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Aim: The evaluation of the influence of continuous transdermal estradiol supplementation combined with oral medroxyprogesterone on the somatotropic axis in postmenopausal women., Material and Methods: 25 women completed the study Group A--13 women received transdermal 17beta-estradiol (Oesclim 50 - Fournier-Solvay) combined with oral 5 mg daily medroxyprogesterone (Gestomikron - Adamed). Group B--12 women without treatment. Basic plasma FSH, estradiol, glucose, insulin, SHBG, hGH, total and free IGF-I, IGFBP-1 as well as IGFBP-3 were measured initially and at the 12th and 24th week of the study., Results: The mean plasma FSH level was reduced and mean plasma estradiol level was increased in group A during estradiol supplementation. Mean plasma level of free IGF-I and free to total IGF-I ratio were increased in group A during 24 weeks of hormone therapy. In the control group (group B) there was the significant increase in mean plasma IGFBP-3 level. Other parameters showed no significant changes in the control group., Conclusion: The administration of transdermal 17beta-estradiol combined with oral medroxyprogesterone increases the IGF-I bioavailability. However this influence do not exceed the physiologial level of IGF-I bioavailability.

Aim: The aim of the present work was to assess the influence of estradiol administration mode on the plasma IGF-I, IGFBP-1, IGFBP-3 levels in postmenopausal women treated with norethisterone acetate., Material and Methods: 39 women were enrolled into the study Group A--14 women received transdermal 17beta-estradiol (Oesclim 50--Fournier-Solvay) combined with oral norethisterone 2.5 mg daily (Primolut-Nor--Schering), Group B--10 women on oral 2 mg 17beta-estradiol combined with oral 1 mg daily norethisterone (Kliogest--Novo-Nordisk). Control group (group C) consisted of 15 postmenopausal women who received no treatment. Basic plasma FSH, estradiol and total IGF-I, IGFBP-1 as well as IGFBP-3 levels were measured initially and at the 52nd week of the study., Results: The mean plasma FSH level was reduced and mean plasma estradiol level was increased in groups A and B during hormone therapy. Mean plasma levels of total IGF-I, IGFBP-1, IGFBP-3 as well as IGFBP-3/IGF-I ratio did not changed significantly during 52 weeks of observation in groups A, B and C. The comparison of plasma IGF-I, IGFBP-1, IGFBP-3 between groups at the initial visit and after 52 weeks showed the lowest concentration f IGBP-3 in group B. Other parameters showed no differences among the three groups., Conclusion: Mode of administration of estradiol did not influenced the plasma levels of IGF-I, IGFBP-1, IGFBP-3 in postmenopausal women treated with norethisterone acetate.

Objective: To compare the influence of low and normal endogenous estradiol concentration on circulating hGH, IGF-I and IGFBP-3 levels as well as on mutual correlations of these parameters., Patients: 45 women (age 30.7 ± 9.0 years, BMI 25.7 ± 8.0) divided into group A - 15 hypoestrogenic women and group B - 30 normoestrogenic controls. Neither of the women was menopausal nor hyperprolactinemic., Methods: Blood sample was taken at the standard conditions prior to the initiation of hormonal supplementation therapy in group A and at the day 3-5 of menstrual cycle in group B. Serum hGH, IGF-I, IGFBP-3, insulin, testosterone, sex hormone binding globulin (SHBG) dihydroepiandrosterone sulphate (DHEAS) and LH as well as prolactin (PRL), FSH and estradiol levels were measured by standard RIA kits., Results: Mean IGF-1, LH, FSH, testosterone and estradiol and PRL plasma levels were lower in group A compared to group B. There were no significant differences in mean SHBG, insulin and DHEAS levels. There were also no differences in mean: age, body mass, BMI as well as percentage of each BMI range between groups. Regardless the estradiol level the IGF-I/age link was found in both groups. A IGF-I/IGFBP-3 relation was found in both groups. IGF-I/estradiol link was seen only in group A. In group B hGH/SHBG link was found, in group A this relation was indirect. A link between hGH and testosterone levels was found only in group B. SHBG was related in group B to IGFBP-3, testosterone and to DHEAS. Insulin/IGFBP-3 link was seen in group B. The stepwise multiple regression revealed DHEAS and LH as predictors of IGF-I level in group A, while in group B none of the parameters predicted IGF-I level. The results of the same analysis in case of hGH are as follows: in group A hGH level was predicted by estradiol and SHBG. In group B none of factors predicted hGH levels., Conclusion: Estradiol plasma level is correlated to circulating IGF-I, albeit the relation seems to be biphasic.

