The use of aromatase inhibitors in

in vitro fertilization
Juan A. Garcia-Velasco, M.D.
IVI-Madrid, Rey Juan Carlos University, Madrid, Spain

The use of aromatase inhibitors (AIs) in IVF patients remains controversial. AIs can be considered for ovulation induction for IVF in
women who are normal and poor responders, are at risk of ovarian hyperstimulation syndrome or thrombosis, who have endometriosis,
and/or are undergoing fertility preservation procedures as a result of estrogen-dependent cancers, primarily breast and endometrial cancers. Although the biologic plausibility of the capacity
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he use of aromatase inhibitors

(AIs) as an adjuvant treatment in
IVF has been assessed in the past
decade (14). AIs can be considered for
ovulation induction for IVF in normal
and poor responders, women at risk of
ovarian hyperstimulation syndrome
(OHSS) or thrombosis, who have
endometriosis, and/or who are
undergoing
fertility
preservation
procedures as a result of estrogendependant cancers, primarily breast
and endometrial cancers. Studies are
heterogeneous, and the evidence is
scarce, mainly owing to unfounded
safety fears or the risk of teratogenesis,
which has limited the generation of
well designed studies based on preliminary retrospective series or pilot trials.
AI use for IVF in hormone-dependent
cancers and the risk for teratogenicity
will not be discussed here, because
they are addressed elsewhere in this section of Views and Reviews.
AIs inhibit aromatization of androgens to estrogens, mainly in the
ovarian granulosa cells, inducing a re-

duction in circulating estrogen levels,

which has several implications for
IVF:
Pituitary escape from estrogen
feedback, leading to elevated
gonadotropins and improved
follicular recruitment
A transient accumulation of these
intraovarian androgens, creating an androgenic microenvironment in the maturing
follicle that may enhance follicular sensitivity to FSH with a relatively short duration, because
letrozole has a short has life
(45 h). This may be of interest
in poor responders, because it
has been shown that along
with ovarian aging a signicant
androgen reduction is observed,
and androgen pretreatment may
improve ovarian performance
and follicle development.
A strong reduction in the secretion
of estrogens from the granulosa
cells. The reduction of circulat-

Received August 9, 2012; revised September 23, 2012; accepted September 24, 2012; published online
October 11, 2012.
J.A.G.-V. has nothing to disclose.
Reprint requests: Juan A. Garcia-Velasco, M.D., Reproductive Endocrinology and Infertility,
IVI-Madrid, Av del Talgo 68, Madrid 28023, Spain (E-mail: juan.garcia.velasco@ivi.es).
Fertility and Sterility Vol. 98, No. 6, December 2012 0015-0282/$36.00
Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
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ing steroid levels is an attractive

option to minimize the risk of
thrombosis in hyperestrogenic
states and/or the risk of complications if OHSS develops, as
well as to provide additional
safety in women who have
hormone-dependent
cancers
undergoing controlled ovarian
hyperstimulation (COH) for fertility preservation.
Inhibition of aromatase could potentially improve endometrial
receptivity, particularly in patients with endometriosis in
whom aromatase is aberrantly
expressed.
According to basic and clinical
studies, there are three different areas
in which the use of aromatase inhibitors may prove benecial for IVF patients: improving cycle outcome in
low-responder patients, reducing the
risk of OHSS, and reducing the risk
that high estrogen levels can pose to
women with a high response to COH.

LOW RESPONDERS
The rationale for using AIs in poor responders to COH is based on their capacity to transiently accumulate
androgens in the ovarian micromilieu,
VOL. 98 NO. 6 / DECEMBER 2012

Fertility and Sterility

which may increase ovarian sensitivity to FSH, because it is
known that androgens play a crucial role in early follicular
development and granulosa cell proliferation (57). Both of
the third-generation AIs, anastrazole and letrozole, which
are highly potent reversible inhibitors, have been used as adjuvant treatments in an attempt to create a hyperandrogenic
intraovarian state in women who previously had a poor response to COH.
The biologic plausibility of the theory of androgenization
is attractive, but is it clinically relevant? We evaluated the impact of letrozole as an adjuvant treatment in 147 women with
a previous IVF cycle cancelled due to low response (8). Letrozole (2.5 mg) was administered to 71 patients during the rst 5
days of the stimulation, whereas the control subjects received
a similar dose of FSH/hMG. Interestingly, letrozole-treated
patients showed signicantly higher levels of follicular uid
T and A (80.3 pg/mL vs. 43.8 pg/mL and 57.9 mg/mL vs.
37.4 mg/mL, respectively). Clinically speaking, patients who
received letrozole had a higher number of oocytes retrieved
(6.1 vs. 4.3) and a higher implantation rate (25% vs. 9.4%).
This initial observation could not be conrmed in a proper
randomized trial, because around the same time the manufacturer of letrozole, based on an inadequately designed study
(9), suggested not using AIs in assisted reproduction. Reassuring data from later publications could not completely resolve
this issue (10).
However, additional publications became available. The
concept that AIs could contribute to the follicular response
was validated in normal responders, both with letrozole (11)
and anastrazole (12), even though embryo quality in this particular population was not improved. A large, prospective trial
compared the impact of letrozole co-treatment in past or potential poor responders with a microdose GnRH agonist are
protocol, nding similar results in stimulation parameters and
a higher pregnancy rate with the microare protocol (13). In
this study, the denition of poor responders in the patients
may not have been exactly the same as in other studies, as patients had a mean number of 9 antral follicles and produced
between 12 and 13 oocytes. Although other potential confounders could have contributed to the different results
such as different protocols, doses, or even GnRH analogues
a larger sample size would have been necessary to verify these
ndings. Nevertheless, further trials suggested that letrozole
co-treatment could be an effective protocol that could be
used in poor ovarian responders, reducing cancellations and
costs, although live birth rates remained low (1418).

