Hormonal prevention of breast cancer: proposal for a change in paradigm.
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Breast Neoplasms↗
Biomedical subjects
R D Hesch
Publications and source records attributed to R D Hesch.
A role for helix 3 of the TRbeta ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone.
Resistance to thyroid hormone (RTH) has hitherto been associated with thyroid hormone beta receptor (TRbeta) mutations which cluster in two regions (alphaalpha 310-353 and alphaalpha 429-461) of the hormone-binding domain and closely approximate the ligand-binding cavity. Here, we describe a third cluster of RTH mutations extending from alphaalpha 234-282 which constitute a third boundary of the ligand pocket. One mutant, T277A, exhibits impaired transactivation which is disproportionate to its mildly reduced ligand affinity (Ka). T3-dependent recruitment of coactivators (SRC-1, ACTR) by mutant receptor-RXR heterodimers was reduced in comparison with wild-type. Cotransfection of SRC-1 restored transactivation by T277A. In the TRbeta crystal structure this helix 3 residue is surface-exposed and is in close proximity to residues L454 and E457 in helix 12 which are known to be critical for coactivator interaction, suggesting that they all constitute part of a receptor-coactivator interface. The transcriptional function of other mutants (A234T, R243W/Q, A268D, Delta276I, A279V, R282S) in this cluster correlated with their reduced Ka and they inhibited wild-type TRbeta action in a dominant negative manner. DNA binding, heterodimerization and corepressor recruitment were preserved in all mutants, signifying the importance of these attributes for dominant negative activity and correlating with the absence of natural mutations in regions bordering the third cluster which mediate these functions.
Amino Acid Sequence↗
[QT syndrome: new diagnostic possibilities].
Electrocardiographic and clinical characteristics are currently used as diagnostic criteria for the long QT-syndrome. In borderline electrocardiographic findings associated with unclear syncope, it is often difficult to ensure or exclude long QT-syndrome. Schwartz and coworkers therefore created a point system as a guide in clinical decision making. In recent years genetic diagnostics have entered the arena of long-QT assessment. Aside from new insights into the pathophysiology of the long QT-disorder, it is expected that genetic diagnostics will offer substantial help to ascertain long QT-syndrome in patients with borderline electrocardiographic and clinical findings and improve risk stratification in long-QT family members. Performing linkage analysis, coupling of autosomal-dominant congenital long QT-syndrome (Romano-Ward Syndrome) to chromosomes 11 (LQT1/11p15.5), 3 (LQT3/3p21), 7 (LQT2/7q35), and 4 (LQT4/4q25-27) was demonstrated. More recently, the disease genes in long QT-syndrome 1, 2, and 3 could be identified. Analysis of the base-pair sequence allowed detection of several different mutations in different families illustrating genetic heterogeneity. Aside from diagnostic aspects, molecular genetics may also guide pharmacological therapy by identifying the specific ion-channel disorder leading to QT-prolongation and sudden death.
Chromosome Mapping↗
Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls.
Recent evidence links osteoporosis, a disease of bone remodeling, to changes in the dynamics of parathyroid hormone secretion. We use nonlinear and linear time series prediction to characterize the secretory dynamics of parathyroid hormone in both healthy human subjects and patients with osteoporosis. Osteoporotic patients appear to lack the periods of high predictability found in normal humans. Our results may provide an explanation for why an intermittent administration of parathyroid hormone is effective in restoring bone mass in osteoporotic patients.
Adult↗
Rapid desensitization of parathyroid hormone dependent adenylate cyclase in perifused human osteosarcoma cells (SaOS-2).
The pulsatile but not the continuous application of parathyroid hormone (PTH) increase bone mass in vivo. To study the effects of intermittent hormonal administration on bone-derived cells in vitro, we established a perifusion system using the human osteosarcoma cell line SaOS-2. Cells were grown in suspension culture attached to collagen beads and were then loaded into a 3 ml syringe for perifusion experiments. The application of PTH(1-34) resulted in a dose-dependent increase of cAMP release by SaOS-2 cells into the effluent medium. Cyclic AMP accumulation was rapidly desensitized by approx. 80% after 30 min of continuous exposure to PTH(1-34) (10(-7) M), while cells remained responsive to forskolin. The recovery of PTH responsiveness required at least 2 h of hormone-free perifusion. Desensitization in the experimental setting was dose-dependent (EC50 = 1 x 10(-10) M PTH(1-34)). Neither 8Br-cAMP (2 x 10(-4) M) nor PMA(1 x 10(-7) M) had an effect on the PTH(1-34)-induced desensitization of the adenylate cyclase. Radioreceptor assays showed that [125I]-[Tyr36]hPTHrP(1-36)amide binding to SaOS-2 cells was decreased by 60-70% by PTH(1-34) (1 x 10(-6) M), bPTH(1-84) (1.8 x 10(-6) M) and bPTH(3-34) (2 x 10(-6) M), whereas 8Br-cAMP (2 x 10(-4) M) had no effect on radioligand binding. PMA (1 x 10(-7) M) appeared to slightly increase [125I]PTHrP binding. This observation is consistent with a small (3-fold) increase in PTH-induced cAMP release as a result of PMA pre-treatment. Receptor internalization was dose-dependent EC50 = 3 x 10(-7) M PTH(1-34)). The maximal effect occurred after 10-30 min and was largely reversible within 2 h. Monensin (3 x 10(-5) M) inhibited the recovery from receptor internalization. We conclude that a perifusion system using SaOS-2 cells is a suitable model to study the effect of discontinuous application of PTH on cAMP release. A rapid, homologous desensitization of PTH(1-34) stimulated cAMP accumulation has been observed that does not appear to involve protein kinase A or C.
