What is the best initial regimen of clomiphene (Clomid) for Polycystic Ovary Syndrome (PCOS)?

From the Guidelines

The best initial regimen for clomiphene citrate in patients with polycystic ovary syndrome (PCOS) is 100 mg daily for 5 days, as it is an acceptable alternative to low-dose gonadotrophins for low multiple birth rates and results in lower costs, although at a lower live birth rate 1.

Key Considerations

• The dose of 100 mg daily for 5 days is supported by the study by Cohlen et al. 1, which suggests that clomiphene citrate or tamoxifen are acceptable alternatives to low-dose gonadotrophins for low multiple pregnancy and birth rates and with lesser costs.
• The American College of Obstetricians and Gynecologists (ACOG) also recommends treatment with clomiphene citrate due to its effectiveness in inducing ovulation in women with PCOS 1.
• It is essential to monitor ovulation through methods such as ultrasound follicle tracking, serum progesterone levels, or urinary LH kits, and to counsel patients about the 5-10% risk of multiple pregnancies and potential side effects including hot flashes, mood changes, and visual disturbances.

Treatment Approach

• Before starting treatment, patients should have baseline evaluations including ruling out other causes of infertility and ensuring normal thyroid function and prolactin levels.
• Treatment should generally be limited to 3-6 ovulatory cycles, as pregnancy rates plateau after this duration.
• If ovulation does not occur at the initial dose, it can be increased by 50 mg increments in subsequent cycles up to a maximum of 150 mg daily.

Rationale

• Clomiphene citrate works by blocking estrogen receptors in the hypothalamus, which increases gonadotropin-releasing hormone pulsatility and subsequently increases FSH and LH secretion from the pituitary, stimulating ovarian follicular development in women with PCOS who typically have anovulation or oligo-ovulation.
• The use of clomiphene citrate is supported by high-quality evidence, including the study by Cohlen et al. 1, which suggests that it is an effective and safe treatment option for women with PCOS.

From the FDA Drug Label

While the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (i.e., clomiphene citrate in conjunction with other ovulation-inducing drugs). Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene citrate. Therefore, patients with polycystic ovary syndrome should be started on the lowest recommended dose and shortest treatment duration for the first course of therapy (see DOSAGE AND ADMINISTRATION)

The best initial regimen of clomiphene for PCOS is to start with the lowest recommended dose and shortest treatment duration for the first course of therapy.

• The lowest dose should be used to minimize the hazard associated with occasional abnormal ovarian enlargement.
• The treatment should be started on or about the 5th day of the cycle.
• Long-term cyclic therapy is not recommended beyond a total of about six cycles (including three ovulatory cycles) 2.
• Patients should be carefully evaluated and monitored for signs of ovarian hyperstimulation syndrome (OHSS) 2.

From the Research

Initial Regimen of Clomiphene for PCOS

• The optimal starting dose of clomiphene citrate (CC) for ovulation induction in anovulatory PCOS women is still a topic of debate 3.
• A study found that nearly 1 out of 2 women is resistant to 50 mg/day of CC, and factors such as higher BMI, waist circumference, serum levels of AMH, total testosterone, and insulin are associated with resistance to 50 mg/day of CC 3.
• Another study proposed a "stair-step" protocol, where the dose of CC is increased from 50 mg to 100 mg to 150 mg if the patient does not respond to the previous dose 4.
• The "stair-step" protocol was found to reduce the time to ovulation by 32-53 days compared to a traditional regimen 4.
• An intermittent CC treatment protocol, where CC is given in a pulsatile manner, was also found to be effective in inducing ovulation in CC-resistant PCOS patients 5.

Comparison of Different Regimens

• A study compared the effectiveness of letrozole and CC combined with human menopausal gonadotropin (HMG) in CC-resistant infertile women with PCOS, and found that the letrozole + HMG group had a higher rate of monofollicular development and lower cycle cancellation rate due to ovarian hyperresponse 6.
• Another study found that gonadotropins (FSH) probably result in more live births than continued CC in women with CC-resistant PCOS, without increasing multiple pregnancies 7.

Factors Influencing Treatment Outcome

• Serum levels of AMH and SHBG were found to be significantly associated with the risk of resistance to 50 mg/day of CC, but no satisfactory thresholds have been established to predict resistance 3.
• The effectiveness of CC treatment may also depend on other factors such as BMI, waist circumference, and serum levels of total testosterone and insulin 3.