The combined contraceptive vaginal ring and bone mineral density in healthy pre-menopausal women.

BACKGROUND: Hormonal contraceptives have been associated with various effects on the bone mineral density (BMD) of pre-menopausal women. The aim of this study was to assess the effects of a vaginal contraceptive ring on BMD in pre-menopausal women and compare them with those of non-hormonal contraceptive use. METHODS: This open-label, multicentre study used dual-energy X-ray absorptiometry to measure BMD in the lumbar spine (L(2)-L(4)) and femoral neck regions. Subjects were assigned 3:1 to receive a contraceptive ring (n = 105) or a non-hormonal contraceptive control (n = 39) and were assessed after 13 and 26 cycles of contraceptive ring treatment or 12 and 24 months of control treatment. RESULTS: No change from baseline in BMD (Z-scores) was seen in contraceptive ring users (n = 73) at either time-point. In the control group (n = 30), BMD increased slightly from baseline resulting in significant differences (P < 0.0001) between the two groups at cycle 26/month 24. These differences are not clinically relevant, although some degree of acquisition of peak bone mass might have been prevented in the contraceptive ring group. The contraceptive ring was generally well tolerated; a higher incidence of treatment-related adverse events was observed in the contraceptive ring group compared with the non-hormonal contraceptive control group. CONCLUSIONS: In healthy pre-menopausal women, 2 years of contraceptive ring use produced no changes in BMD.

Bone mineral density during long-term use of the progestagen contraceptive implant Implanon compared to a non-hormonal method of contraception.

An open, prospective, comparative study was done in healthy women, aged between 18 and 40 years, to study the effects of long-term etonogestrel treatment on bone mineral density (BMD). The control group used a non-hormone-medicated intrauterine device (IUD). The BMD was measured using a dual energy X-ray absorptiometry instrument. Measurements included the lumbar spine (L(2)-L(4)), the proximal femur (femoral neck, Ward's triangle, trochanter) and distal radius. The period of treatment was 2 years and 44 women in the Implanon group and 29 in the IUD group provided data. Groups were comparable at baseline with respect to age, weight, body mass index, BMD and 17beta-oestradiol status. Changes from baseline in BMD in the Implanon group were not essentially different from those in the IUD group. There was no relationship between 17beta-oestradiol concentrations and changes in BMD in this study population. The results of the present study indicate that Implanon((R)) can safely be used in young women who have not yet achieved their peak bone mass.

Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant.

OBJECTIVE: To study the mechanism of action of Implanon, a single-rod contraceptive implant containing etonogestrel, in healthy women during 3 years. DESIGN: Prospective, randomized comparison with Norplant. The study was conducted for 2 years in Sweden but was extended to 3 years in Finland. SETTING: Two outpatient clinics. PATIENT(S): Thirty-two healthy women who were between 18 and 40 years of age with normal ovulatory cycles. Seven women receiving Implanon and three receiving Norplant participated in the third year. INTERVENTION(S): On or between days 1 and 5 of a spontaneous menstrual cycle, the subjects received either the etonogestrel-containing implant (Implanon) or the levonorgestrel-containing implant (Norplant). MAIN OUTCOME MEASURE(S): Ultrasonography was performed and/or progesterone concentrations were determined to confirm ovulation in a control cycle. Follicular development, endometrial thickness, and serum concentrations of 17beta-estradiol and progesterone were assessed twice per week during 4-week periods at regular intervals and after implant removal for 6 weeks to monitor return of ovulation. Times required to remove the respective implants were evaluated, as were possible complications. RESULT(S): Seven women who received Implanon and three who received Norplant completed 3 years of study. There were no pregnancies. Ovulation was observed for the first time with Norplant after 18 months. The first ovulation with Implanon was observed after 30 months. Mean endometrial thickness was <4 mm during treatment with Implanon from month 12 onward. The mean (+/-SD) time to remove Implanon was 5.9 +/- 3.4 minutes. The mean (+/-SD) time to remove Norplant was 17.9 +/- 9.9 minutes. Ovulation resumed promptly after the use of either implant. CONCLUSION(S): Results from this study provide convincing evidence of 3-year contraceptive efficacy with Implanon, mainly by ovulation inhibition.

