Tuesday, September 23, 2014

Rh negative blood assc w/ endo

"Results. We observed a higher proportion of Rh-negative women in the study group, as compared to healthy controls. Multivariate analysis showed that Rh-negative women are twice as likely to develop endometriosis (aOR = 1.90; 95% CI: 1.20-2.90). There was no significant difference in ABO group distribution between patients and controls. There was no difference when taking into account either the clinical forms (superficial endometriosis, endometrioma, and deep infiltration endometriosis) or the rAFS stages. Conclusion. Rh-negative women are twice as likely to develop endometriosis. Chromosome 1p, which contains the genes coding for the Rhesus, could also harbor endometriosis susceptibility genes." http://www.ncbi.nlm.nih.gov/pubmed/25243164

Thursday, September 11, 2014

Nerve fibers and pain in endometriotic lesions

[Relationship between pain and nerve fibers distribution in multiple endometriosis lesions].

[Article in Chinese]



To investigate the relationship between the distribution of nerve fibers in multiple endometriosis lesions and pelvic pain.


From Sept. 2007 to Sept. 2008, 120 endometriosis patients treated in Peking Union Hospital were enrolled in this study, which including 19 cases with stage I, 29 cases with stage II, 44 cases with stage III and 28 cases with stage IV. The pain symptom was evaluated by visual analogue scales (VAS) score and nerve fibers in multiple endometriosis lesions were detected by immunohistochemical staining.


The number of nerve fibers in multiple endometriosis lesions were (29.74+/-17.33)/mm2 in uterosacral ligament, (24.53+/-13.34)/mm2 in vaginal septum, (17.09+/-10.09)/mm2 in uterus rectum crux, (6.77+/-4.21)/mm2 in peritoneal endometriosis lesions, (0.07+/-0.25)/mm2 in endometriosis ovarian cyst wall. The number of nerve fibers in uterosacral ligament was mostly correlated with the degree of pain (r=0.56). The nerve fibers of uterus rectum crux and vaginal septum were correlated with defecation pain (r=0.58 and 0.41) and dyspareunia (r=0.82 and 0.67), which were significantly higher than those in endometriosis leision in peritoneum and ovary. There was no significant different number of nerve fibers among different stage disease (P>0.05).


There was significantly different distribution of nerve fibers in multiple endometriosis lesions, which was correlated with dysmenorrhea, anus pain, dyspareunia and chronic pelvic pain, not with clinical staging.


Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations.



To assess the relationship between endometriotic lesions with associated nerve fibers with both pain and peritoneal fluid (PF) cytokine concentrations based on lesion location.


An observational study.


University hospital.


Premenopausal women undergoing laparoscopy.


The pain experienced by patients was recorded before surgery and ectopic endometrial tissue excised and matching PF collected during laparoscopy. Immunohistochemistry was performed on endometriotic tissue sections to identify nerve fibers and PF cytokine concentrations determined.


The pain experienced by women with endometriosis, the lesion locations, and the prevalence and proximity of nerve fibers to endometriotic lesions, as well as the PF concentrations of multiple cytokines.


Lesions from the rectovaginal septum were significantly more likely to be associated with a nerve fiber and report more menstrual pain than lesions from other regions. The PF glycodelin concentrations were also significantly higher in samples with an endometriotic-associated nerve. In peritoneal endometriotic lesions significantly more menstrual pain was reported when endometriotic lesions were associated with nerve fibers, although no difference was observed between the cytokine concentrations. Ovarian endometriotic lesions were rarely associated with nerve fibers.


The presence of endometriosis-associated nerve fibers appear to be related to both the pain experienced by women with endometriosis and the concentration of PF cytokines; however, this association varies with the lesion location.



2011 Jun 30;95(8):2772-4. doi: 10.1016/j.fertnstert.2011.01.150. Epub 2011 Feb 19.

Nerve fibers and menstrual cycle in peritoneal endometriosis.


There was no difference in the density of nerve fibers across the menstrual cycle in peritoneal endometriotic lesions. These findings may explain why patients with peritoneal endometriosis often have painful symptoms throughout the menstrual cycle.

Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.




