Progesterone Resistance in Endometriosis: an Acquired Property?

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Opinion

Progesterone Resistance in Endometriosis: an Acquired Property? Brett McKinnon,1,* Michael Mueller,1 and Grant Montgomery2 Endometriosis is the growth of endometrial tissue outside the uterus and is characterized by progesterone resistance and changes in global and progesterone target gene expression. However, the mechanism behind this and whether it is innate, acquired, or present in both the eutopic and ectopic tissue in not always clear. We find large-scale gene expression studies in eutopic tissue, indicative of progesterone resistance, are often contradictory, potentially due to the dynamic nature of this tissue, whereas suppressed progesterone receptor expression is supported in ectopic but not eutopic tissue. This suggests more studies are required in eutopic tissue particularly, and that potentially the suppressed progesterone receptor (PR) expression is a consequence of the pathogenic process and exposure to the peritoneal environment.

Highlights There is a consensus on decreased PR expression and altered gene expression in ectopic tissue compared to matching eutopic endometrium. There are several conflicting results on whether there are differences in gene expression in eutopic endometrium of women with and without endometriosis. The main difference in gene expression in normal versus eutopic endometrium is predominantly in the early secretory phase, suggesting that transition from the proliferative to secretory phase is altered in women with endometriosis.

Endometriosis and Progesterone Resistance Endometriosis (see Glossary) is an estrogen-dependent condition characterized by the growth of endometrium outside the uterus. It is extremely prevalent, occurring in 10% of reproductive age women and is associated with pain and infertility [1]. It is a heterogeneous condition commonly separated into superficial peritoneal endometriosis (SUP), ovarian endometriosis (or endometrioma; OMA), and deeply infiltrating endometriosis (DIE) [2] (Box 1). Sampson’s theory of retrograde menstruation [3], which proposes viable endometrial cells are refluxed back through the fallopian tubes and into the peritoneal cavity during menstruation is one of the most commonly cited pathogenesis mechanisms, however, as almost 90% of women undergo retrograde menstruation, other factors must be involved. Current treatment is either via surgical removal or the reduction of systemic estrogen to limit further lesion growth [4]. Progesterone resistance describes the suppressed cellular response to progesterone exposure. In endometriosis it confers endometrial tissue the ability to remain viable at foreign locations and through successive menstrual cycles, as attenuation of progesterone target genes allows for continued growth and cell survival. It is often stated there is a tendency towards progesterone resistance in ectopic endometrial tissue that is found outside the uterus compared to the normal and eutopic endometrium found in the uterus of women without and with endometriosis respectively [1,5,6]. However, there is contrasting literature describing the origin of progesterone resistance in endometriosis and whether it initiates in the ectopic or eutopic tissue.

There is no consistent difference in PR mRNA or protein expression in the eutopic endometrium between women with and without endometriosis. Progesterone resistance in ectopic endometriosis tissue may be acquired (after it has left the normal uterine environment), which could open possibilities for novel therapeutic regimes.

1 Department of Gynecology and Obstetrics, Frauenklinik, Inselspital Bern, Switzerland 2 Genomics of Reproductive Disorders, Institute for Molecular Bioscience, University of Queensland, Australia

Endometrial Progesterone and the PR The endometrium consists of two layers, the functionalis and basalis. The functionalis, responsible for much of the critical uterine functions contains luminal and glandular epithelial cells, stromal cells, as well as endothelial, immune and other cells that are continually shed and

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*Correspondence: [email protected] (B. McKinnon).

https://doi.org/10.1016/j.tem.2018.05.006 © 2018 Elsevier Ltd. All rights reserved.

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Box 1. Theories of Endometriosis Pathogenesis Endometriosis is a heterogeneous disease commonly split into three subcategories: (i) superficial peritoneal (SUP): found on surface peritoneum throughout the peritoneal cavity; (ii) endometrioma (OMA): large fluid-filled cysts on the ovary; and (iii) deeply infiltrating endometriosis (DIE): defined by >5 mm infiltration into underlying tissue, often in the rectovaginal septum [113]. It has been postulated the different subtypes represent either a continuum, or separate entities [82] and as yet no definitive molecular basis for either has been obtained. The exact pathogenesis of endometriosis is not resolved. Originally proposed in 1929, Sampson’s theory of transplantation, in which retrograde menstruation results in the reflux of viable endometrial tissue back through the fallopian tubes and into the peritoneal cavity is still one of the most widely accepted [3]. It is supported by the anatomical distribution of lesions with high incidences at the fimbriated ends of the fallopian tubes (see Figure 1 in main text) where endometrial cell-containing peritoneal fluids will pass and collect [114]. However up to 90% of women experience retrograde menstruation, but only some develop the disease [115]. Other factors must be involved. A role for inflammation has been postulated. Chemokines produced by refluxed endometrial cells stimulate macrophage infiltration and cytokine secretion creating chronic inflammation that supports lesion establishment [116]. Stem/ progenitor cells may also be involved. Stem cells are present in the endometrial basalis and bone-marrow-derived stem cell transport to the uterus is increased during inflammation [117]. As these cells are present in menstrual efflux they may also be present in refluxed menstrual tissue providing viable, proliferating cells to the peritoneal cavity [118]. Both inflammation and stem cells could facilitate SUP lesion development, assisted by aberrations in the underlying mesothelium [119]. Endometriosis in patients without an endometrium, such as women with Mayer–Rokitansky–Küster–Hauser [120] syndrome has stimulated other theories. Coelomic metaplasia, particularly relevant to OMA [121], suggests the underlying mesothelium undergoes transformation into endometrial tissue under estrogenic influences. Extraperitoneal lesions could also stem from lymphatic or hematogenous spread of endometrial tissue [122]. In reality, endometriotic lesions may develop from a combination of some or all of these theories. Recently, large-scale genetic studies have identified variants in at least 14 regions that increase disease susceptibility [58]; many of which are related to biological pathways implicated in the above theories. Each genetic variant may produce a small incremental increase in disease susceptibility with various combinations resulting in different routes of pathogenesis that underlie the disease heterogeneity.

