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Research Article |
Leuven University Fertility Center,4 Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, 3000 Leuven, Belgium
Serono Reproductive Biology Institute,5 Rockland, Massachusetts 02370
Institute of Primate Research,6 00502 Karen-Nairobi, Kenya
ABSTRACT
Endometriosis is associated with chronic inflammation, including an increased macrophage activity with increased secretion of cytokines, such as tumor necrosis factor (TNF) or TNF superfamily member 2, previously known as TNF
. In the present study, we tested the hypothesis that recombinant human TNFRSF1A (r-hTBP1) can inhibit the development of endometriotic lesions in the baboon, an established model for the study of endometriosis. Endometriosis was induced using intrapelvic injection of menstrual endometrium in 20 baboons with a normal pelvis. In the first part of the study, 14 baboons were randomly assigned to subcutaneous treatment with r-hTBP1, placebo, or GnRH antagonist (positive control). In the second part of the study, menstrual endometrium from 6 baboons was randomly incubated with either PBS or r-hTBP1 before intrapelvic seeding. Video laparoscopy was performed 25 days later to document the number, surface area, and estimated volume of endometriotic lesions and adhesions; to calculate the revised American Fertility Society (rAFS) score and stage; and to confirm the histological presence of endometriosis. In the first part, baboons treated with r-hTBP1 or with Antide (Bachem) had a lower endometriosis rAFS score, a lower surface area and estimated volume of peritoneal endometriotic lesions, and a lower histological confirmation rate compared with controls. Because of less adnexal and cul-de-sac adhesions, the number of baboons with endometriosis of stage II, III, or IV was lower among baboons treated with r-hTBP1 or Antide than among controls. In the second part, the surface area of endometriotic lesions was lower, and less severe endometriosis was observed in r-hTBP1-treated baboons. No hypoestrogenic effects were observed in baboons treated with r-hTBP1. In conclusion, r-hTBP1 can effectively inhibit the development of endometriosis without hypoestrogenic effects in baboons.
cytokines, gonadotropin-releasing hormone, immunology, ovulation, steroid hormones
INTRODUCTION
Endometriosis is a common gynecological disorder, estimated to occur in 7–15% of reproductive age women and in up to 50% of patients with pelvic pain or infertility [1]. Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity; the most frequent sites of implantation are the pelvic organs and the peritoneum. Endometriosis is an estrogen-dependent disease and only rarely is observed before menarche and in postmenopausal women. Endometriosis can vary from minimal (i.e., only a few peritoneal lesions) to severe disease (i.e., large ovarian endometriotic cysts with dense adnexal adhesions and/or deep rectovaginal endometriotic nodules). Most studies in women and nonhuman primates suggest that endometriosis is a progressive disease [2], but precisely why endometriosis occurs or is more progressive in some women than in others is not known.
The hypothesis that endometriosis is a consequence of retrograde menstruation and intrapelvic implantation of endometrial tissue [3] is widely accepted. Both retrograde menstruation and intrapelvic injection of endometrium are associated with intrapelvic inflammation [4]. In women with endometriosis, it has been reported that activated macrophages, endometriotic lesions, and mesothelial cells of the peritoneum secrete cytokines, such as tumor necrosis factor (TNF superfamily member 2, previously known as TNF) and interleukin (IL)-1ß. In turn, these cytokines modulate other cytokines and chemokines, such as IL-8, CCL2 (also known as monocyte chemotactic protein or MCP1), and CCL5 (also known as RANTES [Regulated on Activation, Normal T-cell Expressed and Secreted]; for review, see [5]). In addition to regulating the above cytokines/chemokines, increased levels of TNF stimulate synthesis of prostaglandin endoperoxidase synthase-2 (also known as COX-2) in the endometriotic implant. This enzyme increases levels of prostaglandin E2, which is the most potent known stimulator of aromatase in endometriotic stromal cells. Aromatase catalyzes the conversion of androstenedione to estrogens in the human ovary and placenta in premenopausal women. In postmenopausal women, estrogen formation takes place in extraovarian sites, such as the skin and adipose tissue, where TNF, IL-6, and IL-11 regulate aromatase expression through use of an alternative promoter. Thus, a positive-feedback loop for local estrogen production is established [6].
