- Email: [email protected]
Hemodynamic effects of transdermal estradiol alone and combined with norethisterone acetate
Maturitas 27 (1997) 163 – 169
Hemodynamic effects of transdermal estradiol alone and combined with norethisterone acetate Jose´ Alfie a,*, Leonor Lugones b, Alejandra Belardo b, Marta Tutzer b, Carlos R. Galarza a, Gabriel D. Waisman a, Mario I. Ca´mera a a
Unidad de Hipertension Arterial, Ser6icio de Clinica Medica, Hospital Italiano, Buenos Aires, Argentina b Seccio´n Climaterio, Ser6icio de Ginecologia, Hospital Italiano, Buenos Aires, Argentina Accepted 14 March 1997
Abstract A 24 weeks, randomized, two-period, placebo controlled study was conducted to compare the effects of continuous transdermal 17b-estradiol replacement therapy (0.05 mg/day once a week) with placebo on systemic hemodynamics and blood pressure in postmenopausal women. Twenty-nine postmenopausal women (47 – 62 years) free of hormone replacement therapy were randomized in two groups; group 1 received estradiol patches for the first 12 weeks and placebo patches for the second, and group 2 received the same treatments in the reverse order. The effect of combined estradiol plus oral norethisterone acetate (NETA) 1 mg was also evaluated in the subset of women with intact uteri (n= 24). Crossover analysis showed that stroke volume and cardiac output were significantly higher (P B 0.05) and blood pressure was significantly lower (PB 0.05) with estradiol, irrespective of the order in which the treatments were administered. Although correlations between plasma estradiol levels during active treatment and hemodynamic changes were not significant, hemodynamic changes were significantly greater above 63 pg/ml than below this level (PB0.05). Oral norethisterone acetate administration either during transdermal placebo or estradiol arms tended to modify systemic hemodynamics in the same direction than estradiol but the changes did not attained statistical significance. In summary compared with placebo, transdermal 17b-estradiol, replacement to postmenopausal women, increased cardiac output and decreased blood pressure. Although the average magnitude of changes was small, the results suggest that plasma estradiol levels could be a source of individual variability in the hemodynamic response. Oral NETA administration tended to enhance rather than reverse the estradiol-induced changes. © 1997 Elsevier Science Ireland Ltd. Keywords: Transdermal administration; Estradiol; Progestin; Stroke volume; Vascular resistance
* Corresponding author. Tel.: + 54 1 9812757; fax: +54 1 9582923; e-mail: [email protected] 0378-5122/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 8 - 5 1 2 2 ( 9 7 ) 0 0 0 3 0 - 3
164
J. Alfie et al. / Maturitas 27 (1997) 163–169
1. Introduction Postmenopausal estrogen therapy, either alone or combined with progestin, has been associated with lower risk of cardiovascular disease [1]. On the other hand, several evidences have shown that menopause impairs hemodynamic parameters. Therapeutical induction of hypoestrogenemia in premenopausal women decreases cardiac output (CO) [2], whereas time since menopause correlates positively with uterine [3] and cerebral vascular resistance [4], and negatively with aortic flow velocity [5]. It has been reported that oral estrogen replacement to postmenopausal women produces a mild increase in aortic flow velocities [6], stroke volume (SV) and CO [7]. Therefore, in addition to the effects on plasma lipids, improvement of systemic hemodynamic profile could be one of the mechanisms by which hormone replacement therapy exerts its cardioprotective action. Hepatic stimulation of renin substrate production by oral estrogens [8] could partially account for the hemodynamic effects of postmenopausal hormone replacement therapy. On the other hand, whether the cyclic addition of progestin to prevent endometrial hyperplasia modify the hemodynamic effects of estrogens is still an open debate [3 – 9]. In the present placebo-controlled study we assessed the systemic hemodynamic effects of transdermal estradiol in postmenopausal women. In addition, the hemodynamic effect of combined (estradiol plus progestin) hormone replacement therapy was evaluated.
2. Material and methods Suitable patients entered a 24 weeks, randomized, placebo-controlled, two-period cross over study to compare the effects of continuous transdermal estradiol replacement therapy with placebo on blood pressure and its systemic hemodynamic determinants in postmenopausal women. Patients were informed of the aim of the study and gave written consent. Exclusion criteria consisted of the following: (a) history of breast cancer, (b) neoplastic, endocrine, cardiac or vascular diseases, (c) estrogen treatment during the last 2
months prior the beginning of the study, (d) present treatment with drugs that may interfere with circulation or with estradiol metabolism, (e) vaginal bleeding in response to 5 days of 5 mg of oral medroxyprogesterone acetate. (f) moderate, severe, complicated or treated arterial hypertension, (g) inadequate waveform on impedance cardiography tracing. Concomitant medications taken by some patients were: benzodiazepines in five, nonesteroideal anti-inflammatory agents in six, antilipemic agents in three and veralipride in two. During an inclusion period of 16 months, 33 postmenopausal women, aged 47–62 years, were randomized into one of two sequences: placebo patches for the first 12 weeks and transdermal estradiol patches for the second (group 1, n= 16) or the same treatment in the reverse order (group 2, n= 17). From the 33 patients initially recruited to the study, two were excluded for non-compliance (one during active period and the other during the placebo period), and two chose to withdraw, one because of lack of improvement during the active period and the other because of symptomatic impairment when changed from estradiol to placebo. Thus, 14 patients completed the sequence placebo-estradiol (group 1) and 15 the sequence estradiol-placebo (group 2). Twentyfour women had spontaneous and five had surgical menopause. In order to maintain the symmetry of the sequences, norethisterone acetate (NETA) in women with intact uteri was given for the last 12 days of both estradiol and placebo arms. The five hysterectomized women did not received NETA. Estrogen deficiency symptoms were scored according to their intensity (absent 0, mild 1, moderate 2 and severe 3). Hot flushes and sweating were multiplied by four, nervousness and insomnia by two and fatigue, dyspareunia, palpitations, headache and dizziness by one. The transdermal system consisted of a self adhesive acrylic matrix patch [10] delivering a constant dose of 0.05 mg of 17b-estradiol daily over 7 days [11]. Identical patches not containing estradiol were used during the placebo period. Women with intact uteri received 1 mg of NETA orally during the last 12 days of each treatment period.
J. Alfie et al. / Maturitas 27 (1997) 163–169
Thus, the hemodynamic effects of estradiol alone was assessed in 29 patients whereas the effect of progestin addition was assessed in a subsample of 24 patients. Plasma samples during estradiol treatment were not available in two women. Plasma was separated immediately and frozen ( −20°C) until analyzed for 17b-estradiol. Plasma levels of 17b-estradiol were determined by radioimmunoassay (Diagnostic Products Corporation, USA). Hemodynamic measurements were performed at baseline, at the end of each treatment period (immediately before progestin addition), and again between 7 to 12 days of NETA addition. Patients were asked to avoid smoking, drinking tea or coffee in the morning of the hemodynamic study. Blood pressure was determined on the right arm with a mercury sphygmomanometer. Impedance cardiography (Minnesota model 304 B, Surcom) was utilized for noninvasive monitoring SV, using the technique and formula proposed by Kubicek et al. [12]. Tracings of five consecutive cardiac cycles in apnea (passive expiration avoiding Valsalva) were recorded at a paper speed of 50 mm/s and manually measured. Hemodynamic recordings were obtained in quadruplicate, at rest in supine position. The CO was calculated as SV×HR, where HR, heart rate. Mean arterial pressure (MAP) and SVR were calculated by standard formulas. In our laboratory, the correlation coefficient between the simultaneous CO values obtained by impedance cardiography and thermo-dilution in 14 patients was 0.94, and the mean of the paired differences between the two methods was 0.08 l/min [13]. Differences in symptomatic score among baseline, placebo and estradiol treatment were assessed by Friedman test. The analysis of the crossover design was performed by the method of Grizzle [14]. Hemodynamic effects of NETA administration on placebo and estradiol arms were assessed by repeated measures ANOVA and Student –Newman–Keuls test. The relation between hemodynamic changes and plasma estradiol concentration was assessed by correlation analysis and unpaired t-test.
165
3. Results Table 1 lists patient’s characteristics. Plasma 17b-estradiol levels at baseline confirm the menopausal state. Plasma levels obtained at estradiol treatment indicate in average an adequate replacement. Four women reported minor and occasional problems of patch adhesion. Five women reported erythema and one of them also had pruritus at the place of parch adhesion. There was a significant improvement in the score of postmenopausal symptoms intensity from baseline with either estradiol or placebo, irrespective of the order in which treatments were administered. Group 1: baseline, 12.5 (0–23); period 1, 4.5 (0–24); period 2, 2 (0–14); PB 0.05. Group 2: baseline 19.5 (4–34), period 1, 5 (0–18); period 2, 5.5 (0–31); PB 0.05 (values are median and range). Table 2 lists the results of the crossover analysis of hemodynamic data before progestin addition. Compared with placebo, there was a mild although significant decrease in blood pressure and increase in SV and CO while patients were receiving estradiol, irrespective of the order in which it was administered. There was no significant change in HR. The decrease in SVR did not attain statistical significance. Table 1 Patient’s characteristics and plasma estradiol levels according to the sequence of treatment Variables
Group 1, Placebo-estradiol
Group 2, Estradiolplacebo
n Age (years) Body mass index (kg/m2) Natural menopause (years) Patients hysterectomized Plasma E2 level, baseline (pg/ml) Plasma E2 level, active period (pg/ml)
14 55 95 28 93
15 58 94 2693
7 96
7 96
4
1
10 98
12.59 8
62.3 940
53.79 25
Data are expressed as mean9 S.D.
J. Alfie et al. / Maturitas 27 (1997) 163–169
166 Table 2 Crossover analysis Variables
Group
Period 1
Period 2
Sequences
Periods
Treatments
SBP (mmHg)
1 2 1 2 1 2 1 2 1 2 1 2
1209 15 1219 15 729 6 72 9 9 64 9 8 62 9 10 919 16 94 9 23 58229 972 56919 926 11719164 2089226
115 9 13 123 917 70 96 74 910 64 99 63 98 100 919 88 9 19 6347 91259 5535 9 1052 1046 9 170 1274 9 239
ns
ns
B0.05
ns
ns
B0.05
ns
ns
ns
ns
ns
B0.05
ns
ns
B0.05
ns
ns
ns
DBP (mmHg) HR (bpm) SV (ml) CO (ml/min) SVR (dyn.sec.cm−5)
Group 1 (n =14), placebo-estradiol; group 2 (n= 15), estradiol-placebo. Data are expressed as mean9 S.D. SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; SV, stroke volume; CO, cardiac output; SVR, systemic vascular resistance.
Since the crossover analysis did not evidence differences between periods and order of treatments, data of patients in group and 2 were combined for further analysis. Table 3 shows the hemodynamic variables at placebo and estradiol treatments alone and combined with NETA in the 24 women with intact uteri (Table 3). The addition of NETA to placebo and to estradiol tended to decrease blood pressure and SVR and increase SV and CO, but the changes did not reach statistical significance. The combination of estradiol and NETA enhanced the individual effect of each hormone, reaching significantly higher SV (P B0.05) and lower SVR (P B0.05) and SBP (P =0.051) than placebo. In the 27 women who had completed plasma sampling, the correlation’s between plasma concentration of estradiol during active treatment and hemodynamic changes from placebo did not attained statistical significance. However women with plasma estradiol level above 63 pg/ ml (n= 9) showed significantly greater hemodynamic changes (P B 0.05) than women with plasma estradiol below this level (Fig. 1).
4. Discussion Estrogen replacement therapy, either alone or combined with progestin, has been associated with lower risk of cardiovascular disease [1]. Growing evidences support the hypothesis that not only changes in lipid profile but also direct vascular effects participate in the cardioprotective effects of estrogens. In the present study we examined the effects of transdermal estradiol replacement (0.05 mg/day, once a week) and the concomitant administration of oral NETA on systemic hemodynamics in postmenopausal women. Transdermal estradiol administration was associated with a mild although significant fall in blood pressure despite a significant rise in SV and CO. This suggests a concomitant vasodilator effect, however the decrease in SVR did not reach statistical significance. In a previous placebo controlled crossover study, oral estradiol replacement to postmenopausal women also decreased blood pressure [7]. Nevertheless, long-term placebo controlled studies showed no significant effect of unopposed estrogen and different estrogen/ progestin regimens on blood pressure [8– However results showed in Fig. 1 suggest that blood pressure would not be a reliable index of
J. Alfie et al. / Maturitas 27 (1997) 163–169
167
Table 3 Hemodynamic changes at baseline, placebo and estradiol replacement, before and during NETA addition (n =24) Variables
Placebo
Placebo plus NETA
Estradiol
Estradiol plus NETA
SBP (mmHg) DBP (mmHg) HR (bpm) SV (ml) CO (ml/min) SVR (dyn.seg.cm−5)
1209 15 72 99 649 8 90917 5728 91045 12089 223
1179 14 719 9 649 7 969 23 60569 1400 11479 316
117 9 14 70 9 8 63 9 10 96 922 5935 9 1176 1138 9231
116 9 11** 70 97 61 914 99 9 19* 6176 91247 1088 9 212*
Data are expressed as mean9 S.D. The same abbreviations as in Table 2. * PB0.05 and ** P= 0.051 vs. placebo, by repeated measures ANOVA and Student – Newman – Keuls test.
the hemodynamic response to estrogens since a concomitant increase in CO tended to negate the effect of vasodilation on blood pressure. The route of administration of estradiol could influence the hemodynamic response. Previous studies using oral estrogen replacement therapy reported plasma volume expansion [7], improvement in left ventricular filling [16] and suggested a positive inotropic effect [6]. In contrast to the oral route, transdermal delivery avoid the first hepatic
Fig. 1. Bar graph comparing hemodynamic changes from placebo according to plasma estradiol concentration during active treatment in the 27 women who had completed the plasma sampling. The first nine highest plasma estradiol levels, range 63 – 170 pg/ml, (filled bars) showed significantly greater increase (* P B0.05) in SV and CO and decrease in SVR than women with plasma estradiol below 63 pg/ml (empty bars). There no significant differences in the response of blood pressure. Abbreviations are the same as in Table 2.
pass and therefore the increase in renin substrate [8]. Thus hemodynamic changes obtained with estradiol administered through the transdermal route could differ with those obtained with oral estrogens. However, in the present study, the use of transdermal was associated with systemic hemodynamic changes that were comparable to those previously reported using the oral route. Although the average magnitude of changes was small, women with plasma estradiol above 63 pg/ml (33.3% of the patients) showed the greatest hemodynamic changes. This suggests that factors, such as the dose and plasma concentration of the hormone could also determine the presence and magnitude of the hemodynamic effects. It have been reported significant reductions in the impedance to flow in cerebral and uterine vascular beds using transdermal replacement (TTS 50) delivering 0.05 mg/day of estradiol twice a week [3–9]. However the stimulatory effect of 17bestradiol on endothelium-dependent vasodilation was not evident at this dose of transdermal estradiol [17]. Data derived from animal experiments (premenopausal female monkeys fed with an atherogenic diet) suggested that the effect of estradiol on endothelium-dependent vasodilation depends on the plasma concentration of the hormone (above 60 pg/ml) [18]. On the other hand it has been reported that 4 mg of oral estradiol caused a greater increase in SV than did 2 mg daily dose [7]. However, comparing two different studies from the same group, it can be observed that the effect on uterine arteries was similar with transdermal estradiol delivering either 0.05 or 0.1 mg/day [3–19].
168
J. Alfie et al. / Maturitas 27 (1997) 163–169
Progestin addition to prevent endometrial hyperplasia could partially antagonize the stimulatory effect of estradiol on endothelium-dependent vasorelaxation [20] and attenuate the increase in circulating nitrite/nitrate levels (a marker for NO synthase activity) [21]. It has been reported that either norethindrone or medroxyprogesterone acetate partially reverse the reduction in impedance to flow in uterine arteries [3 – 19]. However, hemodynamic changes in the uterine vascular bed could be secondary to the effects of progestin on the endometrium. Accordingly, cerebral pulsatility index did not change during combined medroxyprogesterone plus estradiol treatment as compared with unopposed estradiol [9]. On the other hand it has been shown that compared to estrogen-only treatment, progestin addition did not affect the decrease in plasma endothelin-1 [22] and the increase in systemic PGI2 production (unless progestogens with strong androgenic effect were used) [23]. In addition, both estradiol and progesterone can cause vasorelaxation in isolated human arteries, regardless of the presence or absence of endothelium [24]. Interestingly, in premenopausal women affected by primary infertility, progesterone administration during the luteal phase of gonadotrophin-stimulated cycles resulted in a significant decrease in uterine pulsatility index compared with cycles without luteal support [25]. The present study assessed the effect of NETA administration on transdermal placebo and estradiol arms. Although 7 to 12 days could not be long enough to evaluate the systemic hemodynamic effects of NETA, significant changes in uterine circulation can be detected after a week of progestin addition [19]. Unexpectedly NETA administration tended to change systemic hemodynamic variables in the same direction of estradiol, enhancing rather than reversing the estradiol induced-hemodynamic change on SV. Experimental data showed that testosterone is able to increase the myosin ATPase activity in female hearts [26]. Thus NETA, a 19-nortestosterone derivative, could exert a positive inotropic effect through a testorterone-like activity. In conclusion, in postmenopausal women, a significant increase in SV and CO, and a mild
reduction in blood pressure was associated with transdermal estradiol replacement therapy (0.05 mg/day, once a week). The combination of NETA tended to enhance rather than reverse these changes.
