Identifying target regions for vigilance improvement under hormone replacement therapy in postmenopausal syndrome patients by means of electroencephalographic tomography (LORETA).

RATIONALE: Daytime fatigue, which at the neurophysiological level is due to vigilance decrements, is a frequent complaint in postmenopausal women. OBJECTIVES: In a three-arm, 2-month, parallel group-design study, vigilance-promoting effects of a novel continuous combination (=Climodien 2/3) of estradiol valerate (EV; 2 mg) and dienogest (DNG; 3 mg) were compared with the effects of both EV alone and placebo in 55 insomniac, postmenopausal syndrome patients. METHODS: Low-resolution brain electromagnetic tomography (LORETA) was undertaken to identify the cerebral target regions of hormone replacement therapy. RESULTS: An omnibus significance test revealed Climodien to increase activity in 882 of 2,394 voxels in the alpha-2 band, followed by 733, 706, and 664 voxels in the beta-2, beta-1, and beta-3 bands, and 509 voxels in the delta band, whereas 2 mg EV alone did not produce a significant suprathreshold activity. Current density increased predominantly in the right hemisphere, which had already been described in the literature as the center of the vigilance system. In the fast alpha range, which plays a major role in the context of vigilance, increased activity was found in the right prefrontal, temporal, and superior parietal cortices, i.e., those brain areas of the right-sided fronto-parietal neuronal network that are responsible for sustained attention. A further activity increase was seen in the anterior cingulate gyrus associated with attentional control and conflict monitoring. The right temporal lobe showed increased current density in all frequency bands. CONCLUSIONS: Electroencephalographic tomography (LORETA) identified the right-hemispheric vigilance system as the target region of Climodien.

Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression.

In a double-blind, placebo-controlled study, the antidepressant and vigilance-promoting properties of transdermal oestrogen in post-menopausal depression were investigated utilizing hormonal, syndromal and EEG mapping evaluations. Sixty-nine menopausal women, aged 45-60 years without previous hormonal replacement therapy, diagnosed as major depression without psychotic or suicidal symptoms (DSM-III-R criteria), were randomly assigned to a 3-month treatment with transdermal oestradiol [Estraderm TTS (ETTS) 50 micrograms, applied twice weekly] or placebo. No other psychoactive medication was allowed. After removal of protocol violators, 32 patients were evaluable in each group, which did not differ in age, height or weight. As five patients discontinued prematurely in both groups and in one placebo patient a post-drug EEG could not be obtained, 27 patients remained in the ETTS and 26 in the placebo group for efficacy analysis. While in the placebo group, oestradiol (E2) and follicle stimulating hormone (FSH) remained unchanged, E2 increased and FSH decreased significantly in the ETTS group. Syndromal evaluation showed a significant improvement in the Kupperman Index (KI) as well as Hamilton Depression Rating Scale (HAMD) in both groups, with no inter-group difference. However, EEG mapping demonstrated significant inter-drug differences in brain function, mostly over the left temporal region. While ETTS patients showed an increase of alpha and alpha-adjacent theta activity and a decrease of beta activity, as well as an acceleration of the delta/theta centroid and a slowing of the alpha, beta and total power centroid, no changes occurred in the placebo-treated patients. These neurophysiological findings suggest improvement of vigilance by oestrogen, previously referred to as "mental tonic" effect. There were no changes, however, in the frontal alpha asymmetry index, reflecting left frontal hypo- and right frontal hyperactivation. Thus, this neurophysiological variable represents a state-independent marker for depression. The tolerability of ETTS was very good.

Hypergonadotropic hypogonadic amenorrhea (World Health Organization III) and osteoporosis.

OBJECTIVE: To assess the bone mineral density in World Health Organization (WHO) III women after hormone replacement therapy. DESIGN: We studied the bone mineral density of 41 women with premature ovarian failure (hypergonadotropic hypogonadic amenorrhea--WHO III) before and during hormone replacement therapy. SETTING: All WHO III women were recruited from the Outpatient Department of the First Department of Gynecology and Obstetrics, University of Vienna Medical School, Austria, a public University Hospital. PATIENTS, PARTICIPANTS: Forty-one patients, 30 healthy women. INTERVENTIONS: Twenty-eight of 41 WHO III women received cyclic hormone replacement therapy consisting of 0.625 mg conjugated estrogen (days 1 to 30) and 5 mg medrogeston (days 20 to 30) in addition, with a 7-day interval. MAIN OUTCOME MEASURE: The bone mineral density was evaluated by single photon absorptiometry and dual energy x ray absorptiometry every 6 months (single photon absorptiometry six times, dual energy x ray absorptiometry four times). RESULTS: The bone mineral density in young women with hypergonadotropic hypogonadic amenorrhea (WHO III) was lower than in age-matched controls. Hormone replacement therapy produced an increase in bone mineral density in 28 WHO III women, whereas bone mineral density remained quite constant in the women without therapy. CONCLUSION: Hormone replacement therapy increases the bone mineral density of women with hypergonadotropic hypogonadic amenorrhea. Hormones should be substituted early and consistently in affected patients.

