Showing papers in "Human Reproduction Update in 1998"
TL;DR: An overview of the role of NO in various reproductive organs under physiological and pathological conditions is provided.
Abstract: Following its benchmark discovery, nitric oxide (NO) is now known to play important functional roles in a variety of physiological systems. Within the vasculature, NO induces vasodilation, inhibits platelet aggregation, prevents neutrophil/platelet adhesion to endothelial cells, inhibits smooth muscle cell proliferation and migration, regulates programmed cell death (apoptosis) and maintains endothelial cell barrier function. NO generated by neurons acts as a neurotransmitter, whereas NO generated by macrophages in response to invading microbes acts as an antimicrobial agent. Because neurons, blood vessels and cells of the immune system are integral parts of the reproductive organs, and in view of the important functional role that NO plays in those systems, it is likely that NO is an important regulator of the biology and physiology of the reproductive system. Indeed, in the past 10 years, NO has established itself as a polyvalent molecule which plays a decisive role in regulating multiple functions within the female as well as the male reproductive system. This review provides an overview of the role of NO in various reproductive organs under physiological and pathological conditions.
574 citations
TL;DR: The prerequisite for adenomyosis may be triggered or facilitated by either a 'weakness' of the smooth muscle tissue or an increased intrauterine pressure or both, and relatively high oestrogen concentrations and impaired immune-related growth control in ectopic endometrium may be necessary for the maintenance of adenomeosis.
Abstract: Adenomyosis refers to endometrial glands and stroma located haphazardly deep within the myometrium. Similar histological alterations may be found in extrauterine locations such as the rectovaginal septum. The aetiology and pathogenic mechanism(s) responsible for adenomyosis are poorly understood. Both human and experimental studies favour the theory of endomyometrial invagination of the endometrium, although the de-novo development of adenomyosis from Mullerian rests in an extrauterine location is a possibility. The prerequisite for adenomyosis may be triggered or facilitated by either a 'weakness' of the smooth muscle tissue or an increased intrauterine pressure or both. Relatively high oestrogen concentrations and impaired immune-related growth control in ectopic endometrium may be necessary for the maintenance of adenomyosis. Smooth muscle cell hyperplasia and hypertrophy are a reflection of reactive change secondary to ectopic endometrial proliferation. Further studies are needed for insight into the precise aetiology and pathogenesis of adenomyosis. Adenomyosis is a relatively frequent endomyometrial pathology discovered in multiparous women between 40 and 50 years of age. About 2/3 of women are symptomatic with menorrhagia and dysmenorrhoea; 80% of adenomyotic cases are associated with leiomyomata uteri; and in women with endometrial adenocarcinoma, adenomyosis is relatively often seen. Definite diagnosis is made on hysterectomy specimens, although attempts are made at securing preoperative diagnosis by magnetic resonance imaging and myometrial biopsies. Definite treatment of symptomatic women is hysterectomy.
413 citations
TL;DR: Human oocyte maturation is considered as the reinitiation and completion of the first meiotic division from the germinal vesicle stage (prophase I) to metaphase II, and the accompanying cytoplasmic maturation for fertilization and early embryonic development.
Abstract: Human oocyte maturation is considered as the reinitiation and completion of the first meiotic division from the germinal vesicle stage (prophase I) to metaphase II, and the accompanying cytoplasmic maturation for fertilization and early embryonic development. Immature human oocytes obtained from patients undergoing gynaecological surgery, or ovulation induction or having polycystic ovary syndrome (PCOS) can be matured and fertilized in vitro. To date, 80% of immature oocytes matured to metaphase II when cultured in maturation medium supplemented with gonadotrophins and 85% of matured oocytes fertilized and cleaved in vitro. Following transfer of these embryos, pregnancies and live births have been achieved. However, the capacity for oocyte maturation was different when the immature oocytes were retrieved from PCOS patients and when the oocytes were cryopreserved at germinal vesicle stage.
344 citations
TL;DR: Only recently have amplification methods been established to detect viruses in semen with high sensitivity and specificity, and it is unclear if these infections significantly contribute to male infertility.
Abstract: Bacterial and viral infections of the genital tract may be important aetiological factors for male infertility. Infectious processes may lead to deterioration of spermatogenesis, impairment of sperm function and/or obstruction of the seminal tract. Detection of bacteria in semen does not necessarily signify infection since bacteriospermia may represent contamination, colonization or infection. Reported prevalence of Ureaplasma urealyticum in human semen varies from 10 to 40%. Enterobacteria can even be found in up to 90% of semen samples depending on the sensitivity of detection methods used. Chlamydia trachomatis is the most frequent sexually transmitted bacterial organism in industrialized countries. It is suggested that its main influence is due to sexual transmission resulting in tubal disease and subsequent infertility in the female partner rather than a direct influence on male reproductive functions. The effect of leukocytospermia on male fertility is controversial. This is probably due to different detection methods, different populations studied and to the fact that leukocyte subtypes in semen may have different functions. In addition to potentially negative effects, leukocytes may even have protective effects on spermatozoa. Only recently have amplification methods been established to detect viruses in semen with high sensitivity and specificity. It is unclear if these infections significantly contribute to male infertility.
298 citations
TL;DR: The more impaired the development of an embryo, the more chromosome abnormalities were detected in those embryos, and a strong correlation between some types of dysmorphism with chromosomal abnormalities was found.
