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LE Magazine June 1998


Estrogen Replacement Therapy
Life Extension magazine republishes abstracts on health and longevity topics in each issue, drawn from research papers originally published in science and medical journals throughout the world.

The use of estrogens and progestins and the risk of breast cancer in postmenopausal women
Colditz GA Hankinson SE Hunter DJ Willett WC Manson JE Stampfer MJ Hennekens C Rosner B Speizer FE, N Engl J Med (1995 Jun 15) 332(24):1589-93
BACKGROUND. The effect of adding progestins to estrogen therapy on the risk of breast cancer in postmenopausal women is controversial.
METHODS. To quantify the relation between the use of hormones and the risk of breast cancer in postmenopausal women, we extended our follow-up of the participants in the Nurses' Health Study to 1992. The women were asked to complete questionnaires every two years to update information on their menopausal status, use of estrogen and progestin preparations, and any diagnosis of breast cancer. During 725,550 person-years of follow-up, we documented 1,935 cases of newly diagnosed invasive breast cancer.
RESULTS. The risk of breast cancer was significantly increased among women who were currently using estrogen alone (relative risk, 1.32; 95 percent confidence interval, 1.14 to 1.54) or estrogen plus progestin (relative risk, 1.41; 95 percent confidence interval, 1.15 to 1.74), as compared with postmenopausal women who had never used hormones. Women currently taking hormones who had used such therapy for 5 to 9 years had an adjusted relative risk of breast cancer of 1.46 (95 percent confidence interval, 1.22 to 1.74), as did those currently using hormones who had done so for a total of 10 or more years (relative risk, 1.46; 95 percent confidence interval, 1.20 to 1.76). The increased risk of breast cancer associated with five or more years of postmenopausal hormone therapy was greater among older women (relative risk for women 60 to 64 years old, 1.71; 95 percent confidence interval, 1.34 to 2.18). The relative risk of death due to breast cancer was 1.45 (95 percent confidence interval, 1.01 to 2.09) among women who had taken estrogen for five or more years.
CONCLUSIONS. The addition of progestins to estrogen therapy does not reduce the risk of breast cancer among postmenopausal women. The substantial increase in the risk of breast cancer among older women who take hormones suggests that the trade-offs between risks and benefits should be carefully assessed.

Estrogen Replacement and Ovarian Cancer
Estrogen replacement therapy and fatal ovarian cancer.
Rodriguez C Calle EE Coates RJ Miracle-McMahill HL Thun MJ Heath CW Jr. Am J Epidemiol (1995 May 1) 141(9):828-35 The authors examined the relation between use of estrogen replacement therapy and ovarian cancer mortality in a large prospective mortality study of 240,073 peri- and post-menopausal women, none of whom had a prior history of cancer, hysterectomy or ovarian surgery at enrollment in 1982. During 7 years of follow-up, 436 deaths from ovarian cancer occurred. Cox proportional hazard regression was used to adjust for other risk factors. Use of estrogen replacement therapy was associated with a rate ratio for fatal ovarian cancer of 1.15 (95% confidence interval (CI) 0.94-1.42). The mortality rate ratio increased with duration of use prior to entry to this study to 1.40 (95 CI% 0.92-2.11) with 6-10 years of use and 1.71 (95% CI 1.06- 2.77) with > or = 11 years of use. The increase in mortality associated with > or = 6 years of use was observed in both current users (rate ratio (RR) = 1.72, 95% CI 1.01-2.90) and former users at study entry (RR = 1.48, 95% CI 0.99-2.22), relative to never users. Risk associated with use was not modified by any of the other risk factors. These data suggest that long-term use of estrogen replacement therapy may increase the risk of fatal ovarian cancer.

