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Effects of estradiol alone or in combination with cyproterone acetate on carotid artery pulsatility index in postmenopausal women
Maturitas 46 (2003) 219 /224 www.elsevier.com/locate/maturitas
Effects of estradiol alone or in combination with cyproterone acetate on carotid artery pulsatility index in postmenopausal women Vincenzo De Leo a,*, Antonio la Marca a, Roberto Orlandi c, Donatella Crippa c, Carlo Setacci b, Felice Petraglia a a
Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Obstetrics and Gynecology, Siena, Italy b Chair of Vascular Surgery, University of Siena, Siena, Italy c Shering Medical Department, Milan, Italy Received 24 September 2002; received in revised form 25 March 2003; accepted 17 April 2003
Abstract Ojectives: The incidence of cardiovascular disease (CVD) increases dramatically with the loss of ovarian function. Observational studies indicate that the risk of CVD may be reduced by up to 50% in postmenopausal women who take estrogen replacement therapy. Estrogen therapy reduces internal carotid artery pulsatility index (PI). The improvement in carotid PI following HRT has been proposed as a marker of the cardioprotective effect of estrogen therapy. Cyclical progesterone addition to ERT partially antagonizes the reduction on the carotid artery PI. As progesterone, androgens has been shown to decreases arterial vasodilatation and carotid PI. To our knowledge no information is available regarding the effect of CPA addition on the carotid artery PI in women taking estrogen replacement therapy. Methods: We recruited a total of 30 women in postmenopause for at least 12 months and were in good health. Fifteen women were postmenopausal following surgical bilateral oophorectomy for benign condition. Fifteen postmenopausal women received estradiol valerate for 21 days and CPA (1 mg) for 10 days for 3 months (Group E/CPA). Ovarectomized women (n /15) received estradiol hemihydrate (2 mg) for 3 months (Group E). The main factor investigated was PI, an indicator of impedence to blood flow down stream. Doppler US were performed before the start and at the end of the therapy. Results: The mean reductions respect to basal values were 11.5% in women treated with E and 10.8% in women treated with E/CPA. No significant difference was found between treatment values. Conclusions: The results of the present study demonstrate that cyproterone acetate addition to E do non-antagonize the effect of estrogen on carotid artery PI. The present study demonstrate that both estradiol hemihydrate and estradiol valerate plus cyproterone acetate lead to similar improvement in carotid artery; through this mechanism both treatments could potentially reduce the incidence of cerebrovascular disease in postmenopausal women. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Estradiol; Cyproterone acetate; Carotid artery pulsatility index
* Corresponding author. Present address: Institute of Obstetrics and Gynecology, University of Siena, Policlinico Le Scotte, Viale Bracci, 53100 Siena, SI, Italy. Tel.: /39-0577-23-3465; fax: /39-0577-23-3464. E-mail address: [email protected] (V. De Leo). 0378-5122/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0378-5122(03)00192-0
220
V. De Leo et al. / Maturitas 46 (2003) 219 /224
1. Introduction Cardiovascular disease (CVD) is the leading cause of death in women in the western world. The incidence of CVD increases dramatically with the loss of ovarian function. Ovarian hormones have anti-atherogenic properties influencing all steps in the development of atherosclerosis: accumulation of cholesterol in the arterial wall, arterial smooth muscle cell proliferation platelet aggregation, collagen production and act as a vasoactive substance [1 /6]. Observational studies indicate that the risk of CVD may be reduced by up to 50% in postmenopausal women who take estrogen replacement therapy. Only 30/50% of this reduction is considered due to the beneficial changes in serum lipid profile following estrogen therapy [7,8]. Estrogen reduces vascular resistance and act as a vasodilator in vitro [9]. In women estrogen modulates blood flow in arterial distracts such as vagina, uterine and carotid vessels as well as coronary arteries [1,2]. Downstream resistance to flow estimated as arterial pulsatility index (PI), increases with time from menopause [10]. Estrogen therapy reduces internal carotid artery PI [10 /17]. The improvement in carotid PI following HRT has been proposed as a marker of the cardioprotective effect of estrogen therapy [10 /17]. Progesterone has been shown to antagonize the vasodilatation caused by estradiol in the animal model [18]. Cyclical progesterone addition to ERT partially antagonizes the reduction on the carotid artery PI [19]. As progesterone, androgens has been shown to decreases arterial vasodilatation and carotid PI. In menopausal women, androgen supplementation during HRT partially contrast the beneficial effects of estrogen on cerebral blood flow [20]. Both dydrogesterone and norethisterone partially antagonized the reduction in the carotid artery PI in postmenopausal women of estrogen replacement therapy [19]. Recent reviews demonstrated that the type of progestogen detained differential effect of HRT. On lipid and lipoprotein levels, the least antagonism was seen with medrogestone, progesterone and cyproterone acetate. High antagonistic effect was observed with medroxyprogesterone acetate norgestrel and nor-
ethindrone [21 /27]. Due to low antagonistic effect of CPA on estrogen action, the association of estradiol valerate and cyproterone acetate has been widely prescribed to postmenopausal women. To our knowledge no information is available regarding the effect of CPA addition on the carotid artery PI in women taking estrogen replacement therapy.
