Article in press - uncorrected proof Horm Mol Biol Clin Invest 2010;3(3):449–451 2010 by Walter de Gruyter • Berlin • New York. DOI 10.1515/HMBCI.2010.071
Progestogen effects at vascular level: the endothelial cells
Paolo Mannella*, Tommaso Simoncini and Andrea Riccardo Genazzani Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
Abstract Progesterone and progestogens are active molecules on the cardiovascular system. However, their action is not as wellcharacterized as the effects of estrogens. Data of the last clinical trials suggest the possibility of harmful cardiovascular effects of progestogens, and the debate on the role of progesterone and progestins on the vascular wall is open. From an experimental point of view, each progestogen presents typical effects on the cardiovascular system and their administration results in diverse modifications of the effects of estrogens, sometimes acting synergically, others being neutral or antagonizing effects of estrogens. In this paper, we review the most important data from in vivo and in vitro studies which have been published on the effects of progesterone and progestogens on vascular cells. Endothelium is a target tissue for sex steroids and progesterone is able to regulate endothelial cell function and morphology. Even if the perfect molecule does not exist, the understanding of the molecular basis of each progestogen in vascular tissue is therefore of paramount importance for the most appropriate use with an optimal cardiovascular profile. Keywords: cardiovascular progestogens.
system;
endothelial
cells;
Introduction The cardiovascular system is a target for progesterone (1). Sex steroid hormones have major metabolic effects, resulting principally in modifications of the lipid profile of carbohydrate metabolism and of the hemostatic system. Although these effects principally derive from direct actions on the liver, they have a profound effect on the function of the cardiovascular system. *Corresponding author: Paolo Mannella, MD, PhD, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma, 57, 56100 Pisa, Italy Phone (Office): q39-050-993523, (Lab): q39-050-992690, Fax: q39-050-553410, E-mail: [email protected] Received November 15, 2010; accepted November 16, 2010
However, when discussing progestogens a large class of molecules is considered, which present different functions, receptor affinity and actions in several tissues (Table 1) (2). In particular, each progestogen acts differently on the cardiovascular system (3), and in the past years this assumption has been confirmed from different clinical trials as well as the Women’s Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement Study (HERS). From a practical point of view, progesterone receptors (PRs) are widespread in the entire cardiovascular system, and the two isoforms (PR-A and PR-B) have been demonstrated at the endothelial level in the coronary artery, as well as in the aorta and vascular smooth muscle cells (4, 5).
Vascular cells and progesterone activity The direct role of progesterone on cardiovascular tissues is only partially clarified. Animal studies in PR knockout mice demonstrated that the absence of PRs induces a greater vascular medial hypertrophy and a greater vascular smooth muscle cell proliferation after vascular injury in comparison to control animals (6). In in vivo coronary studies, progesterone exerts protective actions against vasoconstrictor stimuli, modulating the provasodilation response (7) but not all progestogens act similarly. Medroxyprogesterone acetate (MPA) but not progesterone induces coronary hyperreactivity in intact male rhesus monkeys (4). This difference can be extended to other synthetic progestinic compounds (8). Indeed, this action could mediate or interfere with the activity of estrogen on the cardiovascular system. In non-human primates, the contribution of progestins has been investigated, showing the presence of significant modifying effects on estrogen-induced vascular effects (9). The coadministration of natural progesterone did not alter the effect of estrogen. However, in the same model, the addition of cyclic or continuous MPA inhibited the vasodilatory effect of estrogen responses by 50% (10). These data have been confirmed by other groups, showing that progesterone plus estradiol protects, but MPA plus estradiol does not, against coronary artery vasospasm (11), thus highlighting the difference between natural progesterone and MPA. A possible explanation is that this action depends on their androgen agonistic/antagonistic activity (4). In contrast to MPA, the non-androgenic progestin nomegestrol acetate presents protective effects and does not impair the beneficial effects of estrogen on the coronary dilator response in monkeys (8, 12). However, although the concept of deleterious effects of androgenic molecules on the blood vessels is longstanding, this is far from being ascertained, and androgens could have anti-atherogenic and vasodilatory actions at the vascular level.
