Clomid Resistance and Improving Ovulation Response

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About one in four women will not ovulate when taking Clomid. Sometimes, the reason you may not ovulate on Clomid is because the dosage is too low. It's common to start Clomid treatment at 50mg, and then increase to 100mg if you don't respond. In some cases, doctors will try doses up to 250mg. However, if you're still not ovulating even at higher dosages, this is referred to as Clomid resistance.

Clomid resistance isn’t the same situation as when you don’t conceive taking the fertility drug. In that case, you may ovulate, but not get pregnant. In this case, you are not even ovulating. Will you need to move onto stronger drugs or more complex treatments if ovulation doesn’t happen? Not necessarily.

Causes of Clomid Resistance

Your doctor's approach to treating Clomid resistance depends partially on why they think you are not responding. Here are a few known, possible reasons for Clomid resistance:

  • Higher weight: A higher weight can decrease the chances of Clomid working successfully.
  • Hyperprolactinemia: Women with hyperprolactinemia may not respond well to Clomid, without also treating the hyperprolactinemia. Of course, there are times when it's not clear why Clomid is not helping induce ovulation.
  • PCOS: Women with PCOS commonly have trouble with Clomid resistance, especially those who are diagnosed as insulin resistant or with hyperandrogenic levels (high levels of DHEAs and male hormone levels).

Overcoming a Resistance to Clomid

For women with PCOS, treatment with the insulin resistance drug metformin, also known as Glucophage, may help. Ideally, Metformin would usually be prescribed for a period of 3 to 6 months before trying Clomid again. Some studies have shown that besides improving ovulation rates, taking metformin and Clomid together may also increase the pregnancy rate and decrease the risk of miscarriage.

A possible alternative to metformin is N-acetyl-cysteine (NAC), an amino acid and antioxidant that works as an insulin-sensitizing agent. Some studies have found that combining Clomid and NAC may help treat Clomid resistance.

Your doctor may suggest that you lose some weight before retrying Clomid. Losing just 10% of your current body weight may improve Clomid's effect. For those with hyperprolactinemia, treatment with the drug Bromocriptine, either alone or in combination with Clomid, may improve ovulation rates.

Ovarian drilling is an older method of treating Clomid resistance in women with PCOS but is not commonly used today because of the risks. If your doctor suggests ovarian drilling, you may want to question the reason for that choice, when there are other options that can and should be tried first.

Birth Control Pills for Infertility

One interesting way of dealing with Clomid resistance is taking birth control pills for 1 to 2 months before trying another cycle of Clomid. This is recommended for women with high levels of the hormone DHEAs.

It seems a bit counter-intuitive—birth control pills will help you get pregnant? But research studies have shown good results. In one study on the use of birth control pills, just over 65% of Clomid resistant women ovulated, after taking oral birth control pills for two months preceding a treatment cycle.

What If Clomid Still Doesn't Work?

Sometimes, ultrasound will show the follicles growing in response to Clomid, but the midcycle LH surge isn't strong enough to bring on ovulation. In this case, your doctor may prescribe Clomid along with an injection of hCG, like the drug Ovidrel, to trigger ovulation and boost the midcycle LH surge.

If after trying these options, you're still not ovulating on Clomid, your doctor may suggest trying different ovarian stimulating medications.

Letrozole (also known as Femera) is another option for women who don’t ovulate with Clomid. Studies have shown that Letrozole may induce ovulation in some women with PCOS who do not respond to Clomid, as well as some women with unexplained infertility and Clomid resistance.

In one study, women with Clomid resistance and PCOS were more likely to ovulate when taking the medication Letrozole (79.3% ovulated), than when taking Clomid in combination with two, low dose injections of FSH therapy (57% ovulated).

Pregnancy rates were also improved, with 23% of the women taking Letrozole achieving pregnancy, and 14% achieving pregnancy with the Clomid and two injections of low-dose FSH combination.

Letrozole is not, however, sold as a fertility drug. There is some controversy over the safety of its use. Letrozole can cause birth defects if taken during pregnancy. Many argue that the medication is safe and say that the drug should be out of your system by the time pregnancy occurs, though more research needs to be done.

Other options for treating Clomid resistance include low-dose gonadotropin therapy, with or without IUI treatment. This includes drugs like Gonal-F, Follistim, and Ovidrel. (In other words, recumbent FSH and LH fertility drugs.) These drugs are more expensive and come with more side effects than Clomid, but they may induce ovulation when Clomid fails.

A Word From Verywell

Clomid is often the first fertility drug tried after an infertility diagnosis. You may have been trying to conceive for over a year by the time this treatment cycle starts. When it doesn’t work, you may feel worried that this is a sign of things to come. You may worry this means you’re destined for the more expensive treatments, like IVF.

The truth is that Clomid only marks the beginning of infertility treatment. If you don’t ovulate on your first or second cycle or don’t get pregnant, try not to panic. There are many steps along the way before you will be asked to consider the higher-tech fertility treatments.

9 Sources
Verywell Family uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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Additional Reading

By Rachel Gurevich, RN
Rachel Gurevich is a fertility advocate, author, and recipient of The Hope Award for Achievement, from Resolve: The National Infertility Association. She is a professional member of the Association of Health Care Journalists and has been writing about women’s health since 2001. Rachel uses her own experiences with infertility to write compassionate, practical, and supportive articles.