![Learn more about The Renal Drug Database]({"type":"image" , "src" : "/sda/112410/ARN_0571_RDD_728x90px.jpg"})
Abstract
Background. Blood pressure (BP) is one of the most powerful determinants of cardiovascular risk in women. This risk may differ between post-menopausal women with and without vasomotor hot flushes, possibly indicating different vascular responses to hormone therapy (HT). Thus, we compared in a clinical trial the effect of HT on ambulatory BP in normotensive, recently post-menopausal women with or without severe hot flushes.
Methods. A total of 147 women recorded prospectively their hot flushes for 2 weeks; 70 women were symptomatic (≥7 moderate/severe hot flush episodes/day), whereas 77 women were defined as asymptomatic (≤3 mild hot flush episodes/day). Women were treated for 6 months with either transdermal estradiol, oral estradiol with or without medroxyprogesterone acetate, or placebo.
Results. In symptomatic women decreases in BPs were seen during estradiol use. In contrast, in asymptomatic women receiving oral but not transdermal estradiol, increases in 24-h and day-time systolic and diastolic BPs were encountered.
Conclusion. Hot flushes modify the HT-mediated responses in ambulatory BP. In asymptomatic women oral but not transdermal estradiol show potentially harmful cardiovascular effect by increasing BP. Our results give additional justification to prescribing HT primarily for the treatment of troublesome hot flushes and avoiding HT in women without vasomotor symptoms.
| Abbreviations | ||
| ABP | = | ambulatory blood pressure |
| ANOVA | = | analysis of variance |
| BP | = | blood pressure |
| CVD | = | cardiovascular disease |
| DBP | = | diastolic blood pressure |
| E2 | = | estradiol |
| E1 | = | estrone |
| FEI | = | free estradiol index |
| HFWWS | = | hot flush weekly weighted score |
| HT | = | hormone therapy |
| MPA | = | medroxyprogesterone acetate |
| OE | = | oral estradiol |
| SBP | = | systolic blood pressure |
| SEM | = | standard error of mean |
| SHBG | = | sex hormone-binding globulin |
| TE | = | transdermal estradiol |
Key messages
In women without post-menopausal hot flushes, 6 months of unopposed oral estradiol was accompanied with elevations of 24-hour and day-time ambulatory blood pressures, whereas the same therapy led to falls in women with hot flushes.
Thus, hormone therapy should primarily be directed for the treatment of troublesome hot flushes, and if it is being used for some other indication in non-flushing women, a transdermal route of estrogen use should be favored.
Introduction
Blood pressure (BP) is one of the most reliable predictors of cardiovascular risk in women (Citation1). It is conspicuous that even rather modest consistent changes in BP modify the risk of the heart and arteries (Citation2,Citation3). Blood pressure increases in many women after menopause (Citation4,Citation5), but the mechanisms behind this change are poorly understood (Citation6–8). It has been postulated that menopausal vasomotor symptoms may also modify cardiovascular risk factors (Citation9,Citation10), although the exact etiology and mechanisms behind hot flushes are unknown (Citation11). Interestingly, the autonomic nervous system, which has a key role in the control of BP, also regulates vasomotor symptoms (Citation12,Citation13).
Numerous large observational studies showed a protective effect against cardiovascular disease (CVD) for post-menopausal hormone therapy (HT) (Citation14–16), while this was not detected in randomized HT trials (Citation17–19). The populations in observational and randomized HT studies differ in many aspects (Citation20,Citation21), importantly in vasomotor symptoms (Citation13,Citation22,Citation23), which were present in the women in observational studies (Citation14,Citation15), but absent or minimal in randomized trials (Citation17,Citation18); this difference might be one explanation for the conflicting data between observational and randomized HT studies. Thus, we compared in a placebo- controlled trial the responses of 24-hour ambulatory BP (ABP) to transdermal and oral estradiol (E2), the latter alone or in combination with daily medroxyprogesterone acetate (MPA), in recently post-menopausal women with or without severe vasomotor hot flushes.
