Allopregnanolone revisit

Science Other Studies
#1

Dydrogesterone increases allopregnanolone in selected brain areas and in serum of female rats

Nicola Pluchino, M.D., Elena Lenzi, M.D., Elena Casarosa, Ph.D., Vito Cela, M.D., Ph.D., Silvia Begliuomini, M.D., Filippo Ninni, M.D., Letizia Freschi, M.D., Stefano Luisi, M.D., Ph.D., Andrea Riccardo Genazzani, M.D., Ph.D.
Received 1 March 2007; received in revised form 18 March 2007; accepted 18 March 2007. published online 25 May 2007.

Objective

To investigate the effects of dydrogesterone (DYD), a synthetic progestin largely used in hormone therapy, on the central nervous system by studying two markers of the neuroendocrine function: the neurosteroid allopregnanolone and the opioid β-endorphin.

Design

Experimental study on animal model.

Setting

Academic research environment.

Animal(s)

72 Wistar female rats.

Intervention(s)

One group of fertile and one of ovariectomized rats (receiving placebo) were used as control. After ovariectomy, the rats underwent a 2-week oral treatment of DYD (0.2, 0.6, or 1.0 mg/kg per day), alone or with estradiol valerate (E2V; 0.05 mg/kg per day).

Main Outcome Measure(s)

Allopregnanolone and β-endorphin, assessed in different brain areas and in circulation.

Result(s)

Ovariectomy decreased allopregnanolone anywhere except in the adrenal gland and reduced β-endorphin central levels; E2V reversed the effects of ovariectomy; and DYD (1 mg/kg per day) increased allopregnanolone levels in frontal lobe, hippocampus, and hypothalamus. Combined administration of DYD at 1 mg/kg per day plus E2V determined a further increase of allopregnanolone levels in frontal lobe, hippocampus, hypothalamus, and serum. Dydrogesterone did not modify the levels of β-endorphin induced by E2V.

Conclusion(s)

Dydrogesterone interacts with allopregnanolone levels (less with β-endorphin), and it can be considered important modulator of the neuroendocrine function.

#2

Possible way to metabolize Allopregnanolone from Progesterone other than 5-AR:

http://endo.endojournals.org/cgi/content/abstract/111/1/17

The Conversion of Progesterone into 5-Pregnane-3,20-dione, 3β-Hydroxy-5-pregnan-20-one, and Its Fatty Acid Esters by Preparations of Bovine Corpora Lutea*

DANIEL H. ALBERTS, V. V. K. PRASAD and SEYMOUR LIEBERMAN
Departments of Biochemistry and of Obstetrics and Gynecology and the International Institute for the Study of Human Reproduction, College of Physicans and Surgeons of Columbia University New York, New York 10032

Address correspondence and requests for reprints to: Dr. Seymour Lieberman, Department of Obstetrics and Gynecology, College of Physicans and Surgeons of Columbia University, 630 West 168th Street, New York, New York 10032.

Abstract

Homogenates obtained from bovine corpora luteal tissue were found to catalyze the synthesis of 3β-hydroxy- 5-pregnan-20-one (allopregnanolone) from progesterone but not from pregnenolone. The major metabolites of progesterone included allopregnanolone, 5-pregnane-3,20-dione, and fatty acid esters of allopregnanolone. Incubation with labeled pregnenolone resulted in the formation of pregnenolone esters; however, neither allopregnanolone nor esterified derivatives of it were detected. The esterifying enzyme (s) leading to the formation of allopregnanolone esters was associated primarily with the microsome-enriched subcellular fraction and was stimulated by the addition of ATP and coenzyme A. With these added cofactors, the pH optimum was 6.0-6.5. The rate of steroid ester formation was enhanced by the addition to the homogenate fraction of oleic acid, which was incorporated into the steroid ester fraction. Thus, enzymatic activity, with characteristics similar to either cholesteryl ester hydrolase (EC 3.1.1.13) or acyl cholesterol acyltransferase (EC 2.3.1.26), catalyzed the esterification of allopregnanolone. The data suggest that the allopregnanolone esters found in vivo are derived from progesterone rather than from pregnenolone.

Footnotes

  • This work was supported in part by Grants AM-00110, AM-20846, HD-05077, and HD-07061 from the USPHS.

    Current address: Medical and Health Sciences Division, Oak Ridge Associated Universities, Oak Ridge, Tennessee 37830.

Received October 21, 1981.