2. Methods We recruited a total of 30 women. Institution review board approval for the study was obtained. The women had all been in postmenopause for at least 12 months and were in good health. Fifteen women were postmenopausal following surgical bilateral oophorectomy for benign condition. None had taken thyroid hormones, steroids or SERMS in the previous 12 months. Women with known CVD where excluded lipids and blood pressure were in the normal range for all women, 15 postmenopausal women received estradiol valerate for 21 days and CPA (1 mg) for 10 days (Climen, Schering AG) for 3 months (Group E/ CPA). Ovarectomized women (n /15) received estradiol hemihydrate (2 mg) for 3 months (Estrofem, Novonordisk) (Group E). All women were asked to not change their physical activity. No significant differences were found between baseline characteristics between the two groups (Table 1). The main factor investigated was PI, an indicator of impedence to blood flow down stream. Table 1 Demographic details of the study population
Age (year) BMI (kg/ht2) FSH (IU/l) E2 (pg/ml) Tc (mg/dl) LDLc (mg/dl) HDLc (mg/dl) TG (mg/dl) Carotid PI
E/CPA (n /15)
E (n /15)
529/3 279/4.4 589/8 159/4 2259/53 1389/29 659/17 1109/23 0.989/0.1
559/4 269/5.2 619/9 159/5 2189/46 1359/27 629/16 1059/21 0.979/0.1
V. De Leo et al. / Maturitas 46 (2003) 219 /224
Doppler US were performed before the start and at the end of the therapy. The equipment used was a HP Sonos 5500 with a linear 5-MHz probe. Each women rested for 5 min in the supine position before readings were taken. The common carotid arteries and the proximal parts of the internal and external carotid artery were identified. PI was the mean of three consecutive recordings from internal carotid artery. Serum cholesterol, triglycerides, HDL- and LDL-cholesterol (calculated using the Friedewald’s formula) were assessed at baseline and every 4 weeks of treatment for both groups.
3. Statistical analysis The results were expressed as means and standard deviations. Statistical analysis was performed by the t-test for paired and unpaired data. Statistical significance was set at P B/0.05.
4. Results Baseline values of carotid artery PI prior to the treatments were compared and no significant differences were found (Table 1). As shown in the Fig. 1, 3 months of both treatments were followed by a significant reduction in carotid artery PI. The mean reductions respect to basal values were 11.5% in women treated with E and 10.8% in
Fig. 1. Significant reduction in carotid PI after 3 months of therapy with E/CPA (circle) or E alone (square).
221
women treated with E/CPA. No significant difference was found between treatment values. Baseline levels of serum cholesterol, triglycerides, HDL- and LDL-cholesterol were similar in the two groups. Serum cholesterol concentrations fell by 4.5% in group E (P B/0.05) and by 3.4% in group E/CPA (P B/0.05). HDL concentrations did not change significantly at the end of treatment in both groups. For triglycerides, significant increases (P B/0.05) from baseline were observed in both groups at most of the time points studied (59/ 1 and 6.29/1.3% for E/CPA and E, respectively). LDL concentrations significantly decreased (P B/ 0.05) from baseline in both groups at most of the time points studied ( /69/2 and /89/3% for E/ CPA and E, respectively). The LDL/HDL ratio fell by 10% in both groups (P B/0.01) (Fig. 2).