The positive rate and density of PGP9.5-immunoreactive nerve fibers in peritoneal endometriotic leision were 62% (10/16) and (3.8+/-1.7)/mm2 in endometriosis patients with pain, which were significantly higher than 19% (3/16) and (1.7+/-0.5)/mm2 in endometriosis patients without pain (P<0.05) and 25% (5/20) and (1.3+/-0.6)/mm2 in peritoneal tissues in women without endometriosis (P<0.05). However, no differences were found between endometriosis patients without pain and women without endometriosis (P>0.05). Moreover, the density of PGP9.5-immunoreactive nerve fibers in peritoneal lesions in endometriosis patients with pain was positively correlated with the severity of pain (r=0.855, P<0.05). In addition, the density of PGP9.5-immunoreactive nerve fibers in peritoneal lesions was statistically higher in endometriosis patients with chronic pelvic pain and (or) dysmenorrhea than those in endometriosis patients with other type of pain (P<0.05), which was not associated with active lesion, site and staging (P>0.05).


It suggested that PGP9.5-immunoreactive nerve fibers might confer the mechanism of pelvic pain with endometriosis."


"The nerve fiber density (mean +/- standard deviation/mm(2)) in peritoneal endometriotic lesions from hormone-treated women with endometriosis (10.6 +/- 2.2/mm(2)) was statistically significantly lower than in peritoneal endometriotic lesions from untreated women with endometriosis (16.3 +/-10.0/mm(2)). Nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions were slightly reduced in hormone-treated women with endometriosis compared with untreated women with endometriosis.
Progestogens and combined oral contraceptives reduced nerve fiber density and nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions" http://www.ncbi.nlm.nih.gov/pubmed/18976764

Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions.

Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions.



Is the occurrence of pelvic pain in women with ovarian endometrioma associated with coexisting peritoneal lesions (PLs)?


Pelvic pain in women with ovarian endometrioma is usually associated with coexisting PLs. An increased tissue inflammatory reaction with elevated prostaglandin (PG) production may be responsible for the generation of pain.


Severe pelvic pain in women with ovarian endometrioma is reported to be associated with deeply infiltrating endometriosis. However, information on pelvic pain in women with ovarian endometriosis with and without coexistent peritoneal superficial lesions is limited.


Retrospective clinical study with case-controlled biological research using prospectively collected tissue samples derived from women with and without endometriosis and their retrospective evaluation.


We performed a retrospective cohort study conducted in 2988 cases who had laparoscopic surgery for indications of ectopic pregnancy, tubal infertility and other benign gynecologic diseases. We analyzed the occurrence of pelvic pain in the cases with ovarian endometrioma according to the distribution of coexisting PLs and pattern of intrapelvic adhesions. Inflammatory reaction of eutopic and ectopic endometria was measured by immunoreaction to macrophage marker, CD68. The tissue expression of cyclooxygenase (COX) 2 was examined by immunohistochemistry and tissue concentrations of PG F2α were measured by ELISA.


Among the 2988 surgical cases, 350 (11.7%) were found to have ovarian endometrioma at laparoscopy. Coexisting PLs were present in 269 of these women and in this group 85.4% of cases experienced pelvic pain and 14.6% had no pain. In contrast, among the 81 women with ovarian endometrioma only, 38.3% cases experienced pelvic pain and 61.7% cases had no pain and the difference between the groups was statistically significant (P < 0.01). The infiltration of CD68-immunoreactive macrophages was significantly higher in the eutopic and ectopic endometria of women with peritoneal endometriosis than in ovarian endometrioma. The tissue expression of COX2 and levels of PGF2α were significantly higher in both the eutopic and ectopic endometria derived from women with peritoneal endometriosis than in similar tissues derived from women with ovarian endometrioma.


Tuesday, September 2, 2014

Symptoms and Physical and Surgical Findings

Synopsis of endo symptoms: "Typically, pelvic pain consists of dysmenorrhea, intermenstrual pain, and dyspareunia. Dysmenorrhea is the most commonly reported symptom and its severe form, although not entirely predictive, is highly suggestive of endometriosis.[43] Dyspareunia was found less frequently in ovarian endometriosis (77%) compared with peritoneal (88%) and rectovaginal (100%) forms of the disease.[44] Dysmenorrhea is usually progressive, with onset of pain often preceding the onset of menstrual flow. It usually continues throughout the menses and occasionally persists for several days afterward. The pain is most often localized in the low abdomen and deep pelvis; it is bilateral, often radiating to the back and thighs. It is often described as dull and aching and may be associated with rectal pressure, nausea, and episodes of diarrhea.[45] Intermenstrual pain may represent an extension of dysmenorrhea; in severe cases, patients may suffer from pain throughout the menstrual cycle. Intermenstrual pain has been reported in 57 to 68% of women with endometriosis and pain.[44] Endometriosis-related dyspareunia is usually positional and most intense upon deep penetration. It is most intense prior to menstruation, but in severe cases it may preclude vaginal intercourse throughout the month. Dyspareunia is usually associated with endometriosis of the cul-de-sac and rectovaginal septum.[47] Interestingly, dysmenorrhea and dyspareunia are more suggestive of endometriosis if the symptoms begin after years of relatively pain-free menses and coitus.[48]

