La Edad Crítica de la Mujer

MATURITAS Vol.25

Octubre, 1996

JHH Thijssen, AH Maclennan: Editorial Maturitas 25: 2 (OCT 1996) :85-86

IPM Debakker, W Everaerd : Measurement of menopausal hot flushes: Validation and cross-validation. Maturitas 25: 2 (OCT 1996) :87-98

• Specificity and sensitivity of two physiological markers for hot flushes were investigated. One marker, proposed by Freedman, is an increase of sternal skin conductance, the second marker, proposed by Swartzman, is a physiological profile which consists of skin conductance changes in combination with circulation changes. In our laboratory 20 menopausal women, 15 with frequent hot flushes and 5 without hot flushes, and 5 women with regular menstrual cycles were continuously monitored for 2.5 h on subjective hot flush experience, sternal and palmar skin conductance, dorsal and palmar finger temperature and pulse blood volume. Increase in sternal skin conductance proved to be very specific in contrast to Swartzman's physiological profile, although it was less sensitive. Receiver operating characteristics revealed that an increase combined with a preceding decrease in sternal skin conductance as most specific for, and most sensitive to, subjectively reported hot flushes. This was confirmed by a cross- validation with 34 'flushing' menopausal women

M Doren, HPG Schneider. Long-term compliance of continuous combined estrogen and progestogen replacement in postmenopausal women .Maturitas 25: 2 (OCT 1996) : 99-105

• The occurrence of uterine bleeding usually associated with hormonal replacement therapy is not acceptable for many women. Our objective was to review data on compliance and bleeding patterns in 70 postmenopausal women on oral replacement with estradiol 2 mg, estriol 1 mg, and norethisterone acetate 1 mg daily administered in a continuous combined fashion to avoid withdrawal bleeding. After 1 year, compliance was 97%, after 5 and 9 years 76% and 58%. The most common reason for discontinuation was spotting. Reproductive history, body weight and pretreatment estradiol and FSH concentrations were not different between the subgroups with bleeding - 19% - and without bleeding - 81%. The probability to maintain amenorrhoe on HRT did not increase with the length of the postmenopausal interval or weight. Endometrial histology revealed one case of a highly differentiated in situ adenocarcinoma of the endometrium. In the women with bleeding, induced serum estradiol levels were significantly higher and pretreatment SHBG-levels lower compared to the non-bleeders. Whether these findings may be significant for election of patients for continuous combined HRT remains to be determined. In conclusion, we demonstrate that adherence to this treatment regimen apparently provides a choice patients considering long-term HRT should be informed about. However, the lack of parameters to elect patients in conjunction with the problem of uterine bleeding does not permit the recommendation to regard continuous combined HRT as first line therapy for long-term HRT. Criteria need to be developed when to obtain an endometrial histology once uterine bleeding occurs, as the optimal surveillance of this mode of HRT is presently unknown.

S Senoz, B Direm, B Gulekli, O Gokmen . Estrogen deprivation, rather than age, is responsible for the poor lipid profile and carbohydrate metabolism in women. Maturitas 25: 2 (OCT 1996) : 107-114

• The protective effect of estrogen against cardiovascular diseases (CVD) in women disappears after menopause. However, it is not clear whether the change in risk factors after menopause is related to aging or estrogen deprivation. Objective: To assess the risks for CVD and the contribution of aging in estrogen-deprived women. Methods: Forty- one patients with premature ovarian failure (POF) (group 1) and 30 patients with natural menopause (group 2) were investigated with respect to well- known risk factors for CVD. Fifteen young women at reproductive age (group 3) were taken as controls. The median ages (ranges) of the groups were 31 (19- 40), 52 (46-67) and 26 (24-29) years, respectively. Family and personal history for CVD, smoking, oral contraceptive usage, physical examination, blood pressure measurement. body mass index (BMI), blood level of fasting insulin, diabetes mellitus, and the levels of lipoprotein proteins were;he examined parameters regarding the risks for CVD. Results: The levels of triglycerides and very low density lipoprotein (VLDL) cholesterol were not different in the 3 groups. The levels of fasting insulin (11.3 +/- 6.6 vs. 10.2 +/- 5.8 IU/ml), the ratio of fasting insulin to fasting blood glucose (12.2 +/- 6.3% vs. 10.5 +/- 5.4%), high density lipoprotein (HDL) cholesterol (51.9 +/- 12.9 vs. 51.6 +/- 9.7 mg/d), low density lipoprotein (LDL) cholesterol (113 +/- 47 vs. 127 +/- 37 mg/dl) and the ratio of HDL to total cholesterol (27.2 +/- 9.8% vs. 24.1 +/- 6.9%) were not different in women with POF and natural menopause. These parameters were all better in controls with respect to risk for CVD (respectively, 6.5 +/- 2.0 IU/ml, 7.4 +/- 2.2%, 37.9 +/- 5.3 mg/dl, 80 +/- 40 mg/dl, P < 0.05). Conclusion: Risk factors for CVD are related to estrogen deprivation. Aging does not have an important impact on CVD within the age range of this study group.

