Saturday, November 30, 2013

Let's Talk Food! (among other things)

I love food. It doesn't always love me, but I don't care, I love it anyway.


What we eat can either help us or hinder us, especially when you have a chronic illness like endometriosis. As Hippocrates said:
So how can food, herbs, vitamins, and supplements be our medicine for endometriosis? Let's start with the basics of food. Most of us know the more fresh fruits and veggies we have the better. We also realize that a lot of processed food, red meat, sweets, etc are not good. And naturally, alcohol, tobacco, and too much caffeine are not helpful. What you may not have been told is that women with endometriosis can have a lot of food sensitivities. This can be compounded by the fact that a lot of endo ladies also have problems with irritable bowel syndrome, interstitial cystitis, and other immune problems. Generally the first culprits to ferret out are dairy, wheat (gluten), corn, soy, preservatives, and food additives. Google the FODMAPs diet if you have bowel symptoms or IC diet if you have bladder symptoms for more particulars on those.

Here's a great list of vitamins and how they can help endo (so check it out!):  http://www.articlesbase.com/womens-health-articles/endometriosis-part-ii-how-to-treat-endometriosis-with-vitamins-1127429.html

And they also have one on minerals (cool!):  http://www.articlesbase.com/womens-health-articles/endometriosis-part-x-how-to-treat-endometriosis-with-minerals-1160644.html

About those vitamins and minerals. (note: the below quotes are from http://info.spectracell.com/bid/87780/Nutrient-Correlation-Wheel-on-Estrogen) A good source of information on specific nutrients is World's Healthiest Foods (see http://www.whfoods.com/nutrientstoc.php). Food sources are the best way to get your vitamins and minerals et al, as you get a good combo that often works in tandem for their beneficial effect (one vitamin that helps you absorb/use another are often found together in food!). Taking a pill form can be good, but these should be discussed with your health care practioner first!

Let's take them alphabetically:


Vitamin A- good for your skin, eyes (night vision!), mucous membranes, a strong man against viruses (yay immune system!), helps with inflammation, also "helps metabolize the biologically active estrogen (estradiol) to an inactive form (estrone)."




 B vitamins help convert estrogen to its weaker form (by helping your liver) and convert omega-3's into healthy and helpful prostaglandins (anti inflammatory and relaxes uterine muscle). It particular folate (B9) "regulates estrogen’s effect on genes". B6 has been shown to decrease menstrual pain and "protects genes from estrogen-induced damage thus lowering risk of hormone related cancers; Detoxifies excess estrogen via methylation pathway; Estrogen-based oral contraceptives cause B6 deficiency."

Vitamin C is great for the immune system, helps your blood vessels, prevent cataracts, and even reported to lower lead blood levels. Also "Increases the most potent estrogen (estradiol) in women on hormone therapy; Lowers aromatase (enzyme that converts testosterone to estrogen) in ovaries."

Ah, the sunshine vitamin! Actually it's a steroid hormone. Vitamin D helps your bones and teeth (by regulating calcium and phosphorus by means of your parathyroid), is good for your immune system, helps prevent chronic fatigue, helps your muscles, helps inflammation- what a work horse! "Regulates synthesis of estradiol and estrone; Enhances estrogen’s protective effect on bones."

Vitamin E is a good little antioxidant, it even protects vitamin A from oxidizing! It protects your cells' DNA from being damaged, good for your artery walls, good for diabetes and your brain. "Deficiency impairs estrogen detoxification pathway; Some forms of vitamin E inhibit estrogen action, especially in breast tissue; Low levels linked to higher estrogen."

I wondered why I feel better when I eat more spinach. Now I know. It not only protects your bones, your liver, prevent calcification of your arteries, helps your blood clot, but it also "inhibits estrogen activity by binding to estrogen receptors; Lowers the ratio of estradiol (strong estrogen) to estrone (weaker estrogen)."
But enough about vitamins- time for some minerals!
Calcium- we know it's good for bones and teeth. It also is needed for muscle contractions, nerve function, hormone secretion, acid/alkaline balance, and "Calcium-D-glucarate lowers estradiol levels; Helps breakdown estrogen in the liver and convert it to a less toxic form."

 Magnesium- key in metabolism (anyone got fatigue? yes? I thought so), important in bones, energy production, nerves, controlling inflammation and blood sugar, also is a "cofactor for the enzyme that removes toxic forms of estrogen (catechol-O-methyltransferase); Estrogen alters magnesium levels throughout menstrual cycle." Magnesium helps your muscles to relax (I'll take a magsini- shaken, not stirred).

