טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentTereshenkov Irina
SubjectInterference with Steroidogenesis in Human Adrenal Tumor
Cells (H295R) by 5-alpha-Dihydrotestosterone
DepartmentDepartment of Medicine
Supervisors Assistant Professor Michal Lahav
Professor Zeev Blumenfeld


Abstract

     Both the adrenal glands and the ovaries secrete steroid hormones, including androgens (male sex hormones); hyperandrogenic disorders in women may originate from either organ. In such disorders, which typically begin at adolescence, fertility is impaired and there is increased risk of diabetes, cardiovascular diseases and cancer of the uterus later on. Many clinical observations indicate that excess of androgens of adrenal origin causes secondary impairment of ovarian steroidogenesis, and vice versa.  

     The present study examines the hypothesis that abnormally high concentrations of androgenic compounds, synthesized in the ovary, directly affect the activity of adrenocortical steroidogenic enzymes. Thus we examined the effect of androgens on cortisol production in H295R human adrenal tumor cells.

     Low concentrations of the androgen receptor (AR) agonists testosterone, mibolerone, and 5a-dihydrotestosterone (5a-DHT) as well as high concentrations of testosterone, androstenedione, dehydroepiandrosterone, and 5a-androstane-3a,17b-diol were not effective. However, 5a-DHT at high concentrations reduced cortisol and increased the intermediate progesterone. After 5a-DHT removal, steroidogenesis was normalized gradually. 5a-androstane-3,17-dione was even more effective than 5a-DHT, indicating selectivity. Our results suggest that the effect of 5a-DHT was not mediated by AR activation, did not irreversibly damage the cells, and was not due solely to a simple direct allosteric effect.

     When we measured the mRNAs of two of the three enzymes needed for cortisol production from progesterone, 5a-DHT had no effect on either.

     Our present working hypothesis is, that excess of androgens from the ovary causes conversion of adrenal steroids to metabolites that may be inhibitory to some adrenal enzymes.