regrown with each menstrual cycle. During this process steroid hormones control the cellular composition and function. Estrogen, through estrogen receptors (ERs), stimulates epithelial and stromal cell proliferation and endometrial thickening. After ovulation progesterone from the corpus luteum suppresses cell proliferation and induces a complex secretory phenotype designed to support an infiltrating embryo [7]. If pregnancy is not established the corpus luteum regresses and progesterone withdrawal stimulates menstruation and the cycle begins anew. Progesterone mediates its effects through progesterone receptors PRA and PRB. Both isoforms are identical in sequence, although PRA lacks 164 amino acids at the N terminus, as they are transcribed from a single gene via different promoters [8]. The PRs are transcription factors with each isoform mediating a distinct set of target genes. PRA negatively influences PRB [9] and thus their ratio is an important indicator of progesterone activity. Post-translational regulation of PR activity also occurs through the assembly of cochaperone proteins and nuclear transport [10]. Healthy, cycling women have a temporal regulation of PR expression across the menstrual cycle, protein expression appears to peak during the late proliferative phase and decreases through the secretory phase [11,12]. Expression is strongest in the epithelial glandular cells with the PRA/PRB ratio consistent at most stages of the cycle except during the mid secretory phase when PRB becomes the predominant isoform [13]. Some studies have shown that stromal cell expression mirrors epithelial cells, although at lower concentrations [13], although a

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Glossary Basalis: underlying layer of the uterus made up of predominantly of stromal fibroblast and epithelial cells that remains during the menstruation. Corpus luteum: derived from the rupture ovarian follicle after ovulation. After rupture it secrets significant progesterone for a period of 12–14 days. Deeply infiltrating endometriosis (DIE): endometriotic lesions that infiltrate deeper than 5 mm into the underlying tissue and can be found in numerous locations including the rectovaginal septum. DNA methylation: addition of a methyl group to a DNA molecule. Can alter the expression of a specific gene. Ectopic endometrial tissue: endometrium-derived tissue that is present outside the uterine cavity. Endometriosis: growth of endometrial tissue outside the uterine cavity. Endometrium: tissue lining the inside wall of the uterus. It plays an important role in fetal implantation and development. Estrogen receptor (ER): intracellular protein that binds estrogen, translocates to the nucleus, and stimulates gene transcription. Two ER isoforms exist, ERa and ERb. Eutopic endometrium tissue: in this manuscript it refers to endometrial tissue found in women with endometriosis. Functionalis: outer layer of the endometrium that contains epithelial and stromal cells and performs the functional roles associated with the uterus. It is shed during menstruation. Genomic polymorphism: genes that can have more than one allele in the population. Heterogeneous: when two or more things are not similar. miRNA: small sequences of nucleotides usually between 18 and 22 nucleotides in length that can bind complementary mRNA sequences and regulate gene expression. Nuclear factor-kB (NF-kB): group of proteins that forms a nuclear transcription factor activated by responsible for the transcription of numerous inflammatory cytokines.

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dys-synchronous fluctuation in the secretory phase with lower PR concentration in the epithelial cells, but a strong expression in the stromal cells was also documented [12].

Progesterone Resistance in Ectopic Tissue Progesterone resistance in endometriosis was first postulated after it was noticed that progesterone treatment did not induce the conversion of estradiol (E2) to estrone (E1) in ectopic tissue [14]. The enzyme responsible for catalyzing this reaction, 17b-hydroxysteroid dehydrogenase (HSD) is a progesterone target gene highly expressed in the secretory epithelial cells of the endometrium, but not by ectopic cells [15]. Subsequently, numerous studies on both individual genes and large-scale gene expression arrays found significant variation in gene expression between ectopic and matching eutopic tissue [16–21]. Many of which, although not all, were identified as progesterone targets genes. Suppressed PR concentrations were later identified in endometriosis tissue [22,23], suggesting that altered gene transcription in ectopic tissue could result from attenuated PR activity. Studies have since confirmed reduced PRA and PRB expression at all menstrual days examined [24–26]. There are however some conflicting reports of increased PR expression in OMA, with a higher PRB/PRA ratio in OMA compared to matching controls [27], as well as no difference in the PRB mRNA and protein expression between normal endometrium and OMA [28].

Progesterone Resistance in Eutopic Endometrium Regulation of Gene Expression As ectopic endometrial tissue has suppressed PR expression, it was postulated that a similar suppression might exist in the eutopic endometrium of women with endometriosis. Much of the evidence supporting progesterone resistance in eutopic endometrium stems from differences observed in large-scale gene expression studies. The results for these however, are often contradictory (Table 1). Many early studies reported significant, differential gene expression between the normal and eutopic endometrium [29–32] (Table 1), although more recent studies, with narrowly defined cycle stages and larger sample numbers, also report no significant difference [21,33,34] (Table 1).

Normal endometrium: in this manuscript it refers to endometrial tissue from women without endometriosis. Ovarian endometriosis (or endometrioma; OMA): sometimes referred to as endometrioma found on the surface of the ovaries. Can result in an internal compartment that can become filled with fluid. Peritoneal cavity: space created between the lining of the abdominal wall and the lining of the internal organs. Progesterone receptor (PR): intracellular proteins that bind progesterone, translocate to the nucleus, and initiate target gene transcription. Two isoforms of PR exist, PRA and PRB. Proliferative phase: period during the menstrual cycle when ovarian follicles begin to mature and when the menstrual tissue begins to repair and thicken. Secretory phase: occurs after ovulation when the endometrium has reached it thickest and begins preparing for embryo implantation. Superficial peritoneal endometriosis (SUP): endometriotic lesions that are found on the lining of the peritoneal wall and do not infiltrate more than 5 mm below the surface.

It is also interesting to note that when the count of differentially expressed genes in all studies is collated, most are found in the early secretory phase (Table 1). This is consistent with one study that used principle component analysis to show proliferative and secretory phase samples from eutopic endometrial biopsies cluster more closely than those from normal endometrium, suggesting attenuation of the progesterone-mediated transition [31] from the late proliferative to early secretory phase in endometriosis. This study also identified many differentially regulated genes as progesterone target genes, adding weight to a progesterone resistance eutopic endometrium. However, while there was a significant number of progesterone target genes identified, these made up only 2% (70/3204) of all differentially expressed genes [31], raising the possibility other, more generalized differences could be present. Moreover, many studies have not taken into account endometrial cell composition that varies across the menstrual cycle. An excellent study by Barragan et al. [35] showed lineage differentiation gene expression varied between women normal and eutopic endometrial stromal cells in vitro as cells progressed from endometrial mesenchymal stem cells to stromal cells. PR Expression PR expression studies on normal and eutopic endometrium rarely show consistent results (Table 2). A cyclical variation in PR expression peaking in the late proliferative phase [24], similar to healthy women, was originally observed in eutopic endometrium. A subsequent analysis of the PRB:PRA

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Table 1. Large-Scale Gene Expression Studies Comparing Normal and Eutopic Endometrium Refs

Cycle phase

Sample type

Cycle days

Number of samples (endometriosis)

Number of samples (non-endometriosis)

Number of differentially regulated genes

Kao et al. 2003 [29]

Mid secretory

Endometrium

20–22

8

7

206

Proliferative

Endometrium

7–14

6

5

37

15–28

4

5

58

Absenger et al. 2004 [30]

