Full text of DOI:10.1016/S1472-6483(10)61821-4

RBMOnline - Vol 4. No 3. 303–310 Reproductive BioMedicine Online; www.rbmonline.com/Article/47 on web 5 April 2002
Reviews
Clomiphene citrate and ovulation induction*
Hugo Sovino trained in the School of Medicine at the University of Chile and gained distinction in his MD degree there
in 1996. Between 1996 and 1999 he was Obstetrics and Gynecology Resident at the San Juan De Dios Hospital
National Health Service, University of Chile where he obtained his Obstetrics and Gynecology degree, again with
distinction. He has an ongoing Organon fellowship in Reproductive Endocrinology and Infertility at the San Borja
Hospital, National Health Service, University of Chile. He was awarded the Chilean Fertility Society prize in 2001 for
his work entitled ‘Microdeleciones del cromosoma Y en fertilidad masculina’. He is a member of the Chilean Society
of Obstetrics and Gynecology.
Hugo Sovino1,3, Teresa Sir-Petermann2 and Luigi Devoto1
1Instituto de Investigación Materno Infantil, Departamento de Obstetricia y Ginecología, Unidad de Medicina
Reproductiva, Campus Centro, Universidad de Chile, Hospital Clínico San Borja Arriarán
2Unidad de Endocrinología, Campus Occidente, Universidad de Chile. Hospital San Juan de Dios
3Correspondence: PO Box 226–3, Santiago, Chile. Tel: 56 2 5568866; Fax: 56 2 5546890; e-mail: hsovino@yahoo.com
Abstract
Clomiphene can be used to treat anovulation due to hypothalamus or pituitary gland dysfunction, and it normalizes the luteal
phase in stimulated patients. It can be used to estimate ovarian follicle reserve, and may be predictive of ovulation in women
aged ≥35 years or with failed IVF. Contraindications include risk of congenital anomalies, chronic liver disease and visual
disorders. Clomiphene may impair fertility through its effects on cervical mucus and in causing various endometrial
dysfunctions. However, if clomiphene is administered in 50 mg doses, side-effects are avoided and efficacy is similar to that
of a 100 mg dose, although daily dosages of 200 mg/day over 5 days can induce ovulation in ~70% of treated patients.
Gonadotrophin concentrations increase up to days 5–9 when follicles are selected, and clomiphene is effective in patients
with polycystic ovary syndrome (PCOS). Fifty percent of normal patients conceive, a value perhaps biased by the
antagonistic effects of clomiphene on cervical mucus in some women. Clomiphene is valuable for IVF, and is used by some
clinics in combination with HMG or recombinant FSH. Resistance to clomiphene can develop, and human chorionic
gonadotrophin may be needed to induce ovulation in clomiphene cycles. Corticosteroids and human menopausal
gonadotrophin (HMG) can be combined with clomiphene for stimulation, its combination with HMG long having been a
standard protocol in assisted reproduction. PCOS patients may become insulin resistant, a condition improved by the
administration of metformin. Other adverse effects include multiple pregnancies, an increase in the rate of multiple births,
ovarian hyperstimulation and unsubstantiated claims of ovarian cancer.
Keywords: anovulatory infertility, clomiphene, GnRH agonist, IVF, ovulation induction, polycystic ovary syndrome
Clomiphene has two isomeric forms, cis and trans, which in
the current nomenclature correspond to zuclomiphene and
Introduction
enclomiphene respectively (Figure 1). The action of
zuclomiphene is mainly anti-oestrogenic, whereas
enclomiphene has oestrogenic effects. The commercial
Clomiphene citrate (clomiphene), is the most commonly used
drug for ovulation induction, since it is inexpensive, highly
effective and user-friendly. It was first synthesized in 1956 and
has been commercially available since 1961. It constitutes the
treatment of choice in hyperandrogenic chronic anovulation
and other forms of anovulation with an adequate oestrogen
reserve. It is also used in the functional assessment of the
gonadal axis, may be combined with gonadotrophins in the
therapy of selected cases of controlled ovarian
hyperstimulation, and can be used with or without
gonadotrophins in assisted reproductive techniques.
preparation is
a racemic mixture that contains 40%
zuclomiphene and 60% enclomiphene.
