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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 5
Laparoscopicc e l e c t r o c a u t e r y of the ovaries versus
r e c o m b i n a n tt FSH in c l o m i p h e n e citrate resistant
polycysticc ovary s y n d r o m e . I m p a c t on w o m e n ' s
healthh related q u a l i t y of life.
MadelonMadelon van Wely, Neriman Bayram, Patrick M.M. Bossuyt, Fulco van der Veen
Abstract t
Background d
Ovulationn induction with gonadotropins is the standard treatment strategy for women withh clomiphene citrate (CC) resistant polycystic ovary syndrome. Laparoscopic electrocauteryy of the ovaries is an alternative treatment modality, leading to a comparable cumulativee pregnancy rate. In deciding which treatment to opt for, women's health related qualityy of life should be taken into account.
Methods s
AA total of 168 CC resistant women with polycystic ovary syndrome were randomly assignedd to receive either the electrocautery strategy, entailing laparoscopic electrocautery off the ovaries followed by CC and rFSH if anovulation persisted or ovulation induction withh rFSH. We assessed health related quality of life (HRQol) with the standard questionnairess Short Form 36, Rotterdam Symptom Checklist and Center for Epidemiologicall Studies Depression Scale, administered before randomisation and 2 weeks,, 12 weeks and 24 weeks thereafter.
Results s
Thee intention to treat analysis revealed no significant differences between the treatment groupss 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 womenn allocated to electrocautery strategy, with or without CC, although differences weree small. The intention to treat analysis revealed no significant differences between the treatmentt groups on any of the scales at any point during follow-up. In women without ann ongoing pregnancy, those treated with rFSH showed significantly more depressive symptomss than women allocated to electrocautery strategy, with or without CC, although differencess were small.
Conclusions s
Overall,, HRQoL was not affected in both groups. In women still under treatment, rFSH wass slightly more burdensome for women's HRQoL than electrocautery with or without CC. .
Keyy Words: ovulation induction, PCOS, clomiphene citrate resistant, health related qualityy of life, laparoscopic electrocautery, gonadotrophin, randomised controlled trial
Introduction n
Polycysticc ovary syndrome (PCOS) is a endocrine disorder with a great variety of presentationss of the following symptoms and signs; menstrual disturbance, infertility, obesity,, hirsutism, acne and endocrine abnormalities - including elevated LH/FSH ratio, hyperandrogenaemiaa and hyperinsulinaemia - and the appearance of polycystic ovaries onn ultrasonography (Balen and Michelmore, 2002). Infertility due to chronic anovulation iss the common reason for women with PCOS to seek treatment. The drug of first choice forr ovulation induction is clomiphene citrate (CC), administered orally. However, about 20%% of women with PCOS fail to ovulate on CC (Imani et al., 1998) and commonly ovulationn induction with gonadotrophins will be the next treatment option for this womenn .
Laparoscopicc electrocautery of the ovaries is an alternative treatment modality for women withh clomiphene citrate resistant PCOS. Electrocautery of the ovaries has been shown to resultt in resumption of regular ovulatory cycles (Gjonnaess, 1984; Farquhar et al. 2004). Subsequently,, after electrocautery of the ovaries, women with persistent anovulation or recurrencee of anovulation may respond to clomiphene citrate (Gjonnaess, 1984; Greenblattt and Casper, 1987).
Wee recently performed a randomised controlled trial comparing the electrocautery strategyy entailing laparoscopic electrocautery of the ovaries followed by clomiphene citrate andd recombinant FSH (rFSH) if anovulation persisted with ovulation induction with rFSHH (Bayram et al., 2004). No difference could be proven in ongoing pregnancy rate in bothh study groups.
Itt is generally assumed that ovulation induction with gonadotrophins is burdensome due too the necessity of daily injections and because of the risk of multiple follicular developmentt and multiple pregnancy (van Wely et al., 2003; Bayram et al., 2004a). Thereforee ovulation induction with FSH requires extensive monitoring. Electrocautery of thee ovaries is supposed to be a less burdensome treatment option, as it essentially involves aa single procedure with minimal morbidity, eliminates the need for cycle monitoring and cann lead to consecutive ovulations with minimal risks of multiple follicular development andd multiple pregnancies (Donesky and Adashi 1996). Disadvantages are the surgical proceduree itself, the unknown long term effect on ovarian function and possible adhesion formation. .