Acknowledgements We thank the collaboration of Dr Jose´ Tessler, MD in the statistical analysis, and Beta Pharmaceutical for the supply of active and placebo medication and for plasma estradiol measurements.
References [1] Grodstein F, Stampfer MJ, Manso JE. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453 – 61. [2] Eckstein N, Pines A, Fisman EZ. The effect of the hypoestrogenic state induced by gonadotrophin-releasing hormone agonist on Doppler-derived parameters of aortic blood flow. J Clin Endocrinol Metab 1993;77:910 – 2. [3] Hillard TC, Bourne TH, Whitehead MI, Crayford TB, Collins WP, Campbell S. Differential effects of transdermal estradiol and sequential progestogens on impedance to flow within the uterine arteries of postmenopausal women. Fertil Steril 1992;58:959 – 63. [4] 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 – 51. [5] Pines A, Fisman EZ, Drory Y, Levo Y, Shemesh J, Ben-Ari E, Ayalon D. Menopause-Induced changes in Doppler-derived parameters of aortic blood flow in healthy women. Am J Cardiol 1992;69:1104 – 6. [6] Pines A, Fisman EZ, Levo Y. The effects of hormone replacement therapy in normal postmenopausal women: measurements of Doppler-derived parameters of aortic flow. Am J Obst Gynecol 1991;164:806 – 12. [7] Luotola H. Blood pressure and hemodynamics in postmenopausal women during estradiol-17b substitution. Ann Clin Res 1983;15(Suppl 18):1 – 121. [8] Hassager C, Riis BJ, Strøm V, Guyene TT, Christiansen C. The long-term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure. Circulation 1987;76:753 – 8. [9] Penotti M, Nencioni T, Gabrielli L, Farina M, Castiglioni E, Polvani F. Bloow flow variations in internal and middle cerebral arteries induced by postmenopausal hormone replacement therapy. Am J Obstet Gynecol 1993;169:1226 – 32.
J. Alfie et al. / Maturitas 27 (1997) 163–169 [10] Figueroa-Casas PR, Alfonsin A, Arrighi A. Use of a new transdermal delivery system for estrogen replacement therapy in postmenopausal women. Maturitas 1995;20:139 – 44. [11] Stefano, FJ, Carrara, DN. Seven days bioavailability study of a novel transdermal delivery system for estradiol in postmenopausal women. Proc. 21st International Symposium on Controlled Released of Bioactive Materials June 27 – 30, 1994;467–468. [12] Kubicek WG, Kottke FJ, Ramos MU. The Minnesota impedance cardiograph-theory and applications. Biomed Eng 1974;9:410 – 6. [13] Galarza, CR, del Rio, M. Cardiografı´a por impedancia en la evaluacio´n de la funcio´n cardiovascular. In: del Rio M., Romero JC, editors. Funcio´n Cardiovascular. Buenos Aires, Argentina: Propulsora Literaria, 1992:220–233. [14] Grizzle, JE. The two-period change-over design and its use in clinical trials. Biometrics 1979;30:727. [15] The Writing Group of the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial. JAMA 1995;273:199 – 208. [16] Voutilainen S, Hippela¨inen M, Hulkko S. Left ventricular diastolic function by Doppler echocardiography in relation to hormonal replacement therapy in healthy postmenopausal women. Am J Cardiol 1993;71:614–7. [17] Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon III RO. Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women. Am J Cardiol 1995;75:264–8. [18] Williams JK, Shively CA, Clarkson TB. Determinants of coronary artery reactivity in premenopausal female cynomolgus monkeys with diet-induced atherosclerosis. Circulation 1994;90:983–7.
.
169
[19] Marsh MS, Bourne TH, Whitehead MI, Collins WP, Campbell S. The temporal effect of progestogen on uterine artery pulsatility index in postmenopausal women receiving sequential hormone replacement therapy. Fertil Steril 1994;62:771 – 4. [20] Miller VM, Vanhoutte PM. Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. Am J Physiol 1991;261(Regulatory Integrative Comp Physiol 30):R1022 – 7. [21] Roselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17b-estradiol and norethisterone acetate. A two-years follow-up study. Hypertension 1995;25(part 2):848 – 53. [22] Ylikorkala O, Orpana A, Pvolakka, Pyo¨ra¨la¨ T, Viinikka L. Postmenopausal hormonal replacement decreases plasma levels of endothelin-1. J Clin Endocrinol Invest 1995;80:3384 – 7. [23] Ylikorkala O, Kuusi T, Tikkanen MJ, Viinikka L. Desogestrel-and levonorgestrel-containing oral contraceptives have different effects on urinary excretion of prostacyclin metabolites and serum high density lipoproteins. J Clin Endocrinol Metab 1987;65:1238 – 42. [24] Belfort MA, Saade GR, Suresh M, Vedernikov YP. Effects of estradiol-17b and progesterone on isolated human omental artery from premenopausal nonpregnant women and from normotensive and preeclamptic pregnant women. Am J Obstet Gynecol 1996;174:246 – 53. [25] Strigini FAL, Scida PAM, Parri C, Visconti A, Susini S, Genazzani AR. Modifications in uterine and intraovarian artery impedance in cycles of treatment with exogenous gonadotrophins: effects of luteal phase support. Fertil Steril 1995;64:76 – 80. [26] Scheuer J, Malhotra A, Schaible TF. Effects of gonadecand hormonal replacement on rat hearts. Circ Res 1987;61:12 – 9.
