Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid. Management of cyclical menorrhagia with prostaglandin synthetase inhibitor. Endometrial prostaglandins and menorrhagia: influence of a prostaglandin synthetase inhibitor in vivo. An objective evaluation of flurbiprofen and tranexamic acid in the treatment of idiopathic menorrhagia. The effects of mefenamic acid and norethisterone on measured menstrual blood loss. Randomised comparative trial of the levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: a multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts. Effects of mefenamic acid on menstrual hemostasis in essential menorrhagia. Primary and myoma-associated menorrhagia: role of prostaglandins and effects of ibuprofen. Control of menorrhagia by the cyclo-oxygenase inhibitors naproxen sodium and mefenamic acid. Naproxen in menorrhagia. Comparison between mefenamic acid and danazol in the treatment of established menorrhagia. The effects of danazol, mefenamic acid, norethisterone and a progesterone-impregnated coil on endometrial prostaglandin concentrations in women with menorrhagia. Efficacy of mefenamic acid in patients with a complaint of menorrhagia.
To compare the efficacy and acceptability of ethamsylate, mefenamic acid, and tranexamic acid for treating menorrhagia.
                Randomised controlled trial.
                A university department of obstetrics and gynaecology.
                76 women with dysfunctional uterine bleeding.
                Treatment for five days from day 1 of menses during three consecutive menstrual periods. 27 patients were randomised to take ethamsylate 500 mg six hourly, 23 patients to take mefenamic acid 500 mg eight hourly, and 26 patients to take tranexamic acid 1 g six hourly.
                Menstrual loss measured by the alkaline haematin method in three control menstrual periods and three menstrual periods during treatment; duration of bleeding; patient's estimation of blood loss; sanitary towel usage; the occurrence of dysmenorrhoea; and unwanted events.
                Ethamsylate did not reduce mean menstrual blood loss whereas mefenamic acid reduced blood loss by 20% (mean blood loss 186 ml before treatment, 148 ml during treatment) and tranexamic acid reduced blood loss by 54% (mean blood loss 164 ml before treatment, 75 ml during treatment). Sanitary towel usage was significantly reduced in patients treated with mefenamic acid and tranexamic acid.
                Tranexamic acid given during menstruation is a safe and highly effective treatment for excessive bleeding. Patients with dysfunctional uterine bleeding should be offered medical treatment with tranexamic acid before a decision is made about surgery. A well controlled double blind prospective trial was undertaken to determine the efficacy of mefenamic acid in the treatment of menorrhagia. Eighty patients who had unexplained cyclical menorrhagia with secretory endometrium received mefenamic acid orally in a dose of 500 mg 8 hourly or a placebo tablet thrice daily starting from day-one of the cycle for 5 days or till cessation of menses. Mefenamic acid administration caused a statistically significant reduction in the number of days of bleeding from 9.7 +/- 3.1 days before treatment to 4.1 +/- 0.6 days after treatment. It also brought about significant reduction in the amount of bleeding in terms of number of pads used per day, that is from 15.2 +/- 3.1 before treatment to 6.5 +/- 0.02 after treatment. Eighty-six percent patients in the treatment group had control of menorrhagia with the drug compared to 20% in the control group without drugs and this difference was statistically significant. Mefenamic acid proved to be a potent and efficacious agent in the control of unexplained menorrhagia. Prostaglandin levels in the human endometrium were determined on day 2 of the menstrual cycle in eumenorrheic subjects and in patients with menorrhagia, dysmenorrhea, or both. Menorrhagic subjects had significantly higher levels of endometrial prostaglandins of the E and F series when compared with eumenorrheics. Prostaglandin E levels were markedly higher than prostaglandin F. In 10 menorrhagic subjects who completed a double-blind clinical study on the effectiveness of mefenamic acid in lowering menstrual blood loss, 9 exhibited statistically significant reduction in endometrial prostaglandin levels. A decrease in menstrual blood loss was also noted during mefenamic acid treatment in these patients. These findings are consistent with the concept that abnormally high uterine prostaglandin levels may be an important etiologic factor in menorrhagia and support the notion that one of the mechanisms of action of nonsteroidal anti-inflammatory agents in the treatment of this menstrual disorder is inhibition of endometrial prostaglandin production. The effect of flurbiprofen (100 mg x 2 for 5 days) was compared with tranexamic acid (1.5 g x 3 for 3 days, 1 g x 2 