Letrozole is currently the most effective oral fertility drug for most women struggling to get pregnant. In women with polycystic ovary syndrome (PCOS), the most common cause of ovulation problems, letrozole produces a live birth rate of about 25% per cycle compared to roughly 11% with the older standard, clomiphene citrate. But “best” depends on your specific diagnosis, and fertility treatment often involves more than a single pill.
Letrozole: The Current First-Line Option
Letrozole works by temporarily blocking the enzyme that converts hormones into estrogen. When estrogen drops, your brain responds by sending stronger signals to your ovaries, ramping up the hormone (FSH) that drives follicle growth. As the dominant follicle matures and estrogen rises naturally, the feedback loop kicks back in and suppresses the smaller follicles. The result is typically a single mature egg, which is ideal because it keeps the risk of twins and triplets low.
A large meta-analysis comparing letrozole to clomiphene in women with PCOS found letrozole was superior across every meaningful outcome. Ovulation rates were 18% higher. Pregnancy rates were 57% higher. Live birth rates were 54% higher. And the rate of multiple pregnancies was less than half that of clomiphene. Miscarriage rates were the same between the two drugs. It’s taken orally for five days early in your cycle, typically starting on cycle day 3 or 5, and is inexpensive.
Clomiphene Citrate: The Long-Standing Alternative
Clomiphene (often called Clomid) has been used since the 1960s and remains widely prescribed. It works differently from letrozole: instead of lowering estrogen production, it blocks estrogen receptors in the brain, tricking your body into thinking estrogen is low and triggering more FSH release. The problem is that this receptor blockade doesn’t just happen in the brain. It also affects the uterine lining and cervical mucus, potentially making it harder for an embryo to implant even after successful ovulation.
Because letrozole leaves estrogen receptors intact, it avoids this drawback. That difference likely explains much of the gap in live birth rates between the two drugs. Clomiphene still has a role, though. Some women who don’t respond well to letrozole may respond to clomiphene, and your doctor may try both before moving to stronger options. Clomiphene also carries a higher chance of twins, roughly double that of letrozole, which some patients see as a benefit but clinically adds risk to a pregnancy.
Injectable Hormones: A Stronger Approach
When oral medications don’t produce results after several cycles, the next step is usually injectable gonadotropins. These are synthetic versions of the hormones your brain naturally sends to your ovaries (FSH and sometimes LH), delivered by subcutaneous injection. They’re more powerful and more precisely dosed than oral drugs, but they require close monitoring with blood work and ultrasound every few days.
The main risk with injectables is ovarian hyperstimulation syndrome, or OHSS. In mild form, it affects roughly 20% to 33% of women undergoing stimulated cycles, causing bloating and mild discomfort. Moderate to severe cases, which involve significant fluid retention and can require hospitalization, occur in about 3% to 8% of cycles. The risk scales with dose and with how many follicles develop. Your clinic will track follicle size and number to decide whether it’s safe to proceed with a given cycle.
The Trigger Shot: Timing Ovulation
Regardless of whether you take letrozole, clomiphene, or injectables, your cycle may include an hCG trigger shot. This injection mimics the natural hormone surge that tells a mature follicle to release its egg. Ovulation typically happens 36 to 48 hours after the injection, which gives your medical team a precise window. If you’re doing timed intercourse, you’ll be told when to try. If you’re doing intrauterine insemination (IUI), it’s usually scheduled 34 to 36 hours after the shot.
The trigger shot is given when ultrasound monitoring shows at least one follicle has reached about 18 millimeters in diameter. It’s not a fertility drug in the traditional sense, since it doesn’t grow more eggs. It simply ensures the eggs you’ve already developed are released at the right time.
Progesterone: Supporting Early Pregnancy
After ovulation, many fertility protocols include progesterone supplementation during the “luteal phase,” the roughly two weeks between ovulation and when a pregnancy test would turn positive. Progesterone thickens the uterine lining and supports implantation. A meta-analysis of seven trials found that adding progesterone after ovulation induction and IUI increased live birth rates by 38% compared to no supplementation. It’s usually given as a vaginal suppository or oral capsule.
Progesterone support doesn’t appear to reduce miscarriage rates in the general fertility population. However, for women who have had one or more previous miscarriages and experience early pregnancy bleeding, vaginal progesterone has been shown to improve live birth rates compared to placebo. If you have a history of loss, this is worth discussing with your provider.
Metformin for PCOS
Metformin isn’t a fertility drug on its own, but it plays a supporting role for women with PCOS. PCOS is closely linked to insulin resistance, and metformin improves how your body handles insulin. This can restore more regular ovulation in some women and enhance the effectiveness of letrozole or clomiphene when used alongside them. Dosing varies widely, from 500 mg to 3,000 mg daily, with the most common regimens being 500 mg three times a day or 850 mg twice a day. The optimal dose hasn’t been firmly established.
Metformin alone is less effective than letrozole or clomiphene at producing pregnancies. Its main value is as an add-on, particularly for women whose ovulation doesn’t respond adequately to a fertility drug by itself.
How Treatment Typically Progresses
Fertility treatment follows a step-up pattern. Most women start with letrozole (or clomiphene) plus timed intercourse for three to six cycles. If that doesn’t work, the next step is usually the same oral medication combined with IUI, which places washed sperm directly into the uterus around ovulation. After that, injectable gonadotropins with IUI offer a stronger push. IVF is generally reserved for when these less invasive options haven’t succeeded, or when there are additional factors like blocked fallopian tubes or severe male factor infertility.
Each step up increases both the success rate per cycle and the cost, complexity, and monitoring involved. The “best” fertility drug for you depends on where you are in this process, why you’re not conceiving, and how your body responds to each medication. For the majority of women starting treatment, letrozole is the most effective and lowest-risk place to begin.