The 'Developmental Origins' Hypothesis: relevance to the obstetrician and gynecologist.

The recognition of 'fetal origins of adult disease' has placed new responsibilities on the obstetrician, as antenatal care is no longer simply about ensuring good perinatal outcomes, but also needs to plan for optimal long-term health for mother and baby. Recently, it has become clear that the intrauterine environment has a broad and long-lasting impact, influencing fetal and childhood growth and development as well as future cardiovascular health, non-communicable disease risk and fertility. This article looks specifically at the importance of the developmental origins of ovarian reserve and ageing, the role of the placenta and maternal nutrition before and during pregnancy. It also reviews recent insights in developmental medicine of relevance to the obstetrician, and outlines emerging evidence supporting a proactive clinical approach to optimizing periconceptional as well as antenatal care aimed to protect newborns against long-term disease susceptibility.

Maternal muscle mass may influence system A activity in human placenta.

During pregnancy, nutrient partitioning between the mother and fetus must balance promoting fetal survival and maintaining nutritional status of the mother for her health and future fertility. The nutritional status of the pregnant woman, reflected in her body composition, may affect placental function with consequences for fetal development. We investigated the relationship between maternal body composition and placental system A amino acid transporter activity in 103 term placentas from Southampton Women's Survey pregnancies. Placental system A activity was measured as Na(+)-dependent uptake of 10 mumol/L (14)C-methylaminoisobutyric acid (a system A specific amino acid analogue) in placental villous fragments. Maternal body composition was measured at enrollment pre-pregnancy; in 45 infants neonatal body composition was measured using dual-energy x-ray absorptiometry. Term placental system A activity was lower in women with smaller pre-pregnancy upper arm muscle area (r = 0.27, P = 0.007), but was not related to maternal fat mass. System A activity was lower in mothers who reported undertaking strenuous exercise (24.6 vs 29.7 pmol/mg/15 min in sedentary women, P = 0.03), but was not associated with other maternal lifestyle factors. Lower placental system A activity in women who reported strenuous exercise and had a lower arm muscle area may reflect an adaptation in placental function which protects maternal resources in those with lower nutrient reserves. This alteration may affect fetal development, altering fetal body composition, with long-term consequences.

Effect of asoprisnil on uterine proliferation markers and endometrial expression of the tumour suppressor gene, PTEN.

BACKGROUND: The selective progesterone receptor modulator asoprisnil suppresses uterine bleeding and decreases leiomyoma volume while maintaining follicular phase estrogen concentrations. For safety of potential clinical applications, any proliferative effect of asoprisnil on uterine tissues, particularly endometrium, needs to be established. METHODS: In a double-blind, randomized, placebo-controlled study (continuation of previously published trial No. NCT00150644 (Williams et al., 2007 and Wilkens et al., 2008)), 33 patients with symptomatic uterine leiomyomata received placebo, 10 or 25 mg asoprisnil daily for 12 weeks before hysterectomy. Proliferation markers Ki-67 and anti-phospho-histone H3 (PH3) were immunolocalized in endometrium, myometrium and leiomyoma tissue. Endometrial PTEN (phosphatase and tensin homologue, a tumour suppressor gene) expression was also assessed by immunohistochemistry. PH3-positive glandular and stromal cells were counted per measured endometrial area. Endometrial Ki-67 expression was assessed using stereological methods. Stained myometrial and leiomyoma cells were counted per 10 fields (x250). PTEN immunostaining was quantified using a histoscore. Each asoprisnil group was compared with placebo (secretory phase) with significance at 0.05 level. RESULTS: Endometrial epithelial proliferation and PTEN expression were not significantly different between placebo and asoprisnil groups. Decreased stromal Ki-67 expression (P < 0.05) suggested any effect of asoprisnil on endometrial proliferation to be inhibitory. Immunolocalization of PTEN expression was not different between treatment groups in any tissue compartments. Myometrial Ki-67 expression decreased following asoprisnil 25 mg (P < 0.05). CONCLUSIONS: Asoprisnil does not induce proliferation of uterine tissues and does not suppress endometrial PTEN expression.

