Estrogens, Progestins, and Atherosclerosis
http://www.100md.com
《动脉硬化血栓血管生物学》
Department of Pathology/Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
To the Editor:
We feel compelled to comment on the Brief Review "Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials?" by Koh and Sakuma.1 Specifically, although we agree with the suggestion that the effects of estrogen on the vasculature may depend on the extent and severity of existing atherosclerosis, we disagree with the assertion that "added progestin does not negate the beneficial effects of estrogen" and the implication that all progestins affect the vasculature equivalently. Our objections are based on the authors’ incomplete and misleading summary of the animal studies relating to estrogen and progestin effects on atherosclerosis and vascular responsivity.
Koh and Sakuma’s misstatement in this regard is important, because most clinical and epidemiological data on the subject come from studies of populations of older postmenopausal women or those with preexisting atherosclerosis. Evidence is accumulating that hormone replacement therapy may not have cardiovascular benefit in these populations. However, effects on younger women or those with little preexisting atherosclerosis are still unclear and a matter of controversy. Animal studies provide the largest body of data addressing the effects of hormone replacement on atherosclerosis extent and vascular responsivity in individuals with little or no preexisting disease.
The authors state correctly at the beginning of their section Experimental and Animal Studies that "synthetic, not natural progestins, interfered with estrogen protection against vasoconstriction" and cite the studies of Miyagawa et al2 and Miller et al.3 However, they neglect to mention the 2 additional studies of Williams et al4,5 demonstrating antagonistic effects of medroxyprogesterone acetate (MPA) on conjugated equine estrogen (CEE)-induced promotion of endothelium-dependent dilation in atherosclerotic monkeys. The authors also fail to cite a third study of Williams et al6 showing the lack of an antagonistic effect of the progestin nomegestrol acetate. Together, these studies contradict the authors’ contention that progestin does not negate beneficial effects of estrogen. Rather, the data strongly suggest that some progestins, particularly MPA, antagonize the protective effects of estrogen against endothelium-mediated vasoconstriction.
Next, the authors correctly note that cyclic progesterone does not antagonize the effects of estradiol on arterial low-density lipoprotein accumulation in monkeys7 but fail to note a similar lack of an effect of cyclic progesterone on estrogen-mediated inhibition of atherosclerosis in monkeys.8 Furthermore, they fail to cite the studies of Hanke et al in which some, but not all, doses of continuously administered natural progesterone antagonized inhibitory effect of estradiol on atherosclerosis in ovariectomized rabbits.9,10
Finally, when assessing the 2 largest monkey studies bearing on this issue, one reporting that MPA diminishes the atheroprotective effects of estrogen11 and the other finding that MPA does not,12 the authors inexplicably choose to emphasize the latter finding by stating that "this study confirms that MPA did not attenuate the effects of CEE to reduce atherosclerosis." In fact, there are reasons to think that the results of the former study are more clinically relevant than the outcome described in the latter. First, in the Adams study the monkey equivalent of 2.5 mg MPA was administered once a day, as it is to postmenopausal women, whereas in the Clarkson study the same amount was administered in divided doses twice a day. As a result, the endometrial histology in the 2 studies was strikingly different. In the Adams study, endometrial hyperplasia induced by CEE was completely antagonized by MPA13 (as would be expected in postmenopausal women using MPA), whereas in the Clarkson study it was only partially antagonized.14 It seems possible that, because twice daily administration of MPA failed to produce the expected and desired endometrial effect, it would also fail to produce the effect on the artery predicted by the Adams study.
In summary, although in some cases progestins do not appear to antagonize favorable effects of estrogen, it is also clear that in many other cases they do. A complete and unbiased review of existing data does not support the conclusion that "added progestin does not negate the beneficial effect of estrogen" or that all progestins behave similarly. Therefore, it remains possible that some, but not all, forms of hormone replacement therapy might have favorable cardiovascular effects in younger peri- or postmenopausal women without preexisting advanced atherosclerosis. We believe that this remains an important issue that requires further study.
References
Koh KK, Sakuma I. Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials? Arterioscler Thromb Vasc Biol. 2004; 24: 1171–1179.
Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Med. 1997; 3: 324–327.
Miller VM, Vanhoutte P. Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. Am J Physiol. 1991; 261: R1022–R1027.
Williams JK, Honore EK, Washburn, SA, Clarkson, TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries of monkeys. J Am Coll Cardiol. 1994; 24: 1757–1761.
Williams JK, Hall J, Anthony MS, Register TC, Reis SE, Clarkson TB. A comparison of tibolone and hormone replacement therapy on coronary artery and myocardial function in ovariectomized atherosclerotic monkeys. Menopause. 2002; 9: 41–51.
Williams JK, Cline JM, Honore EK, Delansorne R, Paris J. Coadminstration of nomegestrol acetate does not diminish the beneficial effects of estradiol on coronary artery dilator responses in nonhuman primates (Macaca fascicularis). Am J Obstet Gynecol. 1998; 179: 1288–1294.
