{"paper_id":"a1f4da4a-6987-4c82-b84a-9f789e83dd94","body_text":"ENDOMETRIOSIS (P STRA TTON, SECTION EDITOR)\nProgesterone Resistance, Aromatase, and Inflammation:\nThe Important Relationships Between Hormones\nand Inflammation\nPaola Vigano & Elisa Rabellotti & Luca Pagliardini &\nEdgardo Somigliana & Massimo Candiani &\nPaolo Vercellini\nPublished online: 27 April 2012\n# Springer Science+Business Media, LLC 2012\nAbstract Endometriosis is a complex gynecologic disorder\nin which alterations of specific biological processes involv-\ning both the endocrine and the immune systems have been\nidentified. Recently, a reduced endometrial responsiveness\nto progesterone has been suggested as a crucial element in\nthe pathophysiology of the disease but it is unclear whether\nthis reduced sensitivity to the steroid is involved in the\ndisease induction or is simply a consequence of the disease\ncondition. Indeed, endometriosis is associated with a local\nand systemic inflammatory process that is strongly inter-\nrelated to the steroid activity, and both the systems mutually\ninteract in a complex loop that strongly influences the dis-\nease development and maintenance. The link between pros-\ntaglandin E 2 (PGE2), aromatase activity, and local estrogen\nsynthesis represents a paradigm of this loop. A better un-\nderstanding of the pathophysiology of this interaction\nshould enable researchers to develop targeted therapeutics\nthat may limit this self-supporting pathologic loop.\nKeywords Progesterone . Progesterone resistance .\nAromatase . Endometriosis . Inflammation\nIntroduction\nEndometriosis is an estrogen-dependent disorder, defined as\nthe presence of endometrial tissue outside of the uterus in\nlesions of varying sizes and appearance containing endome-\ntrial glands and stroma. Symptoms arise from cyclical\nbleeding into the surrounding tissues, which results in in-\nflammation and formation of scarring and adhesions poten-\ntially causing infertility. Signs and symptoms may include\npainful periods (dysmenorrhea), pelvic pain not associated\nwith menses, painful intercourse (dyspareunia), painful uri-\nnation (dysuria), and painful bowel movements. It may be\nasymptomatic or associated with symptoms of pain and/or\ninfertility [1]. However, endometriosis is much more com-\nplicated than either lesions or symptoms, and because of this\ncomplexity, its classification is evolving from a local disor-\nder to a chronic systemic condition.\nAlthough described in the literature for more than\n300 years [ 2], endometriosis remains a mysterious and elu-\nsive disease that can impact on the general physical, mental,\nand social well being of a woman and can have a profound\neffect on the woman ’s life. From a pathogenetic point of\nview, the disease inheritance is thought to be polygenic with\na complex, multifactorial etiology. The gold standard for the\ndiagnosis of pelvic disease is surgical assessment during\nlaparoscopy [3]. Surgical removal of endometriotic implants\nimproves fertility and commonly provides temporary relief\nfor pain symptoms. However, the cumulative recurrence\nrates after surgery vary greatly depending on the degree of\nendometriosis and possibly also on the extent of surgery [ 4].\nMedical treatments aimed at hormone suppression are ef-\nfective for pain but their cost and side effect profile varies\n[3]. Moreover, they induce a hypoestrogenic state and can\nbe used only for a limited time owing to important and\nsometimes unacceptable side effects [ 5].\nCurr Obstet Gynecol Rep (2012) 1:146 –152\nDOI 10.1007/s13669-012-0013-8\nP . Vigano (*) : E. Rabellotti : L. Pagliardini : M. Candiani\nObstetrics and Gynecology Unit,\nSan Raffaele Scientific Institute,\nMilano, Italy\ne-mail: vigano.paola@hsr.it\nE. Somigliana\nDepartment of Obstetrics, Gynecology and Neonatology,\nFondazione Cà Granda, Ospedale Maggiore Policlinico,\nMilano, Italy\nP . V ercellini\nIstituto Ostetrico e Ginecologico “L. Mangiagalli, ”\nUniversity of Milano,\nMilano, Italy\n\nEndometriosis long has been considered a surgical gyne-\ncological disease. Currently, there is a need for clinical\nmanagement of the disease by multidisciplinary teams that\naddress medical, surgical, and psychological issues. More-\nover, endometriosis is still an unmet clinical need because\nan optimal drug that allows for both pain management and\ncontinued attempts to conceive does not exist. Therefore, a\ngreat effort is directed toward the understanding of the basic\nmechanisms underlying the d isease to identify an ideal\ntreatment that would eliminate endometriotic lesions, pre-\nvent recurrence, and not impede ovulation. The interrela-\ntionship between the inflammatory process associated with\nthe disease and the altered response to steroid hormones\nmay represent an area of interest in this context.