Clomiphene binds to the oestrogen receptor, but contrary to
what happens with oestradiol, its binding is more prolonged
(Adashi et al., 1980). This results in a decrease of the
oestrogenic effect; nevertheless, clomiphene has a certain
agonistic effect, especially in hypo-oestrogenic states.
Following oral intake of clomiphene, absorption is fast,
although the drug has a long half-life. Up to 50% of a dose of
clomiphene can be found 5 days after administration and the
drug and its metabolites are detected in faeces as long as 6
weeks after ingestion (Figure 1).
Structure and action of clomiphene
Chemical structure and pharmacokinetics
From the chemical standpoint, clomiphene is a tri-phenylene
derivative with structural similarities to diethylboestrol.
303
303
*This review will also be published in a Spanish text book entitled
Modern Assisted Conception.

Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.
aimed at predicting a woman’s fertility potential. The most
interesting of these tests are the baseline measurement of FSH
on day 3 of the menstrual cycle, baseline FSH plus oestradiol
on day 3 of the menstrual cycle, the clomiphene citrate test,
GnRH-agonist stimulation test and the measurement of inhibin
B. These tests are intended to evaluate the number of ovarian
follicles and the quality of the oocyte, and the best
characterized and most sensitive of them so far is the
clomiphene citrate test. This was first described in 1987, and
was used to evaluate ovarian reserve in women aged ≥35
years. This functional test involves measuring serum FSH on
day 3 of the menstrual cycle, followed by a new assessment on
day 10 after the administration of clomiphene at a dose of 100
mg/day, from day 5 to day 9 (Figure 3). Conception rates are
low when the sum of FSH values is >26 IU/l (Loumaye et al.,
1990). The sensitivity of the test is 26%, which is much higher
than the isolated measurement of FSH. The specificity for both
tests reaches 96%. The predictive success of the clomiphene
citrate test depends directly on the population studied, since its
highest positive predictive value of 98% is observed in the
evaluation of patients scheduled for IVF. Its value declines
dramatically to 87% when used in a population of women aged
≤33 years (Barnhart and Osheroff, 1999).
Mechanism of action
Two or 3 days after starting clomiphene administration in the
follicular phase of the ovarian cycle, the pulse frequency of LH
increases, suggesting that the main action of the drug is to
increase pulsatile secretion of gonadotrophin-releasing
hormone (GnRH) by the hypothalamus (Sir et al., 1989).
Clomiphene could also have a direct oestrogenic effect on the
gonadotrophs, enhancing sensitivity to GnRH. As
a
consequence of the effects mentioned above, there is an
increase in plasma concentration of gonadotrophins and in the
number of follicles recruited. There is a resulting increase in
plasma concentrations of oestradiol before ovulation and of
progesterone during the luteal phase. Between 30 and 35% of
patients who ovulate with clomiphene do so with a follicular
rupture diameter that is larger than expected, as compared with
spontaneous cycles. Moreover, clomiphene has a direct
oestrogenic effect on the ovary, resembling that described for
the pituitary gland. It sensitizes granulosa cells in the follicle
to the action of gonadotrophins and up-regulates aromatase
activity. Its effects on the cervix and endometrium are mainly
anti-oestrogenic (Figure 2). The different modulating effects
(agonistic or antagonistic) shown by clomiphene on the
effectors of the genital tract might be due to the different
populations of α- or β-oestrogen receptors in those tissues
(Goldstein et al., 2000) (Figure 2).
In summary, there is evidence supporting the predictive value
of this test in a population of women with high risk of failure
in assisted reproductive medicine. This high-risk group
includes women >35 years of age, who respond poorly to
ovarian stimulation, and women who have failed with previous
IVF cycles (Figure 3).
