Progesterone Resistence 2

"CONCLUSION: A stromal cell defect in endometriosis blocks formation of progesterone-dependent production of factors leading to 17beta-hydroxysteroid dehydrogenase type 2 deficiency and defective conversion of estradiol to estrone in epithelium." http://www.ncbi.nlm.nih.gov/m/pubmed/17403431/?i=5&from=/9851796/related

"...initial studies comparing endometrial tissues from women with and without endometriosis examined circulating progesterone levels relative to expected histological responses across the secretory phase of the menstrual cycle^27–29. These investigations revealed that while women with endometriosis exhibit normal circulating ovarian progesterone levels, the endometrium's ability to respond appropriately to this steroid appeared to be reduced^27–29. Subsequent studies confirmed that endometrial tissues from women with endometriosis did not exhibit the changes in specific gene and protein expression normally expected during the progesterone-dominated secretory phase^{12, 30–31}. Perhaps not surprisingly, altered expression of genes and proteins in endometriosis patients was reported to be associated with changes in the expression pattern of progesterone receptor (PR) isotypes (PR-A and PR-B), at both eutopic and ectopic sites of endometrial growth^{11, 32–33}....At present, the biological origin of reduced endometrial progesterone responsiveness among women with endometriosis remains to be fully elucidated; however, a number of research groups have begun to examine whether chronic inflammatory processes may promote the development of endometrial resistance to this steroid. Within the reproductive tract, an important component of steroidal regulation of inflammation involves cellular signaling by members of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) family. This signaling network has been suggested to play a critical role in triggering, or enhancing, the inflammatory processes...Although the studies noted above support the concept that inflammatory processes may represent a potential trigger for the loss of progesterone sensitivity related to endometriosis, the precise cellular and molecular mechanisms leading to this disease phenotype remain elusive. In this regard, a number of recent observations suggest that epigenetic modification, mediated by chronic inflammation, could explain the progesterone resistant endometrial phenotype observed in women with endometriosis. " http://europepmc.org/articles/PMC3718308

 "Throughout the reproductive years, the rise and fall in ovarian hormones elicit in the endometrium waves of cell proliferation, differentiation, recruitment of inflammatory cells, apoptosis, tissue breakdown and regeneration. The activated progesterone receptor, a member of the superfamily of ligand-dependent transcription factors, is the master regulator of this intense tissue remodelling process in the uterus. Its activity is tightly regulated by interaction with cell-specific transcription factors and coregulators as well as by specific posttranslational modifications that respond dynamically to a variety of environmental and inflammatory signals. Endometriosis, a chronic inflammatory disorder, disrupts coordinated progesterone responses throughout the reproductive tract, including in the endometrium. This phenomenon is increasingly referred to as 'progesterone resistance'. Emerging evidence suggests that progesterone resistance in endometriosis is not just a consequence of perturbed progesterone signal transduction caused by chronic inflammation but associated with epigenetic chromatin changes that determine the intrinsic responsiveness of endometrial cells to differentiation cues." http://www.ncbi.nlm.nih.gov/pubmed/22085558 

So we see progesterone resistance in patients with endo and then we see that progesterone helps in the process of metabolizing estrogen: 

"The biologically active estrogen estradiol (E2) is the best-defined mitogen for the growth and inflammation processes in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Progesterone and progestins may relieve pain by limiting growth and inflammation in endometriosis but a portion of patients with endometriosis and pelvic pain do not respond to treatment with progestins. Moreover, progesterone-induced molecular changes in the eutopic (intrauterine) endometrial tissue of women with endometriosis are either blunted or undetectable.  The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B). In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s). These unknown factor(s) act on neighboring epithelial cells to induce the expression of the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD-2), which metabolizes the biologically active estrogen E2 to estrone (E1). In endometriotic tissue, progesterone does not induce epithelial 17beta-HSD-2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17beta-HSD-2 may be due to the lack of PR-B and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue.  The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this local mitogen." http://www.ncbi.nlm.nih.gov/pubmed/16406281 

