Ovulation induction with clomiphene citrate

INTRODUCTION — Clomiphene citrate has been the most widely used treatment for fertility enhancement for the past 40 years. Clomiphene was a revolutionary advance in reproductive medicine and quickly became popular for induction of ovulation because of its ease of administration and minimal side effects. However, letrozole, an aromatase inhibitor, is also effective for ovulation induction in women with polycystic ovary syndrome (PCOS). Available data suggest that live birth rates are higher with letrozole than clomiphene, and many experts now suggest letrozole as first-line therapy for anovulatory women with PCOS.

The pharmacology, indications, and administration of clomiphene citrate will be reviewed here. Other drugs for induction of ovulation, including letrozole, are discussed elsewhere. (See "Overview of ovulation induction" and "Ovulation induction with letrozole".)

PHARMACOLOGY/MECHANISMS OF ACTION — Clomiphene is a nonsteroidal triphenylethylene derivative distantly related to diethylstilbestrol. It acts as a selective estrogen receptor modulator (SERM), similar to tamoxifen and raloxifene. All three drugs are competitive inhibitors of estrogen binding to estrogen receptors (ERs) and have mixed agonist and antagonist activity, depending upon the target tissue. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators".)

The commercially available form of clomiphene is the dihydrogen citrate salt (clomiphene citrate). It contains two stereoisomers: zu-clomiphene (38 percent) and en-clomiphene (62 percent), which were originally called the cis-isomer and trans-isomer, respectively. En-clomiphene is cleared rapidly, while zu-clomiphene has a long half-life [1]. The two clomiphene isomers have mixed estrogenic and antiestrogenic effects that vary among species. En-clomiphene is the more potent isomer with greater antiestrogenic activity and the one primarily responsible for inducing follicular development [2].

Clomiphene is cleared through the liver and excreted in feces. Over 50 percent of an oral dose of 14C-labeled clomiphene citrate is excreted after five days, but traces of radioactivity from the labeled clomiphene appear in the feces up to six weeks after administration. Although this observation raises concerns about fetal exposure to clomiphene, most studies suggest that the frequency of congenital malformations is not increased [3]. (See 'Perinatal outcome' below.)

Clomiphene citrate binds to ERs and exerts its major effects on the hypothalamus, pituitary, ovary, and uterus. Unlike estrogen, clomiphene citrate binds nuclear ERs for a prolonged period and depletes them [1].

Most evidence suggests that the primary site of clomiphene action is the hypothalamus, where it appears to bind to and deplete hypothalamic ERs, thereby blocking the negative feedback effect of circulating endogenous estradiol [4,5]. This results in an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency [6] and increased serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In vitro data suggest that clomiphene citrate also has a pituitary site of action where it causes an increase in the gonadotropin response to GnRH [7]. (See "Physiology of gonadotropin-releasing hormone".)

The ovarian actions of clomiphene are for the most part secondary to the effects of elevated FSH and LH on ovarian follicular development (see "Normal menstrual cycle"). Clomiphene is an estrogen agonist in the absence of estrogen, thereby enhancing FSH stimulation of LH receptors in granulosa cells [8].

Clomiphene acts primarily as an antiestrogen in the uterus, cervix, and vagina. The following findings may explain why pregnancy rates are relatively low when ovulatory rates are so high in women administered clomiphene cycles:

●The normal increase in uterine volume and endometrial thickening that occurs during spontaneous menstrual cycles is largely absent during clomiphene-induced cycles, despite higher estradiol levels [9,10].

●Abnormal luteal phase endometrial morphology has been found in some [11,12], but not all [13], studies.

Data on the effect of clomiphene on cervical mucus are conflicting. While one study found no detrimental effect [14], another noted a decrease in the quality and quantity of cervical mucus at all clomiphene doses [15]. In a meta-analysis, a detrimental effect was seen only with doses ≥100 mg/day [16].

Clomiphene citrate has no apparent progestational, corticotropic, androgenic, or antiandrogenic effects, nor does it interfere with adrenal or thyroid function.

