Primary and myoma-associated menorrhagia: role of prostaglandins and effects of ibuprofen

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.     

Preeclampsia: a review of the role of prostaglandins

The etiology of preeclampsia remains unknown. Because of their widespread and varied effects in the human body, prostaglandins--specifically PGI2, thromboxane A2, PGE, and PGF2 alpha--have come under much investigation as possible etiologic factors. The vasodilating, platelet-disaggregating prostaglandins (PGI2 and PGE) are increased during normal pregnancy and may account for many of the observed hemodynamic changes, which begin as early as the first trimester. In contrast, a relative increase in the vasoconstricting, platelet-aggregating prostaglandins (thromboxane A2 and PGF2 alpha) is seen in preeclampsia. The disruption in the delicate balance between these two opposing pairs of prostaglandins may play an important role in the causation of preeclampsia. The growing body of literature that deals with the relationship between prostaglandins and preeclampsia is discussed.     

Primary dysmenorrhoea: the importance of both prostaglandins E2 and F2 alpha

Menstrual fluid was collected in a contraceptive diaphragm from 16 women with primary dysmenorrhoea and 12 matched control subjects without dysmenorrhoea. Prostaglandins F2 alpha (PGF2 alpha), E2 (PGE2) and 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) were extracted and measured using gas-chromatography: mass spectrometry (GC:MS). The concentrations of both PGF2 alpha and PGE2 were higher on days 1 and 2 in the dysmenorrhoea group than in the control group and the concentration of PGF2 alpha was higher on day 1 than on day 2 in the dysmenorrhoea group. The concentrations of 6-oxo-PGF1 alpha (the stable metabolite of PGI2) were low in both groups. These results confirm suggestions that PGF2 alpha is important in the aetiology of dysmenorrhoea and also indicate that PGE2 may be involved.     

The role of prostaglandins in ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome was produced in the rabbit by administration of human menopausal gonadotropins. It was shown that this syndrome can be prevented by indomethacin, a blocker of prostaglandin biosynthesis. The role of prostaglandins in the pathogenesis of ovarian hyperstimulation syndrome is discussed and the morphological changes in the ovaries due to treatment with HMG and indomethacin are demonstrated.     

Treatment of menorrhagia with the levonorgestrel releasing intrauterine system: effects on ovarian function and uterus

Purpose  To determine the effects of levonorgestrel-releasing intrauterine system (LNG-IUS) on ovarian functions, uterine and fibroid volume. Methods  In this prospective study, LNG-IUS was inserted to 46 women with menorrhagia. The patients were evaluated for serum levels of hemoglobin, FSH, LH and estradiol, ovarian volume, uterine and fibroid volume and Kupperman index scores at the time of insertion, at 6th and 12th months. Results  Serum FSH levels increased in 69% of the device users, the increase of serum FSH levels were statistically significant (P = 0.021). Regression analysis showed significant association between FSH levels and age of the patient (P = 0.001). There were no statistically significant differences in ovarian and uterine volumes. A statistically significant decrease in myoma volumes were observed (P = 0.04). Conclusion  The application of LNG-IUS in reproductive age women seems to decrease fibroid size and increase hemoglobin levels without any significant dysfunction on ovaries.     

The role of chorioamnionitis and prostaglandins in preterm labor.

Spontaneous preterm labor remains a significant cause of high morbidity and mortality in the newborn. Chorioamnionitis with an associated rise in prostaglandins (PGs) is thought to be one of the factors responsible for the onset of preterm labor. In this study, 52 placentas and membranes from gestations of 35 weeks' or fewer were collected. Tissue samples of membranes and placentas were incubated in pseudoamniotic fluid, and the levels of PGs and leukotriene B4 were assayed. Swallowed amniotic fluid aspirated from the infants' stomachs was analyzed for PGs and examined microscopically for the presence of degenerate neutrophilic polymorphonuclear leukocytes (pus cells) and bacterial organisms. Prostaglandins E and F and leukotriene B4 production were significantly higher in the membranes and placentas with chorioamnionitis than in those without. Although the comparison of PG levels in the gastric fluid of infants with and without chorioamnionitis did not reach statistical significance, there was a trend toward higher levels of PGs with chorioamnionitis. Prostaglandin E levels from membranes and placentas and PGF from placentas were significantly elevated in the gastric fluid of infants with pus cells and organisms. These findings support the hypothesis that chorioamnionitis may initiate preterm labor.     

