Hydrosalpinges adversely affect markers of endometrial receptivity

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.      

Clomiphene citrate does not affect the secretion of alpha3, alphaV and beta1 integrin molecules during the implantation window in patients with unexplained infertility.

BACKGROUND: The expression of integrin molecules on the endometrium suggests that certain integrins may participate in the cascade of molecular events leading to successful implantation. A prospective, controlled study was carried out to investigate the effect of clomiphene citrate (CC) on secretions of beta1, alpha3 and alphaV integrin molecules in the endometrium of patients with unexplained infertility during the implantation window. METHODS: A total of 40 endometrial samples was evaluated in both spontaneous (n = 13) and ensuing clomiphene-treated cycles (100 mg on days 5-9) and also from fertile women serving as controls (n = 14) during postovulatory 7th or 8th day of menstrual cycle. A semiquantitative grading system (H-score) was used to compare the immunohistochemical staining intensities. Endometrial thickness and serum oestradiol and progesterone concentrations were also measured on the day of sampling. RESULTS: Staining of alpha(v) but not beta1 and alpha3 integrins was significantly less intense in infertile cases than fertile control cases (1.42 +/- 0.12 versus 2.21 +/- 0.13 respectively, P = 0.012) and this was not restored to normal concentrations with treatment. CONCLUSIONS: Our study indicated that cc treatment significantly decreased the endometrial thickness and increased oestradiol and progesterone concentrations. However, secretion of alpha(v), beta1 and alpha3 integrin molecules, which might play a role in implantation, was not affected.     

Integrin expression in normal and out-of-phase endometria

Integrins have recently been proposed as having a major role in endometrial receptivity. Different patterns of integrin expression have been described during the normal endometrial cycle, and the co- expression of several integrins, mainly alpha1, alpha4 and beta3 has been considered as specific to the 'window of implantation'. In the present study 55 infertile patients underwent two endometrial biopsies during a single menstrual cycle. An early biopsy was done on postovulatory days 6-8, and a late biopsy was performed on postovulatory days 10 to 12. Histological dating as well as immunohistochemical evaluation of alpha1, alpha4, beta1, beta3, beta5, alpha(v)beta3 integrin expression and oestrogen and progesterone receptors were determined in all endometrial biopsies. Oestradiol and progesterone serum concentrations in serum were evaluated on the same days of the endometrial samplings. Nine out of the 55 midluteal biopsies (16.4%) showed out-of-phase endometria, but all biopsies were in phase in the late luteal phase. Differences in integrin expression between in- and out-of-phase biopsies were observed only for alpha(v)beta3 integrin glandular expression during the midluteal phase. Alpha(v)beta3 integrin glandular expression was found in all late luteal phase biopsies. Alpha(v)beta3 expression was closely correlated with histological maturation of the endometrium appearing suddenly at postovulatory day 6-7 and being expressed by all endometria dated as postovulatory day > or = 8, irrespective of midluteal endometrial biopsies being in phase or out of phase. No differences in integrin expression were detected between patients with or without endometriosis or between patients who became spontaneously pregnant and those who did not. In conclusion, further studies are necessary before patterns of integrin expression may offer an alternative to predict uterine receptivity and implantation potential.      

Ovarian stimulation with GnRH agonist, but not GnRH antagonist, partially restores the expression of endometrial integrin beta3 and leukaemia-inhibitory factor and improves uterine receptivity in mice