TKH Chung, SK Yip, P Lam, AMZ Chang, CJ Haines: A randomized, double-blind, placebo-controlled, crossover study on the effect of oral oestradiol on acute menopausal symptoms. Maturitas 25: 2 (OCT 1996) :115-123

• Acute menopausal symptoms occur less frequently in Asian than in Caucasian women. Oestrogen replacement therapy has been shown to be effective in controlling acute symptoms in Caucasians, but the effect of oestrogens is not well documented in Asian women. A randomized, double-blind, placebo- controlled, crossover study of the effect of oral oestradiol on the incidence of acute menopausal symptoms was conducted in 83 Hong Kong Chinese women who had experienced a surgical menopause. Although there was a significant increase in the oestradiol concentration with treatment compared with placebo (P < 0.001), there were no significant differences in the reporting of symptoms between the treatment and placebo groups. There is no obvious explanation for this apparent lack of effect of oestrogen on acute menopausal symptoms in Chinese women. Whilst it may be related to the generally low incidence of symptoms or to a higher dietary intake of phytoestrogens in Chinese women, further studies are necessary to explain these findings.

J Mcmanus, J Mceneny, IS Young, W Thompson: The effect of various oestrogens and progestogens on the susceptibility of low density lipoproteins to oxidation in vitro. Maturitas 25: 2 (OCT 1996) : 125-131

• Objective: To investigate the effect of different oestrogens and progestogens, at various' concentrations, on the oxidation of low density lipoproteins (LDL) in vitro. Method's: Oestradiol, oestrone, oestriol and equilin, as well as medroxyprogesterone acetate, norgestrel and norethisterone, were added to isolated male LDL, before it was oxidised in he presence of copper ions at 37 degrees C. The oxidation process was monitored spectrophotometrically by the production of conjugated dienes. The lag time to oxidation and the maximum rate of propagation of the reaction were used as measures of the resistance and susceptibility of the LDL to oxidation respectively. Results: The lag time was increased from 43.7 +/- 1.5 min (mean +/- SEM) for LDL without any added hormone, to 81.2 +/- 1.0 min by 1 mu M oestradiol (P < 0.01), 77.9 +/- 4.6 min by 1 mu M oestrone (P < 0.01), 67.6 +/- 6.2 min by 1 mu M equilin (P < 0.01), and 51.8 +/- 2.8 min by 1 mu M oestriol (P < 0.05). The maximum rate of propagation of the reaction was decreased From 0.23 +/- 0.01 nmol conjugated dienes/mg LDL-protein/min (mean +/- SEM) (control LDL) to 0.14 +/- 0.006 nmol/mg/min by oestradiol (P < 0.01), 0.15 +/- 0.00Bnmol/mg/min by oestrone (P < 0.01), 0.17 +/- 0.012 nmol/mg/min by equilin (P < 0.01) and 0.19 +/- 0.014 nmol/mg/min (P < 0.05) by oestriol. The progestogens alone had no antioxidant effect, nor did their addition to the oestrogens influence their antioxidant activity. Conclusions: These results demonstrate that all oestrogens investigated have an inhibitory effect on LDL oxidation in vitro. The magnitude of this effect varied, being of the order oestradiol > oestrone > equilin > oestriol.

J Schroder, M Doren, B Schneider, M Oettel : Are the antioxidative effects of 17 beta-estradiol modified by concomitant administration of a progestin? Maturitas 25: 2 (OCT 1996) :133-139

