Published online before print March 18, 2004,
doi:10.1161/01.ATV.0000126372.14332.70
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:955.
© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins
Prevention of Coronary Hyperreactivity in Preatherogenic Menopausal Rhesus Monkeys by Transdermal Progesterone
R. Kent Hermsmeyer ;Rajesh G. Mishra ;Dusan Pavcnik ;Barry Uchida ;Michael K. Axthelm ;Frank Z. Stanczyk ;Kenneth A. Burry ;D. Roger Illingworth ;Juan Carlos Kaski ;Frank J. Nordt
From Dimera Incorporated (R.K.H., R.G.M.) and Oregon Health and Science University (D.P., B.U., M.K.A., K.A.B., D.R.I.), Portland, Ore; University of Southern California (F.Z.S.), Los Angeles, Calif; St. George's Hospital Medical School (J.C.K.), London, UK; and Rhein Consulting Laboratories (F.J.N.), Portland, Ore.
Correspondence to Dr R. Kent Hermsmeyer, Dimera Incorporated, 2525 NW Lovejoy, Suite 311, Portland, OR 97210. E-mail rkh@dimera.net
Objective- To test if transdermal progesterone (P) confers coronary vascular protection in surgically menopausal preatherosclerotic rhesus monkeys.
Methods and Results- Ovariectomized rhesus monkeys fed an atherogenic diet (AD) for 19 months were treated with an investigational transdermal P cream (n=7) or identical placebo cream (n=5) for 4 weeks. Aorta and carotids showed fatty streaks and Oil Red O staining demonstrated lipid deposition. Serum P levels in P-treated rhesus monkeys (0.6 ng/mL) were significantly greater than placebo (0.2 ng/mL). Significant elevation of cholesterol, LDL cholesterol, and HDL cholesterol, was noted in all animals. Lp(a) was significantly attenuated in the AD-fed P-treated monkeys. Coronary angiographic experiments stimulating vasoconstriction by intracoronary injections of serotonin plus U46619 showed exaggerated prolonged actions amplified by AD, but significant protection against severe prolonged vasoconstriction in P-treated monkeys. Immunocytochemistry confirmed co-expression of P and thromboxane prostanoid (TP) receptors in coronaries and aorta. Western blotting demonstrated TP receptor attenuation in vascular muscle after P treatment.
Conclusions- Coronary hyperreactivity, a putative component of coronary artery disease mediated via increased vascular muscle thromboxane prostanoid receptors, can be prevented by subphysiological levels of P, not only in nonatherosclerotic (previously shown) but also in preatherosclerotic primates.
http://atvb.ahajournals.org/cgi/content/abstract/24/5/955
The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 1 265-271
Copyright © 1999 by The Endocrine Society
Original Studies
Two Antiatherogenic Effects of Progesterone on Human Macrophages; Inhibition of Cholesteryl Ester Synthesis and Block of Its Enhancement by Glucocorticoids 1
Wanli Cheng, Ontario D. Lau and Nada A. Abumrad
Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York, 11794
Address all correspondence and requests for reprints to: Nada A. Abumrad, Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794-8661. E-mail: nadaa@physiology.pnb.sunysb.edu.
The effects of progesterone and estradiol on cholesteryl ester (CE) formation by monocyte-derived human macrophages were examined. Formation was assessed from incorporation of 14 C-cholesterol during a 20-h incubation with hormone and from that of 3H-oleate (3 h) after hormone removal. Progesterone inhibited cholesterol into CE and decreased CE cellular levels. Inhibition: 1) was reversed by progesterone removal; 2) was independent of the progesterone receptor (not blocked by the receptor antagonist RU40555); and 3) exhibited specific structural requirements; 11 -OH-progesterone was inhibitory, whereas its stereoisomer 11ß-OH-progesterone was not. In contrast to progesterone, estradiol was ineffective. We had reported that dexamethasone enhanced CE accumulation by human macrophages (1). In this study, we describe similar effects of the endogenous steroid, cortisol, and of the most widely prescribed glucocorticoid, prednisolone. Both steroids increased CE formation from two folds, in the presence of cholesterol-liposomes, to five folds, in the presence of modified low-density lipoprotein. Progesterone (0.1-1 µmol/L), added during glucocorticoid treatment, blocked this increase. The progesterone block: 1) was duplicated by the steroid receptor inhibitor RU40555; 2) was not reversed by hormone removal; and 3) reflected inhibition of glucocorticoid-induced increases in messenger RNA for acyl-CoA-cholesterol:acyl transferase. Thus, progesterone exerted two effects on macrophages: it acutely inhibited CE formation, and it prevented glucocorticoid-induced increases in acyl-CoA-cholesterol-acyl transferase gene expression and CE synthesis.
