Cycle control, tolerability, efficacy and acceptability of the vaginal contraceptive ring, NuvaRing: results of clinical experience in Germany.

OBJECTIVES: To investigate the real-life clinical experience of NuvaRing users in Germany. METHODS: An open-label, prospective, uncontrolled, non-randomized, multicentre postmarketing surveillance study was conducted by 1204 gynaecologists amongst 5823 women requesting contraception. The women underwent routine examinations and contraceptive counselling, and were assessed after three and six cycles of NuvaRing use. RESULTS: Good cycle control was observed and there was a reduction in cycle irregularity and inter-menstrual bleeding, bleeding duration and intensity, and dysmenorrhoea. NuvaRing was well tolerated, and had no significant effect on body weight or blood pressure. Nine women became pregnant unintentionally (two had conceived before they started to use NuvaRing, three due to non-compliance, one because of repeated ring expulsion/loss and three during treatment in spite of having applied this latter as instructed). Most women expressed their satisfaction with NuvaRing; 82% were 'very satisfied/ satisfied', 72% planned to continue using it and 82% would recommend it to others. More than 90% of women found NuvaRing 'without problems/easy' to insert and to remove, and more than 80% of the women and their partners were not disturbed by its presence during intercourse. CONCLUSION: NuvaRing is a highly effective and acceptable method of once-monthly contraception that is safe and well tolerated.

Efficacy and safety of a low-dose 21-day combined oral contraceptive containing ethinylestradiol 20microg and drospirenone 3mg.

OBJECTIVE: The purpose of this study was to assess the efficacy and safety of a new low-dose oral contraceptive containing ethinylestradiol 20microg and drospirenone 3mg (EE 20microg/drsp 3mg). METHODS: This was an open-label, non-comparative, multicentre study conducted at 33 centres in Germany and Switzerland. The combined contraceptive was administered over 26 cycles of treatment, with each cycle consisting of once-daily treatment for 21 consecutive days followed by a 7-day hormone-free interval. RESULTS: A total of 527 women were randomised, of whom 516 (97.9%) started treatment and had at least one study observation. Two pregnancies occurred during 11 165 cycles of treatment, giving a Pearl Index of 0.23 (upper limit of 97.5% CI 0.84). The corresponding 2-year cumulative pregnancy rate was 0.44% (95% CIs 0, 1.05). One of the two pregnancies was attributed to non-compliance with treatment, giving an adjusted Pearl Index of 0.12 (upper limit of 97.5% CI 0.67) over 10 827 compliant cycles. Only three (0.6%) women discontinued treatment because of bleeding problems in this long-term study, suggesting an acceptable bleeding profile. Overall, the study drug was well tolerated and adverse events experienced were typical of hormonal contraceptive use. The majority of women who responded (435 of 501; 86.8%) were satisfied or very satisfied with the study treatment and most (367 of 501; 73.3%) would continue with it if given the choice. CONCLUSION: The EE 20microg/drsp 3 mg combined oral contraceptive is an effective and well tolerated contraceptive with an acceptable bleeding pattern.

[Hystero-salpingo-contrast-sonography with 3-d-ultrasound -- a pilot study]. / Hystero-Salpingo-Kontrastsonographie mit 3D-Ultraschall: eine Pilotstudie.

UNLABELLED: Hystero-salpingo-contrast sonography (HyCoSy) is a sensitive method of assessing tubal patency but cannot completely substitute diagnostic laparoscopy with blue dye and hysteroscopy. Three-dimensional sonography has new imaging facilities which could lead to a reduction of invasive diagnostic procedures. AIM: The aim of this pilot study was to analyse the feasibility of HyCoSy by 3D- and 3D-Doppler-sonography. METHODS: In a prospective setting conventional (2D) HyCoSy was performed in 21 patients with an ultrasound device designed for 3D-ultrasound. After the completion of the 2D procedure, 3D-ultrasound was carried out. In five patients an additional 3D-Doppler-HyCoSy was performed. The generated 3D-volumina were then examined. Laparoscopy with blue dye was performed immediately after the ultrasound examination. RESULTS: A total of 42 Fallopian tubes was assessed. On 2D-ultrasound, visibility of the tubes was excellent in 28 and limited in seven tubes. Of the seven tubes not visible on 2D-ultrasound, four were not patent on laparoscopy. On 3D-ultrasound, visibility of the tubes was excellent in 15 and limited in twelve tubes. 15 tubes were not visible on 3D-ultrasound. 3D-Doppler-HyCoSy revealed excellent assessment in eight of ten tubes, even in one of those with limited visibility on 2D- and 3D-HyCoSy. In 19 patients the assessment of the uterine cavity was excellent by 2D- and 3D-HyCoSy, whereas it was limited in two patients. CONCLUSION: It is possible to visualise the full length of the tubes in a very detailed way from the uterine cavity to the fimbrial end in some patients, but the diagnostic power of HyCoSy is not improved by adding 3D-imaging. The accuracy of 3D-ultrasound seemed to be improved by 3D-Doppler-ultrasound.

