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Hum. Reprod. Advance Access originally published online on September 25, 2006
Human Reproduction 2007 22(1):124-128; doi:10.1093/humrep/del368
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Both GnRH agonist and continuous oral progestin treatments reduce the expression of the tyrosine kinase receptor B and mu-opioid receptor in deep infiltrating endometriosis

S. Matsuzaki1,3, M. Canis1, J.-L. Pouly1, R. Botchorishvili1, P.J. Déchelotte2 and G. Mage1

1 CHU Clermont-Ferrand, Polyclinique-Hôtel-Dieu, Gynécologie Obstétrique et Médecine de la Reproduction and 2 Anatomie et cytologie pathologiques, Clermont-Ferrand, France

3 To whom correspondence should be addressed at: CHU Clermont-Ferrand, Polyclinique-Hôtel-Dieu, Gynécologie Obstétrique et Médecine de la Reproduction, Boulevard Léon Malfreyt, 63058 Clermont-Ferrand, France. E-mail: sachikoma{at}aol.com


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Deep infiltrating endometriosis (DIE) is commonly associated with severe pain. The pain can be managed successfully with GnRH agonists or continuous progestins. The precise molecular mechanism by which DIE causes pain or why hormonal treatment is effective, however, remains unclear. We recently identified three potential candidate genes that might be involved in DIE pain pathways: tyrosine kinase receptor B (TrKB), mu-opioid receptor (MOR) and serotonin transporter (5HTT). We hypothesized that if these three genes were involved in DIE-associated pain, their expression levels would probably be modulated by GnRH agonist or progestin. In this study, we compared mRNA expression levels of TrKB, MOR and 5HTT in DIE among patients pre-operatively treated with GnRH agonist, progestin or without pre-operative medical treatments. METHODS: The expression levels of TrKB, MOR and 5HTT mRNA in DIE were determined using laser capture microdissection and real-time RT–PCR techniques. RESULTS: The expression levels of TrKB in epithelial cells and MOR in stromal cells from DIE were significantly decreased in patients with pre-operative GnRH agonist or progestin. There was no significant difference in 5HTT expression levels among untreated, GnRH agonist- and progestin-treated patients. CONCLUSION: The expression levels of TrKB and MOR genes in DIE appeared to be modulated by GnRH agonist or progestin. However, the functional roles of TrKB and MOR in DIE remain to be clarified.

Key words: deep infiltrating endometriosis/endometriosis-associated pain/laser capture microdissection


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Deep infiltrating endometriosis (DIE) is commonly associated with severe pain (Koninckx and Martin, 1994Go). The pain can be managed successfully with GnRH agonists or continuous progestins (Davis and McMillan, 2003Go). The precise molecular mechanism by which DIE causes pain or why hormonal treatment is effective, however, remains unclear.

We recently identified three potential candidate genes that might be involved in DIE pain pathways (Matsuzaki et al., 2004Go): tyrosine kinase receptor B (TrKB) in endometriosis epithelial cells, and mu-opioid receptor (MOR) and serotonin transporter (5HTT) in endometriosis stromal cells. All the three were up-regulated in DIE as compared with matched eutopic endometrium. The MOR is present in the central and peripheral nervous systems and in non-neural peripheral tissues (Satoh and Minami, 1995Go). There is evidence that the opioid system, particularly its receptors, is altered by the cytokines elaborated during inflammatory pain (Stein et al., 1990Go, 1993Go; Pol et al., 2001Go). Additionally, in many in vivo models, proinflammatory cytokines have been shown to contribute to the development of inflammatory pain and hyperalgesia (Watkins et al., 1995Go; Sommer and Kress, 2004Go). Although it is not clear whether endometriosis-related pain is caused by inflammation, there is strong evidence that proinflammatory cytokines may be involved in endometriosis pathophysiology (Harada et al., 2001Go). Tumour necrosis factor (TNF) and interleukin 6 (IL-6), proinflammatory cytokines, induce MOR gene transcription in both neuronal and immune cells (Kraus et al., 2003Go; Borner et al., 2004Go). TNF induces MOR gene transcription through nuclear factor KappaB (NF-{kappa}B) (Kraus et al., 2003Go). Other proinflammatory chemokines, including CCL2 [monocyte chemotactic protein (MCP-1)], CCL3 [macrophage inflammatory protein 1 alpha (MIP-1{alpha})], CCL5 [regulated on activation and normally T-cell expressed and presumably secreted (RANTES)] and CXCL8 (IL-8) desensitize MORs, thereby decreasing their analgesic function (Szabo et al., 2002Go; Zhang et al., 2004Go). This promotes increased transmission of pain signals in both the central and the peripheral nervous systems (Szabo et al., 2002Go; Zhang et al., 2004Go). Numerous studies have demonstrated that the NF-{kappa}B-mediated induction of MCP-1, RANTES and IL-8 is involved in endometriosis pathophysiology (Oral et al., 1996Go; Sidell et al., 2002Go). TNF{alpha} and IL-6 also up-regulate the expression of brain-derived neurotrophic factor (BDNF), a specific ligand of TrKB in human monocytes (Schulte-Herbruggen et al., 2005Go). The BDNF/TrKB system contributes to stimulus-induced hypersensitivity after inflammation (Mannion et al., 1999Go). After peripheral inflammation, expression of TrKB in the dorsal horn is up-regulated in parallel with the expression of BDNF in the dorsal root ganglion (Mannion et al., 1999Go). A recent study suggested that up-regulation of autocrine expression of BDNF in epithelial cells might be concomitant with transformation to a malignant phenotype capable of invasion along the perineural space in prostate cancer (Dalal and Djakiew, 1997Go). Anaf et al. (2000)Go demonstrated that perineurial and intraneurial invasion by epithelial and stromal cells was associated with pain symptoms in deep endometriosis.

