Influence of 17beta-estradiol on the synthesis of reduced neurosteroids in the brain (in vivo) and in glioma cells (in vitro): possible relevance to mental disorders in women.
Brain neurosteroids modulate gamma-aminobutyric acid type A (GABAA) receptor activity, thereby playing a role in mood disorders. Alterations in 17beta-estradiol (E2) and progesterone (P) are also known to play a significant role in psychopathology in women. The aim of the present study was to evaluate the synthesis of dihydroprogesterone (DHP), tetrahydroprogesterone (THP), and the activity of 5alpha-reductase (5alphaR) which regulates the reduction of P to DHP on exposure to supraphysiological levels of E2 in vitro (C6 glioma cells) and in vivo (mouse brain). The results showed that supraphysiological levels of E2 induced a decrease in the accumulation of both neurosteroids, probably by decreasing the activity of 5alphaR. We hypothesize that the high levels of E2 in pregnancy attenuate the increase in the conversion of P to THP in the brain and that the ratio of E2/P modulates the sedative effect of THP. This process may be relevant to psychopathological disorders that are ascribed to drastic alterations in estrogen levels, such as premenstrual syndrome, pregnancy-related mental disorders, and postpartum "blues".
Maayan
Rachel
R
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Tel Aviv University, Tel Aviv, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel. rmayan@post.tau.ac.il
Fisch
Benjamin
B
Galdor
Moran
M
Kaplan
Boris
B
Shinnar
Nili
N
Kinor
Noa
N
Zeldich
Ella
E
Valevski
Avi
A
Weizman
Abraham
A
D004092:20-alpha-Dihydroprogesterone / Q000096:biosynthesis*; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005910:Glioma; D006728:Hormones / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019964:Mood Disorders / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D011280:Pregnanolone / Q000096:biosynthesis*; D011374:Progesterone / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006728:Hormones; D012333:RNA, Messenger; D004092:20-alpha-Dihydroprogesterone; D011374:Progesterone; D004958:Estradiol; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase