[Differential diagnosis of Poland-syndrome versus unilateral accentuated thelarche]. / DD: Poland-Syndrom -- Unilateral betonte Thelarche. Stellenwert der Panoramasonographie anhand dreier Kasuistiken.

AIM: The syndrome was first described by Poland in 1841. It classically consists of unilateral muscular and osseous anomalies of the thorax and upper limb with defects of the ipsilateral breast and nipple. We report the value of panoramic-sonography in the diagnosis of this rare condition in three patients. METHOD: The three girls, all born in 1990, were independently introduced to our unit of children and adolescent gynaecology because of unilateral "developmental defects" of the breasts at the beginning of puberty. To discriminate a Poland-Syndrome from unilateral accentuation of thelarche standardized clinical and sonographical examinations were performed. RESULTS: In 2 cases we found unilateral aplasia of the glandular tissue of the breast with different distinction of mamilla and pectoralis muscle. The 3 (rd) case showed a hypoplastic breast development with osseous defects of the chest wall, aplasia of the pectoralis muscle and brachydaktylia. CONCLUSION: The standardized panoramic sonography allowed an immediate and safe diagnosis without hazardous radiation exposure.

Survival chances and psychological aspects of quality of life in patients with localized early stage breast cancer.

BACKGROUND: The present analysis focuses on the long term psychological reactions to early stage breast cancer. Two hypotheses were formulated. The first hypothesis draws a direct link between tumour size/survival chances and Quality of life (QoL): The better the survival chances, the better QoL ('biological danger model'). The second hypothesis assumes that localized early breast cancer has excellent prognosis (> 90% five year survival rate), and that therefore QoL differences between various forms of early breast cancer should be minimal ('medico-pragmatic model'). PATIENTS AND METHODS: In a defined rural area with 252.000 inhabitants (small-area-analysis), a total of n = 389 patients with primary breast cancer were recruited. For the present analysis we selected a subgroup (n = 269) from the cohort by tumour size (pTis, pT1a,b, pT1c, and pT2). QoL scores for global quality of life, emotional functioning and future perspective were computed according to the EORTC manual and compared to age-matched norm data of the German population. RESULTS: A total of 690 QoL questionnaires were obtained from n = 269 patients with comparable completion rates within the four subgroups (pTis, pT1a,b, pT1c, and pT2). For all four groups and in all scores there were improvements over time. Generally, pTis always scored highest, pT2 always lowest, the other two groups in between. After one year pTis patients had higher mean scores in global quality of life than the norm. In contrast, pT1a,b were considerably lower than the norm and the difference between these two was 17.2 score points. It seems that the small difference (3.5%) in five year survival chances between pTis and T1 a,b tumours transforms into marked differences regarding quality of life, thus supporting a biological danger model of the survival/QoL relationship. CONCLUSIONS: Our results show that physicians have to realise although their early breast cancer patients have excellent survival chances, psychological distress is present. From a clinical perspective we would recommend that early stage breast cancer patients, and especially patients with occult, pT1a,b tumours be informed about their excellent prognosis. In addition, cognitive therapy might help patients stop worrying about their cancer.

Short version of the Guideline: Early Detection of Breast Cancer in Germany. An evidence-, consensus-, and outcome-based guideline according to the German Association of the Scientific Medical Societies (AWMF) and the German Agency for Quality in Medicine (AeZQ).

The goal of the Guideline "Early Detection of Breast Cancer in Germany" is to assist physicians, healthy women, and patients in the decision-making process in favour of appropriate health care regarding early detection and diagnosis of breast cancer. The principle of early detection of breast cancer embraces the detection of non-invasive stages of breast cancer (UICC stage 0, carcinoma in situ), reducing the frequency of invasive breast cancer development, as well as the identification of breast cancer at an early stage (UICC stage I) having a chance of cure of more than 90%, as shown by a large number of trials. The Guideline summarized in the following paper is a precondition to establishing a nation-wide, comprehensive, quality-assurance program for the early detection and diagnosis of breast cancer. The resulting consequence should be a timely mortality reduction of breast cancer. The cure of early stage disease will additionally be achieved by less intensive treatment methods while largely maintaining the quality of life of breast cancer patients. Implementing the Guideline offers the possibility of a significant improvement in women's health care.

