A prospective dose-finding study of the amount of thermal energy required for laparoscopic ovarian diathermy

S.A.K. Amer1, T.C. Li and I.D. Cooke

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

1 To whom correspondence should be addressed. e-mail: s.amer{at}sheffield.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: This prospective dose-finding study was undertaken to determine the optimal amount of thermal energy required for laparoscopic ovarian diathermy (LOD) in women with polycystic ovary syndrome (PCOS). METHODS: Thirty women with clomiphene-resistant PCOS were included in the study. All women underwent LOD. A modified Monte Carlo up-and-down design was utilized. Women were treated in groups of three (10 groups). The amount of energy applied was standardized at 150 J/puncture. The number of punctures in each group was decreased/increased according to the number of responders in the previous group. The main outcome was ovulation as defined by a serum progesterone concentration of >=30 nmol/l. RESULTS: Four groups (n = 12) were treated with four punctures/ovary, three groups (n = 9) with three punctures, two groups (n = 6) with two punctures and one group (n = 3) with one puncture. Ovulation occurred in 67, 44, 33 and 33% of women treated with four, three, two and one puncture/ovary respectively. The corresponding pregnancy rates were 67, 56, 17 and 0%. The reductions in the free androgen index and the serum concentrations of testosterone and androstenedione after LOD were observed only in women treated with three and four punctures/ovary. CONCLUSION: The clinical response to LOD seems to be dose-dependent, with an increase in the frequency of ovulation and conception with an increasing dose of thermal energy up to 600 J/ovary.

Key words: laparoscopic ovarian drilling/PCOS/polycystic ovary/thermal energy


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Since the introduction of laparoscopic ovarian diathermy (LOD) by Gjonnaess (1984Go) in the early 1980s, LOD has become widely accepted as a second line treatment for induction of ovulation in women with polycystic ovary syndrome (PCOS) after failure of a course of clomiphene citrate (Armar et al., 1990Go; Kovacs et al., 1991Go; Li et al., 1998Go). Not only does LOD produce high ovulation (>80%) and pregnancy (~60%) rates (Li et al., 1998Go), but it also corrects the underlying endocrine abnormalities associated with the disease, such as raised serum concentrations of LH and androgens (Greenblatt and Casper, 1987Go; Armar et al., 1990Go; Abdel-Gadir et al., 1993Go; Liguori et al., 1996Go; Felemban et al., 2000Go). In addition, ovarian drilling may render the ovaries more sensitive to clomiphene citrate (Gjonnaess, 1984Go).

Currently, there is a lack of agreement as to how LOD should be carried out. The amount of thermal energy applied in LOD varied markedly (between three and 25 punctures per ovary at 30–400 W) in different studies (Gjonnaess, 1984Go; Dabirashrafi, 1989Go; Weise et al., 1991Go; Naether et al., 1993Go; Felemban et al., 2000Go). The optimum number of punctures per ovary, which determines the amount of energy delivered to each ovary, has not yet been established. No study has ever investigated the dose–response relationship in LOD. Gjonnaess (1984Go) reported that ovulation occurred more frequently if five or more punctures were applied compared with three punctures per ovary. However, Armar et al. (1990Go) found that four diathermy punctures per ovary, with a power setting of 40 W, were sufficient to achieve good results. On the other hand, Dabirashrafi (1989Go) suggested that the number of punctures should be as low as possible and tailored to the individual ovary in each patient. He reported a case of severe ovarian atrophy following LOD in which eight punctures were created at 400 W. Weise et al. (1991Go) noted a positive correlation between the number of punctures and the reduction in testosterone levels following LOD.

It seems reasonable to assume that the greater the amount of injury to the surface of the ovary, the greater also is the risk of periovarian adhesions. On the other hand, reduction of the thermal injury may affect the efficacy of the procedure.

