Original research articleThe COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates☆,☆☆
Introduction
Unintended pregnancy is a persistent health care problem worldwide. In sub-Saharan Africa, South Central Asia, and Southeast Asia, 60% of women have an unmet need for contraception. In these regions, 49 million women become pregnant unintentionally each year, leading to 21 million unplanned births, 15 million induced unsafe abortions, and 116,000 maternal deaths [1]. In the United States, over 3 million reproductive-aged women experience unintended pregnancies each year, with a direct medical cost to the United States of $11 billion annually [2], [3].
Emergency contraception can prevent pregnancy after unanticipated intercourse or failure of a primary contraceptive method. Effective methods include oral contraceptive hormones, mifepristone, ulipristal acetate (UPA), and intrauterine device (IUD) insertion [4], [5]. Synthetic progestins including UPA are effective but do have side effects, such as inappropriate bleeding between cycles, which may discourage use. In a recent study, UPA prevented two-thirds of pregnancies, while the progestin levonorgestrel prevented less than half [5], [6]. Postcoital IUD insertion is very effective, with a failure rate of less than 5% [7]. IUD insertion requires a trained professional and has a comparatively high cost, making this method an unattractive emergency contraceptive option for many women.
Inhibition of prostaglandin synthesis is an unexploited target for contraception. Prostaglandins produced via cyclooxygenase-2 (COX-2) are important in many processes, which result in oocyte release at ovulation [8]. Reports of reversible infertility in women taking oral COX inhibitors support a key role for COX-derived prostaglandins in ovulatory processes [9]. Prospective studies show that oral administration of COX-2 selective inhibitors to women around the time of ovulation can prevent or delay follicular collapse, a noninvasive indicator of ovulation failure, with minimal impact on ovarian steroid hormones [10], [11], [12], [13]. Direct evidence of ovulation failure was obtained in monkeys, where COX-2 inhibitor administration reduced the rate of oocyte release without altering ovarian steroids [14], [15]. Therefore, inhibition of COX-2 activity specifically around the time of ovulation may have contraceptive efficacy. However, studies to directly test this concept in a primate species have not been reported.
The present study was conducted to provide proof of concept that a COX-2 inhibitor can be effective as a contraceptive. Cynomolgus macaques were utilized as females experience true menstrual cycles, with reproductive processes very similar to those of women. Monkeys were bred around the time of ovulation, and females received the COX-2 inhibitor meloxicam orally to simulate either emergency or monthly contraception. The results indicate that COX-2 inhibitors are candidates for development as emergency contraceptives.
Section snippets
Ethical approvals
All animal protocols were approved by the Eastern Virginia Medical School Animal Care and Use Committee and were conducted in accordance with the National Institutes of Health's Guide of the Care and Use of Laboratory Animals.
Animals
Cynomolgus macaques aged 6–10 years were housed at Eastern Virginia Medical School. All females (n=12) had at least one previous pregnancy with live birth. All males (n=4) were obtained from successful breeding colonies. Husbandry and sample collection were performed as
Emergency contraception model
In the emergency contraceptive model, monkeys experienced a single instance of breeding, and meloxicam was administered once each day for 5 days beginning on the day of breeding. Of the 46 meloxicam treatment cycles studied, 3 resulted in pregnancies, yielding a pregnancy rate in this model of 6.5% with meloxicam. This is significantly lower than the pregnancy rate when animals were bred under the same conditions but received oral vehicle without meloxicam (5 of 15 cycles yielded pregnancies;
Discussion
This is the first study to demonstrate that a COX-2 inhibitor can prevent pregnancy in primates. Previous studies suggested that inhibition of COX-2 may provide a target for contraception. Oral administration of COX-2 selective inhibitors has been shown to delay or prevent follicular rupture in both women and monkeys [10], [11], [12], [13], [14], [15]. We extended these findings by providing the first proof of concept that a COX-2 inhibitor, meloxicam, can prevent pregnancies when administered
Acknowledgments
The authors would like to thank Dr. Michael J. K. Harper for very useful discussions during the design and conduct of this research. They wish to thank the Department of Comparative Medicine at Eastern Virginia Medical School for excellent animal husbandry and technical assistance with pregnancy terminations.
References (34)
Emergency contraception: clinical outcomes
Contraception
(2013)- et al.
Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis
Lancet
(2010) - et al.
Emergency contraception with ultiload CU-375 SL IUD: a multicenter clinical trial
Contraception
(2001) - et al.
Pharmacologic production of luteinized unruptured follicles by prostagladin synthetase inhibitors
Fertil Steril
(1987) - et al.
Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women
Contraception
(2013) - et al.
Reproduction and breeding of nonhuman primates
- et al.
Prostaglandin-induced apoptosis of ovarian surface epithelial cells
Prostaglandins
(1993) - et al.
Cyclooxygenase-2 derived prostaglandin E2 directs oocyte maturation by differentially influencing multiple signaling pathways
J Biol Chem
(2006) - et al.
Multiple female reproductive failures in cyclooxygenase 2-deficient mice
Cell
(1997) - et al.
Maturation and fertilization of non-human primate oocytes are compromised by oral administration of a COX2 inhibitor
Fertil Steril
(2011)
Contraceptive technologies: responding to women's needs
The future of women's contraception: stakes and modalities
Ann N Y Acad Sci
The public cost of births resulting from unintended pregnancies: national and state-level estimates
Perspect Sex Reprod Health
Interventions for emergency contraception
Cochrane Database Syst Rev
Cyclooxygenase-2 and its role in ovulation: a 2004 account
Hum Reprod Update
Delay of ovulation by meloxicam in healthy cycling volunteers: a placebo-controlled, double-blind, crossover study
J Clin Pharmacol
Suppresion of follicular rupture with meloxicam, a cyclooxygenase inhibitor: potential for emergency contraception
Hum Reprod
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REVIEW: Influences of non-steroidal anti-inflammatory drugs on dairy cattle reproductive performance
2020, Applied Animal ScienceCitation Excerpt :When compared with FM, meloxicam has a longer biological half-life (35 h) and is effective for up to 72 h after administration (Königsson et al., 2002). In rodents and women, the effects of meloxicam seem to be negative as meloxicam reduces P/AI and can reduce implantation risk; thus, meloxicam is classified as an emergency contraceptive in these species (McCann et al., 2013; Paksoy and Kirbas, 2017). On the other hand, other observations relative to the effectiveness of meloxicam on reproductive performance have been made in buffalos (Rajkumar et al., 2010), dairy heifers (Erdem and Guzeloglu, 2010), and lactating cows (Amiridis et al., 2009).
The history of emergency contraception
2021, Medecine/Sciences
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Support for this subproject (CIG-10-129) was provided by CICCR (Consortium for Industrial Collaboration for Contraceptive Research), a program of CONRAD (Contraceptive Research and Development), Eastern Virginia Medical School. The views expressed by the authors do not necessarily reflect the views of CONRAD, CICCR, or Eastern Virginia Medical School.
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The authors have nothing to disclose.