Thursday, April 24, 2014

Recurrence of Endo

"Endometriosis could still be regarded as a recurrent disease;
nevertheless recurrence could not be ascribed to the
retrograde menstruation, but to an incomplete surgical

intervention, since it is demonstrated that endometriosis
lesions could be also made up of microscopic foci (Redwine,
2003), and or to different timing of growth of the lesions in the
same patient, probably due to individual susceptibility that is a
typical phenomenon of the diseases inducted by endocrine
disruptors (Mori et al., 2003). Therefore surgery, if complete in
exhausted growth disease can be considered curative.
Contrarily, exposition to endocrine disruptors such as
synthetic estrogens or SERM chemical compounds, though
reducing the symptoms, could increase the growth of

"A systematic review found that post-surgical hormonal treatment of endometriosis compared with surgery alone has no benefit for the outcomes of pain or pregnancy rates, but a significant improvement in disease recurrence in terms of decrease in rAFS score (mean = −2.30; 95% CI = −4.02 to −0.58) (Yap et al., 2004). Overall, however, it found that there is insufficient evidence to conclude that hormonal suppression in association with surgery for endometriosis is associated with a significant benefit with regard to any of the outcomes identified (Yap et al., 2004)....Moreover, even if post-operation medication proves to be effective in reducing recurrence risk, it is questionable that ‘all’ patients would require such medication in order to reduce the risk of recurrence. It has been reported that about 9% of women with endometriosis simply do not respond to progestin treatment (Vercellini et al., 1997), which may result from progesterone receptor isoform B (PR-B) down-regulation (Attia et al., 2000). If PR-B is silenced due to promoter methylation, as reported in endometriosis (Wu et al., 2006b), progestin treatment or OC use may be of little value since the action of progestins is mediated mostly through PR-B. Therefore, the use of post-operation medication indiscriminately may cause unnecessary side effects (and an increase in health care costs) in some patients who may intrinsically have a much lower risk than others and in others who may be simply resistant to the therapy. The identification of high-risk patients who may benefit the most from drug intervention would remain a challenge. Finally, whether a single medication represents the optimal interventional option is debatable. The recent finding that PR-B and nuclear factor-κB (NF-κB) immunoreactivity jointly constitute a biomarker for recurrence (Shen et al., 2008) suggests the possibility that perhaps a combination of drugs may be superior to a single drug in reducing the risk of recurrence, especially if PR-B is silenced due to promoter methylation."

"Several clinical studies suggest that the recurring endometriotic lesions arise from residual lesions or cells not completely removed during the primary surgery. Nisolle-Pochet et al. (1988) reported that in women who received microsurgical resection of ovarian endometriosis, a high prevalence of active endometriosis without signs of degeneration is found after hormonal therapy. Compared with women receiving no treatment, the mitotic index was similar in women treated for 6 months either with lynestrenol (a progestin), gestrinone (an androgenic, antiestrogenic and antiprogestogenic agent) or buserelin (a GnRH agonist) (Nisolle-Pochet et al., 1988). This suggests that hormonal treatment does not lead to a complete suppression of endometriotic foci and that recurring lesions appear to grow from the residual loci. Vignali et al. (2005) found that for those patients who underwent a second surgery, the recurrence of deep endometriosis is observed in the ‘same’ area of the pelvis involved in the first operation. Exacoustos et al. (2006) reported that of 62 patients with recurrent endometriomas, 50 (80.6%) had recurrence on the treated ovary, 7 (11.3%) on the contralateral untreated ovary and 5 (8.1%) on both the treated and untreated ovaries. Overall, the majority of recurrent cases (88.7%) have recurrence involving the treated ovary, suggesting that the recurring cysts seem to grow likely from the residual loci."

"Above all, this report is directly at odds with the one reporting that recurrent symptoms still occur in about 10% of women even ‘after’ hysterectomy and bilateral salphingo-oophorectomy are performed (Namnoum et al., 1995). In fact, some earlier reports also found recurrence after hysterectomy. Sheets and Fetzer (1956) and Andrews and Larsen (1974) reported a 1–3% reoperation rate after hysterectomy with some ovarian conservation. Hammond et al. (1976) reported an 85% reoperation rate 1–5 years after hysterectomy surgery with ovarian conservation. Some anecdotal reports also documented the development of endometriosis after hysterectomy (Goumenou et al., 2003)."

