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A common but poorly understood gynecological disease

Endometriosis is a fairly common gynecological disease since it affects one in ten women. It is related to the presence of tissue resembling the uterine mucosa outside the uterus. Different organs may be affected. The disorder may be asymptomatic. However, in certain cases, it can cause severe pain (particularly during menstrual periods) and/or infertility. Scientists are attempting to shed light on the mechanisms of this disorder and its relationship with infertility.

  • A disease that affects 1 person in 10
  • The symptoms: pain and/or infertilify
  • The gold-standard treatment: surgery
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Report drawn up in collaboration with Daniel Vaiman, head of the Genomics, Epigenetics and Reproductive Physiopathology Unit team (unit 1016 Inserm/CNRS, Institut Cochin, Paris) and Carole Abo, obstetrician/gynecologist and doctoral student from the same team.

Loupe comprendre Understanding the issues surrounding endometriosis

Endometriosis is a disorder characterized by the presence of uterine tissue (or endometrial tissue) outside the uterine cavity. This abnormality causes lesions which are made up of cells with the same characteristics as the uterine mucosa (endometrium) and displaying the same behavior under the influence of ovarian hormones.

10% of all women
40% of women who suffer from chronic pelvic pain

This is a common gynecological disorder, observed in 10% of women. This proportion rises to nearly 40% among women suffering from chronic pelvic pain, particularly during menstrual periods.

There is no screening technique for the disease, whether in the general population or in women at risk. Only those presenting symptoms will require clinical and imaging examinations to establish a diagnosis.

Qu'est ce que l'endométriose ? - animation pédagogique - 45 sec. - 2019

Symptoms: pain and infertility

The symptoms caused by endometriosis are usually pain and infertility. Their severity is not necessarily correlated with the extent of the lesions caused by the disorder.

The main symptom is recurrent pelvic pain which can sometimes be very acute, particularly during menstrual periods. This cyclic nature is a characteristic of the disorder. The lesions are sensitive to female hormones and behave like uterine tissue. These lesions therefore proliferate, bleed, and leave fibrous scars at each menstrual cycle. In certain patients, highly innervated lesions could contribute to the extreme pain sometimes experienced. Outside of menstrual periods, patients may also experience discomfort during sexual intercourse (dyspareunia), or even when passing stools or urine.

The disorder may also be completely asymptomatic. In this case, it is generally discovered incidentally when the patient seeks medical advice due to difficulty conceiving. A large proportion of endometriosis patients are, in fact, infertile. The scientific explanation for this connection has not yet been fully elucidated. The presence of clusters of tissue, particularly ovarian cysts, can create a mechanical barrier to fertilization in the event of serious lesions. Recent studies, moreover, show that the endometrium of patients with endometriosis displays abnormal gene expression and hormone profiles (see below). In these patients, the uterus could therefore have characteristics hostile to the implantation of an embryo.

Endometriosis and cancer?

Endometriosis lesions may be defined as "benign metastases". For endometriosis patients, the risk of developing cancer (usually ovarian cancer) is less than 1 %. This risk concerns rare sub-types of ovarian cancer, such as clear-cell ovarian carcinoma, or endometrioid adenocarcinoma.

Pictogramme localisation Varied sites

The organs most frequently affected by deep infiltrating endometriosis are:

  • the ovaries
  • the uterosacral ligaments
  • the rectum
  • the bladder
  • the vagina

Several organs may be affected in a given patient. In rare cases, endometriosis lesions can even appear in organs far removed from the uterus, for instance, in the lungs or brain. Only two cases involving the latter site have been reported to date. In one of the two cases (reported in 1993), the patient suffered from strokes on the first day of her menstrual period, until the lesion was surgically removed.

Rouages Mechanisms requiring clarification

The mechanisms behind endometriosis are still unclear. However, the main hypothesis is the implantation of uterine tissue, resulting from retrograde menstruation. During menstrual periods, blood can, in fact, pass through the fallopian tubes and reach the abdominal cavity, taking with it endometrial fragments, or indeed pluripotent cells capable of generating new endometrial sites.

Nevertheless, while clinical practitioners estimate that 90% of women experience retrograde bleeding, only 10% develop endometriosis lesions. Individual susceptibility factors thus come into play in the development of this disease. These could be genetic factors. Furthermore, scientists suspect that certain types of environmental exposure may have an impact in this respect.

Pictogramme stétoscope Treatment exclusively when symptoms are present

Endometriosis is detected by clinical and ultrasound or, indeed, MRI examination. However, the definitive diagnosis is based on the analysis of endometrial tissue removed during surgery.

Asymptomatic endometriosis, which is painless and does not give rise to fertility problems, is generally not detected and thus not treated. But when a patient discovers that she has endometriosis due to pain, she is usually offered first-line hormone therapy with a view to stopping her periods (continuous, monophasic, combined contraceptives, progestogens, danazol or GnRH analogs). These treatments reduce the pain related to the hormonal response of endometriosis lesions, making it possible to stabilize the lesions or reduce their volume slightly. However, they do not get rid of them completely.

Surgery is the only treatment which can completely remove the lesions associated with endometriosis. It is performed in the event of incapacitating symptoms and/or infertility. Advances in surgery mean that procedures preserve increasingly more healthy tissue and are increasingly less invasive. For example, an experiment is ongoing at CHU Lyon in the treatment of gastrointestinal nodules: doctors are using ultrasound (high-intensity focused ultrasound or HIFU) to devitalize the nodules, thereby rendering them insensitive, without affecting gastrointestinal integrity and without scarring.

