International Journal of Womens Health

Dovepress
open access to scientific and medical research

REVIEW

Open Access Full Text Article

Potential role of aromatase inhibitors

in the treatment of endometriosis

Hatem Abu Hashim

Department of Obstetrics and
Gynecology, Faculty of Medicine,
Mansoura University, Mansoura, Egypt

Abstract: Endometriosis is an estrogen-dependent chronic inflammatory disease affecting

5%10% of reproductive-age women, with a prevalence of 5%50% in infertile women
and 33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs)
are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular
studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis
of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol.
Thereby, AIs represent an appealing medical option for the management of different aspects
of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims
to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms,
mainly pain and infertility. Notably, several studies have demonstrated that the combination of
AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing
hormone analogs can be used to control endometriosis-associated pain and pain recurrence in
premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory
to other medical or surgical treatment. Some case reports have shown promising results in the
treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation
AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent
in patients with polycystic ovary syndrome and in cases of unexplained infertility. However,
few studies are available regarding the use of AIs to treat endometriosis-associated infertility.
Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosisassociated infertility are needed to clarify its effect. The safety of AIs for ovulation induction or
superovulation has generated a lively discussion. Data from recent retrospective and prospective
studies have supported its safety.
Keywords: endometriosis, aromatase inhibitors, letrozole, anastrozole, pelvic pain,
infertility

Introduction
Correspondence: Hatem Abu Hashim
Department of Obstetrics and
Gynecology, Faculty of Medicine,
Mansoura University, 60 El Gomhoria
Street, Mansoura, Dakahlia 35516, Egypt
Tel 20 50 230 0002
Fax 20 50 222 5838
Email hatem_ah@hotmail.com

Endometriosis is an estrogen-dependent chronic inflammatory disease affecting the

health and well-being of 5%10% of women of reproductive age,1 with a prevalence
of 5%50% in infertile women and 33% of women with chronic pelvic pain.2,3
Endometriosis is characterized by the presence of ectopic endometrial implants
typically occurring in the pelvis, most commonly in the ovaries, pelvic peritoneum,
uterosacral ligaments, pouch of Douglas, and rectovaginal septum. Patients can present
with a wide range of symptoms; however, the cardinal clinical features are infertility
and chronic pelvic pain.4

671

submit your manuscript | www.dovepress.com

International Journal of Womens Health 2014:6 671680

Dovepress

2014 Abu Hashim. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution Non Commercial (unported, v3.0)
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
how to request permission may be found at: http://www.dovepress.com/permissions.php

http://dx.doi.org/10.2147/IJWH.S34684

Dovepress

Abu Hashim

The definitive pathogenesis of endometriosis is still

unknown, but retrograde menstruation, proposed by Sampson
in the 1920s, is still considered the most widely accepted
theory, although many points remain poorly understood concerning this theory.5 Of note, the incidence of retrograde menstruation is similar in women with and without endometriosis,
so the pathogenesis seems to be a multifactorial mechanism
comprising functionally different endometrial tissue in addition to altered immunity and other molecular abnormalities
allowing the survival of the regurgitated endometrial debris.
Subsequently, these endometrial implants go through various
sequential events for the disease to develop.5,6 As endometriosis is an estrogen-dependent disease, conventional treatments
utilized for many years aimed to act indirectly to create an
estrogen-deficient state, eg, gonadotropin-releasing hormone
agonists (GnRHas) and combined oral contraceptive pills
or counteracting estrogen action, eg, progestins, eventually
resulting in inhibition of the endometrial implant growth and
alleviation of symptoms.4
Aromatase P450 is the key enzyme for ovarian estrogen
biosynthesis. It catalyzes the conversion of androstenedione
and testosterone produced in the ovarian theca cells to estrone
and estradiol (E2) in the ovarian granulose cells. Recently,
there has accumulated a body of evidence demonstrating
that endometriotic lesions express aromatase and are able to
synthesize their own E2.5,7,8 In view of this observation, the
use of aromatase inhibitors (AIs) for the management of
endometriosis is an appealing concept. Accordingly, this
review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, particularly
pain and infertility.

Materials and methods

A PubMed search was carried out to identify all the published studies evaluating the efficacy of AIs in treating
endometriosis-associated pain and endometriosis-associated
infertility with the following keywords: endometriosis,
aromatase inhibitors, letrozole, anastrozole, pelvic pain,
and infertility. The last search update was on February 28,
2014. No search limits were used. All relevant articles were
identified and assessed for quality, and their reference lists
were checked in order to identify other studies for potential
inclusion in this review. Relevant evidence was selected for
inclusion in the following order: meta-analyses, systematic
reviews, different guidelines, randomized controlled trials
(RCTs), and prospective cohort studies, followed by other
observational studies, nonsystematic reviews, case series,
and reports.

672

submit your manuscript | www.dovepress.com

Dovepress

Types of aromatase inhibitors

The aromatase P450 enzyme is present in high levels in the
ovarian granulose cells of premenopausal women; meanwhile,
adipose tissue is a major site of aromatase expression in postmenopausal women.9 AIs were first used for the treatment of
postmenopausal estrogen receptor-positive advanced breast
cancer owing to their ability to reduce estrogen production
by inhibition of the aromatase P450 enzyme. Accordingly,
they have the potential to treat estrogen-dependent conditions,
such as endometriosis.8,10
AIs are present in three generations (Figure 1).
Aminoglutethimide, a first-generation inhibitor, induces a
medical adrenalectomy that results in many side effects,
such as lethargy, skin rashes, and nausea. Fadrozole and
formestane are more selective second-generation inhibitors with fewer side effects; however, the only route of
administration is intramuscular. Letrozole, anastrozole, and
exemestane are the third generation of AIs. Letrozole and
anastrozole are triazole derivatives characterized by being
selective, reversible, and potent AIs. Given orally at doses of
15 mg/day, they inhibit estrogen levels by 97% to more than
99%;1113 meanwhile, exemestane is a steroidal irreversible
AI effectively working at a dose of 25 mg/day.12,14

Aromatase inhibitors
from a pathophysiological
perspective of endometriosis
AIs appear to represent a new promising alternative for treatment of endometriosis through the alteration of mechanisms
involved in the molecular development of endometriosis.5,7,8
Aromatase P450/prostaglandin E2 (PGE2) represents an
important pathway involved in the development of endometriotic implants (Figure 2). Aromatase activity is not
detectable in normal endometrium; however, it is expressed
inappropriately in the eutopic endometrium from women
Aromatase inhibitors
1st

Aminoglutethimide

2nd

Fadrozole
Formestane

3rd

Letrozole
Anastrozole
Exemestane

Figure 1 Generations of aromatase inhibitors.

