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Comparison of brachial artery vascular responses among postmenopausal women receiving different doses of tibolone
International Journal of Gynecology and Obstetrics 122 (2013) 75–77
Contents lists available at SciVerse ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Comparison of brachial artery vascular responses among postmenopausal women receiving different doses of tibolone Sebastián Carranza-Lira ⁎, Berenice Cirigo-Hernández, Martha P. Sandoval-Barragán, Julio César Ramos-León UMAE, Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Social Security Mexican Institute, Mexico City, Mexico
a r t i c l e
i n f o
Article history: Received 26 October 2012 Received in revised form 29 January 2013 Accepted 28 February 2013 Keywords: Brachial artery Conventional dose Doppler Low dose Postmenopause Tibolone
a b s t r a c t Objective: To compare the effects of low and conventional doses of tibolone in brachial artery flux parameters among postmenopausal women. Methods: Between March 2011 and September 2012, 24 postmenopausal women attending Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Mexico City, for hormone replacement therapy were consecutively recruited. The women were alternately assigned to receive a daily dose of either 2.5 mg (n = 11) or 1.25 mg (n = 13) of oral tibolone. Before and after treatment, all women underwent a brachial artery Doppler ultrasound. The arterial diameter was measured, and the pulsatility index (PI) and the resistance index (RI) were calculated. A hyperemic stimulus was then induced and these parameters were measured again. Results: Among the 24 women, the time since menopause ranged from 16 to 24 months, and the median treatment duration was 3 months. Both groups showed a significant increase in arterial diameter after treatment. There was no significant difference between the groups in arterial diameter, PI, and RI. The arterial diameter after hyperemic stimulus was significantly lower after treatment than before treatment in both groups. Conclusion: Low and conventional doses of tibolone induced similar changes in brachial artery flux parameters among postmenopausal women. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hormone therapy has been associated with unfavorable cardiovascular outcomes [1]. On the basis of the Women’s Health Initiative study [2], it has been recommended that either low-dose hormone therapy or alternatives to hormone therapy should be used. Low-dose hormone therapy has shown to be useful both for controlling vasomotor symptoms [3] and preventing osteoporosis [4]. Several studies using Doppler ultrasound have evaluated the vascular changes induced by hormone therapy [5,6]. The measurement of flux parameters in the brachial artery or other blood vessels allows an estimation of vascular endothelium status [7]. Tibolone, a progestogen with estrogenic, progestagenic, and androgenic effects, has been used for a long time as part of hormone therapy during the menopause. It also shows favorable effects, such as decreasing aortic wave pulse velocity without modifying flux-mediated vasodilation, after 10 years of use [8]. In addition, a dose of 2.5 mg per day of tibolone has been found to decrease the pulsatility index (PI) of the carotid artery [9], having an effect similar to that of combined conjugated estrogens plus medroxyprogesterone therapy after the first month of treatment [10]. Other studies have reported slightly discordant results; for example, tibolone use at a dose of 2.5 mg per day for 6 months increased arterial diameter and decreased the PI and resistance index (RI) ⁎ Corresponding author at: Puente de piedra 150-422 torre I, Col. Toriello Guerra, CP 14050, México DF, Mexico. Tel./fax: +52 55 55284657. E-mail address: [email protected] (S. Carranza-Lira).
post-hyperemic stimulus [11]. Other studies found that norethisterone plus estradiol and tibolone at a dose of 2.5 mg per day favorably modified flux-mediated vasodilation in healthy postmenopausal women [12]. However, the effects of low-dose tibolone are unknown. As a result, the aim of the present study was to compare the effects of conventional and low tibolone dose on brachial artery flux parameters among postmenopausal women. 2. Materials and methods The present comparative longitudinal study was conducted among naturally postmenopausal women attending the Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Mexico City, Mexico, between March 1, 2011, and September 30, 2012. The study was approved by the local research committee (R-2009-3606-7), and all women consented to participation. The women were divided into 2 groups according to the daily oral dose of tibolone (Livial; Organon Mexicana, Mexico City, Mexico) that they were allocated: group 1 received 2.5 mg (conventional dose, n = 11), and group 2 received 1.25 mg (low dose, n = 13) of tibolone. Consecutive women were allocated alternately to the 2 treatment groups. For all participants, weight, height, waist perimeter, and hip perimeter were measured. The body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) and the waist-to-hip ratio (WHR, calculated as the waist perimeter in centimeters to the hip perimeter in centimeters) were then determined.
0020-7292/$ – see front matter © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijgo.2013.01.023
76
S. Carranza-Lira et al. / International Journal of Gynecology and Obstetrics 122 (2013) 75–77
Throughout the study, 1 ultrasonographer performed all Doppler ultrasounds of the brachial artery with a Model Technos MP instrument fitted with a 7.5-MHz probe (Esaote, Genoa, Italy); the intraobserver variation was below 5%. The arterial diameter was measured, and the PI and RI were calculated. To obtain these measurements, the transducer was placed perpendicular to the distal third of the right brachial artery. The internal diameter was measured when the double line pattern was clearly visible (to assess the actual arterial diameter). The PI (maximal systolic speed minus minimal diastolic speed divided by the average speed during the complete cycle) and the RI (maximal systolic speed minus final diastolic speed divided by the maximal systolic speed) were then calculated. A hyperemic stimulus was induced by placing a deflated sphygmomanometer cuff on the right arm and insufflating it to a pressure 50 mm Hg higher than the systolic pressure for 5 minutes. The cuff was then deflated and withdrawn, and the arterial diameter, PI, and RI were measured again 60 seconds later. These measurements were performed on all participants before and after treatment. The sample size was calculated with Epi Info version 6 (Centers for Disease Control and Prevention, Atlanta, GA, USA). For a confidence level of 90%, a power of 75%, and a 1:1 relationship, it was calculated that 11 patients would be required in each group. The results are reported as median (interquartile range). The data were analyzed with SPSS version 8 (SPSS Inc., Chicago, USA). Comparisons between the groups before and after treatment were done with a Mann−Whitney U test for independent samples. Comparisons between pre- and post-hyperemic stimulus values, as well as between before and after treatment values within each group, were done with the Wilcoxon sum rank test. A P value of less than 0.05 was considered to be statistically significant. 3. Results During the study period, 24 women were recruited: 11 to the conventional dose group and 13 to the low-dose group. The duration since menopause was 24.0 months (14.0–48.0 months) and 16.0 months (12.0–51.0 months) for the conventional and low-dose groups, respectively; the difference was not significant. The duration of treatment was 3 months (2–3 months) for both groups. There were no significant differences in age, weight, height, waist perimeter, hip perimeter, BMI, and WHR between the 2 treatment groups (Table 1). Although it was not the objective of the study, it was noted that all participants reported adequate control of vasomotor symptoms, and none of them reported any adverse effects of the treatment. The Doppler measurements for each group are reported in Table 2. No significant differences were found between the groups in arterial diameter, PI, or RI either pre- or post-hyperemic stimulus (Table 2). Among women in the conventional dose group before treatment, the arterial diameter was significantly lower pre-hyperemic stimulus than post-hyperemic stimulus (3.7 [3.0–4.4] vs 5.3 [3.5–6.3]; P b 0.003), but the PI and RI did not change. After treatment, the arterial diameter
Conventional tibolone (n = 11)
Low-dose tibolone group (n = 13)
P value
3.7 (3.0–4.4)b,c 3.0 (2.3–8.4) 0.81 (0.69–0.91)d
3.6 (2.8–5.0)h 3.8 (2.9–5.2) 0.89 (0.68–0.94)
0.955 0.649 0.608
5.3 (3.5–6.3)b,e 3.4 (2.6–4.6) 0.83 (0.5–0.93)
4.6 (3.5–7.6)h 5.6 (2.2–10.1) 0.97 (0.78–1.06)
>0.99 0.167 0.072
3.0 (2.5–3.8)c,f 4.0 (2.0–5.0) 0.92 (0.9–1.0)d,g
3.0 (2.7–3.9)i 4.7 (2.9–5.6) 0.9 (0.78–0.97)
0.608 0.228 0.207
3.6 (3.5–4.5)e,f 3.5 (2.1–3.8) 0.86 (0.8–1.0)g
4.0 (3.7–4.6)i 3.5 (2.8–4.8) 0.89 (0.74–0.99)
0.303 0.459 0.910
a
Values are given as median (interquartile range) unless stated otherwise. Within each group, values with the same superscript letter were significantly different: b P b 0.003, c P b 0.06, d P b 0.028, e P b 0.05, f P b 0.001, and g P b 0.017 in the conventional tibolone group; and h P b 0.004 and i P b 0.001 in the low-dose tibolone group. b–h
was significantly lower pre-hyperemic stimulus than post-hyperemic stimulus (3.0 [2.5–3.8] vs 3.6 [3.5–4.5]; P b 0.005), the PI did not change, and the RI was significantly higher (0.92 [0.9–1.0] vs 0.86 [0.8–1.0]; P b 0.02) (Table 2). In a comparison of parameters before and after tibolone treatment in the conventional dose group, the arterial diameter pre-hyperemic stimulus showed a tendency to be higher before treatment than after treatment (3.7 [3.0–4.4] vs 3.0 [2.5–3.8]; P b 0.06); similarly, the arterial diameter post-hyperemic stimulus was significantly higher before treatment than after treatment (5.3 [3.5–6.3] vs 3.6 [3.5–4.5]; P b 0.05). The pre-hyperemic stimulus RI was significantly lower before treatment than after treatment (0.81 [0.69–0.91] vs 0.92 [0.9–1.0]; P b 0.028). Among women in the low-dose group before treatment, the arterial diameter was significantly higher pre-hyperemic stimulus than post-hyperemic stimulus (3.6 [2.8–5.0] vs 3.0 [2.7–3.9]; P b 0.004), whereas the PI and RI did not change. After treatment, the arterial diameter was significantly lower pre-hyperemic stimulus than posthyperemic stimulus (3.0 [2.7–3.9] vs 4.0 [3.7–4.6]; P b 0.001), whereas the PI and RI did not change. In a comparison of parameters before and after tibolone treatment in the low-dose group, no differences were found in arterial diameter, PI, or RI, either pre- or post-hyperemic stimulus. The percentage change in vasodilation, PI, and RI pre- and posthyperemic stimulus was compared between the 2 groups (Table 3). The percentage change in RI was significantly lower in the conventional
Parameter Low-dose tibolone (n = 13)
Age, y 49.0 (42.0–52.0) 53.0 (48.0–55.5) Weight, kg 64.5 (59.5–77.0) 61.0 (59.5–67.5) Height, m 1.59 (1.55–1.64) 1.55 (1.51–1.59) Body mass index 26.8 (23.7–29.1) 25.4 (23.5–29.3) Waist perimeter, cm 94.0 (85.0–95.0) 84 (81.5–92.5)1 Hip perimeter, cm 104.0 (96.0–109.0) 100.0 (92.5–101.5) Waist-to-hip ratio 0.89 (0.87–0.91) 0.87 (0.84–0.91) Duration since menopause, mo 24.0 (14.0–48.0) 16.0 (12.0–51.0) a
Before treatment Pre-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index Post-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index After treatment Pre-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index Post-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index
Conventional tibolone group (n = 11)
Table 3 Percentage change in parameters pre- and post-hyperemic stimulus.a
Table 1 General characteristics of the study population.a Characteristic
Table 2 Comparison of parameters between and within the study groups.a
P value
Percentage difference between pre- and post-hyperemic stimulus values Conventional tibolone group (n = 11)
0.167 0.494 0.167 0.820 0.119 0.093 0.733 0.459
Values are given as median (interquartile range) unless stated otherwise.
Before treatment Arterial dilation Pulsatility index Resistance index After treatment Arterial dilation Pulsatility index Resistance index a
36.6 (16.7–54.5) 0 (−34.8 to 20.0) −2.9 (−37.5–2.5) 18.4 (12.5–60) −12.5 (−25.0 to 5.0) −8.5 (−11.1 to 0)
P value
Low-dose tibolone group (n = 13) 20.7 (8.85–47.8) 30.2 (−23.8 to 104.9) 9.9 (−51.5 –33.8) 21.9 (15.3–52.1) −22.2 (−37.3 to 18.5) −3.3 (−17.3 to 5.5)
0.361 0.303 0.041 0.691 0.776 0.608
Values are given as median (interquartile range) unless stated otherwise.