http://jcem.endojournals.org/cgi/content/abstract/84/1/265
Eur J Obstet Gynecol Reprod Biol. 1993 Jan;48(1):61-8. Links
Low-dose progesterone therapy in oestrogenised postmenopausal women: effects on plasma lipids, lipoproteins and liver function parameters.
Bolaji II ,
Grimes H ,
Mortimer G ,
Tallon DF ,
Fottrell PF ,
O'Dwyer EM .
Department of Obstetrics and Gynaecology, University College, Galway, Ireland.
BACKGROUND--Cardiovascular disease among older women is a major health problem and is the leading cause of death in this group in developed countries. The risk is reduced in oestrogen users secondary to favourable lipid changes, but the beneficial effect of oestrogen may be counteracted when concomitant progestogens are administered. OBJECTIVE--To study the effects of a novel hormone replacement therapy regimen on liver enzymes, lipids and lipoproteins in postmenopausal women. DESIGN--Prospective open, non-comparative trial for 12 months. METHODS--40 healthy postmenopausal women, (mean age +/- S.D.), 53.5 +/- 3 years received 0.625 mg of conjugated equine oestrogen daily and 100 mg of micronised oral progesterone (P) for the first 23 days every calendar month for 12 months without interruption. MAIN OUTCOME MEASURE--Gonadotrophins, liver function parameters and lipoproteins were measured before treatment and at the 6th, 9th and 12th months of treatment. RESULTS--Compliance with treatment was confirmed by a 33% decrease in mean serum level of follicle stimulating hormone at the end of 1 year of treatment. In the same period, the mean serum cholesterol, LDL and LDL/HDL ratio decreased by 6%, 16% and 23% of the base line levels, respectively. The percentage changes in triglycerides and HDL from the basal levels were +32% (P < 0.001) and +15% (P < 0.05), respectively. CONCLUSION--These results indicate that near continuous administration of fixed low-dose of P has no adverse effects on the lipid milieu of postmenopausal women when combined with long-term continuous oestrogen replacement therapy provided women with borderline triglyceridaemia are excluded.
PMID: 8449263 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8449263&dopt=Citation
Acta Endocrinol (Copenh). 1993 Aug;129(2):130-3. Links
Differences in serum lipids, lipoproteins, sex hormone binding globulin and testosterone between the follicular and the luteal phase of the menstrual cycle.
Schijf CP ,
van der Mooren MJ ,
Doesburg WH ,
Thomas CM ,
Rolland R .
Department of Obstetrics and Gynaecology, University of Nijmegen, The Netherlands.
Fifty-four healthy women were studied during the follicular and the luteal phase of one menstrual cycle to determine possible cyclic influences on several parameters. After a 12-h overnight fast, blood samples were obtained between 08.00 h and 09.30 h and processed for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoproteins A-I and B and total triglycerides. In the same samples we also measured serum concentrations of follicle-stimulating hormone, luteinizing hormone, 17 beta-oestradiol, progesterone, sex hormone binding globulin and testosterone. Serum total cholesterol, low-density lipoprotein cholesterol and the related apolipoprotein B were decreased significantly with 0.35 mmol/l, 0.44 mmol/l and 15 mg/l, respectively, during the luteal phase as compared to the follicular phase (p < or = 0.01). The ratios of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and of total cholesterol/high-density lipoprotein cholesterol were also significantly lower (p < 0.01) in the luteal phase because high-density lipoprotein cholesterol and its major carrier apolipoprotein A-I as well as serum triglycerides remained unchanged in the two cycle phases compared. Sex hormone binding globulin was significantly higher (p < 0.001) in the luteal phase than in the follicular phase of the investigated cycles, whereas serum testosterone remained unchanged in the two cycle phases compared. Therefore, the free androgen index decreased in the luteal phase (p < 0.01). These results indicate the necessity to define the cycle phase in which blood has been collected during control cycles in studies concentrating on possible effects of oral contraceptives or other administered sex steroids on serum lipids, lipoproteins and androgen metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 8372597 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8372597&dopt=Citation
Journal of Clinical Endocrinology & Metabolism, Vol 73, 373-379, Copyright © 1991 by Endocrine Society
Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with utrogestan in menopausal women
S Moorjani, A Dupont, F Labrie, B De Lignieres, L Cusan, P Dupont, J Mailloux and PJ Lupien
Lipid Research Unit, Laval University Hospital, Sainte-Foy, Quebec, Canada.