InIn deciding which treatment to opt for, women's health related quality of life (HRQoL) shouldd also be taken into account. In our multicenter trial therefore we compared health relatedd quality of life in women after laparoscopic electrocautery followed by clomiphene citratee when anovulation persisted and after ovulation induction with rFSH.
Methods s
Thee study was part of a randomised controlled trial that is reported in detail elsewhere (Bayramm et al., 2004).
Patients s
Womenn who participated in our randomised controlled trial with sufficient Dutch or Englishh language skills to complete questionnaires were eligible for measurement of
health-relatedd quality of life. Consenting women with clomiphene citrate resistant polycysticc ovary syndrome were included in the trial. All included women underwent a diagnosticc laparoscopy. Women with bilateral tubal obstruction, extensive adhesions of ovariess and/or tubes and severe endometriosis were excluded from the trial. Immediately followingg the laparoscopy, women were randomly assigned to receive either the electrocauteryy strategy entailing laparoscopic electrocautery of the ovaries followed by clomiphenee citrate and rFSH if anovulation persisted or ovulation induction with rFSH. Allocationn was performed by using a computer program with block randomisation, stratifiedd for centre. Participating centres called the Centre for Reproductive Medicine in thee Academic Medical Centre, which acted as the trial co-ordination centre. The trial took placee between February 1998 to October 2001 in 29 Dutch hospitals (Bayram et al., 2004).. Electrocautery of the ovaries was immediately performed after randomisation usingg an Erbotom ICC 350 Unit (Erbe BV, Zaltbommel, The Netherlands) and was done withh a bipolar insulated needle-electrode. Depending on the size of the ovary, 5-10 puncturess were created on each ovary, distributed randomly over the surface. If anovulationn persisted for eight weeks after the procedure or if the woman became anovulatoryy again during follow up, treatment with clomiphene citrate was re-introduced. Iff ovulation occurred, this dose was maintained for a maximum of six ovulatory cycles. If noo ovulation occurred the dose was increased to a maximum of 150 mg. If women remainedd anovulatory despite clomiphene citrate ovulation induction with rFSH was startedd as described below.
Womenn allocated to rFSH, received progesterone, immediately after randomisation. Ovulationn 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-upp protocol (Christin-Maitre et al., 2003; Bayram et al., 2004).
Instruments s
Thee objective of this sub-study was to compare health-related quality of life in women afterr electrocautery strategy and ovulation induction with rFSH. Health related quality of lifee (HRQoL) was defined as having a physical, psychological, and social dimension. As thee study population included essentially healthy women who are medically treated for theirr infertility we expected that this population would in general have normal quality of lifee scores. However the stress that comes with their infertility status and child wish may influencee women's HRQoL. We therefore assessed HRQoL with three standard self-administeredd questionnaires with established validity and reliability as we expected that togetherr they would cover most of the relevant HRQoL related effects.
Thee Standard Form 36 (SF-36) is a generic instrument composed of 36 questions organisedd into eight sub-scales: physical functioning, role limitations due to physical problems,, bodily pain, general health perception, vitality, social functioning, role limitationss due to emotional problems, and general mental health (Brazier et al., 1992; Waree et al., 1993; Aaronson et al., 1998). The subscale scores were transformed to a 0 to
1000 scale, with higher scores indicating better quality of life.
Thee Rotterdam Symptom Checklist (RSCL) comprises four sub-scales: physical symptoms,, psychological distress, activity level, and a single item measuring overall qualityy of life (De Haes et al., 1996). The RSCL was originally developed to evaluate HRQoLL in cancer patients. The subscale scores were transformed to a 0 to 100 scale, with higherr scores indicating more symptoms and a lower quality of life.
Thee Center for Epidemiological Studies Depression scale (CES-D) measures the subjectivee experience of depression as characterised by affective, cognitive, behavioural andd psychological symptoms (Bouma et al., 1995). It produces scores between 0 and 60, withh higher scores indicating more feelings of depression. A CES-D score of 16 or greater iss considered to be a rough indicator for presence of clinical depression.
Womenn were asked by their physicians to fill out the questionnaires at home. To compare shortt and long-term treatment effects, we assessed the HRQoL at four time points. The firstt set of questionnaires was completed one to two weeks before randomisation. Women subsequentlyy completed the questionnaires at two weeks, 12 weeks and 24 weeks after randomisation. .