Furthermore (part of this is particular for those with infertility): "On the basis of the role of inflammation in the induction of a progesterone-resistant endometrium, we hypothesize that failure of implantation might be explained, perhaps in part, by alteration in the uterine microbiome in response to inflammation...This hypothesis finds support in the ability of environmental factors to alter progesterone sensitivity...A very important finding derived from this study demonstrated that TCDD-mediated P4 resistance might increase sensitivity to inflammation, even in subsequent generations not exposed to the toxicants, resulting in PTB.[98] By means of extrapolation, these data support the hypothesis that a combination of environmental factors, taken together, are a risk for recurrent pregnancy loss and PTB in humans; the mechanism being creation of a P4-resistant endometrium and the presence of inflammation. Therefore, we conclude that the association between the microbiome of the reproductive tract and circulating serum E2 concentrations may reflect the environment and availability of glycogen. However, progesterone resistance, albeit an unproven relationship to the microbiome, might contribute to implantation failure and infertility. This putative role of undetected endometrial colonization and progesterone resistance requires further investigation." http://www.medscape.com/viewarticle/819586_9  

" In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17betaHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17betaHSD-2 expression." http://www.ncbi.nlm.nih.gov/m/pubmed/9851796/?i=3&from=/16406281/related

"PATIENT(S): Patients with deep endometriosis and fertile women with macroscopically normal pelvic cavities.

INTERVENTION(S): During surgery, 30 endometrial and 16 endometriotic samples were obtained from 30 patients with deep endometriosis. Control endometrial samples were obtained from 24 fertile women with macroscopically normal pelvic cavities who underwent laparoscopic tubal ligation or reversal of tubal sterilization. Epithelial cells and stromal cells from endometrial or endometriotic tissues were microdissected using laser capture microdissection.

MAIN OUTCOME MEASURE(S): Expression levels of aromatase and 17betaHSD2 mRNA in microdissected epithelial and stromal cells were determined using quantitative real-time reverse transcriptase polymerase chain reaction.

RESULT(S): Aromatase mRNA expression was significantly higher in epithelial cells than in stromal cells in both eutopic and ectopic endometrium obtained from endometriosis patients. In the ectopic endometrium of 8 patients (8/16, 50%), 17betaHSD2 expression was not detected in either epithelial or stromal cells. In eutopic endometrium from endometriosis patients, 17betaHSD2 expression in epithelial cells was significantly increased during the early, middle, and late secretory phases compared with the late proliferative phase, whereas no significant cyclical difference was detected in control endometrium.

CONCLUSION(S): Local estrogen concentration may be much higher in epithelial cells than in stromal cells in deep endometriotic tissue. " http://www.ncbi.nlm.nih.gov/m/pubmed/16595205/?i=2&from=/9851796/related

Prevalence of Depression in Endo Patients

Depression, whether an independent diagnosis and exacerbated by endo or as a by-product of endo, is prevalent in endo patients:

"This cross-sectional prospective study evaluated 100 women receiving care at the Outpatients' Clinic for Endometriosis, Department of Obstetrics and Gynecology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil, equally divided into two groups: one suffering from chronic pelvic pain and the other pain-free. The Beck Depression Inventory was used in order to measure depression.

RESULTS:
Depression was detected in 86 and 38% of the women with and without chronic pelvic pain, respectively. Complaints of depression, such as somatic concerns, work inhibition, dissatisfaction, and sadness, were observed at a significantly higher rate in the group with pain. A sensation of failure was the only variable observed more frequently in the pain-free group.

CONCLUSIONS:
Depression is highly prevalent in women with endometriosis, especially those with pelvic pain. Careful evaluation can identify women with depression who may benefit from treatment." http://www.ncbi.nlm.nih.gov/pubmed/16521687 

 It an be further compounded by the use of hormones as treatment, as some hormonal suppressants can cause depression: "The brain in women has been shown to be an estrogen target organ. Common symptoms are shared by women complaining of PMS, postpartum blues, the perimenopausal transition and menopause: depression, sleep disturbance, irritability, anxiety and panic, memory and cognitive dysfunction and a decreased sense of well-being. The antiestrogens progesterone, progestin and tamoxifen may also elicit these same symptoms. It is proposed that whenever brain estrogen levels fall below the minimum brain estrogen requirement, for whatever reason and at whatever age, brain center dysfunction may ensue." http://europepmc.org/abstract/MED/8887186 

 Also it is well shown that endometriosis can cause chronic inflammation: "In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors." http://www.nature.com/nrn/journal/v9/n1/abs/nrn2297.html

25% of Atypical Specimens Proved to be endo study

"All areas of viscera and peritoneum either with typical appearance suggestive of endometriosis or atypical appearance were completely excised and examined histologically. At laparoscopy, all excised lesions were documented in a diagram by the primary surgeon according to anatomic site and visual description and were labeled as either suggestive of endometriosis or otherwise atypical in appearance. The hospital pathology department received entire lesions fixed in formalin and evaluated specimens for presence or absence of endometriosis. Pathologists, who were blinded to the surgeon's suspicion of endometriosis, were provided only the anatomic site of excised tissue. By definition, diagnosis of endometriosis was made when histologic evidence existed of both endometrial glands and stroma.

