In the mid 1980s, the neuroactive steroids 3α,5α-tetrahydroprogesterone or allopregnanolone (3α,5α-THP) and 3α,5α- tetrahydrodeoxycorticosterone (3α,5α-THDOC) were shown to modulate neuronal excitability via their interaction with GABA A receptors. The steroids 3α,5α-THP and 3α,5α-THDOC were able to enhance the GABA-elicited Cl − current.  In addition, these steroids might enhance the binding of muscimol and benzodiazepines to GABA A receptors.  Structure- activity studies (SAR) showed that the 3alpha-OH group is essential for the anesthetic actions of these steroids,  they also have an optimally-placed hydrogen bond accepting group on the β face of the steroid at the C-17 position. The four steroid rings form a rigid framework for positioning these hydrogen groups in three-dimensional space.  Analogues 5 and 6 (Figure 10) are weak modulators of GABA A receptor function because the flexible side chains in these analogues do not have the conformations required for high biological activity. 
While there has been no definite information published as to who should not take pregnenolone, on theoretical grounds, a few cautions can be suggested. Since pregnenolone (especially at high doses) may (in some people) increase estrogen or testosterone levels, I believe that men with prostate cancer (which may be worsened by testosterone) and women with breast or ovarian cancer (which may be worsened by estrogen) should probably take pregnenolone only with their doctors consent and supervision. Men with high PSA (prostate specific antigen) blood levels (possible indicator for undiagnosed or future prostate cancer) should also proceed with caution with pregnenolone use. Lastly, because of pregnenolones anti-GABA, pro-NMDA action, persons known to suffer from epileptic seizures or who are taking an anti-seizure medication such as Dilantin, Depakote or Tegretol should probably only use pregnenolone with their doctors supervision. Finally, as we age, the body produces ever-less of the enzyme which converts pregnenolone to DHEA. Thus, while supplementary pregnenolone taken during middle age and beyond will produce at least some normalization back toward more youthful (and healthful) levels of other steroid hormones, pregnenolone will not completely substitute for other steroid hormone supplements in those with medically demonstrated needs for various specific steroids ., DHEA, cortisol, estrogen, etc.