Hemodynamic effects of transdermal estradiol alone and combined with norethisterone acetate Jose´ Alfie a,*, Leonor Lugones b, Alejandra Belardo b, Marta Tutzer b, Carlos R. Galarza a, Gabriel D. Waisman a, Mario I. Ca´mera a a
Unidad de Hipertension Arterial, Ser6icio de Clinica Medica, Hospital Italiano, Buenos Aires, Argentina b Seccio´n Climaterio, Ser6icio de Ginecologia, Hospital Italiano, Buenos Aires, Argentina Accepted 14 March 1997
Abstract A 24 weeks, randomized, two-period, placebo controlled study was conducted to compare the effects of continuous transdermal 17b-estradiol replacement therapy (0.05 mg/day once a week) with placebo on systemic hemodynamics and blood pressure in postmenopausal women. Twenty-nine postmenopausal women (47 – 62 years) free of hormone replacement therapy were randomized in two groups; group 1 received estradiol patches for the first 12 weeks and placebo patches for the second, and group 2 received the same treatments in the reverse order. The effect of combined estradiol plus oral norethisterone acetate (NETA) 1 mg was also evaluated in the subset of women with intact uteri (n= 24). Crossover analysis showed that stroke volume and cardiac output were significantly higher (P B 0.05) and blood pressure was significantly lower (PB 0.05) with estradiol, irrespective of the order in which the treatments were administered. Although correlations between plasma estradiol levels during active treatment and hemodynamic changes were not significant, hemodynamic changes were significantly greater above 63 pg/ml than below this level (PB0.05). Oral norethisterone acetate administration either during transdermal placebo or estradiol arms tended to modify systemic hemodynamics in the same direction than estradiol but the changes did not attained statistical significance. In summary compared with placebo, transdermal 17b-estradiol, replacement to postmenopausal women, increased cardiac output and decreased blood pressure. Although the average magnitude of changes was small, the results suggest that plasma estradiol levels could be a source of individual variability in the hemodynamic response. Oral NETA administration tended to enhance rather than reverse the estradiol-induced changes. © 1997 Elsevier Science Ireland Ltd. Keywords: Transdermal administration; Estradiol; Progestin; Stroke volume; Vascular resistance
* Corresponding author. Tel.: + 54 1 9812757; fax: +54 1 9582923; e-mail: [email protected] 0378-5122/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 8 - 5 1 2 2 ( 9 7 ) 0 0 0 3 0 - 3
164
J. Alfie et al. / Maturitas 27 (1997) 163–169
1. Introduction Postmenopausal estrogen therapy, either alone or combined with progestin, has been associated with lower risk of cardiovascular disease [1]. On the other hand, several evidences have shown that menopause impairs hemodynamic parameters. Therapeutical induction of hypoestrogenemia in premenopausal women decreases cardiac output (CO) [2], whereas time since menopause correlates positively with uterine [3] and cerebral vascular resistance [4], and negatively with aortic flow velocity [5]. It has been reported that oral estrogen replacement to postmenopausal women produces a mild increase in aortic flow velocities [6], stroke volume (SV) and CO [7]. Therefore, in addition to the effects on plasma lipids, improvement of systemic hemodynamic profile could be one of the mechanisms by which hormone replacement therapy exerts its cardioprotective action. Hepatic stimulation of renin substrate production by oral estrogens [8] could partially account for the hemodynamic effects of postmenopausal hormone replacement therapy. On the other hand, whether the cyclic addition of progestin to prevent endometrial hyperplasia modify the hemodynamic effects of estrogens is still an open debate [3 – 9]. In the present placebo-controlled study we assessed the systemic hemodynamic effects of transdermal estradiol in postmenopausal women. In addition, the hemodynamic effect of combined (estradiol plus progestin) hormone replacement therapy was evaluated.
2. Material and methods Suitable patients entered a 24 weeks, randomized, placebo-controlled, two-period cross over study to compare the effects of continuous transdermal estradiol replacement therapy with placebo on blood pressure and its systemic hemodynamic determinants in postmenopausal women. Patients were informed of the aim of the study and gave written consent. Exclusion criteria consisted of the following: (a) history of breast cancer, (b) neoplastic, endocrine, cardiac or vascular diseases, (c) estrogen treatment during the last 2
months prior the beginning of the study, (d) present treatment with drugs that may interfere with circulation or with estradiol metabolism, (e) vaginal bleeding in response to 5 days of 5 mg of oral medroxyprogesterone acetate. (f) moderate, severe, complicated or treated arterial hypertension, (g) inadequate waveform on impedance cardiography tracing. Concomitant medications taken by some patients were: benzodiazepines in five, nonesteroideal anti-inflammatory agents in six, antilipemic agents in three and veralipride in two. During an inclusion period of 16 months, 33 postmenopausal women, aged 47–62 years, were randomized into one of two sequences: placebo patches for the first 12 weeks and transdermal estradiol patches for the second (group 1, n= 16) or the same treatment in the reverse order (group 2, n= 17). From the 33 patients initially recruited to the study, two were excluded for non-compliance (one during active period and the other during the placebo period), and two chose to withdraw, one because of lack of improvement during the active period and the other because of symptomatic impairment when changed from estradiol to placebo. Thus, 14 patients completed the sequence placebo-estradiol (group 1) and 15 the sequence estradiol-placebo (group 2). Twentyfour women had spontaneous and five had surgical menopause. In order to maintain the symmetry of the sequences, norethisterone acetate (NETA) in women with intact uteri was given for the last 12 days of both estradiol and placebo arms. The five hysterectomized women did not received NETA. Estrogen deficiency symptoms were scored according to their intensity (absent 0, mild 1, moderate 2 and severe 3). Hot flushes and sweating were multiplied by four, nervousness and insomnia by two and fatigue, dyspareunia, palpitations, headache and dizziness by one. The transdermal system consisted of a self adhesive acrylic matrix patch [10] delivering a constant dose of 0.05 mg of 17b-estradiol daily over 7 days [11]. Identical patches not containing estradiol were used during the placebo period. Women with intact uteri received 1 mg of NETA orally during the last 12 days of each treatment period.