Secretory Matsuzaki et al. 2005 [32]

10–14

3

3

4

Early secretory

Late proliferative

15–18

3

3

39

Mid secretory

19–23

3

3

7

Late secretory

24–28

3

3

25

Late proliferative

Burney et al. 2007 [31]

Epithelial cell

10–14

3

3

8

Early secretory

15–18

3

3

51

Mid secretory

19–23

3

3

12

Late secretory

24–28

3

3

3

7–14

6

5

40

15–18

6

3

810

Proliferative

Stromal cell

Endometrium

Early secretory

19–23

9

8

26

Sherwin et al. 2008 [124]

Mid secretory Late secretory

Endometrium

23–28

8

6

9

Meola et al. 2010 [21]

Early proliferative

Endometrium

5–8

17

11

0

Menstrual

Endometrium

1–7

14

8

0

15–20

17

10

0

18–20

17

5

0

Fassbender et al. 2012 [33]

Early secretory Garcia-Velasco et al. 2015 [34]

Mid secretory

Endometrium

ratio via western blotting found a decreased ratio in eutopic compared to normal endometrium, however no accompanying western blot image was provided [36]. In contrast, no difference in PRA or PRB expression in normal and eutopic endometrial biopsies has been reported [22,25]. Increased PRA expression in eutopic compared to normal endometrium, during both the late proliferative and early secretory phases, leading to an increased PRA:PRB ratio and decreased progesterone responsiveness has also been reported [26]. Another study using immunohistochemistry and narrowly defined menstrual phases identified a significantly reduced PRA nuclear expression in epithelial cells, but no difference in stromal cells, or PRB in either cell type [37]. Studies on PR expression in isolated primary endometrial stromal cells in vitro also found no difference in PR mRNA and protein expression between cells derived from normal and eutopic endometrium [38]. However, results from in vitro studies need to be carefully assessed. Once hormonally responsive endometrial cells are isolated and cultured in vitro they are also removed from the natural environmental factors. In this state, differences mediated by hormonal responses may be lost, as reported with stromal cells that have no specific differentially expressed genes between cells isolated at different cycle phases [39,40]. It has also been noted that PR expression is commonly lost in cultured endometrial cells; the mechanism by which is poorly understood [41]. No studies on isolated epithelial cells have yet been performed. Importantly, evidence from many of these studies suggests that eutopic endometrial tissue is not completely progesterone resistant. A detectable progesterone response of isolated eutopic

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Table 2. Studies Comparing PR Expression in Normal and Eutopic Endometrium Refs

Cycle phase

Sample type

Technique

Cycle days

Number of samples (endometriosis)

Number of samples (non-endometriosis)

Change in PR expression in eutopic endometrium

Prentice et al. 1992 [22]

Whole menstrual cycle

Endometrium

Immunohistochemistry

1–28

27

25

No change

Igarashi et al. 2005 [36]

Late proliferative

Endometrium

Western blotting

12–14

13

23

PRB/A ratio down

Bukumelez et al. 2008 [25]

Proliferative

Endometrium

qRT-PCR

7–14

7

4

No change

14–28

2

1

No change

7–14

7

4

No change

14–28

2

1

No change

7–14

13

8

No change

Secretory Immunohistochemistry

Proliferative Secretory Gentilini et al. 2010 [38]

Proliferative Secretory

Isolated endometrial stromal cells

Whole menstrual cycle Bediawy et al. 2015 [26]

Late proliferative

Endometrium

14–28

11

5

No change

Western blot

7–28

8

8

No change

Immunohistochemistry

10–14

5

5

PRA up

Early secretory Late proliferative– early secretory

Wölfler et al. 2016 [123]

qRT-PCR

Early proliferative

Endometrium

14–18

5

5

PRA up

Western blot

10–18

20

18

PRA up

Immunohistochemistry

3–7

5

2

No change

Mid proliferative

8–10

4

1

No change

Late proliferative

11–14

1

1

No change

Early secretory

15–19

2

2

No change

Mid secretory

20–24

2

2

No change

Late secretory

25–28

2

2

No change

endometrial stromal cells resulted in the phrase, selective progesterone response [42], developed to reconcile a progesterone response in cells thought to be progesterone resistant. A selective progesterone response may result from a more generalized difference that reflects a real, innate variance of the endometrium of women with and without endometriosis. Genes encoding DNA-methylation enzymes and their associated processes were found by ingenuity pathway analysis to be among the most common differentially expressed groups of genes in eutopic endometrium [43]. Moreover, it is reported that aberrant methylation profiles influence gene expression in patterns closely resembling the difference in gene expression observed between eutopic and normal endometrium [44]. Differences may also result from technical issues, such as low sample numbers, samples from various or poorly defined menstrual phases, differences in cellular composition, or other technical, or analytical methodology. Eutopic Endometrium and Endometriosis-Associated Implantation Failure Aberrations in eutopic endometrium may lead to implantation defects and contribute to endometriosis-related subfertility [45,46]. Whether this is reliant on progesterone resistance however has been proposed, but not resolved. In additional to an altered progesterone response, a shift towards excessive estrogen activity has been identified [45] with increases Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy

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in secretory phase ERa levels at implantation in women with endometriosis [47]. Inflammation that prepares the endometrial lining for implantation [48] is also altered in women with endometriosis [49], with recently identified differences in uterine natural killer cells [50] and activation of the complement regulatory proteins [51] in eutopic endometrium. Microenvironmental changes can also induce intracellular kinase signaling pathways such as extracellular signal related kinase (ERK)1 that can influence transient PR concentrations in endometrial tissue [52]. Changes in decidualization, an integral component of implantation, have been reported in cultured stromal cells isolated from eutopic endometrium [39,53,54]. Decidualization requires both progesterone and cAMP, and while progesterone is important to the decidualization process, it is unlikely to be under the direct control of an activated PR [55]. Variation in decidualization markers, phosphatase of regenerating liver-3 and insulin like growth factor binding protein-1 in response to cAMP, but not progesterone is reported to occur between stromal cells isolated from normal and eutopic endometrium, supporting a blunted cAMP, rather than an altered progesterone response in endometriosis-related aberrant decidualization [39]. In a small pilot study of 15 patients no significant difference in PR, or other genes related to embryo implantation, including HBEGF, ITGAV, ITGB3, and SPP1 was reported in endometrial tissue between women with and without endometriosis [56], although earlier studies have shown decreased avb3 protein in eutopic endometrium [57].

