Hum. Reprod. Advance Access published online on September 14, 2008
Human Reproduction, doi:10.1093/humrep/den325
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Randomized controlled trial comparing laparoscopic ovarian diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome
1 Department of Obstetrics and Gynaecology, University of Nottingham, Derby City General Hospital, Derby DE22 3NE, UK 2 Reproductive Medicine and Surgery Unit, University of Sheffield, Sheffield Teaching Hospitals, Sheffield S10 2SF, UK
3 Correspondence address. E-mail: saad.amer{at}nottingham.ac.uk
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Abstract |
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BACKGROUND: Laparoscopic ovarian diathermy (LOD) is currently accepted as a successful second-line treatment for ovulation induction (OI) in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome (PCOS). The aim of this study was to test the hypothesis that LOD may be superior to CC as a first-line treatment.
METHODS: The study included 72 anovulatory women with PCOS who were randomized to LOD (n = 36) or CC (n = 36). Women who remained anovulatory after LOD were offered CC. Similarly, women receiving CC who failed to ovulate or conceive were offered LOD. Pregnancy rates were compared between the two groups using 
2 and odds ratio with 95% confidence interval (OR, 95% CI).
RESULTS: After randomization, six women conceived before starting treatment and another patient postponed treatment. The remaining 65 women received the treatment (33 underwent LOD and 32 received CC). After the primary treatment, more pregnancies (44%) occurred in women receiving CC than in those undergoing LOD (27%), although the difference did not reach statistical significance [P = 0.13, OR 2.1 (0.7 – 5.8)]. After adding the second treatment, the pregnancy rate was still higher, but to a less extent, in the CC group [63% versus 52%, P = 0.2, OR 1.6 (0.6 – 4.2)].
CONCLUSIONS: LOD is not superior to CC as a first-line method of OI in women with PCOS. The trial is registered with ClinicalTrials.gov with an identifier number NCT00220545 [ClinicalTrials.gov] .
Key words: laparoscopic ovarian diathermy/clomiphene citrate/ovulation induction/polycystic ovarian syndrome/pregnancy rates
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Introduction |
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Clomiphene citrate (CC) has been widely used as the standard first-line treatment for ovulation induction (OI) in women with anovulatory infertility associated with polycystic ovary syndrome (PCOS) for more than four decades. Although CC treatment will frequently restore ovulation, with ovulation rates of
80%, it is less effective in producing pregnancy, with only 35% of women conceiving during treatment. The largest published study on CC, which included over 4000 patients, was carried out by MacGregor et al. (1968)
who reported a pregnancy rate of 34%. Other relatively smaller studies on CC have reported pregnancy rates of 30 – 43% (Garcia et al., 1977; Gorlitsky et al., 1978; Gysler et al., 1982; Hammond, 1984; Dickey et al., 1996; Kousta et al., 1997; Imani et al., 2002). Furthermore, CC treatment is associated with high miscarriage rates (30%) (Kistner, 1965; Rabau et al., 1967; Franks et al., 1985). The discrepancy between ovulation and conception rates with CC treatment and the higher than expected incidence of miscarriage have been attributed to the antiestrogenic mechanism of action of CC which has a negative effect on the quality and quantity of cervical mucus (Randall et al., 1991) and on endometrial development (Gonen and Casper, 1990).