Analysis s
Baselinee values from women with clomiphene citrate resistant PCOS were tabulated and comparedd with reference values from the general population, where available.
Healthh related quality of life was first compared between treatment groups studied on an intention-to-treatt (ITT) basis. A mixed-model analysis of variance was used to detect changess in health related quality of life over time (time effect), to compare HRQoL betweenn treatment groups (treatment effect), and to examine any interactions between changess in over time and treatment group (time by treatment effect).
Baselinee values were included in the analysis as covariables. Women with missing measurementss were included in the analysis whenever data were available at baseline and forr at least one time point during the trial (Zwinderman, 1992). Mean effects with their 95%% confidence intervals (95% CI) were calculated.
Ann ongoing pregnancy was expected to have a large effect on the HRQoL. Although the cumulativee pregnancy rates were equivalent at 12 months, the time to pregnancy differed betweenn groups. Therefore, a second analysis was performed, limited to the measurements off women without an ongoing pregnancy
Descriptivee data analysis was conducted with the use of the SPSS for Windows 11.0 statisticall software (SPSS Inc.; Chicago, IL, USA). Fixed model repeated measurement analysiss of variance was performed using the mixed procedure for serial measurements of SASS for Windows 6.12 statistical software (SAS Institute Inc., Cary, NC, USA). Adjustmentss were made for multiple comparisons.
Thee power calculation for the randomised trial was based on excluding a difference in the ongoingg pregnancy rate at 12 months after treatment (Bayram et al., 2004). Our hypothesiss for the HRQoL study was that laparoscopic electrocautery of the ovaries would bee less burdensome to women than ovulation induction with rFSH. Using a two-sided significancee level of 0.05, including 168 participants would allow us to detect an effect sizee of 0.44 with a power of at least 80% in an unconditional analysis of variance. This amountss to changes in effect size of 6 to 11 on the different items of the SF-36 scale.
R e s u l t s s Patients s
Onee hundred sixty-eight women were included in the study, of which 83 were allocated too the electrocautery strategy and 85 to rFSH. Three women in the electrocautery strategy groupp and eight women in the rFSH group had insufficient Dutch- or English-language
skillss to complete the questionnaires. Two eligible women in the electrocautery strategy groupp and three women in the rFSH group did not return a baseline and follow-up questionnaire.. In total, health related quality of life data of 152 women were available: 78 allocatedd to the electrocautery strategy and 74 allocated to rFSH. Baseline characteristics off all women are listed in Table 1.
Withinn 24 weeks 26 of the 78 women (38%) in the electrocautery strategy group had reachedd an ongoing pregnancy and 34 of 74 women (46%) had reached an ongoing pregnancyy after ovulation induction with rFSH.
Thee patient flow during the trial is presented in Figure 1. In the electrocautery strategy groupp 22 and 39 women were being treated with clomiphene citrate at week 12 and 24, respectively.. At week 24 seven of the 39 women subsequently started with rFSH.
Healthh related quality of life
Wee compared health-related quality of life (HRQoL) after electrocautery of the ovaries followedd by clomiphene citrate when anovulation persisted versus rFSH. Results of the comparisonss are presented in Table 2a and 2b. As administration of clomiphene citrate afterr electrocautery of the ovaries did not have a significant effect on any of the scales of thee HRQoL, we analysed women that had received electrocautery of the ovaries, with or withoutt clomiphene citrate, as a single group: the electrocautery strategy group.
Short-formm 3 6
Baselinee values were comparable to the values from the reference population, reflecting thee relative healthy status of the participating women. The ITT analysis comparing electrocauteryy strategy and rFSH showed no statistically significant treatment effect on anyy of the SF-36 sub-scales (Table 2a). Two weeks after laparoscopy, women in both groupss reported significantly more limitations in: physical functioning, social functioning,, role limitations due to physical problems, vitality and pain. At 12 and 24 weekss these limitations had disappeared. The occurrence of an ongoing pregnancy resultedd in significantly more role limitations due to physical problems, fewer role limitationss due to emotional problems and a better mental health.
Limitingg the analysis to women without an ongoing pregnancy revealed no significant differencess in treatment or time-effect.