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2010/052
Article in press - uncorrected proof 450 Mannella et al.: Progestogens and endothelial cells
Table 1 Classification and pharmacology of progestins according to Schindler and coworkers (2). Progestin
Progestogenic AntiAntiEstrogenic Androgenic AntiGlucocorticoid Antigonadotropic estrogenic androgenic mineralocorticoid
Progesterone q Dydrogesterone q Medrogestone q 17a-Hydroxy-derivatives Chlormadinone q acetate Cyproterone acetate q Megestrol acetate q Medroxyq progesterone-acetate 19-Nor-progesterone-derivatives Nomegestrol acetate q Promegestone q Trimegestone q Spirolactone-derivatives Drospirenone q 19-Nortestosterone-derivatives Norethisterone q Lynestrenol q " Norethinodrel Levonorgestrel q Norgestimate q 3-Keto-desogestrel q Gestoden q Dienogest q
q – q
q q q
– – –
– – –
" " "
q – –
q " –
q
q
–
–
q
q
–
q q q
q q q
– – –
– " "
qq q –
q q q
– – –
q q q
q q q
– – –
– – –
" – "
– – –
– – "
q
q
–
–
q
–
q
q q q q q q q q
q q " q q q q "
q q q – – – – "
q q " q q q q –
– – – – – – – q
– – – – – – q –
– – – – – – q –
Progesterone and endothelial function However, in the past years, different research groups demonstrated a direct action of progesterone and progestogens on endothelial cells via the recruitment and activation of the PR (13). In ovariectomized rats, progesterone administration induces endothelial nitric oxide synthase (eNOS) activity and expression and therefore the release of nitric oxide, but this effect is not exerted by MPA. Similarly, when estrogen is added, progesterone enhances the estrogen-dependent effect on eNOS, whereas MPA prevents it (13). In different studies (13–16), we demonstrated different effects of progestogens on eNOS expression and activity (Figure 1).
Figure 1 Progesterone (P), levonorgestrel (LNG) and cyproterone acetate (CYP) significantly induce eNOS expression. Medroxyprogesterone acetate (MPA), megestrol (Meg) and norethisterone acetate (NETA) are inactive.
In addition, dydrogesterone and drospirenone shares with progesterone the ability to induce the rapid activation of eNOS, as well as to potentiate the effects induced by estrogen (16, 17). In postmenopausal women, progesterone has synergistic vasodilatory effects on coronary blood flow and myocardial ischemia when added to estrogens. In contrast, MPA does not share this action, therefore indicating that, on this particular target, all progestins are not the same (18). The pharmacology difference between progestogens is pivotal to understand divergent effects of these molecules on the development and progression of the atherosclerotic plaque. In this regard, the relevance of the affinity of MPA for the glucocorticoid receptor becomes evident when the proinflammatory signal transduction to endothelial-leukocyte adhesion molecules is studied. MPA has more prominent anti-inflammatory effects than progesterone when used alone or with estradiol. Indeed, MPA prevents the expression of the adhesion molecules on human endothelial cells to a similar extent such as glucocorticoids and shows more prominent anti-inflammatory properties in selected in vivo inflammation models (19). Endothelial-leukocyte adhesion molecule expression is driven by the transcription factor NF-kB which recognizes specific consensus sequences on the promoter regions of the genes encoding for endothelial-leukocyte adhesion molecules. Steroid hormones regulate NF-kB activation and nuclear translocation (20). MPA efficiently prevents NF-kB nuclear translocation induced by inflammatory stimulation
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Article in press - uncorrected proof Mannella et al.: Progestogens and endothelial cells 451
7.
8.
9. 10. Figure 2 Steroid hormones regulate NF-kB differently.
and this inhibition is much more potent than that of progesterone. This depends on the capacity of MPA to bind both progesterone and glucocorticoid receptor (Figure 2). In this regard, MPA antagonizes the reduction of monocyte chemoattractant protein-1 synthesis induced by estradiol with regard to other progestins, such as norethisterone acetate, which is neutral (21).
11.
12.
13.
