Archives of Gynecology and Obstetrics

https://doi.org/10.1007/s00404-018-4680-1

REVIEW

Unilateral or bilateral laparoscopic ovarian drilling in polycystic ovary

syndrome: a meta‑analysis of randomized trials
Hatem Abu Hashim1   · Osama Foda2 · Mohamed El Rakhawy3

Received: 27 July 2017 / Accepted: 17 January 2018

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose  This systematic review and meta-analysis aimed to compare the effectiveness of unilateral vs. bilateral laparoscopic
ovarian drilling (ULOD vs. BLOD) for improving fertility outcomes in infertile women with clomiphene-resistant polycystic
ovary syndrome (PCOS) as well as its effect on ovarian reserve.
Methods  Searches were conducted on PubMed, ScienceDirect, ClinicalTrials.gov, and CENTRAL databases from January
1984 to January 2017. Only randomized trials comparing ULOD with BLOD were included. The PRISMA Statement was
followed. Main outcomes were ovulation and clinical pregnancy rates per woman randomized. Secondary outcomes were;
live birth and miscarriage rates as well as postoperative serum anti-mullerian hormone (AMH) concentration and antral
follicle count (AFC). Quality assessment was performed by the Cochrane Collaboration risk of bias tool.
Results  Eight eligible trials (484 women) were analyzed. No significant difference was found in rates of ovulation (OR 0.73;
95% CI 0.47–1.11), clinical pregnancy (OR 0.56; 95% CI 0.22–1.41), live birth (OR 0.77; 95% CI 0.28–2.10), or miscarriage
(OR 0.90; 95% CI 0.33–2.84) when ULOD was compared with BLOD. The reduction in AMH was comparable between the
two procedures (MD 0.64 ng/ml; 95% CI − 0.08 to 1.36). A significantly higher AFC at 6-month follow-up was found with
dose-adjusted ULOD (MD 2.20; 95% CI 1.01–3.39).
Conclusions  After carefully weighing up the well-known benefits of BLOD against a potential risk to ovarian reserve, cli-
nicians could be advised to offer the fixed-dose ULOD to their infertile patients with clomiphene-resistant PCOS. This is
concordant with the “primum non nocere” principal if LOD will be envisaged.

Keywords  Unilateral ovarian drilling · Unilateral ovarian diathermy · Polycystic ovary syndrome · PCOS · Ovulation and
pregnancy

Introduction

Polycystic ovary syndrome (PCOS) is a major challenge

Electronic supplementary material  The online version of this
article (https​://doi.org/10.1007/s0040​4-018-4680-1) contains
supplementary material, which is available to authorized users.
* Hatem Abu Hashim
hatem_ah@hotmail.com
1
Department of Obstetrics and Gynecology, Faculty
of Medicine, Mansoura University, Mansoura, Egypt
2
Endocrinology Unit, Department of Internal Medicine,
Mansoura University, Mansoura, Egypt
3
Department of Diagnostic Radiology, Faculty of Medicine,
Mansoura University, Mansoura, Egypt
facing not only researchers, but also the management clini-
cians. PCOS is the most common endocrine disorder among
women in the reproductive age worldwide. In addition, it
is recognized as a leading cause of anovulatory infertility
[1, 2]. In this regard, three joint consensus meetings were
held by the European Society of Human Reproduction and
Embryology (ESHRE) and the American Society of Repro-
ductive Medicine (ASRM) to agree the definition of the
PCOS, outline, and appraise its available treatment options
as well as to evaluate various women’s health aspects of
PCOS [3–5]. Recently, a prevalence rate of ~ 20% has been
reported in view of the Rotterdam diagnostic consensus [6].
Clomiphene citrate represents the first-line pharmacologi-
cal therapy for anovulatory women with PCOS. It is worth

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noting that 15–40% of PCOS women remained anovulatory
despite treatment with 150 mg of clomiphene citrate daily
for three successive cycles and considered to be clomiphene-
resistant [7, 8]. Laparoscopic ovarian drilling (LOD) and
gonadotrophins are recommended to induce ovulation in
those women [4, 9].
LOD was first reported by Halvard Gjönnaess in 1984 as
a minimally invasive and less traumatic technique replac-
ing ovarian wedge resection for surgical treatment of infer-
tile women with PCOS [10]. LOD seems to be as effec-
tive as gonadotrophin treatment, but without an increased
risk of multiple pregnancy or ovarian hyperstimulation
syndrome [4, 9, 11]. However, how LOD induces ovula-
tion has yet to be elucidated. It is strongly believed that the
destruction of ovarian follicles and stromal elements causes
a fall in local and serum androgens as well as inhibin lev-
els leading to an increase in the FSH secretion promoting
follicular growth, i.e., LOD induces ovulation via correc-
tion of the disturbed ovarian-pituitary feedback [11–13]. In
addition, a surgery-mediated increased ovarian blood flow,
releasing a cascade of local growth factors, such as insulin-
like growth factor 1, interacting with FSH to allow follicular
growth, maturation, and subsequent ovulation has been sug-
gested [13]. The main shortcomings of LOD are the risk of
postoperative adhesions and the concern about a negative
impact of the procedure on the ovarian reserve secondary to
excessive ovarian damage [11, 14, 15].
Balen and Jacobs [16], for the first time, put forward
the effectiveness of unilateral LOD (ULOD) in the man-
agement of anovulatory women with PCOS. In this rand-
omized-controlled trial (RCT), 640 Joules (J) were deliv-
ered to one ovary [4 punctures × 4 s × 40 W (watt)] in the
ULOD arm [16]. Subsequently, several RCTs evaluated the
efficacy of ULOD against bilateral LOD (BLOD) in those
women and promising results were demonstrated in terms of
ovulation and pregnancy [17–19]. Recently, a new concept
called ”dose-adjusted” ULOD is introduced, which could be
useful in the treatment of infertile women with clomiphene-
resistant PCOS. It means to tailor the energy applied to
one ovary, according to its preoperative volume using 60 J/
cm3 [20]. When compared with BLOD (with fixed doses
of 1200 J, i.e., 600 J per ovary) among 96 infertile women
with clomiphene-resistant PCOS, a significantly higher ovu-
lation rate during the first postoperative menstrual cycle was
reported in the ULOD group than in the BLOD group (73 vs.
49%; P = 0.014). Meanwhile, the increase in the ovulation
rate over the 6-month period in the ULOD group over the
BLOD group was borderline (82 vs. 64%; P = 0.050) [20].
In addition, both groups experienced a reduction in serum
anti-mullerian hormone (AMH) level after LOD which was
significantly more in the BLOD group in the first follow-up
month and remained as so at the 6-month follow-up period
[21]. Subsequently, this new concept was evaluated against
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Archives of Gynecology and Obstetrics
the fixed-dose BLOD in an RCT among 108 patients with
clomiphene-resistant PCOS [22]. A comparable ovulation
and pregnancy rate was reported at 3-month follow-up
period (65.4 vs. 77.3% and 15.4 vs. 26.4%, respectively).
However, a reduction in the effectiveness of dose-adjusted
unilateral LOD after 6 months was noticed [22]. Thereby,
changing the usual practice of drilling both ovaries to only
one ovary is a challenging issue.
In view of the above-mentioned context and given that
this is a clinically important area to address, this system-
atic review and meta-analysis was conducted to evaluate
the effectiveness of ULOD vs. BLOD for improving fertil-
ity outcomes in infertile women with clomiphene-resistant
PCOS as well as its effect on ovarian reserve based on the
available evidence so far in RCTs.
Materials and methods
Literature search methodology
This systematic review was conducted using only RCTs.
The recommended PRISMA Statement was followed for
reporting [23]. The clinical question posed was: in women
with clomiphene-resistant PCOS, what is the effectiveness
of ULOD compared with BLOD for improving fertility out-
comes (ovulation and pregnancy)?
A search without language restrictions was performed
through the following databases: PubMed, ScienceDirect,
ClinicalTrials.gov (each from January 1984 to January
2017), and Cochrane Central Register of Controlled Trials
(CENTRAL, Issue 1, 2017). To generate a subset of cita-
tions relevant to our research question, the following Medi-
cal Subject Headings (MeSH) and text words were used:
“unilateral Ovarian drilling” OR “unilateral Ovarian dia-
thermy” AND “polycystic ovary syndrome” OR “PCOS”
AND “ovulation” AND “pregnancy”. The reference lists
of retrieved publications were manually searched to iden-
tify any missing relevant publications. The database search
details are described in Table S1.
Study selection
Two reviewers (H.A. and O.F.) independently reviewed the
titles and abstracts of retrieved citations for relevance to our
meta-analysis. Only RCTs which compared ULOD (i.e., one
ovary drilled) with BLOD (i.e., both ovaries drilled) were
selected. Studies were included in the systematic review
when the following criteria were met: (i) infertile patients
with PCOS, diagnosed according to the Rotterdam consen-
sus [at least two out of three criteria: oligo- or anovulation,
clinical and/or biochemical signs of hyperandrogenism, and
polycystic ovarian morphology (PCOM) on ultrasound] [3]
Archives of Gynecology and Obstetrics
or the NIH criteria (both chronic anovulation and clinical or
biochemical signs of hyperandrogenism) [24] or the Andro-
gen Excess criteria (both clinical and/or biochemical signs
of hyperandrogenism with ovarian dysfunction as defined by
oligo/anovulation or polycystic morphology or both) [25].
Clomiphene-resistance was diagnosed as above-mentioned
[7, 8]; (ii) at least one of the following outcomes: ovulation,
clinical pregnancy, live birth and miscarriage rates, post-
operative serum AMH level, or antral follicle count (AFC)
was reported.
Exclusion criteria were: quasi-RCTs, non-RCTs, and
infertility for reasons other than PCOS. Full texts were
obtained by contacting the author when this could not be
obtained online. Any disagreements regarding study eligi-
bility were resolved by consensus after discussion with the
third reviewer (M.E.).
Assessment of methodological quality and data
extraction
Two reviewers (H.A. and O.F.) independently extracted the
data from each included study, according to a data extraction
form designed in accordance with the Cochrane Checklist of
items [26]. This form included the following details: source,
eligibility, methods, participants’ characteristics, interven-
tions, outcomes, and results in addition to any other impor-
tant miscellaneous data. Primary outcome measures were:
ovulation rate [diagnosed by elevated serum luteal phase
progesterone (day 21), transvaginal ultrasound, or both] and
clinical pregnancy rate (defined as the presence of a gesta-
tional sac and fetal cardiac pulsations on ultrasound scan
at 7-week gestation). Secondary outcome measures were:
live birth rate (defined as delivery of a live fetus after 20
completed gestational weeks), miscarriage rate (defined as
loss of a clinical pregnancy before 20-week gestation), and
postoperative serum AMH concentration (ng/ml) and AFC.
The unit of analysis was per woman randomized according
to the intention-to-treat (ITT) principle.
The Cochrane Collaboration risk-of-bias tool was uti-
lized to assess the methodological quality and risk of bias
of included studies [26]. Each article was assessed accord-
ing to seven specific domains (random sequence generation,
allocation concealment, blinding of participants and person-
nel, blinding of outcome assessors, incomplete outcome
data, selective outcome reporting, and other biases). These
domains were evaluated and scored as high, low, or unclear
risk of bias. The GRADE approach was utilized for quality
rating of a body of evidence into: high, moderate, low, and
very low [26]. Two reviewers (H.A. and O.F.) independently
conducted the quality assessment. In case of disagreements,
a consensus was reached after discussion with the third
reviewer (M.E.).
Statistical analysis
The data analysis was performed using RevMan software
5.1 of the Cochrane Collaboration. The fixed-effects model
was used for pooling of results. Odds ratios (OR) with 95%
confidence intervals (CI) were calculated for dichotomous
outcomes. Meanwhile, the mean difference (MD) was used
for continuous outcomes. If any heterogeneity existed (by the
Chi-squared test, with P < 0.1), random-effects model was
employed. If I2 statistic was ≥ 50%, exploration of the causes
of heterogeneity was performed and a sensitivity analysis was
done by excluding the trials that potentially biased the results.
Results
Literature search
The process of literature search and study selection is sum-
marized in the PRISMA flow diagram (Fig. 1). Of the 783
publications screened, 26 were identified as potentially eligi-
ble for inclusion. After examination of the full manuscripts,
18 studies were excluded (Table S2). Eight studies satis-
fied the selection criteria and were included in this review
[16–19, 22, 27–29].
Study characteristics
Of the eight included studies, three were performed in Egypt
[18, 22, 29], two in UK [16, 17], one in India [19], one in
Iran [28], and one in Saudi Arabia [27]. The eight included
studies enrolled 484 participants (240 women received
treatment with ULOD and 244 were treated with BLOD).
The sample size varied across the trials and ranged from
10 to 108 participants. Out of the eight studies, one was
published as oral ASRM conference abstract [29]. Laparo-
scopic ovarian electrocauterization using a monopolar dia-
thermy needle electrode was carried out in seven RCTs (six
RCTs compared fixed-dose ULOD vs. fixed dose BLOD in
341 patients [16–19, 28, 29] and one RCT compared dose-
adjusted ULOD vs. fixed-dose BLOD in 108 patients [22]).
Laser vaporization with KTP/532 laser beam energy was
performed in one RCT among 35 patients [27]. The base-
line of all trials was comparable. The characteristics of the
included studies are presented in Table 1. The risk of bias
summary for included studies is demonstrated in Fig. 2.
Primary outcome measures
Ovulation rate
Ovulation rate per woman randomized was reported in seven
RCTs [16–19, 22, 27, 28]. Data synthesis showed no signifi-
cant difference in ovulation rate when ULOD was compared
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 Archives of Gynecology and Obstetrics

