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Carotid plaque regression on oestrogen replacement: A pilot study
Eur J Vasc Endovasc Surg 11, 347-348 (1996)
Carotid Plaque Regression on Oestrogen Replacement: A Pilot Study A n d r e a A k k a d 1, Tim H a r t s h o r n e 2, P e t e r R. F, Bell 2 and F a r o o k A I - A z z a w i 1. 1Menopause Research Unit, Department of Obstetrics and Gynaecology and 2Vascular Studies Unit, Department of Surgery, Faculty of Medicine, University of Leicester, Leicester, U.K. Objective: To investigate the effect of unopposed oestrogen on atheromatous carotid plaques. Subjects: Seventeen postmenopausaI women with known carotid disease. Methods: Carotid intimal thickness and plaque length and thickness were measured prior to and following 3 and 6 months of treatment, using Duplex ultrasound. A total of 22 plaques werefollowed up. Results: There was a reduction in plaque length after 3 (-8.14%, p =0.001) and 6 months (-28%, p = 0.001) of treatment. The reduction in plaque thickness (-18%, p =0.004) was significant after 6 months of treatment. Reductions in intimaI thickness were not statistically significant. Conclusion: Our results suggest that oestrogen replacement is associated with significant plaque regression.
Introduction
on atheromatous plaques in carotid arteries of naturally or surgically menopausal women. Atherosclerosis related ischaemic vascular events kill The study was conducted in the Menopause more women than all forms of cancer together. 1 When Research Unit, Department of Obstetrics and Gynaecompared to premenopausal women, the athero- colog~ in collaboration with the Vascular Studies sclerotic risk is 3.4 times higher in women after natural Unit, Department of Surgery, University of Leicester. menopause, and up to 5.5 times greater in women Seventeen postmenopausal women with known after bilateral oophorectomy. 2 Animal models have carotid disease (mean age 66.7 years, range 55-75 provided suggestive evidence that atheroma forma- years), were treated with unopposed oestrogen for 6 tion can be inhibited or even reversed by oestrogen months. Their mean time since menopause was 13.6 treatment. The Clarkson group demonstrated a sig- years (5-20 years). Two women were oophorectonificant reduction in atherosclerosis in cynomolgus mised, the remaining 15 had undergone a natural macaques fed a high fat diet and subsequently treated menopause. Fourteen of the participating patients had with oral contraceptives. They observed a deficit of an intact uterus. None of the participating women had 50-75% from the expected plaque extent, rising to a history of previous sex steroid exposure, i.e. contra75-85% when considering the high risk group of ceptive pill or HRT. Oestrogen replacement was given animals onl~ i.e. animals with the most atherogenic orally as Hormonin (600/~g micronised 17~-oestradiol, lipid profile. 3 This finding is particularly interesting, 270/~g oestriol and 1.4 mg oestrone) one tablet daily. as the atheroma of cynomolgus monkeys has been Two of the patients were taking concomitant Simvasfound resistant to regression with lipid lowering tatin, one a calcium antagonist and ten were taking regimens. 4 Studies with angiographic end points have Aspirin. suggested that certain drug regimens may favour The patients' carotid arteries were scanned using plaque regression in humans. 5 In this pilot study we Diasonics VST Masters Duplex Ultrasound scanner set out to examine the effect of oestrogen replacement (Diasonics Ultrasound Inc., Milpitas, CA, U.S.A.) with a 5 MHz linear array scan probe. Intimal thickness (IMT) as well as plaque length (PL) and plaque *Please address all correspondence to: Farook A1-Azzawi, Meno- thickness (PT) were measured prior to treatment and pause Research Unit, Department of Obstetrics and Gynaecolog~ Clinical Sciences Building, Leicester Royal Infirmar~ Leicster LE2 subsequently, following 3 and 6 months of oestrogen 7LX, U.K. replacement. A total of 22 atheromatous plaques were 1078-5884/96/030347+ 02 $12.00/0 © 1996W. B. Saunders Company Ltd.