Conclusion Progesterone is a cardiovascular active sex steroid, which is able to regulate the structure and function of the blood vessels both in physiological as well as in pathological conditions. Natural progesterone and the different synthetic progestins have substantially differing effects and, based on the current data available, it is difficult to draw conclusions on the possible superiority of a single molecule versus the others. Understanding the molecular mechanisms through which these actions are exerted represents an important frontier, which should ultimately allow for the engineering of newer progestins with optimal cardiovascular profiles for the treatment of women.
References
14.
15.
16.
17.
1. White MM, Zamudio S, Stevens T, Tyler R, Lindenfeld J, Leslie K, Moore LG. Estrogen, progesterone, and vascular reactivity: potential cellular mechanisms. Endocr Rev 1995;16:739–51. 2. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH. Classification and pharmacology of progestins. Maturitas 2008;61:171–80. 3. Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000;65:651–8. 4. Mishra RG, Hermsmeyer RK, Miyagawa K, Sarrel P, Uchida B, Stanczyk FZ, Burry KA, Illingworth DR, Nordt FJ. Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys. J Clin Endocrinol Metab 2005;90:3706–14. 5. Perrot-Applanat M, Groyer-Picard MT, Garcia E, Lorenzo F, Milgrom E. Immunocytochemical demonstration of estrogen and progesterone receptors in muscle cells of uterine arteries in rabbits and humans. Endocrinology 1988;123:1511–9. 6. Karas RH, Schulten H, Pare G, Aronovitz MJ, Ohlsson C, Gustafsson JA, Mendelsohn ME. Effects of estrogen on the vascular
18.
19.
20.
21.
injury response in estrogen receptor alpha, beta (double) knockout mice. Circ Res 2001;89:534–9. Hermsmeyer RK, Mishra RG, Pavcnik D, Uchida B, Axthelm MK, Stanczyk FZ, Burry KA, Illingworth DR, Juan C, Nordt FJ. Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus monkeys by transdermal progesterone. Arterioscler Thromb Vasc Biol 2004;24:955–61. Paris JM, Williams KJ, Hermsmeyer KR, Delansorne R. Nomegestrol acetate and vascular reactivity: nonhuman primate experiments. Steroids 2000;65:621–7. Williams JK, Adams MR. Estrogens, progestins and coronary artery reactivity. Nat Med 1997;3:273–4. Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757–61. Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997;3:324–7. Williams JK, Cline JM, Honore EK, Delansorne R, Paris J. Coadministration 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;179:1288–94. Simoncini T, Mannella P, Fornari L, Caruso A, Willis MY, Garibaldi S, Baldacci C, Genazzani AR. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology 2004;145:5745–56. Mannella P, Sanchez AM, Giretti MS, Genazzani AR, Simoncini T. Oestrogen and progestins differently prevent glutamate toxicity in cortical neurons depending on prior hormonal exposure via the induction of neural nitric oxide synthase. Steroids 2009;74:650–6. Simoncini T, Caruso A, Garibaldi S, Fu XD, Giretti MS, Baldacci C, Scorticati C, Fornari L, Mannella P, Genazzani AR. Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate. Obstet Gynecol 2006;108:969–78. Simoncini T, Caruso A, Giretti MS, Scorticati C, Fu XD, Garibaldi S, Baldacci C, Mannella P, Fornari L, Genazzani AR. Effects of dydrogesterone and of its stable metabolite, 20-alphadihydrodydrogesterone, on nitric oxide synthesis in human endothelial cells. Fertil Steril 2006;86(Suppl 4):1235–42. Simoncini T, Genazzani AR. A review of the cardiovascular and breast actions of drospirenone in preclinical studies. Climacteric 2010;13:22–33. Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 2000;36:2154–9. Elovitz M, Wang Z. Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise. Am J Obstet Gynecol 2004; 190:693–701. Simoncini T, Maffei S, Basta G, Barsacchi G, Genazzani AR, Liao JK, De Caterina R. Estrogens and glucocorticoids inhibit endothelial vascular cell adhesion molecule-1 expression by different transcriptional mechanisms. Circ Res 2000;87:19–25. Mueck AO, Seeger H, Wallwiener D. Medroxyprogesterone acetate versus norethisterone: effect on estradiol-induced changes of markers for endothelial function and atherosclerotic plaque characteristics in human female coronary endothelial cell cultures. Menopause 2002;9:273–81.
