Expert Review of Obstetrics & Gynecology

ISSN: 1747-4108 (Print) 1747-4116 (Online) Journal homepage: http://www.tandfonline.com/loi/ierb20

The use of aromatase inhibitors in infertility and

gynecology

Jana Al-Shalati & Togas Tulandi

To cite this article: Jana Al-Shalati & Togas Tulandi (2011) The use of aromatase inhibitors in
infertility and gynecology, Expert Review of Obstetrics & Gynecology, 6:4, 415-421, DOI: 10.1586/
eog.11.30

To link to this article: https://doi.org/10.1586/eog.11.30

Published online: 10 Jan 2014.

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The use of aromatase

inhibitors in infertility
and gynecology
Expert Rev. Obstet. Gynecol. 6(4), 415–421 (2011)

Jana Al-Shalati1 Aromatase inhibitors act by blocking the aromatization of androgen to estrogen. Although the
and Togas Tulandi†1 concentration of estrogen is decreased, they do not have the antiestrogen effect of clomiphene.
This makes them ideal for ovulation induction and controlled ovarian hyperstimulation. Owing
1
Department of Obstetrics and
Gynecology, McGill University, to their ability to decrease estrogen concentration, aromatase inhibitors could also be used for
687 Pine Avenue West, Montréal, estrogen-dependent conditions including endometriosis, myoma and adenomyosis. In addition,
QC, H3A 1A1, Canada they could be useful for stimulation of follicle development in women with estrogen-dependent
†
Author for correspondence:
togas.tulandi@mcgill.ca
neoplasia who wish to preserve their fertility.

Keywords : aromatase inhibitor • endometriosis • fertility preservation • letrozole • myoma • ovulation induction

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Learning objectives
• Evaluate the use of aromatase inhibitors in the management of infertility.
• Describe the current role of aromatase inhibitors among women receiving assisted reproductive
technology.
• Analyze the safety of aromatase inhibitors in the management of infertility.
• Distinguish the efficacy of aromatase inhibitors in the treatment of endometriosis and uterine
myomas.

www.expert-reviews.com 10.1586/EOG.11.30 © 2011 Expert Reviews Ltd ISSN 1747-4108 415

 Review Al-Shalati & Tulandi CME

Financial & competing interests disclosure

Editor
Elisa Manzotti
Editorial Director, Future Science Group, London, UK.
Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.
CME Author
Charles P Vega
Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.
Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.
Author and Credentials
Jana Al-Shalati
Department of Obstetrics and Gynecology, McGill University, 687 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.
Disclosure: Jana Al-Shalati has disclosed no relevant financial relationships.
Togas Tulandi
Department of Obstetrics and Gynecology, McGill University, 687 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.
Disclosure: Togas Tulandi has disclosed no relevant financial relationships.

