Non-steroidal anti-inflammatory drugs as a possible cause for reversible infertility

L. L. F. Mendonça, M. A. Khamashta, C. Nelson-Piercy, B. J. Hunt and G. R. V. Hughes

Lupus in Pregnancy Clinic, St Thomas’ Hospital, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Case reports
 Discussion
 Conclusion
 References
 
Objective. To highlight the possible association between infertility and treatment with long-term non-steroidal anti-inflammatory drug (NSAIDs). NSAIDs act mainly through the inhibition of cyclooxygenase, the enzyme that catalyses the synthesis of prostaglandins, which are essential mediators of ovulation, implantation and placentation of the conceptus.

Methods. Case reports of four women suffering from severe arthritis, on long-term NSAIDs and undergoing extensive investigation and treatment for infertility.

Results. During the last 2 yr, four out of five women with severe arthritis and difficulty conceiving were counselled to stop NSAIDs, and they successfully conceived shortly after the withdrawal of NSAIDs.

Conclusion. NSAIDs, used largely for the treatment of rheumatological conditions, may be responsible for some cases of infertility.

KEY WORDS: Fertility, Luteinized unruptured follicle syndrome, Diclofenac, COX inhibitors


    Introduction
 Top
 Abstract
 Introduction
 Case reports
 Discussion
 Conclusion
 References
 
Non-steroidal anti-inflammatory drugs (NSAIDs) are used largely for the treatment of pain, inflammation and fever, all common features of rheumatic conditions. The main mechanism of action of NSAIDs is through the inhibition of cyclooxygenase (COX), the enzyme that catalyses the synthesis of prostaglandins (PG) [1]. Even though PGs mediate many steps of inflammation, they also have a wide range of physiological functions, including essential steps in the female reproductive cycle. The most common reported adverse effects of NSAIDs are related to the kidneys and gastrointestinal tract. However, by interfering with the synthesis of prostanoids, NSAIDs may interfere with the release of the mature ovum, leading to an ovulation failure known as the luteinized unruptured follicle syndrome [2]. We report four cases of women suffering from severe arthritis, who were on long-term NSAIDs and undergoing extensive investigation and treatment for infertility, and who successfully conceived after the withdrawal of NSAIDs.


    Case reports
 Top
 Abstract
 Introduction
 Case reports
 Discussion
 Conclusion
 References
 
Case 1
A 27-yr-old woman who had been taking diclofenac since the age of 21 because of severe rheumatoid arthritis (RA)–lupus overlap, had been investigated extensively for infertility. No cause had been found, and intra-uterine insemination treatment failed. She was advised to stop NSAIDs. After this she underwent one cycle of in vitro fertilization (IVF), which resulted in the full-term, normal delivery of a healthy baby at 39 weeks. She then tried for a natural pregnancy for a period of 4 yr with no success. Once again she was advised to stop the diclofenac and after one cycle of IVF achieved her second pregnancy. She gave birth to a healthy baby girl at 40 weeks.

Case 2
A 41-yr-old woman presented with secondary infertility. She had had three previous normal pregnancies, the last 6 yr previously. Three years before presentation she had developed symmetrical polyarthritis, which was diagnosed as RA and was treated with hydroxychloroquine and diclofenac. For the last 3 yr she had been trying to conceive. She had been investigated previously for unexplained secondary infertility and all tests were normal. She was advised to discontinue diclofenac and she conceived naturally 5 months later. She delivered a normal healthy son at 40 weeks' gestation.

Case 3
A 32-yr-old woman who had had RA since the age of 25 and who had a 5-yr history of diclofenac therapy presented with infertility. She had been advised by an infertility specialist to discontinue the NSAID and start ovulation induction. She had three cycles of clomiphene citrate after stopping the NSAID and became pregnant in January 1997. She had an uneventful gestation up to 36 weeks, when the foetus died suddenly. In March 1998 she conceived naturally but at 15 weeks' gestation she once again lost the baby. Two months after this miscarriage, she was found to be pregnant again. At 34 weeks she underwent induction of labour because of pre-eclampsia, and delivered a healthy baby.

Case 4
A 30-yr-old woman on diclofenac therapy for joint symptoms related to her RA–lupus overlap presented with a 3-yr history of unexplained infertility. She was counselled to stop the NSAID, and 6 months later conceived naturally. She delivered a normal healthy son at 40 weeks' gestation.


