Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs used to relieve pain, swelling, fever and other effects of inflammation. It is classified into several categories depending on where they act to stop the inflammatory cascade. Many are available over the counter.
They are one of the most widely used drugs in the world, with more than 30 million doses being used on average every day. They act by inhibiting the cyclo-oxygenase (COX) enzyme, which is the rate-limiting enzyme in the prostaglandin biosynthetic pathway.
Prostaglandins are key mediators of inflammation. Unlike the concept that a single gene is expressed, which encodes a single protein, prostaglandin biosynthesis and metabolism depend on multiple proteins, which must be expressed at appropriate levels, as well as on the location of several enzymes within the cells. In addition, prostaglandin production and degradation must be coordinated, and the transport of prostaglandins into and out of the cells must be performed to enable the activity as well as degradation of prostaglandins.
The prostaglandin-mediated regulation of physiological processes, via their role in cellular activity, is associated with the discovery of multiple out-of-target effects and adverse reactions from the use of NSAIDs, including cardiovascular events. Another such important area where NSAIDs have been found to mediate essential physiological processes is the female reproductive cycle.
Prostaglandins in ovulation
The COX enzyme consists of two isoforms that are expressed at different levels and in different body tissues and are regulated by different mechanisms. In animals, COX-1 is expressed at baseline in all tissues and is primarily involved in physiological activities. These include prostaglandin-mediated protection of the gastrointestinal mucosa against erosion and ulceration, and renal function.
COX-2 is expressed at baseline by the central nervous system and the female reproductive system, but is also encoded by an early response inflammatory gene, which allows its expression in other tissues when needed. It responds to inflammation, labor-associated uterine contractions and other stimuli, to cause disease-linked inflammation.
Both COX-1 and COX-2 are found in the uterine epithelium and may be involved in ovulation, fertilization and implantation, whereas in early pregnancy it may aid in placental development via vascular growth.
Just before ovulation, there is an increase in the level of luteinizing hormone (LH). This hormone regulates ovulation, through its impact on every part of prostaglandin biosynthesis, metabolism and transport within the adult follicle.
Elevated prostaglandin E2 (PGE2) concentrations in the follicle drive the expansion of the cumulus oophorus (the cloud of granulosa-theca cells around the developing egg), which converts the expression of the follicular cells to progesterone rather than estrogen. This is accompanied by proteolysis, which causes the epithelium to break down at the apex of the ovary follicle, with the rupture of the follicle and the release of the ovum.
Effects of NSAIDs on ovulation
In one study, women with minor back pain who were placed on three different types of NSAIDs versus a placebo underwent ultrasound assessment to determine if ovulation was occurring. The researchers found that when treated for ten consecutive days, the dominant follicle remained undisturbed between one-third to three-quarters of the women on the NSAIDs, depending on which one they took. Conversely, ovulation occurred in all controls.
The greatest inhibition was produced by diclofenac, where ovulation was reduced by 93%, compared with 75% in those on either naproxen or etoricoxib. The dominant follicle diameter was also reduced in all groups.
Other studies have confirmed these findings. For example, women who were on long-term treatment with these drugs for severe arthritis, and who were unable to conceive despite extensive testing and treatment, managed to conceive after their withdrawal.
What are the implications?
The mechanism of action in this unexpected but disturbing adverse effect appears to be through prostanoid synthesis inhibition. Recent research suggests that the use of NSAIDs in fertile women may inhibit ovulation by preventing rupture of the adult ovarian follicle that releases the ovum into the peritoneal cavity near the opening of the uterine tubes.
Prostanoids induced by COX-2 are essential for the rupture of the adult follicle. If rupture does not occur, the adult follicle remains in a luteinized form due to the high levels of luteinizing hormone that occur during ovulation. The result is luteinized, unpaired follicle syndrome.
Research is slowly but surely building up to indicate that fertility in women is impaired by the chronic use of potent NSAIDs, including naproxen, piroxicam and diclofenac. This applies to both COX-1 and COX-2 inhibitors, although the latter drugs have been developed to reduce or avoid the adverse effects of COX-1 inhibitors. Selective COX-1 inhibitors were intended to relieve inflammation without affecting the protection of the gastric mucosa by prostaglandins in the stomach and similarly in the kidney.
However, the findings that even these drugs may lead to undesirable effects on female reproduction should lead to a complete review of their use in this age and gender group, when used to relieve inflammation in dysmenorrhea or arthritis.
Greater awareness needs to be raised in this regard, and unexplained infertility can sometimes at least be resolved by stopping NSAID use alone. It requires the use of this recommendation to take an accurate drug and medical history, and to stop using NSAIDs, before embarking on costly and ultimately useless examinations and treatment for infertility in such cases.
Study researcher Professor Sami Salman, Department of Rheumatology, University of Baghdad, Iraq, said: “These findings show that even short-term use of these popular over-the-counter drugs can have a significant impact on a woman’s ability to have children. It needs to be better communicated to patients with rheumatic diseases, who can take these drugs on a regular basis with little awareness of the impact. ”
Meanwhile, more research is needed to confirm the true frequency of reproductive failure with NSAID use over the long term. Other researchers have concluded that COX-2 inhibitors may be of limited use as monthly contraceptives unless used with other prostaglandin synthase inhibitors, or with compounds that inhibit prostaglandin production or transport.
The latter class of drugs can potentiate the anovulatory effects of NSAIDs. In addition, these compounds can effectively treat uterine disorders in some cases by modulating progesterone levels, thus favorably affecting women’s health.