Ovulation Induction Protocols: Letrozole, Clomiphene and Gonadotropins Compared

Ovulation induction is one of the most common treatments in fertility practice. It is used to restore ovulation in anovulatory women, most often with PCOS, and to support IUI cycles. Choosing the right agent and monitoring carefully are key to good results and to avoiding multiple pregnancy.

Goals of ovulation induction

• In anovulatory women: to achieve regular ovulation of a single follicle
• In IUI cycles: to achieve one, or at most two, mature follicles

Ovulation induction for IUI is different from controlled ovarian stimulation for IVF, where multiple follicles are deliberately recruited.

Letrozole

Letrozole is an aromatase inhibitor that lowers oestrogen levels, increasing pituitary FSH release.

• Role: international guidelines now recommend letrozole as the first-line medication for ovulation induction in women with PCOS, as trials have shown higher live birth rates than clomiphene in this group
• Typical use: an oral course for five days early in the cycle
• Advantages: tends to produce mono-follicular development and does not have clomiphene's anti-oestrogenic effect on the endometrium

Its use for fertility is off-label in many countries, so appropriate counselling and documentation are important.

Clomiphene citrate

Clomiphene is a selective oestrogen receptor modulator that has been used for decades.

• Typical use: an oral course for five days early in the cycle
• Considerations: its anti-oestrogenic effects can thin the endometrium and affect cervical mucus in some women; there is a higher chance of multiple follicles than with letrozole
• It remains a useful, inexpensive option, especially where letrozole is not suitable

Gonadotropins

Injectable FSH or hMG preparations stimulate the ovaries directly.

• Role: for women who do not respond to oral agents, or in selected IUI cycles
• Approach: low-dose step-up protocols are commonly used to reduce the risk of multiple follicles
• Considerations: more intensive monitoring, higher cost and greater risk of multiple pregnancy and OHSS

Monitoring essentials

Whichever agent is used:

• Perform a baseline ultrasound to exclude cysts
• Track follicles with transvaginal ultrasound to time the trigger or IUI
• Set cancellation criteria in advance - for example, too many follicles above a certain size - and follow them
• Assess the endometrium along with the follicles

Trigger

Once the lead follicle reaches the target size, hCG is commonly used to trigger ovulation, with IUI or intercourse timed accordingly.

Safety: multiple pregnancy and OHSS

The biggest risks of ovulation induction are multiple pregnancy and ovarian hyperstimulation syndrome. Careful dosing, monitoring and willingness to cancel or convert over-responding cycles are the most effective safeguards. Women with PCOS need particular care.

When to move on

If ovulation is achieved but pregnancy does not follow after a reasonable number of cycles - guided by age, duration of infertility and other factors - couples should be counselled about IVF.

Learn ovulation induction hands-on

ReproNest's IUI & Ovulation Induction Masterclass teaches protocol selection, ultrasound monitoring and safe practice. Read our step-by-step IUI guide, or contact us to enrol.