5. Discussion Doppler US is the most accurate non-invasive method to evaluate vascular impedence. PI reflects vascular impedence to distal flow with respect to the point of measurement. Because PI represents distal resistance and vascular compliance, modifications in PI reflect a parallel effect on heart load and hence on heart function. Estradiol alone induced a 11.5% reduction in PI after 3 months of therapy, which is similar to the reduction reported in literature [16,28]. Estradiol increases blood flow in reproductive tissues and lead to relaxation of smooth muscle cells of vessels such as coronary arteries [29 /31]. The increase in arterial PI occurring in women after menopause seems to be due to reduced vascular compliance and increased vascular resistance. Estrogen administration leads to reduction in PI. It has been reported that in suspension of therapy, PI returns to pre-treatment values in 6 month, suggesting a causal relationship between sex steroids and vascular tone [32]. The results of the present study demonstrate that cyproterone acetate addition to estradiol do non-antagonize the effect of estrogen on carotid artery PI. A recent study demonstrated an unfavorable affect of other progestogens, namely dydrogesterone and norethisterone on carotid
222
V. De Leo et al. / Maturitas 46 (2003) 219 /224
Fig. 2. Percentage modifications in lipids after 3 months of therapy with E/CPA (black columns) or E alone (grey columns).
artery PI [19]; others found no effect when medroxyprogesterone acetate was administered [33]. Progestogens have been showed to exert differential effect on lipids and lipoproteins [34], similarly the type of progestogen may differentially affect the beneficial action of estradiol on vascular tone. Estrogen replacement therapy has been shown to reduce the risk of coronary disease [35]. The most probable mechanism of this effect is the modification of lipid profiles [36]. Estradiol is reported to decrease serum triglycerides and total, LDL- and HDL-cholesterol [37]. The administration of a progestin to protect the endometrium reduces the positive effects of estradiol on lipid profiles. However, this reduction depends on dose and the androgenicity of the progestin [34]. The results of our study show that protocols with estradiol valerate and cyproterone acetate have favorable effects on serum lipids. Changes in plasma levels of cholesterol, HDL, LDL, and triglycerides were not significantly different in the two groups. The positive effect of E/CPA association is due to the very low dose of cyproterone acetate. The dose of 1 mg for only 12 days per month is able to prevent estrogen induced endometrial hyperplasia without antagonize the beneficial effect of estradiol. Furthermore cyproterone is an antiandro-
genic progestin which is followed by a positive effect on frequent menopausal disturbances of skin such as hirsutism. In conclusion the present study demonstrate that both estradiol hemihydrate and estradiol valerate plus cyproterone acetate lead to similar improvement in carotid artery; through this mechanism both treatments could potentially reduce the incidence of cerebrovascular disease in postmenopausal women.
References [1] Wagner JD, Clarkson TB, St. Clair RW, et al. Estrogen and progesterone replacement therapy reduces LDL accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys. J Clin Invest 1991;88:1995 / 2002. [2] Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of adding progesterone. Arteriosclerosis 1990;10:1051 /7. [3] Gisclard V, Miller VM, Vanhoutte PM. Effect of 17-beta estradiol on endothelium-dependent responses in the rabbit. J Pharmacol Exp Ther 1998;244:19 /22. [4] Williams JK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation 1990;81:1680 /7. [5] Herrington DM, Braden GA, Williams JK, et al. Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy. Am J Cardiol 1994;73:951 /2.