In this prospective, dose-finding study, we employed the modified Monte Carlo up-and-down model with a view to determining the optimal amount of energy required for LOD in women with PCOS.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
Thirty women with anovulatory infertility associated with PCOS were included in the study. All subjects had polycystic ovaries on transvaginal ultrasound scan according to criteria defined by Adams et al. (1985Go). In addition, each woman had biochemical evidence of PCOS including an elevated LH/FSH ratio (>=2) and/or raised serum concentrations of androgens [testosterone >=2.5 nmol/l, androstenedione >=10 nmol/l or free androgen index (FAI) >4]. These hormones were measured in the early follicular phase (defined as days 2–5) of the menstrual cycle. In women with severe oligomenorrhoea or amenorrhoea, a random blood sample was accepted. FAI is calculated using the formula testosterone x 100/sex hormone-binding globulin (SHBG) (Carter et al., 1983Go; Eden et al., 1989Go). All the women in the study had normal hysterosalpingograms and their partners had normal semen analysis according to World Health Organization criteria (WHO, 1999Go).

All the women had previously failed to respond to incremental doses of clomiphene citrate (50, 100 and 150 mg). They gave informed consent for laparoscopic ovarian drilling using diathermy.

Techniques of laparoscopic ovarian drilling
Three-puncture laparoscopy was performed under general anaesthesia. The pelvis was thoroughly inspected for any pathology and the ovaries were examined for the features of polycystic ovary. A pair of non-toothed grasping forceps was then used to grasp the utero-ovarian ligament and to lift the ovary away from the bowel. A specially designed monopolar electrocautery 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 monopolar diathermy. The probe has a distal stainless steel needle measuring 8 mm in length and 2 mm in diameter projecting from an insulated solid cone of 6 mm maximum diameter. The probe was applied to the surface of the ovary at a right angle to avoid slippage and to minimize surface damage. The electrosurgical unit used was the Force 2 Valleylab electrosurgical generator (Valleylab Inc., Boulder, CO, USA). A monopolar coagulating current at a 30 W power setting was used to make a puncture of ~4 mm diameter and 8 mm depth. As the needle was pushed into the ovarian capsule, electricity was activated for 5 s. The ovary was then cooled down by irrigation using Hartmann’s solution before releasing the ligament. At the end of the procedure, ~200 ml of Hartmann’s solution were left in the pelvis.

Amount of thermal energy
A standardized monopolar coagulation current set at 30 W was applied for a duration of 5 s per puncture, giving a total thermal energy of 150 J (30x5) per puncture.

Monte Carlo up-and-down design
In order to study the dose–response relationship, the Monte Carlo up-and-down design was used, utilizing one of the single response methods reviewed by Bolognese (1983Go) and modified by Li et al. (1988Go). Patients were treated in groups of three (10 groups). The ovaries were treated with a variable number of punctures (i.e. variable amount of thermal energy). The number of responders in each group governed the amount of thermal energy in the next group, as follows: if the number of responders = 3, the number of punctures would be reduced by two; if the number of responders = 2, the number of punctures would be reduced by one; if the number of responders = 1, then the number of punctures would be increased by one; if the number of responders = 0, then the number of punctures would be increased by two. For instance, when four punctures/ovary are applied in a certain group, if all the three patients in this group respond positively, the next group would be treated with two punctures/ovary. If two patients respond to four punctures, the number of punctures will be reduced to three punctures/ovary, and if the number of responders is one, the next group will receive five punctures/ovary. If four punctures result in no response at all, the number of punctures will increase to six punctures/ovary. A positive response was defined when there was endocrinological evidence of ovulation, i.e. progesterone >=30 nmol/l. The amount of thermal energy used in the first group was four punctures (i.e. 600 J) per ovary, i.e. 1200 J per subject.

Post-operative monitoring
Following ovarian diathermy, blood samples were taken weekly to measure the serum concentrations of progesterone until menstruation occured or a level of >=30 nmol/l was detected. 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 if any of the progesterone concentrations 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, clomiphene citrate would be started 6–8 weeks after surgery.

Ethical issues
The South Sheffield Ethics Committee approved this study. All the women participating in the study gave an informed consent.

Statistical analysis
Endocrine parameters before and after LOD were compared using Wilcoxon signed rank tests. P < 0.05 was considered significant. Contingency table analysis was used to compare success rates after LOD across different body mass index (BMI) groups and different menstrual cycle groups.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The characteristics of the 30 women participating in this study are illustrated in Table I.