[Stage 3 recommendations--the early recognition of breast cancer in Germany. Abridged version for medical practitioners]. / Stufe-3-Leitlinie--Brustkrebs-Früherkennung in Deutschland Kurzfassung für Arzte.

The Aim of this level 3 good clinical practice guideline is to help physicians, women and patients in decision making about the appropriate health care for early detection of breast cancer. The principle of early detection of breast cancer comprise the detection and diagnosis of premalignant breast tumors (stage 0, Carcinoma in situ), risk reduction of cancer development as well as the detection and diagnosis of breast cancer at an early stage (stage I), with a 90% chance of cure as shown by a large number of clinical trials. To establish a nation wide, comprehensive quality assuring program for the early detection of breast cancer the guideline summarized in the following paper offers the basis for a timely mortality reduction of breast cancer. The cure of early stage disease will be additionally possible by less invasive treatment allowing patients to maintain quality of life. The guideline leads to a major improvement of women's health care.

The influence of serum leptin concentration on bone mass assessed by quantitative ultrasonometry in pre and postmenopausal women.

OBJECTIVE: the aim of this study was to evaluate the influence of serum leptin concentration on bone mass assessed by quantitative ultrasound (QUS) in a large sample of healthy pre and postmenopausal women. DESIGN: 555 healthy pre and postmenopausal (n=261 and n=294) women (mean age, 49.5+/-17.2 years) not on hormone replacement therapy were recruited on the occasion of a routine gynecological visit. Before entry to the study, all women had answered a detailed questionnaire on important risk factors and gave written informed consent. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) of the os Calcis were measured using the Achilles ultrasonometer (GE/lunar). We systematically investigated the relation of menopause, BMI and leptin on bone mass by allocating women into the following groups: (a) premenopausal women BMI<25 kg/m(2) (N=178); (b) premenopausal women BMI>25 kg/m(2) (N=83); (c) postmenopausal women BMI<25 kg/m(2) (N=125); and (d) postmenopausal women BMI>25 kg/m(2) (N=169). Additionally we investigated the relation of serum leptin concentrations, age and BMI on ultrasonometry variables by performing a multiple linear regression analyses. RESULTS: in the initial analyses premenopausal women showed a significantly (P<0.001) lower mean age, weight, BMI, follicle stimulating hormone (FSH) and leptin concentration, a higher mean height, serum estradiol and ultrasonometry variables in comparison to postmenopausal women. Irrespective of the menopausal status, women with a BMI>25 kg/m(2) had significantly higher leptin concentrations (P<0.001) and BUA (P<0.05) whereas SOS and SI was not significant different, compared to women with a BMI<25 kg/m(2). The multiple linear regression analyses showed that only BMI but not Leptin was related to higher ultrasonometry variables, whereas increasing age was associated with a decrease in ultrasonometry variables. Furthermore, the multiple linear regression analyses confirmed that age and BMI were the only statistically significant independent predictor for ultrasonometry variables. There was no significant influence of leptin on ultrasonometry variables even after controlling for BMI or age, or BMI and age. CONCLUSIONS: serum leptin concentrations are significantly higher in pre and postmenopausal obese women, compared with normal weight controls. Ultrasonometry variables are influenced by age and BMI but not by serum leptin concentrations.

[A guideline for guidelines--methodological report and use of the guideline women's information]. / Eine Leitlinie für Leitlinien: Die methodische Entwicklung und Anwendung der Leitlinie Fraueninformation.