V. De Leo et al. / Maturitas 46 (2003) 219 /224 [6] Collins P, Rosano GM, Sarrel PM, et al. 17-Beta estradiol attenuates acetylcoline-induced coronary arterial constriction in women but no men with coronary heart disease. Circulation 1995;92:24 /30. [7] Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. J Am Med Assoc 1991;265:1861 /7. [8] Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47 /63. [9] Jiang CW, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Endothelium-independent relaxation of rabbit coronary artery by 17 beta-oestradiol in vitro. Br J Pharmacol 1991;104:1033 /7. [10] Gangar KF, Vyas S, Whitehead M, Crook D, Meire H, Campbell S. Pulsatility index in internal carotid artery in relation to transdermal oestradiol and time since menopause. Lancet 1991;338:839 /42. [11] Kallikazaros I, Tsioufis C, Zambaras P, Stefanadis C, Toutouzas P. Conjugated estrogen administration improves common carotid artery elastic properties in normotensive postmenopausal women. Clin Cardiol 2002;25:167 /72. [12] Sendag F, Terek MC, Karadadas N, Bilgin O. Effects of oral and transdermal hormone replacement therapy on internal carotid artery pulsatility indices in postmenopausal women. A prospective, randomized, comparative study. J Reprod Med 2001;46:962 /8. [13] Ozsener S, Sagol S, Oztekin K, Bilgin O. The effect of continuous combined oral estradiol and norethisterone on the renal and internal carotid artery pulsatility indices in postmenopausal women. Int J Gynaecol Obstet 2000;69:281 /2. [14] Battaglia C, Regnani G, Artini PG, Genazzani AR, Primavera MR, Salvatori M, Volpe A. Uterine and cerebral vascularization in postmenopausal women treated with hormone-replacement therapy. Gynecol Endocrinol 1999;13:223 /9. [15] Penotti M, Sironi L, Castiglioni E, Miglierina L, Barletta L, Gabrielli L, Vignali M. Blood flow in the internal carotid and middle cerebral arteries: effects of continuous oral conjugated equine estrogens administration with monthly progestogen supplementation on postmenopausal women. Menopause 1999;6:225 /9. [16] Cacciatore B, Paakkari I, Toivonen J, Tikkanen MJ, Ylikorkala O. Randomized comparison of oral and transdermal hormone replacement on carotid and uterine artery resistance to blood flow. Obstet Gynecol 1998;92:563 /8. [17] Penotti M, Sironi L, Miglierina L, Farina M, Barletta L, Gabrielli L, Vignali M. The effect of tamoxifen and transdermal 17beta-estradiol on cerebral arterial vessels: a randomized controlled study. Am J Obstet Gynecol 1998;178:801 /5. [18] Resnik R, Brink GW, Plumer MH. The effect of progesterone on estrogen-induced uterine blood flow. Am J Obstet Gynecol 1977;128:251 /4.
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[19] Luckas MJ, Gleeve T, Biljan MM, Buckett WM, Aird IA, Drakeley A, Kingsland CR. The effect of progestagens on the carotid artery pulsatility index in postmenopausal women on oestrogen replacement therapy. Eur J Obstet Gynecol Reprod Biol 1998;76:221 /4. [20] Penotti M, Sironi L, Cannata L, Vigano P, Casini A, Gabrielli L, Vignali M. Effects of androgen supplementation of hormone replacement therapy on the vascular reactivity of cerebral arteries. Fertil Steril 2001;76:235 /40. [21] Sitruk-Ware R. Progestogens in hormonal replacement therapy: new molecules, risks, and benefits. Menopause 2002;9:6 /15. [22] Rosano GM, Fini M. Postmenopausal women and cardiovascular risk: impact of hormone replacement therapy. Cardiol Rev 2002;10:51 /60. [23] Rosano GM, Fini M. Comparative cardiovascular effects of different progestins in menopause. Int J Fertil Womens Med 2001;46:248 /56. [24] Stefanick ML. Estrogen, progestogens and cardiovascular risk. J Reprod Med 1999;44:221 /6. [25] Clarkson TB. Progestogens and cardiovascular disease. A critical review. J Reprod Med 1999;44:180 /4. [26] Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000;65:651 /8. [27] Rosano GM, Sarais C, Zoncu S, Mercuro G. The relative effects of progesterone and progestins in hormone replacement therapy. Hum Reprod 2000;15:60 /73. [28] Jackson S, Vyas S. A double-blind, placebo controlled study of postmenopausal oestrogen replacement therapy and carotid artery pulsatility index. Br J Obstet Gynaecol 1998;105:408 /12. [29] Rosenfeld CR, Killam AP, Battaglia FC, Makowski EL, Meschia G. Effect of estradiol-17, on the magnitude and distribution of uterine blood flow in nonpregnant, oophorectomized ewes. Pediatr Res 1973;7:139 /48. [30] Jiang C, Sarrel PM, Poole-Wilson PA, Collins P. Acute effect of 17 beta-estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol 1992;263:271 /5. [31] Jiang CW, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Endothelium-independent relaxation of rabbit coronary artery by 17 beta-oestradiol in vitro. Br J Pharmacol 1991;104:1033 /7. [32] Penotti M, Farina M, Castiglioni E, Gaffuri B, Barletta L, Gabrielli L, Vignali M. Alteration in the pulsatility index values of the internal carotid and middle cerebral arteries after suspension of postmenopausal hormone replacement therapy: a randomized crossover study. Am J Obstet Gynecol 1996;175:606 /11. [33] Penotti M, Nencioni T, Gabrielli L, Farina M, Castiglioni E, Polvani F. Blood flow variations in internal carotid and middle cerebral arteries induced by postmenopausal hormone replacement therapy. Am J Obstet Gynecol 1993;169:1226 /32. [34] Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a)
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V. De Leo et al. / Maturitas 46 (2003) 219 /224
concentrations: analysis of studies published from 1974 to 2000. Fertil Steril 1998;75:898 /915. [35] Ross RK, Paganini-Hill A, Mack TM, Henderson BE. Estrogen use and cardiovascular disease. In: Mishell DR, Jr, editor. Menopause, physiology and pharmacology. Chicago: Year Book, 1987:209 /24. [36] Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in
women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987;75:1102 /9. [37] Chen FP, Lee N, Wang CH, Cherng WJ, Soong YK. Effects of hormone replacement therapy on cardiovascular risk factors in postmenopausal women. Fertil Steril 1998;69:267 /73.
