European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 150–152

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

The impact of salpingectomy and single-dose systemic methotrexate

treatments on ovarian reserve in ectopic pregnancy
Cagdas Sahin a, Enes Taylan a,*, Ali Akdemir a, Banu Ozgurel b, Dilek Taskıran c,
Ahmet M. Ergenoglu a
a
Ege University School of Medicine, Department of Obstetrics and Gynecology, Bornova, Izmir, Turkey
b
Yasar University School of Science and Letter, Department of Actuarial, Bornova, Izmir, Turkey
c
Ege University School of Medicine, Department of Physiology, Bornova, Izmir, Turkey

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To investigate the effects of salpingectomy and methotrexate treatments on ovarian reserve in
Received 21 March 2016 ectopic pregnancy.
Received in revised form 21 June 2016 Study design: In this prospective study, a total of 131 patients with ectopic pregnancy were divided into
Accepted 4 August 2016
3 groups of methotrexate (MTX) only (Group-1, n: 55), salpingectomy only (Group-2, n: 61), and
salpingectomy following MTX (Group-3, n: 15). Pretreatment and post-treatment anti-Müllerian
Keywords: hormone (AMH) levels were evaluated.
Ectopic pregnancy
Results: Significant differences in AMH levels were detected between group 1 and group 2
Salpingectomy
Methotrexate
(2.52  1.28 vs. 1.96  1.66, p = 0.043), and group 1 and group 3 (2.52  1.28 vs. 1.77  0.76, p = 0.035)
Ovarian reserve at one month postoperative. However, these differences disappeared at the 3rd postoperative month. When
AMH levels were compared within the same group, postoperative one month AMH levels were significantly
lower than the preoperative AMH levels only in group 3 (p = 0.03). However, this difference also disappeared
at the 3rd postoperative month.
Conclusion: Systemic single-dose methotrexate treatment, unilateral salpingectomy, and salpingectomy
following methotrexate administration in ectopic pregnancy were reassuring based on pretreatment
and post-treatment AMH levels. Current medical and surgical treatment approaches do not have an
obvious negative effect on ovarian reserve.
ß 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction different types of ectopic pregnancies [4]. Although single-dose

Ectopic pregnancy (EP) is an important cause of maternal
mortality and morbidity that complicates 1–2% of all pregnancies
[1]. Although it can develop in various localizations outside of the
uterine cavity, the most common place for implantation is reported
as the fallopian tubes. Advancements in diagnostic and imaging
techniques have enabled early diagnosis and treatment that have
significantly decreased maternal mortality in recent decades
[2,3]. Current treatment options include medical (Methotrexate)
and surgical (salpingectomy, salpingostomy, or milking)
approaches. As a medical treatment, Methotrexate (MTX), which
is an effective chemotherapeutic agent that acts as a folic acid
antagonist targeting actively proliferating cells, is widely used for
* Corresponding author at: Ege University School of Medicine, Department of
Obstetrics and Gynecology, Bornova TR-35100, Izmir, Turkey.
Fax: +90 232 343 07 11.
E-mail address: enestaylanmd@gmail.com (E. Taylan).
systemic MTX treatment is accepted as a highly effective, non-
invasive treatment for EP, there is an important concern of adverse
effect on fertility by targeting actively dividing cells within the
ovaries. Additionally, surgical treatment may also have a negative
effect on ovarian reserve [5]. However, there are controversial
results according to the effect of MTX and surgical treatment on
ovarian reserve [5–10].
Anti-Müllerian hormone (AMH) is a special glycoprotein that is
mainly secreted by preantral and small antral follicles and detected
at relatively constant levels during different phases of the
menstrual cycle with little impact on outer determinants
[11]. Several studies have reported that AMH levels were also
correlated with the number of oocytes retrieved, the quality of
embryos and clinical pregnancy and live birth rates in patients
undergoing in vitro fertilization (IVF) treatment [12]. Therefore,
AMH level is accepted as a more reliable and objective indicator of
ovarian reserve compared with traditional measures such as FSH
level and antral follicle count (AFC) [13].

