Angiogenesis, vascular endothelial growth factor and the endometrium.
(9/3697)
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. (+info)
Novel insights into human endometrial paracrinology and embryo-maternal communication by intrauterine microdialysis.
(10/3697)
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. (+info)
Marker molecules of human endometrial differentiation can be hormonally regulated under in-vitro conditions as in-vivo.
(11/3697)
An established cell culture system of isolated human endometrial stromal and epithelial cells has been used to study the effects of oestrogen and progesterone, as well as their antagonists, upon endometrial cells. Normal hormonal regulation in vivo was investigated simultaneously in endometrial tissue samples taken at different phases of the menstrual cycle. Several marker molecules analysed by immunohistochemistry appeared to depend strongly on endocrine regulation and could be traced in culture. Immunohistochemically, basic parameters of cell biology were identified in vitro, e.g. cell proliferation (Ki-67), adhesion molecules (beta3 integrin) and paracrine factors (leukaemia inhibitory factor). The most reliable parameters to assess hormonal influences were oestrogen and progesterone receptor molecules. Immunohistochemical localization could be improved by molecular biological analysis using RT-PCR. In the presence of oestrogen, a significant expression of hormone receptors was also shown by RT-PCR, and withdrawal of oestrogens and addition of gestagen, i.e. medroxyprogesterone acetate, caused receptor downregulation. Addition of the anti-oestrogen ICI 182.780 to cell-culture medium significantly decreased the synthesis of progesterone receptors. (+info)
Utero-ovarian interaction in the regulation of reproductive function.
(12/3697)
The physiological regulation of fertile reproductive cycle in mammals depends on interactions between hypothalamus-pituitary, ovarian and uterine stimuli. Over the past 20 years, much has been learned about the interrelation between the affluent and effluent lymph and vascular drainage in and around both ovarian and uterine tissues. An essential feature in the regulation of the fertile cycle is the functional status of the ovary, particularly the corpus luteum. During the time of implantation and the early pregnancy, an active corpus luteum is essential. As human chorionic gonadotrophin (HCG) is important in the maintenance of the corpus luteum, we investigated if it was produced by the cyclic endometrium. Immunohistochemical and in-situ hybridization reactions were performed but neither identified the presence of HCG during the proliferative phase. Positive staining and beta-human chorionic gonadotrophin (beta-HCG) mRNA were observed during the secretory phase in the glandular cells of the endometrium. The results were confirmed by Western blotting of secretory phase endometrium extracts and assessment of the functional secretory capacity of primary endometrial cultures. Polymerase chain reaction (PCR) investigations showed a positive result in the secretory phase. We postulate that, based on the very close morphological interrelation between the uterus and the ovary, the beta-HCG of the endometrium is the primary factor for the maintenance of the corpus luteum and early pregnancy. (+info)
Endometrial oestrogen and progesterone receptors and their relationship to sonographic appearance of the endometrium.
(13/3697)
The rapid development of ultrasonographic equipment now permits instantaneous assessment of follicles and endometrium. The sonographic appearance of the endometrium has been discussed in relation to in-vitro fertilization (IVF) cycles. However, a generally agreed view of the relationship of the sonographic appearance to fecundity in IVF cycles has not emerged. We have studied the relationship between steroid receptors and the sonographic appearance of the preovulatory endometrium in natural cycles and ovulation induction cycles. Preovulatory endometrial thickness was not found to be indicative of fecundity, although a preovulatory endometrial thickness of <9 mm related to an elevated miscarriage rate. The preovulatory endometrial echo pattern did not predict fecundity. No relationships were found among endometrial appearance, endometrial steroid receptors and steroid hormone concentrations in serum. Oestrogen or progesterone receptor concentrations were not related to endometrial thickness or to concentrations of serum oestradiol, the only significant correlation being found between the endometrial concentrations of oestrogen and progesterone receptors. The ratio of progesterone:oestrogen receptor concentration was somewhat less in echo pattern B (not triple line) endometrium compared with pattern A (triple line) endometrium. Oestrogen and progesterone receptor concentrations appeared stable on gonadotrophin induction, though fewer numbers were found during clomiphene cycles than in natural cycles. With regard to the distribution of receptor concentration between clomiphene and natural cycles, most women using clomiphene had very low oestrogen receptor populations. Pregnancy rates were low, in spite of high ovulatory rates during clomiphene treatment and were mainly related to low oestrogen receptor concentrations in preovulatory endometrium. (+info)
Nitric oxide in the endometrium.