Hormone replacement therapy: lipid responses to continuous combined oestrogen and progestogen versus oestrogen monotherapy.

Fifty-five postmenopausal women with climacteric complaints were randomly assigned to treatment with either 2 mg oestradiol valerate (E2V) (cyclic regimen: 21 days of treatment followed by a 7-day treatment-free interval), or 2 mg E2V combined with 1 mg cyproterone acetate (E2V+CPA) daily, over a 6-month period. Treatment was by the oral route in both cases. The aim was to compare the influence of these two hormone replacement therapy regimens on lipid metabolism. Blood samples were obtained before and after 1 and 6 months of treatment. Serum was analyzed for total cholesterol (TC), high-density lipoproteins (HDL), apolipoproteins A1 and B and triglycerides. The low-density lipoprotein (LDL) concentrations were derived by calculation. All parameters were evaluated in terms of mean +/- S.D. There was no significant difference in the response of the blood lipids to the two treatments, as assessed by analysis of variance (P greater than 0.05). Serum levels of TC were found to have fallen after month 1 and 6 by 5.3 and 5.6%, respectively, during E2V treatment and by 2.4 and 0.2% during E2V+CPA treatment. Serum HDL levels had increased after months 1 and 6 by 9.7 and 5.2%, respectively, in the E2V group and by 6.9 and 2% in the E2V+CPA group, which was also confirmed by the increase in apolipoprotein A1 levels. There was, however, a borderline increase in LDL and apolipoprotein B in the E2V+CPA group. Serum triglycerides were reduced and serum levels of SHBG increased during treatment in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Ophthalmic complaints as a climacteric symptom.

The menopausal syndrome is characterized by a variety of emotional and physical symptoms of varying intensity. A total of 1287 women who attended the Outpatient Department for Climacteric Symptoms and Osteoporosis Prophylaxis (1st Department of Gynaecology and Obstetrics, University of Vienna Medical School) constituted the study population. These women, who were seeking relief from various complaints or for prophylactic assessment and treatment, visited the clinic over the period 1988-1989. We placed special emphasis on ophthalmic complaints as evidence of the incipient climacteric period. Of the 430 patients with eye complaints, 98 underwent ophthalmological investigation. Within our patient group, we analyzed the incidence and severity of menopausal eye complaints as well as therapeutic responses to hormone replacement therapy on an epidemiological scale. Potential endocrinological factors are discussed.

Sonographic changes in the endometrium of climacteric women during hormonal treatment.

Vaginal sonography of the endometrium is a new method of monitoring the effects of progestogen replacement therapy during the post-menopausal period. The advantages of transvaginal ultrasonic diagnosis are that the uterus can be seen from the fornix vaginae (that is from close range) and that the examination can be carried out whether the bladder is full or not. The differences in the thickness and structure of the endometrium, and the boundary with the surrounding myometrium, enable most of the endometrial changes that occur during the post-menopausal period to be detected sonographically. In the first group of patients we investigated, endometrial carcinoma was detected in 2 out of 60 women suffering from post-menopausal metrorrhagia, the findings subsequently being confirmed histologically. It was observed that post-menopausal women who have regular bleeding during post-menopausal hormone therapy show signs of endometrial proliferation during oestrogen therapy and of secretion during progestogen therapy.

Beta-endorphin levels during the climacteric period.

Hot flushes are not caused by hypergonadotrophinaemia. This is apparent because peaks of gonadotrophin in the serum do not coincide with cutaneously measured hot flushes while such flushes still occur in hypophysectomized women. Gonadotrophin-releasing hormone and other neurotransmitters (possibly beta-endorphin) affect thermoregulation. The following hypothesis is advanced. During the climacteric period neurotransmitter changes, a decrease in catechol oestrogens, a decrease in alpha-2-adrenoceptor activity and cessation of ovarian steroid production may lead to alterations in endogenous opiate activity and thus to disturbances of thermoregulation, resulting in the occurrence of hot flushes. Low beta-endorphin levels in the peripheral plasma, which rise again following oestrogen treatment, are observed during the climacteric. On the other hand, women with severe hot flushes caused by a stress event show enormously increased beta-endorphin values, which are normalized by hormone substitution therapy acting via still unknown neuroendocrinological feedback mechanisms.

