Sunday, April 27, 2014

Bowel and hormones

"Responding to follicle-stimulating hormone (FSH)
secretion from the pituitary gland, the granulose cells
of the ovarian follicles secrete gradually increasing levels
of estradiol, which peak around day 13, inducing the
pituitary LH surge that heralds ovulation. The intraovarian...
events leading to ovulation involve estrogen induced
production of prostaglandins, primarily
prostaglandin F2α (PGF2α), PGE2, and prostacyclin,
all of which are measurable in follicular fluid.

The release of this prostaglandin-rich fluid is thought to
cause the pain that sometimes occurs with ovulation....

With the decline of the corpus
luteum, estrogen and progesterone levels drop, triggering
the events in the uterine endometrium that lead to menstruation.
These events involve complex interplay of
prostaglandins, cytokines, and other lytic enzymes.
The endometrium also produces prostaglandins,
the predominant one being PGF2α, with lower levels
of PGE2 also produced. PGF2α release leads to
smooth muscle contraction, ischemia, and sensitization
of nerve endings; PGE2 is a smooth muscle relaxant.
Other molecules produced include endothelin-1,
metalloproteinases, TNF-α, and cytokines. Endometrial
prostaglandin levels are three times higher in the
luteal than in the follicular phase.

Levels are highest during menstruation, when most PGF2α release from
the endometrium occurs. Women who experience dysmenorrhea
have greater endometrial prostaglandin levels
than do asymptomatic women, and they have
higher levels of PGF2α in their menstrual fluid (35).
Prostaglandin production has been thought to influence
diarrhea associated with menses by inhibiting
transepithelial ion transport in the small intestine....

Altered prostaglandin levels can result in abdominal
pain, colonic contractions, and diarrhea....

Estrogen, TNF-α, endothelin, and prostaglandins also
exert effects on the GI tract. Estrogen receptors are
found throughout the GI tract (36) in components of
the pelvic floor (37) and in sensory neurons of the dorsal
root ganglia (38), suggesting that female sex hormones
may play a role in IBS symptomatology. Studies
have shown that estrogen and progesterone exert
many effects on the GI tract (36). These hormones
have a relaxing effect on the lower esophageal sphincter
and decrease colonic transit. TNF-α induces
inflammation, delays gastric emptying, increases
colonic transit time, and induces flow of fluid into GI
tissues. Endothelin has potent effects on GI smooth
muscle, leading to contraction of the esophagus, stomach,
and intestines, and has a modulatory effect on GI
motility (39). It also is a potent stimulator of gallbladder
motility, stimulates sphincter of Oddi motility, and
decreases trans-sphincteric flow (39)."

Leptin and its role in endometriosis

We've heard about leptin and its role in weight gain/loss, but did you know leptin does more than that?

"Subsequent work has confirmed that leptin has a pleiotrophic role on the immune response and can rightly be considered, both structurally and functionally, as a proinflammatory cytokine."  (Note: Pleiotrophic means one gene that influence many, so leptin can influence lots of different things.)

Also as a side note- in a very small study, leptin was tied to greater fatigue in CFS patients: "Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology"  Also, "In conclusion, there is an increasing evidence that leptin, besides its central effects on food intake and energy expenditure, is involved (per se or by synergistic action with other cytokines) in the pathogenesis of inflammatory and autoimmune diseases. The evidence that leptin signaling deficiency impairs humoral and cellular immune responses, and attenuates experimental inflammation models, supports the notions that a strategy focused on the block of leptin activity on peripheral cells might have intriguing therapeutic benefits."

