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CLINICAL STUDIES

Delay of Ovulation by Meloxicam in Healthy Cycling Volunteers: A Placebo-Controlled, Double-blind, Crossover Study

M. S. Bata, M. Al-Ramahi, A. S. Salhab, M. N. Gharaibeh and Jill Schwartz

From the Department of Obstetrics and Gynecology (Dr Bata, Dr Al-Ramahi) and the Department of Pharmacology (Dr Salhab, Dr Gharaibeh), Faculty of Medicine, University of Jordan, Amman, Jordan; and CONRAD, Eastern Virginia Medical School, Arlington, Virginia (Dr Schwartz).

Address for reprints: Dr. A. S. Salhab, Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman, Jordan; e-mail: Assalhab{at}ju.edu.jo.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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first cycle visit, transvaginal ultrasound was performed, a blood sample for progesterone and meloxicam analysis was withdrawn, and volunteers were given a luteinizing hormone (LH) urine test kit and meloxicam or placebo.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.

Key Words: Follicle rupture • follicle size • meloxicam • ultrasound • progesterone

Nonsteroidal anti-inflammatory drugs (NSAIDs), one of the most clinically prescribed drugs nowadays, are indicated to relieve a wide range of conditions such as headache, anti-inflammatory conditions, and joint pains. It is believed that NSAIDs act through inhibition of cyclooxygenase (COX) enzymes COX-1 and COX-2, which are responsible for prostaglandins synthesis. Meloxicam, a preferential COX-2 inhibitor, is indicated in clinical practice in the treatment of rheumatoid arthritis and osteoarthritis at doses of 7.5 or 15 mg/d. Concerning meloxicam efficacy, a global assessment indicated that meloxicam 15 mg/d was significantly more effective than 7.5 mg/d. It has been shown that an oral dose 30 mg/d meloxicam was significantly more effective than meloxicam 15 mg/d or piroxicam 20 mg/d.1

The association between inhibition of ovulation in women and the clinical use of NSAIDs was noticed almost a decade ago. There have been several case reports indicating that piroxicam, naproxen, and diclofenac are implicated in human infertility, with restoration of fertility on discontinuation of the drugs.2-4 In addition, indomethacin was demonstrated to inhibit ovulation in rats,5 mice,6 rabbits,7 sheep,8 monkeys,9 and humans.10 Many reproductive processes such as ovulation, fertilization, implantation, decidualization, and parturition depend on prostaglandin synthesis.11 The release of the ovum from a fully formed ovarian follicle is triggered by luteinizing hormone (LH), a pituitary hormone, and subsequent cascade of ovulatory mediators such as prostaglandins, interleukin-1, and tumor necrosis factor–{alpha}.12 Prostaglandins, such as prostaglandin E2 and prostaglandin F2{alpha}, are critical agents in the ovulation process. Their importance is becoming more evident after the discovery of 2 distinct isoforms of COX enzyme, the enzyme that catalyzes the formation of prostaglandins from arachidonic acid.13 The COX-enzyme complex consists of at least 2 distinct enzymes that differ in distribution, regulation, and gene expression.14 COX-2 null mice show renal abnormalities and multiple failures in reproductive functions, including ovulation, fertilization, implantation, and decidulization.15-17 Meanwhile, COX-1 mutant mice were fertile, but homozygous mating tend to yield dead pups for unknown reasons.18

In a double-blind, randomized, placebo-controlled trial conducted recently, the selective COX-2 inhibitor rofecoxib resulted in a delay in follicular rupture (>48 hours after the LH peak) in 4 of 6 women.19

Interested in the contraceptive effect of meloxicam, we recently reported that meloxicam inhibited rabbit ovulation in a dose- and time-dependent fashion.20 Meloxicam inhibited ovulation in rabbits when administered orally, intravaginally, rectally, and intraperitoneally.21 The fact that meloxicam appears to have a greater selective effect against COX-2 isoform than against COX-1 made the drug a relatively safer drug on gastrointestinal tract, kidneys, and platelet aggregation, which are most likely to be associated with COX-1 inhibition. Thus, the potent contraceptive effect of meloxicam in rabbits, along with the relatively safe profile, encouraged us to conduct this clinical trial, having the following objectives in mind: to study the effect of meloxicam on human ovulation, to assess the reversible effect of meloxicam on women during ovulation, and furthermore, to examine the tolerability of meloxicam treatment by volunteer women through a placebo-controlled, double-blind, crossover trial. Because no information is available on the dose and the duration of meloxicam administration on female ovulation, we used the highest therapeutic dose of meloxicam (30 mg/d), which was reported to be used in the treatment of rheumatoid arthritis. Because meloxicam will achieve the steady-state concentration after 4- to 5-day drug administrations, in this study, we adopted a dose regimen of 30 mg/d for 5 consecutive days.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Facilities
The clinical investigations, blood analysis, and meloxicam analysis were conducted at the facilities of Jordan University Hospital, Amman, Jordan.

