Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons.

OBJECTIVE: To determine the effect of inhibiting aromatase activity on endometrial lesion growth and aromatase expression in a baboon model of induced endometriosis. DESIGN: Prospective study. SETTING: Primate research institute. ANIMAL(S): Sixteen olive baboons. INTERVENTION(S): Sixteen olive baboons with induced endometriosis were examined with laparoscopy 10 months after disease inoculation. Animals in group 1 (n = 10) were treated with 1.25 mg/d of the aromatase inhibitor (AI) letrozole, and animals in group 2 (n = 6) were given a placebo for a total of 6 months. MAIN OUTCOME MEASURE(S): Total number of endometriotic lesions, morphology, and volume of lesions, as well as semiquantitative reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction for levels of aromatase cytochrome messenger RNA were measured. Ovarian volumes were evaluated before treatment initiation and every 2 months during the study. RESULT(S): Treatment of group 1 animals with an AI significantly decreased lesion volume from baseline measurements, whereas the placebo-treated animals showed an increase in lesion volume. Aromatase messenger RNA levels in lesions in the AI-treated animals were significantly lower compared with the placebo-treated animals. Ovarian volumes were significantly increased at 6 months of AI treatment compared with pretreatment volumes. CONCLUSION(S): These findings suggest that suppression of aromatase cytochrome P450 may inhibit the in vivo growth of endometriotic lesions in baboons.

Schistosome-induced pathology is exacerbated and Th2 polarization is enhanced during pregnancy.

UNLABELLED: THE AIM of this study was to investigate the immunopathological impact of pregnancy on an ongoing experimental schistosomiasis infection. MATERIALS AND METHODS: Female BALB/c mice were randomly divided into three groups (A, B and C) of 15 animals each. The mice in Groups A and B were infected with 40 S. mansoni cercariae, percutaneously. Six weeks post-infection, the mice in Groups B and C (schistosome-naive controls) were mated. Schistosome-induced morbidity and cytokine recall responses were subsequently evaluated at weeks 7 and 8 post-infection. RESULTS: Hepatic and pulmonary lesions resulting from trapped schistosome eggs were more frequent and more severe in Group B mice than in Group A mice. Group C mice had suppressed mitogen-stimulated interleukin 4 (IL-4) but maintained high intereferon gamma (IFN-gamma) responses. In contrast, Group A mice had elevated mitogen- and parasite-specific IL-4 but muted IFN-gamma responses. Group B mice had an early (week 7) high IL-4 response, even higher than in group A mice. CONCLUSION: Taken together the data suggest that pregnancy exacerbates schistosome-induced morbidity, probably through up-regulation of parasite-specific IL-4.

Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment.

A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues.

Aromatase and endometriosis.

Aromatase p450 (p450arom) is the key enzyme for biosynthesis of estrogen, which is an essential hormone for the establishment and growth of endometriosis. There is no detectable aromatase enzyme activity in normal endometrium; therefore, estrogen is not locally produced in endometrium. Endometriosis tissue, however, contains very high levels of aromatase enzyme, which leads to production of significant quantities of estrogen. Moreover, one of the best-known mediators of inflammation and pain, prostaglandin E (2), strikingly induces aromatase enzyme activity and formation of local estrogen in this tissue. Additionally, estrogen itself stimulates cyclo-oxygenase-2 and therefore increases the formation of prostaglandin E (2) in endometriosis. We were able to target this positive feedback cycle in endometriosis using aromatase inhibitors. In fact, pilot trials showed that aromatase inhibitors could decrease pelvic pain associated with endometriosis.

Steroid receptor and aromatase expression in baboon endometriotic lesions.

OBJECTIVE: To evaluate steroid receptor and aromatase gene expression in endometriotic lesions, and determine the effects of endometriosis on uterine receptivity in a baboon model for endometriosis. DESIGN: Prospective study to determine the expression of steroid receptors, and aromatase in ectopic endometriotic lesions and endometrial genes in the eutopic endometrium of baboons with induced endometriosis by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry. SETTING: University research laboratory and primate research facility. ANIMAL(S): Normally cycling baboons inoculated intraperitoneally with menstrual endometrium to induce endometriosis. INTERVENTION(S): Endometriotic lesions were resected during laparotomy, and endometrium was obtained by endometrectomy or after hysterectomy. MAIN OUTCOME MEASURE(S): Steroid receptor and aromatase expression by RT-PCR and immunocytochemistry in endometriotic lesions and glycodelin and alpha-smooth muscle actin expression and localization in endometrium after chorionic gonadotropin (CG) stimulation. RESULT(S): This study demonstrated that estrogen receptor-alpha (ERalpha) and progesterone receptor (PR) were expressed in both ectopic and eutopic endometrium between 1 and 10 months after inoculation. In contrast, ERbeta was only expressed in the ectopic endometriotic lesions. Aromatase expression was only evident in lesions obtained 10 months after inoculation. Infusion of CG during the luteal phase failed to induce the expression of glycodelin in the glandular epithelium or alpha-smooth muscle actin (alpha-SMA) in stromal cells in animals with endometriosis as early as 1 and 4 months after inoculation. CONCLUSION(S): The ERbeta expression is selectively up-regulated in the endometriotic lesions at all stages of the disease, whereas aromatase expression is not evident until the disease progresses. However, expression of uterine receptivity markers was down-regulated as early as 1 and 4 months after inoculation.