We hypothesized that if the above three genes could indeed be involved in DIE-associated pain, their expression levels would probably be modulated by GnRH agonist or continuous progestins.

In this study, we measured the mRNA expression levels of TrKB in DIE epithelial cells and MOR and 5HTT in DIE stromal cells from patients treated with pre-operative GnRH agonist or continuous oral progestins. We then compared these levels with the expression levels of these genes in DIE from patients receiving no pre-operative medical treatments.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Patients with DIE (rectovaginal nodules), undergoing laparoscopic surgical treatment for pain symptoms, were recruited from May 2001 to April 2005 in the Polyclinique de l’Hotel Dieu, CHU Clermont-Ferrand, France. DIE was defined as the presence of an endometriotic lesion deeper than 5 mm beneath the peritoneal surface. The depth and size of DIE were measured using a ruler just after the collection of tissue in the operating room. During laparoscopic surgical treatment, the severity of endometriosis was scored according to the revised American Society for Reproductive Medicine classification. All tissue samples were obtained with full and informed patient consent. The research protocol was approved by the Consultative Committee for Protection of Persons in Biomedical Research (CCPPRB) of the Auvergne region.

All patients in this study were referred to our department for surgical treatment. We selected patients who had no prior surgical treatment for DIE. Patients were divided into three categories. The first group, who were trying to conceive, received no hormonal treatment such as GnRH agonist or progesterone, and none had used intrauterine contraception for at least 6 months before surgical treatment. All patients had regular 26–32-day menstrual cycles as confirmed by the investigators. Patients in the first group were further selected based on the consistent endometrial dating criteria, as described by Noyes et al. (1950)Go, menstrual history and serum 17beta estradiol and progesterone levels. Finally, 16 patients (eight patients during the proliferative phase and eight during the secretory phase) were selected for this study.

The second group (n = 8) received a GnRH agonist for >4 months (range 4–6 months) before surgical treatment. The third group (n = 8) received continuous oral progesterone treatment for >4 months (range 4–6 months) before surgical treatment. All patients with pre-operative GnRH agonist or progestin did not wish to conceive. They underwent diagnostic laparoscopy for pain symptoms in other hospitals before starting medical treatments. The choice of medical treatments was decided by physicians who performed diagnostic laparoscopy after discussion with patients.

Samples of endometriotic tissue were divided into two portions. One was fixed in 10% formalin–acetic acid and embedded in paraffin for histopathological examination. The other was immediately placed in RNAlater (Ambion, Cambridgeshire, UK) and stored at –20°C until RNA extraction.

Pain assessment
Data on pain symptoms as well as other clinical information were collected via face-to-face interviews conducted between hospital admission and surgery. Pain assessment was done using a 10-point linear analogue scale, with 0 representing no pain and 10 representing the worst possible pain (Vercellini et al., 1996Go; Muzii et al., 1997Go).

