Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors.
Brain sex steroids are derived from both peripheral (primarily gonadal) and local (neurosteroids) sources and are crucial for neurogenesis, neural differentiation and neural function. The mechanism(s) regulating the production of neurosteroids is not understood. To determine whether hypothalamic-pituitary-gonadal axis components previously detected in the extra-hypothalamic brain comprise a feedback loop to regulate neuro-sex steroid (NSS) production, we assessed dynamic changes in expression patterns of steroidogenic acute regulatory (StAR) protein, a key regulator of steroidogenesis, and key hypothalamic-pituitary-gonadal endocrine receptors, by modulating peripheral sex hormone levels in female mice. Ovariectomy (OVX; high serum gonadotropins, low serum sex steroids) had a differential effect on StAR protein levels in the extrahypothalamic brain; increasing the 30- and 32-kDa variants but decreasing the 37-kDa variant and is indicative of cholesterol transport into mitochondria for steroidogenesis. Treatment of OVX animals with E(2), P(4), or E(2) + P(4) for 3 days, which decreases OVX-induced increases in GnRH/gonadotropin production, reversed this pattern. Suppression of gonadotropin levels in OVX mice using the GnRH agonist leuprolide acetate inhibited the processing of the 37-kDa StAR protein into the 30-kDa StAR protein, confirming that the differential processing of brain StAR protein is regulated by gonadotropins. OVX dramatically suppressed extra-hypothalamic brain gonadotropin-releasing hormone 1 receptor expression, and was further suppressed in E(2)- or P(4)-treated OVX mice. Together, these data indicate the existence of endocrine and autocrine/paracrine feedback loops that regulate NSS synthesis. Further delineation of these feedback loops that regulate NSS production will aid in developing therapies to maintain brain sex steroid levels and cognition.
Meethal
Sivan Vadakkadath
SV
Department of Medicine, University of Wisconsin and Geriatric Research, Education and Clinical Center, Veterans Administration Hospital, Madison, Wisconsin 53705, USA.
Liu
Tianbing
T
Chan
Hsien W
HW
Ginsburg
Erika
E
Wilson
Andrea C
AC
Gray
Danielle N
DN
Bowen
Richard L
RL
Vonderhaar
Barbara K
BK
Atwood
Craig S
CS
D000818:Animals; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018377:Neurotransmitter Agents / Q000096:biosynthesis; D010053:Ovary / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis*; D010902:Pituitary Gland / Q000378:metabolism; D011966:Receptors, LHRH / Q000096:biosynthesis*; D000098682:Steroidogenic Acute Regulatory Protein
D012739:Gonadal Steroid Hormones; D018377:Neurotransmitter Agents; D010750:Phosphoproteins; D011966:Receptors, LHRH; D000098682:Steroidogenic Acute Regulatory Protein