Human Reproduction Vol.20, No.8 pp. 2043–2051, 2005 doi:10.

1093/humrep/dei042
Advance Access publication May 5, 2005

Clomiphene citrate—end of an era? a mini-review

Roy Homburg
Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre, De Boelelaan
1117, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Address for correspondence: E-mail: R.Homburg@vumc.nl

The purpose of this review is to examine whether the time has come to replace clomiphene citrate (CC) as the first
line therapy for WHO group II (eu-oestrogenic) infertility, the majority of which is associated with polycystic
ovary syndrome. CC has been the first line therapy for these cases for the last 40 years. It is a simple, cheap treat-
ment, almost devoid of side effects which yields a single live birth rate of ,25% of starters. Non-response to CC
and the gap between ovulation and pregnancy rates have variously been attributed to its anti-estrogen effects, and

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high LH and androgen concentrations. Three possible contenders for the replacement of CC as first-line treatment
are scrutinized: metformin, aromatase inhibitors and low-dose FSH. Each has their advantages and disadvantages,
but none of them, while showing much potential promise, has been proven, as yet, to be a feasible replacement for
CC in this role. For CC, it may not yet be the end of an era but it may be the beginning of the end.

Key words: aromatase inhibitors/clomiphene citrate/low-dose FSH/metformin/PCOS

Introduction Despite the use of CC in controlled ovarian stimulation, its

It is now . 40 years ago that Greenblatt first reported a new
compound, the anti-estrogen MRL-41, capable of inducing
ovulation for anovulatory women (Greenblatt et al., 1961).
Later to become known as clomiphene citrate (CC) this com-
pound has had a remarkably sustained career as the first-line
treatment for women with absent or irregular ovulation due
to hypothalamic –pituitary dysfunction associated with nor-
mal basal levels of endogenous estradiol (WHO group II).
The vast majority of these patients probably some 80% are
now known to be oligo- or anovulatory due to polycystic
ovary syndrome (PCOS). Until the introduction of CC the
only plausible treatment for these patients who wished to
conceive was bilateral wedge resection of the ovaries.
Although this abdominal surgical procedure had some con-
siderable success in restoring ovulation and even inducing
pregnancy it later fell from grace due to the generation of
pelvic adhesions following the operation in a large number
of patients and the emergence of medical means to induce
ovulation. CC was the first medication capable of inducing
ovulation and as such created a welcome revolution in the
treatment of infertility associated with anovulation.
Many years later, a further suggested indication was its
empirical use for ovarian stimulation in idiopathic (‘unex-
plained’) infertility. Here its success was more limited but,
with the introduction of assisted reproductive technology, it
became widely used as a ‘booster’ to ovulatory capacity in
conjunction with intrauterine insemination (IUI) and, with
the rising costs of gonadotrophin preparations, as an adjuvant
to gonadotrophin stimulation of the ovaries in preparation for
IVF.
q The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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original indication of ovulation induction for WHO group II
classification of oligo- or anovulation, particularly when
associated with PCOS, remains its most frequent and most
successfully treated indication. The fact that CC is an orally
administered, relatively cheap preparation, has proved an
enormous advantage over its injected and expensive competi-
tors. However, the field is becoming replete with alternatives
for the same indication and the time is ripe to re-evaluate the
place of CC in our armamentarium of ovulation-inducing
agents.
Mode of action
Clomiphene contains an unequal mixture of two isomers as
their citrate salts, enclomiphene and zuclomiphene. Zuclomi-
phene is much the more potent of the two for induction of
ovulation, accounts for 38% of the total drug content of one
tablet and has a much longer half-life than enclomiphene,
being detectable in plasma 1 month following its adminis-
tration. Rostami-Hodjegan et al. (2004) have suggested that
wide variability in the metabolism of the zuclomiphene
component contributes to variability in response to the drug.
CC is capable of inducing a discharge of FSH from the
anterior pituitary and this is often enough to reset the cycle of
events leading to ovulation into motion. The release of even
small amounts of FSH into the system will often induce ovu-
lation and pregnancy in a proportion of eu-estrogenic anovula-
tory women. This is achieved indirectly, through the action of
CC, a non-steroidal compound closely resembling an estro-
gen, in blocking hypothalamic estrogen receptors, signalling
2043
R.Homburg

Table I. Results of treatment with clomiphene citrate: a collection of published data

