Partial and complete expulsion of the Multiload 375 IUD and the levonorgestrel-releasing IUD after correct insertion.

OBJECTIVE: The contraceptive efficacy of intrauterine devices (IUD) is thought to relate to the position of the IUD in the uterine cavity. Several trials examined the number of copper IUD expulsions, but none evaluated the partial and complete expulsion rate of the levonorgestrel-releasing device (LNG-IUD). STUDY DESIGN: This retrospective cohort study compares the dislocation rate of the Multiload 375 IUD (ML 375) and the LNG-IUD in 214 women (107 subjects with each IUD). Transvaginal ultrasound was used to monitor the IUD position immediately after insertion, after 6 weeks, and later on at intervals of 6 months. The observation period included 3631 cycles. RESULTS: We detected a significantly lower number of dislocations in LNG-IUD users. Previous expulsion was associated with a significantly higher risk for a re-expulsion in both IUD groups. Hypermenorrhea was not associated with an increased dislocation rate in LNG-IUD users. CONCLUSION: Expulsions are less likely to occur with the LNG-IUD, which might contribute to its contraceptive efficacy.

Nonpalpable ultrasonographically not detectable Implanon rods can be localized by magnetic resonance imaging.

Recently, the contraceptive implant Implanon has been introduced in several European countries. In comparison to the six-capsule preparation Norplant, the removal of this single-rod system should be associated with less complications. However, the removal of nonpalpable Implanon rods can be difficult because the implant is not always visible with ultrasound. The aim of this study was to find a radiologic method for the localization of Implanon implants that are nonpalpable and can not be detected by ultrasound. X-ray, ultrasound, computed tomography, and magnetic resonance imaging (MRI) were investigated as methods to localize Implanon in a pig chest preparation and in a woman with a nonpalpable implant. The implant in the woman could be localized unequivocally only by MRI. We conclude that MRI is the best method for the unequivocal localization of nonpalpable, ultrasonographically not detectable Implanon rods. To avoid unnecessary scar tissue formation, it may be appropriate to defer surgery for the removal until definitive localization.

Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism.

Estradiol inhibits endothelin-1 synthesis, an effect that may contribute to the cardiovascular protective effects of estradiol. Recent findings that estradiol inhibits neointima formation in mice lacking estrogen receptors suggests that the cardiovascular protective effects of estradiol may be mediated by means of an estrogen receptor-independent mechanism. Because 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little/no affinity for estrogen receptors, are more potent than estradiol in inhibiting vascular smooth muscle cell growth, we investigated whether these metabolites also inhibit endothelin-1 synthesis by means of an receptor-independent mechanism. Treatment of porcine coronary artery endothelial cells for 4 to 24 hours with 0.001 to 1 micromol/L of estradiol, 2-hydroxyestradiol, or 2-methoxyestradiol concentration-dependently inhibited basal as well as serum-induced (2.5%), TNFalpha-induced (10 ng/mL), angiotensin II-induced (100 nmol/L), and thrombin-induced (4 U/mL) endothelin-1 synthesis. Estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol also inhibited serum-induced mitogen-activated protein kinase activity. As compared with estradiol, its metabolites were more potent in inhibiting endothelin-1 secretion and mitogen activated protein kinase activity. The inhibitory effects of 2-hydroxyestradiol and 2-methoxyestradiol on endothelin-1 release and mitogen-activated protein kinase activity were not blocked by ICI182780 (50 micromol/L), an estrogen receptor antagonist. Our findings indicate that the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol potently inhibit endothelin-1 synthesis by means of an estrogen receptor-independent mechanism. This effect of estradiol metabolites may be mediated by inhibition of mitogen activated protein kinase activity and may contribute to the cardioprotective effects of estradiol.

Increased incidence of numerical chromosome abnormalities in spermatozoa injected into human oocytes by ICSI.

