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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: [email protected]

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

Introduction Clomiphene has two isomeric forms, cis and trans, which in
the current nomenclature correspond to zuclomiphene and
Clomiphene citrate (clomiphene), is the most commonly used enclomiphene respectively (Figure 1). The action of
drug for ovulation induction, since it is inexpensive, highly zuclomiphene is mainly anti-oestrogenic, whereas
effective and user-friendly. It was first synthesized in 1956 and enclomiphene has oestrogenic effects. The commercial
has been commercially available since 1961. It constitutes the preparation is a racemic mixture that contains 40%
treatment of choice in hyperandrogenic chronic anovulation zuclomiphene and 60% enclomiphene.
and other forms of anovulation with an adequate oestrogen
reserve. It is also used in the functional assessment of the Clomiphene binds to the oestrogen receptor, but contrary to
gonadal axis, may be combined with gonadotrophins in the what happens with oestradiol, its binding is more prolonged
therapy of selected cases of controlled ovarian (Adashi et al., 1980). This results in a decrease of the
hyperstimulation, and can be used with or without oestrogenic effect; nevertheless, clomiphene has a certain
gonadotrophins in assisted reproductive techniques. agonistic effect, especially in hypo-oestrogenic states.

Structure and action of clomiphene Following oral intake of clomiphene, absorption is fast,
although the drug has a long half-life. Up to 50% of a dose of
Chemical structure and pharmacokinetics clomiphene can be found 5 days after administration and the
drug and its metabolites are detected in faeces as long as 6
From the chemical standpoint, clomiphene is a tri-phenylene weeks after ingestion (Figure 1).
derivative with structural similarities to diethylboestrol. 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.

Mechanism of action aimed at predicting a woman’s fertility potential. The most

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

304 Figure 1. Clomiphene citrate.

 Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.