Idenficaon
Records idenfied through Addional records idenfied
database searching through other sources
(n=1174) (n=2)

Records aer duplicates removed

(n=783)
Screening

Records screened Records excluded

(n=783) (n=758)

Full-text arcles assessed 18 full-text arcles were excluded:

for eligibility Eleven were not randomized
Eligibility

(n=26) controlled trials (RCTs)

One RCT was a duplicaon
of another study by the
same authors
One RCT addressing unipolar
vs. bipolar bilateral LOD and
Studies included in qualitave not unilateral vs. bilateral
synthesis (n=8); LOD
published arcles (n = 7); one RCT addressing adjusted
oral abstract (n = 1) vs. fixed dose energy in
bilateral LOD
Included

Four RCTs evaluated other

techniques rather than
Studies included in quantave unilateral LOD vs. bilateral
synthesis (meta-analysis) (n=8); LOD
published arcles (n = 7);
oral abstract (n = 1)

Fig. 1  PRISMA flow diagram of the study selection. LOD laparoscopic ovarian drilling

to BLOD (OR 0.73; 95% CI 0.47–1.11; P = 0.14, 7 trials,
404 women) without a significant heterogeneity across the
studies (P = 0.33, I2 = 13%) (Fig. 3). This evidence was
considered to be of moderate quality being downgraded one
level for some potential limitations of the included studies
(Table 2).
Clinical pregnancy rate
The clinical pregnancy rate per woman randomized was
reported in six RCTs [16–19, 22, 28]. There was an evi-
dence of significantly fewer pregnancies following ULOD
compared with BLOD in these six trials (369 women, OR
0.52; 95% CI 0.34–0.79; P = 0.002). However, a significant
heterogeneity was found between the studies (P = 0.003,
I2 = 75%); therefore, a random-effects model was used for
pooling of results. Noteworthy, no significant difference
in clinical pregnancy rate was found between both groups
when data were combined by the random-effects model (OR
0.56; 95% CI 0.22–1.41; P = 0.22, 6 trials, 369 women),
but with persistent significant heterogeneity across the stud-
ies (P = 0.003, I2 = 75%) (Fig. 4). After exclusion of one
study by sensitivity analysis in which dose-adjusted ULOD
was utilized rather than the fixed-dosage method [22], a
total of 261 women (129 in the ULOD group and 132 in
the BLOD group) were included. Pooled analysis with the
fixed-effects model confirmed the non-significant difference
in the pregnancy rate between the two groups (OR 0.89; 95%
CI 0.53–1.48; P = 0.66) without significant heterogeneity
across the studies (P = 0.84, I2 = 0%). This evidence was

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 Table 1  Characteristics of included studies
RCT​ Country Population Mean age and BMI Intervention comparison Outcomes

Al-Mizyen and Grudzinskas
[17]
Balen and Jacobs [16]
UK 20 women with CC-resistant Mean age: ULOD 27 years, ULOD (n = 10), fixed-dose- BLOD (n = 10), fixed-dose- OR, PR, LBR, MR
PCOS BLOD28 years energy to right ovary (640 J energy (640 J per ovary.
Mean BMI: ULOD 19 kg/ per ovary; 4 punctures × 48-month follow-up
m2, BLOD 17 kg/m2 4 s × 40 W). 48-month
follow-up
UK 10 women with CC-resistant Mean age: 29.5 ± 2.3 years ULOD (n = 4), fixed-dose BLOD (n = 6), fixed-doseen- OR, PR
PCOS Mean BMI: 23.2 ± 3.1 kg/m2 energy to right ovary (3) ergy. 3-month follow-up
and left ovary (1) (640 J per
Archives of Gynecology and Obstetrics

ovary; 4 punctures × 4 s ×

40 W). 3-month follow-up
Jamal [27] Saudi Arabia 35 women with CC-resistant Mean age: ULOD ULOD (n = 17) BLOD (n = 18) by KTP/532 OR
PCOS 28.5 ± 2.1 years, BLOD Fixed-dose energy to one laser beam. 3-month
26.2 ± 1.2 years ovary by KTP/532 laser follow-up
Mean BMI: ULOD beam (5 puncture × 5 s ×
25.2 ± 2.4 kg/m2, BLOD 15 W). 3-month follow-up
24.1 ± 1.3 kg/m2
Nasr [29] Egypt 80 women with CC-resistant Mean age: ULOD ULOD (n = 40), fixed- BLOD (n = 40), fixed-dose- AMH
PCOS 28.4 ± 2.2 years, BLOD doseenergy to one ovary. energy. 6-month follow-up
29.2 ± 1.9 years. 6-month follow-up
Mean BMI: not stated
Rezk et al. [22] Egypt 108 women with CC-resist- Mean age: ULOD ULOD (n = 54), dose BLOD (n = 54), fixed-dose- OR, PR, AMH, AFC
ant PCOS 29.7 ± 1.5 years, BLOD adjusted using 60 J/cm3 energy (600 J per ovary; 5
29.8 ± 1.4 years applied to the larger ovary. punctures × 4 s × 30 W).
Mean BMI: ULOD 3- and 6-month follow-up 3- and 6-month follow-up
23.9 ± 2.1 kg/m2, BLOD
24.4 ± 1.8 kg/m2
Roy et al. [19] India 44 women with CC-resistant Mean age: ULOD ULOD (n = 22), fixed- BLOD (n = 22), fixed-dose- OR,PR, LBR, MR
PCOS 28.2 ± 1.7 years, BLOD doseenergy to one ovary energy; 5 punctures per
28.8 ± 2.9 years through 5 punctures. ovary. 12-month follow-up
Mean BMI: not stated 12-month follow-up
Youssef et al. [18] Egypt 87 women with CC-resistant Mean age: ULOD ULOD (n = 43), fixed- BLOD (n = 44), fixed-dose- OR, PR, MR
PCOS 31.1 ± 4.2 years, doseenergy to larger energy (640 J per ovary).
BLOD = 29.8 ± 3.7 years ovary (640 J per ovary) (4 12-month follow-up.
Mean BMI: ULOD punctures × 4 s × 40 W).
26.1 ± 1.9 kg/m2, BLOD 12-month follow-up
25.7 ± 1.8 kg/m2
Zahiri Sorouri et al. [28] Iran 100 women with CC-resist- Mean age: ULOD ULOD (n = 50), fixed- BLOD (n = 50), fixed- OR, PR, MR
ant PCOS 27.6 ± 4.2 years, BLOD doseenergy to right ovary doseenergy, 5 punctures
28 ± 4.3 years through 5 punctures (60 W per ovary (60 W each).
Mean BMI: not stated each). 6-month follow-up 6-month follow-up