Aromatase inhibitors are traditionally used as an adjuvant treat- occur with prolonged use in postmenopausal women. With
ment in postmenopausal women with estrogen receptor-positive shorter use, such as for ovulation regulation, the side effects
breast cancer  [1] . They work by decreasing the conversion of have been minimal [3–6] .
androgen to estrogen. Nononcologic use of aromatase inhibitors
was pioneered by Mitwally and Casper in 2000 [2] , who used Ovarian stimulation
them to induce ovulation. Many studies subsequently proved their For over three decades, clomiphene citrate has been the only
efficacy. Owing to their ability to decrease estrogen, aromatase oral ovulation-inducing agent. Its efficacy is demonstrated in
inhibitors have also been used for other estrogen-dependent the 60–90% ovulation rate. However, the pregnancy rate is only
­conditions such as uterine myoma and endometriosis. 10–40%. This has been attributed to the antiestrogen effect of
The purpose of this article is to review the use of aromatase clomiphene in the endometrium and the cervical mucus [3,4,7] .
inhibitors for a variety of gynecologic conditions. Another class of drugs that has been used for a long time are
the gonadotropins. They are more effective than clomiphene but
Pharmacology of aromatase inhibitors are associated with higher rates of ovarian hyperstimulation and
Aromatase is a microsomal enzyme of cytochrome p450 hemo- multiple pregnancies. In addition, they are expensive and should
protein that catalyzes the conversion of androgens to estrogens. be administered intramuscularly or subcutaneously.
This enzyme works in many sites of the body including the
ovaries, brain, placenta, adipose tissue, liver, bone and breast. Letrozole
Aromatase inhibitors cause to a decrease in estrogen concentra- In the first study of ovulation induction, ten women with
tion, which in turn lead to an increase in FSH secretion from clomiphene-resistant polycystic ovarian syndrome (PCOS) were
the pituitary gland. Increased FSH levels subsequently stimulate treated with letrozole [1] . Ovulation occurred in seven out of
follicle development. ten patients, two patients had a clinical pregnancy and one had a
To date, there have been three generations of aromatase biochemical pregnancy. Subsequent studies confirmed the efficacy
inhibitors (Table 1) . The first-generation inhibitor was gluteth- of letrozole as an ovulation-inducing substance [2–4] .
imide, which induces medical adrenalectomy. It has many side It appears that letrozole is as effective as clomiphene citrate.
effects including lethargy, nausea and skin rash. The second- In two quasi-randomized trials, the authors found that the
generation inhibitors, such as fadrozole and formestane, are ovulation and pregnancy rates of the two medications were
more selective and have fewer side effects. However, they have similar [8,9] . In the first study by Bayar et al., 46 patients were
to be administered intramuscularly. The third-generation randomized to receive either 2.5 mg of letrozole or 100 mg of
inhibitors include one steroidal (examestane) and two nonster- clomiphene daily from day 3 to 7 of the menstrual cycle [8] .
oidal medications (letrozole and anastrazole). They are selective, Endometrial thickness in the midcycle was similar in both
reversible and potent, and are now commonly used in clinical groups. Ovulation and pregnancy rates in the letrozole group
practice. were 81 and 9%, respectively, and in the clomiphene group were
Letrozole is absorbed rapidly after oral intake and secreted 85 and 12%, respectively.
by the kidneys with a half-life of 45 h. The main side effects In the second study, 50 patients were randomized to receive
are related to hypoestrogenism, including hot flushes and bone letrozole with a starting dose of 2.5 mg and increasing by up
mineral loss. Less common side effects are headache, back pain, to 5 mg daily, or clomiphene with starting dose of 50 mg and
leg cramps and arthralgia. However, most of these side effects increasing by up to 100 mg daily from day 5 to 9 of the cycle [9] .

