Background: Recent work revealed two pathways in androgen biosynthesis, namely the classic and an alternative, the backdoor pathway. In this alternative pathway dihydrotestosterone is produced from 17-hydroxyprogesterone without the intermediacy of testosterone using mostly enzymes that are specific to the backdoor path. In the human ovary, regulation of androgen production plays a crucial role in normal physiology and in pathologies such as the polycystic ovary syndrome (PCOS). But the regulation of ovarian androgen production is poorly understood. Therefore, while in the foetal testis a role of the backdoor pathway in androgen production has been suggested, its role in the human ovary remains to be established.
Objective and hypotheses: Characterisation of the backdoor pathway in human ovarian androgen biosynthesis in health and disease.
Method: Pathway analysis was performed on fresh frozen paraffin embedded ovarian tissue samples obtained from the Institute of Pathology Bern, Switzerland. Genes involved in the backdoor pathway were assessed by quantitative RT-PCR (qRT-PCR). Testis and adrenal tissues served as control. For the comparison of normal to aberrant ovarian physiology, we analysed tissue samples of control ovaries and of patients diagnosed with PCOS and ovarian endometriosis. Same tissues were investigated by immunohistochemistry.
Results: Backdoor pathway genes including the aldo-keto reductases AKR1C1 1C4, the 5α-steroid-reductases types 1 and 2 (SRD5A1 and SRD5A2), 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), and the 17β-hydroxysteroid dehydrogenase type 6 (RoDH) are differentially expressed in the human ovary compared to adrenal and testis. Ovarian expression of aldo-keto- and steroid-reductase genes is low. By qRT-PCR, we found no difference in gene expression between normal ovaries and PCOS or endometriosis ovaries.
Conclusion: Genes involved in the backdoor pathway are expressed at low levels in normal and abnormal human ovaries compared to testes and adrenals. Immunohistochemistry experiments are ongoing to show their localization and expression in normal and PCOS ovaries.
Funding: This work is fully supported by the Swiss National Science Foundation. Grant number is 320030-146127 (granted to Prof. C E Flück, University of Berne, Switzerland).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology