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Clinical Endocrinology (2011) 74, 537546 doi: 10.1111/j.1365-2265.2011.04006.

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

generation AI, fadrozole, and finally the first registration of the


Summary third generation of agent, letrozole (Femara, Novartis, Basel, Swit-
zerland), in France in mid-1996. Letrozole inhibits the cytochrome
Aromatase inhibitors (AIs) were originally developed for the treat- P450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex.
ment of advanced breast cancer in postmenopausal women. Their Letrozole (Fig. 1) is the most widely used AI, following extensive
use in reproductive medicine has been extensively studied in the research showing its beneficial effect in the treatment of advanced
past decade. We reviewed the current strategies for ovulation breast cancer. Early animal data showed that letrozole was able to
induction for anovulatory women, mostly women with polycystic reduce the size of the rat uterus to a hair-like fine structure at a dose
ovarian syndrome (PCOS), and the scientific basis for use of AIs in of only a few hundred micrograms per kilogram, and letrozole was
reproductive medicine. The AI, letrozole, is effective in ovulation biologically active at doses as low as 1 lg/kg in producing a signifi-
induction in women with PCOS resistant to clomifene citrate and cant reduction in uterine weight. Following preliminary preclinical
ovarian stimulation for intrauterine insemination and in vitro fer- and phase I trials, which confirmed safety for use in humans,5
tilization (IVF). Letrozole is an attractive option with its oral route phase 2B/3A trials showed the superior efficacy of a 25 mg over
of administration, cost, safety profile and effectiveness in ovulation 05 mg dose of letrozole.6 A phase 3 trial later showed superiority
induction and ovarian stimulation. Letrozole has the potential to of letrozole over tamoxifen as the first-line therapy for postmeno-
be the first-line treatment option for ovulation induction in PCOS pausal women with advanced breast cancer.7
women, while its use in ovarian stimulation for IVF deserves The other widely used third-generation AI is anastrozole (Astra-
further study. Zeneca, Fig. 1), which is used at a dose of 1 mg daily. Given the
(Received 22 December 2010; returned for revision 17 January extensive suppression of plasma oestrogen concentration achieved
2011; finally revised 27 January 2011; accepted 2 February 2011) 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)
Aromatase inhibitors breast cancer.8

Introduction Pharmacokinetics and pharmacodynamics of AIs. Letrozole is rap-


idly and completely absorbed from the gastrointestinal tract with
Aromatase is a member of the cytochrome P450 haemoprotein- absolute bioavailability of 999%. Letrozole can be taken with or
containing enzyme complex superfamily. It catalyses the rate-limit- without food, as absorption is little altered. It is rapidly and exten-
ing final step in oestrogen production and the hydroxylation of sively distributed into tissues with a binding to plasma proteins of
androstenedione to oestrone and testosterone to oestradiol. It is approximately 60%. The main elimination pathway is through the
active in both reproductive (ovaries and placenta) and non-repro- liver with the cytochrome P450 isoenzymes 3A4 and 2A6, convert-
ductive (breast, adipose tissue, brain, muscle, fibroblasts, liver and ing letrozole into a pharmacologically inactive carbinol metabolite,
osteoblasts) tissues.14 CGP44645. The terminal elimination half-life in plasma is about
The first aromatase inhibitor (AI) aminoglutethimide was 2 days, and the maximal suppression of oestrogen concentration is
licensed in 1981. This was followed by the development of second- 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-
Correspondence: William Ledger, Sheffield Teaching Hospital NHS Trust, state levels are maintained over time, and so it can be concluded
University of Sheffield, Tree Root Walk, Jessop Wing, Sheffield, UK. that no continuous accumulation of letrozole occurs.
Tel.: 00441142268317; E-mail: w.ledger@sheffield.ac.uk

