Overload of iron in the pelvic cavity may promote proliferation of endometriosis lesions’ epithelial cells

July 2006

Research on mice, published in Human Reproduction, has led a team from the Catholic University of Louvain to conclude that an overload of iron in the pelvic cavity, while not causing the condition, may make the lesions grow by promoting the proliferation of their epithelial (lining) cells.

Belgian fertility experts believe this may be a step forward in finding the answer to endometriosis. They hope that their findings may lead to better treatment for women, possibly in the next five years.

They have found that treatment with an iron chelater – molecules that bind tightly to metal ions and neutralise their damaging effects on the body – can reduce cell proliferation in the lesions.

Iron deposits are typical features of endometrial lesions and increased concentrations are found in the pelvic cavity of patients with the disease. The researchers, led by Professor Jacques Donnez, head of the Department of Gynaecology, hypothesised that iron overload might be involved in the origin and development of endometriosis. The iron could originate from the breakdown of erythrocytes (oxygen-bearing red blood cells) carried into the pelvic cavity by retrograde menstruation (menstrual blood flowing back into the fallopian tubes).

To test their hypothesis they induced endometriosis in a nude mouse model (mice without immune systems) by injecting human menstrual endometrium into:

• one control mouse, which had only the injection of endometrium;
• one mouse which had an injection of endometrium plus human erythrocytes;
• one mouse which had an injection of endometrium plus an iron chelator – desferrioxamine (DFO).

The experiment was replicated eight times (24 mice). A total of 78 lesions were collected from 22 surviving mice out of the 24, with no statistically significant difference in the number or surface area of lesions in the three groups.

But there was a significant difference between the groups in the amount of iron and the level of macrophages (scavenger cells that surround and kill micro-organisms, remove dead cells and stimulate immune cells).

Said Professor Donnez: “Cell proliferation in the epithelial glands in the lesions and iron load in the pelvis was markedly greater in mice injected with erythrocytes than in control mice, with the overload in the tissue and pelvic cavity being similar in nature to that found in the pelvic cavity of endometriosis patients. There was also a significant increase in the percentage of iron-loaded macrophages compared with the control group. By contrast, iron levels in the DFO-treated mice were similar to the control mice, and cell proliferation was lower than in the control group.

What this clearly suggests is that peritoneal iron overload in patients may well originate from the breakdown of the red blood cells involved in retrograde menstruation. Activated macrophages probably play an important role in degradation of these red blood cells and the resulting peritoneal iron overload could have numerous cytotoxic effects in the peritoneal area.”

Professor Donnez said the DFO treatment decreased significantly the number of lesions containing iron deposits, the iron concentrations in the peritoneal fluid and the percentage of iron-loaded pelvic macrophages.

“An iron chelator could thus be beneficial in endometriosis to reduce the iron content of the peritoneal cavity, moderate its deleterious effects and reduce the cellular proliferation of lesions. Our findings represent a crucial step in finding the answer to endometriosis because we are focusing our research more on the origins and causes of the disease in the context of prevention, than on surgical treatment when the disease is already present. We really hope that, in the future, genetics will help us to determine the population of young women at high risk of endometriosis and that treatment, resulting from our findings, may then prevent the development or evolution of the disease.”

He said it was vital that endometriosis is taken seriously. It affects millions of women in their reproductive years and its prevalence appears to be increasing. “It is a disorder that causes a lot of pain and distress to women and has far-reaching socio-economic implications.”

The researchers have now received a major grant from the Région Wallonne research department in Belgium for further animal trials.

Source

Defrere S, Van Langendonckt A, Vaesen S, Jouret M, Ramos RG, Gonzalez D, Donnez J. Iron overload enhances epithelial cell proliferation in endometriotic lesions induced in a murine model. Human Reproduction 2006;21(11):2810-6.