Selenium helps you produce your thyroid hormones, acts as an antioxidant, lowers joint inflammation. "Estrogen levels affect how selenium is distributed to various tissues in the body."

You may have read that zinc is good for your immune system (and it is), but did you know it helps your body "read" your genes correctly? Another interesting thing- it helps you taste and smell! It's also good for your metabolism and blood sugar. "Estrogen lowers risk of zinc deficiency; Zinc dependent proteins metabolize estrogen."
 
Let's broaden our scope a little bit here.


Probiotics = happy gut. But they also are good for your immune system as your gut plays a big part in your immune system.
Co Q 10 is an antioxidant and therefore good for your immune system. It helps protect your cells, produce energy, and protect your heart.

Omega 3's help decrease inflammation (specifically help reduce cytokines), supports your immune system, they are also good for those healthy and helpful prostaglandins, and are important in balancing out your omega 6 intake. (Zinc and B6 help them work even better!)
And never underestimate the power of clean, fresh, pure, delicious water! After all, we're around 60% water!
 
Another good thing is to get the least processed possibly- including less pesticides. 

 

 
"Foods tainted with certain chemicals appear to encourage the implantation of cells in the abdomen. Those chemicals include polychorinated biphenyls (PCBs), which were commonly used in electrical equipment, hydraulic fluid, and carbonless carbon paper, and organochlorine pesticides, which were commonly used in agriculture. Data from a 2005 study show that women exposed to PCBs may have a higher prevalence of endometriosis. Organochlorines bind to estrogen receptors and mimic hormones that in turn can affect endocrine pathways and alter hormonal function.8
These chemicals presumably do their dirty work by impairing the immune defenses against abnormal cells. Indeed, the natural killer cells and other white blood cells that are supposed to maintain a constant lookout for any abnormal cells have been shown to be weakened in women with endometriosis....These toxins tend to accumulate in animal fat, and the major route of human exposure is through food, particularly fish, as well as other meats and dairy products.10 Chickens, cattle, pigs, and other animals fed grains treated with pesticides and sometimes contaminated with other organochlorines tend to concentrate these compounds in their muscle tissues and milk. While there may also be organochlorine pesticide residues on nonorganic fruits or vegetables, they are less concentrated and easier to remove. Organic produce is grown without chemical pesticides .Lipid-rich foods such as fish and meat are major sources of organochlorines and PCBs, while plants have considerably lower levels of these contaminants."  http://www.pcrm.org/health/health-topics/endometriosis
 
On an ending note, chocolate is good for you.

 There's so much more out there, but we'll call it a day. Take two chocolates and call me in the morning. (I will take my own advice on this one!)




Phytoestrogens: Good, Bad, or Indifferent?

Or who the heck knows? Most of the studies I've gone through seem to be seeking a relationship between phytoestrogens and menopause or phytoestrogens and breast cancer.

Preread notes: Aromatase inhibitors used in the treatment of endo act by keeping aromatase from converting androgen to estrogen.  Genistein and daidzein is in soy. Naringenin is in grapefruit, orange juice, and limes.  Chrysin is in honey (yummy). Zearalenone is a mycotoxin (toxin produced by a fungus) found on maize, wheat, barley, sorghum and rye.

And a little review about estrogen receptors (ER): endo lesion growth seems to be mediated mostly through ERα.  http://endocomprehensive.blogspot.com/2013/11/estrogen-receptors-importance-in.html                   


Okay. Let's dive on in!
 


"Dietary phytoestrogens have been reported to inhibit aromatase activity in placental microsomes, but the effects in the human endometrium are unknown. Aromatase, the rate-limiting enzyme in the conversion of androgens to estrogens, has recently been shown to be expressed in the endometrium of women with endometriosis and is thought to play a role in the pathophysiology of this disease. Therefore, the objective of this study was to screen dietary phytoestrogens for their ability to inhibit aromatase activity in human endometrial stromal cells (ESC) and identify potential novel therapeutic agents for the treatment of endometriosis. The inhibition of aromatase activity by direct interaction with the dietary phytoestrogens genistein, daidzein, chrysin, and naringenin was tested in a cell free assay. Furthermore, test compound effects on aromatase activity in ESC cultures were also examined. Genistein and daidzein were inactive in the human recombinant aromatase assay whereas naringenin and chrysin inhibited aromatase activity. However, genistein (1 nM to 1 mM) stimulated aromatase activity in ESC whereas other phytoestrogens had no effect. Immunopositive aromatase cells were demonstrated in genistein-treated ESC but not in untreated control cultures. Taken together, our data suggest that genistein can increase aromatase activity in ESC likely via increased enzyme expression."   http://rnd.edpsciences.org/index.php?option=com_article&access=standard&Itemid=129&url=/articles/rnd/pdf/2005/06/r5604.pdf