2011 Blackwell Publishing Ltd 537


538 V. C. Y. Lee and W. Ledger

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
Letrozole Anastrozole shown to be embryotoxic and fetotoxic in rabbits at doses equal to
or lower than the dose used in humans, leading to bone anomalies
Fig. 1 The chemical structures of letrozole and anastrozole.
(Novartis information). However, the short half-life (45 h) of
letrozole when compared with other anti-oestrogenic agents means
In healthy postmenopausal women, single oral doses of 01, 05 that if the agent is used in the early follicular phase of the cycle, then
and 25 mg letrozole suppressed serum oestrone by 7578% and a sufficient period of time would pass before implantation to allow
oestradiol by 78% from baseline. With doses of 05 mg and higher, for complete washout of letrozole before the earliest stages of
plasma levels of oestrone and oestrone sulphate are frequently embryogenesis.15 One concerning report of an increase in congeni-
below the limit of detection of the assays, indicating that higher tal cardiac and bone malformation in letrozole-treated pregnancies
oestrogen suppression is achieved with these doses. was presented and published in abstract, but not in a peer-reviewed
Letrozole is highly specific in inhibiting aromatase activity, and paper.16 This report has been criticized because the control group
there is no observed effect on the adrenal steroidogenesis. There are was heterogenous and was not comparable to the treated group in
no clinically relevant changes in the plasma levels of cortisol, aldo- terms of the patients age and background risk of malformation.
sterone, 11-deoxycortisol, 17-hydroxy-progesterone, adrenocorti- After this abstract, the manufacturer, Novartis, wrote to clinicians
cotropic hormone or plasma renin activity in postmenopausal in Canada and the United States stating that letrozole was not safe
patients treated with 015 mg letrozole daily. There is no effect on to use in pregnancy or in women who may become pregnant.
plasma androgen concentrations (androstenedione and testoster- However, a multicentre retrospective analysis did not show any ter-
one) after single doses of 015 mg, indicating that accumulation atogenic effect of letrozole, with a similar rate of congenital malfor-
of androgenic precursors does not occur. Plasma levels of LH and mation to that seen in women conceiving after treatment with CC.
FSH are not affected by letrozole, nor is thyroid function as evalu- This study observed a significantly higher rate of congenital cardiac
ated by TSH, T4 and T3 uptake. anomalies in the CC group.17 A later abstract included nearly 1300
women received letrozole or CC, with no congenital anomalies
Adverse reactions. Adverse reactions observed in clinical trials were found in either group.18 The only randomized trial to assess the
generally mild to moderate, and many were attributed to the outcome of pregnancies after treatment with AI also failed to detect
underlying disease or the physiological consequences of oestrogen any difference in malformation rate after treatment with letrozole
deprivation, including hot flushes, fatigue, increased sweating, or anastrozole when compared with CC.19 In a subsequent study,
joint pain, headache, swelling, back pain and nausea in decreasing the correlation between infertility treatment and congenital anom-
order. They rarely led to discontinuation of treatment. 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-
Development of the use of AIs in gynaecological
tions involved in the care of infertile couples to consider licensing
practice
Letrozole for induction of ovulation or use in assisted reproductive
Following the introduction of AIs for the treatment of breast can- technology (ART).
cer, it was soon realized that these agents had potential for the Anastrozole has been less studied in reproductive medicine but
treatment of other oestrogen-dependant conditions, particularly in has also been reported to cause pregnancy loss or miscarriage if
gynaecological practice. It is important to empathize that use of AIs given to rats during the period of organogenesis, in doses equiva-
in gynaecological practice is off-label although becoming increas- lent to one-third of that given to women. There was also evidence
ingly widespread. One application of particular interest is the use of fetotoxicity with skeletal problems at a dose of 19 times the
of AIs for induction of ovulation in women with WHO type II human dose (AstraZeneca information on file). There are no stud-
anovulation. The first proof of principle report in this area was by ies that report the use of anastrozole in pregnant women.
Mitwally and Casper.9 They were able to show that letrozole was
effective in inducing ovulation in women with polycystic ovarian
Current approaches to ovulation induction in women
syndrome (PCOS) who had either failed to response to treatment
with PCOS
with clomifene citrate (CC) or who had poor endometrial develop-
ment with this agent. The same group of researchers went on to
Clomifene citrate (CC)
report an observational cohort study of poor responders to clomif-
ene, with a 25% pregnancy rate following letrozole treatment.10 Clomifene citrate remains the first-line agent for induction of ovu-
The use of letrozole for superovulation prior to in vitro fertilization lation in women with PCOS.21 CC is an orally active non-steroidal
(IVF) was explored, with particular interest in use of letrozole in compound with both oestrogenic and anti-oestrogenic properties.

