Polycystic ovary syndrome (PCOS) was initially
reported by Stein and Leventhal (
Clomiphene citrate is the first treatment option for
inducing ovulation in these women (
Historically, the surgical treatment of infertile PCOS
women reported by Stein and Leventhal (
The beneficial effects of this method seem to be related
to the destruction of the androgen generating stroma,
which results in reduced production of androgens in
the ovary and its reduced concentration in the blood
circulation. Clomiphene citrate-resistant women may
respond better to medical therapy after this type of
surgery. Sensitivity to exogenic gonadotropins also
increase in such cases (
Several studies have evaluated ovarian cauterization.
In the initial studies, it was hypothesized that a higher
energy level would result in a more efficient procedure.
Subsequently, lower temperatures with a fixed
number of drilled points, regardless of the ovary’s
size or unilateral ovarian cautery have been reported
with the intent to reduce a possible risk of ovarian
atrophy and adnexal adhesions. With such fixed doses
of temperature, the optimal amount of ovulation may
not be achieved or the clinical manifestations of the
disease may persist in individuals with enlarged ovaries
We designed this study because of the inadequate number of studies in this area (particularly in Iran) and by taking into consideration the influence of genetic, regional and nutritional factors on PCOS. We sought to compare the effect of ovarian cauterization between the standard and dose-adjusted (based on the ovarian volume) methods in Iranian women with infertile clomiphene-resistant PCOS.
This randomized clinical trial was conducted in the
Gynaecology Department of Imam Reza Hospital,
Mashhad, Iran from 2016 to 2017. All infertile clomipheneresistant PCOS women who visited the Gynaecology
Department enrolled in this study. The sample size
of this study was calculated at 30 women according to
the following formula and by taking into consideration
information from a previously published study (
The achieved power of this study was 37% based on the antral follicle count (AFC).
At study initiation, the study protocol was fully described to each patient and they were free to withdraw from the study at any time. Their data was regarded as confidential. All patients signed a written informed consent to participate in the study. The Ethics Committee of Mashhad University of Medical Sciences approved this study (IR.MUMS.fm.REC.1395.335). The study was registered in the Iranian Registry for Clinical Trials (IRCT20171210037820N1).
The inclusion criteria were: all women aged 18 to 35 years, not pregnant despite two years without contraception, diagnosed with PCOS based on the Rotterdam criteria, having ruled out other reasons of infertility except for ovulation disorder (normal sperm analysis of the spouse, normal uterine tubes in hysterosalpingography or laparoscopy), clomiphene-resistant, and provided consent to participate in this study.
Exclusion criteria were: withdrawal during the study, patients lost to follow-up, presence of any other pathology during laparoscopy (e.g., endometriosis or adhesion) suggestive of other aetiologies for infertility.
Initially, we recorded the patients’ demographic characteristics and paraclinical data by means of an interview and the patient’s records. We divided the patients into two groups according to a table of random number generator with equal sizes of groups: standard method (group A) and ovarian cautery based on the ovarian volume or the dose-adjusted method (group B). One radiologist performed the transvaginal ultrasonography (TVS) for group B patients by using a Honda sonography device (Honda Electronics, Japan) to measure ovarian volume. This volume was measured on the basis of a cubic centimetre and at three perpendiculars.
A gynaecology laparoscopist performed each laparoscopy via an Olympus laparoscopic machine (Olympus Europa SE & Co., Germany) in the gynaecology theatre of Imam Reza Hospital with patients under general anaesthesia and in the lithotomy position. Abdominal entry was done by the closed technique and via a Veress needle. Only patients who had any history of abdominal surgery had an open laparoscopic procedure. A triple puncture laparoscopy was performed with 3 trocars. The abdominal and pelvic environment, and the patency of the tubes were examined. Patients with adhesions, endometriosis, or any pathology in the pelvic area were excluded from the study.
Next, the ovarian cautery was performed. The uteroovarian ligament was caught with an Atraumatic Grasper (Aesculape Inc., USA) and the ovary was separated from the intestines. Afterwards, the ovarian cautery was carried out with a 4-millimetre monopolar needle electrode (with a straight needle) and with a Vallylab generator that had a voltage of 30 (in both groups) as follows: using the CUT energy, a puncture with the depth of 4 millimetres was initially created on the ovarian capsule and then the coagulation button was activated. After the cautery of each ovary and before releasing the utero-ovarian ligament, the ovary was rinsed with cold normal saline serum to prevent any adhesion or injury to the adjacent viscera. The ligament was then released and examined with regards to the possibility of mechanical injury.
