Mats Åkerlund

Inhibition of uterine contractions of premature labour with an oxytocin analogue. Results from a pilot study

Summary. A competitive inhibitor of the action of oxytocin on the uterus, l‐deamino‐2‐D‐Tyr‐(OEt)‐4‐Thr‐8‐Orn‐oxytocin, was studied for the first time in 13 patients with established, uncomplicated premature labour. Intravenous infusion of 10–100 μg/min of the analogue was given for 1–10 h and the effect was monitored by external cardiotoco‐graphy. In all women an inhibition of uterine activity was observed, and in the majority of patients infused with 25 μg/min and a total dose of about 5 mg or more of the drug total inhibition of uterine contractions was achieved. There were no effects on the maternal and fetal pulse rates, nor were there any other side‐effects. The results of this preliminary study support the concept of an increased concentration of uterine oxytocin receptors being aetiologically important in uncomplicated premature labour. They also suggest that the present oxytocin antagonist could be an interesting therapeutic alternative in the condition, primarily because of the marked selectivity of its effect.

Receptors for and myometrial responses to oxytocin and vasopressin in preterm and term human pregnancy : effects of the oxytocin antagonist atosiban

OBJECTIVE Our purpose was to study myometrial oxytocin and type V1 vasopressin receptors, the in vitro contractile effects of these hormones, and the influence of an oxytocin antagonist. STUDY DESIGN Women delivered by cesarean section preterm (n = 51) and at term (n = 71), with and without labor contractions, gave myometrium for the estimation of oxytocin and V1 vasopressin receptors. The in vitro myometrial effects of the peptides and the influence on these of the competitive oxytocin receptor blocking agent 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin were also tested. RESULTS The median concentration of oxytocin receptors was 116 fmol/mg protein (range 15 to 372 fmol/mg protein) in patients delivered preterm not in labor, 134 fmol/mg protein (27 to 1421 fmol/mg protein) in the beginning of labor, and 46 fmol/mg protein (9 to 140 fmol/mg protein) in advanced labor. At term the corresponding concentrations were 172 (25 to 629), 223 (24 to 414), and 70 (21 to 92) fmol/mg protein. The concentration of V1 vasopressin receptors also decreased in advanced labor. In advanced labor after oxytocin infusion a reduction in the concentration of the receptor for this hormone was observed, which appeared to be related to the duration and dose of treatment. Oxytocin receptors did not vary between women with different indications for cesarean section. The oxytocin effects in vitro and the degree of inhibition by the antagonist of oxytocin responses correlated with the concentration of oxytocin receptors but not with that of V1 vasopressin receptors. No correlation was seen between the response to vasopressin and concentrations of oxytocin or V1 vasopressin receptors. CONCLUSIONS The effect of oxytocin on the myometrium in pregnancy is mediated by an oxytocin receptor, whereas vasopressin acts on both oxytocin and vasopressin receptors. The initiation of labor both preterm and at term may be primarily related to increased release of oxytocin, which is locally produced in the uterus and not detectable in the plasma, but oxytocin and vasopressin receptors may play a role in the regulation of labor. The analog 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin, which blocks both the oxytocin and the V1 vasopressin receptor, should inhibit labor both preterm and at term, the former confirming results of recent clinical studies in Sweden and the United States.

Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women

Objective To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential.

PRIMARY DYSMENORRHOEA AND VASOPRESSIN

The circulating concentrations of arginine vasopressin on day 1 and on day 5 to 7 of the menstrual cycle were measured by radioimmunoassay in six women with primary dysmenorrhoea and five controls. All women had ovulated in the previous cycle, as indicated by the mid‐luteal phase plasma progesterone levels and had normal plasma osmolality and sodium concentrations. The plasma concentrations of progesterone and oestradiol on day 1 of the cycle were also measured, and no significant difference between the two groups was seen. In women with dysmenorrhoea the vasopressin concentration on day 1 was 0.400.038 (SE) μU/ml which was significantly higher than the concentration in normal women on the same day of the cycle 0.20±0.063 (SE) μU/ml (p <0.01). The plasma concentration of vasopressin in normal women on day 5 to 7 was 0.68 0.119 (SE) μU/ml which was significantly higher than on day 1 (p <0.01). A significant difference between day 1 and day 5 to 7 was not seen in dysmenorrheic women, possibly because the values were already elevated on day 1. The results suggest that vasopressin could be a factor of aetiological importance in primary dysmenorrhoea, and also indicate that the vasopressin concentration in plasma can vary according to the day of the menstrual cycle.