AFC antral follicle count, AMH anti-mullerian hormone, BLOD bilateral laparoscopic ovarian drilling, BMI body mass index, CC clomiphene citrate, J Joule, LBR live birth rate, ULOD unilat-
eral laparoscopic ovarian drilling, MR miscarriage rate, n number of cases, OR ovulation rate, PCOS polycystic ovary syndrome, PR pregnancy rate, RCT​randomized-controlled trial, W watt

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Fig. 2  Risk of bias summary for included studies. +, yes (low risk of
bias); −, no (high risk of bias); ?, unclear risk of bias
considered to be of moderate quality being downgraded one
level for some potential limitations of the included studies
(Table 2).
Fig. 3  Forest plot for ovulation rate. BLOD bilateral laparoscopic ovarian drilling, CI confidence intervals, M–H Mantel–Haenszel, ULOD uni-
lateral laparoscopic ovarian drilling
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Secondary outcome measures
Live birth rate
No significant difference in live births was observed when
ULOD was compared with BLOD after combining the
data from two RCTs [17, 19] (OR 0.77; 95% CI 0.28–2.10;
P = 0.61, 2 trials, 64 women) without a significant hetero-
geneity across the studies (P = 0.85, I2 = 0%). The evidence
was considered to be of moderate quality being downgraded
one level for some potential limitations of the included stud-
ies (Table 2).
Miscarriage rate
With regard to the miscarriage rate, no significant effect was
observed under ULOD as compared to BLOD in four RCTs
[17–19, 28] (OR 0.90; 95% CI 0.33–2.84; P = 0.84, 4 trials,
117 women) without a significant heterogeneity across the
studies (P = 0.73, I2 = 0%). This evidence was considered of
low quality being downgraded two levels for some potential
limitations of the included studies and we did not have suffi-
cient precision to identify whether ULOD is associated with
substantial harm, no effect, or substantial benefit (Table 2).
Serum AMH concentration
Combined data of two studies [22, 29] revealed a signifi-
cant reduction in serum AMH concentration 6 months after
ULOD as compared to BLOD (MD 0.67 ng/ml; 95% CI
0.33–1.01, P = 0.0001, 2 trials, 188 women). Heterogeneity
between studies was high (P = 0.03, I2 = 78%); therefore,
a random-effects model was used. Of note, the latter model
revealed no significant difference in serum AMH concen-
tration 6 months after ULOD or BLOD (MD 0.64 ng/ml;
Archives of Gynecology and Obstetrics

Table 2  Methods and results of the meta-analysis

Outcomea No. of No. of patients Statistical method Effect size P value Quality ­assessmentb
stud-
ies

1 Ovulation rate 7 404 OR (M–H, fixed, 95% CI) 0.73 (95% CI 0.47–1.11) 0.14 Moderatec
2 Clinical pregnancy ­ratef 5 261 OR (M–H, fixed, 95% CI) 0.89 (95% CI 0.53–1.48) 0.66 Moderatec
3 Live birth rate 2 64 OR (M–H, fixed, 95% CI) 0.77 (95% CI 0.28–2.10) 0.61 Moderatec
4 Miscarriage rate 4 117 OR (M–H, fixed, 95% CI) 0.90 (95% CI 0.33–2.84) 0.84 Lowd
5 Postoperative AMH 2 188 MD (IV, random, 95% CI) 0.64 ng/ml (95% CI − 0.08 0.08 Lowd
changes at 6 months to 1.36)
6. Postoperative AFC 1 108 MD (IV, fixed, 95% CI) 2.20 (95% CI 1.01–3.39) 0.0003* Lowe
changes at 6 months

AFC antral follicle count, AMH anti-mullerian hormone, CI confidence interval, IV inverse variance, MD mean difference, M–H Mantel–Haen-
szel, OR odds ratio
*Statistically significant difference
a
 Calculated per woman randomized
b
 According to GRADE approach (GRADE Working Group) [26]: high quality: further research is very unlikely to change our confidence in the
estimate of effect; moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may
change the estimate; low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is
likely to change the estimate; very low quality: we are very uncertain about the estimate
c
 Downgraded one level for quality of the included studies
d
 Downgraded two levels for quality of the included studies and the summary effect crossed the line of no effect and substantive benefit and harm
e
 Downgraded two levels being based on a single trial in which no data concerning allocation concealment and blinding were provided
f
 Pooled analysis after exclusion of one study by sensitivity analysis