BACKGROUND: The impact of different ovarian stimulation (OS) protocols on endometrial receptivity remains controversial. In this study, the effects of different OS on the expression of endometrial integrin beta3 subunit and leukaemia-inhibitory factor (LIF) during the implantation window and the implantation rate in mice were investigated. METHODS: Three OS protocols were used, involving either pregnant mare's serum gonadotrophin (PMSG) alone, PMSG plus GnRH agonist or PMSG plus GnRH antagonist. Uterus samples were collected at 48 h after OS or ovulation and were detected with immunohistochemistry, Western blot and RT-PCR analyses. Normal embryos at gestation day 4 were transferred into the uteri of mice in the control and OS groups. RESULTS: All OS groups showed a significant decrease in the expression of both the endometrial integrin beta3 subunit and LIF during the implantation window and the implantation rate. Among the three OS groups, GnRH agonist-treated mice showed a higher endometrial integrin beta3 subunit and LIF expression and a higher implantation rate. No significant difference was found in the measured indices between the GnRH antagonist and PMSG groups. CONCLUSIONS: OS may inhibit the expression of endometrial integrin beta3 subunit and LIF and impair endometrial receptivity in mice. OS with GnRH agonist, but not GnRH antagonist, may partially restore the endometrial physiological secretion and improve uterine receptivity.     

Endometrial integrin expression in women undergoing IVF and ICSI: a comparison of the two groups and fertile controls

BACKGROUND: Integrins are thought to play a vital role in implantation. Three integrins in particular (alpha(4)beta(1), alpha(v)beta(3) and alpha(1)beta(1)) are all present during the implantation window. Defects in their expression have been linked to tubal disease, unexplained infertility and endometriosis. Hence, a reduced endometrial integrin expression would be expected in women attending for IVF due to these causes of infertility when compared with those with male factor infertility attending for ICSI. METHODS: Women attending for IVF (n = 25) and ICSI (n = 25) treatment were recruited, and timed endometrial biopsies were taken during the 'implantation window' (cycle day 20-24). A group of fertile women (n = 15) attending for sterilization was used as controls. RESULTS: There was no significant difference in integrin expression between patients undergoing IVF or ICSI. Neither did these groups differ from the control group. CONCLUSIONS: The endometrium in patients undergoing ICSI treatment is sometimes thought to be more receptive, as the infertility might be due to a male factor. This study shows that there is no significant difference in integrin expression between patients attending for IVF or ICSI and the control group. These data add to the increasing uncertainty about the clinical value of assessing the endometrium with only one marker, in this case integrins.     

A prospective evaluation of the effect of salpingectomy on endometrial receptivity in cases of women with communicating hydrosalpinges.

BACKGROUND: We aimed to assess whether salpingectomy in women with communicating hydrosalpinges influenced endometrial receptivity. METHODS: The inclusion criteria were: women with communicating hydrosalpinges, absence of other confounding infertility factors and aged <40 years. Patients were scheduled for laparoscopy during the putative window of implantation (cycle days 19-21). In patients in whom salpingectomy was decided upon due to the severity of tubal disease (n = 10), an intra-operative endometrial biopsy was performed. Post-treatment endometrial sampling was done between day 19-21 of the fourth consecutive cycle. Pre-treatment and post-treatment samples were assessed by both conventional histologic criteria and alpha(v)beta3 integrin immunostaining, where histological score (HSCORE) was used for quantification. RESULTS: Despite normal histological maturation assessed by conventional criteria, 8/10 hydrosalpinx cases yielded an epithelial HSCORE of <0.7, which was below the accepted threshold. Following salpingectomy, luminal endometrial epithelium demonstrated a significantly increased alpha(v)beta3 integrin expression (Wilcoxon's signed rank test, P = 0.017). Although the mean HSCORE for glandular epithelia improved, it failed to reach statistical significance. Ultrasound visible hydrosalpinges (n = 5) and non-visible cases (n = 5) were also compared. However, neither the pre-treatment integrin expression, nor the postoperative improvement were significantly different between these groups. CONCLUSIONS: We conclude that the surgical treatment of communicating hydrosalpinges may improve endometrial receptivity as assessed by alpha(v)beta3 integrin expression. Women with hydrosalpinges may undergo endometrial evaluation by the molecular markers of implantation, such as alpha(v)beta3 integrin. This evaluation may be decisive in determining the optimal management of cases, and may also be used to assess the efficacy of the treatment. The expression of the implantation markers should be correlated with implantation and clinical pregnancy rates in IVF-embryo transfer programs.     

