1 Center for Reproductive Medicine, Department of Obstetrics and Gynecology and 2 Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Meibergdreef 9, 1109 AZ Amsterdam, The Netherlands
3 To whom correspondence should be addressed at: Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Meibergdreef 9, 1109 AZ Amsterdam, The Netherlands. Email: m.vanwely{at}amc.uva.nl
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Abstract |
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Key words: electrocautery of the ovaries/laparoscopy/ovulation induction/PCOS
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Introduction |
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In these so-called clomiphene citrate-resistant women, ovulation induction with gonadotrophins is a well-established treatment. At present, recombinant FSH (rFSH) is widely used despite its costs, the need for extensive monitoring, and the risk of multiple pregnancy (White et al., 1996; Van Wely et al., 2003
; Bayram et al., 2004
).
Surgery is an alternative treatment modality for PCOS patients. Stein and Leventhal were the first to report that wedge resection of the ovaries in seven women resulted in ovulation and pregnancy (Stein and Leventhal, 1935). The procedure has been abandoned due to the introduction of clomiphene citrate and the risk of postoperative adhesion formation leading to mechanical infertility (Kistner, 1969
; Buttram and Vaquero, 1975
; Weinstein and Polishuk, 1975
; Adashi et al., 1981
; Portuondo et al., 1984
).
In recent years the rapidly expanding field of operative laparoscopy has led to a renewed interest for surgical treatment for PCOS. Several methods of laparoscopic treatment have been studied, including biopsy, electrocautery and laser treatment. Of these techniques electrocautery is most commonly being used, as the required equipment is present in most hospitals. Arguments in favour of the laparoscopic approach include the minimal morbidity associated with a laparoscopic procedure, the eliminated need for cycle monitoring and the low risk of multiple pregnancies (Cohen, 1996; Farquhar et al., 2004
). Furthermore, some CC-resistant women respond once again to CC after laparoscopic electrocautery (Farquhar et al., 2004
; Bayram et al., 2004
).
We recently performed a randomized controlled trial of an electrocautery strategy starting with laparoscopic electrocautery of the ovaries followed by clomiphene citrate and rFSH treatment when anovulation persisted vs ovulation induction with rFSH (Bayram et al., 2004). The electrocautery strategy was found to be equivalent to ovulation induction with recombinant FSH with respect to the ongoing pregnancy rate, but carried a lower risk of multiple pregnancies. The results of our trial prompted the Dutch Health Council as well as the National Institute of Clinical Excellence (NICE) of the British National Health Service to conclude that laparoscopic electrocautery is the preferred treatment in women with CC-resistant PCOS, as multiple pregnancies can largely be prevented (Dutch Health Council guideline, 2003; NICE, 2004).
Potential limitations of laparoscopic electrocautery are the need for general anaesthesia, which some women resent, the unknown long term effect on ovarian function, and the possibility of adhesion formation (Gurgan et al., 1991, 1992
). These risks may not be acceptable in women at high risk of persisting anovulation after electrocautery. It would therefore be helpful if we could identify women with PCOS with a high probability of treatment failure following electrocautery of the ovaries.
We performed a prognostic study with two objectives in mind. Firstly, to better understand the mechanisms of the laparoscopic electrocautery in isolation, we wanted to establish whether clinical, endocrine and ultrasonographic parameters during initial screening of CC-resistant PCOS patients can predict failure to ovulate after laparoscopic electrocautery. As women who remain anovulatory after electrocautery are treated with CC, our second aim was to develop a model to predict failure to reach an ongoing pregnancy after laparoscopic electrocautery and subsequent CC treatment in case of persisting anovulation.
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Materials and methods |
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PCOS was diagnosed on basis of chronic anovulation and presence of polycystic ovaries on transvaginal ultrasonography (The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group 2004a,b
). In addition, women were clomiphene citrate resistant, i.e. they had had persistent anovulation despite 150 mg clomiphene citrate daily for 5 days during one cycle. Anovulation was defined as absent folliculogenesis determined by ultrasonography for 35 days. The primary exclusion criteria were other causes of infertility like hypothalamic amenorrhea, premature ovarian failure, negative post-coital test or ovarian tumor, as well as previous treatment with gonadotrophins, age above 40 years and a partner with male subfertility. We defined male subfertility as a semen analysis that did not meet the WHO criteria for concentration, motility and/or morphology (World Health Organization, 1993). Furthermore, hyperprolactinaemia was a primary exclusion criterion if it was the only demonstrable cause for anovulation. Additional exclusion criteria, evaluated during laparoscopy, were tubal obstruction, extensive adhesions of the ovaries or Fallopian tubes, and endometriosis stages III or IV according to the classification of the American Fertility Society (Revised American Fertility Society classification of endometriosis, 1985
).
An initial clinical, ultrasonographic and endocrine evaluation took place before treatment with laparoscopic electrocautery. Clinical variables studied were age, menarche, duration of infertility, cycle history (amenorrhea or oligomenorrhea), body mass index (BMI) and waist hip ratio (WHR). Oligomenorrhea was defined as cycle intervals of >35 days but <6 months and amenorrhea was defined as cycle intervals of >6 months.
Transvaginal ultrasonographic evaluation included assessment of the ovarian volume. Ovarian volume was determined by the prolate ellipsoid formula, volume =4/3abc, with a, b and c representing the mean radius of the length, width and thickness of the ovaries. The mean radius was determined by taking the mean diameter of length, width and thickness of both ovaries, divided by two. Endocrine evaluation included serum assays for FSH, LH, estradiol, testosterone, androstenedion, sex hormone binding globulin (SHBG), fasting insulin, glucose and leptin. The free androgen index (FAI) was calculated as testosterone*100/SHBG. Blood samples were centrifuged within 2 h after withdrawal and stored at 20 °C until assayed. All hormonal assays were performed at one laboratory (Endocrinology Department, Academic Medical Center Amsterdam) on cryopreserved blood.
All male partners had two semen analyses after a minimal sexual abstinence of 2 days and analysis of the semen was performed within 1 h of ejaculation. After liquefaction, volume, concentration and motility were determined.
The cauterization of the ovaries was performed with an Erbotom ICC 350 Unit (Erbe BV, Zaltbommel, The Netherlands) using a bipolar insulated needle electrode. Depending on the size of the ovary, 510 punctures were created on each ovary, distributed randomly over the surface. Ovulation was assessed by transvaginal ultrasonography at weekly intervals until visualization of a preovulatory follicle of at least 18 mm. Non responders after laparoscopic electrocautery of the ovaries were defined as women who did not ovulate within 8 weeks after electrocautery. If anovulation persisted for 8 weeks after electrocautery or the patient became anovulatory again, treatment was started with 50 mg CC. 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. Patients then completed the study according to protocol after six subsequent ovulations. Patients that did not ovulate on 150 mg CC would receive ovulation induction with rFSH as described previously (Bayram et al., 2004). Outcomes of rFSH treatment are beyond the scope of this study.
Data analysis
We attempted to build two prognostic models to predict treatment failure.
The first prognostic model aimed to predict failure to ovulate after electrocautery of the ovaries. A woman was considered as a case of failure of laparoscopic electrocautery of the ovaries when she remained anovulatory for 8 weeks after electrocautery. The second prognostic study was aimed at predicting failure to reach an ongoing pregnancy after the electrocautery followed by treatment with CC if electrocautery alone was not successful. Here the measure of success was ongoing pregnancy in a woman, defined as a viable pregnancy of at least 12 weeks.
We used multivariable regression analysis to study associations between clinical, ultrasonographic and endocrinological parameters and ovarian response to laparoscopic electrocautery of the ovaries. The first model was built using logistic regression modelling while the second model was built using Cox regression analysis, to better express success rates and failure over successive cycles.
A similar modelling approach was used for both analyses. Two preliminary steps were taken. First, correlations between parameters were studied to prevent the selection of highly correlated parameters in the logistic model. Second, we studied whether the assumption of linearity between the continuous variables and the log odds of ovulation (first model) or pregnancy (second model) was met, using visual inspection and spline functions. If necessary, the continuous variables were transformed to better approach linearity. Then univariate odds ratios (OR), 95% confidence intervals (CI) and P-values were calculated for all potential predictors.
The initial multivariable prognostic models included clinical data only. Subsequently, ultrasonographic and endocrinological variables were added using a stepwise procedure. A significance level of P0.2 was used for selection into the multivariable model (Steyerberg et al., 1999
; Mol et al., 2000
).
Data were analysed using S-PLUS 2000 and SPSS 11.5.1.
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Results |
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Predicting ovarian response within 8 weeks after electrocautery
Of the 83 women treated with laparoscopic electrocautery of the ovaries 27 (32.5%) failed to ovulate within 8 weeks following treatment and were considered to be non-responders. Twenty-eight women reached an ongoing pregnancy.
Table I summarizes the baseline characteristics. No variables had to be transformed to improve linearity. Univariate analysis showed the LH/FSH levels to be significantly associated with response to treatment (Table II).
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From the endocrinological parameters, LH/FSH rate and glucose level were the only ones that could be added to the model. The final multivariable model then contained three variables: age at menarche, LH/FSH rate and glucose level. Of these three variables, LH/FSH level was the strongest predictor. The multivariable-adjusted OR for persistent anovulation was 0.72 for age at menarche (95%CI: 0.491.06), 0.41 for LH/FSH (95%CI: 0.190.87) and 0.67 for glucose level (95%CI: 0.391.14). Women who were younger at menarche, and who had a lower LH/FSH rate and a lower glucose level were more likely to have persistent anovulation.
The reliability of the model was tested by comparing the model probabilities to the observed relative frequencies of women with persistent anovulation in five groups. These groups were based on the quintiles of the calculated probabilities (Figure 1). The group with the highest probability of remaining anovulatory (predicted probability to remain anovulatory of >70%) could be clearly distinguished from women with a probability of remaining anovulatory of <10%. The group of 14 women with the highest probability to remain anovulatory contained those who had an age at menarche below 13, an LH/FSH ratio below 2, and a glucose level below 4.5 mmol/l. In contrast, the group of 14 women that had a mean probability to remain anovulatory of <10% contained those who had an age at menarche above 13, an LH/FSH ratio above 3 and a glucose level above 5 mmol/l.
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In total, 11 women did not complete the study according to protocol. Two anovulatory women dropped out after electrocautery and three women that ovulated after electrocautery dropped out after they became anovulatory at a third cycle. A further two women dropped out after the first treatment cycle with CC (50 mg), three women dropped out after the third CC cycle (150 mg) and one woman dropped out after five treatment cycles with CC (150 mg).
In total, 76 of the 83 women in the study group (92%) had at least one ovulation and 41 women (49%) reached an ongoing pregnancy. There were no multiple pregnancies. All ongoing pregnancies resulted in live births.
The cumulative ongoing pregnancy rate after electrocautery is shown in Figure 3. BMI was found to be not linearly related to the log odds of an ongoing pregnancy after electrocautery followed by CC. Figure 4 shows a symmetric parabola, with a top at a BMI of 28 kg/m2. BMI was then transformed.
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Discussion |
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For the prediction of poor response after laparoscopic electrocautery we decided to focus on ovulation being the primary aim of treatment, rather than conception. From the set of clinical, ultrasonographic and endocrine parameters the LH/FSH ratio came out as the most predictive variable for ovarian response after electrocautery. Women with an LH/FSH ratio below 2 were more likely to remain anovulatory while women with a higher LH/FSH ratio were more likely to ovulate. Year of menarche was the second predictive variable for ovarian response: women who had their menarche at an age below 13 were more likely to remain anovulatory compared to women who had their menarche at an older age. Furthermore, chances of remaining anovulatory appeared to increase with lower fasting glucose levels.
To our knowledge, this study is the first one on prognostic factors for ovarian response following laparoscopic electrocautery to use a multivariable prediction model with prospective data collection. Previous studies on predictors for ovarian response were retrospectively designed or did not use multivariable analyses (Abdel Gadir et al., 1993; Li et al., 1998
; Alborzi et al., 2001
; Kriplani et al., 2001
; Duleba et al., 2003
). We included only women with CC-resistant PCOS, without other causes of infertility including male partner subfertility, which adds to the strength of our study. Furthermore, we considered all parameters known to be associated with PCOS, including female age, type of infertility, age at menarche, cycle history, BMI, size of the ovary, LH/FSH ratio, FAI, DHEAS, androstenedione, glucose, insulin and leptin. A potential weakness of our study is its limited sample size, as it is based on 83 women only. Therefore we cannot exclude that we missed smaller associations of other parameters with ovarian response to electrocautery.
Our results are in accordance with previous reports of raised preoperative LH levels being associated with better ovulation rates (Abdel Gadir et al., 1993; Li et al., 1998
; Kriplani et al., 2001
). In this study, we found the LH/FSH ratio to be a better predictor than LH alone. The size of the ovary and the androgen level were not associated with response to ovarian cautery, which is in agreement with findings in other studies (Alborzi et al., 2001
; Duleba et al., 2003
).
This prognostic study can be of help in understanding the working mechanism of laparoscopic electrocautery. The mechanism of action of electrocautery is believed to be related to endocrine changes following the procedure. A significant reduction in LH and androgen (testosterone, androstenedione and DHEAS) levels in the serum has been observed (Greenblatt and Casper, 1987; Lemieux et al., 1999
; Felemban et al., 2000
). In this respect it makes sense that women with a high LH/FSH ratio were more likely to ovulate after electrocautery.
The group with the highest probability for persistent anovulationwith a mean probability of remaining anovulatory of >70%could be distinguished from women with a probability of <10% of remaining anovulatory. Women more likely to remain anovulatory had an age at menarche below 13, an LH/FSH ratio below 2, and a glucose level below 4.5 mmol/l. We should note, however, that all women with persistent anovulation after electrocautery will receive subsequent ovulation induction with CC. In our study, electrocautery followed by CC turned out to be a very successful treatment strategy resulting in live births in 50% of women, without any multiple pregnancies. Therefore, a model to predict treatment failure after electrocautery followed by CC would be more relevant for clinical practice. Unfortunately, we could not identify parameters that can predict treatment failure after electrocautery followed by CC. A potential explanation is the fact that electrocautery and CC have quite different working mechanisms while only the subpopulation of non-responders to electrocautery will receive CC treatment.
In summary, our multivariable model allows us to distinguish women with a poor chance of ovulating after electrocautery of the ovaries from those with a high chance of ovulating. However, we could not identify a subgroup of women with a low probability of reaching an ongoing pregnancy after electrocautery followed by CC. As laparoscopic electrocautery is now well established as the treatment of first choice for CC-resistant women with PCOS (Dutch Health Council guideline, 2003; NICE, 2004), our findings imply that no single woman should a priori be excluded from this treatment.
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Submitted on May 21, 2004; resubmitted on September 1, 2004; accepted on December 3, 2004.
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