Rarely, endometriosis may present as acute pelvic pain, typically perimenstrual, and usually in the context of hemoperitoneum and rupture or torsion of endometrioma.[58] Endometriosis has also been found in extrapelvic locations, giving rise to atypical symptoms. Nongynecologic organs most often affected by endometriosis include: the intestinal tract, the urinary tract, surgical scars, the lungs and thorax, peripheral nerves, and the central nervous system. Consequently, patients may present with a wide range of cyclic, menses-aggravated symptoms presumably reflecting cyclic bleeding and inflammation. About 0.1% of women who have undergone cesarean section may present with cyclic superficial pain, worsening when coughing and tensing the abdominal wall, that may resemble symptoms of a postoperative hernia.[59-61] Abdominal wall endometriomas are also found in abdominal scars following gynecologic surgeries and in the perineum after episiotomy. Surprisingly, cases of abdominal wall endometriosis have also been described in patients without previous surgical history.[62]

Women with gastrointestinal involvement may suffer from disturbed bowel function, dyschezia, cyclical hematochezia, or even bowel obstruction.[63-67] Hepatic endometriosis may present with cyclic right-sided subcostal pain.[68] Endometriosis of the urinary tract can cause hematuria, dysuria, urgency, and frequency. Bladder detrusor endometriosis presents with symptoms similar to those of interstitial cystitis, whereas renal involvement, although very rare, presents predominantly with abdominal pain and hematuria.[22,69-71] Involvement of the ureter may cause flank and iliac fossa pain due to partial or complete ureteric stenosis. Interestingly, ureteral endometriosis was found in 4.4% of patients with rectovaginal endometriosis.[72] Pulmonary and pleural endometriosis may be manifested by hemoptysis, chest pain, and shortness of breath resembling pulmonary embolism.[73-76] Women with diaphragmatic endometriosis may present with a wide spectrum of symptoms including chronic, cyclical shoulder tip pain.[77,78] Invasion of peripheral nerves can mimic common musculoskeletal problems and may result in cyclic pain such as sciatica, and cerebral endometriosis can lead to perimenstrual headaches or even seizures.[79-83]" http://www.medscape.com/viewarticle/460130_2

"Physical examination may provide a broad range of findings. In some cases, especially of mild endometriosis, the gynecologic examination may be entirely unremarkable. Ideally, the examination should be performed while the patient experiences at least some symptoms, preferably during menstruation, when it may be easiest to detect and localize areas suspected of harboring endometriosis.[84] A general physical examination is rarely rewarding unless the patient presents with focal cyclic symptoms suggestive of endometriosis in nongynecological organs. Abdominal examination often reveals tenderness, usually ill localized and deep. In rare instances of scar endometriomas, painful swelling and focal tenderness may mimic other lesions, such as hematomas, granulomas, or abscesses.

On pelvic examination, external genitalia and the vaginal surface are usually unremarkable. Speculum inspection may reveal bluish implants typical of endometriosis or red, hypertrophic lesions bleeding on contact, usually in the posterior fornix. In a recent retrospective analysis of 160 cases of histologically documented deeply infiltrative endometriosis, lesions were visible during speculum examination in only 14.4% and palpable during manual examination in 43.1% of patients.[85] Propst et al[86] described a new physical finding of lateral cervical displacement due to scarring of the ipsilateral uterosacral ligament that may be associated with endometriosis. The same group also reported an association between cervical stenosis (<4.5mm) and endometriosis in women with chronic pelvic pain.[87] Most commonly, positive physical signs are found on bimanual and rectovaginal examination of pelvic structures. Palpation of the uterus may reveal retroversion, decreased or absent mobility, and tenderness. Endometriomas may be detected as tender or nontender adnexal masses, often fixed to the uterus or to the pelvic sidewall. Tender masses, nodules, and fibrosis may be appreciated on palpation of the upper vagina, cul-de-sac, uterosacral ligaments, or rectovaginal septum. In a case-controlled study, the only signs of endometriosis in infertile patients were uterosacral nodularity and uterosacral tenderness.[88] Focal tenderness has been shown to correlate with the presence of endometriosis as well as the depth and volume of endometrial implants.[89] Koninckx and his associates[84] found that careful palpation during menstruation increases the detection rate of deep endometriosis, endometriomas, and cul-de-sac adhesions by over fivefold compared with a routine examination not timed to the menstruation.

However, a normal clinical examination does not rule out the diagnosis of endometriosis. When compared with surgical evaluation, pelvic examination showed poor sensitivity, specificity, and predictive values ( Table 1 ). A prospective study validating nonsurgical approaches to diagnosis of endometriosis found that pelvic examination was a reliable predictor of ovarian endometriomas but was not helpful in prediction of nonovarian lesions.[90]
It is essential to bear in mind that the physical signs listed here are not specific and none of the findings is diagnostic in and of itself of endometriosis. Caution should be exercised, and in the absence of conclusive evidence to the contrary, a differential diagnosis should include other conditions such as neoplasms or infections.

"Laparoscopic assessment in combination with histological examination of the excised lesions remains the gold standard for diagnosis of endometriosis. Knowledge of the most common locations of endometriosis is required for accurate visual inspection of the pelvic and abdominal cavities. Three different forms of endometriosis must be considered during laparoscopic visualization: peritoneal implants, endometriomas, and deep infiltrating lesions of the rectovaginal septum. An increased awareness of the variations in the appearance of endometriotic lesions has resulted in an almost twofold increase in the diagnosis of endometriosis at laparoscopy.[151]

Peritoneal Implants

Peritoneal implants are most commonly localized in the uterosacral ligaments, cul-de-sac, ovarian fossa, and adjacent pelvic sidewalls. Less frequently, implants can also be found in the upper abdomen as well as on the surface of the bladder and the bowel (predominantly rectum, sigmoid colon, appendix, and cecum).[64,71] Hence careful and close inspection of the entire peritoneal cavity should be performed. Magnification obtained during laparoscopy depends on the distance between the laparoscope and the area inspected; for example, the magnification rate is approximately 3.2 and 1.7 from a distance of 10 and 20 mm, respectively.[152] Magnification allows the recognition of lesions as small as 400 µm for red and 180 µm for clear lesions.[151,153]
The classic peritoneal implant appears as a bluish-black "powder burn" lesion with variable degrees of pigmentation and surrounding fibrosis. Typical dark coloration is the result of hemosiderin deposits from entrapped menstrual debris. However, the majority of peritoneal implants appear as nonpigmented, atypical (subtle) lesions, usually red or white. Jansen and Russell[154] have described the relationship between morphological and histological features of various endometriotic lesions. Lesions that were commonly endometriotic included areas of white opacification (81%), red flame-like lesions (81%), and glandular lesions (67%). Less frequently, histological confirmation of endometriosis was obtained in subovarian adhesions (50%), yellow-brown peritoneal patches (47%), and circular peritoneal defects (45%).[154]
As demonstrated by Nisolle and Donnez,[155] red lesions are highly vascularized and proliferative, usually representing an early stage of endometriosis. In contrast, white lesions contain fibrous tissue and are poorly vascularized. They are metabolically inactive and probably represent healed or latent lesions. Black, pigmented foci represent an advanced stage of the disease and the diagnosis of endometriosis has been histologically confirmed in 76 to 93% of these specimens.[156,157] Biochemical activity and clinical features of various lesions from infertile patients with minimal or mild endometriosis were assessed in a prospective study. White peritoneal implants were associated with less pain than black or red lesions, and both black and red lesions showed similar activity expressed in terms of prostaglandin F2 production.[54] In a prospective study, changing patterns in activity of the peritoneal lesions were observed with no change in the stage of the disease when evaluated at laparoscopy before and 6 months after medical therapy.[158]
Redwine[159] proposed that endometrial peritoneal implants undergo a process of "natural evolution." This concept is supported by the observation that the frequency of red lesions and clear papules declines with patients' age and these implants appear to be replaced by black, and ultimately white, scarred lesions over a period of 7 to 10 years.[159] There is a significant overlap in the time course of the presentation of these defects, and all types of lesions may coexist in the same patient.
Endometriosis may also be detected in the lesions visible only under the microscope or scanning electron microscope.[152,160] The prevalence of endometriosis (including microscopic forms) in asymptomatic patients undergoing laparoscopy was estimated to be as high as 45 to 50%.[161] Novel techniques such as "peritoneal blood painting" and infusion of crystalloid into the cul-de-sac ("bubble test") were developed to improve the detection of subtle lesions.[162,163] However, the clinical significance of microscopic endometriosis remains uncertain. It is conceivable that microscopic endometriosis may be present in the majority of women and that a symptomatic disease may develop only in some.[161]
Because endometriotic implants vary in appearance, the experience and the expertise of the surgeon may greatly influence the selection of the biopsy area and hence the likelihood of a diagnosis of endometriosis. In a prospective study, Walter et al[164] correlated visual diagnosis of endometriosis at laparoscopy with final histological confirmation in 44 patients evaluated for chronic pelvic pain. Use of strict histological criteria resulted in lower rates of confirmed endometriosis because visually detected endometriosis was observed in 36% of cases but confirmed histologically in only 18% of cases.
Peritoneal endometriosis can be associated with other pathological changes such as general hypervascularization and adhesion formation. Adhesions should be evaluated for density (filmy, vascular, dense/fibrotic) and for the extent to which they limit mobility of pelvic organs. Assessment of the severity of periadnexal adhesions is of particular importance in infertile patients because the extent of adhesions is related to the prognosis.[165]"

