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PubMed2004

Endometrial leptin and leptin receptor expression in women with severe/moderate endometriosis.

The leptin system has been implicated in reproductive function, acting at endocrine and paracrine levels. Recently, deregulation of this gene family has been linked to endometrial changes caused by endometriosis. In the present study, we compare the expression of leptin receptor mRNA during the pre-receptive (LH+2) and receptive (LH+9) phases in the eutopic endometrium from patients with severe/moderate endometriosis (n = 30) versus fertile controls (n = 12). In each patient, two endometrial samples were obtained at LH+2 and LH+9 in their natural cycles. When real-time quantitative fluorescent PCR was performed, an up-regulation of OB-RL and all the isoforms investigated was observed at LH+9 versus LH+2 in patients with and without endometriosis. However, no difference was found in the expression pattern of the total leptin receptor OB-RT, or in its long OB-RL and soluble HuB219.3 forms when the eutopic endometria of patients with severe/moderate endometriosis and fertile controls were compared. By means of in situ hybridization, total leptin receptor mRNA was localized in the luminal epithelium and the glands of the endometrium. The immunohistochemical analysis of the long form of leptin receptor was also performed in order to confirm these findings at the protein level. Finally, we have also shown similar leptin mRNA expression in both the control group and patients with endometriosis. In conclusion, we have not identified differences in the endometrial expression and localization of leptin and the leptin receptor when comparing the eutopic endometrium of women with severe/moderate endometriosis and fertile controls.

Adult↗

PubMed2004

FOXO1 and c-jun transcription factors mRNA are modulated in endometriosis.

Endometriosis is a polygenic gynaecological condition affecting 5-15% of women of childbearing age. Major symptoms of the disease are pelvic pain and infertility. No clear link has been established between symptoms and the stage of the disease. Although some aspects have begun to be clarified, clinical understanding of endometriosis remains partial at the molecular level. In this perspective, we targeted isolation of differentially expressed genes in the eutopic endometrial tissue. Our assumption was that the endometrial cells of patients presented an unusual gene expression profile, allowing their implantation and survival in an ectopic site, leading to endometriotic lesions. Here, we report that mRNA steady-state levels of two key transcription factors are modulated in endometriosis. FOXO1 (also known as FKHR) levels were 1.6-fold lower in endometriosis compared to the control group at the onset of the secretory phase (day 15-21), while c-jun mRNA was present at higher amounts in endometriosis (1.5-fold) at the proliferative phase of the menstrual cycle. These results were derived from a large sample composed of 157 control subjects and 209 patients with endometriosis. Gene profiling was conducted by real-time quantitative PCR, and data were quality controlled before statistical analysis. Whether protein levels are affected as well remains to be investigated.

DNA-Binding Proteins↗

PubMed2006

KRAS variation and risk of endometriosis.

Endometriosis is a common gynaecological disease with symptoms of pelvic pain and infertility which affects 7-10% of women in their reproductive years. Activation of an oncogenic allele of Kirsten rat sarcoma viral oncogene homologue (KRAS) in the reproductive tract of mice resulted in the development of endometriosis. We hypothesized that variation in KRAS may influence risk of endometriosis in humans. Thirty tagSNPs spanning a region of 60.7 kb across the KRAS locus were genotyped using iPLEX chemistry on a MALDI-TOF MassARRAY platform in 959 endometriosis cases and 959 unrelated controls, and data were analysed for association with endometriosis. Genotypes were obtained for most individuals with a mean completion rate of 99.1%. We identified six haplotype blocks across the KRAS locus in our sample. There were no significant differences between cases and controls in the frequencies of individual single-nucleotide polymorphisms (SNPs) or haplotypes. We also developed a rapid method to screen for 11 common KRAS and BRAF mutations on the Sequenom MassARRAY system. The assay detected all mutations previously identified by direct sequencing in a panel of positive controls. No germline variants for KRAS or BRAF were detected. Our results demonstrate that any risk of endometriosis in women because of common variation in KRAS must be very small.

Adolescent↗

PubMed1996

Increased prevalence and recurrence of retrograde menstruation in baboons with spontaneous endometriosis.