PATIENT SELECTION — Clomiphene citrate is used to induce ovulation in selected populations of anovulatory women and is used in women with ovulatory infertility to increase follicular number and fertility [1]. As noted, clomiphene citrate is now considered to be a second-line agent for women with polycystic ovary syndrome (PCOS) as letrozole therapy results in higher birth rates. (See "Ovulation induction with letrozole".)

Its use in ovulatory infertility and for men with hypogonadism is reviewed separately. (See "Unexplained infertility", section on 'Clomiphene citrate' and "Treatments for male infertility".)

The primary indication for the antiestrogen clomiphene citrate is infertility secondary to oligoovulation or anovulation in women with PCOS [1]. Some amount of endogenous estrogen is necessary for a response to clomiphene; women with PCOS do produce estrogen (as evidenced by spontaneous menses or withdrawal bleeding in response to a progesterone challenge). Women who are hypoestrogenemic are unlikely to respond (eg, those with hypogonadotropic amenorrhea or primary ovarian insufficiency) (table 1).

Polycystic ovary syndrome — The approach to ovulation induction in women with PCOS is reviewed separately and summarized here briefly (table 1):

●Weight loss – Weight loss should always be attempted before initiating ovulation induction in women with PCOS and obesity because ovulation can be restored with a modest amount of weight loss. If unsuccessful, a multistep approach to ovulation induction is then undertaken (table 1). For infertile women with obesity who are >40 years of age, clinicians need to balance the health benefits of weight loss against the loss of fertility potential that might occur due to a delay in initiation of ovulation induction. Fertility potential declines rapidly after 40 years of age.

●Choice of clomiphene versus letrozole – Most, but not all, women with PCOS ovulate in response to clomiphene citrate. However, higher live birth rates have been observed with the aromatase inhibitor letrozole, particularly in patients with PCOS and obesity [17]. (See "Ovulation induction with letrozole", section on 'Outcomes'.)

Many experts now suggest letrozole rather than clomiphene citrate for all women with PCOS. Ovulation induction is an off-label use of letrozole. Efficacy and safety are reviewed in detail separately. (See "Ovulation induction with letrozole".)

●Metformin – Metformin, a drug whose major effect is to reduce hepatic glucose output and lower serum insulin concentrations, has been used to promote ovulation, but its role is now limited as it appears to be less effective for pregnancy rates than clomiphene. Clinical trial data supporting this are reviewed elsewhere. A consensus group has recommended against the routine use of metformin (including ovulation induction), except in women with glucose intolerance. (See "Metformin for treatment of the polycystic ovary syndrome", section on 'Anovulatory infertility'.)

●Gonadotropins – Gonadotropin therapy is only considered for anovulatory women who have either not ovulated or not conceived after treatment with initial therapies (weight loss, clomiphene, letrozole). Gonadotropin therapy is associated with a higher risk of multiple gestation and ovarian hyperstimulation syndrome than oral ovulation induction agents. (See "Overview of ovulation induction", section on 'Gonadotropin therapy'.)

●Laparoscopic ovarian drilling – Laparoscopic ovarian drilling may be considered in women with PCOS who fail to ovulate despite an adequate trial of clomiphene citrate. (See "Treatment of polycystic ovary syndrome in adults", section on 'Laparoscopic surgery'.)

Other ovulatory disorders — Women with hypogonadotropic hypogonadism (hypothalamic amenorrhea) are hypoestrogenemic and are therefore unlikely to respond to clomiphene citrate, an antiestrogen. However, because clomiphene citrate is easy to administer, we typically give one course prior to initiating pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropin therapy. For those who ovulate, clomiphene citrate can then be continued. (See "Overview of ovulation induction", section on 'Patient-specific approach'.)

In contrast, most ovulation induction strategies for women with primary ovarian insufficiency (premature ovarian failure) are unsuccessful, and we suggest against their use. These women should be offered the option of in vitro fertilization with donor oocytes. We do not suggest a trial of clomiphene citrate in these women. (See "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Fertility'.)

HOW TO USE CLOMIPHENE CITRATE

Pretreatment evaluation — Before initiating therapy, the presence of ovulatory dysfunction must be established. The menstrual history alone may be diagnostic (eg, one can be confident that ovulatory dysfunction is present in women with amenorrhea or irregular menses [>45 day intermenstrual interval]). It is possible that women with cycles in the 35- to 45-day range have intermittent ovulations. We suggest that these women try to conceive on their own without therapy for several months. If they are unsuccessful, they should be referred for ovulation induction. If the diagnosis of ovulatory dysfunction is uncertain, additional testing should be performed. This can include simple, noninvasive tests such as basal body temperature and/or urinary luteinizing hormone (LH) monitoring, although a luteal phase serum progesterone level is more definitive (table 2). (See "Evaluation of the menstrual cycle and timing of ovulation".)

Disorders of pituitary, adrenal, and thyroid origin that can cause anovulation should be excluded prior to the initiation of therapy as targeted treatment of these endocrinopathies can result in normal ovulation. (See "Overview of infertility".)

The pretreatment evaluation should include [1]:

●A complete history and physical examination.

●Laboratory testing – Human chorionic gonadotropin (hCG), thyroid-stimulating hormone (TSH), and prolactin (PRL) to exclude pregnancy, thyroid disease, and hyperprolactinemia as causes of the ovulatory dysfunction, respectively, because these require different treatments. Serum follicle-stimulating hormone (FSH) should also be measured [1] as women diagnosed with primary ovarian insufficiency are unlikely to respond to clomiphene. (See "Evaluation and management of secondary amenorrhea" and "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)

●Women with polycystic ovary syndrome (PCOS) and hirsutism should have a 17-hydroxyprogesterone measured; if nonclassic 21-hydroxylase deficiency is diagnosed, glucocorticoid therapy is a potential alternative for ovulation induction. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on '17-hydroxyprogesterone'.)

●Women with PCOS and obesity should be screened for diabetes and encouraged to lose weight before considering ovulation induction.

●Semen analysis of the partner to identify seminal abnormalities that might contribute to the infertility. (See "Female infertility: Evaluation", section on 'Semen analysis'.)

●Hysterosalpingogram if the clinical history suggests uterine or tubal pathology may also be present and in women over 35 years of age to avoid ineffective treatment when fertility is in decline. In women with no risk factors for tubal disease, the hysterosalpingogram can be postponed but should be performed if women have not conceived after three ovulatory cycles. (See "Female infertility: Evaluation", section on 'Hysterosalpingogram'.)

●An endometrial biopsy may be indicated to assess hyperplastic changes in women with chronic anovulation. This is not routine, however. Indications are described separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

●A pelvic examination or a pelvic ultrasound to rule out ovarian cysts, especially in patients with known tendency to form functional cysts.

●Some experts suggest an assessment of ovarian follicle pool in women over age 37 years. A low serum anti-müllerian hormone (AMH) less than 1 ng/mL would identify a woman with a diminished pool of oocytes who would likely be triaged to assisted reproductive interventions (instead of clomiphene citrate). (See "Female infertility: Evaluation", section on 'Anti-müllerian hormone'.)

Starting a cycle — Clomiphene citrate therapy for ovulation induction is typically started on the fifth day of a cycle, following either spontaneous or induced bleeding. However, the results of therapy (in terms of ovulatory rates, pregnancy, or spontaneous miscarriage) are comparable when clomiphene is started on cycle day 2, 3, 4, or 5 [18,19].

There are no laboratory or clinical parameters that predict the dose necessary to achieve ovulation. The initial dose, empirically, is 50 mg daily for five days; starting with a higher dose does not result in higher pregnancy rates. If ovulation does not occur in the first cycle of treatment, the dose is increased to 100 mg. Thereafter, the dose is increased by increments of 50 mg to a maximum daily dose of 150 mg (100 mg is the maximum dose approved by the US Food and Drug Administration [FDA], and the American Society for Reproductive Medicine [ASRM] suggests that doses >100 mg add little to clinical pregnancy rates) [1]. Once ovulation is achieved, the same dose should be continued for four to six cycles.

The LH surge occurs from 5 to 12 days after the last day of clomiphene administration. The day of ovulation is generally consistent in each cycle once ovulation has been established. The couple is advised to have intercourse every other day for one week beginning five days after the last day of medication.