Meloxicam
Meloxicam (Moven) 15-mg capsules (batch number 3040413; manufacturing date, April 2004; expiry date, April 2007) and placebo capsules (batch number E063; manufacturing date, August 2004; expiry date, August 2007) were supplied by the Advanced Pharmaceutical Industries Co Ltd, Amman, Jordan. Meloxicam and placebo capsules were kept in a locked refrigerator at 10°C until dispensing.

Subjects
Thirty healthy fertile volunteers with no history of gynecologic or reproductive disorder were enrolled in the study. None of the women was using hormonal contraception or any other medication for at least 2 months before the study, and all had a history of regular menstrual cycles (25-30 days). Their mean and range of age, body weight, and height were 31 years (21-38 years), 62 kg (45-85 kg), and 162 cm (150-175 cm), respectively. The exclusion criteria of the study were pregnant women or women planning to get pregnant; nursing women or women with high prolactin or testosterone plasma levels; women using hormonal contraceptive methods; smokers or drug users; or women who are allergic to NSAIDs. All volunteers gave informed consent, which was approved by the Eastern Virginia Medical School Institutional Review Board and the Jordan University Hospital Committees.

Ten women discontinued at different stages of the study for varying reasons: 4 had anovulatory cycles, 3 had menstrual irregularity, 1 was nursing, 1 was overweight, and the last left the country. Therefore, 20 women completed the study. Consented volunteers were covered with a health insurance plan for the whole duration of the study.

Study Design
The study protocol was approved by the Eastern Virginia Medical School Institutional Review Board and Jordan University Hospital Committees. Volunteers were screened by history, physical examination, and laboratory investigation, including blood chemistry profile; hematology, liver, and renal function tests; and hormonal profile including LH, follicle-stimulating hormone, progesterone, prolactin, and testosterone. Volunteers who met study eligibility criteria participated for 4 menstrual cycles, and each cycle consisted of 6 visits.

Cycle 1 (Baseline) and Cycle 3 (Washout)
The first visit (V1). The date of this visit was scheduled by the physician to take place approximately 3 days before the expected ovulation. In this visit, volunteers were given the LH urine test kit to take home, underwent ultrasound examination to detect the dominant follicle, and had blood samples drawn for progesterone level determination.

The second visit (V2). Volunteers reported to the physician the day after the LH urine test was positive. In this visit, the dominant follicle (diameter, 14-16 mm) was visible by transvaginal ultrasound. Also, blood samples were drawn for progesterone-level determination.

Subsequent visits. The other 4 visits (V3, V4, V5, and V6) were arranged every other day. In all these visits, ultrasound examinations were performed, and blood samples were drawn for progesterone-level determination.

Cycle 2 (Meloxicam or Placebo) and Cycle 4 (Placebo or Meloxicam)
First visit (V1). The date of this visit was scheduled by the physician to take place approximately 3 days before the expected ovulation. In this visit, volunteers were given the LH urine test to take home and then underwent ultrasound examination to detect the dominant follicle, and blood samples were drawn for progesterone and meloxicam (blank) levels.

The treatment. Volunteers were randomly and double-blindly allotted to placebo or meloxicam 30 mg once daily for 5 consecutive days. Volunteers were instructed to take the treatment orally starting the next day after V1.

The second visit (V2). Volunteers reported to the physician the day after the LH urine test kit was positive. In this visit, the dominant follicle was monitored by transvaginal ultrasound. Also, blood samples were drawn for progesterone and meloxicam level determination.

Subsequent visits. These other 4 visits (V3, V4, V5, and V6) were arranged every other day. In all of these visits, ultrasound examination was performed, and blood samples were drawn for progesterone and meloxicam level determination.

Ultrasound Scans
The ultrasound machine used in this study was EUB-405 ultrasound scanner (Hitachi Medical Corp, Tokyo, Japan), equipped with Sony videographic printer UP-890 CE (Sony Corp, Tokyo, Japan). Follicular rupture was defined as a decrease of at least 3 mm in mean follicular diameter22 and the appearance of intrafollicular echoes. Delayed follicular rupture was defined as the absence of visible rupture within 48 hours of the appearance of LH in the urine kits19 (ACON Laboratories Inc, San Diego, Calif).