Regulation of PR Expression in Ectopic Endometrial Tissue Genomic Regulation Although there is consistent evidence for reduced expression of PR in ectopic tissue, the mechanism that mediates this reduction has not yet been resolved. Genetic variance increases endometriosis risk [58], however at present, no mutations in the PR gene, or genes that regulate its expression have been confirmed. A genomic polymorphism analysis on the 306-bp insertion from PV/HS-1 Alu subfamily into intron G of the PR gene (PROGINS) [59] identified an association with endometriosis [60,61], although subsequent studies found no relationship [62,63]. A +331 G/A polymorphism in endometriosis patients [64] in the promoter region of the PR gene enhancing PRB expression [65] has also been reported, but should reduce endometriosis risk. Although regions of genetic risk have been identified there is still much work required to understand their functional implications, as well as more still to be identified, leaving open the potential for genetic regulation of PR. Altered methylation may play a role with increased methylation of the PRB gene promoter reported in ectopic endometrial epithelial cells [66,67]. Post-Transcriptional Regulation Post-transcriptional modifications may also influence both PR activity and target gene transcription. Differences in miRNA expression between normal and eutopic endometrium have been observed during the early secretory phase [68], as has the expression of cochaperone proteins that regulate PR activity. Cochaperone expression may be particularly relevant for PRB, as it is the longer version of the gene that has additional co-receptor binding sites (AF3) [69]. FKBP4, important for uterine progesterone activity [70], is suppressed in women with endometriosis [71], potentially through elevated miR-29 endometrial concentrations [72]. miRNA-29 is increased in the eutopic endometrium [73].

Potential for Environment-Induced Suppression of PR in Ectopic Tissue Suppressed PR expression may represent a trait acquired during the pathological process and develops over time (Figure 1). Once endometrial stromal cells are refluxed back into the 6

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Retrograde menstruaon Reflux of viable eutopic endometrial ssue

Fallopain tube NK cells

Uterus

1 SUP endometriosis lesion

Epithelial and stromal cells

Ovary Macrophage

2

Endometrial mesenchymal cell

Eutopic epithelial cell (strong PR expression)

Eutopic stromal cell (strong PR expression)

Peritoneal fluid De novo synthesized hormones

Connual exposure to peritoneal microenvironment

PRA/B

Immune cells and inflammatory cytokines Growth factors and other influences

Ectopic stromal cell (suppressed expression)

3

Ectopic lesion Stromal cells

Ectopic epithelial cells (suppressed expression) Glandular lumen

4 Figure 1. Proposed PR Expression in Eutopic and Ectopic Endometriosis. (1) Sloughed endometrial tissue removed during menstruation and consisting of epithelial and stromal cells, either individually, or bound together, as well as accompanying immune cells and endometrial mesenchymal stem cells enter the peritoneal cavity through retrograde menstruation via the fallopian tube, passing over the ovaries. (2) Eutopic epithelial and stromal cells initially show positive PRA/B expression (green, intracellular receptor) when in the eutopic environment. (3) However, continued exposure to the peritoneal cavity microenvironment, including de novo synthesized estrogen and progesterone, immune cells and their secreted cytokines and other components, such as growth factors, oxidative stress, and increased iron may suppress PR expression. (4) During the transition from eutopic to ectopic endometrial cells and the formation of lesions the epithelial glandular and stromal cells lose their PR expression. Abbreviations: NK cells, natural killer cells; PR, progesterone receptor; SUP, superficial peritoneal endometriosis.

peritoneal cavity, chemokine secretion and immune cell infiltration [74–76] create a chronic inflammatory environment. Hormonal production by the lesions also occurs [77]. Through the activation of kinase signaling pathways, the extracellular environment including hormones, cytokines, and increased oxidation and iron concentrations (Figure 1) will influence a cellular response [78]. Higher PR expression, similar to eutopic endometrium, was reported in recurrent

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compared to primary ectopic endometrial lesions [79], and transplantation of endometrial tissue into the peritoneal environment of the baboon resulted in a reduced PR expression in the eutopic tissue over the period of the study [80], suggesting that not only that the presence of a lesion can influence the eutopic endometrium, but also that PR suppression occurs over time. Regulation of Suppressed PR Expression At present there has been limited investigation into mechanisms suppressing PR in ectopic endometrial tissue. In endometrium and endometrial cancer, PR activity is suppressed at four levels, transcriptional, post-transcriptional, post-translational, and protein stability [41,81]; all of which can be influenced by surrounding microenvironment [82] (Figure 2). At the transcriptional level PGR can be silenced by aberrant DNA methylation on its promoter and first exon [81], with a correlated loss in PRB expression [83] (Figure 2). Increased methylation of the PRB gene promoter was reported in ectopic endometrial, but not in eutopic endometrial epithelial cells [66,67]. Tumor necrosis factor (TNF)a stimulated increased methylation of PR in the immortalized endometriotic epithelium cell line (11Z) [84] and epigenetic changes to DNA methylation enzymes DNMT1, DNMT3A and B in endometriotic lesions [85] could also reduce PR expression (Figure 2). At a post-transcriptional level overexpression of miR-26a and miR-181 have both been shown to block estrogen-dependent PRA and PRB expression in breast cancer cells [86], with miR-26a increased in endometriosis [87] and miR-181a associated with the decidualization of human stromal cells in endometriosis [88] (Figure 2). The extracellular environment can also influence PR expression via post-translational mechanisms and disruption of protein stability. Both estrogen and progesterone are increased in the peritoneal fluid of women with endometriosis and are highest in early stage endometriosis patients, and significantly increased compared to women without the disease [77], which would occur at critical points in lesion development. A negative ligand-dependent activation feedback loop for progesterone reduces PR expression in endometrial cancer and occurs via phosphorylation at serine 294 via mitogen-activated protein kinase (MAPK), leading to protein degradation [89] (Figure 2). The treatment of endometrial stromal cells from both normal endometrium and ectopic endometriotic lesions with the progestin R5020 decreased PR expression in an AKT- and MEK1-independent mechanism [90]. Ligand binding to PR also stimulates MAPK phosphorylation of PR inducing ubiquitination of PR and targeting it to proteasome degradation [89] (Figure 2). De novo synthesis of both estrogen and progesterone and ultimately peritoneal fluid concentrations is dependent on the expression of steroidogenic enzymes, for which the expression and their presence in specific subtype of endometriosis has contradictory reports [91]. Steroidogenic acute regulatory protein that transfers cholesterol to the mitochondria is increased in stromal cells from both SUP and OMA, compared to normal endometrium [77], with no significant difference in cytochrome P450 (CYP)11A, CYP17A, and HSD3B. In contrast, a study on SUP samples and isolated stromal cells from OMA found a significant increase compared to normal endometrial tissue for all of these enzymes [92]. There is surprisingly little data available on DIE lesions, particularly given its potential to have an increased inflammatory response [93], and there is the potential that underlying tissue in OMA, such as the granulosa cells [94], and ovarian stroma [95], both of which have high expression of many steroidogenic enzymes, could influence the results of these studies. Inflammation plays a significant role in the expression of these enzymes. Prostaglandin (PG)E2 stimulates the expression of all these enzymes [93]. In addition to PGE2, other immune 8