SO, according to this, naringenin and chrysin (found in grapefruits, orange & tangerine juice, limes, and honey) have aromatase inhibiting effects, so they keep androgens from being turned into estrogen. However, genistein (soy) increased the aromatase enzymes turning androgen into estrogen.  Let's go a little deeper.

Does dietary consumption have that big of an impact on endometriosis? The study below suggests not:

"Endometriosis is a disease in which uterine tissue proliferates in extrauterine sites. Using a surgical model to simulate endometriosis, we explored the potential for the phytoestrogen genistein, by injection and diet, to sustain endometriosis in rats. Uterine tissue was attached to intestinal mesentery of 8-week-old Sprague Dawley rats. After 3 weeks, the rats were ovariectomized and the implants measured. Following 3 weeks of daily injections or exposure to dietary genistein, animals were necropsied and implants located and measured. Injections of genistein (50 and 16.6 μg/g BW) or estrone (1 μg/rat) sustained the implants; injection of sesame oil (vehicle for estrone), dimethylsulfoxide (DMSO; vehicle for genistein), or genistein at 5.0 μg/g BW did not sustain implants. Dietary genistein (250 or 1000 mg genistein/kg AIN-76A diet) did not support the implants. In ovary-intact rats exposed to 250 mg genistein/kg AIN-76A diet, implant size was not altered, compared to control-fed animals. To assess estrogenic actions of genistein, we measured uterine estrogen receptor alpha (ER-α) and progesterone receptor (PR) isoforms A and B by Western blot analyses. Injections of estrone or genistein (50 or 16.6 μg/g BW) significantly reduced uterine ER-α compared to vehicle-treated animals. PR (B) was significantly increased by all injected doses of genistein or estrone and by the higher dietary dose (1000 mg genistein/kg AIN-76A). PR (A) was significantly increased by injected doses of genistein (16.6 and 5.0 μg/g BW). We conclude that pharmacologic injections, but not dietary physiological concentrations of genistein, support surgically induced endometriosis in rats. Our results suggest a critical role for ER modulation and genistein bioavailability in the maintenance of the implants."  http://toxsci.oxfordjournals.org/content/61/1/68.short

Then there's studies showing that phytoestrogens act as anti-estrogens too:

"Results: Endometrial glandular cells responded to stimulation with genistein and daidzein by alteration of both ERα- and ERβ-mRNA expression. The effects were time- and dose-dependent....We could detect a decrease in ERα- and an increase in ERβ-mRNA expression after stimulation with tested phytoestrogens. Our results are in line with findings that phytoestrogens act as anti-estrogens in organs expressing more ERα and as estrogens in ERβ-presenting organs."  http://ar.iiarjournals.org/content/25/3A/1713.short

So, according to the above, in organs that have more ERα it can act as an anti-estrogen, but in ERβ they act as estrogens. (The central nervous system, cardiovascular, breast, bone, and urogenital all have both receptors. The lung and GI tract have ERβ, and the liver has ERα.) More so, this action is dependent on how much you get and when you get it. For instance, zearalenone (that little fungus producing toxins on maize, wheat, etc) and resveratrol (think grapes) at high doses act as antagonists on both receptors. Also genistein (soy) can be estrogenic but by acting on the ER sites can interfere with estrogen and over time lessen the response they show to estrogen. This is explored more thoroughly below:

"The soy-derived genistein, coumestrol, and equol displayed a preference for transactivation of ERβ compared to ERα and were 10- to 100-fold less potent than diethylstilbestrol. In contrast, zearalenone was the most potent phytoestrogen tested and activated preferentially ERα. All other phytoestrogens tested, including resveratrol and human metabolites of daidzein and enterolactone, were weak ER agonists. Interestingly, the daidzein metabolites 3′,4′,7-isoflavone and 4′,6,7-isoflavone were superagonists on ERα and ERβ. All phytoestrogens tested showed reduced potencies to activate ERα and ERβ compared to diethylstilbestrol on the estrogen-responsive C3 promoter compared to a consensus estrogen response element indicating a degree of promoter dependency. Zearalenone and resveratrol were antagonistic on both ERα and ERβ at high doses.... Due to activation of the ER, these compounds are referred to as phytoestrogens and have the potential to disrupt estrogenic signaling.... Interestingly, although ERβ shows lower binding affinity for and activation by endogenous estrogens, some xenoestrogens preferentially bind and activate ERβ.... the eventually high doses of dietary phytoestrogens (Bingham et al., 1998) warrant a more thorough analysis of the potential dysregulation of ER action by phytoestrogens.... Nevertheless, estrogenic and/or antiestrogenic activities of phytoestrogens like resveratrol and genistein may reduce but also stimulate estrogen-dependent tumor growth depending on dose and timing of exposure....Binding affinity to ER has been used frequently as a surrogate marker for estrogenicity. However, binding to the ER does not necessarily result in agonistic activity and may lead to antagonistic activity on ERα or ERβ. ...ZEA and COUM were the most potent phytoestrogens on ERα, and COUM, GEN, and equol preferentially activated ERβ....Another measure of estrogenic activity is the efficacy. ZEA, COUM, GEN, equol, and RESV had efficacies that were comparable to DES and E2 (Fig. 3). Therefore, these compounds were considered full agonists. ENL and 6OH-ENL showed markedly lower efficacies than DES and were considered partial agonists....Next to the agonistic activity, the antagonistic activity on ER is important for the characterization of endocrine-active compounds....ZEA that showed dose-dependent antagonistic activity on ERα and ERβ, RESV displayed an inverted U-shaped dose response (Fig. 4). At low doses, RESV increased the DES-induced activity of ERα and ERβ, but at high doses it inhibited activity of ERα and ERβ....Activation of the ER depends on the proper recruitment of coactivators that facilitate the transcription of ER target genes (Tremblay and Giguere, 2002). Recruitment of coactivators may, therefore, also determine the ER subtype–specific activation by phytoestrogens....Thus, these results warrant a cautious evaluation of the use of phytoestrogens to prevent estrogen-dependent diseases and require a thorough analysis of the estrogenic and antiestrogenic properties of these compounds. ... In contrast, ZEA was the most potent phytoestrogen tested and activated preferentially ERα. All other phytoestrogens tested including RESV and the daidzein and ENL metabolites were weak to very weak ER agonists....Beneficial effects on estrogen-related diseases are often attributed to antiestrogenic activities of phytoestrogens (Bingham et al., 1998). Analysis of antagonistic activity on ERα and ERβ revealed that only RESV and ZEA displayed apparent inhibitory properties on both ERα and ERβ transactivation. ...ZEA was a more potent antiestrogen than RESV and lacked any additive agonistic effects with DES on ERα and ERβ, indicating its potential to act as a pure ER antagonist at high doses....Recruitment of coactivators to ERα and ERβ is a prerequisite for ER action, and ER coactivators are also important determinants for tissue-specific estrogen action, since coregulators show a tissue-specific expression profile....We showed that all ER agonists tested enhanced recruitment of coactivators at doses similar to that which induced transactivation. This confirmed that coactivator recruitment is necessary for ER action and that a two-hybrid coactivator assay could serve as surrogate marker for ER activation....These studies showed that ERβ-selective phytoestrogens like genistein were more potent to recruit coactivators to ERβ compared to ERα....The isoflavones showed all pure ER agonistic activity. Thus, these compounds should be regarded as potentially estrogenic and, consequently, as potential endocrine disruptors that may cause elevated cell proliferation leading to estrogen-dependent tumor promotion.... The beneficial effects associated with soy intake are likely due in part to non-ER-mediated effects as described above. But, with regard to the adverse and beneficial ER-mediated effects, the timing of exposure is important....In conclusion, the risks and benefits of estrogenic or antiestrogenic effects depend highly on the target tissue as well as the timing and level of exposure. These latter two factors along with further research on the potential tissue-specific effects of phytoestrogens should aid in the assessment of the real risks and benefits of phytoestrogen-containing diets."  http://toxsci.oxfordjournals.org/content/80/1/14.full

"We also found that genistein, though estrogenic, can interfere with the effects of estradiol. In addition, prolonged exposure to genistein resulted in a decrease in estrogen receptor mRNA level as well as a decreased response to stimulation by estradiol."  http://carcin.oxfordjournals.org/content/17/2/271.short
 
Getting a little strange around here...

