Biomedical subjects
Publications and source records attributed to F M Helmerhorst.
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Insufficient suppression of LH (premature elevation) and FSH (prolonged release) give rise to blood concentrations which may cause damaging effects on oocyte viability and too many follicles respectively. During the surge, LH rises from low to high threshold values to initiate processes from initiation of the resumption of oocyte meiosis to the induction of ovulation. In general, it is thought that a dramatic increase in LH concentration is required to attain the high threshold for ovulation. A self-priming mechanism, by which gonadotrophin-releasing hormone (GnRH) enhances the LH (and FSH) responses to its own action, was thought to be responsible. However, normal LH surges in rats consist of <2-7% of the maximal pituitary releasing capacity. The physiological roles of LH and FSH favour a control mechanism that restrains their blood concentrations during most of the cycle. Ovarian proteins, e.g. inhibin and putative gonadotrophin-surge-inhibiting factor/attenuating factor (GnSIF/AF), are involved in this process. We argue that the increased pituitary LH responsiveness during the mid-cycle surge is not the result of a self-priming process that 'dramatically' increases the LH releasing capacity of the pituitary gland. This is probably due to elimination by GnRH of the inhibitory action of the putative ovarian proteins GnSIF/AF.
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The endometrium is a tissue unique for its cyclic destruction and rapid regeneration of blood vessels. Angiogenesis, indispensable for the regeneration process, provides a richly vascularized, receptive endometrium fundamental for implantation, placentation, and embryogenesis. Human endometrial microvascular endothelial cells (hEMVEC) were isolated to better understand the properties and angiogenic behavior of these cells. Unlike human foreskin microvascular endothelial cells (hFMVEC), which proliferated better upon stimulation by basic fibroblast growth factor, hEMVEC were much more sensitive to vascular endothelial growth factor A (VEGF-A) stimulation, probably due to enhanced VEGF receptor 2 expression. In addition, hEMVEC displayed an enhanced expression of the urokinase-type plasminogen activator (u-PA) compared with hFMVEC. No differences were found in tissue-type PA, PA inhibitor-1, and u-PA receptor expression. The high expression of u-PA by hEMVEC was also found in tissue sections. hEMVEC formed capillary-like structures when cultured in 20% human serum on top of three-dimensional fibrin matrices, and VEGF-A or basic fibroblast growth factor increased this tube formation. This is in contrast with hFMVEC, which formed tubes only after simultaneous stimulation by a growth factor and tumor necrosis factor-alpha. The high basal level of u-PA contributes to and may explain the higher angiogenic properties of hEMVEC (in vitro).
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Oral contraceptives and hormone replacement therapy are used by hundreds of millions of women worldwide. Since the early 1960s it is known that female hormones increase the risk of venous thrombosis, myocardial infarction and stroke. This risk is still present with current low-dose oral contraceptives and, even though in absolute terms the risk is small, oral contraceptives form the major cause of thrombotic disease in young women. The risk is higher during the first year of use (up to I per 1000 per year), with the use of desogestrel- or gestodene-containing oral contraceptives ("third generation progestogens") and among women with a prothrombotic predispositon. Hormone replacement therapy increases the risk of venous thrombosis, while results of randomised trials so far do not substantiate the expectation of a beneficial effect on the risk of arterial cardiovascular disease. First results are emerging that specific subgroups of women, with prothrombotic or other abnormalities, may be at risk, especially during the first years of use of hormone substitution.
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Small relative risks (a twofold or lesser increase in disease frequency) become scientifically acceptable with (a) repeated consistent findings from studies that (b) address the most important forms of bias and confounding, and (c) when there is a plausible biologic mechanism. The third-generation oral contraceptive controversy is an example of such a relevant but small relative risk and demonstrates the problem of interpretation and implementation into medical practice guidelines.
BACKGROUND: Results of recent studies show that the risk for venous thrombosis is highest during initial oral contraceptive use. This suggests a subgroup of females who are at immediate risk of thrombosis when exposed to oral contraceptives. OBJECTIVE: To determine whether women with inherited clotting defects who use oral contraceptives develop venous thrombosis at an earlier stage than do those without inherited clotting defects. METHODS: Analysis of the data from the Leiden Thrombophilia Study, a population-based case-control study with data on duration of oral contraceptive use and recently detected genetic coagulation disorders. Patients had a first episode of objectively proven deep vein thrombosis. Patients and controls were considered thrombophilic when they had protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation, or prothrombin 20210 A mutation. RESULTS: Risk of developing deep vein thrombosis was greatest in the first 6 months and the first year of oral contraceptive use. Compared with prolonged use, the risk of developing deep vein thrombosis was 3-fold higher in the first 6 months of use (95% confidence interval [CI], 0.6-14.8) and 2-fold higher in the first year of use (95% CI, 0.6-6.1). Patients who developed venous thrombosis in the early periods of use were more often thrombophilic. Among women with thrombophilia, the risk of developing deep vein thrombosis during the first 6 months of oral contraceptive use (compared with prolonged use) was increased 19-fold (95% CI, 1.9-175.7), and in the first year of use, it was increased 11-fold (95% CI, 2.1-57.3). CONCLUSIONS: Women with inherited clotting defects who use oral contraceptives develop venous thrombosis not only more often but also sooner than do those without inherited clotting defects. Venous thrombosis in the first period of oral contraceptive use might indicate the presence of an inherited clotting defect.