The role of prostaglandins in the immunosuppressive effects of supernatants from adherent cells of murine decidual tissue

Supernatants from short-term cultures of murine decidual tissue (DS) were assessed for their regulatory effects on T cell lymphoproliferation and cytotoxic T lymphocyte (CTL) activity. DS non-specifically suppressed antigen- and mitogen-induced lymphoproliferation, spontaneous thymocyte proliferation, the mixed lymphocyte reaction (MLR) and CTL generation, but had no effect on CTL lytic activity. The immunosuppressive activity was lost after dialysis (14 kDa cut off). Supernatants from indomethacin-treated decidual tissue cultures (indomethacin-DS) lacked suppressive activity in the MLR, mitogen and thymocyte proliferation assays. Indomethacin-DS also showed markedly reduced or no suppressive effects on CTL generation. These findings suggest that prostaglandin production by the decidual component of the placenta could play a role in materno-fetal cellular interactions by regulating T cell lymphoproliferative responses and CTL generation.     

Diagnosis and treatment of menorrhagia

One-third of all women experience heavy menstrual bleeding at some point in their life. In western countries, about 5% of women of reproductive age will seek help for menorrhagia annually. Half of all women who consult for hypermenorrhea have some uterine abnormality, most often fibroids (among patients under 40 years of age) and endometrial polyps (above 40 years of age). Appropriate treatment considerably improves the quality of life of these patients, and it is important to make a rigorous assessment of the patient to provide the best treatment options. This guideline provides instructions on how to examine and treat women of fertile age who have menorrhagia. The subject's own assessment of the amount of menstrual blood loss does not generally reflect the true amount. All patients should undergo a pelvic examination and, if the menstrual pattern has changed substantially or if anaemia is present, a vaginal sonography should be carried out as the most important supplemental examination. Vaginal sonography combined with an endometrial biopsy is a reliable method for diagnosing endometrial hyperplasia or carcinoma, but it is insufficient for diagnosing endometrial polyps and fibroids; these can be diagnosed more reliably by sonohysterography or hysteroscopy. Non-steroidal anti-inflammatory drugs and tranexamic acid reduce menstrual blood loss by 20-60%, and the effectiveness of a hormonal intrauterine system (IUS) is comparable with that of endometrial ablation or hysterectomy. Cyclic progestogens do not significantly reduce menstrual bleeding of women who ovulate. Treatment should be started with one of the drug therapies, i.e. the IUS, tranexamic acid, anti-inflammatory drugs, or oral contraceptive. Drug treatment should be used and evaluated before surgical interventions are considered. With an effective training and feedback system, it is possible to organise the diagnostics, medical treatment and follow-up of heavy menstrual bleeding in the primary health care setting or in outpatient clinics, which reduces the burden on specialist health care.     

The role of prostaglandins in the initiation of parturition

Parturition is composed of five separate but integrated physiological events: fetal membrane rupture, cervical dilatation, myometrial contractility, placental separation and uterine involution. Prostaglandins (PGs) have central roles in each of these, but the most studied is myometrial contraction. Elevated uterine PGs or the enhanced sensitivity of the myometrium to PGs leads to contractions and labour. The regulator of PG synthesis is the mRNA expression of PGHS-2. Cytokines are important stimulators of this gene expression, and cortisol and other factors may be as well. This enzyme is an important therapeutic target in the prevention of preterm labour. Some preterm births occur without an elevation of uterine PGs, even though they are delayed by non-steroidal anti-inflammatory drugs (NSAIDs), suggesting enhanced myometrial sensitivity to PGs. The PGF(2alpha) receptor, FP, is emerging as a central component of uterine sensitivity and may prove to be involved with preterm birth and a reasonable target for tocolysis.     

Ectopic pregnancy: in vitro effects of prostaglandins on the oviduct and corpus luteum

An in vitro model for evaluation of pharmacologic treatment of ectopic pregnancy (EP) was designed. In cases of EP, specimens from the tubal wall, the tubal artery, and the corpus luteum capsule were used for contractility studies. In addition, tissue slices from the corpus luteum of EP were incubated for determination of progesterone production. In vitro administration of prostaglandin F2 alpha (PGF 2 alpha) induced a marked increase in activity of the tubal muscle and pronounced constriction of the tubal artery. PGF2 alpha also reduced the human chorionic gonadotropin-induced increase in progesterone production from the corpus luteum. PGE2 conversely, inhibited the tubal muscle activity and had a moderate constrictive effect on the tubal artery. Furthermore PGE2 increased the progesterone formation from the corpus luteum. In theory, the demonstrated in vitro effects indicate that as opposed to PGE2 compounds, PGF2 alpha compounds may be useful for pharmacologic treatment of EP.     

Efficacy, acceptability and side effects of the levonorgestrel intrauterine system for menorrhagia.

