M. Breckwoldt

Estrogen replacement therapy and cardiovascular protection: lipid mechanisms are the tip of an iceberg.

Cardiovascular disease remains a major cause of mortality among postmenopausal women. After menopause, atherogenesis is promoted by a number of metabolic and vascular changes. A multitude of observational clinical studies have come to the conclusion that estrogen replacement therapy (ERT) reduces cardiovascular risk by approximately 50% and that estrogens favorable effects on the lipid profile can explain only 25-50% of the overall observed reduction. Estrogens are now known to have potent anti-atherogenic properties through lipid and non-lipid mechanisms; both will be highlighted in view of the recent literature. Estrogens induce favorable changes on lipids and lipoproteins, partly by increasing HDL-cholesterol and decreasing both LDL-cholesterol and lipoprotein (a). Non-lipid mechanisms of estrogen action include decreasing insulin resistance, serum fibrinogen, factor VII and plasminogen activator inhibitor-1 (PAI-1). Moreover, estrogens maintain endothelial cell integrity, decrease expression of adhesion molecules, lower systemic blood pressure, promote vasodilatation, decrease platelet aggregability, inhibit vascular smooth muscle cell proliferation, possess potent antioxidant and calcium antagonist activities, inhibit adrenergic responses and downregulate platelet and monocyte reactivity. Also mentioned are recent reports linking estrogen to the renin-angiotensin system, relaxin, serotonin and homocysteine. What was once thought of as a simple action is now being increasingly appreciated as a complex, multifaceted mechanism, which serves to prove that estrogen is a powerful cardiovascular agent.

Twin pregnancies with single fetal death

Objective. Analysis of the fetal outcome of the surviving twin and the cause of fetal death. Patients. Between January 1979 and December 1992, 43 twin pregnancies with single fetal death were observed: in 11 cases (group I) before 16 weeks of gestation, in 11 cases (group II) between 17 and 24 weeks, and in 21 cases (group III) after 24 weeks of gestation.

Ultrasonographic and hormonal studies in physiologic and insufficient menstrual cycles

Intraovarian morphologic alterations in 6 physiologic menstrual cycles were studied by sonography and compared with 13 inadequate cycles with a short or missing luteal phase. In addition, basal body temperature, 17 beta-estradiol, luteinizing hormone, progesterone, testosterone, and dehydroepiandrosterone sulfate levels in serum were measured. The maximal follicle was significantly smaller in insufficient cycles (17.7 +/- 2.9 mm) than in physiologic cycles (23.0 +/- 2.3 mm). Corpus luteum structure was visualized in five of the six physiologic cycles but was not detected in insufficient cycles. Persistent polyfollicular reaction (greater than 3 follicles per ovary) without a dominant follicle larger than 10 mm was detected in the ovaries of three patients with clinical and hormonal signs of polycystic ovarian disease. Ultrasonography can be regarded as a useful additional tool in the evaluation and management of insufficient ovarian cycles.

Pathophysiology of Polyhydramnios in Twin Transfusion Syndrome

In 3 cases of severe twin transfusion syndrome we demonstrate that the concentration of atrial natriuretic factor (ANF) in the cord blood of recipient twins is significantly elevated compared to that of donor twins. The discrepancy between recipient and donor concentration correlates with the volume of transfusion. The following pathophysiological mechanism for explaining polyhydramnios in recipient twins is proposed: chronic overload in recipient twins causes enhanced release of ANF from the fetal heart. Consequently, increased fetal urine production leads to polyhydramnios, which is additionally enhanced by inhibition of ADH release.

Effect of progestins, androgens, estrogens and antiestrogens on3H-thymidine uptake by human endometrial and endosalpinx cells in vitro

SummaryThe present study describes the effects of 11 steroid hormones and 3 non-steroidal antiestrogens on the3H-thymidine uptake by human endometrial and endosalpinx cells in long-term cultures. The compounds were added in various concentrations ranging from 10−9 to 10−4 M. Progesterone and 19-nortestosterone caused a dose-dependent reduction of the3H-thymidine incorporation resulting in a 94–98% inhibition at a concentration of 10−4 M, gestonoroncaproate and d,1-norgestrel were less effective causing a 49% and 40% decrease. Antiproliferative effects were also noted after the addition of androgens (testosterone, 5α-dihydrotestosterone, 5β-dihydrotestosterone and danazol). The inhibitory effect of testosterone was equivalent to progesterone at concentrations of 10−4 M. The addition of estrogens (estrone, estradiol-17β and estriol) and antiestrogens (tamoxifen, N-desmethyl- and 4-OH-tamoxifen) produced a dual respone in monolayer cultures as low concentrations (10−9–10−6 M) were associated with a slightly increased3H-thymidine incorporation while pharmacological concentrations (10−5–10−4 M) were followed by a significant decrease. Cells originating from the endosalpinx did not respond to either estradiol-17β or progesterone. These results suggest that in contrast to endometrium, the proliferation of endosalpinx cells is independent of sex steroids.

Contribution to the pathogenesis of dysmenorrhea.

SummaryMenstrual blood was collected from five eumenorrheic and seven dysmenorrheic women aged between 20 and 35 years for a period of three cycles each.The levels of prostaglandin F2α (PGF2α), prostaglandin E2 (PGE2), 6-keto-prostaglandin F1α (6-k-PGF1α) — the stable metabolite of prostacyclin (PGI2) —, oestradiol, oestrone, and progesterone were determined radioimmunologically.Both eumenorrheic and dysmenorrheic women showed identical blood losses. The levels of oestradiol excreted by the dysmenorrheic women were markedly elevated as compared to the non-dysmenorrheic subjects (2 p < 0.05).Oestrone excretion was in the same order of magnitude in all subjects examined. The concentration of progesterone per menstruation was significantly higher in the eumenorrheic women (2p < 0.02) than in the dysmenorrheic patients. Menstrual excretion of PGF2a was 2.5 times higher in the dysmenorrheic women compared to the normal subjects (2p < 0.05). The levels of PGE2 was identical in both groups. Excretion of 6-k-PGF1α was significantly lower in the dysmenorrheic women than in the eumenorrheic subjects (2p š 0.02).The oestradiol/progesterone ratio showed a distinct predominance of oestradiol in the dysmenorrheic patients. PGF2α dominance in the dysmenorrheic patients is expressed by the PGFα/6-k-PGF1α and the PGF2α/PGE2 ratios.A shift in the oestradiol/progesterone ratio in favour of oestradiol seems to be the underlying pathogenic principle of dysmenorrhea. The oestradiol dominance is associated with a shift in the PGF2α/PGI2 and the PGF2α/ PGE2 proportions. Thus, the PGF2α predominance and a simultaneous reduction of PGI2 in uterine tissue seem to be responsible for dysmenorrheic bleeding.

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.

Ventriculomegaly Diagnosed by Prenatal Ultrasound and Mental Development of the Children

During the last 8 years in our department, fetal ventriculomegaly was diagnosed by prenatal ultrasound in 105 cases. Ventriculomegaly was detected at 25 ± 6 weeks of gestation. In 96 of 105 cases follow-up examinations have been performed both during pregnancy and after delivery. In 47 cases termination of pregnancy, late spontaneous abortion or intrauterine death occurred. 49 cases resulted in live births. Of these, 28 children could be followed up to the age of 36 months, a few children even longer. Myelomeningocele was the most frequent cause of ventriculomegaly (17 cases = 61%). Insertion of ventricular shunt systems was performed in 26 children at a median of 21 days of life. Analysis of postnatal development was performed by the Kaufmann Assessment Battery for Children, or the Munich Functional Development Test. Correlation analysis was performed between parameters of prenatal findings and postnatal development. It could be shown that results of single prenatal ultrasound examinations did not correlate with postnatal development whereas progression of ventriculomegaly was negatively correlated with mental development.

Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) production by luteinized human granulosa cells in vitro; a paracrine signal in corpus luteum formation.

Vascularization is a prerequisite for corpus luteum formation. Angiogenesis is thought to be regulated by vascular growth factors. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) specifically induces endothelial cell proliferation as well as angiogenesis and increases capillary permeability. Recently, VEGF/VPF-mRNA expression was demonstrated in luteinized human granulosa cells (GC) in vitro. In addition, the production of VEGF/VPF by human granulosa can be demonstrated immunocytochemically. VEGF/VPF is thought to mediate its effects through specific cell surface receptors. So far, two VEGF/VPF-receptors (VEGF/VPF-R) have been identified (KDR, and flt-1). A third receptor (flt-4) is highly correlated to KDR and flt-1, but the true ligand for this receptor is still unknown. The appearance of all three receptors is more or less restricted to endothelial cells. To clarify whether VEGF/VPF acts in an auto- or paracrine fashion in human luteinized GC, mRNA was scrutinized for specific expression of the three receptors by Northern blot technique. No specific VEGF/VPF-R or flt-4 transcripts were detectable, indicating that VEGF/VPF is a genuine paracrine growth factor from human luteinized GC directed to endothelial cells.

Effects of estradiol-17β and progesterone on the synthesis of prostaglandin F2α, prostaglandin E2 and prostaglandin I2 by fibroblasts from human endometrium in vitro

Abstract Estradiol-17β increases the production of prostaglandin F2α (PGF2α) in long term monolayer cell cultures of the human endometrium in a dose dependent manner. Progesterone in pharmacological dosage stimulates the syntheses of PGF2α and prostaglandin E2 (PGE2). The synthesis of prostaglandin I2 (PGI2) is not influenced by sex steroids in long term monolayer cell cultures of the human endoterium.