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Pathophysiology and epidemiology of endometriosis

Pathophysiology of endometriosis

The endometriotic disease theory

Pathogenesis of endometriosis

What  causes endometriosis ?

Endometriosis is caused by a genetic or epigenetic change causing the cells to look like endometrium. We proposed this already in 1999 (Koninckx P.R., Kennedy S., Barlow D., Gyn Obstet Invest 1999,47,1-10) , and evidence has been growing sine then.

These changes are caused by accidents during cell division, or by toxins as dioxin, or by mutagenic factors as radiation or viruses.

Some women already have some inherited changes in their cells. This is insufficient to cause endometriosis but it explains the predisposition and the genetic aspect.

What is the original cell ?

The original cell can be the endometrium or more specifically basal endometrium or pale cells from retrograde menstruation during adult life or neonatally. They can be stem cells from the endometrium, from the peritoneal cavity or bone marrow cells.

Anyway, it is less important which is the original cell. Important are the changes in the cell.

How does endometriosis grow ?

These genetic/epigenetic modified cells anyway develop in an abnormal environment as the peritoneal cavity with different hormones and immunology.

Being an hormone responsive tissue, especially deep endometriosis can bleed during menstruation causing oxidative stress and RETIAR (repetitive tissue trauma and repair).

Most lesions grow for a certain time but growth is self limiting. When we make the diagnosis most lesions are no longer growing. Some however either are still growing, or will keep growing.

Endometriosis thus can be considered a benign tumor.

What are the clinical consequences  ?

Most important is that subtle endometriosis is normal endometrium implanted on the peritoneum, with some metaplasia. This is not a disease and does not cause pain or infertility.

Typical, Cystic ovarian and deep endometriosis are 3 different diseases

Endometriosis is not a recurrent disease : if removed completely there are no recurrences. New lesions however can develop.

Endometriosis is not a progressive disease in most women.

Endometriosis is heterogeneous : the type of genetic and epigenetic changes varies. Therefore in most women endometriosis is no longer progressive when the diagnosis is made. However some endometriosis lesions are different, and can remain fast progressive or can react differently to  medical treatment.

This easily explains why endometriosis is heriditary and why progression occurs in some women only.

Sampson’s theory and metaplasia theory becomes historical speculation

Historical considerations

History of pathology

Cullen described already in 1880 rectovaginal endometriosis. Sampson described Cystic ovarian endometriosis in 1921. Because of endometriosis in women without a uterus the metaplasia theory was proposed. Only ofter 1975 we realised that typical lesions were so frequent. In 1986 Janssens described the non-pigmented subtle endometriosis. The history of deep endometriosis starts with the paper of Cornillie and Koninckx in 1989

The Implantation - the metaplasia theory

In 1921 Sampson proposed that menstrual cells that arrive in the peritoneal cavity by retrograde menstruation can implant and can develop further to endometriotic lesions. This theory is attractive since it has been proven that retrograde menstruation occurs in most women, that this fluid contains viable cells and that these cells can implant. Key in this theory is that endometriosis are ‘normal cells in an abnormal environment’ ie the peritoneal cavity.

This theory fails to explain why progression occurs in some women only or why endometriosis is heriditary.

Metaplasia theory is based upon the fact that mesothelial cells in the peritoneum can be transformed by menstrual blood into endometrial cells.

Progression and further development is identical to the implantation theory.

Key in this theory is that implantation/metaplasia is the most important event whereas progression will occur for unknown reasons

Haematogenic and lymfogenic spread

Haematogenic spread explains the occurrence of endometriosis in the lungs and on the pleura.
In deep endometriosis endometrial cells are found in 50% of women in the lymph nodes. The significance of this is unclear.

Why is the pathophysiology so important ?

Scientifically the pathophysiology still is debated and unknown. Clinically, as we wrote before , endometriosis should be considered as 3 different pathologies.

WRONG = 1 disease
ENDOMETRIOSIS
RIGHT= 3 diseases
Typical, Cysqtic and Deep Endometriosis

Pathophysiology

According to the Sampson Theory
endometriosis starts with retrograde menstruation, inplantation of these cells and unavoidable progression thereafter.
Endometriosis thus is considered progressive and recurrent
whereas superficial lesions are considered precursors of  severe lesions
This leads to incomplete surgery if recurrenses are unavoidable.
The Endometriotis disease theory. :
Progression only occurs following genetic or epigenetic changes as occurs in benign tumors.
Endometriosis thus is NOT progressive NOR recurrent
typical, cystic and deep endometriosis are 3 different diseases
and subtle lesions are not precursors of severe lesions
Surgery thus should be complete
.

This also explains the wide variation in incidences of endometriosis in women with pain or infertility

80% have endometriosis
this figure is so high when subtle endometriosis is considered erroneously as a disease.
40% have typical endometriosis
10% have cystic endometriosis
3% have deep endometriosis
.
endometriosis is a cause of pain and infertility
Since almost all women have subtle lesions, finding subtle lesions should not be considered as an explanation for pain or infertility.
Symptoms vary with the type of lesions
subtle : no infertility not pain
typical infertility (?) pain (+ in 50%)
Cystic infertility (++) severe pain (++ in 80%),
deep infertility (?) pain (+++ in 95%).
.
The rAFS classification
with mild (superficial), moderate and severe (cystic) endometriosis
assumes progression
Subtle is not a disease.
Deep endometriosis should be classified separately as the most severe lesions
whereas in the rAFS classification they are mostly classified in class II
.

That 3 different gynaecologists deal with endometriosis results in a VARIABLE approach to diagnosis and treatment

The Fertility Specialist
Fertility specialists have become mainly IVF specialists with only a basic surgical training, sufficient for superficial endometriosis, ie for the most frequent pathology.
Cystic ovarian endometriosis is often considered as easy surgery. Reality however is that insufficient experience often results in ovarian damage and loss of oocyte reserve.
For deep endometriosis they generally perform bowel resections together with the surgeons.
The non surgeons / basic surgeons
Many gynaecologists are mainly involved in medical therapy (or IVF) and/or only perform basic surgery, ie without deep endometriosis with bowel and ureter involvement.
……………In contrast with …………
A small group of gynaecologists is doing surgery for severe endometriosis (without bowel resections). They are getting organised and recognised as ‘pelvic surgeons’.
The pelvic surgeon
This is a small group, since deep endometriosis is not that frequent and thus only a small group can have sufficient experience. In addition deep endometriosis requires expertise in dealing with bowels and ureters. A bowel resection for deep endometriosis is rarely indicated

Deep endometriosis is rare and
the group of pelvic surgeons is small
.

Deep endometriosis is a rare condition,( and technically demanding). Superficial endometriosis is a frequent condition that only requires basic surgical skills : thus many gynaecologist will be involved in superficial endometriosis with (simple) surgery, medical therapy or IVF.
Many basic surgeons and a few pelvic surgeons requires an adequate referral . If referral is inadequate, deep endometriosis will be treated incompletely with medical therapy afterwards. If the disease is not recognised, IVF will be performed with a nodule in the rectovaginal septum, or medical therapy is given for long periods without a diagnosis.
We need centers of excellent surgery for deep endometriosis.

If the gynaecologist does not have the required surgical skills, incomplete surgery or avoidable bowel resections occur.

When deep endometriosis is not recognised and referred, surgery will be incomplete which makes subsequent surgery more difficult. In addition medical therapy often is given in order to avoid surgery, whereas incomplete surgery often is hidden by medical therapy after surgey.

Epidemiology of endometriosis

Epidemiology of endometriosis

Epidemiology of endometriosis

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