Vaginal delivery and neonatal outcome in extremely-low-birth-weight infants below 26 weeks of gestational age.

Outcomes of extremely-low-birth-weight infants (ELBW) with gestational age below 26 weeks based on mode of delivery (vaginal versus cesarean delivery) were retrospectively compared. During the observation period (1997 to 2000) 48 ELBW infants, below 26 weeks of gestational age, had been admitted to the Neonatal Intensive Care Unit (NICU) of the Department of Pediatrics, University of Freiburg, Germany. Twenty-seven (56%) patients were born vaginally and 21 (44%) by cesarean section. Birth weight, umbilical artery pH, and rectal temperature were significantly lower in the cesarean than in the vaginal group. Clinical Risk Index for Babies (CRIB) score showed significantly (p < 0.005) higher values in the cesarean group compared with the vaginal group. Hypothermia (rectal temperature below 36.2 degrees C after birth) was more common in the cesarean group (48%) than in the vaginal group (33%). Eighty-five percent of the fetuses in the vaginal group received antenatal corticosteroids and 88% in the cesarean group. Survival rate was significantly (p < 0.05) higher in infants born vaginally (78%) than in the cesarean group (43%). Several complications occurred less frequently after vaginal birth than after cesarean section: intraventricular hemorrhage grade III to IV (18 versus 33%); periventricular leukomalacia (4 versus 14%); and neonatal septicemia (33 versus 52%), but not statistical significant. In our study group, extremely immature preterm infants had a more favorable outcome if they were born vaginally when compared with infants delivered by cesarean section.

Characterization and identification of cytochrome P450 metabolites of arachidonic acid released by human peritoneal macrophages obtained from the pouch of Douglas.

Cytochrome P450 metabolism of arachidonic acid (AA) was investigated in human peritoneal macrophages which play a central role in chronic pelvic diseases in women (for example in endometriosis). The formation of eicosanoids other than prostaglandins (PGs) by these cells is still unknown. In non-activated macrophages obtained from women in the reproductive age, the main [(3)H]-AA metabolites coeluted with epoxyeicosatrienoic acids, dihydroxyeicosatrienoic acids (DHETs) and hydroxyeicosatetraenoic acids (HETEs) in reverse-phase HPLC. After zymosan activation a shift to PGs pathway was observed. Treatment with low doses of 2,3,7,8-tetrachlorodibenzo- p -dioxin increased the formation of a metabolite coeluting with 5,6-DHET. By gas chromatography/mass spectrometry 5,6-DHET (after beta-naphthoflavone induction), and 14,15-DHET as well as 11,12-DHET (after AA stimulation) were identified as major epoxygenase metabolites, respectively. The enantioselective formation of 12(S)-HETE was demonstrated by chiral-phase HPLC. Our findings demonstrate that non-activated peritoneal macrophages produce substantial amounts of bioactive cytochrome P450 metabolites of AA.

[Physiology of ovarian function]. / Physiologie der Ovarialfunktion.