No of patients Ovulation Pregnancy Abortion Live birth

McGregor et al. (1968) 4098 2869 1393 279 1114

Garcia et al. (1977) 159 130 64 16 48
Gysler et al. (1982) 428 364 184 24 160
Hammond (1984) 159 137 67 10 57
Kousta et al. (1997) 128 113 55 13 42
Messinis and Milingos (1998) 55 51 35 4 31
Imani et al. (2002) 259 194 111 11 98
Total (% of patients) 5268 (100) 3858 (73) 1909 (36) 357 1550 (29)

a lack of circulating estrogen to the hypothalamus and indu-
cing a change in the pattern of pulsatile release of GnRH.
Dose
CC is given orally in a dose of 50– 250 mg per day for 5
days from day 2, 3, 4 or 5 of spontaneous or induced bleed-
of CC for the induction of ovulation, and is generally consist-
ent from series to series.
From these data, a theoretical projection of the results of
CC induction of ovulation in 100 women starting treatment
has been made (Table III, column 2), concluding that 25 of
these 100 will succeed in delivering a singleton, healthy baby.
Although CC will restore ovulation in , 73% of patients,

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ing, starting with the lowest dose and increasing the dose in it will result in pregnancy in only , 36%. The 27% of anovu-
increments of 50 mg/day per cycle until an ovulatory cycle is latory women with normal FSH concentrations who do not
achieved. The starting day of treatment, whether on day 2 or respond at all are considered to be ‘CC resistant’.
through day 5 of the cycle, does not influence the results
(Wu and Winkel, 1989). Although 50 mg/day is the rec-
ommended dose in the first cycle, a meta-analysis of 13 Failure to ovulate
published reports (Rostami-Hodjegan et al., 2004) suggests Inability of CC to induce ovulation is more likely in patients
that only 46% will respond to this dose with ovulation, a who are obese, insulin resistant and hyperandrogenic com-
further 21% will respond to 100 mg and another 8% will ovu- pared with those who do respond (Imani et al., 1998). This
late with 150 mg/day. There is no apparent advantage of careful prospective study pinpointed a high free androgen
using a daily dose of . 150 mg which seems to significantly index as the best predictor of non-response to CC. Although
increase neither the ovulation rate nor follicular recruitment it is virtually impossible to predict who will respond to
(Dickey et al., 1997). Some practitioners often use a starting which dose of CC, if at all (Imani et al., 2002), body weight
dose of 100 mg/day from day 4 or 5, only resorting to has been found to be an impeding factor. Overweight women
50 mg/day in the case of exquisite sensitivity or persistent respond less well (Polson et al., 1989) and the dose of CC
cyst formation. The advantage of starting with a 100 mg needed to induce ovulation correlates with body weight
daily dose rather than 50 mg is that it will cut down the (Lobo et al., 1982).
number of ‘superfluous’ cycles of treatment until ovulation is
achieved and until those resistant to CC are identified. It is
difficult to state what effect, if any, this course of action has Failure to conceive
on the multiple pregnancy rate. It is frustrating that the restoration of ovulation by CC does
not produce a much higher pregnancy rate. This discrepancy
between ovulation and pregnancy rates (only 50% of those
Results who ovulate will conceive) may be partly explained by the
A compilation of published results regarding ovulation and peripheral anti-estrogenic effects of CC at the level of the
pregnancy rates following treatment with CC is shown in endometrium and cervical mucus or by hypersecretion of
Table I. It reveals an ovulation rate of 73% and a pregnancy LH. While the depression of the cervical mucus, occurring in
rate of 36% in data from 5268 patients. To the data on preg- , 15% of patients, may be overcome by performing IUI
nancy, abortion and live birth rates in Table I, I have added
similar data from four further studies dealing with the preg-
Table II. Outcome of pregnancy following treatment with clomiphene
nancies and their outcome. From a grand total of 4054 preg- citrate
nancies, , 20% terminated in a spontaneous abortion
Pregnancies Abortion Live births
and almost all the rest in a live birth (Table II). From this
collection of results, it was very difficult to estimate the Total data from Table 1 1909 357 1550
multiple pregnancy rate which was rarely addressed. How- Ahlgren et al. (1976) 159 18 141
Adashi et al. (1979) 86 23 62
ever, from the available numbers and from other review pub- Correy et al. (1982) 156 16 140
lications (Scialli et al., 1986), this is estimated to be 8– 13%, Dickey et al. (1996) 1744 413 1331
the vast majority being twin pregnancies. Obviously a collec- Total (% of pregnancies) 4054 (100) 827 (20.4) 3224 (79.5)
tion of results of this nature comprises very heterogeneous Results from four further publications dealing with the outcome of pregnancy
series but nevertheless gives a very good idea of the efficiency are added to data from Table I.