Indications and uses
Indications
Contraindications
The main indication for clomiphene is to induce ovulation in
patients with anovulation due to hypothalamic and pituitary
dysfunction. Oestrogen concentrations in these patients are
>50 pg/ml, especially in those with polycystic ovary syndrome
(PCOS), oligomenorrhoea and secondary amenorrhoea of
various aetiologies with low or normal concentrations of
gonadotrophins and prolactin. Clomiphene has also been
proposed for the treatment of short luteal phase, and to assess
The administration of clomiphene is contraindicated during
pregnancy, since it can cause congenital abnormalities. It is
also contraindicated in chronic liver disease, since it is mainly
cleared through the liver, and in the presence of functional
ovarian cysts, which could grow larger. It is also
contraindicated when there is a history of visual disorders
(blurred vision and scotomas) during or after previous therapy
with clomiphene. Its use in women who are infertile through
non-ovulatory factors remains controversial. Furthermore, it is
not recommended in ovulatory patients because its
administration may paradoxically cause disorders leading to a
decrease in fertility. Such disorders include a reduction in the
amount and quality of cervical mucus, abnormal development
and
diagnose
the
function
of
the
hypothalamus–pituitary–ovarian axis.
Evaluation of ovarian follicle reserve
Numerous researchers have proposed various functional tests
304
Figure 1. Clomiphene citrate.

Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.
or dysfunction of the endometrium, reduction in adhesion
proteins (integrins, mainly subunit β3), decline in glandular
density and an increase of vacuolated cells in the endometrium
of ovulatory women (Palomino et al., 1998; Sereepapong et
al., 2000).
discrepancy observed between the ovulation index and the
fecundity index could be due to many factors. These include
the coexistence of a male factor, the existence of other causes
of infertility or an anti-oestrogenic effect of clomiphene on
some effectors of the reproductive tract. This effect is known
to arise in cervical mucus and its interaction with spermatozoa,
in tubal transport of ova, and in the function and
synchronization of the endometrium (Palomino et al., 1998).
These observations suggest that the use of clomiphene in
ovulatory patients would not be beneficial, since it would
reduce their fecundity index.
Ovulatory response and pregnancy
predictors
Forms of use and outcomes
Clomiphene is preferably administered in 50 mg doses for 5
days from days 3–5 of a spontaneous or induced menstrual
flow (Figure 4a). Starting with higher doses fails to provide
any advantages for the following two reasons. First, the
administration of clomiphene at doses of 50 or 100 mg a day
results in similar pregnancy rates. Second, the incidence of
side-effects is dose-dependent, with adverse reactions first
being observed with initial doses of 50 mg/day. Starting
therapy with higher doses (100 mg/day) could result in more
severe reactions. In hyper-reacting women (those who have
developed ovarian cysts or hyperstimulation in previous
cycles), lower doses (12.5–25 mg) may prevent
hyperstimulation. In hyporeacting patients, such as obese
women, induction is started with a dose of 100 mg a day. The
clomiphene dose may be increased progressively up to a
maximum of 200 mg/day for 5 days. Fewer than 50% of
hyporeacting patients will ovulate at that dose. Approximately
50% of normal women ovulate with a dose of 50 mg, and an
additional 20% will ovulate with 100 mg/day, the overall
ovulation rate ranging from 70 to 85%.
Predictors of the ovulatory response to clomiphene are body
mass index, the free androgen index, ovarian volume (Imani et
al., 1998), and low concentrations of IGF-BP-I. On the other
hand, pregnancy predictors with clomiphene are age and the
severity of the cycle disorders, i.e. better responses occur in
women of
a
younger age and with maintained
oligomenorrhoea or amenorrhoea, suggesting that FSH
threshold (amount of FSH required to stimulate the follicular
maturation and the ensuing ovulation) and oocyte quality are
specifically regulated (Imani et al., 1999) (Figure 4).
Clinical treatments using
clomiphene
Use of clomiphene citrate in IVF
Clomiphene citrate (clomiphene) was one of the first drugs
used in the initial protocols for ovulation induction for IVF and
embryo transfer, either alone or in combination with urinary
gonadotrophins (Quigley et al., 1984). However, in the last 10
years, clomiphene has lost popularity, having been replaced by
the combination of GnRH agonists (GnRHa) and
gonadotrophins in almost all centres in which IVF is
performed, including our own.