RISK OF OHSS
It is obvious that today the most effective way to avoid OHSS
is the use of agonist triggering rather than hCG in women under the antagonist protocol, because the corpora lutea have
a short life after agonist triggering. However, thousands of
cycles are still being performed worldwide under the long agonist protocol (19), where agonist triggering is not an option.
Thus, reducing the production of high amounts of E2 by the
granulosa cells may help to minimize the risk of developing
OHSS as well as the risk of thrombosis. The effect of letrozole
has been investigated as an option to inhibit E2 production
VOL. 98 NO. 6 / DECEMBER 2012

and modulate LH levels during the luteal phase. Fatemi

et al. (20) investigated this concept in a pilot study that included three oocyte donors who were given letrozole (5 mg)
and three others who received placebo. Serum E2 concentrations on days 4, 7, and 10 after hCG administration for nal
oocyte maturation were signicantly lower compared with
placebo. However, no differences were observed in progesterone and LH proles during the same period.
Garcia-Velasco et al. (21) performed a randomized trial to
explore the same concept. Thirty volunteers were randomized
to receive letrozole (2.5 mg) or placebo after hCG triggering.
As expected, serum E2 concentrations dropped dramatically
in those receiving AIs (279 pg/mL vs. 1,589 pg/mL) on day
4 after hCG, and similarly on days 7 and 10. Although P did
not change, LH serum concentrations were lower in the control group on days 7 and 10 after hCG, when serum E2 was
higher. The quick reduction in serum E2 levels allowed a faster
recovery of the LH concentrations, an interesting concept not
only for egg donors who are undergoing embryo transfer, but
also for patients undergoing COH for fertility preservation
and women at risk of OHSS who freeze all their embryos or
who cancel hCG administration to reduce the potential risk
that high E2 levels pose. In both studies (20, 21), VEGF
levels or any other vascular permeability factors were not
studied. We should bear in mind that E2 reduction does not
necessarily mean that the risk of severe OHSS is lessened, so
extrapolating lower E2 levels to a lower risk of OHSS is not
necessarily true. However, this reduction in E2 levels
contributes to reduced risk of thrombosis.

ENDOMETRIOSIS
Another potential benet of AIs for patients undergoing IVF
might be to inhibit aromatase, the key enzyme in the biosynthesis of E2, not only in the granulosa cells but also in situ in
endometriotic tissue and the eutopic endometrium of women
with endometriosis, because aromatase is expressed in these
tissues (22).
A pilot study was recently published to study the concept
of dual suppression. A 3-month GnRH agonist course combined with anastrazole (1 mg daily) was used in infertile
women with endometriomas undergoing IVF (23). A signicant reduction in endometrioma volume (29%) and serum
CA-125 concentration (61%) was observed. Although the
pregnancy rate was 45%, a high pregnancy loss was noted;
the live birth rate was 15%, which may be due to poor embryo
quality, as in other endometriosis patients (24). No further
validation of this concept has been made available.
In line with this concept, women with endometriosis
show aberrant endometrial aromatase expression, which is
associated with poor reproductive outcomes (25). Long-term
GnRH agonist therapy has been assayed in an attempt to improve IVF outcome in these women (26, 27), because it
suppresses endometrial aromatase expression (28). Because
AIs are capable of suppressing the P450 aromatase enzyme
in situ, they might hypothetically improve endometrial
receptivity. Very recently, Miller et al. (29) examined the
effect of letrozole on infertile women with endometriosis
undergoing IVF who lacked normal integrin expression,
1357

VIEWS AND REVIEWS

a marker of endometrial receptivity. They conrmed that the
use of aromatase inhibitors might improve the IVF success
rates in a subset of women with endometriosis and
implantation failure.
The use of AIs in IVF patients is still controversial. However, the biologic plausibility of their capacity to improve follicular recruitment by escaping from estrogen feedback, to
transiently increase androgen concentrations to improve follicle development, inhibit aromatase to potentially improve
endometrial receptivity, or decrease estrogen levels and consequently the risk of thrombosis is promising. Even if the
available evidence seems favorable, the results should still
be interpreted with caution, because the efcacy should be
proven in randomized trials. For this purpose, and based on
available safety data (10), a reassuring statement from medical societies and/or the pharmaceutical industry would be
needed. Still, further research is needed on FSH receptor modulation during ovarian stimulation, dose-nding studies
should be performed, the impact on endometrial receptivity
in women with and without endometriosis should be further
analyzed, and the ideal timing for coadjuvant treatment needs
to be dened.

11.

12.

13.

14.

15.

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