NEUROSTEROIDS
[in Menopause - Hormones, and Cancer Proceedings]
edited by M. Neves-e-Castro and B.G. Wren 2002
[MHC CH 1, p1-7]

Outline and Commentary on the 2002 Proceedings
by Timothy D. Bilash MD, MS, OBGYN
June 2003
www.DrTimDelivers.com

Authors
E. Plassart-Schiess and E.E. Baulieu [MHC CH 1]
INSERM U488 and College de France
Hopital du Kremlin-Bicetre
94276 Le Kremlin-Bicetre
France

1. Neurosteroids are found in nervous system as well as reproductive organs, and provide additional information that may be relevant to the understanding of reproductive steroid function and cancer
   
   
2. [see fig1 p2] Steroid Synthesis
   
   
3. in the mitochondria location
   
   
   1. acetate is converted to cholesterol
      
      1. thru HMGCOAreductase
         
      2. cholesterol is starting substance for neuro/reproductive/adrenal steroids
         
      3. acetate is obtained from sugar sources (3 carbon from 6 carbon)
         
         
   2. outer membrane (receptors)
      
      1. GABA receptors
         
         1. benzodiazepines, ETOH
            
         2. chloride channel, allows Cl entry into neuron
            
         3. hyperpolarizes and dampens neuron excitability (depressant)
            
         4. delta subunit inhibits steroid modulation
            
         5. allows cholesterol into inner membane
            
         6. PregenoloneS and DHEAS inhibit GABA effects (excite neurons)
            
         7. TH-Prog enhances GABA effects (depresses neurons)
            
         8. ETOH ???
            
      2. NMDA receptors
         
         1. pregnenoloneS potentiates NMDA receptors
            
         2. may reinforce pregnenonloneS antagonism of GABA
            
            
   3. inner membrane
      
      
      1. synthesis of precursor steroids
         
      2. cholesterol converted to precursor steroids pregnenolone(nPREG), DHEA
         
         1. thru sccP450 in oligodendrocytes and schwann (glial) cells
            
         2. neuropregnenolone (nPREG) function
            
            1. microtubules
               
            2. memory
               
            3. myelin repair
               
               
4. in the endoplasmic reticulum location
   
   
   1. conversion of nPREG and DHEA to intermediate steroids (P and A, delta5) and (Androstenedione, delta4)
      
      1. 3B-HSD
         
      2. regulated by cell density, high cell density inhibits
         
      3. low activity in glial and neurons
         
   2. Sigma-1 receptors
      
      1. DHEAS is a sigma-1 agonist
         
      2. PregenonloneS is a sigma-1 inverse agonist (antagonist???) p 4 [ ]
         
      3. Progesterone is a sigma-1 antagonist
         
         
5. in the cytosol location
   
   
   1. further metabolism of intermediate steroids
      
   2. conversion to sex steroids (E and T)
      
   3. conversion to active sulfate and fatty acid esters
      
   4. conversion to TH-P (tetrahydroprogesterone) in glial cells thru DH-P (dihydroprog)
      
      
   5. microtubules
      
      1. important for growth and maintenance of neurites during neuronal differentiation
         
      2. composed of tubulin and MAPs
         
      3. MAPS (microtubule-associated proteins)
         
         1. Maps major components of neuronal cytoplasm
            
         2. regulate microtubule lattice formation and dynamics
            
         3. determine neronal shape and control the balance between regidity and plasticity in neural processes
            
         4. MAP1, MAP2, TAU families
            
            
   6. Pregnenolone (MAP2) receptors
      
      1. Map2 receptors (microtubule-associated protein type2)
         
         1. MAP2A, MAP2B (hi molecular weight)
            
         2. MAP2C, MAP2D (lo molecular weight)
            
         3. limited to dendrites
            
      2. Pregnenolone acts at level of microtubules via MAP2 receptors
         
         1. co-polymerization with tubulin favors pregnenolone binding
            
         2. accelerates microtubule polymerization, especially at low MAP2 concentrations
            
         3. increases mictrotubule amounts, are normal appearing
            
            1. Taxol causes abnormal appearing microtubules
               
      3. PregnenoloneS and Progesterone have similar affinity to Pregnenolone
         
         1. competitive inhibitors at Pregnenolone receptor (inactive on MAP2)
            