Endometriosis may not be a single disease entity but, rather, a collection of pathological alterations involving many hormonal and immunological factors. The multiplicity of factors involved in this estrogen-dependent disease may explain the relative ineffectiveness of medical therapy and the recurrence of peritoneal endometriosis soon after cessation of conventional medical or surgical therapy [7, 8]. A need exists for new, effective methods to prevent and treat endometriosis. We hypothesize that inhibition of the pelvic inflammation associated with endometriosis can prevent the development of endometriotic lesions and endometriosis-related adhesions and, therefore, may decrease the pain and subfertility associated with endometriosis. Specifically, we proposed that neutralization of TNF activity with recombinant human TNFRSF1A (r-hTBP1), the soluble form of TNF receptor type 1 (TNFRIA), has the potential of significantly abrogating the chronic inflammatory state associated with endometriosis and enhancing the therapeutic efficacy of conventional hormone therapies. Preliminary studies in rats suggest that r-hTBP1 (and Antide) may reduce experimentally induced endometriotic-like foci [9]. Rodents, which provide an excellent first-line model, are not the ideal choice for studying the pathogenesis of endometriosis, especially compared to nonhuman primates. During the past 10 years, the baboon has been developed as the best model for studying the pathogenesis and spontaneous evolution of endometriosis and endometriosis-associated subfertility [10].
A recent study in baboons with spontaneous endometriosis showed that inhibition of TNF activity can reduce the number of existing red lesions [11]. To what extent anti-TNF medication also can prevent endometriosis, however, is not known. Therefore, the objective of the present study was to test the hypothesis that selective blockade of TNF activity can prevent the establishment of endometriotic lesions in the baboon.
MATERIALS AND METHODS
Animals and Laparoscopy
Twenty female baboons (Papio anubis) of proven fertility (weight, 10–17 kg) were studied at the Institute of Primate Research. All animals were tested, and only those that were negative for common pathogens (bacterial and viral infections as well as parasites) were used in the present study. Before study initiation, each animal had undergone at least one menstrual cycle in captivity. Animals were housed in single cages. Each baboon was screened by video laparoscopy during the midluteal phase (
Day 25) of the cycle, as described previously [12]. After the screening laparoscopy, the animals were allowed to recover for one menstrual cycle to allow any subclinical pelvic inflammation caused by the screening laparoscopy to return to baseline, as demonstrated previously [13]. All animal procedures and care were conducted in accordance with the Institute of Primate Research standard operating procedures. The Institutional Scientific Evaluation and Review Committee and the Animal Care and Use Committee of Institute of Primate Research approved the present study.
Induction of Endometriosis
On the first or second day after onset of the second menses following the screening procedure, endometrial tissue was extracted from each baboon by uterine curettage and fragmented through an 18-gauge needle. During laparoscopy, a standardized amount of the resulting paste (1000 ± 250 mg, mean ± SD) was seeded autologously onto various peritoneal sites (uterosacral ligaments, uterovesical fold, pouch of Douglas, ovaries, and fossa ovarica), as described previously [12]. A second video laparoscopy was performed 25 days later (D25 laparoscopy) to document the number, surface area, and volume of the endometriotic lesions to determine the presence, localization, and extent of adhesions and to calculate the revised American Fertility Society (rAFS) score and stage of disease according to the revised classification system of the American Society for Reproductive Medicine (ASRM) [14]. A single investigator (S.C.) performed all laparoscopies and made a detailed pelvic map with systematic photographic and video documentation of the pelvis during each laparoscopy. Adhesions involving ovary, fallopian tube, and cul-de-sac (ASRM adhesions) were graded according to the revised classification system of the ASRM [14]. Other adhesions that were not related to ovary, fallopian tube, and cul-de-sac and that were observed between individual peritoneal endometriotic lesions and pelvic organs were recorded separately. The surface area of an endometriotic lesion (and of an endometriotic lesion-related adhesion) was determined by multiplying length (mm) by width (mm) or, in cases of a circular lesion, by using the formula 
x r2. The volume of a lesion was estimated by multiplying the surface area (mm2) by depth (mm). At least one biopsy sample of endometriotic lesions was taken from each baboon for pathologic confirmation of the disease. Statistical analysis was done using Mann-Whitney U-test, Kruskal-Wallis, chi-square, and Fisher exact tests.
For each baboon, changes in the pattern of the menstrual and the perineal cycle were monitored carefully during the present study. In baboons, perineal inflation and deflation correspond with the follicular and the luteal phase, respectively. Ovulation occurs approximately 3 days before perineal deflation, with a margin of error of 2 days [15]. Daily perineal inspection in each baboon allowed determination of the onset of perineal inflation (start of the perineal cycle, corresponding to initiation of the follicular phase) and perineal deflation during the total duration of the study period.
