Effectiveness of myo-inositol oxygenase in the early diagnosis of experimental acute kidney injury.

OBJECTIVES: The effectiveness of the myo-inositol oxygenase (MIOX) enzyme was investigated in the diagnosis of acute kidney injury (AKI). METHODS: In total, 40 rats were divided into 5 groups (n = 8, for each group) while left kidney ischemia-reperfusion was implemented in groups 2, 3, 4 and 5. Group 1 was the control group. Group 2 underwent 1­hour ischemia and 2­hour reperfusion. Group 3 underwent 1­hour ischemia and 4­hour reperfusion. Group 4 underwent 2­hour ischemia and 2­hour reperfusion. Group 5 underwent 2­hour ischemia and 4­hour reperfusion. RESULTS: Serum creatinine and blood urea nitrogen levels in all ischemia-reperfusion groups were higher than in the control group (p<0.001). Serum MIOX level was higher in groups 2, 3 and 4 than in group 1 (p=0.002). Tissue MIOX level was lower in groups 2, 4, and 5 than in group 1 (p=0.039). Serum and tissue neutrophil gelatinase-associated lipocalin levels were not significantly different between the groups. The injury level in histopathologic examination was as follows: group 1

Tracheobroncopathia osteochondroplastica: Three case reports with literature review.

Tracheobroncopathia osteochondroplastica (TO) is a benign disease of the large airways seen very rarely. It is characterized by 1-3 mm sized ossified nodular lesions in submucosa. Its etiology is unclear, but it is stated that malignancy, chronic inflammation, amyloidosis, and genetic factors might have an effect on it. It was first described by Wilks in a 38-year-old man diagnosed with tuberculosis in 1857. Generally, patients are asymptomatic and TO is diagnosed incidentally. But symptoms become significant with infections and obstruction in tracheabronchial tree. Generally chest radiography is normal, so thorax computed tomography can be remarkable in diagnosis of TO. Besides, final diagnosis can be established by viewing ossified nodules in trachea and bronchus through the fiberoptic bronchoscopy. Amyloidosis, tuberculosis, sarcoidosis, bronchial carcinoma, and tracheobronchial calcinosis must be remembered in differential diagnosis. Also ossifications in submucosa and proof of bone marrow in histopathological examinations are important in diagnosis of TO. Mostly palliative treatment is performed to the symptoms . We want the clinicians to keep in mind for this very rarely seen tracheal disease with three case reports.

Harmful effects of formaldehyde and possible protective effect of Nigella sativa on the trachea of rats.

OBJECTIVE: We aimed in this study to investigate the harmful effects of formaldehyde (FA) inhalation and possible protective effects of Nigella sativa (NS) on rats' trachea. MATERIALS AND METHODS: In this study, 63 adult male rats were used. Animals were divided into nine groups. Group I was used as control group. All other groups were exposed to FA inhalation. Group III, V, VII, and IX were administered NS by gavage. Tissues were examined histologically, and immunohistochemical examination for Bax and caspase-3 immunoreactivity was carried out. RESULTS: Our study demonstrated that FA caused apoptosis in the tracheal epithelial cells. The most apoptotic activity occurred at a 10 ppm dose in a 13-week exposure. Distortion of tracheal epithelium and cilia loss on epithelial surface was present in all groups. However, NS treated Groups VII and IX had decreased apoptotic activity and lymphoid infiltration and protected the epithelial structure, despite some shedded areas. Difference of tracheal epithelial thickness and histological score was statistically significant between Group VI-VII and VIII-IX. CONCLUSION: FA induces apoptosis and tracheal epithelial damage in rats, and chronic administration of NS can be used to prevent FA-induced apoptosis and epithelial damage.

HGF/C-MET PATHWAY HAS A ROLE IN TESTICULAR DAMAGE IN DIABETES INDUCED BY STREPTOZOTOCIN.

