Hum. Reprod. Advance Access originally published online on June 19, 2006
Human Reproduction 2006 21(9):2417-2420; doi:10.1093/humrep/del179
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Tumour necrosis factor-
blockers: potential limitations in the management of advanced endometriosis? A Case Report
Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, Cleveland, OH, USA
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, 9500 Euclid Avenue-A81, Cleveland, OH 44195, USA. E-mail: falcont{at}ccf.org
 |
Abstract |
|---|
 Top Abstract IntroductionCase reportDiscussionConclusionReferences |
|---|
Several studies have shown that tumour necrosis factor (TNF)-
levels are increased in the peritoneal fluid of women with endometriosis, with correlation between TNF- concentrations and the degree of disease. It is also likely that elevation of peritoneal fluids’ TNF- levels may play a role in the pathogenesis of infertility associated with endometriosis. Use of drugs such as etanercept, a TNF- receptor immunoglobulin fusion protein which inhibits TNF- activity, showed in an animal study to reduce the severity of the disease, and the size of endometriotic foci. TNF- blockers were recommended as a possible new line of therapy for endometriosis. Our case involved a 35-year-old Para 0, with rheumatic arthritis and stage 4 endometriosis. After 6 years of constant use of etanercept, she showed no improvement of endometriosis as demonstrated at laparoscopy. However, she underwent a successful IVF after the first attempt. TNF--blocker medications might not be beneficial for patients with advanced endometriosis. However, we cannot exclude the possible effect of these medications on early-stage endometriosis, and further study is required. Some of the immunologic abnormalities in the pelvis of patients with endometriosis could be the consequence of the disease and not the cause, and possibly suppression of immune cells and their products may not have a major effect on endometriotic lesions at an advanced stage. This also could explain why suppression of TNF- showed no effect on infertility. However, use of TNF--blockers before IVF might increase the success rate in advanced endometriosis.
Key words: endometriosis/medical therapy/tumor necrosis factor
|
Introduction |
|---|
|
TopAbstractIntroductionCase reportDiscussionConclusionReferences |
|---|
Endometriosis, the presence of functional endometrium outside the uterine cavity, is a common disease, causing abdominal pain, dysmenorrhoea, dyspareunia and infertility in about 10% of the female population. The pathophysiology of infiltrating endometriosis remains controversial and still an open field of research, but the classical theories about retrograde implantation of endometrium from menstruation and metaplasia of the coelomic epithelium are still current. A series of recent observations of increased macrophage activity and deviations in the complement system suggest, however, that special immunological factors also play a causal role. Dynamic interplay among cytokines may contribute to a favourable microenvironment for the implantation of endometrial cells and the progression of the disease. It has previously been shown that interleukin (IL)-6, IL-8 and tumour necrosis factor-
(TNF-) are significantly elevated in the peritoneal fluid of women with endometriosis (Bedaiwy et al., 2002
; Richter et al., 2005).
TNF- is a secretory factor of active macrophages and has potent inflammatory, cytotoxic and angiogenic properties that are known to be increased in the peritoneal fluid of women with endometriosis compared with women without endometriosis (Bedaiwy et al., 2002; Richter et al., 2005), with a direct correlation between TNF- concentrations and the degree of disease (Richter et al., 2005). Observations that TNF- increases adherence of cultured stromal cells to mesothelial cells suggest that it can facilitate adhesion of ectopic endometrium in the pelvis and also stimulate proliferation of endometrial cells. TNF- enhances metalloprotease expression, thus making endometrial cell invasion easier. It also stimulates angiogenesis by regulating expression of IL-8 (Zhang et al., 1993). However, recent studies were unable to confirm the hypothesis that TNF-, IL-6 and IL-8 promote the in vitro adhesion between endometrial epithelial cells and mesothelial cells (Debrock et al., 2006).
