ENDOMETRIOSIS

The cause of endometriosis is not known. The incidence of the disease is greater than was previously suspected and it probably is increasing. Nulliparous women are more likely to have endometriosis than are women who have had children.The commonest symptoms are lower abdominal pain, disturbance of menstruation, and dysmenorrhea, most often of the increasing or acquired type. Relative and absolute sterility are common partners of endometriosis.A better percentage of correct preoperative diagnoses should be obtained in view of present knowledge.Radical operation on women in the premenopausal age groups with endometriosis is resorted to in far too high a percentage of cases. The good results which can be attained with conservative therapy, including surgical and hormone therapy, should be stressed.There is some evidence that endocrine therapy may control endometriosis. The dangers attending these methods have not as yet been determined.     

Cell culture of biopsied endometriomas after danazol/hormonal therapy: a study of growth features and fertility effects.

The growth features of cells from endometriomas biopsied from patients who had been treated with Danazol or with hormones have not been studied in vitro. Danazol is a versatile drug and despite its recognised efficacy in controlling endometriosis, little is known about is cytotoxicity and mechanism of action. Culture of the biopsied endometriomas permitted qualitative cytotoxic assessments by way of comparison with cultured normal uterine endometrial cells treated in vitro with Danazol. The growth characteristics were studied in monolayer and collagen gel cultures. Cytopathology was characterised by light and electron microscopy. Since endometriosis is associated with infertility in women, data from in vitro fertilisation (IVF) were analysed with respect to treatment modalities as compared with cases suffering fallopian occlusion. Danazol reduced pregnancy chances. Two factors may be responsible: (a) altered follicle development resulting in poor oocyte quality (b) reduced nidation because of long-lasting endometrial cytotoxicity. The experimental findings reported here support the latter explanation. Consequently, Danazol therapy should be conditional; patients wishing to achieve pregnancy should preferably receive hormonal therapy.     

Potential involvement of the immune system in the development of endometriosis

This article presents an overview of immunological factors and their role in the development of endometriosis, with emphasis on inflammatory cytokines, growth and adhesion factors. Although retrograde menstruation is a common phenomenon among women of reproductive age, not all women who have retrograde menstruation develop endometriosis. The development of endometriosis is hypothesised to be a complex process, which may be facilitated by several factors, including the quantity and quality of endometrial cells in peritoneal fluid (PF), increased inflammatory activity in PF, increased endometrial-peritoneal adhesion and angiogenesis, reduced immune surveillance and clearance of endometrial cells, and increased production of autoantibodies against endometrial cells. Potential biomarkers like cytokines and autoantibodies upregulated during development of endometriosis may be useful in the development of a non-surgical diagnostic tool. Although endometriosis can be treated using hormonal suppression, there is need for non-hormonal drugs, which can inhibit the development of endometriosis and alleviate pain or infertility without inhibition of ovulation. New molecules that modulate immune function in endometriosis should be the targets for future research.     

Evaluation of serum CA 125 levels in patients with pelvic pain related to endometriosis

The aim of the study was to investigate the clinical value of the serum CA 125 level for diagnosing and determining the severity of endometriosis and pelvic pain associated with endometriosis. Eighty-six women who underwent operative laparoscopy were enrolled. Sixty-nine women with endometriosis and 17 without endometriosis participated in this study. In all of the patients, endometriosis was diagnosed and classified into stages according to the Revised American Fertility Society (R-AFS) classification. The mean serum CA 125 levels were determined in each patient. We also investigated the relationship between serum CA 125 concentration and the intensity of dysmenorrhea and dyspareunia in the study group. The mean serum CA 125 levels of women with endometriosis were higher than those of the control group (p<0.050). However, the mean serum CA 125 levels were higher in stage IV than in other stages of endometriosis according to the R-AFS classification. On the other hand, the percentage of patients with serum CA 125 levels >35 U/mL was elevated in the subgroups with severe dyspareunia and severe dysmenorrhea versus the asymptomatic subgroup but the differences had no statistical significance. In conclusion, CA 125 serum levels were related to endometriosis and R-AFS score in the evaluated patient series. No correlation was found between serum levels of CA 125 and pelvic pain in patients with endometriosis.     

