Monday, March 6, 2017

Symptoms of endometriosis review

Author(s) [Ref.]
Year
Results for symptoms
Results for signs
Valle [14]
2002
Pelvic pain that often is worse just before and during menstruation, hypermenorrhea, premenstrual staining, dyspareunia, suprapubic pain, dysuria, hematuria, painful defecation (dyschezia), lower back pain.
Local tenderness in cul de sac or uterosacral ligaments, adnexal enlargement or tenderness, pelvic masses.
Spaczynski and Duleba. [15]
2003
Chronic pelvic pain consists of dysmenorrhea, intermenstrual pain, and dyspareunia.
Bluish implants typical of endometriosis or red, hypertrophic lesions bleeding on contact, usually in the posterior fornix. lateral cervical displacement, cervical stenosis. Retroversion, decreased or absent mobility of uterus and tenderness. Tender masses, nodules, and fibrosis appreciated on palpation of the upper vagina, cul-de-sac, uterosacral ligaments, or rectovaginal septum.
Kennedy et al. [16]
2005
Severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (e.g. bowel or bladder associated) with or without abnormal bleeding, infertility and chronic fatigue.
Pelvic tenderness, a fixed retroverted uterus, tender uterosacral ligaments or enlarged ovaries on examination. The diagnosis is more certain if deeply infiltrating nodules are found on the uterosacral ligaments or in the pouch of Douglas, and/or visible lesions are seen in the vagina or on the cervix. The findings may, however, be normal.
Mounsey et al. [17]
2006
Pelvic pain, back pain, dyspareunia, dysmenorrhea loin pain, dyschezia, pain with micturition and infertility.
Tender nodules in the posterior vaginal fornix, uterine motion tenderness, a fixed and retroverted uterus, or tender adnexal masses.
Denny and Mann. [18]
2007
Pain around menstruation, dyspareunia, dyschezia, cyclical dysuria and extreme fatigue.
Not discussed.
Amer [19]
2008
Dysmenorrhoea, dyschezia, hematochezia, dysurea, haematurea, dyspareunia, chronic pelvic pain, heavy and/or irregular periods, premenstrual spotting, infertility.
Tenderness on cervical movement, thickening and tenderness of the uterosacral ligaments, fullness or mass in the pouch of Douglas (POD), fixation and retroversion of the uterus, rectovaginal nodule. Adnexal (or even a pelvi-abdominal) mass in women with large endometriomas.
Luisi et al. [2]
2009
Severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms with or without abnormal bleeding, infertility and chronic fatigue.
Not discussed.
Giudice. [20]
2010
Chronic pelvic pain (lasting ≥6 months), dysmenorrhea, dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can be continuous, and it can be dull, throbbing, or sharp, and exacerbated by physical activity. Bladder- and bowel associated symptoms (nausea, distention, and early satiety) are typically cyclic. Burning or hypersensitivity symptoms that are suggestive of a neuropathic component (infrequently).
A pelvic mass, immobile pelvic organs, and rectovaginal nodules.
Altman and Wolcyzk. [21]
2010
Chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, back pain, dyschezia, rectal pain, diarrhea, constipation, dysuria, hematuria, infertility, chronic fatigue and psychosocial stressors.
Palpable tender nodules in the cul-de-sac or uterosacral ligaments; localized tenderness in the cul-desac, uterosacral ligaments, or rectovaginal septum; pain with uterine movement; enlarged or tender adnexal masses; and fixation of adnexa or uterus in a retroverted position. Red, blue, or hemorrhagic nodules may also be visualized on the external genitalia, vagina, or cervix.
Okeke and Ikeako. [9]
2011
Dysmenorrhea, dyspareunia, menorrhagia and infertility.
Not discussed.
Koninckx et al. [22]
2012
Hypogastric pain, especially dysmenorrhea, deep dyspareunia, severe chronic pain, mictalgia, and dyschezia.
Not discussed.
Acién and Velasco [23]
2013
Dysmenorrhea (during and at the end of menstruation), deep dyspareunia, chronic pelvic pain, and infertility premenstrual spotting for 2–4 days, headache, irritability, or premenstrual tension syndrome.
Not discussed.
Carneiro M M et al. [24]
2013
Dysmenorrhea, dyspareunia, dyschezia, gastrointestinal symptoms, chronic pelvic pain, infertility.
Pelvic tenderness, a fixed retroverted uterus, tender uterosacral ligaments or enlarged ovaries, uterosacral nodularity.
Schrager et al. [25]
2013
Debilitating pelvic pain, dysmenorrhea, dyspareunia, and decreased fertility.
Not discussed.
Mehedintu et al. [26]
2014
Severe dysmenorrhea, non-cyclical chronic pelvic pain, dysfunctional uterine bleeding, infertility, dyspareunia, painful defecation during menstruation, urinary tract symptoms and gastrointestinal symptoms
Not discussed.
Bhattacharjee et al. [27]
2014
Dysmenorrhea, deep dyspareunia, infertility, abnormal uterine bleeding, non-cyclic pain, menstrual cycle abnormalities, constipation, chronic fatigue, heavy or long uncontrollable menstrual periods with small or large blood clots, gastrointestinal problems including diarrhea, bloating and painful defecation, extreme pain in legs and thighs, back pain, mild to extreme pain during intercourse, pain from adhesions which may bind an ovary to the side of the pelvic wall, or they may extend between the bladder and the bowel, uterus, extreme pain with or without the presence of menses, premenstrual spotting, mild to severe fever, headaches, depression, hypoglycemia and anxiety.
Non-specific pelvic tenderness, localized tenderness in the pouch of Douglas, thickened nodular uterosacral ligaments, fixed retroverted uterus, palpable fixed cystic adnexal mass or an obliterated pouch of Douglas, masses, fixity of organs, displacements of cervix & presence of nodules in the rectovaginal pouch or uterosacral ligaments, nodularity or tenderness in the uterosacral ligament, bluish or red powder burn lesions may be seen in the cervix or posterior fornix of the vagina (which may be tender or bleed on touch), bluish nodules in the posterior fornix, a fixed retroverted tender uterus or a firm fixed pouch of Douglas.