Comparative profiles of reliability, cycle control and side effects of two oral contraceptive formulations containing 150 μg desogestrel and either 30 μg or 20 μg ethinyl oestradiol

Objective To compare two oral contraceptive pills, both containing 150 μg desogestrel, but with either 20 μg (Mercilon®) or 30 μg (Marvelon®/Desolett®) ethinyl oestradiol (EE), regarding reliability, cycle control and side effect profile.

Vasopressin and Prostaglandins in Premenstrual Pain and Primary Dysmenorrhea

Abstract. Both vasopressin and PGF2alpha are effective uterine stimulants in the non‐pregnant human uterus, especially around the onset of menstruation. In order to clarify the relationship of these hormones to menstrual pain, plasma concentrations of vasopressin and two prostaglandin metabolites (lS‐keto‐B.H‐dihydro‐PGF2alpha and 11‐ketotetranor PGF metabolites) were measured in serial blood samples taken premenstrually and during menstruation. Five women with premenstrual pain gave 7‐9 blood samples at intervals of 30 minutes on the day preceding the onset of menstruation. From 5 women with severe primary dysmenorrhea a corresponding series of blood samples were taken during the first day of menstruation. Two groups of 5 women with no symptoms served as controls, either premenstrually or during menstruation. In the women with premenstrual pain the vasopressin concentrations were significantly higher than in the corresponding control group. Even higher and markedly fluctuating vasopressin levels were found in the women with dysmenorrhea who, in general, had more intense pain than the women with premenstrual symptoms. In the group with dysmenorrhea there was also a significant rise in plasma concentration of the PG metabolites. No such increase was seen in the group with premenstrual pain. It is concluded that the pathophysiology of premenstrual pain could imply increased vasopressin secretion. The more severe pain in primary dysmenorrhea seems to be the result of a combined effect of vasopressin and PGF2alpha

Pathophysiology of Dysmenorrhea

Abstract. Mechanisms of possible pathophysiological importance in primary dysmenorrhea are discussed. Hyperactivity of the myometrium with accompanying uterine ischemia is considered to be of central importance in the causation of pain. Prostaglandins seem to be involved to a large extent in the development of the myometrial hyperactivity. Other mechanisms of possible importance such as ovarian hormones, cervical factors, vasopressin, nerves, and psychological factors can well act ultimately through prostaglandin release but an action directly on the myometrium and blood flow may also occur.

Stimulation of vasopressin release in women with primary dysmenorrhoea and after oral contraceptive treatment--effect on uterine contractility.

Objective To study aspects of the aetiology of primary dysmenorrhoea and mechanisms underlying the therapeutic effect in this condition of an oral contraceptive.

Effect of SR49059, an orally active V1a vasopressin receptor antagonist, in the prevention of dysmenorrhoea

Objective To investigate the clinical effect of SR49059 when given shortly before the onset of menstruation as a preventative treatment of dysmenorrhoea.

Inhibitory effect of barusiban and atosiban on oxytocin-induced contractions of myometrium from preterm and term pregnant women

Background: A synthetic oxytocin analogue, barusiban, was shown to potently inhibit oxytocininduced activity of myometrium from term pregnant women. The responsiveness to vasopressin was not influenced by the compound. Objective: To test the effect of barusiban and a reference compound, atosiban, on oxytocin-induced activity of myometrium from women at preterm pregnancy in comparison to myometrium from women at term. Methods: Fifteen preterm (30-36 gestational weeks) and 12 term pregnant women (38-41 weeks) who underwent cesarean delivery donated myometrial tissue for the study. Concentration-response curves following oxytocin administration to isolated myometrial stips were recorded in control experiments, in the presence of barusiban at concentrations of 2.5, 25, and 250 nM, and of atosiban at concentrations of 25, 250, and 750 nM. Effective concentration 50% (EC50) and pA2 values were calculated. Results: Both antagonists in higher concentrations increased the EC50 values to oxytocin. The median pA2 value for preterm myometrium with barusiban was 9.76 and with atosiban 7.86. For term myometrium the corresponding pA2 results were 9.89 and 7.81, respectively. None of these pA2 values differed to any statistically significant degree. Conclusion: The selective oxytocin antagonist, barusiban, concentration-dependently inhibits oxytocin-induced myometrial contractions of both preterm and term myometrium at least as potently as atosiban. It remains to be determined if the selectivity of barusiban for the oxytocin receptor confers an advantage over atosiban as a tocolytic in preterm labor.