In group B (on the basis of ovarian volume), the
measurement of energy was based on the following model
In group A, based on the size of the ovary, we created either 4 drills of 5 s or 5 drills of 4 s with a voltage of 30 in order to achieve an energy of 600 joules per ovary (4×5×30=600).
The patients were followed for six months from the first menstrual cycle after the operation. Hormonal levels of anti-Müllerian hormone (AMH), testosterone, dehydroepiandrosterone sulphate (DHEAS), and progesterone were obtained on the third day of the first menstrual cycle after the operation and the progesterone level was measured at the mid-luteal phase of the same cycle. All tests were performed in the same laboratory and without charge.
TVS was also performed from the sixth day of the first menstrual cycle after the operation, every three days up to the 16th day or until the observation of a dominant follicle. Ovulation was confirmed by the observation of an 18 mm dominant follicle or pregnancy. TVS was performed by the same radiologist as before the LOD. In the event of anovulation, subsequent sonographies were not performed. Cycle regularity and the occurrence of pregnancy were examined after six months.
Patients who did not menstruate until a month after ovarian cautery (menstrual cycle over 35 days) were administered 100 mg of intramuscular micronized progesterone to re-establish the menstrual cycle, and the investigations were performed though most of these cases had no ovulation.
We performed SPSS software (version 16) analyses of te raw data. If the quantitative variables were normally distributed, we used the t test and paired t test; for non-normally distributed data, the corresponding non-parametrical tests were used. The chi-square test was used to examine qualitative variables. Repeated measure ANOVA was performed to assess the interaction and overall effect of before/ after assessments in the two groups. The significance level was set at P<0.05.
In this study, 60 infertile clomiphene-resistant PCOS
women received LOD by two methods: standard and
dose-adjusted on the basis of the ovarian volume. The
demographic, clinical and sonographic characteristics
did not differ between the two study groups (
Comparison of demographic, clinical, and sonographic data of infertile clomiphene-resistant PCOS women between the two treatment groups
|Variable||Standardn=30||Dose-adjusted n=30||P value|
|Age (Y)||26.36 ± 4.69||28.53 ± 5.84||0.11|
|History of infertility (Y)||4.42 ± 2.77||4.84 ± 2.73||0.62|
|Type of infertility||0.79|
|Primary||17 (56.6)||18 (60)|
|Secondary||13 (43.4)||12 (40)|
|Clinical manifestations||20 (66.7)||19 (63.3)||0.58|
|Oligomenorrhea||1 (3.3)||3 (10)|
|Oligomenorrhea+Hirsutism Hirsutism||9 (30)||8 (26.7)|
|Regularity of cycles||0.61|
|Regular||9 (30)||8 (26.7)|
|Irregular||21 (70)||22 (73.3)|
|Volume of right ovary (cm3)||--||15.02 ± 7.46|
|Volume of left ovary( cm3)||--||13.34 ± 5.87|
|Endometrial line (mm)||--||6.56 ± 1.93|
|AFC||16.33 ± 2.53||16.80 ± 1.99||0.43|
|AMH (ng/ml)||7.87 ± 4.86||7.46 ± 4.45||0.73|
|Testosterone (ng/dl)||80.52 ± 40.80||81.46 ± 29.14||0.91|
|DHEAS (µg/dL)||173.86 ± 73.32||201.34 ± 77.76||0.16|
Data represented as mean ± SD or frequency (%) as appropriate. PCOS; Polycystic ovary syndrome, AMH; Anti-Müllerian hormone, AFC; Antral follicle count, and DHEAS; Dehydroepiandrosterone sulphate.
Mean numbers of points and cautery time per ovary in the dose-dependent group
|Variable||Right ovary||Left ovary|
|No. of points||5.93 ± 1.66||5.59 ± 1.68|
|Time (seconds)||4.07 ± 0.45||4.24 ± 0.57|
Data are presented as mean ± SD.