2044

Table III. Projected results of treatment
Start with CC resistant on First-line treatment
CC (n ¼ 100) low-dose FSH with low-dose
(n ¼ 100) FSH (n ¼ 100)
No response 27 15 8
Ovulation 73 85 92
No conception 37 45 30
Conception 36 40 62
Miscarriages 8 8 14
Multiple 3 2 3 majority of these are twin pregnancies, but the risk may be
pregnancy
Singleton live 25 30 45
birth
Column 2 (based on actual results from Tables I and II) ¼ 100 anovulatory
(WHO group II) women starting with CC; column 3 (based on data from
Table IV) ¼ 100 CC-resistant women receiving low-dose FSH.
Column 4 are ‘virtual’ data of 100 anovulatory (WHO group II) women
using low-dose FSH as first-line treatment. It is based on the assumptions
that all those who would have conceived if starting with CC (n ¼ 36) plus
40% of CC failures (CC resistant þ ovulation but no conception (n ¼ 26)
would conceive if starting with low-dose FSH.
suppression of endometrial proliferation, unrelated to dose or
duration of treatment but apparently idiosyncratic, indicates a
poor prognosis for conception if the endometrial thickness on
ultrasound scanning does not reach 8 mm at ovulation. In our
experience, the prevalence of endometrial suppression is one
in every 6 –7 patients and, if noted in the first cycle of treat-
ment with CC, it will almost certainly be seen in repeated
cycles in the same woman. There is little point in persisting
after even one cycle, and a step-up to other forms of ovu-
lation induction is recommended.
The main action of CC, indirectly stimulating GnRH
secretion, not only increases the desired FSH release but also
produces an undesirable increase in LH concentrations. This
increase in LH, whose basal level is often already high in
women with PCOS, may compromise pregnancy rates in
those receiving CC (Homburg et al., 1988a; Shoham et al.,
1990). We have demonstrated that pre-treatment with micro-
nized progesterone is capable of modulating LH pulsatility,
reducing LH concentrations and inducing a more favourable
environment for ovulation induction with CC (Homburg
et al., 1988b). This treatment initiated a response to CC and
yielded consequent pregnancies in previous non-responders
to CC.
A course of six ovulatory cycles is usually sufficient to
know whether pregnancy will be achieved using CC before
moving on to more complex treatment as it has been reported
that 71 –87.5% of the pregnancies achieved with CC occur
within the first three cycles of treatment (Gysler et al., 1982;
Kousta et al., 1997; Imani et al., 1998). From our own very
large (unpublished) database, we noted that no further preg-
nancies at all were obtained with CC following seven ovula-
tory cycles, although others have found that a further 5 – 6%
do conceive between treatment cycle number 6 and 12
(Kousta et al., 1997). In properly selected patients with no
other causes of infertility, the cumulative conception rate
may reach as high as 60% after six cycles (Messinis and
Milingos, 1998).
Clomiphene citrate—end of an era?
Outcome of pregnancies
CC blocks the negative feedback mechanism which the even-
tually rising estradiol levels would normally invoke to reduce
discharge of FSH. The continued flow of FSH encourages
multiple follicle development which is relatively common.
The risk of multiple gestation is therefore increased and is
estimated at , 8 – 13% (Schenker et al., 1981; Scialli et al.,
1986; Kousta et al., 1997; Eijkmans et al., 2003). The vast
reduced considerably by ultrasound monitoring and withhold-
ing HCG, IUI or intercourse if more than two follicles
. 15 mm diameter are seen (Homburg and Insler, 2002).
Although there are conflicting reports, the prevalence of
spontaneous abortion of a clinical pregnancy following CC
therapy has a reported mean of , 20% (McGregor et al.,
1968, Dickey et al., 1996; Kousta et al., 1997), slightly
higher than the 12– 15% of clinically recognized spontaneous
miscarriages in the normal population (Warburton and Fraser,
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1964; Wentz and Cartwright, 1988). Although a very contro-
versial issue due to a lack of evidence for a direct causal
relationship, several investigators have found in retrospective
studies that an increased prevalence of miscarriage is associ-
ated with high serum LH concentrations in the mid-follicular
phase (Homburg et al., 1988b; Regan et al., 1990). The
increased prevalence of miscarriage following CC therapy
may, in part, be due to the high LH values induced immedi-
ately after this treatment. Kousta et al. (1997) found signifi-
cantly higher LH levels post-CC in those who miscarried
compared with those who delivered, and just 37% of the
ongoing pregnancy group had LH . 10 IU/l compared with
75% of those who aborted. We postulated that this is due to
a premature maturation of the oocyte caused by high LH con-
centrations and resulting in an ‘aged’ oocyte which is diffi-
cult to fertilize and, if fertilized, is more likely to abort
(Homburg et al., 1988a).
The prevalence of congenital abnormalities following CC
treatment is no different from those seen in spontaneously
conceived pregnancies (Correy et al., 1982).
Side effects
Unpleasant side effects of CC are few and far between,
although some women will complain of hot flushes and some
of nausea. CC is, however, usually very well tolerated. While
mild ovarian enlargement is relatively common, in almost
40 years of practice, I have never seen a full blown ovarian
hyperstimulation syndrome (OHSS) as a result of CC
treatment. Occasional cyst formation can be treated
conservatively.
Monitoring
CC is often given without any observation of the events of
the cycle. However, monitoring of the CC-treated cycle by
ultrasound evaluation of follicular growth and endometrial
thickness on days 12– 14 of the cycle is justified by the
identification of those who are not responding or have
depressed endometrial thickness, and is helpful in the timing
2045
R.Homburg
of natural intercourse or IUI. Confirmation, or otherwise, of
ovulation can be obtained with estimation of the progesterone
