Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein‐dependent mechanism involving hypothalamic‐pituitary‐gonadal axis receptors
Open Access
- 13 July 2009
- journal article
- research article
- Published by Wiley in Journal of Neurochemistry
- Vol. 110 (3), 1014-1027
- https://doi.org/10.1111/j.1471-4159.2009.06192.x
Abstract
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 E2, P4, or E2 + P4 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 E2‐ or P4‐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.Keywords
This publication has 150 references indexed in Scilit:
- Cholesterol transport in steroid biosynthesis: Role of protein–protein interactions and implications in disease statesBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2009
- Steroidogenic Activity of StAR Requires Contact with Mitochondrial VDAC1 and Phosphate Carrier ProteinPublished by Elsevier BV ,2008
- Synthesis and Function of Hypothalamic Neuroprogesterone in ReproductionEndocrinology, 2008
- Gonadotropin-releasing hormone regulates spine density via its regulatory role in hippocampal estrogen synthesisThe Journal of cell biology, 2008
- Living and Dying for SexGerontology, 2004
- Elevated Gonadotropin Levels in Patients With Alzheimer DiseaseMayo Clinic Proceedings, 2001
- Age- and region-specific expressions of the messenger RNAs encoding for steroidogenic enzymes P450scc, P450c17 and 3β-HSD in the postnatal rat brainBrain Research, 1998
- Establishment of immunological probes to study human gonadotropin-releasing hormone receptorsMolecular and Cellular Endocrinology, 1995
- Oestrogen effects on calcitriol levels in post‐menopausal women: a comparison of oral versus transdermal administrationClinical Endocrinology, 1995
- The prevalence of dementia: A quantitative integration of the literatureActa Psychiatrica Scandinavica, 1987