Laparoscopic ovarian diathermy (LOD) has been widely established as an effective second-line method of OI in CC-resistant PCOS patients, with high ovulation (80%) and pregnancy rates (60–80%) (Armar and Lahelin, 1993; Naether et al., 1994; Gjønnaess, 1994; Liguori et al., 1996; Merchant, 1996; Pelosi and Pelosi, 1996; Felemban et al., 2000; Bayram et al., 2004; Farquhar et al., 2005). Theoretically, LOD offers several advantages over CC as a first-line treatment in patients with PCOS. A single treatment leads to repeated physiological ovulatory cycles and potentially repeated pregnancies without the need for repeated courses of medical treatment. Importantly, LOD results in mono-ovulation, with an incidence of multiple pregnancies no higher than background rates. In contrast, CC treatment is associated with a 5–10% chance of twin pregnancy (Scialli, 1986; Imani et al., 1999). The incidence of triplet pregnancies has also been reported to be increased following OI with CC (Levene et al., 1992). Moreover, the chance of miscarriage is significantly lower with LOD than with CC induction of ovulation, possibly because of normalization of the serum levels of LH and/or androgens (Abdel-Gadir et al., 1990). Hypothetically, prolonged use of CC may be associated with an increased risk of ovarian cancer (Rossing et al., 1994), a risk which is not increased by LOD. LOD also allows a rapid check of pelvic anatomy and tubal patency, avoiding the necessity for a separate procedure such as a hysterosalpingogram. Disorders of pelvic anatomy such as endometriosis and adhesions, which could adversely affect fertility, may be detected and treated during laparoscopy for ovarian diathermy. The main drawback of LOD is the need for general anaesthetic and surgery. Other complications such as adhesion formation and the theoretical risk of premature ovarian failure appear to be of little clinical significance. The reported incidence of adhesion formation after LOD varied considerably in different studies from 0% to 100% (Armar and Lahelin, 1993; Greenblatt and Casper, 1993; Naether, 1995). Most of the studies reported mild to moderate adhesions in 35% of cases, which did not seem to affect the pregnancy rate after LOD (Greenblatt and Casper, 1993). Another concern regarding LOD is the lack of standardization of the techniques used and the amount of thermal energy applied by different Reproductive Specialists. However, we have previously addressed this issue by conducting dose finding studies on LOD, in which we have established the optimal amount of energy to be delivered using monopolar needle diathermy (Amer et al., 2002, 2003).
LOD may therefore be seen as a realistic alternative first-line treatment for anovulatory infertility in the presence of PCOS. The aim of this study was to test the hypothesis that LOD as a first line could generate better pregnancy rates with fewer multiple pregnancies and miscarriages than treatment with CC.
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Materials and Methods |
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Subjects
This study was conducted in the Centre for Reproductive Medicine and Fertility, University of Sheffield, between March 2002 and March 2006. Women with anovulatory infertility associated with PCOS were invited to take part in this study. Diagnostic criteria for PCOS included at least two of the following three features: clinical (oligo/amenorrhoea and/or hyperandrogenaemia), biochemical [LH
10 IU/l, LH/FSH ratio 2, testosterone >2.6 nmol/l or free androgen index (FAI) >5] and/or sonographic (polycystic ovaries) features. The study included women aged 18–39, with body mass index (BMI) 
32 kg/m2 and a duration of infertility of 1 year. Other inclusion criteria were at least one patent fallopian tube on hysterosalpingogram and normal semen analysis of the male partner. Exclusion criteria were inability to give informed consent (e.g. due to language barrier) and contraindication to CC or general anaesthetic. In addition, women who had received any OI therapy such as CC, metformin or gonadotrophin during the preceding 6 months were excluded. The study was approved by the South Sheffield Ethics Committee and all participants gave written informed consent.
Randomization
Suitable patients were randomized utilizing a block randomization method using a random number table generated by the pharmacist. This table was held centrally by a trial administrator. Randomization was carried out by telephone. The patient was assigned by the principal investigator to treatment Group A (LOD) or B (CC) according to the randomization. Allocation to treatment was concealed, but once allocated, the treatment was revealed to both the investigator and the patient.
Laparoscopic ovarian diathermy
The techniques of LOD used in this study have previously been published (Amer et al., 2003, 2004). A specially designed monopolar electrocautery probe (Rocket of London, Watford, UK) was used to penetrate the ovarian capsule making four punctures per ovary at a power setting of 30 W applied for 5 s per puncture. The electrosurgical unit used was the Force 2 Valleylab electrosurgical generator (Valleylab Inc., Boulder, CO, USA). The pelvis was thoroughly inspected for any pathology. Any endometriosis and/or peri-adnexal adhesions were treated by diathermy and adhesiolysis, respectively.
Post-operative monitoring
Following LOD, women were asked to keep a record of their menstrual cycles. If menstruation occurred within 6 weeks of the surgery, a blood sample would be taken on Day 21 of the same cycle for measurement of serum concentration of progesterone. Ovulation was diagnosed when the progesterone level was 25 nmol/l. Subsequent cycles were monitored for ovulation by measurement of progesterone on cycle Day 21. If spontaneous menstruation did not occur, a random blood sample would be taken after 6 weeks to measure progesterone. 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. CC was also given to women who experienced a recurrence of the anovulatory status after an initial period of ovulation. If ovulation was achieved either spontaneously or with the help of CC, patients were followed up until they conceived or for up to a period of 12 months after LOD. Conception was diagnosed with a positive urinary pregnancy test (Clearview, hCG II, Unipath Ltd, Bedford, UK) taken 1 week after a missed period. Multiple pregnancies were diagnosed by transvaginal ultrasound scan performed at 7 weeks gestation.