Aim: To compare the effect on total cholesterol and LDL and HDL cholesterol of oral dydrogesterone and medroxyprogesterone administration combined with continuous transdermal supplementation of 17beta-estradiol in postmenopausal women. MATERIAL & METHODS. The prospective study was carried out in 59 healthy postmenopausal women (mean age 54.5 +/- 3.34 years). They were randomized and treated either with continuous transdermal hormonal therapy (HT) (Group A; n=25; 17beta-estradiol at a dose of 0.05 mg/24 hours combined with oral dydrogesterone at a daily dose of 5 mg or group B, n=24; 17beta-estradiol at a dose of 0.05 mg/24 hours combined with oral medroxyprogesterone at a daily dose of 5 mg) or observed as a control group C (n=10). Basal plasma levels of total cholesterol, HDL-cholesterol and LDL-cholesterol as well as basal estrogen and FSH levels were measured before HT and after 6 and 12 months of treatment. At the same time intervals, all the studied parameters were measured for group C., Results: After 6 months of continuous transdermal supplementation of 17beta-estradiol with oral dydrogesterone the plasma level of total cholesterol decreased (6.23 +/- 1.02 mmol/l vs 5.65 +/- 0.96 mmol/l; p < 0.05). The effect was also maintained after 12 months of HT (5.46 +/- 1.0 mmol/l). The plasma level of LDL-cholesterol was also decreased after 6 months of HT (3.87 +/- 0.83 mmol/ I vs 3.42 +/- 0.58 mmol/l; p < 0.05). The effect was also maintained after 12 months of HT (3.48 +/- 0.73 mmol/l). HDL-cholesterol plasma level was increased after 6 months of HT (1.52 +/- 0.45 mmol/l vs 1.76 +/- 0.45 mmol/l; p < 0.05) and was maintained after 12 months. The beneficial changes of plasma levels of total cholesterol, HDL-cholesterol and LDL-cholesterol in group B did not reach the statistical significance. The lipid and lipoproteins mean plasma levels remained unchanged in the control group during 12 months of observation., Conclusion: Adding dydrogestrone or medroxyprogesterone to the continuous transdermal supplementation of 17beta-estradiol did not deteriorate the modificable atherosclerotic risk factors.