Methods
A total of 147 healthy, normotensive women (onset of menopause within preceding 6–36 months, level of follicle-stimulating hormone ≥30 IU/L, age 48–55 years, no previous HT use) were included into this trial. Women with hypertension (BP > 140/90), obesity (body mass index >30 kg/m2), smoking, hysterectomy, clinically significant disease, or drug use were excluded. Hot flushes, recorded prospectively for 2 weeks in a diary, were rated with a hot flush weekly weighted score (HFWWS) (Citation24–27). Women with ≥7 moderate/severe hot flushes/day (n = 70) were classified as ‘symptomatic’ and as likely candidates for the initiation of HT in clinical practice. In contrast, women reporting only ≤3 mild hot flushes/day (n = 77) were classified as ‘asymptomatic’ and as unlikely candidates for HT use in clinical practice (Citation27).
Computerized randomization in blocks of four was made with regard to the symptom status at base-line. The participants were treated with a double-blind, double-dummy technique either with transdermal estradiol hemihydrate gel 1 mg/day (TE), oral estradiol valerate (OE) 2 mg/day alone or in combination with MPA 5 mg/day, or with placebo, for 6 months (). Power analysis was made on the primary outcome measure, i.e. differences in the responses between symptomatic and asymptomatic women to HT in pulse wave analysis (Citation27), and changes in ABP were secondary end-points of this trial. The study was approved by the Helsinki University Women's Hospital Ethics Committee (No. 329/E8/03) and registered in the National Agency for Medicine (EudraCT 2004–005091–16) and the US National Institutes of Health Clinical Research Registry (no. NCT00668603). The study was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki, and written informed consent was obtained from all participants. The enrollment period was from May 2005 to May 2007, and the trial was completed in December 2007.
Figure 1. Flow chart of the study.
Measurement of 24-h ABP
Ambulatory BP measurements for 24 hours were carried out before and at the end of the 6-month HT regimen. Participants wore calibrated oscillometric ABP monitors (SpaceLabs 90217, SpaceLabs Healthcare, Washington, USA) on their non-dominant arm. The monitor was programmed to measure BP at 20-minute intervals during awake time and at 30-minute intervals during sleep; the timings were scheduled according to each participant's pre-estimated bedtimes. The patients were instructed to maintain their normal daily activities during the ABP recordings, but to keep their arm extended and immobile during all measurements. In addition, during the ABP recordings the women recorded their activities and vasomotor symptoms in a diary.
Means of 24-hour, and separately for awake and sleep states, were calculated according to diary entries. Nocturnal dipping in systolic blood pressure (SBP) was defined as the difference between average sleep and awake SBP, expressed as both an absolute value (in mmHg) and as percentage of awake SBP; relative dipping of at least 10% is considered as normal (Citation28).
Laboratory measurements
The levels of estrone (E1) and E2 were assayed as described before (Citation27). Briefly, E1 was assayed by liquid chromatography–tandem mass spectrometry, and the intra- and interassay coefficients of variation were between 7.8% and 12.0%, with a detection limit of 10 picomoles/L. Estradiol was determined by radioimmunoassay (Estradiol-2, Diasorin Inc., Stillwater, MN, USA). The intra- and interassay coefficients of variation were less than 6.1%, and the detection limit was 19 picomol/L. The serum samples were also used for the assessment of sex hormone-binding globulin (SHBG) and thyroid stimulating-hormone with routine laboratory methods. The free estradiol index (FEI) was calculated as the ratio: E2 (nmol/L) × 100 / SHBG (nmol/L). Samples at 6 months were scheduled to be collected 2 hours after the intake or application of the study medication.
Statistical analyses
Normality was assessed with the Shapiro-Wilk test. One-way analysis of variance (ANOVA) or the Kruskal-Wallis test complemented with pair-wise comparisons with the Mann-Whitney U test with Bonferroni adjustments was used to compare the crude relationships between the eight different treatment groups at base-line. Two-way between-groups ANOVA with analysis of covariance was used to explore the impact of hot flushes on the ABP variables during HT. Owing to the multicollinearity between the ABP variables, univariable instead of multivariable approach was used. The effect of treatment was assessed as the absolute change at 6 months controlling for possible confounding variables (the base-line value of the variable, time since last menstruation (converted to ranks owing to its skewed distribution), and the levels of E1 and E2 and the FEI, expressed as percentages from base-line). Partial eta2 (η2) was calculated to describe the proportion of variance in the ABP variables explained by treatment. Statistical analyses were performed with SPSS software for Windows version 14.0, 2005 (SPSS Inc., Chicago, IL, USA). All data are presented as mean ± standard error on mean (SEM). A two-tailed P-value <0.05 was considered statistically significant.
Results
At base-line the participants were comparable in hormone levels () and ABP recordings (). Significant differences between groups were observed for the HFWWS (P < 0.001). In addition, time since menopause differed only between asymptomatic and symptomatic women assigned to placebo (P = 0.024) (). At base-line the number of successful ABP measurements through 24 hours ranged from 42 to 71, with a mean of 62.2 ± 0.4.
Table I. Base-line characteristics. The groups were comparable in pertinent variables except for the hot flush weekly weighted score and time since menopause. The free estradiol index was calculated as (estradiol (nanomoles/L)/sex hormone-binding globulin (nanomoles/L)) × 100. Data are presented as mean ± standard error of mean.
Table II. Hemodynamic variables in the different study groups at base-line. Data presented as mean ± standard error of mean. There were no differences between the groups (P-value > 0.05).
A total of 9 women discontinued the trial (3 withdrew consent, 2 discontinued due to spotting, and 4 did not show up at appointment), and thus, out of the 147 subjects at base-line, 138 (93.9%) were studied with ABP at 6 months (). The number of successful ABP measurements through 24 hours ranged from 31 to 78, with a mean of 61.3 ± 0.6 at 6 months. In symptomatic women all active treatments were effective in alleviating hot flushes (mean decrease in the HFWWS −75.6 ± 5.2) compared to placebo, but no significant differences between the active treatments were found. In asymptomatic women the changes in the HFWWS were comparable with placebo. The rises in the levels of E1, E2, or the FEI were not dependent on the hot flush status (data not shown). All active treatments caused significant increases in all estrogen levels (P < 0.001) compared to placebo (). The increase in E1 was significantly lower with TE than with OE or OE+MPA (P < 0.001 for both). The rises in E2 and the FEI were similar between all three active treatments ().
Table III. The levels of estrogens after 6 months of hormonal treatment, and percentual changes from base-line. Data presented as mean ± standard error of mean.
A significant interaction between the different treatments and the hot flush status was found, and, therefore, the analyses were done separately for each treatment group, always comparing symptomatic and asymptomatic women. The use of OE led to significantly different responses in 24-hour and day-time SBP and diastolic BP (DBP) between symptomatic and asymptomatic women (); 24-hour SBP and DBP rose (3.7 ± 1.2 mmHg and 1.8 ± 0.8 mmHg, respectively) in asymptomatic women, whereas decreases (–1.2 ± 1.2 mmHg and –2.1 ± 0.8 mmHg, respectively) were detected in symptomatic women (P = 0.010, η2 = 0.196 and P = 0.003, η2 = 0.257, respectively) (). (). Similarly, day-time SBP and DBP increased (3.0 ± 1.3 mmHg and 1.8 ± 0.9 mmHg, respectively) in asymptomatic women receiving OE, but the same therapy led to falls (−1.9 ± 1.3 mmHg and −2.4 ± 0.9 mmHg, respectively) in symptomatic women (P = 0.017, η2 = 0.171 and P = 0.003, η2 = 0.244, respectively). The BP-responses to OE during night-time in asymptomatic and symptomatic women resembled those during day-time, but these did not reach statistical significance. A significant difference in the responses between symptomatic and asymptomatic women to placebo was seen only in day-time DBP (P = 0.028, η2 = 0.141) (). The responses in 24-hour, day-time and night-time ABPs to TE and OE+MPA were comparable between symptomatic and asymptomatic women. In asymptomatic women the use of TE led to significant decreases in 24-h SBP and DBP compared with the increases caused by OE (P = 0.001 and P = 0.041, respectively) (). The hot flush status was no determinant for the responses in heart rate or nocturnal dipping to the different treatment regimens () which were, however, dependent on the base-line values, but not on time since menopause or changes in E1, E2, or the FEI.
Table IV. Effect of hormone therapy on ambulatory blood pressure and heart rate in asymptomatic and symptomatic women. Data are presented as absolute changes (mean ± standard error of mean) adjusted for the respective base-line values.
Figure 2. Changes in 24-hour systolic and diastolic blood pressures after 6 months of hormone therapy in symptomatic and asymptomatic women. Data presented as mean ± SE adjusted for the respective base-line levels. A P-value <0.05 was considered statistically significant. P-values are corrected with Bonferroni adjustment for multiple comparisons.
Discussion
We present evidence that vasomotor hot flushes modify the responses of ABP to OE; asymptomatic women responded with elevations in both 24-hour and day-time SBP and DBP during the use of OE. Such an effect was not detected in women exposed to TE, but rather a decrease in 24-h and day-time ABPs was seen. To our knowledge, this is the first study to compare the impact of prospectively recorded hot flushes on ABP responses to oral and transdermal HT in a placebo-controlled setting.
Previous studies have shown modest or no effect of HT on BP in post-menopausal women (Citation29–32). This was the case in the Women's Health In the Lund Area study, although increased BP was common in middle-aged women regardless of hormonal status, and HT did not affect BP (Citation29,Citation32). In the Women's Health Initiative trial, a small approximately 1 mmHg rise in systolic blood pressure in women receiving HT versus placebo was detected, with no change in diastolic BP (Citation30). However, these studies did not specifically assess vasomotor hot flushes in response of BP to HT. We may not deduce the exact mechanisms behind the OE-mediated rises in 24-hour and day-time SBP and DBP seen only in asymptomatic women in our trial. However, OE may stimulate the production of renin substrate in the liver and a consequent release of angiotensin-II; this may result in an elevation of BP (Citation31,Citation33). This reaction may be inhibited, at least in part by hot flush-associated changes in autonomic nervous system functioning (Citation12,Citation13), and that may explain why we saw BP elevations only in asymptomatic women receiving OE. Furthermore, sex steroid receptors show variance in expression and distribution that could have an impact on the effects of sex hormones on BP (Citation34). Interestingly, the presence of hot flushes has been linked with polymorphisms in estrogen-metabolizing cytochrome P450 enzymes (Citation35–38) and estrogen receptors alpha (Citation39) and beta (Citation40). Thus, it is possible that hot flush status implies differences in the function of the vascular bed, and this may become evident particularly in asymptomatic women being exposed to OE. This hypothesis is also supported by our previous data showing that OE leads to less compliant vasculature only in asymptomatic women (Citation27).
The use of TE did not set off increases in ABPs; in fact, TE showed a consistent tendency towards decreases in 24-h and day-time ABPs both in symptomatic and asymptomatic women. Interestingly, there were significant differences of approximately 8 mmHg in 24-h SBP and 4 mmHg in 24-h DBP between the responses to TE and OE in asymptomatic women. This difference could e.g. be partly attributed to the higher circulating levels of E1 during the use of oral rather than transdermal E2, since E1 may have various affinities to estrogen receptors and thus exert different vascular effects (Citation41,Citation42). In fact, transdermal administration of E2 has recently been proposed as a safer alternative of HT use compared to the oral route (Citation33) in regard to its effects on biochemical markers and thromboembolic complications (Citation41,Citation43). Also the possible BP-lowering effect of HT has mainly been attributed to transdermal use (Citation31,Citation33), which was also detected in our trial.
The addition of MPA to OE blunted the responses of ABP in our study. The impact of MPA on the vascular effects of E2 has been widely debated (Citation44–46). Our data support the concept of MPA-related vascular differences in a way that MPA may counteract the vascular effects of OE, perhaps through its androgenic and anti-estrogenic properties (Citation41). Furthermore, MPA exerts considerable glucocorticoid effects that may also counteract the direct effects of estrogen (Citation41).