Fig. 4  Forest plot for clinical pregnancy rate. BLOD bilateral laparoscopic ovarian drilling, CI confidence intervals, M–H Mantel–Haenszel,
ULOD unilateral laparoscopic ovarian drilling

95% CI − 0.08 to 1.36, P = 0.08), however, with persistent AFC

significant heterogeneity between both studies (P = 0.03,
I2 = 78%). A plausible explanation is the difference in the
ULOD technique utilized in each trial (one [29] utilized
fixed and the other [22] utilized the dose-adjusted technique)
(Table 2). This evidence was considered of low quality due
to some potential limitations of the included studies and the
summary effect crossed the line of no effect and substantive
benefit and harm (Table 2).
A significantly higher AFC at 6-month follow-up period was
found with ULOD as compared to BLOD in only one trial
[22] in which the dose-adjusted ULOD was performed (108
women, MD 2.20; 95% CI 1.01–3.39; P = 0.0003). The evi-
dence was considered of low quality being based on a single
trial in which no data concerning the allocation concealment
and blinding were provided (Table 2).

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Discussion
The pooled analysis demonstrated no evidence of a sig-
nificant difference in rates of ovulation, pregnancy, live
birth, or miscarriage when ULOD was compared with
BLOD. Thereby, a suggested recommendation to apply a
ULOD rather than a BLOD is generally concordant with
these data. The concept of using a ULOD with an adjusted
thermal dose, i.e., to tailor the energy according to the
preoperative ovarian volume, compared to the fixed-dose
BLOD was tested only in one RCT [22]. In this trial, dose-
adjusted ULOD was applied to the large ovary following
the formula described by Sunj et al. [20] (the number of
punctures per ovary = 60 J/cm3 divided by 30 W × 4 s).
The authors found that dose-adjusted ULOD applied to the
large ovary was associated with a reduction in its effective-
ness after 6 months as compared to the fixed-dose BLOD
(32.7 vs. 58.5% and 11.5 vs. 49.1% for ovulation and preg-
nancy rates, respectively) [22]. Importantly, a sensitivity
analysis after excluding this study confirmed the non-
significant difference without heterogeneity regarding the
pregnancy rate following ULOD compared with BLOD.
Consequently, the current evidence supports the use of the
fixed-dose ULOD than the dose-adjusted ULOD.
Although LOD is recommended as a successful second-
line therapy in women with clomiphene-resistant PCOS,
a concern exists about a possible negative impact on the
ovarian reserve secondary to excessive ovarian damage
[11]. AMH is a glycoprotein related to the transforming
growth factor-β (TGF-β) family. It is exclusively produced
by granulosa cells of primary, preantral, and small antral
follicles (4–6 mm). Serum AMH shows intra- and inter-
cycle consistency. Thereby, it has been considered as an
important marker of ovarian reserve [30]. Serum AMH
is 2–4-fold higher in women with PCOS than in healthy
women. This is because ovaries with PCOM exhibit an
increased number of AMH-producing small antral folli-
cles [30, 31] and increased production per granulose cells
[32]. A plausible explanation for the reduction in serum
AMH after LOD could be the effect of the thermal dam-
age decreasing its production from the granulosa cells of
primary, preantral, and small antral follicles. However,
does this reflect a real decline in ovarian reserve or just a
postoperative normalization of the AMH overproduction
of ovaries of PCOM remains uncertain?
Although a greater decrease in AMH is plausibly
anticipated with BLOD than the ULOD due to the greater
ovarian tissue damage caused by BLOD, i.e., more punc-
tures and greater total energy, our meta-analysis revealed
no significant difference in serum AMH concentration
6 months after ULOD or BLOD. This result should be
interpreted with caution due to the associated significant
13
Archives of Gynecology and Obstetrics
heterogeneity. Notably, a highly significant difference was
found in one RCT between the dose-adjusted ULOD and
BLOD groups with regard to the AMH level at 3- and 6-
month follow-up periods with lower levels achieved in the
BLOD group [22]. In addition, a significantly higher AFC
at 6-month follow-up period was reported with ULOD
as compared to BLOD [22]. This finding may denote
the insufficient follicle destruction in the dose-adjusted
ULOD, thereby explaining the reported lower ovulation
and pregnancy rates at 6-month follow-up in this trial [22].
At the moment, it is unknown how long the fixed-dose
ULOD has an effect on the ovary with regard to AMH and
AFC compared to BLOD. Therefore, until more data from
RCTs become available, the clinical decision to recom-
mend a fixed-dose ULOD than dose-adjusted ULOD could
be made on the above-mentioned clinical outcomes, i.e.,
rates of ovulation, pregnancy, live birth, and miscarriage.
Our meta-analysis showed no evidence for a difference in
effect between ULOD and BLOD for infertility treatment in
women with PCOS who are clomiphene-resistant, which is
in agreement with the results of an earlier subgroup analysis
in a Cochrane review of five RCTs [33] (four were pub-
lished in full text [16, 18, 19, 34] and one as oral abstract
[35]). However, in our meta-analysis, we excluded one trial
that was included in the Cochrane review after its full-text
revision. The excluded RCT was addressing unipolar vs.
bipolar BLOD and not ULOD vs. BLOD [34]. In addition,
we included the full version of the published RCT by Al-
Mizyen and Grudzinskas [17] rather than the limited abstract
data by the same authors [35] presented in the Cochrane
review. Moreover, we identified four other RCTs [22,
27–29]. Of them, three RCTs [22, 28, 29] were published
after the Cochrane review and their data have been extracted
and added in the analysis. In our meta-analysis, we have
also evaluated ovarian reserve markers in terms of serum
AMH levels and AFC at 6 months postoperatively in view
of the data published after the Cochrane review. Thereby,
we believe that an updated rigorous search of evidence has
been carried out coming with a more elaborate explanation
for the putative effect of ULOD in infertile women with
clomiphene-resistant PCOS.
Weight loss is recommended as a primary therapy for
anovulatory PCOS women who have a BMI ≥ 30 kg/m2.
In those women, weight loss alone may improve the endo-
crine profile, the likelihood of ovulation, and the response
