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Influence of hormonal replacement therapy on the regional cerebral blood flow in postmenopausal women
Maturitas 46 (2003) 255 /262 www.elsevier.com/locate/maturitas
Influence of hormonal replacement therapy on the regional cerebral blood flow in postmenopausal women Radoslaw Slopien´ a, Roman Junik b, Blaz˙ej Meczekalski a, Barbara HalerzNowakowska a, Marzena Maciejewska a, Alina Warenik-Szymankiewicz a,*, Jerzy Sowin´ski b a
Department of Gynecological Endocrinology, University of Medical Sciences of Poznan´, Ul. Polna 33, 60-241 Poznan´, Poland b Department of Endocrinology, University of Medical Sciences of Poznan´, Poznan´, Poland Received 11 April 2001; received in revised form 1 February 2003; accepted 4 March 2003
Abstract Objectives: The aim of this study was evaluation of the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women. Methods: The study group were 20 postmenopausal women, mean age 48.7 years (S.D. 9/4.9 years). The control group were ten regularly menstruating women, mean age 32.6 years (S.D. 9/13.2 years). In the studied group we measured the severity of climacteric syndrome with the use of Kupperman index and serum FSH and 17b-estradiol level with the use of radioimmunological method. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice, the reference region was delineated in the cerebellum. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. Results: Before HRT mean value of the Kupperman index in the study group was 29.8 points (S.D. 9/7.1 points); 17b-estradiol 27 pg/ml (S.D. 9/2 pg/ml); FSH 56 IU/l (S.D. 9/49.5 IU/ l); SPECT study revealed cerebral blood flow impairment in ten women. In all the studied slices cerebral blood flow was lower in the study group than in the controls. After 12 months of HRT the mean value of the Kupperman index in the study group was 13.2 points (S.D. 9/2.1 points) (P B/0.05); 17b-estradiol 44 pg/ml (S.D. 9/25 pg/ml); FSH 36.4 IU/l (S.D. 9/57.3 ng/ml); we found cerebral blood flow increase in all studied slices: right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%* (* P B/0.05). Conclusions: Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17bestradiol level. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Hormonal replacement therapy; Cerebral blood flow; 17b-Estradiol; Postmenopausal
* Corresponding author. Tel.: /48-61-841-9366. E-mail address: [email protected] (A. Warenik-Szymankiewicz). 0378-5122/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0378-5122(03)00144-0
R. Slopien´ et al. / Maturitas 46 (2003) 255 /262
256
1. Introduction Regional cerebral blood flow is a function of brain blood supplementation, which depends on two vascular spaces: extracerebral vessels and intracerebral vessels. Extracerebral vessels are large arteries on the base of brain and their branches like small meningeal vessels in subarachnoideal space. These vessels form further branches, which penetrate through the cerebral cortex to the brain parenchyma where gradually loose surrounding Virchow /Robin space and form intracerebral vessels or intraparenchymal vessels. Intracerebral vessels are: microarteries, small veins and capillary vessels in brain parenchyma. Extracerebral vessels regulate total cerebral blood flow, whereas intracerebral vessels are responsible for regional cerebral blood flow and blood/brain barrier permeability. In general vessels stand for 1/3 of the brain volume [1]. Cerebral blood flow decreases with age. It was also examined in various pathological states like depression or Alzheimer disease. It is also reported that the highest cerebral blood flow reduction is connected with the smallest survival rate [2]. Cerebral blood flow depends among others on vasodilatating action of 17b-estradiol. This action was first observed in the uterine artery [3] then in other arteries like internal carotid artery, middle cerebral artery [4] and coronary arteries [5], aorta [6] and other vessels [7]. Estrogen and progesterone receptors were found to be present in uterine artery as well as other arteries and veins [8]. Receptors density was higher in younger women [8]. Acting on the level of these receptors estrogen
stimulate prostacycline [9] and nitrogen oxide [10] production in the vessel wall, regulate sympatic paravascular nerve endings activity [11] and inhibit endothelin-1 [12] and calcium [13] dependent vessel constriction. The aim of this study was to evaluate the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women.
2. Material and methods The study group were 20 postmenopausal women who applied to Department of Gynecological Endocrinology University of Medical Sciences of Poznan´ because of climacteric symptoms. The control group were ten regularly menstruating women in reproductive age. All patients included into the study gave informed consent. The protocol of the study was approved by Ethical Committee of University of Medical Sciences of Poznan´. The mean age of women from the study group was 48.7 years (S.D. 9/4.9 years). All the studied women were at least 1 year after menopause and the mean time since the menopause in the study group was 1.7 years (S.D. 9/1.9 years). The mean age of the women from the control group was 32.6 years (S.D. 9/13.2 years). The severity of the climacteric syndrome was established with the use of Kupperman index; serum FSH and 17b-estradiol level was measured with the use of radioimmunological method (Orion Diagnostica kits). FSH intra- and interassay coefficient of variations were 4.2 and 6.2%,
Table 1 Mean values of the cerebral blood flow (CBF) in the studied slices in the study group before HRT and in the control group expressed as a percent of cerebellar blood flow Studied slice
The mean value of CBF in the study group before HRT (%) The mean value of the CBF in the control group (%)
Cerebellar right Cerebellar left Thalamic right Thalamic left Ventricular right Ventricular left
76.59/4.9 76.29/5.4 79.29/4.7 789/4.2 76.29/7.2 75.59/6.4
84.39/7.5** 84.69/7.8** 86.69/6.5** 86.29/6.7*** 84.99/8.4* 85.59/10.1**
* Change statistically relevant; P B/0.05. ** Change statistically relevant; P B/0.01. *** Change statistically relevant; P B/0.001.
