PROSTAGLANDINS PROSTAGLANDIN
BIOSYNTHESIS
Antti Kauppila,
INHIBITORS
Jukka Puolakka
AND ENDOMZTRIOSIS
and Olavi Ylikorkala
Department
of Obstetrics and Gynecology University of Oulu SF-90220 Oulu 22, Finland
ABSTRACT Prostaglandins (PGs) may be involved in the development of the symptoms of endometriosis. Therefore 18 patients with pelvic endometriosis were treated in placebocontrolled double-blind trial with different prostaglandin biosynthesis inhibitors. These drugs were: acetylsalicylit acid (0.5 g x 3) exerting a weak PG-synthetase inhibition, indomethacin (25 mg x 3) inhibiting PGysynthetase, and as a representative of fenamates, tolfenamic acid (200 mg x 3), which both inhibits PG-synthetase and antagonizes PGs at the target level. The therapeutic effect was evaluated using a specific endometriosis score separately during menstruation and in premenstrum. Prostaglandin biosynthesis inhibitors did not alleviate premenstrual complaints better than placebo. During menstruation tolfenamic acid relieved endometriotic symptoms more effectively than placebo while indomethacin and acetylsalicylic acid did not differ from placebo. A drug which inhibit both the synthesis and action of PGs can thus be used in the alleviation of secondary dysmenorrhea due to endometriosis. INTRODUCTION The ectopic proliferations of the endometrium in external endometriosis are under the control of ovarian hormones and show a cyclic histological variation. They are possibly related to the uterine endometrium also in biochemical activity, e.g. in production of prostaglandins (PGs). The excessive production of endometrial PGs is very likely the origin of primary dysmenorrhea (1,2,3), which has been effectively treated with various prostaglandin biosynthesis inhibitors (PG-inhibitor) (4,5,6,7,8, Also secondary dysmenorrhea due to I.U.D. has 9,lO). been successfully relieved with PG-inhibitor (11). The patients with endometriosis have had increased PGF24 and PGE levels in their endometriums ( 2). The PGs may thus be znvolved in the development of tne symptoms of endometriosis. Therefore we conducted a placebo controlled
OCTOBER
1979 VOL. 18 NO. 4
655
PROSTAGLANDINS double-blind trial to evaluate the effect of PG-inhibitors on the symptoms of endometriosis. PATIENTS AND METHODS Twenty-four patients with symptomatic endometriosis volunteered for this study. Eighteen women completed the trial (Table 1); the remaining six terminated treatment for a variety of personal reasons. In 13 of the 18 patients endometriosis was diagnosed shortly before Symptom Pelvic pain Lower back pain Pain during walking Dyspareunia Pain on defecation Headache Nausea and vomiting Diarrhoea Insomnia Nervousness
Premenstrually No % 18 15 11 10 7 12 9 2 6 14
100 83 61 56 39 67 50 11 33 78
During menstruation % No 18 15 11 12 6 12 8 5 9 9
100 83 61 67 33 67 44 28 50 50
Table 1. The occurrence of different symptoms in 18 patients with pelvic endometriosis. therapy via laparoscopy; in 5 patients the diagnosis was made during pelvic examination, and three of them had been operated because of endometriosis 4-6 years earlier. The mean age was 33.3 years (22-431, and mean parity 1.4 (O-5). The patients had suffered from endometriosis for a mean of 7.7 years (range l-20). Endometriotic implants were located in the pelvic peritoneum, the sacrouterine ligaments or the retrocervical area in 14 patients while in four the ovaries also were affected. Fifteen women had previously used progestagens for endometriosis, and the interval between the cessation of the progestagen and this investigation was at least 14 months (14-38). Four drugs were used: placebo (1 x 3), acetylsalicylic acid (ASA) (0.5 g x 3), indomethacin (25 mg x 3) and tolfenamic acid (200 mg x 3). Each drug was administered orally from the 20th day of the menstrual cycle to the end of menstruation during two consecutive cycles. The order of the drugs was randomised, and the doubleblind principle was followed. No other medication was used during the investigation.
656
OCTOBER
1979VOL. 18NO. 4
PROSTAGLANDINS A detailed questionnaire for recording the different endometriotic symptoms in premenstrum and during menstruation was designed. The patient filled in the first form prior to the investigation, and after the study cycles she filled in similar questionnaires. A specific score for an objective assessment of the severity of endometriosis was developed. The patient recorded the occurrence of: 1) Pain ______symptoms _ -_-_ (pelvic pain, lower back pain, pain in walking, dyspareunia, pain on defecation, headache, 2) Gastro-intestinal complaints _____________________ ______ (nausea and vomiting, diarrhoea), and 3) Psychic complaints __ ------------- (insomnia, nervousness. Each symptom present prior to the investigation was given a score of 2. The patient rated the severity of each symptom during treatment on a 4-point scale (0 = symptom absent, 1 = milder, 2 = no change, 3 = more severe). After the trial the investigators calculated the sum of the scores ("endometriosis score") before opening the drug code. The Student's test were employed sults.