Laser capture microdissection
Frozen sections of 8-µm thickness were prepared from each frozen endometriotic tissue sample kept in RNAlater (Ambion). Sections were mounted on positively charged slides (Super Frost Plus, Menzel GmbH, Braunschweig, Germany). Haematoxylin–eosin (H&E) staining on frozen sections was performed using the National Cancer Institute (NCI) protocol (http://cgap-mf.nih.gov/Protocols/index.html), with some minor modifications as previously described (Matsuzaki et al., 2004Go, 2005Go).

Briefly, slides were fixed in 70% ethanol for 15 s and stained with H&E, followed by dehydration in two 15-s washes in 95% ethanol, two 60-s washes in 100% ethanol and two final washes in xylene for 3 min each. Slides were air-dried for 5 min and stored in a desiccator for no more than 1 h. Glandular epithelial cells and stromal cells from endometriotic tissues were isolated from the slides using the PixCell II LCM System (Arcturus, Plaisir, France), according to the manufacturer’s instructions. A beam of diameter 7.5 and 15 µm was utilized for epithelial cells and for stromal cells, respectively. Microdissected cells were collected on optically transparent LCM HS caps (Arcturus).

RNA extraction and quantification
After laser capture microdissection (LCM), RNA extraction was performed using the Picopure RNA extraction kit (Arcturus). The caps were placed in microcentrifuge tubes (Eppendorff, le Pecq, France) containing lysis buffer and incubated at 42°C for 30 min. After centrifugation, the caps were removed, and RNA was isolated using the Picopure RNA extraction protocol. To eliminate potential genomic DNA contamination, we treated the RNA samples with DNase I (15 U; DNase I, Courtaboef, Qiagen, France) at RT for 15 min. Finally, total RNA was resuspended in 11 µl RNase-free water and kept at –80°C until needed. RNA quantities were measured with the RiboGreen RNA Quantitation Kit (Molecular Probes Europe BV, Leiden, the Netherlands). All procedures were performed according to the manufacturer’s instructions.

Quantitative real-time RT–PCR with a Light Cycler
Quantitative real-time RT–PCR with a Light Cycler was performed on non-amplified total RNA from microdissected tissues. Total RNA (10 ng) was subjected to an RT reaction using Superscript II Reverse Transcriptase (Invitrogen). Quantitative real-time PCR was performed in a Light Cycler System using the FastStart DNA Master SYBR Green I kit, as recommended by the manufacturer (Roche, Mannheim, Germany). In a total volume of 20 µl, each reaction contained 2 µl SYBR green I reaction mix (consisting of Taq DNA-polymerase reaction buffer, dNTP mix, SYBR green I, MgCl2 and Taq DNA polymerase), 0.5 µM of each primer, 4 mM MgCl2 and 2 µl cDNA, and standard or nuclease-free water as a negative control. Primer sets are as previously described (Matsuzaki et al., 2004Go). Quantification of the targets in the unknown samples was performed using a relative quantification method with external standards. The target concentration is expressed relative to the concentration of a reference housekeeping gene, glyceraldehyde-3-phosphatedehydrogenase (GAPDH). After each run, melting curve analysis was performed to verify the specificity of the PCR.

Statistical analysis
The Statview 4.5 program (Abacus concepts, Inc., Berkeley, CA, USA) was used for all statistical analysis. The Mann–Whitney U-test or Kruskal–Wallis test was applied to compare results from different groups. The threshold for statistical significance was defined at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Clinical characteristics of patients are summarized in Table I. No expression of TrKB was detected in epithelial cells from either GnRH agonist- or progestin-treated DIE (Figure 1A). MOR expression was not detected in stromal cells from any of the eight GnRH agonist-treated patients. Although MOR expression in stromal cells was detectable in four progestin-treated patients, expression levels were significantly lower than those in untreated patients (proliferative phase P < 0.001; secretory phase P < 0.001; Expression levels were very low Mean = 0.001, SD = 0.001; Figure 1B). There was no significant difference in 5HTT expression levels among the three groups (Figure 1C). We detected no significant difference in expression levels of TrKB, MOR and 5HTT between proliferative and secretory phases.