Table 3 shows a comparison of the mean AFC and serum levels of AMH, testosterone, and DHEAS between the two groups, before and after the operation.
Table 4 displays the mean changes in the AFC and serum levels of AMH, testosterone, and DHEAS before and after the operation in each of the studied groups. Repeated measure ANOVA revealed that there was no interaction, nor any difference between the two study groups in terms of AFC (P=0.14), AMH (P=0.71), testosterone (P=0.67), and DHEAS (P=0.12).
The number of antral follicles before the operation was not significantly different between the two groups (independent t test, P=0.43). The same result was obtained after the operation (P=0.10). Intra-group comparisons showed that the decrease in the number of antral follicles was significant in the standard treatment group (paired t test, P=0.02); however, we did not observe any difference in the dose-adjusted group (P=0.24).
Before the intervention, the two groups were matched in terms of AMH level (independent t test, P=0.73). We observed the same result after the intervention (Mann-Whitney test, P=0.94). In the intra-group comparison, there was a significant decrease in the AMH level in the dose-adjusted group (paired t test, P=0.04); however, this difference was not observed in the standard treatment group (paired t test, P=0.17).
Before the intervention, the testosterone level was similar in the two groups (independent t test, P=0.91). The same result was obtained after the intervention (P=0.46). However, the decrease in testosterone level in the standard treatment group was meaningful (paired t test, P=0.02), but this difference was not observed in the dose-adjusted group (paired t test, P=0.14).
Comparison of the hormone profile and AFC between the study groups
|Variable||Before surgery||After surgery|
|Standard n=30||Dose-adjusted n=30||P value||Standard n=30||Dose-adjusted n=30||P value|
|AFC||16.33 ± 2.53||16.80 ± 1.99||0.43||15.10 ± 2.97||16.27 ± 2.55||0.10|
|AMH (ng/ml)||7.87 ± 4.86||7.46 ± 4.45||0.73||7.08 ± 4.28||6.71 ± 3.32||0.94|
|Testosterone (ng/dl)||80.52 ± 40.80||81.46 ± 29.14||0.91||71.28 ± 36.17||77.37 ± 26.68||0.46|
|DHEAS (µg/dL)||173.86 ± 73.32||201.34 ± 77.76||0.16||160.51 ± 60.36||189.13 ± 80.33||0.12|
AFC; Antral follicle count, AMH; Anti-Müllerian hormone, and DHEAS; Dehydroepiandrosterone sulphate. Data represented as mean ± SD.
A comparison of the changes in the hormone profile and AFC before and after the operation in the two groups
|Before surgery||After surgery||P value||Before surgery||After surgery||P value|
|AFC||16.33 ± 2.53||15.10 ± 2.97||0.02||16.80 ± 1.99||16.27 ± 2.55||0.24|
|AMH (ng/ml)||7.87 ± 4.86||7.08 ± 4.28||0.17||7.46 ± 4.45||6.71 ± 3.32||0.04|
|Testosterone (ng/dl)||80.52 ± 40.80||71.28 ± 36.17||0.02||81.46 ± 29.14||77.37 ± 26.68||0.14|
|DHEAS (µg/dL)||173.86 ± 73.32||160.51 ± 60.36||0.16||201.34 ± 77.76||189.13 ± 80.33||0.08|
AFC; Antral follicle count, AMH; Anti-Müllerian hormone, and DHEAS; Dehydroepiandrosterone sulphate. Data represented as mean ± SD.
In addition, both at study initiation and study termination, the level of DHEAS did not significantly differ between the two studied groups (independent t test, P=0.16 at study initiation, P=0.12 at study termination). In the intragroup comparisons, the level of DHEAS decrease was not significant in either group (paired t test, P=0.16 in the standard group and P=0.08 in the dose-adjusted group).
The status of cycle regularity and the occurrence of ovulation and pregnancy among patients were examined from the first post-surgical cycle up to six months. The obtained results are presented in Table 5.
There were regular menstrual cycles reported in 25 (83.3%) patients in the standard treatment group and 21 (70%) patients in the dose-adjusted group. Accordingly, there was no statistically significant difference observed between the two groups (chi-square test, P=0.22).