International Journal of Womens Health 2014:6

Dovepress

Aromatase inhibitors and endometriosis

Retrograde menstruation
Endometriotic
implant
Aromatase P450/PGE2 pathway

17
HSD1

Androstenedione
Aromatase
E1
17
HSD2
E2
++

Apoptosis
Angiogenesis

Altered immune
responses

PGE2
Inflammation & proliferation

Growth of endometriotic implant

Figure 2 Aromatase P450 and pathophysiology of endometriosis.

Notes:  upregulatation; l, increase; n, decrease.
Abbreviations: E1, estrone; E2, estradiol; PGE2, prostaglandin E2; HSD1, hydroxysteroid dehydrogenase type 1 enzyme; HSD2, hydroxysteroid dehydrogenase type
2 enzyme.

with endometriosis. Accordingly, the eutopic endometrium

represents an intracrine source of estrogen. Of note, estrogen
is known to upregulate PGE2, which is a potent inducer of
aromatase activity in endometriotic cells. Thereby, in view of
this abnormal independent estrogen biosynthesis, a positive
feedback loop is formed, leading to repeated proliferation
and inflammation within endometriotic deposits, favoring
endometriotic deposits survival in addition to other various
mechanisms, such as altered immune responses, angiogenesis, and apoptosis.5,7,8 Importantly, the locally produced
estrogen within these endometriotic deposits is mainly the
potent E2 rather than the less biologically active estrone. This
has been attributed to a defective function of stromal cells of
endometriosis, resulting in failure to induce the expression
of the epithelial 17B-hydroxysteroid dehydrogenase type 2
enzyme (17B-HSD2) responsible for the conversion of E2 to
estrone.5,15,16

Aromatase inhibitors for

endometriosis-associated pain
Being an estrogen-dependent chronic inflammatory disease,
endometriosis requires a life-long management plan with
the goal of maximizing the use of medical treatment and
avoiding repeated surgical procedures. Additionally, it is
vexing to both clinicians and patients to treat cases with
recurrent or pain resistant to standard regimes.17 The hormonal drugs investigated combined oral contraceptives,
danazol, gestrinone, medroxyprogesterone acetate and
GnRHas are equally effective, but their adverse effects and
cost profiles differ.18

International Journal of Womens Health 2014:6

The proof that AIs can be effective in alleviating chronic

pelvic pain associated with endometriosis in premenopausal
women stems from its molecular basis. Since endometriotic
implants respond not only to ovarian E2 but also to extraovarian
E2 synthesized by aromatase pathways, standard management,
such as GnRHas, which effectively downregulates ovarian E2
biosynthesis, has little impact on extraovarian E2 production.
In this context, AIs will downregulate extraovarian E2 synthesis, which in turn stimulates ovarian E2 production through
initiation of the follicle-stimulating hormone (FSH) surge.
Accordingly, AIs were combined with standard regimes to
suppress both ovarian and extraovarian E2.1921
There are two systematic reviews in the literature
that examined the potential of AIs for the treatment of
endometriosis-associated pain22,23 (Table 1). Nawathe et al22
looked at eight studies (137 women in total).20,21,2429 Of these,
seven studies were case series/reports of only 40 women,20,2429
and only one was an RCT of 97 women.21 Analysis of the
case series/reports showed that AIs combined with progestins
or the oral contraceptive pill or GnRHas reduced mean pain
scores and lesion size and improved quality of life. Results
from the RCT demonstrated that AIs in combination with
GnRHas for 6 months duration (3.6 mg goserelin 1 mg
anastrozole) significantly improved pain (P0.0001) compared with GnRHas (3.6 mg goserelin) alone, together with
significant improvement in multidimensional patient scores
(P0.0001). Of note, there was no significant reduction in
spine or hip-bone densities. The authors concluded that AIs
appear to have a promising effect on pain associated with
endometriosis, but they admitted the poor quality of evidence
included in their review.22
The second systematic review was conducted recently
by Ferrero et al.23 They identified ten studies with a total of
251 women.1921,28,29,3034 At least ten patients in each study
were considered for inclusion. Five studies were prospective
noncomparative,20,2831 four were RCTs,21,3234 and one was a
prospective patient-preference trial.19 Notably, seven studies
looked at the efficacy of AIs in improving endometriosisrelated pain symptoms, while three RCTs examined the use
of AIs as postoperative therapy in preventing the recurrence
of pain symptoms after surgery for endometriosis.
All the prospective noncomparative studies found
that AIs combined with either progestins or the oral
contraceptive pill reduce the severity of pain symptoms
and improve quality of life.20,2831 The patient-preference
study reported that letrozole plus norethisterone acetate is
more effective in reducing pain and deep dyspareunia than
norethisterone acetate alone. Adverse effects of treatment

submit your manuscript | www.dovepress.com

Dovepress

673

Dovepress

Abu Hashim

Table1 Summary of systematic reviews evaluating the efcacy of aromatase inhibitors in treating endometriosis-associated pain
Study

Sample size

Results

Intervention

Nawathe et al

Eight studies (137 women):

7 case series/reports (n40)
and 1 RCT (n97)

AIs appeared to have a promising effect

on endometriosis-associated pain, but
poor quality of included evidence is to
be considered.

Ferrero et al23

10 studies (n251 women):

5 prospective noncomparative,
4 RCTs, and 1 prospective
patient-preference trial

v In case series/reports, AI plus progestins or

oral contraceptive pill or GnRHas reduced
mean pain scores and lesion size and improved
quality of life.
v In the RCT, AIs plus GnRHas signicantly
improved pain and multidimensional patient
scores compared with GnRHas alone, but no
signicant reduction in bone mineral density.
v In prospective noncomparative studies, AIs
combined with either progestins or oral
contraceptive pill reduced the severity of pain
symptoms and improved quality of life.
v In patient-preference study, letrozole plus
norethisterone acetate was more effective
in reducing pain and deep dyspareunia than
norethisterone acetate alone.
v In 1 RCT, letrozole plus norethisterone acetate
resulted in a lower incidence of side effects and
lower discontinuation rate than letrozole plus
triptorelin (a GnRHa).
v In 2 of the 3 RCTs, postoperative AIs plus
GnRHas for 6 months reduced the risk of
recurrence of endometriosis compared with
GnRHas alone.