2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546


Aromatase inhibitors for ovulation induction and ovarian stimulation 539

It acts as an anti-oestrogen by displacing endogenous oestrogen as little as 5% reduction in body weight restoring ovulation in some
from oestrogen receptors in the hypothalamus and pituitary, which cases.2729 Although the effectiveness of weight reduction in restor-
reduces negative feedback of oestrogens on secretion of both GnRH ing ovulation and on general health of women with PCOS are
from the hypothalamus and of gonadotrophins from the anterior proven,30,31 weight reduction is sometimes difficult to achieve and
pituitary. Hence, the anti-oestrogenic action of CC increases the maintain.
secretion of GnRH and also directly increases secretion of gonado-
trophins. A raised concentration of FSH in the early follicular phase
Tamoxifen
of the cycle improves the likelihood of recruitment of a dominant
follicle leading to ovulation in a previously anovulatory patient. CC Tamoxifen is a triphenylethylene derivative with a structure similar
antagonizes the actions of oestradiol at the level of the pituitary to CC. The suggested dose in ovulation induction is 2040 mg
and hypothalamus, and hence, it is ineffective in hypo-oestrogenic daily, beginning on cycle day 3 for 5 days. It is less frequently used
patients with WHO type I anovulation in whom the normal nega- for ovulation induction as this indication is not licensed, although
tive feedback mechanism, with which CC interferes, is not func- it is sometimes prescribed for women who experience side effects
tional. with CC, and a meta-analysis has showed comparative rates of
If women are ovulatory on a particular dose of CC, then treat- ovulation and pregnancy when compared with CC.32
ment is continued for six cycles or until pregnancy occurs. Further
treatment cycles may be offered after counselling. If women do not
Metformin
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- Insulin resistance is frequently seen in women with PCOS, par-
tant. ticularly in those who are obese.33 The use of insulin-sensitiz-
ing agents in the treatment of PCOS has been extensively
Effectiveness. The ovulation rate using CC in anovulatory women explored, with use of metformin, a biguanide, being the most
is about 7085%, but only about one half conceive with the preg- studied in this context.
nancy rate of 36% and live-birth rate of 29% per patient.21 Metformin acts by inhibiting hepatic glucose production and
The discrepancy between ovulation and pregnancy rate may be increasing peripheral glucose uptake.34 It does not stimulate the
attributable to an anti-oestrogenic effect of CC on endometrium, secretion of insulin or cause hypoglycaemia in healthy subjects.
affecting endometrial receptivity. This hypothesis has been sup- There are unpleasant gastrointestinal side effects including nausea,
ported by studies showing endometrial thinning on ultrasound vomiting, bloating, cramps and diarrhoea. Rare complication
examination of patients treated with CC.22 includes lactic acidosis. Metformin has been used in increasing
doses from 500 to 1500 mg daily for the induction of ovulation in
Side effects. The side effects of CC include hot flushes, breast dis- women with PCOS. When compared with placebo or no treatment,
comfort, abdominal distension, nausea and vomiting, sleeplessness, metformin improves both the ovulation rate and clinical pregnancy
headache, mood swings, dizziness and hair loss. Unusual visual rate, but not the live-birth rate.35 However, when used as mono-
symptoms (visual blurring or persistent after-images) are also therapy, metformin treatment resulted in lower ovulation and clin-
noted in 12% of patients taking CC, which are likely due to anti- ical pregnancy rates when compared with CC.
oestrogenic effects of CC on the visual cortex.23 CC is usually very Results of studies using combinations of CC and metformin have
well tolerated, and side effects are usually completely reversible been variable. Addition of metformin to the treatment of women
once CC is stopped. resistant to CC monotherapy has been shown to lead to improve-
A total of 79% of pregnancies resulting from CC-induced ovu- ment in clinical pregnancy36 and live-birth37 rates. However, addi-
lation are twin pregnancies, and 0305% are triplet.24 As the num- tion of metformin to CC in previously CC-naive women showed
ber of multiple pregnancies resulting from IVF treatment declines, no benefit in either the pregnancy or live-birth rates in an
the proportion of iatrogenic multiples that arise following CC ovu- adequately powered randomized trial.38
lation induction will rise. This significant increase in multiple preg-
nancy rate (with naturally occurring twins being seen in about 2%
Laparoscopic ovarian drilling (LOD)
of pregnancies) is a major drawback to use of CC. Mild ovarian
enlargement and small transient ovarian cysts are relatively Laparoscopic ovarian drilling is a second-line treatment for women
common in CC cycles, but severe ovarian hyperstimulation with PCOS, who are either not responsive to CC or not conceive
syndrome (OHSS) is very rare. 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
Weight loss and lifestyle modifications
androgens to oestrogens. A fall in serum concentrations of andro-
Obese women with PCOS are more likely to be anovulatory than gens and LH and an increase in FSH concentrations have been
thin women with PCOS.25 In addition, overweight women with demonstrated after LOD.
PCOS are less likely to respond to pharmacological induction of The most commonly used energy for LOD is electrocautery. The
ovulation.26 Weight loss has been shown to be an effective strategy procedure includes penetration of the ovarian capsule making four
to restore ovulation in obese anovulatory women with PCOS, with punctures per ovary at a power setting of 30 W applied for 5 s per