Endometrial Cancer and Estrogen
Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women.
esford SA Weiss NS Voigt LF McKnight B, Lancet (1997 Feb 15) 349(9050):458-61
Background: Postmenopausal estrogen therapy reduces the risk of osteoporosis and cardiovascular diseases but is associated with an increased risk of endometrial cancer. We have assessed the impact of a regimen of estrogen with cyclic progestagen on risk of endometrial cancer for postmenopausal women.
Methods: We did a population-based case-control study of women aged 45-74 years in western Washington State, USA. Cases were identified from a regional cancer registry as having histologically confirmed endometrial cancer during 1985-91. 832 (72%) of 1,154 eligible cases completed interviews.
Controls were identified by random digit dialing, screened for intact uterus, frequency matched for age and county, and randomly assigned a reference date within 1985-91. Interviews with 1,114 (73%) of 1,526 eligible controls were done. The women provided information about use of hormone replacement therapy, and reproductive and medical history before diagnosis date (cases) or reference date (controls).
Findings: Relative to women who had never used hormones (for > 6 months), women who had taken unopposed estrogen had a four-fold increase (95% CI 3.1-5.1) in risk of endometrial cancer. Women who used a combined therapy of estrogen with cyclic progestagen (e.g., medroxyprogesterone acetate) had a relative risk of 14 (1.0-1.9). Among women with fewer than 10 days of added progestagen per month, the relative risk was 3.1 (1.7-5.7). Whereas that for women with 10-21 days of added progestagen was 1.3 (0.8-2.2). The use of these combined regimens for 5 or more years was associated with risks of 3.7 (1.7-8.2) and 2.5 (1.1-5.5), respectively, relative to non-users of hormones. Interpretation: Postmenopausal women who use combined therapy of estrogen with cyclic progestagen on a long-term basis have an increased risk of endometrial cancer compared with those who are not on hormone replacement, even when progestagen is added for 10 or more days per month. This increase is much smaller than that associated with unopposed estrogen, but needs to be confirmed.

Soy Protein as Natural Estrogen
Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys.
Wagner JD Cefalu WT Anthony MS Litwak KN Zhang L Clarkson TB, Metabolism (1997 Jun) 46(6):698-705 Estrogen replacement therapy (ERT) decreases the progression of coronary artery atherosclerosis in monkeys. Dietary soy protein also retards the progression of atherosclerosis relative to animal proteins such as casein. Soy protein contains weakly estrogenic compounds called isoflavones or phytoestrogens that may be responsible for the cardioprotective effects. This study was designed as a 2 x 2 factorial to determine the magnitude of soy protein's effects on cardiovascular risk factors relative to casein and lactalbumin, with or without estradiol treatment. Ovariectomized female monkeys were randomized to four treatment groups based on past dietary cholesterol consumption, their origin, and past reproductive history, and studied for 7 months. The animals were divided into (1) a group fed casein and lactalbumin as the protein source (n = 14), (2) a group fed casein and lactalbumin as the protein source plus 17 beta-estradiol (E2) (n = 13), (3) a group fed soybean protein isolate as the protein source (n = 11), and (4) a group fed soybean protein isolate as the protein source plus E2 (n = 10). Soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentrations, a significant improvement in insulin sensitivity and glucose effectiveness as determined by minimal-model analyses, and a decrease in arterial lipid peroxidation. E2-treated monkeys had a significant reduction in fasting insulin levels and insulin-to-glucose ratios, total body weight, and amounts of abdominal fat, and had smaller low-density lipoprotein (LDL) particles. In addition, E2 treatment resulted in a significant reduction (P = .001) in aortic cholesteryl ester content. A similar trend (P = .14) was found for soy protein compared with casein. There also was a significant interaction (P = .02) with soy and E2, such that animals consuming soy protein +E2 had the least arterial cholesteryl ester content.
These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors. Interestingly, the two treatments affected different risk factors and together resulted in the greatest reduction in arterial cholesterol content. Further studies are needed to determine the active component of the soy protein and to assess its long-term effects on the cardiovascular system and other organ systems (such as the bones and reproductive system).