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Progesterone

PGE2

Estrogen

FGF

EGF TNFα

2

Growth hormone receptors

Cytokine receptor

Cell membrane

3 NF-κB

AKT

MAPK

ERK1 AKT/MEK independent PR degraon

Nuclear transport of acvated NF-κB

p-PR

5

Proteosome

MAPK dependent PR degradaon PR Nuclear transport of ligand pR

4 Mutual interaon between NFκB and PR

1

Nuclear membrane

mir-26a, miR-181 Decreased PR producon via methylaon and miRNA producon

DMNT1 DMNT3A PR gene Promoter

Coding region

Figure 2. Possible Mechanisms of PR Suppression. (1) Transcriptional regulation of PR expression has been proposed to occur by increased methylation at the promoter and first exon of PG, as have alterations in methylation enzymes DMNT1 and DMNT3A and B. Post-translation regulation can also influence PR concentrations. (2) The peritoneal fluid contains numerous components including hormones, cytokines, and growth factors that can stimulate surface receptors, and (3) activation of protein kinases including AKT, ERK1, and MAPK that have been shown to suppress PR activity via increased phosphorylation and subsequent degradation via proteasome pathways. (4) Inflammation also stimulates NF-kB activation that has a mutual interaction with PR and can lead to reduced PR expression. The actual molecules responsible are not yet clear, however the cytokine TNFa and the growth factors EGF and FGF have been proposed. Changes in steroidogenic enzymes via cytokine stimulation will also influence local hormone concentrations. (5) Non-AKT, MEK, ligand binding-induced degradation has also been observed as a mechanism of regulating protein concentrations. Abbreviations: DNMT, DNA methyltransferase; EGF, epidermal growth factor; ERK1, extracellular regulated kinase-1; FGF, fibroblast growth factor; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor-kB; PGE2, prostaglandin E2; PR, progesterone receptor; TNFa, tumor necrosis factor-a.

products found elevated in the peritoneal fluid of women with endometriosis may contribute. TNFa and interleukin-6 stimulate CYP19A1 expression in endometriotic stromal cells [96], which in turn increase local estrogen concentrations inducing cyclooxygenase-2 expression [97], leading to further synthesis of PGE2 and a chronic feedback loop. Treatment of endometrial tissue with estrogen increases PR expression, whereas treatment with estrogen and

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progesterone together suppress PR expression, indicating a complex regulation of PR expression by local hormones [98]. Alteration in the inflammatory and hormonal environment compared to that experienced in the endometrium may therefore ultimately influence ectopic PR expression. Chronic inflammation may also influence PR expression directly through the activation of signaling pathways [78]. Nuclear factor (NF)-kB, a major regulator of the inflammatory response and activated by various cytokines increased in the peritoneal fluid of women with endometriosis has an increased nuclear presence in SUP lesions [99]. The expression of the activated, phosphorylated form of the upstream mediator of NF-kB, IKKb is associated with TNFa, although in vitro experiments suggest the activity is predominantly in epithelial and not stromal cells [100]. There is a direct interaction [101] and a mutual antagonism between PR and NF-kB [102,103] (Figure 2). It was also recently published that inflammation influenced PRA and PRB expression in endometrial stromal cells from women with endometriosis [104], and that nuclear receptor expression correlated with inflammatory cytokine concentrations [105]. AKT is an integral part of the PI3K/PTEN pathway, as well as a participant in others. Phosphorylated AKT has been identified in OMA [106], and both eutopic and ectopic endometrial tissue have increased phosphorylated AKT compared to normal endometrium [107]. Inhibition of AKT in endometriotic derived stromal cells increased PR expression, suggesting the continued phosphorylation in lesions exposed to inflammation could induce progesterone resistance. Similar results have been observed in Ishikawa endometrial cancer cells [108] and activation of the PI3K/AKT pathway promotes progesterone resistance in endometrial cancer [109]. Stimulation by epidermal growth factor and fibroblast growth factor in T47D [110] and MCF7 [111] epithelial breast cancer cells resulted in PR phosphorylation and targeting of phosphorylated PR for ubiquitin-mediated degradation, respectively (Figure 2). Summary Therefore, the current data on differences in gene expression in the eutopic endometrium compared to normal endometrium are conflicting. Moreover, the evidence that such differences are directly related to suppressed PR is limited, questioning whether selective progesterone resistance is inherent to the eutopic endometrium of women with endometriosis or is a consequence of something larger. Research with well-defined cycle stages and larger sample numbers is needed. In contrast, solid evidence supports both suppressed PR expression and subsequent gene expression changes in ectopic lesions. Given the altered hormonal and inflammatory environment in the peritoneal cavity of women with endometriosis and their ability to influence PR expression, it is tempting to speculate that suppressed PR activity is an acquired characteristic that results from the constant exposure to the peritoneal environment (Figure 1).

Future Study of Acquired Progesterone Resistance and Potential for New Treatments To assess the influence of progesterone resistance, better experimental evidence is needed, aided by appropriate tools. Longitudinal studies on women with recurrent lesions could help, if both the primary and recurrent lesions can be sourced. Such an approach would require good quality clinical data, but would still be limited by the unknown time between lesion establishment and detection. Given the variation previously reported a comprehensive evaluation of PR expression in endometriosis subtypes would also be worthwhile. 10

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In vitro cellular models could also represent useful tools. Primary endometrial epithelial and stromal cells from the women with endometriosis, characterized functionally and genetically prior to use to eliminate variance would help, as would tightly regulated hormonal culture conditions. The development of such models would provide the opportunity to identify changes in progesterone response or PR expression, as well as factors that influence expression. Models with already suppressed PR expression would also be useful to manipulate PR reexpression. Progesterone is a growth-limiting hormone [42] and a key factor in mediating decidualization [112]. The loss of progesterone responsiveness contributes to lesions being maintained through progressive menstrual cycles. A return of progesterone responsiveness through reestablishing PR expression could inhibit cellular growth and stimulating shedding. This could be used to contribute to current treatments. Similarly, the reciprocal relationship between PR expression and inflammation could allow decreasing inflammation to stimulate increased PR expression. These could be combined with specifically designed hormonal compounds that only minimally suppress systemic estrogen and target PR locally.

Outstanding Questions Is there a difference in PR expression in normal versus eutopic endometrium based on stages of the menstrual cycle? Is there a difference in the endometrium, mediated through variation in the transition through menstrual cycle in women with and without endometriosis? What is the mechanism of PR suppression in ectopic tissue and can it be reversed? Is it possible to use the acquisition of progesterone resistance, or its reversal in developing a novel therapeutic regime for women with endometriosis?