348
A. Akkad et aL
found suitable for follow-up. All analysed scans were performed by one operator, who was blinded to previous measurements. Intra-observer variability was assessed in six serial measurements of IMT, PT and PL in six carotid arteries (4 patients), i.e. 108 serial measurements. The -10 operator was blinded to all measurements during the validation session. Coefficient of Variation was 8% for -20 IMT, 8% for PL and 10% for PT. c~ Non-hysterectomised women underwent outpatient -30 hysteroscopy under local anaesthetic following 6 months of treatment, to exclude endometrial hyper-40 plasia. Standard panoramic CO2 hysteroscopy was performed as described previously. 6 Ten (67%) patients had maintained atrophic endometrium and in -50 I I 3 months ERT 6 months ERT three (20%) patients it was found to be weakly proliferative. Two (13%) of the 15 patients with an 1. Reduction in plaque length and plaque thickness on intact uterus developed simple hyperplasia of the Fig. oestrogen replacement (ERT) in % change from baseline with the endometrium, which regressed to atrophic endomet- 95% Confidence Interval. (El) plaque length; ( , ) plaque thickness. rium following a 6 week course of 10 mg Medrox- *p < 0.004; **p < 0.001. yprogesterone acetate daily. This was confirmed by a repeat hysteroscopy and endometrial biopsy. References Obtained measurements of IMT, PT and PL were analysed using Analysis of Variance (ANOVA) for 1 KNOPP RH. The effects of postmenopausal estrogen therapy on repeated measurements, All results are reported as the incidence of atherosclerotic vascular disease. Obstet Gynecol 1988; 72: 23S-30S. percent reduction from baseline, with the 95% Con2 WITTEMANJCM, GROBBEEDE, KOK FJ, HOFMAN A, VALKENBURG fidence Interval (CI). HA. Increased risk of atherosclerosis in women after the A reduction in mean IMT was observed at 3 (-5%, menopause. Br Med J 1989; 298: 642-644. 3 ADAMS MR, WILLIAMSJK, CLAR_KSONTB, JAYO MJ. Effects of 95% C1-17 to 7) and at 6 months (-6%, 95% C1-26 to oestrogens and progestogens on coronary atherosclerosis and 14). This was not statistically significant. Plaque length osteoporosis in monkeys. Baillieres Clin Obstet Gynaecol 1991; 5: was significantly reduced at 3 (-8%, 95% C1-15 to -2, 915-934. 4 HOLLANDERWr KIRKPATKICKB, PADDOCKJ, COLOMBOM, NAGRAJS, p = 0.001) and at 6 months (-28%, 95% CI -42 to -13, PRUSTYS. Studies on the progression and regression of coronary p = 0.001) of oestrogen replacement. Plaque thickness and peripheral atherosclerosis in the cynomolgus monkey. I. was also reduced at 3 (-1%, 95% C1-12 to 10, NS) and Effects of dipyridamole and aspirin. Exp Mol Pathol 1979; 30: 55-73. 6 months (-18%, 95% CI -30 to -6, p=0.004) of 5 WATERSD, LESPERANCEJ. Regression of coronary atherosclerosis: treatment (Fig. 1). An achievable goal? Review of results from recent clinical trials. Although plaque recession has been observed with Am J Med 1991; 91(Suppl. 1B): 10-17. 6 TAYLOR PJ, HAMOU J. Hysteroscopy. J Reprod Med 1983; 28: lipid lowering agents, ~ the plaques of the two patients 359-389. taking Simvastatin in this study in fact did not reduce 7 DAVIESMJ, KraKLERDM, KATZD. Atherosclerosis: inhibition or in size. Calcium antagonists and Aspirin may act regression as therapeutic possibilities. Br Heart J 1991; 65: 302-310. synergistically or inhibit atherogenesis, 57 ' but there is no evidence that they contribute to plaques regression. Our data therefore suggest significant plaque regres- Accepted 18 August 1995 sion in association with oestrogen replacement.
Eur J Vasc Endovasc Surg Vol 11, April 1996
Carotid Plaque Regression on Oestrogen Replacement: A Pilot Study A n d r e a A k k a d 1, Tim H a r t s h o r n e 2, P e t e r R. F, Bell 2 and F a r o o k A I - A z z a w i 1. 1Menopause Research Unit, Department of Obstetrics and Gynaecology and 2Vascular Studies Unit, Department of Surgery, Faculty of Medicine, University of Leicester, Leicester, U.K. Objective: To investigate the effect of unopposed oestrogen on atheromatous carotid plaques. Subjects: Seventeen postmenopausaI women with known carotid disease. Methods: Carotid intimal thickness and plaque length and thickness were measured prior to and following 3 and 6 months of treatment, using Duplex ultrasound. A total of 22 plaques werefollowed up. Results: There was a reduction in plaque length after 3 (-8.14%, p =0.001) and 6 months (-28%, p = 0.001) of treatment. The reduction in plaque thickness (-18%, p =0.004) was significant after 6 months of treatment. Reductions in intimaI thickness were not statistically significant. Conclusion: Our results suggest that oestrogen replacement is associated with significant plaque regression.
Introduction
on atheromatous plaques in carotid arteries of naturally or surgically menopausal women. Atherosclerosis related ischaemic vascular events kill The study was conducted in the Menopause more women than all forms of cancer together. 1 When Research Unit, Department of Obstetrics and Gynaecompared to premenopausal women, the athero- colog~ in collaboration with the Vascular Studies sclerotic risk is 3.4 times higher in women after natural Unit, Department of Surgery, University of Leicester. menopause, and up to 5.5 times greater in women Seventeen postmenopausal women with known after bilateral oophorectomy. 2 Animal models have carotid disease (mean age 66.7 years, range 55-75 provided suggestive evidence that atheroma forma- years), were treated with unopposed oestrogen for 6 tion can be inhibited or even reversed by oestrogen months. Their mean time since menopause was 13.6 treatment. The Clarkson group demonstrated a sig- years (5-20 years). Two women were oophorectonificant reduction in atherosclerosis in cynomolgus mised, the remaining 15 had undergone a natural macaques fed a high fat diet and subsequently treated menopause. Fourteen of the participating patients had with oral contraceptives. They observed a deficit of an intact uterus. None of the participating women had 50-75% from the expected plaque extent, rising to a history of previous sex steroid exposure, i.e. contra75-85% when considering the high risk group of ceptive pill or HRT. Oestrogen replacement was given animals onl~ i.e. animals with the most atherogenic orally as Hormonin (600/~g micronised 17~-oestradiol, lipid profile. 3 This finding is particularly interesting, 270/~g oestriol and 1.4 mg oestrone) one tablet daily. as the atheroma of cynomolgus monkeys has been Two of the patients were taking concomitant Simvasfound resistant to regression with lipid lowering tatin, one a calcium antagonist and ten were taking regimens. 4 Studies with angiographic end points have Aspirin. suggested that certain drug regimens may favour The patients' carotid arteries were scanned using plaque regression in humans. 5 In this pilot study we Diasonics VST Masters Duplex Ultrasound scanner set out to examine the effect of oestrogen replacement (Diasonics Ultrasound Inc., Milpitas, CA, U.S.A.) with a 5 MHz linear array scan probe. Intimal thickness (IMT) as well as plaque length (PL) and plaque *Please address all correspondence to: Farook A1-Azzawi, Meno- thickness (PT) were measured prior to treatment and pause Research Unit, Department of Obstetrics and Gynaecolog~ Clinical Sciences Building, Leicester Royal Infirmar~ Leicster LE2 subsequently, following 3 and 6 months of oestrogen 7LX, U.K. replacement. A total of 22 atheromatous plaques were 1078-5884/96/030347+ 02 $12.00/0 © 1996W. B. Saunders Company Ltd.