UNLABELLED: Information and education is needed to empower autonomy and self-determination of patients (informed consent). Furthermore reliable and accurate medical information is necessary for patients who want to take an active part in medical decision-making. The aim of this work is to define the requirements helping to assure the development of good qualified information material relevant for women and female patients as "a guideline on women information". An example of its use is given by embeding this guideline in the guideline for early detection of breast cancer in Germany by defining the specific elements required for developing qualified information on this issue for women. METHODS: A systematic, stepwise methodological process according to a level two guideline of the German Association of the Scientific Medical Societies (AWMF) and the Agency for Quality in Medicine (AZQ) was performed with the following elements: 1. Establishing an expert panel, 2. Generating the guideline statements by a formal, consensus based nominal group process, 3. External review process and finding supportive partners for the guideline on women information, 4. Using the guideline for guidelines: implementing the concept in the guideline of early detection of breast cancer in Germany. RESULTS: The "guideline women information" comprises nine elements of quality assuring requirements for the development of gender-specific information material and eleven specific elements which directly relate to the guideline statements on early detection of breast cancer. After external review 30 organisations gave their written support for future implementation of the guideline. The "guideline women information" was integrated as a tool for quality assurance of lay information into the "guideline for early detection of breast cancer in Germany". CONCLUSION: The "guideline women information" is a systematically developed, consensus-based recommendation to improve the development of qualified lay information at the point of its process by defining gender-specific aspects required for good lay information and its evaluation. As a guideline for guidelines its use is demonstrated by integrating this guideline into the "guideline for early detection of breast cancer in Germany" to ensure the development of qualified guideline compliant information.

Influence of pregnancy and breast-feeding on quantitative ultrasonometry of bone in postmenopausal women.

OBJECTIVE: Reproductive factors such as parity and breast-feeding may be associated with low bone mass and osteoporotic fractures in later years. In this study, os calcis quantitative ultrasonometry was used to elucidate the relationship between parity, lactation and bone mass in postmenopausal women. DESIGN: This was a comparison study using subsequent matched pairs analysis as well as multiple linear regression analysis. The study was carried out at five centers in Germany. The study included 2,080 postmenopausal women (age (mean +/- SD) 58.8 +/- 8.2 years), who were attending for routine check-up and in whom diseases and drug treatments known to affect bone metabolism had been excluded. METHODS AND OUTCOME MEASURES: Women underwent quantitative ultrasonometry (QUS) measurement at the heel. Values of the ultrasonometry variables -speed of sound, broadband ultrasound attenuation and stiffness index -were calculated and compared for nulliparous and parous women and for women who had and had not breast-fed. Because of some significant intergroup differences, and to determine any effect of the number of live births and the duration of breast-feeding on ultrasonometry results, second analyses were undertaken using equally sized samples, matched for possible confounding variables such as age and body mass index (matched pairs). In these analyses, nulliparous women were compared with parous women, grouped according to number of live births, and women who had never breast-fed were compared with women who had breast-fed, grouped according to duration of breast-feeding. Furthermore, a multiple linear regression analysis was performed to examine the combined effects of reproductive factors on QUS variables. RESULTS: No statistically significant associations were found between ultrasonometry variables and parity or breast-feeding, even after controlling for confounding variables in matched-pairs analysis or in a multiple linear regression analysis.

Primary breast cancer therapy in six regions of Germany.