Concluding Remarks Although progesterone resistance is a well-established mechanism of endometriosis pathogenesis, there is not a clear picture of where, when, or how it develops. Nor do we completely understand its consequences, but as a characteristic more acutely present in ectopic endometrial lesions there is the potential to target lesions therapeutically while limiting eutopic endometrial side effects. In summary, progesterone resistance is a significant issue in endometriosis research that requires more, well-defined and larger studies (see Outstanding Questions) to fully understand it relevance. Disclaimer Statement The authors report no conflict of interest.

References 1.

Giudice, L.C. and Kao, L.C. (2004) Endometriosis. Lancet 364, 1789–1799

2.

Chapron, C. et al. (2003) Anatomical distribution of deeply infiltrating endometriosis: surgical implications and proposition for a classification. Hum. Reprod. 18, 157–161

3.

Sampson, J.A. (1928) Peritoneal endometriosis, due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am. J. Obstet. Gynecol. 15, 101–110

11. Ingamells, S. et al. (1996) Endometrial progesterone receptor expression during the human menstrual cycle. J. Reprod. Fertil. 106, 33–38 12. Mote, P.A. et al. (2000) Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma. Hum. Reprod. 15 (Suppl 3), 48–56 13. Lessey, B.A. et al. (1988) Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J. Clin. Endocrinol. Metab. 67, 334–340

4.

Dunselman, G.A. et al. (2014) ESHRE guideline: management of women with endometriosis. Hum. Reprod. 29, 400–412

5.

Patel, B.G. et al. (2017) Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet. Gynecol. Scand. 96, 623–632

14. Vierikko, P. et al. (1985) Steroidal regulation of endometriosis tissue: lack of induction of 17 beta-hydroxysteroid dehydrogenase activity by progesterone, medroxyprogesterone acetate, or danazol. Fertil. Steril. 43, 218–224

6.

Lode, L. et al. (2017) Abnormal pathways in endometriosis in relation to progesterone resistance: a review. J. Endometr. Pelvic Pain Disord. 9, 245–251

15. Zeitoun, K. et al. (1998) Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J. Clin. Endocrinol. Metab. 83, 4474–4480

7.

Young, S.L. (2013) Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity. Reprod. Biomed. Online 27

16. Eyster, K.M. et al. (2002) DNA microarray analysis of gene expression markers of endometriosis. Fertil. Steril. 77, 38–42

8.

Gronemeyer, H. et al. (1991) Progestin receptors: isoforms and antihormone action. J. Steroid Biochem. Mol. Biol. 40, 271–278

9.

Scarpin, K.M. et al. (2009) Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl. Recept. Signal. 7, e009

10. Smith, D.F. (2000) Chaperones in progesterone receptor complexes. Semin. Cell Dev. Biol. 11, 45–52

17. Eyster, K.M. et al. (2007) Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium. Fertil. Steril. 88, 1505–1533 18. Matsuzaki, S. et al. (2006) Differential expression of genes in eutopic and ectopic endometrium from patients with ovarian endometriosis. Fertil. Steril. 86, 548–553 19. Matsuzaki, S. et al. (2004) DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection. Mol. Hum. Reprod. 10, 719–728

Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy

11

TEM 1334 No. of Pages 14

20. Wu, Y. et al. (2006) Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology 147, 232–246 21. Meola, J. et al. (2010) Differentially expressed genes in eutopic and ectopic endometrium of women with endometriosis. Fertil. Steril. 93, 1750–1773

41. Yang, S. et al. (2011) Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol. Metab. 22, 145–152 42. Bulun, S.E. et al. (2006) Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol. Cell. Endocrinol. 248, 94–103

22. Prentice, A. et al. (1992) Ovarian steroid receptor expression in endometriosis and in two potential parent epithelia: Endometrium and peritoneal mesothelium. Hum. Reprod. 7, 1318–1325

43. Zelenko, Z. et al. (2012) Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis. Reprod. Sci. 19, 152–162

23. Bergqvist, A. et al. (1993) Immunohistochemical analysis of oestrogen and progesterone receptors in endometriotic tissue and endometrium. Hum. Reprod. 8, 1915–1922

44. Houshdaran, S. et al. (2016) Aberrant endometrial DNA methylome and associated gene expression in women with endometriosis. Biol. Reprod. 95, 93

24. Attia, G.R. et al. (2000) Progesterone receptor isoform A but not B is expressed in endometriosis. J. Clin. Endocrinol. Metab. 85, 2897–2902

45. Lessey, B.A. and Kim, J.J. (2017) Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why. Fertil. Steril. 108, 19–27

25. Bukulmez, O. et al. (2008) Inflammatory status influences aromatase and steroid receptor expression in endometriosis. Endocrinology 149, 1190–1204

46. Prapas, Y. et al. (2012) History of endometriosis may adversely affect the outcome in menopausal recipients of sibling oocytes. Reprod. Biomed. Online 25, 543–548

26. Bedaiwy, M.A. et al. (2015) Abundance and localization of progesterone receptor isoforms in endometrium in women with and without endometriosis and in peritoneal and ovarian endometriotic implants. Reprod. Sci. 22, 1153–1161

47. Lessey, B.A. et al. (2006) Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women. Reprod. Biol. Endocrinol. RBE 4 (Suppl 1), S9

27. Misao, R. et al. (1999) Dominant expression of progesterone receptor form B mRNA in ovarian endometriosis. Horm. Res. Paediatr. 52, 30–34 28. Smuc, T. et al. (2009) Disturbed estrogen and progesterone action in ovarian endometriosis. Mol. Cell. Endocrinol. 301, 59– 64 29. Kao, L.C. et al. (2003) Expression profiling of endometrium from women with endometriosis reveals candidate genes for diseasebased implantation failure and infertility. Endocrinology 144, 2870–2881

48. Dekel, N. et al. (2014) The role of inflammation for a successful implantation. Am. J. Reprod. Immunol. 1989 72, 141–147 49. Déchaud, H. et al. (1998) Evaluation of endometrial inflammation by quantification of macrophages, T lymphocytes, and interleukin-1 and -6 in human endometrium. J. Assist. Reprod. Genet. 15, 612–618 50. Glover, L.E. et al. (2018) Uterine natural killer cell progenitor populations predict successful implantation in women with endometriosis-associated infertility. Am. J. Reprod. Immunol. 79, e12817