348
A. Akkad et aL
found suitable for follow-up. All analysed scans were performed by one operator, who was blinded to previous measurements. Intra-observer variability was assessed in six serial measurements of IMT, PT and PL in six carotid arteries (4 patients), i.e. 108 serial measurements. The -10 operator was blinded to all measurements during the validation session. Coefficient of Variation was 8% for -20 IMT, 8% for PL and 10% for PT. c~ Non-hysterectomised women underwent outpatient -30 hysteroscopy under local anaesthetic following 6 months of treatment, to exclude endometrial hyper-40 plasia. Standard panoramic CO2 hysteroscopy was performed as described previously. 6 Ten (67%) patients had maintained atrophic endometrium and in -50 I I 3 months ERT 6 months ERT three (20%) patients it was found to be weakly proliferative. Two (13%) of the 15 patients with an 1. Reduction in plaque length and plaque thickness on intact uterus developed simple hyperplasia of the Fig. oestrogen replacement (ERT) in % change from baseline with the endometrium, which regressed to atrophic endomet- 95% Confidence Interval. (El) plaque length; ( , ) plaque thickness. rium following a 6 week course of 10 mg Medrox- *p < 0.004; **p < 0.001. yprogesterone acetate daily. This was confirmed by a repeat hysteroscopy and endometrial biopsy. References Obtained measurements of IMT, PT and PL were analysed using Analysis of Variance (ANOVA) for 1 KNOPP RH. The effects of postmenopausal estrogen therapy on repeated measurements, All results are reported as the incidence of atherosclerotic vascular disease. Obstet Gynecol 1988; 72: 23S-30S. percent reduction from baseline, with the 95% Con2 WITTEMANJCM, GROBBEEDE, KOK FJ, HOFMAN A, VALKENBURG fidence Interval (CI). HA. Increased risk of atherosclerosis in women after the A reduction in mean IMT was observed at 3 (-5%, menopause. Br Med J 1989; 298: 642-644. 3 ADAMS MR, WILLIAMSJK, CLAR_KSONTB, JAYO MJ. Effects of 95% C1-17 to 7) and at 6 months (-6%, 95% C1-26 to oestrogens and progestogens on coronary atherosclerosis and 14). This was not statistically significant. Plaque length osteoporosis in monkeys. Baillieres Clin Obstet Gynaecol 1991; 5: was significantly reduced at 3 (-8%, 95% C1-15 to -2, 915-934. 4 HOLLANDERWr KIRKPATKICKB, PADDOCKJ, COLOMBOM, NAGRAJS, p = 0.001) and at 6 months (-28%, 95% CI -42 to -13, PRUSTYS. Studies on the progression and regression of coronary p = 0.001) of oestrogen replacement. Plaque thickness and peripheral atherosclerosis in the cynomolgus monkey. I. was also reduced at 3 (-1%, 95% C1-12 to 10, NS) and Effects of dipyridamole and aspirin. Exp Mol Pathol 1979; 30: 55-73. 6 months (-18%, 95% CI -30 to -6, p=0.004) of 5 WATERSD, LESPERANCEJ. Regression of coronary atherosclerosis: treatment (Fig. 1). An achievable goal? Review of results from recent clinical trials. Although plaque recession has been observed with Am J Med 1991; 91(Suppl. 1B): 10-17. 6 TAYLOR PJ, HAMOU J. Hysteroscopy. J Reprod Med 1983; 28: lipid lowering agents, ~ the plaques of the two patients 359-389. taking Simvastatin in this study in fact did not reduce 7 DAVIESMJ, KraKLERDM, KATZD. Atherosclerosis: inhibition or in size. Calcium antagonists and Aspirin may act regression as therapeutic possibilities. Br Heart J 1991; 65: 302-310. synergistically or inhibit atherogenesis, 57 ' but there is no evidence that they contribute to plaques regression. Our data therefore suggest significant plaque regres- Accepted 18 August 1995 sion in association with oestrogen replacement.
Eur J Vasc Endovasc Surg Vol 11, April 1996