The treatment of premenstrual tension with mefenamic acid: analysis of prostaglandin concentrations

Summary. Eighty patients with premenstrual tension were treated prospectively with mefenamic acid for a mean period of 13 months. Most of them (86%) reported significant relief of premenstrual tension. Symptoms of dysfunctional menorrhagia or primary dysmenorrhoea were also alleviated. In 19 patients, the plasma concentrations of prostaglandin (PG) E₂, PGF_2α and 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) were measured at intervals throughout three menstrual cycles. During the first cycle the patients received no treatment; in the subsequent two cycles they received either mefenamic acid or placebo in a randomized double-blind crossover manner. Similar measurements were made in 22 matched control subjects. The plasma concentrations of PGE₂, PGF_2α and PGFM were significantly lower in the 19 patients in all three menstrual cycles compared with the values in the control subjects. Excess synthesis of prostaglandins of the 1 series may occur in premenstrual tension and, by precursor depletion, result in decreased synthesis of the 2-series prostaglandins.     

Studies in menorrhagia: (a) mefenamic acid, (b) endometrial prostaglandin concentrations

Twenty-two women with unexplained heavy menstrual blood loss (average loss for two cycles of >80 ml) were treated with the prostaglandin synthetase inhibitor menfenamic acid during two consecutive menstruations. There was a significant reduction in menstrual blood loss on mefenamic acid therapy, the median loss being 137 ml before treatment and 76 ml while on treatment. Reduction in menstrual loss was achieved in 20 of the 22 patients but varied from a 2% to 78% reduction. The greater the menstrual loss before treatment, the more it was reduced on mefenamic acid therapy. Endometrial concentrations of prostaglandins E2 and F2 alpha in the follicular phase of the cycle were similar whether or not patients had menorrhagia. In the luteal phase, however, 6 of 14 patients with menorrhagia had higher endometrial prostaglandin E2 and F2 alpha concentrations than all 13 controls.     

Long-term treatment of menorrhagia with mefenamic acid

Thirty-six women with menorrhagia were treated with mefenamic acid during all menstrual periods for more than 1 year. These women had experienced objective and subjective benefit--menstrual blood loss was reduced and other menstrual symptoms improved during a preliminary 4-cycle double-blind placebo-controlled trial with mefenamic acid (placebo cycles: 65.6 +/- 5.3 ml; mefenamic acid cycles: 45.3 +/- 5.1 ml, mean +/- SEM). This reduction in menstrual blood loss was maintained at 6 to 9 months (49.2 +/- 9.9 ml) and at 12 to 15 months (42.8 +/- 4.8 ml) after the trial. These reductions were significant at the 6- to 9-month (paired t test = 2.18; P less than .05) and the 12- to 15-month interval (paired t test =- 4.40; P less than .001). Significant sustained reductions in blood loss were seen in the women with menorrhagia due to ovulatory dysfunctional bleeding and in those who had undergone tubal sterilization. Significant reductions were also seen in dysmenorrhea, headache, nausea, diarrhea, depression, number of sanitary towels used, and number of mefenamic acid capsules taken. A significant increase in serum ferritin was found between admission and completion of the follow-up trial in 11 women (P less than .01).     

Hormonal studies in women with premenstrual tension

Serum hormone concentrations were determined at intervals during the last 17 days of the menstrual cycle in 35 patients with premenstrual tension (PMT) and 11 control subjects without symptoms. The maximum mean concentration of oestradiol occurred 17 days before menstruation in the patients and 14 days before in the controls. The maximum concentrations of progesterone were similar in the two groups but the mean concentrations rose earlier in the cycle in the patients with PMT. These results suggested that the patients tended to ovulate earlier in the cycle than the controls and on the basis of the ovulatory surge in gonadotrophins two groups could be identified, group A who showed signs of ovulation 14 days or less before menstruation (17 patients, 9 controls) and group B who ovulated more than 14 days before menstruation (18 patients, 2 controls). There were no significant differences between the groups in prolactin, thyroid stimulating hormone or testosterone levels, but cortisol concentrations were uniformly higher in both groups of patients compared with those in the controls. Follicular growth was assessed with ultrasound in 18 patients and 16 control subjects. Mean follicular diameters were significantly lower in the patients than in the control group at the time of ovulation. Oestradiol determinations done at the same time correlated with the diameters and were also significantly lower in the patient group. The results suggest that ovulation tends to occur prematurely in women with PMT.     

Hormonal studies in women with premenstrual tension

Summary. Serum hormone concentrations were determined at intervals during the last 17 days of the menstrual cycle in 35 patients with premenstrual tension (PMT) and 11 control subjects without symptoms. The maximum mean concentration of oestradiol occurred 17 days before menstruation in the patients and 14 days before in the controls. The maximum concentrations of progesterone were similar in the two groups but the mean concentrations rose carlier in the cycle in the patients with PMT. These results suggested that the patients tended to ovulate earlier in the cycle than the controls and on the basis of the ovulatory surge in gonadotrophins two groups could be identified, group A who showed signs of ovulation 14 days or less before menstruation (17 patients, 9 controls) and group B who ovulated more than 14 days before menstruation (18 patients, 2 controls). There were no significant differences between the groups in prolactin, thyroid stimulating hormone or testosterone levels, but cortisol concentrations were uniformly higher in both groups of patients compared with those in the controls. Follicular growth was assessed with ultrasound in 18 patients and 16 control subjects. Mean follicular diameters were significantly lower in the patients than in the control group at the time of ovulation. Oestradiol determinations done at the same time correlated with the diameters and were also significantly lower in the patient group. The results suggest that ovulation tends to occur prematurely in women with PMT.     

