Ovulation induction using laparoscopic ovarian drilling in women with polycystic ovarian syndrome: predictors of success

S.A.K. Amer1,2, T.C. Li1 and W.L. Ledger1

1 Department of Obstetrics and Gynaecology, The University of Sheffield, Jessop Wing, Sheffield Teaching Hospitals, Tree Root Walk, Sheffield S10 2SF, UK

2 To whom correspondence should be addressed. Email: s.amer{at}sheffield.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Although laparoscopic ovarian drilling (LOD) has been widely used to induce ovulation in women with polycystic ovarian syndrome (PCOS), predicting the clinical response to this treatment remains to be elucidated further. This study was carried out to identify factors that may help to predict the outcome of LOD. METHODS: This retrospective study included 200 patients with anovulatory infertility due to PCOS who underwent LOD between 1990 and 2002. The influence of the various patients' pre-operative characteristics on the ovulation and pregnancy rates after LOD was evaluated. In addition, women were divided into two or three categories according to the severity of each of the various clinical and biochemical parameters of PCOS. The success rates were compared between the categories of each factor using contingency table analyses. Multiple logistic regression analysis was used to identify independent predictors of success of LOD. RESULTS: Women with body mass index (BMI) ≥35 kg/m2, serum testosterone concentration ≥4.5 nmol/l, free androgen index (FAI) ≥15 and/or with duration of infertility >3 years seem to be poor responders to LOD. In LOD responders, serum LH levels >10 IU/l appeared to be associated with higher pregnancy rates. CONCLUSION: Marked obesity, marked hyperandrogenism and/or long duration of infertility in women with PCOS seem to predict resistance to LOD. High LH levels in LOD responders appear to predict higher probability of pregnancy.

Key words: laparoscopic ovarian drilling/polycystic ovarian syndrome/polycystic ovary


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Polycystic ovarian syndrome (PCOS) is the most common cause of anovulatory infertility, being found in ~75% of cases (Hull, 1987Go). Laparoscopic ovarian drilling (LOD) has been widely used to induce ovulation in PCOS women after failure of treatment with clomiphene citrate (CC). Many authors have reported high ovulation (~80%) and pregnancy (~60%) rates following LOD (Gjonnaess, 1984Go; Abdel Gadir et al., 1990Go; Kovacs et al., 1991Go; Armar and Lachelin, 1993Go; Naether et al., 1994Go; Li et al., 1998Go; Felemban et al., 2000Go; Amer et al., 2002aGo). However, ~20–30% of anovulatory PCOS women fail to respond to LOD. The mechanism of action of LOD is not fully understood and therefore it is not exactly clear why some PCOS patients do not respond to this treatment. A possible explanation is that the amount of ovarian tissue destroyed during LOD is not sufficient to produce an effect in some patients. However, others believe that ovarian diathermy works by increasing the sensitivity of the ovaries to endogenous FSH, and that only a minimal amount of thermal injury is required. Hence another possible explanation of failure to respond is an inherent resistance of the ovary to the effects of drilling.

If it were possible to identify the factors that determine the sensitivity of PCOS patients to LOD, then fruitless treatment could be avoided and success rates improved. In a previous study, our group reported on the factors affecting the pregnancy rates in 111 patients with PCOS after LOD (Li et al., 1998Go). In this extended study, we reappraise the various clinical, biochemical and ultrasonographic factors that determine the clinical response to LOD in a larger series of PCOS patients. We also report on the factors which appear to influence the duration of the beneficial effects of LOD in the responders.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Between 1990 and 2002, 250 patients with anovulatory infertility due to PCOS underwent LOD at the Reproductive Medicine Unit, Sheffield Teaching Hospitals. Thirty-eight women had laser ovarian drilling and were excluded from analysis, as this modality treatment was discontinued in our unit several years ago. Twelve patients underwent ovarian drilling using diathermy but received only two punctures per ovary and were also excluded from the analysis, as we have shown in a previous study that two punctures per ovary are associated with poor outcome (Amer et al., 2002bGo). Of the 111 patients in our earlier report (Li et al., 1998Go), 80 were included in the current study and the remaining 31 were excluded as they underwent laser ovarian drilling. The hospital records of the remaining 200 patients were reviewed and the clinical, biochemical and ultrasonographic data before LOD were documented. All the women had anovulatory infertility of >1 year's duration, and had been treated unsuccessfully with CC of up to 150 mg/day for 5 days in the early follicular phase of the menstrual cycle prior to LOD. In 161 women, CC failed to induce ovulation (CC resistance). The remaining 39 patients ovulated but failed to conceive after CC treatment for 6–9 months. In addition, 11 women had received HMG therapy for ovulation induction and failed to conceive.