Sixty-three postmenopausal women were assigned to four treatment groups and received either Premarin or percutaneous 17 beta-estradiol (Oestrogel) alone or in combination with micronized progesterone (Utrogentan). The oral administration of estrogen alone to hysterectomized women resulted in: 1) a significant increase in triglyceride levels in plasma and all major lipoprotein fractions, 2) a significant increase in very low density lipoprotein cholesterol, 3) a significant decrease in low density lipoprotein (LDL) cholesterol but not LDL apo B concentration, 4) a significant increase in all the lipid components of high density lipoprotein (HDL) as well as apo AI, 5) and a significant increase in HDL2 cholesterol. In contrast, percutaneous administration of estrogen to hysterectomized women only increased HDL2 cholesterol and the triglyceride and cholesterol content of the whole HDL fraction. These results suggest that the route of estrogen administration is important in determining effects on lipoprotein metabolism. The same two estrogens were given to women with natural menopause, along with utrogestan, a micronized progesterone. The simultaneous administration of Utrogestan reversed the HDL cholesterol elevating effect of percutaneous estrogen alone, but it had no effect on other plasma lipoproteins. On the other hand, utrogestan in combination with oral estrogen had several potential beneficial effects on plasma lipoproteins. This combination did not negate the effects of oral estrogen alone on HDL, rather it further increased the concentrations of HDL cholesterol and apo AI. It also did not negate the LDL cholesterol lowering effect of oral estrogen alone. Furthermore, utrogestan lowered the magnitude of hypertriglyceridemia induced by oral estrogen alone. These results suggest that Utrogestan has lower potency of androgenic action and has desirable effects when given in cyclic combination with estrogen.
http://jcem.endojournals.org/cgi/content/abstract/73/2/373
International Journal of Epidemiology
Volume 19, Number 2 Pp. 297-302
© 1990 Oxford University Press
Relationship of Menopausal Status and Sex Hormones to Serum Lipids and Blood Pressure
ZUNYOU WU ,XIKE WU and YANWEN ZHANG
Department of Epidemiology, Anhui Medical University Meishan Road, Hefei, Anhui Province, P. R. of China.
Wu Z (Department of Epidemiology, Anhui Medical University, Meishan Road, Hefei, Anhui Province, P.R. of China), Wu X and Zhang Y. Relationship of menopausal status and sex hormones to serum lipids and blood pressure. International Journal of Epidemiology 1990, 19 : 297-302.
Arterial blood pressure and serum lipids were measured in 598 Chinese women aged 40-54 years. Menopausal or post-menopausal women had higher means of serum cholesterol, triglyceride and HDL-cholesterol, and had higher prevalence of hypertension, hypotension, hypercholesterolaemia and hypertriglyceridaemia than premenopausal counterparts. There were no differences in means of systolic and diastolic pressures among pre-menopausal, menopausal and postmenopausal women. Fat Synergic Index was first used in this study instead of Quetelex Index, and it was found that Fat Synergic Index is the strongest factor which affects serum cholesterol, triglyceride, HDL-cholesterol and systolic and diastolic blood pressure in multiple linear regression analyses. The role of oestradiol, progesterone and testosterone in three serum-lipid multiple regression models are different, but they are similar in systolic and diastolic blood pressure regression models. Conditional logistic regression analysis found that progesterone is a protective factor only and testosterone is one of the risk factors for hypertension.
Revised 1 August 1989
http://ije.oxfordjournals.org/cgi/content/abstract/19/2/297