Blood samples for determination of estradiol and progesterone were obtained in each baboon at the time of the induction laparoscopy and again at the D25 laparoscopy.
Histology
Biopsies were formalin-fixed and embedded in paraffin blocks, sectioned (thickness, 5 µm), stained with hematoxylin-eosin, and examined using a light microscope. Histological confirmation of the clinical diagnosis of endometriosis was defined as the presence of both endometrial glands and stroma in biopsy specimens of suspected endometriotic lesions.
Drug Treatment
The r-hTBP1 (lot BS05) used in the present study is a genetically engineered version of TNFRSR1A (TNF-receptor superfamily member 1A) and was supplied by Serono. A GnRH antagonist, Antide (batch 9001), was used as a positive control and was supplied by Bachem. Antide was chosen because of work done previously with r-hTBP1 in the rat model for endometriosis [9]. The PBS was made locally in the laboratories at the Institute of Primate Research.
In the first part of the study, using r-hTBP1 s.c., 14 baboons were randomly assigned to treatment with either PBS as placebo (n = 4; 1–2 ml s.c. on Days 0, 2, 4, 6 and 8 after induction), GnRH antagonist (n = 5; Antide, 2 mg/kg s.c. on Days 0, 3, 6, and 9 after induction), or r-hTBP1 (n = 5; 1 mg/kg s.c. on Days 0, 2, 4, 6, and 8 after induction). All s.c. injections were given during a 10-min period of general anesthesia, induced by an i.m. injection of 1 mg/kg of ketamine (Ketamin; Sanofi) and 0.5 mg/kg of xylazine (Xylalin; Apharmo).
In the second part of the study, using r-hTBP1 ex vivo, menstrual endometrium from six baboons was randomly incubated for 30 min with either PBS (n = 3, 1 ml) or r-hTBP1 (n = 3, 0.1 mg) before intrapelvic seeding. All animals were killed at the end of the present study.
Hormone Assays
Both serum estradiol and progesterone levels were analyzed on a fully automated, random access immunoanalyzer (Bayer-Technikon Immuno 1) using a heterogeneous, competitive magnetic separation assay. The analytical sensitivity of the estradiol assay was 5 pg/ml for estradiol and 0.1 ng/ml for progesterone. The functional sensitivity of the estradiol assay was 15 pg/ml, with functional sensitivity defined as the analyte concentration in serum at which a total imprecision of a 20% coefficient of variation (CV) is observed. The within-run CV was less than 5% for both the estradiol and progesterone assays. All samples were performed in triplicate with the same lot of kits on the same day.
Statistical Analysis
Data were analyzed using Mann-Whitney U-test, Kruskal-Wallis, paired Wilcoxon, chi-square, and Fisher exact tests. A level of P < 0.05 was considered to be statistically significant (StatView program).
RESULTS
Endometriosis
The presence of endometriosis was histologically confirmed in all baboons. The number, surface area, and estimated volume of lesions, along with the rAFS score and stage of disease, are shown in Table 1.
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In the first part of the present study, a lower rAFS score (P = 0.002, Kruskal-Wallis test) was observed in baboons treated with r-hTBP1 (all score 4) or with Antide (all score 4) than in primates treated with PBS (median, 13.5; range, 6–38). A strong trend (P = 0.06, Mann-Whitney test) toward decreased surface area of endometriotic lesions was observed in both treatment groups when compared to the PBS group. The median estimated volume (mm3) of endometriotic lesions also was significantly lower (P = 0.03, Mann-Whitney U-test) in baboons treated with r-hTBP1 (median, 37; range, 5–199) or Antide (median, 77; range, 10–238) than in those treated with PBS (median, 472; range, 98–1468).
Adhesions involving ovary, fallopian tube, and cul-de-sac (adhesions included in ASRM staging) were completely absent in all baboons treated with either r-hTBP1 or Antide. Consequently, the number of baboons with endometriosis of stage II, III, or IV was lower in baboons treated with r-hTBP1 (all stage I, P = 0.008, Fisher exact test) or with Antide (all stage I, P = 0.008, Fisher exact test) than in baboons treated with PBS (n = 2 with stage II, n = 2 with stage III). The median surface area of adhesions (unrelated to ASRM scoring or staging) between individual peritoneal endometriotic lesions and pelvic organs, however, varied between 0 and 434 mm2 and was comparable in the three groups (data not shown). The macroscopic appearance of endometriotic lesions and adhesions in the three treatment groups is shown in Figure 1. In the second part of the present study, the median surface area (mm2) of endometriotic lesions was lower (P = 0.05, Mann-Whitney U-test) in r-hTBP1 treated baboons (median, 25; range, 14–49) than in PBS-treated controls (median, 86; range, 58–95). Furthermore, less severe endometriosis was observed in the 3 r-hTBP1 treated baboons (all stage I) than in the 3 PBS-treated baboons (n = 2 with stage IV, n = 1 with stage I).
