Sunday, September 2, 2018

More genes related to endometriosis

"...the study identified 19 genetic variants associated with endometriosis, and many of those variants are also associated with other serious health conditions such as ovarian cancer, cardiovascular disease and high cholesterol....In this case the study found several variants in genes involved in sex hormone metabolism, specifically the genes GREB1, FN1, KDR, CCDC170, ESR1, SYNE1, and FSHB." 

Friday, October 20, 2017

Symptoms translates to less productivity

"Women who experienced 3 endometriosis symptoms concurrently lost a significantly greater number of employment hours because of absenteeism and presenteeism compared with those experiencing 1 or 2 symptoms (P < 0.001). Regression analyses showed that a range of endometriosis symptoms predicted employment and household losses because of presenteeism and absenteeism."

Thursday, April 20, 2017

Musings on mullerian

This is purely my conjecture based on my readings. The literature refers to peritoneal endometriosis,  ovarian endometriosis,  and deep infiltrating endometriosis. Current theory points to defects when our pelvic organs are developed (Mullerianosis) that leave stem cells in the wrong place. This might also explain why other mullerian disorders such as adenomyosis are frequently seen in endometriosis patients as well.  These stem cells are acted upon by hormones (puberty) to develop as glands and stroma and begin the process of making nerves and blood vessels to support itself - as any good stem cell should. However that tissue should not be in those wrong sites and an inflammatory response happens.  Factors from the environment (food, physical activity,  stress,  etc) play a role in presentation of illness. This is why diet etc might affect symptoms but will not rid the person of the lesions. The different locations of stem cells left behind might influence how they are acted upon by hormones and affect their presentation and the ability to extract them all (trying to spare the ovarian tissue for fertility).

The literature also refers to different stages of the lesions based on color - clear,  white,  tan,  red,  black. The different stage can produce different effects on the amount of pain and inflammation it causes.

Monday, March 6, 2017

Symptoms of endometriosis review

Author(s) [Ref.]
Results for symptoms
Results for signs
Valle [14]
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]
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]
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]
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]
Pain around menstruation, dyspareunia, dyschezia, cyclical dysuria and extreme fatigue.
Not discussed.
Amer [19]
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]
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]
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]
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]
Dysmenorrhea, dyspareunia, menorrhagia and infertility.
Not discussed.
Koninckx et al. [22]
Hypogastric pain, especially dysmenorrhea, deep dyspareunia, severe chronic pain, mictalgia, and dyschezia.
Not discussed.
Acién and Velasco [23]
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]
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]
Debilitating pelvic pain, dysmenorrhea, dyspareunia, and decreased fertility.
Not discussed.
Mehedintu et al. [26]
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]
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.

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."

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."

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.""

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." 

"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."

"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."

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."!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"      

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:
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).


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.[]"
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." 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)." 

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.
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:

  "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."