Another good point brought up below, is that most tests are done in vitro (think lab) as opposed to in vivo (living human beings like us) and there is a difference.

"Some suspected endocrine disruptors have been shown to interact not only with the ER but also with the androgen receptor or to interfere with steroid hormone synthesis or metabolism (20)....Most suspected endocrine disruptors have been tested in in vitro systems (radioligand competition, transactivation assays) and these tests may underestimate or overestimate their in vivo estrogenic potency. The estrogenic potency of bisphenol A in vitro is 1000- to 5000-fold lower than that of E2, but in vivo bisphenol A was rather effective in stimulating PRL release from the pituitary.... Development of in vivo reporter systems for the assessment of the estrogenic activity of suspected endocrine disruptors might be necessary....The estrogenic potency of compounds is a complicated phenomenon that is the result of a number of factors, such as differential effects on the transactivation functionalities of the receptor, the particular coactivators recruited and the cell- and target gene promoter-context (62)....The reason for these differences in transcriptional activity of the ER subtypes is at the moment unknown, but it might reflect differential expression of transcriptional coactivators or differential stability of the receptor proteins.... Most prominently, phytoestrogens have been suggested to exert strong antiestrogenic effects, thereby inhibiting development of hormone-related cancers (39, 72). In our study, only zearalenone exhibited some antagonistic activity. All other phytoestrogens, including the flavonoids that are present in soy foods, showed only agonistic activity. In previous in vitro studies, involving ERα, only agonistic or at best partial antagonistic activities instead of complete antagonistic activities were reported (36, 37, 38, 75). Several other mechanisms for the proposed chemopreventive effects of flavonoids have been suggested, including induction of cancer cell differentiation, inhibition of protein tyrosine kinases, suppression of angiogenesis, and direct antioxidant effects (41, 76). These alternative mechanisms generally occur at flavonoid concentrations much higher (>5 μm) than the concentrations at which estrogenic effects are detected (<100 nm), and show a different structure-activity relationship; moreover, the effects are observed in cells in the absence of ER expression, and therefore it seems unlikely that all of these effects are ER mediated (41, 77, 78). On the other hand, because both ER subtypes are expressed in bone and the cardiovascular system (4, 79, 80, 81) and given the quite strong estrogenic activity of certain phytoestrogens, the potential beneficial effects of increased food intake of phytoestrogens in the prevention of postmenopausal osteoporosis and cardiovascular diseases should be further investigated (82)."  http://endo.endojournals.org/content/139/10/4252.full

"These data taken together demonstrate alterations in the ovary following neonatal exposure to genistein. Given that human infants are exposed to high levels of genistein in soy-based foods, this study indicates that the effects of such exposure on the developing reproductive tract warrant further investigation....In summary, we have shown that neonatal genistein exposure produces multiple effects on the morphology and function of the mouse ovary. Furthermore, we have begun to elucidate the mechanisms by which genistein elicits such effects. The ectopic induction of ERα expression in the granulosa cells of the ovary appears to be associated more with the tyrosine-kinase inhibitory properties of genistein rather than its estrogen actions, although indirect effects secondary to estrogenization of the hypothalamic-pituitary axis cannot be ruled out. In contrast, the induction of MOFs in the ovary, which appears to be a direct effect and unrelated to the changes in ERα expression, is dependent on the presence of functional ERβ within the ovary. Future investigations into the mechanisms of the diverse effects of genistein will prove invaluable in evaluating the possible effects of phytoestrogens on reproductive function."  http://www.biolreprod.org/content/67/4/1285.full

"...genistein has an ERβ-selective affinity and potency but an ERα-selective efficacy."  http://molpharm.aspetjournals.org/content/54/1/105.short

"Our results demonstrate that ERb can act as a negative
or positive dominant regulator of ER activity. This is
manifested through reduced transcriptional activity at
low concentrations of estradiol (E2); increased antag-
onistic effects of tamoxifen on E2 stimulated activity;
and enhanced agonistic action of the phytoestrogenic
compound genistein....

Estrogen levels vary in females during the menstrual
cycle, pregnancy and at menopause. These fluctuations
may influence the estrogenic activity in tissues contain-
ing ERb. Tissues expressing predominantly ERb could
be expected to be resistant to low levels of E2 with
respect to regulation of ERE-containing genes.
ERb expression may also amplify the
agonistic effect of the isoflavonoid genistein in tissuesthat also express ERa.
The concentrations of genistein required for activation of ERs and in
 
particular ERb are well within the range of what can
be measured in the circulation of individuals on a diet
rich in isoflavonoids." 