S. Carranza-Lira et al. / International Journal of Gynecology and Obstetrics 122 (2013) 75–77 Table 4 Percentage change in flux parameters before and after treatment.a Parameter
Percentage difference between before and after P value treatment values Conventional tibolone (n = 11)
Low-dose tibolone (n = 13)
Pre-hyperemic stimulus Arterial dilation −9.1 (−33.3 to 2.7) −16.7 (−40.5 to 19.7) Pulsatility index 38.9 (−60.4 to 64.8) 9.8 (−30.8 to 83.2) Resistance index 11.1 (3.3–38.5) −1.2 (−20.1–29.6) Post-hyperemic stimulus Arterial dilation −28.6 (−39.7 to 9.1) −6.3 (−38.8 to 9.0) Pulsatility index 4.2 (−41.3 to 61.5) −35.3 (−67.9 to 51.3) Resistance index 11.1 (−4.3 to 40.0) 0 (−22.9 to 12.9) a
0.569 0.955 0.134 0.733 0.569 0.186
Values are given as median (interquartile range) unless stated otherwise.
group than in the low-dose group (−2.9 [−37.5 to 2.5] vs 9.9 [−51.5 to 33.8]; P b 0.041) before treatment, but there were no significant differences in the other parameters (Table 3). Similarly, the percentage change in vasodilation, PI, and RI before and after treatment was compared between the 2 groups (Table 4). No significant differences were found in any of the parameters (Table 4).
77
groups after treatment, although the PI showed a greater (albeit non-significant) decrease in the low-dose group. The percentage change between before and after treatment measurements, although not statistically significant, showed that low-dose tibolone resulted in a less intense decrease in vasodilation and a greater decrease in the PI compared with conventional dose tibolone. The present study has some limitations, including the small sample size. In addition, it is possible that there was an allocation bias regarding the low-dose tibolone group, because the percentage change in the RI post-hyperemic stimulus was greater in this group than in the other group before treatment, which might mean that these women already had endothelial damage. The present considerations indicate that studies with a larger sample size are warranted to verify the findings, and also to determine whether the observed decrease in arterial diameter and increase in RI with a higher dose of tibolone might contribute to other disturbances in the cardiovascular system. Taken together, the results of the study show that both tibolone doses had similar effects, but low-dose tibolone seemed to have a less intense effect on the RI. Thus, it can be concluded that both doses of tibolone induced similar changes in brachial artery flux parameters. Conflict of interest
4. Discussion The authors have no conflicts of interest. Measurement of Doppler flux parameters is useful for evaluating the status of vascular endothelium [8–12]. In the present study on the effect of low-dose tibolone on flux parameters pre- and posthyperemic stimulus, no differences in arterial dilation, PI, and RI were found between women given a conventional dose of tibolone and those given a low dose. In both study groups, the arterial diameter was significantly higher post-hyperemic stimulus than pre-hyperemic stimulus both before and after treatment. In the conventional dose group only, the RI post-hyperemic stimulus was significantly lower after treatment than before treatment, as previously reported [11]. Furthermore, in the conventional dose group the arterial diameter, both pre- and post-hyperemic stimulus, was significantly lower after treatment than before treatment. Overall, the study has shown that conventional and low doses of tibolone produce similar results. Arterial dilation was observed in both groups before and after treatment. Notably, however, arterial dilation was lower in the conventional dose group after treatment than before treatment. This finding contrasts with a previous report in which the post-hyperemic stimulus arterial diameter was greater after treatment [11], but is in agreement with another study in which no changes were found in vasodilation after 10 years of tibolone treatment [8]. This observation warrants further consideration because it might indicate that low-dose tibolone does not impair the vascular response. As mentioned above, the pre-hyperemic stimulus RI in the conventional tibolone dose group was higher after treatment than before treatment; this contrasts with previous studies in which it decreased [9–11]; again, this observation might indicate that a low dose of tibolone does not impair vascular function. Taken together, the present data show that the increase in vasodilation was not as great as when no hormone influence was present. Regarding the percentage change in flux parameters between preand post-hyperemic stimulus, similar results were found for both
References [1] Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288(1): 49–57. [2] Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33. [3] Carranza-Lira S, Gooch AL, Velasco-Díaz G, Solano J, Arzola-Paniagua A. Low and ultra low-dose estrogen therapy for climacteric symptom control—preliminary report. Int J Fertil Womens Med 2006;51(4):171–5. [4] Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med 1999;130(11): 897–904. [5] 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(4):408–12. [6] De Leo V, la Marca A, Orlandi R, Crippa D, Setacci C, Petraglia F. Effects of estradiol alone or in combination with cyproterone acetate on carotid artery pulsatility index in postmenopausal women. Maturitas 2003;46(3):219–24. [7] Takase B, Uehata A, Akima T, Nagai T, Nishioka T, Hamabe A, et al. Endotheliumdependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol 1998;82(12):1535–9 A7–8. [8] Bruce D, Rymer J, Robinson J, Millasseau S, Chowienczyk P. The long-term effects of tibolone on aortic stiffness and endothelial function. Climacteric 2005;8(3): 221–9. [9] Castelo-Branco C, García-Fantini M, Haya J. Vascular reactivity and atheromatous plaques in post-menopausal women on tibolone treatment. Open prospective study with Doppler ultrasonography in internal carotid artery. Maturitas 2005;50(4): 259–65. [10] Battaglia C, Mancini F, Persico N, Penacchioni P, Regnani G, Volpe A, et al. Tibolone, oral or transdermal hormone replacement and colour Doppler analysis: a prospective, randomised pilot study. Maturitas 2004;48(4):446–55. [11] Carranza-Lira S, Cuan-Martínez JR, Rosales-Ortíz S. Brachial artery responses in menopausal women using tibolone. Int J Gynecol Obstet 2008;101(1):43–6. [12] Cagnacci A, Renzi A, Cannoletta M, Pirillo D, Arangino S, Volpe A. Tibolone and estradiol plus norethisterone acetate similarly influence endothelium-dependent vasodilatation in healthy postmenopausal women. Fertil Steril 2006;86(2):480–3.
