Conjugated equine estrogens, estrone sulphate and estradiol valerate oral administration in ovariectomized rats: effects on central and peripheral allopregnanolone and beta-endorphin.
OBJECTIVE
Several natural or synthetic estrogenic molecules are commonly used in oral hormone replacement therapy for the relief of menopausal complaints and for the primary prevention of cardiovascular disease and osteoporosis. Little information is available concerning the comparative efficacy of different compounds on neuroendocrine function. The opioid peptide beta-endorphin (beta-EP), and the neurosteroid allopregnanolone are considered markers of neuroendocrine function and their synthesis and action is regulated by gonadal steroids. The present study aimed to investigate the effects of a 2-week oral treatment with estradiol valerate (EV), estrone sulphate (ES), or conjugated equine estrogen (CEE) on central and peripheral beta-EP and allopregnanolone levels in ovariectomized (OVX) female rats.


METHODS
Twelve groups of Wistar OVX rats received oral EV (0.05, 0.1, 0.5 and 1 mg/Kg/day) or ES (0.1, 0.5, 1 and 2 mg/Kg/day), or CEE (0.1, 0.5, 1 and 2 mg/Kg/day) for 14 days. One group of fertile and one group of OVX rats were used as controls. beta-EP content was assessed in hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma, while allopregnanolone content was assessed in hypothalamus, hippocampus, anterior pituitary, adrenals and serum.


RESULTS
Ovariectomy induced a significant decrease in beta-EP and allopregnanolone content in hypothalamus, hippocampus, pituitary, and serum, while it increased allopregnanolone content in the adrenals. In OVX rats, the administration of each molecule reversed the ovariectomy-induced beta-EP and allopregnanolone changes in a dose-dependent fashion, therefore completely restoring their concentration. At higher doses, the estrogenic compounds induced significantly higher levels of allopregnanolone and beta-EP than in fertile rats. CEE induced higher allopregnanolone levels in hypothalamus, anterior pituitary and serum than the other estrogenic molecules, and in the hippocampus with respect to EV alone. CEE produced higher beta-EP levels in the hippocampus and hypothalamus with respect to EV and ES.


CONCLUSIONS
In the examined tissue and serum estrogens restore the ovariectomy induced changes in allopregnanolone and beta-EP content in a dose-dependent manner; the magnitude of these effects is not uniform and it is related to the different tissues and the employed compounds.
Stomati
Massimo
M
Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics "P. Fioretti", University of Pisa, Via Roma 35, 56100, Pisa, Italy.
Bernardi
Francesca
F
Luisi
Stefano
S
Puccetti
Simone
S
Casarosa
Elena
E
Liut
Martina
M
Quirici
Barbara
B
Pieri
Matteo
M
Genazzani
Alessandro D
AD
Luisi
Michele
M
Genazzani
Andrea R
AR
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000494:pharmacology*; D004970:Estrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects; D010052:Ovariectomy; D010902:Pituitary Gland / Q000187:drug effects; D011280:Pregnanolone / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014599:Uterus / Q000187:drug effects; D001615:beta-Endorphin / Q000097:blood / Q000187:drug effects* / Q000378:metabolism
D004966:Estrogens, Conjugated (USP); D004970:Estrone; D004958:Estradiol; D001615:beta-Endorphin; D011280:Pregnanolone; C017296:estrone sulfate