416 Expert Rev. Obstet. Gynecol. 6(4), (2011)

 CME The use of aromatase inhibitors in infertility & gynecology Review

The mean number of dominant follicles and the pregnancy rates

Table 1. Three generations of aromatase inhibitors. 
in both groups were comparable. However, the endometrial
thickness was thicker in the letrozole group (6.9 vs 5.9 mm). Generation Aromatase inhibitor
In both studies, randomization was achieved by allocating one First generation Aminoglutethimide
group of patients with odd numbers into the letrozole group and
those with an even number into the clomiphene group. Both the Second generation Fadrozol
physicians and the patients were not blinded, and these factors Formestane
are potential biases.
Third generation Letrozole (nonsteroidal)
In a nonblinded randomized trial, Badawy et al. evaluated 769
infertile women treated with 100 mg of clomiphene citrate (n = 420), Anastrazole (nonsteroidal)
5 mg of letrozole (n = 269) or 1 mg of anastrazole (n = 107) [10] .
Examestane (steroidal)
Human chorionic gonadotropin was administered when the domi-
nant follicle reached 18 mm. The control group was age-matched letrozole (2.5 mg/day) or clomiphene treatment (100 mg/day)
women who conceived spontaneously (n = 200). Pregnancy rates in anovulatory women, one small single-blind randomized
among all groups were comparable; 11.1% in letrozole group, 12.1% study reported a pregnancy rate of 34.5% in the letrozole–
in clomiphene group, 10.5% in anastrozole group, and 7% in c­ontrol metformin group and 16.6% in the clomiphene–metformin
group. The miscarriage rates were also similar. group [14] . The full-term pregnancy rate was higher in the letro-
In 2008, the American College of Obstetrics and Gynecology zole–metformin group.
stated that letrozole may have a role in the treatment of Table 2 shows the ovulation rate, pregnancy rate and endometrial
clomiphene-resistant patients [11] . However, there is no evidence thickness in women treated with letrozole. Multiple pregnancies
that it is more effective than clomiphene for ovulation induction. are almost nonexistent.
They concluded that the role of aromatase inhibitors in ovula-
tion induction is being investigated. In any event, it appears that Letrozole in idiopathic infertility
letrozole may have advantages over clomiphene citrate, includ- Letrozole also appears beneficial in couples with unexplained
ing reduced rates of multiple pregnancies, reduced estradiol level infertility. Compared with clomiphene, it is associated with
and less of an antiestrogen effect on the endometrium. a higher pregnancy rate, lower estradiol levels, fewer follicles,
thicker endometrium and better endometrial blood flow as
Letrozole in women with PCOS observed on Doppler ultrasound [13] . Increasing the dose of
In a randomized trial in women with PCOS, Atay et al. reported letrozole to 7.5 mg appears to be unnecessary. Al-Fozan et al.
favorable results with 2.5 mg letrozole over clomiphene 100 mg randomized 154 women to receive 7.5 mg letrozole or 100 mg
daily from day 3 to 7 of the cycle [11] . They found that the ovu- of clomiphene daily. The pregnancy rate was 11.5% in letrozole
lation rate and the pregnancy rate in the letrozole group (82.4 group and 8.9% in the clomiphene group. The miscarriage rate
and 21.6%, respectively) were significantly higher than in the was higher in the clomiphene group [15] .
clomiphene group (63.6 and 9.1%, respectively). The number of
dominant follicles in the letrozole group (1.2) was lower than in Anastrazole
the clomiphene group (2.4), while the endometrial thickness in Another third-generation aromatase inhibitor is anastrozole.
the letrozole group was greater. Al-Omari et al. compared the efficacy of letrozole versus anas-
In another randomized study, 438 women with PCOS were trozole in 22 PCOS patients. The results were in favor of letrozole
randomized to receive 5 mg of letrozole or 100 mg of clomiphene with a higher ovulatory rate (84.4 vs 60%) and pregnancy rate (27
daily for 5 days [12] . The total number of follicles was higher in vs 16.6%). The doses of letrozole and anastrozole were 2.5 mg/day
the clomiphene group than in the letrozole group (6.8 ± 0.3 vs for 5 days and 1 mg/day for 5 days, respectively. It is possible that
4.4 ± 0.4). However, there were no differences in the ovulation the anastrazole dose was too low [16] .
rates (67.5% letrozole vs 70.9% clomi-
Table 2. Rates of ovulation, pregnancy and multiple pregnancy,
phene), the pregnancy rates per cycle
and endometrial thickness in women treated with letrozole.
(15.1% letrozole vs 17.9% clomiphene)
and miscarriage rates (12.1 letrozole vs Study (year) Patients Ovulation Pregnancy Endometrial Multiple Ref.
9.7% clomiphene). (n) rate (%) rate (%) thickness pregnancy
Clomiphene is still considered the (mm)
first line of treatment of anovulation in Mitwally et al. 12 75 25 14.2 0 [2]
women with PCOS. To date, letrozole (2001)
is still an off-label medication for ovula- Bayar et al. (2006) 21 81 10 6.9 0 [8]
tion purposes [13] . Its use should be pre- [11]
Atay et al. (2006) 51 82 21.6 8.4 0
ceded by a thorough discussion with the
[9]
patient regarding the risk and benefits. Baruah et al. 25 19 6.9 Not stated
When metformin was added to (2009)

www.expert-reviews.com 417
 Review Al-Shalati & Tulandi CME

Letrozole & gonadotropin Tulandi et al. reported that, compared with clomiphene, the
The use of aromatase inhibitors in conjunction with gonadotro- rate of overall congenital malformations, major malformation rate
pins is associated with a significant decrease in the gonadotro- and all congenital cardiac anomalies were lower in the letrozole
pin requirement [17,18], with comparable pregnancy rates. This is group [28] . The fact that letrozole has a short half-life (45 h)ensures
despite thinner endometrium in the combined treatment than in that the drug will be cleared completely from the body before
the gonadotropin-only regime [19] . implantation time. This puts the possibility of teratogenic effects
resulting from medication in doubt. It seems that, compared
Letrozole in assisted reproductive technology with gonadotropin or letrozole, clomiphene was associated with
The role of aromatase inhibitors in assisted reproductive tech- a higher risk of neural tube defects and severe hypospadias [29] .
nologies remains to be seen. In 2004, Goswami et al. treated a
group of nonresponder women with letrozole plus FSH or long Aromatase inhibitors for gynecologic conditions
gonadotropin-releasing hormone (GnRH) agonist protocols There have been many studies evaluating the use of aromatase
plus FSH. The letrozole group required a lower dose of gona- inhibitors in ovulation induction and regulation. Their use in
dotropin and had lower estradiol levels. The clinical outcomes other gynecologic conditions has not been widely addressed.
were comparable.
A similar result was reported by Schoolcraft et al. [20] . They ran- Fertility preservation
domized 534 poor responders to a GnRH agonist flare protocol or Owing to their ability to decrease estrogen concentration, aro-
GnRH antagonist/letrozole protocol. The pregnancy rate in the matase inhibitors are especially useful in the induction of follicle
letrozole group was lower than in the GnRH analogues (GnRHa) development in women with estrogen-dependent neoplasia, such
flare group (37 vs 52%). In another study among poor responders, as breast cancer [30,31] . Oktay et al. used a combination of letrozole
the investigators reported that the addition of letrozole to FSH and gonadotropin in women with breast cancer for the purpose of
treatment led to a higher number of oocytes retrieved and a higher oocyte or embryo cryopreservation [1] . A similar protocol could
implantation rate [21] . The pregnancy rate in the combined group be used for young women with endometrial cancer undergoing
appeared to be higher, but it did not reach statistical significance. fertility preservation [32] .

Dose & duration of treatment with letrozole Endometriosis

Based on dosing for breast cancer treatment in postmenopausal The main aim of endometriosis treatment is to deprive the
women, letrozole is usually given in the dose of 2.5 mg from day 3 to endometriotic implant of estrogen [33,34] . There have been case
7 of the cycle. However, when the dose of 5 mg was compared with reports demonstrating the efficacy of aromatase inhibitors in the
2.5 mg, Al-Fadhli et al. found that the 5 mg dose was associated treatment of severe endometriosis [35] .
with a higher pregnancy rate (26.3 vs 5.9%) [22] . In another rand- In a randomized study of comparative treatment of endometrio-
omized trial, Badawy et al. reported that a 7.5 mg daily dose was sis with anastrazole/GnRH agonist or GnRHa alone, the authors
associated with a higher number of follicles compared with the 2.5- found that the combined group was associated with a statistically
or 5-mg dose [23] . However, the pregnancy rates were comparable. significant decrease in estradiol level, longer pain-free time periods
Letrozole can also be given in a single dose (20 mg). In a small and decreased recurrence [36] .
study, it was reported that the ovulation and pregnancy rates of
the single dose were similar to the 5-day regime [24] . Myoma & adenomyosis
The ideal duration of the treatment is yet to be established. Myoma is another condition that is estrogen dependent [37] .
Badawy et al. randomized 218 women with PCOS to 5 mg of Parsanezhad et al. randomized 70 women with single uterine myo-
letrozole daily for 5 days (days 1–5) or 2.5 mg letrozole for 10 days mas equal or more than 5 cm in size into two groups. The first
(days 1–10). The pregnancy rate in the long protocol (17.4%) group received 2.5 mg/day of letrozole and the second group was
was significantly higher than in the short regime (12.4%) [25] ; treated with triptorelin 3.75 mg/month for 12 weeks. The reduction
however, more studies are needed. in myoma size was higher in the letrozole group (45 vs 33.2%) [38] .
Adenomyosis is another condition that could be treated medically
Safety with on aromatase inhibitor. In a case report, a combination of anas-
The safety of letrozole as an ovulation-inducing agent has been trazole and GnRHa was associated with a 60% reduction of uterine
addressed by several groups [23–25] . Concerns regarding the volume in 8 weeks and improvement in symptomatology [39] .
safety of letrozole were raised at an abstract presentation at the
2005 American Society for Reproductive Medicine (ASRM) Expert commentary
meeting [26] . As a result, Health Canada (ON, Canada) and Aromatase inhibitors are a group of medications that act by blocking
Novartis Pharmaceuticals (QC, Canada) warned against using the aromatization of androgen to estrogen. Unlike clomiphene, they
letrozole for ovulation induction  [27] . This finding was chal- do not have an antiestrogen effect. This makes them ideal for ovula-
lenged when the incidence of congenital anomalies was evalu- tion induction and controlled ovarian hyperstimulation. They are
ated in a study of 911 babies born after fertility treatment with fairly inexpensive, active orally and appear to be safe for the fetus.
either letrozole or clomiphene. In addition, the risk of multiple pregnancies is almost nonexistent.