The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata.

BACKGROUND: Asoprisnil is a selective progesterone receptor modulator with mixed progesterone agonist/antagonist activity which controls uterine bleeding via an endometrial effect. This study examined full-thickness endometrial, leiomyoma and myometrial morphology in hysterectomy specimens from patients with uterine leiomyomata, after treatment with asoprisnil for 3 months. METHODS: In this double-blind, randomized, placebo-controlled study, 33 subjects with uterine leiomyomata were randomized to receive asoprisnil 10, 25 mg or placebo for an average of 95 days prior to hysterectomy. Samples of endometrium, myometrium and leiomyoma tissue were subjected to systematic morphological assessment with quantification of mitotic activity. RESULTS: In patients treated with 10 or 25 mg asoprisnil, a unique pattern called 'non-physiologic secretory effect' was evident in endometrium, recognizable through partially developed secretory glandular appearances and stromal changes. Endometrial thickness was decreased, and there were low levels of mitotic activity in endometrial glands and stroma. Unusual thick-walled muscular arterioles and prominent aggregations of thin-walled vessels were present in endometrial stroma, but not in myometrium or non-endometrial vascular beds. Mitotic activity was decreased in leiomyomata. CONCLUSIONS: Asoprisnil induces unique morphological changes and is associated with low levels of glandular and stromal proliferation in endometrium, and in leiomyomata. These changes are likely to contribute to the amenorrhoea experienced after exposure to the medication.

L-serine uptake by human placental microvillous membrane vesicles.

The human fetus requires more glycine than any other amino acid but placental glycine transfer to the fetus is insufficient to meet fetal demand. L-Serine could represent a major metabolic source of glycine for the human fetus but little is known about the kinetics and physiology of L-serine uptake by the human placenta. We have characterised the amino acid transport systems involved in the uptake of L-serine by the microvillous membrane of the human placental syncytiotrophoblast and compared the uptake rates to those of glycine. L-Serine uptake into microvillous membrane (MVM) vesicles was primarily mediated by system A (MeAIB inhibitable) and system L (BCH inhibitable). Further characterisation using specific substrates of LAT1 and LAT2 found the pattern of L-serine uptake was consistent with that expected for uptake mediated by LAT2. Uptakes were performed with tracer levels of (14)C-L-serine, physiological levels of L-serine, or with physiological levels of amino acids. As amino acid concentrations rose, the proportion of uptake by System L decreased while uptake by uncharacterised Na(+)-independent systems increased. Uptake of Lserine into MVM vesicles had a V(max) of 2.1+/-0.4 nmol/mg protein/min, which was significantly higher than for glycine (V(max) 1.0+/-0.2 nmol/mg protein/min). This indicates that MVM vesicles have a higher uptake capacity for L-serine than glycine, despite a greater demand for glycine over serine for fetal protein synthesis. Further studies are now required to define the fate of L-serine taken up by the placenta and its importance for the fetus.

Progesterone inhibits insulin-like growth factor binding protein-1 (IGFBP-1) production by explants of the Fallopian tube.

The Fallopian tube provides the environment for early embryo growth, a process which is influenced by insulin-like growth factors (IGFs) in the tubal fluid. Whether the bioavailability of tubal IGFs is modulated by locally produced IGF-binding protein (IGFBP-1) is not clear. An explant culture system from human Fallopian tube mucosa was, therefore, developed enabling the potential for IGFBP-1 production by this tissue to be examined directly. Initial characterization of the system established that the explants maintained responsiveness to steroids. Thus, oviduct-specific glycoprotein production, a major product of the oviduct in vivo, continued to be made via an estrogen-sensitive pathway in the culture. The presence of mRNA for IGFBP-1 was established within the explants by the use of quantitative RT-PCR and IGFBP-1 protein was measured by enzyme-linked immunosorbent assay. Although insulin and estradiol had no consistent effect on IGFBP-1, addition of progesterone had a significant inhibitory effect on IGFBP-1 production, both at the mRNA and protein levels. A dose-range of progesterone revealed an incremental inhibitory effect of progesterone on IGFBP-1 output (maximal effect, 25-50 nmol/l), consistent with physiological inhibition of this process during the luteal phase. We suggest that progesterone might, therefore, play a role in controlling the bioavailability of IGFs to the embryo during early development within the Fallopian tube.