Meloxicam Determination
Meloxicam Standards
Meloxicam (1 g) in a powder form (batch number 8250381) was donated by Boehringer Ingelheim Pharm KG (Biberach an der Riss, Germany). Also, meloxicam powder (100 g; batch number 9700009015) was obtained from the Advanced Pharmaceutical Industries Co Ltd (Amman, Jordan). Purity was checked by high-performance liquid chromatography (HPLC) and UV spectrum against the sample obtained from Boehringer Ingelheim. All other reagents and solvents were HPLC grade.

Chromatography of Meloxicam
From the collected samples of heparinized blood, plasma was removed after centrifugation at 2000g for 5 minutes. All plasma samples were extracted and analyzed for meloxicam in duplicate, according to the method described by Dasandi et al (2002).23 Briefly, samples (50 or 100 µL) were extracted for meloxicam by acetonitrile, perchloric acid, and methylene chloride. The extraction recovery was 93% ± 5%.

Chromatographic Conditions
Analysis was performed using Agilent HPLC 1100 system (Agilent Technologies, Palo Alto, Calif) coupled to diode array detector (G1315A DAD) fixed to 355.8-nm wavelength. The analytical column used was HP C18 (5 µ, 4.6 x 250 mm; Hewlett-Packard, Palo Alto, Calif). The mobile phase consisted of sodium acetate buffer (170 mmole, pH 3.3); acetonitrile (50:50 volume/volume), with a flow rate of 1.5 mL/min. Under these conditions, the retention times observed for piroxicam (internal standard) and meloxicam were 2.31 and 2.97 minutes, respectively, and meloxicam detection limit was 0.1 µg/mL. The assay was linear over the concentration range of 0.1 to 5.0 µg/mL with correlation coefficient of .996.

Data Processes and Statistical Analysis
Data of ultrasound measurements and progesterone plasma levels during the study were analyzed descriptively and then inferentially. The descriptive analysis involved the generation of frequency distributions and the computation of means for each level of the explanatory factors employed in the inferential analysis. Means at each visit were also computed. Pearson correlation coefficients among the 6 visits have been computed, and subject effect has been regarded as random, whereas the remaining explanatory factors were regarded to have fixed effects. The structural dependence among the 6 time measurements for progesterone and ultrasound has been established. This structural dependence justifies the inferential analysis of the collected data using repeated-measures and multiway analysis of variance involving the following as explanatory factors: the 4 underlying factors of a crossover design (sequence, cycle, subjects, and treatment) as well as a factor representing the time effect. A second dimension in the descriptive analysis of the data involved graphing mean and individual progesterone, ultrasound, and meloxicam measurements over the subsequent visits; then area under such curves was computed using the trapezoidal rule. The statistics software used for data analysis was SAS version 8.2 under Windows XP (SAS Institute, Cary, NC). The inferential statistical analysis was conducted under the crossover design structure with repeated measurements on the response outcome. SAS PROC MIXED procedure was used to conduct this analysis. The .05 level of significance was adopted for the establishment of statistical significance, and Duncan Multiple Range procedure at .05 level was used for multiple comparison purposes.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Because volunteers presented for the study at different days of their menstrual cycles, Table I was constructed to summarize the mean of days of volunteer visits during the 4 different cycles of the study.


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  		Table I Mean Day of Visits in the 4 Cycles of the Studya

 


Figure 1
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  		Figure 1. Mean diameter of dominant follicle measured by transvaginal ultrasound scans for volunteers (n = 20) in the 6 visits of the 4 cycles of the study. {circ}––{circ}, meloxicam; bullet––bullet, placebo; {blacktriangleup}––{blacktriangleup}, baseline; {square}––{square}, washout cycle.

 
Ultrasound Examinations
Figure 1 shows the effect of meloxicam on the dominant follicle diameter. The mean follicle diameter increased consistently and linearly until the day of visit 4. During meloxicam treatment, the mean maximum follicle diameter before rupture was 32.71 ± 10.95 mm (V4), and the mean day of follicle rupture was 20.4 ± 4.04 (Table I, V4). In placebo treatment, the mean maximum follicle diameter was 21.09 ± 4.5 mm (V2), and the mean day of follicle rupture was day 15.2 ± 3.46 (Table I, V2). Thus, meloxicam treatment resulted in approximately a 5-day (>120-hour) delay in follicle rupture, as well as 12.3 mm (60%) increase in maximum diameter of dominant follicle. In cycle 1 (baseline cycle) or in cycle 3 (washout cycle), the mean maximum follicle diameter before rupture was 20.37 mm and 21.03 mm, respectively (Figure 1). Also, the mean day of follicle rupture was similar in the baseline cycle, washout cycle, and placebo cycle (Table I, V2).