418 Expert Rev. Obstet. Gynecol. 6(4), (2011)

 CME The use of aromatase inhibitors in infertility & gynecology Review

Owing to their property in decreasing estrogen concentration, the value of assisted reproductive techniques. Whether longer
aromatase inhibitors could also be used for estrogen-dependent duration of treatment leads to a better pregnancy rate remains
conditions including endometriosis, myoma and adenomyosis. In to be seen. Compared with gonadotropins, the use of aromatase
addition, they could be useful for stimulation of follicle develop- inhibitors is associated with a reduced estrogen concentration.
ment in women with estrogen-dependent neoplasia who wish to Accordingly, they can be used for fertility preservation in women
preserve their fertility. with estrogen-dependent cancer.
Aromatase inhibitors have a role in the treatment of estrogen-
Five-year view dependent conditions including endometriosis, myoma or adeno-
The risk of multiple pregnancies associated with ovulation induc- myosis. More studies are required to establish their place in the
tion or superovulation could be minimized with the increased treatment of such disorders.
use of aromatase inhibitors. More studies are needed to prove

Key issues
• Letrozole is the most commonly used aromatase inhibitor. It is selective, reversible and effective.
• Aromatase inhibitors are effective for ovulation induction and superovulation. The results are comparable with those of clomiphene
citrate, with a minimal risk of multiple pregnancies and they are not associated with the antiestrogen effect on the endometrium or
the cervix.
• The role of aromatase inhibitors in assisted reproductive technology needs further exploration.
• Compared with clomiphene, letrozole seems to be associated with a lower risk of neural tube defects and severe hypospadias.
• Aromatase inhibitors can be used for fertility preservation in women with estrogen-dependent neoplasias, including breast cancer.
• Aromatase inhibitors can be used for the treatment of estrogen-dependent conditions such as endometriosis, myoma and
adenomyosis.

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420 Expert Rev. Obstet. Gynecol. 6(4), (2011)

 CME The use of aromatase inhibitors in infertility & gynecology Review

The use of aromatase inhibitors in infertility and gynecology

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1. A 28-year-old nulliparous woman with a history of 3. The patient from question 1 eventually requires ART.
polycystic ovarian syndrome (PCOS) and infertility Which of the following statements best summarizes
presents. What should you consider before the role of aromatase inhibitors in ART?
discussing the possibility of treatment with letrozole
£ A Only letrozole appears to significantly improve
for her infertility? pregnancy rates in ART
£ A Pregnancy rates associated with letrozole seem at £ B Only anastrazole appears to significantly improve
least as high as those for clomiphene pregnancy rates in ART
£ B Letrozole is associated with a high miscarriage rate
£ C Letrozole significantly reduces the efficacy of FSH in
£ C Letrozole is associated with a higher risk for multiple promoting pregnancy
pregnancies compared with other fertility drugs £ D There is no established role for aromatase inhibitors
£ D The addition of metformin to letrozole significantly in ART
reduces its efficacy in infertility treatment
4. The patient from question 1 has a successful
2. What should you consider regarding the potential pregnancy. You see her 10 years later for pelvic pain,
adverse effects associated with aromatase and she is diagnosed with endometriosis and uterine
inhibitors? myomas. What should you consider regarding the
use of aromatase inhibitors for these conditions?
£ A Letrozole is associated with higher rates of neural
tube defects only compared with clomiphene £ A Adding anastrazole to a GnRH agonist will increase
estradiol levels
£ B Letrozole is associated with higher rates of severe
hypospadias only compared with clomiphene £ B Anastrazole may help prevent recurrence of
endometriosis
£ C Letrozole is associated with higher rates of neural
tube defects and severe hypospadias compared with £ C Letrozole is less effective than GnRH agonists in
clomiphene reducing the size of myomas
£ D Letrozole is associated with lower rates of neural tube £ D Letrozole should not be added to GnRH agonists in
defects and severe hypospadias compared with the treatment of endometriosis or uterine myomas
clomiphene

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