Influence of oral contraceptive use on bone density in climacteric women.

The aim of the study was to investigate the influence of long-term administration of oral contraceptives on bone density in climacteric women. The existence of a correlation between long-term use and bone density was confirmed.

The role of prolactin in the menopause.

Within a study on menopausal discomforts, 2322 women were seen for the first time at the Outpatients Department for Climacteric Disturbances and Prophylaxis of Osteoporosis at our clinic. Amongst routine hormonal examination we measured prolactin levels. We found hyperprolactinemia in 23 women. Furthermore, in 224 women who initially had normal hPRL values, an estrogen-gestagen replacement therapy was administered and within this we found a significant increase of the prolactin levels (P < 0.005). The role of prolactin in the climacteric period as well as the mechanism of the estrogen effect upon prolactin secretion are subjects of discussion.

Forearm bone density and grip strength in women after menopause, with and without estrogen replacement therapy.

Peaking in young adulthood, both bone mass and muscle strength decrease with ageing, but bone loss may accelerate after the menopause and can be delayed by estrogen replacement therapy (ERT). This study was designed to evaluate whether, like bone density, the muscle strength was affected by the onset of menopause and/or ERT. First grip strength (GS) of young female adults (group III; n = 18; age (+/- S.E.M.) 21.8 +/- 0.4 years) was compared to that of postmenopausal women, who were divided into two groups. Group I (n = 22; age 59.6 +/- 1.6 years) was 12.5 +/- 1.7 years after the menopause and received no ERT, and group II (n = 21; age 59.5 +/- 1.1 years) was 8.3 +/- 1.2 years after the menopause and had received ERT for 3.9 +/- 2.3 years at the time of the study. GS of the postmenopausal women was significantly (P < 0.005) lower than that of the young female adults. GS did not differ significantly between both postmenopausal groups. Further analysis revealed a weak negative correlation of years since menopause with forearm bone density (r = -0.37, P < or = 0.023 for group II and III together), but not with GS. It is concluded that the later onset of menopause and estrogen replacement therapy do not seem to have a noticeable influence on muscle strength.

Hormone replacement therapy and intraocular pressure.

OBJECTIVES: To evaluate the effect of hormone replacement therapy (HRT) on intraocular pressure (IOP) in menopausal women. METHODS: The IOP of 25 white menopausal women without an abnormal ophthalmologic history was measured before and during HRT regimen. IOP fluctations were recorded before and 1, 4, and 12 weeks after the beginning of HRT. These measurements were obtained according to a standardized time schedule (08:00, 12:00, 16:00, and 19:00 h). RESULTS: The mean IOP in the left eye decreased from 16.2 +/- 2.4 mmHg before therapy to 14.0 +/- 2.1 mmHg after 12 weeks of therapy (P < 0.001). In the right eye, whose IOP was at 15.3 +/- 2.3 mmHg before therapy there was a decrease to 14.0 +/- 1.9 mmHg after 12 weeks of therapy (P < 0.001). CONCLUSION: Hormone replacement therapy has a positive effect on IOP in menopausal women.

Reduction of intraocular pressure in a glaucoma patient undergoing hormone replacement therapy.

OBJECTIVES: To show the reducing effect of estrogens and progestins on the elevated intraocular pressure (IOP) in the case of a 56-year-old woman showing typical climacteric complaints, who was admitted to the menopause outpatient unit. She also suffered from a primary open-angle glaucoma treated with betaophtiole eye drops with intraocular pressures of 16-20 mmHg under this local therapy. METHODS: IOP patterns were monitored by means of standardised daily pressure profiles four times a day before as well as 4 and 12 weeks after the beginning of hormone replacement therapy (HRT). The local glaucoma therapy remained unchanged. RESULTS: During HRT, IOP levels were reduced from 16-20 mmHg before therapy to 12-15 mmHg at week 4 and to 13-15 mmHg at week 12 after the beginning of HRT. CONCLUSION: The finding of a close chronological relationship between the onset of menopause and the development of a glaucoma is a potentially new indication for HRT.

Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls.

