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Pathophysiology of endometriosis : the genetic-epigenetic theory

A theory remains valid as long as compatible with all observations

The Sampson theory - the metaplasia theory - the hematogenic spread are no longer acceptable

Sampson Theory
Pathophysiology of endometriosis
In 1927 Sampson suggested that cells from retrograde menstruation could implant and develop. (For details see GORDTS S, KONINCKX P, BROSENS I. Pathogenesis of deep endometriosis. Fertil Steril 2017;108:872-85.). Since this could not explain all forms of endometriosis, the metaplasia theory was proposed, and later the hematogenic and lymphangenic spread

This was nice historical speculation but today, these theories are no longer valid.


The Genetic-epigenetic theory

Observations on endometriosis

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

Infection and endometriosis





But it is NOT associated with cardiovascular disease
endometriosis and cardiovascular risk


The initiation of endometriosis lesions

Pathophysiology of endometriosis: The genetic epigenetic theoryOxidative stress

  • all women are born with some genetic-epigenetic defects
  •  additional incidents occur during life because of
    • pollution
    • oxidative stress mainly retrograde menstruation
    • infection
  • beyond a treshold of incidents endometriosis lesions initiate
    • Thus each type of lesion has a different set of incidents
    • Thus 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 (RETIAR)
  • 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.

Clinical consequences of the genetic-epigenetic theory

  • subtle endometriosis is normal endometrium implanted on the peritoneum. This is not a disease and does not cause pain or infertility.
  • the original cell is no longer important for understanding endometriosis
  • we understand why the response of similar looking lesions can be very different
  • the role of oxidative stress and of infection and of the peritoneal mirobiome explains
    • the importance of food intake
    • the problem of repetitive retrograde menstruation
    •  how to organise prevention of endometriosis
    • the importance of 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.

The genetic epigenetic theory is an update of the endometriotic disease theory of 1999

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







Historical considerations

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

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. However, retrograde menstruation occurs in most women, and not all women develop endometriosis. 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.

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.

The problems caused by the Sampson theory

Sampson was WRONG = 1 disease
The genetic epigenetic theory RIGHT= 3 diseases
Typical, Cystic and Deep Endometriosis
According to the Sampson Theory
endometriosis starts with retrograde menstruation, implantation and unavoidable progression.
Endometriosis thus is considered progressive and recurrent
and subtle lesions are considered precursors of  severe lesions
This leads to incomplete surgery since recurrenses are unavoidable.
The genetic-epigenetic theory. :
The disease starts with 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 explains why the literature can be so misleading

80% of women with pain or infertility have endometriosis
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

Deep endometriosis seems to become more prevalent and more severe.

Epidemiology of endometriosis

Epidemiology of endometriosis

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