OBJECTIVE: The aim of the study was to investigate the role of Hepatocyte Growth Factor (HGF)/c-Met pathway in testicular damage provoked by streptozotocin (STZ)- induced diabetes and the effects of insulin treatment on the HGF/c-Met pathway. METHODS: Total 21 paraffin-embedded testicular tissues of control (n=7), streptozotocin (STZ)-induced diabetic (n=7) and insulin-treated diabetic (n=7) Wistar albino rats were used in this study. Testicular damage was examined histologically and by Johnsen's score was also evaluated. Immunohistochemical stainings of HGF and c-Met were analysed by using antibodies against HGF and c-Met. RESULTS: We found the degeneration in seminiferous tubule epithelium and disorganization of spermatogenetic cell series in testis tissues of diabetic rats. We also determined decrease both in seminiferous tubule diameter and Johnsen's scores in diabetic group. The expressions of HGF and c-Met in seminiferous tubule epithelium and in spermatogenic cells (especially spermatocytes and spermatids) were significantly increased in diabetic rats compared to those of control. Insulin treatment significantly reduced the diabetes-induced morphological changes and HGF/c-Met over expressions in the diabetic rat testis. CONCLUSION: HGF/c-Met pathway might have a role in diabetes- induced testicular damage. Drugs acting on this pathway might be effective to prevent or delay the testicular damage induced by diabetes.

Effects of isoflurane in an intoxication model: experimental study.

BACKGROUND: Isoflurane is a volatile anaesthetic that has been commonly used since 1980. The major metabolites of isoflurane are fluoride ion and trifluoroacetate, both excreted in the urine. AIM: This study manage to show the histopathological findings of ingested isoflurane on liver, kidney and lugs in an animal model. Twenty-one rabbits were selected and divided into three groups: Group Isoflurane-5 (I-5); Group Isoflurane-10 (I-10); and Group Control (C). Each group consisted of seven rabbits. I-5 and I-10 received 5 ml/kg and 10 ml/kg of liquid isoflurane, respectively, via nasogastric tube, while C received 5 ml/kg saline (0.9% NaCI). All animals in I-5 and I-10 were sacrificed without anesthetic drug administration. Tissue samples from livers, kidneys and lungs were collected, preserving tissue unity and avoiding infliction of any trauma. Samples were fixed in 10% formalin solution, embedded in paraffin blocks and sliced into 5 µm sections. To investigate the effects of isoflurane, sections were examined under light microscope and histopathological changes were scored. RESULTS: Mean injury scores and the appearance of portal lymphocyte infiltration in liver samples showed significant increases in I-5 and I-10 compared to C (p = 0.005, p = 0.001 and p = 0.001, respectively). Mean lung injury scores revealed significant increases after isoflurane treatment in I-5 and I-10 compared to C (p = 0.026 and p = 0.017, respectively). CONCLUSIONS: Ingested isoflurane led to mild liver and lung injuries in rabbits.

High rate of allergies among women with endometriosis.

Women with endometriosis frequently suffer from autoimmune inflammatory diseases, allergies and asthma. This study was conducted to examine whether the prevalence of allergies is higher in patients with endometriosis than in the control group, and to show potential correlation with endometriosis stages. We evaluated the medical files of 501 women with laparoscopically-diagnosed endometriosis and 188 women without endometriosis enrolled in Yale University Hospital. Main outcome measures used were allergy on medications, complaints of sinus or perennial allergic rhinitis, asthma, family history of allergic disease, and correlation with stages of endometriosis. Our results indicated that the overall risk of women with endometriosis and positive history of allergies was 4.28 (95% CI, 2.9-6.3) (p < 0.001). Significant excesses were identified for medications, sinus allergic rhinitis, and asthma; also, women with endometriosis were significantly more likely to report a positive family history of allergies. Overall, our study indicated a link between endometriosis and increased risk of allergic autoimmune disorders that should further be explored.

Effect of the new legislation and single-embryo transfer policy in Turkey on assisted reproduction outcomes: preliminary results.

