Myometrial oxytocin receptor mRNA concentrations at preterm and term delivery - the influence of external oxytocin.

The hormonal system for induction of term and preterm labour is not fully understood. Therefore, we investigated myometrial gene expressions for neurohypophyseal hormones and their receptors, prostaglandin F(2alpha) and ovarian steroid receptors in women delivered by Caesarean section. Myometrial tissue for real time PCR was collected from 39 women delivered at term before and after the onset of labour and preterm. Women delivered electively at term had significantly higher oxytocin receptor mRNA expressions (2.52 +/- 0.37 oxytocin receptor/actin; median +/- SEM) than those delivered with ongoing labour at term (1.01 +/- 0.34; p = 0.015) and those at preterm (1.08 +/- 0.25; p = 0.004). Sub-analyses revealed that the difference at term pregnancies solely was related to patients receiving oxytocin during labour (p = 0.007). These patients had higher oxytocin peptide mRNA levels than those without labour at term (p = 0.009). PGF(2alpha) receptor mRNA concentrations were 27.80 +/- 3.55, 11.46 +/- 2.87 and 19.54 +/- 5.52 PGF receptor/actin, respectively, for the groups. Women without labour at term had higher concentration than those with labour (p = 0.005). Our results suggest that oxytocin, its receptor and the PGF(2alpha) receptor are involved in the regulation of labour through a paracrine mechanism.

Reproductive hormones in plasma over the menstrual cycle in primary dysmenorrhea compared with healthy subjects.

The pathogenesis of primary dysmenorrhea is still poorly understood. The objective of the present investigation was to study differences in plasma concentrations of reproductive hormones in women with primary dysmenorrhea vs. healthy controls. In a prospective, parallel-group study we determined the plasma concentrations of oxytocin, vasopressin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-estradiol (17beta-E2), progesterone and prostaglandin F 2alpha metabolite (15-keto-13,14-dihydro-PGF 2alpha) over one menstrual cycle in eight women with primary dysmenorrhea and eight healthy volunteers. In dysmenorrheic women the plasma concentration of oxytocin was significantly higher at menstruation (p = 0.0084) and that of vasopressin significantly lower at ovulation (p = 0.0281) compared with healthy women. They had also higher FSH levels in the early follicular phase (p = 0.0087) and at menstruation (p = 0.0066) and the 17beta-E2 concentration was higher in the late follicular phase (p = 0.0449). No differences were seen for LH, progesterone and PGF 2alpha metabolite. The differences of oxytocin, vasopressin, FSH and 17beta-E2 concentrations found in plasma suggest an involvement of these hormones in mechanisms of primary dysmenorrhea. These mechanisms seem to be mainly regulated through the hypothalamus and pituitary. The influence of oxytocin on the non-pregnant uterus seems to be more important than earlier believed.

Endometrial expression of vasopressin, oxytocin and their receptors in patients with primary dysmenorrhoea and healthy volunteers at ovulation.

OBJECTIVE: To investigate gene expressions for neurohypophyseal and ovarian hormones as well as their receptors in the endometrium of women with primary dysmenorrhoea and healthy subjects at ovulation. STUDY DESIGN: A group of eight women with moderate to severe dysmenorrhoea and eight healthy subjects were compared in parallel between 18 and 35 years of age, regularly menstruating, non-overweight and nulliparous. The study was performed at The Department of Obstetrics and Gynecology, University Hospital of Lund, Sweden. Endometrial biopsies were taken around the time of ovulation, which was determined by repeated ultrasound examinations. Receptor and gene expressions for oxytocin and vasopressin in the tissue were measured. RESULTS: The gene expression for oxytocin receptor was significantly lower in dysmenorrhoic than in healthy women, in median 1.21 and 3.44 oxytocin-receptor/actin, respectively (p=0.048). The expressions for oxytocin peptide, vasopressin V1a receptor, oestrogen receptor alpha, beta and progesterone receptor did not differ between the two groups. Expression of vasopressin peptide was not detectable. CONCLUSION: A lower oxytocin receptor gene expression at mid-cycle could be involved in the aetiology of primary dysmenorrhoea. However, the importance of a paracrine effect of oxytocin and its receptor at ovulation warrants further investigation.

Intrauterine pressure, ischemia markers, and experienced pain during administration of a vasopressin V1a receptor antagonist in spontaneous and vasopressin-induced dysmenorrhea.

BACKGROUND: A model to study the effect of vasopressin V1a antagonist in dysmenorrhea. METHODS: A double-blind, randomized, placebo-controlled, cross-over trial was performed. Eight patients with primary dysmenorrhea and eight tuballigated, healthy subjects participated on days 1-2 of two consecutive menstruations. At each menstruation a bolus injection of 10 pmol/kg of vasopressin was administered before and during infusion of either 300 microg/min of atosiban or placebo. Intrauterine pressure was measured as area under the curve throughout the experiments. Ischemia markers in plasma and pain recorded by a visual analog scale were measured before and after each vasopressin injection as well as before and after the start of either atosiban or placebo infusion. RESULTS: Vasopressin injections elevated area under the curve in both healthy volunteers and dysmenorrhea subjects. The vasopressin-induced rise in area under the curve was lower during atosiban administration than during infusion of placebo in both groups. None of the ischemia markers differed between or within groups at vasopressin injections or atosiban/placebo infusions. In subjects with dysmenorrhea the increase in pain following the administration of vasopressin was significantly lower during atosiban than during placebo infusion. Healthy volunteers experienced only slight discomfort after the vasopressin injections. CONCLUSIONS: Atosiban reduces vasopressin-induced intrauterine pressure in both healthy volunteers and dysmenorrheics, and reported pain in subjects with dysmenorrhea. The ischemia markers are not a useful biomarker index in women with dysmenorrhea. The dysmenorrhea pain evoked by vasopressin correlated poorly with area under the curve, which may suggest that the effect is mediated by more than one V1a-like receptor. We conclude that this model with recordings in healthy women is useful in the evaluation of drug candidates for primary dysmenorrhea.

Validation of a test model of induced dysmenorrhea.

BACKGROUND: The myometrial hyperactivity and reduced uterine blood flow of primary dysmenorrhea is to a large extent caused by increased vasopressin secretion. A new therapeutic approach for this condition is to develop antagonists of uterine vasopressin V1a receptors. We studied a test model of vasopressin-induced dysmenorrhea in healthy, sterilized women and compared responses against those in dysmenorrheic subjects. METHODS: Eight women with primary dysmenorrhea and eight sterilized, healthy women participated in recordings of intrauterine pressure and experienced pain on days 1-2 of two menstruations. We tried to identify biochemical markers in plasma of uterine ischemia. Furthermore, the effects of repeated bolus injections of 10 pmol/kg b w of vasopressin or placebo on these parameters were assessed. RESULTS: The vasopressin injections caused statistically significant increases in the area under the intrauterine pressure curve (AUC) in both healthy volunteers and patients with dysmenorrhea, the overall responses being greater in healthy volunteers. The experienced pain measured by visual analog scale in individual dysmenorrheic subjects tended to show higher maximal post-dose scores for the vasopressin injections than for placebo. Maximum visual analog scale scores and maximum AUCs in individual subjects tended to be related. Mean creatine kinase MB levels were higher in women with dysmenorrhea than in healthy subjects both before and after vasopressin administration, the converse being observed for C-reactive protein levels. CONCLUSIONS: The present model appears to be useful for evaluating new drugs for the treatment of primary dysmenorrhea.