\nLocal Inflammatory Processes\nThere is a general agreement that a sterile, local inflamma-\ntion occurs in the peritoneal cavity of women with endome-\ntriosis and that an altered function of immune-related cells\ncharacterizes the peritoneal environment [ 6]. Interestingly,\nbased on mouse model of endometriosis, both macrophages\nin the peritoneal fluid and macrophages infiltrating ectopic\nlesions display features of alternative activation, suggesting\nthat signals in the peritoneal cavity of endometriotic patients\nand restricted to the ectopic tissue switch the differentiation\nprogram of endogenous blood-derived precursors toward an\nalternative reparative phenotype [ 7]. Adoptively transferred,\nalternatively activated M2 macrophages dramatically en-\nhance endometriotic lesion growth through the secretion of\ndifferent arrays of soluble factors. V arious cytokines and\ngrowth factors are indeed increased in peritoneal fluid of\nwomen with endometriosis, and in the setting of chronic\nlocal tissue destruction, it is also likely that autoreactivity\ndevelops. For instance, interleukin-8 and monocyte chemo-\ntactic peptide-1 (MCP-1) are found to be elevated in the\nperitoneal fluid of women with endometriosis and levels\nhave been correlated with the severity of the disease [ 6].\nTherefore, endometriosis itself does favor a peritoneal\ninflammatory situation that contributes to maintaining the\ndisease. Moreover, macrophages are important for maintain-\ning the viability of newly formed vessels and represent a\npotential therapeutic target in endometriosis. Tie2-\nexpressing macrophages (TEMs) have nonredundant func-\ntions in promoting angiogenesis and growth of experimental\ntumors and they have been shown to infiltrate areas sur-\nrounding newly formed endometriotic blood vessels and\nendometriotic lesions. TEM depletion arrested the growth\nof established lesions without toxicity. Lesion architecture\nwas disrupted with (1) loss of glandular organization, (2)\nreduced neovascularization, and (3) activation of caspase 3\nin CD31(+) endothelial cells [ 8].\nAbnormal Immune Response at Systemic Level\nIn recent years, there have been discussions suggesting that\nendometriosis might even be regarded as an autoimmune\ndisease [6]. Some investigators have reported common clin-\nical elements between patients with endometriosis and\npatients with various autoimmune processes [ 9, 10], where-\nas others have reported that endometriosis exhibits a gene\nexpression signature reminiscent of autoimmune disorders\n[11]. Endometriosis lesions are characterized by the pres-\nence of abundant plasma cells, and one of the most upregu-\nlated cytokines in these lesions is BlyS, a cytokine known to\nbe critical for normal B-cell development; high levels of\nBlyS overstimulate various B cell responses, leading to the\ninitiation and exacerbation of autoimmune responses [ 12].\nIn support for an abnormal development of immune\nresponse at systemic level as well, specific genes involved in\nleukocyte activation such as interleukin-2 receptor gamma\n(IL-2RG), were shown to be differentially expressed in\nblood leukocytes of women with endometriosis com-\npared to those present in control women [ 13]. Finally,\nbased on population-based epidemiological studies,\nwomen with endometriosis have an increased risk for\nnon-Hodgkin’s lymphoma, thus suggesting an underlying\nimmune system–associated pathology and a more generalized\ndysfunction [14, 15].\nNotwithstanding these findings supporting the critical\nrole of immunologic/inflammatory phenomena in the natu-\nral history of endometriosis, two important issues are still to\nbe clarified: (1) whether these events are only an epiphe-\nnomenon or are causally related to the disease and more\nimportantly, (2) to what extent these events may affect the\nsystemic immunologic status.