Clomiphene Citrate and Letrozole
On this page
Direct answer
Clomiphene citrate is a selective oestrogen receptor modulator that induces ovulation by blocking oestrogen feedback at the hypothalamus, which raises pituitary FSH. Letrozole is an aromatase inhibitor that lowers oestradiol and produces a similar FSH rise, and current guidance favours it as first-line ovulation induction in PCOS.
What you must remember
- Clomiphene mechanism: It blocks hypothalamic oestrogen receptors, so GnRH and gonadotropin release increase.
- Clomiphene regimen: Commonly 50 mg daily for five days, starting around day 3 to 5 of the cycle, increased stepwise to a maximum of 150 mg.
- Letrozole regimen: Commonly 2.5 mg daily for five days from about day 3 to 7, increased to 5 mg or 7.5 mg in later cycles.
- Clomiphene side effects: Hot flushes, ovarian enlargement, abdominal discomfort and visual blurring, with thinning of the endometrium possible.
- Clomiphene limit: Usually restricted to about six cycles, after which resistance is assumed.
- Letrozole advantage: No anti-oestrogenic effect on the endometrium and generally fewer multiple pregnancies than clomiphene.
- Monitoring: Ultrasound follicle tracking and a mid-luteal progesterone confirm ovulation.
Comparing the two agents
Both drugs act on the same feedback loop but by different routes, and the comparison below is the one most exam vignettes test.
| Feature | Clomiphene citrate | Letrozole |
|---|---|---|
| Mechanism | Blocks oestrogen receptors in the hypothalamus | Blocks aromatase, lowering oestradiol |
| Usual dose | 50 mg for five days, stepwise to 150 mg | 2.5 mg for five days, up to 5 or 7.5 mg |
| Endometrial effect | Possible thinning and anti-oestrogenic effect | Little effect |
| Multiple pregnancy | Relatively higher | Relatively lower |
Letrozole is generally preferred in PCOS under current guidance. Ovulation rates of roughly 70 to 80 percent are commonly quoted for clomiphene, but books differ on exact figures, so the figure should be treated as approximate.
Failure is judged after a full course of cycles, not after a single cycle. Pregnancy is confirmed by a serum test, and the cycle record should show follicle size and mid-luteal progesterone.
Side effects are asked about at each review, since visual symptoms and abdominal pain need prompt action.
Where the exam tries to catch you
Ovulation induction questions often hinge on the next step after failure, or on a side effect that must not be ignored.
- Trap: Believing visual blurring on clomiphene is harmless. Correct: Visual disturbance needs the drug stopped and an eye review, because it is a recognised side effect that must be assessed.
- Trap: Repeating clomiphene at a higher dose after several failed cycles. Correct: After clomiphene resistance or the recommended maximum number of cycles, letrozole or gonadotropin therapy is the next step.
- Trap: Assuming clomiphene is contraindicated in PCOS. Correct: Clomiphene is a recognised ovulation inducer in PCOS, but letrozole is now favoured as first-line in many guidelines.
Frequently asked questions
What is the mechanism of clomiphene citrate in ovulation induction?
Clomiphene citrate is a selective oestrogen receptor modulator that blocks oestrogen receptors in the hypothalamus. This removes negative feedback, raising GnRH and pituitary FSH and LH, which recruits follicles for ovulation.
Why is letrozole favoured in PCOS for ovulation induction?
Letrozole is favoured in PCOS under current guidance because it produces ovulation with generally fewer multiple pregnancies than clomiphene. It also does not thin the endometrium through an anti-oestrogenic effect.
Which side effects of clomiphene are important to counsel about?
Clomiphene causes hot flushes, ovarian enlargement, abdominal discomfort and visual disturbances such as blurring. Visual symptoms warrant stopping the drug and an eye review, and the risk of multiple pregnancy must also be counselled.
What is the next step after clomiphene resistance?
After clomiphene resistance, the next step is usually letrozole or gonadotropin therapy, guided by ultrasound monitoring. Clomiphene should not simply be repeated at a higher dose beyond the recommended maximum number of cycles.