• Objective: Estrogens are known to exhibit antioxidative effects. At present little information exists on the influence of co- administered progestins upon this effect. Therefore we investigated the influence of levonorgestrel, a potent antiestrogenic progestin, on the inhibition of the low-density lipoprotein (LDL) oxidation by 17 beta-estradiol or 17 beta-estradiol valerate in vitro and ex vivo. Methods: After isolation from blood, the in vitro oxidation of LDL was induced by copper ions and measured continuously by monitoring the formation of conjugated dienes. In 21 female ovariectomized White New Zealand rabbits the antioxidative action of 17 beta-estradiol alone or in combination with levonorgestrel after subcutaneous infusion for 3 days was determined using the copper-induced LDL-oxidation as an endpoint. Eleven postmenopausal women were exposed to sequential estrogen-progestin replacement therapy (day 1-21: 2 mg estradiol valerate/day, day 10-21: 0.15 mg levonorgestrel/day). Blood samples were collected at three times: on day 1, on day 10, on day 22 (after the combination phase). The lag time of ex vivo oxidation of LDL, the plasma estradiol and estrone levels were estimated. Results: In the chosen cell-free system, 17 beta- estradiol increased the lag time of the LDL- oxidation in a dose-dependent manner. Levonorgestrel showed neither pro-oxidative nor antioxidative effects when administered alone in different concentrations. Go-administration of different doses of levonorgestrel did not modify the antioxidative action of estrogen either. The two ex-vivo models confirmed these results. In rabbits the co-administered 19-nortestosterone derivative levonorgestrel did not impair or reverse the estradiol-dependent effect. In postmenopausal women the daily oral administration of levonorgestrel in conjunction with 17 beta- estradiol valerate did not diminish the antioxidative action of this estrogen given for the first 9 days. Conclusion: The antioxidative potential of estradiol and estradiol valerate is maintained in the presence of levonorgestrel.

T Mikkola, V Ranta, A Orpana, O Ylikorkala, L Viinikka :Effect of physiological concentrations of estradiol on PGI(2) and NO in endothelial cells Maturitas 25: 2 (OCT 1996): 141-147

• Objectives: To elucidate the mechanisms by which estrogens protect against occlusive vascular disorders, we studied the effect of 17 beta- estradiol on the production of prostacyclin (PGI(2)) and nitric oxide (NO) in primary cultures of human umbilical vein endothelial cells (HUVECs). Methods: To study the effect of 17 beta-estradiol on PGI(2) production, HUVECs were incubated in the absence and presence of 17 beta-estradiol (0.01-10 nmol/l) encapsulated within beta-cyclodextrin for 12 h in serum-free medium. To study the effect of 17 beta-estradiol (100 nmol/l) on maximal calcium- dependent NO production: we used different approaches. First, HUVECs were incubated with 2 mu mol/l calcium ionophore A23187 with or without 17 beta-estradiol (100 nmol/l) for 24 h in serum-free medium. Second, HUVECs were preincubated with or without 17 beta-estradiol (100 nmol/l) for 12 h in medium supplemented with 2% fetal calf serum, and thereafter incubated in serum-free medium with 2 mu mol/l of A23187 and with 100 nmol/l of 17 beta- estradiol (cells which contained 17 beta-estradiol during the preincubation period as well as cells which did not) or without it (only cells which did not contain 17 beta-estradiol during the preincubation period) for 6 h or 24 h. Results: 17 beta-Estradiol (0.1 nmol/l) increased the concentration of 6-keto-prostaglandin F-1 alpha, a stable metabolite of PGI(2) in the incubation medium, by 16%, and no further increase occurred with higher 17 beta-estradiol concentrations. The stimulation was prevented by tamoxifen. 17 beta- Estradiol did not affect NO production in any of our experiments measured as accumulation of nitrate and nitrite in the experimental medium. Conclusions: The stimulatory effect on PGI(2) production of physiological concentrations of 17 beta-estradiol, shown now for the first time, may provide one explanation for the ability of 17 beta-estradiol to protect against occlusive vascular disorders.

N Einerjensen, J Zhao, KP Andersen, K Kristoffersen: Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas 25: 2 (OCT 1996):149-153

• Objectives: The natural medicines, Cimicifuga and Melbrosia, are widely sold. Cimicifuga is an extract of Cimicifuga racemosa (L.), and Melbrosia is a mixture of Gelee Royale, perga-pollen and pollen. Cimicifuga and Melbrosia are used through self-medication to relieve symptoms of hot flushes and other menstrual or menopausal discomfort in many of the Danish women consulting private gynaecologists. A gynaecologist tends to treat these symptoms with oestrogen, so the present experiments were therefore made to investigate whether Cimicifuga and Melbrosia have oestrogenic effects as defined by the classical biological methods: uterine growth in immature mice and vaginal cornification in ovariectomized rats. Methods: Vehicle, 6, 60 or 600 mg/kg Cimicifuga or 30, 300 or 3000 mg/kg Melbrosia was administered orally for 3 days to groups of 10 immature mice and the uterus weight measured on the fourth day. Similarly, vehicle, 6, 60, 600 mg/kg Cimicifuga or 3, 30, 300 mg/kg Melbrosia was injected subcutaneously in groups of 12 ovariectomized rats for 3 days and vaginal smears investigated for signs of cornified cells. All experiments were repeated once. Results: No signs of an oestrogenic effect connected with the preparations were found in any of the experiments. Conclusions: II can be concluded that the eventual beneficial effects on menstrual or menopausal discomfort connected with Cimicifuga and Melbrosia self-medication cannot be explained as a traditional oestrogenic effect as measured in biological experiments.

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