Therapies that interfere with the action of TNF-, such as the chimeric anti-TNF- monoclonal antibody, infliximab or the TNF- receptor immunoglobulin fusion protein, etanercept, have been recommended as possible new lines of therapy for endometriosis. Recent studies showed that etanercept effectively reduces the amount of spontaneously occurring active endometriosis in the baboon (Barrier et al., 2004). No clinical study has been reported on TNF--blocker efficacy on human’s endometriosis. We report a case of severe endometriosis, with 6 years’ constant use of etanercept for the treatment of rheumatic arthritis, and we review the impact of this treatment on endometriosis.
|
Case report |
|---|
|
TopAbstractIntroductionCase reportDiscussionConclusionReferences |
|---|
A 35-year-old Para 0 with a history of rheumatic arthritis and endometriosis presented with infertility. Her BMI was 22.2 kg m–2. The diagnosis of rheumatic arthritis was made at age of 21, and since then, she has been constantly receiving multiple medical therapy regimens related to her severe arthritis, including different generations of non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying antirheumatic drugs (DMARDs). Prednisone has also been used constantly since the age of 24. Leflumide, which is a DMARD agent that affects macrophage activity and decreases TNF-
production, was used by the patient for 4 years and then was switched to rofecoxib at age 29.
Given her refractory joint stiffness and pain, etanercept (Enbrel, 2004; Wyeth-Ayerst/Immunex Inc, Seattle, WA, USA) was added to her medical regimen by her rheumatologist at the age of 29. The patient reported good symptom relief by taking 25-mg injection, s.c. twice a week, of etanercept and continued it for 5 years before a dose increase was required 6 months before the last surgery. The dose was increased to 25 mg s.c. three times weekly.
Her menarche was at 14, and she initially had regular periods without any dysmenorrhea. However, she developed some menstrual cycle disorder at age 22, and she was placed on oral contraceptives (OCP) for 10 years. She denied any appreciable pelvic pain or dysmenorrhea while she was on OCP.
At the age of 32, she stopped taking OCPs to get pregnant. Immediately after stopping her OCP, she started experiencing some dysmenorrhea. After 1 year of unsuccessful attempt for pregnancy, she underwent a diagnostic laparoscopy. Severe endometriosis (stage 4) was confirmed with a score of 42 based on American Fertility Society’s (AFS) Revised Classification of Endometriosis Scoring System (ASRM, 1996). Endometiotic lesions were ablated with the use of laser and bipolar cautery. Also, the presence of typical endometrioma on the left ovary was reported, and the cyst was removed. Of note, this surgery was performed after 4 years’ constant use of etanercept.
The patient’s infertility problem remained unresolved for the next 2 years, and during these years, the patient was still using etanercept and prednisone; however, rofecoxib was switched to celecoxib. Her periods were regular and ovulatory with moderate pelvic pain, which was aggravated during her periods. At age 35, the patient decided to proceed with IVF. A screening ultrasound showed bilateral ovarian complex cyst for which she underwent a second laparoscopic surgery at the Cleveland Clinic Foundation (CCF). At the time of the second surgery, she had been on the etanercept for almost 6 years. During this surgery, severe endometriosis (stage 4) was noted with a score of 48 based on AFS Scoring System (ASRM, 1996). Bilateral ovarian endometriomas were found (Figures 1 and 2). Figure 3 demonstrates microscopic view of tissue obtained from the right pelvic sidewall’s endometriotic lesion. All visible lesions were microscopically excised. The patient was started on leuprolide acetate post-op. Two months after her second laparoscopic surgery, she underwent a successful IVF and is presently pregnant with twins. The patient stopped taking etanercept and celecoxib 4 weeks after conception.
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionCase reportDiscussionConclusionReferences |
|---|
Unfortunately, all of the established medical treatments of endometriosis suppress ovulation. Furthermore, some standard forms of medical therapy, such as GnRH agonists, are associated with significant side effects and possible long-term osteoporosis (Olive, 2003
). Furthermore, recurrence of pain is common after discontinuing GnRH-agonist therapy. Data showed the median time to recurrence of pain was 5.2 months for patients treated with GnRH agonists and 6.1 months for patients treated with danazol (Miller et al., 1998).