Thanks to surgery, painful symptoms may disappear for many years, or even indefinitely. However, difficulty in terms of surgery is amplified in the presence of diffuse small lesions or when surgery gives rise to an unfavorable risk/benefit ratio, for example, with a risk of incontinence.

Règles et douleur – Interview – 4 min 38 – Film extrait de la série POM Bio à croquer, 2013

Pictogramme microscope Challenges facing research

Investigating for susceptibility genes

Scientists are attempting to shed light on the mechanisms of this complex disorder and its relationship with infertility. They are particularly working to identify susceptibility genes, so as to elucidate their role and discover markers for risk.

Investigating for susceptibility genes

Several major studies have enabled the routine genomic analysis of cohorts of women with or without endometriosis. Among them, a Japanese study involving 1,907 patients and 5,292 controls (women without endometriosis) and an international study including 3,194 patients and 7,060 controls led to the identification of genetic variations significantly associated with the disorder. Some twenty genes are thought to be concerned.

However, these variations only slightly increase the relative risk of developing this disorder: when taken together these genes account for barely 6% of endometriosis cases, and numerous women presenting these "at-risk" variations have a very high probability of not developing the disorder. These genetic data absolutely cannot be used as markers for risk in clinical practice. However, they are useful to researchers as they serve as starting points to understanding the biological mechanisms related to endometriosis.

Inserm researchers have attempted a more targeted approach, working exclusively with women presenting with an ovarian endometrioma. A global epigenetics study evidenced differences in DNA methylation (chemical modifications causing differences in gene expression) between the cells constituting the lesions and patient endometrial cells, particularly at the extremities of the chromosomes. This phenomenon is associated with specific forms of the enzyme DNMT3L (belonging to the DNA methyltransferase category). One of these forms multiplies by seven the risk of developing the disease! It could therefore be used as a diagnostic and prognostic tool.

What about the environment and endocrine disruptors?

Researchers consider that each case of endometriosis can be attributed to 50% genetic factors and 50% environmental factors. For instance, scientists are questioning the possible role of endocrine disruptors or that of polyunsaturated fatty acids and other dietary components able to cause epigenetic abnormalities. A recent study conducted in mice shows, for instance, that prenatal exposure of mice to bisphenol A could contribute to the development of a disorder resembling endometriosis in female mice.

Facilitating diagnosis

At present, the definitive diagnosis of endometriosis is based on the analysis of an endometriosis nodule fragment obtained by biopsy. However, this biopsy is performed during laparoscopic surgery, a procedure which cannot be scheduled "just" for diagnosis purposes. As such, biopsies are only performed in combination with another surgical procedure.

To resolve this unfavorable situation, a team from CHU Angers is testing a new simpler and less invasive technique: the use of an endometrial tissue tracer which can be observed using an imaging technique known as the PET scan (positron emission tomography). The forms of endometriosis which are sensitive to estrogens express an estrogen receptor (ER). The researchers are testing the use of a labeled estrogen analog, 18F-FES (16α-[18F]Fluoro-17β-estradiol), to trace these receptors in the affected areas and detect endometrial lesions via imaging. Called EndoTEP, this project should make it possible to determine the sensitivity and specificity of this diagnostic technique, in relation to standard techniques.

Shedding light on the relationship between endometriosis and infertility

Scientists suspect that there may also be biological and physiological differences between women who suffer from endometriosis and other women, which could be behind the reduced fertility often associated with this disorder. Research conducted at Hôpital Cochin has recently shown, for example, that expression of three out of the four genes coding for prostaglandin receptors, chemical mediators of inflammation, increases 10 to 20-fold in the uterine endometrium of patients suffering from endometriosis compared to women without the disorder. This level even increases forty-fold in endometrial tissue extracted from the lesions. At the same time, the expression of a key enzyme in prostaglandin synthesis, PTGS2, increases nearly 10-fold in the endometrium of patients suffering from endometriosis. Other biological avenues appear to be worth exploring so as to understand infertility in these patients, such as ovarian function and reserve in women with endometriosis.

Clinical research is also focusing on the optimization of endometriosis treatment in infertility. A hospital clinical research program which will enroll 120 patients with infertility and colorectal deep infiltrating endometriosis is starting at CHU Lille (EndoFERT). The objective is to evaluate the benefit on fertility of endometriosis surgery prior to in vitro fertilization (IVF). For this, the researchers set up a randomized, controlled trial in which half of the participants will undergo complete resection of the endometrial tissue prior to IVF and the other half will proceed directly to IVF without surgery. The authors will evaluate the chances of conceiving in the two groups following two attempts at IVF. The study is scheduled to end in 2020.

AP-HP is enrolling endometriosis sufferers in the ComPaRe cohort on Endometriosis

The objective is to bring together 5,000 patients in France (mainland or overseas territories), for a broad diversity of profiles and to collect various data on their symptoms, treatments, experiences, everyday life, etc.

These data will enable the scientific team, led by Marina Kvaskoff, epidemiologist researcher at Inserm, to study the natural history of the disease and the factors that influence it. The objective is to better understand the disease, identify its various forms and their causes, and study its impact on patient health and quality of life.

Volunteers wishing to participate in ComPaRe must register and answer questionnaires on a secure online platform.