Agnus Castus Benefits
In vitro prolactin but not LH and FSH release is inhibited by compounds in extracts of Agnus castus: direct evidence for a dopaminergic principle by the dopamine receptor assay.
Jarry H Leonhardt S Gorkow C Wuttke W, Exp Clin Endocrinol (1994) 102(6):448-54
Women suffering from premenstrual mastodynia often respond to stimuli of prolactin (Prl) release with a hypersecretion of this hormone. Pharmacological reduction of Prl release by dopamine agonists or treatment with extracts of Agnus castus (AC) improve the clinical situation of patients with such premenstrual symptoms. Extracts of AC contain compounds which inhibit in vivo Prl release in women as well as in vitro from dispersed rat pituitary cells. It is yet unknown whether this inhibitory action of AC is only exerted on Prl release or whether release of other pituitary hormones like LH and FSH is also affected. The effects of AC on LH and FSH release were examined in vitro using rat pituitary cell cultures. To rule out that the Prl- inhibiting properties of AC are at least in part due to a cytotoxic component, pituitary cell cultures were subjected to the MTT test. To assess whether the Prl inhibitory effect of AC preparations is due to compounds acting as dopamine (DA) agonists, we used the corpus striatum membrane DA receptor binding assay. Our results demonstrate for the first time that AC extract contains an active principle that binds to the D2 receptor. Thus, it is very likely that it is this dopaminergic principle which inhibits Prl release in vitro from rat pituitary cells. Furthermore we give evidence for the specificity of action of AC on hormone release, since gonado-tropin secretion remained unaffected. The findings of the present study support the therapeutical usefulness of AC extracts for treatment of premenstrual mastodynia which is associated with hypersecretion of Prl. Furthermore, the beneficial effects of AC appear to be due to the inhibition of pituitary Prl release.

Effects of Black Cohosh
Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats.
Duker EM Kopanski L Jarry H Wuttke W, Planta Med (1991 Oct) 57(5):420-4
Remifemin is an ethanolic extract of the rhizome of Cimicifuga racemosa (CR) [black cohosh] and is used to relieve climacteric hot flushes. In the present study the effects of this preparation on LH and FSH secretion of menopausal women were investigated. After an 8-week treatment, LH but not FSH levels were significantly reduced in patients receiving the Cimicifuga extract. To further characterize the endocrinologically active principles of this plant extract, a lipophilic extract of CR was prepared and subjected to Sephadex chromatography. Fractions obtained were tested for their ability to reduce LH secretion in ovariectomized (ovx) rats and to compete in vitro with 17 beta-estradiol for estrogen receptor binding sites. Three types of endocrinologically active compounds were obtained: (1) Constituents which were not ligands for the estrogen receptor but suppress LH release after chronic treatment, (2) constituents binding to the estrogen receptor and also suppressing LH release, and (3) compounds which are ligands for the estrogen receptor but without an effect of LH release. It is concluded that the LH suppressive effect of CR extracts observed in menopausal women and ovx rats is caused by at least three different synergistically acting compounds.

Effects of Picamilon
The new cerebrovascular preparation Picamilon.
Mirzoian R.S.; Gan'shina T.S., Farmakol Toksikol (USSR) Jan-Feb 1989, 52 (1) p23-6
Picamilon, a sodium salt of N-nicotinoyl-gamma-aminobutyric acid, was shown to induce a significant increase of cerebral blood flow in conscious cats. Picamilon was found to inhibit neurogenic spasms of cerebral vessels that was followed by suppression of tonic activity and refectory discharges in sympathetic nerves. Picamilon led to restoration of the initial condition of cerebral hemodynamics disturbed by a previous administration of serotonin.

Picamilon vs. Retinal Abiotrophy
Vasoactive agent Picamilon in pigmented retinal abiotrophy.
Davydova G.A.; Mukha A.I., Otdel Patologii Setchatki, Mosk. NI Institut Glaznykh Boleznej, Minzdravmedproma Rossii, Moskva Russian Federation Vestnik Oftalmologii (Russian Federation), 1995, 111/3 (20-22) Eighty patients with pigmented retinal abiotrophy (PRA) and 20 controls were examined. The perfusion pressure and arteriovenous coefficient are markedly reduced in patients with stages 1-2 PRA, in comparison with controls. Deterioration of the visual function in patients with stages 3-4 PRA vs. that in stages 1-2 was associated with a more marked reduction of the hemodynamic parameters and the status of ocular vessels. Picamilon therapy in a dose of 2 ml of 10% solution once a day intramuscularly for 10 days led to improvement of the visual function and ocular hemodynamics in patients with PRA. Treatment efficacy was higher in patients with disease stages 1-2. Picamilon is recommended for the treatment of patients with PRA.