J. Alfie et al. / Maturitas 27 (1997) 163–169
Thus, the hemodynamic effects of estradiol alone was assessed in 29 patients whereas the effect of progestin addition was assessed in a subsample of 24 patients. Plasma samples during estradiol treatment were not available in two women. Plasma was separated immediately and frozen ( −20°C) until analyzed for 17b-estradiol. Plasma levels of 17b-estradiol were determined by radioimmunoassay (Diagnostic Products Corporation, USA). Hemodynamic measurements were performed at baseline, at the end of each treatment period (immediately before progestin addition), and again between 7 to 12 days of NETA addition. Patients were asked to avoid smoking, drinking tea or coffee in the morning of the hemodynamic study. Blood pressure was determined on the right arm with a mercury sphygmomanometer. Impedance cardiography (Minnesota model 304 B, Surcom) was utilized for noninvasive monitoring SV, using the technique and formula proposed by Kubicek et al. [12]. Tracings of five consecutive cardiac cycles in apnea (passive expiration avoiding Valsalva) were recorded at a paper speed of 50 mm/s and manually measured. Hemodynamic recordings were obtained in quadruplicate, at rest in supine position. The CO was calculated as SV×HR, where HR, heart rate. Mean arterial pressure (MAP) and SVR were calculated by standard formulas. In our laboratory, the correlation coefficient between the simultaneous CO values obtained by impedance cardiography and thermo-dilution in 14 patients was 0.94, and the mean of the paired differences between the two methods was 0.08 l/min [13]. Differences in symptomatic score among baseline, placebo and estradiol treatment were assessed by Friedman test. The analysis of the crossover design was performed by the method of Grizzle [14]. Hemodynamic effects of NETA administration on placebo and estradiol arms were assessed by repeated measures ANOVA and Student –Newman–Keuls test. The relation between hemodynamic changes and plasma estradiol concentration was assessed by correlation analysis and unpaired t-test.
165
3. Results Table 1 lists patient’s characteristics. Plasma 17b-estradiol levels at baseline confirm the menopausal state. Plasma levels obtained at estradiol treatment indicate in average an adequate replacement. Four women reported minor and occasional problems of patch adhesion. Five women reported erythema and one of them also had pruritus at the place of parch adhesion. There was a significant improvement in the score of postmenopausal symptoms intensity from baseline with either estradiol or placebo, irrespective of the order in which treatments were administered. Group 1: baseline, 12.5 (0–23); period 1, 4.5 (0–24); period 2, 2 (0–14); PB 0.05. Group 2: baseline 19.5 (4–34), period 1, 5 (0–18); period 2, 5.5 (0–31); PB 0.05 (values are median and range). Table 2 lists the results of the crossover analysis of hemodynamic data before progestin addition. Compared with placebo, there was a mild although significant decrease in blood pressure and increase in SV and CO while patients were receiving estradiol, irrespective of the order in which it was administered. There was no significant change in HR. The decrease in SVR did not attain statistical significance. Table 1 Patient’s characteristics and plasma estradiol levels according to the sequence of treatment Variables
Group 1, Placebo-estradiol
Group 2, Estradiolplacebo
n Age (years) Body mass index (kg/m2) Natural menopause (years) Patients hysterectomized Plasma E2 level, baseline (pg/ml) Plasma E2 level, active period (pg/ml)
14 55 95 28 93
15 58 94 2693
7 96
7 96
4
1
10 98
12.59 8
62.3 940
53.79 25
Data are expressed as mean9 S.D.
J. Alfie et al. / Maturitas 27 (1997) 163–169
166 Table 2 Crossover analysis Variables
Group
Period 1
Period 2
Sequences
Periods
Treatments
SBP (mmHg)
1 2 1 2 1 2 1 2 1 2 1 2
1209 15 1219 15 729 6 72 9 9 64 9 8 62 9 10 919 16 94 9 23 58229 972 56919 926 11719164 2089226
115 9 13 123 917 70 96 74 910 64 99 63 98 100 919 88 9 19 6347 91259 5535 9 1052 1046 9 170 1274 9 239
ns
ns
B0.05
ns
ns
B0.05
ns
ns
ns
ns
ns
B0.05
ns
ns
B0.05
ns
ns
ns
DBP (mmHg) HR (bpm) SV (ml) CO (ml/min) SVR (dyn.sec.cm−5)
Group 1 (n =14), placebo-estradiol; group 2 (n= 15), estradiol-placebo. Data are expressed as mean9 S.D. SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; SV, stroke volume; CO, cardiac output; SVR, systemic vascular resistance.
Since the crossover analysis did not evidence differences between periods and order of treatments, data of patients in group and 2 were combined for further analysis. Table 3 shows the hemodynamic variables at placebo and estradiol treatments alone and combined with NETA in the 24 women with intact uteri (Table 3). The addition of NETA to placebo and to estradiol tended to decrease blood pressure and SVR and increase SV and CO, but the changes did not reach statistical significance. The combination of estradiol and NETA enhanced the individual effect of each hormone, reaching significantly higher SV (P B0.05) and lower SVR (P B0.05) and SBP (P =0.051) than placebo. In the 27 women who had completed plasma sampling, the correlation’s between plasma concentration of estradiol during active treatment and hemodynamic changes from placebo did not attained statistical significance. However women with plasma estradiol level above 63 pg/ ml (n= 9) showed significantly greater hemodynamic changes (P B 0.05) than women with plasma estradiol below this level (Fig. 1).