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respectively; sensitivity was 0.18 mIU/ml. 17bEstradiol intra- and interassay coefficient of variations were 7.8 and 8.2%, respectively; sensitivity was 10 pg/ml. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). SPECT was performed in a dimly lit and quiet room after the intravenous administration of hexamethylpropylene-amine oxime (HMPAO) labeled with 740 MBq (20 mCi) partechnate 99 mTc. According to producer’s instruction (Ceretec, Amersham) tracer was administered 20 min after preparation and the tomography was performed 5 /40 min after tracer infusion. Rotating gamma camera (Siemens, Diacam) with high resolving power scanning collimator was used. Obtained data were analyzed with 64/64 matrix on the McIntosh computer with system ICON. Cerebral blood flow was measured by a semiquantitative method. The reference region was delineated on the cerebellum. The value of the regional cerebral blood flow was expressed as a ratio of the tracer accumulation in the brain to the tracer accumulation in the cerebellum. Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice. Analyzed slices contained following brain areas: / cerebellar slice: prefrontal region, lower part of the temporal region, hippocampus, pons and cerebellum; / thalamic slice: lower part of the prefrontal region, lower part of the frontal region, basal nuclei, thalamus, upper part of the temporal region; / ventricular slice: central part of the prefrontal region, lower part of the parietal region, parieto-occipital region, upper part of the occipital region. Brain flow impairment was diagnosed when regional blood flow in the examined brain region was lower than 70% of the blood flow in the reference region. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. In HRT we used: 2 mg of 17b-estradiol and 1 mg
257
of norethisterone acetate in 16 women; 2 mg of estradiol valerate and 2 mg of dienogest in four women. Possible contraindications to HRT were excluded and all examinations recommended before beginning of such treatment were performed (coagulation tests, lipid profile, liver function tests and vaginal ultrasonography with endometrial evaluation). We excluded also states which influence regional cerebral blood flow as: hypertension, neurological, psychiatric and brain vessels disorders, alcohol abuse, cigarettes smoking, drugs and HRT during 6 months before the beginning of the study. In statistical analysis we used following methods: / Wilcoxon test in comparison of Kupperman index value and serum 17b-estradiol and FSH level before and after HRT. / Mann /Whitney test in analysis of relation between regional cerebral blood flow and severity of climacteric syndrome. T -Student test in comparison of regional cerebral blood flow in the study and control groups and before and after HRT.
3. Results The mean age of the women from the study group was 48.7 years (S.D. 9/49 years) and the mean duration of menopause was 1.7 years (S.D. 9/4.9 years). Mean value of the Kupperman index in the study group was 29.8 points (S.D. 9/7.1 points); we found severe climacteric syndrome (Kupperman index value higher than 35 points) in five women (25%) and moderate climacteric syndrome (Kupperman index value 21/35 points) in 15 women (75%). The serum 17b-estradiol level was lower than 14 pg/ml in ten women and the mean value of the 17b-estradiol level for the rest of the study group was 27 pg/ml (S.D. 9/2 ng/ml) and FSH was 56 IU/l (S.D. 9/49.5 IU/l). The mean age of the women from the control group was 32.6 years (S.D. 9/13.2 years). All the women from the control group were menstruating regularly.
258
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SPECT study revealed impairment of the cerebral blood flow in ten women (50% of the study group). In three women we found regional decrease of the cerebral blood flow which regarded: / parietal lobes (two women); / left temporal lobe (one woman); / frontal lobes (one woman). In seven women we found focal decrease of cerebral blood flow which regarded: / / / /
left temporal lobe (four women); right temporal lobe (one woman); left frontal lobe (one woman); basal nuclei (one woman).
Mean values of cerebral blood flow in studied slices in the study group and in the control group are presented in Table 1. In all the studied slices
the cerebral blood flow was lower in the study group than in the controls (differences were statistically relevant in all the studied slices). Exemplary SPECT study result in a patient before HRT is presented on the Fig. 1. The differences in the regional cerebral blood flow between women with severe climacteric syndrome and moderate climacteric syndrome were not significant. We did not found statistically relevant difference in regional blood flow for any of climacteric symptoms. Regional cerebral blood flow in any of the studied slices did not correlate with serum 17bestradiol or FSH level. We repeated SPECT examination after 1 year of HRT in ten women who had impairment in the cerebral blood flow at the beginning of the study. The mean value of the Kupperman index in this group was 13.2 points (S.D. 9/2.1 points), the decrease of severity of climacteric symptoms was
Fig. 1. Exemplary SPECT study result in a patient before HRT.
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statistically relevant (P B/0.05), in all women we found moderate climacteric syndrome. The mean serum 17b-estradiol level in the group in which we repeated cerebral blood flow assessment was 44 pg/ml (S.D. 9/25 pg/ml) (increase not relevant) and FSH 36.4 IU/l (S.D. 9/57.3) (decrease not relevant). After 1 year of HRT we found cerebral blood flow impairment in two women. It was regional impairment in one patient and it regarded left temporal lobe and in the other it was a focal impairment and it regarded left temporal lobe. The mean values of cerebral blood flow in studied slices after 1 year of HRT are presented in Table 2. Exemplary SPECT study result in a patient after HRT is presented on the Fig. 2. After 1 year of HRT we found increase of regional cerebral blood flow in all studied brain slices and this increase reached following values (*change statistically relevant; P B/0.05): / / / / / /
right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%*.
Table 2 Mean values of the cerebral blood flow (CBF) in the studied slices before and after 1 year of HRT expressed as a percent of cerebellar blood flow Studied slice
The mean value of The mean value of the CBF before HRT (%) CBF after HRT (%)
Cerebellar right Cerebellar left Thalamic right Thalamic left Ventricular right Ventricular left
76.59/4.9
81.79/6.5
76.29/5.4
80.39/7.3
79.29/4.7
839/4.1
789/4.2 76.29/7.2
81.39/5.1 83.79/4.3*
75.59/6.4
82.29/5.3*
*Change statistically relevant; P B/0.05.
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4. Discussion Cerebral blood flow in our study was measured with the use of SPECT method. This is a functional study method, which allows to find focal ischemic changes of 1 cm of diameter. Cerebral blood flow assessment was performed in women with moderate and severe climacteric syndrome and revealed blood flow impairment in ten women (50% of the study group). Focal blood flow reduction was found in seven patients. These kind of blood flow decrease is usually related to cerebrovascular disease, in which blood flow reduction affects mostly white matter and gray matter and hypoperfusion foci are unsymmetrical in various brain regions [14]. Regional blood flow impairment was seen in three women. Regional blood flow impairment is typical for such diseases as depression and Alzheimer disease. In depression blood flow impairment affects mostly frontal lobe (more frequently left frontal lobe is affected) [15]. In Alzheimer disease temporal and parietal blood flow decrease is reported, in the course of disease blood flow impairment spreads on frontal lobes [16]. Blood flow reduction in right parietal lobe is connected with cognitive functions impairment [16]. Regional blood flow in studied slices was not dependent on age, time since menopause and on the climacteric syndrome severity. The mean age of the women from the study group was relatively low as for postmenopausa. This is related with our department role */we work as referral clinic and the mean age of our postmenopausal patient is lower than in general population. The other reason may be an impact of the social and economical changes, which may lead to slight decrease of the age of menopause in our society. Doppler studies in women after menopause revealed the increase of pulsatility index (PI) with age in relation to the internal carotid artery (16.72%) and the medial cerebral artery (17.59%) [17]. In this study there was no dependence between regional cerebral blood flow and serum 17bestradiol level. Such a relationship was found in other studies. It is reported that in women after menopause there is a negative correlation between serum 17b-estradiol level and PI in the internal
260
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Fig. 2. Exemplary SPECT study result in a patient after 12 months of HRT.
carotid artery and the middle cerebral artery [18]. This relationship is supported by the studies of Cacciatore et al. who revealed that before age of 50 cerebral blood flow is higher in women than in men [19]. Greene showed that in hypoestrogenic women cerebral blood flow is decreased [20]. The same author revealed that in postmenopausal women during hot flash further decrease of cerebral blood flow, which resembles a view typical for Alzheimer disease is observed [21]. In all the studied slices cerebral blood flow was lower in the study group than in the regularly menstruating women. As we have not found any relation between the age and cerebral blood flow both in the study and in the control group we suggest that this is an effect of the menopause and estrogen deprivation in the study group. After 1 year of HRT we found increase in cerebral blood flow in all studied brain slices.
This improvement was statistically relevant in ventricular slices (P B/0.05). The improvement of the blood flow was higher than percentage error of the repeated SPECT studies reported by Heikkinen et al. (2.2%) [22] and other authors [23]. The improvement in the cerebral blood flow coexisted with serum 17b-estradiol level increase. The mean serum 17b-estradiol level after 1 year of HRT was higher than 40 pg/ml what confirms the efficacy of the treatment. Increase of the cerebral blood flow after HRT was observed in various clinical studies [24]. Okhura et al. found that conjugated estrogen in dose 0.625 twice a day produce the cerebral blood flow increase (29.59/10.2%) and the cerebellar blood flow increase (29.39/10.4) after 3 weeks of therapy [25]. Smaller blood flow increase in our study is probably a result of lower estrogen dosage and the use of gestagen. It is also reported that transdermal 17b-estradiol in a dose 50 mg/day
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decreases PI in the internal carotid artery by 19% after 6 weeks of treatment. Oral or transdermal estradiol with norethisterone acetate increases gradually the regional cerebral blood flow since second month of treatment until the end of the 52 weeks period of treatment [26]. Shaywitz et al. revealed that conjugated estrogen given in a dose of 1.25 mg/day for 2 months increase various brain regions activity in positron emission tomography (PET) during verbal and nonverbal memory tests [27]. It is also reported that estrogen administration improves the cerebral blood flow in women with cerebrovascular disease [28] and may prevent vascular dementia [29,30]. In relation to gestagen influence on the vascular tone Hillard et al. found, that norethindrone acetate in a dose of 0.7 mg/day or medroxyprogesterone acetate in a dose of 10 mg/day added to transdermal estradiol in a dose of 50 mg/day results in partial canceling of 17b-estradiol effect on the blood flow in uterine artery [31]. During this treatment PI in the uterine artery was lower than before the treatment (34%) but higher than in a case of treatment with 17b-estradiol alone [31].