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Progestogen effects at vascular level: the endothelial cells
Paolo Mannella*, Tommaso Simoncini and Andrea Riccardo Genazzani Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
Abstract Progesterone and progestogens are active molecules on the cardiovascular system. However, their action is not as wellcharacterized as the effects of estrogens. Data of the last clinical trials suggest the possibility of harmful cardiovascular effects of progestogens, and the debate on the role of progesterone and progestins on the vascular wall is open. From an experimental point of view, each progestogen presents typical effects on the cardiovascular system and their administration results in diverse modifications of the effects of estrogens, sometimes acting synergically, others being neutral or antagonizing effects of estrogens. In this paper, we review the most important data from in vivo and in vitro studies which have been published on the effects of progesterone and progestogens on vascular cells. Endothelium is a target tissue for sex steroids and progesterone is able to regulate endothelial cell function and morphology. Even if the perfect molecule does not exist, the understanding of the molecular basis of each progestogen in vascular tissue is therefore of paramount importance for the most appropriate use with an optimal cardiovascular profile. Keywords: cardiovascular progestogens.
system;
endothelial
cells;
Introduction The cardiovascular system is a target for progesterone (1). Sex steroid hormones have major metabolic effects, resulting principally in modifications of the lipid profile of carbohydrate metabolism and of the hemostatic system. Although these effects principally derive from direct actions on the liver, they have a profound effect on the function of the cardiovascular system. *Corresponding author: Paolo Mannella, MD, PhD, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma, 57, 56100 Pisa, Italy Phone (Office): q39-050-993523, (Lab): q39-050-992690, Fax: q39-050-553410, E-mail: [email protected] Received November 15, 2010; accepted November 16, 2010
However, when discussing progestogens a large class of molecules is considered, which present different functions, receptor affinity and actions in several tissues (Table 1) (2). In particular, each progestogen acts differently on the cardiovascular system (3), and in the past years this assumption has been confirmed from different clinical trials as well as the Women’s Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement Study (HERS). From a practical point of view, progesterone receptors (PRs) are widespread in the entire cardiovascular system, and the two isoforms (PR-A and PR-B) have been demonstrated at the endothelial level in the coronary artery, as well as in the aorta and vascular smooth muscle cells (4, 5).
Vascular cells and progesterone activity The direct role of progesterone on cardiovascular tissues is only partially clarified. Animal studies in PR knockout mice demonstrated that the absence of PRs induces a greater vascular medial hypertrophy and a greater vascular smooth muscle cell proliferation after vascular injury in comparison to control animals (6). In in vivo coronary studies, progesterone exerts protective actions against vasoconstrictor stimuli, modulating the provasodilation response (7) but not all progestogens act similarly. Medroxyprogesterone acetate (MPA) but not progesterone induces coronary hyperreactivity in intact male rhesus monkeys (4). This difference can be extended to other synthetic progestinic compounds (8). Indeed, this action could mediate or interfere with the activity of estrogen on the cardiovascular system. In non-human primates, the contribution of progestins has been investigated, showing the presence of significant modifying effects on estrogen-induced vascular effects (9). The coadministration of natural progesterone did not alter the effect of estrogen. However, in the same model, the addition of cyclic or continuous MPA inhibited the vasodilatory effect of estrogen responses by 50% (10). These data have been confirmed by other groups, showing that progesterone plus estradiol protects, but MPA plus estradiol does not, against coronary artery vasospasm (11), thus highlighting the difference between natural progesterone and MPA. A possible explanation is that this action depends on their androgen agonistic/antagonistic activity (4). In contrast to MPA, the non-androgenic progestin nomegestrol acetate presents protective effects and does not impair the beneficial effects of estrogen on the coronary dilator response in monkeys (8, 12). However, although the concept of deleterious effects of androgenic molecules on the blood vessels is longstanding, this is far from being ascertained, and androgens could have anti-atherogenic and vasodilatory actions at the vascular level.