\nRecently, we performed a large-scale gene expression\nstudy on peripheral blood mononuclear cells (PBMCs) from\nendometriosis patients, comparing gene expression profile\nin the severe diseased stage with the profile established after\na conventional surgical treatment for removal of endometri-\notic lesions [ 16]. Genes identified in PBMCs as downregu-\nlated after the surgical intervention, and thus potentially\ninduced\nby the disease presence, were shown to be common\nto those identified with a similar approach in psoriasis, a\nnongynecologic chronic inflammatory diseases [ 17], strong-\nly indicating a relevant influence of endometriosis on sys-\ntemic immune regulatory molecules. Among the genes\nidentified, Pre –B-cell colony enhancing factor 1 (PBEF),\ndual specificity phosphatase 1 (DUSP1), FOS, RHOB, and\nS100P . PBEF has been implicated in the pathogenesis of a\nnumber of different human diseases that share an inflamma-\ntory basis such as rheumatoid arthritis and type 2 diabetes\n[18]. DUSP1, FOS, RHOB, and S100P were identified by\ntranscriptional profiling in atrial myocardial samples after a\ncardiopulmonary bypass (CPB) that is known to induce\nCurr Obstet Gynecol Rep (2012) 1:146 –152 147\n\nmediators of the inflammatory response [ 19]. Based on all\nthese findings, the impact of endometriosis at systemic level\nshould be recognized as more significant than previously\nenvisioned and the possible consequences of this influence\nshould be considered in relation to the long-term effects of a\nchronic systemic inflammation.\nEvidence for an Inflammation-Associated Progesterone\nResistance\nProgesterone is a master regulator of endometrial tissue and it\nis estimated to regulate expression of hundreds of genes\nduring the various phases of the menstrual cycle. Two natural\nisoforms of progesterone receptors (PRs), PR-A and PR-B,\nare coexpressed in all normal progesterone target tissues and\nthe human PR-A isoform differs from the PR-B isoform\nbecause it lacks the first 164 amino acids contained in the\nPR-B. The physiological importance of maintaining the cor-\nrect relative expression levels of PR isoforms in tissues is\nindicated by detection of aberrant ratios of PR isoforms in\nhuman endometrial and breast cancers [ 20]. In this type of\ncancer cells, alteration of the PR-A/PR-B ratio is known to\nfavor cellular invasion and metastasis [21, 22]. Overexpressed\nPR-B levels are often found in highly malignant endometrial\ncancers and selective ablation of the A isoform in knockout\nmice results in endometrial hyperproliferative and premalig-\nnant changes [23]. Recently, the equal PR-A to PR-B ratio of\nthe normal endometrium has been suggested to be extensively\nderegulated also in the endometriotic tissue, leading to an\nimpaired stromal differentiation and a consequent relative\nresistance to progesterone action in endometriosis [ 24–27].\nStudies addressing progesterone resistance in endometriosis\nare summarized in Table 1.\nAccording to Attia et al. [ 24], the progesterone resistance\nin the endometriotic tissue can be explained by the complete\nabsence of PR-B transcripts and protein and the presence of\nPR-A in ectopic lesions. Similar findings have been reported\nin epithelial cells selected from a small number of ectopic\nsamples [ 26]. Moreover, because a number of progesterone\ntarget genes are deregulated also in the eutopic endometrium\nof women with endometriosis [ 28], there has been sugges-\ntive indications that endometrium of affected women could\nreflect the alteration found in the endometriotic lesions. In\nkeeping with this idea, PR-B expression was shown to be\nstatistically lower in endometrium from women with endo-\nmetriosis as compared with that of normal women at both\nprotein [ 25] and messenger RNA (mRNA) level [ 26]. Con-\nversely, more recently, Bukulmez et al. [ 27] failed to find\nany significant difference in PR-A and PR-B mRNA ex-\npression between control endometrium and eutopic endo-\nmetrium of women affect ed, although confirming a\nsignificant reduction of both PR isoforms in endometriomas.\nOur results are completely in line with those obtained by\nBukulmez et al. [ 27] for the eutopic endometrium showing\nno differences in PR-A and PR-B expression between en-\ndometrial stromal cells derived from women with and with-\nout endometriosis at both mRNA and protein level [ 29]. On\nthe other hand, in a previous study [ 30], we have demon-\nstrated that in cells from women with endometriosis but not\nfrom those without the disease, progesterone can induce\nendometrial stromal cell migration and cytoskeleton rear-\nrangement, two events that occur during cell invasion.\nTherefore, based on the data reported so far, it has been\nhypothesized that a reduced PR-B expression might be\nresponsible for elevated local estradiol levels, impaired dif-\nferentiation, deficient apoptosis, and increased cell invasion\nobserved in the pathologic tissue. On this basis, the efficacy\nof endometriotic lesion suppression with progestins has\nbeen recently questioned based on this purported progester-\none resistance in both eutopic and ectopic endometrium of\nwomen with the disease. This would explain why about 9 %\nof patients do not respond to progestin treatment [ 4].