The ovarian function including follicular maturation, ovulation and corpus luteum formation is regulated by a complex control system composed of hypothalamus, pituitary and the ovary itself. These organs communicate via positive and negative feedback loops and can be considered as a functional entity. Special neurons in the hypothalamus produce gonadotropin-releasing hormone (GnRH) being delivered to the anterior pituitary lobe by the pituitary portal vessels. GnRH binds to specific receptors inducing synthesis and release of the gonadotropins FSH and LH into the circulation. After binding to their specific receptors at the ovary FSH and LH induce follicular maturation, ovulation and corpus luteum formation. The ovary responds to gonadotropin stimulation in dual fashion: secretion of sexsteroids and the liberation of a fertilizable oocyte. In addition the ovary is also able to secrete peptide-hormones such as inhibin and activin. Sexsteroids and inhibin modulate the pulsatile secretion of GnRH and gonadotropins. Cooperation of theca- and granulosa cells at the ovarian level and the corpus luteum formation are described and the significance of growth factors and cytocines is emphasized. The effects of estradiol and progesterone are highlighted by the morphological response of the endometrium. The ovary is actively involved in maintaining cyclicity, as reflected by the processes of follicular growth, follicle rupture and formation of the corpus luteum with the dramatic morphological changes involved.

[Low-dose oral contraception and bone density]. / Niedrig dosierte orale Kontrazeptiva und Knochendichte.

Oral contraceptives (OC) with 20 or 30 mcg Ethinyl-Estradiol (EE) inhibit bone remodeling in all age groups investigated until today as far as the biochemical parameters are considered. In perimenopausal women, OC with 20 or 30 mcg EE reduce the decrease in bone density and may, depending on the starting point, induce an increase in bone density. OC with 20 mcg EE might impede the formation of a physiological peak bone mass in very young women (probably women less than 20 years of age) by a reduction of bone metabolism. This possibility provoked a certain insecurity. However, it should not lead to the consequence that a safe contraceptive method is refused to young women. Unfortunately, there is still a lack of reliable studies allowing a final statement on the effect of low-dose OC on bone density in teenagers. Such studies are urgently needed so that we are able to guarantee in very young women that a reasonable contraception has not to be payed by a long-term risk for the skeletal health. The administration of a progestagen-only pill might be an alternative method for contraception in adolescence. A preparation containing 30 mcg of Levonorgestrel, nearly out of use today, could be of particular interest. A British study (20) has shown that during regular peroral administration of 30 mcg Leveonorgestrel per day, mean serum estradiol concentration decreased only slightly, from 653 to 500 pmol/l. This Estradiol concentration should still allow a normal bone metabolism and therefore a normal formation of the peak bone mass. However, the data actually available do not point convincingly to the conclusion that OC with 20 mcg EE or less might result in an insufficient estrogen concentration for normal bone metabolism. To reach peak bone mass, other factors than estrogens only are needed, such as Calcium, Vitamin D and physical activity.

Does tamoxifen change oestrogen and progesterone receptor expression in the endometrium and breast?

We studied the expression of oestrogen and progesterone receptors (ER, PR) in postmenopausal women receiving tamoxifen for breast cancer. In addition the literature addressing the question of ER and PR expression in breast tissue during treatment with tamoxifen was reviewed. We demonstrated consistent expression of ER and PR in endometria from patients receiving tamoxifen, with a trend towards a higher proportion of receptor positive specimens during tamoxifen. In breast cancer tissue, the ER content seemed to be reduced following tamoxifen treatment. After short time exposure to tamoxifen, the PR appeared to be increased, longer treatment caused the PR to go down to pretreatment levels or below.

Tamoxifen for breast cancer prevention.

Tamoxifen is of proven efficacy in the treatment of breast cancer. New data indicate that it might be able to reduce the occurrence of receptor positive breast cancer when taken as a preventative. However trade-offs for this reduction are an increased incidence of endometrial carcinomas and thromboembolic events. Therefore the use of tamoxifen as preventative ought to be restricted to clinical studies or a well defined high risk situation. Whether raloxifen is superior to tamoxifen remains to be shown.

Steroid receptor expression in endometria from women treated with tamoxifen.

Breast cancer patients receiving tamoxifen (Tam) are at an increased risk for developing endometrial carcinomas, possibly due to the partial estrogenic effect of Tam on endometrial cells. Progestational therapy has not routinely been included in Tam regimens. It was our aim to determine the presence of estrogen receptors (ERs) and progesterone receptors (PRs) in normal and abnormal endometria from postmenopausal women with breast cancer who were treated with Tam. Standard immunohistochemical staining of ERs and PRs was performed on paraffin sections from formalin-fixed uterine curettings or hysterectomy specimens from 40 patients who had received 20-40 mg of Tam daily for a minimum of 3 months. For comparison, normal endometria from 20 women who had not received Tam (11 premenopausal, 9 postmenopausal) were also studied for ER and PR expression. Staining was evaluated using semiquantitative immunoreactivity scores (IRS) ranging from 0 (negative) to 12 (strongly positive). In the group of patients receiving Tam, ERs and PRs were detected in the nuclei of glandular cells in 24/24 cases of endometrial atrophy (ER/PR-IRS, 2-12), in 8/8 endometrial polyps (ER-IRS, 6-12; PR-IRS, 4-12), in 4/4 adenomatous endometrial hyperplasias (ER-IRS, 3-8; PR-IRS, 1-12), and in 4/4 well-differentiated endometrioid adenocarcinomas (ER-IRS, 2-12; PR-IRS, 6-8). Of the 11 endometria from premenopausal patients who had not received Tam, 8 were ER+/PR+ (ER-IRS, 1-12; PR-IRS, 1-12), 1 was ER+/PR- (ER-IRS, 3; PR-IRS, 0), 1 was ER-/PR+ (ER-IRS, 0; PR-IRS, 2), and 1 was ER-/PR- (ER/PR-IRS, 0). Among 9 atrophic endometria from women not treated with Tam, 6 were ER+/PR+ (ER-IRS, 4-12; PR-IRS, 3-6), 1 was ER+/PR- (ER-IRS, 4; PR-IRS, 0), and 2 were ER-/PR- (ER/PR-IRS, 0). The consistent finding of ER and PR expression in endometria from postmenopausal women receiving Tam further supports the suspected estrogenic effect exerted by Tam on endometrial cells. Progestational therapy could be beneficial in the prevention of Tam-induced abnormal endometrial proliferations.

PGE2 and PGF2 alpha release by human peritoneal macrophages in endometriosis.

OBJECTIVE: To test for differences in the amount and activity of peritoneal macrophages present in the peritoneal fluid of women with, and without endometriosis using prostaglandin release by macrophages in culture as a marker. PATIENTS: Women of reproductive age undergoing laparoscopy for infertility or chronic pelvic pain with postoperative diagnosis of endometriosis and women undergoing laparoscopy for sterilization. METHODS: Peritoneal fluid was aspirated during laparascopy, volume was recorded, macrophages were isolated via a Ficoll Paque gradient and kept in primary culture. PGE2 and PGF2 alpha release of the cells were measured before and after stimulation with zymosan. RESULTS: Women with endometriosis had significantly more peritoneal macrophages than controls. Peritoneal macrophages of women with endometriosis released significantly more PGE2 than those of the control group: 8.4 +/- 2.0 versus 1.4 +/- 0.4 ng/ml/10(6) cells (mean +/- SEM, p = 0.0005) and PGF2 alpha: 10 +/- 4.3 (endometriosis) versus 1.8 +/- 0.4 (control) ng/ml/10(6) cells (mean +/- SEM, p = 0.045). CONCLUSION: There is a significant increase in the amount of prostaglandins released by peritoneal macrophages from women with endometriosis. These prostaglandins might alter uterine and tubal contractility, thereby affecting fertility.

Benefits and risks of hormone replacement therapy (HRT).

In western countries more than 30% of the female population are postmenopausal. Approximately 30% of postmenopausal women suffer from clinical symptoms of the climacteric such as vasomotor symptoms, associated with hot flushes, night sweat, insomnia and depressive mood. Sufficient hormonal replacement therapy (HRT) will abolish specific menopausal symptoms in over 90% of patients, unspecific symptoms such as headache respond to placebo and HRT equally well. The question of cancer risk related to HRT will be addressed in this review. In combination with progestins, estrogens are obviously protective regarding ovarian and endometrial cancer. The association between HRT and breast cancer risk is presently unclear. Epidemiological data available so far do not provide compelling evidence as to a cause and effect relationship between HRT and breast cancer risk. There seems to be an overall trend towards a slightly increased risk with increasing duration of HRT use. Guidelines for HRT use in women with a history of endometrial and breast cancer are provided in this article.

Recurrent cytogenetic aberrations and loss of constitutional heterozygosity in ovarian carcinomas.