Wagner JD, Clarkson TB, St Clair RW, Schwenke DC, Shively CA, Adams MR. Estrogen and progesterone therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postemenopausal cynomolgus monkeys. J Clin Invest. 1991; 88: 1995–2002.
Adams MR, Kaplan JR, Manuck SB, Koritinik DR, Parks JS, Wolfe MS, Clarkson TB. Inhibition of coronary artery atherosclerosis by 17-? estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis. 1990; 10: 1051–1057.
Hanke H, Hanke S, Finking G, Muhic-Lohrer A, Muck AO, Schmahl FW, Haasis R, Hombach V. Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits. Quantification of cellular proliferation by bromodeoxyuridine. Circulation. 1996; 94: 175–181.
Hanke, H, Hanke, S, Bruck B, Brehme U, Gugel N, Finking G, Muck AO, Schmahl FW, Hombach V, Haasis R. Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis. Atherosclerosis. 1996; 121: 129–138.
Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 217–221.
Clarkson TB, Anthony MS, Wagner JD. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys. J Clin Endocrinol Metab. 2001; 86: 5396–5404.
Cline JM, Soderqvist G, Register TC, Williams JK, Adams MR, Von Schoultz B. Assessment of hormonally active agents in the reproductive tract of female nonhuman primates. Toxicol Pathol. 2001; 29: 84–90.
Cline JM, Register TC, Clarkson TB. Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys. Menopause. 2002; 9: 242–252.
Estrogens, Progestins, and Atherosclerosis
Kwang Kon Koh
Vascular Medicine and Atherosclerosis Unit, Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea
Ichiro Sakuma
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
In response:
We very much appreciate the concern raised regarding our review article.1
Adams et al claim we asserted in our review that added progestin does not negate the beneficial effects of estrogen and that all progestins affect the vasculature equivalently . They also blamed us for an incomplete citation of the animal studies; however, this is not true. In our review, we quoted and presented both positive and negative studies. Indeed, there have been more than a few studies showing controversial results regarding the effects on vasomotion in both animal and clinical studies. We summarized these controversial results and concluded inconsistency in the effect of vasomotion. However, we could not cover all published animal studies because this particular issue was not a unique scope of our review.
We agree with their hypothesis that some forms of hormone replacement therapy might have favorable cardiovascular effects in younger peri- or postmenopausal women without preexisting advanced atherosclerosis. This conclusion is one of the purposes of our review. We proposed the importance of the stage of atherosclerosis at the time of initiation of hormone or estrogen replacement therapy.
References
Koh KK, Sakuma I. Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized, controlled trials? Arterioscler Thromb Vasc Biol. 2004; 24: 1171–1179.(Michael R. Adams; J. Koud)
To the Editor:
We feel compelled to comment on the Brief Review "Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials?" by Koh and Sakuma.1 Specifically, although we agree with the suggestion that the effects of estrogen on the vasculature may depend on the extent and severity of existing atherosclerosis, we disagree with the assertion that "added progestin does not negate the beneficial effects of estrogen" and the implication that all progestins affect the vasculature equivalently. Our objections are based on the authors’ incomplete and misleading summary of the animal studies relating to estrogen and progestin effects on atherosclerosis and vascular responsivity.
Koh and Sakuma’s misstatement in this regard is important, because most clinical and epidemiological data on the subject come from studies of populations of older postmenopausal women or those with preexisting atherosclerosis. Evidence is accumulating that hormone replacement therapy may not have cardiovascular benefit in these populations. However, effects on younger women or those with little preexisting atherosclerosis are still unclear and a matter of controversy. Animal studies provide the largest body of data addressing the effects of hormone replacement on atherosclerosis extent and vascular responsivity in individuals with little or no preexisting disease.
The authors state correctly at the beginning of their section Experimental and Animal Studies that "synthetic, not natural progestins, interfered with estrogen protection against vasoconstriction" and cite the studies of Miyagawa et al2 and Miller et al.3 However, they neglect to mention the 2 additional studies of Williams et al4,5 demonstrating antagonistic effects of medroxyprogesterone acetate (MPA) on conjugated equine estrogen (CEE)-induced promotion of endothelium-dependent dilation in atherosclerotic monkeys. The authors also fail to cite a third study of Williams et al6 showing the lack of an antagonistic effect of the progestin nomegestrol acetate. Together, these studies contradict the authors’ contention that progestin does not negate beneficial effects of estrogen. Rather, the data strongly suggest that some progestins, particularly MPA, antagonize the protective effects of estrogen against endothelium-mediated vasoconstriction.
Next, the authors correctly note that cyclic progesterone does not antagonize the effects of estradiol on arterial low-density lipoprotein accumulation in monkeys7 but fail to note a similar lack of an effect of cyclic progesterone on estrogen-mediated inhibition of atherosclerosis in monkeys.8 Furthermore, they fail to cite the studies of Hanke et al in which some, but not all, doses of continuously administered natural progesterone antagonized inhibitory effect of estradiol on atherosclerosis in ovariectomized rabbits.9,10
Finally, when assessing the 2 largest monkey studies bearing on this issue, one reporting that MPA diminishes the atheroprotective effects of estrogen11 and the other finding that MPA does not,12 the authors inexplicably choose to emphasize the latter finding by stating that "this study confirms that MPA did not attenuate the effects of CEE to reduce atherosclerosis." In fact, there are reasons to think that the results of the former study are more clinically relevant than the outcome described in the latter. First, in the Adams study the monkey equivalent of 2.5 mg MPA was administered once a day, as it is to postmenopausal women, whereas in the Clarkson study the same amount was administered in divided doses twice a day. As a result, the endometrial histology in the 2 studies was strikingly different. In the Adams study, endometrial hyperplasia induced by CEE was completely antagonized by MPA13 (as would be expected in postmenopausal women using MPA), whereas in the Clarkson study it was only partially antagonized.14 It seems possible that, because twice daily administration of MPA failed to produce the expected and desired endometrial effect, it would also fail to produce the effect on the artery predicted by the Adams study.
In summary, although in some cases progestins do not appear to antagonize favorable effects of estrogen, it is also clear that in many other cases they do. A complete and unbiased review of existing data does not support the conclusion that "added progestin does not negate the beneficial effect of estrogen" or that all progestins behave similarly. Therefore, it remains possible that some, but not all, forms of hormone replacement therapy might have favorable cardiovascular effects in younger peri- or postmenopausal women without preexisting advanced atherosclerosis. We believe that this remains an important issue that requires further study.
References
Koh KK, Sakuma I. Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials? Arterioscler Thromb Vasc Biol. 2004; 24: 1171–1179.
Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Med. 1997; 3: 324–327.
Miller VM, Vanhoutte P. Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. Am J Physiol. 1991; 261: R1022–R1027.
Williams JK, Honore EK, Washburn, SA, Clarkson, TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries of monkeys. J Am Coll Cardiol. 1994; 24: 1757–1761.
Williams JK, Hall J, Anthony MS, Register TC, Reis SE, Clarkson TB. A comparison of tibolone and hormone replacement therapy on coronary artery and myocardial function in ovariectomized atherosclerotic monkeys. Menopause. 2002; 9: 41–51.
Williams JK, Cline JM, Honore EK, Delansorne R, Paris J. Coadminstration of nomegestrol acetate does not diminish the beneficial effects of estradiol on coronary artery dilator responses in nonhuman primates (Macaca fascicularis). Am J Obstet Gynecol. 1998; 179: 1288–1294.
Wagner JD, Clarkson TB, St Clair RW, Schwenke DC, Shively CA, Adams MR. Estrogen and progesterone therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postemenopausal cynomolgus monkeys. J Clin Invest. 1991; 88: 1995–2002.
Adams MR, Kaplan JR, Manuck SB, Koritinik DR, Parks JS, Wolfe MS, Clarkson TB. Inhibition of coronary artery atherosclerosis by 17-? estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis. 1990; 10: 1051–1057.
Hanke H, Hanke S, Finking G, Muhic-Lohrer A, Muck AO, Schmahl FW, Haasis R, Hombach V. Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits. Quantification of cellular proliferation by bromodeoxyuridine. Circulation. 1996; 94: 175–181.
Hanke, H, Hanke, S, Bruck B, Brehme U, Gugel N, Finking G, Muck AO, Schmahl FW, Hombach V, Haasis R. Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis. Atherosclerosis. 1996; 121: 129–138.
Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 217–221.
Clarkson TB, Anthony MS, Wagner JD. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys. J Clin Endocrinol Metab. 2001; 86: 5396–5404.
Cline JM, Soderqvist G, Register TC, Williams JK, Adams MR, Von Schoultz B. Assessment of hormonally active agents in the reproductive tract of female nonhuman primates. Toxicol Pathol. 2001; 29: 84–90.
Cline JM, Register TC, Clarkson TB. Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys. Menopause. 2002; 9: 242–252.
Estrogens, Progestins, and Atherosclerosis
Kwang Kon Koh
Vascular Medicine and Atherosclerosis Unit, Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea
Ichiro Sakuma
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
In response:
We very much appreciate the concern raised regarding our review article.1
Adams et al claim we asserted in our review that added progestin does not negate the beneficial effects of estrogen and that all progestins affect the vasculature equivalently . They also blamed us for an incomplete citation of the animal studies; however, this is not true. In our review, we quoted and presented both positive and negative studies. Indeed, there have been more than a few studies showing controversial results regarding the effects on vasomotion in both animal and clinical studies. We summarized these controversial results and concluded inconsistency in the effect of vasomotion. However, we could not cover all published animal studies because this particular issue was not a unique scope of our review.
We agree with their hypothesis that some forms of hormone replacement therapy might have favorable cardiovascular effects in younger peri- or postmenopausal women without preexisting advanced atherosclerosis. This conclusion is one of the purposes of our review. We proposed the importance of the stage of atherosclerosis at the time of initiation of hormone or estrogen replacement therapy.
References
Koh KK, Sakuma I. Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized, controlled trials? Arterioscler Thromb Vasc Biol. 2004; 24: 1171–1179.(Michael R. Adams; J. Koud)