Comparison of Tibolone and Conjugated Equine Estrogens Effects on Carotid Artery Atherosclerosis of Postmenopausal Monkeys

Abstract

Background and Purpose-Tibolone is a tissue-specific compound that has favorable effects on bone and menopausal symptoms without stimulating endometrium or breast, but lowers concentrations of plasma high-density lipoprotein (HDL) cholesterol (HDLC). This study was designed to determine whether the HDL lowering with tibolone exacerbated common or internal carotid artery atherosclerosis and to evaluate tibolone treatment relative to conjugated equine estrogens (CEE) alone or in combination with medroxyprogesterone acetate (MPA). Methods-Carotid artery atherosclerosis was compared in groups of surgically postmenopausal cynomolgus monkeys treated with CEE, CEEϩMPA, or either of 2 doses of tibolone versus untreated monkeys. Results-Despite a 30% to 52% lowering of HDLC with tibolone, there was no significant effect on carotid artery atherosclerosis. CEE and CEEϩMPA, however, inhibited carotid artery atherosclerosis by Ϸ60%. Key Words: carotid atherosclerosis Ⅲ conjugated equine estrogens Ⅲ hormone replacement therapy Ⅲ tibolone Ⅲ monkeys I schemic stroke among middle-aged and older women is an important public health concern. 1 The exact pathogenesis of these events remains uncertain; however, positive associations with increasing atherosclerosis extent and inverse associations with concentrations of plasma high-density lipoprotein (HDL) cholesterol (HDLC) seem clear. [2][3][4] Although the effect of traditional hormone replacement therapy on stroke prevalence is controversial, [5][6][7][8] it is important to know whether newer menopausal therapies have either adverse or beneficial effects on atherosclerosis of common and internal carotid arteries. Conclusions-InTibolone, used widely in several countries for the treatment of menopausal symptoms 9,10 and for the prevention of postmenopausal osteoporosis, 11,12 is being considered for use in the United States. Tibolone is metabolized into 3 biologically active metabolites; the 3-␤ hydroxy metabolite and the 3-␣ hydroxy metabolite have estrogen agonist properties, whereas the ␦-4 ketoisomer has progestogenic and androgenic effects. The ␦-4 isomer, produced primarily within the endometrium, protects the endometrium from the agonist effects of the 2 estrogenic metabolites. 13,14 Tibolone treatment of postmenopausal women has some beneficial effects on plasma lipid/lipoprotein concentrations (reductions in plasma triglyceride 15,16 and lipoprotein[a] concentrations) 17 ; however, concern has arisen about its "cardiovascular safety" because of reductions in HDLC. 15,18 We have reported the long-term effects of tibolone on coronary artery atherosclerosis of surgically postmenopausal cynomolgus monkeys relative to the effects of conjugated equine estrogen (CEE) treatment and treatment with CEE plus medroxyprogesterone (MPA) administered continuously. 19 Reported herein are the common carotid and internal carotid artery atherosclerosis results from that long-term study. Specifically, we investigated whether the large decreases in HDLC associated with tibolone treatment would ...

Long-term sertraline treatment and depression effects on carotid artery atherosclerosis in premenopausal female primates

“…39 Images of stained sections were captured using a Hammamatsu NanoZoomer digital slide scanner. Intimal area (IA; mm 2 ) and maximum medial thickness (MXMT; mm) were measured as described previously 44 using Image-Pro Plus version 9.1 imaging software (Media Cybernetics Inc, Bethesda, MD). For consistency one investigator (MGSM) measured all arteries, blinded to treatment.…”

Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone

“…4). Comparable plasma levels of the unconjugated tibolone metabolites have previously been found in cynomolgus monkeys given 0.2 mg/kg/day [45][46][47][48] and in postmenopausal women [29][30][31][32][33] treated with 2.5 mg/day. From the individual concentration-time curves, the area under the curve (AUC) values have been calculated and the AUCs of metabolites with similar endocrine effects have been combined: tibolone and 4 -tib (both having androgenic and progestagenic activities); 3␣OH-tib and 3␤OH-tib (both oestrogenic), 3␣ and 3␤ mono-S tib (both inactive, but may be reversed to the corresponding active hydroxy metabolites) and 3␣ and 3␤ diS (both inactive).…”

“…The study was approved by the Institutional Animal Care and Use Committee, performed at Huntingdon Life Sciences (USA and UK) and complied with the Animal Welfare Act Regulations and Good Laboratory Practice standards. The cynomolgus monkeys have been selected in view of their marked similarity to humans as found in a previous study with monkeys fed an atherogenic diet demonstrating protection by tibolone against bone loss, without stimulation of the breast and endometrium [45][46][47][48]. After receiving tibolone (Org OD14, 0.5 mg/kg/day by nasogastric gavage) for 36 days, one monkey was euthanized and autopsied at each of the following times: 1, 1.25, 2.25, 4, 6 and 24 h after the final dose.…”

Tibolone and Its Metabolites Induce Antimitogenesis in Human Coronary Artery Smooth Muscle Cells: Role of Estrogen, Progesterone, and Androgen Receptors

“…Indeed, in a rabbit model, Zandberg et al (9) demonstrated that tibolone prevents high-cholesterol, diet-induced atherosclerosis (cholesterol accumulation in the aortic arch, fatty streak, and foam cell formation) and neointimal thickening both in the presence and absence of endothelial lesions. Similarly, Clarkson et al (25) demonstrated that decreases in HDL levels in response to tibolone did not increase coronary atherosclerosis.…”