Etanercept (Enbrel, 2004; Wyeth-Ayerst/Immunex Inc, Seattle, WA, USA) is one of the new generation candidates for the treatment of endometriosis without interference with ovulation. Etanercept is a s.c. administered novel fusion protein which inhibits TNF- activity by competitively binding to it and preventing interactions with its cell-surface receptors. Etanercept was approved by the US Food and Drug Administration (FDA) for the treatment of multi-drug resistant rheumatoid arthritis in 1998. The most frequent adverse reactions are headaches, injection site reaction and respiratory tract infection. The most serious are allergic reactions and reactivation of tuberculosis. Etanercept may affect defenses against infections and should be used with caution in patients predisposed to infection. The drug is considered a category B drug, that is, there seems to be no evidence of fetal risk in humans.
Although etanercept has proven effective in reducing endometriotic lesions in animal models (Barrier et al., 2004), our case showed lack of benefit of etanercept or other drugs targeting macrophage activity such as leflumide in a human model with an advanced stage of endometriosis. As we can see in this patient, 6 years’ constant use of etanercept had little or no effect on the progression of endometriosis.
At the time of the first exploration of the patient’s pelvis, severe endometriosis with AFS score of 42 was noted after 4 years’ use of etanercept. It should be noted that before starting the etanercept, the patient had been on leflumide for an additional 4 years. Leflumide is a DMARD agent that affects macrophage activity and decreases TNF-. The second exploration, 15 months after the first one, showed aggravation of the disease (from AFS score of 42 to 48) despite increased dose of etanercept during this period of time. An important limitation in interpreting the results of medical therapy in patients with advanced disease is the use of the AFS Scoring System. A high AFS score may be associated with extensive adhesions. It is unlikely that etanercept or any TNF blocker would alter established adhesions. However, in this case, the advanced endometriosis was associated with active endometriosis lesions in the ovary and peritoneum as shown in the figures and histology, and the use of multiple anti-inflammatory drugs including etanercept and leflumide did not have an effect.
The patient’s symptoms (dysmenorrhea, deep dyspareunia and intermenstrual pain) were increased, right after stopping birth-control pills in spite of using high-dose anti-inflammatory drugs and etanercept. It is to be noted that the OCP was successful in controlling the symptoms without any measurable affect on the disease progress. This implies that the suppression of a menstrual cycle without the suppression of the disease is effective in relieving symptoms.
It is unclear what the exact cause of the endometriosis-related infertility is. Recent studies showed that the elevation of peritoneal fluid cytokine levels in patients with endometriosis might play a role in the pathogenesis of infertility associated with endometriosis. Evidence suggests that abnormal production of TNF- in endometriosis is responsible in part for the associated infertility through its effect on sperm motility, function and development. A recent study also showed the use of infliximab in vitro may reverse the toxic effects induced by TNF- in human spermatozoa (Said et al., 2005). Although the use of anti-TNF- in our case did not improve the spontaneous fertility of the patient, she underwent a successful IVF in just one cycle. The impact of the use of etanercept on IVF success for patients with advanced endometriosis needs further investigation.
Estrogen has been shown to stimulate vascular endothelial growth factor (VEGF) production by non-activated and activated peritoneal fluid macrophages, which are more frequently found in patients with endometriosis (McLaren et al., 1996). Both the eutopic endometrium of women with endometriosis and the ectopic endometrial tissue may have the inherent capability to produce estrogen locally, as they were found to express P450 aromatase (Noble et al., 1996). Estrogens can indirectly up-regulate the synthesis and secretion of a potent monocyte chemotactic and activating factor by stromal and epithelial cells isolated from endometriosis lesions. There is also synergistic stimulatory action between estrogen and the pro-inflammatory cytokine IL-1 exerted at the level of ectopic endometrial cells. This suggests that estrogen may contribute to the up-regulation of an immunologic reaction of endometriotic tissue not only by an endocrine pathway but also by a paracrine mechanism (Ali Akoum et al., 2000). This integration of the immune to endocrine system suggests that further research into the possible role of anti-inflammatory agents in treating endometriosis requires this concept to be explored further.