Abstract: The presence of numerical chromosome abnormalities in human embryos was studied using fluorescence in-situ hybridization with four or more chromosome-specific probes. When most cells of an embryo are analysed, this technique allows differentiation to be made between aneuploidy, mosaicism, haploidy and polyploidy. Abnormal types of fertilization, such as unipronucleated, tripronucleated zygotes and zygotes with uneven pronuclei, were studied using this technique. We have found a strong correlation between some types of dysmorphism with chromosomal abnormalities. In addition, the more impaired the development of an embryo, the more chromosomal abnormalities were detected in those embryos. Maternal age and other factors were linked to an increase in chromosome abnormalities (hormonal regimes, temperature changes), but not to intracytoplasmic sperm injection.
290 citations
TL;DR: The inclusion of an accurately evaluated normal sperm morphology count as an integral part of the standard semen analysis makes this analysis still the most cost-effective means of evaluating the male factor.
Abstract: The aim of the study was to conduct a structured review of the literature published on the use of normal sperm morphology, as an indicator of male fertility potential in the in-vitro fertilization (IVF) situation, and to establish the universal predictive value of this semen parameter. Published literature in which normal sperm morphology was used to predict fertilization and pregnancy, during the period 1978-1996, was reviewed. A total of 216 articles were identified by the sourcing methodology, but only 49 provided data that could be tabulated and analysed. Of these, only 18 provided sufficient data for statistical analysis. Fifteen studies used the strict criteria to evaluate sperm morphology, two used World Health Organization (WHO) guidelines and one used both the strict criteria and the WHO guidelines. All the studies (n = 10) using the 5 and 14% normal sperm morphology thresholds (strict criteria) produced positive predictive values for IVF success. In the prediction of pregnancy, 82% (9/11) and 75% (6/8) of the studies produced positive predictive values when using the 5% and 14% thresholds respectively. Aggregating the data produced around the 5% normal sperm morphology threshold (strict criteria), the overall fertilization rates were 59.3% (1979/3337; per oocyte) for the 4% group, and the overall pregnancy rates were 15.2% (60/395; per cycle) and 26.0% (355/1368; per cycle) respectively. The no-transfer rates across the 5% threshold were 24.0% (86/359; per cycle) in the 4% group. The inclusion of an accurately evaluated normal sperm morphology count as an integral part of the standard semen analysis makes this analysis still the most cost-effective means of evaluating the male factor.
247 citations
TL;DR: The vanishing twin phenomenon is reviewed to provide information pertaining to frequency, aetiology, and potential complications, as well as the impact of sonographic technology on the growing understanding of the events in early multiple pregnancy.
Abstract: This article reviews the scientific literature discussing the vanishing twin phenomenon. Information pertaining to frequency, aetiology, and potential complications, as well as the impact of sonographic technology on our growing understanding of the events in early multiple pregnancy is provided.
235 citations
TL;DR: The endometriotic disease theory considers superficial endometRIotic implants and their remodelling as a physiological process in most women, and concentrates on the causes of severe endometricriosis such as differences in the eutopic endometrium.
Abstract: Peritoneal fluid and the intraovarian milieu are a specific microenvironment. Peritoneal fluid originates mainly as an ovarian exudation product caused by increased vascular permeability, with cyclic variation in volume and steroid hormones which are always higher than in plasma. It contains large amounts of macrophages and their secretion products, and has a large exchange area with plasma through the peritoneum, which is highly permeable for small molecules. Diffusion becomes virtually zero for molecules with a molecular weight of >100000 Da. In women with the luteinized unruptured follicle (LUF) syndrome, concentrations of oestrogens and progesterone are much lower in the luteal phase. Endometriosis is associated with sterile low-grade inflammation, increased concentrations of activated macrophages and many of their secretions, such as cytokines, growth factors and angiogenic factors. Concentrations of CA-125 and of glycodelins are also increased, secreted locally by the endometrial cells. Natural killer (NK) cell function declines, possibly mediated by glycodelins or local intercellular adhesion molecule (ICAM) -1 shedding. The ovary is also a specific microenvironment, with steroid hormone concentrations 1000-fold higher in follicles than in plasma. Endometrial and superficially implanted cells are influenced by peritoneal fluid concentrations so that local environment, rather than inherent cellular differences could explain differences between superficial endometriosis and eutopic endometrium. Differences between superficial implants and endometriotic disease, deep infiltrating or cystic ovarian endometriosis, may thus arise via different endocrine environments. Superficial endometrial implants are regulated by peritoneal fluid factors, whereas deep endometriosis and cystic ovarian endometriosis are influenced by blood or ovarian factors. The endometriotic disease theory considers superficial endometriotic implants and their remodelling as a physiological process in most women, and concentrates on the causes of severe endometriosis such as differences in the eutopic endometrium from women with and without endometriosis (which may indicate hereditary differences), the invasiveness of some endometriotic cells in vitro, focal 'shielding' of endometriotic foci by adhesions, and inhibition of NK activity by ICAM-1 and glycodelins. Endometriotic disease is thus seen as a benign tumour. The type of cellular lesion, hereditary and immunological environments and local hormone concentrations in the ovary and in peritoneal fluid, will decide expression as cystic ovarian endometriosis, deep endometriosis or adenomyosis externa, and whether the latter is associated with adhesions.
231 citations
TL;DR: The data suggests that the key to maturation and embryo viability in vitro resides in the follicle cell compartment rather than the oocyte, and major improvements in the yield of viable embryos from in-vitro matured oocytes can be anticipated from a systematic analysis of somatic signals from the pre-ovulatory follicle.
