Klaus Klinga

Reduced cerebrospinal fluid estradiol levels are associated with increased β-amyloid levels in female patients with Alzheimer's disease

Recent in-vitro studies indicate that estrogens such as 17beta-estradiol (E2) may decrease the production of beta-amyloid 1-42 (Abeta42), a peptide central for the formation of senile plaques in Alzheimers disease (AD). To test this hypothesis in a clinical study, cerebrospinal fluid levels of E2 were compared between 30 female AD patients and 11 female patients with non-dementing diseases such as major depression and investigated with respect to beta-amyloid 1-40 and Abeta42 levels. E2 levels were significantly (P<0.05) lower in the AD group than in controls; within the AD group E2 levels were inversely correlated with Abeta42 concentrations (r=-0.36, P=0.05). This is the first clinical study providing evidence for an influence of E2 on Abeta42 metabolism in vivo. This observation corresponds to the putative beneficial effects of estrogen replacement therapy on the development and course of AD.

Factors influencing the prognostic role of oestrogen and progesterone receptor levels in breast cancer—results of the analysis of 670 patients with 11 years of follow-up

In the last two decades, the prognostic role of the steroid hormone receptors has been the subject of a myriad of publications. Nevertheless, its relevance after long-term follow-up is still not clear. The confusion about the prognostic value is mainly due to the difficulty in comparing analyses. Despite different study-designs and statistical approaches, oestrogen (ER) and progesterone (PR) receptors are widely accepted as prognostic factors. Data from 670 breast cancer patients with a median follow-up of 11.4 years were analysed retrospectively. ER and PR were measured by the dextran-coated charcoal (DCC) assay. To investigate the time dependence of the prognostic relevance of ER and PR, separate analyses were done for follow-up shorter and longer than 5 years. Special focus was directed at patients < or =50 and >50 years, node-negative women, in particular those without adjuvant therapy. Univariate and multivariate analyses were performed. In univariate analysis, ER and PR were associated with a significantly longer overall survival at the cut-off levels 10, 20 or 100 fmol/mg protein. The significant survival benefit occurred in the first 5 years of follow-up and remained unchanged in the following period. In the multivariate analyses, only the PR was of significant prognostic value (for PR> or =20 fmol/mg P=0.036, for PR> or =100 P=0.01, Cox analysis). In patients younger than 51 years, only PR was an independent prognosticator at the cut-off level of 100 fmol/mg protein, while in patients >50 years both hormone receptors were not significant. In N0 patients, only the PR reached long-term prognostic independence at a cut-off point of > or =100 fmol/mg (P=0.018). In addition, in the group of node-negative women < or =50 years without adjuvant therapy the PR level reached prognostic significance. The hormone receptor status was a prognostic factor only during the first 5 years of follow-up. Our data suggest that age, lymph node status, length of follow-up and probably the ER/PR assay are important for the evaluation of ER and PR as prognostic variables. In most analyses, PR appeared to be superior to ER in predicting the prognosis of primary breast cancer patients.

Estrogen as an adjuvant therapy to antipsychotics does not prevent relapse in women suffering from schizophrenia: results of a placebo-controlled double-blind study

The expected therapeutic effect of estrogen as an adjunct treatment to antipsychotics in women suffering from schizophrenia for relapse prevention was to be tested under real-life conditions. A multicenter, randomized, placebo-controlled, double-blind, cross-over study based on an A-B-A-B (and/or B-A-B-A) design was applied. Forty-six hypoestrogenic women with schizophrenia hospitalized for the first time or repeatedly were included in the study. Their average age was 37.9 and they had been suffering from schizophrenia for 8.4 years. During the drug treatment phases, they received a three-phase estrogen-gestagen combination drug (17beta-estradiol+norethisterone acetate) in addition to an antipsychotic drug. Significant effects of the adjuvant hormone replacement therapy on the estradiol levels could be observed, and high and low levels of estradiol prevailed in the active drug and placebo phases, respectively. We did not find any difference either in defined relapse events or in the psychopathology between estradiol replacement and placebo phases. Neither did the required antipsychotic doses or the tolerance data differ between the two phases. Thus, the results of our study do not confirm the hypothesis that a combined estradiol/antipsychotic therapy is superior to an antipsychotic monotherapy for relapse prevention.

Influence of severe obesity on peripheral hormone concentrations in pre- and postmenopausal women

To investigate the influence of obesity on hormonal parameters in 186 apparently healthy women and in 176 women suffering from severe obesity the serum concentrations of FSH, LH, estrone (E1), estradiol (E2), androstenedione (A) and testosterone (T) were determined radioimmunologically. The climacteric onset of increased FSH production is 4 yr earlier (P less than 0.001) in obese than in normal women. Parallel to the rise of FSH there is a significantly premature decrease of the E1 and E2 concentrations in obese women. The typical elevation of the LH was found similar and not significantly different in the two collectives. The mean A levels are significantly lower (P less than 0.01) in obese than in normal women in all age groups. The T concentrations do not depend on the age of the women during the investigated period (41 to 60 yr) and are significantly higher (P less than 0.001) in the obese than in the normal women. There is a significant (P less than 0.001) correlation between the concentrations of A and E1 both in the obese and the normal women. An increased conversion of androgens to estrogens by adipose tissue is not revealed by the peripheral serum concentrations. Our data clearly demonstrate that in obese women the onset of ovarian insufficiency is significantly earlier than in normal women.

Maternal peripheral testosterone levels during the first half of pregnancy.

Peripheral serum testosterone levels were determined in 180 women during weeks 7 to 20 of pregnancy with a specific radioimmunoassay. After a normal pregnancy and delivery 90 serum samples were randomly selected from mothers of boys and 90 serum samples from mothers of girls. The testosterone concentrations were correlated with the sex of the fetuses. The mean testosterone level +/- S.D. in pregnant women with female fetuses was 597 +/- 167 pg. per milliliter. In pregnant women with male fetuses the testosterone concentrations were on the average significantly higher (p less than 0.01), with a mean value of 828 +/- 298 pg. per milliliter. The course of the testosterone concentrations in women with male fetuses showed an increase beginning in week 7, reaching a maximum during weeks 9 to 11, followed by a decrease until weeks 15 to 20. During weeks 9 to 11 of pregnancy fetal sex determination was possible in 28 per cent of the males and in 5 per cent of the females, with a probability of 95.5 per cent.

Distribution of Estrogen and Progesterone Receptors on Primary Tumor and Lymph Nodes in Individual Patients with Breast Cancer

Primary breast cancer tissue and lymph nodes were obtained from 55 patients, Histologically, 34 of these patients had positive and 21 negative lymph nodes. Estrogen receptors (ER) and progesterone receptors (PR) were determined by a dextran-coated charcoal assay. The tumor tissue was ER positive in 58% of the cases and PR positive in 34%. The malignant lymph nodes were ER positive in 56% and PR positive in 24%. ER in 14% and PR in 5% of the benign lymph nodes could be detected. The primary tumor tissue and the corresponding malignant lymph nodes showed an identical ER and PR status, i.e. both tumor sites were receptor positive or both receptor negative, in 68 and 74%, respectively. However, 21% of the patients had receptor-positive tumors but receptor-negative lymph nodes. Receptor-positive lymph nodes in combination with receptor-negative tumors occurred in only 11% for ER and 6% for PR. These data show that receptor-positive malignant lymph nodes mostly display the same receptors status as the corresponding primary tumor, whereas receptor-negative lymph nodes may be combined with receptor-positive tumors.

Weight percentile at birth. II. Prediction by endocrinological and sonographic measurements

In a prospective study of 847 singleton pregnancies, the importance of various endocrine methods (serum estriol, HPL, SP1, beta-HCG, estradiol-17 beta, urinary estrogen excretion) and of two sonographic measurements (biparietal and thoracic diameter) for the diagnosis of growth retardation in the third trimester was studied. HPL and estriol determinations were best suited for the diagnosis of growth retardation. The thoracic diameter correlated most closely with the birthweight of the newborns. Sensitivity in relationship to growth retardation was between 17 and 35% for the HPL and estriol determinations as well as for both sonographic methods. Specificity was around 90% for these methods. The validity for all methods improved as the time of birth approached. Through the simultaneous measurement of one of the hormones and the thoracic diameter, an antepartal diagnosis of up to 50% of the hypo- and hypertrophic growth disorders was achieved. In the first two years of life a relationship between development and the HPL and estriol concentrations could be observed which was independent of the weight percentile at birth.

Steroids in human myometrium and peripheral blood during the menstrual cycle.

Blood samples were collected prior to vaginal hysterectomy from nine women in the proliferative phase of the cycle and from 15 women in the secretory phase, and from each uterus five grams of the fundus were obtained. The concentrations of progesterone (P), 20alpha-dihydroprogesterone (20alpha-DHP), estradiol-17beta (E2), and estriol (E3) were determined in serum and in the tissue with the use of specific radioimmunoassays. The concentrations of P and 20alpha-DHP in serum and myometrium were significantly higher in the secretory than in the proliferative phase. Furthermore, the concentration of P in myometrium was significantly higher than in serum in the secretory phase, indicating a specific uptake of P by the myometrium. The concentration of E2 was about 10 times higher in the myometrium than in the serum during both phases of the cycle and appeared to be independent of the serum levels. This indicates a specific but limited uptake of E2 by the myometrium. The E3 levels in the tissue showed no significant differences during the menstrual cycle, whereas in the serum the E3 concentrations were higher in the secretory than in the proliferative phase of the cycle.

Estrogen screening in evaluation of fetal outcome and infant's development

In an unselected obstetric population of 869 women serial determinations of estriol in serum and urine were performed from the 28th week of pregnancy until delivery. Clinical management was based on ultrasound and nonstress/contraction stress tests only. Data on the development of the infants were available after 1 year in 759 cases (89%) and after 2 years in 661 cases (78%). Serum free estriol (E3) screening during weeks 28-34 of pregnancy revealed a significantly increased risk for reduced Apgar scores, growth retardation and postnatal complications in pregnancies with decreased levels (p less than 0.001). The development of the children was disturbed by a higher incidence of childhood diseases, retardation in speech and bowel and bladder control. The urinary estrogen determinations (UE) during this period of pregnancy showed only a vague connection with birth weight and Apgar scores (p less than 0.05) and no connection to the infants development. Serial determinations of E3 after the 35th week of pregnancy increased the significance for all parameters tested. If the estrogen concentration was determined in the last 2 weeks before delivery, 50% of the SGA and 60% of the endangered cases could be diagnosed. After reduced E3 serial levels neurological sequelae, reduced body weight, retarded speech and late development of bowel and bladder control were significantly more frequent at age two than after normal E3 levels. The differences obtained by serial UE determinations were less evident. Considering cost-benefit-calculations, an E3 screening of every pregnant woman cannot recommended. In pregnancies at risk serial E3 determinations allow better prognostication of fetal well-being. In the case of reduced E3 values maximum post partum care should be made available for all newborns. Special support should be given to the early infants development after reduced E3 values have been observed.

In vitro adriamycin sensitivity test and hormonal receptors in primary breast cancer

Abstract Cytoplasmatic estrogen (ER) and progesterone (PgR) receptors were determined by the dextran coated charcoal method in 90 primary breast cancer tissues. In parallel common intrinsic chemoresistance to cytotoxic drugs was examined, using a simple standardized in vitro short term predictive test (3H-uridine incorporation adriamycin inhibition test). The in vitro response rate to adriamycin is negatively correlated to steroid receptor content, which was classified receptor-negative, -poor, and -rich. Estrogen receptor-negative cancers demonstrate an increased incidence of in vitro responses to adriamycin ( 23 38 compared to receptor-rich cancers ( 7 41 ). The same hold true for the relationship progesterone receptor content/in vitro sensitivity to chemotherapy. Results are most clearcut in cases of identical (ER, PgR) receptor content, where response to adriamycin was observed in 17 26 receptor negative cancers against 1 12 with receptor positive specimens. These tools may predict prognosis of early recurrence following mastectomy, and may be useful in stratifying patients for individual adjuvant hormone and/or chemotherapy regimens.