Concerning the maximum increase of follicle diameter, considerable variations (data not shown) were presented among subjects treated with meloxicam. Of 20 volunteers who completed the study, 5 volunteers experienced maximum increase in follicle diameter before V4, whereas in 7 volunteers, the increase in follicle diameter was detected at V4, and in 8 volunteers, the increase in follicle diameter was detected after V4. In the placebo group, only 3 volunteers experienced the increase in follicle diameter after V4. Therefore, meloxicam resulted in a delay of follicle rupturing and in disharmony of the rupturing onset.


Figure 2
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  		Figure 2. Mean plasma progesterone levels for volunteers (n = 20) in the 6 visits of the 4 cycles of the study. {circ}––{circ}, meloxicam; bullet––bullet, placebo; {blacktriangleup}–––{blacktriangleup}, baseline; {square}––––{square}, washout cycle.

 
The Effect of Meloxicam on Plasma Progesterone
Figure 2 demonstrates the effect of meloxicam on plasma progesterone. This figure shows the expected pattern of steady increase in the plasma progesterone level during the luteal phase. The least increase in progesterone plasma level (33.7%) at V4 was observed during meloxicam treatment (Figure 2). However, there were no statistically significant (placebo, baseline, washout, or meloxicam) differences in progesterone levels in blood when all cycles were compared with each other.

The Reversible Effect of Meloxicam on Follicle Diameter and Plasma Progesterone Level
The protocol design of this study allows us to examine the reversible effect of meloxicam on the follicle diameter and the plasma progesterone level in 10 volunteers who were randomized to meloxicam treatment during cycle 2 and placebo treatment in cycle 4. Figure 3 summarizes the results of the reversibility data. During meloxicam treatment (cycle 2), the mean dominant follicle diameter before rupture was 32.5 ± 11.5 mm (V4), and the mean day of follicle rupture was 20.9 ± 4.7 (V4). However, when those 10 volunteers were placed on placebo treatment during cycle 4, the mean dominant follicle diameter was 20.8 mm, and the mean day of follicle rupture was 13.7 ± 2.67 (V2). Thus, ovarian function in participants treated with meloxicam returned to baseline in the subsequent cycle. Another proof of reversibility of meloxicam effect issued from the results of plasma progesterone levels in these women. As seen in Figure 4, there was a similar pattern of increase in the plasma progesterone level during meloxicam and placebo treatment specifically at the luteal phase. Still, the extent of progesterone increase during meloxicam treatment was lower than the placebo.


Figure 3
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  		Figure 3. Mean diameter of dominant follicle measured by transvaginal ultrasound scans in the reversibility experiment (n = 10) in the 6 visits of the treatment cycles. {circ}––{circ}, meloxicam cycle 2; bullet––bullet, placebo cycle 4. Bars represent the standard deviation of the mean. *P < .05.

 

Figure 4
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  		Figure 4. Mean plasma progesterone levels in the reversibility experiment (n = 10) in the 6 visits of the treatment cycles. {circ}––{circ}, meloxicam cycle 2; bullet––bullet, placebo cycle 4.

 


Figure 5
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  		Figure 5. Mean plasma meloxicam level of volunteers (n = 20) in the 6 visits of the meloxicam treatment cycle. Bars represent standard deviation of the mean.

 
Meloxicam Plasma Level
Figure 5 shows the mean plasma levels of meloxicam in the 20 volunteers. The level of meloxicam in plasma has the highest concentration (5.5 ± 4.54 µg/mL) at V2; then meloxicam level dropped to 2.8 ± 3.01 µg/mL at V4 and 0.3 ± 0.76 µg/mL at V6. It is worth remembering that the volunteer started meloxicam administration 1 day after the first visit (V1); there is, on average, an estimated 2.5-day (0-12 days) relapse time between the first dose of meloxicam administration and the day of V2. Thus, at least 3 doses of meloxicam were administered by V2.