Beta cell differentiation during early human pancreas development.

Understanding gene expression profiles during early human pancreas development is limited by comparison to studies in rodents. In this study, from the inception of pancreatic formation, embryonic pancreatic epithelial cells, approximately half of which were proliferative, expressed nuclear PDX1 and cytoplasmic CK19. Later, in the fetal pancreas, insulin was the most abundant hormone detected during the first trimester in largely non-proliferative cells. At sequential stages of early fetal development, as the number of insulin-positive cell clusters increased, the detection of CK19 in these cells diminished. PDX1 remained expressed in fetal beta cells. Vascular structures were present within the loose stroma surrounding pancreatic epithelial cells during embryogenesis. At 10 weeks post-conception (w.p.c.), all clusters containing more than ten insulin-positive cells had developed an intimate relationship with these vessels, compared with the remainder of the developing pancreas. At 12-13 w.p.c., human fetal islets, penetrated by vasculature, contained cells independently immunoreactive for insulin, glucagon, somatostatin and pancreatic polypeptide (PP), coincident with the expression of maturity markers prohormone convertase 1/3 (PC1/3), islet amyloid polypeptide, Chromogranin A and, more weakly, GLUT2. These data support the function of fetal beta cells as true endocrine cells by the end of the first trimester of human pregnancy.

Progesterone up-regulates WT1 mRNA and protein, and alters the relative expression of WT1 transcripts in cultured endometrial stromal cells.

OBJECTIVE: To determine the change in expression of the Wilms tumor suppressor gene product, WT1, by progesterone alone in endometrial stromal cell culture and to study its relationship with prolactin, a marker of decidualization. In addition, to examine the change in ratio of WT1 isoforms with and without exon 5 message. METHODS: Endometrial biopsies were taken from eight patients who had hysterectomy. Stromal cells were isolated and cultured in the presence of progesterone alone (12 days) or progesterone and 8-bromo-cyclic adenosine monophosphate (cAMP) (6 days). RNA was extracted from cells, and reverse transcription, real-time polymerase chain reaction (PCR), and conventional PCR were done to analyze WT1 mRNA expression. Immunocytochemistry was performed on equivalent cells to study WT1 protein expression. Decidualization was identified by increased prolactin concentrations in the media and immunocytochemical markers IGFBP-1 and collagen IV. RESULTS: Reverse transcription and real-time PCR revealed a significant increase in WT1 mRNA with increasing progesterone concentrations when decidualization was occurring (n = 6, P =.002). Increasing progesterone concentrations also increased the proportion of the WT1 transcript containing a 17-amino-acid insert (+ exon 5 expression); changes in WT1 exon 5 expression have been shown to be involved in control of proliferation and differentiation. Significant correlations between WT1 message and prolactin existed at physiologic progesterone concentrations (6.25, 12.5, 25, and 50 nM; P <.05) until prolactin concentrations reached a plateau at 100 nM. At concentrations of progesterone alone (> 25 nM) and progesterone with 8-bromo-cAMP, WT1 protein was localized to the nuclei of many of the decidualized stromal cells. CONCLUSION: The changing expression of WT1 isoforms in endometrial stromal cells caused by progesterone may be important for differentiation into the decidualized phenotype.

Elastin distribution in the myometrial and vascular smooth muscle of the human uterus.

