Clomiphene citrate in the management of anovulation: a review of mechanisms, outcomes, and clinical challenges

To review the mechanism of action, epidemiology, clinical efficacy, factors influencing treatment outcomes, and limitations of clomiphene citrate (CC).

A systematic literature search was conducted using electronic databases. The search strategy employed a combination of relevant MeSH terms and keywords. The final selection was limited to complete, peer-reviewed articles.

Clomiphene citrate (CC) is the first-line oral ovulation induction agent for WHO Group II anovulation, most commonly polycystic ovary syndrome. It acts primarily at the hypothalamus, depleting estrogen receptors to increase gonadotropin-releasing hormone pulsatility and stimulate gonadotropin release. Although effective in restoring ovulation in approximately 73% of treated women, pregnancy rates remain significantly lower (~36%), highlighting a pronounced ovulation‒pregnancy gap. This discrepancy is largely attributed to CC's peripheral anti-estrogenic effects, which can cause endometrial suppression and hostile cervical mucus, thereby impairing implantation. Treatment success is influenced by factors such as obesity, insulin resistance, and hyperandrogenism, which are key predictors of CC resistance. While generally well-tolerated, side effects include hot flashes, mood swings, headaches, visual disturbances, and a notable risk of multiple pregnancies (8%-10%).

While CC remains a cornerstone for inducing ovulation, its peripheral anti-estrogenic effects and significant rate of resistance necessitate adjunctive strategies, careful patient selection, and a transition to advanced therapies when needed to improve live birth outcomes.