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  		Table I. Clinical characteristics of patients

 

Figure 1
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  		Figure 1. Results of quantitative real-time RT–PCR of deep infiltrating endometriosis (DIE) from patients without pre-operative medical treatments, with pre-operative GnRH agonists or continuous oral progestins. Expression levels of TrKB (A), MOR (B) or 5HTT (C) mRNA are given relative to the expression levels of the reference gene, GAPDH. Results are presented as the mean ± SD. P, patients during the proliferative phase (n = 8); S, patients during the secretory phase (n = 8); GnRHa, patients with pre-operative GnRH agonists (n = 8); Prog, patients with pre-operative continuous oral progestins (n = 8); a, P < 0.001 versus GnRHa and Prog.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
This study demonstrated no MOR mRNA in stromal cells from GnRH agonist-treated DIE and no TrKB mRNA in epithelial cells from either GnRH agonist- or progestin-treated DIE. MOR mRNA expression in stromal cells from progestin-treated DIE was detectable. However, its expression level was significantly lower than that of non-treated DIE. We detected no significant difference in 5HTT expression between treated and untreated patients.

On the basis of our findings, we propose two possible explanations for this observation. First, both GnRH agonist and progestin treatment reduce TNF{alpha}-induced NF-{kappa}B activation in endometriotic stromal cells (Sakamoto et al., 2003Go; Horie et al., 2005Go). In addition, GnRH agonist treatment attenuates IL-6 production by endometriotic stromal cells (Iwabe et al., 2003Go). Thus, GnRH agonist and progestin may down-regulate the MOR and TrKB through suppression of TNF and IL-6. A second explanation is that down-regulation of proinflammatory chemokines, such as MCP-1, RANTES and IL-8, could result in decreased down-regulation of the analgesic functions of the MOR. There is evidence that both GnRH agonist and progestin down-regulate IL-8 (Mannion et al., 1999Go; Schulte-Herbruggen et al., 2005Go) and that progestin down-regulates RANTES (Zhao et al., 2002Go) through suppression of NF-{kappa}B activation. MOR is also expressed on the cells of the immune system. Further investigation should be performed to clarify in which cell type, nervous cells, immune cells or both, MOR is up-regulated in endometriosis stromal cells. In addition, it is necessary to investigate protein expression levels of MOR and TrKB in endometriotic tissues.

Endometriosis is a common cause of both pelvic pain and infertility in reproductive-age women. Current hormonal treatments such as GnRH agonist and continuous progestins, though effective for managing pain, are not useful for women trying to conceive, as these drugs suppress ovulation. Thus, an ideal drug for the treatment of endometriosis would be the one that minimizes the adverse effect of anovulation (D’Hooghe, 2003Go). The present findings suggest the involvement of neuroimmune interactions in the pathogenesis of endometriosis-associated pain. Mediators in the neuroimmune pathways may represent alternate targets for non-hormonal treatments, which would be more compatible with ongoing fertility.

However, there are several methodological limitations to this study. First, this is not a randomized study. It would be unethical to randomize patients with severe pain into the three groups of no treatment, GnRH agonist and progestin. Some patients, trying to conceive, do not wish to receive any pre-operative hormonal treatments. In addition, side effects and cost profiles of GnRH agonist and progestin treatments differ (Kennedy et al., 2005Go), although there is evidence that both treatments are equally effective. Second, a recent study by Parker et al. (2006)Go suggested that myometrial junctional zone abnormalities or adenomyosis may contribute to chronic pelvic pain in women with endometriosis. Because we did not systematically perform a pre-operative magnetic resonance imaging (MRI) scan, it is not clear whether some patients had myometrial junctional zone abnormalities in the present study. In addition, it is not clear whether some patients had adenomyosis, because no patients underwent hysterectomy in this study. Further studies should be necessary to investigate whether these findings are consistent with endometriosis patients without myometrial junctional zone abnormalities or adenomyosis.

This study demonstrated that expression levels of TrKB and MOR genes in DIE were modulated by GnRH agonist or progestin. However, the functional roles of TrKB and MOR in DIE remain to be clarified. Further in vivo and in vitro studies should be necessary to investigate whether TrKB and MOR genes could be involved in endometriosis-associated pain pathways.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
This study was supported in part by grants PHRC 2003 and PHRC 2004 of CHU Clermont-Ferrand.

We are grateful to all the staff at the Polyclinique de l’Hotel Dieu, CHU Clermont-Ferrand, particularly to all residents and staff in the operating room. We are indebted to all the staff in the Department of Pathology, CHU Clermont-Ferrand, l’Hotel Dieu.


   Footnotes
 
Presented in part at the 61st Annual Meeting of the American Society for Reproductive Medicine, Montréal, Quebéc, Canada (October 15–19, 2005). Back


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 References
 
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Submitted on April 4, 2006; resubmitted on June 15, 2006; resubmitted on July 17, 2006; accepted on August 9, 2006.


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