http://dx.doi.org/10.1016/j.ejogrb.2016.08.028
0301-2115/ß 2016 Elsevier Ireland Ltd. All rights reserved.
 C. Sahin et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 150–152
The aim of this study was to investigate the effects of
salpingectomy and methotrexate treatment on ovarian reserve
in ectopic pregnancy by measuring AMH levels.
Materials and methods
This research was designed as a prospective study and
conducted in the Ege University School of Medicine Department
of Obstetrics and Gynecology after approval was obtained from the
University Ethics Committee (Clinical Trials ID: NCT02714998).
From January 2013 to February 2015, 131 patients diagnosed with
EP were included in the study. Patients with a history of ovarian
surgery, endometriosis, and systemic chemotherapy that could
have a potential negative effect on ovarian reserve were excluded.
History of infertility and assisted reproduction technology (ART)
treatments were also exclusion criteria because of possible
unknown ovarian pathologies and altered ovarian physiology,
respectively. Patients who were treated with multiple doses of
MTX or underwent surgical approaches, such as salpingostomy or
milking techniques, were also withdrawn from the study.
In the present study, patients were enrolled into 3 groups with
the treatment indications of ectopic pregnancy [14]. Patients who
were clinically stable and with b-hCG levels <10,000 IU/ml,
without visible fetal cardiac activity on ultrasound or adnexal fetal
mass >4 cm in size selected for systemic single dose of MTX
treatment. After observation of normal renal and liver function
tests, a single dose of systemic MTX (50 mg/m2) was administrated
and b-hCG levels were measured on the 4th and 7th days of MTX
treatment. A greater than 15% reduction in levels was accepted as
successful medical treatment and these patients were assigned to
group 1 (MTX only). Patients who did not fulfill the criteria or those
who were hemodynamically unstable underwent the laparoscopic
unilateral salpingectomy procedure directly and were assigned to
group 2 (salpingectomy only). Patients with unsuccessful systemic
single-dose MTX administration subsequently underwent laparo-
scopic unilateral salpingectomy and composed group 3 (salpin-
gectomy following MTX). Altogether, groups of MTX only (group
1), salpingectomy only (group 2), and salpingectomy following
single dose of MTX (group 3) were consisted of 55, 61, and
15 patients, respectively.
All patients’ demographic profiles (age, smoking status, body
mass index, gravid, parity) were recorded. To determine the
ovarian reserve pretreatment and in the 1st and 3rd months after
treatment, AMH plasma levels were assayed using the Gen II ELISA
(Beckman Coulter Inc., CA, USA) commercial kit according to the
manufacturer’s instructions and the results are presented in ng/ml.
Quantitative data were tested for normality using the
Kolmogorov–Smirnov test. Normally distributed variables were
compared using one-way ANOVA followed by the Bonferroni post
hoc test to assess differences. Non-normally distributed variables
were compared using the Kruskal–Wallis test. SPSS statistical
software, version 11 was used for statistical analysis. A P value of
<0.05 was considered to indicate statistical significance.
Results
A total of 131 patients diagnosed with EP were involved in this
research. Patient age, body mass index (BMI), smoking, gravid,
parity, pretreatment AMH levels and post-treatment (1st and 3rd
months) AMH levels were the parameters evaluated
(Tables 1 and 2). There were no statistically significant differences
between the 3 groups according to demographic features including
age, smoking, BMI, and parity. There were no differences between
the 3 groups according to pretreatment AMH levels (p = 0.213).
Comparing the AMH levels after treatment, there were only
significant differences in levels of post-treatment AMH at the 1st
151
Table 1
Comparison of patient characteristics and AMH levels.
Group-1 Group-2 Group-3 P value
(n: 55) (n: 61) (n: 15)
Age (years) 29.6  4.04 30.9  4.76 28.1  5.84 0.083a
Gravid 1.75  1.23 2.41  1.87 1.27  1.28 0.014a
Parity 0.8  0.84 0.75  0.86 0.53  0.74 0.547b
Smoking 11 (20%) 15 (24.6%) 3 (20%) 0.071b
BMI (kg/m2) 24.6  4.15 24.8  4.05 24.4  3.79 0.909a
a
One-way ANOVA test was used.
b
Kruskal–Wallis test was used. Data are expressed as mean  standard deviation.
month in groups of 1 vs. 2 and 1 vs. 3 (p = 0.043 and p = 0.035,
respectively). However, these differences disappeared at the 3rd
month after treatment.
We also compared pretreatment and post-treatment AMH level
changes in each group of patients and only found statistically
significant decrease in AMH levels in group 3 patients after the 1st
month of treatment compared with pretreatment levels (p = 0.03).