Endometrial vascular and glandular expression of integrin alpha(v)beta3 in women with and without endometriosis

The integrin alpha(v)beta3 functions in both cell-cell and cell- extracellular matrix adhesion, and has reported roles in platelet aggregation, immune function, tissue repair, tumour invasion, angiogenesis and uterine receptivity. The aim of this study was to use immunohistochemistry to describe the vascular and glandular expression of integrin alpha(v)beta3 in formalin fixed, paraffin embedded endometrium obtained from women with (n = 29) and without (n = 24) endometriosis. The results showed a significant increase in the percentage of vessels expressing alpha(v)beta3 in the endometrium of women with endometriosis compared with controls (P = 0.0001). This difference was more pronounced in the secretory phase (P = 0.001) than the proliferative phase (P = 0.016). There was no correlation between vascular alpha(v)beta3 expression and the endothelial cell proliferation index (P > 0.05). Vascular sprouts were not observed in any of the 53 endometrial tissues obtained from women with or without endometriosis throughout the menstrual cycle. Results from semi- quantitative scoring of gland immunostaining showed that neither controls (P = 0.3329) nor the endometriosis group (P = 0.2260) had any significant changes in terms of alpha(v)beta3 expression between the different stages of the menstrual cycle. There was also no difference in glandular alpha(v)beta3 expression between women with and without endometriosis (P = 0.4302). These results provide evidence for increased endometrial angiogenesis in women with endometriosis compared with controls, and suggest that glandular expression of alpha(v)beta3 is not related to uterine receptivity per se.      

alphavbeta3 integrin expression and pinopod formation in normal and out-of-phase endometria of fertile and infertile women

BACKGROUND: There is scanty and contradictory information regarding the comparison of traditional histological dating criteria of the endometrium with the expression of the new markers of endometrial receptivity such as alphavbeta3 integrin and pinopods. Also, definite data with respect to the potential correlation existing between these different new markers in defining the putative window of implantation are lacking. METHODS: The temporal relationship between alphavbeta3 integrin expression and pinopod formation in normal and out-of-phase endometrial biopsies from normal healthy women (n = 12) and infertile patients (n = 36) was investigated. Two endometrial biopsies (postovulatory day +7 to +8 and 4 days later) were performed during a single menstrual cycle in each subject. Estradiol and progesterone serum concentrations were quantified on the same days as endometrial sampling. RESULTS: No statistically significant difference regarding alphavbeta3 integrin expression, pinopod formation, and hormone concentrations was found between fertile controls and infertile patients irrespective of endometria being in-phase or out-of-phase. Although a coordinate high level of expression of alphavbeta3 integrin and pinopod on postovulatory days 7-8 was observed, there was an evident lack of temporal co-expression of these markers over the luteal phase in the endometrial samples investigated. CONCLUSIONS: There is a clear dissociation in the temporal expression of the most cited markers postulated to frame the window of implantation. The functional significance (if any) of these new markers remains to be established.     

Endometrial markers of uterine receptivity utilizing the donor oocyte model

BACKGROUND: Ethical constraints limit the ability to study peri-implantation phase human endometrium. In this study, the donor oocyte model was used to study candidate endometrial markers of uterine receptivity. METHODS: Archived, paraffin-embedded tissue obtained by endometrial biopsy during cycle days 21-23 of patients undergoing 'mock' hormonal treatment cycles were evaluated by standard histological criteria and immunohistochemical staining for alpha v beta 3 integrin and glycodelin. All of these patients (n = 101) had undergone a donor oocyte embryo transfer cycle utilizing the exact same hormonal protocol. RESULTS: Histological evaluation revealed 62 (61.3%) in-phase, 34 (33.7%) dyssynchronous, 2 (2.0%) immature and 3 (3.0%) advanced endometria. The clinical outcomes of patients with either in-phase or dyssynchronous endometria were similar. Very strong correlations were noted between endometrial glandular dating and either alpha v beta 3 integrin or glycodelin immunostaining intensity (P < 0.001 for both). Glycodelin and alpha v beta 3 integrin immunostaining intensities were also highly correlated with each other (P < 0.001). CONCLUSIONS: Throughout the time period corresponding to the putative window of maximal endometrial receptivity (cycle days 21-23) a dynamic process was observed in exogenous hormonal replacement cycles characterized by a rapid histological advancement of endometrial glandular elements as well as progressive alpha v beta 3 integrin and glycodelin expression.     