Incidence and Estimated Prevalence of Endometriosis and Adenomyosis in Northeast Italy: A Data Linkage Study

Despite being quite frequent and having serious implications in terms of symptomatology and fertility, data on incidence and prevalence of endometriosis and adenomyosis following gold standard definitions are dramatically lacking. The average time from onset of symptoms to diagnosis in industrialized countries still ranges from five to ten years. Using the regional centralized data linkage system, we calculated incidence and prevalence of endometriosis and adenomyosis in the female population of Friuli Venezia Giulia region, Italy, for the years 2011–2013. Cases were defined as new diagnoses from hospital discharge records, following procedures allowing direct visualization for endometriosis and hysterectomy for adenomyosis, with or without histological confirmation. Diagnoses were considered “new” after verifying women had not been diagnosed in the previous ten years. Incidence of endometriosis and adenomyosis in women aged 15–50 years is 0.14%. Prevalence, estimated from incidence, is 2.00%. Adenomyosis, representing 28% of all diagnoses, becomes increasingly prevalent after the age of 50 years. Our results shows how the study of both endometriosis and adenomyosis should not be limited to women of premenopausal age. Further efforts are needed to sensitize women and health professional, and to find new data linkage possibilities to identify undiagnosed cases.     

Progesterone and transforming growth factor-beta coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis.

Endometriosis is a benign, though aggressive, disease of the female reproductive tract that consists of endometrial stromal and epithelial cells growing at an extrauterine site. Although it is widely accepted that the majority of cases of endometriosis result from the ectopic implantation of refluxed menstrual tissue, the precise mechanisms by which this disease becomes established are not well understood. Matrix metalloproteinases (MMPs), enzymes which are important for extracellular matrix turnover, have recently been implicated in the development of endometriosis. MMPs appear to be overexpressed in endometriotic lesions, but expression levels decrease following successful medical therapy. Intriguingly, although transforming growth factor-beta (TGF-beta) mediates progesterone suppression of specific endometrial MMPs, this growth factor is overexpressed in women with endometriosis. In the current study, we used an established experimental model of endometriosis to explore MMP regulation by TGF-beta. Our findings indicate that blocking the action of TGF-beta opposes progesterone-mediated suppression of MMPs and blocks the ability of this steroid to prevent experimental endometriosis. However, we also show that the action of TGF-beta does not lead to a sustained suppression of MMPs as observed following progesterone treatment. Taken together, our data suggest that in the absence of a normal progesterone response, common in ectopic lesions of endometriosis, sensitivity to TGF-beta may be altered, resulting in a failure to regulate MMPs.     

Progesterone receptor modulators and progesterone antagonists in women's health

Both progesterone receptor modulators (PRMs) as well as pure progesterone antagonists (PAs) have numerous proven and potential therapeutic applications in female health care. Mifepristone, a PRM with only marginal agonistic activity, together with a prostaglandin can terminate pregnancies of less than 9 weeks duration; mifepristone is also used in the preparation of women at later gestational stages whose pregnancies are terminated with prostaglandins or surgery. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death and promotes dilation of the non-pregnant primigravid uterus. It is also effective in the treatment of missed abortion. Together with methotrexate, mifepristone can be used in the medical treatment of ectopic pregnancy. Both PAs and PRMs display antiproliferative effects on the endometrium. Because of this, they have application in the treatment of endometriosis, an estrogen-dependent condition. They may also be utilized to reduce myoma size, acting as both a PA and antiproliferative agent. Unlike GnRH agonists, long-term use in endometriosis and myoma is not associated with loss of bone and hypoestrogenism. PRMs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. Some PRMs have potential use as hormone replacement therapy in women during menopause or in those with dysfunctional uterine bleeding.     

