Effects of peroral and transdermal oestrogen replacement therapy on glucose and insulin metabolism.

OBJECTIVE: Conflicting data have been reported previously on the effects of oestrogen replacement therapy on glucose tolerance, and the effects on glycosylated haemoglobin GHbA(1c) have been studied only among diabetics. The objective of this study was to evaluate the effects on glucose and insulin metabolism among nondiabetic women and to compare the outcomes of peroral and transdermal modes of administration. DESIGN: The effects of peroral oestradiol valerate 2 mg/day with placebo gel were compared to those of transdermal 17 beta-oestradiol gel (1 mg oestradiol/day) and placebo tablets in a randomised, double-blind, double-dummy study for six months. PATIENTS: Seventy-nine hysterectomised, nondiabetic postmenopausal women, 39 women in the peroral oestrogen group and 40 in the gel group. MEASUREMENTS: Oral glucose tolerance tests (OGTT) with blood glucose, serum C-peptide and insulin determinations were performed. GHbA(1c), IGF-I and IGFBP-1 were measured at baseline and after six months of therapy. In addition, insulin sensitivity and insulin secretion indices were obtained from OGTT. RESULTS: A small significant reduction in the GHbA(1c) concentration was observed during both peroral (P < 0.05) and transdermal oestrogen therapy (P < 0.05). However, no effect on insulin sensitivity was observed. The response to a standard 75 g oral glucose load was similar in the study groups. Compared with the baseline values, the area under the curve for C-peptide decreased by 8% both in the peroral group (P < 0.05) and in the gel group (P < 0.01). The fasting and postchallenge glucose and insulin levels or insulin release indices were not significantly altered. Peroral oestrogen decreased IGF-I and increased IGFBP-1, but these findings were not associated with the changes in glucose metabolism. CONCLUSIONS: Neither peroral nor transdermal oestradiol replacement therapy seemed to induce any negative effects on glucose metabolism over a time period of 6 months.

Regulation of plasma low density lipoprotein levels in postmenopausal women.

To study the regulation of plasma low density lipoprotein (LDL) cholesterol in postmenopausal women (n = 79), fasting plasma lipids and lipoproteins, the fractional catabolic rate (FCR) and production rate for LDL apolipoprotein B (apo B), cholesterol absorption, apolipoprotein E phenotype and polymorphisms of the apo B and 7alpha-hydroxylase genes were determined. The level of LDL cholesterol was related to FCR (r= -0.757, P < 0.001) and the production (r= 0.531, P < 0.001) of LDL apo B and body mass index (r = 0.265, P <0.05). In contrast, cholesterol absorption efficiency, apolipoprotein E phenotype, EcoRI and XbaI polymorphisms of the apo B gene and the polymorphism of 7alpha-hydroxylase gene were found to have no significance for the regulation of LDL cholesterol concentration in these postmenopausal women.

Mechanisms regulating LDL metabolism in subjects on peroral and transdermal estrogen replacement therapy.

To study the mechanisms of low density lipoprotein (LDL) cholesterol lowering by peroral and transdermal estrogen replacement therapy (ERT), 79 hysterectomized postmenopausal women aged 48 to 62 years were randomized in a double-blind double-dummy trial to receive either peroral estradiol valerate (2 mg/d) or transdermal estradiol gel (1 mg/d) for 6 months. Plasma LDL cholesterol decreased from 4. 19+/-0.83 (mean+/-SD) to 3.39+/-0.78 mmol/L (P<0.001) in the peroral group and from 4.11+/-0.86 to 3.72+/-0.78 mmol/L (P<0.001) in the transdermal estrogen group. Peroral estrogen did, but transdermal treatment did not, enhance the fractional catabolic rate (FCR) and production of LDL apolipoprotein B (apoB). However, the decrease of LDL cholesterol was related to an increase in FCR for LDL apoB on both peroral and transdermal ERT (r=-0.645, P<0.001 and r=-0.627, P<0.001, respectively). These changes were associated with changes in the serum estrogen level. Both therapies reduced absorption of dietary cholesterol by 6% to 10% (P<0.05). The effects of estrogen were not modified by the polymorphisms of apoE and apoB or cholesterol 7alpha-hydroxylase. In conclusion, the ERT-induced LDL cholesterol-lowering effect is related to changes in estrogen level, which presumably enhance LDL receptor activity, which is manifested as an increase in FCR for LDL apoB. The small decrease in the absorption efficiency of dietary cholesterol does not seem to contribute largely to the cholesterol lowering on either transdermal or peroral ERT.

Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels.

Low levels of insulin-like growth factor binding protein-1 (IGFBP-1) have recently been associated with several risk factors for cardiovascular disease. The effects of estrogen replacement therapy (ERT) on plasma IGFBP-1 levels are, however, unclear. A double-blind, placebo-controlled study for 6 months was conducted in 73 hysterectomized postmenopausal women randomized into two groups: oral estradiol (E2) valerate, 2 mg/day (n = 35) and transdermal E2 gel, 1 mg/day (n=38). Plasma IGFBP-1, insulin-like growth factor-I (IGF-I) and lipoprotein(a) (Lp(a)) were determined at baseline, 3 and 6 months. The groups were similar for age and BMI. The baseline levels of estrone (E1), E2, IGFBP-1, IGF-I and Lp(a) did not differ between the groups. During treatment, serum estradiol concentrations increased in both groups. During oral ERT, IGFBP-1 levels increased by 104% (P<0.001), whereas IGF-I levels decreased by 13% (mean, P<0.05). IGF-I and IGFBP-1 levels remained unchanged in the transdermal group. Lp(a) levels decreased by 23% (median, P<0.001) in the oral group, but were unaffected by transdermal therapy. The change in IGFBP-1 concentrations during oral ERT showed an inverse correlation to that in Lp(a) (r = -0.40, P<0.05, Spearman correlation). In conclusion, oral ERT seems to enhance plasma levels of IGFBP-1, which may be one reason for the reduced Lp(a) levels.

Effect of an estradiol gel with monthly or quarterly progestogen on menopausal symptoms and bleeding.

OBJECTIVE: To assess the acceptability, efficacy and endometrial safety of transdermal estradiol gel (Divigel/Sandrena) combined with monthly or quarterly oral progestogen (medroxyprogesterone acetate). METHODS: This 12-month, multicenter, open-label study was carried out at 12 study centers in Finland and Sweden. A total of 395 postmenopausal women received 1 mg estradiol in 1 g gel, daily, with oral medroxyprogesterone acetate 10 mg for the first 12 days every month (groups I and III) or every 3 months (group II). The main outcome measures were relief of climacteric symptoms, bleeding patterns and endometrial safety. RESULTS: All regimens reduced the severity of hot flushes, sweating episodes and vaginal dryness. In groups I and III, approximately 80% and 70% of women, respectively, had regular monthly withdrawal bleeding (excepting the first cycle), with irregular bleeding in 8.3% and 5.3% of treatment months. In group II, approximately 94% of women had regular tri-monthly withdrawal bleeding, with irregular bleeding in 10.7% of the treatment months. Endometrial hyperplasia was observed in 0.3% of women. More than 87% of subjects completed the study, and 97% of these rated the gel as acceptable or convenient. CONCLUSIONS: Both the 1- and 3-month regimens were equally effective in controlling climacteric symptoms and protecting against endometrial hyperstimulation. The bleeding patterns were comparable between groups and were similar to those reported for oral estrogens. Estradiol gel was highly acceptable to the majority of women.

The effects of transdermal oestradiol and oral progestogens on haemostasis variables.