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Histology
The histological confirmation rate of endometriosis (Table 2) was significantly lower (P = 0.043, chi-square test) in biopsy specimens obtained from baboons treated s.c. with r-hTPB1 or Antide (23/39, 59%) than in those obtained from animals treated s.c. with PBS (19/22, 86%). The histological confirmation rate according to lesion phenotype was comparable in the 3 groups (Table 2).
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Effect of Interventions and Treatment on Perineal/Menstrual Cycle and on Serum Steroid Levels
After the induction laparoscopy, 12 (1 of the r-hTBP1 s.c. group, all 5 of the Antide s.c. group, 3 of the PBS s.c. group, 1 of the r-hTBP1 ex vivo groups, and 2 of the PBS ex vivo group) of the 20 baboons had a delay of at least 4 days before they resumed their perineal cycle. At the D25 laparoscopy, based on perineal inspection, 6 baboons (1 in the r-hTBP1 s.c. group, 3 in the Antide s.c. group, and 2 in the PBS s.c. group) had failed to resume their cycle, 9 baboons were still in the follicular phase, and only 5 baboons (1 from the r-hTBP1 s.c. group, 1 from the PBS s.c. group, 2 from the r-hTBP1 ex vivo group, and 1 from the PBS ex vivo group) had reached the luteal phase. In the first part of the present study (s.c. treatment), the median number of cycling days between the induction laparoscopy and the D25 laparoscopy was significantly lower in the baboons treated with Antide (0 days) than in those treated with r-hTBP1 (25 days, P = 0.05, Mann-Whitney U-test) but not significantly lower than those observed in primates injected with PBS (4.5 days, P = 0.2, Mann-Whitney U-test). After the treatment cycle, baboons treated s.c. with r-hTBP1 and with PBS had the first day of their subsequent menstrual or perineal cycle within a median of 36 and 69 days, respectively, after the last s.c. injection (P = 0.1, Mann-Whitney test). In the second part of the study (ex vivo treatment), the median number of cycling days between induction laparoscopy and D25 laparoscopy was comparable in baboons with endometrium that underwent ex vivo exposure to either r-hTBP1 or PBS before induction.
Serum estradiol levels were equivalent in all groups (median, 30–32 pg/ml) at induction laparoscopy in both parts of the present study. At the D25 laparoscopy, serum estradiol levels appeared to be elevated but were not significantly higher in the r-hTBP1 group (median, 35 pg/ml) than in the Antide group (median, 21 pg/ml, P = 0.08, Mann-Whitney U-test) or the PBS control group (median, 26 pg/ml; P > 0.1, Mann-Whitney test) (Fig. 2). In the Antide group, 2 baboons had estradiol levels less than 15 pg/ml (below the sensitivity level of our assay) at the D25 laparoscopy. In the first part of the study, r-hTBP1-treated baboons had a marginally higher serum estradiol level at the D25 laparoscopy (median, 35 pg/ml) than at the induction laparoscopy (median, 30 pg/ml), although the difference did not reach statistical significance (P = 0.07, paired Wilcoxon test). In the Antide-treated group, a nonsignificant trend toward lower median estradiol levels at the D25 laparoscopy (21 pg/ml) than at the induction laparoscopy (31 pg/ml) was observed. In baboons receiving PBS s.c., no significant differences were found in median estradiol levels at D25 laparoscopy and at induction laparoscopy (Fig. 2).
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Progesterone levels rarely were demonstrable in the majority of baboons at both the induction and D25 laparoscopy (data not shown). Two of 5 baboons that were in the early luteal phase at D25 laparoscopy had progesterone levels compatible with the early luteal phase (2.3 and 4.3 ng/ml, respectively).