Because of the observations that pregnancy rates are low after six cycles of treatment and that 12 or more cycles may increase the risk of ovarian neoplasms [20], the American College of Obstetricians and Gynecologists (ACOG) has suggested that clomiphene treatment be limited to fewer than 12 cycles and that the number of gonadotropin cycles be minimized, as well [21]. We suggest further evaluation and/or a change in therapy for women who do not conceive after three to six ovulatory clomiphene citrate cycles.

Monitoring — The response to treatment should be monitored. Determination of the ovulatory LH surge by urinary LH kits is what most clinicians recommend in practice. Urinary LH monitoring also provides information on appropriate timing of intercourse during a given cycle [22]. The LH surge typically occurs 5 to 12 days after clomiphene administration is completed. Ovulation generally occurs 14 to 26 hours after the detection of the urinary LH surge and almost always within 48 hours [23]. Therefore, the interval of highest fertility is the day of the LH surge and the following two days.

A basal body temperature chart can also be used and does not increase the cost of treatment. Conversion of a uniphasic to a biphasic basal temperature curve suggests retrospectively that ovulation has occurred. However, basal body temperature charting can be tedious for some patients and is not useful for timing of intercourse, as the temperature rise occurs one to five days after the midcycle LH surge and up to four days after ovulation.

A mid-luteal (one week after ovulation or one week before the expected menses) serum progesterone concentration greater than 3 ng/mL (ideally greater than 10 ng/mL) provides reliable evidence that ovulation has occurred. An endometrial biopsy to confirm the adequacy of the luteal phase is not recommended.

Some expert groups, such as the Royal College of Obstetricians and Gynecologists (RCOG) and the National Institute for Health and Clinical Excellence (NICE), suggest serial transvaginal ultrasound to monitor the number and size of developing follicles and to time hCG administration if necessary. Serial transvaginal ultrasound may also provide evidence of ovulation (follicle enlargement followed by collapse suggests ovulation). Some advocate ultrasound monitoring of just the first clomiphene cycle in order to exclude hyper-response [24,25]. However, adding ultrasonographic monitoring is costly and does not appear to improve pregnancy rates significantly [26]. (See "Evaluation of the menstrual cycle and timing of ovulation".)

Routine physical and ultrasound examinations to detect ovarian enlargement are not always necessary before every new treatment cycle but should be considered in symptomatic patients. The management of ovarian enlargement/theca lutein cysts from ovarian stimulation is controversial. We recommend withholding clomiphene in these cases until the cyst(s) disappear either spontaneously or after suppression with oral contraceptive pills or gonadotropin-releasing hormone (GnRH) agonists.

OUTCOMES

Letrozole versus clomiphene — Most, but not all, women with polycystic ovary syndrome (PCOS) ovulate in response to clomiphene citrate. However, higher live birth rates have been observed with the aromatase inhibitor letrozole, particularly in patients with PCOS and obesity (see "Ovulation induction with letrozole", section on 'Comparison with clomiphene'). Many experts now suggest letrozole rather than clomiphene citrate for all women with PCOS. Ovulation induction is an off-label use of letrozole. Efficacy and safety are reviewed in detail separately. (See "Ovulation induction with letrozole".)

Clomiphene citrate

Ovulatory and pregnancy rates — In women with PCOS, an ovulatory rate of 80 percent and a cumulative pregnancy rate of 30 to 40 percent can be expected [3,27,28]. The incidence of miscarriage and congenital anomalies appears to be similar to that in spontaneous pregnancies, and the rate of ectopic pregnancy is probably not increased [29]. The risk of ovarian hyperstimulation syndrome is less than 1 percent. The risk of multiple gestations is increased (7 percent in the trial noted above) [17]. (See 'Multiple gestation' below and 'Perinatal outcome' below and "Overview of ovulation induction", section on 'Ovarian hyperstimulation syndrome'.)