Feeling a little overwhelmed? Me too.

But let's keep going. Men have estrogen receptors too!

 "Results: Using concentrations of genistein that have been detected in sera of Asian men on regular soy-diet we found down-regulation of androgen receptor at both mRNA and protein level. The relative binding affinity to the AR was below 4% when compared to methyltrienologe (R1881) and there was no modulation of AR transcriptional activity by genistein concentrations up to 1 μM. We also demonstrated inhibition of PSA secretion after genistein treatment. As the anti-estrogen ICI 164 384 abolished the inhibitory effect of genistein and ER-β, but not ER-α is expressed in LNCaP cells we postulate that the mechanism of genistein action on androgen receptor is mediated through ER-β.
Conclusion: Using physiological concentrations of genistein we showed AR down-regulation by genistein in prostate cancer cells occurring via ER-β. This likely results in a modified response to hormonal stimuli and may help to explain the low incidence of prostate cancer in the Asian population."  http://www.sciencedirect.com/science/article/pii/S0302283803004688

"Emerging data is suggesting that estrogens, in addition to androgens, may also be contributing to the development of prostate cancer (PCa). In view of this notion agents that target estrogens, in addition to androgens, may be a novel approach for PCa chemoprevention and treatment. Thus, the identification and development of non-toxic dietary agents capable of disrupting androgen receptor (AR) in addition to estrogen receptor (ER) could be extremely useful in the management of PCa. Through molecular modeling we found carnosol, a dietary diterpene fits within the ligand binding domain of both AR and ER-α....The major finding of the study is the demonstration that carnosol can modulate both AR and ER-α activity. Using both prostate and breast cancer cell lines that each express AR and ER-α we found carnosol decreases the expression of AR and ER-α in a dose dependent manner. In addition, we have provided evidence that carnosol induces apoptosis in prostate cancer cells, however, further studies are needed to determine if there is any role for the ER-β which has been shown to have pro-apoptotic properties. We have also observed carnosol to be unique to other proposed dual AR and ER-α antagonists (e.g. tamoxifen, toremifene, fulvestrant) in that there is no evidence of carnosol acting as an agonist at the AR or ER-α. When carnosol was administered orally tumor formation was inhibited in athymic nude mice implanted with PCa cells. The attributes of carnosol to simultaneously disrupt AR and ER-α are unique compared to other FDA approved agents and may be further developed or chemically modified to develop a dual AR/ER-α disruptor." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978906/   
(carnosol is found in rosemary)

Let's come up for air.

So, in conclusion, it's still not clear. A regular diet of phytoestrogens (eating tofu or soymilk every day, taking pill forms of phytoestrogens) may not be the best thing to do until we have further research, but an occasional/rare bit probably won't hurt you (unless you're sensitive to soy). Like salt, soy is being processed in much of our food these days, so we may be getting more than we realize. Eating less processed food probably a good idea for our health overall, as is getting a variety of foods. Of course, we haven't even talked about xenoestrogens from environmental sources yet. We'll save that for another time. Let's head for the decompression chamber...

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 http://endo-update.blogspot.com/.  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...to 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. http://jpet.aspetjournals.org/content/303/3/1001.full.pdf   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"  http://www.ncbi.nlm.nih.gov/pubmed/23242524
 
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! http://www.merriam-webster.com/medical/aromatase)]:
 
"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."  http://www.medscape.com/viewarticle/473018_3
 
"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."  http://www.medscape.com/viewarticle/473018_3
 
"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.http://www.medscape.com/viewarticle/473018_3
 
 
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." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228389/
 
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." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135533/
 
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."  http://my.clevelandclinic.org/heart/prevention/estrogen-hormones/default.aspx
"Estrogens play a key role in regulation of bone mass and strength by controlling activity of bone-forming osteoblasts and bone-resorbing osteoclasts."  http://www.ncbi.nlm.nih.gov/pubmed/19751412

"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." 
http://www.medscape.com/viewarticle/406718_2

 
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)."  http://endo-update.blogspot.com/
 
(Check out his blog- it's pretty cool!)
 