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/1/15 6:58 PM
2010/052
Article in press - uncorrected proof 450 Mannella et al.: Progestogens and endothelial cells
Table 1 Classification and pharmacology of progestins according to Schindler and coworkers (2). Progestin
Progestogenic AntiAntiEstrogenic Androgenic AntiGlucocorticoid Antigonadotropic estrogenic androgenic mineralocorticoid
Progesterone q Dydrogesterone q Medrogestone q 17a-Hydroxy-derivatives Chlormadinone q acetate Cyproterone acetate q Megestrol acetate q Medroxyq progesterone-acetate 19-Nor-progesterone-derivatives Nomegestrol acetate q Promegestone q Trimegestone q Spirolactone-derivatives Drospirenone q 19-Nortestosterone-derivatives Norethisterone q Lynestrenol q " Norethinodrel Levonorgestrel q Norgestimate q 3-Keto-desogestrel q Gestoden q Dienogest q
q – q
q q q
– – –
– – –
" " "
q – –
q " –
q
q
–
–
q
q
–
q q q
q q q
– – –
– " "
qq q –
q q q
– – –
q q q
q q q
– – –
– – –
" – "
– – –
– – "
q
q
–
–
q
–
q
q q q q q q q q
q q " q q q q "
q q q – – – – "
q q " q q q q –
– – – – – – – q
– – – – – – q –
– – – – – – q –
Progesterone and endothelial function However, in the past years, different research groups demonstrated a direct action of progesterone and progestogens on endothelial cells via the recruitment and activation of the PR (13). In ovariectomized rats, progesterone administration induces endothelial nitric oxide synthase (eNOS) activity and expression and therefore the release of nitric oxide, but this effect is not exerted by MPA. Similarly, when estrogen is added, progesterone enhances the estrogen-dependent effect on eNOS, whereas MPA prevents it (13). In different studies (13–16), we demonstrated different effects of progestogens on eNOS expression and activity (Figure 1).
Figure 1 Progesterone (P), levonorgestrel (LNG) and cyproterone acetate (CYP) significantly induce eNOS expression. Medroxyprogesterone acetate (MPA), megestrol (Meg) and norethisterone acetate (NETA) are inactive.
In addition, dydrogesterone and drospirenone shares with progesterone the ability to induce the rapid activation of eNOS, as well as to potentiate the effects induced by estrogen (16, 17). In postmenopausal women, progesterone has synergistic vasodilatory effects on coronary blood flow and myocardial ischemia when added to estrogens. In contrast, MPA does not share this action, therefore indicating that, on this particular target, all progestins are not the same (18). The pharmacology difference between progestogens is pivotal to understand divergent effects of these molecules on the development and progression of the atherosclerotic plaque. In this regard, the relevance of the affinity of MPA for the glucocorticoid receptor becomes evident when the proinflammatory signal transduction to endothelial-leukocyte adhesion molecules is studied. MPA has more prominent anti-inflammatory effects than progesterone when used alone or with estradiol. Indeed, MPA prevents the expression of the adhesion molecules on human endothelial cells to a similar extent such as glucocorticoids and shows more prominent anti-inflammatory properties in selected in vivo inflammation models (19). Endothelial-leukocyte adhesion molecule expression is driven by the transcription factor NF-kB which recognizes specific consensus sequences on the promoter regions of the genes encoding for endothelial-leukocyte adhesion molecules. Steroid hormones regulate NF-kB activation and nuclear translocation (20). MPA efficiently prevents NF-kB nuclear translocation induced by inflammatory stimulation
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/1/15 6:58 PM
Article in press - uncorrected proof Mannella et al.: Progestogens and endothelial cells 451
7.
8.
9. 10. Figure 2 Steroid hormones regulate NF-kB differently.
and this inhibition is much more potent than that of progesterone. This depends on the capacity of MPA to bind both progesterone and glucocorticoid receptor (Figure 2). In this regard, MPA antagonizes the reduction of monocyte chemoattractant protein-1 synthesis induced by estradiol with regard to other progestins, such as norethisterone acetate, which is neutral (21).
11.
12.
13.