As limitations to our trial we acknowledge that we studied only lean white women, and thus our results may not be generalizable to obese women or women belonging to other ethnic groups. Moreover, we studied only normotensive women, and the effect of HT in hypertensive women may be different; such women are common in routine menopausal practice (Citation32). In addition, physical inactivity is an established cardiovascular risk factor (Citation47), but unfortunately we did not have detailed data on the physical activity of our volunteers. Furthermore, we gave HT only for 6 months, and a longer treatment period could bring out additional differences. However, 2- to 6-month HT treatments have commonly been used in previous ABP-studies (Citation31). Finally, a larger study population might yield different results.
The strengths of our trial include the prospective recording of hot flushes. Furthermore, we used ABP measurements, the gold standard of assessing risk related to BP, which enabled an accurate estimation of 24-hour BPs, and separate analyses of day- and night-time BPs (Citation28). Additionally, we gave estradiol both orally and transdermally, because the cardiovascular responses to them differ (Citation31,Citation33,Citation34,Citation41,Citation42).
In conclusion, our data indicate that the use of OE is accompanied with elevations of 24-hour and day-time BPs, but only in asymptomatic women. Thus, our data give additional justification to prescribing HT primarily for the treatment of troublesome hot flushes. Furthermore, if HT is being used primarily for bone protection or some other indication in non-flushing women, a transdermal route of estrogen use should be favored due to its BP-lowering potential.
Acknowledgements
This study was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, and the Helsinki University Central Hospital Research Fund.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension. 2009;54:11–8.
- Svetkey LP. Management of prehypertension. Hypertension. 2005;45:1056–61.
- Conen D, Ridker PM, Buring JE, Glynn RJ. Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study. BMJ. 2007;335:432–40.
- Zanchetti A, Facchetti R, Cesana GC, Modena MG, Pirrelli A, Sega R, . Menopause-related blood pressure increase and its relationship to age and body mass index: the SIMONA epidemiological study. J Hypertens. 2005;23:2269–76.
- Collins P, Rosano G, Casey C, Daly C, Gambacciani M, Hadji P, . Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists. Eur Heart J. 2007;28:2028–40.
- Casiglia E, Tikhonoff V, Caffi S, Bascelli A, Schiavon L, Guidotti F, . Menopause does not affect blood pressure and risk profile, and menopausal women do not become similar to men. J Hypertens. 2008;26:1983–92.
- Cifkova R, Pitha J, Lejskova M, Lanska V, Zecova S. Blood pressure around the menopause: a population study. J Hypertens. 2008;26:1976–82.
- Coylewright M, Reckelhoff JF, Ouyang P. Menopause and hypertension: an age-old debate. Hypertension. 2008;51: 952–9.
- Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Matthews KA. Hot flashes and subclinical cardiovascular disease: findings from the Study of Women's Health Across the Nation Heart Study. Circulation. 2008;118:1234–40.
- Tuomikoski P, Haapalahti P, Ylikorkala O, Mikkola TS. Vasomotor hot flushes and 24-hour ambulatory blood pressure in recently postmenopausal women. Ann Med. 2010;42:216–22.
- Stearns V, Ullmer L, Lopéz J, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet. 2002;360:1851–61.
- Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med. 2005;23:117–25.
- Deecher DC, Dorries K. Understanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stages. Arch Womens Ment Health. 2007;10: 247–57.
- Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, . Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–37.
- Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133: 933–41.
- Taskinen MR. Oestrogen replacement therapy and coronary heart disease. Ann Med. 1998;30:43–51.
- Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, . Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–13.
- Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–33.
- Nair GV, Klein KP, Herrington DM. Assessing the role of oestrogen in the prevention of cardiovascular disease. Ann Med. 2001;33:305–12.
- Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res. 2002;53:605–19.
- Mikkola TS, Clarkson TB, Notelovitz M. Postmenopausal hormone therapy before and after the women's health initiative study: what consequences? Ann Med. 2004;36:402–13.
- Mikkola TS, Ylikorkala O. Hormone therapy and cardiovascular disease—still much to be learnt. Gynecol Endocrinol. 2005;20:116–20.