(14/3697)
Nitric oxide (NO) is an important mediator of paracrine interactions, especially within the vascular system. It is a powerful inhibitor of platelet aggregation and a potent vasodilator. NO is also a neurotransmitter and it plays a role in cell-mediated cytotoxicity. NO-generating enzymes (nitric oxide synthases, NOS) have been described in the endometrium of a number of species, suggesting that NO might be involved in endometrial function. In human endometrium, endothelial NOS and inducible NOS have been localized to glandular epithelium in the non-pregnant uterus. Weak inducible NOS immunoreactivity has been observed in decidualized stromal cells. NO might participate in the initiation and control of menstrual bleeding. Furthermore, it may play a part in the inhibition of platelet aggregation within the endometrium, where menstrual haemostasis is thought to occur primarily by vasoconstriction rather than clot organization. Endometrially derived NO could also suppress myometrial contractility. Recent attention has focused on the part that NO might play in maintaining myometrial quiescence during pregnancy. NO also appears to relax the non-pregnant myometrium, an action which could be exploited for the medical treatment of primary dysmenorrhoea. (+info)
Mechanism of action and clinical effects of antiprogestins on the non-pregnant uterus.
(15/3697)
Considerable progress has been made in elucidating the mechanism of action of antiprogestins. The biological response to a progesterone antagonist depends on many factors. The usual effect is that of an antagonist, but progesterone agnostic or even antioestrogenic or oestrogenic effects have also been observed. The present review focuses on the clinical applications of antiprogestins in the non-pregnant uterus. Whereas high doses of antiprogestins block ovulation, low doses impair endometrial development without affecting ovulation, hormonal levels or bleeding patterns Indeed, the endometrium is the tissue which is the most sensitive to antiprogestins. The effect of antiprogestins is to produce a delay in endometrial maturation and to postpone the appearance of the implantation window. This concept of 'endometrial contraception' requires further testing in humans, although the principle has been proven in monkeys. In contrast to the low doses of mifepristone which delay endometrial maturation, a minimum dose of 50 mg is required to produce endometrial bleeding. Late luteal phase antiprogestin administration does not disturb ovulation, hormonal levels or bleeding patterns. This has clinical application, and mifepristone has been used together with prostaglandins in women with delayed menses to successfully prevent implantation. Mifepristone has also been shown to be an effective post-coital agent. However, when used on a regular basis once monthly at the end of the cycle as a potential contraceptive, the results are disappointing. Because of their antiproliferative and anti-oestrogenic effects on the endometrium, antiprogestins are also used in the treatment of oestrogen-dependent conditions such as endometriosis and fibromyomas. In humans, chronic administration of high doses of antiprogestins has on rare occasions been associated with endometrial hyperplasia, presumably a consequence of unopposed oestrogen activity. This does not occur with low doses (1 mg daily for 5 months). (+info)
Bovine endometrial epithelial cells as a model system to study oxytocin receptor regulation.
(16/3697)
Endometrial epithelial cell cultures were established from bovine uterine tissue collected during the oestrous cycle from commercially slaughtered animals. These cells were shown to express moderately high levels of oxytocin receptors (OTR) (up to 30000 per cell) after about one week in culture. These receptors have been characterized at the molecular, pharmacological and functional level and shown to be identical to those expressed in the bovine endometrium in vivo. Preliminary experiments to investigate the regulation of the OTR and its gene using this system, have shown that expression is to a large degree constitutive, the receptors being spontaneously upregulated during culture. Sex steroids at concentrations close to or above the serum limits observed in vivo appeared to have no effect, although the cells were shown to express mRNA for the specific steroid receptors throughout culture. Only the blastocyst product, interferon-tau, showed a significant effect, downregulating both OTR and their gene transcripts in the cultured endometrial epithelial cells. Although more extensive studies are necessary, these results support the view that the OTR gene is controlled in part at least by a combination of constitutive and inhibitory elements. (+info)