22

AIs effectively reduced the severity of

endometriosis-related pain symptoms;
however, their long-term efcacy,
adverse effects, and patient satisfaction
warrant further investigations.

Abbreviations: RCT, randomized controlled trial; AI, aromatase inhibitor; GnRHa, gonadotropin-releasing hormone agonist.

were significantly more frequent in patients treated with

the double-drug regimen than in those receiving norethisterone acetate alone (43.2% versus 18.4%, respectively;
P0.020). At the completion of treatment, no significant
difference was observed in patient satisfaction between the
two study groups (56.1% of those receiving the doubledrug regimen and 63.4% of the patients receiving norethisterone acetate alone were either satisfied or very satisfied
with their treatment). Pain symptoms quickly recurred
at 6- and 12-month follow-up after the discontinuation
of treatment without significant differences between the
two study groups.19
Treatment with letrozole plus norethisterone acetate
resulted in a lower incidence of side effects and lower discontinuation rate than letrozole plus triptorelin (a GnRHa),
as demonstrated in one RCT.34 Two RCTs reported that the
use of postoperative AIs plus GnRHas for 6 months reduced
the risk of recurrence of endometriosis when compared
with GnRHas alone.21,33 Ferrero et al23 concluded that AIs
effectively reduce the severity of endometriosis-related pain
symptoms. Additionally, they recommended more trials to
investigate whether the long-term administration of AIs is
superior to the currently available endocrine therapies in
terms of improvement of pain, adverse effects, and patient
satisfaction.

674

submit your manuscript | www.dovepress.com

Dovepress

More recently, the endometriosis guideline published

by the European Society of Human Reproduction and
Embryology demonstrated that the existing evidence from
the aforementioned two systematic reviews was of moderate
quality. Owing to the severe side effects identified, including
vaginal dryness, hot flushes, and diminished bone mineral
density (BMD), the society recommended that
In women with pain from rectovaginal endometriosis
refractory to other medical or surgical treatment, clinicians
can consider prescribing aromatase inhibitors in combination with oral contraceptive pills, progestagens, or GnRH
analogues, as they reduce endometriosis-associated pain

(grade B recommendation).35,36

The use of AIs for the treatment

of postmenopausal endometriosis
It is noteworthy that evidence regarding the use of AIs
in postmenopausal endometriosis is rather limited compared to premenopausal patients, mainly due to the lower
prevalence of the disease among postmenopausal patients.
In a review article, Oxholm et al37 demonstrated that only
Punnonen et al,38 Henriksen,39 and Ranney40 investigated the
prevalence of endometriosis in postmenopausal women, and
reported prevalences of 2.2%, 3.7%, and 4.8%, respectively,

International Journal of Womens Health 2014:6

Dovepress

in populations of woman diagnosed with endometriosis.

Accordingly, Oxholm et al37 estimated that endometriosis
can affect between 2% and 5% of postmenopausal patients.
In this subset of patients, surgery is preferred as first-line
treatment for possible risk of malignancy or malignant
transformation.41,42 However, recurrence rates are increased
after surgery,25 and not all patients are suitable candidates
for surgery. Therefore, medical treatment is worth trying in
these circumstances.
In view of their ability to downregulate estrogen production via inhibition of aromatase P450, AIs were first used for
the treatment of postmenopausal estrogen receptor-positive
advanced breast cancer.10 In this context, estrogen activity
in postmenopausal women is related only to the production
from extraovarian sources, mainly adipose tissue via aromatization of androgens produced from the adrenal glands,43
or from exogenous administration as hormonal replacement
therapy.44,45 Consequently, AIs appear to be effective in treating postmenopausal endometriosis through the blockade of
extraovarian estrogen production compared to traditional
treatments with GnRHas, progestins, and danazol.25,27
At present, there are no RCTs available in the literature assessing the use of AIs in postmenopausal patients.
Currently available evidence is limited to case reports only.
Polyzos et al12 reviewed five case reports looking at the potential of AIs for the treatment of postmenopausal endometriosis
in which patients age ranged from 47 to 61 years.25,27,4648
Of note, all patients had either surgical (ie, underwent total
abdominal hysterectomy and bilateral oophorectomy at an
earlier age)25,27,46,47 or natural menopause.48 In addition, most
of them received hormonal replacement therapy and had been
previously treated for endometriosis with either surgery,
GnRHas, or progestins.
Polyzos et al12 demonstrated that the use of letrozole or
anastrozole in all treated patients resulted in improvement
of endometriosis-associated pain over a treatment period of
415 months. Additionally, letrozole appeared to improve
urinary tract and bowel symptoms related to endometriosis.
Notably, letrozole but not exemestane had significant beneficial effect on symptom relief in one patient; however,
the latter was utilized for only 15 days.46 Additionally, AIs
significantly reduced the size of the endometriotic lesions,
as measured by imaging techniques. Only one case with
ureteral endometriosis did not respond to a 15-month course
of anastrozole therapy, due to extensive ureteral fibrosis
necessitating further surgery.47
In this review, Polyzos et al12 identified only one patient
who suffered from hot flushes after 4 months of letrozole

International Journal of Womens Health 2014:6

Aromatase inhibitors and endometriosis

administration, who improved after coadministration of

micronized E2 0.5 mg daily without pain recurrence. Two
patients received bisphosphonates, and one of them reported
a mild reduction in BMD following 9 months treatment
with 1 mg anastrozole. The authors concluded that AIs may
represent a promising new treatment for postmenopausal
endometriosis, either as first-line treatment, when surgery is
contraindicated, or as a second line in the case of postoperative recurrence. However, they admitted careful assessment
of patients risk profiles and further research to clarify the
long-term effects and side effects of these agents.12