Although the lack of response to the TNF- blocker medication does not diminish the potential role of immunologic alteration as an initiating factor for endometriosis, this case may reinforce a critical role of estrogen on the pathophysiology of endometriosis and more specifically on the maintenance of disease. This case also suggests that, once endometriosis is established, and especially with advanced disease, anti-inflammatory agents may have little or no effect on the progression of the disease and might be considered just for symptom relief. However, we cannot exclude the possible effect of this medication on early-stage endometriosis, given the data on inhibitory effect of TNF- blocker on animals.
|
Conclusion |
|---|
|
TopAbstractIntroductionCase reportDiscussionConclusionReferences |
|---|
TNF-
-blocker medications might not be beneficial for patients with advanced endometriosis. However, we cannot exclude the possible effect of these medications on early-stage endometriosis, and further study is required. The immunologic abnormalities in the pelvis of patients with established endometriosis could be the consequence of the disease and not the cause. Suppression of TNF- showed no effect on infertility in our case; however, use of etanercept before IVF might increase the success rate in advanced endometriosis.
|
References |
|---|
|
TopAbstractIntroductionCase reportDiscussionConclusionReferences |
|---|
Ali Akoum, Christine Jolicoeur, Annie Boucher. (2000) Estradiol amplifies interleukin-1-induced monocyte chemotactic protein-1 expression by ectopic endometrial cells of women with endometriosis. J Clin Endocrinol Metab 85:2896–904.
ASRM. (1996) Revised American Society for Reproductive Medicine Classification of endometriosis. Fertil Steril 67:5817–821.
Barrier BF, Bates GW, Leland MM, Leach DA, Robinson RD, Propst AM. (2004) Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril 81:Suppl 1, 775–779.
Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, Agarwal A, et al. (2002) Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 7:2426–431.
Debrock S, De Strooper B, Vander Perre S, Hill JA, D’Hooghe TM, et al. (2006) TNF-alpha, interleukin-6 and interleukin-8 do not promote adhesion of human endometrial epithelial cells to mesothelial cells in a quantitative in vitro model. Hum Reprod 21:3605–609.
Enbrel®. (2004) (Immunex Corporation, Thousand Oaks, CA) (etanercept) Prescribing Information.
McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Muller KH, Sharkey AM, Smith SK. (1996) Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest 98:2482–489.[Web of Science][Medline]
Miller JD, Shaw RW, Casper RF, Rock JA, Thomas EJ, Dmowski WP, Surrey E, Malinak LR, Moghissi K. (1998) Historical prospective cohort study of the recurrence of pain after discontinuation of treatment with danazol or a gonadotropin-releasing hormone agonist. Fertil Steril 70:2293–296.[CrossRef][Web of Science][Medline]
Noble LS, Simpson ER, Johns A, Bulun SE. (1996) Aromatase expression in endometriosis. J Clin Endocrinol Metab 81:1174–179.[Abstract]
Olive DL. (2003) Medical therapy of endometriosis. Seminars in Reproductive Medicine 21:2209–222.[CrossRef][Web of Science][Medline]
Richter ON, Dorn C, Rosing B, Flaskamp C, Ulrich U, et al. (2005) Tumor necrosis factor alpha secretion by peritoneal macrophages in patients with endometriosis. Arch Gynecol Obstet 271:2143–147.[CrossRef][Medline]
Said TM, Agarwal A, Falcone T, Sharma RK, Bedaiwy MA, Li L, et al. (2005) Infliximab may reverse the toxic effects induced by tumor necrosis factor alpha in human spermatozoa: an in vitro model. Fertil Steril 83:61665–1673.[CrossRef][Web of Science][Medline]
Zhang RJ, Wild RA, Ojago JM, et al. (1993) Effect of tumor necrosis factor-alpha on adhesion of human endometrial stromal cells to peritoneal mesothelial cells: an in vitro system. Fertil Steril 59:61196–1201.[Web of Science][Medline]
Submitted on February 20, 2006; resubmitted on April 19, 2006; accepted on April 25, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P.R. Koninckx, M. Craessaerts, D. Timmerman, F. Cornillie, and S. Kennedy Anti-TNF-{alpha} treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial Hum. Reprod., September 1, 2008; 23(9): 2017 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Z. Zhao, D. R. Nyholt, L. Le, S. Thomas, C. Engwerda, L. Randall, S. A. Treloar, and G. W. Montgomery Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample Hum. Reprod., September 1, 2007; 22(9): 2389 - 2397. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||