 
 
 
 
 
 



Monday, November 25, 2013

Central Sensitization

Chronic pain is complex. There's no question about it. And treating it seems to become a guessing game of trial and error that often leaves us and our health care providers frustrated. Most of what I'll be talking about right now is leading up to the concept of central sensitization. They've been connecting it with arthritis and other musculoskeletal disorders...and now with endo.

Here's an excellent article about pain. I may end up quoting it all! Seriously. Read it!!    http://www.medscape.org/viewarticle/481798 

They wind it up by saying "Why does local injury resulting from trauma lead to chronic, intractable pain in some patients? Tissue injury leads to a constellation of changes in spinal excitability, which includes elevated spontaneous firing, increased response amplitude and duration, decreased threshold, enhanced discharge to repeated stimuli, and expanded receptive fields.[3] The persistence of these changes, which are collectively termed central sensitization, appears to be fundamental to the prolonged enhancement of pain sensitivity that defines chronic pain. Various medications and local anesthetic neural blockade may limit the magnitude of this CNS windup..."

I'll try to spell it out a little further but keep it concise- I will be using their quotes frequently below:

Severe trauma, including surgical trauma, sets off a downhill spiral of events. "Severe trauma" involves an inflammatory response (lots of inflammation involved with endo)- "cytokines and chemokines, substances that are meant to mediate the process of healing and tissue regeneration. However, these agents are also irritants and change the properties of the primary sensory neurons surrounding the area of trauma.Thus, the major features triggering inflammatory pain include damage to the high-threshold nociceptors (peripheral sensitization), modifications and modulation of the neurons in the nervous system, and amplification of the excitability of neurons within the CNS."

With that inflammation you get the COX-2 enzymes involved and they increase prostaglandins which increases, you guessed it, sensitivity (aka pain!). So you've got neurotransmitters that either create excitement or calm it down. "The process of peripheral and central sensitization is maintained, at least theoretically and experimentally, through the excitatory neurotransmitter, glutamate, which is believed to be released when the N-methyl-D-aspartate (NMDA) receptor is activated." So your nerves get all excited and they are jacked up like a 2 year old on red bulls and sugar at Christmas. Recurrent pain keeps the nerves excited and they just can't calm down. Nerves not calming down. Now we're getting into central sensitization.


"Central sensitization describes changes that occur in the brain in response to repeated nerve stimulation. Following repeated stimulation, levels of neurotransmitters and brain electrical signals change as neurons develop a 'memory' for responding to those signals. Frequent stimulation results in a stronger brain memory, so that the brain will respond more rapidly and effectively when experiencing the same stimulation in the future.... the enhanced reflex excitability after peripheral tissue damage does not depend on continuing peripheral input; rather, hours after a peripheral injury, spinal dorsal horn neuron receptive fields continued to expand."  Just like repeating something over and over again helps you to recall it quicker, your nerves can travel that path of pain quicker. Or like with exercise, they say you get 'muscle memory.' You get 'nerve memory.' Even without the original stimulus (the original thing that caused the nerves to fire off "pain!" in the first place). (Again the quotes are from http://www.medscape.org/viewarticle/481798)
 
So what has this to do with endo? I'm glad you asked.

"It has previously been reported in the literature that women with endometriosis frequently experience more comorbid conditions than the general population including interstitial cystitis, migraines, fibromyalgia, and chronic fatigue syndrome [1,2,3]. These overlapping pain syndromes and endometriosis share similar clinical presentations, which include multifocal pain coupled with somatic symptoms like:
  • fatigue
  • insomnia
  • cognitive/memory problems
  • psychological distress
  • anxiety
  • depression
"These syndromes may share a similar pathophysiologic mechanism of central nervous system pain and central sensitisation. A difficult aspect of evaluating patients with pain and sensitisation is in understanding how their pain impacts their day to day life and functioning. In order to better understand how pain affects women with chronic pelvic pain related to endometriosis, Dr Gemmill and her team assessed the interrelationship among chronic regional and multifocal pain, sleep disturbances, anxiety, and depression. 'The interrelationship among these symptoms affects women’s quality of life and may reflect central pain sensitisation. Research to better understand the interrelationship among generalised body pain, migraines, sleep disturbances, and psychological distress such as anxiety and depression and other aspects of quality of life in women with chronic pelvic pain related to endometriosis may guide future treatments.'"  http://endometriosis.org/news/congress-highlights/asrm2012-central-sensitivity-syndrome-and-endometriosis-associated-symptoms/

"The aim of this study was to test the hypothesis that persistent nociceptive input from endometriotic tissues leads to central sensitization manifested by somatic hyperalgesia and increased referred pain areas to experimental saline-induced muscle pain in patients with endometriosis, compared to healthy control subjects....Manifestation of central sensitization in women with endometriosis is demonstrated by increased muscle nociceptor input in the form of increased post-saline pain intensity, pain areas at the FDI, and hypersensitivity to pressure stimulation. These findings provide new insights into the complex pain mechanisms associated with endometriosis."  http://www.ncbi.nlm.nih.gov/pubmed/14622679

What the heck can I do about it?!?
 If only I knew... There's not really a lot about it out there that I have found so far. There's some anecdotal but not that many studies I've located.