New legislation concerning assisted reproduction treatments was introduced in Turkey in March 2010 in order to reduce the number of multiple pregnancies. This new legislation limits the number of embryos to be transferred to one under 35 years of age in the first or second treatment cycles and to two in the third or further cycles or for 35 and older ages. The aim of this multicentre study was to investigate the effect of this new law on clinical pregnancy and multiple pregnancy rates. Outcomes were compared in equal periods of 2.5 months before and after the new law, and further investigation was conducted for two different age groups: <35 and ≥ 35. The clinical pregnancy rates decreased from 39.9 to 34.5% and multiple pregnancy rates decreased from 23.1 to 5.3% (P<0.001) for the overall population. The outcomes of the <35 age group and ≥ 35 age group were also similar to that of the overall population. These results suggest that under the new legislation multiple pregnancy rates are significantly reduced without causing a significant decline in the pregnancy rates.

Endometriosis-associated Lyme disease.

The aim of this study is to report three cases of patients with endometriosis and infertility, and associated with Lyme disease. The medical files of 405 women with endometriosis and 200 without endometriosis were studied retrospectively. We report 3 cases with endometriosis and Lyme disease. Of 405 patients with endometriosis treated in our study over a 6-year period, 3(0.8%) had Lyme disease. All cases presented with typical erythema migraines, fever and fatigue. The serological findings were positive for Borrelia burgdorferi, for 3 cases. Two out of 3 women underwent IVF-ET procedures and one of them conceived in the first cycle without complication during pregnancy or after childbirth recorded. We concluded that women with endometriosis are more likely to have chronic fatigue syndrome, systemic lupus erythematous, Sjögren's syndrome, rheumatoid arthritis, multiple sclerosis, and other autoimmune inflammatory and endocrine diseases. A review of the literature confirms the uniqueness of the co-existence of Lyme disease in women with endometriosis in these cases.

Association of endometriosis with family history of non-Hodgkin's lymphoma: presentation of 10 cases.

PURPOSE: Women with endometriosis have been reported to be at increased risk of developing non-Hodgkin's lymphoma (NHL). The purpose of this article was to investigate the familial risk of NHL in women with endometriosis. We report on 10 cases with endometriosis and positive family history of NHL. METHODS: The medical records of 405 women with endometriosis and 200 without endometriosis were retrospectively analysed. All of the cases were diagnosed by laparoscopy. Ten cases of endometriosis having first-degree relatives with NHL are reported. RESULTS: We found no case with endometriosis and NHL. In contrast, we found 10/405 (2.5%) women with endometriosis and first-degree relatives with NHL. Their mean age was 38.3 years (range 29-46). The main complaint was infertility. The mean age at onset of endometriosis was 32 years (range 22-43). The stages of endometriosis were: stage II (n=4), stage III (n=2) and stage IV (n=4). All of these patients had first-degree relatives with a history of NHL. Five had mothers with NHL, 5 had fathers and one had a sister. CONCLUSION: These cases could suggest a link between a family history of NHL and subsequent development of endometriosis in the first-generation women. Moreover, there was no evidence of association between endometriosis and NHL.

Regulation and activation of ezrin protein in endometriosis.

BACKGROUND: Ezrin protein and its activated form phospho-ezrin play a role in cell morphology, motility and adhesiveness. In this study, we hypothesized that these proteins play a role in the pathogenesis of endometriosis by promoting adhesion and invasion of endometrial stromal cells (ESCs) in ectopic sites. METHODS: We compared the expression of ezrin and phospho-ezrin in normal endometrium from women without endometriosis with their expression in eutopic and ectopic endometrial tissues from women with endometriosis, using immunohistochemistry and western blot analysis. Paired eutopic and ectopic endometrial tissue samples from women with endometriosis (n = 13) and normal endometrium from women without endometriosis (n = 12) were collected. Invasive potential of ESCs from each of these samples was compared using Matrigel membrane invasion assay. RESULTS: Eutopic and ectopic endometrial tissues from women with endometriosis have higher ezrin and phospho-ezrin levels as confirmed by immunohistochemistry and western blot analysis (P < 0.05). The Matrigel membrane invasion assay revealed that ectopic ESCs have more invasive characteristics, more protrusions and higher ezrin staining than normal ESCs (P < 0.05). CONCLUSIONS: Ezrin can be a potential marker for endometrial cell invasion and may play a role in the pathogenesis of endometriosis.

Epidemiological factors influencing IVF outcome: Evidence from the Yale IVF program.

Age, BMI, lifestyle, menstrual status and obstetric history can modulate the endocrine system and, therefore, have been hypothesised to play a role in in-vitro fertilisation (IVF) outcome. We designed a retrospective study, set in a medical school hospital. We evaluated the medical files of 297 infertile women who underwent laparoscopy and consecutive IVF-ET treatment in the Yale IVF unit between 1996 and 2002. The study group consisted of 151 women who conceived after IVF-ET and the control group of 146 women who underwent 288 IVF-ET cycles without pregnancy. The main outcome measure was the impact of epidemiological factors on the IVF outcome. There was no association between IVF outcome and race, BMI, age at menarche, length of cycle, duration and amount of flow, menstrual symptoms, other medical problems, medical history of allergies, and family history of endometriosis and cancer. We found that the degree of smoking and alcohol use was not a factor when comparing women with and without pregnancy after IVF (34.5% vs 29.5%, and 33.7% vs 27%, respectively). The rate of duration of infertility tended to be lower in pregnant women (35.9+/-23.4 months) vs (42.3+/-30.2) non-pregnant women. As expected, we also confirmed the inverse association between the age of women and IVF outcome. Overall, body attributes, lifestyle, family history, menstrual and reproductive factors were not related to IVF-ET outcome.

HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium.

Hox genes are well-known transcriptional regulators that play an essential role in directing embryonic development. Mice that are homozygous for a targeted disruption of the Hoxa10 gene exhibit uterine factor infertility. We have recently demonstrated that HOXA10 is expressed in the adult human uterus. To examine expression of HOXA10 during the menstrual cycle, Northern blot analysis and in situ hybridization were performed. Expression of HOXA10 dramatically increased during the midsecretory phase of the menstrual cycle, corresponding to the time of implantation and increase in circulating progesterone. Expression of HOXA10 in cultured endometrial cells was stimulated by estrogen or progesterone. Stimulation of HOXA10 by progesterone was concentration-dependent within the physiologic range, and the effect of estrogen was inhibited by cycloheximide. These results identify sex steroids as novel regulators of HOX gene expression. HOXA10 may have an important function in regulating endometrial development during the menstrual cycle and in establishing conditions necessary for implantation in the human.

Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis.

BACKGROUND: Women with endometriosis who are treated with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have a lower pregnancy rate compared to women with tubal factor infertility. It has been suggested that the administration of gonadotrophin releasing hormone (GnRH) agonists for a few months prior to IVF or ICSI increases the pregnancy rate. OBJECTIVES: To determine the effectiveness of administering GnRH agonists for three to six months prior to IVF or ICSI in women with endometriosis. SEARCH STRATEGY: We used computer searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the National Research Register (NRR) and the MDSG Specialised Register of controlled trials. We handsearched proceedings of annual meetings of the American Society for Reproductive Medicine (ASRM) and the European Society for Human Reproduction and Embryology (ESHRE). We reviewed lists of references in original research and review articles. We contacted experts in various countries to identify unpublished trials. SELECTION CRITERIA: We included randomised controlled trials using any GnRH agonist prior to IVF or ICSI to treat women with any degree of endometriosis diagnosed by laparoscopy or laparotomy DATA COLLECTION AND ANALYSIS: Two independent review authors abstracted data (HNS and JGV). We sent e-mails to investigators to seek additional information. We assessed the validity of each study using the methods suggested in the Cochrane Handbook. The data were checked by the third review author (SD) and any disagreement was resolved by arbitration with the fourth review author (AA). We generated 2 x 2 tables for principal outcome measures. The Peto-modified Mantel-Haenszel technique was used to calculate odds ratios (OR) and assess statistical heterogeneity between studies. MAIN RESULTS: Three randomised controlled trials (with 165 women) were included. The live birth rate per woman was significantly higher in women receiving the GnRH agonist compared to the control group (OR 9.19, 95% CI 1.08 to 78.22). However, this was based on one trial reporting "viable pregnancy" only. The clinical pregnancy rate per woman was also significantly higher (three studies: OR 4.28, 95% CI 2.00 to 9.15). The information on miscarriage rates came from two trials with high heterogeneity and, therefore, results of the meta-analysis were doubtful. The included studies provided insufficient data to investigate the effects of administration of GnRH agonists on multiple or ectopic pregnancies, fetal abnormalities or other complications. AUTHORS' CONCLUSIONS: The administration of GnRH agonists for a period of three to six months prior to IVF or ICSI in women with endometriosis increases the odds of clinical pregnancy by fourfold. Data regarding adverse effects of this therapy on the mother or fetus are not available at present.