Objective: Ovarian hormonal function may be as important contributing factor to hGH-IGF-I-IGFBP-3 axis as age., Aim: To examine plasma hGH, IGF-1 and IGFBP-3 levels in women with premature ovarian failure compared to healthy normal controls and postmenopausal ones., Patients: Group A-15 women with premature ovarian failure (POF) (mean: age 38.9+/-5.2 years, FSH 101.4+/-29.0 IU/l; 17beta-estradiol 22.5+/-14.6 ng/l). Group B consisted of 15 menopausal women (mean: age 54.7+/-2.7 years; FSH 81.9+/-32.1 IU/l; 17beta-estradiol 17.1+/- 8.0 ng/l). Group C - controls - 15 normally menstruating women (mean: age 37.1+/-9.0 years; FSH 6.2+/-1.0 IU/l; 17beta-estradiol 144.8+/-117.1 ng/l)., Methods: Body mass and BMI were measured. Basic fasting plasma hGH, IGF-I, IGFBP-3, insulin, testosterone and LH as well as prolactin (PRL), FSH and estradiol were assessed by RIA kits. Statistical analysis. Shapiro-Wilk test, Mann-Whitney u-test, Spearman rang correlation coefficient, stepwise multiple regression., Results: Mean serum IGF-I level was the lowest (p<0.005) in group B (172.0+/-54.6 microg/l) and the highest in group C (273.6+/-109.0 microg/l). The mean plasma IGF-I level in group A was similar (NS) (208.3+/-66.5 microg/l) to that found in group B and lower (p<0.02) compared with that in group C. The lowest (p<0.005) serum IGFBP-3 level was found in group B (3.1+/-0.7 microg/l) compared to group C (4.4+/-0.3 microg/l). The mean plasma IGFBP-3 level (3.1+/-1.0 microg/l) in group A was lower than in group C (p<0.005) but identical as in group B. No statistically significant differences between groups were observed in mean hGH levels. Women in group A and C were younger (p<0.001) than those in group B. The lowest mean estradiol level was found in groups A and B. The highest was in group C (p<0.001). Mean plasma LH and FSH levels were higher (p<0.001) in groups A and B vs group C. In group C there were links between IGF-I and age (r=-0.60; p=0.014) The IGF-I/age relation disappeared in the groups A and B (rA=-0.26; rB=0.10; NS). The same regards IGFBP-3/ age link (rA=-0.44, NS; rB=0,31;NS). Estradiol level was related to hGH levels in group C (r=-0.54; p<0.05). In none of groups hGH/IGF-1 as well as IGFBP-3/hGH relations were found. Prolactin accounted for 69% of the variance in IGF-I level in the group B (p=0.003) and for 24% in group A (NS). Testosterone accounted for 88% (p=0.004) of the variance in IGF-I level in group B and IGFBP-3 was responsible for 86% (p=0.038) of the variance in IGF-I level in group C. Again IGFBP-3 was responsible for 47% (p=0.023) in group A and for 49% (p=0.04) in group B of the hGH variance., Conclusions: 17b-estradiol may be as important contributor to insulin-like growth factor-I (IGF-I) plasma level as age in hypoestrogenic, hypogonadotropic women.

The aim of the present study was to investigate direct effects of estrogen (E2) or progesterone (P4) given separately vs. estrogen+progesterone on local IGF-I, IGFBP-3 and IGFBP-2 secretion. Explants obtained from estrogen receptor positive plus progesterone receptor positive (ER+/PR+) and hormone receptors negative (ER-/PR-) tumors were incubated with E2, P4 or both. Tamoxifen was added to E2-exposed cultures; mifepristone (RU 486) was added to P4, and both were given to E2+P4-supplemented cultures. In hormone-dependent and hormone-independent tissues, treatment with estrogen+progesterone increased IGF-I and IGFBP-2 secretion with concomitant decrease in IGFBP-3, in the same manner as E2 or P4 given alone. Tamoxifen decreased the E2- and E2+P4-stimulated IGF-I secretion by hormone-dependent breast cancer explants. RU 486 decreased the P4- and E2+P4-stimulated IGF-I secretion with parallel stimulation of IGFBP-3 secretion by ER+/PR+ explants. Estradiol and progesterone had a synergistic action on IGFBP-2 secretion by hormone-dependent breast cancer explants. In conclusion, the presented data suggest that there is no synergistic action of E2 and P4 in influencing IGF/IGFBPs ratio and, additionally, suggest a protective action of antiestrogen and antiprogestagen against excessive IGF-I secretion.