Contents lists available at SciVerse ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Comparison of brachial artery vascular responses among postmenopausal women receiving different doses of tibolone Sebastián Carranza-Lira ⁎, Berenice Cirigo-Hernández, Martha P. Sandoval-Barragán, Julio César Ramos-León UMAE, Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Social Security Mexican Institute, Mexico City, Mexico
a r t i c l e
i n f o
Article history: Received 26 October 2012 Received in revised form 29 January 2013 Accepted 28 February 2013 Keywords: Brachial artery Conventional dose Doppler Low dose Postmenopause Tibolone
a b s t r a c t Objective: To compare the effects of low and conventional doses of tibolone in brachial artery flux parameters among postmenopausal women. Methods: Between March 2011 and September 2012, 24 postmenopausal women attending Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Mexico City, for hormone replacement therapy were consecutively recruited. The women were alternately assigned to receive a daily dose of either 2.5 mg (n = 11) or 1.25 mg (n = 13) of oral tibolone. Before and after treatment, all women underwent a brachial artery Doppler ultrasound. The arterial diameter was measured, and the pulsatility index (PI) and the resistance index (RI) were calculated. A hyperemic stimulus was then induced and these parameters were measured again. Results: Among the 24 women, the time since menopause ranged from 16 to 24 months, and the median treatment duration was 3 months. Both groups showed a significant increase in arterial diameter after treatment. There was no significant difference between the groups in arterial diameter, PI, and RI. The arterial diameter after hyperemic stimulus was significantly lower after treatment than before treatment in both groups. Conclusion: Low and conventional doses of tibolone induced similar changes in brachial artery flux parameters among postmenopausal women. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hormone therapy has been associated with unfavorable cardiovascular outcomes [1]. On the basis of the Women’s Health Initiative study [2], it has been recommended that either low-dose hormone therapy or alternatives to hormone therapy should be used. Low-dose hormone therapy has shown to be useful both for controlling vasomotor symptoms [3] and preventing osteoporosis [4]. Several studies using Doppler ultrasound have evaluated the vascular changes induced by hormone therapy [5,6]. The measurement of flux parameters in the brachial artery or other blood vessels allows an estimation of vascular endothelium status [7]. Tibolone, a progestogen with estrogenic, progestagenic, and androgenic effects, has been used for a long time as part of hormone therapy during the menopause. It also shows favorable effects, such as decreasing aortic wave pulse velocity without modifying flux-mediated vasodilation, after 10 years of use [8]. In addition, a dose of 2.5 mg per day of tibolone has been found to decrease the pulsatility index (PI) of the carotid artery [9], having an effect similar to that of combined conjugated estrogens plus medroxyprogesterone therapy after the first month of treatment [10]. Other studies have reported slightly discordant results; for example, tibolone use at a dose of 2.5 mg per day for 6 months increased arterial diameter and decreased the PI and resistance index (RI) ⁎ Corresponding author at: Puente de piedra 150-422 torre I, Col. Toriello Guerra, CP 14050, México DF, Mexico. Tel./fax: +52 55 55284657. E-mail address: [email protected] (S. Carranza-Lira).