Of those who ovulate, approximately 50 percent do so at a dose of 50 mg [24,30], another 20 to 25 percent at 100 mg, and 10 percent at 150 mg [27,28,31]. There is no benefit to increasing the clomiphene dose in subsequent cycles once ovulation occurs. A literature review including data from over 5000 patients with a variety of indications for clomiphene therapy reported an ovulation rate of 73 percent and a pregnancy rate of 36 percent [32]. Of patients who became pregnant, the miscarriage rate was approximately 20 percent and the multiple pregnancy rate was 8 to 13 percent. Almost all of the pregnancies that did not miscarry resulted in a live birth. A theoretical projection of the results of clomiphene induction of ovulation in 100 women concluded that 25 of the 100 would succeed in delivering a singleton healthy baby.

The ovulatory rate is lower with increasing age, body mass index (BMI), insulin resistance, and free androgen index (figure 1) [1,33]. (See "Overview of ovulation induction", section on 'Clomiphene citrate'.)

After six months of treatment, the pregnancy rate per cycle falls substantially despite regular ovulation [34]. In addition, pregnancy rates are lower among women who ovulate only after receiving higher doses of clomiphene. Failure to conceive despite ovulatory cycles, particularly at higher doses, may be due to clomiphene's antiestrogenic effects on the quantity and quality of cervical mucus [4] and on the endometrium, impairing implantation [12]. (See 'Endometrial effects' below.)

As noted above, a hysterosalpingogram should be performed, if not already done, in any woman who fails to conceive within three to six treatment cycles (see 'Pretreatment evaluation' above). Failure to conceive after a maximum of six ovulatory treatment cycles indicates a need to further evaluate for factors potentially causing infertility or to change to another treatment strategy.

Multiple gestation — Induction of ovulation by clomiphene increases the probability of multifetal pregnancy: twins have been reported in 6.9 to 9 percent of pregnancies, triplets in 0.3 to 0.5 percent, quadruplets in 0.3 percent, and quintuplets in 0.13 percent [3,35]. The risk may be reduced by ultrasound monitoring and withholding human chorionic gonadotropin (hCG), intrauterine insemination (IUI), or intercourse if more than two follicles >15 mm diameter are seen. Additional information on outcomes of multiple gestations is discussed elsewhere [36]. (See "Neonatal complications of multiple births".)

Perinatal outcome — Most [28,37-40], but not all [41], studies suggest that the frequencies of congenital malformations and spontaneous abortion are not increased in pregnancies after clomiphene therapy. Similar findings have been reported for letrozole. (See "Ovulation induction with letrozole", section on 'Fetal safety'.)

●In one report of 1034 pregnancies and 935 newborns after clomiphene-induced ovulation [37], spontaneous abortion and visible congenital malformations occurred in 14.2 and 2.3 percent, respectively; rates were comparable with those in mothers who spontaneously ovulated.

●In contrast, a newer report by the National Birth Defects Prevention Study of the Centers for Disease Control and Prevention (CDC) examined 30 different congenital anomalies in a multicenter, case-control study of deliveries between 1997 and 2005 [41]. The exposure of interest was clomiphene citrate use for two months before conception through the first month of pregnancy. Several significant associations between clomiphene use and congenital anomalies were observed, but because of the small number of cases in several categories and the inability to assess the effects of clomiphene separately from subfertility, these results should be interpreted with caution.

●There is no evidence of developmental delays or learning disabilities in children whose mothers took clomiphene [42]. Several studies have found a mildly increased risk of preterm birth in pregnancies (singleton and multiple) after assisted reproduction compared with natural pregnancies [43-46]. This effect has not been shown to be specific to clomiphene and is likely to be due, at least in part, to comorbidities in subfertile women [47] rather than the ovulation stimulation.

●There does not appear to be an increase in cancer risk in children conceived using ovulation induction drugs.

Role of modified regimens

Higher doses — High-dose clomiphene citrate (200 to 250 mg daily) may be given for 8 to 10 days in women who are refractory to standard doses. This extended regimen of clomiphene is sometimes used for women who cannot receive exogenous gonadotropins, but the overall experience is limited and the dose exceeds current US Food and Drug Administration (FDA) recommendations. We suggest against the use of these high doses. (See "Overview of ovulation induction", section on 'Gonadotropin therapy'.)