The aim of this study was to evaluate the effects of treatment of breast cancer explants with tamoxifen (TMX) or RU486 on GH secretory dynamics in the presence of exogenous estrogen (E2), progesterone (P4) or both. Explants obtained during surgery were divided according to their sex steroid hormone receptor status. P4 (10(-7) M) or 17beta-estradiol (10(-5) M) or both were tested in vitro for their ability to induce hGH secretion and cell proliferation. TMX (10(-7) M) was added to E2, RU486 (10(-7) M) to P4, and both were applied to E2 plus P4-supplemented cultures. The stimulatory action of P4 on GH secretion was noted in hormone-dependent (ER+/PR+) but not in hormone-independent explants (ER-/PR-). RU486 did not abolish this effect. The stimulatory action of P4 on GH release was not parallel to the stimulation of cell proliferation. E2 alone was without effect on GH secretion by both types of breast cancer explants. Combined treatment with both steroids stimulated GH secretion and cell proliferation by (ER+/PR+) explants. Both TMX and RU486 reversed this effect on cell proliferation while only RU486 abolished augmentation of GH secretion. In none of the hormone-dependent breast cancers, the combined treatment with E2 and P4 had any effect on GH secretion and cell proliferation. Taken together, these results lead us to the hypothesis that P4 but not E2 potentiates local GH secretion by hormone-dependent breast cancer explants. The fact that RU486 reversed neither GH secretion nor cell proliferation in hormone-dependent explants indicates its non-receptor-mediated mechanism of action.

Background: Increased incidence of cardiovascular diseases frequently reported in postmenopausal women may follow disturbed activity of cardiac autonomic nervous system (cANS). Our purpose was to evaluate the influence of continuous combined hormonal replacement therapy (ccHRT) on cANS reflected by parameters of heart rate variability (HRV)., Method: Thirty four healthy postmenopausal women aged 56+/-6 years (7+/-4 years after last menorrhoea) were divided into 2 equal groups--women receiving ccHRT (serum estradiol--81+/-75 ng/l, FSH--45+/-27 IU/l) and control group (serum estradiol--31+/-45 ng/l, FSH--74+/-32 IU/l). The ccHRT women have been receiving daily 50 mg of 17beta-estradiol (Oesclim 50, Fournier) in transcutaneous depot and 5 mg of oral progesterone (Duphaston, Solway Pharma) for recent 1.4+/-0.6 years. All recordings began at 8.00 a.m. and were carried out in supine position and resting conditions (room temperature 24 degrees C). The protocol applied consisted of 5 min. of resting ECG recording, 5 min. of deep breathing (DB) test, 6 min of sham feeding (SF) and 5 min. of ECG recording after SF., Results: Analysis of the resting HRV didn't reveal any significant differences between the compared groups. In the control group during DB increases of mean LF (455+/-500 vs. 1381+/-1540; p<0.001) and LF/HF (1.5+/-1.1 vs. 5.4+/-4.3; p=0.002) ratio were observed. No influence of SF on HRV was noticed in this group. In the ccHRT women significant increases of mean LF (189+/-125 vs. 728+/-929; p=0.02) and LF/HF ratio (3.1+/-4.8 vs. 9+/-7.3; p=0.002) were observed during DB. SF revealed significant increases of mean RR (841+/-92 vs. 918+/-82; p<0.001), SDNN (35+/-14 vs. 43+/-20; p=0.02), LF (189+/-125 vs. 372+/-434; p=0.03) and HF (150+/-133 vs. 300+/-332; p=0.01)., Conclusions: Our results revealed increased reactivity of the HRV parameters to vagal stimulation by DB and SF in the postmenopausal women receiving ccHRT that suggests increased activity of cANS in the analysed group. Application of ccHRT restores the premenopausal reactivity of cANS.