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Table I. The characteristics of 30 women who had laparoscopic ovarian drilling for anovulatory infertility due to POCS
 
Dose ranging
The results of the treatment are illustrated in Table II. Four groups of patients (n = 12) were treated with 600 J (four punctures) per ovary, three groups (n = 9) with 450 J (three punctures) per ovary, two groups (n = 3) with 300 J (two punctures) per ovary and one group (n = 3) with 150 J (one puncture) per ovary.


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Table II. The results of Monte Carlo up-and-down dose finding in the study of LOD for PCOS
 
Ovulation
Figure 1a shows the rate of spontaneous ovulation achieved using different doses of thermal energy. The incidence of spontaneous ovulation was 67% (8/12) for 600 J per ovary, 44% (4/9) for 450 J, 33 (2/6) for 300 J and 33% (1/3) for 150 J. After administering clomiphene citrate to women who did not ovulate spontaneously, the ovulation rates increased to 92, 78, 83 and 67% in women treated with a total dose of 600, 450, 300 and 150 J per ovary respectively. The overall rate of ovulation was 80% (24/30).



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Figure 1. The rates of spontaneous ovulation, conception and conversion of oligo/amenorrhoea to regular cycles in women with PCOS after laparoscopic ovarian diathermy (LOD) using different doses of thermal energy (numbers of punctures).

 
Conception
Figure 1b shows the conception rates achieved with different doses of thermal energy during the first year after surgery. Amongst the 12 women treated with 600 J (four punctures) per ovary, eight (67%) conceived. Of the nine women treated with 450 J, five (56%) conceived, and of the six women treated with 300 J, one (17%) conceived. There were no conceptions amongst the three women treated with 150 J. Overall, amongst the 30 women in this study, 14 (47%) conceived within 12 months after surgery. Amongst the 14 pregnancies achieved, two (14%) ended in miscarriages, one was terminated for social reasons and the remaining 11 pregnancies continued to full term. The two miscarriages occurred in women treated with 450 J per ovary.

Menstrual pattern
As shown in Figure 1c, the rate of conversion from oligo/amenorrhoea to regular menstrual cycles after ovarian diathermy is higher in women treated with 600 and 450 J (73 and 75%), respectively, compared with those treated with 300 and 150 J (33 and 50%) respectively.

Endocrine changes
The endocrine changes after ovarian diathermy, using different amounts of thermal energy, are shown in Table III. In view of the small number of patients treated with 150 J/ovary, they were combined with patients receiving 300 J/ovary to allow statistical analysis.


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Table III. Endocrine changes after LOD in 30 women with anovulatory infertility due to PCOS
 
The overall results showed a statistically significant (P < 0.01) reduction of the median serum concentration of LH from 12.7 IU/l pre-operatively to 6.5 IU/l after LOD (Table IIIa). Similarly, the LH/FSH ratio significantly (P < 0.01) decreased from 2.8 to 1.2. Although, the serum concentrations of LH and the LH/FSH ratio decreased in all groups, statistical significance (P < 0.05) was only obtained in women treated with the highest dose (600 J/ovary). However, there is no obvious correlation between the number of punctures and the magnitude of changes of these hormones. There were no significant changes in the serum FSH levels after ovarian diathermy in women treated with 600, 450 or 300/150 J respectively (Table IIIa).

With regard to the androgens, the results in Table IIIb show a reduction of FAI and the serum concentrations of testosterone and androstenedione after LOD in women receiving higher doses of thermal energy (450 and 600 J). However, these changes did not reach statistical significance, except for androstenedione. On the other hand, the levels of these hormones showed a trend towards a small, but statistically insignificant, increase after LOD in women treated with 150 and 300 J/ovary. The changes in the serum concentrations of SHBG were variable and statistically insignificant.

The impact of BMI and menstrual pattern on the outcome of LOD
The success rates after LOD were compared between women with normal (<28 kg/m2), moderately elevated (28–32 kg/m2) and markedly elevated BMI (>32 kg/m2) using contingency table analyses. Similarly, success rates were compared between women with regular menstrual cycles, oligomenorrhoea and amenorrhoea. The results showed a trend towards a higher ovulation rate (59%) in women with normal BMI (n = 17) compared with ovulation rates of 37 and 40% in women with moderately elevated (n = 8) and markedly elevated BMI (n = 5) respectively. However, the differences did not reach statistical significance. The corresponding pregnancy rates were 53, 37 and 40%. Women with oligomenorrhoea (n = 19) showed a higher ovulation rate (63%) compared with that (33 and 25%) of women with regular cycles (n = 3) and amenorrhoea (n = 8), respectively, but statistical significance was not achieved. The corresponding pregnancy rates were 59, 33 and 25%.