Aromatase inhibitors for

endometriosis-associated infertility
In advanced stages of endometriosis (revised American
Society for Reproduction Medicine [ASRM] stage III/IV
endometriosis), infertility could be attributed to extensive
adhesions with distorted pelvic anatomy. However, the
mechanisms of infertility associated with minimalmild
endometriosis (ASRM stage I/II endometriosis) remain
controversial. Many factors have been raised, including
abnormal folliculogenesis, elevated oxidative stress, altered
both immune functions as well as hormonal milieu in the
follicular and peritoneal environments, and reduced endometrial receptivity. These factors lead to poor oocyte quality,
impaired fertilization, and implantation.49,50 Accordingly,
infertility associated with minimalmild endometriosis represents a therapeutic dilemma.51 Evidence to date indicates that
ovulation suppression with medical therapy is not beneficial
for endometriosis-associated infertility and should not be
offered.35,36,52,53 On the other hand, ablation of endometriotic
lesions plus adhesiolysis improves fertility in minimalmild
endometriosis.18,35,36,53,54
There is some evidence from RCTs that intrauterine
insemination together with controlled ovarian stimulation instead of expectant management may be effective in
improving live-birth rates in patients with minimalmild
endometriosis.35,36,55,56 In a retrospective controlled study,
Werbrouck et al57 concluded that performing intrauterine
insemination with controlled ovarian stimulation within
6 months after surgical treatment in infertile women with
minimalmild endometriosis may be beneficial, since pregnancy rates were similar to those achieved in unexplained
infertility. Notably, the effect appears to be predominantly
due to ovarian stimulation, since intrauterine insemination
alone may not be beneficial.35,36,58
Third-generation AIs, especially letrozole, have been
introduced as a new treatment modality in the armamentarium

submit your manuscript | www.dovepress.com

Dovepress

675

Dovepress

Abu Hashim

of ovulation-inducing agents for anovulatory infertile women

in 2001.59 Letrozoles ovulation-inducing effects have been
attributed to the inhibition of androgenestrogen conversion, thus releasing the hypothalamuspituitary axis from
negative feedback and increasing secretion of pituitary
FSH. Additionally, increased follicular sensitivity to FSH
owing to increased intrafollicular androgens was reported
as a peripheral working mechanism.60,61 Letrozole is usually
given orally at doses of 2.57.5 mg/day for 5 days, from the
third to the seventh day of the menstrual cycle.62
Compared with clomiphene citrate (CC), letrozole downregulates E2 synthesis rather than competitively inhibiting
its action. Additionally, letrozole has a relatively shorter
half-life (^2 days versus ^2 weeks in CC), thereby avoiding
the peripheral antiestrogenic effects commonly associated
with CC on the endometrium and cervical mucus. With this
background, it was postulated that AIs may have superior
ovulation-induction properties in terms of follicular growth
and endometrium development, which are important for
embryo implantation.60,61 Accordingly, letrozole has challenged CC as an ovulation-induction agent in patients with
polycystic ovary syndrome,62,6366 and in cases of unexplained
infertility.62,66,67
According to the present state of knowledge, several
studies have reported that the combination of AIs with
conventional therapy may result in improvement of
endometriosis-associated pain, as declared earlier. However,
few studies are available regarding the use of AIs to treat
endometriosis-associated infertility (Table 2).
In a prospective RCT, Alborzi et al33 compared the
pregnancy rate and recurrence of symptoms and signs in

144 endometriotic patients who received medical therapy

for 2 months after laparoscopic surgery, with a 12-month
follow-up period after restoration of the regular cycle.
Patients were divided into three groups: group 1 (47 cases),
who received letrozole 2.5 mg/day; group 2 (40 patients),
who had triptorelin (GnRHa) 3.75 mg intramuscularly
every 4 weeks; and group 3 (57 patients), who received no
medication. There were no statistically significant differences reported among the three groups with regard to the
pregnancy rate (23.4% in group 1 versus 27.5% and 28.1%
in groups 2 and 3, respectively) or disease-recurrence rate
(6.4% in group 1 versus 5% and 5.3% in groups 2 and 3,
respectively). Notably, laparoscopy with histological confirmation of endometriosis was carried out for all patients;
meanwhile, recurrence was defined by recurrent symptoms
only (in the form of dysmenorrhea, dyspareunia, and pelvic
pain). The authors found that functional cysts developed in
24.3% in the letrozole group compared with only 2.5% in
the triptorelin group and none of the third group, and the
difference was statistically significant (P0.001). Overall,
the authors concluded that after considering the cost and side
effects of those short-term medications, their prescription
was not recommended.
In a recent RCT, Abu Hashim et al68 evaluated pregnancy
rates following superovulation with either letrozole or CC
(combined with intrauterine insemination) in 136 women
with primary infertility who had not achieved pregnancy
612 months after laparoscopic treatment for minimalmild
endometriosis. Women were randomized to 5 mg/day letrozole
(69 women, 220 cycles) or 100 mg/day CC (67 women, 213
cycles) for 5 days, combined with intrauterine insemination

Table 2 Summary of recent studies evaluating the efcacy of aromatase inhibitors in treating endometriosis-associated infertility
Study

Design

Indication

Intervention

Outcome

Alborzi et al33

RCT (n144)

Laparoscopic and histological

diagnosis of endometriosis

Abu Hashim
et al68

RCT (n136)

Minimal/mild endometriosis,
no pregnancy 612 months
after laparoscopy

Letrozole 2.5 mg/day versus

triptorelin 3.75 mg IM every month
versus no medication for 2 months
after laparoscopic surgery, with a
12-month follow-up
Letrozole versus CC
Combined with IUI

Lossl et al69

Prospective pilot
study (n20)

Patients with endometriomas

undergoing IVF/ICSI

No signicant differences among the

3 groups with regard to the pregnancy
rate (23.4% versus 27.5% and
28.1%, respectively) or the diseaserecurrence rate
Letrozole is not more effective than
CC, as clinical pregnancy rate per
cycle and cumulative pregnancy rate
after 4 cycles were comparable in
both groups; total number of follicles
and E2 higher in CC group
Signicant reduction of endometriomal
volume and serum CA125 by 29%
and 61%, respectively; 25% clinical
pregnancy rate and 15% live-birth rate

Prolonged combined
downregulation by anastrozole
1 mg and goserelin 3.6 mg prior
to IVF

Abbreviations: RCT, randomized controlled trial; IM, intramuscularly; CC, clomiphene citrate; IUI, intrauterine insemination; E2, estradiol; IVF, in vitro fertilization;
ICSI, intracytoplasmic sperm injection.