concentration in the assumed mid-luteal phase which is pre-
ferable to a basal body temperature chart. The added expense
of careful monitoring is neutralized by the prevention of pro-
tracted periods of possibly ineffective therapy and delay in
the inception of more efficient treatment.
Adjuvants
In order to improve the outcome of treatment with CC,
several adjuvants to CC treatment have been suggested. A
correctly timed ovulation-triggering dose of HCG (5000 –
10000 IU) is only theoretically warranted when the reason for
a non-ovulatory response is that the LH surge is delayed or
absent despite the presence of a well developed follicle.
Although the routine addition of HCG at mid-cycle seems to
add little to the improvement of conception rates (Agarwal
and Buyalos, 1995), we have found it very useful, if given
when an ultrasonically demonstrated leading follicle attains a
diameter of 19– 24 mm, for the timing of intercourse or IUI.
The addition of dexamethazone as an adjunct to CC
therapy in a dose of 0.5 mg at bedtime is said to suppress
adrenal androgen secretion and induce responsiveness to CC
in previous non-responders, mostly hyperandrogenic women
with PCOS and elevated concentrations of dehydroepiandro-
sterone sulphate (DHEAS) (Daly et al., 1984). However,
glucocorticoid steroid therapy often induces side effects
including increased appetite and weight gain, and should
probably be reserved for women who have congenital adrenal
hyperplasia as a cause for their anovulation.
Indications other than ovulation induction
CC has also been employed for ovarian stimulation in ovulat-
ing women, mainly for idiopathic (unexplained) infertility
and often combined with IUI. The rationale is presumably
that CC overcomes a subtle defect in ovulatory function or
increases the number of mature follicles so increasing the
likelihood of pregnancy (Guzick et al., 1998). Here the
success rate has been, understandably, notably less than in
anovulatory women. In a collection of data on the efficacy of
treatment for unexplained infertility, the use of CC alone pro-
duced a pregnancy rate of 5.6% per cycle and CC combined
with IUI 8.3% per cycle (Guzick et al., 1998). While this is
significantly superior to timed intercourse alone, it should be
remembered that the baseline level from merely expectant
treatment in these cases ranges from 1.3 to 4.1%.
In IVF, co-treatment with CC and gonadotrophins has
enjoyed brief periods of popularity as an attempt to decrease
costs of medications. However, this co-treatment never
seemed to achieve the same results as the more favoured
protocols of today, and this combination is rarely used now.
Possible alternatives to clomiphene
Three possible contenders have emerged as the replacement
of CC as primary, first-line treatment for oligo- or
2046
anovulation and WHO group II infertility: (i) metformin; (ii)
aromatase inhibitors; and (iii) recombinant FSH.
Metformin
PCOS is associated with , 75% of all cases of anovulatory
infertility. Insulin is of prime importance in the pathophysio-
logy of PCOS. The rate of insulin resistance in women with
PCOS is 50 –80%, which means that a very large proportion
of cases of anovulation and infertility is associated with
hyperinsulinaemia and that the lowering of insulin concen-
trations provides a new therapeutic pathway. Weight loss in
the obese is a very effective way of achieving this, but
weight loss and lifestyle change often seem to be insurmoun-
table objects for the obese patient with PCOS and are not
applicable for lean patients. The alternative possibility of
using insulin-lowering drugs (particularly metformin) is
presently undergoing a thorough examination.
Metformin is an oral biguanide, well established for the
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treatment of hyperglycaemia, that does not cause hypoglycae-
mia in normoglycaemic patients. It is an insulin sensitizer
which reduces insulin secretion and, consequently, lowers
circulating total and free androgen levels with a resulting
improvement of the clinical sequelae of hyperandrogenism.
Importantly, it also seems to have a direct action on ovarian
theca cells to decrease androgen production (Attia et al.,
2001; Mansfield et al., 2003).
Metformin is taken orally in a dose of 1500 –2500 mg.
About 15 –20% of patients may suffer from gastrointestinal
side effects. The indications for giving metformin to women
with anovulatory PCOS have become progressively wider as
it seems to be difficult to predict which individuals will
respond well with this medication (Fleming et al., 2002). The
difficulties of accurately measuring insulin sensitivity in all
PCOS patients and the suggestion that metformin may also
be effective in non-hyperinsulinaemic subjects (Baillargeon
et al., 2004) has encouraged ‘blanket’ treatment with metfor-
min of all PCOS patients in many centres. The wisdom of
this strategy awaits ratification or, as noted by Harborne et al.
(2003) in a critical review of the literature, clinical practice
is ahead of the evidence.
Here I will consider the best available evidence for the
treatment of anovulatory infertility with metformin, both as a
single agent and in combination with CC.
Metformin alone. There are now a large number of studies
published on the effect of metformin in a dose of 1500 –
2550 mg/day in women with PCOS. The majority of these
studies have demonstrated a significant improvement in insu-
lin concentrations, insulin sensitivity and serum androgen
concentrations, accompanied by decreased LH and increased
sex hormone-binding globulin (SHBG) concentrations
(Nestler et al., 2002). The restoration of regular menstrual
cycles by metformin has been reported in a large majority of
published series, and the reinstatement of ovulation occurred
in 78 –96% of patients (Velazquez et al., 1997; Nestler et al,
1998, Nestler et al., 2002; Moghetti et al., 2000; Ibanez et al.,
2001; Fleming et al., 2002; Harborne et al., 2003;
Baillargeon et al., 2004; Kashyap et al., 2004). Fleming et al.
(2002), in the largest randomized placebo-controlled trial,

