory.
Ninee cycles were terminated because of poor response (five cycles), risk of ovarian hyperstimulationn syndrome (two), risk of multiple pregnancy (one), and other (one). The meann duration of stimulation was 18.2 (SD 7.3) days and for use of recombinant follicle stimulatingg hormone was 2057 (1556) IU.
Off the 56 (67%) ongoing pregnancies in the electrocautery group, one resulted in quintupletss in a patient also given recombinant follicle stimulating hormone, and successfull embryo reduction led to the live birth of twins. Neither electrocautery alone norr subsequent treatment with clomiphene citrate resulted in multiple pregnancy.
Recombinantt follicle stimulating hormone
Off the 85 patients allocated recombinant follicle stimulating hormone, 69% (188 of 272) off the cycles were ovulatory. Reasons for termination of the 80 cycles were poor response (344 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) dayss and for use of recombinant follicle stimulating hormone was 1957 (975 SD) IU. Off the 57 ongoing pregnancies in the women allocated recombinant follicle stimulating hormone,, eight were twin pregnancies and one was a triplet pregnancy. Neonatal death
occurredd in one of the twin pregnancies at 26 weeks' gestation. The triplet pregnancy endedd with premature delivery at 22 weeks.
Safety y
Noo patient had perioperative complications or ovarian hyperstimulation syndrome. Ovulationn induction with recombinant follicle stimulating hormone resulted in significantlyy more multiple pregnancies than with the electrocautery strategy (rate ratio 0.11,0.011 to 0.88).
Discussion n
Ann electrocautery strategy was as effective as recombinant follicle stimulating hormone alonee for inducing ovulation in patients with clomiphene citrate resistant polycystic ovary syndrome.. Although the ongoing pregnancy rate after six months was lower after electrocauteryy alone than with recombinant follicle stimulating hormone, this difference wass abolished after administration of clomiphene citrate and recombinant follicle stimulatingg hormone when anovulation persisted, leading to cumulative ongoing pregnancyy rates of 67% in both groups. We cannot, however, exclude small differences, as ourr power calculation was based on lower expected pregnancy rates after recombinant folliclee stimulating hormone and after the electrocautery strategy than were observed in bothh study arms. In retrospect, we believe that our power calculation was informative and justifiable,, but the confidence intervals are wide and do not exclude the 5% difference. Threee published trials and two abstracts compared surgical treatment with gonadotrophinss in patients with clomiphene citrate resistant polycystic ovary syndrome (Abdell et al., 1993; Farquhar et al., 2002; Lazovic et al., 1998; Vegetti et al., 1998; Vicino ett al., 2000). These under-powered studies found no differences in rates for ovulation, pregnancy,, and miscarriage.
Thee strength of our design is that patients received further treatment if they did not respondd to electrocautery, with obvious clinical benefits from these additional interventions.. The cumulative ongoing pregnancy rate after electrocautery and clomiphenee citrate was 49%, eliminating the need for recombinant follicle stimulating hormone.. The ongoing pregnancy rate in women who were treated with recombinant folliclee stimulating hormone was 67%, avoiding the need for in vitro fertilisation and embryoo transfer.
Bipolarr electrocautery allows control of the energy source and has an autostop function andd resulted in discrete, reproducible punctures, with low risk of adhesion formation. The highh pregnancy rate after the addition of clomiphene citrate and recombinant follicle stimulatingg hormone suggests that postoperative adhesion formation is not an important problem.. Disadvantages of the electrocautery strategy are the potential risks from surgery carriedd out under general anaesthesia. Because ovulation induction with gonadotrophins iss a non-invasive procedure it does represent a safer alternative.
Recombinantt follicle stimulating hormone was given in a chronic low dose step up regimenn because of its efficacy and safety compared with other regimens (Bayram et al., 2004).. The high percentage of ongoing pregnancies in this treatment arm could be explainedd by strict adherence of the gynaecologists to the protocol, because close monitoringg of patients is mandatory and strict criteria for terminating cycles are defined.
Ourr results provide a scientific basis for counselling patients with clomiphene citrate resistantt polycystic ovary syndrome, particularly as many fail to respond to treatment. The generalisabilityy of our results is likely to be widened by the multicentre approach. We have shownn that both the electrocautery strategy and recombinant follicle stimulating hormone aree effective at ovulation inducing, with comparable cumulative pregnancy rates at 12 months.. No cases of ovarian hyperstimulation syndrome occurred and miscarriage rates weree comparable between treatment arms.
Thee major difference between the two strategies is that multiple pregnancies can largely bee prevented by treating women with electrocautery and clomiphene citrate before recombinantt follicle stimulating hormone. Although there is a need to minimise the frequencyy of multiple pregnancies, so far there has been little effort to issue guidelines or regulationss (Cohen and Jones, 2001).Our study may be a first step towards reducing multiplee pregnancies while maintaining good pregnancy rates.