The ubiquitousness of premenstrual tension in gynecologic practice

One hundred thirty-seven premenopausal women with premenstrual tension underwent laparoscopy for bleeding, pain and/or infertility. Endometriosis was the associated gynecologic disease observed most frequently (66 patients). Other associated disorders were primary dysmenorrhea (31), poststerilization syndrome (24), chronic pelvic inflammatory disease (8) and leiomyoma uteri (8). Screening for prolactin and thyroid-stimulating hormone in patients with galactorrhea (74) revealed one patient with pituitary microadenoma and two with primary hypothyroidism. The midluteal progesterone levels were significantly decreased, whereas the midluteal estradiol 17 beta levels were significantly elevated. Because of the frequent association of premenstrual tension with other gynecologic diseases, screening for premenstrual tension in all premenopausal women is recommended.     

A clinical trial using danazol for the treatment of premenstrual tension

Forty women with premenstrual tension received either placebo, 100, 200 or 400 mg danazol daily for 3 months in a pilot study arranged as a double-blind trial. Thirteen patients withdrew by the third month usually because they complained of no improvement. They had significantly higher pretrial symptom scores than those who continued. In patients treated with danazol, symptom scores for breast pain during the second and third months and for irritability, anxiety and lethargy during the third month were significantly (P less than 0.05) lower than scores in those given placebo. Most symptoms improved on placebo in the first month but by the third month only three remained improved. In contrast eight symptoms were improved on 200 mg danazol by the third month. By the end of the trial more than 75% of patients who were still taking danazol were essentially free of breast pain, lethargy, anxiety and increased appetite, but results for other common symptoms were no better than with placebo.     

A clinical trial using danazol for the treatment of premenstrual tension

Summary. Forty women with premenstrual tension received either placebo, 100, 200 or 400 mg danazol daily for 3 months in a pilot study arranged as a double-blind trial. Thirteen patients withdrew by the third month usually because they complained of no improvement. They had significantly higher pretrial symptom scores than those who continued. In patients treated with danazol, symptom scores for breast pain during the second and third months and for irritability, anxiety and lethargy during the third month were significantly ( P <0.05) lower than scores in those given placebo. Most symptoms improved on placebo in the first month but by the third month only three remained improved. In contrast eight symptoms were improved on 200 mg danazol by the third month. By the end of the trial more than 75% of patients who were still taking danazol were essentially free of breast pain, lethargy, anxiety and increased appetite, but results for other common symptoms were no better than with placebo.     

The use of prostaglandin inhibitors for the premenstrual syndrome

The premenstrual syndrome (PMS) is a complex of symptoms that usually occurs seven to ten days before menses in large numbers of women. These symptoms typically cease during the 24 hours after the onset of menses. PMS affects many areas of the body, with each afflicted woman having her personal set of symptoms. Frequently encountered signs and symptoms include breast tenderness and swelling, weight gain, headache, abdominal cramping and bloating, food cravings, thirst, nausea, joint pain, acne, dizziness, hyperalgesia and one or more psychologic symptoms: irritability, lethargy and fatigue, depression, anxiety, hostility and aggression. Theories relating PMS to hormonal imbalance, vitamin deficiency or psychosomatic aberration have failed to explain this condition fully. Treatments using hormones, vitamins, oral contraceptives or diuretics have failed to relieve all the symptoms of PMS. The prostaglandin (PG) theory proposes that these nearly ubiquitous substances, produced in pathophysiologic amounts in brain, breast, gastrointestinal tract, kidney and reproductive tract, can trigger many of the PMS symptoms. If that is true, then a PG inhibitor could counteract excessive PG production and successfully control those PMS symptoms related to prostaglandin excess or imbalance. Therapy based upon this theory can proceed to the use of PG inhibitors in conservative steps. First, permanent deletion of xanthine-containing beverages (coffee, tea, cola and chocolate) from the diet can reduce nervousness, irritability and breast tenderness. Luteal phase salt restriction, with a mild diuretic used if necessary the last week before menses, adds to this effect. For the 20-25% of women who need more help, either a PG inhibitor or natural progesterone (to oppose the action of PGs), given when PMS begins, brings relief. In women with depressive PMS complaints, small daily doses of an antidepressant may prove helpful.     

