Effects of tibolone and conventional hormone replacement therapies on arterial and hepatic cholesterol accumulation and on circulating endothelin-1, vascular cell adhesion molecule-1, and E-selectin in surgically menopausal monkeys.
OBJECTIVE
Menopause and aging are associated with a marked increase in the incidence of coronary heart disease as well as reductions in circulating estrogen, progestogen, and androgen levels. The synthetic compound tibolone and its metabolites have estrogenic, progestogenic, and androgenic characteristics. In the present study, we compared the effects of tibolone, estrogen replacement therapy, and estrogen plus progestogen replacement therapy on arterial and hepatic lipid accumulation and on circulating soluble adhesion molecule and endothelin-1 concentrations in surgically postmenopausal cynomolgus monkeys.


METHODS
Animals were fed an atherogenic diet for 2 years while receiving either no hormone treatment (control, n = 31) or the following treatments at doses designed to mimic the human dose on a daily caloric intake basis: tibolone at 2.5 mg/day (HiTib, n = 31), tibolone at 0.625 mg/day (LoTib, n = 29), conjugated equine estrogens (CEE) alone at 0.625 mg/day (CEE, n = 29), or CEE plus continuous medroxyprogesterone acetate (MPA) at 2.5 mg MPA/day (CEE + MPA, n = 30).


RESULTS
Relative to the control group, iliac artery total cholesterol content was not different in the HiTib, LoTib, and CEE + MPA groups but was significantly lower in the group receiving CEE only (P < 0.05). In contrast, hepatic free cholesterol content was reduced in all treatment groups [HiTib (P < 0.01), LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.05)], whereas hepatic total and esterified cholesterol content were reduced in the HiTib, CEE, and CEE + MPA groups (all P < 0.05). HiTib and CEE groups had lower hepatic triglyceride levels per milligram of protein (P < 0.05). Iliac arterial cholesterol content was highly correlated with hepatic cholesterol content and with previously published histomorphometrically determined coronary artery atherosclerosis, supporting the use of the iliac artery as a surrogate for the coronary artery in the monkey. Circulating levels of soluble vascular cell adhesion molecule-1 were significantly reduced in the HiTib (P < 0.02) and CEE (P < 0.05) groups, whereas soluble E-selectin was reduced in the CEE group only (P < 0.01). Plasma endothelin-1 was significantly reduced in the LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.01) groups.


CONCLUSIONS
These results suggest that while tibolone caused marked depression of high-density lipoprotein cholesterol and a resultant twofold increase in the total plasma cholesterol/high-density lipoprotein cholesterol ratio, those effects did not result in exacerbation of iliac artery atherosclerosis, perhaps because of beneficial effects on vascular biology or hepatic metabolism.
Register
Thomas C
TC
Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. register@wfubmc.edu
Wagner
Janice D
JD
Zhang
Li
L
Hall
Jason
J
Clarkson
Thomas B
TB
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000097:blood / Q000187:drug effects; D004036:Diet, Atherogenic; D004359:Drug Therapy, Combination; D019040:E-Selectin / Q000097:blood / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood; D004951:Esterification; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology; D005260:Female; D007083:Iliac Artery / Q000187:drug effects* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009652:Norpregnenes / Q000494:pharmacology*; D010052:Ovariectomy; D017698:Postmenopause / Q000378:metabolism*; D045167:Progesterone Congeners / Q000494:pharmacology
D000726:Androgen Antagonists; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D019332:Endothelin-1; D020847:Estrogen Receptor Modulators; D004966:Estrogens, Conjugated (USP); D008075:Lipoproteins, HDL; D009652:Norpregnenes; D045167:Progesterone Congeners; D017258:Medroxyprogesterone Acetate; C027385:tibolone