Clinical Endocrinology (2011) 74, 537546
REVIEW ARTICLE
Aromatase inhibitors for ovulation induction and ovarian
stimulation
Vivian Chi Yan Lee*, and William Ledger*
*Sheffield Teaching Hospital NHS Trust, University of Sheffield, Sheffield, UK and Queen Mary Hospital/Hong Kong University, Hong
Kong
Summary
Aromatase inhibitors (AIs) were originally developed for the treat-
ment of advanced breast cancer in postmenopausal women. Their
use in reproductive medicine has been extensively studied in the
past decade. We reviewed the current strategies for ovulation
induction for anovulatory women, mostly women with polycystic
ovarian syndrome (PCOS), and the scientific basis for use of AIs in
reproductive medicine. The AI, letrozole, is effective in ovulation
induction in women with PCOS resistant to clomifene citrate and
ovarian stimulation for intrauterine insemination and in vitro fer-
tilization (IVF). Letrozole is an attractive option with its oral route
of administration, cost, safety profile and effectiveness in ovulation
induction and ovarian stimulation. Letrozole has the potential to
be the first-line treatment option for ovulation induction in PCOS
women, while its use in ovarian stimulation for IVF deserves
further study.
(Received 22 December 2010; returned for revision 17 January
2011; finally revised 27 January 2011; accepted 2 February 2011)
Aromatase inhibitors
Introduction
Aromatase is a member of the cytochrome P450 haemoprotein-
containing enzyme complex superfamily. It catalyses the rate-limit-
ing final step in oestrogen production and the hydroxylation of
androstenedione to oestrone and testosterone to oestradiol. It is
active in both reproductive (ovaries and placenta) and non-repro-
ductive (breast, adipose tissue, brain, muscle, fibroblasts, liver and
osteoblasts) tissues.14
The first aromatase inhibitor (AI) aminoglutethimide was
licensed in 1981. This was followed by the development of second-
Correspondence: William Ledger, Sheffield Teaching Hospital NHS Trust,
University of Sheffield, Tree Root Walk, Jessop Wing, Sheffield, UK.
Tel.: 00441142268317; E-mail: w.ledger@sheffield.ac.uk
2011 Blackwell Publishing Ltd
doi: 10.1111/j.1365-2265.2011.04006.
generation AI, fadrozole, and finally the first registration of the
third generation of agent, letrozole (Femara, Novartis, Basel, Swit-
zerland), in France in mid-1996. Letrozole inhibits the cytochrome
P450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex.
Letrozole (Fig. 1) is the most widely used AI, following extensive
research showing its beneficial effect in the treatment of advanced
breast cancer. Early animal data showed that letrozole was able to
reduce the size of the rat uterus to a hair-like fine structure at a dose
of only a few hundred micrograms per kilogram, and letrozole was
biologically active at doses as low as 1 lg/kg in producing a signifi-
cant reduction in uterine weight. Following preliminary preclinical
and phase I trials, which confirmed safety for use in humans,5
phase 2B/3A trials showed the superior efficacy of a 25 mg over
05 mg dose of letrozole.6 A phase 3 trial later showed superiority
of letrozole over tamoxifen as the first-line therapy for postmeno-
pausal women with advanced breast cancer.7
The other widely used third-generation AI is anastrozole (Astra-
Zeneca, Fig. 1), which is used at a dose of 1 mg daily. Given the
extensive suppression of plasma oestrogen concentration achieved
with AIs, the agent was developed as a possible replacement for
tamoxifen, another anti-oestrogenic compound, for the treatment
of breast cancer in postmenopausal women.6 After a decade of its
clinical use, a recent Cochrane review revealed a survival benefit
over other endocrinological therapies in advanced (metastatic)
breast cancer.8
Pharmacokinetics and pharmacodynamics of AIs. Letrozole is rap-
idly and completely absorbed from the gastrointestinal tract with
absolute bioavailability of 999%. Letrozole can be taken with or
without food, as absorption is little altered. It is rapidly and exten-
sively distributed into tissues with a binding to plasma proteins of
approximately 60%. The main elimination pathway is through the
liver with the cytochrome P450 isoenzymes 3A4 and 2A6, convert-
ing letrozole into a pharmacologically inactive carbinol metabolite,
CGP44645. The terminal elimination half-life in plasma is about
2 days, and the maximal suppression of oestrogen concentration is
achieved in 4878 h after single oral dose administration. With
continuous daily administration of 25 mg, the plasma concentra-
tion at steady-state levels is reached within 26 weeks. The steady-
