Professional Documents
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REVIEW ARTICLE
*Sheffield Teaching Hospital NHS Trust, University of Sheffield, Sheffield, UK and Queen Mary Hospital/Hong Kong University, Hong
Kong
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
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
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
Infertile patients
Investigations
Anovulatory patients
D2D6
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
First author, year (study design) No. of women Days of OS FSH dosage (IU) ET (mm) E2 (pg/ml) Oo IR (%) PR (%)
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
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