2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546


540 V. C. Y. Lee and W. Ledger

puncture.40 A recent Cochrane review41 found that the ovulation randomized trial showed a significantly thicker endometrium,
rate after LOD in CC-resistant PCOS women was approximately higher ovulation rate and pregnancy rate in the letrozole group
80%. There was no difference in the rates of miscarriage, ongoing with a significantly lower number of mature follicles.48 A study
pregnancy or live birth between patients who underwent LOD and restricted to women with unexplained infertility also showed
patients treated with gonadotrophins for ovulation induction. comparable endometrial thickness and pregnancy rate per
There were significantly fewer multiple pregnancies in the LOD cycle.49
than in the gonadotrophin-treated groups (1% vs 16%; OR 013; More recent studies in women with PCOS resistant to CC have
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- comparable endometrial thickness when compared with placebo50
vant therapy with CC or gonadotrophins was required to achieve and when compared with CC combined with metformin.51 Letroz-
equivalent pregnancy and live-birth rate in one randomized trial.42 ole also had a comparable ovulation rate, live-birth rate and
An economic evaluation43 has shown that the cost of a live birth miscarriage rate with a significantly thicker endometrium when
after LOD is approximately one-third lower than the equivalent compared with LOD52 and with CC,53 although the latter differ-
cost of gonadotrophin treatment. 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
Gonadotrophins
than in CC group.54
Gonadotrophins are used as second-line therapy for women with There has also been a prospective study comparing the two com-
PCOS who have failed to respond to CC. Gonadotrophin treatment mercially available third-generation AIs, anastrozole and letrozole.
requires daily injection with monitoring of ovarian response using Letrozole was associated with a significantly higher ovulation rate
measurement of serum oestradiol and ultrasound monitoring of (844% vs 600%) and pregnancy rate (270% vs 166%) when com-
follicle growth. This is costly and time-consuming and leads to a pared with anastrozole.55 One randomized trial has compared the
relatively narrow therapeutic window for monofollicular develop- two AIs in women with PCOS who were resistant to CC. Both AIs
ment.44 These difficulties, coupled with the relatively high multiple had comparable ovulation rate (62634%) and pregnancy rate
pregnancy rate after gonadotrophin ovulation induction, mean (1215%), with a significantly lower number of mature follicles
that this approach is usually reserved as the last resort before pro- and thinner endometrium in letrozole group.56
ceeding to other more invasive treatment such as IVF. Women with The multiple pregnancy rate was significantly lower in women
PCOS have a high number of antral follicles, which predispose to treated with letrozole (25 or 5 mg daily), compared with CC, and
risk of treatment cancellation owing to over-response.45 Pregnancy letrozole resulted in more monofollicular cycles.57,58 One random-
rates are 2025% per cycle.46 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
Why do we need alternatives?
letrozole than 150 mg CC, with no multiple pregnancies in either
Although there are several therapeutic options for the treatment of group.53 However, a recent RCT concluded that the chance of twin
WHO type II anovulation, none is suitable for every case. Each pregnancy was comparable between CC and letrozole (83% vs
strategy has its own drawbacks. In particular, obese patients with 91%),19 and a case report has described a triplet pregnancy.59
PCOS are more likely to have anovulation and are more prone to A recent meta-analysis60 revealed a statistical significance in
be resistant to all the above-mentioned treatments. The next step favour of the AIs over CC for both pregnancy and live birth. The
would usually be IVF, which involve a high cost, high multiple odds ratio (OR) for pregnancies per patient was 20 (95% CI 11
pregnancy rate and the risk of OHSS. Other alternatives are 38, P = 0.025), and the OR for deliveries per patient was 24 (95%
needed, which can reduce the cost and multiple pregnancy rate CI 1246, P = 0.011).
while achieving an acceptable pregnancy rate in CC-resistant Further randomized trials comparing letrozole and CC as the
women. 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
Aromatase inhibitors
Fig. 2.
Aromatase inhibitor blocks the conversion of testosterone and
androstenedione to oestradiol and oestrone, respectively, and
The use of letrozole in ovarian stimulation for IUI and
hence inhibit the oestrogen-negative feedback on the hypotha-
IVF
lamicpituitary axis. This leads to increased gonadotrophin secre-
tion, which in turn leads to ovarian follicular growth and Gonadotrophin injection to induce multiple follicle development,
development. AIs were first used in ovulation induction in 20019 superovulation, has formed an integral part of IVF since the
(see Table 1). A head-to-head comparison to CC in women with 1980s. However, gonadotrophin superovulation has drawbacks,
PCOS without prior exposure to CC showed comparable ovula- including risk of OHSS and the inconvenience and discomfort of
tion rate, live-birth rate and endometrial thickness, but a signifi- daily injections. Over the last decade, the concept of mild stimula-
cantly low oestradiol level in the letrozole group,47 while another 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 Gonadotrophin injection