UNLABELLED: The aim of the study was to investigate brain function in menopausal depression by EEG mapping, as compared with menopausal syndrome patients without depression and normal controls, and to correlate neurophysiological with clinical and hormonal findings in order to elucidate the pathogenesis of depression in the menopause. METHODS: One hundred and twenty-nine menopausal women, aged 45-60 years, with no previous hormonal replacement therapy were investigated in regard to hormones (estradiol [E2], follicle stimulating hormone [FSH]), clinical symptomatology (Kupperman Index [KI], Hamilton depression score [HAMD]) and brain function (EEG mapping). Based on KI and DSM-III-R research criteria for major depression, 3 groups were available for statistics (after removal of protocol violators): group A had a KI of <15 and no depression (n = 29); group B had a KI of > or = 15 and no depression (n = 29) and group C had a KI of > or = 15 and fulfilled the criteria for major depression (n = 60). RESULTS: EEG maps of depressed patients demonstrated less total power and absolute power in the delta, theta and beta band, more relative delta and less alpha power as well as a slower delta/theta and faster alpha and beta centroid than controls, suggesting a vigilance decrement. Group B did not differ from group A. Correlation maps showed significant relationships between estradiol levels and EEG measures (the lower the E2, the worse the vigilance) and between the EEG measures and the Hamilton depression (HAMD) score (the worse the vigilance, the higher the depression score). There were no correlations between the hormones E2 and FSH and the syndromes KI and HAMD. In the target variable, the asymmetry index, depressed patients showed less alpha power over the right than left frontal lobe, whereas normal controls exhibited the opposite. Group B did not differ from group A. The frontal asymmetry index was significantly correlated with the Hamilton depression score and suggests right frontal hyper- and left frontal hypoactivation in depression. CONCLUSIONS: Although hormonal findings are not directly linked to psychic changes, low estradiol levels do contribute to a decreased vigilance at the neurophysiological level , which is in turn correlated with higher depressive and menopausal symptomatology at the behavioural level. Depression is further correlated to a right frontal hyper- and left frontal hypoactivation.

[Hormone replacement therapy with 17 beta-estradiol dydrogesterone: results of a 3-month open-label study]. / Hormonersatztherapie mit 17 beta-Ostradiol-Dydrogesteron: Ergebnisse einer dreimonatigen Anwendungsbeobachtung.

Hormone replacement therapy is well known for its beneficial effects on climacteric symptoms and is also used for the prevention of osteoporosis. In a prospective open label study we evaluated the efficacy and safety of hormone replacement therapy with 17 beta estradiol dydrogesterone (Femoston, 17 beta estradiol/continuously and dydrogesterone/sequentially). We observed 704 women who were treated with 17 beta estradiol-dydrogesterone over three months. 448 of the women previously had not used hormone replacement therapy, 224 women had been treated with a different hormone replacement therapy before they were entered into the study; for 20 women this information was not available. The physicians were asked to assess the severity of climacteric symptoms at baseline and after three months of hormone replacement therapy. In addition, the following parameters were evaluated before and at the end of the study: blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, blood glucose, alkaline phosphatase and gamma glutamyltransferase. Twelve women did not tolerate 17 beta estradiol-dydrogesterone and therefore dropped out of the study. Climacteric symptoms clearly improved after treatment with 17 beta estradiol-dydrogesterone. During our open label prospective study, a significant decrease in blood pressure and serum levels of total cholesterol, LDL cholesterol and the LDL/HDL ratio were observed, whereas serum levels of HDL cholesterol increased significantly. Surprisingly, triglyceride levels also decreased significantly. Serum levels of alkaline phosphatase decreased significantly in women who had received a different hormone replacement therapy before they took 17 beta estradiol-dydrogesterone. We conclude that hormone replacement therapy with 17 beta estradiol-dydrogesterone is highly effective and well tolerated. Hormone replacement therapy with 17 beta estradiol-dydrogesterone appears to have a positive effect on blood pressure and the serum lipid profile. We therefore hypothesise that prolonged treatment with 17 beta estradiol-dydrogesterone may reduce morbidity and mortality secondary to cardiovascular diseases.

[Steroid hormone receptors in synovial tissue]. / Zur Frage von Steroidhormonrezeptoren in der Synovialis.

Among the variety of symptoms of the postmenopausal syndrome joint pain seems to be an important problem for the patient as well as for her doctor. Because of the excellent response of the hormone substitution therapy it is asked if the synovial membrane is a target organ for oestradiol. Biopsies from the knee joint of ten women (not having any hormone therapy)--excised during knee joint surgery--were examined. Only in two cases oestrogenreceptors were found. Accordingly the synovial membrane cannot be seen as a direct target organ for oestradiol and so other mechanisms must play a role in the pathogenesis of postmenopausal joint pain.

