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Clomiphene is a fertility treatment that can help women who are experiencing difficulty getting pregnant.
It works by increasing the activity of estrogen in the body to stimulate the release of an egg from the ovaries (ovulation). Clomiphene therapy leads to pregnancy in 30–40% of women with polycystic ovary syndrome (PCOS) and certain other fertility issues within three months of treatment.
Here’s how this medication works for female fertility.
What is clomiphene?
Clomiphene, sold under the brand names Clomid and Serophene, is a type of medication known as a selective estrogen receptor modulator (SERM). It works by increasing the activity of estrogen, one of the dominant female hormones, in certain parts of the body (Seli, 2021).
Estrogen plays an important role in fertility. During the menstrual cycle, the brain, ovaries, and uterus communicate using different hormones, which are like little chemical messengers, to control the release of an egg from the ovaries and build up the lining of the uterus to ready it for a fertilized egg.
Some people, including people with PCOS, may not release an egg each month—a condition called ovulatory dysfunction—making it difficult to get pregnant. Clomiphene increases hormone levels to help trigger the release of an egg from the ovaries.
Can anyone start clomiphene therapy?
If you’ve been trying for a year or more and haven’t become pregnant, a healthcare provider may recommend the use of clomiphene. There are many reasons why some people have difficulty getting pregnant.
It can be related to the shape of your uterus, genetics, male infertility, and more. Rates of ovulation often fall as we get older, and can be associated also with having overweight or insulin-resistance (a feature of type 2 diabetes) (Seli, 2021).
If you’re having trouble getting pregnant, visit your healthcare provider. They will ask you questions about your medical history and may perform certain tests or examinations to determine the source of the fertility issues. Here are some of the tests they might perform:
- Blood tests: A healthcare provider will check the levels of hormones involved in ovulation and in maintaining pregnancy following conception, including HCG (human chorionic gonadotropin), TSH (thyroid stimulating hormone), prolactin, and FSH (follicle stimulating hormone). AMH (anti-mullerian hormone) is often tested to look for PCOS as well as the ovarian reserve (the amount of eggs you have in your ovaries).
- Semen analysis: Sometimes the issue is related to the male factor, so they may perform a semen analysis to check the quality and quantity of sperm for a male partner.
- Pelvic exam: This can be a vaginal or rectal exam using a gloved hand or a pelvic ultrasound. During an ultrasound, a long wand is placed inside the vagina and uses sound waves to examine the shape and orientation of the uterus. While these exams should not be painful, they can be a bit uncomfortable. Be sure to communicate any discomfort or pelvic pain you are feeling to your provider.
- Hysterosalpingogram: This long word just means a picture of your uterus and fallopian tubes, the tiny tube-like structures that carry eggs from the ovaries to the uterus after ovulation. Along with an ultrasound, a healthcare provider can use this test to see if you have ovarian cysts (fluid-filled sacs on the ovaries), which can contribute to fertility problems.
- Biopsy: A biopsy of the endometrium (the lining of the uterus) involves taking a small tissue sample and have it evaluated in a lab. This is used mainly if you’re experiencing irregular vaginal bleeding.
If your ovaries haven’t been releasing eggs consistently or a healthcare provider can’t find why you haven’t become pregnant yet, clomiphene might be the next step.
Most healthcare providers require that you wait a full year before going through evaluation or starting treatments like clomiphene, though guidelines are different based on a woman’s age and medical history (Lindsay, 2015).
How does clomiphene therapy work?
Clomiphene therapy is usually started on the fifth day of your menstrual cycle (where day 0 is the first day of bleeding). It can also be started on days 2, 3, or 4.
You’ll typically be prescribed 50 mg per day for five days. Couples are advised to have sex every other day for one week, starting five days after the last day of medication.
If this doesn’t work in the first cycle, the dose can be increased to 100–150 mg. Higher doses of 200–250 mg may be given if lower doses aren’t effective. If clomiphene therapy doesn’t work after three to six treatment cycles, a change in treatment may be recommended (Seli, 2021).