OBJECTIVE: To evaluate the effects of 1 g (1 mg oestradiol) transdermal oestradiol gel continuously combined with 10 mg medroxyprogesterone acetate orally 12 days either monthly or every third month on haemostasis variables. DESIGN: An open, parallel stratified study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. PARTICIPANTS: A total of 48 peri- and postmenopausal women less than 65 years of age participated in this study. Twenty-seven women, who had from 2 months to 3 years since their last period were included in group I. Twenty-one women, who were more than 3 years postmenopausal, comprised group II. MAIN OUTCOME MEASURES: The following parameters were determined: von Willebrand factor antigen, factor VII antigen, fibrinogen, antithrombin, protein C, protein S, plasminogen activator inhibitor activity, tissue plasminogen activator antigen, prothrombin fragment 1 + 2, thrombin-antithrombin complex and platelets. RESULTS: Both regimens decreased fibrinogen, factor VII antigen as well as antithrombin. CONCLUSIONS: These changes were mainly 'in an anti-thrombotic direction'. The overall impression is that the transdermally administered oestrogen in combination with an oral progestogen induced favourable, although slight changes in the haemostatic system. The possible influence of these changes on the risk of cardiovascular disease remains yet to be studied.

Metabolic changes induced by peroral oestrogen and transdermal oestradiol gel therapy.

OBJECTIVE: To investigate changes in plasma lipid and lipoprotein levels induced by peroral oestrogen replacement and transdermal oestradiol gel therapy. DESIGN: The effects of peroral oestradiol valerate tablets (2 mg) and placebo gel were compared with 1g transdermal oestradiol gel (1mg oestradiol) and placebo tablets in a randomised, double-blind, double-dummy study for 6 months. SETTING: Department of Internal Medicine, University of Oulu and Oulu Deaconess Institute, Oulu, Finland. POPULATION: Seventy-nine hysterectomised, postmenopausal women, 39 women in the peroral oestrogen group and 40 in the gel group. MAIN OUTCOME MEASURES: Cholesterol and triglycerides in total plasma and in various lipoprotein fractions, and sex hormones. RESULTS: In the peroral oestrogen group total and LDL cholesterol were decreased and HDL cholesterol and triglycerides were increased. In the oestradiol gel group plasma total, LDL and VLDL cholesterol and the ratio of LDL/HDL cholesterol were significantly decreased, but no change in HDL cholesterol and triglycerides was observed. Overall the decrease in LDL levels was correlated with the increase in oestrogen levels. CONCLUSIONS: Both peroral and transdermal replacement therapy had beneficial effects on plasma lipids by lowering total and LDL cholesterol and LDL/HDL cholesterol ratio. These changes seem to be associated with changes in oestrogen levels.

Uterine findings by transvaginal sonography during percutaneous estrogen treatment in postmenopausal women.

OBJECTIVES: To evaluate the effect of hormone replacement treatment (HRT) with percutaneous estradiol and cyclical peroral medroxyprogesterone acetate (MPA) every month or every third month on the uterus and endometrium of postmenopausal women. METHODS: Uterine size and endometrial thickness were measured by transvaginal sonography in 159 postmenopausal women before HRT, and after 6 and 12 months on HRT during 9-12 days of the MPA administration periods. RESULTS: During HRT, uterine size and endometrial thickness increased. The percentage increase in uterine diameter varied between 3.8% and 19.6%, and endometrial thickness varied between 28.7% and 76.4%, being greater in the group receiving MPA every third month than in the groups receiving MPA every month. Myomas grew during the first 6 months on HRT but increased no further during the next 6 months on HRT. CONCLUSIONS: The increases in uterine size, myomas and endometrial thickness during HRT were moderate and not problematic and occurred mainly during the first 6 months on HRT.

Inhibition of human erythrocyte and gastroduodenal catechol-O-methyltransferase activity by nitecapone.

The effect of increasing single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor, nitecapone, on enzyme activity in red cells (RBC) and gastroduodenal COMT activity has been studied in healthy male volunteers. A dose-dependent decrease in RBC COMT activity was seen in all cases after 1 to 150 mg of the drug. The highest dose of 300 mg did not produce much more inhibition of COMT than 150 mg. The inhibition was not complete; at the highest doses the COMT activity was reduced by 50-60%. The effect and the duration of the inhibition in RBC COMT was strongly correlated with plasma nitecapone concentrations in the dose range up to 150 mg. RBC COMT activity recovered fully in 4 h after medication. Gastric mucosal COMT activity was several-fold higher than that in RBCs. It was also dose-dependently inhibited at the two doses (25 and 100 mg) studied. The inhibition of gastric and duodenal COMT was greater than that in RBCs. This also indicates that nitecapone is locally active in the gastroduodenal tract. The results confirm nitecapone as a potent COMT inhibitor in human tissues. New COMT inhibitors may provide a valuable approach to the treatment of Parkinson's disease in combination with L-dopa and dopa decarboxylase inhibitor therapy.