Immunology of endometriosis.

Endometriosis is classically described as the presence of both endometrial glandular and stromal cells outside the uterine cavity, mainly in the pelvis. The pathogenesis of this enigmatic disorder still remains controversial despite extensive research. Although multiple theories have been put forth to explain the pathophysiology and pathogenesis of endometriosis, the retrograde menstruation theory of Sampson is the most widely accepted. However, since retrograde menstruation occurs in most of the reproductive age women, it is clear that there must be other factors which may contribute to the implantation of endometrial cells and their subsequent development into endometriotic disease. There is substantial evidence to support that the alterations in both cell-mediated and humoral immunity contribute to the pathogenesis of endometriosis. Increased number and activation of peritoneal macrophages, decreased T cell and natural killer (NK) cell cytotoxicities are the alterations in cellular immunity and result in inadequate removal of ectopic endometrial cells from the peritoneal cavity. Moreover, increased levels of several cytokines and growth factors which are secreted by either immune and endometrial cells seem to promote implantation and growth of ectopic endometrium by inducing proliferation and angiogenesis. In addition to the impaired capacity of the immune cells to mediate endometrial cell removal, inherent resistance of the ectopic endometrial cells against immune cells is another interesting concept in the pathogenesis of endometriosis. Endometriosis has also been considered to be an autoimmune disease, since it is often associated with the presence of autoantibodies, other autoimmune diseases, and possibly with recurrent immune-mediated abortion.

Interleukin-8 expression and modulation in human preovulatory follicles and ovarian cells.

Just before the time of ovulation, the number of neutrophils increases markedly in the thecal layer of the leading follicle. A preovulatory rise in chemotactic activity for neutrophils in human follicular fluid has also been detected. We hypothesized that interleukin-8 (IL-8), a neutrophil chemoattractant/activating factor and a potent angiogenic agent, may be an important modulator of leukocyte chemotaxis in ovulatory function. In this regard we investigated the expression and modulation of IL-8 in human follicular fluid samples from patients undergoing in vitro fertilization-embryo transfer therapy and in ovarian stromal and granulosa-lutein cell cultures. The concentration of IL-8 in pre-hCG follicular fluid samples (n = 4) was 16 +/- 12 (mean +/- SEM) pg/ml, and that in post-hCG samples (n = 101) was 262 +/- 45 pg/ml (P = 0.001). In post-hCG samples, the concentration of IL-8 in an individual follicle correlated with the size of that follicle (r = 0.61; P = 0.02). We also observed a correlation between serum IL-8 levels (22 +/- 3 pg/ml) and follicular fluid levels (303 +/- 143 pg/ml), with a 14-fold gradient (r = 0.71; P = 0.01) in 11 patients tested for both. IL-8 messenger RNA (mRNA) and the protein were expressed constitutively in ovarian stromal cell cultures, and the level was increased by IL-1 alpha and tumor necrosis factor-alpha in a time- and concentration-dependent manner. hCG and LH induced higher levels of IL-8 mRNA expression and protein production. Granulosalutein cells also expressed IL-8 mRNA and protein, and the levels were increased by IL-1 alpha and tumor necrosis factor-alpha. Importantly, progesterone suppressed both basal and IL-1 alpha-stimulated IL-8 expression in stromal and granulosa-lutein cell types. In summary, we found that IL-8 levels are elevated in periovulatory follicular fluid, and both granulosa-lutein and ovarian stromal cells express the mRNA and produce the protein. The modulation of IL-8 in these cell cultures by steroid and trophic hormones suggests that IL-8 may play an important role in the physiology of ovulation, such as timely follicular rupture and neovascularization of the corpus luteum.