Rotterdamm symptom checklist
Thee I T T analysis found no significant treatment or time effect for physical symptoms, psychologicall distress and overall quality of life on the RSCL (Table 2b). For activity level, aa statistically significant interaction between changes in health related quality of life over timee and treatment group was observed. At two weeks the activity level was significantly impairedd in women allocated to electrocautery strategy. Activity level was restored to baselinee values at 12 and 24 weeks after diagnostic laparoscopy. In the rFSH group, no suchh changes from baseline in activity level were seen.
Thee occurrence of an ongoing pregnancy resulted in a lower psychological distress score. AA sub-analysis limited to women without an ongoing pregnancy revealed no significant differencess in treatment or time-effect.
CES-D D
treatmentt effect (table 2b). The occurrence of an ongoing pregnancy resulted in a lower CES-DD score, indicating it to be less likely for these women to have depressive symptoms. Limitingg the analysis to women without an ongoing pregnancy revealed no changes from baselinee in depression score in women treated with the electrocautery strategy. In the rFSHH group however, more depressive symptoms were reported at two weeks as compared too their baseline values. The mean difference between electrocautery strategy and rFSH wass 4.8 points (95% CI: 0.3 to 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). Thee observed increase in CES-D scores does not automatically imply that these subjects hadd a clinical depression. A CES-D score of 16 and greater is taken to signify that a person showss depressive symptoms. Of the 24 non-pregnant women in the rFSH group, seven (29%)) had a score of 16 or greater before diagnostic laparoscopy and nine (38%) at 24 weekss after diagnostic laparoscopy. For the 41 non-pregnant women in the electrocautery strategyy group these numbers were 22 (53%) and 14 (34%) respectively (Figure 3).
Discussion n
Thiss study compared the health related quality of life in women with clomiphene citrate resistantt PCOS, after laparoscopic electrocautery of the ovaries followed by clomiphene citratee when anovulation persisted, versus ovulation induction with rFSH.
Thee intention to treat analysis showed no overall differences between both study groups onn any of the scales at any point of follow-up. Two weeks after laparoscopy, women in bothh groups reported significantly more limitations in physical functioning, social functioning,, vitality and pain as compared to baseline but these limitations had disappearedd 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 rFSHH group had not received a diagnostic laparoscopy.
Alll SF-36 scores and the RSCL scores for psychological distress and overall quality of life weree comparable to a normal healthy reference population of women. The RSCL scores forr physical symptoms, however, were somewhat higher than determined for a healthy referencee population. Indeed headaches and abdominal aches were more often noticed in bothh treatment groups possibly due to the stress accompanying infertility treatment (Abbeyy et al. 1992). There was no reference value available for the RSCL activity item. As thee mean activity scores were all between 1 and 8 on a scale of 0 to 100 (good to bad), thesee women appeared to have a healthy activity level.
Childd wish was the reason why the participating women sought help. Therefore, pregnancyy was expected to have an effect on the HRQoL. In our analysis we controlled forr ongoing pregnancy rather than clinical pregnancy. This was done because the occurrencee of an ongoing pregnancy was the endpoint of our randomised controlled trial. Hence,, women with a miscarriage until gestational age of 12 weeks would remain in thee trial.
Ass expected, an ongoing pregnancy had a significant effect on health related quality of life, ass could be observed on the mean scores for role limitations due to physical problems and mentall health of the SF-36 questionnaire, the psychological distress score of the RSCL questionnaire,, and the depression score of the CES-D questionnaire.
Limitingg the analysis to women without an ongoing pregnancy for these sub-scales revealedd that women in the rFSH group had significantly more depressive symptoms than womenn that received electrocautery of the ovaries with or without clomiphene citrate, althoughh the absolute difference was small.
Thee subanalysis was performed in women that did not become pregnant. If these women wouldd be more inclined to leave the study the resulting selective drop-out may have affectedd the course of the HRQoL values. As the cumulative pregnancy rates were comparablee in both study arms such a selective drop-out would likely have affected the HRQoLL values in a similar way in both groups. Furthermore, we cannot exclude that in thee electrocautery group expectations regarding treatment outcome at the moment of a changee in treatment from wait into CC and from CC into rFSH may have been of influencee on the emotional well being. This effect could explain the observed difference inn CES-D score in non-pregnant women.
Too our surprise, all HRQoL measurements taken before diagnostic laparoscopy and randomisationn were worse in the group that was to receive electrocautery of the ovaries withh or without clomiphene citrate than in women that were to be treated with rFSH. Thiss difference was not reflected in the baseline characteristics of the participants. For this reason,, we took the baseline measurements into account in our analysis.