Addition of ovulatory dose hCG — An absent or inadequate midcycle luteinizing hormone (LH) surge may result in a failure to ovulate or a short luteal phase, despite clomiphene-induced follicular development. In this situation, exogenous hCG (single-dose 10,000 international units intramuscular [IM]) may be added to the regimen. It is given when transvaginal ultrasonography shows that the leading follicle has reached 18 to 20 mm in diameter [48]. It should be noted that premature administration of hCG acts like a premature LH surge and may result in follicular atresia.

In many institutions, hCG is routinely used to induce ovulation and to time IUI. However, we do not suggest routine administration of exogenous hCG for women in whom an endogenous LH surge can be detected, as it does not enhance the efficacy of clomiphene-IUI treatment in these women [49-52].

A progressive rise in the serum estradiol concentration is also evidence for advancing follicular development and maturation, but serial transvaginal ultrasound to monitor follicle size is superior and should be used to time hCG administration. Ovulation occurs approximately 36 to 44 hours after the injection.

Other

●A progestin is often administered to "shed" the endometrium before starting clomiphene in women with PCOS. However, available data suggest that conception and live birth rates may be lower in women after a spontaneous period or progestin-induced withdrawal bleed compared with anovulatory cycles without progestin withdrawal [53].

●Progesterone supplementation may also be used for luteal phase support in women treated with clomiphene citrate, although a benefit has not been demonstrated [54].

●Addition of IUI does not appear to improve pregnancy rates [55]. Therefore, we suggest against routinely adding IUI in women (without male factor infertility) undergoing ovulation induction with clomiphene.

●As noted above, clomiphene, like tamoxifen and raloxifene, is a selective estrogen receptor modulator (SERM). Tamoxifen has been used as an ovulation induction agent, but clomiphene therapy resulted in a higher ovulation rate in one randomized trial (64 versus 52 percent for clomiphene and tamoxifen, respectively) [56]. In a second trial, clomiphene and raloxifene were similarly effective in inducing ovulation [57].

Adverse effects

Common side effects — Hot flashes are common, occurring in 10 to 20 percent of women [21,58]. They may result from hypoestrogenism at the hypothalamic level due to clomiphene blockade of estrogen receptors. Additional problems related to the hyperestrogenic environment induced by clomiphene citrate include abdominal distention and pain (5.5 percent), nausea and vomiting (2.2 percent), and breast discomfort (2 percent). These symptoms abate soon after cessation of therapy.

Mood swings, depression, and headaches can also occur but are rarely serious enough to consider terminating treatment.

Side effects of clomiphene are not dose related, as they can occur at the 50 mg dose. Uncomplicated ovarian enlargement develops in approximately 14 percent of women, but true ovarian hyperstimulation syndrome is rare. (See "Overview of ovulation induction", section on 'Multiple gestation'.)

We withhold clomiphene in women with ovarian enlargement and/or cyst(s) until the ovaries return to pretreatment size. Ovarian enlargement can be assessed by symptoms and pelvic examination; routine ultrasound monitoring is unnecessary.

Visual disturbances — Visual symptoms, such as blurring, double vision, and/or scotomata, develop in 1 to 2 percent of women and are usually reversible. However, because they may persist, their onset warrants discontinuation of therapy [59]. They have been thought to represent retinal toxicity, but in one study of eight women with clomiphene-associated visual blurring or persistent afterimages, rechallenge appeared to affect the visual cortex rather than the retina [60].

Endometrial effects — Clomiphene citrate, while used to improve luteal function, may also cause an iatrogenic luteal phase defect when used to induce ovulation in anovulatory women [61]. The mechanism may be related to antiestrogenic effects of clomiphene citrate on the endometrium or inhibition of steroidogenesis in granulosa and lutein cells. Increasing the dose of clomiphene does not correct the luteal phase defect. However, preovulatory hCG and/or supplemental progesterone may prevent the problem.

Strategies to prevent thin endometrium — Strategies such as giving half-dose clomiphene (25 mg/day), early administration (starting day 1), or adding exogenous estrogen have been tried to minimize the antiestrogenic effect of clomiphene on the endometrium, with limited success.

Cancer risks — The use of clomiphene citrate for ovulation induction does not appear to be associated with an excess risk of ovarian or breast cancer. This topic is reviewed in detail separately. (See "Overview of ovulation induction", section on 'Cancer risks'.)

One retrospective cohort study reported an excess risk of endometrial cancer with clomiphene, but this has not been confirmed [62]. The relatively small number of uterine cancers and incomplete ascertainment of cases preclude a definite conclusion regarding uterine cancer risk. This study does not provide sufficient evidence to change current recommendations for clomiphene use. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome" and "Society guideline links: Female infertility".)

SUMMARY AND RECOMMENDATIONS

●The best candidates for clomiphene citrate are women with polycystic ovary syndrome (PCOS). While clomiphene has been the most widely used ovulation induction agent for these women for many years, letrozole appears to result in higher live birth rates. For this reason, it is becoming the drug of choice (table 1). (See 'Polycystic ovary syndrome' above.)

●For oligoovulatory women with PCOS undergoing ovulation induction, we now suggest letrozole as first-line therapy over clomiphene citrate, (Grade 2B). Before starting letrozole, the clinician must discuss that this use of the drug is not US Food and Drug Administration (FDA) approved and that clomiphene is an alternative. (See "Ovulation induction with letrozole", section on 'Suggested approach'.)

●For women with PCOS and a body mass index (BMI) >30 kg/m², we also suggest diet and exercise to promote weight loss. (See "Treatment of polycystic ovary syndrome in adults", section on 'Women pursuing pregnancy'.)

●Women with hypogonadotropic hypogonadism (hypothalamic amenorrhea) are hypoestrogenemic and are therefore unlikely to respond to clomiphene citrate, an antiestrogen. However, because clomiphene citrate is easy to administer, we suggest giving one course of clomiphene citrate prior to initiating pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropin therapy (Grade 2C). For those who ovulate, clomiphene citrate can then be continued. (See 'Other ovulatory disorders' above.)

●Most ovulation induction strategies for women with primary ovarian insufficiency (premature ovarian failure) are unsuccessful, and we suggest against their use. These women should be offered the option of in vitro fertilization with donor oocytes. We do not suggest a trial of clomiphene citrate in these women. (See 'Other ovulatory disorders' above.)

●Clomiphene is initially begun on cycle day 3, 4, or 5 at a dose of 50 mg daily for five days. If ovulation does not occur in the first cycle of treatment, the dose is increased to 100 mg. Thereafter, the dose is increased by increments of 50 mg to a maximum daily dose of 150 mg until ovulation is achieved. The couple is advised to have intercourse every other day for one week beginning five days after the last day of medication. (See 'How to use clomiphene citrate' above.)

●Most clinicians have their patients use home urinary luteinizing hormone (LH) kits for monitoring their cycles. A mid-luteal serum progesterone level may be obtained once to document that clomiphene citrate caused ovulation. Serial transvaginal ultrasound may also be used, although it increases the cost without having a significant effect on pregnancy rates. (See 'Monitoring' above.)

●Further evaluation or change in therapy is indicated for women who do not conceive after having six ovulatory cycles. (See 'Starting a cycle' above.)

●Risks and complications should be discussed. The most common of these are hot flashes (10 to 20 percent), uncomplicated ovarian enlargement (14 percent), and multiple gestation (primarily twins, <10 percent). True ovarian hyperstimulation is rare. Less frequent side effects include abdominal distention and pain, nausea/vomiting, breast discomfort, visual symptoms, mood swings, and headaches. Visual symptoms warrant discontinuation of therapy. (See 'Adverse effects' above.)

●Clomiphene citrate does not appear to be associated with adverse perinatal outcomes or an increased risk of congenital malformations. (See 'Perinatal outcome' above.)

●For women who are being monitored with ultrasound, exogenous human chorionic gonadotropin (hCG; single-dose 10,000 international units intramuscular [IM]) is indicated in women who have an absent or inadequate midcycle LH surge. (See 'Addition of ovulatory dose hCG' above.)