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Research Study Warns about Adverse Effects of NSAIDs on Ovulation

Jan 4, 2016

A presentation at the 2015 European League Against Rheumatism (EULAR) Annual Congress, researchers warned that nonsteroidal anti-inflammatory drugs (NSAIDs) may adversely affect ovulation.

NSAIDs are among the most commonly prescribed drugs for pain and inflammation and are frequently used by women of childbearing age. NSAIDs are known to have adverse gastrointestinal, cardiovascular, and renal effects and, when they are taken near the end of pregnancy, NSAIDs may prolong labor, result in premature closure of the fetal ductus arteriosus, and increase the risk of postpartum bleeding, Medscape Multispecialty reports.

NSAIDs are prostaglandin inhibitors that block cyclo-oxygenase (COX)-1 and COX-2 enzyme production. COX-2 is active in the ovaries during follicle development and inhibition of COX-2 by NSAIDs and COX-2 inhibitors (e.g., celecoxib) may cause luteinized unruptured follicle syndrome (LUFS) in some patients, Medscape reports. LUFS is characterized by a failure of ovulation. While the woman shows clinical signs of ovulation-elevated body temperature and progesterone levels-follicular rupture and ovum release do not occur. The medical literature has presented sporadic reports of delayed ovulation and/or LUFS associated with the use of NSAIDs.

COX-2 inhibitors may have additional adverse effects on fertility, Medscape reports. COX-2 expression plays a role not only in ovulation but also in fertilization, implantation, and maintenance of pregnancy. COX isoforms are important in generating prostaglandins, which are essential for formation of enzymes that cause the rupture of the egg follicles and prostaglandins crucial in the establishment of the placenta.

Small clinical trials have shown that NSAIDs and COX-2 inhibitors produce a reversible delay in follicular rupture. Unruptured follicles were observed in a significantly higher proportion in women using these drugs. The effect reversed when the drug was discontinued, Medscape reports.

Prof. Sami Salman, of the Department of Rheumatology at the University of Baghdad, and colleagues presented data about the effect of these drugs on fertility at the 2015 European League Against Rheumatism (EULAR) Annual Congress. Their trial randomly assigned 39 women of childbearing age with minor back pain to one of four groups:

  • Diclofenac, 100 mg once daily
  • Naproxen, 500 mg twice daily
  • Etoricoxib (a COX-2 inhibitor not available in the United States), 90 mg once daily
  • A control group that received placebo

The study participants began treatment on day 10 of their menstrual cycles, after a follicle had developed in preparation for ovum release. The assigned medications were taken for 10 consecutive days. Participants' progesterone levels were determined at baseline, and each woman received an ultrasound to assess the size of the dominant follicle. The assessments were repeated after 10 days of treatment. Among the women taking NSAIDs, only 6.3 percent ovulated in the diclofenac group, 25 percent ovulated in the naproxen group, and 27.3 percent ovulated in the etoricoxib group, compared with 100 percent ovulation in the control group. All three NSAID groups experienced decreases in progesterone level, and about one third of women developed functional cysts due to unruptured follicles. Ovulation returned to normal once the women discontinued NSAID or COX-2 inhibitor use, Medscape reports.

Though there has not yet been a large-scale, prospective controlled trial showing a causal link between NSAID or COX-2 inhibitor use and female infertility, the EULAR investigators concluded that caution is warranted because of the drugs' potential adverse effects on female fertility. The researchers suggest that women who plan to conceive should temporarily avoid NSAIDs and Cox-2 inhibitors and consider substituting acetaminophen where needed, according to Medscape.

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