"Initial work on mapping of pain associated with the endometriosis lesions resulted in some thought-provoking findings. The classic black lesions were found to be painful in only 11% of patients when the lesion was touched. Similarly, white lesions were painful in 20% of patients with red lesions at 37%, and clear lesions at 32% were the most painful (Table 1). These results added further reason as to why initial therapy had such poor results. Surgeons would only “see” the black lesions and removed them, but these were the least painful lesions. The most painful clear lesions were not “seen” at laparotomy and therefore remained, as did the pain. What became apparent next, while mapping the patient, was the fact that the pain extended 28 mm beyond the visible border of the lesion onto what looked like “normal” peritoneum ((Figure 1). Therefore, if the surgeon only removed the lesion at its border, the microscopic disease in the previously identified normal looking peritoneum was left, and persistence or recurrence of the symptoms was encountered.

"Palpation of the lesions of endometriosis produced the cramps, not the uterus. Patients, postoperatively, reported that once they identified the cramps of endometriosis, they noticed that they were different than menstrual cramps. Furthermore, palpation of the endometriosis lesions on patients without a uterus and both ovaries removed reproduced the cramps of endometriosis. This confirmed the findings of other researchers who have concluded that a hysterectomy often does not change the course of the pain of endometriosis since it is the lesions, not the uterus, which are responsible for the cramp-like pain. The location of the lesion in relationship to the pelvis can, in most instances, reproduce the symptoms the patient experiences. Lesions on the utero-sacral ligament, when palpated, cause pain or cramps in the back. Palpation of lesions on the side wall of the pelvis result in pain or cramps radiating down the leg.

"What is most interesting is that right-left orientation of the pelvis does not exist in some patients. That is to say, palpation of a lesion of endometriosis on the left side of the pelvis may produce pain that the patient perceives as being on the right side of the abdomen, and the opposite is also true. How many times has a laparoscopy under general anesthesia been done on a patient complaining of right-sided pain where the surgeon saw a normal looking pelvis on the right—only to wake up the patient and tell her, “I saw nothing on the right side of your pelvis that would cause your pain.” It now becomes apparent why the results of the survey of the Endometriosis Association's members revealed that the average length of time from the onset of symptoms to the treatment of the endometriosis was 9.28 years and an average of 2.3 operations. 

"As has been shown over the years, results of therapy, based only on what the physician sees, is marginal at best, especially in minimal endometriosis (ie, stage 1 and stage 2).

"The data revealing the failure of the approach of “treat and see,” based on what the surgeon observed at laparoscopy under general anesthetic, is strong and reveals that a new approach is needed. An approach based on patient confirmed diagnosis and patient-based analysis of the results of therapy needs to be looked at in greater detail. The only person who knows where the pain starts and ends is the patient herself. She is also the only one who can confirm when the pain is no longer present."         http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015350/                       

Video from Dr. David Redwine on the appearance of endometriosis:

Added note "It's important to note that the amount of pain is not necessarily related to the extent or size of the growths. Tiny growths, called petechiae, have been found to be more active in producing prostaglandins, which may explain the significant symptoms that seem to occur with smaller growths." http://www.crat.org/Endometriosis_Info.html