Saturday, December 28, 2013

Pain and depression medications

So if your doctor suggests putting you on an antidepressant to help with your chronic pain, should you be offended, thinking they're saying that you don't really have a reason for pain? Should you look at them like they've just reenacted the scene from Moonstruck?

Before you do, let's look at it a little first. Pain is a complex process.

How does pain work?

First you have a source of stimuli (an injury, inflammation, infection, etc)- these are called noxious stimuli. Appropriate name I say! "There are three categories of noxious stimuli:
The injured cells release certain chemicals that lets your system know it needs some help there. "This noxious stimulation causes a release of chemical mediators from the damaged cells including:

These chemicals activate special nerves, called nociceptors, which send a signal to your brain via the spinal cord. When this signal reaches the spinal cord it determines whether immediate action is necessary- like if you stick your finger on a hot oven and you jerk it away- your instant reflexes are from your spinal cord. Even if the spinal cord signals you to jerk your finger away, that signal still travels to your brain. Now up until it reaches the brain, your body uses special fibres to differentiate the type of pain or "stimuli" called C fibres and A delta fibres.

C fibresA-delta fibres
Receptor type:
  • Polymodal respond to more than one type of noxious stimuli:
  • Mechanical
  • Thermal
  • Chemical
Pain quality:
  • Diffuse
  • Dull
  • Burning
  • Aching
  • Referred to as ‘slow’ or second’ pain
Receptor type:
  • High-threshold mechanoreceptors respond mechanical stimuli over a certain intensity.
Pain quality:
  • Well-localised
  • Sharp
  • Stinging
  • Pricking
  • Referred to as ‘fast’ or ‘first’ pain   

Once the signals get to the brain, certain neurotransmitters take over. "In order for the pain impulses to be transmitted across the synaptic cleft to the NDHN, excitatory neurotransmitters are released, which bind to specific receptors in the NDHN. These neurotransmitters are:
  • adenosine triphosphate;
  • glutamate;
  • calcitonin gene-related peptide;
  • bradykinin;
  • nitrous oxide;
  • substance P.
"The pain impulse is then transmitted from the spinal cord to the brain stem and thalamus via two main nociceptive ascending pathways. These are the spinothalamic pathway and the spinoparabrachial pathway. The brain does not have a discrete pain centre, so when impulses arrive in the thalamus they are directed to multiple areas in the brain where they are processed."

[Side note: "Neurotransmitters are biochemical messengers that carry pain signals from one nerve cell to the next. The three main neurotransmitters that send pain signals to the brain are substance P, NMDA (n-methyl-d-aspartate), and glutamate. Excess amounts of these chemicals, especially substance P, make it easier for pain signals to reach the brain."]

So, the signal goes to your thalamus to be directed to different areas for a complete analysis. Think of it like the CSI tv shows- everything gets analyzed! ("New imaging techniques have mapped out at least 200 areas of the brain that respond to different types of pain."  Your brain keeps and catalogs everything about that pain experience- how was it compared to other pain, what was happening at the time, how quickly did it resolve, any complications.... Your brain is a pack rat of 1930's Depression baby quality-- "I might need this one day..."! Because the thalamus sends the signal to be analyzed by different areas of the brain, you experience pain in several different ways. "Perception of pain is the end result of the neuronal activity of pain transmission and where pain becomes a conscious multidimensional experience. The multidimensional experience of pain has affective-motivational, sensory-discriminative, emotional and behavioural components."

"The modulation of pain involves changing or inhibiting transmission of pain impulses in the spinal cord. The multiple, complex pathways involved in the modulation of pain are referred to as the descending modulatory pain pathways (DMPP) and these can lead to either an increase in the transmission of pain impulses (excitatory) or a decrease in transmission (inhibition).
Descending inhibition involves the release of inhibitory neurotransmitters that block or partially block the transmission of pain impulses, and therefore produce analgesia. Inhibitory neurotransmitters involved with the modulation of pain include:
  • endogenous opioids (enkephalins and endorphins);
  • serotonin (5-HT);
  • norepinephirine (noradrenalin);
  • gamma-aminobutyric acid (GABA);
  • neurotensin;
  • acetylcholine;
  • oxytocin.
Endogenous pain modulation helps to explain the wide variations in the perception of pain in different people as individuals produce different amounts of inhibitory neurotransmitters. Endogenous opioids are found throughout the central nervous system (CNS) and prevent the release of some excitatory neurotransmitters, for example, substance P, therefore, inhibiting the transmission of pain impulses."

