Hiroaki Ishihara

Endometriosis: the pathophysiology as an estrogen-dependent disease.

Endometriosis, defined as the presence of endometrial glands and stroma outside of the uterine cavity, develops mostly in women of reproductive age and regresses after menopause or ovariectomy, suggesting that the growth is estrogen-dependent. Indeed, the lesions contain estrogen receptors (ER) as well as aromatase, an enzyme that catalyses the conversion of androgens to estrogens, suggesting that local estrogen production may stimulate the growth of lesions. The expression patterns of ER and progesterone receptors in endometriotic lesions are different from those in the eutopic endometrium. Moreover, estrogen metabolism, including the expression pattern of aromatase and the regulation of 17 beta-hydroxysteroid dehydrogenase type 2 (an enzyme responsible for the inactivation of estradiol to estrone), is altered in the eutopic endometrium of women with endometriosis, adenomyosis, and/or leiomyomas compared to that in the eutopic endometrium of women without disease. Immunostaining for P450arom in endometrial biopsy specimens diagnosed these diseases with sensitivity and specificity of 91 and 100%, respectively. This is applicable to the clinical diagnosis of endometriosis. The polymorphisms in the ER-alpha gene, the CYP19 gene encoding aromatase, and several other genes are associated with the risk of endometriosis. Studies of these will lead to better understandings of the etiology and pathophysiology of endometriosis.

Gonadotropin-releasing hormone agonist and danazol normalize aromatase cytochrome P450 expression in eutopic endometrium from women with endometriosis, adenomyosis, or leiomyomas

OBJECTIVE To investigate whether GnRH agonists or danazol therapy normalizes estrogen metabolism in the eutopic endometrium of women with endometriosis, adenomyosis, or leiomyomas. DESIGN Prospective clinical study. SETTING University hospital. PATIENT(S) Fifty-three women with endometriosis, adenomyosis, or leiomyomas. INTERVENTION(S) Patients received GnRH agonist or danazol. Biopsy samples of the endometrium were obtained before and after endocrine therapy. Nontreated endometrial explants were cultured in the presence of either drug. MAIN OUTCOME MEASURE(S) Reverse transcription polymerase chain reaction-Southern blot and immunohistochemical analyses of the endometrial expression of aromatase cytochrome P450, estrogen receptor, progesterone receptor, and Ki-67. Nontreated endometrial explants were cultured in the presence of either drug. RESULT(S) Messenger RNA and protein of aromatase cytochrome P450 were greatly reduced in the eutopic endometrium of patients treated with GnRH agonist for 2 months or more or with danazol for 1 month or more. Culture of endometrial explants with GnRH agonist (10(-9)-10(-7) M) did not change the amount of aromatase cytochrome P450, whereas danazol (10(-7)-10(-6) M) efficiently reduced aromatase cytochrome P450 expression. CONCLUSION(S) Therapy with GnRH agonist or danazol decreases expression of aromatase cytochrome P450 in diseased eutopic endometrium. Endocrine therapy normalized in part the impaired hormonal expression of the eutopic endometrium. GnRH agonist reduced aromatase cytochrome P450 expression mainly by promoting a hypoestrogenic state, whereas danazol reduced aromatase cytochrome P450 in part by direct action on the eutopic endometrium.

Genetic Contribution of the Interleukin-10 Promoter Polymorphism in Endometriosis Susceptibility

PROBLEM: Interleukin‐10 (IL‐10) is an important immunomodulatory cytokine. The aim of this study was to investigate whether polymorphisms of the IL‐10 gene promoter polymorphisms may be responsible in part for genetic susceptibility to endometriosis.

Association of HLA class I and class II alleles with susceptibility to endometriosis.

Although the exact etiology of endometriosis is unclear, several lines of evidence support roles for both cell-mediated and humoral immunity in its pathogenesis. To assess the association between HLA genotypes and endometriosis, we investigated the frequencies of HLA-A, -B, -C, and -DRB1 antigens or alleles in 123 Japanese patients with endometriosis and 165 healthy women as controls. Significant positive association with endometriosis was observed for HLA-B7 (OR = 2.7, 95% CI = 1.5-5.1, p(u) = 0.0022, p(c) = 0.0440) and for Cw*0702 (OR = 2.1, 95% CI = 1.2-3.3, p(u) = 0.0026, p(c) = 0.0398). An increased frequency of DRB1*0101 was observed in endometriosis patients compared with control subjects (OR = 2.3, 95% CI = 1.2-4.4, p(u) = 0.0143), but was not statistically significant after correction for multiple comparisons. Two-locus analysis indicated that the susceptibility to endometriosis was primarily associated with B7, and that the increased frequencies of Cw*0702 and DRB1*0101 in patients reflected the linkage disequilibrium between B7 and Cw*0702 and DRB1*0101. Most of the B7 antigens were encoded by the B*0702 allele, which was in complete linkage disequilibrium with A24, Cw*0702, and DRB1*0101. Therefore, our results indicated that the HLA-A24-B*0702-Cw*0702-DRB1*0101 haplotype was associated with endometriosis susceptibility. Our findings may provide an important clue to elucidating the pathogenesis of endometriosis.