676

submit your manuscript | www.dovepress.com

Dovepress

International Journal of Womens Health 2014:6

Dovepress

for up to four cycles. Although the total number of follicles

and serum E2 on the day of human chorionic gonadotropin
administration were significantly higher in the CC group,
the clinical pregnancy rate per cycle and the cumulative
pregnancy rate after four cycles were comparable in both
groups (15.9% versus 14.5% and 64.7% versus 57.2% in the
letrozole and CC groups, respectively). Two twin pregnancies occurred in the CC group. In addition, miscarriage and
live-birth rates were also comparable between both groups
(11.4% versus 12.9% and 44.9% versus 40.3% in the letrozole
and CC groups, respectively). From this study, we concluded
that superovulation with letrozole is not more effective than
CC combined with intrauterine insemination for women with
minimalmild endometriosis who have not achieved pregnancy after 612 months following laparoscopic treatment.
In a prospective pilot study of 20 infertile patients with
endometriomas undergoing in vitro fertilization (IVF)/
intracytoplasmic sperm injection, Lossl et al69 tested the effect
of prolonged combined downregulation by anastrozole and
GnRHas prior to IVF based on the concept that this combined regimen may efficiently suppress estrogen biosynthesis
through a combined pituitary, ovarian, peripheral, and in situ
action. Patients received goserelin 3.6 mg subcutaneously
on treatment days 1, 28, and 56, and one daily tablet of
anastrozole 1 mg from day 1 to day 69. Controlled ovarian
stimulation was initiated from day 70. The primary outcome
measure was signs of inactivation of the endometriosis during
downregulation, such as decreased endometriomal volume
and serum CA125 level. Secondary outcomes were evaluation of standard IVF parameters, including pregnancy and
delivery rates, as well as endocrine response.
Interestingly, the authors found that prolonged combined
anastrozole and goserelin downregulation significantly
reduced endometriomal volume and serum CA125 level. The
median change in endometriomal volume was minus 29%
(95% confidence interval: 339%, P =0.007) and the CA125
level was reduced by 61% (95% confidence interval: 2174%,
P =0.001) from day 1 to day 70. In the IVF/intracytoplasmic sperm-injection cycle, the median number of oocytes
retrieved was 7.5 (range 6.010.0) and the fertilization rate
was 0.78 (range 0.381.0). Notably, nine of the 20 patients
(45%) conceived. Four of them were biochemical pregnancies, another two patients had early spontaneous abortions,
and only three patients (15%) delivered healthy children (two
singletons and one twin). The observed high pregnancy loss
(six patients) could have been accidental, but impaired quality
of the oocytes and/or the endometrium following prolonged
combined downregulation should be considered. The authors

International Journal of Womens Health 2014:6

Aromatase inhibitors and endometriosis

admitted the need for further adequately powered RCTs to

test possible enhanced endometriosis inactivation and signs
of improved IVF-cycle outcome by this combined anastrozole
and goserelin downregulation compared to downregulation
by the agonist alone.69
No serious adverse events were reported in this study.
Attacks of flare-up in the form of vaginal spotting/bleeding
occurred in 16 women (80%), two women (10%), and one
woman (5%) after the first, second, and third injections of
goserelin 3.6 mg, respectively, with functional ovarian cysts
demonstrated by ultrasound. This could be attributed to the
profound suppression of E2 during the combined treatment,
which may have activated pituitary FSH secretion to a higher
extent than treatment with the agonist alone.69

Side effects of aromatase inhibitors

The side effects associated with the use of third-generation
AIs (letrozole, anastrozole) are mostly hypoestrogenic in
nature, and include vaginal dryness, hot flushes, headache,
back pain, leg cramps, and arthralgia. However, its long-term
use is associated with increased risks of osteoporosis and
fracture rate owing to diminished BMD.11,12 Fracture rates of
2%11% have been reported in some studies in which AIs
were utilized as adjuvant therapy for hormone receptor-positive breast cancer patients.70,71 Notably, the American Society
of Clinical Oncologists recommends that BMD screening
should be repeated annually for breast cancer patients using
AI adjuvant therapy, and bisphosphonate therapy should be
administered when measurement of the BMD in terms of
T-score are 2.5 or lower.72
Other studies evaluated the use of add-back therapy with
progestins and oral contraceptive pills in premenopausal
women, and demonstrated no significant changes in BMD
during their use.20,28 However, another trial showed that the
use of goserelin (GnRHa) plus anastrozole resulted in significant bone loss after 6 months of treatment compared to
goserelin-alone therapy, and that this effect persisted even
after cessation of treatment. However, none of these patients
became osteopenic or osteoporotic.21

Safety of aromatase inhibitors

The safety of AIs for ovulation induction or superovulation has
generated a lively discussion. A poorly done abstract published
by the ASRM in 2005,73 which never resulted in a paper, raised
concerns of increased cardiac and bone malformations in newborns of letrozole-treated pregnancies compared with controls.
However, there were numerous issues regarding the methodology of this report. The control group was strongly criticized,