\nHowever, within the context of basic research on endo-\nmetriosis, it is often difficult to distinguish between a pri-\nmary etiologic factor and alterations occurring with time or\nunder peculiar hormonal and inflammatory conditions at\nboth transcriptional and nontranscriptional levels. The in-\nflammatory environment constitutes, in itself, a trigger for\nepigenetic reprogramming (eg, through local extracellular\nacidosis and deposit of reactive substances). Reactive halo-\ngen compounds, which are a byproduct of many chemical\nTable 1 Studies addressing and\nrelating to progesterone response\nin endometriosis\nAltered progesterone\nsensitivity\nGenetic evidence Near et al. [ 58]\nDirect phenotype evidence Attia et al. [ 24], Igarashi et al. [ 25],\nWu et al. [ 26], Bukulmez et al. [ 27],\nAghajanova et al. [ 59], Gentilini et al. [ 29]\nIndirect phenotype evidence Burney et al. [ 28], Kao et al. [ 60],\nBulun et al. [ 61], Aghajanova et al. [62 ]\nFunctional evidence Bruner-Tran et al. [ 63], Nayyar et al. [ 64],\nGentilini et al. [ 30]\nClinical evidence V ercellini et al. [ 65]\n148 Curr Obstet Gynecol Rep (2012) 1:146– 152\n\nreactions produced by inflammatory processes, cause DNA\nmethylation alteration. Chemical transformations of DNA\nmethylation contributes to disruption of the epigenetic code,\nwhich could result in a disturbed readout by the\nmethylation-binding proteins involved in both activating\nand silencing genes [ 31]. Therefore, it cannot be excluded\nthat secondary events, such as the increased inflammatory\nresponse observed in ectopic endometrium, may contribute\nto the differential receptor expression pattern demonstrated\nin some endometriotic lesions.\nFinally, it should be considered that exposure to environ-\nmental endocrine disruptors in utero and during neonatal life\ncan lead to epigenetic modification of numerous genes\ncritical to reproductive tract development and function [ 32,\n33]. Recent evidence suggests that genes that may impact a\nwoman’s risk for endometriosis may be among them, for\ninstance the PR [ 4, 34–37]. Indeed, an endometriosis-like\nphenotype in mice both at histologic and molecular level\ncan be elicited by early, developmental exposure to endo-\ncrine disruptors [ 36, 38].\nTherefore, the origin and the mechanisms underlying the\nsupposed progesterone resistance in endometriosis require\nfurther investigation.\nTargeting the “Aromatase” Enzyme for Treatment\nEndometriosis requires estrogen for its continued growth,\nand if deprived of these hormones, it tends to regress.\nAromatase is a cytochrome P450 enzyme that catalyzes\nthe rate-limiting step in estrogen biosynthesis, the conver-\nsion of androgens to estrogens [ 39]. The enzyme is\nexpressed by many human cell types including ovarian\ngranulosa cells, placental syncytiotrophoblasts, adipose\ncells, and skin fibroblasts. Estrogen action is classically\nbelieved to occur via an endocrine mechanism. Studies on\naromatase expression in breast cancer demonstrated that\nparacrine mechanisms play an important role in estrogen\naction in this tissue. Estrogens also display an “intracrine”\neffect; estrogens produced by aromatase activity in the cy-\ntoplasm of leiomyoma smooth muscle cells or in endometri-\notic stromal cells can exert their effects by readily binding to\ntheir nuclear receptor within the same cell [ 39]. It has been\nsuggested, albeit not consistently [ 40, 41], that aromatase is\nexpressed at higher levels in endometriosis implants than in\nnormal endometrium, thus providing the ectopic mucosa\nwith excessive proliferative stimulus [ 42–44]. Prostaglandin\nE\n2 (PGE2) was identified as the most potent inducer of\naromatase activity in endometriotic cells, and estrogen, in\nturn, was found to upregulate PGE\n2 formation by stimulat-\ning cyclooxygenase type 2 enzyme. Thus, a positive feed-\nback loop for continuous local estrogens and PGE 2\nproduction is established in the pathologic tissue itself,\npossibly favoring the proliferative and inflammatory char-\nacteristics of endometriosis. These findings suggest that the\naberrant expression of aromatase in endometriotic tissue\nmight be involved in the pathogenetic mechanisms of this\ndisease promoting survival and growth of the disease\nlesions. The mechanisms that mediate the regulation of\naromatase activity in endometriotic tissue also have been\ninvestigated. The most critical mechanism is mediated by\nthe aberrantly expressed key transcriptional enhancer SF-1\nin endometriotic tissue. SF-1 binds to a specific response\nelement in the promoters of a number of steroidogenic genes\nin the ovary and mediates the responsiveness of a portion of\nthese genes to cyclic adenosine monophosphate (cAMP). In\nendometriotic stromal cells, PGE\n2 induces coordinate bind-\ning of SF-1 to the promoters of steroidogenic acute regula-\ntory protein (StAR) and aromatase gene to co-activate their\nexpression [ 39]. SF-1 is expressed specifically in endome-\ntriosis but not in eutopic endometrium due to an epigenetic\nmechanism that permits binding of activator versus inhibitor\ncomplexes to its promoter. These observations represent the\nmolecular bases for use of aromatase inhibitors to treat\nendometriosis [ 45] and have prompted performance of sev-\neral pilot studies using one of the two available reversible\naromatase inhibitors (ie, anastrozole and letrozole), which\ncompete with androgens for aromatase-binding sites [ 46,\n47]. Aromatase inhibitors have been tested in surgically\ninduced models of endometriosis in mice. The administra-\ntion of letrozole (10 μg/day subcutaneously) for 4 weeks to\nwild-type mice demonstrated a dose-dependent suppressive\neffect on the growth of ectopic tissue [ 48].\nHowever, again it is unclear if the increased expression of\nthis cytochrome P-450 complex constitutes the very reason for\nsurvival and proliferation of regurgitated endometrial cells, or\nif it is the consequence of local inflammation, because of\nprostaglandins [ 49], in which case, aromatase inhibitors\nwould simply treat an epiphenomenon. Moreover, in humans,\nthe premenopausal ovary is generally considered to be resis-\ntant to blockade of estrogen production by aromatase inhib-\nitors because any lowering of plasma estrogen levels would\ncause reflexive increases in gonadotrophins [50]. This would\nthen induce increased ovarian production of estrogens. In-\ndeed, aromatase inhibitors have been suggested to correct\novulatory dysfunction as well as to increase the number of\nfollicles in controlled ovarian stimulation protocols [ 51].\nTherefore, in premenopausal women, these compounds must\nbe used together with other drugs (eg, gonadotropin-releasing\nagonists, danazol, oral contraceptives [OCs], and progestins)\nthat could effectively suppress gonadotropins and reduce\novarian activity [52–54]. Clearly, when these combined regi-\nmens are used for endometriosis, it is impossible to assess how\nmuch of the effect on pain is related to which of the two\nmedications [55]. When the efficacy of letrozole plus nore-\nthisterone acetate (NETA) was compared with that of NETA\nCurr Obstet Gynecol Rep (2012) 1:146 –152 149\n\nalone in women with rectovaginal endometriosis [ 56], the\nreported intensity of pelvic pain was slightly lower in the\ncombined regimen group, but owing to the side effects of\nletrozole (mainly joint pain and myalgia), satisfaction with\ntreatment was higher in patients who used NETA alone. After\ntreatment discontinuation, symptoms recurred without signif-\nicant between-group differences, demonstrating that also aro-\nmatase inhibitors are neither cytoreductive nor curative. In\nfact, histological examination of endometriotic lesions excised\nafter treatment with letrozole shows preservation of endome-\ntrial glands and high stromal proliferative activity [55].\nAromatase inhibitors seem effective in treating severe post-\nmenopausal endometriosis through blockade of extraovarian\nestrogen production [ 57], but their use in premenopausal\nendometriosis should be considered with caution [47].\nConclusions\nEndometriosis is a common condition with a variety of differ-\nent phenotypes. The disease has been associated with proges-\nterone resistance, and recently, this reduced sensitivity to this\nsteroid has been linked to the inflammatory process associated\nwith the disease. It remains unclear whether this progesterone\nresistance contributes to the original development of the con-\ndition or reflects the changes in endocrine –immune relation-\nships that evolve as a consequence of the disease progression.\nIn any case, these endocrine–immune changes may represent\nnovel targets for disease treatment. Although it has been\ndemonstrated to be clinically less efficacious than originally\nenvisioned, the targeting of the aromatase enzyme represents a\nparadigm of this approach. Reducing the impact of the inflam-\nmatory environment that may affect the progression of endo-\nmetriosis or improving endometrial response at both eutopic\nand ectopic sites will be key to the development of better\ntherapeutic strategies for this disease.\nDisclosures No potential conflicts of interest related to this article\nwere reported.\nup-to-date critical overview on the current treatments for\nendometriosis .\n2. Knapp VJ. How old is endometriosis? 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