to ovulation induction therapy in addition to successful
pregnancy outcomes [9]. Noteworthy, in a previous system-
atic review and meta-analysis, we demonstrated that lean
women respond significantly better to LOD than their obese
counterparts [relative risk (RR) 1.43, 95% CI 1.22–1.66;
RR 1.73, 95% CI 1.39–2.17 for ovulation and pregnancy
rates, respectively] [36]. Recently, Chiofalo et  al. [37]
raised the possibility of fasting as a complementary step
Archives of Gynecology and Obstetrics
for the management of obese women with PCOS. Fasting
can reduce Insulin Growth Factor-1 (IGF-1), Insulin-like
Growth Factor-Binding Protein 1 (IGFBP1), and glucose
and insulin levels, and, consequently, has beneficial effects
on ovarian function. The authors demonstrated that different
forms of fasting, such as intermittent fasting (e.g., alternate
day fasting, or twice weekly fasting) and periodic fasting
(e.g., for several days or longer every two or more weeks) are
currently under investigation. Moreover, they highlighted the
need for RCTs to compare the efficacy of fasting regimens
alone and in combination with common pharmacological
strategies in PCOS [37].
Viewed collectively, LOD should be regarded as an alter-
native, not the exclusive option in the management of clo-
miphene-resistant PCOS. Thereby, when deciding for those
women, alternative medical treatments (e.g., combined met-
formin–clomiphene, other insulin sensitizers, and letrozole)
as well as surgical options (e.g., transvaginal hydrolaparos-
copy) should be considered. Accordingly, the final decision
should be tailored to each woman, taking into account her
own personal values and circumstances, e.g., economics and
side effects, in addition to what are available in a country
or clinic [38].
Insulin resistance and hyperinsulinaemia are impli-
cated in the pathophysiology of PCOS. Accordingly, met-
formin has represented the landmark of PCOS therapy in
the last 20 years [39, 40]. The use of inositols, a carbocy-
clic polyol, as a pharmacological treatment for PCOS has
sparked a heated discussion since 1999 [41]. Myo-inositol
and d-Chiro-inositol are the two most commonly studied
isomers. It can serve as a precursor to second messengers
(involved in glucose action) and phospholipids in human
cells. There is accumulating evidence on this topic. Several
investigators have reported a reduction of insulin resist-
ance and hyperandrogenism and as well as improvements
of hormonal parameters, metabolic patterns, and reproduc-
tive function in PCOS women who had treatment with both
isomers [42–45]. A recent international consensus confer-
ence recommended using Myo:Chiro inositol in PCOS in a
40:1 ratio [46].
Transvaginal hydrolaparoscopy (THL) was first reported
by Fernandez et  al. [47] as a new approach for ovarian
drilling in women with PCOS (THLOD). This procedure
was done under general anesthesia. Patients were placed in
lithotomy position and 300 ml of normal saline solution was
instilled into the peritoneal cavity through the posterior vagi-
nal fornix through a Veress needle. Then, a 2.9 mm scope
with a 30° lens was inserted with an introducer sheath via a
4 mm posterior colpotomy incision. Using a 5F bipolar elec-
trosurgical probe introduced through the auxiliary channel of
the sheath, the ovarian cortex was drilled at 10–15 points at
a depth of 10 mm with a power setting of 110–130 W [47].
Subsequently, the efficacy of THLOD in terms of ovulation
and pregnancy rates in patients with clomiphene-resistant
PCOS was reported in several studies [48–52]. Thereby,
THLOD should be considered as a viable alternative to LOD
in women with clomiphene-resistant PCOS.
Noteworthy, in a case–control study on 123 women with
clomiphene-resistant PCOS, Giampaolino et al. [53] evalu-
ated the effects of THLOD on ovarian volume and power
Doppler flow indices. A significant reduction was achieved
in these parameters as compared to its preoperative values
(ovarian volume: 7.85 vs. 11.72 cm3, P < 0.01; vasculari-
zation index: 2.50 vs. 4.81, P < 0.01; vascularization flow
index: 1.10 vs. 2.16, P < 0.01; flow index: 32.05 vs. 35.37,
P < 0.01). Thereby, they hypothesized that the mechanism
of action of THLOD is similar to those occurring after LOD,
with the ovarian stromal blood flow being decreased fol-
lowing the destruction of androgen-production stroma [53].
Moreover, a significant reduction in serum AMH levels
after THLOD was also demonstrated by the same authors
in an RCT (5.84 ± 1.16 vs. 4.83 ± 1.10 ng/ml, P < 0.0001
for preoperative and postoperative AMH values, respec-
tively) [54]. However, the reduction in AMH levels after
THLOD was comparable to that after LOD (4.83 ± 1.10 vs.
5.00 ± 1.29 ng/ml for THLOD and LOD, respectively) [54].
In another interesting study, Giampaolino et al. [55] reported
significantly fewer postoperative ovarian adhesion forma-
tion in patients treated with THLOD in comparison with
those treated with LOD [15.5 vs. 70.2%, respectively, and
a relative risk of 0.22 (95% CI 0.133–0.350)]. The authors
ascribed this finding to the instillation of saline solution into
the peritoneal cavity rather than pneumoperitoneum during
THLOD and the shorter duration of the procedure [55].
The current meta-analysis has several strengths. First,
it provides quantitative estimates of the effectiveness of
ULOD vs. BLOD for improving fertility outcomes in infer-
tile women with clomiphene-resistant PCOS as well as its
effect on ovarian reserve based on the available evidence so
far in RCTs. Second, the PRISMA statement was followed to
assure a rigorous reporting methodology. Third, the eligible
RCTs had strict inclusion and exclusion criteria, and base-
line characteristics of the patients were largely comparable.
Thereby, the patient population was representative. Finally,
the Cochrane Collaboration guidelines for data extraction
and quality assessment regarding a potential risk of different
types of biases have been followed in all included studies.
Hence, we believe that the chance of reviewer bias has been
minimized.
On the other hand, this meta-analysis has several limita-
tions. First, the impact of the dose-adjusted ULOD on fertil-
ity outcomes and the ovarian reserve compared with BLOD
has been investigated only in one RCT [22] which could
influence the results. However, a sensitivity analysis with the
exclusion of this study confirmed the non-significant differ-
ence in the pregnancy rate between the two groups without
13