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OBJECTIVE: To investigate ovulation inhibition with drospirenone, a novel progestogen that has a profile similar to natural progesterone, when given alone or in combination with ethinylestradiol. METHOD: Hormonal parameters (LH, FSH, 17beta-estradiol and progesterone) and peripheral parameters (cervical score, spinnbarkeit and crystallization), as well as follicle size assessed by ultrasonography, were measured in two groups of healthy women. Forty-eight women aged 19-35 years were randomly assigned to receive 0.5 mg, 1.0 mg, 2.0 mg or 3.0 mg of drospirenone over a single treatment cycle, and 52 women aged 20-35 years were randomized to receive either 2 mg drospirenone/30 microg ethinylestradiol or 3 mg drospirenone/30 microg ethinylestradiol over three treatment cycles. Baseline measurements were taken during a control pretreatment cycle. RESULTS: Adequate ovarian suppression with drospirenone alone was evident at dose levels of 2 and 3 mg, and at 3 mg all subjects had anovulatory cycles. Although both combined preparations (2 mg and 3 mg drospirenone/30 microg ethinylestradiol) inhibited the hypothalamic-pituitary-ovarian axis, follicular maturation leading to escape ovulation was observed in three subjects in the 2 mg drospirenone/30 microg ethinylestradiol group. Only one of these ovulations was considered to be definitely the result of treatment failure. All cycles in the 3 mg drospirenone/30 microg ethinylestradiol group were anovulatory. No statistically significant difference was found between treatment groups. CONCLUSION: The combination of 3 mg drospirenone/30 microg ethinylestradiol (Yasmin, Schering AG) reliably inhibits ovulation, with a low frequency of follicular maturation, and provides a reasonable safety margin.
In singleton pregnancies after in-vitro fertilization (IVF), increased rates of obstetric and perinatal complications have been reported. Studies that compared IVF twin pregnancies with spontaneously conceived twins have yielded conflicting results. We compared 96 IVF twin pregnancies to 96 controls after elaborate matching. The design of our study precluded matching by zygosity. The monozygosity rate was higher in the control group and this implies that beforehand the risk for a less favourable outcome in the control group was higher than in the IVF group. However, the average birthweight of the IVF children was less than that of children in the control group (P = 0.04). This was not due to more intrauterine growth retardation in the IVF group. The mean gestational age at birth was 5 days shorter in IVF than control pregnancies, and although this difference was not significant it might explain the lower birthweight in the IVF group. The discordance rate in the IVF group was significantly increased. We found no difference in perinatal mortality and morbidity. We conclude that this study provides further evidence for a different outcome of IVF twin pregnancies in comparison with spontaneously conceived twin pregnancies.
Drospirenone is a new synthetic progestogen with both progestational, antimineralocorticoid and antiandrogenic properties. In combination with ethinylestradiol, it is being developed as an oral contraceptive which will contain 30 micrograms ethinylestradiol and 3 mg drospirenone (Yasmin, Schering AG, Germany). The effects of drospirenone alone, and in combination with ethinylestradiol, upon the renin-angiotensin-aldosterone system (RAAS) have been evaluated in healthy female volunteers. RAAS activity was assessed by measurement of plasma renin substrate (PRS) concentration (otherwise known as angiotensinogen), plasma renin activity (PRA), and plasma aldosterone (P-Aldo) concentration. An antimineralocorticoid effect was observed when volunteers received drospirenone alone at doses in the range 0.5-3.0 mg/day for one cycle. The effect was dose-dependent for P-Aldo but was not dose-dependent for PRA. When ethinylestradiol (30 micrograms) was combined with either 2 mg or 3 mg drospirenone and given to volunteers for three cycles, an increase in PRS was observed with both preparations, which was indicative of estrogenic stimulation, and increases in PRA and P-Aldo were shown which were indicative of an antimineralocorticoid effect of drospirenone. Increases in PRA and P-Aldo were significantly higher with the preparation containing 3 mg drospirenone in cycle 1 but not in cycle 3. The effect of the preparation containing 30 micrograms ethinylestradiol/3 mg drospirenone upon RAS activity was also compared with that of a commercially available preparation also containing 30 micrograms ethinylestradiol but combined with 150 micrograms desogestrel (Marvelon). Over a period of 13 cycles, increases in PRS were seen with both treatments, the effect being slightly more pronounced with 30 micrograms ethinylestradiol/150 micrograms desogestrel. A markedly greater increase in PRA was seen following treatment with 30 micrograms ethinylestradiol/3 mg drospirenone, and, in cycle 3, this difference was statistically significant. In contrast, P-Aldo was increased markedly with 30 micrograms ethinylestradiol/3 mg drospirenone in all measured cycles, whereas, in the 30 micrograms ethinylestradiol/150 micrograms desogestrel group, changes were minimal. The increases in PRA and P-Aldo are interpreted as endogenous counter-regulation against the antimineralocorticoid activity of drospirenone. PRS increases under all combinations are an expression of estrogenic stimulation. Measurement of body weight and blood pressure in the studies with combined ethinylestradiol and drospirenone revealed that drospirenone was associated with either stable body weight or with a slight loss in body weight, while blood pressure remained largely unchanged. Overall, the results indicate that 30 micrograms ethinylestradiol/3 mg drospirenone has a distinct antimineralocorticoid effect.