demonstrated a significantly increased frequency of ovulation
with metformin (850 mg, twice a day) compared with placebo
in a group of 92 oligomenorrhoeic women with PCOS.
Although significant, the increased frequency of ovulation
was modest [relative risk (RR) 1.29, 95% confidence interval
(CI) 1.00 –1.66]. In a systematic review (Kashyap et al.,
2004), metformin was found to be 50% better than placebo
for ovulation induction in infertile PCOS patients (RR 1.5,
CI 1.13– 1.99). In a meta-analysis (Lord et al., 2003), the
superiority of metformin over placebo in inducing ovulation
was emphatic [odds ratio (OR) 3.88, CI 2.25– 6.69].
Interpretation of studies evaluating the effect of metformin
as a sole agent for the induction of ovulation is made difficult
by their heterogeneity as regards selection of patients whether
hyperinsulinaemic, hyperandrogenaemic, diagnosis of PCOS,
obese or slim, duration of metformin administration and dose,
etc. Although it now seems obvious that metformin is superior
to placebo in inducing ovulation, none of the studies was pow-
ered to assess pregnancy as an outcome.
Comparisons of CC with metformin as single agents for
the induction of ovulation and attainment of pregnancy must
therefore await the results of a sufficiently powered random-
ized controlled trial (RCT), directly comparing the two.
Metformin þ CC. The combination of CC and metformin, at
the present state of knowledge, seems to be more effective
than either CC or metformin given alone regarding both ovu-
lation induction and pregnancy. This would seem to be the
case reflected by two meta-analyses (Lord et al., 2003;
Kashyap et al., 2004). In the first, metformin þ CC was
found to be more effective than CC alone in achieving ovu-
lation (OR 4.41, CI 2.37 –8.22) and also demonstrated a sig-
nificant effect for the combination on pregnancy rates (OR
4.4, CI 1.96 – 9.85). In the second, metformin þ CC was 3 –
4 times superior to CC alone for both ovulation induction
and achievement of pregnancy. However, caution is advised
as numbers are small in both these analyses, and some
recently conducted large RCTs comparing metformin þ CC
versus CC alone are not demonstrating any significant differ-
ences. As these results have not yet been officially published,
judgment should be reserved, but initial enthusiasm will
probably be dampened.
It is, however, interesting to examine the individual pub-
lished studies. In an RCT performed on CC-resistant infertile
patients with PCOS, compared with CC and placebo, metfor-
min markedly improved ovulation and pregnancy rates when
combined with CC (Vandermolen et al., 2001). In a large
study, 46 anovulatory obese women with PCOS who did not
ovulate on metformin or placebo for 35 days were given
50 mg of CC daily for 5 days while continuing metformin or
placebo. Of those on metformin, 19 of 21 ovulated compared
with two of 25 on placebo (Nestler et al., 1998). In an inter-
esting RCT, CC-resistant women with PCOS received either
metformin for 6 months and then CC, or HMG alone for ovu-
lation induction (George et al., 2003). In this small study, as
metformin þ CC was equally as effective as HMG, less
expensive and more convenient, it was suggested as an inter-
mediary step for CC-resistant patients, worth trying before
resorting to HMG.
Clomiphene citrate—end of an era?
Safety. The evidence is so far encouraging concerning the
efficiency and safety of metformin as a single agent or in
combination with CC for induction of ovulation in women
with hyperinsulinaemic PCOS (Homburg, 2002). In addition,
metformin seem to be safe when continued throughout preg-
nancy, having no increase in congenital abnormalities, terato-
genicity or adverse effect on infant development (Glueck
et al., 2002). Preliminary data even suggest that this strategy
can significantly decrease the high miscarriage rate usually
associated with PCOS and reduce the incidence of gestational
diabetes, pre-eclampsia and fetal macrosomia (Glueck et al.,
2002; Jacubowicz et al., 2002). The apparent lack of terato-
genicity of metformin has earned it a B classification and,
hopefully, these apparently beneficial effects of metformin
given throughout pregnancy will be confirmed by future
studies.
The glitazones, notably rosiglitazone and pioglitazone,
which also have the property of lowering insulin concen-