"The identification of biomarkers for recurrence, which so far has received little attention, may help illuminate the causes of recurrence. For example, cyclooxygenase-2 (COX-2) overexpression may be a biomarker for recurrence of ovarian endometrioma (Yuan et al., 2008). COX-2, along with COX-1, is a rate-limiting enzyme involved in the biosynthesis of prostaglandin (PG) E2 (PGE2) from arachidonic acid. PGE2 has been shown to be a key stimulator in the expression of steroidogenic acute regulatory protein (StAR) and aromatase (Noble et al., 1997; Tsai et al., 2001). The aberrant expression of StAR and aromatase is thought to promote the development of endometriosis (Tsai et al., 2001; Bulun et al., 2005). In contrast to COX-1, which is constitutively expressed, the expression of COX-2 is usually induced by pro-inflammatory agents and growth factors (Herschman, 1994; Smith et al., 1996).

Increased expression of COX-2 has been shown to lead to increased vascular endothelial growth factor-A expression (Tsujii et al., 1998), leading to enhanced angiogenesis. Overexpression of COX-2 may also enhance cell migration and invasiveness (Tsujii and DuBois, 1995; Tsujii et al., 1997). Since endometriotic cells are known to be invasive (Gaetje et al., 1995), the increased COX-2 expression may cause residual endometriotic cells to migrate and invade to new sites and establish new colonies. Therefore, as a result of COX-2 overexpression, the enhanced resistance to apoptosis and increased proliferative potential, coupled with enhanced angiogenesis and invasiveness, may render patients with higher COX-2 expression more susceptible to recurrence.... it is possible that endometriotic stem cells may also exist just like cancer stem cells (Starzinski-Powitz et al., 2003). These endometriotic stem cells, if do exist and are not removed completely in the primary surgery, may be the source of new endometriotic lesions, leading eventually to recurrence.

Indeed, the human endometrium is remarkable in its capability of proliferation and cyclic regeneration during a woman’s entire reproductive lifespan, and this capability has raised the suspicion that adult stem cells may reside in the endometrium (Gargett, 2004). In fact, it has been shown that in female bone marrow transplant recipients, the donor-derived cells can differentiate into uterine endometrium, suggesting that stem cells are involved in the maintenance of endometrium (Taylor, 2004). The identification of cell surface markers for endometrial stem cells is currently an area of intense research, as evidenced by the many recent publications on the subject (Cervello et al., 2007; Du and Taylor, 2007; Gargett, 2007). The successful identification of endometrial stem cells markers might also help resolve the riddles of recurrence of endometriosis. "

"Given the debilitating nature and the enormous economic burden of endometriosis, it is time to address the unmet medical need for the control of recurrence of endometriosis.

As some randomized controlled clinical trials clearly demonstrated (Beretta
et al., 1998; Alborzi et al., 2004), what kind of surgical technique to be used in removing endometriotic lesions makes a difference with regard to recurrence risk. In addition, several studies have shown that the completeness or not in removing endometriotic lesions also impacts on the recurrence rate (Fedele et al., 2005) is doubtful that the primary surgery, however beautifully and skillfully performed, would remove all viable endometriotic ‘cells’ or microscopic endometriotic lesions invisible to the naked eyes under the laparoscopy and eliminate recurrence altogether. Theoretically, just one single viable cell can, under suitable milieu and conditions, propagate and grow into a colony. Therefore, even if when all laparoscopically visible endometriotic ‘tissues’ are completely removed, the residual endometriotic ‘cells’, microscopic lesions (or perhaps endometriotic stem cells) still can potentially grow into a critical mass, cause inflammation and symptoms, and result in recurrence. The documented invasiveness (Gaetje et al., 1995), reduced apoptosis of endometriotic cells (Dmowski et al., 1998; Imai et al., 2000) and the postulated positive feedback loop within endometriotic lesions (Bulun et al., 2005; Guo, 2006) all indicate that this is a plausible scenario. The preponderance of clinical data also supports this scenario."