So, leptin can be proinflammatory and influence many different responses in the body (including energy/fatigue and immune response!). From previous studies we have looked at, we have seen the role of the proinflammatory cytokines in endometriosis. Now let's look at leptin's role in endometriosis:

"Leptin is known as the protein primarily released by fat cells and it acts in an endocrine fashion via the leptin receptor in the hypothalamus to regulate satiety status. Recently, the role of leptin has become more and more versatile after the discovery of leptin and its receptor in peripheral tissues including ovary, uterus and placenta (Cioffi et al., 1997; Karlsson et al., 1997; Masuzaki et al., 1997; Alfer et al., 2000; Gonzalez et al., 2000a; Kitawaki et al., 2000). Leptin has been reported to exert immunoregulatory, proinflammatory, mitogenic and angiogenic effects in several tissues (Gainsford et al., 1996; Wolf et al., 1999; Caprio et al., 2001). This makes it a potential candidate for contributing to the progress of endometriosis. A recent report even demonstrated that leptin levels in peritoneal fluid and serum of patients with pelvic endometriosis are increased (Matarese et al., 2000). However, the cellular origin and mechanism by which leptin modulates the formation of endometriosis is not clear. We herein present evidence showing that leptin and its receptor are differentially expressed in endometriosis and are involved in the proliferation of endometrial stromal cells....

"...leptin stimulated a significant increase in eutopic as well as ectopic endometrial stromal cell proliferation. However, this mitogenic effect of leptin was somewhat different in eutopic endometrial stromal cells compared with ectopic endometriotic stromal cells. In eutopic endometrial stromal cells, leptin caused a greater extent of cell proliferation and at much lower doses (Figure 8A). In stromal cells obtained from ectopic endometriotic implants, only high doses of leptin (3 and 10 ng/ml) induced cell proliferation and the induction was less pronounced (Figure 8B).... 

"...we showed that both leptin transcripts and protein are highly expressed in ectopic endometriotic lesions. In eutopic endometrium, leptin was not detected in a half of the samples and only extremely low amounts of leptin were detected in the other half of the endometria. In concordance with our finding, contradictory reports have shown either positive or negative leptin expression in normal human endometrium (Alfer et al., 2000; Gonzalez et al., 2000a; Kitawaki et al., 2000). The reasons for differences in leptin transcript expression in eutopic endometrium are not known. Nevertheless, leptin was highly expressed in ectopic endometriotic lesions. The elevation of leptin in ectopic endometriosis was not due to differences in the stages of menstrual cycles or body mass as evidenced by marked increase of leptin in ectopic endometriotic tissues as compared to the eutopic endometrium collected from the same patients (n = 4). In addition, the mean BMI was not different between eutopic and endometriosis groups. Thus, elevated expression of leptin in ectopic endometriotic tissues may reflect the distinct biochemical nature of endometriotic lesions. Whether this is causal or consequent to the pathogenesis of pelvic endometriosis remains to be determined.

"Our result showing that leptin is markedly expressed in ectopic endometriotic lesions supports previous reports that the peritoneal fluid concentration of leptin was increased in women with endometriosis (Matarese et al., 2000; De Placido et al., 2001). Furthermore, peritoneal macrophages purified from patients with peritoneal endometriosis, ovarian endometrioma, or without any pelvic implants did not express leptin as analysed by RT–PCR (n = 6 per group, data not shown), indicating that the ectopic endometriotic lesion may have an important contribution to the elevated leptin concentration in peritoneal fluid. However, the contribution made by peritoneal fat cells should not be excluded and warrants further investigation. One report (De Placido et al., 2001), showing that peritoneal fluid concentrations of leptin are elevated in patients with peritoneal endometriosis but not ovarian endometriosis, has raised questions regarding which determinants cause the differences. It is hypothesized that these two kinds of endometrial lesions may have distinct leptin biosynthesizing capacity. In that particular report, the cellular origin of leptin contributing to the peritoneal fluid was not examined. In the present report, we have detected the leptin transcript and protein in both peritoneal implants and ovarian endometrioma and the quantity of leptin transcripts was not different between these two groups. Thus, it appears that a distinct leptin biosynthesis capacity may not be the determinant leading to differential leptin concentrations in peritoneal fluid with these two kinds of endometriosis. Alternatively, the authors suggested that a possible explanation is that leptin may be sequestrated into the cystic fluid of the endometrioma instead of being diffused into peritoneal fluid. This seems likely given our current result showing that similar amounts of leptin were produced. However, more direct evidence is needed before any conclusion can be drawn.