Prophylactic use of phenoxymethylpenicillin and tinidazole in mandibular third molar surgery, a comparative placebo controlled clinical trial.

A clinical double-blind placebo controlled trial was carried out in 136 patients to test the value of the prophylactic use of phenoxymethylpenicillin and tinidazole in mandibular third molar surgery. The three patient groups were uniform with regard to the background data such as age and weight of the patients and the clinical status of the operated tooth, as well as to the observations made at surgery. No statistically significant differences were found between the study groups in the parameters used for evaluation. The results indicate that neither penicillin nor tinidazole have more effect on postoperative complications following operative extraction of wisdom teeth, than placebo tablets.

Effects of picrotoxin on sensitivity and receptive field properties of ganglion cells in the frog retina.

Action potentials of single ganglion cells were recorded with microelectrodes in excised and opened frog (Rana temporaria L.) eyes before and after picrotoxin application. Area threshold curves were measured both before and after drug application. The drug decreased or abolished the lateral inhibition observed when the cones and green rods were stimulated in the inhibitory receptive fields. In the response pattern interruption often occurs after the first action potentials. Picrotoxin shortened this pause and lengthened the subsequent train of action potentials, i.e., the cell responded with smooth and sustained discharges after picrotoxin application. Picrotoxin also temporarily decreased the sensitivity of the green rod-mediated signals from the excitatory receptive field. Picrotoxin decreased red rod-mediated sensitivity in the completely dark-adapted retina. After an 1-1.5% bleach of the rhodopsin in the dark-adapted eye, the early course of dark-adaptation was similar with and without picrotoxin but after drug application the adaptation curve levelled off at a higher threshold. The organization of the receptive field is discussed in relation to the anatomy, electrophysiology and histochemistry of the cells transmitting the signals from the receptors to the ganglion cells. The role of gamma aminobutyric acid as an inhibitory transmitter in the horizontal and amacrine cell layers is also considered.

Dark-adaptation in frog rods: changes in the stimulus-response function.

1. Aspartate-isolated photoresponses of the frog's rods to weak and strong flashes have been recorded during dark-adaptation after bleaching a fraction of rhodopsin (generally 4--30%). Stimulus--response functions were measured before the bleach and in the steady state after dark-adaptation. 2. The movements of the operating curve, i.e. the stimulus--response function plotted in a log-log diagram, are interpreted in terms of a model of outer segment adaptation, where the adaptation processes are associated with the transmitter release (Q-adaptation), the number of active sodium channels and leakage channels in the plasma membrane of the outer segment (M-adaptation), and the transmitter background (c1-adaptation). 3. A small bleach in a fully dark-adapted, non-bleached retina brings about a displacement of the operating curve predominantly to the right. The shift back to the left is approximately exponential, typical time constants being 6--12 min. 4. A strong exposure (bleaching 15--30% of rhodopsin) in a previously partially bleached retina brings about a nearly vertical displacement of the operating curve: after the bleach the maximum photoresponse is strongly reduced, and during intermediate adaptation the operating curve returns mainly upwards. 5. Cumulatively increasing permanent displacements of the operating curve are observed in the steady states after successive dark-adaptation transients. The permanent displacements are predominantly to the right and they increase with increasing temperature. 6. The experimental results, as interpreted according to the model, indicate that the Q-adaptation process is dominant in physiological conditions (small or moderate bleaches), whereas the M-adaptation becomes important only after rather large bleaches and especially after several successive bleaches in an isolated retina.

Directional selectivity and colour coding in the frog retina.