Fig. 2 Algorithm for management of WHO type II


ART treatment: SIUI or IVF
anovulatory infertility.

fertilization rates and embryo quality mean that fewer oocytes are trophin when compared with previous failed IUI cycles, with the
required by the laboratory. Advances in embryo cryopreservation clinical pregnancy rate of 21%. It was followed by the first RCT on
with the use of vitrification have improved pregnancy rates in fro- the use of letrozole in POR in IVF treatment cycles published in
zen embryo transfer cycles, and increasing use of single embryo 2004.11 The study used concurrent treatment with letrozole and
transfer in good prognosis cases has again reduced the need for recombinant gonadotrophin in a long protocol GnRH agonist
many embryos. These developments have allowed adoption of mild regime. The study confirmed the findings from IUI of significantly
stimulation followed by elective single-embryo transfer, a policy lower dosage of gonadotrophins with a comparable pregnancy rate.
that has been shown in a randomized controlled trial to achieve Further trials used simultaneous regimen of letrozole and gonado-
a similar live-birth rate over 1 year time when compared with trophins in a GnRH antagonist protocol.12,13,66 One observational
conventional IVF with double-embryo transfer.62 The cost related study revealed a better implantation rate with a more favourable
to the pregnancy complications brought along by the multiple follicular fluid hormonal profile,12 and one RCT confirmed the use
pregnancies resulted from ART treatment could be greatly reduced of lower dosage of gonadotrophins and lower cancellation rate
with the use of mild stimulation protocol with elective single- owing to poor response.13 Comparisons between the combination
embryo transfer,63 and mild stimulation would significantly reduce of letrozole and gonadotrophin, and a microdose flare protocol
the possibility of OHSS. Both embryo quality and endometrial gave further conflicting results. One prospective trial showed a
receptivity may be improved in the more physiological hormonal non-significant increase in ongoing pregnancy rate in the micro-
environment seen with mild stimulation.64 dose flare group,67 whereas another retrospective casecontrol
Although most studies of mild stimulation have employed low study revealed a significantly higher implantation rate in the letroz-
doses of gonadotrophins, both CC and AIs have been used to stim- ole group.68 The most recent RCT, with a small sample size, sug-
ulate multiple follicle development for IVF. Early studies mainly gested higher implantation and clinical pregnancy rates in the
concerned women who responded poorly to gonadotrophins [poor microdose flare protocol although these findings were not statisti-
ovarian responders (POR)] or patients with diminished ovarian cally significant.69
reserve (see Table 2). One of the earliest observational cohort stud-
ies in poor responders in a stimulated intrauterine insemination
Optimal dosage and duration
(IUI) programme used a sequential regime of letrozole for 5 days
followed by gonadotrophin injections.65 There were significantly The dosage of letrozole differed between studies. The initial dose of
more mature follicles using significantly lower dosage of gonado- 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 transfer on day 5 following oocyte collection, avoiding risk of ter-
The same group of investigators compared the use of a single dose atogenicity.
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
The use in poor ovarian responders
of researchers have used 255 mg letrozole daily, for either ovula-
tion induction or ovarian stimulation. One group used 75 mg Although letrozole has been used in several studies of poor
letrozole daily in stimulated IUI,72 and another study reported sig- responders to superovulation, its use has usually been combined
nificantly more mature follicles in the long letrozole group with gonadotrophin injection, resulting in a shorter stimulation
(25 mg daily for 10 days) than the short letrozole group (5 mg duration and lower dosage of gonadotrophin.11,13 A randomized
for 5 days), with a significantly higher pregnancy rate per cycle and trial of letrozole compared with gonadotrophins would be of inter-
no harmful effect on the endometrium as shown by comparable est. This group of patients will not produce a large cohort of
endometrial thickness on ultrasound.73 Higher doses appear to oocytes whatever stimulation regime is used, and if letrozole is able
stimulate growth of more follicles, suggesting that doses >25 mg to induce development of a similar number of follicles as gonado-
daily, with the duration of exposure of >5 days, may be required in trophins, as suggested by a retrospective analysis,74 the costs of
mild IVF superovulation with letrozole. Although most studies treating this group of patients could be substantially reduced.
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-
The use of letrozole in fertility preservation in patients
mens have been tested and found efficacious, including a single
with cancer
dose of 20 mg and a long stimulation for 10 days.71,73
The oral route of administration, lack of side effects and The low serum oestradiol concentrations seen during letrozole
absence of ovarian hyperstimulation make letrozole attractive as treatment offer an advantage when providing superovulation for
an agent for superovulation. Use of letrozole instead of gonado- fertility preservation in young patients with oestrogen-dependent
trophins would greatly reduce the number of injections needed cancers, particularly breast cancer. Using letrozole for ovarian
in a cycle of treatment, reducing the burden placed on the stimulation may reduce the risk of stimulating tumour growth and
patient. The short half-life of letrozole would allow it to be com- metastasis.75 A small case series also reported the successful use of
pletely cleared from the circulation by the time of blastocyst letrozole in patients with endometrial carcinoma.76