DISCUSSION
The present study was performed in baboons, an established model for the study of endometriosis [10], because the results of earlier studies in rats with induced ectopic endometrium [9] had supported our hypothesis that administration of r-hTBP1 would prevent, or at least interfere with, the establishment of endometriosis. Animal models are needed for studying endometriosis, because properly controlled studies are not possible in humans because of ethical and practical considerations. Rodent models [16] are not the optimal choice for the study of endometriosis, because they lack spontaneous endometriosis and a menstrual cycle. Surgical induction of ectopic endometrial lesions in rodents also may cause surgery-related adhesions [10]. The main advantage of the rat model [16], however, is its low cost relative to nonhuman primates; therefore, it has been used as a first-line model to test the potential efficacy of new drugs in the treatment of endometriosis, including r-hTBP1 [9]. Baboons offer a more suitable model for the study of endometriosis, because phylogenetically, they are very similar to humans and have almost identical reproductive anatomy and physiology, an accessible cervix (allowing transcervical endometrial biopsies in parous baboons), peritoneal fluid in the pouch of Douglas, and spontaneous endometriosis [10]. Furthermore, moderate to severe experimental endometriosis can be induced successfully by the intrapelvic injection of menstrual endometrium [12]. In addition, the baboon is a larger primate than the rhesus or cynomolgus monkey, allowing repetitive blood and peritoneal fluid sampling and complex experimental surgery [10].
Delay in the resumption of cyclicity after the induction laparoscopy occurred in 60% of baboons and may be explained by the accumulated stress caused by general anesthesia, surgery, and s.c. injections (each time combined with a 10-min period of general anesthesia). Although the number of baboons studied in our project are small, the fact that Antide-treated baboons constituted 50% of the 6 baboons that had not started their cycle at the D25 laparoscopy suggests that Antide treatment caused a longer suppression of cyclicity than the other treatment modalities, as could be expected from a GnRH antagonist [17].
The serum levels of estradiol and progesterone in the present study were comparable to the levels expected during the follicular phase [18]. In baboons, estradiol levels are between 30 and 50 pg/ml throughout the menstrual cycle except for 3 days preceding ovulation, when they increase to 200–300 pg/ml. In contrast with humans, no luteal-phase peak in serum estradiol levels occurs in baboons [18]. Progesterone secretion in baboons is similar to that in humans, but the maximal luteal-phase progesterone concentration is only 70% of that found in women. In a typical 33-day ovulatory cycle in baboons, progesterone levels increase to 10 ng/ml between Cycle Days 20 and 25 and gradually decrease to 7 ng/ml by Cycle Day 30, followed by a rapid decline to nondetectable levels by Cycle Day 33 [18]. In view of the delay in the resumption of menstrual and perineal cyclicity, it is not surprising that only 5 baboons in the present study were in the early luteal phase by Day 25 and that progesterone levels were only detectable in 2 of these animals.
In the present study, r-hTBP1 was as effective as Antide in partially preventing the development of endometriotic lesions and in fully preventing the establishment of pelvic adhesions in ovary, fallopian tube, and cul-de-sac. This observation was supported further by the lower histological confirmation rate in biopsies from treated baboons compared to those from controls. Neither Antide nor r-hTBP1 fully prevented the development of endometriosis in the present study, which may be related to the excessive amount of menstrual endometrium used for the induction of endometriosis, which does not represent the normal amount of retrograde menstruation in baboons [12, 19]. Therefore, it may not be surprising that 4 of 7 baboons from the PBS control group (s.c. or ex vivo treatment) had endometriosis of stage III or IV. Thus, whereas r-hTBP1 and Antide did not appear to prevent fully the onset of endometriosis in all our animals, baboons developing endometriosis had only limited peritoneal disease (rAFS stage I endometriosis) without adhesions, as determined by laparoscopy.
An intriguing observation in the present study is the absence of ovarian, tubal, and cul-de-sac adhesions in r-hTBP1- and Antide-treated groups compared to PBS controls, yet no difference was observed in the median surface area of adhesions between individual peritoneal lesions and pelvic organs among these 3 groups. We speculate that the creation of a hypoestrogenic or an anti-inflammatory pelvic milieu inhibits the general adhesion formation between reproductive organs at the moment of pelvic injection of menstrual endometrium but not the later, secondary development of adhesions arising from endometriotic lesions.
The lower histological confirmation rate of endometriosis in r-hTBP1- and Antide-treated groups compared to the control group can be explained by several factors. First, it is possible that macroscopic lesions in these groups were smaller (supported by the overall reduced total volume and surface area of endometriosis in these groups) and that is was harder to obtain a reliable biopsy specimen from these lesions. Second, it is possible that during r-hTBP1 and Antide treatment, microscopic endometriotic glands or stroma were inactivated and, consequently, disappeared but that the tissue still appeared with the macroscopic phenotype of an endometriotic lesion, also determined by fibrosis and angiogenesis.
