Clinically relevant progestins regulate neurogenic and neuroprotective responses in vitro and in vivo (PDF)
Liu,Lifei; Zhao,Ligin; She,Hongyun; Chen,Shuhua; Ming Wang,Jun; Wong,Charisse; McClure,Kelsey; Sitruk-Ware,Regine; Diaz Brinton,Roberta
Endocrinology 151(12): 5782-5794
Publication date: 2010
Previously, we demonstrated that progesterone (P) promotedadult rat neural progenitor cell (rNPC) proliferation with concomitantregulation of cell-cycle gene expression via the P receptormembrane component/ERK pathway. Here, we report the efficacyof seven clinically relevant progestins alone or in combinationwith 17-estradiol (E) on adult rNPC proliferation and hippocampalcell viability in vitro and in vivo. In vitro analyses indicatedthat P, norgestimate, Nestorone, norethynodrel, norethindrone,and levonorgestrel (LNG) significantly increased in rNPC proliferation,whereas norethindrone acetate was without effect, and medroxyprogesteroneacetate (MPA) inhibited rNPC proliferation. Proliferative progestinsin vitro were also neuroprotective. Acute in vivo exposure toP and Nestorone significantly increased proliferating cellnuclear antigen and cell division cycle 2 expression and totalnumber of hippocampal 5-bromo-2-deoxyuridine (BrdU)-positivecells, whereas LNG and MPA were without effect. Mechanistically,neurogenic progestins required activation of MAPK to promoteproliferation. P, Nestorone, and LNG significantly increasedATP synthase subunit (complex V, subunit ) expression, whereasMPA was without effect. In combination with E, P, Nestorone,LNG, and MPA significantly increased BrdU incorporation. However,BrdU incorporation induced by E plus LNG or MPA was paralleledby a significant increase in apoptosis. A rise in Bax/Bcl-2ratio paralleled apoptosis induced by LNG and MPA. With theexception of P, clinical progestins antagonized E-inducedrise in complex V, subunit . These preclinical translationalfindings indicate that the neurogenic response to clinical progestinsvaries dramatically. Progestin impact on the regenerative capacityof the brain has clinical implications for contraceptive andhormone therapy formulations prescribed for pre- and postmenopausalwomen.