The role of inflammation,oxidative stress,angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression

Endometriosis is a frequent and chronic illness in young women which could be defined by the existence of endometrial stroma and glands outside of the normal site of the lining of the uterus. It has painful symptoms. The advanced stage of endometriosis may lead to gynecological malignancies, such as ovarian cancer, and other complications, including infertility. However, its exact physiopathology is not well known. Recent studies have shown the possible roles of inflammation along with oxidative stress. Additionally, angiogenesis and apoptosis dysregulation contribute to endometriosis pathophysiology. Therapeutic strategies and continuing attempts, to conquer endometriosis should be done regarding molecular signaling pathways. Thus, the present review summarizes current studies and focuses on molecular mechanisms.     

Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosis.

The objective of the present paper was to assess the presence of hormonal alterations in infertile women with stage I or II endometriosis (Group III, n = 20) compared to fertile women without endometriosis (Group I, n = 14) and to fertile women with endometriosis (Group II, n = 7). Serum levels of FSH, LH, estradiol, TSH, and PRL were measured between days 1 and 5 of the early follicular phase; in the luteal phase, three serum samples were collected for progesterone measurement, and endometrial biopsies were performed. Serum estradiol levels were lower (p = 0.035) in infertile patients with endometriosis than in fertile patients without endometriosis. Six infertile patients with endometriosis presented prolactin levels above 20 ng/ml. This was not observed in the other groups. Luteal insufficiency was more frequent in infertile patients with endometriosis (78.9%) than in fertile patients with (42.9%) or without endometriosis (0%). In a multiple logistic regression analysis, only the presence of endometriosis and infertility was significantly associated with luteal insufficiency. The serum levels of LH, FSH, and TSH were not significantly different among the groups. Luteal insufficiency and altered prolactin secretion were associated with endometriosis, and could be important mechanisms causing infertility in this group of patients.     

Impact of endometriosis on embryo quality and endometrial receptivity in women undergoing assisted reproductive technology

ART is an important treatment method for infertile patients with endometriosis. However, the effects of endometriosis on embryo quality and endometrial receptivity remain unclear. Thus, we aimed to simultaneously investigate the impact of endometriosis and its stage on embryo quality and endometrial receptivity in women undergoing ART. We retrospectively analyzed the data from patients with and without endometriosis who underwent oocyte retrieval and/or high-quality embryos transfer between July 2015 and December 2020, including 1312 IVF cycles and 608 IVF or frozen-thawed embryo transfer (FET) cycles, respectively. The endometriosis group had a lower percentage of good cleavage-stage embryos and fertilization rates than those in the control group (p = 0.038 and 0.008, respectively). The number of retrieved oocytes, MII oocytes, cleavage, blastocysts, and blastulation rates was comparable between two groups. We found no significant difference in clinical pregnancy, implantation, live birth, miscarriage, or multiple pregnancy rates between the two groups among patients who transferred high-quality embryos. Stratification analysis showed that patients with stage III-IV endometriosis had fewer retrieved oocytes than those with stage I-II endometriosis (p = 0.012) and marginally fewer retrieved oocytes than the control group (p = 0.051). The stage I-II group had the lowest percentage of good cleavage-stage embryos, which was significantly lower than that of the control group (p = 0.043). In FET cycles, patients with stage III-IV endometriosis had a higher miscarriage rate than those in the control group (p = 0.023). Our results suggest that endometriosis does not alter endometrial receptivity but affects embryo quality, oocyte fertilization ability, and ovarian response.     

Participation of women medical Physicists in European scientific events: The European experience

PurposeThough the number of women scientists is increasing over the years, studies show that they are still under-represented in leadership roles. The purpose of this work is to establish the percentage of women Medical Physicists (wMPs) that have participated in European scientific events and evaluate it as an indication of the current position of women in the field of Medical Physics in Europe and to propose possible ways to encourage their participation.Materials and MethodsData regarding the participants in European scientific events of Medical Physics were collected. The participants were divided into categories according to the program of the events and their gender was identified. The percentage of wMPs in each category was evaluated.ResultsThe participation of wMPs attending courses is greater than 50%. The categories with the greatest participation are “Organizing Committees”, “Chairpersons-Moderators” and “Oral Presentations”. The categories with the lower participation of wMPs are “Scientific Committee”, “Symposiums” and “Invited Speakers”. None of wMPs were represented as “Course Directors”.ConclusionsThe attendance of wMPs in courses is slightly greater than average. However, wMPs do not have an equally important recognition in special invited roles in conferences. They are still under-represented in “Scientific Committees”, “Invited Speakers”, “Symposiums” and “Course directors”. wMPs should be encouraged to participate even more actively in European conferences and the organizing committees should invite more wMPs in special roles. More studies concerning the status of female MPs in each country separately should be encouraged as they will help in understanding the position of wMPS in Europe.     

Unique molecular markers in human endometriosis: implications for diagnosis and therapy

Endometriosis originates in the uterine lining and affects ~20% of reproductive-age women. The disease often causes chronic pelvic pain, affects ovulatory function and influences fertility. Although laparoscopic diagnosis of uterine endometriosis is quite specific, direct visualisation can be difficult or inaccurate in some circumstances, and it is not useful for diagnosing extra-abdominal disease. Laparoscopy is an invasive procedure, has significant morbidity and cannot be carried out frequently to monitor efficacy of therapy and the possibility of recurrence. Thus, a specific, non-invasive diagnostic test is required. One intriguing area of research uses the technology of radioimmunotargeting, which has previously been used for cancer detection. This technique could have potential for the specific detection and eventual treatment of endometriosis. A marker, eosinophil peroxidase (EPO), has been identified that is expressed in ~90% of endometriosis specimens, and is not expressed or only weakly expressed in normal endometrium. The US Food and Drug Administration has approved a monoclonal antibody to EPO for investigation as an immunoimaging agent in cancers that exhibit eosinophilia. EPO targeting using this antibody could be useful for detecting and/or treating endometriosis.     

The possible anti-inflammatory role of circulating human leukocyte antigen levels in women with endometriosis after treatment with danazol and leuprorelin acetate depot

BACKGROUND: Endometriosis is defined as an inflammatory condition of the female reproductive tract, a state often associated with infertility and miscarriage. Many exogenously administered factors (treatments) control the disease via as yet unknown pathways. Possible candidate molecules involved in these mechanisms could be the serum-soluble human leukocyte antigens (sHIA) that have been detected in a variety of human body fluids and that are associated with several diseases. AIMS: We here examine how danazol and leuprorelin acetate depot treatments exert their anti-inflammatory action. It is plausible that subtle alterations mediated by these treatments and in relation to sHLA may explain the pathophysiology of endometriosis and provide insights towards new therapeutic protocols. METHODS: Indirect enzyme-linked immunosorbent assay (ELISA), using specific monoclonal antibodies, determined serum-soluble class-I and class-II HLA levels. ELISA readings from treated women were compared with normal healthy subjects. RESULTS: Serum-soluble class-I and class-II HLA levels are statistically significantly lower (P < 0.001) in women with endometriosis than in the control groups. However, danazol but not leuprorelin acetate depot administration augments soluble HLA class I and class II (P < 0.01 and P < 0.001, respectively) to normal levels during the treatment period, an increase that may account for the anti-inflammatory effect and the remission observed. CONCLUSIONS: It is shown that one of the underlying causes of endometriosis may be the lack of both circulating class-I and class-II antigen levels. Danazol administration acts via an induced release of these antigens, whose presence correlates with the degree of the inflammatory alleviation obtained. We thus provide evidence that the inflammatory state of the disease appears to be associated with soluble HLA levels because, 3 months after ceasing therapy, the circulating antigens in the serum return to the same levels that correspond to the pathological condition.     

Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue

Endometriosis is a chronic, painful disease whose etiology remains unknown. Furthermore, treatment of endometriosis can require laparoscopic removal of lesions, and/or chronic pharmaceutical management of pain and infertility symptoms. The cost associated with endometriosis has been estimated at 22 billion dollars per year in the United States. To further our understanding of mechanisms underlying this enigmatic disease, animal models have been employed. Primates spontaneously develop endometriosis and therefore primate models most closely resemble the disease in women. Rodent models, however, are more cost effective and readily available. The model that we describe here involves an autologous transfer of uterine tissue to the intestinal mesentery (Figure 1) and was first developed in the rat and later transferred to the mouse. The goal of the autologous rodent model of surgically-induced endometriosis is to mimic the disease in women. We and others have previously shown that the altered gene expression pattern observed in endometriotic lesions from mice or rats mirrors that observed in women with the disease. One advantage of performing the surgery in the mouse is that the abundance of transgenic mouse strains available can aid researchers in determining the role of specific components important in the establishment and growth of endometriosis. An alternative model in which excised human endometrial fragments are introduced to the peritoneum of immunocompromised mice is also widely used but is limited by the lack of a normal immune system which is thought to be important in endometriosis. Importantly, the mouse model of surgically induced endometriosis is a versatile model that has been used to study how the immune system, hormones and environmental factors affect endometriosis as well as the effects of endometriosis on fertility and pain.     

Cytochrome P450c17α 5′-untranslated region *T/C polymorphism in endometriosis

Estrogen plays a role in the pathogenesis of endometriosis. The CYP17 gene codes for the cytochrome P450c17α enzyme that is involved in the estrogen biosynthesis. We aimed to investigate if CYP17 polymorphism could be used as marker to predict the susceptibility of endometriosis. Women were divided into two groups: (1) severe endometriosis (n=119); (2) non-endometriosis groups (n=128). A 169-bp fragment encompassing the T/C polymorphic site in 5′-untranslated promoter region (5′-UTR) of the CYP17 was amplified by the polymerase chain reaction, treated with restriction enzyme MspA1I, and electrophoresis. The polymorphism was divided into restriction-enzyme indigestible (T homozygote), T/C heterozygote, and digestible (C homozygote). Genotypes and allelic frequencies for this polymorphism in both groups were compared. We observed a higher but non-significant percentage of T homozygote in the endometriosis women compared with the non-endometriosis women. Proportions of T homozygote/heterozygote/C homozygote for CYP17 in both groups were: (1) 26.1/46.2/27.7% and (2) 17.2/45.3/37.5% (p-value=0.131). T allele was related with higher susceptibility of endometriosis. T and C allele frequencies in both groups were: (1) 49.2/50.8%; (2) 39.8/60.2% (p-value=0.046). Despite the CYP17* T allele appearing to be asscoiatd with a trend of increased risk of endometriosis, CYP17 5′-UTR gene polymorphism might not be a useful marker for prediction of endometriosis susceptibility.     

A Low-Testosterone State Associated with Endometrioma Leads to the Apoptosis of Granulosa Cells

Although endometriosis is suspected to be a cause of premature ovarian insufficiency (POI), the mechanism(s) underlying this process have not been elucidated. Recently, androgens were shown to promote oocyte maturation and to play a role in folliculogenesis. In addition, several reports have documented low testosterone levels in the follicular fluid obtained from endometriosis patients. We therefore examined whether the low levels of serum testosterone are associated with the apoptosis of granulosa cells in follicles obtained from endometriosis patients. Serum samples were collected from 46 patients with endometriosis and from 62 patients without endometriosis who received assisted reproductive therapy. Specimens of the ovaries obtained from 10 patients with endometrioma were collected using laparoscopy. The mean serum testosterone concentration in the patients with endometriosis was significantly lower than that observed in the patients without endometriosis. Furthermore, high expression of a pro-apoptotic Bcl-2 member, BimEL, in the follicles was found to be associated with a low serum testosterone level. We clarified the underlying mechanisms using a basic approach employing human immortalized granulosa cells derived from a primary human granulosa cell tumor, the COV434 cell line. The in vitro examination demonstrated that testosterone inhibited apoptosis induced by sex steroids depletion via the PI3K/Akt-FoxO3a pathway in the COV434 cells. In conclusion, we elucidated the mechanism underlying the anti-apoptotic effects of testosterone on granulosa cells, and found that a low-testosterone status is a potentially important step in the development of premature ovarian insufficiency in patients with endometriosis.     

Comparison of dienogest effects upon 3,3′–diindolylmethane supplementation in models of endometriosis and clinical cases

Dienogest (DNG) administration is a well-established treatment for endometriosis but bleeding irregularities remain its main disadvantage. Changes in diet, mainly to vegetable consumption, are beneficial in the treatment of estrogen-related pathologies but their use for endometriosis has been poorly studied. In this study, addition of the phytochemical 3,3′-diindolylmethane (DIM) to DNG therapy has been investigated in in vitro and ex vivo models for endometriosis and in a small cohort of women with endometriosis. Endometrial Ishikawa cells were treated with DNG or DIM at dosages from 10^?10?M to 10^?5?M for up to 72?h. Cell proliferation was measured by assessing BrdU incorporation. Endometrial tissue from women with endometriosis and controls was incubated with DNG or a combination of DNG and DIM. Tissue viability was determined using a modified colorimetric MTS assay. 17β-estradiol secretion was quantified by an electro-chemiluminescence immunoassay. Finally, DNG as monotherapy or in combination with DIM was randomly administered to women with endometriosis (n?=?8) over 3 months. Bleeding patterns and associated pelvic pain were assessed by Visual Analogue Scale (VAS). DNG and DIM significantly reduced cell proliferation in Ishikawa cells. Ex vivo, DIM reduced viability and estradiol secretion specifically in endometriotic but not in normal endometrial tissue. This effect was enhanced by combination with DNG. Endometriosis associated pelvic pain was significantly reduced in patients taking the DNG-DIM combination therapy compared to those taking DNG alone. Bleeding pattern (number and duration of episodes) was significantly improved by addition of DIM to the DNG treatment. In conclusion, addition of DIM enhances effects of DNG ex vivo and may ameliorate bleeding patterns in endometriosis patients.     

Towards endometriosis diagnosis by gadofosveset-trisodium enhanced magnetic resonance imaging

Endometriosis is defined as the presence of endometrial tissue outside the uterus. It affects 10-15% of women during reproductive age and has a big personal and social impact due to chronic pelvic pain, subfertility, loss of work-hours and medical costs. Such conditions are exacerbated by the fact that the correct diagnosis is made as late as 8-11 years after symptom presentation. This is due to the lack of a reliable non-invasive diagnostic test and the fact that the reference diagnostic standard is laparoscopy (invasive, expensive and not without risks). High-molecular weight gadofosveset-trisodium is used as contrast agent in Magnetic Resonance Imaging (MRI). Since it extravasates from hyperpermeable vessels more easily than from mature blood vessels, this contrast agent detects angiogenesis efficiently. Endometriosis has high angiogenic activity. Therefore, we have tested the possibility to detect endometriosis non-invasively using Dynamic Contrast-Enhanced MRI (DCE-MRI) and gadofosveset-trisodium as a contrast agent in a mouse model. Endometriotic lesions were surgically induced in nine mice by autologous transplantation. Three weeks after lesion induction, mice were scanned by DCE-MRI. Dynamic image analysis showed that the rates of uptake (inwash), persistence and outwash of the contrast agent were different between endometriosis and control tissues (large blood vessels and back muscle). Due to the extensive angiogenesis in induced lesions, the contrast agent persisted longer in endometriotic than control tissues, thus enhancing the MRI signal intensity. DCE-MRI was repeated five weeks after lesion induction, and contrast enhancement was similar to that observed three weeks after endometriosis induction. The endothelial-cell marker CD31 and the pericyte marker α-smooth-muscle-actin (mature vessels) were detected with immunohistochemistry and confirmed that endometriotic lesions had significantly higher prevalence of new vessels (CD31 only positive) than the uterus and control tissues. The diagnostic value of gadofosveset-trisodium to detect endometriosis should be tested in human settings.     

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.