https://bmcwomenshealth.biomedcentral.com/articles/10.1186/s12905-015-0196-z

Sunday, August 7, 2016

Pain and fatigue and being female: ASIC3 channels

We have acid sensors in our body that detects a drop in pH which is involved in pain perception (among other things).

"Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities...Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, Zn2+, and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel’s large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-HT2. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133903/

Estrogen can potentiate the action of ASICs.

"E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception."  http://press.endocrine.org/doi/abs/10.1210/en.2015-1557?journalCode=endo#sthash.0DpqNTD7.dpuf

Pain causes fatigue through similar means. Testosterone seems to lessen this effect.

"Chronic pain and fatigue often occur together -- as many as three in four people with chronic, widespread musculoskeletal pain report having fatigue; and as many as 94 percent of people with chronic fatigue syndromes report muscle pain. Women make up the majority of patients with these conditions..."The differences in fatigue between males and females depends on both the presence of testosterone and the activation of ASIC3 channels, which suggests that they are interacting somehow to protect against fatigue," Sluka said. "These differences may help explain some of the underlying differences we see in chronic pain conditions that include fatigue with respect to the predominance of women over men."" https://www.sciencedaily.com/rel.../2008/04/080407153037.htm

Endometriosis is an inflammatory condition and ASIC play a role in inflammation.