5. Conclusions Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17b-estradiol level.
References [1] McMinn RMH, Hutchins RT. Color atlas of human anatomy. Chicago: Year Book Medical Publishers, 1981. [2] Jagust WJ, Haan MN, Reed BR, et al. Brain perfusion imaging predicts survival in Alzheimer disease. Neurology 1998;51:1009 /13. [3] Bourne TH, Hillard TC, Whitehead MI, et al. Oestrogens, arterial status and postmenopausal women. Lancet 1990;1:1470 /1. [4] Penotti M, Nencioni T, Gabrielli L, et al. Blood flow variations in internal carotid and middle cerebral arteries induced by postmenopausal hormone replacement therapy. Am J Obstet Gynecol 1993;169:1226 /32.
261
[5] Eckstein N, Nadler E, Barnea O, et al. Acute effects of estradiol on the rat heart. Am J Obstet Gynecol 1994;171:844 /8. [6] Pines A, Fisman EZ, Levo Y, et al. The effects of hormonal replacement therapy in normal postmenopausal women: measurements of Doppler-derived parameters of aortic flow. Am J Obstet Gynecol 1991;164:806 /12. [7] Sarrel PM. Ovarian hormones and the circulation. Maturitas 1990;12:287 /8. [8] Padwick ML, Whitehead M, Coffer A, et al. Demonstration of an oestogen related protein in female tissues. In: Studd JWW, Whitehead MI, editors. The menopause. Oxford: Blackwell Scientific, 1988:227 /33. [9] De Zeigler D, Bessis R, Frydman R. Vascular resistance of uterine arteries: physiological effects of estradiol and progesterone. Fertil Steril 1991;55:775 /9. [10] Gislard V, Millard PH, VanHoute P. Effects of estradiol on endothelium dependent responses in the rabbit. J Pharmacol Exp Ther 1988;244:19 /22. [11] Klangkalya B, Chan A. The effects of ovarian hormones on b-adrenergic and muscarinic receptors in rat heart. Life Sci 1988;42:2307 /14. [12] Jiang C, Sarrell PM, Poole-Wilson PA, et al. Acute effects of estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol 1992;263:271 /5. [13] Jiang C, Sarrell PM, Lindsay DC, et al. Endotheliumindependent relaxation of rabbit coronary artery by estradiol in vitro. Br J Pharmacol 1991;104:1033 /7. [14] Risberg J. Diagnosis of dementia by regional cerebral blood low measurements using Xe133. Acta Neurol Scand 1996;168:59 /62. [15] Austin MP, Dougall N, Ross M, et al. Single photon emission tomography with 99mTc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum. J Affect Dis 1992;26:31 /44. [16] Greene RA, Kletzky OA, Klein RA. Comparison between cerebral blood flow in hypoestrogenic women and patients with Alzheimer’s disease. Neurobiol Aging 1998;19:180. [17] Penotti M, Farina M, Sironi L, et al. Cerebral artery blood flow in relation to age and menopausal status. Obstet Gynecol 1996;88:106 /9. [18] Battaglia C, Regnani G, Artini G, et al. Uterine and cerebral vascularisation in postmenopausal women treated with hormone replacement therapy. Gynecol Endocrinol 1999;13:223 /9. [19] Cacciatore B, Paakkari I, Toivonen J, et al. Randomised comparison of oral and transdermal hormonal replacement therapy on carotid and uterine artery resistance to blood flow. Obstet Gynecol 1998;92:563 /8. [20] Greene RA, Kletzky OA, Klein RA. Comparison between cerebral blood flow in hypoestrogenic women and patients with Alzheimer’s disease. Neurobiol Aging 1998;19:180. [21] Greene RA. International Congress on Alzheimer Disease. Amsterdam, 1998. [22] Heikkinen J, Kuikka JT, Ahonen A, et al. A Finnish multicentre quality assurance project in bone scintigraphy
262
[23]
[24]
[25]
[26]
[27]
R. Slopien´ et al. / Maturitas 46 (2003) 255 /262 and brain SPET: a phantom study. Nucl Med Commun 1992;15:795 /805. Catafau AM, Parellada E, Lomena F, et al. Baseline, visual deprivation and visual stimulation 99Tcm-HMPAOrelated changes in visual cortex can be detected with a single head SPET system. Nucl Med Commun 1996;17:480 /4. Gangar KF, Vyas S, Whitehead MI, et al. Pulsatility index in the internal carotid artery is influenced by transdermal oestradiol and time since menopause. Lancet 1991;338:839 /42. Okura T, Teshima Y, Isse K, et al. Estrogen increases cerebral and cerebellar blood flows in postmenopausal women. Menopause 1995;2:13 /8. Cacciatore B, Paakkari I, Toivonen J, et al. Randomised comparison of oral and transdermal hormonal replacement therapy on carotid and uterine artery resistance to blood flow. Obstet Gynecol 1998;92:563 /8. Shaywitz SE, Shaywitz BA, Pugh KR, et al. Effect of estrogen on brain activation patterns in postmenopausal
[28]
[29]
[30]
[31]
women during working memory tasks. J Am Med Assoc 1999;281:1197 /202. Chang RJ, Plouffe L, Schaffer K. Physiology of the menopause, In: Lorrain J, editor. Comprehensive management of menopause. Springer Verlag, New York, Berlin, Heildelber, London, Paris, Tokyo, Hong Kong, Barcelona, Budapest, 1994. Brambilla BJ, McKinlay S. A perspective study of factors affecting age at menopause. J Clin Epidemiol 1989;42:1031 /9. Lau TK, Wan D, Yim SF, et al. Prospective randomized, controlled study of the effect of hormonal replacement therapy on peripheral blood flow velocity in postmenopausal women. Fertil Steril 1998;70(2):284 /8. Hillard TC, Bourne TH, Whitehead MI, et al. 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.