"To address whether the elevation of leptin expression in endometriotic implants would be involved in development of endometriosis via autocrine/paracrine mechanisms, we next characterized the expression profile of the leptin receptor in eutopic as well as ectopic endometriotic implants. Immunohistostaining showed that OB-R is expressed in both stromal and epithelial cells in eutopic endometrium. In ectopic endometriotic implants, OB-R was also positively stained....Furthermore, a recent work showed that progesterone but not estradiol reduced OB-RL expression in endometrium (Koshib et al., 2001), indicating that high concentrations of progesterone in the luteal phase may suppress the expression of OB-RL. The reasons for the discrepancies between these studies are not clear since different kinds of antibodies and/or quantification methods were used. Thus, the expression pattern of OB-R during the menstrual cycle cannot be definitely concluded at this point. The expression of the OB-R transcript in this study was inversely related to the expression pattern of leptin and the severity of endometriosis. We believe that this is due, at least in part, to the down-regulation effect of leptin on its own receptor. Indeed, the in-vitro study using eutopic endometrial stromal cells demonstrated that leptin dose-dependently inhibited the mRNA for its receptor (both the long form and total forms of leptin receptor). The physiological significance of receptor down-regulation by its homologous ligand is a safeguarding system that prevents overstimulation by the ligand, as has been reported for prostaglandin F and its receptor (Tsai and Wiltbank, 1998a; Tsai et al., 1998). Whether this down-regulation of OB-R by leptin plays any significant role in disease progression remains an open question and requires further investigation.

"...One of the examples is the acquisition of estrogen-producing ability in ectopic endometriotic implants (Noble et al., 1996; Bulun et al., 1999, 2000). Our recent data have also indicated that ectopic endometriotic cells of early endometriosis express high quantities of steroidogenic acute regulatory protein and produce high levels of progesterone (Tsai et al., 2001c). As a consequence, the ectopic endometriotic tissues become independent of the survival factors generated from gonads, and proliferate continuously throughout the cycle.
"In summary, differential expression of leptin and its receptor in eutopic and ectopic endometrium suggests that leptin may have a critical role in endometriosis development. Elevated leptin expression by endometriosis lesions appears to enhance the proliferation of ectopic endometriotic stromal cells. Our findings may open a new field of investigation into the actions of leptin in the pathogenesis of endometriosis and provide a reasonable rationale for developing a therapeutic regime for endometriosis by targeting leptin and its action."

So leptin (similar to the effects of estrogen) causes the endo lesions to proliferate. Not only that, but leptin has a more pronounced affect on endo lesions than it does on the lining of our uterus.  Also of note, is that progesterone seems to reduce the expression of leptin receptors (that's that OB-R you see in the study) in endo lesions (so this may be why progestin/progesterone may help with endo pain). In addition, it is noted from previous studies the endo lesions acquire the ability to produce their own estrogen and progesterone! So even if you have had ovaries removed, endo lesions left behind can still thrive as they can produce their own hormones. Weird little buggers!

"It (Leptin) may also play a role in endometriosis through its inflammatory and angiogenic properties. Nevertheless, studies evaluating serum and peritoneal fluid (PF) levels of leptin in patients with endometriosis report conflicting results: some describe increased levels [2, 510], while others report no differences between patients with endometriosis and controls [7, 1114]. Moreover, the possibility of an association between PF leptin levels and severity of endometriosis is also controversial, with some studies suggesting a negative correlation [2, 6, 8] and others showing a positive correlation with more severe forms of peritoneal endometriosis [5, 7, 13, 15].
Interestingly, only a few studies so far have evaluated leptin receptor gene and/or protein expression in endometrial tissue of women with endometriosis [1618]. Lima-Couy et al. [16] evaluated the three isoforms of leptin receptor—total (OB-RT), long (OB-RL), and short (HuB219.3)—in the eutopic endometrium of patients with moderate and severe endometriosis. Those authors observed increased receptor expression in the period corresponding to embryo implantation, with no difference between patients and controls. Some authors [17, 19] have reported expression of leptin receptor in both eutopic and ectopic endometria.