a significant heterogeneity across the studies. Second, the
overall quality of the evidence was rated as moderate to low.
The reasons for downgrading the evidence included poor
reporting on study methods (especially with respect to ran-
domization, allocation concealment, and blinding) and some
secondary outcome comparisons were included in only one
or two studies (Table 2). Thereby, it could be argued that the
findings of this meta-analysis should be interpreted with cau-
tion. Third, funnel plot analysis to test for publication bias
was not performed because of the relatively small number of
included studies. Such analysis warrants the inclusion of ten
or more studies in the review to be performed. Finally, this
review only had two studies with 1-year follow-up data [18,
19] and one study with 2-year follow-up data [17]; thereby,
more long-term effects remain uncertain.
Conclusions
This systematic review and meta-analysis demonstrates no
evidence of a significant difference in rates of ovulation,
pregnancy, live birth, or miscarriage when the fixed-dose
ULOD was compared with BLOD. The reduction in ovar-
ian reserve was comparable between the two procedures.
This evidence is considered of moderate-to-low quality.
Thereby, after carefully weighing up the well-known ben-
efits of BLOD against a potential risk to ovarian reserve,
clinicians could be advised to offer the fixed-dose ULOD to
their PCOS patients. This is concordant with the “primum
non nocere” principal if LOD will be envisaged. Further
research, including adequately powered and blinded RCTs,
is needed to evaluate long-term effects of the fixed-dose
ULOD, especially the ovarian reserve assessment. Larger
RCTs are awaited to investigate whether either the dose-
adjusted or fixed-dose ULOD should be used. Certainly, it
would add important data to the body of evidence.
Author contributions  All authors contributed to the development of the
manuscript and all authors consented to its submission and publication.
Specific contributions are as follows; HAH: design and institution of
the study protocol, collection, and analysis of data, drafting, review,
and final preparation of the article, and approval of the final version.
OF: design and institution of the study protocol, collection and analy-
sis of data, drafting, review and final preparation of the article, and
approval of the final version. MELR: institution of the study protocol,
analysis of data, review, and approval of the final version.
Compliance with ethical standards  12:207–212
Funding  No funding
Conflict of interest  We declare that we have no conflict of interest.
Ethical approval  Not applicable.
13
Archives of Gynecology and Obstetrics
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