Influence of hormonal replacement therapy on the regional cerebral blood flow in postmenopausal women Radoslaw Slopien´ a, Roman Junik b, Blaz˙ej Meczekalski a, Barbara HalerzNowakowska a, Marzena Maciejewska a, Alina Warenik-Szymankiewicz a,*, Jerzy Sowin´ski b a
Department of Gynecological Endocrinology, University of Medical Sciences of Poznan´, Ul. Polna 33, 60-241 Poznan´, Poland b Department of Endocrinology, University of Medical Sciences of Poznan´, Poznan´, Poland Received 11 April 2001; received in revised form 1 February 2003; accepted 4 March 2003
Abstract Objectives: The aim of this study was evaluation of the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women. Methods: The study group were 20 postmenopausal women, mean age 48.7 years (S.D. 9/4.9 years). The control group were ten regularly menstruating women, mean age 32.6 years (S.D. 9/13.2 years). In the studied group we measured the severity of climacteric syndrome with the use of Kupperman index and serum FSH and 17b-estradiol level with the use of radioimmunological method. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice, the reference region was delineated in the cerebellum. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. Results: Before HRT mean value of the Kupperman index in the study group was 29.8 points (S.D. 9/7.1 points); 17b-estradiol 27 pg/ml (S.D. 9/2 pg/ml); FSH 56 IU/l (S.D. 9/49.5 IU/ l); SPECT study revealed cerebral blood flow impairment in ten women. In all the studied slices cerebral blood flow was lower in the study group than in the controls. After 12 months of HRT the mean value of the Kupperman index in the study group was 13.2 points (S.D. 9/2.1 points) (P B/0.05); 17b-estradiol 44 pg/ml (S.D. 9/25 pg/ml); FSH 36.4 IU/l (S.D. 9/57.3 ng/ml); we found cerebral blood flow increase in all studied slices: right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%* (* P B/0.05). Conclusions: Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17bestradiol level. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Hormonal replacement therapy; Cerebral blood flow; 17b-Estradiol; Postmenopausal
* Corresponding author. Tel.: /48-61-841-9366. E-mail address: [email protected] (A. Warenik-Szymankiewicz). 0378-5122/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0378-5122(03)00144-0
R. Slopien´ et al. / Maturitas 46 (2003) 255 /262
256
1. Introduction Regional cerebral blood flow is a function of brain blood supplementation, which depends on two vascular spaces: extracerebral vessels and intracerebral vessels. Extracerebral vessels are large arteries on the base of brain and their branches like small meningeal vessels in subarachnoideal space. These vessels form further branches, which penetrate through the cerebral cortex to the brain parenchyma where gradually loose surrounding Virchow /Robin space and form intracerebral vessels or intraparenchymal vessels. Intracerebral vessels are: microarteries, small veins and capillary vessels in brain parenchyma. Extracerebral vessels regulate total cerebral blood flow, whereas intracerebral vessels are responsible for regional cerebral blood flow and blood/brain barrier permeability. In general vessels stand for 1/3 of the brain volume [1]. Cerebral blood flow decreases with age. It was also examined in various pathological states like depression or Alzheimer disease. It is also reported that the highest cerebral blood flow reduction is connected with the smallest survival rate [2]. Cerebral blood flow depends among others on vasodilatating action of 17b-estradiol. This action was first observed in the uterine artery [3] then in other arteries like internal carotid artery, middle cerebral artery [4] and coronary arteries [5], aorta [6] and other vessels [7]. Estrogen and progesterone receptors were found to be present in uterine artery as well as other arteries and veins [8]. Receptors density was higher in younger women [8]. Acting on the level of these receptors estrogen
stimulate prostacycline [9] and nitrogen oxide [10] production in the vessel wall, regulate sympatic paravascular nerve endings activity [11] and inhibit endothelin-1 [12] and calcium [13] dependent vessel constriction. The aim of this study was to evaluate the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women.
2. Material and methods The study group were 20 postmenopausal women who applied to Department of Gynecological Endocrinology University of Medical Sciences of Poznan´ because of climacteric symptoms. The control group were ten regularly menstruating women in reproductive age. All patients included into the study gave informed consent. The protocol of the study was approved by Ethical Committee of University of Medical Sciences of Poznan´. The mean age of women from the study group was 48.7 years (S.D. 9/4.9 years). All the studied women were at least 1 year after menopause and the mean time since the menopause in the study group was 1.7 years (S.D. 9/1.9 years). The mean age of the women from the control group was 32.6 years (S.D. 9/13.2 years). The severity of the climacteric syndrome was established with the use of Kupperman index; serum FSH and 17b-estradiol level was measured with the use of radioimmunological method (Orion Diagnostica kits). FSH intra- and interassay coefficient of variations were 4.2 and 6.2%,
Table 1 Mean values of the cerebral blood flow (CBF) in the studied slices in the study group before HRT and in the control group expressed as a percent of cerebellar blood flow Studied slice
The mean value of CBF in the study group before HRT (%) The mean value of the CBF in the control group (%)
Cerebellar right Cerebellar left Thalamic right Thalamic left Ventricular right Ventricular left
76.59/4.9 76.29/5.4 79.29/4.7 789/4.2 76.29/7.2 75.59/6.4
84.39/7.5** 84.69/7.8** 86.69/6.5** 86.29/6.7*** 84.99/8.4* 85.59/10.1**
* Change statistically relevant; P B/0.05. ** Change statistically relevant; P B/0.01. *** Change statistically relevant; P B/0.001.
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respectively; sensitivity was 0.18 mIU/ml. 17bEstradiol intra- and interassay coefficient of variations were 7.8 and 8.2%, respectively; sensitivity was 10 pg/ml. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). SPECT was performed in a dimly lit and quiet room after the intravenous administration of hexamethylpropylene-amine oxime (HMPAO) labeled with 740 MBq (20 mCi) partechnate 99 mTc. According to producer’s instruction (Ceretec, Amersham) tracer was administered 20 min after preparation and the tomography was performed 5 /40 min after tracer infusion. Rotating gamma camera (Siemens, Diacam) with high resolving power scanning collimator was used. Obtained data were analyzed with 64/64 matrix on the McIntosh computer with system ICON. Cerebral blood flow was measured by a semiquantitative method. The reference region was delineated on the cerebellum. The value of the regional cerebral blood flow was expressed as a ratio of the tracer accumulation in the brain to the tracer accumulation in the cerebellum. Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice. Analyzed slices contained following brain areas: / cerebellar slice: prefrontal region, lower part of the temporal region, hippocampus, pons and cerebellum; / thalamic slice: lower part of the prefrontal region, lower part of the frontal region, basal nuclei, thalamus, upper part of the temporal region; / ventricular slice: central part of the prefrontal region, lower part of the parietal region, parieto-occipital region, upper part of the occipital region. Brain flow impairment was diagnosed when regional blood flow in the examined brain region was lower than 70% of the blood flow in the reference region. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. In HRT we used: 2 mg of 17b-estradiol and 1 mg
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of norethisterone acetate in 16 women; 2 mg of estradiol valerate and 2 mg of dienogest in four women. Possible contraindications to HRT were excluded and all examinations recommended before beginning of such treatment were performed (coagulation tests, lipid profile, liver function tests and vaginal ultrasonography with endometrial evaluation). We excluded also states which influence regional cerebral blood flow as: hypertension, neurological, psychiatric and brain vessels disorders, alcohol abuse, cigarettes smoking, drugs and HRT during 6 months before the beginning of the study. In statistical analysis we used following methods: / Wilcoxon test in comparison of Kupperman index value and serum 17b-estradiol and FSH level before and after HRT. / Mann /Whitney test in analysis of relation between regional cerebral blood flow and severity of climacteric syndrome. T -Student test in comparison of regional cerebral blood flow in the study and control groups and before and after HRT.
3. Results The mean age of the women from the study group was 48.7 years (S.D. 9/49 years) and the mean duration of menopause was 1.7 years (S.D. 9/4.9 years). Mean value of the Kupperman index in the study group was 29.8 points (S.D. 9/7.1 points); we found severe climacteric syndrome (Kupperman index value higher than 35 points) in five women (25%) and moderate climacteric syndrome (Kupperman index value 21/35 points) in 15 women (75%). The serum 17b-estradiol level was lower than 14 pg/ml in ten women and the mean value of the 17b-estradiol level for the rest of the study group was 27 pg/ml (S.D. 9/2 ng/ml) and FSH was 56 IU/l (S.D. 9/49.5 IU/l). The mean age of the women from the control group was 32.6 years (S.D. 9/13.2 years). All the women from the control group were menstruating regularly.
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SPECT study revealed impairment of the cerebral blood flow in ten women (50% of the study group). In three women we found regional decrease of the cerebral blood flow which regarded: / parietal lobes (two women); / left temporal lobe (one woman); / frontal lobes (one woman). In seven women we found focal decrease of cerebral blood flow which regarded: / / / /
left temporal lobe (four women); right temporal lobe (one woman); left frontal lobe (one woman); basal nuclei (one woman).
Mean values of cerebral blood flow in studied slices in the study group and in the control group are presented in Table 1. In all the studied slices
the cerebral blood flow was lower in the study group than in the controls (differences were statistically relevant in all the studied slices). Exemplary SPECT study result in a patient before HRT is presented on the Fig. 1. The differences in the regional cerebral blood flow between women with severe climacteric syndrome and moderate climacteric syndrome were not significant. We did not found statistically relevant difference in regional blood flow for any of climacteric symptoms. Regional cerebral blood flow in any of the studied slices did not correlate with serum 17bestradiol or FSH level. We repeated SPECT examination after 1 year of HRT in ten women who had impairment in the cerebral blood flow at the beginning of the study. The mean value of the Kupperman index in this group was 13.2 points (S.D. 9/2.1 points), the decrease of severity of climacteric symptoms was
Fig. 1. Exemplary SPECT study result in a patient before HRT.
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statistically relevant (P B/0.05), in all women we found moderate climacteric syndrome. The mean serum 17b-estradiol level in the group in which we repeated cerebral blood flow assessment was 44 pg/ml (S.D. 9/25 pg/ml) (increase not relevant) and FSH 36.4 IU/l (S.D. 9/57.3) (decrease not relevant). After 1 year of HRT we found cerebral blood flow impairment in two women. It was regional impairment in one patient and it regarded left temporal lobe and in the other it was a focal impairment and it regarded left temporal lobe. The mean values of cerebral blood flow in studied slices after 1 year of HRT are presented in Table 2. Exemplary SPECT study result in a patient after HRT is presented on the Fig. 2. After 1 year of HRT we found increase of regional cerebral blood flow in all studied brain slices and this increase reached following values (*change statistically relevant; P B/0.05): / / / / / /
right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%*.