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trations, are also under investigation for similar indications.
It is too premature to judge their effect on ovulation induc-
tion for WHO group II anovulation. A positive effect for
rosiglitazone when used alone and more so when combined
with CC was demonstrated for ovulation induction in women
with PCOS (Ghazeeri et al., 2003). In women with PCOS but
normal insulin sensitivity, metformin proved more efficient
than rosiglitazone in restoring ovulation (Baillargeon et al.,
2004).
Aromatase inhibitors
A compound capable of inducing ovulation but devoid of the
adverse anti-estrogen effects of CC could be a serious chal-
lenger for the role of first-line treatment for WHO group II
oligo/anovulation.
Aromatase inhibitors are non-steroidal compounds that
suppress estrogen biosynthesis by blocking the action of the
enzyme aromatase which converts androstenedione and tes-
tosterone to estrogens. Letrozole, the most widely used
aromatase inhibitor, has mainly been employed for the treat-
ment of post-menopausal women with advanced breast
cancer. It is given orally in a dose of 2.5 –5 mg/day and is
almost free of side effects.
It has been hypothesized, in particular by Mitwally and
Casper (2001), that the efficient estrogen-lowering properties
of the aromatase inhibitors could be utilized to temporarily
release the hypothalamus from the negative feedback effect
of estrogen so inducing an increased discharge of FSH.
Although the final pathway, the sought-after discharge of
FSH, is common to both aromatase inhibitors and CC, their
mechanism of action is obviously very different and this
would seem to confer several advantages to aromatase inhibi-
tors for the induction of ovulation.
Unlike CC, which blockades and depletes estrogen recep-
tors, aromatase inhibitors have no effect on estrogen recep-
tors. Aromatase inhibitors should, therefore, not have any
deleterious effect on cervical mucus or endometrium, quite
frequently a side effect of CC which interferes with the
attainment of a pregnancy during ovulation induction therapy
and is probably the main reason for the gap between
2047
R.Homburg
ovulation and pregnancy rates. This can theoretically be
avoided when aromatase inhibitors are used for the same
purpose.
With aromatase inhibitors, estrogen production is even-
tually advanced by the induced FSH discharge but, in con-
trast to the use of CC, the hypothalamus is able to respond to
the estrogen feedback with a negative feedback mechanism.
This will modulate an overzealous discharge of FSH which
in turn is more likely to result in a monofollicular ovulation
with moderate estrogen concentrations. This is all the more
poignant as aromatase inhibitors have a much shorter half-
life (, 2 days) than CC. This confers an additional theoretical
advantage to aromatase inhibitors as the prevalence of mul-
tiple pregnancies could therefore be expected to be less than
that witnessed with the use of CC for ovulation induction.
The solid, evidence-based data that are needed to convert
these hypothetical advantages into demonstrable practical
expression are, at the time of writing, still thin on the ground.
However, much groundwork to examine the use of the
aromatase inhibitor letrozole in reproductive medicine has
come from the team of Casper and Mitwally.
In a preliminary trial, 12 anovulatory PCOS patients and
10 ovulatory patients were given letrozole 2.5 mg/day on
days 3– 7 of the cycle. Endometrial thickness, which had
been severely depressed in previous CC-treated cycles, was
markedly improved by letrozole which was as efficient as CC
for ovulation induction. A direct comparison of letrozole
with 50 mg/day of CC in ovulatory women in an RCT
showed similar effects on stimulation of folliculogenesis,
whilst endometrial thickness was maintained by letrozole
despite much lower estradiol concentrations than with CC at
mid-cycle (Fisher et al., 2002).
A comparison of a very large number of cycles for timed
intercourse or IUI included natural (423), CC- (994) and letro-
zole- (167) treated cycles (Mitwally and Casper, 2003). The
pregnancy rate with letrozole was more than twice that in
natural or CC-stimulated cycles, while both multiple preg-
nancy and abortion rates were significantly lower in letrozole
