Sex hormones,their receptors and bone health

Sex steroids regulate skeletal maturation and preservation in both men and women, as already recognized in the 1940s by Albright and Reifenstein. The impact of gonadal insufficiency on skeletal integrity has been widely recognized in adult men and women ever since. In the context of their skeletal actions, androgens and estrogens are no longer considered as just male and female hormones, respectively. Androgens can be converted into estrogens within the gonads and peripheral tissues and both are present in men and women, albeit in different concentrations. In the late 1980s, sex steroid receptors were discovered in bone cells. However, the understanding of sex steroid receptor activation and translation into biological skeletal actions is still incomplete. Due to the complex metabolism, sex steroids may have not only endocrine but also paracrine and/or autocrine actions. Also, circulating sex steroid concentrations do not necessarily reflect their biological activity due to strong binding to sex hormone binding globulin (SHBG). Finally, sex steroid signaling may include genomic and non-genomic effects in bone and non-bone cells. This review will focus on our current understanding of gonadal steroid metabolism, receptor activation, and their most relevant cellular and biological actions on bone.     

Stressproteine bei der Pathogenese des Prostatakarzinoms

Therapeutic resistance is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress proteins, including heat shock proteins and clusterin. These molecular chaperones interact with various client proteins to assist in their folding and enhance cellular recovery from stress conditions. Cellular stress and cell death are linked, as the induction of chaperones appear to function at key regulatory points in the control of apoptosis. On this basis and on the role of stress proteins in the regulation of steroid receptors, kinases, caspases, and other protein remodeling events, it is not surprising that molecular chaperones have been implicated in resistance to anticancer treatments. Recently, several chaperones have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the events initiated by treatment-induced stress and discuss the potential role of chaperone inhibitors in prostate cancer treatment.     

Thyroid disorders and steroid receptor proteins

65 patients with various thyroid disorders were studied for estrogen and progesterone receptor binding proteins. Two-thirds of all patients with both benign and malignant disease demonstrated positive protein receptor assays. No differences were seen among disease processes, sex, or age. While the therapeutic implications of this random association between steroid receptors and thyroid disorders are unknown, the authors recommend that patients with thyroid malignancies be studied for estrogen and progesterone receptor binding proteins and potential inhibitory or therapeutic steroid responses.     

Measurement of nuclear oestrogen receptors in human breast tumours

Recent reports suggest that oestrogen receptors detected in the cytosolic fraction of homogenized human breast tumours might be mainly nuclear receptor released into the cytoplasm during tissue processing. This study thus compares the tumour content of steroid hormone receptors in conventional cytosolic receptor assays with direct measurements of receptor in the cell nucleus. Unoccupied cytoplasmic oestrogen receptors (cER), cytoplasmic progesterone receptors (cPR) and total (occupied plus unoccupied) nuclear oestrogen receptors (nER) have been measured in parallel in human breast tumour tissue using biochemical radioreceptor assay. Of 125 tumours, 62% and 61% were positive for cER and cPR, respectively, 50% contained nER with high affinity for oestradiol (nER I) and 13% expressed nER with low affinity for oestradiol (nER II). The concentration of cER correlated significantly with age, cPR and log nER I. A significant proportion of tumours which were positive for both cytosol receptors also possessed nuclear receptors with high and low affinity for oestrogen. It is possible that this group of tumours which are positive for cER, cPR, nER I and nER II will respond well to hormone therapy.     

Chaperone proteins--essential proteins for cellular activity

Molecular chaperones are an ubiquitous, abundant and highly conserved group of proteins which bind and stabilize proteins at intermediate stages of folding, assembly, translocation across membranes and degradation. They first came to attention because of their specific induction during the cellular response of all organisms to heat shock, but are now known to be constitutively and abundantly expressed in the absence of any stress. Despite the obvious importance of stress responses, only recently has scrutiny focused on the role of heat shock proteins in the control of disease pathology. Knowledge about Hsp functions in bacteria is much further advanced than in eukaryotes, but already some hints of Hsp involvement in mammalian diseases have emerged.     