state levels are maintained over time, and so it can be concluded
that no continuous accumulation of letrozole occurs.
537
538 V. C. Y. Lee and W. Ledger
Letrozole Anastrozole
Fig. 1 The chemical structures of letrozole and anastrozole.
In healthy postmenopausal women, single oral doses of 01, 05
and 25 mg letrozole suppressed serum oestrone by 7578% and
oestradiol by 78% from baseline. With doses of 05 mg and higher,
plasma levels of oestrone and oestrone sulphate are frequently
below the limit of detection of the assays, indicating that higher
oestrogen suppression is achieved with these doses.
Letrozole is highly specific in inhibiting aromatase activity, and
there is no observed effect on the adrenal steroidogenesis. There are
no clinically relevant changes in the plasma levels of cortisol, aldo-
sterone, 11-deoxycortisol, 17-hydroxy-progesterone, adrenocorti-
cotropic hormone or plasma renin activity in postmenopausal
patients treated with 015 mg letrozole daily. There is no effect on
plasma androgen concentrations (androstenedione and testoster-
one) after single doses of 015 mg, indicating that accumulation
of androgenic precursors does not occur. Plasma levels of LH and
FSH are not affected by letrozole, nor is thyroid function as evalu-
ated by TSH, T4 and T3 uptake.
Adverse reactions. Adverse reactions observed in clinical trials were
generally mild to moderate, and many were attributed to the
underlying disease or the physiological consequences of oestrogen
deprivation, including hot flushes, fatigue, increased sweating,
joint pain, headache, swelling, back pain and nausea in decreasing
order. They rarely led to discontinuation of treatment.
Development of the use of AIs in gynaecological
practice
Following the introduction of AIs for the treatment of breast can-
cer, it was soon realized that these agents had potential for the
treatment of other oestrogen-dependant conditions, particularly in
gynaecological practice. It is important to empathize that use of AIs
in gynaecological practice is off-label although becoming increas-
ingly widespread. One application of particular interest is the use
of AIs for induction of ovulation in women with WHO type II
anovulation. The first proof of principle report in this area was by
Mitwally and Casper.9 They were able to show that letrozole was
effective in inducing ovulation in women with polycystic ovarian
syndrome (PCOS) who had either failed to response to treatment
with clomifene citrate (CC) or who had poor endometrial develop-
ment with this agent. The same group of researchers went on to
report an observational cohort study of poor responders to clomif-
ene, with a 25% pregnancy rate following letrozole treatment.10
The use of letrozole for superovulation prior to in vitro fertilization
(IVF) was explored, with particular interest in use of letrozole in
women who had responded poorly to conventional treatment with
injectable gonadotrophins.1113
One major concern of the use in OI or superovulation is the pos-
sible teratogenicity of letrozole. Exposure of pregnant rats to doses
of letrozole that were equal to or lower than the daily recom-
mended human dose led to an increase in post-implantation foetal
loss and an increase in vertebral anomalies.14 Letrozole was also
shown to be embryotoxic and fetotoxic in rabbits at doses equal to
or lower than the dose used in humans, leading to bone anomalies
(Novartis information). However, the short half-life (45 h) of
letrozole when compared with other anti-oestrogenic agents means
that if the agent is used in the early follicular phase of the cycle, then
a sufficient period of time would pass before implantation to allow
for complete washout of letrozole before the earliest stages of
embryogenesis.15 One concerning report of an increase in congeni-
tal cardiac and bone malformation in letrozole-treated pregnancies
was presented and published in abstract, but not in a peer-reviewed
paper.16 This report has been criticized because the control group
was heterogenous and was not comparable to the treated group in
terms of the patients age and background risk of malformation.
After this abstract, the manufacturer, Novartis, wrote to clinicians
in Canada and the United States stating that letrozole was not safe
to use in pregnancy or in women who may become pregnant.
However, a multicentre retrospective analysis did not show any ter-
atogenic effect of letrozole, with a similar rate of congenital malfor-
mation to that seen in women conceiving after treatment with CC.
This study observed a significantly higher rate of congenital cardiac