Meloxicam Tolerability
Seventeen volunteers, either on meloxicam or placebo treatment, did not report any serious side effects. Heartburn (1) and an early menses (1) were reported during placebo treatment. Furthermore, 3 participants developed an enlarged follicle, ranging between 40 to 65 mm in diameter. One participant developed an enlarged follicle during the placebo, the baseline, and the washout cycles. The same participant reported an intense abdominal pain after meloxicam treatment. The other 2 participants experienced enlarged follicles during meloxicam treatment. The clinical investigators observed all these participants until the follicle collapsed during the preouvulatory phase of the following cycle. Sore throat developed in 2 volunteers (placebo and meloxicam), and right iliac pain developed in 1 volunteer during the placebo treatment.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
The results of this study demonstrated that there is more than a 5-day delay in follicle rupture during meloxicam treatment as compared to placebo. These results are consistent with the recent study using rofecoxib (a selective COX-2 inhibitor) in volunteers19 and with the results of Athanasiou et al, who reported delayed follicular rupture in 5 of 6 cases after indomethacin treatment (by 2 to 12 days).24 Furthermore, it was reported that indomethacin administration resulted in 4 of 8 trapped oocytes in rhesus monkeys without alteration of normal luteal function.9

The 5-day delay in follicle rupture observed in our study raises a question about viability of ova. Further research is warranted to address the question of ova viability after such delay. It is known that the survival time of the mature and fertilizable oocyte after release from the ovary in the female reproductive tract is about 24 hours.25 However, no information is available on the viability of the delayed ovum after being released.

In this study, unlike previous reports,19 an appreciable, although not significant, decrease in plasma progesterone levels was demonstrated in women on meloxicam treatment. In a previous study, a decrease in progesterone levels was reported after using indomethacin.10 Thus, the luteolytic effect exerted by meloxicam supports the antifertility effect of meloxicam and is in agreement with what we reported earlier in rabbit experiments.20

The results of this study demonstrated the reversibility of antiovulatory effect of meloxicam. In the literature, the reversibility of the effects of NSAIDs on ovulation was demonstrated in women who were taking these types of medications on a long-term basis. These women demonstrated signs of normal ovulation within 1 menstrual cycle after medication with NSAIDs was terminated.2-4 In this study, ovarian function in participants treated with meloxicam returned to baseline in the subsequent cycle.

Meloxicam provides effective therapy for osteoarthritis and rheumatoid arthritis in daily oral doses of 7.5, 15, or 30 mg.1,26-29 In population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients, meloxicam was administered to patients once daily for 3 weeks or 3 months at doses between 7.5 and 60 mg. For these reasons, the dose of 30 mg meloxicam daily for 5 days in a cycle was thought to exhibit the anticipated antiovulatory effect in our volunteers. From our results, it is clear that this dose was adequate. Actually, smaller doses (eg, 7.5 or 15 mg/d) and/or shorter duration of meloxicam administration might be effective. Thus, future investigations may be warranted.

More recently, COX-2 inhibitors have been associated with an increased risk of serious cardiovascular events (heart attack and stroke) when used for long periods of time or in very high-risk settings. Earlier studies found a 5-time higher incidence of myocardial infarction in patients taking rofecoxib as compared to naproxen or meloxicam. Furthermore, it was suggested that meloxicam may be of benefit in the prevention of acute myocardial infarction in patients with unstable angina pectoris because of its anti-inflammatory activity.30

In this study, most participants reported no serious adverse effects during the course of treatment. However, 3 volunteers had an enlarged follicle diameter of 40 mm or more and were observed until the follicle regressed. The follicle enlargement observed in our study can not be distinguished from luteinized unruptured follicle syndrome described earlier by Hamilton et al.31 Furthermore, such follicle enlargement had been reported when rofecoxib was used in volunteered women.19

In conclusion, meloxicam administered once a day orally at a dose of 30 mg for 5 consecutive days exhibited a pronounced delay in follicle rupture and a minimal depression of plasma progesterone level in volunteered women. Furthermore, this study demonstrated that the delay in follicle rupture, follicle enlargement, and the depression in progesterone plasma levels were reversible. In addition, this study showed that the meloxicam scheduled doses were well tolerated by volunteers.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
Special thanks to the University of Jordan's Dean of Scientific Research and to the Assistant to President for Financial Funds for their continuous encouragement and help. Furthermore, the investigators appreciate the cooperation of the General Director of Jordan University Hospital and the Director of the Hospital Laboratories and the Chief of Toxicology Laboratory for meloxicam analysis. The investigators would like to thank the Advanced Pharmaceutical Industries Co Ltd, Amman, Jordan, for supplying Moven capsules for this study. We appreciate the work and cooperation of Dr Hisham Hilo in preparing the statistical data and analysis. Sincere thanks to Wafa Al Rabaya, the project coordinator, Suha Al-Rahma and Ferial Mubarak for providing the technical assistance of meloxicam analysis, and to Wafa Al-Shaer for her excellent secretarial and typing assistance. Special thanks are extended to Hasan Shishani for the artwork and to Sarah Beddingfield for monitoring the study.

A generous support for this project was provided by the CICCR, a program of CONRAD Eastern Virginia Medical School, Arlington, Virginia.

DOI: 10.1177/0091270006289483


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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