4. Discussion Estrogen replacement therapy, either alone or combined with progestin, has been associated with lower risk of cardiovascular disease [1]. Growing evidences support the hypothesis that not only changes in lipid profile but also direct vascular effects participate in the cardioprotective effects of estrogens. In the present study we examined the effects of transdermal estradiol replacement (0.05 mg/day, once a week) and the concomitant administration of oral NETA on systemic hemodynamics in postmenopausal women. Transdermal estradiol administration was associated with a mild although significant fall in blood pressure despite a significant rise in SV and CO. This suggests a concomitant vasodilator effect, however the decrease in SVR did not reach statistical significance. In a previous placebo controlled crossover study, oral estradiol replacement to postmenopausal women also decreased blood pressure [7]. Nevertheless, long-term placebo controlled studies showed no significant effect of unopposed estrogen and different estrogen/ progestin regimens on blood pressure [8– However results showed in Fig. 1 suggest that blood pressure would not be a reliable index of
J. Alfie et al. / Maturitas 27 (1997) 163–169
167
Table 3 Hemodynamic changes at baseline, placebo and estradiol replacement, before and during NETA addition (n =24) Variables
Placebo
Placebo plus NETA
Estradiol
Estradiol plus NETA
SBP (mmHg) DBP (mmHg) HR (bpm) SV (ml) CO (ml/min) SVR (dyn.seg.cm−5)
1209 15 72 99 649 8 90917 5728 91045 12089 223
1179 14 719 9 649 7 969 23 60569 1400 11479 316
117 9 14 70 9 8 63 9 10 96 922 5935 9 1176 1138 9231
116 9 11** 70 97 61 914 99 9 19* 6176 91247 1088 9 212*
Data are expressed as mean9 S.D. The same abbreviations as in Table 2. * PB0.05 and ** P= 0.051 vs. placebo, by repeated measures ANOVA and Student – Newman – Keuls test.
the hemodynamic response to estrogens since a concomitant increase in CO tended to negate the effect of vasodilation on blood pressure. The route of administration of estradiol could influence the hemodynamic response. Previous studies using oral estrogen replacement therapy reported plasma volume expansion [7], improvement in left ventricular filling [16] and suggested a positive inotropic effect [6]. In contrast to the oral route, transdermal delivery avoid the first hepatic
Fig. 1. Bar graph comparing hemodynamic changes from placebo according to plasma estradiol concentration during active treatment in the 27 women who had completed the plasma sampling. The first nine highest plasma estradiol levels, range 63 – 170 pg/ml, (filled bars) showed significantly greater increase (* P B0.05) in SV and CO and decrease in SVR than women with plasma estradiol below 63 pg/ml (empty bars). There no significant differences in the response of blood pressure. Abbreviations are the same as in Table 2.
pass and therefore the increase in renin substrate [8]. Thus hemodynamic changes obtained with estradiol administered through the transdermal route could differ with those obtained with oral estrogens. However, in the present study, the use of transdermal was associated with systemic hemodynamic changes that were comparable to those previously reported using the oral route. Although the average magnitude of changes was small, women with plasma estradiol above 63 pg/ml (33.3% of the patients) showed the greatest hemodynamic changes. This suggests that factors, such as the dose and plasma concentration of the hormone could also determine the presence and magnitude of the hemodynamic effects. It have been reported significant reductions in the impedance to flow in cerebral and uterine vascular beds using transdermal replacement (TTS 50) delivering 0.05 mg/day of estradiol twice a week [3–9]. However the stimulatory effect of 17bestradiol on endothelium-dependent vasodilation was not evident at this dose of transdermal estradiol [17]. Data derived from animal experiments (premenopausal female monkeys fed with an atherogenic diet) suggested that the effect of estradiol on endothelium-dependent vasodilation depends on the plasma concentration of the hormone (above 60 pg/ml) [18]. On the other hand it has been reported that 4 mg of oral estradiol caused a greater increase in SV than did 2 mg daily dose [7]. However, comparing two different studies from the same group, it can be observed that the effect on uterine arteries was similar with transdermal estradiol delivering either 0.05 or 0.1 mg/day [3–19].
168
J. Alfie et al. / Maturitas 27 (1997) 163–169
Progestin addition to prevent endometrial hyperplasia could partially antagonize the stimulatory effect of estradiol on endothelium-dependent vasorelaxation [20] and attenuate the increase in circulating nitrite/nitrate levels (a marker for NO synthase activity) [21]. It has been reported that either norethindrone or medroxyprogesterone acetate partially reverse the reduction in impedance to flow in uterine arteries [3 – 19]. However, hemodynamic changes in the uterine vascular bed could be secondary to the effects of progestin on the endometrium. Accordingly, cerebral pulsatility index did not change during combined medroxyprogesterone plus estradiol treatment as compared with unopposed estradiol [9]. On the other hand it has been shown that compared to estrogen-only treatment, progestin addition did not affect the decrease in plasma endothelin-1 [22] and the increase in systemic PGI2 production (unless progestogens with strong androgenic effect were used) [23]. In addition, both estradiol and progesterone can cause vasorelaxation in isolated human arteries, regardless of the presence or absence of endothelium [24]. Interestingly, in premenopausal women affected by primary infertility, progesterone administration during the luteal phase of gonadotrophin-stimulated cycles resulted in a significant decrease in uterine pulsatility index compared with cycles without luteal support [25]. The present study assessed the effect of NETA administration on transdermal placebo and estradiol arms. Although 7 to 12 days could not be long enough to evaluate the systemic hemodynamic effects of NETA, significant changes in uterine circulation can be detected after a week of progestin addition [19]. Unexpectedly NETA administration tended to change systemic hemodynamic variables in the same direction of estradiol, enhancing rather than reversing the estradiol induced-hemodynamic change on SV. Experimental data showed that testosterone is able to increase the myosin ATPase activity in female hearts [26]. Thus NETA, a 19-nortestosterone derivative, could exert a positive inotropic effect through a testorterone-like activity. In conclusion, in postmenopausal women, a significant increase in SV and CO, and a mild
reduction in blood pressure was associated with transdermal estradiol replacement therapy (0.05 mg/day, once a week). The combination of NETA tended to enhance rather than reverse these changes.
