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NSAIDS, Aspirin & Infertility - Journal Abstracts

Doctors may not mention this to women who are trying to get pregnant, but the use of non-steroidal anti-inflamatory drugs, including Advil, Motrin and Aleve, and aspirin cause ovulation problems. Specifically, the use of these medications can cause a failure of the follicles to burst and release eggs -- called luteinizing unruptured follicle syndrome (LUF or LUFS). Below are some abstracts on the subject. Full journal articles may be ordered through Medline or found at medical libraries.

Citation: 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 Aug;46(8):925-32. Address: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Jordan, Amman, Jordan.
This study aimed to assess the effect of meloxicam on female ovulation. Twenty consented fertile females were monitored for 4 menstrual cycles: a baseline cycle, 2 treatment cycles, and a washout cycle between treatment cycles. In the first cycle visit, transvaginal ultrasound was performed, a blood sample for progesterone and meloxicam analysis was withdrawn, and volunteers were given a luteinizing hormone (LH) urine test kit and meloxicam or placebo. Volunteers started the treatment on the following day and asked to return the day the LH kit was positive to detect the dominant follicle. At subsequent visits, transvaginal ultrasound and progesterone and meloxicam levels were investigated. Compared to placebo, a 5-day delay in follicle rupture, a 55.7% increase in the mean maximum follicle diameter, and 33.5% decrease of plasma progesterone level were observed in the meloxicam-treated group. Such demonstrated meloxicam effects were reversed in participants who were randomized to meloxicam first and then placebo. Only minor side effects were reported by volunteers during the course of treatment. It is concluded that meloxicam resulted in a reversible delay of ovulation, an increase in follicular diameter, and a decrease in plasma progesterone level.
PubMed ID: 16855077

Citation: Gaytan, M; Morales, C; Bellido, C; Sanchez-Criado, J E; Gaytan, F Title Non-steroidal anti-inflammatory drugs (NSAIDs) and ovulation: lessons from morphology. Histology and Histopathology. vol. 21, no. 5 (2006 May): 541-56.
Ovulation constitutes the central event in ovarian physiology, and ovulatory disfunction is a relevant cause of female infertility. Non-steroidal anti-inflammatory drugs (NSAIDs), widely used due to their analgesic and anti-inflammatory properties, consistently inhibit ovulation in all mammalian species investigated so far, likely due to the inhibition of cyclooxygenase 2 (COX-2), the inducible isoform of COX, that is the rate-limiting enzyme in prostaglandin (PG) synthesis. COX-2 inhibition has major effects on ovulation, fertilization and implantation, and NSAID therapy is likely implicated in human infertility and could be an important, frequently overlooked, cause of ovulatory disfunction in women. Although there is compelling evidence for a role of PGs in ovulation, the molecular targets and the precise role of these compounds in the ovulatory process are not fully understood. Morphological studies from rats treated with indomethacin (INDO), a potent inhibitor of PG synthesis, provide evidence on the actions of NSAIDs in ovulation, as well as on the possible roles of PGs in the ovulatory process. Cycling rats treated with INDO during the preovulatory period show abnormal ovulation, due to disruption of the spatial targeting of follicle rupture at the apex. Noticeably, gonadotropin-primed immature rats (widely used as a model for the study of ovulation) show age-dependent ovulatory defects similar to those of cycling rats treated with INDO. These data suggest that NSAID treatment disrupts physiological mechanisms underlying spatial targeting of follicle rupture at the apex, which are not fully established in very young rats. We summarize herein the ovulatory defects after pharmacologic COX-2 inhibition, and discuss the possible mechanisms underlying the anti-ovulatory actions of NSAIDs.
ISSN: 1699-5848
PubMed ID: 16493584