submit your manuscript | www.dovepress.com

Dovepress

677

Dovepress

Abu Hashim

being chosen from a database of normal deliveries (36,050

deliveries) that would have had a lower risk of pregnancy
complications and congenital malformations than an infertile
population. Moreover, there was an apparent underrepresentation of congenital anomalies in this control group, since babies
identified as abnormal on prenatal ultrasound were delivered at
a tertiary care hospital rather than a community hospital.74
Subsequently, two retrospective studies did not confirm
the initial findings of increased teratogenicity in pregnancies
achieved with AIs.74,75 In a large multicenter retrospective
study, Tulandi et al75 reviewed 911 newborns conceived after
infertility treatment. Notably, they found the rate of congenital malformations and chromosomal abnormalities was
not significantly different, but slightly higher, in newborns
from CC-treated compared with letrozole-treated women
(4.8% versus 2.4%, respectively). Particularly, the major cardiac congenital abnormality rate (eg, ventricular septal defect,
transposition of great vessels, right ventricle atresia, pulmonary valve atresia) was significantly higher with CC than with
letrozole (1.8% versus 0.2%, respectively; P0.02).75 Another
retrospective study by Forman et al74 looked at 477 newborns,
and reported fewer malformations with letrozole (0) than
with CC (2.6%) or spontaneous pregnancy (3.2%). Notably,
a recent randomized trial assessing pregnancy outcomes after
treatment with AIs in 796 infertile women confirmed the
positive results for the safety for newborns from the previous two retrospective studies.76 Taken together, the previous
concerns for the safety of AIs appear to be vanishing. Notably,
their shorter half-life virtually ensures elimination from the
body before implantation, thereby raising their safety margin
compared with the relatively slowly eliminated CC.62
Monofollicular growth has been regarded as an advantage after using letrozole for ovulation induction. This could
be attributed to its rapid elimination from the body in view
of its shorter half-life, thereby modulating excessive FSH
discharge.61,77 However, a comparable twin-pregnancy rate
between CC and letrozole (8.3% versus 9.1%) in women with
unexplained infertility was reported in an RCT.76 In addition,
a triplet pregnancy after using letrozole for ovulation induction in an infertile woman with polycystic ovary syndrome
was published as a case report.78 Therefore, although AIs are
associated with a higher rate of monofollicular growth, pregnancies with increased rates of twins or higher-order multiples
may be a potential complication of this treatment.

Conclusion
Endometriosis is an estrogen-dependent chronic inflammatory
disease characterized by the presence of active endometrial

678

submit your manuscript | www.dovepress.com

Dovepress

tissue outside the uterus. Infertility and chronic pelvic pain

are considered the cardinal clinical features of this enigmatic
disease. The aromatase P450 enzyme catalyzes the final and
rate-limiting step in the biosynthesis of estrogen, and is present
in several human tissues, including the ovaries and adipose tissue. Notably, molecular studies revealed that this key enzyme
in the biosynthesis of E2 has been demonstrated inside endometriotic tissue, indicating local synthesis of E2. Therefore,
AIs, especially the potent and highly selective third generation,
were utilized for the treatment of endometriosis.
Notably, several studies have found that the combination of
AIs with conventional therapy, such as oral contraceptive pills,
progestins, or GnRHas, can be used to control endometriosisassociated pain and pain recurrence in premenopausal women,
particularly those with pain due to rectovaginal endometriosis
refractory to other medical or surgical treatment. Additionally,
the use of progestins or oral contraceptive pills with AIs will
act as add-back therapy to prevent reduction in BMD and
risks of osteoporosis associated with prolonged use of AIs
alone. Some case reports have shown promising results in
the treatment of postmenopausal endometriosis as first-line
treatment, when surgery is contraindicated, or as a second line
in the case of postoperative recurrence. This point warrants
validation in larger prospective trials.
Due to the downregulation of estrogen synthesis and
reduced pituitary feedback, AIs stimulate endogenous
gonadotropin secretion. AIs, especially letrozole, have
challenged CC as an ovulation-induction agent in patients
with polycystic ovary syndrome and in cases of unexplained
infertility. However, few studies are available regarding the
use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the
treatment of endometriosis-associated infertility are needed
to clarify its effect. The safety of AIs for ovulation induction or superovulation is a major concern. Data from recent
retrospective and prospective studies support their safety.

Disclosure
The author reports no conflicts of interest in this work.

References

1. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268279.

2. McLeod BS, Retzloff MG. Epidemiology of endometriosis:
an assessment of risk factors. Clin Obstet Gynecol. 2010;53(2):
389396.
3. Guo SW, Wang Y. The prevalence of endometriosis in women with
chronic pelvic pain. Gynecol Obstet Invest. 2006;62(3):121130.
4. Giudice LC. Clinical practice. Endometriosis. N Engl J Med.
2010;362(25):23892398.
5. Burney RO, Giudice LC. Pathogenesis and pathophysiology of
endometriosis. Fertil Steril. 2012;98(3):511519.

International Journal of Womens Health 2014:6

Dovepress
6. Carvalho L, Podgaec S, Bellodi-Privato M, Falcone T, Abro MS. Role
of eutopic endometrium in pelvic endometriosis. J Minim Invasive
Gynecol. 2011;18(4):419227.
7. Bulun S, Zeitoun K, Takayama K, Sasano H. Molecular basis for
treating endometriosis with aromatase inhibitors. Hum Reprod Update.
2000;6(5):413418.
8. Nothnick WB. The emerging use of aromatase inhibitors for endometriosis treatment. Reprod Biol Endocrinol. 2011;9:87.
9. Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril. 2006;85(5):13071318.
10. Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with
aromatase inhibitors and inactivators versus standard hormonal
therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst.
2006;98(18):12851291.
11. Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of
endometriosis. Fertil Steril. 2012;98(6):13701379.
12. Polyzos NP, Fatemi HM, Zavos A, et al. Aromatase inhibitors in postmenopausal endometriosis. Reprod Biol Endocrinol. 2011;9:90.
13. Ferrero S, Venturini PL, Ragni N, Camerini G, Remorgida V.
Pharmacological treatment of endometriosis: experience with aromatase
inhibitors. Drugs. 2009;69(8):943952.
14. Geisler J, King N, Anker G, et al. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in
postmenopausal breast cancer patients. Clin Cancer Res. 1998;4(9):
20892093.
15. Bulun SE, Cheng YH, Pavone ME, et al. 17B-Hydroxysteroid
dehydrogenase-2 def iciency and progesterone resistance in
endometriosis. Semin Reprod Med. 2010;28(1):4450.
16. Cheng YH, Imir A, Fenkci V, Yilmaz MB, Bulun SE. Stromal cells of
endometriosis fail to produce paracrine factors that induce epithelial
17B-hydroxysteroid dehydrogenase type 2 gene and its transcriptional
regulator Sp1: a mechanism for defective estradiol metabolism. Am J
Obstet Gynecol. 2007;196(4):391. e1e7; discussion 391. e7e8.
17. Practice Committee of American Society for Reproductive Medicine.
Treatment of pelvic pain associated with endometriosis. Fertil Steril.
2008;90(Suppl 5):S260S269.
18. Royal College of Obstetricians and Gynaecologists. The investigation and management of endometriosis. 2006. Available from: http://
www.rcog.org.uk/files/rcog-corp/GTG2410022011.pdf. Accessed
June 4, 2014.
19. Ferrero S, Camerini G, Seracchioli R, Ragni N, Venturini PL,
Remorgida V. Letrozole combined with norethisterone acetate
compared with norethisterone acetate alone in the treatment of pain
symptoms caused by endometriosis. Hum Reprod. 2009;24(12):
30333041.
20. Amsterdam LL, Gentry W, Jobanputra S, Wolf M, Rubin SD, Bulun SE.
Anastrazole and oral contraceptives: a novel treatment for endometriosis.
Fertil Steril. 2005;84(2):300304.
21. Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of postsurgical administration of goserelin plus anastrozole compared to
goserelin alone in patients with severe endometriosis: a prospective
randomized trial. Hum Reprod. 2004;19(1):160167.
22. Nawathe A, Patwardhan S, Yates D, Harrison GR, Khan KS. Systematic
review of the effects of aromatase inhibitors on pain associated with
endometriosis. BJOG. 2008;115(7):818822.
23. Ferrero S, Gillott DJ, Venturini PL, Remorgida V. Use of aromatase
inhibitors to treat endometriosis-related pain symptoms: a systematic
review. Reprod Biol Endocrinol. 2011;9:89.
24. Razzi S, Fava A, Sartini A, De Simone S, Cobellis L, Petraglia F.
Treatment of severe recurrent endometriosis with an aromatase inhibitor
in a young ovariectomised woman. BJOG. 2004;111(2):182184.
25. Takayama K, Zeitun K, Gunby RT, Sasano H, Carr BR, Bulun SE.
Treatment of severe postmenopausal endometriosis with an aromatase
inhibitor. Fertil Steril. 1998;69(4):709713.
26. Shippen ER, West WJ Jr. Successful treatment of severe endometriosis
in two premenopausal women with an aromatase inhibitor. Fertil Steril.
2004;81(5):13951398.