How long does it take to work?
Typically, an egg is released from the ovaries 5–12 days after the fifth day of treatment. Some doctors check this by measuring a hormone called progesterone (which increases during ovulation) or performing an ultrasound (Seli, 2021).
For people with PCOS who take clomiphene, about 30–40% will become pregnant in three cycles (three months) of treatment. Roughly half of those women get pregnant while taking a 50 mg dose, while the rest required higher doses to get pregnant.
For PCOS, healthcare providers may measure other hormones to see if another therapy can be used. Treatments include metformin, a diabetes medication that can help regulate ovulation.
People on clomiphene have an increased rate of multiple pregnancies, which means getting pregnant with twins or triplets. About 7% of clomiphene-treated conceptions are twins.
Possible side effects
If you have a history of liver disease, let your healthcare provider know before starting this medication. Common adverse effects from this drug include (Seli, 2017; LiverTox, 2017):
- Hot flashes
- Abdominal pain
- Nausea and vomiting
- Breast discomfort
- Mood swings
- Visual disturbances
- Rarely, liver injury
Speak with a healthcare provider if you start experiencing visual disturbances while taking clomiphene. No increased rate of birth defects has been reported following clomiphene therapy (Seli, 2021).
Does clomiphene interact with other medications?
Clomiphene is safe to use with most medications and supplements. Using it with bexarotene, a drug used to treat cutaneous T-cell lymphoma (a type of cancer), may make clomiphene less effective.
Additionally, a combination of clomiphene and ospemifene––a drug that helps alleviate pain associated with sex and vaginal dryness––may increase the risk of blood clots, stroke, and some cancers. Be sure to tell your healthcare provider if you’re experiencing symptoms like chest pain, shortness of breath, or pain in your arms or legs during treatment (Drugs.com, 2021).
- Clomiphene Interactions. (n.d.) In Drugs.com. Retrieved online Nov. 11, 2021 from https://www.drugs.com/drug-interactions/clomiphene.html
- Diamond, M. P., Legro, R. S., Coutifaris, C., Alvero, R., Robinson, R. D., Casson, P., Christman, G. M., et al. (2015). Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. The New England Journal of Medicine, 373(13), 1230–1240. doi:10.1056/NEJMoa1414827. Retrieved from https://www.nejm.org/medical-articles/original-article
- Legro, R. S., Brzyski, R. G., Diamond, M. P., Coutifaris, C., Schlaff, W. D., Casson, P., et al (2014). Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. The New England Journal of Medicine, 371(2), 119–129. doi:10.1056/NEJMoa1313517. Retrieved from https://www.nejm.org/doi/10.1056/NEJMoa1313517
- Lindsay, T. J. & Vitrikas, K. R. (2015). Evaluation and treatment of infertility. American Family Physician, 91(5), 308–314. Retrieved online on Nov. 17, 2021 from https://pubmed.ncbi.nlm.nih.gov/25822387/
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (2017). Clomiphene. In LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Retrieved online Nov. 11, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK548008/
- Seli, E. & Arici, A. (2021). UpToDate: Ovulation Induction with clomiphene citrate. Retrieved online on Nov. 11, 2021 from https://www.uptodate.com/contents/ovulation-induction-with-clomiphene-citrate?source=history_widget#H21
- Wheeler, K. M., Sharma, D., Kavoussi, P. K., Smith, R. P., & Costabile, R. (2019). Clomiphene Citrate for the Treatment of Hypogonadism. Sexual Medicine Reviews, 7(2), 272–276. doi:10.1016/j.sxmr.2018.10.001. Retrieved from https://www.sciencedirect.com/science/article/abs/pii/S2050052118301094?via%3Dihub
Yael Cooperman is a physician and works as a Senior Manager, Medical Content & Education at Ro.