Patterns of expression of integrin molecules in human endometrium throughout the menstrual cycle.

A heterogeneous group of cells interact with each other and with the surrounding matrix to form the complex structure of human endometrium. Since the integrin superfamily of molecules is involved in the cell-cell and cell-matrix interactions, this study was designed to screen, in situ, the cellular distribution of CDW49a-f molecules in human endometrium throughout the menstrual cycle. The integrin molecules were localized by immunohistochemistry using monoclonal antibodies. Glandular epithelium expressed all integrin molecules. With the exception of CDW49d (alpha 4 beta 1), surface epithelium also expressed all these molecules. Endothelial cells were positive for all integrin molecules except CDW49a (alpha 1 beta 1). Endometrial lymphoid cells were positively immunostained for CDW49a, d and e (alpha 5 beta 1) and were negative for CDW49b (alpha 2 beta 1), CDW49c (alpha 3 beta 1) and CDW49f (alpha 6 beta 1). Regional differences in the expression of integrin molecules were observed. As compared to the functionalis epithelium, basalis epithelium characteristically exhibited higher expression of CDW49a, d and e. Two integrins in endometrium, CDW49a and d exhibited changes related to the menstrual cycle. CDW49a, which was not expressed in glandular epithelial cells in the proliferative phase, was strongly expressed in these cells after ovulation and its expression was diminished in the late secretory phase. This molecule was not expressed in the stromal cells, however, predecidual cells characteristically expressed this molecule in the late secretory phase. CDW49d was only expressed in the glandular epithelial cells in the mid-proliferative to mid-secretory phases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human peripheral blood mononuclear cells enhance cell-cell interaction between human endometrial epithelial cells and BeWo-cell spheroids

BACKGROUND: Previously, it was reported that T-lymphocytes derived from non-pregnant mice promote murine embryo implantation. In order to examine the immunological regulation of endometrial receptivity in humans, the effects of peripheral blood mononuclear cells (PBMCs) on endometrial epithelial cell (EEC) function were monitored by a newly developed attachment assay using primary human EEC culture and BeWo cell-derived spheroids. METHODS AND RESULTS: EECs isolated from 25 women in the mid- and late proliferative and early, mid- and late secretory phases were subjected to monolayer culturing. Spheroids were constructed from BeWo cells, a human choriocarcinoma cell line, by incubation with continuous rolling, after which their interaction with cultured EECs was studied. The mean (+/- SEM) number of attached spheroids was significantly higher (P < 0.01) in the EEC culture derived from women in the mid-secretory phase (90 +/- 2.9%) than the other groups (ranging from 0 to 5.8 +/- 3.7%), which is in agreement with the existence of a so-called 'implantation window'. After 72 h co-culture of EECs with PBMCs, the number of attached spheroids significantly increased in the EEC cultures derived from the late proliferative and early secretory phases [65.0 +/- 21.7 versus 5.0 +/- 2.0% (P < 0.05) and 83.1 +/- 4.1 versus 4.4 +/- 1.9% (P < 0.01)]. CONCLUSIONS: This attachment assay appears to be a useful method with which to assess endometrial receptivity. Functional change of EECs induced by PBMCs suggests possible regulation of endometrial receptivity by immune cells.     

Effect of the Yuzpe regimen of emergency contraception on markers of endometrial receptivity

This exploratory study was designed to determine whether treatment with the Yuzpe regimen of emergency contraception altered endometrial integrin expression or other markers of uterine receptivity. Nineteen parous women were followed for two menstrual cycles. In the second cycle, each participant took 100 mg ethinyl oestradiol and 1 mg norgestrel on the day of the urinary luteinizing hormone (LH) surge and repeated the dose 12 h later. In both cycles, endometrial biopsy, phlebotomy and vaginal sonogram were performed 8-10 days after the urinary LH surge. No significant difference was found between untreated and treated cycles in most measures of endometrial histology or in endometrial expression of beta3 integrin subunit, leukaemia inhibitory factor, glycodelin, or progesterone receptors assessed by immunohistochemical techniques. Five statistically significant changes were noted in treated cycles: a reduction in endometrial MUC-1 expression, an increase in endometrial oestrogen receptor, lower luteal phase serum oestrogen concentration, reduced endometrial thickness, and greater proportion of glandular supranuclear vacuoles. The relationship of these findings to the contraceptive action of the Yuzpe regimen is unclear.     

Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology

In humans, embryonic implantation and reproduction depends on the interaction of the embryo with the receptive endometrium. To gain a global molecular understanding of human endometrial receptivity, we compared gene expression profiles of pre-receptive (day LH+2) versus receptive (LH+7) endometria obtained from the same fertile woman (n = 5) in the same menstrual cycle in five independent experiments. Biopsies were analysed using the Affymetrix HG-U95A array, a DNA chip containing approximately 12,000 genes. Using the pre-defined criteria of a fold change >/=3 in at least four out of five women, we identified 211 regulated genes. Of these, 153 were up-regulated at LH+7 versus LH+2, whereas 58 were down-regulated. Amongst these 211 regulated genes, we identified genes that were known to play a role in the development of a receptive endometrium, and genes for which a role in endometrial receptivity, or even endometrial expression, has not been previously described. Validation of array data was accomplished by mRNA quantification by real time quantitative fluorescent PCR (Q-PCR) of three up-regulated [glutathione peroxidase 3 (GPx-3), claudin 4 (claudin-4) and solute carrier family 1 member 1 (SLC1A1)] genes in independent LH+2 versus LH+7 endometrial samples from fertile women (n = 3) and the three up-regulated genes throughout the menstrual cycle (n = 15). Human claudin-4 peaks specifically during the implantation window, whereas GPx-3 and SLC1A1 showed highest expression in the late secretory phase. In-situ hybridization (ISH) experiments showed that GPx-3 and SLC1A1 expression was restricted to glandular and luminal epithelial cells during the mid- and late luteal phase. The present work adds new and important data in this field, and highlights the complexity of studying endometrial receptivity even using global gene-expression analysis.     

Mid-luteal serum inhibin-A concentration as a marker of endometrial differentiation.

BACKGROUND: Recent studies have indicated that the corpus luteum is a major source of circulating inhibin-A and serum concentrations of inhibin-A may reflect the human luteal function. The present prospective study was undertaken to determine the usefulness of mid-luteal serum concentrations of inhibin-A as markers of endometrial receptivity (as assessed by histological dating and alphavbeta3 integrin expression) and whether they are better predictors of endometrial function than serum progesterone. METHODS: Consecutive infertile women (experimental group, n = 50) with regular menstrual cycles, and fertile women who were requesting contraception and had regular menstrual patterns and normal secretory endometria (control group, n = 10) were included. In all women basal body temperature, luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A, and endometrial biopsies were used in the same cycle to assess luteal function. RESULTS: Out-of-phase mid-secretory endometria were detected in 17 of the 50 infertile women. Lack of alphavbeta3 integrin expression was detected in 27 of the 50 mid-luteal endometrial biopsies. Thus, hormonal concentrations were compared in the mid-luteal phase between the following eight groups of women: group 1 (n = 10), control fertile women; group 2 (n = 50), infertile women (all); subdivided into group 3 (n = 33), with in-phase biopsies; group 4 (n = 17), with out-of-phase endometria; group 5 (n = 23), expressing alphavbeta3 integrin in endometria; group 6 (n = 27), whose endometria did not express alphavbeta3 integrin; group 7 (n = 18), with both in-phase endometrial biopsy and alphavbeta3 integrin expression; and finally group 8 (n = 12), whose endometria were out-of-phase and did not express alphavbeta3 integrin. Mid-luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A of the seven infertile groups were similar to those of the control group of fertile women. No statistically significant difference between the infertile groups was observed for any hormonal parameter considered. CONCLUSION: Mid-luteal serum inhibin-A determination does not accurately reflect endometrial function/maturation and it is not a better indicator of endometrial luteal phase dysfunction than mid-luteal serum progesterone.     