Clomiphene citrate
CC was given in incremental doses starting with a daily dose of 50 up to 150 mg on Days 2–6 of a menstrual period or after a progestogen withdrawal bleed using medroxyprogesterone acetate (Provera®, Pharmacia, Kent, UK).
Monitoring of CC treatment
Ovulation was monitored by measuring the serum concentration of progesterone on Day 21 of the menstrual cycle. A serum progesterone level of 25 nmol/l was used to indicate ovulation. Once this occurred on a certain dose, CC was continued in the same dose for six cycles with measurement of serum progesterone concentrations on cycle Day 21. If patients remained anovulatory on the maximum dose of CC, or if they fail to conceive after six ovulatory cycles, they were offered LOD. Patients were followed up until they conceived or for up to a period of 12 months after commencement of CC. Pregnancy and multiple pregnancies were diagnosed as above.
Sample size
The primary outcome measure in this trial was cumulative pregnancy rate at 12 months. Secondary outcome measures included ovulation, miscarriage, multiple pregnancy and live birth rates. From our review of the literature, we hypothesized pregnancy rates of 35% with CC and 70% with LOD. On the basis of this analysis, 36 patients were required in each arm to detect this difference with a 5% level of significance and 80% power.
Statistical analysis
Data were entered into the Statistical Package for Social Sciences (SPSS) version 14. Analysis was performed on an intention-to-treat basis. The results in the two groups were compared using 2 and odds ratio with 95% confidence interval. Statistical significance was assumed when P < 0.05.
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Results |
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A total of 83 consecutive patients with anovulatory PCOS who fulfilled the criteria of inclusion were approached to participate in the study. Eleven patients were excluded: five declined and six had a language barrier. The five patients who declined had a preference to a certain treatment and did not wish to be randomized.
Overall, 72 patients were included in the study, of whom 36 were allocated to LOD and 36 to CC. Of the 72 women randomized, six (three from the LOD group and three from the CC group) conceived before starting treatment and one patient from the CC group decided to postpone her treatment for personal reasons. The remaining 65 women (33 in the LOD group and 32 in the CC group) completed their treatment (Fig. 1). All the 72 women recruited in the study were anovulatory and had polycystic ovary morphology on ultrasound scan, but only 65 had clinical or biochemical evidence of hyperandrogenaemism. According to the 2003 ESHRE/ASRM (Rotterdam) consensus, PCOS is diagnosed when two of three features are present including: (i) oligo- and/or anovulation, (ii) clinical and/or biochemical signs of hyperandrogenism and (iii) polycystic ovaries (ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004). On the other hand, according to the 1990 National Institutes of Health (NIH) definition, both anovulation and hyperandrogenism must be present for the diagnosis of PCOS (Zawadzki and Duniaf, 1992). Therefore, all patients in the current study fulfilled the 2003 ESHRE/ASRM (Rotterdam) criteria of PCOS, but only 65 fulfilled the 1990 NIH criteria for PCOS. All the women who did not have hyperandrogenaemia (n = 7) had an elevated LH:FSH ratio. The baseline characteristics of patients in both groups were similar (Table I).
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Following LOD, 22 patients received CC either due to persistence of anovulation (n = 12) or recurrence of anovulation after an initial period of ovulation (n = 10). Of the 32 women who received CC, 11 underwent LOD either due to persistence of anovulation (n = 7), failure to conceive despite regular ovulation (n = 2) or development of complications (see below) (n = 2).
Ovulation
The ovulation rate per patient after LOD was 64% (21/33), which was not statistically (P = 0.32) different from that of CC (24/32, 76%), although there was a trend towards a higher rate in the CC group. After adding the second treatment, ovulation rates increased in the two groups to 85% (28/33) and 84% (27/32), respectively (P = 1.0). The ovulation rates per cycle after the primary treatment were 70% (62/88) after LOD and 66% (70/106) during CC treatment.
Pregnancy
Table II shows the pregnancy rates in the two groups on an intention-to-treat basis. Among the 36 PCOS women allocated to LOD, three (8%) conceived before LOD, nine (25%) conceived after LOD alone and an additional eight (22%) women conceived after adding CC giving a cumulative pregnancy rate of 56% (20/36) at 12 months follow-up. In the CC group, three (8%) women conceived before treatment, 14 (39%) conceived with CC alone and an additional six (17%) conceived after LOD giving a cumulative pregnancy rate of 64% (23/32) at 12 months. The results were not statistically different between the two groups.
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Table III shows the conception rates in women receiving active treatment. After the primary treatment alone, more pregnancies (14/32, 44%) occurred in women receiving CC than in those (9/33, 27%) undergoing LOD, although the difference did not reach statistical significance [P = 0.13, OR 2.1 (95% CI, 0.7–5.8)]. The pregnancy rates after adding the second treatment were still higher, but to a lesser extent, in the CC group (CC ± LOD) than those in the LOD group (LOD ± CC). The difference was not statistically significant [63% versus 52%, P = 0.2, OR 1.6 (0.6–4.2)]. Pregnancy outcomes are also summarized in Table III. Two of the 17 pregnancies (12%) in the LOD group and two of the 20 pregnancies (10%) in the CC group experienced miscarriage.
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Figure 2 shows the cumulative pregnancy rates over time from commencement of treatment in the two groups. At 12 months follow-up, the pregnancy rate after LOD was 52%, which was not statistically [P = 0.26, OR 1.6 (0.6–4.2)] different from that (63%) of CC.
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Adverse effects/complications
One woman (3%) in the CC group developed moderate ovarian hyperstimulation syndrome (OHSS) during the luteal phase of her second cycle of CC treatment at a dose of 50 mg/day. She presented with abdominal pain, bloatedness, nausea and vomiting and felt generally unwell. An ultrasound scan revealed her ovaries to be moderately enlarged with several large follicles. A small amount of ascites was also detected. She was treated in hospital with i.v. fluids, anticoagulant therapy, analgesia and anti-emetics. After 1 day, she recovered well and was discharged from the hospital. OHSS symptoms and signs resolved after 1 week. Following this episode, CC was discontinued and the patient underwent LOD. She conceived in the first post-operative menstrual cycle and had an uncomplicated pregnancy. Another patient in the CC group (3%) experienced significant depression during her third cycle of CC. She initially received CC 50 mg per day, which was not associated with any side effects. As she did not respond to CC 50 mg, the dose of CC was increased to 100 mg. She developed depression in the second cycle of the high CC dose. Clomiphene was discontinued and the patient received antidepressant therapy for 3 months. No multiple pregnancies were observed in this study. In the LOD group, one patient (3%) experienced significant left-sided pelvic pain after LOD. She underwent a second laparoscopy, which revealed one small band of adhesion between the left ovary and the pelvic side wall. This was divided with scissors. Post-operatively, the pain disappeared. No other patients reported pain after LOD.
Pelvic pathology found and treated at laparoscopy
Of the 33 women who underwent LOD, 13 (39%) were found to have pelvic pathology including endometriosis in 10 (30%) patients and adhesions in three (9%) (Table IV). Among the 10 patients with endometriosis, three had minimal disease (few spots of endometriosis) and seven had mild disease (superficial peritoneal implants mostly affecting uterosacral ligaments and pouch of Douglas with no adhesions). In the three patients with adhesions, the disease was unilateral in two cases and bilateral in one case. The adhesions were peri-adnexal in all patients, but distorting the tubo-ovarian relationship only in two cases. Similarly, among the 11 women in the CC group who underwent LOD, five (45%) had pelvic disease including endometriosis in four (36%) and adhesions in one (9%) patient. Endometriosis was minimal in three patients and severe with adhesions in one patient. All the endometriotic implants were diathermized with monopolar electrocautery and adhesions were divided using scissors.
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Discussion |
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In this randomized controlled trial, we have for the first time evaluated the effectiveness of LOD as a first-line method of OI in infertile women with PCOS by comparing it with CC.
The data from this study did not confirm the theoretical superiority of LOD over CC as a first treatment for anovulatory infertility in women with PCOS. On the contrary, CC produced more pregnancies and live births than LOD, although the difference was not statistically significant due to the relatively small sample size. After adding the secondary treatment, the difference in pregnancy rates between the two strategies was small, but still in favour of CC as the primary treatment. In other words, whether LOD or CC was the first line of OI (followed by the other treatment if necessary), the chances of pregnancy were not statistically different at 12 months follow-up, although there was a trend towards a better outcome with CC. The miscarriage rates were similar in the two groups, although the study was not sufficiently powered to detect a significant difference in miscarriages.