days 4 and 5) in the treatment of 15 women with idiopathic menorrhagia. The mean blood loss during two medication-free periods was 295 +/- 52 ml. A significant (p less than 0.01) reduction in menstrual blood loss was recorded during treatment with both flurbiprofen and tranexamic acid. The menstrual blood loss was significantly (p less than 0.01) lower during treatment with tranexamic acid (155 +/- 33 ml) than with flurbiprofen (223 +/- 44 ml). Various side effects were recorded by 7 of 15 women during treatment with tranexamic acid and by 4 women of 15 during treatment with flurbiprofen. Many women with menorrhagia suffer simultaneously from dysmenorrhea. Thus although tranexamic acid was generally more effective in reducing menstrual blood loss, flurbiprofen provides an important therapeutic alternative to antifibrinolytic agents, especially in patients with concomitant dysmenorrhea. Although there are numerous medical treatments for menorrhagia, in many instances neither the precise diagnosis nor the response to therapy have been assessed objectively. Menorrhagia (menstrual blood loss more than 80 mL per cycle) was diagnosed objectively in 32 (44%) of 72 women with a subjective complaint of heavy menses. All of the 32 women had ovulatory cycles. After random allocation to treatment with either mefenamic acid (500 mg three times daily during menses, N = 17) or norethisterone (5 mg twice daily on days 19-26 of the cycle, N = 15) for two additional cycles, the median menstrual blood loss was reduced from 123 mL (range 86-237) to 81 mL (22-193) (P less than .001) and from 109 mL (81-236) to 92 mL (43-189) (P less than .002) with mefenamic acid and norethisterone, respectively. Apart from a decrease in the median number of days of bleeding, from 7 (5-8) to 5 (3-8) in those women treated with mefenamic acid, no other differences were seen between the groups. We conclude that mefenamic acid and norethisterone were similarly effective in reducing the degree of menstrual blood loss in women with proved menorrhagia, but that 52 and 67% of the women, respectively, remained menorrhagic after 2 months of treatment. To compare the efficacy and tolerability of the levonorgestrel intrauterine system (LNG IUS) with mefenamic acid in the management of objective idiopathic menorrhagia.
                Phase III, Single centre, open, randomised, comparative, parallel group study.
                District General Hospital in the United Kingdom.
                Fifty-one women with objective menorrhagia.
                Twenty-five women randomised to receive the LNG IUS and 26 to oral mefenamic acid for six cycles.
                Change from baseline in menstrual blood loss (MBL), total menstrual fluid loss (TMFL) and pictorial blood loss assessment chart (PBAC) score at the third and sixth cycle of treatment.
                After six cycles the median menstrual blood loss was 5 mL in the LNG IUS group and 100 mL in the mefenamic acid group (P < 0.001). Median TMFL was 27 mL in the LNG IUS group and 157 mL in the mefenamic acid group (P < 0.001). Median PBAC score was 25 in the LNG IUS group and 159 in the mefenamic acid group. Changes in menstrual blood loss correlated strongly to changes in TMFL (r= 0.88) but PBAC correlated less well to blood loss and total fluid loss (r= 0.53 and r= 0.58).
                Both the LNG IUS and mefenamic acid significantly decreased menstrual blood loss, TMFL and PBAC scores. The LNG IUS produced greater reductions in all parameters than mefenamic acid. Comparison of the different measurements suggests that TMFL assessment may be an easier and a more relevant measure of symptom severity than menstrual blood loss. Prostaglandin synthesis inhibitors decrease menstrual blood loss by 30% to 50% in patients with essential menorrhagia. To obtain insight into their mechanism of action, we measured menstrual blood loss in menorrhagic women, who were receiving mefenamic acid (500 mg, three times daily) (n = 6) or placebo (n = 5) in a double-blind way. In addition we studied the morphology of early menstrual hemostasis. The subjects' uteri were extirpated in the first 24 hours of menstruation, and light and electron microscopy were used to perform morphologic and morphometric studies. In the group treated with mefenamic acid mean menstrual blood loss was decreased by 40%. In uteri of the women treated with mefenamic acid hemostatic plugs were further transformed, and fewer vessels without a plug were observed than in uteri of the group receiving placebo. These data suggest that mefenamic acid may act through an improvement of platelet aggregation and degranulation and through increased vasoconstriction. The release of 6-keto-prostaglandin F1 alpha(6-keto-PGF1 alpha), a metabolite of prostacyclin (PGI2) and thromboxane B2 (TxB2), a metabolite of thromboxane A2 (TxA2), was estimated in endometrial biopsies taken from 12 menorrhagic and 12 healthy women during the