Abnormal Pattern of Lymphocyte Subpopulations in the Endometrium of Infertile Women with Chronic Endometritis

Problem  Endometrial lymphocytes play a critical role in endometrial receptivity. This study aimed at evaluating the variations induced by chronic endometritis (CE) on endometrial lymphocyte subsets. We compared the results in infertile women diagnosed with CE with those in unexplained infertile women without any sign of CE.
Method of study  Twenty-three women referring for unexplained infertility had hysteroscopy and endometrial biopsy in the follicular phase; in nine women, CE was diagnosed (group CE+), while in 14 it was not (group CE−). All patients in the late secretory phase of the subsequent cycle underwent endometrial biopsy. By flow cytometry, the percentage and phenotype of the endometrial lymphocyte subpopulations were analyzed.
Results  The secretory endometrium of patients with CE displayed significantly lower percentage of CD56⁺ CD16⁻ and of CD56^bright CD16⁻ cells (47.8% ± 18.6 and 30.1% ± 20.5 versus 79.5% ± 3.9 and 67.3% ± 8.1, respectively; P  < 0.01) as compared with group CE(−), while the percentage of CD3⁺ cells was significantly higher (25% ± 12.2 versus 10.5 ± 5; P  < 0.01).
Conclusion  Infertile women with CE showed an abnormal percentage of endometrial lymphocyte subsets compared with unexplained infertile women suggesting that different mechanisms underlie the adverse pregnancy outcome of the two groups of patients.     

The effect of antiprogestin on integrin expression in human endometrium: an immunohistochemical study

Integrins are cell surface receptors for the extracellular matrix and connect extracellular cell adhesion proteins to cytoskeletal components. Several investigators have recently described the expression of different integrins in the human endometrium as markers of receptivity. In the present study we investigated the effect of various doses of the antiprogestin mifepristone on the endometrial expression of integrins during the implantation phase. Endometrial biopsies from healthy fertile women were obtained in the midluteal phase. The study included one control and one, two or three treatment cycles. In treatment cycles either 2.5 (n = 9) or 5 mg (n = 5) of mifepristone was administered once weekly, 0.5 mg daily (n = 5), or 200 mg as a single dose administered on day 2 after the luteinizing hormone surge (day LH + 2; n = 8). By using polyclonal antibodies against integrin alpha(v)beta3, subunit beta3 and subunit alpha4 we found reduced immunostaining for alpha4 and beta3 subunit in glandular epithelium after treatment with mifepristone while alpha(v)beta3, expression appeared to be unaffected. No differences between treatment groups were noted. This study demonstrates that treatment with mifepristone interferes with integrin distribution during the implantation window. This may imply that the contraceptive effect of mifepristone is primarily due to impaired endometrial receptivity. However, since no effect was shown on the distribution of the vitronectin receptor, this integrin might be regulated differently by other factors such as cytokines.      

