1 Department of Endocrinology and Metabolism, School of Medicine, Pamukkale University, 20100 Denizli, 2 Departments of Obstetrics and Gynaecology, School of Medicine, Kocatepe University, and 3 Department of Biochemistry, School of Medicine, Kocatepe University, 03200 Afyon, Turkey
4 To whom correspondence should be addressed at: Siteler M, 6220 S. No. 16 Ferah Apt. Kat. 2, 20100 Denizli, Turkey. e-mail: sfenkci{at}yahoo.com
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Abstract |
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Key words: CRP/diabetes/HRT/lipid-glucose metabolism/proteinuria
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Introduction |
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There is a lack of overall agreement about whether postmenopausal women can use HRT for the purpose of cardiovascular protection. Although study subjects were relatively old, the results of the Heart and Estrogen/progestin Replacement Study (HERS) (Hulley et al., 1998) and the Womens Health Initiative (WHI) Writing Group, (2002) studies suggested that HRT had no advantages for prevention of coronary heart disease (CHD). There was an increase in cardiovascular events in the first year, but, interestingly, fewer events were seen after 2 years of treatment in the hormone group in the HERS. On the other hand, it has been reported that HRT improves lipidlipoprotein profiles (Hulley et al., 1998
; Herrington et al., 2000
; Shlipak et al., 2000
; Erenus et al., 2001
; Sendag et al., 2002
; Ranta et al., 2002
) and endothelial and vascular smooth muscle function, and has potentially beneficial effects on vascular relaxation in peripheral and coronary vasculatures (Lieberman et al., 1994
; Reis et al., 1994
; Perera et al., 2002
). Noticeably, concerns remain about the use of HRT for cardiovascular protection, which is more intricate than was initially believed. Although there were some recent reports on the use of HRT in diabetic or hypertensive postmenopausal women (Cornu et al., 2000
; Cacciatore et al., 2001
; Darko et al., 2001
; Perera et al., 2001, 2002), the effects of short-term transdermal HRT on glycaemic control, lipid metabolism, C-reactive protein and urine protein in these high-risk groups have not been studied adequately.
This study was planned to evaluate the effects of 12 weeks of transdermal HRT on mean serum lipid sub-fractions, fasting glucose, fructosamine, glycated haemoglobin (HbA1c), C-reactive protein (CRP), creatinine, 24 h urine protein levels, creatinine clearance and blood pressure.
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Materials and methods |
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Menopause was confirmed by the absence of menstruation for at least 12 months and by high serum levels of FSH (>30 mIU/ml) and low serum levels of estradiol (E2) (<20pg/ml). The subjects had not received HRT previously. Gynaecological examination, comprising endometrial biopsy and mammogram, were normal in all subjects.
All study subjects received 12 weeks of transdermal continuous 17-estradiol (0.05 mg/day) with transdermal sequential norethisterone acetate (NETA) 0.25 mg/day (Estracombi TTS, Novartis, Switzerland). This work was approved by the local medical ethics committee and all participants gave informed consent before the onset of study.
All metabolic and physical examinations were performed at the onset of the study and then again after 12 weeks of receiving HRT. Blood pressure was measured with a mercury sphygmomanometer during two clinical evaluations by an average of three measurements taken in the sitting position before the morning dose of the anti-hypertensive therapy. On the fourth day of the third hormonal cycle (in the estrogen only phase) blood samples were taken after a 10 h fast and serum total cholesterol (total cholesterol), triglyceride (TG), high density cholesterol (HDL-cholesterol), VLDL-cholesterol, apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), serum creatinine (sCr), urine creatinine (uCr), 24 h urine protein, fructosamine, HbA1c and glucose levels were determined in an Hitachi 911 automated analyser by using commercial kits supplied from Roche Diagnostics. Low-density cholesterol (LDL cholesterol) levels were calculated by using Friedewalds formula. Serum CRP was turbidimetrically determined by clinical chemistry system (SPACE, Schiapparelli Biosystems, Netherlands), which gives a quantitative result. For biochemical measurements, the intra-assay coefficients of variation (CV) values ranged between 0.8 2.1%, and the between-run CV values ranged between 1.22.7%.
Statistical analysis
Statistical analysis was carried out with Wilcoxon Two Related-Samples and MannWhitney tests. The data are expressed as means ± SEM. Statistical significance was set at P < 0.05 and the categorical variables were expressed as percentages. Data were analysed using SPSS (Statistical Package for the Social Science, version 10.0) for Windows 98 (Microsoft Corp.).
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Results |
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HRT was associated with statistically significant decreases in serum mean fasting glucose and fructosamine levels, and with a non-significant reduction in serum mean HbA1c level in the DM-HRT group. Significant changes were seen in mean serum VLDL and HDL-cholesterol levels in the HT-HRT group. The increase in mean serum Apo-A1 level and the reduction in mean serum Apo-B level were statistically significant in both treatment groups. The changes in mean serum lipid sub-fractions, fasting glucose, fructosamine and HbA1c levels are given in Table I.
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Discussion |
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In this study, transdermal HRT did not have any worsening effect on glucose metabolism in diabetic patients, moreover the mean serum fasting glucose and fructosamine levels decreased significantly. These outcomes were consistent with some previous studies, which used the transdermal route for HRT (Andersson et al., 1999; Duncan et al., 1999
). On the other hand the patients enrolled in this study had well-controlled diabetic regulation. Glucose homeostasis and route of HRT administration may contribute to the effect of estrogen on glucose metabolism. In addition to these data, Cornu et al. (2000
) showed that there was no significant difference between the transdermal and oral routes for glucose homeostasis criteria. In our hypertensive normo-glycaemic postmenopausal women, transdermal HRT did not have any significant effect on glucose metabolism. These results were consistent with data from the Postmenopausal Estrogens/progestins Intervention (PEPI) trial (The Writing Group, 1995), which suggested that the greatest benefit concerning glucose metabolism was achieved in patients who were hyperinsulinaemic at the beginning of HRT.
The lipid profile in type 2 diabetic patients usually comprises higher triglycerides and LDL-cholesterol, and lower HDL-cholesterol (Lehto et al., 1997). Most of the studies that deal with the effect of HRT on lipid metabolism have indicated that there is an improvement in lipid profile (Hulley et al., 1998
; Samaras et al., 1999
; Herrington et al., 2000
; Manwaring et al., 2000
; Chen et al., 2001
; Erenus et al., 2001
; Shlipak et al., 2001
; Sendag et al., 2002
). Effects of HRT on lipid metabolism due to routes of administration are different. Although a reduction in serum total cholesterol, LDL cholesterol or triglyceride levels was seen in the transdermal route (Perrera et al., 2001
; Ranta et al., 2002
; Sendag et al., 2002
), it was suggested that the oral route had a more favourable effect on lipid profile than the transdermal route, except triglycerides (Darko et al., 2001
; Vehkavaara et al., 2001
; Sendag et al., 2002
).
The current study demonstrated that transdermal HRT caused a significant increase in Apo-A1 levels and a significant reduction in Apo-B levels and did not show any noteworthy harmful effect on lipid sub-fractions in all study subjects. For instance, serum HDL-cholesterol levels increased by 14.8 and 7.9% in hypertensive normo-glycaemic (P < 0.05) and diabetic patients (P = NS) respectively, and also there were no significant changes in total cholesterol, LDL cholesterol and triglyceride levels in either treatment groups. These outcomes might have been dependent on using short-term (3 months) HRT and the transdermal route.
We kept antihypertensive medication constant during the study period and HRT did not have any worsening effect on mean blood pressure in high-risk postmenopausal women. It was shown that HRT did not have an adverse effect on blood pressure control in postmenopausal women (Szekacs et al., 2000a). The neutral effects of estrogen on blood pressure might have been achieved by the transdermal route (Affinito et al., 2001
) or an improvement in parameters of macro-vascular function such as endothelium-mediated vasodilatation by an increase in the biological actions of nitric oxide and a decrease in the action of angiotensin-converting enzyme (ACE) activity (Bush et al., 1998
; Gerhard et al., 1998
; Konukoglu et al., 2000
; Cefalu, 2001
; Nogawa et al., 2001
).
This study showed that 3 months of transdermal HRT in high-risk postmenopausal women did not have any adverse effect on proteinuria and serum creatinine levels. Szekacs et al. (2000b) demonstrated that HRT improved proteinuria in the diabetic patient. The ability of estrogen to reduce oxidative stress may be beneficial to ameliorate nephropathy.
Elevated serum C-reactive protein was reported as a risk factor for future cardiovascular events (Ridker et al., 1998). CRP represents the increased proinflammatory effect and increases plaque vulnerability and propensity to thrombosis (Cushman et al., 1999a
,b). Our subjects in this study comprised high-risk postmenopausal women and there was not an increase in CRP level. It was reported that HRT increased the risk of new cardiovascular events occurring in the first year and the risk reduction occurred in subsequent years (Hulley et al., 1998
). Consistent with this is the observation that serum CRP rapidly becomes elevated in healthy HRT users (Ridker et al., 1999
; van Baal et al., 1999
), although, in our study groups, using short-term transdermal HRT, we were unable to confirm this conclusion; an outcome consistent with the results of Vehkavaara et al. (2001
) and Prelevic et al. (2002
).
There were many questions about the risk and benefits of estrogen/progestin use in postmenopausal women. The outcomes of the WHI study (Writing Group for the Womens Health Initiative Investigators, 2002), which is a randomized placebo-controlled trial, were derived from the use of a daily combined regimen of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in postmenopausal women with an intact uterus. Although no difference was seen in death rates between the study groups, a small but significantly increased risk of non-fatal cardiac events was found in the postmenopausal women using combined HRT, which in combination with an increased risk of breast cancer led inevitably to a discontinuation of the study. This outcome may not be valid for the transdermal route of HRT administration, and also the fact that study subjects were relatively older in this study than in the other studies might have affected this result.
There were no detrimental effects of transdermal HRT on lipid profile, glucose metabolism, CRP and urine protein levels in our well-controlled, relatively younger diabetic or hypertensive patients in short-term interval. Additional research will be necessary to determine the effects of long-term transdermal HRT in high-risk postmenopausal women.
We conclude that decisions about HRT should be taken on a case-by-case basis, and in doing so it is important to include the potential personal benefits and risk profile, especially in high-risk postmenopausal women.
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Submitted on July 23, 2002; resubmitted on September 30, 2002; accepted on December 5, 2002.