Magnetic resonance imaging and transvaginal ultrasonography in women of reproductive age suggest that the myometrium consists of inner and outer layers. It was hypothesized that these structural and functional differences in the myometrium might be associated with a variation in elastin distribution. Fifty-one hysterectomy specimens representing all phases of the normal menstrual cycle were studied by immunocytochemistry, orcein staining and image analysis. Elastin was present within the outer myometrial smooth muscle, but was less widely distributed in the inner smooth muscle. Immunoreactivity and staining were observed in the myometrial arteries and arterioles and within the basal portions of endometrial arterioles. Elastin was also present in perivascular tissue, particularly near the large vessels. More extravascular (i.e. perivascular and smooth muscle) elastin was present in the outer myometrium in all cases, although no distinct layering was observed. Semi-quantitative analysis of the elastin distribution in 11 full thickness specimens demonstrated a decreasing gradient from outer to inner myometrium rather than distinct layering. Contrary to previous reports, these data suggest that the external region of the myometrium is more elastic than the inner region and that elastin is found throughout the arteriolar tree of the human uterus.

The levonorgestrel intrauterine system: the benefits of reduced bleeding.

The levonorgestrel intrauterine system (LNG-IUS) offers a new therapeutic concept that combines a highly efficient contraceptive with a treatment that reduces menstrual blood loss in both normal women and those with menorrhagia. Initially developed to decrease the risk of expulsion of the intrauterine contraceptive device by reducing myometrial contractility, recent clinical studies have shown that the LNG-IUS provides excellent contraception without many of the adverse effects associated with the conventional intrauterine contraceptive device. The main mechanism of action of the LNG-IUS appears to be at the level of the endometrium, where the high dose of local progestogen causes decidualization, epithelial atrophy and direct vascular changes. Whilst some women experience systemic hormonal effects, circulating concentrations of levonorgestrel are low in comparison to those seen after the levonorgestrel progestogen-only pill. The LNG-IUS results in a dramatic reduction in menstrual blood loss. In turn, this has led researchers to investigate the LNG-IUS as an alternative to surgery for the treatment of dysfunctional uterine bleeding, uterine fibroids and adenomyosis. The system has also been used as a means of delivering progestogen for endometrial protection in postmenopausal hormone replacement regimens. The main side-effect of the LNG-IUS is irregular breakthrough bleeding. This is most common in the first 6 months after insertion. Detailed counselling is crucial to explain this anticipated effect, in order to reduce unnecessary discontinuation of treatment. After 6 months' treatment with the LNG-IUS, 20% of women become amenorrheic, rising to 50% after 5 years. Again, it is important to explain that this is an expected phenomenon, that it is not related to disorders of the hypothalamic-pituitary-ovarian axis, and that this 'bleed-free' status might indeed be viewed as a positive feature in its own right.

The levonorgestrel intrauterine system: the benefits of reduced bleeding.

The levonorgestrel intrauterine system (LNG-IUS) offers a new therapeutic concept that combines a highly efficient contraceptive with a treatment that reduces menstrual blood loss in both normal women and those with menorrhagia. Initially developed to decrease the risk of expulsion of the intrauterine contraceptive device by reducing myometrial contractility, recent clinical studies have shown that the LNG-IUS provides excellent contraception without many of the adverse effects associated with the conventional intrauterine contraceptive device. The main mechanism of action of the LNG-IUS appears to be at the level of the endometrium, where the high dose of local progestogen causes decidualization, epithelial atrophy and direct vascular changes. Whilst some women experience systemic hormonal effects, circulating concentrations of levonorgestrel are low in comparison to those seen after the levonorgestrel progestogen-only pill. The LNG-IUS results in a dramatic reduction in menstrual blood loss. In turn, this has led researchers to investigate the LNG-IUS as an alternative to surgery for the treatment of dysfunctional uterine bleeding, uterine fibroids and adenomyosis. The system has also been used as a means of delivering progestogen for endometrial protection in postmenopausal hormone replacement regimens. The main side-effect of the LNG-IUS is irregular breakthrough bleeding. This is most common in the first 6 months after insertion. Detailed counselling is crucial to explain this anticipated effect, in order to reduce unnecessary discontinuation of treatment. After 6 months' treatment with the LNG-IUS, 20% of women become amenorrheic, rising to 50% after 5 years. Again, it is important to explain that this is an expected phenomenon, that it is not related to disorders of the hypothalamic-pituitary-ovarian axis, and that this 'bleed-free' status might indeed be viewed as a positive feature in its own right.