Cancer is regarded as the result of the accumulation of multiple genetic changes leading to either the activation of oncogenes and increased expression of mitogenic pathways or the inactivation of tumor suppressor genes. It was our interest to investigate malignant ovarian tumors with cytogenetic and molecular techniques to evaluate their consistent genetic alterations. Cytogenetic analysis was performed on 30 short-term cultured ovarian carcinomas. Fifteen tumors revealed clonal cytogenetic abnormalities, 10 of which had very complex karyotypes. The most consistent finding was a 19p+ marker chromosome which was present in half of the cytogenetically abnormal tumors with complex chromosome aberrations. Four tumors showed structural rearrangements resulting in loss of 11p13-pter material. Parallel DNA extracts from 18 tumor samples and corresponding normal white blood cells were analyzed by Southern blotting using 4 polymorphic probes spanning the region 11p15.1 to 11p15.5 and one polymorphic probe mapped to 19p13. Regarding the 11p probes, reduction to homozygosity in the tumor DNA was found in 9 of 17 informative cases. Loss of 19p alleles was found in 5 of 13 informative tumors. Our findings suggest that tumor suppressor genes located on the short arms of chromosomes 11 and 19 are involved in the development of human ovarian cancer.

Parents' needs after ultrasound diagnosis of a fetal malformation: an empirical deficit analysis.

We studied 56 pregnant women and 24 partners after ultrasound examination in the 18-24h gestational week revealed a fetal malformation. The subjects were followed through the process of examination, information sharing and counselling about the option of terminating the pregnancy. Regardless of sociodemographic variables or attitude towards the pregnancy, the diagnosis was always traumatic. A detailed critique of the physician's behavior and function emphasized his important role in the process of coming to terms with the malformation and gave clear indications of the positive expectations parents had. The affected patients expected the role of the professionally competent expert to be combined with that of the empathetic approachable counsellor, whose ste-by-step explanation would allow them to decide for themselves whether to terminate the pregnancy. The partner's participant was an essential aid to adjustment. It remains to be seen to what extent the functions of the doctor are realistic and justified.

Comparison of the emetogenic potential between cisplatin and carboplatin in combination with alkylating agents.

Platinum-based polychemotherapy is widely used in the treatment of gynecological cancer. Emesis is one of the most disturbing side-effects of platinum therapy. We performed a study to evaluate and compare the emetogenic potential and the different emesis pattern after cisplatin and carboplatin under antiemetic treatment with ondansetron. One hundred and twenty-two patients with either cisplatin-containing (n = 70) or carboplatin-containing (n = 52) first-line chemotherapy were included. Treatment with cisplatin led more frequently to emesis and patients suffered from more severe emesis than carboplatin treated patients. Delayed emesis was observed after both platinum analogues but occurred more frequently and lasted longer after cisplatin.

[Obstetric complications, incidence and indications of cesarean section in uterus myomatosus]. / Geburtshilfliche Komplikationen, Frequenz und Indikationen der Kaiserschnittentbindungen bei Uterus myomatosus.

An increasing percentage of patients with uterine leiomyomas was observed in the Department of Obstetrics, University of Freiburg, on comparing the years 1970-79 (0.25%) and 1980-89 (0.64%). While first trimester bleeding, pain and premature labour, being typical obstetrical complications, were encountered in a comparable frequency, atonic bleeding was observed more often during the nineteen-eighties. Pain and premature labour were often present, if the leiomyomas were large, irrespective of both their number or localization. Atonic bleeding was observed more frequently, if large leiomyomas were present. A correlation between the presence of uterine leiomyomas and placental deficiency, premature birth, and EPH gestosis seems uncertain. The total complication rate among all pregnant patients with uterine leiomyomas was 65% from 1980-89. The Caesarean section rate among patients with uterine leiomyomas increased during the evaluated time span, and reached 51% during the 1980's, as compared to a general frequency of Caesarean sections of 19% during the latter time period; this increase in frequency seems to be rather in keeping with a generally increasing Caesarean section rate as opposed to a changing indication for surgery in patients with myomas. The myomas themselves caused Caesarean sections in 50% of cases, while in the remaining 50% of patients, Caesarean sections were performed for general obstetrical reasons. The probability to be delivered by Caesarean section was especially high amongst patients with multiple myomas or with an isthmic myoma. Our study supports a conservative approach in the case of pregnancy and uterine leiomyomas.