or dysfunction of the endometrium, reduction in adhesion discrepancy observed between the ovulation index and the
proteins (integrins, mainly subunit β3), decline in glandular fecundity index could be due to many factors. These include
density and an increase of vacuolated cells in the endometrium the coexistence of a male factor, the existence of other causes
of ovulatory women (Palomino et al., 1998; Sereepapong et of infertility or an anti-oestrogenic effect of clomiphene on
al., 2000). some effectors of the reproductive tract. This effect is known
to arise in cervical mucus and its interaction with spermatozoa,
These observations suggest that the use of clomiphene in in tubal transport of ova, and in the function and
ovulatory patients would not be beneficial, since it would synchronization of the endometrium (Palomino et al., 1998).
reduce their fecundity index.
Ovulatory response and pregnancy
Forms of use and outcomes predictors
Clomiphene is preferably administered in 50 mg doses for 5 Predictors of the ovulatory response to clomiphene are body
days from days 3–5 of a spontaneous or induced menstrual mass index, the free androgen index, ovarian volume (Imani et
flow (Figure 4a). Starting with higher doses fails to provide al., 1998), and low concentrations of IGF-BP-I. On the other
any advantages for the following two reasons. First, the hand, pregnancy predictors with clomiphene are age and the
administration of clomiphene at doses of 50 or 100 mg a day severity of the cycle disorders, i.e. better responses occur in
results in similar pregnancy rates. Second, the incidence of women of a younger age and with maintained
side-effects is dose-dependent, with adverse reactions first oligomenorrhoea or amenorrhoea, suggesting that FSH
being observed with initial doses of 50 mg/day. Starting threshold (amount of FSH required to stimulate the follicular
therapy with higher doses (100 mg/day) could result in more maturation and the ensuing ovulation) and oocyte quality are
severe reactions. In hyper-reacting women (those who have specifically regulated (Imani et al., 1999) (Figure 4).
developed ovarian cysts or hyperstimulation in previous
cycles), lower doses (12.5–25 mg) may prevent Clinical treatments using
hyperstimulation. In hyporeacting patients, such as obese clomiphene
women, induction is started with a dose of 100 mg a day. The
clomiphene dose may be increased progressively up to a Use of clomiphene citrate in IVF
maximum of 200 mg/day for 5 days. Fewer than 50% of
hyporeacting patients will ovulate at that dose. Approximately Clomiphene citrate (clomiphene) was one of the first drugs
50% of normal women ovulate with a dose of 50 mg, and an used in the initial protocols for ovulation induction for IVF and
additional 20% will ovulate with 100 mg/day, the overall embryo transfer, either alone or in combination with urinary
ovulation rate ranging from 70 to 85%. gonadotrophins (Quigley et al., 1984). However, in the last 10
years, clomiphene has lost popularity, having been replaced by
The method that proposes starting patients on clomiphene on the combination of GnRH agonists (GnRHa) and
day 5 of the menstrual cycle is empirical, yet, it can be gonadotrophins in almost all centres in which IVF is
reasonably justified on the basis of the following observations performed, including our own.
on ovarian physiology. Clomiphene induces an increase in
gonadotrophins on days 5–9 of the cycle, i.e. when the follicle In spite of the 20 years that has elapsed since the birth of a
is selected. Follicular maturation beginning at that time is child through IVF techniques, there continues to be no
characterized by the development of a preovulatory follicle, consensus among researchers regarding the best scheme for
the elevation of circulating oestrogens, a preovulatory surge of ovarian stimulation capable of providing optimal ovarian
LH and discharge of LH leading to ovulation with high post- responses together with successful outcomes. One of the
ovulatory levels of progesterone (Figure 4b). critical factors impinging on the routine use of IVF is the high
cost of drugs, especially those schemes using recombinant
Cycles induced with clomiphene in patients presenting with FSH and GnRHa. This factor, together with the high costs of
PCOS differ from those of ovulatory women, since the former the new techniques that are becoming increasingly frequent,
show higher oestrogen and progesterone concentrations
(Kettel et al., 1993). The early administration of clomiphene Table 1. Results of IVF with clomiphene citrate (clomiphene)
could theoretically produce multiple follicular maturation, or gonadotrophin-releasing hormone agonist (GnRHa),
generating a higher incidence of multiple pregnancies. associated with human menopausal gonadotrophin (HMG).
Nevertheless, no differences have been observed in ovulation,
pregnancy, or miscarriage rates with clomiphene administered HMG+ HMG GnRHa +
from days 2, 3, 4 or 5 of the cycle in the usual protocols for clomiphene HMG
ovulation induction. Following the final dose of clomiphene
on day 9 of the cycle, the LH surge may occur at any time Cycles started (n) 1063 395 689
between 5 and 12 days after the last dose. It occurs most Cycles cancelled (%) 23.5 35.2 10.9
frequently at 6–7 days after the last dose, especially with Oocytes per aspirate (n) 6.4 7.4 11.1
clomiphene from days 5–9 of the cycle (Figure 4a). This Embryos per aspirate (n) 3.9 4.1 5.9
observation is important in the planning of coitus. Couples are No. pregnancies
told they must have sexual intercourse for a week, starting on per aspirate (%) 58 (21.8) 28 (16.4) 30 (22.5)
day 5 after the last clomiphene tablet. No. of births
per aspirate (%) 44 (17.3) 23 (12.9) 21 (18.1)
Only 40–50% of ovulatory patients become pregnant. The 305
 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 the discontinuation of oral contraceptives (Branigan and Estes,
expensive for many infertile couples needing IVF. In view of 1999). This observation enabled researchers to design the
this situation, it is necessary to reassess ovulation induction ‘minimal stimulation study’, using clomiphene at 100 mg/day