The clinical efficiency of r-hTBP1 and Antide is unlikely to be explained by the same mechanism. Antide, a GnRH antagonist, has been tested at a dose of 2 mg/kg on Days 0 (proestrus), 3, 6, and 9 in the rat model for endometriosis and induced a temporary hypoestrogenic status up to 9 days after the last injection. Estradiol levels returned to normal 15 to 21 days after the last injection [17]. These data in rats may explain why estradiol levels in the present study were marginally, but not significantly, lower in the Antide-treated baboons at the D25 laparoscopy than at the induction (Day 0) laparoscopy. It can be hypothesized that, like in rats, the hypoestrogenic status in Antide-treated baboons only lasted up to 9 days (Cycle Day 18) after the last Antide injection on Cycle Day 9, with a gradual return to normal estradiol levels by Day 25. At the same time, it is important to realize that rat estrous cycles are 4–5 days in duration. Therefore, return to normal estradiol levels in 15–21 days postinjection in the rat would be equivalent to 4 or 5 estrous cycles, whereas this same duration in time would be within only 1 menstrual cycle of the baboon. On the other hand, a significant hypoestrogenic effect of Antide in the present study also is suggested by the lower median number of cycling days between induction laparoscopy and D25 laparoscopy in the Antide-treated group than in the r-hTBP1-treated group.
Related to this temporary hypoestrogenic effect of Antide, suppression of ectopic endometriotic lesions in rats was observed only up to 15 days after the last Antide injection, and implant size spontaneously returned to pretreatment values 21 days after the last Antide injection [20]. These data may explain why a maximal suppression effect of endometriotic lesions was still observed in Antide-treated baboons at the D25 laparoscopy (16 days after the last Antide injection) even though estradiol levels were, at that moment, returning to normal values.
Unlike Antide, the clinical effectiveness of r-hTBP1 observed in the present study cannot be explained by hypoestrogenism. First, r-hTBP1-treated baboons had a higher median number of cycling days between induction laparoscopy and D25 laparoscopy compared to that in Antide-treated animals. Second, r-hTBP1-treated baboons did not show a significant reduction but, rather, a marginal increase in estradiol levels at D25 laparoscopy compared to the induction laparoscopy. Third, clinical studies evaluating the efficacy and side effects of TNF inhibitors or TNF-receptor inhibitors in patients with Crohn's disease or ulcerative colitis have, to our knowledge, so far not reported any significant effect on the menstrual cycle or on ovulation [21, 22]. Fourth, r-hTBP1 is considered to be devoid of any reproductive toxic effects on mice and their offspring (unpublished data). Similarly, treatment with infliximab, a chimeric monoclonal IgG1 antibody against TNF, did not cause maternal toxicity, embryotoxicity, or teratogenicity in mice. Furthermore, spontaneous pregnancies without obvious adverse outcome have been reported in women exposed to infliximab [23]. Therefore, we hypothesize that r-hTBP1 could be used in the prevention and treatment of endometriosis without inhibition of follicular maturation, ovulation, and menstruation and, thus, may represent the first effective medical treatment of patients with endometriosis and infertility that does not interfere with the menstrual cycle. This would offer a significant advantage in the medical treatment of endometriosis, because current medical treatment in endometriosis, including GnRH agonists and GnRH antagonists, is aimed at reaching a reversible hypoestrogenic and amenorrheic state, causing temporary suppression of endometriotic lesions during which conception is not possible and after which endometriosis reoccurs [8].
In conclusion, the present study has shown that, in baboons, r-hTBP1 is promising not only in treatment of the developed disease [11] but also for inhibition of the development of endometriotic lesions and associated adhesions without causing the hypoestrogenic effects observed with conventional therapy. Thus, r-hTBP1 may be effective in the prevention and treatment of human endometriosis and endometriosis-related pain and subfertility.
FOOTNOTES
1 Supported by Serono, Inc. (Geneva, Switzerland). T.M.D'H. was sponsored by the Belgian Fund for Scientific Research and the Leuven University Research Council. 
2 Correspondence: Thomas M. D'Hooghe, Leuven University Fertility Center, Dept. of Ob/Gyn, University Hospital Gasthuisberg, B3000 Leuven, Belgium. FAX: 32 16 343607; thomas.dhooghe{at}uz.kuleuven.ac.be
3 These authors contributed equally to this work.
Received: 1 May 2005.
First decision: 1 June 2005.
Accepted: 16 September 2005.
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