The normal functions of integrins and their involvement in pathology

Ordered cell-cell and cell-matrix adhesive interactions are a fundamental feature of all multicellular organisms. Numerous studies in recent years have confirmed that both types of cell adhesion are mediated by cell surface receptors known as "adhesion molecules". These receptors can be divided into a limited number of families. Knowledge gained from basic research into cell adhesion is now being applied to clinical problems, and some of these have been summarized here. Integrins are heterodimeric proteins mediating cell-cell and cell-extracellular matrix adhesive connections and signal transduction across the plasma membrane. The important roles of integrins are in Leukocyte Adhesion Deficiency, in viral diseases, neural development and cancer. Suggestive data now points to roles in functions characterized in part by morphological rearrangements, such as learning and memory, and injury responses.     

Novel mediators of FTY720 in human lymphocytes

FTY720 (FTY), a novel immunosuppressive drug, can be distinguished from other immunosuppressive drugs by a completely different mechanism of action. FTY induces altered lymphocyte trafficking, leading to peripheral blood lymphopenia and to increased lymphocyte counts in lymph nodes. FTY mediates its immune-modulating effects by binding to sphingosine 1-phosphate receptors expressed on lymphocytes. In an attempt to identify mediators of the FTY-induced signal transduction, we used a proteomic approach. FTY-treated peripheral blood lymphocytes (PBLs) were investigated for the expression of 622 proteins. We identified 15 differentially expressed proteins in PBLs possibly related to FTY action. As indicated by protein function, several identified proteins could be linked to the cytoskeleton/cell motility, to cell adhesion, and vesicle trafficking. No changes were found concerning the expression of various apoptosis regulators as well as the immunophilins FKBP12 and calcineurin. Our data suggest that FTY affects cytoskeleton rearrangements, cell adhesion, and vesicle trafficking/sorting in human PBLs.     

Osteoclasts isolated from membranous bone in children exhibit nuclear estrogen and progesterone receptors

Osteoclasts were isolated from membranous bone from four children without metabolic bone disease who were undergoing craniotomy for either tumor or trauma. Both freshly isolated osteoclasts and those cultured for 4-7 days exhibited the following characteristics: production of tartrate-resistant acid phosphatase (9.5-14.8 units), contraction in response to application of 100 mg/ml of human calcitonin, and formation of resorption lacunae on devitalized bone wafers. Nuclear estrogen and progesterone receptors were demonstrated by immunohistochemical techniques and quantitated in two of the patients by radioimmunoassay (estrogen receptor RIA, 23.6 and 23.8 cpm/micrograms protein; progesterone receptor RIA, 36.7 and 74.2 cpm/micrograms protein). The demonstration of sex steroid hormone receptors in the nucleus of osteoclasts derived from children with normal membranous bone has established a potential mechanism whereby direct modulation of bone resorption by the sex steroid estrogen and progesterone may occur.     

Cholinergic innervation and muscarinic receptors in the human prostate

OBJECTIVE: In light of recent interest in the use of muscarinic receptor antagonists for the treatment of male lower urinary tract symptoms, understanding how such drugs work not only on the bladder but also on the prostate is important. METHODS: A literature review was conducted to identify studies on the cholinergic innervation and presence and function of muscarinic acetylcholine receptors in the human prostate. RESULTS: The available studies demonstrate a dense cholinergic innervation within both stromal and epithelial compartments of the prostate. Concomitantly, the human prostate expresses muscarinic receptors at densities exceeding those of alpha(1)-adrenoceptors. They mainly belong to the M(1) subtype and are found on epithelial cells, but a smaller population of M(2) receptors is found on stromal cells. Both populations have been shown to be functional in signal transduction assays. However, in line with the sparse receptor density on stromal smooth muscle cells, contractile responses of the prostate are only small. Data from prostate cancer cell lines and from botulinum toxin injections into the benign prostate raise the possibility that muscarinic receptors may promote prostatic growth. Animal data suggest that muscarinic receptors may be of primary importance in the genesis of prostatic secretions, but this needs to be confirmed in humans. CONCLUSIONS: Taken together it appears that direct effects on the prostate need to be considered when using muscarinic receptor antagonists in men. They may primarily involve alterations of glandular secretion and prostatic growth.     