    Discussion
 Top
 Abstract
 Introduction
 Case reports
 Discussion
 Conclusion
 References
 
Recently, a small number of cases of infertility associated with the chronic use of NSAIDs have been reported in the literature [24]. We present here four further cases of women seen in our lupus pregnancy clinic during the last 2 yr with histories of primary or secondary infertility. They had in common severe inflammatory joint disease and chronic use of diclofenac. Two had been submitted to extensive investigation for infertility, and discontinuation of the NSAID was followed by successful conception after 2–6 months. Conception was spontaneous in three cases and followed one cycle of IVF in the fourth case.

The ability of NSAIDs to suppress inflammation is related primarily to their ability to inhibit enzymes involved in arachidonic acid metabolism. NSAIDs act by inhibiting the COX enzyme responsible for the synthesis of PGs. PGs perform a wide range of physiological functions involving the regulation of normal cell activity, and this same mechanism helps to explain many of the adverse effects of NSAIDs. There are two distinct isoforms of COX, COX-1 and COX-2, which are coded for on different chromosomes. Although they have the same catalytic activity, they differ in distribution, expression and regulation. COX-1 is constitutively expressed in nearly all tissues and has physiological functions. The actions of PG in preventing gastric erosions and ulceration in the gastrointestinal tract, and in the maintenance of normal kidney function, are generally well known and are sustained mainly via COX-1. COX-2, however, is an enzyme that is coded for by an early response gene and is involved in pathological inflammatory processes. Although COX-2 also exists in constitutive form in certain tissues (such as the brain, spinal cord and female reproductive system), its expression is induced by a variety of stimuli, including inflammation and the induction of contractions during labour.

PGs are essential mediators of ovulation. They induce the mobilization of granulosa and theca interna cells within the ovaries, and the COX-2-dependent PGs probably lead to the generation of proteolytic enzymes that rupture the follicles [5]. COX-2 has also been implicated as a mediator in other stages of the female reproductive cycle. COX-2 knockout mice are largely infertile, producing very few offspring because of a reduction in ovulation. Both COX-1 and COX-2 are expressed in the uterine epithelium at different stages of early pregnancy and may be important in ovulation, fertilization and implantation of the ovum, as well as in angiogenesis for the establishment of the placenta (decidualization) [6, 7].

Most of the above findings come from animal studies. However, there is growing evidence of possible impairment of fertility in women receiving chronic treatment with potent NSAIDs. Piroxicam, naproxen and diclofenac have been implicated in cases of unexplained infertility [24]. The discovery of COX-2 has allowed the design of specific COX-2 inhibitors, which reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. The first COX-2-selective inhibitor has recently been introduced in the UK for the treatment of inflammatory conditions. Mainly because selective COX-2 inhibitors possess anti-inflammatory effects with improved gastrointestinal tolerability compared with conventional NSAIDs affecting both COX-1 and COX-2, it is expected that these drugs may overcome the use of other, less specific NSAIDs. However, the broader spectrum of biological activity of COX-2 should be kept in mind, especially when prescribing these drugs to women during their childbearing years for the treatment of painful and inflammatory disorders such as dysmenorrhoea and rheumatological conditions.

Of the last five patients seen by us and counselled to stop NSAIDs, four successfully conceived. The four cases described here, although not proving a direct cause-and-effect relationship, do highlight the need for greater general awareness of the potential side-effects of inhibitors of PG synthesis. A careful medical and drug history (particularly concerning the use of potent NSAIDs) may resolve some cases of primary and secondary infertility without the need to proceed with expensive and invasive investigation and treatment.


    Conclusion
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 Abstract
 Introduction
 Case reports
 Discussion
 Conclusion
 References
 
Patients with rheumatological conditions and unexplained infertility should be asked about the use of NSAIDs before being subjected to extensive investigation or IVF. Reproductive failure due to NSAIDs is rarely reported, but its true frequency may be underestimated.


    Acknowledgments
 
We would like to thank Dr Daghni Rajasingam and Dr Hassan Shehata for their helpful comments and suggestions.


    Notes
 
Correspondence to: M. A. Khamashta, Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK. Back


    References
 Top
 Abstract
 Introduction
 Case reports
 Discussion
 Conclusion
 References
 

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Submitted 20 August 1999; revised version accepted 28 January 2000.