For PCOS patients who don’t ovulate, a first order goal is the resumption of ovulation for which oral medications like clomiphene citrate (CC) or letrozole are often used. Clomiphene citrate and letrozole promote the brain’s natural production of gonadotropins—hormones that facilitate ovulation. Clomiphene citrate, a selective estrogen receptor modulator (SERM), does this by blocking the brain’s ability to sense estrogen levels while letrozole, an aromatase inhibitor, stops estrogen production altogether by blocking the conversion of androgens to estrogens. Both result in the same outcome: restoration of proper gonadotropin production. Both clomiphene citrate and letrozole are orally administered and relatively inexpensive compared with pharmaceutical gonadotropins.

Generally speaking, the data suggest that PCOS patients who don’t ovulate are more likely to conceive using letrozole than with clomiphene citrate. As a result, many doctors believe letrozole should be used first, and if it doesn’t work, then clomiphene citrate could be tried. Below we characterize the most important attributes when comparing both drugs.

The New England Journal of Medicine Study

Our analysis comparing clomiphene and letrozole relies heavily on a 2014 New England Journal of Medicine study. This study compared live birth rates amongst PCOS patients after five doses of either letrozole or clomiphene. To the positive, the study was large (750 patients), randomized, and conducted at multiple centers. To the negative, it consisted largely of a single group (Caucasian Americans), recorded a high rate of people who “dropped out” (or could not be accounted for) and had only a 3-year time horizon to record “anomalies amongst offspring.”

Rates of Success

As you can see, letrozole outperformed clomiphene citrate in that a higher percentage of letrozole patients recorded a live birth. That was driven by higher rates of ovulation. However, it does not appear that letrozole’s outperformance of clomiphene citrate was equal between groups. As you can see, it appears letrozole more dramatically outperformed clomiphene citrate when the PCOS patient had a BMI over 30.

Adverse Events

Risk of Multiples & Why This Matters

Generally speaking, letrozole produces fewer twin and triplet deliveries. This matters because multiple gestation pregnancies are more likely to pose a risk to the person delivering (e.g. parent, gestational surrogate) and the offspring as you can see in the data below. Doctors favor approaches that mitigate the risk of twin or triplet deliveries.

Women with PCOS are at higher risk of multiple follicles developing at the same time which increases their risk of multiple pregnancies. One study compared live birth and multiple pregnancy rates in 765 Chinese patients (who underwent IUI) after treatment with either clomiphene citrate, letrozole, or gonadotropins (which we’ll discuss later) and found that letrozole was statistically as likely to induce mono-follicular growth (the growth of only one follicle at a time) as gonadotropins, with clomiphene citrate showing a significantly lower likelihood of inducing mono-follicular development (Huang et al., 2018). This represents a major positive for letrozole in the discussion of whether to start with letrozole or clomiphene citrate.

While the large sample size in this study adds to the strength of its findings, its lack of randomization or ethnic diversity of study subjects means the data may not necessarily be broadly applicable. Still, these data bolster support for _letrozole as a first-line intervention for ovulation induction in women with PCOS. _

According to the 2018 PCOS evidence-based guidelines, “Health professionals and women need to be aware that the risk of multiple pregnancy appears to be less with letrozole, compared to clomiphene citrate.”

Serious Adverse Events in Offspring (after 20 weeks of pregnancy)

One previously commonly held concern about letrozole was that it correlated with negative outcomes for the offspring. In a 2014 New England Journal of Medicine study, investigators noted a rate of 5%–6% of “serious adverse events” (e.g. congenital anomaly, fetal or neonatal death) and concluded that there was no statistically significant difference between letrozole and clomiphene citrate with respect to this outcome. Investigators noted, “these rates are also similar to the rate in a population of healthy, fertile women who conceived without undergoing treatment for assisted reproduction (5.8%).” However, offspring tracking lasted only three years and, as a result, complications that may have arisen after the limited time horizon could not be accounted for. Still, the data indicate that neither clomiphene citrate nor letrozole increases the risk of serious adverse events in offspring.

Other Adverse Events for Patients

Additionally, investigators note a differing response to the drugs amongst patients who took letrozole (higher rates of fatigue and dizziness) and clomiphene (greater rates of hot flashes), as you can see below.