Ovulation occurred in 26 (86.7%) patients in the standard group and in 21 (70%) patients from the doseadjusted group, which was not statistically significant (chi-square test, P=0.11).
Finally, 11 (36.7%) patients in the standard group and 8 (26.7%) patients in the dose-adjusted group became pregnant during 6 months, which indicated no meaningful difference between the two groups (chi-square test, P=0.40).
Intragroup comparisons on cycle regularity indicated a significant increase after the operation compared to before the operation in the standard treatment (30 vs. 83.3%) and dose-adjusted (26.7 vs. 70%, P<0.001) groups.
No case of premature ovarian failure was observed in our study population. Cycle regularity was experienced in 9 (30%) patients in the standard group before the operation and in 25 (83.3%) patients after the operation. In the dosedependent group 8 (26.7%) patients had cycle regularity before the operation and 21 (70%) had cycle regularity after the operation. This was a significant change in both groups (P<0.001).
A comparison of cycle regularity, ovulation, and pregnancy between the study groups
|Variable||Standard n=30||Dose-dependent n=30||P value|
|Regularity of cycles||0.22|
|Regular||25 (83.3)||21 (70)|
|Irregular||5 (16.7)||9 (30)|
|Yes||26 (86.7)||21 (70)|
|No||4 (13.3)||9 (30)|
|Yes||11 (36.7)||8 (26.7)|
|No||19 (63.3)||22 (73.3)|
Data represented as frequency (%).
We measured progesterone levels in both groups in the first postoperative menstrual cycle. There was no significant difference between the two groups (P=0.11). However, the mean progesterone level in patients with (12.44 ± 2.20) and without ovulation (2.93 ± 0.20) was significantly different (P<0.001). No case of early ovarian failure was observed in the studied subjects.
The results of our study indicated no difference in the
number of antral follicles after the operation in both
groups. However, the decrease in the number of antral
follicles was significant in the standard treatment group.
Such results corresponded to those reported by Nasr et al.
AMH is one of the new predictive indicators of ovarian
Given that the increase in androgens in PCOS is the
result of the insulin’s ability to increase the secretion of
androgens in ovarian theca cells, the remarkable decrease
in the level of androgens after drilling among patients who
receive cauterization with a volume dependent dose might
be justified by the hypothesized destruction of androgen
generating stromal cells. It is believed that the effects of
LOD on androgen levels are influenced by the amount of
energy entrapped by the ovaries and, for this reason, low
doses may be less successful (
Both groups had a nonsignficant decrease in DHEAS
levels. A review of previous literature has revealed
that the existing data on DHEAS are ambiguous. LOD
seems to have a minimal effect on adrenal function, even
among women affected by hyperinsulinemia, and the
improvement of hyperandrogenism is probably secondary
to the decrease in LH concentration and reduced androgen
production by the ovarian stroma (
In our study, the regularity of menstrual cycles
increased from 30 to 83.3% in the standard treatment
group. The regularity of menstrual cycles in the doseadjusted group increased from 26.7 to 70%. This was
a significant increase in both groups. The intra-group
changes were different compared to the Zakherah et al.
In a study by Nasr et al. (
In our study, ovulation occurred in 86.7% of patients
in the standard treatment group and 70% of those in the
dose-adjusted group; 36.7% of patients in the standard
treatment group and 26.7% in the dose-adjusted group
became pregnant. The findings of our study contradicted
those reported by Zakherah et al. (
In a study by Salem et al. (
Ramezani et al. (
Our study had certain limitations; the small sample size which led to a low power, decreased cooperation of patients for the ultrasound study and the postoperative lab tests, as well as the impossibility of performing TVS in all subjects due to limited facilities in this center.
The results of this study indicated a significant decrease in antral follicles and testosterone in the standard treatment group in comparison to the dose-adjusted group along with a significant decrease in AMH level in the dose-adjusted group. The changes in DHEAS were insignificant in both groups.
Cycle regulation, and the occurrence of ovulation and pregnancy showed that both methods were efficient; however, there were no statistically significant differences. In terms of the effects of ovarian cautery on these variables, neither of the two methods was superior. It is possible that the small number of samples examined and the differences in the sample selection method or the racial and regional differences might have led to the difference in the results of our study with previous researches. Therefore, conducting similar regional studies with a larger sample sizes are highly recommended.