Steroid metabolism in human reproductive organs

Abstract

Androgens are involved in the development of prostate cancer. Both UGT2B17 and CYP7B1 are involved in the metabolism of androgens and are highly abundant in the prostate.

Deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. The phenotypic outcome of the deletion was studied by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally a case–control study of prostate cancer was performed, including 176 cases diagnosed with prostate cancer and 161 healthy controls. Individuals homozygous for the insertion allele expressed 30 times higher levels of UGT2B17 mRNA in prostate tissue compared to heterozygous carriers, who had a significantly increased risk of prostate cancer (OR 2.15, CI 1.29–3.58).

We screened the human CYP7B1 gene for possible polymorphisms. Only one single polymorphism was detected, a C–G change in the promoter. Expression studies with reporter constructs showed significantly higher transcriptional activity of the G variant in Hek293 cells (2.7-fold ) The allele frequency was 4.04% in Swedes and 0.33% among Koreans. No association to prostate cancer could be found when tested in the previously described case–control study.

In a population-based case-control study including 507 women with miscarriage in the first trimester of pregnancy and 908 controls with a normal first-trimester pregnancy, it was determined whether the cytochrome P450 1B1 (CYP1B1) Val432Leu polymorphism is associated with risk of miscarriage. Carriers of the Val/Val genotype were at higher risk of miscarriage in the first trimester of pregnancy compared to Leu/Leu carriers (OR 1.46; 95% CI 1.02–2.08).

When the same single nucleotide polymorphism (SNP) was investigated in a case– control study of recurrent miscarriages, 206 women who had had three or more miscarriages were compared to 618 controls who had at least one pregnancy and who never miscarried. The OR for Val/Val genotype carriers was 1.00 (95 % CI 0.64–1.56), giving no association with repeated miscarriage. Thyroid disease and smoking was significantly associated with recurrent miscarriages.

The association between abnormal progression of the first stage of labour and expression of enzymes involved in the androgen metabolism as well as estrogen receptors alpha and beta in human myometrium was investigated. Twenty women with an abnormal cervical ripening were compared to 12 women with a normal progression of cervical dilatation and 15 women that had not been in labour. Estrogen receptor alpha had a significant role in the progression of human labour. Estrogen receptor beta, AKR 1C1-4, CYP 19A1, CYP7B1 and 5alpha reductase type 1 expression in the myometrium are independent of the progression in the first stage of labour.