Jessop Wing, Sheffield Teaching Hospitals, University of Sheffield, Tree Root Walk, Sheffield S10 2SF, UK
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Abstract |
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Key words: endocrine effects/laparoscopic ovarian drilling/long-term follow-up/polycystic ovary syndrome/polycystic ovaries
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Introduction |
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In a long-term follow-up study, Gjonnaess reported on the late endocrine effects of LOD in 51 women (Gjonnaess, 1998). He concluded that ovarian electrocautery in women with PCOS normalizes the serum levels of androgens and LH and that the results appear to be sustained for 1820 years. However, this study did not include a control population and it is therefore unclear to what extent the long-term observations could be attributed to the impact of LOD alone. This is particularly important as a study by Elting et al. suggested that some women with PCOS do have spontaneous improvement in their menstrual characteristics with increasing age, without any treatment (Elting et al., 2000
). The same criticism also applies to the study by Naether et al., who reported on the long-term effect of LOD on serum androgen (testosterone and dehydroepiandrosterone) levels in 206 patients (Naether et al., 1994
). In a previous study, we reported on the clinical outcome at medium- and long-term follow-up of the same group of patients (Amer et al., 2002
). In this study, we wish to report our observations of the medium- and long-term endocrine and ovarian changes in women who underwent LOD for PCOS and compare our observations with a group of women with the same condition but without surgical intervention (comparison group). We also wish to examine factors that affect the results at long-term follow-up.
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Materials and methods |
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Comparison group
A total of 34 women with anovulatory infertility associated with PCOS who were diagnosed during the same time period of the study but had not undergone LOD were identified from the same hospital. These women constituted the comparison group. All the women had anovulatory infertility of >1 year duration. Two subjects decided to postpone fertility treatment after their initial diagnosis and the remaining 32 women received CC. Twenty-eight of these subjects attended for interview, blood tests and a transvaginal scan.
PCOS
The diagnosis of PCOS in both groups of women was based on the following criteria. (i) Early follicular phase (defined as days 25 of the menstrual cycle) serum LH:FSH ratio >2 and/or raised serum androgen concentrations [testosterone 2.5 nmol/l, androstenedione
10 nmol/l or free androgen index (FAI) >4]. FAI was calculated using the formula: testosterone x100/sex hormone-binding globulin (SHBG) (Carter et al., 1983
; Eden et al., 1989
). In women who were oligo/amenorrhoeic, a random blood sample was acceptable. (ii) There was ultrasonographic evidence of ovarian stromal hypertrophy and multiple small (68 mm) follicles arranged in the periphery (Adams et al., 1985
).
LOD
The techniques of LOD used in our centre have previously been published (Li et al., 1998; Amer et al., 2002
).
Ultrasound scanning
Patients underwent transvaginal scanning prior to LOD (n = 101) and at medium- (13 years, n = 36) and long-term (49 years, n = 67) intervals after surgery. Two ultrasound machines of the same model (Toshiba, model Sonolayer SSA-250A, with a convex 6-MHz transvaginal ultrasound probe) have been used in our unit during the 9 year follow-up period. At medium- and long-term follow-up, women with regular menstrual cycles were scanned on days 25 of the cycle, whereas women with severe oligomenorrhoea were not timed according to the menstrual cycle. 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 of a prolate ellipsoid: 0.523xlengthxwidthxthickness, according to the method of Sample et al. (Sample et al., 1977). The mean volume of the right and left ovary was calculated for each subject.
Collection of blood samples
Blood samples were taken from women in both groups early in the follicular phase (defined as days 25 of the menstrual cycle) or at a random time in women with severe oligomenorrhoea or amenorrhoea. The samples were collected from the patients prior to LOD and at different intervals following surgery: short- (<1 year), medium-(13 years) and long-term (49 years).
Hormonal assays
Serum hormonal concentrations were measured using well-established assays, which have been validated in our laboratory at the Department of Clinical Chemistry, Royal Hallamshire Hospital. These assays, which have previously been described (Okon et al, 1998; Li et al, 2000
), were not changed between 1991 and 2000, i.e. the same assays were used at the different periods of follow-up.
Follow-up data
The endocrinological and ultrasonographic data were documented before and at different intervals (short-, medium- and long-term) after LOD. The age of the patients, when the diagnosis of the condition was made and other demographic details, including body mass index (BMI), primary or secondary infertility and the duration of infertility, were also documented.
Statistical analysis
For statistical analysis the data were entered into the Statistical Package for Social Sciences (SPSS) for PC version 10.0.5. Continuous data were compared by MannWhitney U-test and Wilcoxon signed ranks test. Comparisons of categorical data were carried out using 2x2 contingency table analyses. Significance was assumed if P < 0.05.