Worries About Impact on the Endometrium

Pregnancy begins when the embryo implants in the uterus so it’s critical for the uterus to be “receptive” to absorbing the embryo. There is general consensus that letrozole is superior to clomiphene citrate when it comes to endometrial receptivity, which can be quantified in a number of ways. One study that examined the effects of clomiphene citrate on the endometrium showed that its presence correlated with decreased blood flow to the uterus during the luteal phase—a critical window for implantation (Hsu et al., 1995). Below are three studies that illustrate the varied findings on the subject. One study found that patients using clomiphene citrate experienced thinning of the uterus when compared to untreated patients. Another study showed both clomiphene citrate and letrozole increasing endometrial thickness but with clomiphene citrate being superior in this regard. The final study showed letrozole to be superior to clomiphene citrate in increasing the thickness of the endometrium.

It’s important to note that endometrial thickness is only one measure of uterine receptivity and health. One concern with clomiphene citrate is its anti-estrogen effect on the uterus whereas letrozole has been shown to maintain a natural uterine environment in this regard (Cortínez et al., 2005). Since estrogen is crucial to increasing endometrial receptivity during the implantation window, this represents another area in which letrozole is considered to be preferable to clomiphene citrate.

Adding Metformin to Letrozole or Clomiphene Citrate

A number of PCOS patients who don’t ovulate won’t be helped by using drugs like letrozole or clomiphene citrate alone. In those cases, clinicians have a number of options (which we characterize below) and while each can improve rates of success, factors like cost, physical burden to the patient and the risk of multiples often dictate the sequence of which approach doctors are prepared to try.

What Is Metformin

Metformin is a class of drug known as an insulin sensitizer and is marketed under the trade names Glucophage, Glumetza, Riomet, and Fortamet. Due to its proven capacity to increase the body’s sensitivity to insulin, it has been used for decades in patients with type II diabetes (T2D). Metformin reduces glucose production from glycogen stores in the liver, decreases the absorption of glucose from the intestines, and promotes the uptake and use of glucose by peripheral tissues (such as the skeletal muscle). Together this helps to improve your body’s sensitivity to insulin and reduce the amount of insulin your body needs to release into the blood for the desired effect. Because one of the actions of insulin is to stimulate the production of androgens in the ovaries, lowering insulin levels can decrease androgen levels and increase ovulation rates (Legro, 2012). In some patients this can be enough to achieve a pregnancy. Metformin can play a variety of roles in helping PCOS patients conceive in combination with other approaches (e.g. ovulation induction, IUI, IVF) and we will repeatedly refer to it. While metformin is often accessible, it also has drawbacks (which we’ll cover in detail below), and should be discontinued once a patient is believed to be pregnant.

Success Rates

Below are two studies that show how metformin performs when added to either clomiphene citrate or letrozole. While these are well-run studies, they do not involve patients who had previously been unsuccessful with clomiphene citrate or letrozole alone. With that, let’s look at the results.

A “meta analysis” (a systematic assessment of multiple independent trials) of nine studies showed that generally speaking using metformin in addition to clomiphene citrate can produce promising results. For context, versus clomiphene citrate alone, adding metformin to clomiphene citrate improves rates of ovulation and clinical pregnancy, but ultimately live birth rates were comparable between the two groups. As to whether patients taking the combined drugs were more likely to miscarry once pregnant, and if that is borne out in a statistically significant way, remains unclear.

In a smaller study when metformin was added to letrozole, the improved rates of pregnancy didn’t reach statistical significance and the live birth rate was no different.

Risks and Other Considerations

One question would be, “if adding metformin to clomiphene citrate is productive, why not add it immediately—why wait to fail with clomiphene citrate?” One reason is that metformin is generally associated with gastrointestinal side effects including nausea, vomiting and diarrhea which, although often mild, can sometimes be troublesome enough to warrant discontinuation of treatment.

On the other hand, metformin combined with clomiphene citrate can be used as second-line pharmacological therapy to improve ovulation in women with PCOS who remain anovulatory to clomiphene citrate alone (i.e., clomiphene citrate-resistant), although gonadotropins are more effective (Costello 2019).

Additionally, it is important that metformin use be stopped by the end of the first trimester at the latest, but preferably upon detection of a fetal heartbeat, due to findings that it increases the risk of excess weight in offspring (Hanem et al. 2018).