post-hyperemic stimulus [11]. Other studies found that norethisterone plus estradiol and tibolone at a dose of 2.5 mg per day favorably modified flux-mediated vasodilation in healthy postmenopausal women [12]. However, the effects of low-dose tibolone are unknown. As a result, the aim of the present study was to compare the effects of conventional and low tibolone dose on brachial artery flux parameters among postmenopausal women. 2. Materials and methods The present comparative longitudinal study was conducted among naturally postmenopausal women attending the Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Mexico City, Mexico, between March 1, 2011, and September 30, 2012. The study was approved by the local research committee (R-2009-3606-7), and all women consented to participation. The women were divided into 2 groups according to the daily oral dose of tibolone (Livial; Organon Mexicana, Mexico City, Mexico) that they were allocated: group 1 received 2.5 mg (conventional dose, n = 11), and group 2 received 1.25 mg (low dose, n = 13) of tibolone. Consecutive women were allocated alternately to the 2 treatment groups. For all participants, weight, height, waist perimeter, and hip perimeter were measured. The body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) and the waist-to-hip ratio (WHR, calculated as the waist perimeter in centimeters to the hip perimeter in centimeters) were then determined.
0020-7292/$ – see front matter © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijgo.2013.01.023
76
S. Carranza-Lira et al. / International Journal of Gynecology and Obstetrics 122 (2013) 75–77
Throughout the study, 1 ultrasonographer performed all Doppler ultrasounds of the brachial artery with a Model Technos MP instrument fitted with a 7.5-MHz probe (Esaote, Genoa, Italy); the intraobserver variation was below 5%. The arterial diameter was measured, and the PI and RI were calculated. To obtain these measurements, the transducer was placed perpendicular to the distal third of the right brachial artery. The internal diameter was measured when the double line pattern was clearly visible (to assess the actual arterial diameter). The PI (maximal systolic speed minus minimal diastolic speed divided by the average speed during the complete cycle) and the RI (maximal systolic speed minus final diastolic speed divided by the maximal systolic speed) were then calculated. A hyperemic stimulus was induced by placing a deflated sphygmomanometer cuff on the right arm and insufflating it to a pressure 50 mm Hg higher than the systolic pressure for 5 minutes. The cuff was then deflated and withdrawn, and the arterial diameter, PI, and RI were measured again 60 seconds later. These measurements were performed on all participants before and after treatment. The sample size was calculated with Epi Info version 6 (Centers for Disease Control and Prevention, Atlanta, GA, USA). For a confidence level of 90%, a power of 75%, and a 1:1 relationship, it was calculated that 11 patients would be required in each group. The results are reported as median (interquartile range). The data were analyzed with SPSS version 8 (SPSS Inc., Chicago, USA). Comparisons between the groups before and after treatment were done with a Mann−Whitney U test for independent samples. Comparisons between pre- and post-hyperemic stimulus values, as well as between before and after treatment values within each group, were done with the Wilcoxon sum rank test. A P value of less than 0.05 was considered to be statistically significant. 3. Results During the study period, 24 women were recruited: 11 to the conventional dose group and 13 to the low-dose group. The duration since menopause was 24.0 months (14.0–48.0 months) and 16.0 months (12.0–51.0 months) for the conventional and low-dose groups, respectively; the difference was not significant. The duration of treatment was 3 months (2–3 months) for both groups. There were no significant differences in age, weight, height, waist perimeter, hip perimeter, BMI, and WHR between the 2 treatment groups (Table 1). Although it was not the objective of the study, it was noted that all participants reported adequate control of vasomotor symptoms, and none of them reported any adverse effects of the treatment. The Doppler measurements for each group are reported in Table 2. No significant differences were found between the groups in arterial diameter, PI, or RI either pre- or post-hyperemic stimulus (Table 2). Among women in the conventional dose group before treatment, the arterial diameter was significantly lower pre-hyperemic stimulus than post-hyperemic stimulus (3.7 [3.0–4.4] vs 5.3 [3.5–6.3]; P b 0.003), but the PI and RI did not change. After treatment, the arterial diameter
