Wednesday, November 27, 2013

Thankful for Researchers

On this day before Thanksgiving, I have to say I'm thankful for the super smart, dedicated people involved in research. Really- we owe these people a lot! One in particular I'd like to mention is the fellow who is behind  Besides a great blog explaining some of the research being done on endometriosis, he's working on a PhD studying endometriosis. Thank you!!

Specifically he's studying on an enzyme involved in taking a poor, weak little estrogen and transforming it into a body builder estrogen.

"All I have to do is take some AKR1C3 and I go from this!"
He's also studying PGE2. Now this is interesting. PG stands for prostaglandin and E2 is a type of that. Don't confuse it with PGE1 which has a lot to do with vasodilation and meds to treat erectile dysfunction. Ever hear about NSAIDs being COX-inhibitors and that's how they help you feel better? Well, PGE2s are products of COXs. Now COX 1's are protective- they help keep your gut from eroding. COX 2's get to going when there's inflammation.
 As I understand it, they're the help flags your body releases when there's been an injury. It goes "Aack! Help! Injury!" (okay, not really) that tells your body to respond to protect itself. It does this by increasing blood flow, swelling, and also increases pain sensitization.   It kind of gets the immune system revved up. It signals your brain to raise your body temp (aka fever) to help kill off any bugs that might take the opportunity to invade. But wait! It does more! It also softens the cervix and helps smooth muscle to contract- which is great if you're pregnant and in labor. But how does PEG2 relate to endo? Well....
"Prostaglandin E2 (PGE2) plays an important role in the pathogenesis of endometriosis. In previous studies, we have reported that selective inhibition of PGE2 receptors PTGER2 and PTGER4 decreases survival and invasion of human endometriotic epithelial and stromal cells through multiple mechanisms....selective inhibition of PTGER2 and PTGER4 as potential nonsteroidal therapy to expand the spectrum of currently available treatment options for endometriosis in child-bearing age women"
Now it REALLY gets interesting [First a note about aromatase. No, not an aromatherapy technique. It is "an enzyme or complex of enzymes that promotes the conversion of an androgen (as testosterone) into estrogens (as estradiol)." (Thanks Merriam and Webster!]:
"Prostaglandin E2 (PGE2) was found to be the most potent known inducer of aromatase activity in endometriotic stromal cells.[22] In fact, this PGE2 effect was found to be mediated via the cAMP-inducing EP2 receptor subtype (our unpublished observations). Moreover, estrogen was reported to increase PGE2 formation by stimulating cyclooxygenase type 2 (COX-2) enzyme in endometrial stromal cells in culture.[24] Thus, a positive feedback loop for continuous local production of estrogen and prostaglandins (PGs) is established, favoring the proliferative and inflammatory characteristics of endometriosis."
"Holy Inflammation, Batman!"
Wait, Robin! There's more!
"Additionally, aromatase mRNA was also detected in the eutopic endometrial samples of women with moderate to severe endometriosis (but not in those of disease-free women) albeit in much smaller quantities compared with endometriotic implants.[6] This may be suggestive of a genetic defect in women with endometriosis."
"There may be many other molecular mechanisms that favor the development of endometriosis: abnormal expression of proteinase type enzymes that remodel tissues or their inhibitors (matrix metalloproteinases, tissue inhibitor of metalloproteinase-1), certain cytokines (IL-6, RANTES [regulated on activation, normal T cell expressed and secreted]), and growth factors (epidermal growth factor) represent some of the mechanisms.[8-11] Alternatively, a defective immune system that fails to clear peritoneal surfaces of the retrograde menstrual efflux has been proposed in the development of endometriosis.[5,25] The development of endometriosis in an individual woman probably requires the coexistence of a threshold number of these aberrations. Nonetheless, the clinical importance of aromatase expression pertains because we could treat endometriosis using aromatase inhibitors.
So, does treating endo with aromatase inhibitors- used in breast and ovarian cancer- actually help? Well, let's look at how the medications actually work:
"Aromatase inhibitors and inactivators interfere with the body's ability to produce estrogen from androgens by suppressing aromatase enzyme activity. Before menopause, ovarian aromatase is responsible for the majority of circulating estrogen and is exquisitely sensitive to changes in luteinising hormone (LH). Following menopause, aromatase in fat and muscle may be responsible for much of the circulating estrogen. Aromatase in highly estrogen-sensitive tissues, such as the breast, uterus, vagina, bone, brain, heart and blood vessels, provides local estrogen in an autocrine fashion."
Does it help?
"In human subjects, aromatase alone, or in combination with steroids, appears to be effective in reduction of endometriosis-associated symptoms such as pelvic pain. Aromatase inhibitors appear to be most beneficial in the treatment of endometriosis in women with recurrent endometriosis who have not had success with more conventional treatment regimes such as gonadtropin releasing agonists/antagonists or steroidal analogues. However, one must keep in mind that aromatase inhibitors exhibit suboptimal tolerability and greater costs compared to some of the more conventional therapies. Clearly, aromatase inhibitor therapy may have a place in endometriosis treatment of a subset of patients suffering from the disease and benefits and limitations of these compounds must be discussed with patients. Future effort should be directed towards performing larger, multi-center trials with aromatase inhibitors to provide a more robust assessment of the efficacy of these compounds in the treatment of endometriosis and its associated symptoms."
Unfortunately, as the last quote states, it isn't well tolerated and isn't cost effective. All that suppression of estrogen can over the long term be harmful- particularly for your bones and heart.
"Estrogen’s known effects on the cardiovascular system include a mix of positive and negative:
  • Increases HDL cholesterol (the good kind)
  • Decreases LDL cholesterol (the bad kind)
  • Promotes blood clot formation, and also causes some changes that have the opposite effect.
  • Relaxes, smooths and dilates blood vessels so blood flow increases
  • Soaks up free radicals, naturally occurring particles in the blood that can damage the arteries and other tissues."
"Estrogens play a key role in regulation of bone mass and strength by controlling activity of bone-forming osteoblasts and bone-resorbing osteoclasts."

"Estrogen directly influences brain function through estrogen receptors located on neurons in multiple areas of the brain....Estrogen has been shown to protect isolated neurons in vitro from oxidative stress, ischemic injury, hypoglycemic injury, and damage by amyloid protein, which is implicated in the pathogenesis of Alzheimer's disease.[2] It also stimulates production of nerve growth factors, thereby promoting neuronal growth and viability, repair of damaged neurons, and dendritic branching."

So, estrogen does a lot of good for us, so we really don't wanna be hatin' on it. What the researcher I mentioned above is doing is working on non-hormonal ways to treat endo.
"Most drugs for the treatment of endometriosis are hormone based which is why women can get so many side effects from them, some of which can be very unpleasant. However my research will focus on non-hormonal ways of treating endometriosis, which may one day lead to drug treatments with fewer side effects (although that day could be a long way off)."
(Check out his blog- it's pretty cool!)