OBJECTIVE: To evaluate the efficacy, acceptability, and possible side effects of a levonorgestrel-releasing intrauterine system for menorrhagia. METHODS: Sixty-three women with menorrhagia but without uterine enlargement, endometrial hyperplasia with atypia, or endometrial carcinoma were enrolled in this prospective, open, nonrandomized clinical trial. An intrauterine system releasing 20 microg/day of levonorgestrel (LNG-IUS; Mirena, Shering, Finland) was inserted in the postmenstrual phase. Menstrual pattern, number of bleeding days, and subjective and objective estimation of menstrual blood loss using a pictorial blood loss assessment chart (PBAC) were recorded before insertion and at specific intervals for 4 years. Hemoglobin levels and endometrial thickness were evaluated at baseline and at 12 months. Treatment continuation and hysterectomy rates were noted as well as side effects. RESULTS: The device was expelled spontaneously in 6 patients (9.52%) and removed prematurely in 9 patients (14.3%); 3 patients (4.8%) were lost to follow-up; and 45 patients (71.4%) continued with the LNG-IUS. Menorrhagia was cured in 35 (77.7%) of these 45 patients at 3 months and in all patients at 36 months. There was a significant decrease in the mean number of bleeding days (P=0.01) and PBAC score (P=0.00) at 1 month, and the decrease continued with treatment duration. The subjective blood loss reduction was considerable as well, and at 12 months the mean+/-SD rise in hemoglobin concentration was 1.06+/-1.7 g/dL (P=0.000). Endometrial thickness was decreased by 3.4+/-3.53 mm (P=0.0001) at 12 months. The most common side effect was intermenstrual spotting during the first 6 months, and 18 patients (28.57%) developed amenorrhea. CONCLUSION: Using the LNG-IUS is an effective and well-accepted option overall for the medical management of menorrhagia.     

Analysis of the role of prostaglandins in the fertilization process

This study was designed to elucidate the role of prostaglandins (PG) in the fertilization process, using indomethacin (ID), an inhibitor of PG biosynthesis, and mouse in vitro fertilization as a model for analysis. Spermatozoal viability, as assessed via motility, was not suppressed by ID at 100 and 150 micrograms/ml in 3-h incubation, but markedly by 200 micrograms/ml in 1-h incubation. On the other hand, ovum viability was not affected even by 200 micrograms/ml ID in 5-h incubation, as assessed via dye-excretion and morphology. Fertilization rates for 0, 100, 150 and 200 micrograms/ml ID were 58.8, 54.8, 24.3 and 18.9%, respectively; at 150 micrograms/ml and more, significant inhibition was noted. The reduction in spermatozoal viability at 200 micrograms/ml ID was not detected after supplementation of 50 micrograms/ml PGF2 alpha. Fertilization rates were 23.1 and 20.7% in the groups at 150 and 200 micrograms/ml ID with PG solvent, respectively. After supplementation of 50 micrograms/ml PGF2 alpha, the rates were 55.8% and 64.0%, respectively. The degenerated eggs significantly increased. The polyspermic eggs also tended to increase in the ID 200 micrograms/ml groups; however, after PGF2 alpha supplementation, the number of such eggs tended to decrease. Based on these facts, it is concluded that PG may play their role in fertilization not only via sperm, but also via eggs.     

Therapeutic effects of the levonorgestrel-releasing intrauterine system in the treatment of idiopathic menorrhagia

OBJECTIVE: To investigate the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of idiopathic menorrhagia. DESIGN: Measurements of menstrual blood loss (MBL), hemoglobin, and serum ferritin before and after LNG-IUS insertion. SETTING: National Research Institute for Family Planning and Beijing Gynecology and Obstetrics Hospital, Beijing, People's Republic of China. PATIENT(S): Thirty-four patients with MBL over 80 mL. INTERVENTION(S): Insertion of the LNG-IUS on cycle days 5-7 and follow-up at 3-month intervals for 3 years. MAIN OUTCOME MEASURE(S): Measurement of MBL, serum ferritin, and hemoglobin for evaluation of efficacy of treatment. RESULT(S): A significant reduction of MBL to 23.4 mL (78.7% decrease), 26.4 mL (83.8% decrease), 2.7 mL (97.7% decrease), and 13.7 mL (85.0% decrease) at 6, 12, 24, and 36 months, respectively. After 6 months, one-third of the patients experienced amenorrhea, and one-fourth, spotting. Hemoglobin increased significantly from 121.5 g/L preinsertion to 135.5 g/L after 36 months, while serum ferritin levels increased significantly from 21.9 ng/mL before insertion to 92.8 ng/mL after 36 months. In women using the LNG-IUS for 3-4 years, the E2 levels in 20 samples were 239.4 pmol/L, P levels were 11.1 nmol/L, and serum LNG levels were maintained at an average of 511 pmol/L. CONCLUSION(S): The significant reduction of MBL and the increase in hemoglobin and serum ferritin levels in the treatment of menorrhagia with the LNG-IUS has great implications for women's reproductive health, particularly in developing countries.