Conventional tibolone (n = 11)
Low-dose tibolone group (n = 13)
P value
3.7 (3.0–4.4)b,c 3.0 (2.3–8.4) 0.81 (0.69–0.91)d
3.6 (2.8–5.0)h 3.8 (2.9–5.2) 0.89 (0.68–0.94)
0.955 0.649 0.608
5.3 (3.5–6.3)b,e 3.4 (2.6–4.6) 0.83 (0.5–0.93)
4.6 (3.5–7.6)h 5.6 (2.2–10.1) 0.97 (0.78–1.06)
>0.99 0.167 0.072
3.0 (2.5–3.8)c,f 4.0 (2.0–5.0) 0.92 (0.9–1.0)d,g
3.0 (2.7–3.9)i 4.7 (2.9–5.6) 0.9 (0.78–0.97)
0.608 0.228 0.207
3.6 (3.5–4.5)e,f 3.5 (2.1–3.8) 0.86 (0.8–1.0)g
4.0 (3.7–4.6)i 3.5 (2.8–4.8) 0.89 (0.74–0.99)
0.303 0.459 0.910
a
Values are given as median (interquartile range) unless stated otherwise. Within each group, values with the same superscript letter were significantly different: b P b 0.003, c P b 0.06, d P b 0.028, e P b 0.05, f P b 0.001, and g P b 0.017 in the conventional tibolone group; and h P b 0.004 and i P b 0.001 in the low-dose tibolone group. b–h
was significantly lower pre-hyperemic stimulus than post-hyperemic stimulus (3.0 [2.5–3.8] vs 3.6 [3.5–4.5]; P b 0.005), the PI did not change, and the RI was significantly higher (0.92 [0.9–1.0] vs 0.86 [0.8–1.0]; P b 0.02) (Table 2). In a comparison of parameters before and after tibolone treatment in the conventional dose group, the arterial diameter pre-hyperemic stimulus showed a tendency to be higher before treatment than after treatment (3.7 [3.0–4.4] vs 3.0 [2.5–3.8]; P b 0.06); similarly, the arterial diameter post-hyperemic stimulus was significantly higher before treatment than after treatment (5.3 [3.5–6.3] vs 3.6 [3.5–4.5]; P b 0.05). The pre-hyperemic stimulus RI was significantly lower before treatment than after treatment (0.81 [0.69–0.91] vs 0.92 [0.9–1.0]; P b 0.028). Among women in the low-dose group before treatment, the arterial diameter was significantly higher pre-hyperemic stimulus than post-hyperemic stimulus (3.6 [2.8–5.0] vs 3.0 [2.7–3.9]; P b 0.004), whereas the PI and RI did not change. After treatment, the arterial diameter was significantly lower pre-hyperemic stimulus than posthyperemic stimulus (3.0 [2.7–3.9] vs 4.0 [3.7–4.6]; P b 0.001), whereas the PI and RI did not change. In a comparison of parameters before and after tibolone treatment in the low-dose group, no differences were found in arterial diameter, PI, or RI, either pre- or post-hyperemic stimulus. The percentage change in vasodilation, PI, and RI pre- and posthyperemic stimulus was compared between the 2 groups (Table 3). The percentage change in RI was significantly lower in the conventional
Parameter Low-dose tibolone (n = 13)
Age, y 49.0 (42.0–52.0) 53.0 (48.0–55.5) Weight, kg 64.5 (59.5–77.0) 61.0 (59.5–67.5) Height, m 1.59 (1.55–1.64) 1.55 (1.51–1.59) Body mass index 26.8 (23.7–29.1) 25.4 (23.5–29.3) Waist perimeter, cm 94.0 (85.0–95.0) 84 (81.5–92.5)1 Hip perimeter, cm 104.0 (96.0–109.0) 100.0 (92.5–101.5) Waist-to-hip ratio 0.89 (0.87–0.91) 0.87 (0.84–0.91) Duration since menopause, mo 24.0 (14.0–48.0) 16.0 (12.0–51.0) a
Before treatment Pre-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index Post-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index After treatment Pre-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index Post-hyperemic stimulus Arterial diameter, mm Pulsatility index Resistance index
Conventional tibolone group (n = 11)
Table 3 Percentage change in parameters pre- and post-hyperemic stimulus.a
Table 1 General characteristics of the study population.a Characteristic
Table 2 Comparison of parameters between and within the study groups.a
P value
Percentage difference between pre- and post-hyperemic stimulus values Conventional tibolone group (n = 11)
0.167 0.494 0.167 0.820 0.119 0.093 0.733 0.459
Values are given as median (interquartile range) unless stated otherwise.
Before treatment Arterial dilation Pulsatility index Resistance index After treatment Arterial dilation Pulsatility index Resistance index a
36.6 (16.7–54.5) 0 (−34.8 to 20.0) −2.9 (−37.5–2.5) 18.4 (12.5–60) −12.5 (−25.0 to 5.0) −8.5 (−11.1 to 0)
P value
Low-dose tibolone group (n = 13) 20.7 (8.85–47.8) 30.2 (−23.8 to 104.9) 9.9 (−51.5 –33.8) 21.9 (15.3–52.1) −22.2 (−37.3 to 18.5) −3.3 (−17.3 to 5.5)
0.361 0.303 0.041 0.691 0.776 0.608
Values are given as median (interquartile range) unless stated otherwise.