schemes, to reduce costs while avoiding any negative impact, for 8 days starting on day 3 of the cycle in a group of 36
to the greatest possible extent, on success rates. Clomiphene is candidates for IVF. These patients had undergone down-
cheaper to use and it is safe, but its usage in the new IVF regulation with oral contraceptives 2 months prior to ovulation
schemes requires complete evaluation. Some investigators induction. No LH surge was observed in this group of patients.
believe that the use of clomiphene in IVF schemes is not Their average number of mature oocytes recovered was 3.2,
justified, in view of its adverse effects on the endometrium, with a 90% fertilization rate and an average number of 2.5
which could influence the outcomes of treatment. At present, embryos transferred, and a 32.8% pregnancy rate per
clomiphene is used in some IVF programmes in combination aspiration. These outcomes were similar to those obtained in
with human menopausal gonadotrophin (HMG), prior to the IVF stimulated cycles, and this schedule has the advantages of
use of GnRHa. 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 Association with other drugs
lesser need for HMG and higher concentrations of progesterone
in the luteal phase, which often renders luteal support There is a group of patients, estimated as between 10% and
unnecessary. Table 1 shows the results obtained from IVF 20%, in whom doses of 150 mg clomiphene citrate per day for
cycles between 1983 and 1990, at the New Orleans Fertility 5 days do not result in ovulation after three or more attempts,
Institute, comparing HMG/clomiphene, HMG alone and and/or who fail to conceive after 4–6 months of this induction
GnRHa/HMG (Dickey et al., 1998). Clinical pregnancies and protocol. This group of patients is said to be clomiphene
birth rates were higher with HMG/clomiphene than with HMG resistant. When this phenomenon occurs, clomiphene may be
alone, and the results were similar to those obtained with administered with other drugs, after evaluating the individual
GnRHa/HMG. The main advantage seen with GnRHa/HMG patient characteristics (body mass index, hirsutism, acanthosis
was that fewer cycles were cancelled, which is probably related nigricans, galactorrhoea), together with a baseline functional
to the beneficial effect of GnRH agonists, in reducing premature assessment including ultrasonography, total testosterone, sex
luteinization caused by an early LH surge. As a result, more hormone binding globulin, free androgen index, DHEA-S,
oocytes are obtained, and that in turn makes it possible to prolactin and progesterone in the luteal phase. This is followed
generate more cryopreserved embryos with this therapy. 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 Depending on the aetiology of the condition, several drugs can
preovulatory state, and an average number of two or three be administered with clomiphene citrate, including the
oocytes are aspirated from each woman (Marrs et al., 1984). following. The first is human chorionic gonadotrophin (HCG),
The combination of clomiphene and gonadotrophins yields a which is used when anovulation persists in spite of good
better ovarian response, with more oocytes and with better follicular development and adequate oestrogen production. It
morphology, as compared with clomiphene alone (Quigley et is administered at doses of 5000–10,000 IU, when the
al., 1984). This observation could be explained by several dominating follicle reaches a diameter of ≥18 mm and the
mechanisms. When clomiphene is administered for 5 days concentration of oestrogens exceeds 200 pg/ml. HCG can also
during the early follicular phase (days 3–7 of the cycle), it not be added in cases of luteal failure.
only stimulates the secretion of FSH, but also LH, which may
result in relatively high concentrations of LH during the Corticosteroids are especially indicated in hyperandrogenic
follicular phase (Messinis and Templeton, 1986). This could chronic anovulation, preferably of adrenal origin, using
cause early luteinization of granulosa cells, and so alter the 0.5–1.0 mg dexamethasone q.h.s, which leads to a 70–90%
outcomes of pregnancy (Stanger and Yovich, 1985). increase in the ovulation rate. Dopaminergic agonists are
indicated in chronic anovulation associated with
A new strategy for the use of clomiphene in combination with hyperprolactinaemia. Pituitary gonadotrophins are used when
GnRH antagonist for ovulation induction has been proposed ovulation does not occur, but moderate follicular development
recently (Olivennes et al., 2000; Reissmann et al., 2000). The is achieved.
physiological rationales supporting this association are mainly
based on the ability of GnRHa to reduce high concentrations It is possible to administer clomiphene and HMG sequentially,
of LH generated by clomiphene. Antagonists, contrary to the which permits substantial reductions in the dose of HMG
action of GnRHa, competitively block GnRH receptors at the required to produce ovulation. Progesterone is indicated when
pituitary level, preserving the post-receptor mechanism of the the administration of clomiphene produces a deficient luteal
latter intact. Nevertheless, it is necessary to conduct further phase. It is used as pure progesterone in the luteal phase (72 h
studies, including an adequate number of patients, in order to after ovulation) at doses of 12.5 mg i.m. or 25 mg b.i.d. as
validate the bases of these new schemes. vaginal suppositories, or orally in the form of micronized
progesterone. Ethynyl oestradiol is used at low doses to
A study using the down-regulation of the improve the quality of the cervical mucus and the endometrial
hypothalamus–pituitary–ovarian axis with oral contraceptives thickness, with a consequent increase in pregnancy rates (Gerli
in patients with clomiphene-resistant PCOS showed that the et al., 1999).
308 LH surge can be prevented or reduced in the cycle following
 Reviews - Clomiphene citrate and ovulation induction - H Sovino et al.

Hyperinsulinaemia must be corrected. Anovulatory women Adverse effects

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