Modulation of the levels of interleukin-8 messenger ribonucleic acid and interleukin-8 protein synthesis in human endometrial stromal cells by transforming growth factor-beta 1.

Selected functions of uterine endometrium of ovulatory women before and during pregnancy appear to be modulated by cytokines and other paracrine-acting factors. Some of these functions are regulated, in turn, by cyclic changes in ovarian steroid secretion or by pregnancy-induced endocrine and paracrine factors. The recruitment of specific types and numbers of bone marrow-derived cells into the endometrium occurs in a predictable manner with hormonal changes of the ovarian cycle, during the process of endometrial decidualization, at the time of blastocyst implantation, and during pregnancy, parturition, and the puerperium. As part of an investigation of the regulation of the leukocyte population of endometrium/decidua, this study was conducted to evaluate further the regulation of interleukin-8 (IL-8) gene expression by transforming growth factor-beta (TGF beta). IL-8 is a neutrophil chemoattractant/activating and T cell chemotactic factor as well as a chemotactic factor for fibroblasts. IL-8 is produced by mesenchymal cells of many tissues, including human endometrial stromal cells in culture. The level of IL-8 messenger ribonucleic acid (mRNA) in endometrial stromal cells and the accumulation of immunoreactive IL-8 in medium are increased by TGF beta 1 treatment of these cells. This response to TGF beta 1 is attributable primarily to an increase in the stability of IL-8 mRNA through a process that is dependent on protein synthesis. Transcription of the IL-8 gene in endometrial stromal cells is not increased, but, rather, is slightly decreased, by treatment with TGF beta 1. The findings of this study indicate that TGF beta may act in endometrial stroma to modulate the stability of IL-8 mRNA.

Interleukin-8 in the human fallopian tube.

The human fallopian tube is a dynamic structure that undergoes cyclic variation in its functional epithelium. This epithelium contains both secretory and ciliated cells. The mechanisms regulating the growth and function of the tubal epithelium are not fully understood. Interleukin-8 (IL-8) is one potential local regulatory factor. We therefore characterized the IL-8 system, which includes IL-8, its receptors A and B, and its degradative enzyme aminopeptidase N, in the human fallopian tube by immunohistochemistry. Immunohistochemistry was performed on isthmic, ampullary, and fimbrial fallopian tubal segments obtained from women undergoing gynecological surgical procedures for benign conditions (n = 52). IL-8 was found in the human fallopian tube predominantly in the epithelial cells. It was present in greater amounts in the distal compared with the proximal tube. IL-8 receptors A and B localized in the tube in similar patterns. The degradative enzyme aminopeptidase N is found in tubal stromal tissue at the epithelial stromal border and perivascularly and may limit the systemic effects of epithelial IL-8. The IL-8 system seems to be an active component of tubal physiology.

Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in human endometrium.