S. Carranza-Lira et al. / International Journal of Gynecology and Obstetrics 122 (2013) 75–77 Table 4 Percentage change in flux parameters before and after treatment.a Parameter
Percentage difference between before and after P value treatment values Conventional tibolone (n = 11)
Low-dose tibolone (n = 13)
Pre-hyperemic stimulus Arterial dilation −9.1 (−33.3 to 2.7) −16.7 (−40.5 to 19.7) Pulsatility index 38.9 (−60.4 to 64.8) 9.8 (−30.8 to 83.2) Resistance index 11.1 (3.3–38.5) −1.2 (−20.1–29.6) Post-hyperemic stimulus Arterial dilation −28.6 (−39.7 to 9.1) −6.3 (−38.8 to 9.0) Pulsatility index 4.2 (−41.3 to 61.5) −35.3 (−67.9 to 51.3) Resistance index 11.1 (−4.3 to 40.0) 0 (−22.9 to 12.9) a
0.569 0.955 0.134 0.733 0.569 0.186
Values are given as median (interquartile range) unless stated otherwise.
group than in the low-dose group (−2.9 [−37.5 to 2.5] vs 9.9 [−51.5 to 33.8]; P b 0.041) before treatment, but there were no significant differences in the other parameters (Table 3). Similarly, the percentage change in vasodilation, PI, and RI before and after treatment was compared between the 2 groups (Table 4). No significant differences were found in any of the parameters (Table 4).
77
groups after treatment, although the PI showed a greater (albeit non-significant) decrease in the low-dose group. The percentage change between before and after treatment measurements, although not statistically significant, showed that low-dose tibolone resulted in a less intense decrease in vasodilation and a greater decrease in the PI compared with conventional dose tibolone. The present study has some limitations, including the small sample size. In addition, it is possible that there was an allocation bias regarding the low-dose tibolone group, because the percentage change in the RI post-hyperemic stimulus was greater in this group than in the other group before treatment, which might mean that these women already had endothelial damage. The present considerations indicate that studies with a larger sample size are warranted to verify the findings, and also to determine whether the observed decrease in arterial diameter and increase in RI with a higher dose of tibolone might contribute to other disturbances in the cardiovascular system. Taken together, the results of the study show that both tibolone doses had similar effects, but low-dose tibolone seemed to have a less intense effect on the RI. Thus, it can be concluded that both doses of tibolone induced similar changes in brachial artery flux parameters. Conflict of interest
4. Discussion The authors have no conflicts of interest. Measurement of Doppler flux parameters is useful for evaluating the status of vascular endothelium [8–12]. In the present study on the effect of low-dose tibolone on flux parameters pre- and posthyperemic stimulus, no differences in arterial dilation, PI, and RI were found between women given a conventional dose of tibolone and those given a low dose. In both study groups, the arterial diameter was significantly higher post-hyperemic stimulus than pre-hyperemic stimulus both before and after treatment. In the conventional dose group only, the RI post-hyperemic stimulus was significantly lower after treatment than before treatment, as previously reported [11]. Furthermore, in the conventional dose group the arterial diameter, both pre- and post-hyperemic stimulus, was significantly lower after treatment than before treatment. Overall, the study has shown that conventional and low doses of tibolone produce similar results. Arterial dilation was observed in both groups before and after treatment. Notably, however, arterial dilation was lower in the conventional dose group after treatment than before treatment. This finding contrasts with a previous report in which the post-hyperemic stimulus arterial diameter was greater after treatment [11], but is in agreement with another study in which no changes were found in vasodilation after 10 years of tibolone treatment [8]. This observation warrants further consideration because it might indicate that low-dose tibolone does not impair the vascular response. As mentioned above, the pre-hyperemic stimulus RI in the conventional tibolone dose group was higher after treatment than before treatment; this contrasts with previous studies in which it decreased [9–11]; again, this observation might indicate that a low dose of tibolone does not impair vascular function. Taken together, the present data show that the increase in vasodilation was not as great as when no hormone influence was present. Regarding the percentage change in flux parameters between preand post-hyperemic stimulus, similar results were found for both
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