The potential risk of transmitting chromosomally abnormal spermatozoa from infertile males into oocytes through intracytoplasmic sperm injection (ICSI) has prompted us to investigate the male pronuclei of tripronuclear zygotes (3PN) obtained after ICSI. To specify the type of anomalies, we used triple colour fluorescent in-situ hybridization (FISH) with three specific probes for chromosomes X, Y and 18. From a total of 163 paternal complements of ICSI-3PN zygotes, 90 (55.2%) had Y-chromosome signals. Eighty-three of these were normal, four had the disomy XY and three were diploid. In the remaining 73 ICSI-3PN zygotes without Y-chromosome signals, the origin of paternal pronuclei was extrapolated through chromosome constitution of the first polar body. Five anomalies were found in this group of zygotes, giving a total rate of numerical chromosome aberrations for fertilizing spermatozoa of 7.4%. In contrast to ICSI, only two disomies (1.5%) were found in the control group of IVF-3PN zygotes. Compared with the incidence of chromosome anomalies between paternal-derived pronuclei of ICSI- and IVF-3PN zygotes, the difference was statistically significant (P < 0.025). This study provides the first direct evidence of a higher incidence of numerical chromosome anomalies in sperm-fertilized human oocytes after ICSI.

Cellular and biochemical mechanisms by which environmental oestrogens influence reproductive function.

The biology and physiology of the male as well as female reproductive system is hormonally regulated. Abnormalities in the dynamics of hormone production, metabolism and elimination, as well as their binding to certain target tissues, has been associated with pathophysiological conditions of the reproductive system. Although oestrogens are known to be one of the major hormone groups in regulating the reproductive function and the fertilization process, the cellular and biochemical mechanism or mechanism(s) via which oestrogens induce their effects are still not fully defined. Moreover, in a modern environment we are also exposed to a wide battery of environmental agents which are structurally similar to oestrogens, and termed 'environmental oestrogens'. Because environmental oestrogens have been shown to mimic some of the effects of oestradiol, it has been postulated that these exogenous chemicals may influence or interfere with the oestrogen-dependent reproductive processes, and may be associated with beneficial as well as deleterious effects on the reproductive system. In this regard, two classes of environmental oestrogens have been widely studied, i.e. phyto-oestrogens (plant-derived dietary oestrogens) and xeno-oestrogens (industrial chemicals, including polychlorinated biphenyls, DDT, TCDD, dioxins, etc.). The main focus of this review is to provide an overview on the cellular and biochemical mechanism(s) by which xeno-oestrogens and phyto-oestrogens influence the oestrogen-dependent reproductive functions and induce their deleterious or protective effects on the reproductive system.

Vascular effects of environmental oestrogens: implications for reproductive and vascular health.

Environmental oestrogens are defined as xenobiotics structurally resembling oestrogen, and are divided into two broad categories, xeno-oestrogens and phyto-oestrogens. Environmental oestrogens may contribute importantly to the increased incidence of reproductive disorders in the modern environment. Although the mechanisms by which environmental oestrogens induce their deleterious effects on the reproductive system remain poorly defined, it is likely that the vascular effects of these compounds play a critical role. In this regard, oestradiol strongly regulates both angiogenesis and vascular remodelling by influencing the growth and function of vascular endothelial cells (EC) and smooth muscle cells (SMC). Since blood vessels, by undergoing angiogenesis, vascular regression and vascular remodelling, actively participate in the normal functioning of reproductive organs, environmental oestrogens-by mimicking or antagonizing the vascular effects of oestradiol-may induce abnormalities in vascular function and structure leading to reproductive disorders such as pre-eclampsia, endometriosis, impaired follicular development, inefficient implantation, impotence and infertility. The purpose of the present review is to summarize the evidence regarding the vascular effects of xeno-oestrogens and phyto-oestrogens and to discuss the implications for these effects on the reproductive system.

The effect of the menstrual cycle and of ethinylestradiol on nitric oxide, endothelin-1 and homocysteine plasma levels.