- van der Schouw YT, Grobbee DE. Menopausal complaints, oestrogens, and heart disease risk: an explanation for discrepant findings on the benefits of post-menopausal hormone therapy. Eur Heart J. 2005;26:1358–61.
- Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol. 2000;95:726–31.
- Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol. 2001;19:4280–90.
- Panay N, Ylikorkala O, Archer DF, Gut R, Lang E. Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric. 2007;10:120–31.
- Tuomikoski P, Ebert P, Groop PH, Haapalahti P, Hautamäki H, Rönnback M, . Effect of hot flushes on vascular function; a randomized controlled trial. Obstet Gynecol. 2009;114:777–85.
- Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med. 2006;354:2368–74.
- Enström I, Lidfeldt J, Lindholm LH, Nerbrand C, Pennert K, Samsioe G. Does blood pressure differ between users and non-users of hormone replacement therapy? The Women's Health In the Lund Area (WHILA) Study. Blood Press. 2002;11:240–3.
- Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, . Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523–34.
- Mueck AO, Seeger H. Effect of hormone therapy on BP in normotensive and hypertensive postmenopausal women. Maturitas. 2004;49:189–203.
- Samsioe G, Lidfeldt J, Nerbrand C, Nilsson P. The Women's Health In the Lund Area (WHILA) study—an overview. Maturitas. 2010;65:37–45.
- L'Hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008;60:185–201.
- Khalil RA. Sex hormones as potential modulators of vascular function in hypertension. Hypertension. 2005;46:249–54.
- Visvanathan K, Gallicchio L, Schilling C, Babus JK, Lewis LM, Miller SR, . Cytochrome gene polymorphisms, serum estrogens, and hot flushes in midlife women. Obstet Gynecol. 2005;106:1372–81.
- Woods NF, Mitchell ES, Tao Y, Viernes HM, Stapleton PL, Farin FM. Polymorphisms in the estrogen synthesis and metabolism pathways and symptoms during the menopausal transition: observations from the Seattle Midlife Women's Health Study. Menopause. 2006;13:902–10.
- Crandall CJ, Crawford SL, Gold EB. Vasomotor symptom prevalence is associated with polymorphisms in sex steroid-metabolizing enzymes and receptors. Am J Med. 2006;119: S52–60.
- Schilling C, Gallicchio L, Miller SR, Langenberg P, Zacur H, Flaws JA. Genetic polymorphisms, hormone levels, and hot flashes in midlife women. Maturitas. 2007;57: 120–31.
- Malacara JM, Perez-Luque EL, Martinez-Garza S, Sanchez-Marin FJ. The relationship of estrogen receptor-alpha polymorphism with symptoms and other characteristics in post-menopausal women. Maturitas. 2004;49:163–9.
- Takeo C, Negishi E, Nakajima A, Ueno K, Tatsuno I, Saito Y, . Association of cytosine-adenine repeat polymorphism of the estrogen receptor-beta gene with menopausal symptoms. Gend Med. 2005;2:96–105.
- Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric. 2005; 8:3–63.
- Miller VM, Duckles SP. Vascular actions of estrogens: functional implications. Pharmacol Rev. 2008;60:210–41.
- Hemelaar M, van der Mooren MJ, Rad M, Kluft C, Kenemans P. Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review. Fertil Steril. 2008;90:642–72.
- Clarkson TB, Appt SE. MPA and postmenopausal coronary artery atherosclerosis revisited. Steroids. 2003;68:941–51.
- Koh KK, Sakuma I. Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials? Arterioscler Thromb Vasc Biol. 2004;24:1171–9.
- Kuhl H, Stevenson J. The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits—an attempt to interpret the Women's Health Initiative results. Gynecol Endocrinol. 2006;22:303–17.
- Shakir YA, Samsioe G, Nyberg P, Lidfeldt J, Nerbrand C. Cardiovascular risk factors in middle-aged women and the association with use of hormone therapy: results from a population-based study of Swedish women. The Women's Health in the Lund Area (WHILA) study. Climacteric. 2004;7:274–83.
![Subscribe to The Renal Drug Database.]({"type":"image" , "src" : "/sda/112412/ARN_0571_RDD_300x250px.jpg"})