Chemicals that inhibit the development of new blood vessels could prove to be a new way of treating endometriosis

Chemicals that inhibit the development of new blood vessels could prove to be a new way of treating endometriosis, according to research from The Netherlands and the USA presented today (Monday 28 June) at the 20th annual meeting of the European Society of Human Reproduction and Embryology.

However, the researchers warned that the work is still at an early stage, with the current investigations taking place in mice, so it would be a few years before the findings could translate into improved treatments for women with the disease.

Endometriosis is a disease of the lining tissue of the womb. It can be very painful and can have a serious impact on the lives of women. At present, there is no satisfactory treatment or cure for the condition, which affects between 10-25% of women of reproductive age.

Annemiek Nap, a doctor at the University Hospital Maastricht, The Netherlands, told the conference that she and her colleagues tested whether angiostatic therapy (therapy that inhibits the development of blood vessels) could prevent new endometriosis lesions growing and whether it could interfere with the maintenance and growth of existing lesions.

They used four angiostatic compounds: anti-human vascular endothelial growth factor (anti-hVGF), TNP-470, endostatin and anginex. They tested the compounds on human endometrium that had been transplanted into 49 mice and allowed to grow into endometriotic lesions. "We thought that using human endometrium would make the model as close to the human situation as possible," said Ms Nap.

"We found that angiostatic therapy inhibits the number of newly developed blood vessels around lesions. However, the mature vessels, which are protected by smooth muscle cells, were not inhibited. We also observed that the number of endometriotic lesions in mice treated with angiostatic agents was lower than the number of endometriotic lesions in mice not treated with angiostatic agents."

The most effective of the four angiostatic compounds was endostatin. "It is not completely obvious why this is the case, but one explanation might be that endostatin inhibits the migration of the endothelial[2] cells more than the proliferation," said Ms Nap.

Her findings mean that angiostatic therapy could be useful as an adjuvant treatment for endometriosis. "Angiostatic therapy mainly inhibits the development of new vessels. However, it also interferes effectively with the maintenance and growth of endometriotic lesions, and thus may be a promising way of preventing the recurrence of endometriosis after surgical or hormonal therapy. Once endometriosis is diagnosed, a woman could have angiostatic therapy to prevent more lesions forming or the existing ones growing, and then after surgery, the therapy could be continued to prevent a recurrence."

Dr Christian Becker, a postdoctoral research fellow in the Department of Vascular Biology at the Children's Hospital, Boston, USA, and an obstetrician/gynaecologist at the Charite-Campus Benjamin Franklin in Berlin, tested the effect of endostatin on mouse endometriosis (i.e. on mouse endometrium, rather than human endometrium transplanted to mice). He found that endostatin halved the growth and numbers of endometriosis lesions. "Also, the extent of the disease in terms of millimetres squared was significantly smaller in the endostatin group compared to the control group, with 1.1 mm2 versus 5.2 mm2 in one group, and 3.2mm2 versus 6.1mm2 in the other group."

Importantly, he found that endostatin did not have any side effects, and in particular it did not affect the hormone levels and menstrual cycles of the mice.

"This may be clinically relevant as current therapy for endometriosis is aimed at suppressing the patient's hormones. For women who do not want to become pregnant this may not be a big problem, but as infertility is often connected to endometriosis it is problematic to suppress the patient's hormones, either by giving an oral contraceptive pill or gonadotrophin releasing hormone (GnRH) analogues. These patients definitely will not be able to conceive under that medication. With endostatin, however, it would be possible to become pregnant.

"Results from this study show, that as endometriosis is an angiogenesis-dependent disease, treatment with endostatin may present a new and safe therapeutic approach."

Dr Becker said that it might be necessary to study endostatin in animals that are better models for humans than mice. However, because endostatin has completed early phase 1 trials for the treatment of cancer, there are data available on its toxicity in humans. "I believe it should be possible to try endostatin in endometriosis patients in the foreseeable future.

"So far, medical treatment for endometriosis is highly unsatisfactory, due to strong side-effects and a high rate of recurrence. It is, therefore, imperative to find a new therapeutic strategy. Endostatin or other angiogenesis inhibitors could be one of these approaches."

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