First thing is to catch it early. An ounce of prevention is worth a pound of cure. The earlier you catch it, hopefully the easier it'll be break those neural pathways. "Once central sensitization is established, larger doses of analgesics are required to suppress it. Preemptive analgesia, or treatment before pain progresses, may reduce the impact of all these stimuli on the CNS. Woolf[3] demonstrated that the morphine dose needed to prevent central hyperexcitability, given before brief noxious electrical stimulation in rats, was one tenth the dose required to abolish activity after it had developed. This translates to clinical practice. In a clinical trial of 60 patients undergoing abdominal hysterectomy,[4] those who received 10 mg of morphine intravenously at the time of induction of anesthesia required significantly less morphine for postoperative pain control. Furthermore, pain sensitivity around the wound (secondary hyperalgesia) was also reduced in the morphine pretreated group." http://www.medscape.org/viewarticle/481798

So if you're looking at this, chances are it's gone beyond "early." What else is available? 
"Expert opinion: Acetaminophen, serotonin-reuptake inhibitor drugs, selective and balanced serototin and norepinephrine-reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, N-methyl-d-aspartate (NMDA)-receptor antagonists, calcium-channel alpha(2)delta (a2δ) ligands, transcranial magnetic stimulation, transcutaneous electric nerve stimulation (TENS), manual therapy and stress management each target central pain processing mechanisms in animals that – theoretically – desensitize the CNS in humans. To provide a comprehensive treatment for ‘unexplained’ chronic pain disorders characterized by central sensitization, it is advocated to combine the best evidence available with treatment modalities known to target central sensitization."  http://informahealthcare.com/doi/abs/10.1517/14656566.2011.547475
 
My doctor has mentioned Naltrexone before, so I looked it up specifically. It sounds like it has an anti inflammatory effect.

"Interest has been growing in the immune pathways involved in pain. At the heart of the research are the body's glial cells -- including microglia and astrocytes -- which disperse inflammatory cytokines when activated by certain biological triggers, such as opioids. These cytokines can send messages to neurons that counter analgesia...To hamper that inflammatory response, researchers have been targeting the toll-like-receptor-4 (TLR-4) on glial cells. Indeed, Younger said naltrexone can stifle the immune response and, ultimately, symptoms of fibromyalgia by blocking TLR-4 on microglia....

"Younger and colleagues found that patients reported an overall greater reduction in pain when they were on low-dose naltrexone than when they took placebo (48.5% versus 27.4%, P=0.006). In addition to the half of patients who reported feeling very much or much improved when on low-dose naltrexone, an additional quarter felt minimally improved, Younger said. He added that there was no impact on fatigue or sleep quality, and patients reported low-dose naltrexone to be as tolerable as placebo (89.2% versus 89.4% rated on a 100-point scale). Side effects reported more commonly with low-dose naltrexone were vivid dreams (37% versus 13% on placebo) and headache (16% versus 3%). Other drugs may have also improved pain via the immune pathway, including naloxone, fluorocitrate, minocycline, and dextromethorphan, Younger said. Generic versions of some of these drugs are available, which would make them significantly less expensive, he added."  http://www.medpagetoday.com/MeetingCoverage/AAPM/31371

PS Someone had a good question about adhesions. I haven't found a direct link between adhesions and central sensitization, but I did find an article about nerve involvement in adhesions.

"Nerve fibers, identified histologically, ultrastructurally, and immunohistochemically, were present in all the peritoneal adhesions examined. The location of the adhesion, its size, and its estimated age did not influence the type of nerve fibers found. Further, fibers expressing the sensory neuronal markers calcitonin gene-related protein and substance P were present in all adhesions irrespective of reports of chronic abdominopelvic pain. The nerves comprised both myelinated and nonmyelinated axons and were often, but not invariably, associated with blood vessels."    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422013/