Clomiphene citrate use for ovulation induction: When, why, and how?

Ovulatory disorders are common causes of subfertility and infertility in women of reproductive age. Several pharmacologic agents are available to induce or augment ovulation, with varying rates of success. These medications include clomiphene citrate (a selective estrogen receptor modulator), aromatase inhibitors, urinary and recombinant gonadotropins, gonadotropin-releasing hormone (GnRH) analogs, and insulin-sensitizing agents. Clomiphene citrate is considered a first-line treatment because of its low cost, relative ease of use, and minimal side effects. It has been 50 years since the first clinical trial demonstrated that administration of clomiphene citrate induces ovulation in more than 75% of amenorrheic women.¹

How does clomiphene citrate induce ovulation?

Previously considered an antiestrogen, clomiphene citrate recently was reclassified as a selective estrogen receptor modulator.² It is known to be both an estrogen agonist and antagonist; however, its agonist properties manifest only when endogenous estrogen levels are extremely low. In general, its antagonistic effects prevail. Clomiphene citrate administration leads to depletion of estrogen receptors at the level of the pituitary and hypothalamus, interrupting the negative feedback that estrogen normally produces. As a result, GnRH secretion is improved and stimulates pituitary production of follicle-stimulating hormone (FSH), which in turn drives follicular growth and maturation with emergence of 1 or more dominant follicles.³

Clear indications for clomiphene citrate use include anovulation or oligo-ovulation and luteal phase deficiency. Clomiphene citrate has also been used in women with unexplained infertility, although limited data exist to justify such use.⁴

Anovulation and oligo-ovulation

An estimated 25% of female infertility has been attributed to anovulation or oligo-ovulation.⁵ The World Health Organization classifies disorders of ovulation into 3 groups: group I disorders are secondary to hypothalamic pituitary failure, group II disorders are a result of hypothalamic pituitary dysfunction, and group III disorders are secondary to ovarian failure.⁶ Clomiphene citrate is primarily used in group II disorders.⁷ This particular group includes women with anovulation or oligo-ovulation with normal basal levels of endogenous estradiol, including women with polycystic ovary syndrome (PCOS), a condition of uncertain etiology occurring in 6% to 7% of women of reproductive age.⁸ Group II disorders also includes women with hyperprolactinemia and unexplained anovulation.⁶ Women with low endogenous estrogen secondary to either hypergonadotropic or hypogonadotropic states have little or no response to clomiphene citrate.⁹

Diagnosis of anovulation or oligo-ovulation can usually be made by menstrual history alone; however, if the diagnosis is uncertain, testing can be helpful. Diagnostic tests to document ovulation include measurement of midluteal serum progesterone and daily basal body temperature (BBT) as well as monitoring of urinary luteinizing hormone (LH) excretion for LH surge.¹⁰ Clinicians should attempt to treat any underlying medical conditions or causes of anovulation or oligo-ovulation such as obesity, diabetes mellitus, thyroid disorders, or other endocrinopathies prior to initiating clomiphene citrate therapy. There is little value to ovulation induction in the presence of tubal, uterine, or severe male factor infertility; therefore, appropriate screening, including semen analysis and hysterosalpingography, also should be performed prior to use of clomiphene citrate.¹⁰

In a recent Cochrane Review by Brown et al¹¹ that included 15 randomized controlled trials (RCTs), clomiphene citrate was shown to be more effective than placebo in increasing the pregnancy rate in anovulatory patients with possible PCOS (odds ratio [OR], 5.8; 95% confidence interval [CI], 1.6–21.5). Further, in an RCT by Legro et al¹² that included 626 patients with PCOS, clomiphene citrate use resulted in a live-birth rate of 22.5% versus 7.2% with the use of metformin (P<.001), although an increased rate of multiple pregnancy was observed in the clomiphene citrate group.