Vascular signaling through cholesterol-rich domains: implications in hypertension

PURPOSE OF REVIEW: Lipid rafts are emerging as key players in the integration of cellular responses. Alterations in these highly regulated signaling cascades are important in structural, mechanical and functional abnormalities that underlie vascular pathological processes. The present review focuses on recent advances in signal transduction through caveolae/lipid rafts, implicated in hypertensive processes. RECENT FINDINGS: Caveolae/lipid rafts function as sites of dynamic regulatory events in receptor-induced signal transduction. Mediators of vascular function, including G-protein coupled receptors, Src family tyrosine kinases, receptor tyrosine kinases, protein phosphatases and nitric oxide synthase, are concentrated within these microdomains. The assembly of functionally active nicotinamide adenine dinucleotide phosphate oxidase and subsequent reactive oxygen species production are also dependent on interactions within the caveolae/lipid rafts. Recent findings have also demonstrated the importance of actin-cytoskeleton and focal adhesion sites for protein interactions with caveolae/lipid raft. SUMMARY: Many vascular signaling processes are altered in hypertension. Whether these events involve lipid rafts/caveolae remains unclear. A better understanding of how signaling molecules compartmentalize in lipid rafts/caveolae will provide further insights into molecular mechanisms underlying vascular damage in cardiovascular disease.     

Immunocytochemical localization of estrogen and progesterone receptors in human thyroid

The presence of steroid hormone receptors has previously been suggested in thyroid tissue by biochemical means. Our studies were designed to confirm these results and to localize the specific receptor-containing cell type using a novel immunocytochemical method. Monoclonal antibodies specific to estrogen receptors (ER) and progesterone receptors (PgR) were used to localize these steroid hormone receptors in the human thyroid gland. Frozen tissue sections from surgical specimens excised from 22 patients of both sexes with benign thyroid disease were studied. The sections were incubated with rat antiestrophilin and antiprogesterone receptor antibodies and were then exposed to rabbit anti-rat IgG and to rat peroxidase-antiperoxidase complex. The reaction product was visualized with diaminobenzidine tetrahydrochloride and hydrogen peroxide. Four specimens were positive for both ER and PgR, 16 were ER-positive and PgR-negative, and two were negative for both ER and PgR. Positive reactivity was limited to the follicular lining cell nuclei and varied from focal to diffuse. The immunohistochemical findings confirmed the presence of ER and PgR in the thyroid tissue and demonstrated for the first time that these receptors are present only in the nuclei of the lining cells of the thyroid follicle. The role of steroid hormone receptors in the thyroid in health and disease remains to be explained.     

心肌延迟预处理效应机制的研究进展

延迟预处理是一个涉及多种应激-反应基凶表达,并最终导致心肌保护蛋白合成的复杂过程.除缺血之外,热刺激、锻炼和细胞因子等亦可触发相同的信号转导过程.更蘑要的是,许多药物,如NO供体、A1受体激动剂、内毒素衍生物和阿片受体激动剂等均可诱导出类似于缺血预处理的延迟预处理效应.这说明这种内源性调节反应可用于治疗目的 .现就延迟预处理效应的触发环节、信号转导系统和介导凶素作一综述.     

Comments on the St. Gallen Consensus 2003 on the Primary Therapy of Early Breast Cancer

This final paper of the proceedings of the recent Eighth St. Gallen Conference 2003 on the Primary Therapy of Early Breast Cancer comments on the Consensus Paper put forth by the international expert panel and emphasizes new information, that has emerged during the 2 years since the seventh such meeting in 2001. More than 3200 breast cancer specialists from various medical fields-coming from 75 countries and all six continents-have attended the meeting and the process of scientific consensus development. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The Panel modified and simplified the risk categories so that only endocrine receptor-absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors was also recognized as indicating endocrine non-responsiveness.Some important areas highlighted especially in the 2003 consensus include: recognition of the separate nature of endocrine non-responsive breast cancer, both invasive cancers and ductal carcinoma in situ (DCIS); improved understanding of the mechanisms of acquired endocrine resistance, offering exciting prospects for extending the impact of successful sequential endocrine therapies; presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine responsive disease; promise of newly defined prognostic and predictive markers.