Expression of macrophage inflammatory protein-3alpha in an endometrial epithelial cell line,HHUA, and cultured human endometrial stromal cells

It has been demonstrated that human endometrial epithelial cells (EEC) and stromal cells (ESC) produce a variety of chemokines in vivo and in vitro. To evaluate the expression of macrophage inflammatory protein (MIP)-3alpha in endometrial cells, the production of MIP-3alpha by an EEC line, HHUA, and cultured ESC stimulated with various inflammatory mediators was evaluated by ELISA. Unstimulated HHUA and ESC constitutively secreted MIP-3alpha. Tumour necrosis factor-alpha and interleukin-1beta significantly stimulated the secretion of MIP-3alpha by HHUA and ESC. Lipopolysaccharide also stimulated the secretion of MIP-3alpha by ESC, but not by HHUA. These results show that the concentration of MIP-3alpha in the endometrium is modulated by these inflammatory mediators. MIP-3alpha may contribute to the normal and pathological processes of human reproduction by regulating the trafficking of immature dendritic cells and memory T lymphocytes into the endometrium.     

Endocrinology: Physiological oestradiol and progesterone replacement cycles in women with ovarian failure: a model to study endometrial maturation and sex steroid receptor regulation by exogenous hormones

High endometrial receptivity has been achieved with physiologicaloestradiol and progesterone replacement cycles in women withovarian failure. To understand whether different protocols usingthe oral route or the transdermal route can influence the endometrialmaturation and the regulation of sex steroid receptors, we studied33 women with ovarian failure treated by two commonly used protocolsand assessed endometrial receptivity using light microscopy,scanning electron microscopy and immunohistochemistry for oestrogenand progesterone receptors on biopsies taken to include differentperiods of the luteal phase. The morphology in these patientswas similar to that observed in women with normal ovulatorycycles, indicating that the morphological response is not dependenton the type of oestradiol, oral or transdermal, in the replacementcycles as compared to the endogenous oestradiol in the menstrualcycle. The relative distribution of steroid receptors betweenthe epithelium and stroma varies similarly to that observedduring the luteal phase of the menstrual cycle. These resultsconfirm the role of progesterone, especially the importanceof the number of days of exposure to it, in the disappearanceof steroid receptors from endometrial glands. These observationsgive a better understanding of endometrial receptivity aroundthe time of presumed implantation and confirm clinical resultsconcerning the best timing of oocyte transfer.     

Apoptosis in endometrial glandular and stromal cells in women with and without endometriosis

BACKGROUND: The aetiology of endometriosis is unknown. Ectopic dissemination of the endometrial cells gives origin to endometriotic lesions, but occurs in women with and without endometriosis. It has been suggested that increased ectopic cell survival facilitates their implantation. The objectives of this study were to evaluate endometrial apoptosis in women with endometriosis according to: (i) cyclic changes, (ii) glandular and stromal contribution, and (iii) stage of the disease. METHODS: The subjects were women undergoing diagnostic laparoscopy and endometrial biopsies for suspected endometriosis. Spontaneous apoptosis was evaluated using TdT-mediated dUTP-biotin nick end-labelling (TUNEL) assay. Apoptotic cells per 10 mm(2) (apoptotic index) in an area of 10-50 mm(2) in 5 microm endometrial tissue sections were counted and location of these cells was recorded. RESULTS: The apoptotic index in glandular epithelium was lower in endometriosis than controls (26.0 +/- 5.5 versus 51.2 +/- 9.7, P = 0.03) but not in the stroma (36.3 +/- 6.4 versus 48.4 +/- 11.3, NS). In controls, apoptosis was highest during the late secretory/menstrual and early proliferative phases and cyclic variability was apparent. In endometriosis, this cyclic variability was lost. There was a trend toward decreased apoptosis with increasing stage of the disease, but the differences lacked statistical significance. CONCLUSIONS: Spontaneous apoptosis is decreased in the endometrial glands in women with endometriosis, especially during late secretory/menstrual and early proliferative phases of the cycle. This may indicate increased viability of endometrial cells shed during menses, facilitating their ectopic survival and implantation.