Picamilon Clinical Study
The results of clinical study of the drug Picamilon (an analysis of some data of neurologic and psychiatric clinics)
A. P.huaichenko, R. P. Kruglikova-Lvova, The Pharmacological Committee of the Ministry of Health of USSR, 25, Kropotkinaky per., Moscow! NPO, "Vitamins," 14 A, Nauchny proezd, Moscow 117246, USSR The analysis of results of Picamilon clinical investigation in 16 neurologic and psychiatric clinics on 984 patients with various diseases is presented. Picamilon efficiency and good tolerance were established. Picamilon was recommended by the Pharmacological Committee of the Ministry of Health of the USSR for application in medicine for insults therapy, for treatment of transient disorders and chronic insufficiency of blood circulation and also as a tranquillizer without the sedative component and myorelaxation; Picamilon is recommended for asthenic disorders within the limits of different psychical diseases and for treating depressions of old age. As a therapeutic and prophylactic remedy, Picamilon is recommended for rehabilitation of capacity for work and for increasing of stability towards physical and psychological burden. Picamilon is used in narcology in the period of abstinence. Blood Flow Effect Picamilon and cerebrovascular disorders R.S. Mirzoyan, T. S. Ganahina, Institute Of Pharmacology, 8, Baltiyakaya St., Moscow, 125315, USSR Picamilon induces a significant increase in cerebral blood flow in conscious animals. Cerebrovascular effect of Picamilon is more potent and durable than that of GABA (aminalon), nicotinic acid, cinnarizin, nicergolin, xantinol nicotinat, dihydroergotoxin and papaverin. Under Picamilon action there was observed the reduction in neurogenic spasms of cerebrovascular vessels accompanied by the inhibition of tonic activity and refectory discharges in sympathetic nerves. Picamilon recovers the cerebral has disturbed by serotonin.

Picamilon in Cortex
Microvascular effects of picamilon in the cortex
P. N. Alexandrov, T. S. GanShina, M. Yu. Kosoj, R.S. Mirzoyan, Institute of Pharmacology, 8, Baltiyskaya st., Moscow, 125315, USSR Picamilon when locally applied at a dose of 0.2 ml of' 5% solution was found to induce the dilatation of pial arterioles. The most pronounced dilatation was observed in vessels with the initial diameter of 10-20 nm. With arteriole diameter being increased the dilatatory effect of the drug diminished. When differently administered Picamilon causes the increase in cortex blood flow in conscious rats and rabbits.

Picamilon, Survival
Cerebrovascular activity of Picamilon in the post-ischemic period
S.A. Rozhnova, M.D. Gaevy, G.Y. Kovalev, Pharmaceutical Institute, 11, Kalinin prosp., Pyatigorsk 357533, USSR Antihypoxic properties of Picamilon on white rats and cats under narcosis have been studied. Cerebrum metabolism induced were determined during the experiment. Preliminary administration of Picamilon in the dose of 55 mg/kg increased the percentage of animal survival after circulatory hypoxia, promoted reduction and stimulation of' glucose and oxygen utilization processes, decreased the-intensity of cerebral blood flow and increased the functional cerebrovascular stability towards acute hypotension, influenced positively on cerebrovascular auto-regulatory reactions in the post-ischaemic period.

Picamilon, Learning
Effects of Picamilon on learning and memory in water and radial mazes
G. V. Kovalev, A. G. Voznesensky, V. A. Sazhin, Medical Institute, 1, pavshikh bortsov Sq., Volgograd, 400066, USSR As compared with piracetam in the dose of 200 mg/kg, Picamilon in the dose of 56 mg/kg caused more pronounced nootropic effects on learning of rats in the water maze and electroshock amnesia under these conditions. Picamilon in the dose of 10 mg/kg enhanced short-term and long-term memory in the 8 arm radial maze. Piracetam in the dose 200 mg/kg had no effect on acquisition of rats in radial maze.