The long term health consequences of polycystic ovary syndrome.

Women with polycystic ovary syndrome have both insulin resistance and beta cell dysfunction. Consequently, they are at increased risk of developing diabetes and cardiovascular disease. Women with polycystic ovary syndrome present to clinicians at a young age and as such offer a unique opportunity to identify insulin resistant patients at an early stage. This enables the modification of risk factors and diagnosis of diabetes before the onset of macro- and micro-vascular symptoms. Increased emphasis should thus be placed on long term risk management and diabetic screening with advice on smoking, exercise and, if appropriate, weight loss. Where possible drugs that exacerbate insulin resistance should be avoided and consideration should be given to the use of insulin sensitising agents, particularly in the obese.

A randomised comparison and economic evaluation of laparoscopic-assisted hysterectomy and abdominal hysterectomy.

OBJECTIVES: To determine the safety, cost effectiveness and effect on quality of life of laparoscopic-assisted vaginal hysterectomy (LAVH) compared with total abdominal hysterectomy (TAH) in the management of benign gynaecological disease. DESIGN: Randomised controlled trial and economic evaluation. SETTING: Three hospitals in the West of Scotland. PARTICIPANTS: Two hundred women scheduled for an abdominal hysterectomy for benign gynaecological disease. MAIN OUTCOME MEASURES: Conversion rate of LAVH to TAH, complication rates, NHS resource use and costs, quality of life using EuroQol 5 D visual analogue scale, and achievement of milestones. RESULTS: The overall incidence of operative complications was 14% in the TAH group and 8% in the LAVH group, with an 8% conversion rate. Length of operation was significantly greater in the women having LAVH at 81 +/- 30 min vs 47 +/- 16 min (P < 0.001). There was no difference in analgesic requirements between the groups although there was a significantly shorter hospital stay for those having LAVH. The rate of post-surgery recovery, satisfaction with operation and quality of life at four weeks post-operative were similar in the two groups of women. LAVH was significantly more expensive than TAH and remained more expensive for all but the most extreme scenario. CONCLUSIONS: This study demonstrates that despite the decreased length of hospital stay, LAVH is more expensive than TAH. In addition, recovery following operation and patient satisfaction were not affected by the route chosen. It is unlikely that LAVH represents an efficient use of NHS resources.

Measurements of the dielectric properties of peripheral blood mononuclear cells and trophoblast cells using AC electrokinetic techniques.

The separation of trophoblast cells from the maternal circulation could provide a valuable diagnostic tool for prenatal diagnosis of genetic abnormalities. This has been attempted using antibody methods, but due to non-specificity of the antibodies, maternal cell contamination remains a problem. We have investigated the potential of dielectrophoretic separation methods as a means of isolating trophoblast cells from mixed peripheral blood mononuclear cells. To determine the potential of this method the dielectric properties of trophoblast cells and mixed peripheral blood mononuclear cells were measured using dielectrophoretic crossover and single cell electrorotation methods. Both dielectrophoretic crossover data and electrorotation data gave an average specific membrane capacitance of the peripheral blood mononuclear cells of 11.5 mF m(-2). Trophoblast cells prepared using three different methods had a higher average specific membrane capacitance in the range 13-18 mF m(-2). The differences in capacitance between the cell types could be exploited as the basis of an AC electrokinetic-based system for the separation of trophoblast cells from peripheral blood mononuclear cells.

Spatially regulated differentiation of endometrial vascular smooth muscle cells.

Angiogenesis within the human endometrium involves the development of arterioles and elaboration of a capillary network. It was postulated that maturation of these arterioles involves a spatially regulated process of vascular smooth muscle cell (VSMC) differentiation. The endometrial vascular tree was therefore examined immunohistochemically for evidence of longitudinal and radial gradients of VSMC phenotype. Twenty-three hysterectomy specimens and 15 first trimester decidual tissues were studied. Five cytoskeletal markers (alpha and gamma-smooth muscle (sm) actin, sm myosin, desmin, vimentin), three endothelial markers (CD31, CD34, factor VIII related antigen) and two steroid receptors (oestrogen and progesterone) were detected immunohistochemically. alpha-sm actin was present throughout the wall of basal arterial segments and extended longitudinally towards the endometrial surface. Sm myosin expression was more restricted longitudinally and radially within in the vascular tree. The expression of gamma-sm actin was even more restricted than myosin. In first trimester decidua, however, gamma-sm actin was widely distributed within the wall of spiral arteries that were not invaded by trophoblast. Oestrogen and progesterone receptors were present in peri-vascular stromal cells but absent from vascular smooth muscle and endothelium. Endometrial VSMC differentiation involves a progressive increase in cytoskeletal complexity and occurs in a spatially regulated fashion.

Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea.

Hyperinsulinaemic insulin resistance is commonly associated with hyperandrogenaemia, and menstrual dysfunction. The aim of this study was to examine the effects of the insulin sensitizing drug, metformin, on ovarian function, follicular growth, and ovulation rate in obese women with oligomenorrhoea. Twenty obese subjects with oligomenorrhoea [polycystic ovarian syndrome; (PCOS)] were observed longitudinally for 3 weeks prior to and for 8 weeks during treatment with metformin (850 mg twice per day). Fifteen patients completed the study. The frequency of ovulation was significantly higher during treatment than before treatment (P = 0.003). A significant decline in both testosterone and luteinizing hormone concentrations was recorded within 1 week of commencing treatment. Patients with elevated pretreatment testosterone concentrations showed the most marked increase in ovulation rate (P < 0.005), and significant reductions in circulating testosterone from 1.02 to 0.54 ng/ml (P < 0.005) after only 1 week of treatment. However, the sub-group with raised fasting insulin showed less marked changes, and the sub-group with normal testosterone concentrations showed no effect of treatment. Metformin had a rapid effect upon the abnormal ovarian function in hyperandrogenic women with PCOS, correcting the disordered ovarian steroid metabolism and ovulation rate; however, there appeared to be no effect in cases where the circulating androgen concentration was normal.

Leukocytes infiltrate the myometrium during human parturition: further evidence that labour is an inflammatory process.

Inflammatory mediators in the cervix, placenta and fetal membranes play a crucial role in human parturition. The aim of this study was to determine whether the upper and lower segments of the myometrium are infiltrated by inflammatory cells during pregnancy and parturition. Myometrial biopsies were obtained from non-pregnant women, and pregnant women at term before and after the onset of spontaneous labour. Subpopulations of inflammatory cells were identified using immunocytochemistry. The intercellular adhesion molecules, 1 and 2, platelet endothelial cell adhesion molecule, vascular cell adhesion molecule and E-selectin were immunolocalized to investigate their involvement in leukocyte accumulation. Histological analysis demonstrated that inflammatory cells, predominantly neutrophils and macrophages, infiltrate human myometrium during spontaneous labour at term. The infiltrate is predominant in the lower uterine segment but is also present in the upper segment. Increased expression of E-selectin was found on the vascular endothelium of biopsies obtained during labour, suggesting a role for this molecule in the accumulation of leukocytes. These results suggest that inflammatory cell infiltration is part of the physiological mechanisms that occur in the myometrium during parturition. Further understanding of this process may suggest new strategies aimed at preventing preterm delivery.

Myometrial constitutive nitric oxide synthase expression is increased during human pregnancy.