Aromatase cytochrome P450 and estrogen and progesterone receptors in uterine sarcomas: correlation with clinical parameters.

We examined the immunohistochemical expression of aromatase cytochrome P450 (P450arom), estrogen receptor (ER), progesterone receptor (PR), and Ki-67 in postoperative uterine sarcomas (n = 31) and the corresponding eutopic endometria (n = 20) to evaluate the relationships between the endocrine character of uterine sarcomas and the clinical features. In sarcoma tissues, P450arom was detected in 55% of cases, ER in 42%, PR in 42%, and Ki-67 in 90%. In eutopic endometria, P450arom was detected in 60% of cases, ER in 60%, and PR in 35%. There were correlations in the steroid-related proteins between the tumors and endometria (P = 0.001-0.026). The positivity of endometrial P450arom (P = 0.04) and ER (P = 0.006) was higher in surviving patients than dead patients regardless of the menstrual state. The results demonstrate correlation between the expression of P450arom, ER, and PR in tumors and eutopic endometria. Intense expression of the steroid-related proteins was associated with better survival.

Synergistic effect of interleukin-6 promoter (IL6 -634C/G) and intercellular adhesion molecule-1 (ICAM-1 469K/E) gene polymorphisms on the risk of endometriosis in Japanese women.

Problem  Endometriosis is an immune‐related, chronic inflammatory disease with a polygenic predisposition. The aim of this study was to investigate whether the interleukin‐6 (IL‐6) gene promoter region polymorphism (−634C/G) and the intercellular adhesion molecule‐1 (ICAM‐1) gene 469K/E polymorphism are responsible in part for the genetic susceptibility to endometriosis.

Association of Killer Cell Immunoglobulin‐like Receptor Genotypes with Susceptibility to Endometriosis

Problem  Endometriosis is an immune‐related chronic inflammatory disease with a polygenic predisposition. The aim of this study was to investigate whether polymorphisms in killer cell immunoglobulin‐like receptors (KIRs) is responsible, in part, for genetic susceptibility to endometriosis.

Association of Two Polymorphisms in the Peroxisome Proliferator-Acativated Receptor-γ Gene With Adenomyosis, Endometriosis, and Leiomyomata in Japanese Women

Objective: The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor that plays an important role in many diseases. This study investigated whether two polymorphisms (Pro12Ala in exon B and C161T in exon 6) of the PPAR-γ2 gene are related to adenomyosis, endometriosis, or leiomyomata. Methods: A total of 390 patients with adenomyosis, endometriosis, and/or leiomyomata were classified into four groups: 103 patients with adenomyosis (21 adenomyosis only and 82 adenomyosis with endometriosis and/or leiomyomata), 95 patients with endometriosis only, 100 patients with leiomyomata only, and 92 patients with endometriosis and leiomyomata. Results: There was no association between distribution of genotype or allele frequencies for the PPAR-γ Pro12Ala polymorphism and the presence of adenomyosis, endometriosis, and/or leiomyomata. However, compared with results for controls, the PPAR-γ 161CC genotype and 161C allele frequencies were significantly increased in patients with adenomyosis (genotype: χ2 = 9.185, corrected P value [Pc] = .0169; allele: χ2 = 8.337, Pc = .0155) and in patient with endometriosis (genotype: χ2 = 6.748, Pc = .0375; allele: χ2 = 6.413, Pc = .0453). Conclusion: The results suggest that the PPAR-γ 161CC genotype could be a genetic risk factor for adenomyosis and endometriosis, whereas the Pro12Ala polymorphism was not associated with these estrogen-dependent benign uterine diseases in a Japanese population.

Immunohistochemical localization of aromatase and apoptosis-associated proteins in ovarian serous cystadenocarcinoma arising from ovarian endometriosis

An immunohistochemical study was made of a case of serous cystadenocarcinoma that had been shown to have arisen from ovarian endometriosis. Aromatase cytochrome P450 (P450arom), an enzyme responsible for estrogen biosynthesis, was localized in the epithelial linings of the endometriosis and faintly in the transitional part, whereas it was not expressed in the carcinoma tissue. In contrast, estrogen receptors, progesterone receptors, and apoptosis-associated proteins, Fas, Fas ligand, and Bax were expressed in both endometriosis and carcinoma tissues of the tumor, whereas Bcl-2 was not expressed in either tissue of the tumor. It was suggested that the undifferentiated shift of the histologic grade might result in the loss of P450arom and that the malignant transformation was not caused by an altered balance of apoptosis-associated proteins. Accumulation of these studies may lead to a better understanding of the nature of malignant transformation of ovarian endometriosis.