Citation: Skomsvoll, Johan Fredrik; Rodevand, Erik; Koksvik, Hege Svean; Salvesen, Kjell Asmund; von During, Vidar; Rygnestad, Tarjei; Ostensen, Monika Reversible infertility from nonsteroidal anti-inflammatory drugs Tidsskrift for Den Norske Laegeforening. vol. 125, no. 11 (2005 Jun 2): 1476-8.
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors may interfere with ovulation and the rupture of the follicle, causing reversible infertility. METHOD: Literature review. RESULTS: Reversible infertility is shown both in animal and human studies of these drugs. As determined by ultrasound, the drugs may delay or inhibit ovulation. These findings are also confirmed by a few randomized controlled studies showing an increase in time from the luteinizing hormone surge to rupture of the follicle and an increased size of the unruptured follicle. Most of the hormone analyses show values in accordance with the ovulation/menstrual cycle. Also, two epidemiological studies have shown an association between NSAID use and spontaneous abortion. These studies have methodological weaknesses and their findings have to be elucidated in future studies. INTERPRETATION:Women with fertility problems should avoid not only the selective cyclooxygenase-2 inhibitors, but also the traditional NSAIDs. However, women with rheumatic disease responding well to therapy should consult their physicians before stopping treatment. Reduced dose of a NSAID and temporary stop of drug treatment early in the menstrual cycle, or alternative drug treatment, may be a solution. NSAIDs should not be used in the last eight weeks of pregnancy.
Date Completed: 20050610
ISSN: 0807-7096
PubMed ID: 15940311

Citation: NSAIDs and female infertility. Prescrire International. vol. 11, no. 60 (2002 Aug): 115-6.
(1) There have been isolated reports of reversible female infertility linked to NSAIDs. The likely mechanism is ovulatory failure due to non rupture of mature follicles. (2) If a woman who presents with infertility is found to be taking a NSAID, the role of the drug should be considered before launching costly, invasive investigations or starting medically assisted reproduction.
Date Completed: 20020903
ISSN: 1167-7422
PubMed ID: 12199265

Citation: Nonsteroidal anti-inflammatory drugs and reversible female infertility: is there a link? Drug Safety : an International Journal of Medical Toxicology and Drug Experience. vol. 25, no. 8 (2002): 545-51. Stone, Sophia; Khamashta, Munther A; Nelson-Piercy, Catherine
Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed to women of child-bearing age. Three case series highlight the possibility of a link between NSAIDs and reversible infertility. The pharmacological target of NSAIDs is cyclo-oxygenase (COX), which catalyses the first rate-limiting step in the production of prostaglandins. COX-2, one of two isoenzymes, is active in the ovaries during follicular development. Its inhibition is thought to cause luteinised unruptured follicle (LUF) syndrome, an anovulatory condition characterised by clinical signs of ovulation but in the absence of follicular rupture and ovum release. The evidence linking regular NSAID use to reversible LUF syndrome comes from animal studies and three clinical studies. COX-2-deficient mice have severely compromised ovulation in the presence of apparently normal follicular development. Experimental administration of prostaglandins induced ovulation in rabbits and this was blocked by the administration of indomethacin. The three clinical studies demonstrated the induction of delayed follicular rupture or LUF in previously ovulating women by the administration of NSAIDs. A link can therefore be identified between NSAID use and reversible female infertility and NSAID withdrawal should be considered prior to or concurrent with fertility investigations.
Date Completed: 20020919
ISSN: 0114-5916
PubMed ID: 12113640

Citation: 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 non-steroidal anti-inflammatory drugs., Br J Rheumatol 35: 5, 458-62, May, 1996. Address: Rheumatic Diseases Unit Western General Hospital Edinburgh.
The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.

Citation: Akil M, Amos RS, Stewart P, Infertility may sometimes be associated with NSAID consumption., Br J Rheumatol 35: 1, 76-8, Jan, 1996. Address: Department of Rheumatology Leicester Royal Infirmary UK.
Non-steroidal anti-inflammatory drugs are widely used in the treatment of inflammatory joint diseases. Many patients suffering from these disorders are young women during their childbearing years. We report three cases of infertility where the cause may have been NSAID-induced 'luteinized unruptured follicle' syndrome. This phenomenon is well recognized in obstetric circles, and we would like to bring it to the attention of rheumatologists since it is not documented in the rheumatological literature.