"Microglia, the major immune cells in central nervous system, act as the surveillance and scavenger of immune defense and inflammatory response. Previous studies suggest that there might be close relationship between acid-sensing ion channels (ASICs) and inflammation, however, the exact role of ASICs in microglia during inflammation remains elusive...Taken together, these results suggest that ASICs participate in neuroinflammatory response, which will provide a novel therapeutic strategy for controlling the inflammation-relevant neuronal diseases." http://www.ncbi.nlm.nih.gov/pubmed/25377529 

"Nonsteroid anti-inflammatory drugs (NSAIDs) are major drugs against inflammation and pain. They are well known inhibitors of cyclooxygenases (COXs). However, many studies indicate that they may also act on other targets. Acidosis is observed in inflammatory conditions such as chronic joint inflammation, in tumors and after ischemia, and greatly contributes to pain and hyperalgesia. Administration of NSAIDs reduces low-pH-induced pain." http://www.jneurosci.org/content/21/20/8026.long

"ASICs (Acid Sensing Ion Channels) are of particular interest because they are directly activated by extracellular acidity, which is a major cause of pain. Indeed, many painful conditions such as ischemia, inflammation, tumor development or tissue incision are accompanied by tissue acidification. ASIC are excitatory ion channels that are expressed in neurons, including nociceptive sensory neurons. In humans, the use of amiloride, a nonspecific inhibitor of ASICs, has demonstrated their role in the perception of pain induced by subcutaneous injections of acidic solutions. ASICs thus appear as new candidates capable of mediating pain in humans. A growing number of data suggests that, in addition to protons, ASICs may also be activated by one or more endogenous compounds produced during inflammation. The purpose of this research project is to identify these compounds by testing the effects of human inflammatory exudates on ASICs activity. The discovery of such compounds would definitely validate ASICs as novel therapeutic targets for pain treatment in humans." https://clinicaltrials.gov/ct2/show/NCT01867840



Wednesday, February 17, 2016

Endo and immune system

The presence of endometriosis can cause disruption in the immune system:

"In the genetic regulation of Müllerian structures development, a key role is played by Hoxa and Wnt clusters, because they lead the transcription of different genes according to the different phases of the organogenesis, addressing correctly cell-to-cell interactions, allowing, finally, the physiologic morphogenesis. Accumulating evidence is suggesting that dysregulation of Wnt and/or Hox genes may affect cell migration during organogenesis and differentiation of Müllerian structures of the female reproductive tract, with possible dislocation and dissemination of primordial endometrial stem cells in ectopic regions, which have high plasticity to differentiation. We hypothesize that during postpubertal age, under the influence of different stimuli, these misplaced and quiescent ectopic endometrial cells could acquire new phenotype, biological functions, and immunogenicity. So, these kinds of cells may differentiate, specializing in epithelium, glands, and stroma to form a functional ectopic endometrial tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697788/#!po=2.17391

Tuesday, December 29, 2015

Inflammatory markers and endometriosis

What can I say? It's complicated.


Endometriosis is an inflammatory disease, so a lot of people have questions about blood tests that look at inflammation. Let's look at what inflammatory markers are and specifically at CRP:

"Serum proteins that are produced in response to inflammation can be referred to as inflammatory markers. These proteins are mainly produced by the liver in response to stress and can also be called acute phase reactants. Pro-inflammatory cytokines such as IL-1, IL-6, and TNF-alpha induce synthesis of some acute phase reactants that include CRP, fibrinogen and haptoglobin. Other proteins, like albumin, are not sensitive to inflammatory cytokines for increased synthesis; instead chronic stress (inflammation) results in a lower synthesis rate with resultant decreased serum concentrations. The inflammatory markers are not diagnostic of inflammation, but reflect abnormalities that are seen in autoimmune diseases, infections, malignancies and other illnesses.