anomalies in the CC group.17 A later abstract included nearly 1300
women received letrozole or CC, with no congenital anomalies
found in either group.18 The only randomized trial to assess the
outcome of pregnancies after treatment with AI also failed to detect
any difference in malformation rate after treatment with letrozole
or anastrozole when compared with CC.19 In a subsequent study,
the correlation between infertility treatment and congenital anom-
alies was again not established regardless of the type of infertility
treatment.20 To date, there has not been a response from medicines
regulators in USA or Europe to requests from national organiza-
tions involved in the care of infertile couples to consider licensing
Letrozole for induction of ovulation or use in assisted reproductive
technology (ART).
Anastrozole has been less studied in reproductive medicine but
has also been reported to cause pregnancy loss or miscarriage if
given to rats during the period of organogenesis, in doses equiva-
lent to one-third of that given to women. There was also evidence
of fetotoxicity with skeletal problems at a dose of 19 times the
human dose (AstraZeneca information on file). There are no stud-
ies that report the use of anastrozole in pregnant women.
Current approaches to ovulation induction in women
with PCOS
Clomifene citrate (CC)
Clomifene citrate remains the first-line agent for induction of ovu-
lation in women with PCOS.21 CC is an orally active non-steroidal
compound with both oestrogenic and anti-oestrogenic properties.
2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546
 Aromatase inhibitors for ovulation induction and ovarian stimulation
It acts as an anti-oestrogen by displacing endogenous oestrogen
from oestrogen receptors in the hypothalamus and pituitary, which
reduces negative feedback of oestrogens on secretion of both GnRH
from the hypothalamus and of gonadotrophins from the anterior
pituitary. Hence, the anti-oestrogenic action of CC increases the
secretion of GnRH and also directly increases secretion of gonado-
trophins. A raised concentration of FSH in the early follicular phase
of the cycle improves the likelihood of recruitment of a dominant
follicle leading to ovulation in a previously anovulatory patient. CC
antagonizes the actions of oestradiol at the level of the pituitary
and hypothalamus, and hence, it is ineffective in hypo-oestrogenic
patients with WHO type I anovulation in whom the normal nega-
tive feedback mechanism, with which CC interferes, is not func-
tional.
If women are ovulatory on a particular dose of CC, then treat-
ment is continued for six cycles or until pregnancy occurs. Further
treatment cycles may be offered after counselling. If women do not
respond to the 50-mg dose, then incremental dose of 50 mg up to
150 mg are given before the patients is labelled as clomifene resis-
tant.
Effectiveness. The ovulation rate using CC in anovulatory women
is about 7085%, but only about one half conceive with the preg-
nancy rate of 36% and live-birth rate of 29% per patient.21
The discrepancy between ovulation and pregnancy rate may be
attributable to an anti-oestrogenic effect of CC on endometrium,
affecting endometrial receptivity. This hypothesis has been sup-
ported by studies showing endometrial thinning on ultrasound
examination of patients treated with CC.22
Side effects. The side effects of CC include hot flushes, breast dis-
comfort, abdominal distension, nausea and vomiting, sleeplessness,
headache, mood swings, dizziness and hair loss. Unusual visual
symptoms (visual blurring or persistent after-images) are also
noted in 12% of patients taking CC, which are likely due to anti-
oestrogenic effects of CC on the visual cortex.23 CC is usually very
well tolerated, and side effects are usually completely reversible
once CC is stopped.
A total of 79% of pregnancies resulting from CC-induced ovu-
lation are twin pregnancies, and 0305% are triplet.24 As the num-
ber of multiple pregnancies resulting from IVF treatment declines,
the proportion of iatrogenic multiples that arise following CC ovu-
lation induction will rise. This significant increase in multiple preg-
nancy rate (with naturally occurring twins being seen in about 2%
of pregnancies) is a major drawback to use of CC. Mild ovarian
enlargement and small transient ovarian cysts are relatively
common in CC cycles, but severe ovarian hyperstimulation
syndrome (OHSS) is very rare.
Weight loss and lifestyle modifications
Obese women with PCOS are more likely to be anovulatory than
thin women with PCOS.25 In addition, overweight women with
PCOS are less likely to respond to pharmacological induction of