Abstract: Embryonic development is readily compromised by imperfections introduced during the process of oocyte maturation. We discuss the nature and causes of these imperfections, particularly in oocytes exposed to inappropriate hormonal regimes in vivo or to culture systems designed to induce the maturation of oocytes in vitro. The acquisition of developmental competence involves the synthesis and storage of a wide range of molecules during oocyte growth followed by the reprogramming and ordered utilization of these stored products during maturation, fertilization and early embryogenesis. The regulatory signals for these molecular changes are produced by the follicle cells in response to circulating levels of gonadotrophins; we report that some ovarian stimulation protocols distort these signals thereby disrupting molecular reprogramming of the oocyte and reducing subsequent developmental competence. The aspiration of immature oocytes from antral follicles followed by their maturation in vitro is a potential alternative to hormonal stimulation of patients in IVF treatment. Although relatively successful in a variety of animals, the production of fully viable human embryos by in-vitro maturation is still unsatisfactory despite the use of a wide variety of culture protocols. Our data suggests that the key to maturation and embryo viability in vitro resides in the follicle cell compartment rather than the oocyte. Because of rapid luteinization changes, follicle cells in culture probably fail to provide the maturing oocyte with the necessary ordered set of instructive signals and nutrients needed for the acquisition of developmental competence. Although much remains to be discovered about the nature, concentration and transmission of signals, nevertheless it is already clear that different steroids, matrix metalloproteinases and growth factors are involved in conferring viability on the maturing oocyte. Major improvements in the yield of viable embryos from in-vitro matured oocytes can be anticipated from a systematic analysis of somatic signals from the pre-ovulatory follicle.
224 citations
TL;DR: This review outlines studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labour, and indicates that cervical softening occurs progressively in the last one-third of pregnancy.
Abstract: Preterm labour and resultant preterm birth are the most important problems in perinatology. Countless efforts have failed to establish a single effective treatment of preterm labour, partly because the mechanisms regulating the uterus and cervix during pregnancy are not well understood. New knowledge is needed to inhibit early progression of labour (uterine contractility and cervical ripening), and adequate quantitative tools to evaluate the uterus and cervix during pregnancy are lacking. In this review, we outline studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labour. This step is not easily identifiable with present methods to assess the uterus or cervix. In the uterus, this seemingly irreversible step consists of changes in the electrical properties to make muscle more excitable and responsive to produce forceful contractions. In the cervix, the step consists of softening of the connective tissue components. Progesterone appears to have a dominant role in controlling both the uterus and cervix, as antiprogestins induce early, preterm conditioning leading to preterm labour. Apparently, nitric oxide (NO) also controls conditioning of the uterus and cervix. In the uterus, NO, in concert with progesterone, inhibits uterine contractility. At term, NO production by the uterus and placenta are decreased and allow labour to progress. In contrast, NO in the cervix increases at the end of pregnancy and it may be the final pathway for stimulating cervical ripening by activation of metalloenzymes. The progress of labour can be assessed non-invasively using electromyographic (EMG) signals from the uterus (the driving force for contractility) recorded from the abdominal surface. Uterine EMG bursts detected in this manner characterize uterine contractile events during human and animal pregnancy. A low uterine EMG activity, measured transabdominally throughout most of pregnancy, rises dramatically during labour. EMG activity also increases substantially during preterm labour in humans and rats. This method may be used one day to predict impending preterm labour and identify control steps and treatments. A quantitative method also assesses the cervix, using an optical device which measures collagen fluorescence in the cervix. The collascope estimates cervical collagen content from a fluorescent signal generated when collagen cross-links are illuminated with excitation light of about 340 nm. The system has proved useful in rats and humans at various stages of pregnancy, and indicates that cervical softening occurs progressively in the last one-third of pregnancy. In rats, collascope readings correlate with resistance measurements made in the isolated cervix, which may help to assess cervical function during pregnancy, and indicate control and treatments.
219 citations
TL;DR: The actions of the products of the VEGF gene are outlined, and the hormonal and non-hormonal control of their localization in the human endometrium and biological actions on vasculature and coagulation are described.
Abstract: Angiogenesis is an essential component of endometrial renewal. The formation of new vessels depends on interactions between various hormones and growth factors, and this review focuses on the expression of angiogenic growth factors in the human endometrium. Peptide and non-peptide angiogenic factors interact during endometrial renewal, including epidermal growth factor (EGF), transforming growth factors (e.g. TGF-beta), platelet-derived endothelial growth factor/thymidine phosphorylase (PD-ECGF/TP), tumour necrosis growth factors and vascular endothelial growth factor (VEGF). Their role in the proliferation and migration of endothelial cells from pre-existing vessels is described, concentrating on VGEF and its receptors (VEG-R1 and -R2), and the fibroblast growth factor (FGF) family. The actions of the products of the VEGF gene are outlined, and the hormonal and non-hormonal control of their localization in the human endometrium and biological actions on vasculature and coagulation are described. Finally, the role of VEGF in menorrhagia is assessed.
TL;DR: Evidence is found that similar receptors are present on decidual NK cells belonging to both the Killer Inhibitory Receptor (KIR) and CD94 families that indicate that decidUAL NK cells do have receptors for trophoblast HLA class I molecules.
Abstract: During the luteal phase and the early months of pregnancy, there is a dense mucosal infiltration of CD56+ natural killer (NK) cells. These uterine NK cells have a phenotype (CD56bright, CD16-, mCD3-) which distinguishes them from peripheral blood NK cells (CD56dim, CD16bright, mCD3-). The uterine NK cells are in close association with extravillous trophoblast (EVT) cells which infiltrate into the decidua and maternal spiral arteries. This subpopulation of trophoblast expresses two human leukocyte antigen (HLA) class I molecules, HLA-G and HLA-C. Circulating NK cells express receptors for HLA class I molecules. We have recently found evidence that similar receptors are present on decidual NK cells belonging to both the Killer Inhibitory Receptor (KIR) and CD94 families. The repertoire of NK receptors expressed varies between different women. The findings indicate that decidual NK cells do have receptors for trophoblast HLA class I molecules. Experiments are underway to determine the effects of this interaction on NK cell function.