30. Absenger, Y. et al. (2004) Cyr61, a deregulated gene in endometriosis. Mol. Hum. Rep. 10, 399–407

51. Palomino, W.A. et al. (2018) The endometria of women with endometriosis exhibit dysfunctional expression of complement regulatory proteins during the mid secretory phase. J. Reprod. Immunol. 125, 1–7

31. Burney, R.O. et al. (2007) Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148, 3814–3826

52. Tapia-Pizarro, A. et al. (2017) hCG activates Epac-Erk1/2 signaling regulating Progesterone Receptor expression and function in human endometrial stromal cells. Mol. Hum. Reprod. 23, 393–405

32. Matsuzaki, S. et al. (2005) DNA microarray analysis of gene expression in eutopic endometrium from patients with deep endometriosis using laser capture microdissection. Fertil. Steril. 84, 1180–1190

53. Klemmt, P.A.B. et al. (2006) Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity. Fertil. Steril. 85, 564–572

33. Fassbender, A. et al. (2012) Combined mRNA microarray and proteomic analysis of eutopic endometrium of women with and without endometriosis. Hum. Reprod. 27, 2020–2029 34. Garcia-Velasco, J.A. et al. (2015) Is endometrial receptivity transcriptomics affected in women with endometriosis? A pilot study. Reprod. Biomed. Online 31, 647–654 35. Barragan, F. et al. (2016) Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis. Biol. Reprod. 94, 118 36. Igarashi, T.M. et al. (2005) Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fertil. Steril. 84, 67–74 37. Petousis, S. et al. (2018) Unexplained infertility patients present the mostly impaired levels of progesterone receptors: prospective observational study. Am. J. Reprod. Immunol. 79, e12828 38. Gentilini, D. et al. (2010) Endometrial stromal progesterone receptor-A/progesterone receptor-B ratio: no difference between women with and without endometriosis. Fertil. Steril. 94, 1538–1540 39. Aghajanova, L. et al. (2009) Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis. Biol. Reprod. 80, 105–114 40. Aghajanova, L. et al. (2011) Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol. Reprod. 84, 801–815

12

54. Su, R.-W. et al. (2015) Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization. J. Clin. Endocrinol. Metab. 100, E433–E442 55. Gellersen, B. and Brosens, J. (2003) Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J. Endocrinol. 178, 357–372 56. Broi, M.G.D. et al. (2017) Expression of PGR, HBEGF, ITGAV, ITGB3 and SPP1 genes in eutopic endometrium of infertile women with endometriosis during the implantation window: a pilot study. JBRA Assist. Reprod. 21, 196–202 57. Lessey, B.A. et al. (1994) Aberrant integrin expression in the endometrium of women with endometriosis. J. Clin. Endocrinol. Metab. 79, 643–649 58. Sapkota, Y. et al. (2017) Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat. Commun. 8, 15539 59. Rowe, S.M. et al. (1995) Ovarian carcinoma-associated TaqI restriction fragment length polymorphism in intron G of the progesterone receptor gene is due to an Alu sequence insertion. Cancer Res. 55, 2743–2745 60. Wieser, F. et al. (2002) PROGINS receptor gene polymorphism is associated with endometriosis. Fertil. Steril. 77, 309–312 61. Lattuada, D. et al. (2004) Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS? Clin. Endocrinol. 61, 190–194 62. Treloar, S.A. et al. (2005) Association between polymorphisms in the progesterone receptor gene and endometriosis. Mol. Hum. Reprod. 11, 641–647

Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy

TEM 1334 No. of Pages 14

63. Trabert, B. et al. (2011) Genetic variation in the sex hormone metabolic pathway and endometriosis risk: an evaluation of candidate genes. Fertil. Steril. 96, 1401–1406.e3

83. Sasaki, M. et al. (2001) Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer. Cancer Res. 61, 97–102

64. van Kaam, K.J.a.F. et al. (2007) Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum. Reprod. 22, 129–135

84. Wu, Y. et al. (2008) Prolonged stimulation with tumor necrosis factor-alpha induced partial methylation at PR-B promoter in immortalized epithelial-like endometriotic cells. Fertil. Steril. 90, 234–237

65. Berchuck, A. et al. (2004) Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers. Cancer Epidemiol. 13, 2141–2147

85. Wu, Y. et al. (2007) Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis. Fertil. Steril. 87, 24–32

66. Wu, Y. et al. (2006) Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics 1, 106– 111

86. Maillot, G. et al. (2009) Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer Res. 69, 8332–8340

67. Meyer, J.L. et al. (2014) DNA methylation patterns of steroid receptor genes ESR1, ESR2 and PGR in deep endometriosis compromising the rectum. Int. J. Mol. Med. 33, 897–904

87. Teague, E.M.C.O. et al. (2010) The role of microRNAs in endometriosis and associated reproductive conditions. Hum. Reprod. Update 16, 142–165

68. Burney, R.O. et al. (2009) MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis. Mol. Hum. Reprod. 15, 625–631

88. Zhang, Q. et al. (2015) MicroRNA-181a is involved in the regulation of human endometrial stromal cell decidualization by inhibiting Krüppel-like factor 12. Reprod. Biol. Endocrinol. 13, 23

69. Tranguch, S. et al. (2007) Progesterone receptor requires a cochaperone for signalling in uterine biology and implantation. Reprod. Biomed. Online 14, 39–48 Spec No 1

89. Lange, C.A. et al. (2000) Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc. Natl. Acad. Sci. 97, 1032–1037

70. Tranguch, S. et al. (2007) FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific. J. Clin. Invest. 117, 1824–1834 71. Hirota, Y. et al. (2008) Deficiency of immunophilin FKBP52 promotes endometriosis. Am. J. Pathol. 173, 1747–1757 72. Marbaix, E. et al. (1996) Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases. Proc. Natl. Acad. Sci. 93, 9120–9125 73. Joshi, N.R. et al. (2016) Progesterone resistance in endometriosis is modulated by the altered expression of microRNA-29c and FKBP4. J. Clin. Endocrinol. Metab. 2016–2076 74. Hornung, D. et al. (2001) Chemokine bioactivity of RANTES in endometriotic and normal endometrial stromal cells and peritoneal fluid. Mol. Hum. Reprod. 7, 163–168 75. Hornung, D. et al. (1997) Immunolocalization and regulation of the chemokine RANTES in human endometrial and endometriosis tissues and cells. J. Clin. Endocrinol. Metab. 82, 1621– 1628 76. Bersinger, N.A. et al. (2011) Dose-response effect of interleukin (IL)-1b, tumour necrosis factor (TNF)-a, and interferon-g on the in vitro production of epithelial neutrophil activating peptide-78 (ENA-78), IL-8, and IL-6 by human endometrial stromal cells. Arch. Gynecol. Obstet. 283, 1291–1296 77. Tsai, S.J. et al. (2001) Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J. Clin. Endocrinol. Metab. 86, 5765– 5773 78. McKinnon, B.D. et al. (2016) Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics. Hum. Reprod. Update 22, 382–403 79. Bergqvist, A. and Ferno, M. (1993) Estrogen and progesterone receptors in endometriotic tissue and endometrium: Comparison according to localization and recurrence. Fertil. Steril. 60, 63–68 80. Jackson, K.S. et al. (2007) The altered distribution of the steroid hormone receptors and the chaperone immunophilin FKBP52 in a baboon model of endometriosis is associated with progesterone resistance during the window of uterine receptivity. Reprod. Sci. 14, 137–150 81. Ren, Y. et al. (2007) Down-regulation of the progesterone receptor by the methylation of progesterone receptor gene in endometrial cancer cells. Cancer Genet. Cytogenet. 175, 107–116 82. Liu, X. et al. (2018) Histological and immunohistochemical characterization of the similarity and difference between ovarian endometriomas and deep infiltrating endometriosis. Reprod. Sci. 25, 329–340

