Tuesday, January 30, 2007

Immune System Involvement with Endometriosis

I love doing research, so of course I have found out a few interesting things about endometriosis.

The nutshell version:
Baboons get endo too. It may be an autoimmune disorder. Contrary to popular belief, there is no evidence that the immune system attacks embryos in endo. Weaknesses in the immune system can promote and sustain endometriosis. The immune system of women with endo pumps out too many of certain kinds of molecules. Once those molecules can be more easily isolated in the blood or abdominal fluid of women with suspected endo, the invasive approach of diagnosing endo through laparoscopic surgery could be avoided. Proteins that bind to the molecules and thereby prevent them from attaching to endo cells instead are already in development. This new form of therapy could be used to treat endo noninvasively while keeping a woman's estrogen levels and ability to conceive intact.

The longer, more descriptive story:

*Baboons & Endometriosis*
As a primatologist I think it's interesting to know that baboons get endometriosis too. Apparently 83% of baboons have what's called "retrograde menstruation" which occurs when endometrial tissue from inside the uterus flows backwards through the fallopian tubes and out in to the abdominal cavity. This is one theory for the origin of endometriosis. However, retrograde menstruation occurs in about 80% of human women too and only 10% of women actually have endo. 25% of baboons have it. So, that's not much of a theory.

*Immune System Involvement*
What do I think is happening? Well, affected women could have been born with stem cells that become endometriosis at puberty when they get bathed in hormones, specifically estrogen. That could be the problem. Or, every woman is born with cells that become endometriosis but they are normally removed by the immune system. Affected women might have an immune system that fails to recognize and then kill the endo cells.

It's important to know the cause of endometriosis so that better therapies can be developed. Currently the standard procedure is to treat it hormonally by getting a woman to stop producing estrogen, or at least not so much of it. If a woman wants to keep endometriosis under control, her only option is to prevent ovulation. For women who want to produce a family, that's not much of an option.

"Although endometriosis can be treated using hormonal suppression, there is need for non-hormonal drugs, which can inhibit the development of endometriosis and alleviate pain or infertility without inhibition of ovulation. New molecules that modulate immune function in endometriosis should be the targets for future research" say the authors of an interesting study published in the Journal of Reproductive Biology and Endocrinology.

The article suggests that what actually happens in endometriosis is that cytokines (proteins synthesized by immune cells which promote inflammation) make endometrial cells proliferate (divide and multiply) and implant/adhere to nearby organs (like ovaries, bladder, colon, etc). So, inflammation is definitely the problem and one particular protein called TNF, tumor necrosis factor, is the real culprit.

Given that inflammation is associated with endometriosis, it stands to reason that immunosuppresive therapy (corticosteroids) could provide relief as it does for a wide variety of auto-immune disorders like rheumatoid arthritis. However, baboons who received the drugs didn't show any regression of endometriosis. The authors hope that more specific immunosuppressive drug therapies could be developed so that rather than attacking the entire immune system, only one part of it, perhaps the TNF, could be targeted.

*Endometriosis May be an Autoimmune Disorder*
The article also suggests that endometriosis may be an autoimmune disorder - the immune system produces antibodies that go unchecked. They secrete too many cytokines and too much inflammation, thus the problem. Meanwhile, other cytokines tell the endometrial tissue to vascularize (form new capillaries). What does that mean? Basically a superhighway is built to transport ever more inflammatory cells to the area. It grows like cancer.

*Impaired Embryo Implantation*
I often come across statistics and anecdotes from women trying to conceive with endo that suggest one reason women with endo have trouble getting pregnant is not that the fallopian tubes are blocked as is commonly thought, but rather that the fertilized embryo fails to implant into the uterine wall, i.e. the place where endometriosis is actually supposed to grow. This explains why so many women with this condition experience repeated "chemical pregnancies," miscarriages, and IVF failure.

The article has this to say, however, "The failure of NK cells to scavenge autologous endometrial cells may allow development of endometriosis. It has been hypothesized that natural killer cells in the endometrium can attack the implantation site of the embryo as it tries to attach to the uterine wall and that autoantibodies can play a role in this process. However, a recent review has shown that there is no proven relationship between abortion, recurrent abortion and endometriosis, and at present there is no proof that endometriosis- associated subfertility is caused by impaired embryo implantation."

-- Translation --
One kind of really-important-for-keeping-you-healthy, immune cell (natural killer cell) was thought to prevent the embryo from implanting in the uterus, but this turns out to not be the case. In fact, there is no evidence that failure to implant is the reason women with endometriosis have trouble becoming pregnant.

*The Immune System - What's Really Happening*
So what the heck is going on with endometriosis and the immune system?
T-cells (those immune cells that attack "germs" and what not and are depleted in people who have AIDS) are less toxic to cells they are supposed to kill. So, they don't kill the endometriosis like they are supposed to in affected women (and baboons!). Also, various other molecules that normally work to initiate programmed cell death (apoptosis) and also mark cells for elimination by the immune system - fail. So, endometriosis flies under the radar of the immune system and then fails to respond to the immune system's own form of euthanasia. Lovely. Absolutely lovely.

*New Diagnosis & Treatment Ideas*
The authors of the study I read think that invasive surgery, the gold standard for an official endometriosis diagnosis, could be rendered unnecessary by measuring the levels of two cytokines in abdominal fluid: TNF and IL-6 (interleukin 6). They say, "Endometriosis could be diagnosed if TNF-alpha levels in PF were higher than 15 pg/ml (100% sensitivity and 89% specificity) and if IL-6 levels in serum were above 2 pg/ml (90% sensitivity and 67% specificity)."

Endo can be treated by surgery and by hormonal suppression (progestins, continuous use of oral contraceptives, danazol, GnRH agonists). Danazol is also an immunosuppressive drug (steroid) that in addition to turning a woman into a She-Man, also makes her immune system quiet down. It shuts of TNF and some other cytokines like IL-1 (not 6).

The authors would really like to see other forms of treatment that don't deplete estrogen and therefore retain a woman's ability to not only get pregnant, but still look feminine. I would appreciate that too! Mouse, rat, and baboon models are being used to develop proteins that will give stuff like TNF and IL-6 something else to bond to instead of the endometrial cells. Already, a protein (recombinant human tumour necrosis factor-binding protein-1) has been shown to decrease endometriosis by 64% - in mice. Cool.


Punchanella said...

i tend to disagree with the stem cell explanation of endometriosis.

retrograde menstruation seems more likely to me. i see the logic of saying that 80% of women have retrograde menstruation, yet only 10% have 'endometriosis', but to assume retrograde mensturation = endo is probably too simplistic. if other factors such as hormone levels, stress levels, diet quality etc. etc. are taken into account (which vary enormously), it might be easier to understand why not ALL women with retrograde menstruation develop endo. just my thoughts... as a scientist and endo sufferer.

thanks for blogging about it!

Field Notes said...

thanks for your comment punchanella

There's also the link between dioxin and endo. I don't have the reference offhand, but I recall seeing a published article about how lab primates exposed to dioxin developed endo.

I live downwind from a paper processing plant that is one of the biggest producers of dioxin in the state. It's a risk factor.

Anonymous said...

Having had endo and hysterectomy, I will comment on these new findigs. There are several research reports that link other immune diseases with endo such as lupus, reumatoid arthritis and fibromyalgia and allergies... and I have allergies and fibromyalgia - which I developed after my hysterectomy... So, I think and have thought for over 20 years that the immune system plays a part in this.. and wondered why my immune system did not destroy the invaders.. So this is great news as my daughter also has endo and allergies...