(Notice that serotonin and norepinephrine in there? That helps inhibit pain signals from reaching the brain? Remember that!)

After an injury is healed the nociceptors should stop firing. However if they are constantly excited, like in endo, you get chronic pain. Sometimes even once an area is healed, the nociceptors will keep firing.

"The exact mechanisms involved in the pathophysiology of chronic pain are complex and remain unclear. It is believed that following injury, rapid and long-term changes occur in parts of the CNS that are involved in the transmission and modulation of pain (nociceptive information) (Ko and Zhuo, 2004). A central mechanism in the spinal cord, called ‘wind-up’, also referred to as hypersensitivity or hyperexcitability, may occur. Wind-up occurs when repeated, prolonged, noxious stimulation causes the dorsal horn neurones to transmit progressively increasing numbers of pain impulses."

"The gate theory says that as these pain messages come into the spinal cord and the central nervous system (before they even get to the brain), they can be amplified, turned down or even blocked out. There are many accounts of how people injured on the battlefield or in sports games don’t feel any pain from their injuries until afterwards. This has to do with the brain being busy doing other things and shutting the gate until it can pay attention to the messages. Large diameter nerve fibres (A-beta fibres) responsible for transmitting signals of touch to the brain have the ability to close the pain gate and so block signals from other smaller diameter nerve fibres which transmit pain. An example of this would be when a child falls over and hurts her knee — if she rubs her knee, the signal from that sensation of touch temporarily blocks the pain signal travelling from the injured knee to the brain....

"At the cellular level, several processes can contribute to pain becoming chronic.
  • Pain receptors and neurones along the pain pathway may become too easily activated.
  • Connections between the neurons in the pathway can be altered.
  • The brain and spinal cord may fail to dampen down the pain signals.
  • Pain receptors that are normally silent (dormant) can become activated by inflammation.
  • After nerve injury, nerves may regrow but function abnormally.
Chronic pain can persist for months or even years after an initial injury and can be difficult to treat. People with chronic pain may experience sleeplessness, anxiety and depression, all of which can compound the problem."

Now to tie in that thing about serotonin and norepinephrine helping block pain signals and depression medications:

"Clinical symptoms of depression can be grouped into three basic categories: emotional (depressed mood, lack of motivation, disinterest in social activity, anxiety), cognitive (inability to concentrate, poor memory), and physical (insomnia, headache, fatigue, and stomach, back, and neck pain)....Theories about the biologic basis for depression have evolved over more than 25 years. The principal biochemical basis for depression has focused on two neurotransmitters: serotonin and norepinephrine.[9,10] These two neurotransmitters have also been implicated in the underlying pathophysiology of chronic pain.[4–7] Serotonergic and norepinephrine neurons overlap in the brain, and these two systems interact biochemically and neuroanatomically. In patients with depression, alterations or reductions of these two neurotransmitters and their respective receptors become dysfunctional over time, leading to a dysregulated system....

"The link between the higher brain centers involved with depression and pain and the peripheral body regions occurs in the brain stem, with neurotransmission relayed through the spinal cord. Abnormal body activity and functions (e.g., musculoskeletal) are suppressed from the consciousness by the serotonin and norepinephrine descending pathways in the spinal cord that originate in the brain stem.[12,13] ...A painful stimulus from the periphery can affect multiple pathways, eliciting the complex set of mechanisms leading to and found within the central nervous system....

"As stated earlier, numerous receptor systems located on these two nociceptor pathways exist that form the starting point of pain and its interactions with depression. Glutamate, a major excitatory neurotransmitter, affects both pathways and could serve as one common pharmacologic model for the rapid action of the Ad fibers and the slower actions of C fibers.[5] Many other receptor systems and their corresponding stimuli complete this discussion of the circuitry of pain modulation that incorporates depressive symptomatology. This discussion focuses only on serotonin and norepinephrine pathways. Other models are certainly involved, most notably, enkephalin and opioid peptide links....