Acknowledgements We thank the collaboration of Dr Jose´ Tessler, MD in the statistical analysis, and Beta Pharmaceutical for the supply of active and placebo medication and for plasma estradiol measurements.
References [1] Grodstein F, Stampfer MJ, Manso JE. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453 – 61. [2] Eckstein N, Pines A, Fisman EZ. The effect of the hypoestrogenic state induced by gonadotrophin-releasing hormone agonist on Doppler-derived parameters of aortic blood flow. J Clin Endocrinol Metab 1993;77:910 – 2. [3] Hillard TC, Bourne TH, Whitehead MI, Crayford TB, Collins WP, Campbell S. Differential effects of transdermal estradiol and sequential progestogens on impedance to flow within the uterine arteries of postmenopausal women. Fertil Steril 1992;58:959 – 63. [4] 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 – 51. [5] Pines A, Fisman EZ, Drory Y, Levo Y, Shemesh J, Ben-Ari E, Ayalon D. Menopause-Induced changes in Doppler-derived parameters of aortic blood flow in healthy women. Am J Cardiol 1992;69:1104 – 6. [6] Pines A, Fisman EZ, Levo Y. The effects of hormone replacement therapy in normal postmenopausal women: measurements of Doppler-derived parameters of aortic flow. Am J Obst Gynecol 1991;164:806 – 12. [7] Luotola H. Blood pressure and hemodynamics in postmenopausal women during estradiol-17b substitution. Ann Clin Res 1983;15(Suppl 18):1 – 121. [8] Hassager C, Riis BJ, Strøm V, Guyene TT, Christiansen C. The long-term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure. Circulation 1987;76:753 – 8. [9] Penotti M, Nencioni T, Gabrielli L, Farina M, Castiglioni E, Polvani F. Bloow flow variations in internal and middle cerebral arteries induced by postmenopausal hormone replacement therapy. Am J Obstet Gynecol 1993;169:1226 – 32.
J. Alfie et al. / Maturitas 27 (1997) 163–169 [10] Figueroa-Casas PR, Alfonsin A, Arrighi A. Use of a new transdermal delivery system for estrogen replacement therapy in postmenopausal women. Maturitas 1995;20:139 – 44. [11] Stefano, FJ, Carrara, DN. Seven days bioavailability study of a novel transdermal delivery system for estradiol in postmenopausal women. Proc. 21st International Symposium on Controlled Released of Bioactive Materials June 27 – 30, 1994;467–468. [12] Kubicek WG, Kottke FJ, Ramos MU. The Minnesota impedance cardiograph-theory and applications. Biomed Eng 1974;9:410 – 6. [13] Galarza, CR, del Rio, M. Cardiografı´a por impedancia en la evaluacio´n de la funcio´n cardiovascular. In: del Rio M., Romero JC, editors. Funcio´n Cardiovascular. Buenos Aires, Argentina: Propulsora Literaria, 1992:220–233. [14] Grizzle, JE. The two-period change-over design and its use in clinical trials. Biometrics 1979;30:727. [15] The Writing Group of the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial. JAMA 1995;273:199 – 208. [16] Voutilainen S, Hippela¨inen M, Hulkko S. Left ventricular diastolic function by Doppler echocardiography in relation to hormonal replacement therapy in healthy postmenopausal women. Am J Cardiol 1993;71:614–7. [17] Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon III RO. Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women. Am J Cardiol 1995;75:264–8. [18] Williams JK, Shively CA, Clarkson TB. Determinants of coronary artery reactivity in premenopausal female cynomolgus monkeys with diet-induced atherosclerosis. Circulation 1994;90:983–7.
.
169
[19] Marsh MS, Bourne TH, Whitehead MI, Collins WP, Campbell S. The temporal effect of progestogen on uterine artery pulsatility index in postmenopausal women receiving sequential hormone replacement therapy. Fertil Steril 1994;62:771 – 4. [20] Miller VM, Vanhoutte PM. Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. Am J Physiol 1991;261(Regulatory Integrative Comp Physiol 30):R1022 – 7. [21] Roselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17b-estradiol and norethisterone acetate. A two-years follow-up study. Hypertension 1995;25(part 2):848 – 53. [22] Ylikorkala O, Orpana A, Pvolakka, Pyo¨ra¨la¨ T, Viinikka L. Postmenopausal hormonal replacement decreases plasma levels of endothelin-1. J Clin Endocrinol Invest 1995;80:3384 – 7. [23] Ylikorkala O, Kuusi T, Tikkanen MJ, Viinikka L. Desogestrel-and levonorgestrel-containing oral contraceptives have different effects on urinary excretion of prostacyclin metabolites and serum high density lipoproteins. J Clin Endocrinol Metab 1987;65:1238 – 42. [24] Belfort MA, Saade GR, Suresh M, Vedernikov YP. Effects of estradiol-17b and progesterone on isolated human omental artery from premenopausal nonpregnant women and from normotensive and preeclamptic pregnant women. Am J Obstet Gynecol 1996;174:246 – 53. [25] Strigini FAL, Scida PAM, Parri C, Visconti A, Susini S, Genazzani AR. Modifications in uterine and intraovarian artery impedance in cycles of treatment with exogenous gonadotrophins: effects of luteal phase support. Fertil Steril 1995;64:76 – 80. [26] Scheuer J, Malhotra A, Schaible TF. Effects of gonadecand hormonal replacement on rat hearts. Circ Res 1987;61:12 – 9.