Ovulationn induction with rFSH requires daily injections and intensive monitoring and bearss the risk of multiple follicular development and multiple pregnancy (Bayram et al., 2004).. Laparoscopic electrocautery of the ovaries on the other hand, essentially requires a singlee procedure only. Therefore we had expected that ovulation induction with rFSH wouldd be more burdensome to women. This assumption has not been confirmed, a small differencee was seen in the CES-D scale in the sub-analysis only. We cannot exclude that differencess also exist in other HRQoL items, however, as the study was powered to excludee a difference in pregnancy rates, the sample size was probably not sufficient to detectt small changes in HRQoL.
InIn our randomised controlled trial the ongoing pregnancy rate was comparable in both studyy groups (Bayram et al, 2004). After electrocautery of the ovaries and additional treatmentt with clomiphene citrate an ongoing pregnancy rate of almost 50% was seen, eliminatingg the need for ovulation induction with rFSH in half of the clomiphene resistantt women with PCOS. The cumulative ongoing pregnancy rate per woman of electrocauteryy of the ovaries, followed by clomiphene citrate and rFSH when anovulation persistedd was equivalent to that of ovulation induction with rFSH alone in a time span of 122 months (67% in both treatment groups: rate ratio 1.01; 95% confidence interval 0.81 too 1.24). However, the major difference between the two treatment arms was the occurrencee of multiple pregnancies. All multiple pregnancies occurred after ovulation inductionn with rFSH (rate ratio 0.11; 9 5 % confidence interval 0.01 to 0.86). Multiple pregnanciess are a major obstetric, psychological and economic problem (Ozturk and Templeton,, 2002). Reduction or prevention of the occurrence of multiple pregnancies shouldd be the major goal of treatment in clomiphene citrate resistant women with PCOS. Ourr findings on HRQoL do not supply any additional data for the recommendation that electrocauteryy strategy should be the treatment of choice in this patient group.
Thiss 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) wass obtained from Serono, The Netherlands.
TableTable 1. Baseline characteristics
Characteristics s
Meann age (years) (SD) Meann body mass index (SD) Meann waist hip ratio (SD)
Meann duration of infertility (years) (SD) Typee of infertility N (%) Primary y Secondary y Parityy N (%) Nulliparous s Muciparous s Educationn N (%)
Onlyy primary school Secondaryy school University y Electrocautery y strategy y N=83 3 28.55 (3.7) 27.99 (6.3) 0.833 (0.09) 2.88 (2.2) 633 (76) 200 (24) 644 (77) 199 (23) 211 (25) 522 (63) 10(12) ) rFSH H N=85 5 28.77 (4.1) 27.33 (8.8) 0.844 (0.08) 2.88 (2.1) 644 (75) 211 (25) 666 (78) 199 (22) 244 (29) 466 (54) 15(18) ) SDD = standard deviation Randomizedd (n=168) «« « ^ ^ r r Electrocauteryy strategy (n=83) Receivedd electrocautery (n=83) HRQoLL measurement (n=78)# l l Electrocautery y weekk 2 (n=72) weekk 12 (n=47) week24(n=21) ) i i f f Electrocauteryy + CC weekk 2 (n=0) weekk 12(n=22) weekk 24 (n=39) r r
Availablee for analysis (n=75)
Excludedd from analysis (n=3): baseline butt no follow-up measurement
i i r r Recombinantt FSH (n=85) Receivedd rFSH (n=85) HRQoLL measurement (n=74)# 1 1 r r rFSH H weekk 2 (n=69) weekk 12 (n=66) weekk 24 (n=58)
I I
Availablee for analysis (n=73) Excludedd from analysis (n=l): baseline butt no follow-up measurement
## Baseline HRQoL measurement completed before randomisation
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FigureFigure 2. Changes in CES-D score compared to baseline values in non-pregnant women
(means(means standard errors). Closed circles = electrocautery strategy; open circles = rFSH.
weekk 24 weekk 12 weekk 2 WMWMM///W/MW/M/A WMWMM///W/MW/M/A
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00 0.1 0.2 0.3 0.4 Proportionn with CES-D above 16FigureFigure 3. Histogram expressing the proportion of non-pregnant women with a CES-D score
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