However, similar to the other differences mentioned above, this
difference disappeared at the 3rd month after treatment.
Discussion
Despite the increasing incidence of EP since the mid-twentieth
century due to numerous factors, advancements in early diagnosis
and treatment have decreased maternal morbidity and mortality
[2]. As the current treatment options are focused on decreasing the
mortality and morbidity related to EP, fertility preservation is
another important issue for reproductive-aged women. Therefore,
management of treatment approaches for these patients can be
challenging according to potential risks for ovarian reserve.
However, there are controversial study results in the literature.
Uyar et al. reported that there was no significant effect of single-
dose MTX treatment on ovarian reserve [6]. Also, Boots et al.
investigated the effect of single-dose MTX administration for EP
after in vitro fertilization (IVF) on ovarian reserve and concluded
that it does not compromise ovarian reserve, responsiveness or
subsequent IVF success [7]. Similar results were reported in a large
cohort study by Hill et al. [8]. They concluded that the number of
doses of MTX treatment was not correlated with the change in
values of FSH, AFC, and oocyte yield. However, Ulug et al. proposed
the opposite in their study. They stated that single or multiple
doses of MTX combined with salpingectomy decreases ovarian
reserve markers including AMH and follicle counts [9]. In a recent
article by Ye et al. the effect of salpingectomy on ovarian reserve
was retrospectively evaluated in a study group of 198 patients who
underwent unilateral or bilateral salpingectomy before IVF
treatment. They proposed that salpingectomy has a negative
effect on ovarian reserve [5]. On the contrary, Lin et al. proposed
that salpingectomy has no effect on ovarian reserve [10]. In
addition to this, Almog et al. asserted that salpingectomy does not
influence ovarian response in controlled ovarian hyperstimulation
for IVF treatment [15].
Chemotherapy and radiotherapy treatments for various malig-
nancies in reproductive-aged women have shown that ovarian
reserve is decreased in a dose-dependent manner [16]. MTX, which
is a folic acid antagonist acting as an inhibitor of nucleic acid
synthesis and cell division, is a commonly used chemotherapeutic
agent that is associated with early ovarian failure in childhood
cancer survivors [17]. Also, salpingectomy is suggested as a
negative effector of ovarian reserve, possibly due to a decrease in
ovarian blood supply through the ascending branch of the uterine
artery in the mesosalpinx [18].
In our study, we showed that there were no significant effects
on ovarian reserve comparing single-dose MTX treatment and
152 C. Sahin et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 150–152
Table 2
Comparison of patient AMH levels.
Group-1
(n: 55)
Pretreatment AMH level (ng/ml) 2.52  1.40
Post-treatment AMH level – 1 month (ng/ml) 2.52  1.28
Post-treatment AMH level – 3 months (ng/ml) 2.62  1.25
a
One-way ANOVA test was used.
b
Post hoc Bonferroni test was used. Data are expressed as mean  standard deviation.
salpingectomy based on a highly accepted ovarian reserve test of
AMH measurement. Although the early period after treatment
demonstrated a significant decrease of AMH in salpingectomy only
and salpingectomy following single-dose MTX treatment, in the
late period of the third month, this finding disappeared. This fact
indicates the quite likely reversible effect of altered blood flow
secondary to salpingectomy on ovarian germinal cells. One of the
limitations of our study was that we could not make an inference
about the impact of multiple doses of MTX treatment on ovarian
reserve and fertility outcomes compared with salpingectomy, as
we excluded these patients in order to simplify and consolidate the
study design.
In accordance with previous studies, we also demonstrated that
salpingectomy following MTX treatment has no significant effect
on ovarian reserve by comparison with MTX only and salpingect-
omy only. However, a relatively low number of patients who
underwent salpingectomy following single-dose MTX treatment is
the second limitation of this study.
As a conclusion, based on the results of the majority of studies
and our present study, current applications of single-dose systemic
MTX treatment and laparoscopic unilateral salpingectomy are safe
treatment options for EP with no obvious harmful effect on ovarian
reserve.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
This study was supported by the Ege University School of
Medicine Scientific Research Projects Fund, under the project code
of 2013-TIP-043.
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