Implantation is the process by which the blastocyst becomes intimately connected with the maternal endometrium/decidua. The independently developing preimplantation blastocyst then becomes dependent on the maternal environment for its continued development. Although the factors involved in the regulation of blastocyst implantation are incompletely understood, recent studies strongly suggest a critical role for leukemia inhibitory factor (LIF) in mice. We showed previously that LIF acts on human trophoblasts to shift their differentiation toward the anchoring phenotype by increasing the synthesis of fibronectin. In the present study, we first evaluated the temporal expression of LIF in the human endometrium in order to gain further insights into the role of LIF in human implantation. We established the LIF is expressed in the endometrium in a menstrual cycle-dependent manner. The most abundant LIF messenger ribonucleic acid (mRNA) levels are observed in the mid- and late-luteal phase samples. LIF mRNA was also present in decidual tissues of first trimester of pregnancy, but levels were lower than those found in the midluteal endometrium. We then investigated the regulation of LIF expression in human endometrial cells in culture by cytokines, steroid hormones, and growth factors. We could not show any direct stimulatory evidence of steroid hormones (estradiol and progestins) on LIF mRNA expression or protein production by endometrial cells in culture. On the other hand, we showed that interleukin-1, tumor necrosis factor-alpha, platelet-derived growth factor, epidermal growth factor, and transforming growth factor-beta are potent inducers of LIF expression in endometrial stromal cells in culture in a concentration- and time-dependent manner. Interferon-gamma acted to inhibit LIF expression induced by these cytokines. In contrast, we found high constitutive and relatively less regulated levels of LIF mRNA in the endometrial gland cells. The timing of the expression of LIF in the endometrium suggests a potential role in the implantation. The regulation of the expression of LIF may have an important role in the physiological and pathological processes involving human implantation.

Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium.

Under the influence of sex steroids, human endometrium undergoes sequential development in preparation for implantation. Hoxa11 is essential for implantation in the mouse. Here we describe a potential role for HOXA11 in human endometrial development and implantation. Northern analysis demonstrates that HOXA11 is expressed in a menstrual cycle phase-dependent fashion in adult human endometrium. HOXA11 messenger RNA levels dramatically increase at the time of implantation and remain increased in pregnancy. In vitro, HOXA11 expression is increased in response to estrogen or progesterone. There is a dose-responsive increase over the physiologic range of progesterone concentration. Pretreatment with Cyclohexamide does not decrease the response to estrogen. Steroids are novel regulators HOX gene expression. The spatial and temporal pattern of HOXA11 expression in the human endometrium suggests a role in endometrial development, implantation, and maintenance of pregnancy.

Interleukin-8 induces proliferation of endometrial stromal cells: a potential autocrine growth factor.

Proliferation of endometrium is dependent on sex steroid hormones, but specific growth factors are likely to play an important role in regulating this process. A number of cytokines and growth factors are synthesized in the endometrium in response to sex steroid hormones and act to regulate endometrial function. Endometrial cells produce interleukin-8 (IL-8) both in vivo and in vitro. We hypothesized that IL-8, a neutrophil chemoattractant/activating factor and a potent angiogenic agent that has been shown to stimulate growth in other cell types, may directly stimulate proliferation of endometrial cells. We first investigated the effect of IL-8 and mouse antihuman-IL-8 neutralizing antibody on endometrial stromal cell proliferation using both a colorimetric assay and thymidine uptake. We then investigated the modulation of endometrial stromal cell IL-8 production and proliferation by antisense oligonucleotides specific for IL-8. There was a concentration-dependent increase of cell proliferation with IL-8 (2-fold at 1 ng/mL; P < 0.01 between control and concentrations above 0.01 ng/mL) and a concentration-dependent inhibition of cell proliferation with anti-IL-8 antibody (to 30% of the control at 1 microg/mL; P < 0.01 between control and concentrations above 0.1 microg/mL). IL-8 antisense oligonucleotide treatment decreased IL-8 production by endometrial stromal cells in culture as well as cell proliferation when it is compared with scrambled (nonsense) oligonucleotide treatment (P < 0.01). Addition of IL-8 (1 ng/mL) reversed the proliferation inhibitory effect of IL-8 antisense oligonucleotides. We propose that IL-8 may act as an autocrine growth factor in the endometrium, and suggest that it may also play a role in the pathogenesis of endometriosis.