C-reactive protein (CRP)

"C-reactive protein (CRP/CRP-high sensitivity) was discovered and named for its reactivity to the C polysaccharide in the cell wall of S. pneumoniae. CRP, an innate immune protein, helps opsonize pathogens for phagocytosis and activates the complement system. CRP production is under the control of IL-1, IL-6, and TNF-alpha. Changes in serum CRP concentration change more quickly than ESR and therefore CRP may be a better reflection of current inflammation. Unlike the ESR, CRP is a fairly stable serum protein whose measurement is not time-sensitive and is not affected by other serum components. The magnitude of inflammation directly relates to the concentration of CRP. Levels < 0.2 mg/dl are considered normal, while those >1.0 mg/dL are suggestive off inflammation and/or infection. More recently, the use of high sensitivity CRP has been utilized. This test may better quantify lower levels of inflammation and has been important in evaluating cardiac disease and other inflammatory states.2, 3" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832720/?report=reader      
 

So what does this have to do with endometriosis?

Endometriosis is an inflammatory disease, so one might expect the markers to be high. But not necessarily in blood tests:
 
"Findings:
There was no significant difference between the CRP serum level in patients with endometriosis and infertile women without endometriosis. There was a significant difference in peritoneal level of CRP between case and control groups (p < 0.05).

Conclusions:

The findings suggested that measurement of this marker in patients’ serum or plasma cannot be used to diagnose endometriosis. It is further recommended that a combination of different markers might be helpful in this regard that could be studied in future."
 
So we may not see an increase in the blood test but there is a difference in the peritoneal samples:
 
"Compared to the control group, the CRP level of the peritoneal fluid were higher in patients with endometriosis (p<0.05). Pelvic endometriosis is a chronic inflammatory disease that is in association with a general inflammatory response in the peritoneal cavity.[,] This disease is known to have an immunological background.[] Macrophage constitutes 82- 99% of the all the cell population of peritoneal fluid.[] Literature has repeatedly reported an increase of total peritoneal fluid cell numbers, cell concentration and macrophages in endometriosis patients in compare to the control.[] The study of Dunselman et al. also confirmed that there is an increase in the number and concentration of peritoneal cells in patients with endometriosis as compared to the control group.[]" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696960/
 
While we're on the subject, let's discuss CA-125 levels:
 
It's a test that looks at markers for certain cancers, but if your doctor orders it and it's high, don't let it scare you. "...many noncancerous conditions can increase the CA 125 level.
Many different conditions can cause an increase in CA 125, including normal conditions, such as menstruation, and noncancerous conditions, such as uterine fibroids." http://www.mayoclinic.org/tests-procedures/ca-125-test/basics/definition/prc-20009524 It can also be high in people with endometriosis: "Studies published since continue to demonstrate a correlation between raised CA125 levels and endometriosis (Abrao et al., 1999; Somigliana et al., 2004; Agic et al., 2008; Seeber et al., 2008), and some imply a correlation with stage of disease (Chen et al., 1998; Amaral et al., 2006; Martinez et al., 2007; Rosa e Silva et al., 2007). One study has indicated that CA125 may be more accurate at diagnosing women with later stages of disease, in concordance with the review by Mol (Maiorana et al., 2007)." http://humupd.oxfordjournals.org/content/16/6/651.full 

Remember, all these tests might be a mere indication of endometriosis, but they are very nonspecific. The only way to accurately diagnose endometriosis is through surgery.

Mast cells:

"Mast cells may contribute to the development of pain and hyperalgesia in endometriosis
October 2006
The presence of increased activated and degranulating mast cells in deeply infiltrating endometriosis, which are the most painful lesions, and the close histological relationship between mast cells and nerves strongly suggest that mast cells could contribute to the development of pain and hyperalgesia in endometriosis, possibly by a direct effect on nerve structures.

Researchers set out to detect and quantify mast cells in peritoneal, ovarian, and deep infiltrating endometriosis and to study the relationship between mast cells and nerves in endometriosis.

