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Drug on Radar - Nonsteroidal Anti-inflammatory Drugs and Infertility Can
over-the-counter pain relievers cause infertility in women? Darrell Hulisz Associate Professor, Department of Family Medicine, Case Western Reserve University; Clinical Pharmacist, University Hospitals, Case Medical Center, Cleveland, Ohio Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed class of drugs worldwide and are frequently used by women of childbearing age. The adverse gastrointestinal, cardiovascular, and renal effects of NSAIDs are well known. Similarly, most clinicians likely understand that using NSAIDs in near-term pregnancy may have adverse effects, including potential prolongation of labor, premature closure of the fetal ductus arteriosus, and increased risk for postpartum bleeding.[1] However, the potential for NSAIDs to adversely affect ovulation has received much less attention, even though this potential complication was described in the medical literature over 2 decades ago.[2-6] NSAIDs are prostaglandin inhibitors that block cyclo-oxygenase (COX)-1 and COX-2 enzyme production. The COX enzyme system catalyzes the production of biologically important prostaglandins. One isoenzyme, namely COX-2, is active in the ovaries during follicular development. Inhibition of COX-2 by NSAIDs and COX-2 inhibitors (e.g., celecoxib) is thought to potentially cause reversible luteinized unruptured follicle syndrome (LUFS) in a subset of patients.[1,6] This syndrome is characterized by a failure of ovulation. While clinical signs of ovulation (e.g., elevated body temperature and progesterone levels) do occur, follicular rupture and ovum release are absent. COX-2 inhibitors may have further adverse effects on fertility. COX-2 expression is thought to occur not only in ovulation but also in fertilization, implantation, and maintenance of pregnancy.[7] COX isoforms are important in the generation of prostaglandins that are essential for formation of proteolytic enzymes causing rupture of the egg follicles as well as prostaglandins crucial in angiogenesis for establishment of the placenta.[6,7] Sporadic case series reports of delayed ovulation and/or LUFS in association with NSAID use have appeared in the medical literature.[4-6] Prospective, randomized, controlled trials of small sample sizes have demonstrated that NSAIDs and COX-2 inhibitors produce a reversible delay in follicular rupture.[8-10] The studies show a fairly consistent pattern of apparently insignificant differences in biological variables, such as menstrual cycle length or overall endocrine profiles of cycles in women receiving NSAIDs and COX-2 inhibitors vs placebo. However, unruptured follicles were more often observed in a significantly higher proportion of women using these agents, and this effect is reversible upon drug discontinuation. On the contrary, at least two small randomized trials[11,12] and one prospective observational cohort study[13] seem to provide reassurance that delayed follicular rupture is unlikely to cause infertility. The most recent data were presented at this year's European League Against Rheumatism (EULAR) Annual Congress by Salman and colleagues.[14] This prospective trial randomly assigned 39 women of childbearing age with minor back pain to one of four groups, as follows: 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; or A control group that received placebo. Participants began treatment starting on day 10 of their menstrual cycles to ensure that a follicle developed in preparation for ovum release. Study medications were taken for 10 consecutive days. At baseline, progesterone levels were determined, and each woman received an ultrasound to assess the size of the dominant follicle on the affected ovary. After 10 days of treatment, these assessments were repeated. Of the women receiving NSAIDs, only 6.3% ovulated in the diclofenac group, 25% ovulated in the naproxen group, and 27.3% ovulated in the etoricoxib group, compared with 100% of the control group. All three treatment 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. The investigators concluded that caution is warranted due to potential adverse effects of these drugs on female fertility, and avoidance of NSAIDs and COX-2 inhibitors should be considered in women planning to conceive. It is important to note that these study results have only been published as a poster presentation in a journal supplement as part of the EULAR meeting proceedings.[14] In conclusion, no large-scale, prospective controlled trials have proven a causal link between NSAID or COX-2 inhibitor use and female infertility; however, small controlled studies and case reports have demonstrated an association between the use of these drugs and LUFS, delayed ovulation, or ovulation failure. In the future, more robust studies are warranted to determine the clinical significance of these findings and to delineate differences, if any, between NSAIDs and COX-2 inhibitors. Given that NSAIDs and COX-2 inhibitors are commonly prescribed and used over-the-counter by women of childbearing age, clinicians should be aware of these potential adverse effects, particularly in women experiencing infertility. For now it seems prudent to advise temporary withdrawal of these drugs and substitution with acetaminophen when clinically appropriate in women with fertility concerns. References 1. Stone S, Khamashta MA, Nelson-Piercy C. Nonsteroidal anti-inflammatory drugs and reversible female infertility: is there a link? Drug Saf. 2002;25:545-551. 2. Priddy AR, Killick SR, Elstein M, et al. The effect of prostaglandin synthetase inhibitors on human preovulatory follicular fluid prostaglandin, thromboxane, and leukotriene concentrations. J Clin Endocrinol Metab. 1990;71:235-242. Abstract 3. Athanasiou S, Bourne TH, Khalid A, et al. Effects of indomethacin on follicular structure, vascularity, and function over the periovulatory period in women. Fertil Steril. 1996;65:556-560. Abstract 4. Akil M, Amos RS, Stewart P. Infertility may sometimes be associated with NSAID consumption. Br J Rheumatol. 1996;35:76-78. Abstract 5. Smith G, Roberts R, Hall C, Nuki G. Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking nonsteroidal anti-inflammatory drugs. Br J Rheumatol. 1996;35:458-462. Abstract 6. Mendon??a LL, Khamashta MA, Nelson-Piercy C, Hunt BJ, Hughes GR. Non-steroidal anti-inflammatory drugs as a possible cause for reversible infertility. Rheumatology (Oxford). 2000;39:880-882. Abstract 7. Matsumoto H, Ma W, Smalley W, Trzaskos J, Breyer RM, Dey SK. Diversification of cyclooxygenase-2-derived prostaglandins in ovulation and implantation. Biol Reprod. 2001;64:1557-1565. Abstract 8. Pall M, Frid??n BE, Br??nnstr??m M. Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. Hum Reprod. 2001;16:1323-1328. Abstract 9. Bata MS, Al-Ramahi M, Salhab AS, Gharaibeh MN, Schwartz J. Delay of ovulation by meloxicam in healthy cycling volunteers: a placebo-controlled, double-blind, crossover study. J Clin Pharmacol. 2006;46:925-932. Abstract 10. Jesam C, Salvatierra AM, Schwartz JL, Croxatto HB. Suppression of follicular rupture with meloxicam, a cyclooxygenase-2 inhibitor: potential for emergency contraception. Hum Reprod. 2010;25:368-373. Abstract 11. Edelman AB, Jensen JT, Doom C, Hennebold JD. Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women. Contraception. 2013;87:352-357. Abstract 12. Uhler ML, Hsu JW, Fisher SG, Zinaman MJ. The effect of nonsteroidal anti-inflammatory drugs on ovulation: a prospective, randomized clinical trial. Fertil Steril. 2001;76:957-961. Abstract 13. Matyas RA, Mumford SL, Schliep KC, et al. Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women. Hum Reprod. 2015;30:1714-1723. Abstract 14. Salman S, Sherif B, Al-Zohyri A. Effects of some non-steroidal anti-inflammatory drugs on ovulation in women with mild musculoskeletal pain. Ann Rheum Dis. 2015;74(Suppl 2):117-118. |
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