Conclusion Progesterone is a cardiovascular active sex steroid, which is able to regulate the structure and function of the blood vessels both in physiological as well as in pathological conditions. Natural progesterone and the different synthetic progestins have substantially differing effects and, based on the current data available, it is difficult to draw conclusions on the possible superiority of a single molecule versus the others. Understanding the molecular mechanisms through which these actions are exerted represents an important frontier, which should ultimately allow for the engineering of newer progestins with optimal cardiovascular profiles for the treatment of women.
References
14.
15.
16.
17.
1. White MM, Zamudio S, Stevens T, Tyler R, Lindenfeld J, Leslie K, Moore LG. Estrogen, progesterone, and vascular reactivity: potential cellular mechanisms. Endocr Rev 1995;16:739–51. 2. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH. Classification and pharmacology of progestins. Maturitas 2008;61:171–80. 3. Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000;65:651–8. 4. Mishra RG, Hermsmeyer RK, Miyagawa K, Sarrel P, Uchida B, Stanczyk FZ, Burry KA, Illingworth DR, Nordt FJ. Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys. J Clin Endocrinol Metab 2005;90:3706–14. 5. Perrot-Applanat M, Groyer-Picard MT, Garcia E, Lorenzo F, Milgrom E. Immunocytochemical demonstration of estrogen and progesterone receptors in muscle cells of uterine arteries in rabbits and humans. Endocrinology 1988;123:1511–9. 6. Karas RH, Schulten H, Pare G, Aronovitz MJ, Ohlsson C, Gustafsson JA, Mendelsohn ME. Effects of estrogen on the vascular
18.
19.
20.
21.
injury response in estrogen receptor alpha, beta (double) knockout mice. Circ Res 2001;89:534–9. Hermsmeyer RK, Mishra RG, Pavcnik D, Uchida B, Axthelm MK, Stanczyk FZ, Burry KA, Illingworth DR, Juan C, Nordt FJ. Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus monkeys by transdermal progesterone. Arterioscler Thromb Vasc Biol 2004;24:955–61. Paris JM, Williams KJ, Hermsmeyer KR, Delansorne R. Nomegestrol acetate and vascular reactivity: nonhuman primate experiments. Steroids 2000;65:621–7. Williams JK, Adams MR. Estrogens, progestins and coronary artery reactivity. Nat Med 1997;3:273–4. Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757–61. Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997;3:324–7. Williams JK, Cline JM, Honore EK, Delansorne R, Paris J. Coadministration 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;179:1288–94. Simoncini T, Mannella P, Fornari L, Caruso A, Willis MY, Garibaldi S, Baldacci C, Genazzani AR. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology 2004;145:5745–56. Mannella P, Sanchez AM, Giretti MS, Genazzani AR, Simoncini T. Oestrogen and progestins differently prevent glutamate toxicity in cortical neurons depending on prior hormonal exposure via the induction of neural nitric oxide synthase. Steroids 2009;74:650–6. Simoncini T, Caruso A, Garibaldi S, Fu XD, Giretti MS, Baldacci C, Scorticati C, Fornari L, Mannella P, Genazzani AR. Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate. Obstet Gynecol 2006;108:969–78. Simoncini T, Caruso A, Giretti MS, Scorticati C, Fu XD, Garibaldi S, Baldacci C, Mannella P, Fornari L, Genazzani AR. Effects of dydrogesterone and of its stable metabolite, 20-alphadihydrodydrogesterone, on nitric oxide synthesis in human endothelial cells. Fertil Steril 2006;86(Suppl 4):1235–42. Simoncini T, Genazzani AR. A review of the cardiovascular and breast actions of drospirenone in preclinical studies. Climacteric 2010;13:22–33. Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 2000;36:2154–9. Elovitz M, Wang Z. Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise. Am J Obstet Gynecol 2004; 190:693–701. Simoncini T, Maffei S, Basta G, Barsacchi G, Genazzani AR, Liao JK, De Caterina R. Estrogens and glucocorticoids inhibit endothelial vascular cell adhesion molecule-1 expression by different transcriptional mechanisms. Circ Res 2000;87:19–25. Mueck AO, Seeger H, Wallwiener D. Medroxyprogesterone acetate versus norethisterone: effect on estradiol-induced changes of markers for endothelial function and atherosclerotic plaque characteristics in human female coronary endothelial cell cultures. Menopause 2002;9:273–81.
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