The diagnosis of PCOS was based on the following criteria. (i) The early follicular phase (defined as days 2–5 of the menstrual cycle) serum LH/FSH ratio was ≥2 and/or raised serum androgen levels [testosterone ≥2.5 nmol/l, androstenedione ≥10 nmol/l or free androgen index (FAI) >4]. The FAI was calculated using the formula testosterone x 100/sex hormone- binding globulin (SHBG). In women with severe oligomenorrhoea or amenorrhoea, a random blood sample was accepted. (ii) There was ultrasonographic evidence of ovarian stromal hypertrophy and multiple (≥10), small (6–8 mm) follicles arranged in the periphery (Adams et al., 1985Go).

Hormonal assays
Serum hormonal concentrations (LH, FSH, testosterone, SHBG and androstenedione) were measured using well-established assays, which have been validated in our laboratory at the Department of Clinical Chemistry, Royal Hallamshire Hospital. Details of these assays have been published previously (Okon et al., 1998Go; Li et al., 2000Go).

Ultrasound scanning
Most patients underwent transvaginal scanning prior to LOD (n = 175). The ovarian volume was documented in 69 patients. Two ultrasound machines of the same model (Toshiba, Sonolayer SSA-250A, with a convex 6 MHz transvaginal ultrasound probe) were in use during the period of the study. Each ovary was localized in relation to the iliac vessels, and scanned from inner to outer margins in longitudinal cross-sections and from upper to lower ends in transverse cross-sections. The three diameters of the ovary were measured (longitudinal, anteroposterior and transverse). The ovarian volume was calculated using the formula for a prolate ellipsoid: 0.523 x length x width x thickness, according to the method of Sample et al. (1977)Go. The mean volume of the right and left ovary was calculated for each subject.

Laparoscopic ovarian drilling
The techniques of LOD used in our centre have been described previously (Li et al., 1998Go; Amer et al., 2002aGo). In most cases, a three-puncture laparoscopy was performed. A specially designed diathermy probe (Rocket of London, Watford, UK) was used to penetrate the ovarian capsule at a number of points with the aid of a short burst of diathermy. The electrosurgical unit used was the Force 2 Valleylab electrosurgical generator (Valleylab Inc., Boulder, CO). A monopolar coagulating current at 30 W power setting was used and the duration of each penetration was ~5 s. Three to 10 punctures were made in each ovary depending on its size, each measuring 4 mm in diameter and 7–8 mm in depth. About 200 ml of Hartmann's solution were instilled in the pelvis at the end of the procedure.

Post-operative monitoring
Following ovarian drilling, women were asked to keep a record of their menstrual cycle. If the patient started a menstrual period within 6 weeks of the surgery, a blood sample was taken on day 2 of that cycle for measurement of serum concentrations of LH, FSH, testosterone, androstenedione and SHBG. Another blood sample was taken on day 21 of the same cycle for measurement of serum concentration of progesterone. Ovulation was diagnosed when the progesterone level was ≥30 nmol/l. If spontaneous menstruation did not occur, a random blood sample was taken to measure all the above hormones at 6 weeks following surgery. If the patient did not ovulate as evidenced by the low progesterone levels or lack of menstruation, CC would be started 6–8 weeks after surgery. If ovulation was achieved either spontaneously or with the help of CC, patients were followed-up until they conceived or for up to 12 months after LOD.

Analysis of data
The data were entered into the Statistical Package for Social Science (SPSS) for windows version 11. The influence of patients' pre-operative characteristics including age, body mass index (BMI), duration of infertility, presence or absence on acne/hirsutism, menstrual pattern, LH/FSH ratio, serum concentrations of LH and testosterone, FAI and ovarian volume on the outcome of LOD was evaluated. For BMI, LH, LH/FSH ratio, testosterone and FAI, women were divided into three categories: normal or slightly elevated, moderately elevated and markedly elevated (Table I). With regard to ovarian volume, women were divided into two categories: patients with ovarian volume <14 ml and those with ≥14 ml. Ovulation and pregnancy rates after LOD were compared between the different categories of each factor. For ordered categorical data including BMI, testosterone levels, FAI, LH levels, LH/FSH ratio and duration of infertility, the {chi}2 test for linear trend was used to assess trend across the categories. For the other categorical variables including age, hirsutism, acne, menstrual pattern and ovarian volume, Pearson {chi}2 test was used to compare ovulation and pregnancy rates between the categories of each factor. Multiple logistic regression analysis for categorical data was used to identify independent predictors of success of LOD. Backward stepwise elimination was used for the multivariate logistic analysis of prediction of patients being responders to LOD. P > 0.10 was used as a cut-off level for exclusion of non-significant individual parameters from the prognostic model. The Cox and Snell square measure of goodness of fit was used to check for lack of fit of the final model.