The method that proposes starting patients on clomiphene on
day 5 of the menstrual cycle is empirical, yet, it can be
reasonably justified on the basis of the following observations
on ovarian physiology. Clomiphene induces an increase in
gonadotrophins on days 5–9 of the cycle, i.e. when the follicle
is selected. Follicular maturation beginning at that time is
characterized by the development of a preovulatory follicle,
the elevation of circulating oestrogens, a preovulatory surge of
LH and discharge of LH leading to ovulation with high post-
ovulatory levels of progesterone (Figure 4b).
In spite of the 20 years that has elapsed since the birth of a
child through IVF techniques, there continues to be no
consensus among researchers regarding the best scheme for
ovarian stimulation capable of providing optimal ovarian
responses together with successful outcomes. One of the
critical factors impinging on the routine use of IVF is the high
cost of drugs, especially those schemes using recombinant
FSH and GnRHa. This factor, together with the high costs of
the new techniques that are becoming increasingly frequent,
Cycles induced with clomiphene in patients presenting with
PCOS differ from those of ovulatory women, since the former
show higher oestrogen and progesterone concentrations
(Kettel et al., 1993). The early administration of clomiphene
could theoretically produce multiple follicular maturation,
generating a higher incidence of multiple pregnancies.
Nevertheless, no differences have been observed in ovulation,
pregnancy, or miscarriage rates with clomiphene administered
from days 2, 3, 4 or 5 of the cycle in the usual protocols for
ovulation induction. Following the final dose of clomiphene
on day 9 of the cycle, the LH surge may occur at any time
between 5 and 12 days after the last dose. It occurs most
frequently at 6–7 days after the last dose, especially with
clomiphene from days 5–9 of the cycle (Figure 4a). This
observation is important in the planning of coitus. Couples are
told they must have sexual intercourse for a week, starting on
day 5 after the last clomiphene tablet.
Table 1. Results of IVF with clomiphene citrate (clomiphene)
or gonadotrophin-releasing hormone agonist (GnRHa),
associated with human menopausal gonadotrophin (HMG).
HMG+
clomiphene
HMG
GnRHa +
HMG
Cycles started (n)
Cycles cancelled (%)
Oocytes per aspirate (n) 6.4
Embryos per aspirate (n) 3.94.1
No. pregnancies
1063
23.5
395
35.2
7.4
689
10.9
11.1
5.9
per aspirate (%)
No. of births
per aspirate (%)
58 (21.8)
28 (16.4) 30 (22.5)
23 (12.9) 21 (18.1)
44 (17.3)
305
Only 40–50% of ovulatory patients become pregnant. The

Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.
Figure 2. Sites of action of clomiphene citrate.
Figure 3. Clomiphene citrate test.
306
Figure 5. Monitoring of clomiphene citrate.

Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.
a.
Figure 4a.
Form of use of
clomiphene.
b.
Figure 4b.
Ovulation
induction with
clomiphene
citrate in patients
with polycystic
ovary syndrome.
307

Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.
such as intracytoplasmic sperm injection, makes it very
expensive for many infertile couples needing IVF. In view of
this situation, it is necessary to reassess ovulation induction
schemes, to reduce costs while avoiding any negative impact,
to the greatest possible extent, on success rates. Clomiphene is
cheaper to use and it is safe, but its usage in the new IVF
schemes requires complete evaluation. Some investigators
believe that the use of clomiphene in IVF schemes is not
justified, in view of its adverse effects on the endometrium,
which could influence the outcomes of treatment. At present,
clomiphene is used in some IVF programmes in combination
with human menopausal gonadotrophin (HMG), prior to the
use of GnRHa.
the discontinuation of oral contraceptives (Branigan and Estes,
1999). This observation enabled researchers to design the
‘minimal stimulation study’, using clomiphene at 100 mg/day
for 8 days starting on day 3 of the cycle in a group of 36
candidates for IVF. These patients had undergone down-
regulation with oral contraceptives 2 months prior to ovulation
induction. No LH surge was observed in this group of patients.
Their average number of mature oocytes recovered was 3.2,
with a 90% fertilization rate and an average number of 2.5
embryos transferred, and a 32.8% pregnancy rate per
aspiration. These outcomes were similar to those obtained in
IVF stimulated cycles, and this schedule has the advantages of
being cheap and simple, while presenting low risks for the
patients (Branigan and Estes, 2000).