"For many years, antidepressants have been used in different chronic pain syndromes with or without the presence of clinical depression....The studies also indicated that the antidepressant's beneficial effect on pain does not seem to be related to its effect on mood....Based on the interrelationship between pain and depression, the serotonin and norepinephrine reuptake inhibitors (SNRIs) may be preferred over other antidepressant pharmacologic classes (e.g., selective serotonin reuptake inhibitors [SSRIs]) because of their dual action on noradrenergic (norepinephrine) and serotonergic (serotonin) activities in the central nervous system. Animal models have shown a dose-dependent response with SNRIs' ability to decrease pain sensitivity, whereas SSRIs were ineffective....Most of the above-mentioned clinical trials were conducted mainly with duloxetine and other agents in a double-blind, placebo-controlled environment. These studies demonstrate that antidepressants are safe and effective treatments of physical painful symptoms whether or not comorbid depression and/or anxiety are present for a relatively short time period of up to 12 weeks. An early response was noted during the first few weeks, with continued benefits throughout the study."

"Physical pain and depression have a deeper biological connection than simple cause and effect; the neurotransmitters that influence both pain and mood are serotonin and norepinephrine. Dysregulation of these transmitters is linked to both depression and pain. Antidepressants that inhibit the reuptake of both serotonin and norepinephrine may be used as first-line treatments in depressed patients who present with physical symptoms."

[Lengthy quote below is courtesy of]

"Living with chronic pain should be enough of a burden for anybody. But pile on depression -- one of the most common problems faced by people with chronic pain -- and that burden gets even heavier.
Depression can magnify pain and make it harder to cope. The good news is that chronic pain and depression aren't inseparable. Effective treatments can relieve depression and can help make chronic pain more tolerable....
"Pain provokes an emotional response in everyone. Anxiety, irritability, and agitation -- all these are normal feelings when we're hurting. Normally, as pain subsides, so does the stressful response.
But what if the pain doesn't go away? Over time, the constantly activated stress response can cause multiple problems associated with depression. Those problems can include:
  • chronic anxiety
  • confused thinking
  • fatigue
  • irritability
  • sleep disturbances
  • weight gain or loss
"Some of the overlap between depression and chronic pain can be explained by biology. Depression and chronic pain share some of the same neurotransmitters -- the chemical messengers traveling between nerves.  They also share some of the same nerve pathways. The impact of chronic pain on a person's life overall also contributes to depression. 'The real pain comes from the losses' caused by chronic pain, according to Feinberg. 'Losing a job, losing respect as a functional person, loss of sexual relations, all these make people depressed.' Once depression sets in, it magnifies the pain that is already there. 'Depression adds a double whammy to chronic pain by reducing the ability to cope,' says Beverly E. Thorn, professor of psychology at the University of Alabama and author of the book Cognitive Therapy for Chronic Pain....
"The fact that chronic pain and depression involve the same nerves and neurotransmitters means that antidepressants can be used to improve both chronic pain and depression. 'People hate to hear, 'it's all in your head.' But the reality is, the experience of pain is in your head,' says Feinberg. 'Antidepressants work on the brain to reduce the perception of pain.' Tricyclic antidepressants have abundant evidence of effectiveness. However, because of side effects their use is often limited. Some newer antidepressants are prescribed by doctors to treat certain painful chronic syndromes and seem to work well with fewer side effects. 
      Physical Activity    
"Many people with chronic pain avoid exercise. 'They can't differentiate chronic pain from the 'good hurt' of exercise,' says Feinberg. But, the less you do, the more out of shape you become. That means you have a higher risk of injury and worsened pain. The key is to break this cycle. 'We now know that gentle, regular physical activity is a crucial part of managing chronic pain,' says Thorn. Everyone with chronic pain can and should do some kind of exercise. Consult with a physician to design an exercise plan that's safe and effective for you. Exercise is also proven to help depression. 'Physical activity releases the same kind of brain chemicals that antidepressant medications release -- [it's] a natural antidepressant,' says Thorn."
So, yes, antidepressants could help improve your pain levels. If you think about it, things that increase the good/helpful neurotransmitters and decrease the excitatory/make ya hurt neurotransmitters like eating healthy (think lots of fresh fruits, veggies, omega 3's, etc etc, less processed food) and exercise (yay endorphins!) and things that help control your stress (yoga, meditation, something that makes you laugh) can help too. So, remember to make taking time to take care of yourself a priority. If you don't, you will have a hard time taking care of the ones you love. So take care of yourself for their sake! :)


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!):

And they also have one on minerals (cool!):

About those vitamins and minerals. (note: the below quotes are from A good source of information on specific nutrients is World's Healthiest Foods (see 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."
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.                   

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."

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."

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."

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."

"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."
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)."

"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."

"...genistein has an ERβ-selective affinity and potency but an ERα-selective efficacy."

"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."

"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."   
(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  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!)