The pharmacodynamics and efficacy of Implanon. An overview of the data.

Implanon is a long-acting reversible contraceptive method, consisting of a single rod that is applied subdermally. Ovulation inhibition was determined by serum progesterone (P) levels and ultrasound scanning (USS) of the ovaries. Ovarian function was further assessed by serum estradiol (E2) levels. The effects of Implanon on serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) and on cervical mucus were also investigated, by means of Insler scores and sperm penetration tests. The effect of the endometrium was assessed by endometrial biopsies and USS. The Pearl index was calculated over 13 studies performed according to Good Clinical Practice (GCP), including 1716 women using Implanon. Return of ovulation after implant removal was determined by P levels and USS of the ovaries. The contraceptive efficacy of Implanon was high, with zero pregnancies during 53,530 cycles (4103 woman-years), resulting in a Pearl index of 0.0 (95% confidence interval, 0.00-0.09). This was achieved by inhibition of ovulation, which was reflected by suppressed P levels, as the primary mode of action. Ovulation was inhibited, but otherwise ovarian activity was still present (follicle growth, E2 synthesis). The FSH serum concentrations were only slightly lower than preinsertion levels and LH surges were prevented. The viscosity of the cervical mucus was increased. The endometrium was thin but not atrophic; it showed primarily inactive or weak proliferation. Return of ovulation after removal of Implanon was rapid.

Single bolus compared with a fractionated dose injection technique of bupivacaine for extradural Caesarean section: effect on uteroplacental and fetal haemodynamic state.

We studied 26 healthy parturients undergoing elective Caesarean section, allocated randomly to receive extradural block with 0.5% plain bupivacaine in a double-blind manner in either a single bolus or fractionated doses. After a 3-ml test dose, an additional 20 ml of bupivacaine were given over a 5-min period in the single bolus group (n = 13) and over a 25-min period in the fractionated dose group (n = 13). We studied the effects of bupivacaine on blood flow velocities in the maternal placental and non-placental uterine and fetal umbilical arteries before and four times during establishment of extradural block using a pulsed colour Doppler technique. Median sensory block reached T3 in the single-dose group compared with T4 in the fractionated-dose group. Two subjects in each group required i.v. ephedrine to correct transient hypotension (systolic arterial pressure < 90 mm Hg). Blood flow velocity waveform indices of the uterine and umbilical arteries did not differ significantly within or between groups during the study. There was no significant difference in neonatal outcome, as assessed by Apgar scores and umbilical artery pH values. In conclusion, we observed no deterioration in uteroplacental circulation after administration of a single bolus dose of bupivacaine.

Medroxyprogesterone acetate supplementation diminishes the hypoestrogenic side effects of gonadotropin-releasing hormone agonist without changing its efficacy in endometriosis.

OBJECTIVE: To examine the effects of concomitant use of goserelin and medroxyprogesterone acetate (MPA) in the treatment of endometriosis. DESIGN: Thirty-eight women with laparoscopically confirmed endometriosis were treated with once-a-month s.c. injections of goserelin acetate 3.6 mg (Zoladex depot; Zeneca Pharmaceutics, Cheshire, United Kingdom) randomly combined with either MPA (100 mg daily; n = 19) or a placebo (one tablet daily; n = 19) in a double-blind trial. Symptoms and side effects were monitored for a treatment period of 6 months and a follow-up period of 6 months. Blood and urine samples were collected for the assessment of endocrine and biochemical parameters. A second-look laparoscopy was performed 6 months after the treatment in 29 women. RESULTS: The extent of endometriosis was diminished similarly in both treatment groups, as were pelvic symptoms. Fewer women in the MPA group had hot flushes and sweating at 3 and 6 months of treatment. Sex hormone-binding globulin decreased in the MPA group but not in the placebo group. Consequently, the E2 index (E2/SHBG X 100), reflecting the free fraction of E2, fell more in the placebo group than it did in the MPA group. The increased urinary excretion of calcium observed during placebo treatment was prevented by MPA. CONCLUSION: High-dose MPA combined with a GnRH agonist (GnRH-A) diminished some antiestrogenic effects of the agonist. A reduction in hypoestrogenic side effects and a possible bone-sparing effect can be regarded as beneficial, especially as the good effect of the GnRH-a on endometriotic implants and pelvic symptoms prevailed.