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Table I. Categories according to each factor

 
Factors affecting the duration of the regular menstrual pattern in the responders after LOD were evaluated by comparing all the above clinical and biochemical parameters between two groups of women: LOD responders who continued to have regular menstrual cycles 1 year after treatment and those who resumed their oligo/amenorrhoeic status after the same period of time. Student's t-test test was used for this comparison. Significance was assumed if P < 0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 200 patients with anovulatory infertility associated with PCOS who underwent LOD were included in this study. The characteristics of this group of women are shown in Table II.


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Table II. The characteristics of 200 PCOS women who had LOD for anovulatory infertility

 
Amongst the 200 patients included in the study, 113 (57%) ovulated spontaneously after LOD and a further 43 patients ovulated after the addition of CC, giving an overall ovulation rate of 156 out of 200 (78%). Of the 200 women in the study, seven had not yet completed their 12 months follow-up after treatment at the time of writing. Amongst the remaining 193 patients, 97 (50%) conceived. One patient conceived with twins, giving a multiple pregnancy rate of 1%. Of the 97 pregnancies, nine (9%) ended in miscarriages and two (2%) were ectopic pregnancies.

Factors affecting the success rates of LOD
Table III illustrates the ovulation and pregnancy rates following LOD in PCOS patients with different categories of BMI, serum testosterone and LH concentrations, FAI, LH/FSH ratio, ovarian volume, duration of infertility, menstrual pattern and women with and without acne/hirsutism. The results show that women with marked obesity (BMI ≥35 kg/m2) achieved significantly (P < 0.05) lower ovulation and pregnancy rates (44 and 13%, respectively) compared with those (84 and 46%) of moderately overweight (BMI 29–34 kg/m2) women and those (81 and 57%) of women with normal and slightly elevated BMI (<29 kg/m2). However, in women who ovulated in response to LOD (LOD responders), BMI had no impact on the pregnancy rate. Responders with BMI <29 kg/m2 achieved a 68% (64 out of 94) pregnancy rate which was not significantly different from those of women with moderately elevated BMI (55%, 26 out of 47) and women with BMI ≥35 kg/m2 (57%, four out of seven).


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Table III. Ovulation and pregnancy rates in 200 PCOS patients after LOD related to different categories of age, body mass index (BMI), acne, hirsutism, serum concentrations of LH and testosterone, LH/FSH ratio, free androgen index (FAI), duration of infertility and ovarian volume

 
As far as the androgens are concerned, ovulation and pregnancy rates showed significant reduction with increasing androgen levels: in women with testosterone levels ≥4.5 nmol/l, the rates were 33 and 10%, respectively, which were significantly (P < 0.05) lower than those (76 and 48%) of women with moderately elevated testosterone (2.6–4.4 nmol/l). Patients with normal serum testosterone levels (<2.6 nmol/l) showed significantly (P < 0.05) higher success rates (86 and 56%) than the other groups. Similarly, the success rates (36 and 15%) of women with FAI ≥15 were significantly (P < 0.01) lower than that of the other groups (Table III). Multiple logistic regression analysis showed the duration of infertility to be the most important independent predictor of ovulation after LOD, followed by FAI and then BMI. The final logistic regression model had an R2 (Cox and Snell) of 0.296. Overall, 85% of the responses to LOD were correctly predicted by this model. As far as conception is concerned, duration of infertility then FAI were the most important predictors of success. The final model had an R2 of 0.367. Overall, 79% of conceptions after LOD were correctly predicted by this model.

There was a trend towards higher conception rates with increasing levels of LH, although statistical significance was not reached (Tables III). Further analysis revealed that once ovulation was achieved, serum LH levels had a statistically significant impact on the pregnancy rate: LOD responders with pre-treatment serum LH concentrations ≥10 IU/l achieved a significantly (P < 0.05) higher pregnancy rate (69%, 72 out of 104) than that (50%, 21 out of 42) of responders with serum LH concentrations <10 IU/l.