Effects of estradiol alone or in combination with cyproterone acetate on carotid artery pulsatility index in postmenopausal women Vincenzo De Leo a,*, Antonio la Marca a, Roberto Orlandi c, Donatella Crippa c, Carlo Setacci b, Felice Petraglia a a
Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Obstetrics and Gynecology, Siena, Italy b Chair of Vascular Surgery, University of Siena, Siena, Italy c Shering Medical Department, Milan, Italy Received 24 September 2002; received in revised form 25 March 2003; accepted 17 April 2003
Abstract Ojectives: The incidence of cardiovascular disease (CVD) increases dramatically with the loss of ovarian function. Observational studies indicate that the risk of CVD may be reduced by up to 50% in postmenopausal women who take estrogen replacement therapy. Estrogen therapy reduces internal carotid artery pulsatility index (PI). The improvement in carotid PI following HRT has been proposed as a marker of the cardioprotective effect of estrogen therapy. Cyclical progesterone addition to ERT partially antagonizes the reduction on the carotid artery PI. As progesterone, androgens has been shown to decreases arterial vasodilatation and carotid PI. To our knowledge no information is available regarding the effect of CPA addition on the carotid artery PI in women taking estrogen replacement therapy. Methods: We recruited a total of 30 women in postmenopause for at least 12 months and were in good health. Fifteen women were postmenopausal following surgical bilateral oophorectomy for benign condition. Fifteen postmenopausal women received estradiol valerate for 21 days and CPA (1 mg) for 10 days for 3 months (Group E/CPA). Ovarectomized women (n /15) received estradiol hemihydrate (2 mg) for 3 months (Group E). The main factor investigated was PI, an indicator of impedence to blood flow down stream. Doppler US were performed before the start and at the end of the therapy. Results: The mean reductions respect to basal values were 11.5% in women treated with E and 10.8% in women treated with E/CPA. No significant difference was found between treatment values. Conclusions: The results of the present study demonstrate that cyproterone acetate addition to E do non-antagonize the effect of estrogen on carotid artery PI. The present study demonstrate that both estradiol hemihydrate and estradiol valerate plus cyproterone acetate lead to similar improvement in carotid artery; through this mechanism both treatments could potentially reduce the incidence of cerebrovascular disease in postmenopausal women. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Estradiol; Cyproterone acetate; Carotid artery pulsatility index
* Corresponding author. Present address: Institute of Obstetrics and Gynecology, University of Siena, Policlinico Le Scotte, Viale Bracci, 53100 Siena, SI, Italy. Tel.: /39-0577-23-3465; fax: /39-0577-23-3464. E-mail address: [email protected] (V. De Leo). 0378-5122/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0378-5122(03)00192-0
220
V. De Leo et al. / Maturitas 46 (2003) 219 /224
1. Introduction Cardiovascular disease (CVD) is the leading cause of death in women in the western world. The incidence of CVD increases dramatically with the loss of ovarian function. Ovarian hormones have anti-atherogenic properties influencing all steps in the development of atherosclerosis: accumulation of cholesterol in the arterial wall, arterial smooth muscle cell proliferation platelet aggregation, collagen production and act as a vasoactive substance [1 /6]. Observational studies indicate that the risk of CVD may be reduced by up to 50% in postmenopausal women who take estrogen replacement therapy. Only 30/50% of this reduction is considered due to the beneficial changes in serum lipid profile following estrogen therapy [7,8]. Estrogen reduces vascular resistance and act as a vasodilator in vitro [9]. In women estrogen modulates blood flow in arterial distracts such as vagina, uterine and carotid vessels as well as coronary arteries [1,2]. Downstream resistance to flow estimated as arterial pulsatility