Objective: The aim was to compare the direct effect of most toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as well as of naturally occurring congener mixture of polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) extracted from fly ash on the placental steroidogenesis. The concentration of all 17 toxic congeners was reported and the toxic equivalent (TEQ) was calculated as a 27.7 micrograms-TEQ/kg of fly ash., Methods: Placental cotyledons were harvested immediately after expulsion of placenta. The cells were prepared according to KLIMAN et al. (1986). To examine TCDD and PCDDs/PCDFs mixture action on cytochrome P450 side change cleavage enzyme (P450 scc) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity the placental cells were cultured either in basal conditions or with the addition of 25-hydroxycholesterol (25-OH) or pregnenolone (P5)., Results: TCDD in all doses used decreased basal P4 secretion, while did not show any effect on 25-hydroxycholesterol (25-OH) and pregnenolone (P5) supplemented cultures. In all variants of culture PCDDs/PCDFs mixture was without effect on basal and substrate supplemented progesterone (P4) secretion suggesting a reduction in the activity of cytochrome P450scc or 3 beta-HSD. To examine TCDD and PCDDs/PCDFs mixture action on aromatase cytochrom P450 (P450 arom) activity the placental cells were cultured in basal condition or with the addition of dehydroepi-androsterone (DHEA) or testosterone (T). Significant increase of estradiol secretion under the influence of TCDD in DHEA and T supplemented cultures suggests its action on the activity of P450 arom., Conclusion: The discrepancy found between the action of pure TCDD and dioxin mixture on placental steroids secretion is possibly due to an additional effect of pentachlorodibenzo-p-dioxin (PeCDD) and pentachlorodibenzo-furan (PeCDF) which covered > 50% of the total toxic equivalents (TEQ) present in this mixture.

Muscle segment homeobox genes, which regulate developmental programs and are expressed in embryonic and adult tissue, play a role in development of some malignancies. There are no reports on the expression of these families of genes in breast cancer tissue. The aim of this study was to compare expression of Msx2 gene in breast cancer of different genotypes as well as in surrounding nonmalignant tissues. Explants obtained during surgery were divided according to their sex steroid receptor status determined by immunocytochemistry. Four explants obtained from malignant and nonmalignant tissue of each individual patient were incubated in a control medium or with the addition of progesterone (10 - 7 M) alone, estradiol 17 ß (10 - 5 M) or both. The relative level of Msx2 transcripts was evaluated by a semiquantitative RT-PCR and cell proliferation by Alamar Blue test. Results of RT-PCR analysis showed that the relative expression of Msx2 gene depended on the presence of ER/PR receptors both in nonmalignant and malignant tissues Relative amount of Msx2 mRNA was the highest in surrounding nonmalignant ER + /PR - and ER - /PR + tissue, whereas in ER - /PR - and ER + /PR + tissue it was 1.4–1.6-fold lower. Tumorigenesis led to about a twofold decrease in the relative amount of Msx2 mRNA except for ER + /PR + immunophenotype, where no changes were observed. Addition of estradiol or progesterone to the culture of ER - /PR - type tissue explants did not change significantly the relative amount of Msx2 gene mRNA. An opposite effect was observed in ER + /PR - type of tissue. Addition of estradiol alone, or estradiol and progesterone together to tissue culture explants decreased two to three fold the relative amount of Msx2 gene mRNA in both, malignant and surrounding tissues. Progesterone alone had no effect on Msx2 gene expression in this type of tissue. The most complicated regulation was observed in ER + /PR + type of tissue. Culture of tissue explants supplemented with estradiol significantly increased the relative amount of Msx2 gene mRNA in the surrounding tissue. Progesterone enhanced the stimulatory effect of estradiol in surrounding tissues but not in the malignant tissue. Increased expression of Msx2 correlated with an increased proliferation in ER - /PR - and ER + /PR + types, but not in ER + /PR - type of tissues. In conclusion, obtained results provide evidence that estrogen affects Msx2 gene expression. Significant changes in the relative amount of Msx2 gene mRNA and lack of canonical ERE element in 5'-upstream sequence of this gene suggest that regulation takes place indirectly probably by protein-protein interaction. The decrease in the relative amount of Msx2 gene mRNA in ER + /PR - type tumor suggests that progesterone also affects Msx2 gene expression by an indirect mechanism(s). [ABSTRACT FROM AUTHOR]