[Ambroxol versus betamethasone for the promotion of antepartum lung maturity in pathological pregnancies]. / Ambroxol versus Betamethason zur Förderung der antepartalen Lungenreife bei pathologischen Schwangerschaften.

Although glucocorticoids have been universally implemented to stimulate fetal lung maturity, their effectiveness and side effects are still widely contested. In search of alternative drugs a double-blind study was conducted between June 1981 and June 1984 comparing betamethasone, a conventional corticoid, and ambroxol, a bromhexine metabolite for efficacy and tolerance in prenatal prevention of the respiratory distress syndrome (RDS) in premature infants and full-term neonates. The therapeutic efficacies of betamethasone and ambroxol for this indication proved to be comparable. Since the possible risks of corticoid therapy in abnormal pregnancies are repeatedly discussed in the literature and in daily clinical practice. 137 patients with EPH gestosis, placental insufficiency, diabetes mellitus, and premature rupture of the membranes were selected from the original group of 308 patients. Only minor side effects (e.g. nausea) were present in a few of the 137 cases undergoing treatment with the 2 test substances. No side effects were observed in the neonates. The incidence of fetal RDS was comparable in both groups (2.9% with ambroxol, 2.2% with betamethasone). Transient and mild RDS cases were slightly more frequent in the ambroxol group than in the betamethasone group. To date, contraindications to ambroxol treatment in abnormal pregnancies are unknown and since generally the rate of potential side effects is considered to be lower in comparison with corticoid treatment, the use of ambroxol especially in abnormal pregnancies corresponding indication can be recommended.

[Osteoporosis and estrogens]. / Osteoporose und Ostrogene.

5 major risk factors for osteoporosis have been identified: age, initial bone density, the menopause, bioavailability of calcium, and sporadic factors. Age appears to be the major determinant of bone mass. During a lifetime, a woman will typically lose 50% of her trabecular bone and 35% of her cortical bone. Bone density is affected by the amount of bone developed during growth, as well as by the subsequent rate of loss. Strong evidence has shown that loss of ovarian function leads to an accelerated phase of bone loss. Bone turnover rates increase, but resorption occurs faster than formation. This acceleration slows with time, reaching the level of the underlying slower phase of bone loss approximately 10 years after the onset of menopause. The role of calcium intake in preventing osteoporosis remains a matter of debate. Other factors shown to affect the risk of osteoporosis include low weight, smoking, alcohol intake, and degree of physical activity. The fact that not all postmenopausal women develop osteoporosis suggest that other, as yet determinant factors may play a role in this condition.

[Micromanipulatory sperm injection--a new method in the treatment of infertile males]. / Mikromanipulatorische Spermainjektion--ein neuer Weg in der Behandlung infertiler Männer?

Three couples were selected for this preliminary sperm injection study with their consent, since in all three cases the zona free hamster egg penetration test was negative and in one couple previous attempts of in vitro fertilization were unsuccessful. Of 22 eggs, recovered from three patients, 9 from each patient 3 were injected with sperm, while the others were inseminated by the standard IVF-protocol. Before manipulating human eggs extended experiments were performed with animals eggs, so decreasing the rate of damage to under 10%. Additionally we optimized the method by using an individual adapted equipment. Manipulation was performed by penetration of the zona pellucida with a 5 to 7 mu thick injection pipet into the perivitilline space so damaging of the egg cytoplasm was avoided. This special technique for sperm injection was not used till now in this indication. From the nine eggs used in this experiment one egg developed a pronucleus and one egg developed to a four-cell stage. We could not achieve a pregnancy.

[Psychosomatic aspects of females in the climacteric. The climacteric--psychosomatics--personality structure]. / Untersuchungen zur Psychosomatik an Frauen im Klimakterium. Klimakterium--Psychosomatik--Persönlichkeitsstruktur.

In this experimental study, the feelings of climacterium in two groups of menopausal women were compared (a test group with climacteric complaints vs a control group without complaints). 70 patients were given a questionnaire: EWL by Janke and Debus, FPI and Giessen-test. The evaluation of the socio-economic data exhibited the fact, that patients in the group with complaints took more drugs than the other group and were more inclined to weight gain. Gynecological data showed significant differences in the beginning and the experience of menstruation. Psychological tests of the group with complaints showed a lack of self-assurance and increased anxiety. These women had also a tendency toward psychosomatic disorders and were less assertive in their social contacts. The discriminant analysis of menopausal and personality variables classified the women equally into the group with complaints compared to the control group.