"RESULTS: Interval rates of reoperation and recurrence/persistence of disease and extent or invasiveness of disease when found at reoperation did not increase with the passage of time after surgery. The maximum cumulative rate of recurrent or persistent disease was 19%, achieved in the 5th postoperative year.

CONCLUSION: Laparoscopic excision of endometriosis results in a low rate of minimal persistent/recurrent disease. The natural history of endometriosis after surgery suggests a rather static nature of the disease."

"Main outcome measures Effect of laparoscopic excision on pain scores and quality of life, operative findings, type of surgery, length of surgery and incidence of intra- and post-operative complications.

Results Patients with endometriosis were seve
rely ill with significant pain and impairment of quality of life and sexual activity. Four months after radical laparoscopic excision for deep endometriosis there was significant improvement in all the parameters measured including their quality of life based on EuroQOL evaluation: EQ-5D (0.595:0.729, P= 0.002) and EQ thermometer (68.9:77.7, P= 0.008); SF12 physical score (44.8:51.9, P= 0.015); sexual activity (habit P= 0.002, pleasure P= 0.002 and discomfort P≤ 0.001). Only the mental health score of SF12 failed to show any statistical improvement (47 1:48.4, P= 0.84). Symptomatically, there was a significant reduction in dysmenorrhoea (median 8.0:4.0, P≤ 0.001), pelvic pain (median 7.0:2.0, P≤ 0.001), dyspareunia (median 6.0:0.0, P≤ 0.001) and rectal pain scores (median 4.0:0.0, P≤ 0.001). Complications were noted, but were deemed to be acceptable for the extent of the surgery.

Conclusions This is an early analysis of the first 57 cases studied, but structured evaluation suggests that meaningful improvements in clinical symptoms and quality of life can be obtained with this approach with acceptable levels of operative morbidity. Further follow up of this series is required, but early evidence would suggest that the technique should be further evaluated as part of a randomised trial."

"Recent findings: Large, long-term, prospective studies and a placebo-controlled, randomized, controlled trial suggest that laparoscopic excision is an effective treatment approach for patients with all stages of endometriosis. The result of such laparoscopic excision may be improved if affected bowel, bladder and other involved structures are also excised. Adjuvant therapies such as the levonorgestrel intrauterine system and pre-sacral neurectomy may further improve outcomes. Ovarian endometrioma are invaginations of the uterine cortex, and surgical stripping of this cortex removes many primordial follicles. Despite this apparent disadvantage, stripping of the capsule is associated with better subsequent pregnancy rates and lower recurrence rates than the more conservative approach of thermal ablation to the superficial cortex.

Summary: Laparoscopic excision is currently the ‘gold standard’ approach for the management of endometriosis, and results may be improved with careful use of appropriate techniques and suitable adjuvant therapies."

"Surgical excision can be carried out by laparoscopy, laparotomy or vaginally using sharp dissection, electrosurgery or with the use of a CO2 laser. Excision is the treatment of choice because of a high pregnancy rate, a complete cure of pain in most women, and a low recurrence rate....The choice of treatment will therefore depend on the local expertise with minimal invasive surgery, certainly if a first excision has been incomplete and pain symptoms recur."

 All that research posting says that: endo has been found in fetuses so it is probable that endo is laid down before we are born. Most of the time recurrence is missed disease [due to surgical skill level or microscopic endo/"residual loci" (which I know there is debate about but I'm just paraphrasing the above research)]. Recurrence is seen most especially with the presence of endometriomas (ovarian endo)- again this is this thought to be endo left within the ovary that then surfaces. But reoccurrence can happen even with the best of the best. They don't know why this recurrence happens (since it is not due to retrograde menstruation since it happens in women post hysterectomy) but it is theorized that even one cell left may "colonize" (similar to the way a cancer would- note that endo is NOT cancerous) or from stem cells (cell differentiation). Also of note, it is shown that some women are genetically predisposed to not respond to progestins to suppress endo, so this may be part of the reason why hormonal meds help some women and don't help others. Even if hormonal meds are used, they do not get rid of the lesions but suppress their expression. If you come off the meds or they lose their efficacy then endo will rear its ugly head. So, in summary, excision will a highly skilled surgeon is your best bet but there are no guarantees. Now, we still have to deal with comorbid conditions too- PFD, IC, thyroid issues, gluten sensitivities, etc.....