90. Eaton, J.L. et al. (2013) Increased AKT or MEK1/2 activity influences progesterone receptor levels and localization in endometriosis. J. Clin. Endocrinol. Metab. 98, E1871–E1879 91. Huhtinen, K. et al. (2012) Estrogen biosynthesis and signaling in endometriosis. Mol. Cell. Endocrinol. 358, 146–154 92. Attar, E. et al. (2009) Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J. Clin. Endocrinol. Metab. 94, 623–631 93. Bertschi, D. et al. (2013) Enhanced inflammatory activity of endometriotic lesions from the rectovaginal septum. Mediators Inflamm. 2013, 450950 94. Bulun, S.E. et al. (1994) Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads. J. Clin. Endocrinol. Metab. 78, 1616–1621 95. Havelock, J.C. et al. (2006) The post-menopausal ovary displays a unique pattern of steroidogenic enzyme expression. Hum. Reprod. 21, 309–317 96. Velasco, I. et al. (2006) Aromatase expression in endometriotic tissues and cell cultures of patients with endometriosis. Mol. Hum. Reprod. 12, 377–381 97. Tamura, M. et al. (2004) Estrogen up-regulates cyclooxygenase-2 via estrogen receptor in human uterine microvascular endothelial cells. Fertil. Steril. 81, 1351–1356 98. Prange-Kiel et al. (2001) Regulation of estrogen receptor alpha and progesterone receptor (isoform A and B) expression in cultured human endometrial cells. Exp. Clin. Endocrinol. Diabetes 109, 231–237 99. González-Ramos, R. et al. (2007) Nuclear factor-kappa B is constitutively activated in peritoneal endometriosis. Mol. Hum. Reprod. 13, 503–509 100. Kocbek, V. et al. (2016) TNFa induced IKKb complex activation influences epithelial, but not stromal cell survival in endometriosis. Mol. Hum. Reprod. 101. Allport, V.C. et al. (2001) Human labour is associated with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expression and is involved with the “functional progesterone withdrawal”. Mol. Hum. Reprod. 7, 581–586 102. McKay, L.I. and Cidlowski, J.A. (1998) Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism. Mol. Endocrinol. 12, 45–56 103. Kalkhoven, E. et al. (1996) Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. J. Biol. Chem. 271, 6217–6224

Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy

13

TEM 1334 No. of Pages 14

104. Grandi, G. et al. (2016) Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J. Reprod. Immunol. 117, 30–38

115. Halme, J. et al. (1984) Retrograde menstruation in healthy women and in patients with endometriosis. Obstet. Gynecol. 64, 151–154

105. Grandi, G. et al. (2017) The association between progestins, nuclear receptors expression and inflammation in endometrial stromal cells from women with endometriosis. Gynecol. Endocrinol. 0, 1–4

116. Hornung, D. et al. (2001) Regulated on activation, normal T-cellexpressed and -secreted mRNA expression in normal endometrium and endometriotic implants: assessment of autocrine/ paracrine regulation by in situ hybridization. Am. J. Pathol. 158, 1949–1954

106. Yagyu, T. et al. (2006) Activation of mammalian target of rapamycin in postmenopausal ovarian endometriosis. Int. J. Gynecol. Cancer 16, 1545–1551 107. Cinar, O. et al. (2009) Differential regulation of Akt phosphorylation in endometriosis. Reprod. Biomed. Online 19, 864–871 108. Pant, A. et al. (2012) Inhibition of AKT with the orally active allosteric AKT inhibitor, MK-2206, sensitizes endometrial cancer cells to progestin. PLoS One 7, e41593 109. Gu, C. et al. (2011) Inhibiting the PI3K/Akt pathway reversed progestin resistance in endometrial cancer. Cancer Sci. 102, 557–564 110. Daniel, A.R. et al. (2007) Linkage of progestin and epidermal growth factor signaling: phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth. Steroids 72, 188–201

117. Du, H. and Taylor, H.S. (2007) Contribution of bone marrowderived stem cells to endometrium and endometriosis. Stem Cells 25, 2082–2086 118. Gargett, C.E. et al. (2016) Endometrial stem/progenitor cells: the first 10 years. Hum. Reprod. Update 22, 137–163 119. Young, V.J. et al. (2014) The peritoneum is both a source and target of TGF-b in women with endometriosis. PLoS One 9, e106773 120. Elliott, J.E. et al. (2011) Presurgical management of dysmenorrhea and endometriosis in a patient with Mayer-RokitanskyKuster-Hauser syndrome. Fertil. Steril. 96, e86–e89 121. Nisolle, M. and Donnez, J. (1997) Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil. Steril. 68, 585–596

111. Vicent, G.P. et al. (2006) Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Mol. Cell 24, 367–381

122. Jerman, L.F. and Hey-Cunningham, A.J. (2015) The role of the lymphatic system in endometriosis: a comprehensive review of the literature. Biol. Reprod. 92, 64

112. Brar, A.K. et al. (1997) Progesterone-dependent decidualization of the human endometrium is mediated by cAMP. Endocrine 6, 301–307

123..Wölfler, M. et al. (2016) Altered expression of progesterone receptor isoforms A and B in human eutopic endometrium in endometriosis patients. Ann. Anat. 206, 1–6

113. Chapron, C. et al. (2010) Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions. Hum. Reprod. 25, 884–889

124..Sherwin, J.R.A. et al. (2008) Global gene analysis of late secretory phase, eutopic endometrium does not provide the basis for a minimally invasive test of endometriosis. Hum. Rep. 23, 1063–1068

114. McKinnon, B.D. et al. (2014) Hormonal contraceptive use and the prevalence of endometriotic lesions at different regions within the peritoneal cavity. BioMed Res. Int. 2014, 590950

14

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