MEASUREMENTS AND MAIN RESULTS:

Diagrams detailing appearance, anatomic site, and surgeon's suspicion of endometriosis versus atypical lesions were compared with final histologic diagnosis. The greatest number of patient lesions were excised from cul-de-sac (n = 309). For this site, using visual criteria for diagnosis of endometriosis, positive predictive value was 93.9%, sensitivity was 69.3%, negative predictive value was 41.9%, and specificity was 83.1%. Prevalence was noted to be 79.0% and accuracy was 72.2%. In addition, atypical-appearing tissue not presumed to be endometriosis was confirmed to be endometriosis histologically in 24.3%. In examining tissue specimens from multiple anatomic sites, laparoscopic visual diagnosis of typical endometriosis generally had high positive predictive value. However, both sensitivity and negative predictive value were lower than expected because of atypical lesions subsequently diagnosed as endometriosis.

CONCLUSIONS:

These data suggest that when the surgical objective is complete eradication of endometriosis, the surgeon must be prepared to excise all lesions suggestive of endometriosis and tissue atypical in appearance as in most anatomic sites approximately 25% of atypical specimens proved to be endometriosis."

Endometriosis and Associated Disorders Survey

If you have been surgically diagnosed with endometriosis, here is a survey being collected on the disorders associated with endo:  https://www.surveymonkey.com/s/KYGL8GF

Histology (what the path report shows) and Endometriosis

When your doctor sends specimens from your surgery to the pathologist for confirmation, the pathologist will be looking for glands and/or stroma ("Histologic demonstration of a combination of endometrial glands and stroma in biopsy specimens obtained from outside the uterine cavity is required to make the diagnosis of endometriosis." http://emedicine.medscape.com/article/271899-overview).

 

When they find those glands and/or stroma, then endometriosis is confirmed. If they do not find them, then it is inconclusive (meaning it may be endo but they could not positively identify in the specimen sent). It can be inconclusive for several reasons:

"Although the histologic diagnosis of endometriosis is usually straightforward, many diagnostic problems can arise as a result of alterations or absence of its glandular or stromal components. The diagnostic difficulty in such cases can be compounded by tissue that is limited to a small biopsy specimen. The appearance of the glandular component can be altered by hormonal and metaplastic changes, as well as cytologic atypia and hyperplasia... In some cases, the endometriotic glands are sparse or even absent (stromal endometriosis). The stromal component can be obscured or effaced by infiltrates of foamy and pigmented histiocytes, fibrosis, elastosis, smooth muscle metaplasia, myxoid change, and decidual change....Inflammatory and reactive changes within, adjacent to, or at a distance from foci of endometriosis can complicate the histologic findings...The histologic diagnosis of endometriosis can also be challenging when it involves an unusual or unexpected site. Five such site-specific problematic areas considered are endometriosis on or near the ovarian surface, superficial cervical endometriosis, vaginal endometriosis, tubal endometriosis, and intestinal endometriosis... Finally, endometriotic foci can occasionally be intimately admixed with another process, such as peritoneal leiomyomatosis or gliomatosis, resulting in a potentially confusing histologic appearance." http://www.ncbi.nlm.nih.gov/pubmed/17592255

"Positive histology for endometriosis was confirmed in 75% of cases, the histology was negative in 18.7% and in 6.3% was non-diagnostic. The study confirmed that correlation between laparoscopic findings and positive histology was dependant on the site of lesion and the stage of endometriosis. As more information was provided to the laboratory and as the pathologists became accustomed to looking for the disease, there was a higher detection of endometriosis." http://informahealthcare.com/.../10.1080/01443610802217918

"Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection is usually adequate but histological confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (> 4 cms in diameter), and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy." http://guidelines.endometriosis.org/diagnosis.html

"Stromal endometriosis, characterised histologically by small microscopic nodules or plaques of endometrioid-type stroma, sometimes with a whorled pattern and prominent vascularity and erythrocyte extravasation, was identified in 44.9% of the biopsies. In 6.6% of the biopsies, stromal endometriosis occurred without typical endometriosis. The foci of stromal endometriosis usually had a superficial location just beneath the mesothelial surface or protruding above this. Associated histological features present in some cases included reactive mesothelial proliferation, inflammation, giant cell or granuloma formation, haemosiderin pigment deposition, microcalcification and decidualisation and myxoid change.

CONCLUSIONS:

Stromal endometriosis, usually in the form of superficial nodules or plaques, is a relatively common form of endometriosis which typically occurs in association with typical endometriosis but occasionally on its own. Pathologists should be aware of the existence of this form of endometriosis, the morphological features of which may be subtle. The typical location, intimately associated with surface mesothelium, may suggest that stromal endometriosis derives from mesothelial or submesothelial cells via a metaplastic process." http://www.ncbi.nlm.nih.gov/pubmed/19155237

More details (and pictures!) if you are curious: http://www.slideshare.net/.../the-pathology-of-endometriosis

“Although the histological diagnosis of endometriosis is usually easy to make, there are diagnostic problems in relation to certain aspects such as the atypias and neoplastic alterations of the endometriotic glandular and stromal components and in cases of endometriosis in unusual places the small size of specimens available for histological examination does not aid the correct diagnosis….

Usually both, glands and stroma are observed but occasionally the diagnosis can be

made when only one component is present. Endometriosis is distinct from adenomyosis or

endometriosis interna which is defined by the presence of endometrial components in the

myometrium. These two entities were linked in the past by common terminology but

present different clinical presentation, epidemiologic and etiologic patterns….

The location and the age of the endometriotic lesion and the patients’ age affect the

morphological appearance of endometriosis and may lead to diagnostic difficulties….

Typically endometriosis in women of reproductive age presents histologically as one or

more endometrioid glands surrounded by stromal cells, resembling the endometrial stromal

cells of the proliferative phase. The glandular epithelium is one layer thick with cuboidal or

tall cells and eosinophilic cytoplasm. Nuclei are ovoid with vertical orientation and very

rare mitoses. The whole picture is usually consistent with inactive or irregular proliferative

endometrium, although typical proliferative or secretory changes may be observed. Cilia

may be observed as well. Stromal cells are supported by a delicate reticulin network in

which hyperemic small vessels may be observed. In the case of exogenous administration of

progestins, cyclically functionic endometriosis or pregnancy, a stromal decidual reaction

may be observed. A diffuse infiltration of histiocytes is usually observed. The histiocytes

convert the red blood cells into glucolipid and brown pigment (pseudoxanthoma cells) .The

pigment is usual a ceroid such as lipofuscin and to a lesser extend hemosiderin .The amount

of the pigment increases with the age of the lesion. Inflammatory cells may be present and a

small component of smooth muscle cells especially in the wall of endometrioid cysts may be

observed. Not all the above described elements are easily identified in endometriosis.” http://cdn.intechopen.com/pdfs-wm/36756.pdf

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)." 
http://weillcornell.org/.../Frissora_-_Practical...

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." http://www.ncbi.nlm.nih.gov/pubmed/16929139  (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" http://www.translational-medicine.com/content/11/1/93  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." http://www.febsletters.org/article/S0014-5793(04)01389-4/fulltext

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-R_L expression in endometrium (Koshib et al., 2001), indicating that high concentrations of progesterone in the luteal phase may suppress the expression of OB-R_L. 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_2α 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."

http://molehr.oxfordjournals.org/content/8/5/456.full

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, 5–10], while others report no differences between patients with endometriosis and controls [7, 11–14]. 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 [16–18]. Lima-Couy et al. [16] evaluated the three isoforms of leptin receptor—total (OB-R_T), long (OB-R_L), 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-R_L 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-R_L 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-R_L 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." http://www.hindawi.com/journals/ogi/2013/879618/


"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."  http://www.ncbi.nlm.nih.gov/pubmed/11994543

"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."  http://www.ncbi.nlm.nih.gov/pubmed/23184927