The incidence of premenstrual tension in a gynecologic clinic

A menstrual symptom questionnaire was used to assess the incidence of premenstrual tension (PMT) in 1,395 regularly menstruating women not on hormonal contraceptives or any other hormonal therapy during routine visits to a gynecologic clinic. Nineteen symptoms were divided into four PMT subgroups: PMT-A (anxiety, irritability, mood swings, nervous tension), PMT-H (weight gain, swelling of extremities, breast tenderness, abdominal bloating), PMT-C (headache, craving for sweets, increased appetite, heart pounding, fatigue and dizziness or fainting) and PMT-D (depression, forgetfulness, crying, confusion, insomnia). The ages of the patients ranged from 13 to 54 years, with a mean +/- S.D. of 32 +/- 8.5 years. Using strict criteria for PMT, 702 patients scored positive for at least one subgroup of PMT, giving an incidence of 50%. When the patients were divided into five-year age groups, a peak incidence of 60% was observed in the third decade of life. The most common PMT subgroups were PMT-A and PMT-H, occurring either alone or in combination. The least common subgroup was PMT-D, occurring in only 12 patients and by itself. The mean cycle length in pure PMT-D patients was significantly shorter (p less than 0.05) than in patients without PMT.     

Treatment of primary dysmenorrhea with mefenamic acid

Thirty-five patients (16--23 years old) who had severe primary dysmenorrhea were each treated with 500 mg of mefenamic acid every eight hours for a maximum of three days during menstruation for three consecutive cycles. A total of 194 treated cycles could be evaluated, 110 cycles with mefenamic acid and 84 with placebo. Mefenamic acid produced complete relief of all the symptoms of dysmenorrhea in 31 (88.6%) patients in all 98 treated cycles and, in another two patients, moderate relief in five of the six cycles. While on placebo, only five patients (13%) experienced moderate to slight relief in 11 of the 15 cycles. It is concluded that the mefenamic acid is safe and effective in most patients for the relief of primary dysmenorrhea and represents a rational short-term therapy for this syndrome.     

Mefenamic acid in the treatment of premenstrual syndrome

The use of mefenamic acid in the treatment of premenstrual syndrome (PMS) was investigated in 15 women over six menstrual cycles. A randomized, double-blind, cross-over, placebo-controlled design was used to overcome the methodologic criticisms of other medication trials in this condition. Mefenamic acid significantly improved many of the physical, mood, and performance symptoms associated with PMS. The physical symptoms that showed marked improvement were fatigue, headache, and general aches and pains (P less than .001). Most mood symptoms were improved, the most significant being freedom from mood swings (P less than .005).     

Comparison of the effects of Matricaria chamomila (Chamomile) extract and mefenamic acid on the intensity of premenstrual syndrome

The study aimed to compare the effects of Chamomile Extract and Mefenamic acid (MA) on the intensity of Premenstrual syndrome (PMS) symptoms.This study was a clinical randomized double blind trial, carried out with 90 students living in the dorms of Iran. The participants filled the daily forms about the intensity of PMS for two consecutive months. Once the definitive diagnosis of PMS was made, the participants were divided into two groups, each receiving either Chamomile capsule 100 mg or MA 250 mg three times a day. Intensity reduction of emotional symptoms was significantly higher among Chamomile Extract-users (30.1 ± 26.6 and 33.4 ± 25.3 percent) than that among MA-users (11.6 ± 25.7 and 10.7 ± 26.8 percent) after two cycles intervention (p < 0.001). Intensity reduction of physical symptoms was not significantly different (p > 0.05) among groups. Consumption of Chamomile seems to be more effective than MA in relieving the intensity of PMS associated symptomatic psychological pains.     

Comparison between mefenamic acid and danazol in the treatment of established menorrhagia

Forty women with established menorrhagia were treated with either mefenamic acid (500 mg thrice daily for 3-5 days in two cycles) or danazol (100 mg twice daily for 60 days) in an open parallel group randomized study. Mefenamic acid reduced mean menstrual blood loss from 160 ml to 127 ml (20%, P less than 0.01). Danazol reduced mean menstrual loss from 163 ml to 65 ml (60%, P less than 0.001). The percentage reduction in menstrual blood loss was significantly greater in the danazol group than in the mefenamic acid group, but the adverse side-effects occurred significantly more often in the danazol group (75%) than in the mefenamic acid group (30%, P less than 0.005). Overall, approximately half the women in each group were prepared to continue with the treatment they received to reduce their menstrual bleeding.     

Comparison between mefenamic acid and danazol in the treatment of established menorrhagia

Summary. Forty women with established menorrhagia were treated with either mefenamic acid (500 mg thrice daily for 3–5 days in two cycles) or danazol (100 mg twice daily for 60 days) in an open parallel group randomized study. Mefenamic acid reduced mean menstrual blood loss from 160ml to 127ml (20%, P<0·01). Danazol reduced mean menstrual loss from 163 ml to 65 ml (60%, P<0·001). The percentage reduction in menstrual blood loss was significantly greater in the danazol group than in the mefenamic acid group, but the adverse sideeffects occurred significantly more often in the danazol group (75%) than in the mefenamic acid group (30%, P<0–005). Overall, approximately half the women in each group were prepared to continue with the treatment they received to reduce their menstrual bleeding.