Studies from six regions of Germany (Aachen (W1), Dresden (E1), Jena (E2), Marburg (W2), Munich (W3), and Stuttgart (C1)) have been compared to verify and assess the quality of healthcare using breast cancer as an example. All of the data collection was carried out in comprehensive cancer centres and is population-based, with the exception of C1. Classic prognostic factors and the initial treatment of 8661 women with breast cancer, diagnosed between 1996 and 1998, were examined. Primary therapy, breast conserving therapy (BCT), and the use of subsequent local radiation and/or systemic therapy (chemotherapy or hormonal therapy) were analysed. BCT was performed on 39.3-57.7% of patients. By pT-category, the proportion of BCT in the six regions were as follows: for pTis between 37.8 and 64.3%, for pT1 between 51.7 and 71.5%, for pT2 between 25.9 and 51.1%, for pT3 between 0 and 13.1% and for pT4 between 0 and 15.2%. Multivariate analyses, adjusted for age and biological factors, showed a significant influence of the treating hospital on the mastectomy rate. The use of radiotherapy after BCT (80%) was quite homogeneous in the six regions. The application of radiotherapy after mastectomy, however, varied between 10.4 and 32.2%. In all regions, for premenopausal patients, the use of adjuvant systemic therapy almost reflected the St. Gallen-Consensus recommendations. In contrast, post-menopausal women with positive lymph nodes were not always treated according to these standards. In all regions, age had an influence on the administration of treatment: elderly breast cancer patients received less BCT, less radiotherapy and less adjuvant therapy than recommended in the St. Gallen-Consensus. Feedback of the results was made available to each hospital, providing a comparative summary of patient care that could be used by the participating hospitals for self-assessment and quality-control.

Quality of life profile: from measurement to clinical application.

Quality of life (QoL) can be assessed in an accurate, valid and reliable way by means of standardized QoL questionnaires and is an important endpoint in clinical trials today. The aim of this study is to implement quality of life as a diagnostic tool for problem-oriented follow-up care of cancer patients. This is done in the framework of an intervention study in the area of regional health care research using qualitative analysis and the methodological concept of barrier analysis. We developed the diagnostic tool by generating individual, graphic QoL profiles based on patients' responses to the EORTC QLQ-C30 and the corresponding disease-specific modules BR23 for breast cancer and CR38 for rectal cancer. The clinical application is investigated by assessing physicians' responses. The QoL profile is judged as a useful diagnostic tool by all participating physicians. It enables physicians to assess the QoL of the patient and incorporate the knowledge they gain in their daily practice. Especially in breast cancer follow-up care QoL profiles give added value to both patients and doctors. The next implementation steps have to extend the concept of QoL to larger groups of patients and physicians by overcoming the restraining factors as identified in the barrier analysis.

[Validity of the breast imaging reporting and data system BI-RADS(TM) for clinical mammography in men]. / Anwendbarkeit des Breast Imaging Reporting and Data System (BI-RADS(TM)) auf die klinische Mammographie des Mannes.

AIM: The implementation of diagnostic standards enhances quality assurance. The American College of Radiology's Breast Imaging-Reporting and Data System (BI-RADS(TM)) is intended to standardize terminology in the mammography report, the assessment of the findings, and the recommendation af action to be taken. The purpose of this study was to assess the value of the standardized system for clinically apparent male breast tumors. Do the special male anatomy and physiology limit the applicability of an evaluation system designed for female screening mammograms? METHODS: 4 investigators with different degrees of experience retrospectively evaluated 160 male mammograms. Our study was based on the 36 cases which could be correlated to histopathological findings: gynecomastia in the majority of cases, but also 4 invasive ductal carcinoma, 1 leiomyosarcoma and 1 ductal carcinoma in situ. RESULTS: Assessment of the mammograms by BI-RADS(TM) (3(rd) Edition 1998) correctly placed all cases of malignancy into categories 4 and 5 without respect to the investigators's level of experience. CONCLUSION: Therefore, we conclude that the BI-RADS(TM)-classification can successfully be used to classify male mammograms with a high positive predictive value for malignancy. Knowledge of gender-specific imaging characteristics increases the specificity at a constant high level of sensitivity.

[Scientific presentation using modern media]. / Wissenschaftliche Präsentationen unter Verwendung neuer Medien.

When showing slides with so called "Blue Prints", it is often difficult to explain complex graphics despite the help of a Laserpointer. The Notebook and Videoprojector aid modern presentations in the step by step development of complex graphics. The audience's eyes are directly guided towards the projected image; the attention of the audience is more easily won and held through animation and moving pictures. The central messages of a scientific work can be more simply and clearly conveyed. This method also allows an up-dating of the picture contents at short notice, which is not possible with the common slide. Considering these advantages, modern media should be promoted within the framework of conferences, seminars and further education courses despite the need of greater technical and material equipment.

[Sonographic variability of lactating adenoma demonstrated by a longitudinal evaluation of 4 cases]. / Sonographische Variabilität laktierender Adenome am Beispiel von 4 langzeitüberwachten Fällen.

AIM: Lactating adenoma are circumscribed benign breast lesions developing during pregnancy or lactation due to overall enhanced proliferation of steroid hormone dependent tissue. Sonography is the method of choice for imaging mainly because of the physiologically dense breast tissue. Which is the predictive value of sonography in the diagnosis of lactating adenoma? Are sonographic characteristics dependent on age of gestation or time of lactation? Which diagnostic procedure should be recommended? METHOD: We report the long time course of four patients with histologically proven (core-needle biopsy, 16 Gauge) lactating adenoma, first diagnosed during pregnancy, which were followed up sonographically (1997-2000) with real-time B-mode, panorama-mode (Siescape) and colour-sonography. RESULTS: Demonstrating a high inter- and intraindividual variability the tumors were biggest around parturitation. Despite ongoing lactation tumors regressed in size, but did not vanish completely even after definite termination of breast feeding. Evaluation of sonographical characteristics did not allow to rule out malignancy. CONCLUSION: Three percent of all breast cancers at childbearing age coincide with pregnancy and lactation, therefore, an early histologic diagnosis is absolutely necessary. Sonographically guided core-needle biopsies allow to exclude malignancy without negative effects on breast feeding.

[Radiation therapy after mastectomy--interdisciplinary consensus puts and end to a controversy. German Society of Senology]. / Strahlentherapie nach Mastektomie--Interdisziplinärer Konsensus beendet Kontroverse. Deutsche Gesellschaft für Senologie]

BACKGROUND: Recent publications of the Danish Breast Cancer Cooperative Group together with data from the British Columbia Trial have stirred major discussions concerning the role of radiation therapy after mastectomy. Different treatment approaches are to be found even within the same cancer center. The German Society of Senology, a cooperative group of all medical disciplines involved in the treatment of breast cancer, has therefore worked out a consensus statement. MATERIAL AND METHOD: The recently published literature and experts opinions, in particular randomized studies since 1997, meta-analyses from the Early Breast Cancer Trialists' Collaborative Group, epidemiological investigations with regard to the time course of distant metastases in breast cancer as well as the current consensus of the American Society for Therapeutic Radiology and Oncology served as the basis for discussion and consulting. RESULTS OF THE CONSENSUS: (1) An optimally performed mastectomy is a major prerequisite for tumor cure. Radical (R0) resection of the tumor as well as dissection of at least 10 lymph nodes from the axillary level I and II should be accomplished. If axillary lymph nodes are involved, the surgical removal of these lymph nodes is not only of diagnostic, but also of therapeutic value, as it reduces the risk for locoregional relapses. (2) Most probably, locoregional relapses do not only indicate, but are also a source for distant metastases. (3) Radiation therapy of the chest wall and the regional lymph nodes increases the overall survival in risk patients and reduces the risk of locoregional relapses. Moreover, radiation therapy improves the prognosis in case of residual tumor or an incomplete axillary dissection. Unequivocal and reasonable indications for radiation therapy after mastectomy include T3/T4-carcinoma, T2-carcinoma > 3 cm, multicentric tumor growth, lymphangiosis carcinomatosa or vessel involvement, involvement of the pectoralis fascia or a safety margin < 5 mm, R1- or R2 resection and more than 3 axillary lymph node metastases. Further reasonable indications, albeit not yet evaluated in clinical trials, include multifocality, extensive intraductal component, negative hormone receptor status, G3-differentiation grade, diffuse micro-calcifications, 1 to 3 axillary lymph node metastases, multiple, non-complete biopsies and age < 35 years. (4) An endocrine therapy with tamoxifen concurrent to radiation therapy is also reasonable--despite some contradictory in-vitro data--as it enhances the apoptotic cell death. The CMF-regimen is usually performed as sandwich procedure, but can also be applied concurrently to radiation therapy, if indicated. Conversely, an anthracycline-containing chemotherapy should be finished prior to postoperative radiation therapy. CONCLUSIONS: Adjuvant radiation therapy after mastectomy improves the 10-year-survival probability up to 10%, at least for risk patients. The hypotheses of Halsted and Fisher do not exclude each other. There are patients, in which the one, and there are patients, in which the other hypothesis applies.