t-test, paired t-test and chi-square for statistical analysis of the re-
RESULTS The trial was completed with 35 placebo, 32 ASA, 36 indomethacin and 34 tolfenamic acid cycles. In the remaining seven cycles the patient either stopped the medication because of side-effects or reported incompletely. During menstruation tolfenamic acid (p< 0.01) and ASA (p
BIOSYNTHESIS
Antti Kauppila,
INHIBITORS
Jukka Puolakka
AND ENDOMZTRIOSIS
and Olavi Ylikorkala
Department
of Obstetrics and Gynecology University of Oulu SF-90220 Oulu 22, Finland
ABSTRACT Prostaglandins (PGs) may be involved in the development of the symptoms of endometriosis. Therefore 18 patients with pelvic endometriosis were treated in placebocontrolled double-blind trial with different prostaglandin biosynthesis inhibitors. These drugs were: acetylsalicylit acid (0.5 g x 3) exerting a weak PG-synthetase inhibition, indomethacin (25 mg x 3) inhibiting PGysynthetase, and as a representative of fenamates, tolfenamic acid (200 mg x 3), which both inhibits PG-synthetase and antagonizes PGs at the target level. The therapeutic effect was evaluated using a specific endometriosis score separately during menstruation and in premenstrum. Prostaglandin biosynthesis inhibitors did not alleviate premenstrual complaints better than placebo. During menstruation tolfenamic acid relieved endometriotic symptoms more effectively than placebo while indomethacin and acetylsalicylic acid did not differ from placebo. A drug which inhibit both the synthesis and action of PGs can thus be used in the alleviation of secondary dysmenorrhea due to endometriosis. INTRODUCTION The ectopic proliferations of the endometrium in external endometriosis are under the control of ovarian hormones and show a cyclic histological variation. They are possibly related to the uterine endometrium also in biochemical activity, e.g. in production of prostaglandins (PGs). The excessive production of endometrial PGs is very likely the origin of primary dysmenorrhea (1,2,3), which has been effectively treated with various prostaglandin biosynthesis inhibitors (PG-inhibitor) (4,5,6,7,8, Also secondary dysmenorrhea due to I.U.D. has 9,lO). been successfully relieved with PG-inhibitor (11). The patients with endometriosis have had increased PGF24 and PGE levels in their endometriums ( 2). The PGs may thus be znvolved in the development of tne symptoms of endometriosis. Therefore we conducted a placebo controlled
OCTOBER
1979 VOL. 18 NO. 4
655
PROSTAGLANDINS double-blind trial to evaluate the effect of PG-inhibitors on the symptoms of endometriosis. PATIENTS AND METHODS Twenty-four patients with symptomatic endometriosis volunteered for this study. Eighteen women completed the trial (Table 1); the remaining six terminated treatment for a variety of personal reasons. In 13 of the 18 patients endometriosis was diagnosed shortly before Symptom Pelvic pain Lower back pain Pain during walking Dyspareunia Pain on defecation Headache Nausea and vomiting Diarrhoea Insomnia Nervousness
Premenstrually No % 18 15 11 10 7 12 9 2 6 14
100 83 61 56 39 67 50 11 33 78
During menstruation % No 18 15 11 12 6 12 8 5 9 9
100 83 61 67 33 67 44 28 50 50
Table 1. The occurrence of different symptoms in 18 patients with pelvic endometriosis. therapy via laparoscopy; in 5 patients the diagnosis was made during pelvic examination, and three of them had been operated because of endometriosis 4-6 years earlier. The mean age was 33.3 years (22-431, and mean parity 1.4 (O-5). The patients had suffered from endometriosis for a mean of 7.7 years (range l-20). Endometriotic implants were located in the pelvic peritoneum, the sacrouterine ligaments or the retrocervical area in 14 patients while in four the ovaries also were affected. Fifteen women had previously used progestagens for endometriosis, and the interval between the cessation of the progestagen and this investigation was at least 14 months (14-38). Four drugs were used: placebo (1 x 3), acetylsalicylic acid (ASA) (0.5 g x 3), indomethacin (25 mg x 3) and tolfenamic acid (200 mg x 3). Each drug was administered orally from the 20th day of the menstrual cycle to the end of menstruation during two consecutive cycles. The order of the drugs was randomised, and the doubleblind principle was followed. No other medication was used during the investigation.
656
OCTOBER
1979VOL. 18NO. 4
PROSTAGLANDINS A detailed questionnaire for recording the different endometriotic symptoms in premenstrum and during menstruation was designed. The patient filled in the first form prior to the investigation, and after the study cycles she filled in similar questionnaires. A specific score for an objective assessment of the severity of endometriosis was developed. The patient recorded the occurrence of: 1) Pain ______symptoms _ -_-_ (pelvic pain, lower back pain, pain in walking, dyspareunia, pain on defecation, headache, 2) Gastro-intestinal complaints _____________________ ______ (nausea and vomiting, diarrhoea), and 3) Psychic complaints __ ------------- (insomnia, nervousness. Each symptom present prior to the investigation was given a score of 2. The patient rated the severity of each symptom during treatment on a 4-point scale (0 = symptom absent, 1 = milder, 2 = no change, 3 = more severe). After the trial the investigators calculated the sum of the scores ("endometriosis score") before opening the drug code. The Student's test were employed sults.
t-test, paired t-test and chi-square for statistical analysis of the re-
RESULTS The trial was completed with 35 placebo, 32 ASA, 36 indomethacin and 34 tolfenamic acid cycles. In the remaining seven cycles the patient either stopped the medication because of side-effects or reported incompletely. During menstruation tolfenamic acid (p< 0.01) and ASA (p