TL;DR: Evidence is reviewed for increased endometrial angiogenesis in women with endometriosis when compared with normal subjects, indicating that the endometrium of patients with endometricriosis shows enhanced endothelial cell proliferation.
Abstract: Excessive endometrial angiogenesis is proposed as an important mechanism in the pathogenesis of endometriosis. Evidence is reviewed for the hypothesis that the endometrium of women with endometriosis has an increased capacity to proliferate, implant and grow in the peritoneal cavity. Data is summarized indicating that the endometrium of patients with endometriosis shows enhanced endothelial cell proliferation. Results are also reviewed indicating that the cell adhesion molecule integrin alphavbeta3 is expressed in more blood vessels in the endometrium of women with endometriosis when compared with normal women. Taken together, these results provide evidence for increased endometrial angiogenesis in women with endometriosis when compared with normal subjects. Endometriosis is one of the family of angiogenic diseases. Other angiogenic diseases include solid tumours, rheumatoid arthritis, psoriasis and diabetic retanopathy. Excessive endometrial angiogenesis suggests novel new medical treatments for endometriosis aimed at the inhibition of angiogenesis.
TL;DR: The clinical picture of endometriosis characterises this disease as a hyperactivation of genuine archimetrial functions such as proliferation, inflammatory defence and peristalsis, and a key event appears to consist in the local production of extraovarian oestrogen by a pathological expression of the P450 aromatase
Abstract: Endometriosis is considered primarily a disease of the endometrial-subendometrial unit or archimetra. The clinical picture of endometriosis characterises this disease as a hyperactivation of genuine archimetrial functions such as proliferation, inflammatory defence and peristalsis. While the aetiology of the disease remains to be elucidated, a key event appears to consist in the local production of extraovarian oestrogen by a pathological expression of the P450 aromatase. The starting event may consist in a hyperactivity of the endometrial inflammatory defence, a hyperactivity of the endometrial oxytocin/oxytocin receptor system or in the pathological expression of the P450 aromatase system itself. Regardless of which of these levels the starting event is localized in, they influence each other on both the level of the archimetra and the endometriotic lesions. Locally elevated oestrogen levels inevitably up-regulate the endometrial oxytocin mRNA and increased levels of oxytocin result in uterine hyperperistalsis, increased transtubal seeding of endometrial tissue fragments and finally subfertility and infertility by impairment of the uterine mechanism of rapid and sustained sperm transport. Locally increased levels of oestrogen lead, on both the level of the endometrial-subendometrial unit and the endometriotic lesion, to processes of hyperproliferation. These processes result, on the level of the uterus, in an infiltrative growth of elements of the archimetra into the neometra and, on the level of the endometriotic lesion, in infiltrative endometriosis. There is circumstantial evidence that trauma might be an important initial event that induces the specific biochemical and cellular responses of the archimetra. This model is able to explain both the pleiomorphic appearance of endometriosis and the, up until now, enigmatic infertility associated with mild and moderate endometriosis.
TL;DR: Magnetic resonance imaging, high resolution vaginal ultrasound and uterine biopsy have improved early detection of adenomyosis, and investigations are indicated in women with menstrual pain or menorrhagia not responding to drug therapy.
Abstract: The treatment of adenomyosis has been limited by the difficulty and delay associated with the diagnosis, often not until after hysterectomy. Magnetic resonance imaging, high resolution vaginal ultrasound and uterine biopsy have improved early detection of adenomyosis. Drug therapy may be effective in controlling symptoms but the frequent coexistence of endometriosis and the lack of controlled studies make their efficacy difficult to quantify. Conservative surgery involving endomyometrial ablation, laparoscopic myometrial electrocoagulation or excision has proven to be effective in >50% of patients, although follow-up has been restricted to 3 years. Hysterectomy will still be necessary in severe cases of adenomyosis. Early diagnosis may improve treatment. Investigations are indicated in women with menstrual pain or menorrhagia not responding to drug therapy.
TL;DR: It is demonstrated that decidual PRL gene transcription is driven by an alternative upstream promoter (dPRL), approximately 6 kb upstream of the pituitary transcription start site, and this action was probably indirect as its kinetics differed from classic CRE-mediated responses.
Abstract: Decidualization of human endometrial stromal (ES) cells in vitro is induced by cAMP analogues and ligands that elevate cellular cAMP levels in a manner resembling the gonadotrophins, prostaglandin E2 and relaxin (RLX). This differentiation process is marked by the onset of decidual prolactin (PRL) production in the late luteal phase of the cycle. Using transfection assays and a primary ES cell culture system, we have demonstrated that decidual PRL gene transcription is driven by an alternative upstream promoter (dPRL), approximately 6 kb upstream of the pituitary transcription start site. In primary cell cultures, RLX not only acutely but also permanently elevated cellular cAMP levels and induced PRL secretion after 6 days. Northern and Western blot analyses revealed all regulatory subunit isoforms (RIalpha, RIbeta, RIIalpha, RIIbeta) and catalytic subunits Calpha and Cbeta of protein kinase A (PKA) in ES cells. Transcript levels of PKA subunit isoforms are not altered during decidualization, but in decidualized ES cells exposed to elevated cellular cAMP levels by stimulation with RLX for >6 days, RIalpha protein levels were significantly reduced, whereas levels of all other forms remained unchanged. Reducing the availability of R subunits changed the R:C subunit ratio in favour of C and increased kinase activity. In transient transfections of undifferentiated ES cells, the dPRL promoter was activated by 8-Br-cAMP and by C subunit (Cbeta) of PKA. This induction, and the differentiation-dependent activity of the dPRL promoter in transfected decidualized cells, was effectively abolished by the co-expression of protein kinase inhibitor (PKI). A fragment of 332 bp of 5'-flanking region of the dPRL transcription start site was sufficient to mediate full inducibility by cAMP. cAMP activation of the dPRL promoter in ES cells was biphasic as an initial weak induction within 12 hours was followed by a subsequent, much more intense induction after 12 hours. The secondary induction was not seen with a control construct driven by a consensus cAMP response element (CRE) linked to a minimal promoter. The early response of the dPRL promoter depended upon a non-palindromic CRE at position -12 and mutation of this sequence led to omission of the early, but not of the delayed, induction. The major activation of the dPRL promoter depended upon a different region between position -332 and -270 since its deletion significantly reduced inducibility by cAMP. Its action was probably indirect as its kinetics differed from classic CRE-mediated responses, and it was specific to ES cells.
TL;DR: Data support the view that uterus and Fallopian tubes represent a functional unit that is acting as a peristaltic pump and that the increasing activity of this pump during the follicular phase of the menstrual cycle is reflected by an increased transport into the oviduct ipsilateral to the ovary bearing the dominant follicle.
Abstract: The transport function of the uterus and oviducts and its modulation by oxytocin has been examined using hysterosalpingoscintigraphy, recording of intrauterine pressure, electrohysterography and Doppler sonography of the Fallopian tubes After application to the posterior vaginal fornix, a rapid (within minutes) uptake of the labelled particles into the uterus was observed during the follicular and during the luteal phase of the cycle in all patients Transport into the oviducts, however, could only be demonstrated during the follicular phase Transport was directed predominantly into the tube ipsilateral to the ovary bearing the dominant follicle; the contralateral oviduct appeared to be functionally closed The proportion of patients exhibiting ipsilateral transport did increase concomitant with the increase of the diameter of the dominant follicle That ipsilateral transport has biological significance is suggested by the observation that the pregnancy rate following spontaneous intercourse or insemination was significantly higher in those women in whom ipsilateral transport could be demonstrated than in those who failed to exhibit lateralization Oxytocin administration was followed by a dramatic increase in the amount of material transported to the ipsilateral tube, as demonstrated by radionuclide imaging and by Doppler sonography following instillation of ultrasound contrast medium Continuous recording of intrauterine pressure before and after oxytocin administration did show an increase in basal tonus and amplitude of contractions and a reversal of the pressure gradient from a fundo-cervical to a cervico-fundal direction These actions of oxytocin were accompanied by an increase in amplitude of potentials recorded by electrohysterography These data support the view that uterus and Fallopian tubes represent a functional unit that is acting as a peristaltic pump and that the increasing activity of this pump during the follicular phase of the menstrual cycle is reflected by an increased transport into the oviduct ipsilateral to the ovary bearing the dominant follicle In addition, they strongly suggest a critical role of oxytocin in this process Failure of this mechanism appears to be a cause of subfertility or infertility, as indicated by the low pregnancy rate following intrauterine insemination or normal intercourse in the presence of patent Fallopian tubes It may be regarded as a new nosological entity for which we propose the term tubal transport disorder (TTD) Since pregnancy rate of such patients is normal when treated with in-vitro fertilization (IVF), hysterosalpingoscintigraphy seems to be useful for the choice of treatment modalities in patients with patent Fallopian tubes suffering from infertility
TL;DR: Non-invasive imaging techniques that have proven useful in diagnosing adenomyosis are focused on, including hysterosalpingography, transabdominal and endovaginal ultrasound, as well as magnetic resonance imaging.
Abstract: This review focuses on non-invasive imaging techniques that have proven useful in diagnosing adenomyosis, including hysterosalpingography, transabdominal and endovaginal ultrasound, as well as magnetic resonance imaging. An understanding of the histopathological features of this disease is crucial when attempting to interpret the associated imaging findings. The muscular hyperplasia accompanying the heterotopic endometrial tissue actually produces the typical gross appearance of adenomyosis and corresponds to areas of decreased echogenicity or signal intensity on ultrasound and magnetic resonance imaging respectively. The heterotopic endometrial tissue also contributes to the imaging appearance of adenomyosis, and with the advent of high resolution imaging techniques, these changes are being detected with increasing frequency, including the presence of myometrial nodules, linear striation, poor definition and nodularity of the endo-myometrial junction, pseudowidening of the endometrium, and myometrial cysts or haemorrhagic foci. The purpose of this review is to (i) present the spectrum of imaging findings of adenomyosis, (ii) illustrate potential pitfalls in diagnosis and (iii) review the accuracy and role of currently available noninvasive imaging techniques.
TL;DR: This review covers the biochemistry of nitric oxide (NO) and possible interactions with other free radicals and suggests that NO may be one of several systems that act in concert to maintain a symbiotic relationship between mother and fetus.
Abstract: Pre-eclampsia, one of the most significant health problems in human pregnancy, complicates approximately 6-8% of all gestations and is the leading cause of fetal growth retardation, infant morbidity and mortality, premature birth and maternal death. Recent research implicates free radicals in the pathophysiology of pre-eclampsia. This review covers the biochemistry of nitric oxide (NO) and possible interactions with other free radicals. Studies in the rat show that pregnancy is associated with enhanced production and responsiveness to NO in both reproductive tissues and blood vessels. Rats infused with NG-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) have been used as an animal model of pre-eclampsia, and the effects of steroid hormones on blood pressure in this model have been tested. Results suggest that pre-eclampsia may be a state of NO deficiency. However, in humans there seem to be contradictions regarding the involvement of NO in maternal adaptation to pregnancy. It is suggested that NO may be one of several systems that act in concert to maintain a symbiotic relationship between mother and fetus. However, the input of each system may be genetically determined.
TL;DR: In-vivo visualization of the myometrial zonal anatomy by T2-weighted magnetic resonance (MR) imaging suggests that junctional zone hyperplasia is further characterized by loss of normal innerMyometrial function.
Abstract: Human non-gravid myometrium differentiates in response to ovarian sex steroids into a subendometrial layer or junctional zone and an outer myometrial layer. Compared to the outer myometrial layer, the junctional zone myocytes are characterized by higher cellular density and lower cytoplasmic-nuclear ratio. These structural differences allow in-vivo visualization of the myometrial zonal anatomy by T2-weighted magnetic resonance (MR) imaging. The human myometrium is also functionally polarized. Video-vaginosonography studies have shown that propagated myometrial contractions in the non-pregnant uterus originate only from the junctional zone and that the frequency and orientation of these contraction waves are dependent on the phase of the menstrual cycle. The mechanisms underlying zonal myometrial differentiation are not known, but growing evidence suggests that ovarian hormone action may be mediated through cytokines and uterotonins locally released by the basal endometrial layer and endometrio-myometrial T-lymphocytes. Irregular thickening of the junctional zone due to inordinate proliferation of the inner myometrium, junctional zone hyperplasia, is a common MR finding in women suffering from menstrual dysfunction. Preliminary data suggest that junctional zone hyperplasia is further characterized by loss of normal inner myometrial function. Although irregular thickening of the junctional zone has been associated with diffuse uterine adenomyosis, the precise relationship between subendometrial smooth muscle proliferation and myometrial invasion by endometrial glands and stroma remains to be established.
TL;DR: Until proven otherwise, postmenopausal women should be considered particularly at increased risk for vascular complications during pregnancy, which is likely to increase progressively with the number of years elapsed since the onset of postmenopause.
Abstract: The objective of this report is to provide an update of our current knowledge about the impact of maternal age on pregnancy outcome. Pregnancy in women > or =35 years old is associated with a higher maternal and perinatal mortality. The older gravida also has a higher chance of being delivered by Caesarean section. Most of the complications associated with older age are caused by age-related confounders such as leiomyomas, type II diabetes, hypertension and multiparity. Diabetes and hypertension increase almost linearly with age. Pregnant women with diabetes or hypertension are at increased risk of adverse pregnancy outcome irrespective of age. The currently available literature indicates that premenopausal pregnant women of advanced age who are in good health do not need special care besides the normal obstetric practice. At present, establishing pregnancy in postmenopausal women is more an ethical than a medical issue, partly because the information reported on pregnancy in postmenopausal women is insufficient to determine a reliable risk profile. In these women cardiovascular ageing accelerates. Therefore, until proven otherwise, postmenopausal women should be considered particularly at increased risk for vascular complications during pregnancy. This risk is likely to increase progressively with the number of years elapsed since the onset of postmenopause.
TL;DR: Treatment with a GnRHa may reduce paracrine activity in the peritoneal cavity via hypo-oestrogenism and provide proof of successful therapy, indicating an important role for paracine activity inThe establishment and maintenance of endometriosis.
Abstract: During the past decade, macrophage-derived substances such as prostanoids, cytokines, growth factors and angiogenic factors have been detected in the peritoneal fluid of women with endometriosis. In particular, growth-promoting and angiogenic factors are considered to be substantially involved in the pathogenesis of endometriosis. In this study, vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta) and intercellular adhesion molecule 1 (ICAM-1), substances recently detected in the peritoneal fluid of women with endometriosis, were assessed with regard to their concentrations in different stages of endometriosis and changes of the peritoneal paracrine activity after medical treatment with a gonadotrophin releasing hormone agonist (GnRHa). Peritoneal fluid was obtained from patients with endometriosis during laparoscopy before and after a 4-month treatment with a GnRHa. VEGF, TGF-beta and ICAM-1 could be detected in all women presenting with various stages of active endometriosis. After GnRHa therapy, all patients showed significant decreases in mean concentrations of VEGF (194+/-77 pg/ml), TGF-beta (902+/-273 pg/ml) and ICAM-1 (157+/-52 ng/ml). Patients with stage III and IV endometriosis (according to the rAFS score) had much higher concentrations of VEGF and TGF-beta before treatment compared with those patients with mild endometriosis (rAFS stages I and II). The most striking decrease in concentration was for TGF-beta, from 902 pg/ml before to 273 pg/ml after therapy. These results indicate an important role for paracrine activity in the establishment and maintenance of endometriosis. Indeed, treatment with a GnRHa may reduce paracrine activity in the peritoneal cavity via hypo-oestrogenism and provide proof of successful therapy.
TL;DR: Four case reports of ovarian tissue cryobanking are presented and the consequences of chemotherapy and radiotherapy on gonadal function, as well as the indications for freezing ovarian tissue are reviewed.
Abstract: For patients who are planning to have chemotherapy, radiotherapy or to undergo bilateral oophorectomy, loss of ovarian function will result in premature ovarian menopause and loss of fertility. For these women, although there is no successful method for the cryopreservation of human oocytes, ovarian tissue cryobanking is proposed with a view to its autotransplantation at a later date or the isolation and in-vitro maturation of oocytes. Embryo preservation is indeed not an option for single women and even for married women because delaying treatment for at least 2 months of in-vitro fertilization cycles is inappropriate and life-threatening. Following the success of animal experiments, there have been reports of ovarian cryopreservation for women having to receive chemotherapy and/or radiotherapy. We present four case reports of ovarian tissue cryobanking and review the consequences of chemotherapy and radiotherapy on gonadal function, as well as the indications for freezing ovarian tissue.
TL;DR: It is concluded that the endometrial environment in adenomyosis differs widely from that in normal fertile women, and abnormal immune responses might be involved in poor reproductive performance in adanomyosis.
Abstract: Adenomyosis is characterized as ectopic endometrial tissues within the myometrium in the uterus. The only difference between adenomyosis and endometriosis is the site of endometriotic tissues: inside or outside of the uterus. It is well known that endometriosis is frequently associated with various autoimmune phenomena. This short review covers various aspects of the immune cascade found in adenomyosis. In adenomyosis, a series of immune responses is activated, including changes in both cellular and humoral immunity, i.e. a strong expression of cell surface antigens or adhesion molecules, an increased number of macrophages or immune cells, and deposition of immunoglobulins and complement components. Furthermore, the disease exhibited high frequency of autoantibodies in peripheral blood. Thus, an immunological 'vicious circle' is formed in the endometrium in adenomyosis. Endometrial cells seem to be under immunological stress, protecting themselves by exposing heat shock proteins. It is concluded that the endometrial environment in adenomyosis differs widely from that in normal fertile women. These abnormal immune responses might be involved in poor reproductive performance in adenomyosis.
TL;DR: The results and the review of literature indicate that uterine peristalsis during the follicular phase of the menstrual cycle is controlled by oestradiol released from the dominant follicle with the probable involvement of oxytocin, which is presumably stimulated together with its receptor within the endometrial-subendometrial unit and therefore acting in an autocrine/paracrine fashion.
Abstract: Uterine peristalsis, directing sustained and rapid sperm transport from the external cervical os or the cervical crypts to the isthmic part of the tube ipsilateral to the dominant follicle, changes in direction and frequency during the menstrual cycle, with lowest activity during menstruation and highest activity at mid cycle. It was therefore suggested that uterine peristalsis is under the control of the dominant follicle with the additional involvement of oxytocin. To test this hypothesis, vaginal sonography of uterine peristalsis was performed in the early, mid and late proliferative phases, respectively, of cycles of women treated with oestradiol valerate and with human menopausal gonadotrophin following pituitary downregulation, with clomiphene citrate and with intravenous oxytocin, respectively. Administration of oestradiol valerate resulted in oestradiol serum concentrations comparable with the normal cycle with a simulation of the normal frequency of peristaltic contractions. Elevated oestradiol concentrations and bolus injections of oxytocin resulted in a significant increase in the frequency of peristaltic contractions in the early and mid follicular phases, respectively. Chlomiphene tended, though insignificantly so, to suppress the frequency of peristaltic waves in the presence of elevated oestradiol concentrations. In the late follicular phase of the cycle extremely elevated oestradiol concentrations as well as the injection of oxytocin resulted only in an insignificant further increase of peristaltic frequency. In the normal cycles, as well as during extremely elevated oestradiol concentrations and following oxytocin administration, the peristaltic contractions were always confined to the subendometrial layer of the muscular wall. The results and the review of literature indicate that uterine peristalsis during the follicular phase of the menstrual cycle is controlled by oestradiol released from the dominant follicle with the probable involvement of oxytocin, which is presumably stimulated together with its receptor within the endometrial-subendometrial unit and therefore acting in an autocrine/paracrine fashion. Since unphysiological stimulation with oestradiol and oxytocin did not significantly increase the frequency of uterine peristalsis in the late follicular phase of the cycle it is assumed that normal preovulatory frequency of uterine peristalsis is at a level which cannot be significantly surpassed due to phenomena of refractoriness of the system.
TL;DR: The expression of a second set of genes including tumour necrosis factor alpha (TNF-alpha) and ebaf, may be the appropriate signal for the closure of the 'implantation window', for making the endometrium refractory to implantation and for preparing it for the menstrual shedding.
Abstract: Human endometrium is the end organ of the hypothalamic-pituitary-ovarian axis. Therefore, endometrium is susceptible to changes in the cases of infertility that originate from disturbances in the normal functioning of this axis. In addition, some cases of unexplained infertility may be due to altered endometrial function. This disturbed endometrial function may originate from lesions in the molecular repertoire that are crucial to implantation. Human endometrium becomes receptive to implantation by the blastocyst within a defined period during the menstrual cycle. The duration of this so-called 'endometrial receptivity' or 'implantation' period seems to span from few days after ovulation to several days prior to menstruation. Successful implantation results from a co-ordinated series of events that would allow establishment of a timely dialogue between a receptive endometrium and an intrusive blastocyst. The members of the molecular repertoire that make endometrium receptive to implantation are gradually being recognized. Among these are the cytokines, integrins, heat shock proteins, tastin and trophinin. In addition, the expression of a second set of genes including tumour necrosis factor alpha (TNF-alpha) and ebaf, may be the appropriate signal for the closure of the 'implantation window', for making the endometrium refractory to implantation and for preparing it for the menstrual shedding.
TL;DR: Analysis of this mRNA in myometrial biopsies from 17 patients undergoing emergency Caesarean section showed how it decreased with advancing labour, and it is speculated that this decrease in OTR mRNA represents in-vivo OTR desensitization.
