Clomiphene

• Ovulation Induction
• Polycystic Ovary Syndrome (PCOS)
• Female Infertility
• Anovulatory Infertility

Clomiphene citrate is a selective estrogen receptor modulator (SERM) primarily used to induce ovulation in women with anovulatory infertility. This medication has been a cornerstone of fertility treatment for decades due to its oral administration, established efficacy, and relatively low cost compared to injectable gonadotropins.

Mechanism of Action

Clomiphene citrate is a nonsteroidal compound that acts as a competitive antagonist of estrogen receptors, particularly in the hypothalamus. By blocking estrogen receptors in the hypothalamus, clomiphene prevents the normal negative feedback of estrogen, leading the hypothalamus to perceive low estrogen levels. This triggers increased secretion of gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to release more follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The elevated FSH promotes follicular development in the ovaries, and the LH surge triggers ovulation. Clomiphene is a racemic mixture of two isomers, with the zuclomiphene isomer having more estrogenic activity and enclomiphene having more anti-estrogenic activity.

Available Formulations

Clomiphene citrate is available as oral tablets in 50 mg strength. The tablets are typically white and scored for dose adjustment if needed. Generic formulations are widely available.

Medical Uses

Clomiphene is FDA-approved for the treatment of ovulatory dysfunction in women desiring pregnancy. It is used in patients with polycystic ovary syndrome (PCOS), hypothalamic dysfunction, and other causes of anovulation when the pituitary and hypothalamus are capable of responding to stimulation. Off-label uses include male hypogonadism treatment (to stimulate testosterone production) and empiric treatment for unexplained infertility. Clomiphene is considered first-line therapy for ovulation induction due to its oral route, efficacy, and cost-effectiveness.

Dosing Guidelines

The initial recommended dose is 50 mg daily for 5 days, typically started on cycle day 3, 4, or 5 (day 1 being the first day of menstrual bleeding). If ovulation does not occur at 50 mg, the dose may be increased to 100 mg daily for 5 days in subsequent cycles. Most clinicians do not exceed 100-150 mg daily. If ovulation occurs but pregnancy is not achieved, the same dose may be continued for up to 6 ovulatory cycles. Treatment beyond 6 cycles is generally not recommended. Monitoring with ultrasound and estrogen levels helps optimize treatment and reduce multiple pregnancy risk.

Important Safety Information

Clomiphene is contraindicated during pregnancy due to potential teratogenicity; a pregnancy test should be performed before each treatment cycle. Other contraindications include liver disease, uncontrolled thyroid or adrenal dysfunction, ovarian cysts (except PCOS), abnormal uterine bleeding of undetermined origin, and organic intracranial lesions. Multiple pregnancy (primarily twins) occurs in approximately 5-8% of pregnancies. Ovarian hyperstimulation syndrome (OHSS) is rare with clomiphene but can occur. Visual disturbances require immediate discontinuation.

Drug Interactions

There are limited documented drug interactions with clomiphene. It should not be used with other fertility medications unless under specialist supervision. Clomiphene may affect thyroid function tests. No significant interactions with commonly used medications have been reported. However, patients should avoid using clomiphene during pregnancy or while breastfeeding.

Special Populations

Clomiphene is absolutely contraindicated during pregnancy (Category X). It should not be used during breastfeeding. The medication is not indicated for use in males (though used off-label for hypogonadism) or pediatric patients. Patient selection is important; the medication is most effective in women with intact hypothalamic-pituitary-ovarian axis function. Women with low estrogen levels or premature ovarian insufficiency typically do not respond to clomiphene. Baseline liver function should be assessed as hepatic dysfunction is a contraindication.