Dexamethasone

Dexamethasone (DEX) is a steroid drug that mimics hormones produced by the adrenal glands. It is sometimes administered to women with PCOS who are experiencing symptoms of adrenal androgen excess (acne, hirsutism, and androgenic alopecia) as determined by elevated dehydroepiandrosterone sulfate (DHEA-S) levels. One study that combined DEX with clomiphene citrate showed improvement in folliculogenesis, ovulation, and pregnancy rates.

Success Rates

There have been studies, like the one below published in Fertility & Sterility that show adding DEX to clomiphene citrate (CC) in CC-resistant patients dramatically improves outcomes. We should note two things: First, the patient population was in their mid-20’s (and thus may have recorded particularly higher rates of success) and second, they were categorized as having normal levels of DHEA-S.

Why DEX Isn't Used More Often

Generally speaking, dexamethasone is not commonly used as an adjunct for the treatment of anovulation in PCOS women because of its side effects, including mood changes, numbness of the arms and legs, swelling of the fingers and hands and unintended weight gain. Also, long-term use of dexamethasone can be associated with bone loss.

That said, few studies that look at the benefits of adding DEX for PCOS characterize or dwell on any major issues or adverse effects of taking the drug. (Basirat et al., 2016).

Laparoscopic ovarian drilling (LOD)—sometimes referred to as laparoscopic ovarian surgery—is a surgical procedure whereby a surgeon uses a laser or electrocautery to puncture the ovary(ies) several times in hopes of resuming ovulation. It has been proposed that the punctures reduce androgen and inhibin levels and cause a rise in follicle stimulating hormone (FSH) that could in turn lead to maturation—rather than arrest—of oocytes (Seow et al., 2020). LOD has also been shown to reduce the risk of multiples and of OHSS, with a success rate at inducing ovulation estimated in studies to be between 30–90% (Seow et al., 2020, Mitra et al., 2015). That said, LOD is not an option many doctors consider early in the process of treating PCOS patients.

Rates of Success

Some studies indicate that LOD can help improve live birth rates. The degree to which LOD helps in comparison to the alternatives is a matter of debate. According to studies cited by the 2023 International Evidence Based Guidelines for the Assessment and Management of PCOS, rates of success look comparable to other oral medications.

A Cochrane Analysis (a systematic review of research in health care and health policy that is published in the Cochrane Database of Systematic Reviews) came to the conclusion that at best LOD was comparable to oral medication in rates of success and at worst was about half as effective. However laparoscopic ovarian surgery is considered second line therapy for more complicated patients which may explain some of the success rates.

Regardless, LOD is often an option to consider, but given its debated rates of success and drawbacks (see below), it’s principally considered for patients who will require surgery anyhow or who have not had success with oral medications.

Drawbacks of LOD & Why It’s Not “First Line”

There are multiple concerns some experts have with the approach and 2023 International Evidence Based Guidelines for the Assessment and Management of PCOS call for patients to be sufficiently educated on the drawbacks.

Adverse Events

One adverse complication associated with laparoscopic ovarian surgery is the development of pelvic adhesions between the ovary and the abdomen or bowel, and the associated complications of pain or compromised pregnancy. LOD techniques have gone through multiple refinements and so to ascribe adhesion risk is difficult, but according to one review of over 24 studies on the subject, investigators concluded that, although mitigating the risk of adhesions was elusive, their presence did not seem to affect pregnancy rates (Mitra et al., 2015).

Another complication associated with laparoscopic ovarian surgery is ovarian damage if too many puncture sites are placed in the ovary. For this reason, many physicians prefer to avoid surgery, particularly if medications are successful in inducing ovulation. As with any surgical procedure the risks may well vary by who is doing the procedure. We’ve yet to see long-term data on how LOS actually impacts ovarian function, especially in PCOS patients who may likely start with a robust ovarian supply.

As with other approached to ovulation induction in PCOS women, marked obesity, severe androgen excess and long duration of infertility predict reduced pregnancy rates with laparoscopic ovarian surgery.

Finally, doctors also cite concerns of excessive bleeding from the procedure and the need to use general anesthesia as reasons to be measured in the use of LOD.

Cost

LOD is a surgery and as a result, will drive significantly higher up-front costs than taking oral medication (e.g. letrozole, clomiphene citrate, metformin) which often equate to less than a few hundred US dollars or Euros. However, there are studies to suggest LOD is economically practical in comparison to other approaches, like use of gonadotropin, which we’ll discuss next.

