Letrozole and progesterone are two of the most commonly prescribed fertility medications, and they do completely different jobs. Letrozole helps you ovulate. Progesterone supports the lining of your uterus after ovulation.
Knowing which problem each one solves explains why you have been offered one and not the other. If you are still working out your results, start with how to read your fertility test results.
What do letrozole and progesterone actually do?
Letrozole triggers ovulation, and progesterone prepares the lining of your uterus to hold a pregnancy. They are not interchangeable, and they are rarely prescribed for the same problem.
Letrozole is an aromatase inhibitor, which means it temporarily lowers how much oestrogen your body makes.¹ Your brain reads that dip as a signal to release more follicle-stimulating hormone, which pushes a follicle to mature and release an egg.
Progesterone works later in the cycle. After you ovulate, the emptied follicle produces progesterone, which turns the lining of your uterus into a surface an embryo can implant into.²
So letrozole addresses not releasing an egg. Progesterone addresses a lining that is not adequately supported. If you ovulate reliably every month, letrozole is unlikely to be the thing that changes your odds.
Letrozole is now first-line treatment for ovulation induction
Letrozole is the first medication to try when you are not ovulating, under the international guideline led by Monash University here in Australia.³˒⁴
The condition this applies to most often has a new name. In 2026, polycystic ovary syndrome was renamed polyendocrine metabolic ovarian syndrome, or PMOS, through a global consensus process published in The Lancet.⁵
The condition has not changed, only the name. Most clinics and search results still say PCOS.
The guideline places clomiphene second line, alone or combined with metformin, gonadotrophins or ovarian surgery.³ Those recommendations date from 2023 and were reissued in June 2026 with the updated terminology.
In practice, letrozole is a tablet taken for about five days early in your cycle. Your GP or clinic then checks whether you ovulated, usually with a blood test or an ultrasound.
Is letrozole better than clomiphene?
Yes, if you are not ovulating. Letrozole produces more live births than clomiphene in women with PMOS.
The largest trial randomly assigned 750 women to letrozole or clomiphene for up to five treatment cycles. Cumulative live births were 27.5% with letrozole and 19.1% with clomiphene, a rate ratio of 1.44 with a 95% confidence interval of 1.10 to 1.87.⁶
This was a double-blind randomised controlled trial, the strongest design available for this question, and it was publicly funded, by the US National Institute of Child Health and Human Development and others.
A 2022 Cochrane review pooled 41 randomised trials and 6,522 women and found the same result, rated high-certainty evidence.¹ Roughly 10 women need letrozole rather than clomiphene for one additional live birth.¹
Miscarriage rates and twin rates were no different between the two, also high-certainty evidence.¹
Does letrozole help if your cycles are already regular?
Probably not. Letrozole's advantage is specific to women who are not ovulating, and it did not outperform clomiphene in unexplained infertility.
This is where a lot of online advice overreaches. The AMIGOS trial randomly assigned 900 women with unexplained infertility, all already ovulating, to gonadotrophin injections, clomiphene or letrozole for up to four cycles.⁷
Live birth occurred in 32.2% of the gonadotrophin group, 23.3% of the clomiphene group and 18.7% of the letrozole group. Pregnancy rates on letrozole were significantly lower than on gonadotrophin, and not significantly different from clomiphene.⁷
Letrozole did have one clear advantage, fewer multiple pregnancies than gonadotrophin, and every multiple in the letrozole group was twins rather than triplets.⁷
So letrozole treats not ovulating. It is not a general fertility booster. If you are not certain whether you ovulate, ovulation tracking and the fertile window covers how to confirm it.
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Progesterone helps in some situations and not others
Progesterone is well supported in IVF and helps one specific group of women with early pregnancy bleeding. It does not appear to prevent recurrent miscarriage.
These three situations get blended together online. Keeping them apart is the only way to work out which one applies to you.
In IVF and other assisted reproduction, the medications used to stimulate your ovaries leave your own progesterone low, so progesterone is given to support the lining.
A Cochrane review found higher live birth or ongoing pregnancy rates with progesterone than with placebo or no treatment. It rated that evidence very low quality, because the trials were small and poorly reported.²
That is why your IVF clinic prescribes pessaries as a matter of routine, and why your GP may not prescribe them for a natural cycle.
Does progesterone prevent miscarriage?
Only in one specific situation. Vaginal progesterone slightly increases live births if you have bleeding in early pregnancy and have had at least one previous miscarriage.
The PRISM trial randomly assigned 4,153 women with early pregnancy bleeding to vaginal progesterone or placebo. Live births were 75% with progesterone and 72% with placebo, which did not reach statistical significance.⁸
A Cochrane network meta-analysis then separated the groups out. With bleeding and no previous miscarriage, progesterone made little or no difference.
With bleeding and one or more previous miscarriages, it did increase live births, rated high-certainty evidence.⁹
The size of that effect is often overstated. It is a relative increase of about 8%, which is not the same as eight more live births in every 100 women.
For recurrent miscarriage without bleeding, the most recent Cochrane review pooled data from eight trials and 1,276 women and found probably little or no difference.¹⁰
Australia's recurrent pregnancy loss guideline reflects that uncertainty, describing progesterone from early pregnancy as having "some evidence" rather than making a clear recommendation.¹¹
Why letrozole is prescribed off-label in Australia
Letrozole is registered in Australia for breast cancer, not for fertility, so prescribing it to induce ovulation is off-label.
The Australian Product Information lists its approved use as treating postmenopausal women with hormone receptor positive breast cancer.¹² Ovulation induction does not appear in it.
Off-label does not mean experimental or unsafe. It means the manufacturer has not applied to the TGA to add this use, which is common for older medicines where there is no commercial case for the paperwork.
The international guideline addresses this directly, noting that medical therapy is generally not approved specifically for PMOS and that recommended use is therefore evidence-based but off-label.³
The safety data is reassuring. The 750-woman trial found no significant difference in overall congenital anomalies, though there were four major anomalies in the letrozole group and one in the clomiphene group.⁶
What this means for you
If you are not ovulating, letrozole is the medication your GP or fertility specialist is most likely to start with, and the evidence behind that choice is strong.
If you are ovulating normally, letrozole is unlikely to change your odds, and it is fair to ask what the plan is instead. A low AMH does not change that answer either, because AMH is not a fertility score.
Progesterone is worth asking about if you are doing IVF, or if you have early pregnancy bleeding and have had a previous miscarriage. Outside those situations the evidence does not support it.
Three questions worth taking to your appointment.
Am I ovulating, and how do we know?
If I am, what is this medication meant to change?
And how many cycles before we reassess?
Fertility is also not only about your cycle. Sperm health and paternal preconception covers the half that often goes untested.
References
Written by Bella · BBiomedSc, MEpi · Clinical epidemiologist
I read pregnancy research so you do not have to. More about me
Published: 6th October 2026 · Last reviewed: 6th October 2026
How I review research: Editorial policy
Educational only, not medical advice. Full disclaimer
This article is for educational purposes only and does not constitute medical advice. Research findings describe patterns across populations and may not apply to you. Always discuss your own situation with your GP, midwife or obstetrician.