Comparison between the demographic characteristics of the four groups of women receiving different numbers of punctures at LOD showed no statistically significant differences in age, BMI or menstrual pattern.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, we employed the Monte Carlo up-and-down design, in 30 women with anovulatory PCOS to investigate the dose–response relationship of LOD.

Monte Carlo up-and-down design
The concept of the up-and-down design for dose finding, which was first introduced by Bliss (1935Go) and later reviewed by Bolognese (1983Go), involves assigning each subject’s dose based on the previous observation. If the previous observation was a non-response, then the dose is increased according to a pre-chosen dosage increment. If the previous observation was a response, then the dose is decreased to the next lower level. With such an approach, the doses will migrate toward/within the effective dose range, according to the predefined response, i.e. between the threshold dose (the lowest level at which a subject will respond) and the plateau dose (the lowest dose such that all subjects who will respond are observed to respond). Several up-and-down designs have been described depending on the nature of the therapeutic method being investigated, e.g. the design involving one observation of each of 30 subjects or observations in a group of three subjects in 10 groups. In the latter case, the dose will be decreased or decreased based on the number of responders in the preceding group. The increment could be doubled if, for example, all subjects in the preceding group responded or did not respond. The latter design has been chosen for this study as it suited the nature of the treatment (ovarian diathermy).

The number of subjects in this study was chosen to be 30 as this number has been considered by many authors to be enough to produce meaningful results (Bolognese, 1983Go). The dose of thermal energy used in the first group was chosen based on the available evidence from a previous report by Armar et al. (1990Go) who found that four diathermy punctures per ovary were sufficient to achieve good results.

Dose–response relationship
We have demonstrated in this study, for the first time, that the response to LOD is governed by a dose–response relationship. As illustrated in Figure 1a, the frequency of spontaneous ovulation after ovarian diathermy increases with an increase in the amount of thermal energy up to 600 J (four punctures) per ovary. Furthermore, there was a tendency for the dose of thermal energy to move from 150 toward 600 J, resulting in four groups (12 subjects) being treated with 600 J and only one group (three subjects) receiving 150 J. This indicates that 150 J/ovary could be the threshold dose, i.e. the lowest dose at which a response could be seen, and 600 J/ovary may be the plateau dose, i.e. the lowest dose at which all subjects who will respond are observed to respond.

When clomiphene citrate was later given to the non-responders, the incidence of ovulation increased in all groups and did not show a dose–response relationship. This indicates that a small dose of thermal energy, e.g. two punctures (300 J), only may be sufficient to sensitize the ovary to clomiphene citrate.

Two previous studies reported on the relationship between the number of punctures made during LOD and the success rates. Gjonnaess (1984Go) found that better results were achieved when five or more punctures (2–4 mm deep) were made in each ovary at 200–300 W for 2–4 s each puncture (energy on average = 250 W x 3 s x >=5 = >= 3750 J per ovary). On the other hand, Armar et al. (1990Go) found that four diathermy punctures (8 mm deep) per ovary at 40 W for 4 s per puncture (energy = 40 W x 4 s x 4 = 640 J) were sufficient to achieve good results. The discrepancy between our results and those reported by Gjonnaess (1984Go) could be explained by the differences in the techniques of LOD, in particular the instrument used and the depth of penetration. Gjonnaess (1984Go), using the biopsy or sterilization forceps, which delivered the thermal energy to a depth of 2–4 mm, i.e. superficially, required a high amount of energy to achieve good results. In contrast, with deeper penetration of the ovarian surface using the diathermy needle (Rocket of London, Watford, UK), we achieved good results with a much lower energy requirement. Our results are consistent with the findings of Armar et al. (1990Go) who used a similar instrument. Similarly, Felemban et al. (2000Go), using a diathermy needle, delivered the energy to a depth of 8 mm and achieved good success rates with amounts of thermal energy (40 W x 2 s x 10–15 = 800–1200 J per ovary) much lower than that applied by Gjonnaess (1984Go). It is therefore possible to conclude that deeper penetration of the ovarian surface during LOD allows significant reduction of the amount of thermal energy without compromising the outcome.

