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Pathophysiology of endometriosis : the genetic-epigenetic theory

Observations on endometriosis

Observations on endometriosis

The genetic epigenetic theory for the first time permits to explain ALL observations made on endometriosis.

 

The mechanism is as follows

Pathophysiology of endometriosis: The genetic epigenetic theory

Pathophysiology of endometriosis: The genetic epigenetic theory

  • all women are born with some genetic-epigenetic defects
  •  additional incidents occur during life because of pollution or oxidative stress
  • beyond a treshold of incidents endometriosis lesions start
    • each type of lesion has a different set of incidents
    • even similarly looking lesions can have very different sets of incidents eg progesterone resistance

Growth of endometriosis lesions

  • The set of genetic-epigenetic incidents will determine the evolution towards typical, cystic or deep lesions
  • Growth is moreover influenced by the immunology and the peritoneal fluid environment inherited at birth, and the oxidative stress of retrograde menstruation
  • also bleeding in the lesions will cause a 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.

The consequences of the genetic-epigenetic theory

  • 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.
  • the original cell is less important for understanding endometriosis
  • we finally understand that the respons of individual lesions can be very different
  • the crucial role of oxidative stress explains
    • the importance of food intake
    • the problem of repetitive retrograde menstruation
    •  prevention of endometriosis
    • adolescent endometriosis
  • Endometriosis thus can be considered a benign tumor.
  • Endometriosis is
    • not a recurrent disease : if removed completely there are no recurrences. New lesions however can develop.
    • 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 theory is an update of the endometriotic disease theory of 1999

We proposed the endometriotic disease theory is already in 1999 (Koninckx P.R., Kennedy S., Barlow D., Gyn Obstet Invest 1999,47,1-10)

 

 

 

 

 

 

Historical considerations of pathophysiology

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.

Pathophysiology is important for clinical therapy

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
.

 

Epidemiology of endometriosis

Epidemiology of endometriosis

Epidemiology of endometriosis

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