2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546


544 V. C. Y. Lee and W. Ledger

tocol in women with poor ovarian response: a preliminary report.


Future prospects Human Reproduction, 19, 20312035.
This review has focussed on the use of letrozole in treatment of 12 Garcia- Velasco, J.A., Moreno, L., Pacheco, A. et al. (2005) The
infertility. Letrozole has the potential to develop into a first-line aromatase inhibitor letrozole increases the concentration of intrao-
varian androgens and improves in vitro fertilization outcome in
treatment for certain groups of patients needing ovulation induc-
low responder patients: a pilot study. Fertility and Sterility, 84, 82
tion or IVF. Further evidence of lack of teratogenicity is needed,
87.
along with studies to determine the optimal dosage and duration of 13 Ozmen, B., Sonmezer, M., Atabekoglu, C.S. et al. (2009) Use of
administration, endometrial receptivity and implantation. aromatase inhibitors in poor-responder patients receiving GnRH
AIs may also have a wider role in gynaecology. Letrozole has antagonist protocols. Reproductive Biomedicine Online, 19, 478
been used successfully to treat a variety of oestrogen-dependant 485.
conditions, including endometriosis and adenomyosis,7779 uterine 14 Tiboni, G.M., Marotta, F., Rossi, C. et al. (2008) Effects of the aro-
fibroids,80 endometrial stromal sarcoma81 and medical abortion.82 matase inhibitor letrozole on in utero development in rats. Human
Again, the low cost and oral route of administration make it an Reproduction, 23, 17191723.
attractive alternative to other current therapies. A transdermal 15 Requena, A., Herrero, J., Landeras, J. et al. (2008) Use of letrozole
patch containing letrozole has been shown to be effective in animal in assisted reproduction: a systematic review and meta-analysis.
Human Reproduction Update, 14, 571582.
studies83 and requires study in the human. New fourth-generation
16 Biljan, M.M., Hcmmings, R. & Brassard, N. (2005) The outcome of
AIs may have further advantages in that they may not cross the pla-
150 babies following the treatment wilh letrozole or lelrozole and
centa, giving added reassurance of safety in reproductive medicine gonadotrophins. Fertility and Sterility, 84(Suppl.), 1033.
and even during pregnancy. 17 Tulandi, T., Martin, J., Al-Fadhli, R. et al. (2006) Congenital mal-
formations among 911 newborns conceived after infertility treat-
ment with letrozole or clomiphene citrate. Fertility and Sterility, 85,
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2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 537546