index (PI), increases with time from menopause [10]. Estrogen therapy reduces internal carotid artery PI [10 /17]. The improvement in carotid PI following HRT has been proposed as a marker of the cardioprotective effect of estrogen therapy [10 /17]. Progesterone has been shown to antagonize the vasodilatation caused by estradiol in the animal model [18]. Cyclical progesterone addition to ERT partially antagonizes the reduction on the carotid artery PI [19]. As progesterone, androgens has been shown to decreases arterial vasodilatation and carotid PI. In menopausal women, androgen supplementation during HRT partially contrast the beneficial effects of estrogen on cerebral blood flow [20]. Both dydrogesterone and norethisterone partially antagonized the reduction in the carotid artery PI in postmenopausal women of estrogen replacement therapy [19]. Recent reviews demonstrated that the type of progestogen detained differential effect of HRT. On lipid and lipoprotein levels, the least antagonism was seen with medrogestone, progesterone and cyproterone acetate. High antagonistic effect was observed with medroxyprogesterone acetate norgestrel and nor-
ethindrone [21 /27]. Due to low antagonistic effect of CPA on estrogen action, the association of estradiol valerate and cyproterone acetate has been widely prescribed to postmenopausal women. To our knowledge no information is available regarding the effect of CPA addition on the carotid artery PI in women taking estrogen replacement therapy.
2. Methods We recruited a total of 30 women. Institution review board approval for the study was obtained. The women had all been in postmenopause for at least 12 months and were in good health. Fifteen women were postmenopausal following surgical bilateral oophorectomy for benign condition. None had taken thyroid hormones, steroids or SERMS in the previous 12 months. Women with known CVD where excluded lipids and blood pressure were in the normal range for all women, 15 postmenopausal women received estradiol valerate for 21 days and CPA (1 mg) for 10 days (Climen, Schering AG) for 3 months (Group E/ CPA). Ovarectomized women (n /15) received estradiol hemihydrate (2 mg) for 3 months (Estrofem, Novonordisk) (Group E). All women were asked to not change their physical activity. No significant differences were found between baseline characteristics between the two groups (Table 1). The main factor investigated was PI, an indicator of impedence to blood flow down stream. Table 1 Demographic details of the study population
Age (year) BMI (kg/ht2) FSH (IU/l) E2 (pg/ml) Tc (mg/dl) LDLc (mg/dl) HDLc (mg/dl) TG (mg/dl) Carotid PI
E/CPA (n /15)
E (n /15)
529/3 279/4.4 589/8 159/4 2259/53 1389/29 659/17 1109/23 0.989/0.1
559/4 269/5.2 619/9 159/5 2189/46 1359/27 629/16 1059/21 0.979/0.1
V. De Leo et al. / Maturitas 46 (2003) 219 /224
Doppler US were performed before the start and at the end of the therapy. The equipment used was a HP Sonos 5500 with a linear 5-MHz probe. Each women rested for 5 min in the supine position before readings were taken. The common carotid arteries and the proximal parts of the internal and external carotid artery were identified. PI was the mean of three consecutive recordings from internal carotid artery. Serum cholesterol, triglycerides, HDL- and LDL-cholesterol (calculated using the Friedewald’s formula) were assessed at baseline and every 4 weeks of treatment for both groups.
3. Statistical analysis The results were expressed as means and standard deviations. Statistical analysis was performed by the t-test for paired and unpaired data. Statistical significance was set at P B/0.05.
4. Results Baseline values of carotid artery PI prior to the treatments were compared and no significant differences were found (Table 1). As shown in the Fig. 1, 3 months of both treatments were followed by a significant reduction in carotid artery PI. The mean reductions respect to basal values were 11.5% in women treated with E and 10.8% in
Fig. 1. Significant reduction in carotid PI after 3 months of therapy with E/CPA (circle) or E alone (square).
