Adult granulosa cell tumors of the ovary: a retrospective study of 30 cases with respect to the expression of steroid synthesis enzymes / 부인종양

OBJECTIVE: Some, but not all, granulosa cell tumors are characterized by estrogen production. This study was designed to determine whether there are clinical or pathological variations in granulosa cell tumors in relation to the expression of sex steroid synthesis enzymes. METHODS: Clinical symptoms, serum hormonal values, and histology of 30 granulosa cell tumor patients who underwent surgery between 2002 and 2014 were retrospectively reviewed. RESULTS: Most patients presented with abnormal genital bleeding including abnormal menstrual cycles. Eight of 16 patients older than 50 years had endometrial hyperplasia and one had endometrial cancer. Serum 17β-estradiol (E2) levels tended to be higher in patients over 50 years of age (p=0.081). Serum follicle-stimulating hormone (FSH) levels were low in all patients irrespective of serum E2 levels. Magnetic resonance imaging revealed a thicker endometrium in older as compared to younger patients (p<0.05). Tumor cells in the majority of cases were positive for inhibin α and P450 aromatase, irrespective of age and serum E2 levels. P450 17α-hydroxylase (P450c17) expression varied among cases. P450c17 was strongly positive in luteinized tumor cells and weakly positive in theca cells and fibroblasts. High E2 levels were associated with P450c17-positive cells in the tumor (p<0.05). CONCLUSION: The expression of hormone-synthesizing enzymes divides granulosa cell tumors into 2 distinct types; tumors with P450c17-positive cells show elevated serum E2 and related clinical symptoms, while tumors without these cells show symptoms related to FSH suppression by inhibin.

Interaction among peroxisome proliferators-activated receptor alpha, cytochrome P450 oxysterol 7α-hydroxylase and estrogen receptor and its association with intrahepatic cholestasis in pregnant rats / 中华妇产科杂志

Objective To investigate the relationship between interaction of peroxisome proliferators-activated receptor alpha (PPARα), cytochrome P450 oxysterol 7α-hydroxylase (CYP7B1) and estrogen receptor (ER) and intrahepatic cholestasis in pregnant rats. Methods Eighty clean SD pregnant rats were selected and divided into four groups randomly with 20 in each. Since the 13th day of pregnancy,rats in the control group was injected subcutaneously with refined vegetable oil 2.0 ml · kg-1 · d -1 , those in the low-dose, moderate-dose and high-dose groups received 17-α-ethynylestradiol (EE) 1.0 mg · kg-1 · d-1,1.25 mg · kg-1 · d-1 and 1.5 mg · kg-1 · d-1, respectively. All rats were sacrificed at the 21at day of pregnancy and maternal hepatic tissues were collected. The serum levels of alanine aminotransferase(ALT), aspartate transaminase (AST), total bile acid (TBA) and bilirubin (BIL) were determined by enzyme linked immunosorbent assay (ELISA). The mRNA expressions of PPARα, CYP7B1, Erα and Erβ in maternal rat livers were examined by real-time PCR. Results (1) Biochemical indicators: the serum levels of ALT,AST, TBA and BIL were significantly lower in the control group than in the rest 3 groups,respectively [ control group: (41.1 ± 2.8 ) U/L, (44.4 ± 3.6) U/L, (26.4 ± 5.6 ) μmol/L and( 2.8 ± 0.2)U/L;low-dose group: (48.2 ±3.4) U/L,(47.9 ±3.7) U/L,(36.4 ±4.2) μmol/L and (4.2 ±0.2) U/L;moderate-dose group: (70.4 ± 5.3 ) U/L, (68.4 ± 5.6) U/L, (64.3 ± 3.8 ) μmol/L and ( 6.2 ± 1.2)U/L; high-dose group: (72.4 ±7.6) U/L, (70.2 ±3.8) U/L, (72.4 ±7.8) μmol/L and (8.2 ±2.2)U/L, P<0.05], and those in the moderate or high-dose groups were higher than in the low-dose group (P<0.05). (2) mRNA expression of Erα and Erβ: the mRNA expression of Erα in pregnant rat livers increased in a dose-dependent manner, which were all significantly higher than that in the control group,respectively ( low-dose group: 0.76 ± 0.02 ); moderate -dose group: ( 0.99 ± 0.04; high-dose group:1.21 ±0.01 ;control group:0.65 ±0.01, P <0.05), but no difference was found among the 4 groups in the mRNA expression of Erβ ( P > 0.05 ). (3) mRNA expression of CYP7B1 and PPARα: the mRNA expression of CYP7B1 in pregnant rat livers increased from the low-dose group to the high-dose group, and were all higher than that of the control group ( low-dose group: 0.93 ± 0.01; moderate-dose group: 0.99 ±0.06; high-dose group: 1.22 ± 0.04; control group: 0.75 ± 0.02, P < 0.05 ). However, the mRNA expression of PPARα decreased from the low-dose group to the high-dose group, and were all lower than that of the control group (low-dose group: 0.83 ± 0.05; moderate-dose group: 0.71 ± 0.02; high-dose group:0.64 ± 0.03; control group: 1.35 ± 0. 05; P < 0.05 ) . Conclusions The down regulated mRNA expression of PPARα, caused by higher dose of estrogen, may increase the expression of CYP7B1 due to the ineffectiveness of the inhibition of PPARα on CYP7B1, which may further stimulate the Erα activity and then induce intrahepatic cholestasis. Abnormal expression of PPARα, CYP7B1 and ER may play a role in the pathogenesis of estrogen-induced intrahepatic cholestasis.

Genetic polymorphism of CYP17 and breast cancer risk in Korean women

CYP17 gene is involved in steroidogenesis and steroid metabolism. Epidemiologic results on the association between the CYP17 polymorphism and breast cancer risk have been inconsistent. We examined the association between the MspAI polymorphism at +27 relative to the start of transcription in the 5'-untranslated region of CYP17 gene and breast cancer risk in Korean women. Four hundred and sixty-two incident cases and 337 controls were recruited from three teaching hospitals in Seoul during 1994-2001. Polymorphism of the CYP17 gene was determined by a single base extension assay. Demographic and lifestyle characteristics were identified using structured questionnaire. Age-adjusted (aOR) and multivariate odds ratios (mOR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression. The proportions of A1/A1, A1/A2 and A2/A2 genotypes among controls were 20.8%, 45.1% and 34.1%, respectively. Compared to the A1/A1 genotype, A1/A2 or A2/A2 genotype was not statistically significantly associated with overall breast cancer risk (i.e., mOR=1.01, 95% CI=0.69-1.47 and mOR=0.76, 95% CI=0.51-1.14, respectively). However, a significant association between CYP17 A2/A2 genotype and breast cancer was observed among women aged 50 years or less (mOR=0.58, 95% CI=0.34-0.99, P=0.04) and leaner women (body mass index < 22 kg/m2) (mOR=0.48, 95% CI=0.23-0.97, P=0.04). Our results suggest that genetic polymorphism in 5'-untranslated region of CYP17 might play a role in breast cancer development in Korean women among younger women aged less than 50 or leaner women with body mass index less than 22 kg/m2.