On the other hand, the LH/FSH ratio, the presence or absence of acne, the menstrual pattern and ovarian volume did not have any significant impact on the ovulation or pregnancy rates after LOD (Tables III).

In a subgroup of PCOS women (n = 122) with duration of infertility ≤3 years, FAI <15, testosterone <4.5 nmol/l and BMI <35 kg/m2, ovulation and pregnancy rates of 89 and 66%, respectively, were observed. When patients with duration of infertility ≥3 years were excluded, the ovulation and pregnancy rates in the remaining 87 women increased to 91 and 77%, respectively.

Factors affecting the duration of the beneficial effects in the responders to LOD
Amongst the 185 PCOS women who had oligo/amenorrhoea before LOD, 112 (60%) experienced regular menstrual cycles post-operatively. Follow-up data on the menstrual pattern 1 year after LOD were available in 63 of those 112 patients; 31 continued to have regular cycles and 32 became oligo/amenorrhoeic. Table IV shows the impact of various clinical and biochemical factors on the duration of the regular menstrual cycles after LOD. The results show that women with lower serum LH concentrations and/or a lower LH/FSH ratio are more likely to have a more sustained effect of LOD.


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Table IV. Possible factors affecting the duration of regular menstrual cycles in 63 PCOS patients who underwent LOD: comparison between women (n = 31) who continued to have regular menstrual cycles 1 year after LOD and those (n = 32) who became oligomenorrhoeic after the same period

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, we have evaluated the impact of various clinical, biochemical and ultrasonographic features of PCOS on the clinical outcome of LOD in 200 PCOS women. In addition, we have also reported on the factors affecting the duration of the beneficial effects of LOD.

Eight percent of PCOS women in this study had apparently regular menstrual cycles prior to LOD. Although chronic anovulation in women with PCOS is usually associated with menstrual irregularities (Franks, 1995), several authors have reported that 16–24% of these women do have apparently ‘regular’ menstrual cycles (Goldzieher and Axelrod, 1963; Naether et al., 1994Go; Balen et al., 1995; Carmina and Lobo, 1999). Furthermore, many anovulatory PCOS patients ovulate occasionally and some may resume regular menstrual cycles for variable periods of time. This explains why some anovulatory PCOS patients conceive spontaneously while being investigated for infertility or waiting for treatment.

Our data showed three main factors to have a significant impact on the efficacy of LOD, namely BMI, hyperandrogenism and duration of infertility. Women with marked obesity (BMI ≥35 kg/m2), marked hyperandrogenism (testeosterone ≥4.5 nmol/l, FAI ≥15) and/or with duration of infertility longer than 3 years seem to be resistant to LOD. With regards to LH levels, there was no impact on the ovulation rate but, once ovulation was achieved, LH levels had a significant impact on the pregnancy rates. Age, the presence or absence of acne, the menstrual pattern, LH/FSH ratio and ovarian volume did not seem to influence the outcome of LOD. Only a small number (n = 10) of patients in our study population were aged ≥35 years, and therefore the impact of age on the success of LOD can not be determined conclusively in this study.

Body mass index and LOD
PCOS women with BMI ≥35 kg/m2 achieved significantly lower ovulation and pregnancy rates after LOD compared with moderately overweight and normal weight women. However, although BMI had a significant impact on the overall ovulation rate (Table III), it did not seem to influence the overall pregnancy rates (Table III). Furthermore, we found that once ovulation was achieved, the BMI had no impact on the pregnancy rate. These findings are consistent with our earlier report (Li et al., 1998Go) which showed that BMI had no impact on the overall conception rates after LOD. The findings in the present study are in agreement with a previous report by Gjonnaess (1994)Go who reviewed 252 patients who underwent LOD and found that women with marked obesity (BMI ≥36 kg/m2) achieved significantly lower ovulation rates compared with women with normal and moderately elevated BMI. Gjonnaess (1994)Go also found that once ovulation was established, BMI has no impact on conception rates. More recently, in accordance with our observations, Duleba et al. (2003)Go reported that lean PCOS women (BMI ≤25 kg/m2) achieved higher conception rates than overweight women (BMI >25 kg/m2) after laparoscopic wedge resection using a harmonic scalpel in 33 PCOS patients. It is not clear why obese PCOS women should be refractory to LOD. Several previous studies have shown an inverse relationship between BMI and the response to medical methods of ovulation induction including CC (Lobo et al., 1982Go; Dickey et al., 1997Go) and gonadotrophin therapy (Fedorcsák et al., 2001).