compared with CC cycles. A small pilot study comparing CC
(100 mg/day) with letrozole in IUI cycles demonstrated sig-
nificantly less estradiol and fewer follicles developing in the
letrozole cycles (Fatemi et al., 2003).
The conclusion for the moment is that, although some
groundwork has been done, before aromatase inhibitors can
be regarded as possible replacements for CC for the first-line
treatment of anovulatory infertility, some solid, evidence-
based medicine is badly needed.
The use of aromatase inhibitors should theoretically result
in an accumulation of androgens whose conversion to estro-
gens is being blocked. This would, theoretically, be an
unwanted by-product, especially for women with PCOS who
already have an excessive production of androgens. However,
paradoxically, this may be a further advantage as androgens
may have a stimulatory role in early follicular growth by
augmenting follicular FSH receptor expression and therefore
amplifying FSH effects (Weil et al., 1999). This may explain
the relative success of combined letrozole and FSH for ovar-
ian stimulation in improving the response to FSH, reported in
2048
two studies. The first (Mitwally and Casper, 2002) is a report
in which a group of poor responders to FSH for IUI were
given co-treatment with letrozole, 2.5 mg/day from day 3 to
day 7 of the cycle. A lower FSH dose and a significantly
higher number of mature follicles were achieved with the
combined treatment. These preliminary findings were con-
firmed in a large series, albeit retrospective and non-random-
ized, comparing stimulation with FSH alone (145 cycles) or
the combined therapy (60 cycles) (Healey et al., 2003). The
addition of letrozole to gonadotrophin treatment again
decreased the dose of gonadotrophins and increased the num-
ber of pre-ovulatory follicles. Prospective, randomized trials
are needed to verify these interesting findings.
A subgroup of infertile women have been found to express
high levels of aromatase P450 in the endometrium, and this
was associated with poor IVF outcomes (Brosens et al.,
2004). This raises the interesting question of whether letro-
zole or anastrozole could alleviate this situation and improve
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results.
Many other questions regarding the use of aromatase
inhibitors in the treatment of infertility still remain (de
Ziegler, 2003). Trials with aromatase inhibitors have, reason-
ably, mimicked treatment with CC, being administered on
days 3 –7 of the cycle. Would treatment beyond day 7 inter-
fere with the estradiol rise induced by rising FSH concen-
trations and have a deleterious effect on the endometrium
and oocyte quality? In his commentary, de Ziegler (2003)
also questions the timing of aromatase inhibitor adminis-
tration when the intention is to enhance the sensitivity to
FSH receptors by increasing follicular androgen content.
Would it not be more logical to prime with aromatase inhibi-
tors before exposure to FSH? Further, although the dose of
2.5 mg of letrozole is standard for the treatment of breast
cancer, should the same dose be used for the treatment of
infertility? Biljan et al. (2002), for example, found that a
daily dose of 5 mg/day produced more mature follicles appar-
ently by further extending the FSH window.
It is a little too early to enthuse optimistically about the
chances of letrozole and anastrozole conquering the fertility
market, but now the initial pilot studies have been completed,
I believe that there is enough there to encourage serious trials
for this potentially valuable, simple and inoffensive
treatment.
Low-dose FSH
The third possible alternative to CC as first-line treatment for
WHO group II infertility is low-dose FSH. In contrast to the
conventional gonadotrophin regimen for treating this group
of patients, in particular those with PCOS, the low-dose
protocol is designed to attain and maintain follicular
development, ideally one dominant follicle, without exceed-
ing the FSH threshold requirement of the ovary (Polson et al.,
1987). Now in common use, the common complications of
conventional gonadotrophin therapy have been severely
reduced. With low-dose FSH, multiple pregnancy rates
should not exceed 6% and OHSS is almost completely elimi-
nated, while acceptable pregnancy rates are achieved
(Table IV). A consistent rate of 70% of monofollicular