The theoretical advantages of combining HMG and clomiphene
are the strength of the luteal phase supported by clomiphene, a
lesser need for HMG and higher concentrations of progesterone
in the luteal phase, which often renders luteal support
unnecessary. Table 1 shows the results obtained from IVF
cycles between 1983 and 1990, at the New Orleans Fertility
Institute, comparing HMG/clomiphene, HMG alone and
GnRHa/HMG (Dickey et al., 1998). Clinical pregnancies and
birth rates were higher with HMG/clomiphene than with HMG
alone, and the results were similar to those obtained with
GnRHa/HMG. The main advantage seen with GnRHa/HMG
was that fewer cycles were cancelled, which is probably related
to the beneficial effect of GnRH agonists, in reducing premature
luteinization caused by an early LH surge. As a result, more
oocytes are obtained, and that in turn makes it possible to
generate more cryopreserved embryos with this therapy.
Association with other drugs
There is a group of patients, estimated as between 10% and
20%, in whom doses of 150 mg clomiphene citrate per day for
5 days do not result in ovulation after three or more attempts,
and/or who fail to conceive after 4–6 months of this induction
protocol. This group of patients is said to be clomiphene
resistant. When this phenomenon occurs, clomiphene may be
administered with other drugs, after evaluating the individual
patient characteristics (body mass index, hirsutism, acanthosis
nigricans, galactorrhoea), together with a baseline functional
assessment including ultrasonography, total testosterone, sex
hormone binding globulin, free androgen index, DHEA-S,
prolactin and progesterone in the luteal phase. This is followed
by the evaluation of the cervical mucus, endometrial thickness
and follicular size during the follicular follow-up.
As clomiphene is only used at doses between 50 and 150
mg/day, more than one follicle may progress to the
preovulatory state, and an average number of two or three
oocytes are aspirated from each woman (Marrs et al., 1984).
The combination of clomiphene and gonadotrophins yields a
better ovarian response, with more oocytes and with better
morphology, as compared with clomiphene alone (Quigley et
al., 1984). This observation could be explained by several
mechanisms. When clomiphene is administered for 5 days
during the early follicular phase (days 3–7 of the cycle), it not
only stimulates the secretion of FSH, but also LH, which may
result in relatively high concentrations of LH during the
follicular phase (Messinis and Templeton, 1986). This could
cause early luteinization of granulosa cells, and so alter the
outcomes of pregnancy (Stanger and Yovich, 1985).
Depending on the aetiology of the condition, several drugs can
be administered with clomiphene citrate, including the
following. The first is human chorionic gonadotrophin (HCG),
which is used when anovulation persists in spite of good
follicular development and adequate oestrogen production. It
is administered at doses of 5000–10,000 IU, when the
dominating follicle reaches a diameter of ≥18 mm and the
concentration of oestrogens exceeds 200 pg/ml. HCG can also
be added in cases of luteal failure.
Corticosteroids are especially indicated in hyperandrogenic
chronic anovulation, preferably of adrenal origin, using
0.5–1.0 mg dexamethasone q.h.s, which leads to a 70–90%
increase in the ovulation rate. Dopaminergic agonists are
indicated in chronic anovulation associated with
hyperprolactinaemia. Pituitary gonadotrophins are used when
ovulation does not occur, but moderate follicular development
is achieved.
A new strategy for the use of clomiphene in combination with
GnRH antagonist for ovulation induction has been proposed
recently (Olivennes et al., 2000; Reissmann et al., 2000). The
physiological rationales supporting this association are mainly
based on the ability of GnRHa to reduce high concentrations
of LH generated by clomiphene. Antagonists, contrary to the
action of GnRHa, competitively block GnRH receptors at the
pituitary level, preserving the post-receptor mechanism of the
latter intact. Nevertheless, it is necessary to conduct further
studies, including an adequate number of patients, in order to
validate the bases of these new schemes.
