Elsevier

Contraception

Volume 88, Issue 6, December 2013, Pages 744-748
Contraception

Original research article
The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates,☆☆

https://doi.org/10.1016/j.contraception.2013.09.006Get rights and content

Abstract

Objective

Cyclooxygenase-2 (COX-2) inhibitors reduce prostaglandin synthesis and disrupt essential reproductive processes. Ultrasound studies in women demonstrated that oral COX-2 inhibitors can delay or prevent follicle collapse associated with ovulation. The goal of this study was to determine if oral administration of a COX-2 inhibitor can inhibit reproductive function with sufficient efficacy to prevent pregnancy in primates.

Study Design

The COX-2 inhibitor meloxicam (or vehicle) was administered orally to proven fertile female cynomolgus macaques using one emergency contraceptive model and three monthly contraceptive models. In the emergency contraceptive model, females were bred with a proven fertile male once 2±1 days before ovulation, returned to the females' home cage, and then received 5 days of meloxicam treatment. In the monthly contraceptive models, females were cocaged for breeding with a proven fertile male for a total of 5 days beginning 2±1 days before ovulation. Animals received meloxicam treatment (1) cycle days 5–22, or (2) every day, or (3) each day of the 5-day breeding period. Female were then assessed for pregnancy.

Results

The pregnancy rate with meloxicam administration using the emergency contraception model was 6.5%, significantly lower than the pregnancy rate of 33.3% when vehicle without meloxicam was administered. Pregnancy rates with the three monthly contraceptive models (75%–100%) were not consistent with preventing pregnancy.

Conclusions

Oral COX-2 inhibitor administration can prevent pregnancy after a single instance of breeding in primates. While meloxicam may be ineffective for regular contraception, pharmacological inhibition of COX-2 may be an effective method of emergency contraception for women.

Implications

COX-2 inhibitors can interfere with ovulation, but the contraceptive efficacy of drugs of this class has not been directly tested. This study, conducted in nonhuman primates, is the first to suggest that a COX-2 inhibitor may be effective as an emergency contraceptive.

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)

  • J.E. Darroch et al.

    Contraceptive technologies: responding to women's needs

    (2011)
  • J. Hugon-Rodin et al.

    The future of women's contraception: stakes and modalities

    Ann N Y Acad Sci

    (2010)
  • A. Sonfield et al.

    The public cost of births resulting from unintended pregnancies: national and state-level estimates

    Perspect Sex Reprod Health

    (2011)
  • L. Cheng et al.

    Interventions for emergency contraception

    Cochrane Database Syst Rev

    (2012)
  • J. Sirois et al.

    Cyclooxygenase-2 and its role in ovulation: a 2004 account

    Hum Reprod Update

    (2004)
  • M.S. Bata et al.

    Delay of ovulation by meloxicam in healthy cycling volunteers: a placebo-controlled, double-blind, crossover study

    J Clin Pharmacol

    (2006)
  • C. Jesam et al.

    Suppresion of follicular rupture with meloxicam, a cyclooxygenase inhibitor: potential for emergency contraception

    Hum Reprod

    (2010)
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      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).

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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.

    ☆☆

    The authors have nothing to disclose.

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