Footnote e
Wee thank the following for inclusion and treatment of patients in this study:
Dr.. M.C. Armeanu (Kennemer Gasthuis, lokatie DEO, Haarlem); Dr. R.E. Bernardus (Ziekenhuiss Gooi Noord, Blaricum); Dr. H.E. Bobeck (Rode Kruis Ziekenhuis, Beverwijk);; Dr. R.S.G.M. Bots, B. Roozenburg (Sint Elisabeth Ziekenhuis, Tilburg); Prof.. dr. D.D.M. Braat (Universitair Medisch Centrum, St. Radboud, Nijmegen); J.. Dawson (Gelre Ziekenhuizen, lokatie Juliana, Apeldoorn); Dr. H.J.H.M. van Dessel, T.J.G.. Griffioen (Twee Steden Ziekenhuis, Tilburg); A.B. Dijkman, G.L.M. Lips, J.A. Schrickxx (Boven-IJ Ziekenhuis, Amsterdam); Dr. J.P.R. Doornbos (Zaans Medisch Centrumm De Heel, Zaandam); C.J.H. Dargel, Dr. P.A. van Dop, Dr. B.C. Schoot (Catharinaa Ziekenhuis, Eindhoven); Dr. G.A.J. Dunselman (Academisch Ziekenhuis Maastricht,, Maastricht); Dr. M.H. Emanuel, Dr. K. Wamsteker (Spaarne Ziekenhuis, Haarlem);; Ph.A. Engelen (Slotervaart Ziekenhuis, Amsterdam); Dr. D.A. Gietelink (Amphiaa Ziekenhuis, lokatie Langendijk, Breda); Dr. CJ.C.M. Hamilton (Jeroen Bosch Ziekenhuis,, lokatie Groot Ziekengasthuis, 's Hertogenbosch); Prof. dr. M J . Heineman (Academischh Ziekenhuis Groningen, Groningen); Dr. D.J. Hemrika, P.A. Flierman (Onze Lievee Vrouwe Gasthuis, Amsterdam); Dr. P.W.H. Houben (Gemini Ziekenhuis, Den Helder);; Dr. Y.M. van Kasteren (Medisch Centrum Alkmaar, Alkmaar); W.M. Killian (Ziekenhuiss Amstelveen, Amstelveen); M.D. Kloosterman (Ziekenhuis Rijnstate, Arnhem);; Dr. R.A. Leerentveld (Isala Klinieken, lokatie Sophia, Zwolle); P. Paaymans
(Streekziekenhuiss Midden-Twente, Hengelo); C.N.M. Renckens (Westfries Gasthuis, Hoorn);; Dr. R.A.K. Samlal (Ziekenhuis Gelderse Vallei, Ede); Prof. dr. E Scheele (Sint Lucass Andreas Ziekenhuis, lokatie Lucas, Amsterdam); Dr. W J . van der Velde (Waterlandziekenhuis,, Purmerend); Dr. M.A.H.M. Wiegerinck, E. Moret (Maxima Medischh Centrum, Veldhoven). We also thank M.M. Denyn and VI. Mauer for their invaluablee assistance.
Funding:: Serono Benelux provided financial support for recombinant follicle stimulating hormonee during the first eight months of the study when this drug was not funded by the healthh services. FvdV was supported by a grant from the Health Insurance Funds Council (OGG 97/007), Amstelveen, Netherlands. Competing interests: None declared.
Ethicall approval: The study was approved by the institutional review boards of all participatingg hospitals.
Eligiblee patients (n=213)
Diagnosticc laparoscopy (n=177)
Exclusionss (n=36):
Refusedd to participate (n=27)
Becamee pregnant before laparoscopy (n=5) Languagee barrier (n=1)
Tooo obese for general anaesthesia (n=3) Excludedd during diagnostic laparoscopy (n=9) Randomisedd during diagnostic laparoscopy (n=168)
Electrocauteryy strategy (n=83) Recombinantt FSH (n=85) Ongoingg pregnancies (n=28)
Completedd protocol (n=3) Discontinuedd treatment (n=5) Protocoll violation (n=2)* Anovulatoryy patients given
clomiphenee citrate (n=45)
Ongoingg pregnancies (n=13) Completedd protocol (n=5) Discontinuedd treatment (n=6) Anovulatoryy patients given
recombinantt FSH (n=21 +2*) Ongoingg pregnancies (n=15) Completedd protocol (n=8) Analysedd (n=83) Ongoingg pregnancies (n=57) Completedd protocol (n=12) Discontinuedd treatment (n=16) Analysedd (n=85)
FigureFigure 1. Flow of participants through trial.
TableTable 1. Characteristics of women allocated to electrocautery strategy or ovulation induction
withwith recombinant follicle stimulating hormone. Values are numbers (percentages) of women unlessunless stated otherwise.
Characteristicss Electrocautery Recombinant strategyy FSH
N=833 N=85
Meann age (years) (SD) 28.5 (3.7) 28.7 (4.1) Typee of infertility N (%) Primaryy 63 (76) 64 (75) Secondaryy 20 (24) 21 (25) Parityy N (%) Nulliparous s Multiparous s
Meann duration of infertility (years) (SD) Meann body mass index (SD)
Meann waist hip ratio (SD) Meann LH/FSH ratio (SD)
Meann testosterone (nmol/1) (SD) Meann free androgen index (SD) Meann volume ovaries (ml) (SD)
Meann total motile sperm count (xlO6) (SD)
644 (77) 199 (23) 2.88 (2.2) 27.99 (6.3) 0.833 (0.09) 1.99(0.96) ) 4.0(1.7) ) 14.00 (10.5) 10.66 (4.5) 1088 (136) 6666 (78) 199 (22) 2.88 (2.1) 27.33 (8.8) 0.844 (0.08) 1.93(0.90) ) 3.9(1.3) ) 13.33 (10.2) 11.6(6.5) ) 966 (106) SDD = standard deviation
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FigureFigure 2. Cumulative ongoing pregnancy rate over time from electrocautery or
ovulationovulation induction with recombinant follicle stimulating hormone.
70 0
electrocautery y strategy y
122 16 20 24 28 32 36 40 44 48 52
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