This study was done to test the hypothesis that the incidence and recurrence of retrograde menstruation is higher in baboons with spontaneous endometriosis than in those without. A total of 399 laparoscopies was performed on 113 female baboons. Group 1 consisted of 84 animals with a normal pelvis (including 23 that later underwent induction of endometriosis and were assigned to group 4), group 2 comprised nine baboons with spontaneous endometriosis acquired during the last 2 years of the study, group 3 had 18 baboons with long-term spontaneous disease, and group 4 comprised 25 animals with induced endometriosis. Retrograde menstruation was defined by the presence of blood-stained peritoneal fluid (red or dark brown) during menses. Recurrence of retrograde menstruation was analysed during the first two laparoscopies in 13 baboons. Peritoneal fluid was 10 times more frequently blood-stained during menses (62%) than during non-menstrual phases (6%). Retrograde menstruation was observed more frequently in animals with spontaneous disease (groups 2 and 3, 83%) than in animals with a normal pelvis (group 1, 51%). Recurrence of retrograde menstruation was observed more frequently in baboons with spontaneous endometriosis (5/5) than in those without (3/8). The results of this study demonstrate that retrograde menstruation is common in baboons, with a higher prevalence and recurrence in animals with spontaneous endometriosis than in those without.

Animals↗

PubMed1988

Endometriosis and infertility: our experience over five years.

During a 5-year period, we diagnosed endometriosis by laparoscopy in 163 infertile patients (7.9% of the infertile population). Seventy-one women presented with minimal endometriosis, 32 women a mild form, 38 women a moderate form and 22 women a severe form. Only 40 patients (24.5%) were found to have endometriosis as the only abnormality in a complete fertility work-up. One hundred and twenty patients were treated with Danazol (600 mg daily for 4-6 months) and 33 of them conceived (27.5%). Twenty-eight patients received conservative surgical treatment associated with Danazol therapy and 11 of them conceived (39.2%). In the 15 patients with minimal endometriosis, who had no therapy but expectant management, there were two conceptions within one year (13.3%). The anticipation of minimal disease in patients with endometriosis as the only abnormality produced about the same results as achieved by active treatment (pregnancy rate of 33.3% after expectant management and 36.3% after treatment). These results suggest that minimal endometriosis can be anticipated only when there are no co-existing factors of infertility.

Adult↗

PubMed1991

CA 125 in peritoneal fluid from patients with endometriosis.

This study was performed to evaluate CA 125 in peritoneal fluid as an indicator of endometriosis. Peritoneal fluid from patients with mostly minimal and mild endometriosis (n = 43) and normal controls (n = 17) was collected at laparoscopy or laparotomy. The median concentration of CA 125 in peritoneal fluid did not differ significantly between patients and controls (79 IU/ml versus 76 IU/ml). In patients with endometriosis, a significantly increasing concentration of CA 125 in peritoneal fluid was seen from the early follicular to the late luteal phase; a similar change was not observed in the controls. In 14 patients, peritoneal fluid was sampled again after treatment with danazol and a significant reduction in median CA 125 concentration (76.5 IU/ml versus 57 IU/ml), peritoneal fluid volume (17.5 ml versus 10.5 ml) as well as reduced endometriosis scores (4 versus 2) were found. In controls, the concentration of CA 125 was about 10 times higher in peritoneal fluid than in serum. As the peritoneal levels of CA 125 did not differ significantly between patients with endometriosis and controls and as the reduction seen after danazol treatment did not correlate with the decrease of endometriotic implants, it is concluded that the monitoring of CA 125 in peritoneal fluid will not be useful in the diagnosis or control of endometriosis.

Adult↗

PubMed1992

Ovarian steroid receptor expression in endometriosis and in two potential parent epithelia: endometrium and peritoneal mesothelium.

Endometriosis is an oestrogen dependent condition and it is expected that the tissue of origin of endometriosis will express receptors for the ovarian steroids. Two epithelia, endometrium and peritoneal mesothelium, are the potential parent epithelium. Oestrogen and progesterone receptor expression has been studied immunohistochemically in (i) timed endometrial biopsies from 25 normal subjects and 27 patients with endometriosis, (ii) 25 endometriotic biopsies and (iii) 42 peritoneal biopsies. Endometrium but not peritoneal mesothelium expresses both oestrogen and progesterone receptors. No difference in the intensity of staining between endometria of normal subjects compared with the endometria of patients with endometriosis was noted. In paired endometrial and endometriotic biopsies, the intensity of staining for the oestrogen receptor in stromal cells and for the progesterone receptor in both glandular and stromal cells was less in the endometriotic biopsies. These data provide circumstantial evidence for an endometrial origin for endometriosis although quantitative differences exist in receptor expression between endometrium and endometriosis.

Endometriosis↗

PubMed1993

Scanning electron microscopic and immunohistochemical studies of pelvic endometriosis.

The pathogenesis of pelvic endometriosis has been studied by using scanning electron and light microscopy, observing the surface structure of bluish lesions obtained from 26 patients during laparotomy. Paraffin sections included another 17 tissue samples of endometriosis, based on immunohistochemical responses to epithelial membrane antigen, keratin and vimentin. Ultrastructurally, the surface epithelial cells could not be detected in 13 out of 17 pelvic peritoneal endometriosis samples. In one case in which the surface peritoneal cells were seen histologically to dip into the subperitoneal stroma, many surface peritoneal infoldings were observed, and ciliated cells were detected at the edge of these infoldings. Ovarian endometriosis was composed of three types of cells, none of which had any cilia. These findings were observed in continuity with adjacent normal mesothelial cells. No characteristic structure of the endometrial surface was observed for the bluish lesion, but the gland surface of endometriosis located in the subperitoneal stroma initially had ciliated cells. The immunoreactions in both the columnar mesothelial cells with surface peritoneal infoldings and the glands of endometriotic tissues were similar to those of normal endometrial glands, but different from those of normal mesothelial cells. Pelvic endometriosis might originate by a process of metaplasia from the pelvic peritoneum.

Adult↗

PubMed1994

Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation.

A retrospective analysis of our in-vitro fertilization (IVF) and oocyte donation programmes was carried out in order to gain clinical knowledge of the factors involved in the aetiology of the endometriosis-associated infertility. Comparison between the IVF outcomes from 96 cycles in 78 patients with tubal infertility and from 96 cycles in 59 women with endometriosis indicates that endometriosis patients have a poor IVF outcome in terms of reduced pregnancy rate per cycle (P < 0.0004), reduced pregnancy rate per transfer (P < 0.002), and reduced implantation rate (P < 0.003). The analysis of patients undergoing oocyte donation for different reasons, including low response with or without endometriosis, showed that patients with this disease have the same chances of implantation and pregnancy as other recipients when the oocytes came from donors without known endometriosis. However, when the results of oocyte donation were classified according to the origin of the oocytes donated, patients who received embryos derived from endometriotic ovaries showed a significantly (P < 0.05) reduced implantation rate as compared to the remaining groups. Taken together, all these observations suggest that infertility in endometriosis patients may be related to alterations within the oocyte, which in turn result in embryos with decreased ability to implant.

Adult↗

PubMed1994

Oestrogen and progesterone receptors in endometriosis: heterogeneity of different sites.

The expression of receptors for the ovarian steroid hormones oestrogen and progesterone was studied immunohistochemically using monoclonal antibodies in samples of endometriosis and endometrium in 22 patients. In nine patients samples of endometriosis from more than one site were studied. There was marked heterogeneity in expression of receptors in endometriosis, both when comparing lesions with the corresponding endometrium and also between samples of endometriosis collected from different sites within the same patient. It was suggested that local environmental factors related to the site, depth and degree of fibrosis of the lesions determine the amount of steroid hormone stimulation reaching the lesions and account for the observed difference between endometriosis and endometrium and between endometriosis lesions of different sites.

Endometriosis↗

PubMed1991

Prevalence and laparoscopic appearance of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus).

The prevalence of spontaneous endometriosis was investigated by laparoscopy in 52 baboons (Papio anubis and Papio cynocephalus) of proven fertility. Clinical endometriosis was diagnosed in 9 (17%) and 4 (8%) baboons with or without a previous hysterotomy, respectively. Endometriosis was confirmed by histology in 75% of these animals. The 37 endometriotic lesions were classified as typical (13%), subtle (57%), or suspicious (30%); and the percentage of histological confirmation was 100%, 61%, and 50%, respectively. Lesions were found on the uterosacral ligaments and in Douglas' pouch (46%), on the uterine peritoneum and the uterovesical fold (38%), and on uterine-omental adhesions (11%). Only 5% of the lesions were localized on the ovarian ligament, whereas ovarian endometriosis was not found. This study for the first time demonstrates that spontaneous endometriosis occurs in healthy baboons with proven fertility. It also shows that the laparoscopic appearances, the histological aspect, and the localization of the pelvic lesions are comparable to those found in women. We therefore conclude that the baboon is a good animal model for the study of endometriosis.

Animals↗

PubMed1997

Immunoblot detection of decreased antibodies to haptoglobin-like protein in the serum of infertile women with or without endometriosis.

The purpose of this study was to find out differences in the levels of antibodies to distinct antigens in the serum of fertile versus infertile patients with and without endometriosis and to identify these antigens. Blood was collected from 61 patients undergoing laparoscopy for pelvic pain, infertility, or tubal ligation. Serum antibodies against serum antigens with apparent molecular masses of 22 kDa and 18 kDa were assessed by immunoblot analysis. Gel filtration, HPLC DEAE ion-exchange chromatography, NH2-terminal sequencing, and double immunodiffusion were used to characterize and identify these proteins. The relative amount of antibodies reacting with 22- and 18-kDa proteins detected in a standard preparation of antigens was significantly lower in the serum of infertile patients with endometriosis (0.20 +/- 0.05 and 0.57 +/- 0.10) and without endometriosis (0.21 +/- 0.06 and 0.53 +/- 0.08) compared to that of control fertile women without endometriosis (0.53 +/- 0.08 and 1.09 +/- 0.13). After purification by chromatography, the NH2-terminal amino acid sequence of the proteins in the 22- and 18-kDa range was identical through 20 amino acids with the alpha chain of the human haptoglobin. Double immunodiffusion implied immunochemical identity between commercial human haptoglobin and the purified proteins. We conclude that infertile patients with and without endometriosis show reduced serum levels of antibodies against a haptoglobin-like protein. These results would indicate an alteration of the immune system or changes in the levels of these antigens in infertility and/or endometriosis.

Adult↗

PubMed1999

An update on the classification of endometriosis.

The challenge of creating a satisfactory classification of endometriosis remains to be answered. The ability of the current classification schemes to predict pregnancy outcome or to aid in the management of pelvic pain is recognized to be inadequate. Further revisions of the current classification scheme are anticipated as the understanding of how endometriosis contributes to infertility and pelvic pain evolves. In any revision of the classification system, use of empirically derived weights and breakpoints to define disease stages based on outcome data in larger clinical trials should be attempted. It is also possible that additional factors such as CA-125 level or lesion characteristics may be shown to play an important role in prognosis. If so, these will need to be accounted for in the classification scheme. Careful and consistent use of the recommendations of the American Society for Reproductive Medicine classification of endometriosis subcommittee should allow for collection of data for use in further revisions. It is quite possible that a classification scheme that is designed to predict outcome with respect to pregnancy may be totally inadequate in assessing patients who have endometriosis and pelvic pain. Factors found to be important in the assessment of pelvic pain may be different from those involved with the pathophysiology of endometriosis and infertility. The AFS form suggested for use in the management of endometriosis in the presence of pelvic pain allows for recording of variables such as depth of invasion, histology, as well as documenting adjunct investigations and preoperative physical findings. Such prospective data collection and review in large centers may provide a large clinical base from which to derive empirical point scores and breakpoints in a classification scheme.

Endometriosis↗

PubMed1983

Immunoglobulin content of the endometrium in women with endometriosis.

A study of the immunoglobulin content of endometria from women with and without endometriosis has shown that, in women with endometriosis, both IgG and IgA are more commonly found in the interstitium of the endometrial stroma than is the case in endometria from women without this disease. It is thought that the increased stromal content of immunoglobulins in endometriosis is simply a passive reflection of elevated serum IgG and IgA levels. Both the incidence and extent of positive endometrial glandular epithelial staining for IgG and IgA are markedly increased in women with endometriosis: the excess of intraepithelial IgA is probably simply a consequence of the excess of stromal IgA, but the increased epithelial staining for IgG lends support to the concept that many women with endometriosis develop autoantibodies directed against an endometrial epithelial antigen. No relationship could be demonstrated, however, between IgG deposition in the endometrium of women with endometriosis and a history of infertility.

Endometriosis↗

PubMed1986

Management of endometriosis and its associated adhesions with the CO2 laser laparoscope.

One hundred fifty-eight patients with endometriosis were treated with the carbon dioxide laser laparoscope and followed for 15 months. The revised American Fertility Society classification of endometriosis was used to stage the disease. The median revised American Fertility Society points per patient was 29.4. Removal of adhesions, periureteral endometriosis, and superficial bowel endometriosis was accomplished. Complications consisted of bleeding, extravasation of fluid, and uterine and bladder puncture. No serious complications requiring laparotomy were encountered. Significant relief of dysmenorrhea and dyspareunia as well as enhanced fertility was achieved. Second-look laparoscopy confirmed efficient removal of endometriosis. Pain relief and pregnancy data are presented. Endometriosis and its related adhesions can be removed precisely and relatively bloodlessly with the carbon dioxide laser laparoscope. Expertise in advanced laparoscopy and a thorough knowledge of use of the carbon dioxide laser and its bioeffects are prerequisites to performing this procedure.

Carbon Dioxide↗

PubMed1995

Recurrent endometriosis: a review of biological and clinical aspects.

The recurrence of pelvic endometriosis some time after the initial treatment is a common finding in clinical practice. When symptoms of endometriosis reappear several months after treatment, it is difficult to distinguish between recurrence and persistence of the disease. In this review, the current hypotheses about the biological basis of endometriosis recurrence/persistence are discussed. The results of several clinical trials estimating the recurrence rate of endometriosis after medical, surgical, and combined treatments are presented. In addition, a critical analysis of the tools available for the diagnosis of recurrent endometriosis is made, and some therapeutic options to treat recurrent endometriosis are discussed with recommendations for their use.

Endometriosis↗

PubMed2003

Immunomodulators and aromatase inhibitors: are they the next generation of treatment for endometriosis?

PURPOSE OF REVIEW: This article will present an overview of current and new hormonal and non-hormonal medical treatment in the management of endometriosis, with special emphasis on immunomodulators and aromatase inhibitors. RECENT FINDINGS: Recent research shows a very promising role for new hormonal medication (aromatase inhibitors, estrogen and progesterone receptor modulators) and anti-inflammatory drugs (tumor necrosis factor-alpha inhibitors, matrix metalloproteinase inhibitors, cyclooxygenase-2 inhibitors) in the management of endometriosis. SUMMARY: The ideal drug in the treatment of endometriosis alleviates pain and cures sub-fertility without inhibition of ovulation or menstruation and without significant side effects or teratological effects. Such a drug would allow conception during treatment and would fundamentally change the management of endometriosis from a surgical approach to medical management. Although such a drug does not yet exist, promising research using tumor necrosis factor inhibitors indicates that this could become possible in the not too distant future. We strongly recommend testing new medication for the prevention or treatment of endometriosis in the baboon model, an established research model for fundamental and preclinical research in endometriosis.

Adjuvants, Immunologic↗

PubMed2006

Endometriosis and assisted reproduction: the role for reproductive surgery?

PURPOSE OF REVIEW: The aim of this review paper is to discuss the relationship between endometriosis and assisted reproductive technology. More specifically, the following clinically relevant issues will be discussed. (1) Does the presence of endometriosis affect the outcome of assisted reproductive technology? (2) Does surgical treatment for endometriosis prior to or after assisted reproductive technology treatment affect the outcome of assisted reproductive technology? (3) Is assisted reproductive technology a risk factor for the recurrence of endometriosis after medical or surgical therapy? RECENT FINDINGS: The review is based on recently published review papers/meta-analyses or international guidelines as published by the European Society of Human Reproduction or the American Society of Reproductive Medicine, updated with a selective review of recent papers searching PubMed with the key words 'Endometriosis', 'Assisted Reproduction', 'IVF', 'IUI' and 'Reproductive Surgery'. SUMMARY: At the end of this review, a practical proposal for the clinical management of women with endometriosis-associated subfertility is proposed, based on our own experience.

Endometriosis↗