Conceptions and menstrual pattern
The dose–response relationship was confirmed further by the conception rate and the conversion to regular menstrual patterns after ovarian diathermy, which showed an increase with the increase in the amount of thermal energy (Figure 1b and c).

The optimal amount of thermal energy for LOD
In a previous retrospective study, we have demonstrated that increasing the number of punctures to more than three (up to 10) punctures/ovary does not result in a significant improvement in the success rates (Amer et al., 2002Go). It can therefore be concluded that 3–4 punctures (450–600 J) per ovary represent the optimum dose of energy required for LOD, i.e. reducing the dose below that level is associated with poorer results and increasing the dose above it does not improve the outcome.

Distribution of the total amount of thermal energy
Having identified the optimum amount of thermal energy to be delivered to the ovarian stroma at LOD, the optimal distribution of that dose of energy remains to be evaluated. Balen and Jacobs (1994Go) compared unilateral with bilateral ovarian diathermy in 10 patients with anti-estrogen-resistant PCOS. They reported a 75% ovulation rate in women who underwent unilateral ovarian diathermy applying four punctures using 40 W for 4 s, i.e. 640 J. They also found that unilateral ovarian diathermy resulted in ovulation from the contralateral ovary in the first cycle and then alternatively from each ovary. Although the numbers in this study are small, it clearly indicates that the effects of LOD depend on the destruction of a certain amount of ovarian tissue, whether this is inflicted on one ovary or divided between the two ovaries. It is therefore possible that the optimal amount of energy could be delivered to one ovary only without compromising the success rates. The potential benefit of such an approach in minimizing post-operative adhesion formation requires further evaluation.

Endocrine changes
Numerous previous studies have shown that LOD results in a fall in the serum levels of androgens and LH (Aakvaag and Gjonnaess, 1985Go; Greenblatt and Caspor, 1987Go; Abdel-Gadir et al., 1993Go; Naether et al., 1993Go; Liguori et al., 1996Go; Felemban et al., 2000Go; Amer et al., 2002Go). In this study, the reduction of the serum LH concentrations was observed with all the doses of thermal energy. The magnitude of reduction of LH did not show any dose dependency. Statistical significance was only observed in the group of women treated with 600 J. The lack of statistical significance in the other groups may be due to the small numbers of patients included. The exact mechanism of LH reduction after LOD is still not fully understood.

On the other hand, the reductions of FAI and the serum concentrations of testosterone and androstenedione after LOD were only observed in women receiving higher doses of thermal energy (450 and 600 J). It may therefore be concluded that the effect of LOD on the androgen levels is influenced by the amount of energy delivered to the ovary, and a small amount may not reduce these levels. It is also observed that the reduction of androgens was associated with higher success rates in the two groups treated with higher amounts of energy. This may support the hypothesis that LOD works by the destruction of androgen-producing tissue in the ovary. The resulting fall of the serum androgen concentrations may result in a fall in estrone (E1) concentrations due to decreased peripheral aromatization of androgens. It has been speculated that this fall in E1 is responsible for decreased positive feedback on LH and decreased negative feedback on FSH at the level of the pituitary.

The impact of BMI and menstrual pattern on the outcome of LOD
Our data showed that PCOS women with normal BMI and those with oligomenorrhoea have a tendency to respond better to LOD than women with higher BMI and amenorrhoea. The lack of statistical significance may be due to the small numbers in each group. This will therefore need to be evaluated further in a larger group of patients. There were no statistically significant differences in the BMI and menstrual patterns between the four groups of women. It is therefore unlikely that the differences in the outcome of LOD observed between the four groups in this study are due to variations in BMI or menstrual pattern.

Conclusion
In conclusion, we have demonstrated that the clinical and endocrine response to LOD is governed by a dose–response relationship. Four punctures per ovary using a power setting of 30 W for a duration of 5 s per puncture (i.e. 600 J per ovary) appear to be sufficient to produce an optimal response (67% spontaneous ovulation rate and 67% conception rate). Reducing the thermal energy below that level reduces the chances of spontaneous ovulation, and conception.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on November 4, 2002; accepted on April 15, 2003.





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