Gonadotropins are drugs aimed at stimulating existing follicles to develop so they can eventually release a mature egg. Unlike SERMs (clomiphene citrate) and aromatase inhibitors (letrozole), they take the form of injectable hormones. Gonadotropins are often a burden to self-administer and cost significantly more money than oral medications like clomiphene citrate, letrozole and the like. Gonadotropins are often used in combination with IUI and IVF, we’ll refer back to them repeatedly, and in this specific chapter we’ll discuss them when trying to conceive through intercourse. PCOS patients need to be especially careful with gonadotropin use and it’s critical they only use gonadotropins under the supervision of a doctor who can regularly monitor the growth of their follicles.

Success Rates Summary

Below are two credible studies demonstrating that PCOS patients who do not achieve a pregnancy using clomiphene citrate or letrozole can be helped by using gonadotropins. The type of gonadotropin (e.g. recombinant) administered does not seem to significantly influence outcome.

While the data on the risk of multiples-per-pregnancy and ovarian hyperstimulation syndrome (OHSS; which we’ll cover below) from these studies are reassuring, both are significant risks to PCOS patients and likely a function of the clinic’s expertise in monitoring patients. For this reason, it’s critical PCOS patients select a clinic set up to provide regular transvaginal ultrasound monitoring (and that is prepared to call off the cycle) when using gonadotropins.

Concerns and Considerations

Multiple Gestation Pregnancy & the Importance of Monitoring

Singleton pregnancies are the goal of controlled ovarian stimulation as multiple gestation pregnancies are more likely to pose a risk to the person delivering (e.g. parent, gestational surrogate) and the offspring, as you can see in the data below.

Gonadotropins can stimulate multiple follicles to develop at once (multifollicular development), increasing the likelihood of multiple eggs being fertilized and implanting in the uterus. This risk is especially high in patients with PCOS.

To prevent these multiple gestation pregnancies, patients undergoing gonadotropin stimulation require close monitoring of follicular development by ultrasound. This allows the physician to adjust drug doses to encourage monofollicular growth (growth of only one follicle at a time) and to make the call to cancel a cycle in the event that too many follicles develop. An experienced physician will generally aim for no more than 2 “dominant” follicles larger than 18mm in diameter in order to optimize for monofollicular development. Additionally, PCOS patients should be started on low gonadotropin doses, usually in the range of 37.5 to 75 IU/day, compared with the typical starting dose of 150 IU/day, and the dose incrementally altered until a single dominant follicle begins to develop (Thessaloniki, 2008, Orvieto 2009).

Ovarian Hyperstimulation Syndrome (OHSS)

Ovarian hyperstimulation syndrome (OHSS) occurs when the ovaries receive an excessively high signal to recruit and develop follicles. Symptoms include pain, swelling of the ovaries, and abdominal distention. In severe cases, patients might experience life-threatening complications including blood clots and difficulty breathing, which is why OHSS requires prompt medical attention.

Due to the heightened risk of OHSS in PCOS patients, the GnRH antagonist protocol is the protocol of choice in this population. Briefly, this involves the use of drugs called GnRH antagonists (GnRH-ant) to block the release of naturally-produced gonadotropins that would ordinarily exert additional stimulatory effects on follicles in addition to the stimulation of the injected hormones.

Below are data amongst PCOS patients (undergoing IVF) who used gonadotropins and as you can see, the risk of hyperstimulation was dramatically lower amongst those on the antagonist protocol.

Metformin and Letrozole as Adjuncts to Reduce OHSS

Both metformin and letrozole have been clinically shown to reduce OHSS when co-administered with gonadotropins.

In certain subsets of PCOS patients especially prone to OHSS, specifically those with high serum Anti-Müllerian hormone (AMH) levels, the co-administration of letrozole during the GnRH-ant protocol has been shown to reduce incidences of OHSS. For this reason, your doctor may add metformin to your controlled ovarian stimulation protocol, as metformin co-administration with gonadotropins has been shown to significantly reduce OHSS risk in PCOS patients (Palomba et al., 2011). In addition, a small prospective randomized controlled pilot study suggests that letrozole use during ovarian hyperstimulation for in vitro fertilization may have a similar beneficial effect, although its use under this circumstance is currently unclear (Tshzmachyan, 2020).