Can progestin be limited to every third month only in postmenopausal women taking estrogen?

We evaluated whether a progestin, added for 14 days every 3 months to estrogen replacement therapy, is capable of preventing the development of endometrial hyperplasia in postmenopausal women during a treatment period of 2 years. Postmenopausal women (263) in 10 hospitals and medical centers in Finland participated in this non-randomized prospective multicenter trial. The women received estradiol valerate 2 mg daily for 84 days and 20 mg of medroxyprogesterone acetate daily for days 71-84 followed by seven drug-free tablets. This regimen was repeated four times per year. The first year of treatment was completed by 227 (86%) women and the second year by 143 out of 146 women. The incidence of unscheduled and heavy bleedings was higher in women who were postmenopausal for less than 3 years. Endometrial biopsies demonstrated progestational response in 64% at 12 and 24 months, respectively. The 3 month regimen prevented development of endometrial hyperplasia but was not able to restore a hyperplastic endometrium to normal.

Aggressive direct treatment of a fetus with supraventricular tachycardia and hydrops fetalis.

We report a case, in which direct fetal therapy by amiodarone injected into the umbilical vein during the last trimester of pregnancy was used for the treatment of fetal supraventricular tachyarrhythmia in the presence of severe hydrops fetalis. Eight injections were needed due to the recurrence of supraventricular tachycardia 1-9 days after the initial normalization of fetal tachycardia after each puncture. A severe fetal hydrops was maintained despite the achievement of sinus rhythm, and thus two ascites draining procedures were performed during the last 3 days before delivery to expand the fetal lungs. A normorhythmic hydropic baby was born by Cesarean section at 34 weeks + 6 days. Only mild respiratory difficulties occurred after birth. Her electrocardiogram suggests a Wolff-Parkinson-White syndrome but the overall recovery has been uneventful.

Endobrush sampling for endometrial cancer.

The two intra-uterine cytological sampling methods Endobrush and Pistolet were compared for clinical applicability in 66 premenopausal and 47 postmenopausal women. The taking of the specimens succeeded in 94% of the cases with the Endobrush method and in 99% with the Pistolet method. The two intra-uterine sampling methods were both almost painless. The Endobrush and the Pistolet specimens were filtered and stained by the Papanicolaou method. The Endobrush specimens were also used to make smears, which were also stained by the Pap method. According to the separate evaluations of two cytologists the Endobrush smear yielded specimens with a large or moderate number of cells in 59.0 to 71.4%, the Endobrush filter method in 73.6 to 76.5% and the Pistolet filter method in 71.4 to 76.8%. Specimens with good or moderate quality were found in 83.3%, 86.8 to 89.6% and 93.7 to 99.1%, respectively. Unsatisfactory specimens accounted for only 2.8-0.9% of the cases. All four endometrial carcinomas were placed in Pap classes 3 to 5 on the basis of the Endobrush and Pistolet filter specimens. The diagnostic quality of the smears was inferior to that of the filter specimens. The results suggest that the Endobrush filter method yields cytological endometrial samples which are similar in cell number, quality and diagnostic value to those obtained by the Pistolet method. Endobrush method is also simple, quick and painless, and therefore well acceptable to patients and suitable for clinical use.

Tiaprofenic acid in the treatment of primary dysmenorrhoea.