Ethical considerations
The South Sheffield Ethics Committee approved this study.
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Results |
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FSH concentrations
There was no significant change in the serum concentrations of FSH after LOD in either group (Figure 1b). The mean serum FSH concentrations remained
5 IU/l throughout the follow-up periods after LOD. At long-term follow-up, the FSH levels ranged between 1.1 and 13.5 IU/l. Up to 9 years after surgery, there was no case of premature ovarian failure (POF) among women who underwent LOD.
Androgen concentrations
In Figure 2, the serum concentrations of testosterone, androstenedione and SHBG and the FAI before LOD and at the three periods of follow-up are shown. The mean serum testosterone concentration and FAI decreased significantly after LOD and remained low throughout the follow-up periods. The mean serum concentration of androstenedione showed no significant change shortly after LOD, but showed a significant reduction at medium- and long-term follow-up. The number of subjects in the comparison group who had their androgen levels measured at medium-term follow-up was too small for it to be possible to make direct comparison between the two groups. The serum testosterone concentrations and FAI of women who had not undergone LOD did not show significant change at long-term follow-up (Figure 2
). However, the mean serum androstenedione concentration of the comparison group decreased significantly (P < 0.05) at that time.
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Ultrasound findings
In Figure 3a, the proportion of women with ultrasound evidence of polycystic ovaries (PCO) prior to treatment and at medium- and long-term follow-up, are shown. The results show that the proportion of women with ultrasound evidence of PCO significantly (P < 0.01) decreased after LOD and remained low during the follow-up periods. By contrast, no similar changes were observed in the comparison group during the corresponding follow-up periods. Figure 3b
shows the mean ovarian volume for both groups of women before treatment and at medium- and long-term follow-up. The mean ovarian volume decreased significantly (P < 0.05) at medium-term follow-up after LOD and the effect was sustained for up to 9 years. On the other hand, the ovarian volume in the comparison group did not show significant changes during the same periods of follow-up.
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LH
Age at the time of follow-up had a significant impact on the serum concentrations of LH after LOD. Women 36 years old had significantly (P < 0.01) lower levels of LH (7.5 IU/l) than those (10.4 IU/l) of younger (
35 years) women. In contrast, BMI at the time of long-term follow-up did not appear to have any significant impact on the serum LH concentrations. In women with a BMI >25 kg/m2, the mean serum concentration of LH was 9.5 IU/l, which was not significantly different to that of women with a BMI
25 kg/m2 (8.9 IU/l).
FSH
Age at the time of long-term follow-up did not have a significant impact on the serum concentrations of FSH. Fourteen patients were aged 3945 years and their FSH concentrations ranged between 2.4 and 8.1 IU/l with a mean value of 4.9.
Androgens
As far as androgen levels are concerned, age did not have a significant impact on FAI and the serum concentrations of testosterone and androstenedione at the time of long-term follow-up. On the other hand, the mean serum concentrations of testosterone (1.7 nmol/l) and androstenedione (6.5 nmol/l) in women with BMI >25 kg/m2 were significantly (P < 0.05) higher than those of women with BMI 25 kg/m2 (1.2 and 4.9 nmol/l).
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Discussion |
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Endocrine outcome
We confirm the previously reported endocrine changes shortly after LOD, including lowering of the LH:FSH ratio and the serum concentrations of LH and androgens (Gjonnaess, 1984,1994
; Aakvaag and Gjonnaess, 1985
; Gjonnaess and Norman, 1987
; Greenblatt and Casper, 1987
; Sumioki et al., 1988
; Armar et al., 1990
; Sakata et al., 1990
; Kovacs et al., 1991
; Taskin et al., 1996
; Felemban et al., 2000
). These endocrine changes seemed to last during the medium- and long-term follow-up periods (up to 9 years). This observation is comparable with an earlier report by Gjonnaess who demonstrated that the endocrine changes after LOD were stable for 1820 years (Gjonnaess, 1998
). Naether et al. also showed that serum testosterone concentrations decreased after LOD and remained low for up to 6 years (Naether et al., 1994
). However, we confirm in this study that these long-term endocrine changes are produced by ovarian drilling rather than the effect of advancing age, since the serum concentrations of LH and androgens in women who underwent LOD were significantly lower than those of the comparison group at corresponding periods of follow-up.