ovulation.26 Weight loss has been shown to be an effective strategy
to restore ovulation in obese anovulatory women with PCOS, with
2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546
539
as little as 5% reduction in body weight restoring ovulation in some
cases.2729 Although the effectiveness of weight reduction in restor-
ing ovulation and on general health of women with PCOS are
proven,30,31 weight reduction is sometimes difficult to achieve and
maintain.
Tamoxifen
Tamoxifen is a triphenylethylene derivative with a structure similar
to CC. The suggested dose in ovulation induction is 2040 mg
daily, beginning on cycle day 3 for 5 days. It is less frequently used
for ovulation induction as this indication is not licensed, although
it is sometimes prescribed for women who experience side effects
with CC, and a meta-analysis has showed comparative rates of
ovulation and pregnancy when compared with CC.32
Metformin
Insulin resistance is frequently seen in women with PCOS, par-
ticularly in those who are obese.33 The use of insulin-sensitiz-
ing agents in the treatment of PCOS has been extensively
explored, with use of metformin, a biguanide, being the most
studied in this context.
Metformin acts by inhibiting hepatic glucose production and
increasing peripheral glucose uptake.34 It does not stimulate the
secretion of insulin or cause hypoglycaemia in healthy subjects.
There are unpleasant gastrointestinal side effects including nausea,
vomiting, bloating, cramps and diarrhoea. Rare complication
includes lactic acidosis. Metformin has been used in increasing
doses from 500 to 1500 mg daily for the induction of ovulation in
women with PCOS. When compared with placebo or no treatment,
metformin improves both the ovulation rate and clinical pregnancy
rate, but not the live-birth rate.35 However, when used as mono-
therapy, metformin treatment resulted in lower ovulation and clin-
ical pregnancy rates when compared with CC.
Results of studies using combinations of CC and metformin have
been variable. Addition of metformin to the treatment of women
resistant to CC monotherapy has been shown to lead to improve-
ment in clinical pregnancy36 and live-birth37 rates. However, addi-
tion of metformin to CC in previously CC-naive women showed
no benefit in either the pregnancy or live-birth rates in an
adequately powered randomized trial.38
Laparoscopic ovarian drilling (LOD)
Laparoscopic ovarian drilling is a second-line treatment for women
with PCOS, who are either not responsive to CC or not conceive
with CC treatment.39 The mechanism of action of LOD is thought
to be related to the destruction of ovarian androgen-producing
tissue and the consequent decrease in peripheral conversion of
androgens to oestrogens. A fall in serum concentrations of andro-
gens and LH and an increase in FSH concentrations have been
demonstrated after LOD.
The most commonly used energy for LOD is electrocautery. The
procedure includes penetration of the ovarian capsule making four
punctures per ovary at a power setting of 30 W applied for 5 s per
540 V. C. Y. Lee and W. Ledger
puncture.40 A recent Cochrane review41 found that the ovulation
rate after LOD in CC-resistant PCOS women was approximately
80%. There was no difference in the rates of miscarriage, ongoing
pregnancy or live birth between patients who underwent LOD and
patients treated with gonadotrophins for ovulation induction.
There were significantly fewer multiple pregnancies in the LOD
than in the gonadotrophin-treated groups (1% vs 16%; OR 013;
95% CI 003059). In patients remaining anovulatory 8 weeks shown that letrozole gave a significantly higher ovulation rate and a
after LOD or those who subsequently became anovulatory, adju-
vant therapy with CC or gonadotrophins was required to achieve
equivalent pregnancy and live-birth rate in one randomized trial.42
An economic evaluation43 has shown that the cost of a live birth
after LOD is approximately one-third lower than the equivalent
cost of gonadotrophin treatment.
Gonadotrophins
Gonadotrophins are used as second-line therapy for women with
PCOS who have failed to respond to CC. Gonadotrophin treatment
requires daily injection with monitoring of ovarian response using
measurement of serum oestradiol and ultrasound monitoring of
follicle growth. This is costly and time-consuming and leads to a
relatively narrow therapeutic window for monofollicular develop-
ment.44 These difficulties, coupled with the relatively high multiple
pregnancy rate after gonadotrophin ovulation induction, mean
that this approach is usually reserved as the last resort before pro-
ceeding to other more invasive treatment such as IVF. Women with
PCOS have a high number of antral follicles, which predispose to
risk of treatment cancellation owing to over-response.45 Pregnancy
rates are 2025% per cycle.46
Why do we need alternatives?
Although there are several therapeutic options for the treatment of
WHO type II anovulation, none is suitable for every case. Each
strategy has its own drawbacks. In particular, obese patients with
PCOS are more likely to have anovulation and are more prone to
be resistant to all the above-mentioned treatments. The next step
would usually be IVF, which involve a high cost, high multiple
pregnancy rate and the risk of OHSS. Other alternatives are
needed, which can reduce the cost and multiple pregnancy rate
while achieving an acceptable pregnancy rate in CC-resistant
women.
Aromatase inhibitors
Aromatase inhibitor blocks the conversion of testosterone and
androstenedione to oestradiol and oestrone, respectively, and
hence inhibit the oestrogen-negative feedback on the hypotha-
lamicpituitary axis. This leads to increased gonadotrophin secre-
tion, which in turn leads to ovarian follicular growth and
development. AIs were first used in ovulation induction in 20019
(see Table 1). A head-to-head comparison to CC in women with
PCOS without prior exposure to CC showed comparable ovula-
tion rate, live-birth rate and endometrial thickness, but a signifi-
cantly low oestradiol level in the letrozole group,47 while another
randomized trial showed a significantly thicker endometrium,
higher ovulation rate and pregnancy rate in the letrozole group
with a significantly lower number of mature follicles.48 A study
restricted to women with unexplained infertility also showed
comparable endometrial thickness and pregnancy rate per
cycle.49
More recent studies in women with PCOS resistant to CC have
comparable endometrial thickness when compared with placebo50
and when compared with CC combined with metformin.51 Letroz-
ole also had a comparable ovulation rate, live-birth rate and
miscarriage rate with a significantly thicker endometrium when
compared with LOD52 and with CC,53 although the latter differ-
ence was not statistically significant. In frozen embryo cycles in
which ovulation was stimulated with letrozole or CC, the endome-
trial thickness in the letrozole group was also significantly thicker
than in CC group.54
There has also been a prospective study comparing the two com-
mercially available third-generation AIs, anastrozole and letrozole.
Letrozole was associated with a significantly higher ovulation rate
(844% vs 600%) and pregnancy rate (270% vs 166%) when com-
pared with anastrozole.55 One randomized trial has compared the
two AIs in women with PCOS who were resistant to CC. Both AIs
had comparable ovulation rate (62634%) and pregnancy rate
(1215%), with a significantly lower number of mature follicles
and thinner endometrium in letrozole group.56
The multiple pregnancy rate was significantly lower in women
treated with letrozole (25 or 5 mg daily), compared with CC, and
letrozole resulted in more monofollicular cycles.57,58 One random-
ized trial using higher dosage of letrozole, 75 mg daily for 5 days,
in women with PCOS who failed to respond to 100 mg CC, showed
a non-significantly higher pregnancy rate (406% vs 188%) for
letrozole than 150 mg CC, with no multiple pregnancies in either
group.53 However, a recent RCT concluded that the chance of twin
pregnancy was comparable between CC and letrozole (83% vs
91%),19 and a case report has described a triplet pregnancy.59
A recent meta-analysis60 revealed a statistical significance in
favour of the AIs over CC for both pregnancy and live birth. The
odds ratio (OR) for pregnancies per patient was 20 (95% CI 11
38, P = 0.025), and the OR for deliveries per patient was 24 (95%
CI 1246, P = 0.011).
Further randomized trials comparing letrozole and CC as the
first-line treatment in PCOS women are needed, as are more safety
data from studies of AIs in ovulation induction. A suggested algo-
rithm for the use of AIs in ovulation induction is summarized in
Fig. 2.
The use of letrozole in ovarian stimulation for IUI and
IVF
Gonadotrophin injection to induce multiple follicle development,
superovulation, has formed an integral part of IVF since the
1980s. However, gonadotrophin superovulation has drawbacks,
including risk of OHSS and the inconvenience and discomfort of
daily injections. Over the last decade, the concept of mild stimula-
tion has emerged.61 Improvements in IVF embryology with better
2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546
 Table 1. Use of letrozole in ovulation induction