Quantitative ultrasound of the os calcis in postmenopausal women with spine and hip fracture.

Quantitative ultrasonometry (QUS) of the os calcis has been shown to predict hip fracture in late postmenopausal women, and vertebral and forearm fracture in early postmenopausal women. Speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index (SI) of the os calcis were measured using the Achilles ultrasonometer (Lunar, Madison, WI). Osteoporosis risk factors were assessed by a detailed questionnaire. We examined 1314 normal women from age 48 to 79 yr, with a mean age 60 +/- 7.5 yr. In addition, we examined women of similar age, of whom 80 had suffered a hip fracture and 40 a spine fracture. The short-term precision in vivo expressed as the coefficient of variation was 1.2% for BUA, 0.2% for SOS, and 1.3% for SI. A total of 813 women were measured at both the right and left heel. There was high correlation between the two sides (r = 0.80-0.93) (p < 0.001), with no systematic offset. The ultrasound variables decreased significantly (p < 0.001) with age in healthy women; the annual decrease was -0.4% for BUA, -0.07% for SOS, and -0.7% for SI. BUA, SOS and SI discriminated (p < 0.001) between fracture and non-fracture subjects, but the fracture groups were 2 to 4 yr older. The T-score in the controls averaged -2.1 while that in the fracture patients averaged about -3.0. After control for age, years since menopause, and body size, BUA, SOS as well as the SI remained significantly lower (11 to 12% for SI) in women with fracture. The Z-score was -0.8 (p < 0.01) in spine fracture cases, and -0.9 (p < 0.001) in hip fracture patients. QUS provides a gradient of fracture risk comparable to X-ray densitometry of the axial skeleton, and gives comparable Z- and T-scores in younger postmenopausal women. It provides a precise, radiation-free, low-cost, and rapid method for fracture risk assessment in clinical practice.

Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines.

Eighty percent of human ovarian and endometrial cancers express receptors for luteinizing hormone-releasing hormone (LHRH). These receptors might be used for targeted chemotherapy with cytotoxic LHRH analogs such as AN-152, in which doxorubicin is linked to agonist carrier [D-Lys6]LHRH. The antiproliferative effects of doxorubicin and AN-152 were assessed in LHRH receptor-positive ovarian (EFO-21, EFO-27) and endometrial (HEC-1A, Ishikawa) cancer cell lines as well as in LHRH receptor negative ovarian SKOV-3 and endometrial MFE-296 lines. The mechanism of action of AN-152 was investigated by a blockage of receptors using an excess of the LHRH agonist [D-Trp6]LHRH. In some cases, confocal laser-scanning microscopy was used to visualize the accumulation of AN-152 or doxorubicin within the cells. In 3 of 4 LHRH receptor-positive cell lines (EFO-21, HEC-1A, Ishikawa) AN-152 was more effective than doxorubicin in inhibiting cell proliferation. The effect of AN-152 was shown to be receptor-mediated because it could be reduced by competitive blockade of the LHRH receptors with [D-Trp6]LHRH. In contrast, AN-152 was less active than doxorubicin in LHRH receptor-negative lines. Confocal laser-scanning microscopy showed an intranuclear accumulation of AN-152 and competitive inhibition thereof by [D-Trp6]LHRH in LHRH receptor-positive cell lines, but no intracellular accumulation of AN-152 could be detected in the receptor-negative SKOV-3 line. These results suggest a selective receptor-mediated action of AN-152 in receptor-positive cell lines.

Luteinizing hormone-releasing hormone agonist triptorelin and antagonist cetrorelix inhibit EGF-induced c-fos expression in human gynecological cancers.

OBJECTIVES: Spontaneous and epidermal growth-factor-induced proliferation of human gynecological cancer cell lines is dose- and time-dependently reduced by treatment with the luteinizing hormone-releasing hormone (LHRH) agonist triptorelin and antagonist Cetrorelix. This antiproliferative activity is probably directly mediated through the LHRH receptors expressed by the tumor cells interacting with growth-factor-dependent mitogenic signal transduction. We have examined whether epidermal growth-factor (EGF)-induced expression of the early response gene c-fos is reduced by LHRH analogs. METHODS: Human endometrial (Ishikawa, Hec-1A), ovarian (EFO-21, EFO-27, SK-OV-3), and breast cancer cell lines (MCF-7) were rendered quiescent by incubation (72 h) in the absence of fetal calf serum and phenol red. This was followed by a 15-min incubation in the absence or presence of the LHRH agonist triptorelin (100 nM) or the antagonist Cetrorelix (100 nM) before the cells were stimulated for 10 min with EGF (100 nM). C-fos mRNA expression was determined by semi-quantitative RT-PCR using a synthetic DNA fragment as internal standard. C-Fos protein synthesis was determined by SDS-PAGE and semi-quantitative Western blotting. RESULTS: In cells derived from endometrial and ovarian cancer, maximal c-fos mRNA expression (seven- to ninefold over basal level) was obtained 30 min after EGF stimulation. In the breast cancer cell line MCF-7 this effect was obtained 60 min after EGF treatment. In all of the lines expressing LHRH receptor, EGF-induced c-fos mRNA expression as well as c-Fos protein synthesis was dose-dependently reduced by treatment with LHRH agonists and antagonists. At 100 nM concentrations of the LHRH analogs, c-fos expression was reduced to baseline levels. No effect of LHRH analogs on EGF-induced c-fos expression was observed in the ovarian cancer cell line SK-OV-3, which does not express the LHRH receptor. CONCLUSIONS: These results suggest that the binding of LHRH agonists and antagonists to their receptors inhibits the mitogenic signal transduction pathway of the EGF receptor in endometrial, ovarian, and breast cancer cell lines. The coupling of both signal transduction systems mediates the antiproliferative effect of LHRH analogs.

The influence of menopause and body mass index on serum leptin concentrations.

OBJECTIVE: The aim of this study was to evaluate the influence of menopausal status, serum estradiol and body mass index (BMI) on serum leptin concentration in a large sample of pre- and postmenopausal women. DESIGN: 434 healthy women (mean age +/-s.d., 52.2 +/- 10.3 years) were recruited at the University of Marburg on the occasion of a routine gynecological visit. Two hundred and eighteen (50.2%) women were premenopausal (mean age, 36.5 +/- 10.4 years) and not on oral contraceptives or hormone replacement therapy (HRT) and 216 (49.8%) women were postmenopausal (mean age 61.8 +/- 8.9 years) not on HRT. To evaluate the influence of menopausal status, estradiol level and BMI on serum leptin concentrations, women were allocated to one of the four groups: (a) premenopausal women BMI <25 kg/m(2) (n=137), (b) premenopausal women BMI >25 kg/m(2) (n=81), (c) postmenopausal women BMI <25 kg/m(2) (n=94) and (d) postmenopausal women BMI >25 kg/m(2) (n=122). RESULTS: Irrespective of the menopausal status, women with a BMI >25 kg/m(2) had significantly higher leptin concentrations in all age groups compared with women with a BMI <25 kg/m(2) (P<0.001). The multiple linear regression analyses showed that BMI was the only statistically significant independent predictor for leptin. In comparison to postmenopausal women, premenopausal women showed a significantly lower mean age, weight, BMI and FSH concentration (P<0. 001), a higher mean height and serum estradiol (P<0.01 and P<0.001 respectively) but significantly lower serum leptin concentration (P<0.01). The multiple linear regression model showed no significant influence of menopausal status or serum estradiol on serum leptin concentration, even after controlling for BMI. CONCLUSIONS: Serum leptin concentrations are significantly higher in pre- and postmenopausal obese women, compared with normal weight controls. Serum leptin concentrations are not influenced by menopausal status or serum estradiol level.