      4. so cell growth effects mediated thru MAP2/mictotubules
         
         1. [see fig 3a p 6]
            
         2. Pregnenolone (stimulates)
            
         3. Pregnenolone-S (inhibits)
            
         4. Progesterone (inhibits)
            
            
   7. DHEA, DHEAS,Testosterone, Cortisol, Estradiol
      
      1. different mechanism on microtubules than pregnenolone
         
         1. have low affinity at MAP2 receptors (not MAP2)
            
         2. DHEAS only negligible, DHEA weak competitors at Pregnenolone receptor
            
      2. DHEAS increases dendrite length containing MAP2 marker
         
      3. DHEA increases dendrite length containing TAU marker
         
      4. so these ovarian and adrenal hormones have no MAP2 effects on neurons (except Progesterone, Preg, PregS
         
         
   8. 2-methoxyestradiol is a major estradiol metabolite***
      
      1. 2-methoxyestradiol inhibits cell growth
         
         1. hi 2-methoxyestradiol = inhibits microtubule polymerization at high concentrations [MHC p 5]
            
         2. low 2-methoxyestradiol = allows microtubule polymerization, but abnormal morphology similar to Taxol effect at low concentrations
            
      2. binds directly to purified tubulin without MAP (polymerized and unpolymerized by glutamate)
         
      3. doesnt act at pregnenolone receptor (MAP2), so different mode of action from pregnenolone
         
      4. ???1/2 life
         
         
6. in the nucleus (nuclear steroid receptors)
   
   
   1. E receptors/ Estrogen
      
      1. E2 induces P receptors
         
      2. bind circulating and hypothalamic (local in brain) E
         
      3. stimulates growth and differentiation
         
         
   2. P receptors/ Progesterone
      
      1. E2 induces Pr receptors in hypothalamic neurons, oligodendrocytes (not cortex)
         
      2. P decreases Pr receptors
         
      3. P production stimulated by adjacent neurons
         
      4. P receptors can also activate without ligand by phosphorylation
         
      5. P inhibits E growth and differentiation in oligodendrocytes and astrocytes, thru binding to P receptors
         
         1. nuclear receptor binding
            
         2. progesterone synthesis
            
      6. P stimulates myelin protein synthesis in schwann glial cells
         
         1. sciatic nerve Schwann cells
            
            
   3. dont know if nerve and peripheral receptors the same [p3]
      
      
      
7. Neurosteroid Hormone Review
   
   
   1. major steroid metabolite forms affecting breast cancer
      
      1. free steroid
         
      2. sulfate esters
         
         1. converted to sulfate esters by sulfatase
            
         2. free hormone from sulfate esters by sulfotransfersase
            
         3. sulfate metabolites modulate GABA, NMDA, Sigma1 receptors
            
            1. autocrine/paracrine (local)
               
      3. fatty acid esters
         
         
   2. specific hormones
      
      
      1. Pregnenolone (PREG)
         
         1. most abundant and active neurosteroid in rat brain (with PregS)
            
         2. acts at level of microtubules
            
         3. via pregnenolone receptor (MAP2 microtubule-associated protein type2)
            
         4. [see fig2 p3]
            
      2. Pregnenolone Sulfate (PREG-S)
         
         1. most abundant neurosteroids in rat brain (with Preg), most active
            
         2. binds to pregnenolone receptor
            
         3. enhances GABA
            
         4. potentiates NMDA receptor
            
         5. sigma-1 inverse agonist
            
      3. Progesterone (PROG)
         
         1. sigma-1 antagonist
            
         2. progestins
            
            1. medroxyprogesterone acetate
               
            2. norethindrone actetate
               
         3. TetrahydroProgesterone (TH-P)
            
            1. by 3a-oxioreductase, in glial cells (helper actions, stimulate myelin???)
               
            2. enhances GABA
               
      4. DHEA
         
      5. DHEAS
         
         1. stimulates GABA effect
            
         
         
         

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