Nitric oxide (NO), derived from L-arginine by the action of nitric oxide synthase (NOS), is a mediator of many diverse biological activities, including vasodilation, neurotransmission and inhibition of platelet adhesion. A role for NO in the maintenance of rat and rabbit pregnancy is supported by a variety of studies. A recent study in women demonstrated that myometrial inducible NOS (iNOS) expression was greater in the early third trimester than either the late third trimester or in the non-pregnant condition, suggesting that increased iNOS expression is involved in the maintenance of human pregnancy. Constitutive NOS (cNOS) expression was not determined. The aim of this study was to compare constitutive NOS (both eNOS and bNOS) expression in the human non-pregnant uterus, preterm pregnant uterus (25-34 weeks gestation) and term pregnant uterus (>37 weeks gestation) using immunohistochemistry and Western blotting. Preterm pregnant samples were taken from women with a variety of pathologies necessitating early delivery. We found that eNOS and bNOS protein concentrations were greater in the preterm pregnant myometrium than non-pregnant myometrium. eNOS, but not bNOS, protein concentration was lower in myometrial samples obtained at term compared with those obtained preterm. We conclude that the constitutive isoforms of NOS are also up-regulated in human pregnancy and may play a role in the maintenance of myometrial quiescence.

Expression of intercellular adhesion molecules ICAM-1 and ICAM-2 in human endometrium: regulation by interferon-gamma.

The purpose of this study was to localize intercellular adhesion molecule (ICAM)-1 and ICAM-2 in human endometrium and myometrium throughout the menstrual cycle, and to determine whether the expression of these molecules is regulated by interferon (IFN)-gamma. ICAM-1 and ICAM-2 distribution was examined in endometrial biopsies by immunocytochemistry, and Northern blotting was used to quantify ICAM-1 and ICAM-2 mRNA expression in isolated endometrial glands. Stromal fibroblast cultures were exposed to IFN-gamma and the effect on expression of ICAM-1 and ICAM-2 was determined by immunocytochemistry and Northern blotting. ICAM-1 was localized in vivo to the apical surface of the glandular epithelium, the vascular endothelium and endometrial stromal cells throughout the menstrual cycle. Stromal expression of ICAM-1 was up-regulated in menstrual specimens. Northern blotting confirmed the presence of ICAM-1 mRNA in isolated endometrial glands. The expression of ICAM-1 antigen and message was increased in stromal cell culture after incubation with IFN-gamma in a time-dependent manner, suggesting that this cytokine stimulates the expression of ICAM-1 in the endometrial stroma. ICAM-2 antigen expression was restricted to the vascular endothelium. ICAM-2 mRNA was absent in endometrial glands. The widespread distribution of ICAM-1 in human endometrium suggests that this molecule is involved in the process of menstruation, the functioning of glands, blood vessels and stroma, and in regulating leukocyte trafficking into the tissue. ICAM-2 is restricted to the vascular endothelium where it might modulate leukocyte invasion of the stroma and myometrial connective tissue.

Medical management of dysfunctional uterine bleeding.

Complaints of excessive menstrual bleeding (menorrhagia) have a substantial impact on gynaecological services and in most cases no organic pathology is identified. Up to 50% of women who present with menorrhagia have blood losses within the normal range. Medical therapy is indicated for patients who do not wish surgery, or for whom surgery is unsuitable. Nonsteroidal anti-inflammatory drugs and tranexamic acid offer a simple therapy to be taken during menses, with reductions in menstrual blood loss (MBL) of 25-35% and 50% respectively. Danazol and the gonadatrophin-releasing hormone analogues are highly effective, but their side-effects make them suitable only for short-term use. The combined oral contraceptive pill and the levonorgestrel intrauterine system give reductions in MBL of 50% and 80%, with additional contraceptive cover. Cyclical progestogens are the most commonly prescribed therapy in the United Kingdom but they are ineffective for the management of ovulatory menorrhagia unless taken at high doses (10-15 mg daily) for 3 weeks out of 4.