Thirty-one patients with primary dysmenorrhoea were treated in a double-blind, six-period, cross-over clinical trial with tiaprofenic acid, naproxen sodium and a placebo in randomized order, each for 2 consecutive cycles. Complete disappearance of the symptoms or pronounced therapeutic effects were obtained with tiaprofenic acid, naproxen sodium and the placebo in 74%, 65% and 35% of cases, respectively, while these treatments were ineffective in 3%, 6% and 38% of cases, respectively. Tiaprofenic acid was superior to the placebo for relieving pelvic pain and overall discomfort and for reducing the need for bed-rest. Naproxen sodium compared favourably with the placebo with respect to pelvic pain and overall discomfort. The effects of tiaprofenic acid and naproxen sodium were not significantly different. Tiaprofenic acid had no side-effects, whereas tiredness was experienced in 3 cases of naproxen sodium treatment. The results indicate that tiaprofenic acid is a useful alternative for the treatment of primary dysmenorrhoea.

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.

Ibuprofen prevents IUCD-induced increases in menstrual blood loss.

To study the effects of a copper-releasing intrauterine contraceptive device (IUCD) and a prostaglandin (PG) synthesis inhibitor, ibuprofen, on menstrual blood loss, 28 healthy women received either a Fincoid 350 or a ML Cu375 device and were then treated in a double-blind randomized manner with ibuprofen (1200 mg daily) or a placebo during their next three menstruations. The preinsertion menstrual blood loss (2 cycles) was normal for healthy women (median 38 ml) with no difference between women who subsequently received either Fincoid 350 or ML Cu375 and ibuprofen or placebo treatment. The median increase in menstrual blood loss after the insertion of an IUCD was 74% (P less than 0.01) in women receiving placebo treatment, and this rise was not dependent on the type of IUCD. Ibuprofen treatment prevented the increase in blood loss following IUCD insertion, but it failed to shorten the duration of menstruation. Four women reported side-effects (tiredness, irritability, sweating, dyspepsia) during ibuprofen treatment, and two women did so during placebo treatment. It is concluded that IUCDs with a large copper surface also increase menstrual blood loss, but that this increase can be prevented with ibuprofen treatment.

Biochemical and clinical effects of treating the premenstrual syndrome with prostaglandin synthesis precursors.

The clinical and biochemical effects of a prostaglandin synthesis precursor (Efamol) containing linoleic acid and its metabolite, gamma-linolenic acid, were studied in 30 women with severe, incapacitating premenstrual syndrome. Efamol treatment alleviated the premenstrual symptoms in general and depression especially better than did a placebo. The capacity of platelets to release thromboxane B2 during spontaneous clotting was decreased in patients undergoing Efamol treatment (141 +/- 59 ng/ml, mean +/- SD) as compared to those undergoing placebo treatment (186 +/- 44 ng/ml, p less than 0.01) and control subjects (176 +/- 40 ng/ml, n = 25, p less than 0.05). No changes were found in plasma 6-keto-prostaglandin F1alpha or in FSH, LH, prolactin, progesterone, estradiol and testosterone. The data suggest that prostaglandins might play a role in the pathophysiology of the premenstrual syndrome.

Amniotic fluid 6-keto-prostaglandin F1 alpha and thromboxane B2 during labor.

Production of the antiaggregatory and vasodilatory prostacyclin (prostaglandin I2) and the proaggregatory and vasoconstrictory thromboxane A2 during human labor was studied by measuring serial concentrations of the stable metabolites of these prostanoids, 6-keto-prostaglandin F1 alpha and thromboxane B2, respectively, in the amniotic fluid of 43 parturients whose labor was induced by amniotomy. The concentration of 6-keto-prostaglandin F1 alpha at amniotomy in 28 healthy parturients (92.7 +/- 12.1 pg/ml, mean +/- SE) was higher (p less than 0.02) than that in 15 preeclamptic women (48.6 +/- 5.5 pg/ml). The concentration of thromboxane B2 at amniotomy was 292.4 +/- 56.1 pg/ml, with no difference between the healthy and preeclamptic parturients. Both prostanoid levels rose consistently during labor, reaching peak levels when the cervix was fully dilated, but this rise started only after the established uterine contractility. Epidural anesthesia and paracervical blockade had no effect on 6-keto-prostaglandin F1 alpha and thromboxane B2 in the amniotic fluid, whereas oxytocin infusion was accompanied by reduced levels of thromboxane B2. The rise in amniotic fluid 6-keto-prostaglandin F1 alpha was reduced at every stage of labor in the preeclamptic women (n = 15), and its maximal increase (112.4 +/- 28.3 pg/ml) was smaller (p less than 0.005) than in the healthy women (n = 28, 240.8 +/- 21.4 pg/ml). The ratio of 6-keto-prostaglandin F1 alpha to thromboxane B2 also shifted to thromboxane B2 dominance in the preeclamptic parturients. It is concluded that a relative prostacyclin deficiency deteriorates in preeclamptic women during labor.