221
women treated with E/CPA. No significant difference was found between treatment values. Baseline levels of serum cholesterol, triglycerides, HDL- and LDL-cholesterol were similar in the two groups. Serum cholesterol concentrations fell by 4.5% in group E (P B/0.05) and by 3.4% in group E/CPA (P B/0.05). HDL concentrations did not change significantly at the end of treatment in both groups. For triglycerides, significant increases (P B/0.05) from baseline were observed in both groups at most of the time points studied (59/ 1 and 6.29/1.3% for E/CPA and E, respectively). LDL concentrations significantly decreased (P B/ 0.05) from baseline in both groups at most of the time points studied ( /69/2 and /89/3% for E/ CPA and E, respectively). The LDL/HDL ratio fell by 10% in both groups (P B/0.01) (Fig. 2).
5. Discussion Doppler US is the most accurate non-invasive method to evaluate vascular impedence. PI reflects vascular impedence to distal flow with respect to the point of measurement. Because PI represents distal resistance and vascular compliance, modifications in PI reflect a parallel effect on heart load and hence on heart function. Estradiol alone induced a 11.5% reduction in PI after 3 months of therapy, which is similar to the reduction reported in literature [16,28]. Estradiol increases blood flow in reproductive tissues and lead to relaxation of smooth muscle cells of vessels such as coronary arteries [29 /31]. The increase in arterial PI occurring in women after menopause seems to be due to reduced vascular compliance and increased vascular resistance. Estrogen administration leads to reduction in PI. It has been reported that in suspension of therapy, PI returns to pre-treatment values in 6 month, suggesting a causal relationship between sex steroids and vascular tone [32]. The results of the present study demonstrate that cyproterone acetate addition to estradiol do non-antagonize the effect of estrogen on carotid artery PI. A recent study demonstrated an unfavorable affect of other progestogens, namely dydrogesterone and norethisterone on carotid
222
V. De Leo et al. / Maturitas 46 (2003) 219 /224
Fig. 2. Percentage modifications in lipids after 3 months of therapy with E/CPA (black columns) or E alone (grey columns).
artery PI [19]; others found no effect when medroxyprogesterone acetate was administered [33]. Progestogens have been showed to exert differential effect on lipids and lipoproteins [34], similarly the type of progestogen may differentially affect the beneficial action of estradiol on vascular tone. Estrogen replacement therapy has been shown to reduce the risk of coronary disease [35]. The most probable mechanism of this effect is the modification of lipid profiles [36]. Estradiol is reported to decrease serum triglycerides and total, LDL- and HDL-cholesterol [37]. The administration of a progestin to protect the endometrium reduces the positive effects of estradiol on lipid profiles. However, this reduction depends on dose and the androgenicity of the progestin [34]. The results of our study show that protocols with estradiol valerate and cyproterone acetate have favorable effects on serum lipids. Changes in plasma levels of cholesterol, HDL, LDL, and triglycerides were not significantly different in the two groups. The positive effect of E/CPA association is due to the very low dose of cyproterone acetate. The dose of 1 mg for only 12 days per month is able to prevent estrogen induced endometrial hyperplasia without antagonize the beneficial effect of estradiol. Furthermore cyproterone is an antiandro-
genic progestin which is followed by a positive effect on frequent menopausal disturbances of skin such as hirsutism. In conclusion the present study demonstrate that both estradiol hemihydrate and estradiol valerate plus cyproterone acetate lead to similar improvement in carotid artery; through this mechanism both treatments could potentially reduce the incidence of cerebrovascular disease in postmenopausal women.
References [1] Wagner JD, Clarkson TB, St. Clair RW, et al. Estrogen and progesterone replacement therapy reduces LDL accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys. J Clin Invest 1991;88:1995 / 2002. [2] Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of adding progesterone. Arteriosclerosis 1990;10:1051 /7. [3] Gisclard V, Miller VM, Vanhoutte PM. Effect of 17-beta estradiol on endothelium-dependent responses in the rabbit. J Pharmacol Exp Ther 1998;244:19 /22. [4] Williams JK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation 1990;81:1680 /7. [5] Herrington DM, Braden GA, Williams JK, et al. Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy. Am J Cardiol 1994;73:951 /2.
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