First author, year No of follicles

(study design) No. of women Populations Regimen (>18 mm) ET (mm) OR (%) PR (%) LBR (%)

Mitwally & Casper, 2001 (Prospective, pilot study)

Let 10 (IUI or TI) PCOS resistant to CC 25 mg D37 2 078 70 3/7 (PR) 2/7 (OPR)
Mitwally & Casper, 2002 (Prospective observational)
Let 12 anovulatory PCOS Poor responders 25 mg D37, rFSH 50225 21 (>15 mm) 81 75 25
(to CC) in IUI IU from D7
Let 10 unexplained Same as above Same 23 8 10
Al Fozan, 2004
Let 74 pt (115 cycles) Unexplained (IUI) 75 mg D37 13* 71 115 Two ectopic
CC 80 pt (123 cycles) Same as above 100 mg D37 11* 82 89 367
miscarriage rate
Al Omari, 2004 (RCT)
Let 22 pt PCOS resistant to CC 25 mg D37 17 82* 844* 188*
Anas 18 pt Same as above 1 mg D37 23 65* 60* 97*
Mitwally & Casper, 2005 (Prospective)
Let Not specified Infertile pt with patent tubes 20 mg D3 17 (>15 mm) 85 15
Let Not specified Infertile pt with patent tubes 25 mg D37 19 88 18
Bayar, 2006 (RCT)

2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546

Let 38 pt (99 cycles) PCOS 25 mg D37 1 8 657 (65/99) 91 81
CC 36 pt (95 cycles) PCOS 100 mg D37 1 8 747 (71/95) 74 74
Bayar, 2006 (RCT)
Let 21 pt (52 cycles) Unexplained 25 mg D37 1 8 10
CC 25 pt (67 cycles) Unexplained 100 mg D37 1 8 12
Atay, 2006 JIMR (RCT)
Let 55 pt PCOS 25 mg D37 12* 84* 824* 216*
CC 51 pt PCOS 100 mg D37 24* 52* 636* 91*
Begum, 2009 (RCT)
Let 32 pt PCOS resistant to 100 mg CC 75 mg D37 104* 625* 406*
CC 32 pt Same as above 150 mg D37 90* 375* 188*
Badawy, 2009 (RCT)
Let (long) 110 pt (225 cycles) PCOS resistant to CC 25 mg D110 31* 112 657 174*
Let (short) 108 pt (219 cycles) Same as above 5 mg D15 18* 104 618 124*
Badawy, 2008 (RCT)
Anas 109 pt (279 cycles) PCOS resistant to CC 1 mg D37 31* 102* 634 151 37*
Let 111 pt (295 cycles) Same as above 25 mg D37 23* 91* 62 122 52*
Kamath, 2010 (RCT)
Let 18 PCOS resistant to CC 25 mg D26 78 333* 56 56
Placebo 18 Same as above 74 0 0 0
Abu, 2010 (RCT)
Let 123 pt (285 cycles) PCOS resistant to CC 25 mg D37 23* 95 649 147
Met + CC 127 pt (297 cycles) PCOS resistant to CC 500 mg 68 week, 150 mg D37 31* 91 696 144
Abu, 2010 (RCT) CPR/pt
Let 128 pt (512 cycles) PCOS resistant to CC 25 mg D37 88* 654 281 89
LOD 132 pt (525 cycles) Same as above LOD + 6 months FU 79* 693 28 892
Aromatase inhibitors for ovulation induction and ovarian stimulation

ET, endometrial thickness; PR, pregnancy rate; Let, letrozole; CC, clomifene citrate; Anas, anastrozole; Met, metformin; ET, endometrial thickness; OR, ovulation rate; PR, pregnancy rate; OPR, ongoing pregnancy
rate; LBR, live birth rate; PCOS, polycystic ovarian syndrome; IUI, intrauterine insemination; TI, timed intercourse; rFSH, recombinant follicle stimulating hormone; LOD, laparoscopic ovarian drilling; CPR/pt,
clinical pregnancy rate per patient.
541

*Statistically significant (P < 0.05).

