Neuroactive Pregnanolone Isomers during Pregnancy

Abstract

The pregnanolone isomers (PI) allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), isopregnanolone (3beta-hydroxy-5alpha-pregnan-20-one), epipregnanolone (3beta-hydroxy-5beta-pregnan-20-one), progesterone, and estradiol were measured in 138 pregnant women. The sampling was carried out from the first through the 10th month of pregnancy. Gas chromatography-mass spectrometry analysis and RIA were used for the measurement of steroid levels. The ratios of individual PI were similar to those found previously around parturition: about 25:10:7:1 for allopregnanolone, pregnanolone, isopregnanolone, and epipregnanolone, respectively. All the PI showed a significant increase during pregnancy, which was more pronounced in the 3alpha-steroids. The results indicated changing ratios between 3alpha- and 3beta-PI and between 5alpha- and 5beta-PI throughout pregnancy. The constant allopregnanolone/isopregnanolone ratio found through pregnancy weakened the hypothesis of the role of isopregnanolone in the onset of parturition. The ratio of estradiol (stimulating uterine activity) to 5alpha-PI and epipregnanolone exhibited significant changes during pregnancy in favor of estradiol up to the sixth or seventh month, in contrast to the constant estradiol/pregnanolone ratio. A pregnancy-stabilizing role of pregnanolone, counterbalancing the stimulating effect of estradiol on the onset of parturition, was suggested.

Progesterone selectively increases amygdala reactivity in women

“…This allopregnanolone level is similar to that during early pregnancy. 36,37 However, progesterone had no significant effect on the mood 24 or state anxiety 25 questionnaires (all P > 0.2) and did not significantly modulate response accuracy or reaction times in the behavioral task (all P > 0.05). These factors therefore appear to have little explanatory value in relation to the observed differences in brain activity between the progesterone and placebo conditions.…”

“…52 In the present study, an increased responsiveness of the amygdala was observed after increasing the progesterone and the allopregnanolone concentrations from the follicular phase to levels that are naturally occurring during the luteal phase and early pregnancy, respectively. 36,37 The increased amygdala response might therefore be specific for this concentration change, while higher supraphysiological concentrations might eventually decrease amygdala activity, 15 in parallel with increased sedation in humans. 53 These results therefore show that changes in progesterone level that are within the physiological range can increase amygdala activity.…”

Physiological Relevance of Pregnanolone Isomers and Their Polar Conjugates with Respect to the Gender, Menstrual Cycle and Pregnancy

“…In pregnant women, the levels of 5Ǐ/ǐ-PM including the GABAergic 3Ǐ-PI are persistently elevated (M. Hill, et al, 2007;M. Hill, Parizek, Kancheva, et al, 2010;Kancheva, et al, 2007;Luisi, et al, 2000;Mickan & Zander, 1979;Parizek, et al, 2005;Pearson Murphy, Steinberg, Hu, & Allison, 2001). Their concentrations in women after luteo-placental shift reach values about two orders of magnitude higher than the concentrations detected in the FP (Parizek, et al, 2005).…”

“…Hill, Parizek, Kancheva, et al, 2010;Kancheva, et al, 2007;Luisi, et al, 2000;Mickan & Zander, 1979;Parizek, et al, 2005;Pearson Murphy, Steinberg, Hu, & Allison, 2001). Their concentrations in women after luteo-placental shift reach values about two orders of magnitude higher than the concentrations detected in the FP (Parizek, et al, 2005). Pearson Murphy et al show that the levels of C21 steroids including 5α/β-PM rise greatly during pregnancy, being the highest for progesterone (562-fold the FP level), 5Ǐ-DHP (161-fold), 3ǐ,5Ǐ-THP (56-fold), 3Ǐ,5Ǐ-THP (37-fold), pregnenolone (30-fold), 5ǐ-DHP (16-fold) and 3ǐ,5ǐ-THP (16-fold) at 37 th week of gestation (Pearson Murphy, et al, 2001).…”

“…Hill, Parizek, Cibula, et al, 2010;M. Hill, Parizek, Kancheva, et al, 2010;Luisi, et al, 2000;Parizek, et al, 2005;Pearson Murphy, et al, 2001). These findings allow a speculation whether the conjugated 3Ǐ,5ǐ-THP might serve as an endogenous antinociceptive agent around parturition (Hering, et al, 1996;Kallela, Haasio, & Korttila, 1994).…”