Laparoscopic electrocautery of the ovaries versus recombinant FSH in clomiphene citrate-resistant polycystic ovary syndrome. Impact on women's health-related quality of life

M. van Wely1,3, N. Bayram1, P.M.M. Bossuyt2 and F. van der Veen1

1 Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology (H4-205), Academic Medical Centre, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands and 2 Department of Clinical Epidemiology and Biostatistics

3 To whom correspondence should be addressed. Email: m.vanwely{at}amc.uva.nl


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Ovulation induction with gonadotrophins is the standard treatment strategy for women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). Laparoscopic electrocautery of the ovaries is an alternative treatment modality, leading to a comparable cumulative pregnancy rate. In deciding which treatment to opt for, women's health-related quality of life (HRQoL) should be taken into account. METHODS: A total of 168 CC-resistant women with PCOS were randomly assigned to receive either the electrocautery strategy, entailing laparoscopic electrocautery of the ovaries followed by CC and recombinant FSH (rFSH) if anovulation persisted, or ovulation induction with rFSH. We assessed women's HRQoL with the standard questionnaires Short Form-36, Rotterdam Symptom Checklist and Center for Epidemiological Studies Depression Scale, administered before randomization and 2, 12 and 24 weeks thereafter. RESULTS: The intention to treat analysis revealed no significant differences between the treatment groups on any of the scales at any point during follow-up. In women without an ongoing pregnancy, those treated with rFSH showed significantly more depressive symptoms than women allocated to the electrocautery strategy, with or without CC, although differences were small. CONCLUSIONS: Overall, HRQoL was not affected in both groups. In women still under treatment, rFSH was slightly more burdensome for women's HRQoL than electrocautery with or without CC.

Key words: health-related quality of life/laparoscopic electrocautery/ovulation induction/PCOS/randomized controlled trial


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Polycystic ovary syndrome (PCOS) is an endocrine disorder with a great variety of presentations of the following symptoms and signs: menstrual disturbance, infertility, obesity, hirsutism, acne and endocrine abnormalities—including elevated LH/FSH ratio, hyperandrogenaemia and hyperinsulinaemia—and the appearance of polycystic ovaries on ultrasonography (Balen and Michelmore, 2002Go). Infertility due to chronic anovulation is the common reason for women with PCOS to seek treatment. The drug of first choice for ovulation induction is clomiphene citrate (CC), administered orally. However, ~20% of women with PCOS fail to ovulate on CC (Imani et al., 1998Go) and commonly ovulation induction with gonadotrophins will be the next treatment option for these women.

Laparoscopic electrocautery of the ovaries is an alternative treatment modality for women with CC-resistant PCOS. Electrocautery of the ovaries has been shown to result in resumption of regular ovulatory cycles (Gjonnaess, 1984Go; Farquhar et al., 2001Go). Subsequently, after electrocautery of the ovaries, women with persistent anovulation or recurrence of anovulation may respond to CC (Gjonnaess, 1984Go; Greenblatt and Casper, 1987Go).

We recently performed a randomized controlled trial comparing the electrocautery strategy, entailing laparoscopic electrocautery of the ovaries followed by CC and recombinant FSH (rFSH) if anovulation persisted, with ovulation induction with rFSH (Bayram et al., 2004Go). No difference could be proven in ongoing pregnancy rate in both study groups.

It is generally assumed that ovulation induction with gonadotrophins is burdensome due to the necessity of daily injections and because of the risk of multiple follicular development and multiple pregnancy (Bayram et al., 2001Go; van Wely et al., 2003Go). Therefore, ovulation induction with FSH requires extensive monitoring. Electrocautery of the ovaries is supposed to be a less burdensome treatment option, as it essentially involves a single procedure with minimal morbidity, eliminates the need for cycle monitoring and can lead to consecutive ovulations with minimal risks of multiple follicular development and multiple pregnancies (Donesky and Adashi, 1996Go). Disadvantages are the surgical procedure itself, the unknown long-term effect on ovarian function and possible adhesion formation.

In deciding which treatment to opt for, women's health-related quality of life (HRQoL) should also be taken into account. In our multicentre trial, therefore, we compared HRQoL in women after laparoscopic electrocautery followed by CC when anovulation persisted and after ovulation induction with rFSH.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The study was part of a randomized controlled trial that is reported in detail elsewhere (Bayram et al., 2004Go).