Menstrual blood loss in dysmenorrhoea: effects of proquazone and indomethacin.

Abnormal production of uterine prostaglandins (PG) causes primary dysmenorrhoea and excessive menstrual blood loss (MBL). We measured here MBL in primary dysmenorrhoea and found it to be normal during treatment with opiate analgesics (33.5 +/- 21.6 ml; mean +/- SD. n = 13), placebo (33.4 +/- 18.6 ml; n = 8), proquazone (31.8 +/- 18.0 ml; n = 8) and indomethacin (26.4 +/- 18.7 ml; n = 8). Proquazone and indomethacin relieved pain and other dysmenorrhoeic symptoms similarly in 33 women.

Hormonal and metabolic effects of intravenous infusion of prostacyclin in healthy women.

To study the hormonal and metabolic effects of prostacyclin (PGI2), 6 healthy women were infused iv with PGI2 (1, 2, 4, and 8 ng/kg/min. each for 20 min) dissolved in glycine buffer, or with glycine buffer only. Serial blood samples collected before, during and after the infusion were assayed for FSH, LH, prolactin, growth hormone, thyrotrophin, oestradiol, progesterone, testosterone, cortisol, thyroxine, triiodothyronine, renin, aldosterone, glucose, insulin, glucagon, cholesterol, high density lipoprotein-cholesterol, triglycerides, alkaline phosphatase, alanine and aspartate aminotransferases, bilirubin, sodium, potassium, chloride, calcium, inorganic phosphorous, creatinine and uric acid. PGI2 infusions were accompanied by increased levels of prolactin, growth hormone and cortisol, probably due to the stressful side-effects during PGI2 infusion. In addition, plasma renin activity, glucagon and blood glucose increased, whereas the other variables measured did not change. These PGI2-effects should be kept in mind, when PGI2 is used in clinical practice.

Lack of effect of circulating prostacyclin on contractility of the non-pregnant human uterus.

To study the effect of prostacyclin (PGI2) on the contractility of the non-pregnant human uterus, the intrauterine pressures in the isthmus and fundus of the uterus were recorded before, during and after intravenous PGI2 at different phases of two consecutive menstrual cycles in eight women. Infusions of 1-8 ng of PGI2 min-1 kg-1 for 20 min caused no changes in intrauterine pressure either during menstruation or any other phase of the cycle when compared with the contractility patterns in the same woman during the control infusion. Thus these data suggest that circulating PGI2 is not involved in regulating the contractility of the non-pregnant human myometrium.

Prostacyclin production increases during human parturition.

The role of prostacyclin (PGI2) in human parturition was studied by measuring the concentrations of its main metabolite, 6-keto-prostaglandin F1 alpha, before, during and after term labour in the plasma of 9 women and after delivery in umbilical artery and vein plasma. The mean level of 6-keto-PGF1 alpha rose significantly over the course of labour. The mean level was 266 pg/ml before labour, 341 pg/ml in the presence of regular contraction, 387 pg/ml at a cervical dilatation of 5 cm, 386 pg/ml at delivery, and 397 pg/ml at the expulsion of the placenta. The 6-keto-PGF1 alpha concentration dropped to below pre-labour levels of 233 pg/ml within 2 hours of delivery, and this level was maintained for the first four postpartum days. The mean levels of 6-keto-PGF1 alpha in the umbilical artery and vein plasma, 1667 and 1193 pg/ml respectively, were significantly higher than the maternal plasma levels. PGI2 is characterized by its antiaggregatory and vasodilating abilities, so that the rise in PGI2 during labour may play a role in the prevention of intrapartum thromboembolic complications in the maternal and the uteroplacental circulation.