luteal phase of the cycle. The releases of 6-keto-PGF1 alpha and TxB2 were normal, but the ratio TxB2/6-keto-PGF1 alpha was inversely related to menstrual blood loss in women with measured menstrual blood loss exceeding 70 ml. In the second part of the study, 24 women with excessive menstrual bleeding (13 with primary menorrhagia, 10 with uterine fibromyomas, one with haemostatic factor VIII deficiency) were treated at random with ibuprofen (600 mg/day and 1200 mg/day) and with a placebo. Ibuprofen 1200 mg/day reduced (P less than 0.01) median blood loss from 146 ml (range 71-374 ml) to 110 ml (30-288 ml) in primary menorrhagia but had no effect on blood loss in women with uterine fibroids and factor VIII deficiency. Blood loss was normal in six women and was not affected by ibuprofen. Thus, our data suggest that there is a PGI2 dominance in the endometrium of patients with menorrhagia. In addition, primary, but neither fibromyoma nor coagulation defect-associated menorrhagia, can be treated by ibuprofen. Thirty-five patients with menorrhagia were treated in a double-blind crossover study with naproxen sodium and mefenamic acid after measurement of their blood loss during control menstrual cycles. Treatment with these compounds reduced the excessive bleeding by an average of 46 and 47% respectively. Drugs in the prostaglandin synthetase inhibitor group are considered to have an important place in the treatment of menorrhagia. nan 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. The effects of four medical treatments have been assessed on menstrual blood loss (MBL) and endometrial prostaglandin (PG) concentrations in 30 women with objectively confirmed menorrhagia. Patients were randomly treated with danazol, 200 mg daily (n = 6), mefenamic acid, 500 mg three times daily during menses (n = 8), norethisterone, 5 mg twice daily from day 15-25 of the cycle (n = 8) or a progesterone-impregnated coil releasing 65 micrograms progesterone daily (n = 8). Endometrial biopsies were obtained in the mid-luteal phase before and after treatment in 23 cases, and assayed for PG content using radioimmunoassay. Treatment with norethisterone had no effect on either MBL or the concentration of PGs in the endometrium. MBL was significantly reduced after treatment with mefenamic acid (P = 0.05, n = 6) and the progesterone coil (P less than 0.05, n = 6), and was reduced in each of 4 cases treated with danazol in whom endometrial biopsies were available. Although there was no consistent change in endometrial PG concentrations in either the mefenamic acid or danazol groups, the lower MBL after insertion of the progesterone coil was associated with a reduced endometrial content of PGE, PGF2 alpha and "total" PG (6oxo PGF1 alpha + PGE + PGF2 alpha)-P = 0.05. Whereas the cyclooxygenase inhibitor mefenamic acid is likely to exert its effect on endometrial PGs at the time of menstruation itself, the continuous administration of progesterone throughout the menstrual cycle could result in both an impairment in estrogen receptor generation leading to reduced estrogen-mediated cyclooxygenase activity, and an increase in endometrial PG metabolism. Sixty-nine patients with a convincing history of menorrhagia completed a 4-cycle double-blind randomized placebo-controlled crossover trial of mefenamic acid taken during menstruation. Only 30 of these patients demonstrated objective menorrhagia with a measured menstrual loss greater than 80 ml during the placebo cycles, but the remainder reported passing clots and/or using 2 pads at a time. Fourteen of these women (20%) had a loss of less than 35 ml while taking placebos. This raises serious questions about the establishment of menorrhagia based on history alone. Overall, there was a mean reduction of 28.1% in menstrual blood loss between placebo and mefenamic acid cycles (P less than .001). The greatest reduction recorded was 80%, and most of the large percentage reductions were seen in patients with high loss during placebo cycles. Significant reductions in blood loss (P less than .001) were seen in patients with ovulatory dysfunctional uterine bleeding and menorrhagia that developed after tubal interruption. There was also an indication based on small sample sizes that mefenamic acid reduced blood loss in women with anovulatory dysfunctional uterine bleeding, fibroids, intrauterine devices, and von Willebrand disease. No reduction was seen during the mefenamic acid cycle in the group with a loss of less than 35 ml during the placebo cycle. There was a significant shortening of duration of bleeding (P less than .003). Fifteen patients (21.7%) experienced no objective reduction in blood loss.
NSAIDs reduce HMB when compared with placebo but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, no significant difference in efficacy was demonstrated between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCC or another type of intrauterine system, Progestasert.