The use of the estrogen ethinylestradiol is associated with an increased cardiovascular risk. It is not known whether this might be caused by an influence of ethinylestradiol on endothelium-derived factors or on the cardiovascular risk factor homocysteine. Our aim was to evaluate whether a short-term treatment with ethinylestradiol results in changes of nitric oxide (NO), endothelin-1 and homocysteine. Participants were ten healthy women with regular menstrual cycles. NO, homocysteine, endothelin-1, estradiol and progesterone were measured during one cycle and before and after treatment with ethinylestradiol at 50 microg/day. Homocysteine and NO did not change significantly during the menstrual cycle or after treatment. However, endothelin-1 levels decreased during the cycle (from 3.89 ng/l to 2.93 ng/l p < 0.05) and after ethinylestradiol (from 2.94 ng/l to 2.26 ng/l p<0.03). Analysis of the pretreatment data showed a positive correlation between homocysteine and NO and between NO and endothelin-1. Treatment with ethinylestradiol caused a shift in the balance between NO and endothelin-1 in the direction of vasodilatation. This finding is one factor concerning the effects of ethinylestradiol on the vascular system but does not explain the cardiovascular risk of this substance.

The incidence of actinomyces-like organisms in Papanicolaou-stained smears of copper- and levonorgestrel-releasing intrauterine devices.

Actinomyces-like organisms (ALOs) are a common finding in Papanicolaou-stained cervico-vaginal smears (PAP smears) of women using an intrauterine device (IUD). The incidence of ALOs positive PAP smears depends on the type of IUD. Pelvic actinomycosis is a severe disease that may require hysterectomy and salpingo-oophorectomy. In a retrospective study we compared the incidence of ALOs positive PAP smears in users of the new levonorgestrel-releasing intrauterine device (LNG-IUD) (n = 52) with the incidence in Multiload Copper IUD (ML375) users (n = 104). All IUDs had been inserted from 1996-1998. Women with a follow-up period of more than 9 months were included into the final analysis (LNG-IUD: n = 34; ML375: n = 65). The incidence of ALOs in LNG-IUD users (2.9%) was significantly lower than in ML375 users (20%). Clinical consequences of ALOs positive PAP smears are discussed controversially. The low incidence in the LNG-IUD users probably leads to less IUD-removals, reinsertions and less pelvic-inflammatory-diseases.

A prospective study on the effects of depot medroxyprogesterone acetate on trabecular and cortical bone after attainment of peak bone mass.

OBJECTIVE: To study the annual change of bone mass in women aged 30-45 years being treated with depot medroxyprogesterone acetate (DMPA) in order to evaluate whether the bone mass depends on the duration of DMPA use or the oestradiol level. DESIGN: Prospective longitudinal study over an interval of 12 months. SETTING: A family planning centre of a university hospital. PATIENTS: Thirty-six current users of DMPA. INTERVENTIONS: Injection of 150 mg DMPA every 12 weeks. MEASUREMENTS: Bone mass was measured at the distal radius by peripheral quantitative computed tomography (reproducibility 0.3%). RESULTS: Mean annual changes (SD) in trabecular and cortical bone mass were 0.06 (1.6%) [P = 0.8] and -0.26% (0.6) [P < 0.04]. The decrease in cortical bone mass was not significant because the changes were within the precision error of the method used for the measurements. Duration of DMPA use and oestradiol levels were not associated to the bone parameters. CONCLUSION: We did not find a negative impact of DMPA on the bone mass of premenopausal women aged 30-45 years.

Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity.

Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors is unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estrogen receptors. We examined the effects of various clinically used estrogens in the presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured human aortic SMC DNA synthesis ([(3)H]thymidine incorporation), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis, platelet-derived growth factor-induced SMC migration, and mitogen-activated protein kinase activity were significantly inhibited by physiological (10(-9) mol/L) concentrations of 17beta-estradiol and low concentrations (10(-8) to 10(-7) mol/L) of 17beta-estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17alpha-estradiol, or estrone sulfate. The inhibitory effects of 17beta-estradiol and other inhibitory estrogens were completely reversed by 100 micromol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC biology are in part receptor-mediated. Because the cardioprotective effects of hormone replacement therapy are most likely mediated by modification of SMC biology, whether hormone replacement therapy protects a given postmenopausal woman against cardiovascular disease will depend partially on the affinity of the estrogen for estrogen receptors in vascular SMCs.