Table 2 Mean values of the cerebral blood flow (CBF) in the studied slices before and after 1 year of HRT expressed as a percent of cerebellar blood flow Studied slice
The mean value of The mean value of the CBF before HRT (%) CBF after HRT (%)
Cerebellar right Cerebellar left Thalamic right Thalamic left Ventricular right Ventricular left
76.59/4.9
81.79/6.5
76.29/5.4
80.39/7.3
79.29/4.7
839/4.1
789/4.2 76.29/7.2
81.39/5.1 83.79/4.3*
75.59/6.4
82.29/5.3*
*Change statistically relevant; P B/0.05.
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4. Discussion Cerebral blood flow in our study was measured with the use of SPECT method. This is a functional study method, which allows to find focal ischemic changes of 1 cm of diameter. Cerebral blood flow assessment was performed in women with moderate and severe climacteric syndrome and revealed blood flow impairment in ten women (50% of the study group). Focal blood flow reduction was found in seven patients. These kind of blood flow decrease is usually related to cerebrovascular disease, in which blood flow reduction affects mostly white matter and gray matter and hypoperfusion foci are unsymmetrical in various brain regions [14]. Regional blood flow impairment was seen in three women. Regional blood flow impairment is typical for such diseases as depression and Alzheimer disease. In depression blood flow impairment affects mostly frontal lobe (more frequently left frontal lobe is affected) [15]. In Alzheimer disease temporal and parietal blood flow decrease is reported, in the course of disease blood flow impairment spreads on frontal lobes [16]. Blood flow reduction in right parietal lobe is connected with cognitive functions impairment [16]. Regional blood flow in studied slices was not dependent on age, time since menopause and on the climacteric syndrome severity. The mean age of the women from the study group was relatively low as for postmenopausa. This is related with our department role */we work as referral clinic and the mean age of our postmenopausal patient is lower than in general population. The other reason may be an impact of the social and economical changes, which may lead to slight decrease of the age of menopause in our society. Doppler studies in women after menopause revealed the increase of pulsatility index (PI) with age in relation to the internal carotid artery (16.72%) and the medial cerebral artery (17.59%) [17]. In this study there was no dependence between regional cerebral blood flow and serum 17bestradiol level. Such a relationship was found in other studies. It is reported that in women after menopause there is a negative correlation between serum 17b-estradiol level and PI in the internal
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Fig. 2. Exemplary SPECT study result in a patient after 12 months of HRT.
carotid artery and the middle cerebral artery [18]. This relationship is supported by the studies of Cacciatore et al. who revealed that before age of 50 cerebral blood flow is higher in women than in men [19]. Greene showed that in hypoestrogenic women cerebral blood flow is decreased [20]. The same author revealed that in postmenopausal women during hot flash further decrease of cerebral blood flow, which resembles a view typical for Alzheimer disease is observed [21]. In all the studied slices cerebral blood flow was lower in the study group than in the regularly menstruating women. As we have not found any relation between the age and cerebral blood flow both in the study and in the control group we suggest that this is an effect of the menopause and estrogen deprivation in the study group. After 1 year of HRT we found increase in cerebral blood flow in all studied brain slices.
This improvement was statistically relevant in ventricular slices (P B/0.05). The improvement of the blood flow was higher than percentage error of the repeated SPECT studies reported by Heikkinen et al. (2.2%) [22] and other authors [23]. The improvement in the cerebral blood flow coexisted with serum 17b-estradiol level increase. The mean serum 17b-estradiol level after 1 year of HRT was higher than 40 pg/ml what confirms the efficacy of the treatment. Increase of the cerebral blood flow after HRT was observed in various clinical studies [24]. Okhura et al. found that conjugated estrogen in dose 0.625 twice a day produce the cerebral blood flow increase (29.59/10.2%) and the cerebellar blood flow increase (29.39/10.4) after 3 weeks of therapy [25]. Smaller blood flow increase in our study is probably a result of lower estrogen dosage and the use of gestagen. It is also reported that transdermal 17b-estradiol in a dose 50 mg/day
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decreases PI in the internal carotid artery by 19% after 6 weeks of treatment. Oral or transdermal estradiol with norethisterone acetate increases gradually the regional cerebral blood flow since second month of treatment until the end of the 52 weeks period of treatment [26]. Shaywitz et al. revealed that conjugated estrogen given in a dose of 1.25 mg/day for 2 months increase various brain regions activity in positron emission tomography (PET) during verbal and nonverbal memory tests [27]. It is also reported that estrogen administration improves the cerebral blood flow in women with cerebrovascular disease [28] and may prevent vascular dementia [29,30]. In relation to gestagen influence on the vascular tone Hillard et al. found, that norethindrone acetate in a dose of 0.7 mg/day or medroxyprogesterone acetate in a dose of 10 mg/day added to transdermal estradiol in a dose of 50 mg/day results in partial canceling of 17b-estradiol effect on the blood flow in uterine artery [31]. During this treatment PI in the uterine artery was lower than before the treatment (34%) but higher than in a case of treatment with 17b-estradiol alone [31].
5. Conclusions Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17b-estradiol level.
References [1] McMinn RMH, Hutchins RT. Color atlas of human anatomy. Chicago: Year Book Medical Publishers, 1981. [2] Jagust WJ, Haan MN, Reed BR, et al. Brain perfusion imaging predicts survival in Alzheimer disease. Neurology 1998;51:1009 /13. [3] Bourne TH, Hillard TC, Whitehead MI, et al. Oestrogens, arterial status and postmenopausal women. Lancet 1990;1:1470 /1. [4] Penotti M, Nencioni T, Gabrielli L, et al. Blood flow variations in internal carotid and middle cerebral arteries induced by postmenopausal hormone replacement therapy. Am J Obstet Gynecol 1993;169:1226 /32.
261
[5] Eckstein N, Nadler E, Barnea O, et al. Acute effects of estradiol on the rat heart. Am J Obstet Gynecol 1994;171:844 /8. [6] Pines A, Fisman EZ, Levo Y, et al. The effects of hormonal replacement therapy in normal postmenopausal women: measurements of Doppler-derived parameters of aortic flow. Am J Obstet Gynecol 1991;164:806 /12. [7] Sarrel PM. Ovarian hormones and the circulation. Maturitas 1990;12:287 /8. [8] Padwick ML, Whitehead M, Coffer A, et al. Demonstration of an oestogen related protein in female tissues. In: Studd JWW, Whitehead MI, editors. The menopause. Oxford: Blackwell Scientific, 1988:227 /33. [9] De Zeigler D, Bessis R, Frydman R. Vascular resistance of uterine arteries: physiological effects of estradiol and progesterone. Fertil Steril 1991;55:775 /9. [10] Gislard V, Millard PH, VanHoute P. Effects of estradiol on endothelium dependent responses in the rabbit. J Pharmacol Exp Ther 1988;244:19 /22. [11] Klangkalya B, Chan A. The effects of ovarian hormones on b-adrenergic and muscarinic receptors in rat heart. Life Sci 1988;42:2307 /14. [12] Jiang C, Sarrell PM, Poole-Wilson PA, et al. Acute effects of estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol 1992;263:271 /5. [13] Jiang C, Sarrell PM, Lindsay DC, et al. Endotheliumindependent relaxation of rabbit coronary artery by estradiol in vitro. Br J Pharmacol 1991;104:1033 /7. [14] Risberg J. Diagnosis of dementia by regional cerebral blood low measurements using Xe133. Acta Neurol Scand 1996;168:59 /62. [15] Austin MP, Dougall N, Ross M, et al. Single photon emission tomography with 99mTc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum. J Affect Dis 1992;26:31 /44. [16] Greene RA, Kletzky OA, Klein RA. Comparison between cerebral blood flow in hypoestrogenic women and patients with Alzheimer’s disease. Neurobiol Aging 1998;19:180. [17] Penotti M, Farina M, Sironi L, et al. Cerebral artery blood flow in relation to age and menopausal status. Obstet Gynecol 1996;88:106 /9. [18] Battaglia C, Regnani G, Artini G, et al. Uterine and cerebral vascularisation in postmenopausal women treated with hormone replacement therapy. Gynecol Endocrinol 1999;13:223 /9. [19] Cacciatore B, Paakkari I, Toivonen J, et al. Randomised comparison of oral and transdermal hormonal replacement therapy on carotid and uterine artery resistance to blood flow. Obstet Gynecol 1998;92:563 /8. [20] Greene RA, Kletzky OA, Klein RA. Comparison between cerebral blood flow in hypoestrogenic women and patients with Alzheimer’s disease. Neurobiol Aging 1998;19:180. [21] Greene RA. International Congress on Alzheimer Disease. Amsterdam, 1998. [22] Heikkinen J, Kuikka JT, Ahonen A, et al. A Finnish multicentre quality assurance project in bone scintigraphy
262
[23]
[24]
[25]
[26]
[27]
R. Slopien´ et al. / Maturitas 46 (2003) 255 /262 and brain SPET: a phantom study. Nucl Med Commun 1992;15:795 /805. Catafau AM, Parellada E, Lomena F, et al. Baseline, visual deprivation and visual stimulation 99Tcm-HMPAOrelated changes in visual cortex can be detected with a single head SPET system. Nucl Med Commun 1996;17:480 /4. Gangar KF, Vyas S, Whitehead MI, et al. Pulsatility index in the internal carotid artery is influenced by transdermal oestradiol and time since menopause. Lancet 1991;338:839 /42. Okura T, Teshima Y, Isse K, et al. Estrogen increases cerebral and cerebellar blood flows in postmenopausal women. Menopause 1995;2:13 /8. Cacciatore B, Paakkari I, Toivonen J, et al. Randomised comparison of oral and transdermal hormonal replacement therapy on carotid and uterine artery resistance to blood flow. Obstet Gynecol 1998;92:563 /8. Shaywitz SE, Shaywitz BA, Pugh KR, et al. Effect of estrogen on brain activation patterns in postmenopausal
[28]
[29]
[30]
[31]
women during working memory tasks. J Am Med Assoc 1999;281:1197 /202. Chang RJ, Plouffe L, Schaffer K. Physiology of the menopause, In: Lorrain J, editor. Comprehensive management of menopause. Springer Verlag, New York, Berlin, Heildelber, London, Paris, Tokyo, Hong Kong, Barcelona, Budapest, 1994. Brambilla BJ, McKinlay S. A perspective study of factors affecting age at menopause. J Clin Epidemiol 1989;42:1031 /9. Lau TK, Wan D, Yim SF, et al. Prospective randomized, controlled study of the effect of hormonal replacement therapy on peripheral blood flow velocity in postmenopausal women. Fertil Steril 1998;70(2):284 /8. Hillard TC, Bourne TH, Whitehead MI, et al. 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.