International Journal of Womens Health 2014:6

Aromatase inhibitors and endometriosis

27. Fatemi HM, Al-Turki HA, Papanikolaou EG, Kosmas L, De Sutter P,
Devroey P. Successful treatment of an aggressive recurrent postmenopausal endometriosis with an aromatase inhibitor. Reprod Biomed
Online. 2005;11(4):455457.
28. Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment
of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril. 2004;81(2):290296.
29. Hefler L, Grimm C, van Trotsenburg M, Nagele F. Role of the vaginally
administered aromatase inhibitor anastrozole in women with rectovaginal endometriosis: a pilot study. Fertil Steril. 2005;84(4):10331036.
30. Remorgida V, Abbamonte LH, Ragni N, Fulcheri E, Ferrero S. Letrozole
and desogestrel-only contraceptive pill for the treatment of stage IV
endometriosis. Aust N Z J Obstet Gynaecol. 2007;47(3):222225.
31. Remorgida V, Abbamonte HL, Ragni N, Fulcheri E, Ferrero S. Letrozole
and norethisterone acetate in rectovaginal endometriosis. Fertil Steril.
2007;88(3):724726.
32. Roghaei MA, Tehrany HG, Taherian A, Koleini N. Effects of letrozole
compared with danazol on patients with confirmed endometriosis:
a randomized clinical trial. Int J Fertil Steril. 2010;4(2):6772.
33. Alborzi S, Hamedi B, Omidvar A, Dehbashi S, Alborzi S, Alborzi M.
A comparison of the effect of short-term aromatase inhibitor (letrozole)
and GnRH agonist (triptorelin) versus case control on pregnancy rate
and symptom and sign recurrence after laparoscopic treatment of
endometriosis. Arch Gynecol Obstet. 2011;284(1):105110.
34. Ferrero S, Venturini PL, Gillott DJ, Remorgida V. Letrozole and norethisterone acetate versus letrozole and triptorelin in the treatment of
endometriosis related pain symptoms: a randomized controlled trial.
Reprod Biol Endocrinol. 2011;9:88.
35. ESHRE Endometriosis Guideline Development Group. Management of
women with endometriosis. 2013. Available from: http://endometriosis.
eshre.eu/docs/ESHRE%20guideline%20on%20endometriosis%20
2013_3.pdf. Accessed June 4, 2014.
36. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline:
management of women with endometriosis. Hum Reprod. 2014;
29(3):400412.
37. Oxholm D, Knudsen UB, Kryger-Baggesen N, Ravn P. Postmenopausal
endometriosis. Acta Obstet Gynecol Scand. 2007;86(10):11581164.
38. Punnonen R, Klemi PJ, Nikkanen V. Postmenopausal endometriosis.
Eur J Obstet Gynecol Reprod Biol. 1980;11(3):195200.
39. Henriksen E. Endometriosis. Am J Surg. 1955;90(2):331337.
40. Ranney B. Endometriosis. 3. Complete operations. Reasons, sequelae,
treatment. Am J Obstet Gynecol. 1971;109(8):11371144.
41. Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after
a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol.
1997;176(3):572579.
42. Borgfeldt C, Andolf E. Cancer risk after hospital discharge diagnosis
of benign ovarian cysts and endometriosis. Acta Obstet Gynecol Scand.
2004;83(4):395400.
43. Ackerman GE, Smith ME, Mendelson CR, MacDonald PC, Simpson ER.
Aromatization of androstenedione by human adipose tissue stromal cells
in monolayer culture. J Clin Endocrinol Metab. 1981;53(2):412417.
44. Goumenou AG, Chow C, Taylor A, Magos A. Endometriosis arising
during estrogen and testosterone treatment 17 years after abdominal
hysterectomy: a case report. Maturitas. 2003;46(3):239241.
45. Sesti F, Vettraino G, Pietropolli A, Marziali M, Piccione E. Vesical and
vaginal recurrent endometriosis in postmenopause following estrogen
replacement therapy. Eur J Obstet Gynecol Reprod Biol. 2005;118(2):
265266.
46. Mousa NA, Bedaiwy MA, Casper RF. Aromatase inhibitors in the
treatment of severe endometriosis. Obstet Gynecol. 2007;109(6):
14211423.
47. Bohrer J, Chen CC, Falcone T. Persistent bilateral ureteral obstruction secondary to endometriosis despite treatment with an aromatase
inhibitor. Fertil Steril. 2008;90(5):2004. e7e9.
48. Sasson IE, Taylor HS. Aromatase inhibitor for treatment of a recurrent
abdominal wall endometrioma in a postmenopausal woman. Fertil
Steril. 2009;92(3):1170. e1e4.