It is surprising to see that, despite its untoward peripheral antiestrogenic effect, CC as a single treatment produced more pregnancies than LOD (44% versus 27%, respectively), although the difference did not reach statistical significance. This may be explained by the fact that although ovulation rates were similar in the two groups, a significant number (10/21, 47%) of women who ovulated after LOD experienced a recurrence of their anovulatory status.
Our data also showed that when offered to women after CC-resistance/failure (n = 11), LOD achieved a good pregnancy rate (6/11, 55%), which is two times the pregnancy rate (27%) resulting from LOD as a first line. It is therefore possible to conclude that LOD may be more effective in CC-resistant PCOS women than in women without previous knowledge of their response to CC. The effectiveness of LOD as a second-line treatment has previously been reported in many studies (Bayram et al., 2004; Farquhar et al., 2005). We therefore recommend that CC remains the first-line treatment in anovulatory PCOS and LOD should remain as a second-line treatment.
The power calculation in this study was based on previously reported pregnancy rates following CC and LOD (35% versus 70%, respectively) as detailed in the introduction. Furthermore, we thought that a clinically significant difference should be large enough to justify replacing a simple medical therapy with a surgical intervention. Looking for a smaller difference, which would require larger numbers, may not be clinically important and is unlikely to lead to a change in clinical practice.
In this study, women failing to respond to the primary treatment (LOD or CC) were offered the other treatment. However, the study is not a crossover design as we have placed more emphasis on the analysis of results after the primary treatment. The study protocol followed the usual clinical practice, which involves giving CC to women not responding to LOD and vice versa. Patients who receive CC after LOD still benefit from LOD. Several previous studies have shown that LOD sensitizes the ovary to CC (Gjonnaess, 1984). In a crossover study, women should have a washout period before moving on to the second treatment so that the effect will be purely that of the second treatment. Moreover, in a crossover design, every patient receives both treatments in either order for a specified duration. In such trials, each patient serves as her own control, which was not the case in the current study.
The incidence of pelvic disease (adhesions and/or endometriosis) in this study was surprisingly high but similar in the two groups (39% in the LOD group and 45% in 11 women in the CC group who underwent LOD). In theory, surgical elimination of pelvic disease is expected to improve the chances of pregnancy. On the contrary, treatment of endometriosis and adhesions in the LOD group did not appear to improve the chances of pregnancy. This finding disagrees with evidence from the study of the Canadian Group randomized trial (Marcoux et al., 1997) suggesting that laparoscopic surgery for minimal and mild endometriosis may improve chances of pregnancy. However, our data are consistent with another randomized trial by the Italian Group (Parazzini, 1999) which did not show any beneficial effect of laparoscopic treatment of endometriosis on chances of pregnancy. This matter therefore remains uncertain and requires further evaluation. One criticism of the current study could be that treatment of pelvic disease in the LOD group could have biased the study towards better outcome in this group. However, it would be unethical to deny women a treatment which is potentially beneficial to their fertility. Furthermore, even if such treatment could have enhanced success rates in the LOD group, this would be considered an advantage to LOD which makes it superior to CC.
The complication rates in this study were low in both groups with only one patient (3%) developing pelvic pain due to mild peri-adnexal adhesion after LOD and two patients (6%) in the CC group developing complications (OHSS and depression). However, we cannot comment on the rate of adhesion formation after LOD without a second look laparoscopy. Nevertheless, significant adhesions causing pelvic pain do not appear to be common after LOD. It is therefore possible to confirm the safety and rarity of significant side effects/complications when using either LOD or CC.
In conclusion, CC appears to be more effective than LOD as a first-line method of OI, despite the theoretical advantages of the latter. CC should therefore remain the standard first-line OI in anovular women with PCOS. However, LOD could be recommended as a first line if laparoscopy is indicated for other reasons in these women, and as an adjunct to CC treatment should monotherapy fail to produce a pregnancy after a limited duration of exposure. The value of detecting and treating sub-clinical endometriosis requires further evaluation.
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Funding |
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The study was supported by a grant from the University of Sheffield (Devolved funds).
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Submitted on October 5, 2007; resubmitted on July 21, 2008; accepted on August 4, 2008.
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