Hyperandrogenism and LOD
Our data showed that increasing serum levels of testosterone and/or increasing FAI are associated with a statistically significant reduction of the chances of success of LOD. Furthermore, a subgroup of PCOS women with marked hyperandrogenism (testosterone ≥4.5 nmol/l, FAI ≥15) appeared to be resistant to LOD. This is in disagreement with our earlier report (Li et al., 1998Go) as well as that ofAbdel-Gadir et al. (1993)Go which showed that androgen levels had no impact on the success of LOD. This disagreement could be due to the relatively smaller sizes of the groups studied in the earlier reports compared with the current one. The results of the present study were consistent with those of Gjonnaess (1994)Go who found that women with low levels of SHBG (i.e. high levels of free testosterone), whether they were of normal weight or overweight, were less likely to respond to LOD. It is difficult to explain the relative resistance of hyperandrogenic PCOS patients to LOD since the exact mechanism of action of this treatment is yet to be determined. A possible explanation could be that the amount of destruction of androgen-producing ovarian tissue during LOD is relatively insufficient in women with marked hyperandrogenism. This may result in persistence of the androgenic intraovarian microenvironment characteristic of PCOS which could explain the persistence of anovulation after LOD. It remains to be elucidated whether an increased number of punctures or increased total power used during LOD in women with marked hyperandrogenism could result in reduction of the androgen levels, which may in turn result in an improvement of the outcome.

The duration of infertility and LOD
There was an inverse relationship between the duration of infertility and the chances of success of LOD. Indeed the duration of infertility has been found to be the most important independent predictor of success of LOD. Whilst ovulation rates did not show a significant decrease in women with infertility of ≥3 years, conception rates showed a marked decrease of >50% (from 72 to 33%). A further significant drop in both the ovulation and conception rates was observed in patients with >6 years of infertility, with only an 18% chance of conception compared with 72% in women with infertility of <3 years. These findings are consistent with our earlier report (Li et al., 1998Go) which showed that women with a duration of infertility >3 years were less likely to respond to LOD. A possible explanation for this is that women with longer duration of infertility are more likely to have other subtle subfertility factors.

Serum LH and LOD
Pre-treatment LH levels did not seem to influence the ovulation rates of LOD (Table III). However, once ovulation is achieved, LH levels appear to have a significant impact on pregnancy rate. LOD responders with higher LH levels (≥10 IU/l) have a significantly higher chance of conception than those with lower LH levels. This is in agreement with our earlier report (Li et al., 1998Go). Interestingly, some recent studies have reported that patients receiving CC had a significantly higher probability of conception once ovulation had been achieved by CC if their pre-treatment LH levels were elevated (Kousta et al., 1997Go; Imani et al., 1999Go). These observations seem to contradict in vivo evidence of the detrimental effects of elevated LH levels on oocyte maturation and capacity for fertilization. The mechanism of action of LOD remains to be fully elucidated, and the role of LH in the pathogenesis of PCOS remains open to speculation.

Factors affecting the duration of the beneficial effects of LOD
In the present study, LOD responders who had lower pre-treatment LH levels or a lower LH/FSH ratio were more likely to continue to benefit from the treatment for a longer period compared with those who had higher pre-treatment LH or LH/FSH ratio who were more likely to experience a recurrence of their anovulatory status after several months of treatment. A possible explanation for this is that the higher LH or LH/FSH ratio may be indicative of greater severity of the condition with a higher chance of early recurrence of the anovulatory status. However, these results should be interpreted with caution as 44% of women who resumed a regular menstrual pattern after LOD were lost to follow-up 1 year after the operation. This may explain the finding that increased BMI, a long history of infertility and hyperandrogenism were not predictive of recurrence of anovulation, despite the fact that these factors were associated with an immediate resistance to LOD.

In conclusion, we have identified a subgroup of PCOS patients who seem to be resistant to LOD including women with duration of infertility >3 years, BMI ≥35 kg/m2, FAI ≥15 and/or testosterone ≥4.5 nmol/l. We therefore recommend the consideration of alternative methods of treatment for this group of patients such as weight reduction, metformin, gonadotrophin therapy or IVF. In addition, our observation may help in selecting and counselling patients concerning their chances of a successful outcome after LOD. LH and the LH/FSH ratio seem to be good predictors of the duration of the beneficial effects of LOD.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on December 12, 2003; accepted on May 7, 2004.