Differential regulation of dehydroepiandrosterone and estrogen on bone and uterus in ovariectomized mice.
Dehydroepiandrosterone (DHEA) may be useful in the treatment of postmenopausal osteoporosis (PMO). Our present study has found the preferable stimulatory effect of DHEA on bone, in contrast to the proliferative effects of estradiol (E2) on the endometrium and the uterus, which suggests that DHEA has greater potential clinical value than estrogens in prophylaxis and therapeutics for PMO.


BACKGROUND
A series of findings raise the possibility that DHEA may be useful in the treatment of PMO. Our present study thus aimed at the differential effects of DHEA and E2 on bone and the uterus in ovariectomized mice as well as the involvement of aromatase, ERalpha, ERbeta, and AR in the effects.


METHODS
Ovariectomized and sham BALB/c mice were given daily treatment with either DHEA or E2 for three months, respectively. Bone mineral density was determined by DEXA after the last treatment. Mice were necropsied in 3 months after the treatment to analyze the ultrastructure of their femur osteoblasts (OBs) with a transmission electron microscope (TEM); DHEA, DHEA sulfate (DHEAS) and E2 levels were assayed by EIA; production in vitro of E2 in the uterus or tibia was assayed to evaluate the profile of P450arom activity; ERalpha and ERbeta mRNA levels in the uterus and tibia were determined by real-time PCR. The primary murine OBs were treated with DHEA and E2, respectively for 72 h. Real-time polymerase chain reaction (PCR) and western blot were carried out to evaluate aromatase, ERalpha, ERbeta and AR expression in OBs.


RESULTS
Both DHEA and E2 significantly improved BMD and OB ultrastructure; E2 but not DHEA has significantly increased uterus wet weight, endometrium epithelial and gland thickness. Dehydroepiandrosterone not only increased serum, femoral DHEA, DHEAS and E2 concentration, but also increased uterine DHEA and DHEAS other than E2 concentration in site, while E2 only increased serum, uterine and femoral E2 concentration, but failed to alter the concentrations of DHEA and DHEAS. Moreover, DHEA significantly increased tibia P450arom enzyme activity, while E2 increased uterine and tibia aromatase activity. Furthermore, DHEA increased uterine ERbeta and ERalpha, and ERbeta transcription in the tibia, while E2 increased ERalpha transcription in the uterus and tibia. Dehydroepiandrosterone increased aromatase, ERalpha, ERbeta and AR expression in OBs, and increased significantly, but E2 apparently decreased the ratio of ERbeta/ERalpha.


CONCLUSIONS
Although both DHEA and E2 augment BMD, the proliferative effects of E2 on the endometrium and uterus reflect the different modes of action on bone and the uterus, indicating that the preferable stimulatory effect of DHEA on bone appears to the more potential clinical values than estrogens in prophylaxis and therapeutics for PMO. But applicability of the findings from rodents in humans needs further study.
Wang
L
L
Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, 413 Zhaozhou Road, Shanghai, 200011, China.
Wang
Y-D
YD
Wang
W-J
WJ
Li
D-J
DJ
D015502:Absorptiometry, Photon; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D015519:Bone Density; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013977:Tibia / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D011944:Receptors, Androgen; D003687:Dehydroepiandrosterone; D004958:Estradiol; D001141:Aromatase