Patients
Women who participated in our randomized controlled trial with sufficient Dutch or English language skills to complete questionnaires were eligible for measurement of HRQoL. Consenting women with CC-resistant PCOS were included in the trial. All included women underwent a diagnostic laparoscopy. Women with bilateral tubal obstruction, extensive adhesions of ovaries and/or tubes and severe endometriosis were excluded from the trial. Immediately following the laparoscopy, women were randomly assigned to receive either the electrocautery strategy, entailing laparoscopic electrocautery of the ovaries followed by CC and rFSH if anovulation persisted, or ovulation induction with rFSH. Allocation was performed by using a computer program with block randomization, stratified for centre. Participating centres called the Centre for Reproductive Medicine in the Academic Medical Centre, which acted as the trial co-ordination centre. The trial took place between February 1998 and October 2001 in 29 Dutch hospitals (Bayram et al., 2004Go). Electrocautery of the ovaries was performed immediately after randomization using an Erbotom ICC 350 Unit (Erbe BV, Zaltbommel, The Netherlands) and was done with a bipolar insulated needle electrode. Depending on the size of the ovary, 5–10 punctures were created on each ovary, distributed randomly over the surface. If anovulation persisted for 8 weeks after the procedure or if the woman became anovulatory again during follow-up, treatment with CC was reintroduced. If ovulation occurred, this dose was maintained for a maximum of six ovulatory cycles. If no ovulation occurred, the dose was increased to a maximum of 150 mg. If women remained anovulatory despite CC, ovulation induction with rFSH was started as described below.

Women allocated to rFSH received progesterone immediately after randomization. Ovulation induction with rFSH (follitropin alpha, Gonal-F; Serono Benelux BV, The Hague, The Netherlands) started on cycle day (CD) 3, according to the chronic low-dose step-up protocol (Christin-Maitre and Hugues, 2003Go; Bayram et al., 2004Go).

Instruments
The objective of this substudy was to compare HRQoL in women after electrocautery strategy and ovulation induction with rFSH. HRQoL was defined as having a physical, psychological and social dimension. As the study population included essentially healthy women who are medically treated for their infertility, we expected that this population would in general have normal quality of life scores. However, the stress that comes with their infertility status and wish for a child may influence women's HRQoL. We therefore assessed HRQoL with three standard self-administered questionnaires with established validity and reliability as we expected that together they would cover most of the relevant HRQoL-related effects.

The Standard Form-36 (SF-36) is a generic instrument composed of 36 questions organized into eight subscales: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems, and general mental health (Brazier et al., 1992Go; Ware et al., 1993Go; Aaronson et al., 1998Go). The subscale scores were transformed to a 0–100 scale, with higher scores indicating better quality of life.

The Rotterdam Symptom Checklist (RSCL) comprises four subscales: physical symptoms, psychological distress, activity level, and a single item measuring overall quality of life (De Haes et al., 1996Go). The RSCL was developed originally to evaluate HRQoL in cancer patients. The subscale scores were transformed to a 0–100 scale, with higher scores indicating more symptoms and a lower quality of life.

The Center for Epidemiological Studies Depression scale (CES-D) measures the subjective experience of depression as characterized by affective, cognitive, behavioural and psychological symptoms (Bouma et al., 1995Go). It produces scores between 0 and 60, with higher scores indicating more feelings of depression. A CES-D score of ≥16 is considered to be a rough indicator for the presence of clinical depression.

Women were asked by their physicians to fill out the questionnaires at home. To compare short- and long-term treatment effects, we assessed the HRQoL at four time points. The first set of questionnaires was completed 1–2 weeks before randomization. Women subsequently completed the questionnaires at 2, 12 and 24 weeks after randomization.

Analysis
Baseline values from women with CC-resistant PCOS were tabulated and compared with reference values from the general population, where available.

HRQoL was first compared between treatment groups studied on an intention-to-treat (ITT) basis. A mixed-model analysis of variance was used to detect changes in HRQoL over time (time effect), to compare HRQoL between treatment groups (treatment effect), and to examine any interactions between changes over time and treatment group (time by treatment effect).

Baseline values were included in the analysis as covariables. Women with missing measurements were included in the analysis whenever data were available at baseline and for at least one time point during the trial (Zwinderman, 1992Go). Mean effects with their 95% confidence intervals (95% CIs) were calculated.

An ongoing pregnancy was expected to have a large effect on the HRQoL. Although the cumulative pregnancy rates were equivalent at 12 months, the time to pregnancy differed between groups. Therefore, a second analysis was performed, limited to the measurements of women without an ongoing pregnancy.

Descriptive data analysis was conducted with the use of the SPSS for Windows 11.0 statistical software (SPSS Inc., Chicago, IL). Fixed model repeated measurement analysis of variance was performed using the mixed procedure for serial measurements of SAS for Windows 6.12 statistical software (SAS Institute Inc., Cary, NC). Adjustments were made for multiple comparisons.

The power calculation for the randomized trial was based on excluding a difference in the ongoing pregnancy rate at 12 months after treatment (Bayram et al., 2004Go). Our hypothesis for the HRQoL study was that laparoscopic electrocautery of the ovaries would be less burdensome to women than ovulation induction with rFSH. Using a two-sided significance level of 0.05, including 168 participants would allow us to detect an effect size of 0.44 with a power of at least 80% in an unconditional analysis of variance. This amounts to changes in effect size of 6 to 11 on the different items of the SF-36 scale.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Patients
A total of 168 women were included in the study, of which 83 were allocated to the electrocautery strategy and 85 to rFSH. Three women in the electrocautery strategy group and eight women in the rFSH group had insufficient Dutch or English language skills to complete the questionnaires. Two eligible women in the electrocautery strategy group and three women in the rFSH group did not return a baseline and follow-up questionnaire. In total, HRQoL data of 152 women were available: 78 allocated to the electrocautery strategy and 74 allocated to rFSH. Baseline characteristics of all women are listed in Table I.


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Table I. Baseline characteristics

 
Within 24 weeks, 26 of the 78 women (38%) in the electrocautery strategy group had reached an ongoing pregnancy, and 34 of 74 women (46%) had reached an ongoing pregnancy after ovulation induction with rFSH.

The patient flow during the trial is presented in Figure 1. In the electrocautery strategy group, 22 and 39 women were being treated with CC at weeks 12 and 24, respectively. At week 24, seven of the 39 women subsequently started with rFSH.



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Figure 1. Flow diagram.

 
Health-related quality of life
We compared HRQoL after electrocautery of the ovaries followed by CC when anovulation persisted versus rFSH. Results of the comparisons are presented in Table IIa and bTable IIa and b. As administration of CC after electrocautery of the ovaries did not have a significant effect on any of the scales of the HRQoL, we analysed women who had received electrocautery of the ovaries, with or without CC, as a single group: the electrocautery strategy group.


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Table IIa. Specification of the SF-36 questionnaire

 

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Table IIb. Specification of the RSCL and CES-D questionnaires

 
SF-36
Baseline values were comparable with the values from the reference population, reflecting the relative healthy status of the participating women. The ITT analysis comparing electrocautery strategy and rFSH showed no statistically significant treatment effect on any of the SF-36 subscales (Table IIa). Two weeks after laparoscopy, women in both groups reported significantly more limitations in: physical functioning, social functioning, role limitations due to physical problems, vitality and pain. At 12 and 24 weeks, these limitations had disappeared. The occurrence of an ongoing pregnancy resulted in significantly more role limitations due to physical problems, fewer role limitations due to emotional problems and a better mental health.

Limiting the analysis to women without an ongoing pregnancy revealed no significant differences in treatment or time effect.

RSCL
The ITT analysis found no significant treatment or time effect for physical symptoms, psychological distress and overall quality of life on the RSCL (Table IIb). For activity level, a statistically significant interaction between changes in HRQoL over time and treatment group was observed. At 2 weeks, the activity level was significantly impaired in women allocated to the electrocautery strategy. Activity level was restored to baseline values at 12 and 24 weeks after diagnostic laparoscopy. In the rFSH group, no such changes from baseline in activity level were seen.

The occurrence of an ongoing pregnancy resulted in a lower psychological distress score.

A subanalysis limited to women without an ongoing pregnancy revealed no significant differences in treatment or time effect.

CES-D
The ITT analysis of the depression scale scores did not reveal any significant time or treatment effect (Table IIb). The occurrence of an ongoing pregnancy resulted in a lower CES-D score, indicating it to be less likely for these women to have depressive symptoms.

Limiting the analysis to women without an ongoing pregnancy revealed no changes from baseline in depression score in women treated with the electrocautery strategy. In the rFSH group, however, more depressive symptoms were reported at 2 weeks as compared with their baseline values. The mean difference between the electrocautery strategy and rFSH was 4.8 points (95% CI 0.3–9.3, P=0.04). These differences persisted during rFSH treatment, as could be observed at 12 and 24 weeks after diagnostic laparoscopy (Figure 2).



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Figure 2. Changes in CES-Dscore compared to baseline values in non pregnant women (means±standard errors). Closed circles = electrocautery strategy; open circlesequals;rFSH.

 
The observed increase in CES-D scores does not automatically imply that these subjects had a clinical depression. A CES-D score of ≥16 is taken to signify that a person shows depressive symptoms. Of the 24 non-pregnant women in the rFSH group, seven (29%) had a score of ≥16 before diagnostic laparoscopy, and nine (38%) at 24 weeks after diagnostic laparoscopy. For the 41 non-pregnant women in the electrocautery strategy group, these numbers were 22 (53%) and 14 (34%), respectively (Figure 3).



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Figure 3. Histrogram expressing the proportion of non-pregnant women with a CES-D core of 16 or larger for both strategies before and at 2, 12 and 24 weeks after laparoscopy.LEO laparoscopy electrocautery of the ovary

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
This study compared the HRQoL in women with CC-resistant PCOS, after laparoscopic electrocautery of the ovaries followed by CC when anovulation persisted, versus ovulation induction with rFSH.