The proportion of women with high LH concentrations (>10 IU/l) decreased significantly from 70 to 33% shortly after LOD, but increased back to 45% during the medium-term follow-up (13 years). This latter increase, although statistically insignificant, shows a trend toward an increase in serum LH concentrations >1 year after surgery. One may therefore speculate that the effect of LOD wore off in a proportion of women (15%) 1 year after surgery. At long-term follow-up, the proportion of women with high LH concentrations decreased to a level (31%) seen at short-term follow-up after LOD. This latter decrease may be explained by a phenomenon related to the natural history of the disease, in that the clinical and endocrine features of PCOS become less pronounced with advancing age (Dahlgren et al., 1992
; Elting et al., 2000
). This is further supported by the observation that older women (
36 years) at the time of long-term follow-up had significantly lower serum LH concentrations compared with younger (<36 years) subjects. However, it appears that ovarian drilling has contributed to the long-term changes of serum LH concentrations since the proportion of women with LH >10 IU/l at long-term follow-up after surgery were significantly lower than those of the comparison group during the corresponding follow-up period. A trend towards a reduction in the proportion of women with high serum concentrations of LH at long-term follow-up was not observed in the comparison group, possibly due to the small number of women included in that group.
There was a trend toward a decrease of serum androgen levels with the increasing number of years after LOD, possibly due to the effect of advancing age (Figure 2). A similar trend toward a decrease of androgen levels was also observed in the comparison group; in particular, the significant reduction of serum androstenedione concentrations at long-term follow-up. The impact of advancing age on serum concentrations of androgens was not observed, possibly due to the effect of an increasing BMI with age, which is associated with an increase in androgen levels.
In our cohort of patients, there were no cases of premature ovarian failure (POF) up to 9 years after LOD. At long-term follow-up, 14 women were aged 3945 years and their FSH concentrations ranged between 2.4 and 8.1 IU/l. We can therefore conclude that using the techniques described in this study is safe and is not associated with an increased risk of premature menopause.
Ultrasound changes
In this study, we report for the first time on the long-term impact of ovarian drilling on sonographic features of the ovaries. Ovarian drilling resulted in a significant reduction in the ovarian volume and the effect was sustained throughout the follow-up periods. In one study, Tulandi et al. reported on the short-term effect of ovarian drilling on the ovarian volume as measured by three-dimensional (3D) ultrasound (Tulandi et al., 1997). They found that ovarian drilling resulted in a transient increase followed by a significant reduction in ovarian volume from a pre-operative mean value of 12.2 ml to 6.9 ml 3 weeks after surgery. In the present study, we confirm this reduction in the ovarian volume after ovarian drilling (from 11 to 8.5 ml). In addition, we have shown that this change in ovarian volume seems to last for up to 9 years.
The mechanism of this reduction of the ovarian volume by ovarian drilling is not clear. Tulandi et al. measured the volume of ovarian tissue destroyed by the needle electrode in an excised ovary using a 3D projection of coloured serial microscopic images (Tulandi et al., 1997). They found that a single drilling would destroy an average of 0.4 ml of stromal tissue. They concluded that 1015 drillings in an ovary would result in a total tissue destruction of 46 ml. This could account for the observed reduction of the ovarian volume. It may also explain why the magnitude of reduction of the ovarian volume in our study (from 11 to 8.5 ml), in which we applied 310 punctures per ovary, is smaller than that (from 12.2 to 6.9 ml) observed by Tulandi et al. who made 1015 punctures per ovary (Tulandi et al., 1997
). However, it is not clear whether these findings in an excised ovary can be extrapolated to the intact ovary. Another possible explanation for the reduction of ovarian volume is the normalization of ovarian function produced by ovarian drilling. This is supported by the hypothesis that the typical morphological features of PCOS, although still not fully understood, are due to changes in ovarian function, e.g. thecal hyperactivity and chronic anovulation (Hughesden, 1982
).
It may be argued that the difference in ovarian volumes could be the result of inter-observer variability or the use of different ultrasound machines. These points are unlikely to be valid, as firstly, earlier studies have demonstrated that real-time 2D pelvic ultrasonography is a relatively accurate and reliable method of determining ovarian volume (Campbell et al., 1982; Goswamy et al., 1988
; Higgins et al., 1990
). Secondly, in our unit two similar ultrasound machines have been used throughout the 9 year follow-up period.
It may also be argued that the reduction of ovarian volume after ovarian drilling is a sign of excessive ovarian tissue destruction and could be associated with an increased risk of ovarian damage and POF. However, as discussed above, in our cohort of patients there was no POF, even though 14 patients were aged 3945 years. We can therefore conclude that this reduction of the ovarian size is a sign of normalization of ovarian function in women with PCOS, rather than ovarian damage.
The long-term beneficial effects of ovarian drilling on ovarian morphology are further supported by the significant reduction in the incidence of women with ultrasound evidence of PCO at medium- and long-term follow-up compared with the pre-operative level.
In conclusion, our data show that LOD normalizes ovarian function and morphology in women with PCOS and that these effects seem to be sustained for up to 9 years in most patients.
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Acknowledgements |
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Notes |
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References |
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Submitted on April 15, 2002; accepted on July 16, 2002.