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BACKGROUND: The magnitude of the relative risk of venous thrombosis caused by low-dose oral contraceptive use is still debated because previous studies might have been affected by diagnostic suspicion and referral bias. METHODS: We conducted a case-control study in which the effect of diagnostic suspicion and referral bias was excluded. The study was performed in 2 diagnostic centers to which patients with clinically suspected deep vein thrombosis of the leg were referred. History of oral contraceptive use was obtained before objective testing for thrombosis. Young females with an objective diagnosis of deep vein thrombosis were considered case patients, and those who were referred with the same clinical suspicion but who had no thrombosis served as control subjects. Participants were seen between September 1, 1982, and October 18, 1995: 185 consecutive patients and 591 controls aged 15 to 49 years with a first episode of venous thrombosis and without malignant neoplasms, pregnancy, or known inherited clotting defects. RESULTS: The overall odds ratio for oral contraceptive use was 3.2 (95% confidence interval [CI], 2.3-4.5); after adjustment for age, family history of venous thrombosis, calendar time, and center, the odds ratio was 3.9 (95% CI, 2.6-5.7). In the idiopathic group (120 patients and 413 controls, excluding recent surgery, trauma, or immobilization), the odds ratio for oral contraceptive use was 3.8 (95% CI, 2.5-5.9); after adjustment, the odds ratio was 5.0 (95% CI, 3.1-8.2). CONCLUSIONS: In this study, in which patients and controls were subj ect to the same referral and diagnostic procedures, we found similar relative risk estimates for oral contraceptive use as in previous studies. We conclude that diagnostic suspicion and referral bias did not play an important role in previous studies and that the risk of venous thrombosis with use of current brands of oral contraceptives still exists.
OBJECTIVE: Recently, it has been proposed that hereditary coagulation abnormalities leading to an increased venous thrombosis risk may play a role in the development of preeclampsia. We tested this hypothesis in women who have had preeclampsia compared with matched control subjects. STUDY DESIGN: We conducted a case-control study of 163 women with preeclampsia during 1991-1996. Control subjects were matched for age and delivery date. Patients and control subjects were tested for the presence of factor V Leiden, prothrombin 20210A allele, protein C, protein S, and antithrombin deficiency. Logistic regression methods were used for data analysis. RESULTS: The prevalence of these genetic risk factors was similar in the patient group (12.9%) and the control group (12.9%; odds ratio, 1.0; 95% confidence interval, 0.5-3.9). Unexpectedly, we found a high prevalence of factor V Leiden in the control group (9.2%). CONCLUSION: We found no differences in the prevalence of genetic risk factors of thrombosis in women with preeclampsia compared with control subjects.
A prospective study on intracytoplasmic sperm injection (ICSI) was performed to evaluate the effect of the position of the polar body relative to the opening of the injection needle during sperm injection, and of the person who performs the injections on fertilization, cleavage, and pregnancy rates. This study included 173 couples undergoing 313 ICSI cycles from September 1995 to December 1997. All injections were performed by two persons. For each injected oocyte the person who performed the injection was recorded as well as the position of the polar body during injection (6 o'clock: animal pole towards the opening of the needle; 12 o'clock: animal pole away from the opening of the needle). Of 2630 oocytes retrieved, 2232 were injected. Significantly more oocytes developed two pronuclei after injection with the polar body at 6 o'clock versus 12 o'clock (P = 0.01; 51 versus 45% respectively) and after injection by person 1 versus person 2 (P = 0.02; 50 and 45% respectively). Higher pregnancy rate (P = 0.046) was found after transfer of embryos from oocytes injected with the polar body at 6 o'clock (36%) versus 12 o'clock (18%). This was the result of a significant interaction (P = 0.03) between the position of the polar body and the person performing the injections. Given the higher fertilization rate in the 6 o'clock group, it is recommended that oocytes be injected with the polar body at 6 o'clock. The higher pregnancy rate as a result of polar body position and the interaction between polar body position and the operator suggest variations in injection technique.