"Therefore, the aims of the present study were (a) to assess leptin and OB-RL gene expression in ectopic and eutopic endometria of women with endometriosis and in eutopic endometrium of non-endometriosis controls, (b) to determine the leptin/BMI ratio in serum and PF in both groups, (c) to assess the immunoreactive presence of OB-RL in endometrium and endometriotic implants, and (d) to investigate the relationship among these variables....Conclusions: The present data suggest that serum leptin/BMI ratio is associated with the presence of endometriosis. Nevertheless, the clinical applicability of the leptin/BMI ratio for prediction of endometriosis still requires confirmation. Moreover, the increased expression of leptin and OB-RL in ectopic endometrium suggests a modulatory interaction between leptin and its active receptor and a role of leptin, an inflammatory and angiogenic cytokine, in the initiation or development of endometrial implants."

"Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Abstract: Endometriosis is a polygenic disease with complex, multifactorial aetiologies affecting approximately 10% of women of reproductive age. Leptin is the product of the ob gene, which is related to reproductive function and immunological alteration. The angiogenic and mitogenic action of leptin may influence the formation of endometriosis. This study was aimed at determining whether leptin and leptin receptor expression differs in eutopic and ectopic endometria collected from laparoscopy and at investigating the pathophysiological role of leptin in the development of endometriosis. Leptin mRNA was undetectable in seven out of 14 eutopic endometria and only a minute amount was detected in the remaining samples. In contrast, there was a marked increase in leptin mRNA and protein expression in ectopic endometriotic lesions of patients with endometriosis (P < 0.05). Receptors for leptin were immunologically stained in eutopic endometrium as well as in ectopic endometriotic implants. However, the levels of mRNA for the long and total forms of leptin receptors were suppressed in association with the severity of endometriosis (P < 0.05). Administration of leptin stimulated its own mRNA expression in ectopic endometriotic stromal cells but decreased steady-state concentrations of mRNA encoding for leptin receptor (n = 6). In addition, leptin significantly enhanced both eutopic and ectopic endometrial stromal cell proliferation (P < 0.05). In conclusion, the differential distribution of mRNA for leptin and its receptor suggests an important autocrine and paracrine role for leptin in human endometriosis. The mitogenic and auto-augmentation effects of leptin may further contribute to the pathogenesis of endometriosis."

"Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. Leptin acts as a potential growth stimulator in several normal and neoplastic cells. Recent studies have shown the presence of increased levels of leptin in the peritoneal fluid of patients with endometriosis, implicating leptin in the pathogenesis of endometriosis. However, the specific function of leptin in the induction of mitogenesis in endometriosis is not known. This study investigated the expression of the leptin receptor (ObR) in endometrioma tissues and immortalized endometriotic cells, and the effect of leptin on cell growth. ObR expression was higher in endometriomas than in the normal endometrium, and it was detected in 74% of epithelial and 30% of stromal endometrioma tissues. In addition, human endometriotic epithelial cells (11Z and 12Z) showed a high level of ObR when compared with endometrial cells and endometriotic stromal cells (22B). Furthermore, leptin treatment stimulated the growth of 11Z and 12Z cells, but not that of 22B cells. Knockdown of the ObR in 11Z and 12Z cells impaired the ability of leptin to induce cell growth. Leptin induced the activation of Janus Kinases 2 (JAK2), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) in endometriotic epithelial cells. Moreover, pretreatment with the JAK2/STAT3 inhibitor AG490 and the ERK inhibitor PD98059 significantly inhibited leptin-induced cell growth. The present results show that the ObR is induced in endometriosis, and that leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways."

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.....