submit your manuscript | www.dovepress.com

Dovepress

679

Dovepress

Abu Hashim
49. [No authors listed]. Revised American Society for Reproductive
Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):
817821.
50. Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A.
Pathogenic mechanisms in endometriosis-associated infertility. Fertil
Steril. 2008;90(2):247257.
51. Rossmanith WG. Minimal endometriosis: a therapeutic dilemma?
Gynecol Endocrinol. 2009;25(11):762764.
52. Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM,
Vandekerckhove P. Ovulation suppression for endometriosis for women
with subfertility. Cochrane Database Syst Rev. 2007;(3):CD000155.
53. [No authors listed]. Practice bulletin no 114: management of
endometriosis. Obstet Gynecol. 2010;116(1):223236.
54. Jacobson TZ, Duffy JM, Barlow D, Farquhar C, Koninckx PR, Olive D.
Laparoscopic surgery for subfertility associated with endometriosis.
Cochrane Database Syst Rev. 2010;(1):CD001398.
55. Deaton JL, Gibson M, Blackmer KM, Nakajima ST, Badger GJ,
Brumsted JR. A randomized, controlled trial of clomiphene citrate
and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril. 1990;54(6):
10831088.
56. Tummon IS, Asher LJ, Mar tin JS, Tulandi T. Randomized controlled
trial of superovulation and insemination for infertility associated with
minimal or mild endometriosis. Fertil Steril. 1997;68(1):812.
57. Werbrouck E, Spiessens C, Meuleman C, DHooghe T. No difference in
cycle pregnancy rate and in cumulative live-birth rate between women
with surgically treated minimal to mild endometriosis and women with
unexplained infertility after controlled ovarian hyperstimulation and
intrauterine insemination. Fertil Steril. 2006;86(3):566571.
58. Nulsen JC, Walsh S, Dumez S, Metzger DA. A randomized and longitudinal study of human menopausal gonadotropin with intrauterine
insemination in the treatment of infertility. Obstet Gynecol. 1993;82(5):
780786.
59. Mitwally FM, Casper RF. Use of an aromatase inhibitor for induction
of ovulation in patients with an inadequate response to clomiphene
citrate. Fertil Steril. 2001;75(2):305309.
60. Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil
Steril. 2006;85(2):277284.
61. Casper RF, Mitwally MF. Review: aromatase inhibitors for ovulation
induction. J Clin Endocrinol Metab. 2006;91(3):760771.
62. Pritts EA. Letrozole for ovulation induction and controlled ovarian
hyperstimulation. Curr Opin Obstet Gynecol. 2010;22(4):289294.
63. Casper RF. Letrozole versus clomiphene citrate: which is better for
ovulation induction? Fertil Steril. 2009;92(3):858859.
64. Abu Hashim H. Clomiphene citrate alternatives for the initial management of polycystic ovary syndrome: an evidence-based approach. Arch
Gynecol Obstet. 2012;285(6):17371745.

65. Misso ML, Wong JL, Teede HJ, et al. Aromatase inhibitors for
PCOS: a systematic review and meta-analysis. Hum Reprod Update.
2012;18(3):301312.
66. Pavone ME, Bulun SE. The use of aromatase inhibitors for ovulation
induction and superovulation. J Clin Endocrinol Metab. 2013;98(5):
18381844.
67. Fouda UM, Sayed AM. Extended letrozole regimen versus clomiphene
citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial. Reprod
Biol Endocrinol. 2011;9:84.
68. Abu Hashim H, El Rakhawy M, Abd Elaal I. Randomized comparison of superovulation with letrozole vs. clomiphene citrate in an IUI
program for women with recently surgically treated minimal to mild
endometriosis. Acta Obstet Gynecol Scand. 2012;91(3):338345.
69. Lossl K, Loft A, Freiesleben NL, et al. Combined down-regulation
by aromatase inhibitor and GnRH-agonist in IVF patients with
endometriomas a pilot study. Eur J Obstet Gynecol Reprod Biol.
2009;144(1):4853.
70. Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women
with endocrine-responsive early breast cancer to anastrozole after 2
years adjuvant tamoxifen: combined results of ABCSG trial 8 and
ARNO 95 trial. Lancet. 2005;366(9484):455462.
71. Buzdar AU. The ATAC (Arimidex, Tamoxifen, Alone or in Combination)
trial: an update. Clin Breast Cancer. 2004;5 Suppl 1:S6S12.
72. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of
Clinical Oncology 2003 update on the role of bisphosphonates
and bone health issues in women with breast cancer. J Clin Oncol.
2003;21(21):40424057.
73. Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies
following the treatment with letrozole or letrozole and gonadotropins.
Fertil Steril. 2005;84 Suppl 1:S95
74. Forman R, Gill S, Moretti M, Tulandi T, Koren G, Casper R. Fetal safety
of letrozole and clomiphene citrate for ovulation induction. J Obstet
Gynaecol Can. 2007;29(8):668671.
75. Tulandi T, Martin J, Al-Fadhli R, et al. Congenital malformations among
911 newborns conceived after infertility treatment with letrozole or
clomiphene citrate. Fertil Steril. 2006;85(6):17611765.
76. Badawy A, Shokeir T, Allam AF, Abdelhady H. Pregnancy outcome
after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstet Gynecol Scand. 2009;88(2):
187191.
77. Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome after the use
of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol.
2005;192(2):381386.
78. Dicken CL, Nakhuda GS, Guarnaccia MM, Sauer MV, Lobo RA. Triplet
pregnancy after ovulation induction with an aromatase inhibitor. Fertil
Steril. 2008;90(4):1199. e9e11.

Dovepress

International Journal of Womens Health

Publish your work in this journal

The International Journal of Womens Health is an international, peerreviewed open-access journal publishing original research, reports,
editorials, reviews and commentaries on all aspects of womens
healthcare including gynecology, obstetrics, and breast cancer. The
manuscript management system is completely online and includes

a very quick and fair peer-review system, which is all easy to use.
Visit http://www.dovepress.com/testimonials.php to read real quotes
from published authors.

Submit your manuscript here: http://www.dovepress.com/international-journal-of-womens-health-journal

680

submit your manuscript | www.dovepress.com

Dovepress

International Journal of Womens Health 2014:6