Excision of endometriosis from different anatomical locations was undertaken in 69 women, who were undergoing laparoscopic excision of endometriosis for pain. Thirty-seven biopsies of normal tissue were obtained from women without endometriosis.
The women with deeply infiltrating lesions had significantly higher preoperative pain scores than women with peritoneal or ovarian endometriosis. Mast cells and degranulating mast cells are significantly more abundant in endometriotic lesions than in non-affected tissues. Deep infiltrating lesions show a significantly higher number of mast cells, activated mast cells, and mast cells located <25 mum from nerves than peritoneal and ovarian lesions. The authors found significantly more degranulating mast cells in deep infiltrating lesions than in peritoneal lesions.
Source
Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noel JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 2006;86(5):1336-43"
 

For a lot more on peripheral biomarkers of endometriosis see: http://humupd.oxfordjournals.org/content/16/6/651.full

  "Endometriotic lesion removal significantly alters the inflammatory profile both locally and systemically in women with endometriosis. Our findings indicate that ectopic lesions are the major drivers of systemic inflammation in endometriosis." http://www.ncbi.nlm.nih.gov/pubmed/26698677 

Saturday, December 19, 2015

A few things that have helped me

Everyone is different with what will help them feel better. For me, a healthy diet with some specific changes and yoga are what I have found help me the most.
 
Specific diet changes include going gluten free (there has been research to support  this in endo patients- http://endocomprehensive.blogspot.com/2014/03/gluten-free-and-endo.html), eating food as close to nature as possible/least processed, avoiding my trigger foods (lactose, gluten, cruciferous veggies, etc- see the FODMAPs diet for IBS), and reducing sugary foods/bad carbs.
 
I also found the following items the most helpful to include in my diet:
 
Plenty of clear fresh water. Add in some lemon. Spring water seems to help the most, but I have a water filter too.


 Blueberries (probably any berry would be good)
 
Spinach. I don't whether it's the iron, the magnesium, or what, but organic spinach helps.
 

Albacore tuna. I've gotten some great deals on sustainably caught, low mercury canned tuna. Perhaps the omega-3's that help?
 
 
 
Egg white protein powder. I make a smoothie with this and spinach and I can tell I feel better. I have wondered if the l glutamine helps my gut. I can tell a difference between the egg white versus the whey.
 
I think the extra B vitamins and perhaps the low dose of vitex in this drink mix help. I drink it in the morning in my green tea.
 
Again, eating organic whenever possible, seems to help.
 
 
Again, these are things that have helped me and are not recommendations for what will work with anyone else. I can't say it made my endometriosis better, but it did help my health overall and improve my ability to deal with my endo and its ramifications.
 
 
PS Here's a link to some of the yoga poses I find most helpful to me: http://endocomprehensive.blogspot.com/2014/07/my-current-yoga-poses-that-help.html 
 

Saturday, October 3, 2015

Similar stem cells, different gene exclusions

"Tissue of DIE and SE appears to have similar stem cell-related genes. Nevertheless, there are differences in gene expression between SE and DIE." So the stem cells of superficial and deep infiltrating endometriosis are similar but the gene expression is different. So what causes the deep infiltrating to be expressed differently? Hormonal influence? Diet? Toxins? http://www.ncbi.nlm.nih.gov/pubmed/26426155

Monday, August 24, 2015

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors.

Since endo is most likely laid down embryonically, I don't know that this necessarily points to pathogenesis of endo (especially as the levels decrease after the removal of the lesions) but the presence of endo certainly produces an inflammatory state.
 
2015 Aug 10. pii: 1501138.

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors.

Abstract

Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neoangiogenesis or establishment of new blood supply is one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and proinflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells, and HUVECs with IL-17A revealed significant increase in angiogenic (vascular endothelial growth factor and IL-8), proinflammatory (IL-6 and IL-1β), and chemotactic cytokines (G-CSF, CXCL12, CXCL1, and CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on Matrigel in a dose-dependent manner. Thus, we provide the first evidence, to our knowledge, that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data show a likely important role of IL-17A in promoting angiogenesis and proinflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.
Copyright © 2015 by The American Association of Immunologists, Inc.