Abstract: sites/cell by exposing the cells to oxytocin for up to 20 h. In contrast, Western blotting data showed that the total amount of OTR protein was not affected by oxytocin treatment for up to 24 h. Flow cytometry experiments demonstrated that OTRs were not internalized during this treatment. However, RNase protection assays and Northern analysis showed that in cultured myometrial cells OTR mRNA was reduced by oxytocin treatment to reach a new low steady-state concentration. Analysis of this mRNA in myometrial biopsies from 17 patients undergoing emergency Caesarean section showed how it decreased with advancing labour. Samples obtained after 12 h of labour contained approximately 50 times less OTR
TL;DR: Use of the intrauterine microdialysis device has shown that the urinary HCG preparations routinely used for ovulation induction and luteal support may directly alter endometrial function.
Abstract: The regulation of human implantation is still unknown. Evidence from mice suggests an essential role for several paracrine mediators but species differences with implantation in the human preclude the extrapolation of these concepts to humans. An intrauterine microdialysis device (IUMD), consisting of microdialysis tubing glued into a balloon catheter on one side and into a polypropylene tube on the other, allows a dynamic and accurate in-vivo measurement of uterine paracrine interactions in humans. Inserted into the uterine cavity in the form of a loop, it can be continuously perfused with saline to reveal a number of relevant cytokines and growth factors in uterine effluents of non-pregnant women in both follicular and luteal phases. These included interleukin (IL)-1alpha, IL-1beta, IL-6, leukaemia inhibitory factor (LIF), macrophage colony-stimulating factor (M-CSF), epidermal growth factor, vascular endothelial growth factor (VEGF), insulin-like growth factor binding protein-1 (IGFBP-1), prolactin, and human chorionic gonadotrophin (HCG). The source of intrauterine HCG is unclear since endometrial mRNA for the HCG beta-subunit is not revealed using reverse transcriptase polymerase chain reaction analysis. Applying urinary HCG locally via the IUMD profoundly alters endometrial secretory parameters. Prolactin, IGFBP-1, and M-CSF are significantly inhibited and VEGF is regulated in a biphasic manner involving early stimulation followed by inhibition of intrauterine levels. Use of the IUMD has thus shown that the urinary HCG preparations routinely used for ovulation induction and luteal support may directly alter endometrial function.
TL;DR: Investigation of the relationship between leukocyte populations, steroid hormone receptor expression, proliferative activity, bcl-2 expression and apoptosis in eutopic and ectopic endometrium from women with endometriosis or adenomyosis at different phases of the menstrual cycle indicates different aetiologies for these disorders.
Abstract: The aetiology of endometriosis, a common and disabling disorder, is presently unknown, although immune dysfunction could allow ectopic endometrial fragments to survive outside the uterine cavity. These studies investigate the relationship between leukocyte populations, steroid hormone receptor expression, proliferative activity, bcl-2 expression and apoptosis in eutopic and ectopic endometrium from women with endometriosis or adenomyosis at different phases of the menstrual cycle. Significantly increased oestrogen receptor expression, bcl-2 expression and numbers of CD8+ leukocytes were found in ectopic compared with eutopic endometrium in endometriosis, and CD56+ endometrial granulated lymphocytes (eGLs) were significantly reduced in ectopic endometrium. Apoptotic cells were rarely found in control and subject endometria. In contrast with endometriosis, adenomyotic lesions showed identical steroid hormone receptor expression, proliferative activity, bcl-2 expression and leukocyte subpopulations to eutopic endometrium, indicating different aetiologies for these disorders. The unusual CD56+ CD16- eGLs present in large numbers in late secretory phase eutopic endometrium were highly purified (>98%) by immunomagnetic separation. Except for a negligible cytotoxic activity of eGLs from early proliferative samples, cytotoxic activity of eGLs from non-pregnant endometrium during the menstrual cycle was comparable with those in peripheral blood, predominantly CD56+ CD16+ natural killer cells. eGLs from non-pregnant endometrium and early pregnancy showed a variable proliferative response to 5 and 100 U/ml interleukin-2 over 48-h and 120-h time courses. eGLs are evidently functionally important in the eutopic endometrium. Their absence in endometriotic lesions together with increased CD+8 T-cell numbers and increased oestrogen receptor and bcl-2 expression may have significant effects on the development and progression of endometriosis.
TL;DR: The results demonstrate how progesterone-dependent components produce a receptive pattern, which can serve as a useful and precise marker in the clinical diagnosis of the luteal phase.
Abstract: Endocrine and paracrine controls regulate the endometrium during the luteal phase of the cycle to permit implantation. Part of this differentiation process is the production of a specific secretion which fills the intrauterine cavity and glandular lumen. Its molecular composition originates from the gland secretion, from transudations from stroma, from the endometrial blood vessels, and last, but not least, from cellular components of apoptotic and exfoliated cells. We have studied the secretions of all phases during the menstrual cycle using patterns evaluated by SDS-PAGE, by laser densitometry or Western blots. Uterine secretion electrophoresis (USE) permits detailed analyses of the intrauterine micromilieu and allows clinical assessment of the receptive stage of endometrium during the luteal phase. Several individual protein bands have been defined as characteristic markers for such receptive pattern. We have isolated and identified the molecular structure of several of these proteins, e.g. histones, cyclophilin, transthyretin, haptoglobin and uteroglobin. Investigations on the endocrine regulation of these proteins, were carried out on the uterine secretions of patients treated with progesterone antagonists (mifepristone and onapristone). The results demonstrate how progesterone-dependent components produce a receptive pattern, which can serve as a useful and precise marker in the clinical diagnosis of the luteal phase. Essential progesterone-dependent components differentiating during the luteal phase may provide new targets for contraceptive interventions by preventing the physiological changes typical of receptivity.