The impulse discharge of ganglion cells was recorded with extracellular micro-electrodes in the excised and opened eye of the common frog, Rana temporaria. The responses of different ganglion cell types to a standard moving spot with various spot-background contrasts are described. Information about such stimulus parameters as the size and contrast as a moving object is given by different classes of ganglion cells with preferences for different stimulus features. Of 171 sustained cells with small receptive fields 29 were found directionally selective, i.e. they responded well to movements only in some directions. Experiments with double stimulus fields suggest that this selectivity is due to an amacrine cell-mediated lateral inhibition nonsymmetrically arranged around the centre of the receptive field. The dichromatic colour vision of the frog is based on partly opponent signals from yellow-sensitive cones and blue-sensitive green rods. These opponent inputs make the ganglion cells respond to blue spots moving against a yellow-green background, irrespective of the relative intensities of the two colours. When the green rods are stimulated with blue light the ganglion cells produce long "on"-responses with significantly lower impulse frequencies than the short cone-mediated responses.

Effects of alcohol on ganglion cell receptive field properties and sensitivity in the frog retina.

Previous results have shown that alcohol has an effect on vision and on the excitability of retinal neurons. Action potentials of single ganglion cells were recorded by microelectrodes in opened and excised eyes from frogs (Rana temporaria L.). Histologically two types of synapses have been described in the retina: conventional synapses and synapses with a ribbon or bar shaped component surrounded by a rather uniform layer of synaptic vesicles. The "ribbon synapses" are presynaptic contacts in receptor and bipolar cells while horizontal and amacrine cells have conventional synapses. Tests with ethanol doses up to 0.2% indicated stronger effects on the conventional synapses than on the ribbon synapses. Alcohol decreased or abolished the lateral inhibition ( inhibitory surround) mediated by the amacrine cells and depressed the signals from the green rods, which apparently are mediated by horizontal cells. Further alcohol decreased the sensitivity of the signals from the completely dark-adapted red rods in the retina, and increased the sensitivity of the cone-mediated responses for class 3 and deviating class 4 cells, when measured against a background light. Alcohol also increased the latency of the response up to 55 msec. depending on the size of the stimulus field.

Receptive field organization of ganglion cells in the frog retina: contributions from cones, green rods and red rods.

1. The impulse discharge of ganglion cells was recorded with extracellular micro-electrodes in the excised and opened eye of the common frog, Rana temporaria. 2. When a single unit was isolated, the cell type was first determined according to the Maturana, Lettvin, McCulloch & Pitts (1960) classification with the aid of varying moving and stationary stimuli. 3. Class 4 cells respond only to a decrease of light when cones are stimulated but respond to an increase of light when green rods are stimulated. A distinct class of deviating class 4 cells was found that give a brief high frequency burst at 'off' from their small excitatory receptive fields (ERF); unlike typical class 4 cells they possess a purely inhibitory surrounding field (IRF).4. The contributions from the cones and the green and red rods were isolated by measuring the thresholds of the discharges with on-off stimuli of varying wave-lengths against strong yellow backgrounds, or against a very weak background or no background at all. The spatial distribution of the contributions to the ERF was determined by mapping threshold profiles, and additional information about ERF and IRF was obtained from area-threshold curves. 5. The cone-mediated ERFs were found to be 0-06-0-50 mm wide (1-5-12 degrees of visual field), which agrees well with the sizes of the dendritic trees of the ganglion cells. The green rod-mediated ERFs can be 0-5-1-5 mm wide and have less distinct boundaries than the cone-mediated. The green rod-mediated ERF of an individual ganglion cell is always larger than the cone-mediated ERF of the same cell. The red rod-mediated ERFs seem to be somewhat larger than the cone-mediated but smaller than the green rod-mediated. 6. The green rods contribute only to the on thresholds of class 1, 2 and 4 cells, but both to on and off in typical class 3 cells, while the cones contribute to on and off in classes 1-3 and only to off in class 4.7. When the red rods begin to contribute during dark adaptation they seem to enter the cone but not the green rod channels. 8. All three receptor types contribute to the IRF surrounding the ERF of classes 1, 2, 3 and deviating class 4 cells. Normal class 4 cells have no IRF. 9. The organization of the receptive fields is discussed in relation to the anatomy and electrophysiology of the cell types transmitting the signals from the receptors to the ganglion cells.