Zanagnolo V, Dharmarajan AM, Endo K, Wallach EE, Effects of acetylsalicylic acid (aspirin) and naproxen sodium (naproxen) on ovulation, prostaglandin, and progesterone production in the rabbit., Fertil Steril 65: 5, 1036-43, May, 1996. Address: Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore Maryland USA.
OBJECTIVE: To determine the effects of acetylsalicylic acid (aspirin) and naproxen sodium (naproxen) on ovulation, ovarian prostaglandins (PG), and P production in the rabbit via in vivo and in vitro studies.
DESIGN: Aspirin and naproxen were administered i.v. 6.5 and 7 hours, respectively, after hCG administration to New Zealand White adult female rabbits. Laparotomy was performed 24 hours after hCG administration. For in vitro experiments, control animals underwent laparotomy 6.5 (aspirin) and 7 hours (naproxen) after hCG administration. The treated animal received aspirin and naproxen; laparotomy was performed 1 hour later. One ovary was perfused for 6 hours with aspirin or naproxen whereas the contralateral ovary served as a control and was perfused with control medium (M199; GIBCO, Grand Island, New York). Perfusate samples were collected at 1-hour intervals for PG and P determination. SETTING: A conventional laboratory setting. INTERVENTIONS: In vivo experiments used i.v. administration of 100 mg/kg aspirin and 10 and 50 mg/kg naproxen. In vitro perfusion was also carried out with 100 micrograms/mL aspirin and 10 and 50 micrograms/mL naproxen added to the perfusate. MAIN OUTCOME MEASURES: Ovulatory efficiency (no. of ovulations/no mature follicles) and ovarian vein PG and P concentration were determined.
RESULTS: Ovulatory efficiency was 88% for control, 41% for in vivo aspirin-treated, and 40% (10 mg/kg) and 0% (50 mg/kg) for naproxen-treated rabbits. Aspirin and naproxen were associated with decreased ovulatory efficiency when administered in vitro to both in vivo control and in vivo treated ovaries (control-medium = 70%; control-aspirin = 14%; aspirin-medium = 34%; aspirin-aspirin = 0%; control-naproxen = 25%; naproxen-medium = 38%; naproxen = 0% with 10 microgram/mL, and control-naproxen = 13%; naproxen-medium = 0%; naproxen = 0% with 50 micrograms/mL). Prostaglandin F2 alpha was undetectable in the perfusate of those ovaries perfused of those ovaries perfused either with aspirin or naproxen. Ovarian venous concentration of P in the perfusate was similar in all groups.
CONCLUSIONS: Aspirin and naproxen significantly reduced ovulatory efficiency and PG production both in vivo and in vitro in hCG-treated rabbits. A critical period of 6.5 and 7 hours after hCG administration was established.

Espey LL. Kohda H. Mori T. Okamura H. Rat ovarian prostaglandin levels and ovulation as indicators of the strength of non-steroidal anti-inflammatory drugs., Source Prostaglandins. 36(6):875-9, 1988 Dec. Address: Institution Biology Department, Trinity University, San Antonio, Texas 78284.
Immature Wistar rats were treated with pregnant mare's serum gonadotropin and human chorionic gonadotropin to induce ovulation. The non-steroidal anti-inflammatory drugs indomethacin, diclofenac, flurbiprofen, and phenylbutazone inhibited both the ovulation rate and the normal increase in ovarian prostaglandin E during ovulation. Tolmetin, ibuprofen, and aspirin did not have any significant effect. There was a significant correlation between the ovulation rate and the level of ovarian prostaglandin E following treatment with these drugs. When indomethacin was given in graded doses, there was also a correlation between ovulation rate and the dose-dependent inhibition of ovarian prostaglandin E.

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