It is possible to administer clomiphene and HMG sequentially,
which permits substantial reductions in the dose of HMG
required to produce ovulation. Progesterone is indicated when
the administration of clomiphene produces a deficient luteal
phase. It is used as pure progesterone in the luteal phase (72 h
after ovulation) at doses of 12.5 mg i.m. or 25 mg b.i.d. as
vaginal suppositories, or orally in the form of micronized
progesterone. Ethynyl oestradiol is used at low doses to
improve the quality of the cervical mucus and the endometrial
thickness, with a consequent increase in pregnancy rates (Gerli
et al., 1999).
A
study
using
the
down-regulation
of
the
hypothalamus–pituitary–ovarian axis with oral contraceptives
in patients with clomiphene-resistant PCOS showed that the
LH surge can be prevented or reduced in the cycle following
308

Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.
Hyperinsulinaemia must be corrected. Anovulatory women
who present with polycystic ovary syndrome and
hyperinsulinaemia are more resistant to clomiphene therapy.
The best treatment for such patients, who are usually obese, is
weight reduction, since both hyperinsulinaemia and
hyperandrogenism diminish when there is weight loss. Weight
reduction should represent at least 5% of the initial weight.
This metabolic improvement is linked to an increase of the
ovulation and pregnancy rates. It has been shown that when
the body mass index drops under 27, both insulin and free
testosterone concentrations fall, so improving fecundity.
Adverse effects
Adverse effects include multiple pregnancies in up to 6–8% of
cases; most of these are twins, but triplets have been reported
in 1%, quadruplets in 0.3% and quintuplets in 0.1% of
clomiphene-induced pregnancies. Furthermore, there is a 23%
rate of missed abortions, probably associated with early
resumption of oocytic meiosis due to hypersecretion of LH.
Ovarian hyperstimulation syndrome is observed in 13% of
cases treated with clomiphene, but it is usually mild. Other
minor effects include visual disorders, flushes, nausea and
breast discomfort. Ovarian cancer is an adverse effect
associated with the use of drugs to induce ovulation (Rossing
et al., 1994), although recent papers report no association
between ovarian or breast cancer and the use of clomiphene
(Potashnick et al., 1999). On the basis of these initial studies
(Rossing et al., 1994), the United Kingdom Committee for
Medical Safety recommended the use of clomiphene for 6
consecutive cycles only.
It is reasonable to think that patients with PCOS and obesity
are likely to be insulin resistant, so we recommend checking
the baseline glucose concentrations and the concentrations
after challenge with 75 g glucose, together with assays of
insulin plasma concentrations in baseline and post-challenge
conditions. If these plasma concentrations are >15 mIU/ml at
baseline or >60 mIU/ml post-challenge, the patient is
considered to be insulin-resistant and is started on metformin.
Metformin improves insulin sensitivity, but its primary effect
is a significant reduction of liver gluconeogenesis, hence
decreasing the production of glucose by the liver. Metformin
therapy reduces hyperinsulinaemia, both the baseline
concentrations and the LH-stimulated concentrations, and also
produces a fall in free testosterone concentrations in women
with PCOS who are overweight. A recent study (Nestler et al.,
1998) showed that the ovulation response to clomiphene is
enhanced by up to 90% in these women with the addition of
metformin, as compared with 8% with placebo and
clomiphene.
Conclusions
Clomiphene citrate continues to be the most commonly used
drug to induce ovulation in the treatment of
normogonadotrophic anovulatory infertility with normal
oestrogen concentrations. Its popularity is due to its low cost,
scarce adverse reactions and easy monitoring. However, its
ability to stimulate follicular stimulation is limited and it can
induce high LH concentrations. Together with other adverse
aspects in reproductive function, this limits the use of
clomiphene in the development of an optimum scheme in IVF
programmes. Consequently, clomiphene citrate is the
recommended drug for the treatment of infertility associated
with PCOS, where the main objective is to obtain development
of a single follicle and a reduction in multiple pregnancies.
The use of oral contraceptives has been described in the cycle
prior to IVF with minimal stimulation. Oral contraceptives are
administered two cycles before the use of clomiphene, and
decrease the LH surge, providing similar outcomes in terms of
pregnancy rates when compared with the cycles in which
GnRHa and gonadotrophins are used. The cost of treatment
can be significantly reduced by the use of this protocol
(Branigan and Estes. 2000).
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