LHRH might act as a negative autocrine regulator of proliferation of human ovarian cancer.

OBJECTIVE: More than 80% of human ovarian cancers express LHRH and its receptor. The proliferation of human ovarian cancer cell lines is reduced by both LHRH agonists and antagonists. This study was designed to further clarify the possible biological function of this LHRH system. DESIGN: As LHRH agonists and antagonists uniformly reduce proliferation of human ovarian cancer in a dose-dependent way, the effect of low concentrations of authentic LHRH was studied. In addition, longer periods of treatment (up to 9 days) were analyzed. To assess the physiological role of LHRH produced by ovarian cancer cells it was neutralized by adequate concentrations of a specific LHRH antiserum. METHODS: Human ovarian cancer cells EFO-21 and EFO-27, which express LHRH and its receptor, were incubated for 1-9 days with increasing concentrations (1pmol/l to 10 micromol/l) of authentic LHRH or with concentrations of LHRH antiserum capable of neutralizing at least 1nmol/l LHRH. Proliferation was assessed by counting cells. RESULTS AND CONCLUSIONS: Authentic LHRH reduced time- and dose-dependently proliferation (by maximally mean+/-s.e.m. 32.7 +/- 4.4%, Newman-Keuls, P < 0.001) of both ovarian cancer cell lines. At very low concentrations (1pmol/l) a marginal reduction of proliferation or no effect was observed. A mitogenic effect of authentic LHRH was never detected. Treatment of ovarian cancer cell cultures with antiserum to LHRH significantly increased (up to mean+/-s.e.m. 121.0 +/- 2.8% of controls, Newman-Keuls P <0.001) proliferation of EFO-21 and EFO-27 cells. These findings suggest that LHRH produced by human ovarian cancer cells might act as a negative autocrine regulator of proliferation.

The effect of long-term, non-suppressive levothyroxine treatment on quantitative ultrasonometry of bone in women.

OBJECTIVE: To evaluate the impact of long-term, non-suppressive levothyroxine (L-T(4)) treatment on quantitative ultrasonometry in women. DESIGN: This was a case-control study. SUBJECTS AND METHODS: Altogether 667 women (mean age+/-s.d., 49.5+/-13.1 years) were studied. Of these, 156 (23%) had non-toxic goitre or hypothyroidism and had been taking L-T(4) (75-100 microg/day) for at least 5 years (mean+/-s.d., 12.5+/-7.5 years); the remaining 511 (77%) women were not receiving L-T(4). All women had completed a questionnaire on risk factors for thyroid dysfunction and osteoporosis, and those with diseases or treatments known to effect bone metabolism - other than thyroxine or hormone replacement therapy (HRT) - were excluded. Women underwent quantitative ultrasonometry (QUS) at the heel. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and the stiffness index (SI) were compared, first, in all women taking L-T(4) and controls and, secondly, in women taking L-T(4) and controls pair-matched for age, weight, body mass index (BMI), menopausal status and HRT use. RESULTS: Even after matching for age, weight, BMI, menopausal and HRT status, women taking L-T(4) had significantly lower values for SOS and SI (P<0.05), but not for BUA. However, absolute T- and Z-scores for SI were not low in either the study or control groups. Lower values were associated, but not significantly so, with years since the menopause and duration of L-T(4) treatment. CONCLUSIONS: Long-term, non-suppressive L-T(4) treatment in women with goitre or hypothyroidism was associated with a slight reduction in QUS values, which was more pronounced in postmenopausal women. This group could be at higher risk for osteoporotic fracture.