Table IV. Results of treatment of clomiphene-resistant patients with low
dose, step-up FSH
No. of patients
No. of cycles
Pregnancies (% patients)
Fecundity/cycle
Uni-ovulation
OHSS
Multiple pregnancies
Updated from Homburg and Howles (1999).
ovulation in achieved in these cycles (Homburg and Howles,
1999). The classical low-dose regimen is step-up, employing
a low starting dose (usually 50– 75 IU of FSH) with small
incremental dose rises (25 – 37.5 IU) on the starting dose if
necessary after 14 days and then at weekly intervals. Once
follicular development is initiated, that dose is maintained
until criteria for HCG administration are reached.
Until now, low-dose FSH has only been administered to
CC-resistant patients, and the results in Table IV only refer
to these patients. Based on this collection of published
results, Table III, column 3 illustrates a projection of these
results for 100 patients starting treatment, terminating in 30
singleton live births and two multiple pregnancies. If low-
dose FSH were to be used as first-line treatment, rather than
CC, based on the assumption that all those who would have
conceived on CC and 40% of those who would be CC resist-
ant would also conceive on low-dose FSH, 45 of 100 starters
could expect a singleton live birth and three a multiple preg-
nancy (Table III, column 4). If this supposition is confirmed,
then the treatment – conception interval would be consider-
ably reduced and efficiency greatly increased by eliminating
the time and the need for monitoring and treatment costs of
3 –12 cycles of CC therapy. Although costs of medication
and patient comfort obviously differ, these may well be
negated by a much more efficient first-line treatment.
One, single centre, randomized trial has tested this hypoth-
esis (Lopez et al., 2004) but, unfortunately, the size of the
groups (38 patients in each arm) did not allow firm con-
clusions. Nevertheless, the RR and 95% confidence intervals
were 1.78 (0.92 – 3.54) for pregnancy rate per woman and
1.83 (0.79 – 4.40) for live births per woman in favour of FSH.
These are almost identical figures to those that had been pre-
dicted, prior to this study, in Table IV, based on assumptions
and previous results (1.72 for pregnancy rates and 1.80 for
live birth rates in favour of FSH).
A sufficiently powered, multicentre, multinational trial is
now well under way to compare CC with low-dose FSH as
first-line treatment for women with anovulatory infertility
associated with PCOS. Combined with a cost-efficiency
assessment, it will tell us whether replacing CC with
low-dose FSH is a feasible proposition.
Other possible first-line therapies
The use of pulsatile GnRH for the treatment of anovulatory
(WHO group II) infertility has largely been abandoned.
Although a normal pattern of pulsatile release of GnRH can
be superimposed on the abnormal pattern found in these
Clomiphene citrate—end of an era?
women, results regarding pregnancy rates have been impeded
by obesity, hyperandrogenaemia and a high miscarriage rate,
although multiple pregnancies could be largely avoided
841
1556 (Homburg et al., 1989).
320 (38%) Laparoscopic ovarian drilling, although a very viable
20% second- or third-line therapy for anovulation associated with
70%
0.14% PCOS, especially in normal weight patients with a high LH
5.7% concentration, has not seriously been considered as an
alternative to CC as first-line treatment.
Conclusions
The possibility of replacing CC as first-line treatment for
anovulatory eu-estrogenic infertility with either metformin,
aromatase inhibitors or low-dose FSH still needs to be sub-
stantiated. RCTs are underway to examine all these possibili-
ties, all of which are theoretically well based. At least until
the publication of the results of these trials, CC will remain
Downloaded from humrep.oxfordjournals.org by guest on February 25, 2011
the first-line treatment for eu-estrogenic anovulatory inferti-
lity although, in my humble opinion, aromatase inhibitors
and/or low-dose FSH therapy may well take its place in the
next few years.
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Submitted on November 12, 2004; resubmitted on February 13, 2005;
accepted on April 3, 2005
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2051