Accumulating evidence supports the notion that the progression of endometriotic lesions is catalyzed by an aberrant immune response noted in the peritoneal cavity of women with endometriosis (23
). It is uncertain if the initial development of the disease is related to this inflammatory response. However, retrograde menstruation or iatrogenic seeding of the peritoneum with endometrial tissue will incite an inflammatory reaction (31
). This is manifested by greater amounts of activated macrophages, cytokines, chemokines and growth factors in the peritoneal fluid of endometriosis patients in contrast to controls (29
). The discovery that these lesions possess the functional aromatase enzyme whereas normal endometrium from control subjects does not (33
), allows for a reconciliation of separate pathophysiologies—namely, the inflammatory component and the estrogen dependency of the disease. This union of processes is accomplished by the immune-induced synthesis of prostaglandin endoperoxidase synthase-2 leading to greater levels of prostaglandin E2, which, in turn, is a potent stimulator of the aromatase II promoter in endometriotic stromal cells (34
PPAR-γ is a pleiotropic nuclear hormone receptor that binds to specific DNA response elements and may regulate gene expression indirectly, negatively or positively, through competition with other transcription factors (35
). The true active endogenous PPAR-γ ligand has yet to be determined. The highest expression is found in adipose tissue where it is principally involved in adipocyte differentiation. Nevertheless, accumulating evidence purports a role for PPAR-γ ligands in regulating cell growth (36
), apoptosis (36
), inhibiting angiogenesis in human endometrial cells (39
) and repressing inflammatory mediators (8
). In fact, most anti-inflammatory properties of PPAR-γ ligands are thought to arise through down-regulating proinflammatory mediators in macrophages (41
) likely preceded by inhibiting the transcription factor nuclear factor-κB (NF-κB) (42
). Since NF-κB appears to be constitutively activated in endometriotic cells and thus may play a central role in the pathophysiology of endometriosis (47
), the utilization of an immunomodulatory drug such as rosiglitazone to ameliorate the immunological dysfunction seen with endometriosis represents an alternate novel treatment.
Since recent in vitro
and animal model studies have implicated PPAR-γ ligands as potential modulators of inflammation-related diseases such as inflammatory bowel disease, psoriasis and rheumatoid arthritis, (48
), their use in endometriosis is not far-fetched. Several in vitro
studies with thiazolidinediones (TZDs) and endometriotic cells (15
) led to their use in endometriosis animal models. To date there have been two published studies using TZDs in the rat model of endometriosis with one revealing decreased induction of lesions (51
) and another showing regression of established disease (19
). Since rodents do not have menses or develop spontaneous endometriosis, the ectopic autologous transplantation of uterine tissue in this model (52
) may not sufficiently replicate human endometriosis. With this in mind, the baboon endometriosis model was established by intrapelvic seeding of menstrual eutopic endometrium on top of the pelvic organs (20
In the present study, a TZD, rosiglitazone, was used to assess if it could significantly diminish endometriotic lesions that were documented prior to treatment. The comparison groups were a placebo control, placebo treated baboons, and an active comparator or active control, GnRH-antagonist treated cohort. For two reasons a GnRH-antagonist was utilized rather than a GnRH-agonist: (A) due to a 30 day treatment, we wanted to avoid the agonist flare effect seen with a GnRH-agonist and (B) the IPR has experience with GnRH-antagonist administration for gonadal suppression used in baboon fertility studies. This study presents the first sub-human primate evidence that treatment with a TZD can reduce the surface area (~50% decrease in relative change compared to placebo) of induced peritoneal endometriosis. Furthermore, our results advocate that rosiglitazone may augment the progression of endometriotic lesions from the more active red lesions to the older, typical, blue-black puckered implants though this did not reach statistical significance in our small sample size.
The staging laparoscopies were conducted at various times of the menstrual phase () so the estradiol values were not illustrative of true suppression. However, by final laparoscopy, three of the Ganirelix baboons had progesterone levels below 0.21 ng/mL (below the sensitivity level of our assay) suggesting an ovarian suppressive effect while no other baboon in any other treatment group showed this low level. Moreover, two rosiglitazone baboons showed luteal phase levels of progesterone. The limited clinical studies on the reproductive influence of rosiglitazone are confined to the polycystic ovary syndrome population and reveal an improved ovulation rate and generous restoration of normal menstrual cycles (53
). These references support our observation that there was no untoward endocrinological effect of rosiglitazone versus the placebo group.
Cycle day and perineal cycle stage with respect to surgeries.
An ideal therapy option for treating endometriosis pain should possess a modicum of side effects, low-cost burden, proven efficacy at diminishing pelvic pain and spare fertility potential during treatment. Clinical data have exonerated rosiglitazone from the increased hepatoxicity risk as seen with other TZDs (57
). Rosiglitazone is classified as a pregnancy category C drug due to animal evidence of growth retardation in mid to late gestation with 20 and 75 times the human dose. No evidence of teratogenicity exists in either preclinical or clinical trials. Rosiglitazone had no untoward effects on the growth and morphology of an in vitro
rat embryo culture model despite concentrations as high as 10 times human peak plasma levels (58
). Studies on early human pregnancy have shown that rosiglitazone can be transported across the placenta in the late phase of the first trimester from 8-to-12 weeks (59
) but in an ex vivo
human perfusion model there was negligible transfer of rosiglitazone across the placenta (60
). This would suggest that it may be safe to take the TZD up until the time a pregnancy is confirmed.
Taken together, this study suggests that the PPAR-γ agonist rosiglitazone may reduce the quantitative burden of endometriotic disease in baboons with established disease without affecting the menstrual cycle. Moreover, the specific change from red lesions to more typical implants for rosiglitazone treated baboons compared to placebo or GnRH-antagonist groups hints at a possible conversion of active endometriotic lesions. Only further study in humans can determine if these results translate into diminished pelvic pain with rosiglitazone treatment.