542 V. C. Y. Lee and W. Ledger
Infertile patients
Investigations
Anovulatory patients
(WHO type II anovulation, PCOS)
Weight loss and life style
modification
Clomifene citrate (50150 mg)
D2D6
Pregnancy resulted Aromatase inhibitor (letrozole,
25 mg D2D6)
Metformin (+/ clomifene citrate) Laparoscopic ovarian drilling
ART treatment: SIUI or IVF
fertilization rates and embryo quality mean that fewer oocytes are
required by the laboratory. Advances in embryo cryopreservation
with the use of vitrification have improved pregnancy rates in fro-
zen embryo transfer cycles, and increasing use of single embryo
transfer in good prognosis cases has again reduced the need for
many embryos. These developments have allowed adoption of mild
stimulation followed by elective single-embryo transfer, a policy
that has been shown in a randomized controlled trial to achieve
a similar live-birth rate over 1 year time when compared with
conventional IVF with double-embryo transfer.62 The cost related
to the pregnancy complications brought along by the multiple
pregnancies resulted from ART treatment could be greatly reduced
with the use of mild stimulation protocol with elective single-
embryo transfer,63 and mild stimulation would significantly reduce
the possibility of OHSS. Both embryo quality and endometrial
receptivity may be improved in the more physiological hormonal
environment seen with mild stimulation.64
Although most studies of mild stimulation have employed low
doses of gonadotrophins, both CC and AIs have been used to stim-
ulate multiple follicle development for IVF. Early studies mainly
concerned women who responded poorly to gonadotrophins [poor
ovarian responders (POR)] or patients with diminished ovarian
reserve (see Table 2). One of the earliest observational cohort stud-
ies in poor responders in a stimulated intrauterine insemination
(IUI) programme used a sequential regime of letrozole for 5 days
followed by gonadotrophin injections.65 There were significantly
more mature follicles using significantly lower dosage of gonado-
Gonadotrophin injection
Fig. 2 Algorithm for management of WHO type II
anovulatory infertility.
trophin when compared with previous failed IUI cycles, with the
clinical pregnancy rate of 21%. It was followed by the first RCT on
the use of letrozole in POR in IVF treatment cycles published in
2004.11 The study used concurrent treatment with letrozole and
recombinant gonadotrophin in a long protocol GnRH agonist
regime. The study confirmed the findings from IUI of significantly
lower dosage of gonadotrophins with a comparable pregnancy rate.
Further trials used simultaneous regimen of letrozole and gonado-
trophins in a GnRH antagonist protocol.12,13,66 One observational
study revealed a better implantation rate with a more favourable
follicular fluid hormonal profile,12 and one RCT confirmed the use
of lower dosage of gonadotrophins and lower cancellation rate
owing to poor response.13 Comparisons between the combination
of letrozole and gonadotrophin, and a microdose flare protocol
gave further conflicting results. One prospective trial showed a
non-significant increase in ongoing pregnancy rate in the micro-
dose flare group,67 whereas another retrospective casecontrol
study revealed a significantly higher implantation rate in the letroz-
ole group.68 The most recent RCT, with a small sample size, sug-
gested higher implantation and clinical pregnancy rates in the
microdose flare protocol although these findings were not statisti-
cally significant.69
Optimal dosage and duration
The dosage of letrozole differed between studies. The initial dose of
25 mg daily was derived from pharmacokinetic studies undertaken
2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546
 Aromatase inhibitors for ovulation induction and ovarian stimulation 543

Table 2. Use of letrozole in in vitro fertilization

First author, year (study design) No. of women Days of OS FSH dosage (IU) ET (mm) E2 (pg/ml) Oo IR (%) PR (%)

GnRHa long protocol

Goswami, 2004 (RCT)
Let + rFSH 13 150 (0)* 85 (04) 227 (45)* 16 (08) 23
rFSH 25 2865 (228)* 74 (04) 380 (46)* 21 (07) 24
Antagonist protocol
Garcia-Velasco, 2005 (Prospective observational)
Let + rFSH 71 93 (03) 3627 (116) 96 (05) 770 (67) 61 (04)* 25* 224
rFSH 76 89 (02) 3804 (127) 98 (03) 813 (60) 43 (03)* 94* 152
Verpoest, 2006 (RCT)
Let + rFSH 10 103* 138 (92) 313 50
rFSH 10 81* 96 (77) 125 20
Ozmen, 2009 (RCT) (/ET)
Let + rFSH 35 2980 (435)* 93 (26) 1870 (159)* 49 (16) 258
rFSH 35 3850 (580)* 97 (32) 2015 (175)* 48 (14) 20
Microflare protocol
Schoolcraft, 2008 (Prospective)
Let + rFSH 179 99 (13) 4223 (743) 1403 (965)* 12 (6) 15 37*
GnRHa + rFSH 355 101 (16) 3938 (975) 3147 (1189)* 13 (53) 21 52*
Yarali, 2009 (Retrospective) (/ET)
Let + rFSH 212 90 (25)* 4020 (1178)* 97 (24) 794 (711)* 41 (34)* 145* 228
GnRHa + rFSH 673 102 (40)* 4538 (1493)* 101 (25) 1805 (1228)* 67 (45)* 98* 174
Davar, 2010 (RCT)
Let + FSH 45 85 (11)* 3158 (563)* 83 (13) 477 (54)* 28 (27)* 38 53
GnRHa + FSH 49 92 (12)* 3458 (533)* 84 (12) 1065 (706)* 44 (27)* 77 143