The ITT analysis showed no overall differences between both study groups on any of the scales at any point of follow-up. Two weeks after laparoscopy, women in both groups reported significantly more limitations in physical functioning, social functioning, vitality and pain as compared with baseline, but these limitations had disappeared at 12 weeks, suggesting that these effects were entirely due to the diagnostic laparoscopy. The burden of laparoscopy would not have been present if women in the rFSH group had not received a diagnostic laparoscopy.

All SF-36 scores and the RSCL scores for psychological distress and overall quality of life were comparable with those of a normal healthy reference population of women. The RSCL scores for physical symptoms, however, were somewhat higher than determined for a healthy reference population. Indeed headaches and abdominal aches were noticed more often in both treatment groups, possibly due to the stress accompanying infertility treatment (Abbey et al., 1992Go). There was no reference value available for the RSCL activity item. As the mean activity scores were all between 1 and 8 on a scale of 0–100 (good to bad), these women appeared to have a healthy activity level.

The wish for a child was the reason why the participating women sought help. Therefore, pregnancy was expected to have effect on the HRQoL. In our analysis, we controlled for ongoing pregnancy rather than clinical pregnancy. This was done because the occurrence of an ongoing pregnancy was the end point of our randomized controlled trial. Hence, women with a miscarriage up to gestational age of 12 weeks would remain in the trial.

As expected, an ongoing pregnancy had a significant effect on HRQoL, as could be observed on the mean scores for role limitations due to physical problems and mental health of the SF-36 questionnaire, the psychological distress score of the RSCL questionnaire and the depression score of the CES-D questionnaire.

Limiting the analysis to women without an ongoing pregnancy for these subscales revealed that women in the rFSH group had significantly more depressive symptoms than women who received electrocautery of the ovaries with or without CC, although the absolute difference was small.

The subanalysis was performed in women who did not become pregnant. If these women would be more inclined to leave the study, the resulting selective drop-out may have affected the course of the HRQoL values. As the cumulative pregnancy rates were comparable in both study arms, such a selective drop-out would probably have affected the HRQoL values in a similar way in both groups. Furthermore, we cannot exclude that in the electrocautery group, expectations regarding treatment outcome at the moment of a change in treatment from waiting to CC and from CC to rFSH may have been of influence on the emotional well being. This effect could explain the observed difference in CES-D score in non-pregnant women.

To our surprise, all HRQoL measurements taken before diagnostic laparoscopy and randomization were worse in the group that was to receive electrocautery of the ovaries with or without CC than in women that were to be treated with rFSH. This difference was not reflected in the baseline characteristics of the participants. For this reason, we took the baseline measurements into account in our analysis.

Ovulation induction with rFSH requires daily injections and intensive monitoring, and bears the risk of multiple follicular development and multiple pregnancy (Bayram et al., 2004Go). Laparoscopic electrocautery of the ovaries, on the other hand, essentially requires a single procedure only. Therefore, we had expected that ovulation induction with rFSH would be more burdensome to women. This assumption has not been confirmed; a small difference was seen in the CES-D scale in the subanalysis only. We cannot exclude that differences also exist in other HRQoL items; however, as the study was powered to exclude a difference in pregnancy rates, the sample size was probably not sufficient to detect small changes in HRQoL.

In our randomized controlled trial, the ongoing pregnancy rate was comparable in both study groups (Bayram et al., 2004Go). After electrocautery of the ovaries and additional treatment with CC, an ongoing pregnancy rate of almost 50% was seen, eliminating the need for ovulation induction with rFSH in half of the CC-resistant women with PCOS. The cumulative ongoing pregnancy rate per woman undergoing electrocautery of the ovaries, followed by CC and rFSH when anovulation persisted was equivalent to that of ovulation induction with rFSH alone in a time span of 12 months (67% in both treatment groups: rate ratio 1.01; 95% CI 0.81–1.24). However, the major difference between the two treatment arms was the occurrence of multiple pregnancies. All multiple pregnancies occurred after ovulation induction with rFSH (rate ratio 0.11; 95% CI 0.01–0.86). Multiple pregnancies are a major obstetric, psychological and economic problem (Ozturk and Templeton, 2002Go). Reduction or prevention of the occurrence of multiple pregnancies should be the major goal of treatment in CC-resistant women with PCOS. Our findings on HRQoL do not supply any additional data for the recommendation that an electrocautery strategy should be the treatment of choice in this patient group.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was supported in part by grant OG 93/007 from the Health Insurance Funds Council, Amstelveen, The Netherlands. Financial support for rFSH treatment (Gonal-F) was obtained from Serono, The Netherlands.


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Submitted on January 6, 2004; resubmitted on April 19, 2004; accepted on June 15, 2004.





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