Toshio Hayashi, MD, PhD Hatsuyo Kano, MD Daigo Sumi, MS Akihisa Iguchi, MD, PhD Department of Geriatrics Nagoya University Graduate School of Medicine Nagoya, Japan
Izumi Ito, MD, PhD Hidetoshi Endo, MD, PhD Department of Internal Medicine National Chubu Hospital Oobu, Japan.
To the Editor: Hormone replacement therapy (HRT) decreases coronary events in postmenopausal women. However, the Heart and Estrogen Replacement Study showed that such therapy carries a risk of thrombotic complications.[1] The effects of HRT in older women are thus controversial. The direct action of estradiol on the vessel wall has been studied vigorously in this decade. In our previous study, we demonstrated that estradiol retards the progression of severe atherosclerosis in rabbits.[2] More than 50% of its antiatherosclerotic effects were subsequently suggested to be due to this direct action.[3] HRT is believed to be ineffective for osteoporosis in older people because of the low bone turnover in such patients. In this study, we investigated the vascular and bone effects of estrogen on octogenarian females. We selected estriol (E3), which shows a degree of extragenital effects comparable with that of 17β estradiol (E2) but weak genital influence.[4] We investigated 24 older women (mean age ± standard deviation: 80.3 ± 3.5) who were administered 1 g/day CaC12 with (HRT group; n = 12) or without (control group; n = 12) 2 mg/day E3 (Mochida Pharmaceutical Co., Tokyo, Japan) for 110 weeks. Their bone mineral densities (BMDs) were —3.5 ± 0.3 of average BMD. They were in geriatric nursing homes but were active and had no history of ischemic cardiovascular diseases. All patients provided informed consent. Vascular function was evaluated as described previously.[5] In brief, the changes in diameter of the right brachial artery were measured during reactive hyperemia as percentage flow-mediated dilatation (%FMD) and after sublingual nitroglycerin spray (300 jug), which causes endothelium-independent vasodilatation (percentage nitro-glycerin-induced dilatation (%NTG-D)). Blood sampling was performed at 0, 8, 30, 70, and 110 weeks after treatment. Two unpaired Students t tests and Pearson’s correlation coefficient were performed. Serum concentrations of total cholesterol; triglyceride; and apoproteins B100, C2, and E were unchanged in all patients. In contrast, levels of high-density lipoprotein cholesterol and apoprotein A1 were significantly increased after 70 weeks of treatment. The values of plasma E3, 17β-E2, and estrone (E1) at 0, 8, and 110 weeks (in pg/ml) were as follows: for E3, less than 5, 43.6 ± 7.2, and 41.4 ± 8.1, respectively (P<.01 vs the value at 0 weeks); for E2, 4.6 ± 0.8, 30.8 ± 8.1, and 16.2 ± 3.8, respectively (P<.01 vs the value at 0 weeks); and for E1, less than 5, 10.8 ± 4.9, and 7.8 ± 3.9, respectively (P<.05 vs the value at 0 weeks). All these levels were unchanged in the control group. The %FMD in the HRT group was increased during the 110 weeks (Figure 1). No difference in %NTG-D was demonstrated between the two groups (Figure 1). Plasma nitrite/nitrate (NO2—/NO3—) and cyclic guanosine 3'5' monophosphate (cGMP) levels also were increased by HRT (data not shown). BMD was estimated by a digital image processing and x-ray film of right hand bone mass, which showed a significant linear correlation with BMD measured by dual energy x-ray absorptiometry in vertebrae (r = 0.796).[6] BMD was increased by HRT but was slightly decreased in the control group (Figure 1). Bone formation was assessed by serum osteocalcin and by carboxyl terminal propeptide of type I procollagen and was shown to decrease more in the HRT group (data not shown). Bone resorption, as assessed by urinary excretion of pyridinoline cross-linked peptides and tartrate-resistant acid phosphatase, slightly increased in the control group but decreased in the HRT group, and the difference between groups was significant (data not shown). No abnormal data were noted in the other biochemical measurements. No adverse effects were observed except for genital bleeding in two treated cases. This is the first clinical report of an as-much-as-2-year-long, E3-induced improve-ment in endothelial function and bone metabolism in octogenarian women. The effect of HRT in older women for primary prevention of coronary disease was not determined. Because nitric oxide (NO) has many antiatherosclerotic effects, improvement of NO-related responses to estrogen may partially explain its antiatherosclerotic effects, which was supported by the increase in NO2~/NO3~ and cGMP observed here. FMD constitutes NO function, and its impairment was reported to precede coronary artery disease.[7] In the octogenarian women studied here, bone turnover was not slow, which is consistent with the results of recent papers.[8,9] In this work, E3 treatment improved BMD. E3 was well tolerated throughout the study. Their high plasma E3 (80 and 76 pg/ml) and E2 (53 and 81 pg/ml) concentrations, which were the highest among all patients, may have caused the genital bleeding observed in two patients. Although our data could not distinguish which hormone (E3 or E2) was responsible for the results in this study, it seems likely that E3 was responsible. Because E3 produces little mitogenic activity, it is less likely to cause side effects such as endometrial cancer. In addition, E3 binds with the same receptors as E2 and can thereby act to protect the reproductive organs.[10] Unlike E2, E3 does not affect the plasma coagulation factors or plasminogen levels.[11] Because estrogen upregulates NO synthase in human osteoblast-like cells, E3 may improve osteoporosis as a bone formation factor and by inhibiting bone resorption.[12] However, the possibility of E2 exerting such effects is slight, because its concentration decreased after 70 weeks. We assume the interference of a transient increase of plasma E2 concentration in response to occupation of common receptors by E3. In conclusion, in the present study, E3 increased BMD and improved endothelial function without significant adverse effects in octogenarian women with osteoporosis.
Figure 1. Upper left: Endothelial function assessed by measuring dilatation of brachial artery using high-resolution external vascular ultrasound in response to reactive hyperemia (flow-mediated dilatation). Mean percentage increase ± standard deviation in vessel diameter is shown. Upper right: Endothelial independent function assessed by measuring dilatation of artery in response to sublingual nitroglycerin infusion. Percentage increase is shown. No significant differences were observed. Lower: Mean ± standard deviation changes in bone mineral density from baseline to week 110, expressed as mean percentage change. *P<.05 vs control group, P<.05 vs value of 0 weeks.
References
Hulley S, Grady D, Vittinghoff E et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. HERS Research Group. JAMA 1998;280:605-613.
Hayashi T, Sumi D, Iguchi A et al. Physiological concentration of estradiol retards progression of severe atherosclerosis. Arteriol Thromb Vascul Biol 2000;20:1613-1621.
Sullivan JM. Estrogen replacement. Circulation 1996;94:2699-2702.
Esposito G. Estriol: A weak estrogen or a different hormone? Gynecol Endocrinol 1991;5:131-153.
Celermajer DS, Sorensen KE, Gooch VM. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111-1115.
Hayashi Y. Assessment of bone mass by image analysis of bone roentgenograms: A quantitative digital image processing (DIP) method. Rad Med 1990;8:173-178.
Clarkson P, Celemajer DS, Powe AJ et al. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation 1997;96:3378-3383.
Blacke DM, Cummings SR, Browner WS et al. Axial bone density predicts fractures in older women. J Bone Miner Res 1992;7:633-638.
Jones G, Nguyen T, Eisman JA et al. Progressive loss of bone in the femoral neck in elderly people: Longitudinal findings from the Dubbo osteoporosis epidemiology study. BMJ 1996;309:691-695.
Bergink EW. Oestriol receptor interactions: Their biological importance and therapeutic implications. Acta Endocrinologica 1980;233:9-16.
Head KA. Estriol: Safety and efficacy. Altern Med Rev 1998;3:101-113.
Armour K, Ralston SH. Estrogen upregulates endothelial constitutive nitric oxide synthase expression in human osteo-blast like cells. Endocrinology 1998;139:799-802.