OS, ovarian stimulation; ET, endometrial thickness; E2, oestradiol; Oo, oocytes; IR, implantation rate; PR, pregnancy rate; (/ET), PR per embryo transfer; Let,
letrozole.
*Statistically significant (P < 0.05).

to determine optimum treatment for patients with breast cancer.70
The same group of investigators compared the use of a single dose
of 20 mg letrozole on day 3 with 25 mg for 5 days.71 There was a
comparable pregnancy rate between the two groups. The majority
of researchers have used 255 mg letrozole daily, for either ovula-
tion induction or ovarian stimulation. One group used 75 mg
letrozole daily in stimulated IUI,72 and another study reported sig-
nificantly more mature follicles in the long letrozole group
(25 mg daily for 10 days) than the short letrozole group (5 mg
for 5 days), with a significantly higher pregnancy rate per cycle and
no harmful effect on the endometrium as shown by comparable
endometrial thickness on ultrasound.73 Higher doses appear to
stimulate growth of more follicles, suggesting that doses >25 mg
daily, with the duration of exposure of >5 days, may be required in
mild IVF superovulation with letrozole. Although most studies
have used a similar stimulation protocol and duration as CC,
namely 5 days in the early follicular phase,9,10,47,50,51,65 other regi-
mens have been tested and found efficacious, including a single
dose of 20 mg and a long stimulation for 10 days.71,73
The oral route of administration, lack of side effects and
absence of ovarian hyperstimulation make letrozole attractive as
an agent for superovulation. Use of letrozole instead of gonado-
trophins would greatly reduce the number of injections needed
in a cycle of treatment, reducing the burden placed on the
patient. The short half-life of letrozole would allow it to be com-
pletely cleared from the circulation by the time of blastocyst
transfer on day 5 following oocyte collection, avoiding risk of ter-
atogenicity.
The use in poor ovarian responders
Although letrozole has been used in several studies of poor
responders to superovulation, its use has usually been combined
with gonadotrophin injection, resulting in a shorter stimulation
duration and lower dosage of gonadotrophin.11,13 A randomized
trial of letrozole compared with gonadotrophins would be of inter-
est. This group of patients will not produce a large cohort of
oocytes whatever stimulation regime is used, and if letrozole is able
to induce development of a similar number of follicles as gonado-
trophins, as suggested by a retrospective analysis,74 the costs of
treating this group of patients could be substantially reduced.
The use of letrozole in fertility preservation in patients
with cancer
The low serum oestradiol concentrations seen during letrozole
treatment offer an advantage when providing superovulation for
fertility preservation in young patients with oestrogen-dependent
cancers, particularly breast cancer. Using letrozole for ovarian
stimulation may reduce the risk of stimulating tumour growth and
metastasis.75 A small case series also reported the successful use of
letrozole in patients with endometrial carcinoma.76

2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546

544 V. C. Y. Lee and W. Ledger
Future prospects
This review has focussed on the use of letrozole in treatment of
infertility. Letrozole has the potential to develop into a first-line
treatment for certain groups of patients needing ovulation induc-
tion or IVF. Further evidence of lack of teratogenicity is needed,
along with studies to determine the optimal dosage and duration of
administration, endometrial receptivity and implantation.
AIs may also have a wider role in gynaecology. Letrozole has
been used successfully to treat a variety of oestrogen-dependant
conditions, including endometriosis and adenomyosis,7779 uterine
fibroids,80 endometrial stromal sarcoma81 and medical abortion.82
Again, the low cost and oral route of administration make it an
attractive alternative to other current therapies. A transdermal
patch containing letrozole has been shown to be effective in animal
studies83 and requires study in the human. New fourth-generation
AIs may have further advantages in that they may not cross the pla-
centa, giving added reassurance of safety in reproductive medicine
and even during pregnancy.
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