8-Bromo Cyclic Adenosine Monophosphate↗
Is there low-dimensional chaos in pulsatile secretion of parathyroid hormone in normal human subjects?
In many biological systems information is transferred by hormonal ligands, and it is assumed that these hormonal signals encode developmental and regulatory programs in mammalian organisms. The specificity of the biological response on activation by a hormone has so far been located within the interaction of a specific conformation of the ligand with the corresponding receptor structure. According to these classical explanations, the constant circulating hormonal pool described by the rate of its production and metabolic clearance is a major determinant of this interaction. Recently it has become apparent that hormone pulses contribute to this hormonal pool. Phase-space analysis of dynamic parathyroid hormone (PTH) secretion allowed the definition (in comparison to normal subjects) of a relatively quiet "low dynamic" secretory pattern in osteoporosis, and a "high dynamic" state in hyperparathyroidism. We now investigate whether this pulsatile secretion of PTH in healthy humans exhibits characteristics of low-dimensional deterministic chaos. Our findings suggest that this indeed appears to be the case. PTH secretion thus seems to be a first example of a chaotic hormonal rhythm in human physiology.
Adult↗
Pulse amplitude and frequency modulation of parathyroid hormone in early postmenopausal women before and on hormone replacement therapy.
Although the pathophysiology of postmenopausal osteoporosis has been investigated extensively, it is still not established in what respect PTH is related to the events. Recently, consistent data on the pulsatile secretion of PTH in man have been published. In this study intact PTH was measured in six early postmenopausal women before and after 6 months of hormone replacement therapy (HRT; 0.6 mg conjugated estrogens and 5 mg medrogestone). In addition to parameters of calcium metabolism and bone mass and to control HRT, intact PTH was measured in blood drawn over 6 h every 2 min. With HRT there was a 30% reduction in PTH secretion. Both the amount secreted per pulse (baseline, 26.8 +/- 6.9 ng/L; HRT, 21.4 +/- 7.6 ng/L; P < 0.05) as well as the basal secretion (baseline, 232.6 +/- 117.6 ng/L.h; HRT, 145.5 +/- 80.0 ng/L.h; P < 0.01) were reduced, whereas the pulse count per h remained constant (baseline, 5.1 +/- 2.2; HRT, 5.1 +/- 1.3). Power spectrum analysis showed a shift in spectral maxima consistent with these findings. Ionized and total calcium were slightly, but nonsignificantly, reduced with treatment. In summary we conclude that in early postmenopausal women, HRT reduces the secretion of PTH by reducing both the basal secretion and the amount secreted per pulse. It is conceivable that some of the known effects of HRT on bone metabolism might be mediated by the modulation of PTH secretion.
Calcium↗
Pulse amplitude and frequency modulation of parathyroid hormone in primary hyperparathyroidism.
Pulsatile secretion of PTH in human subjects has been described recently. However, the pattern of PTH secretion in primary hyperparathyroidism (pHPT) remains to be characterized. In this study intact PTH was measured in 9 female patients with pHPT. As a control group we present data from 10 postmenopausal women. In addition to parameters of calcium metabolism and bone mass, PTH was measured in samples drawn over 4 or 6 h every 2 min by central venous blood sampling. The mean intact PTH concentration was 39.0 +/- 20.3 ng/L in healthy women and 193.2 +/- 127.9 ng/L in female patients with pHPT (P < 0.01). Pulse rhythm analysis showed significant differences between both groups for total PTH secretion per h (patients, 1196.4 +/- 485.3 ng/L; control group, 271.7 +/- 132.2 ng/L), basal PTH secretion per h (patients, 852.4 +/- 459.1 ng/L; control group, 185.6 +/- 126.1 ng/L), and average PTH secretion per pulse (patients, 112.6 +/- 54.8 ng/L; control group, 23.2 +/- 7.1 ng/L). Both patients and control subjects had, on an average, five pulses per h, and the pulsatile secretion accounted for about 50% of the total secretion. Differences in power spectrum analysis were consistent with these findings. The cross-correlation of PTH and calcium indicates an impaired feedback regulation in pHPT. PTH secretion in female patients with pHPT results from both an increased basal secretion and an increased amplitude of PTH pulses. Other features of secretion are the same as those in normal women. Feedback regulation of PTH and calcium is impaired in pHPT.
Aged↗
[A structural parameter for characterizing early trabecular changes in the spine in osteoporosis].
The pattern of the spongiosa in lumbar vertebrae demonstrated by ultra high resolution CT was treated statistically. Comparison of normals with osteoporotic vertebrae showed no significant difference in the large dominant trabeculae. However, there is a significant difference when quantifying the fine structures which are not to resolve lying between the larger trabeculae.
Adult↗
Temporal patterns of alpha 1-receptor stimulation regulate amplitude and frequency of calcium transients.
The pulsatile release of neurotransmitters and many hormones might encode specific biological information according to temporal pattern. We tested this hypothesis by applying pulsed alpha 1-adrenoceptor stimulation to single aequorin-injected hepatocytes. The amplitude of free Ca2+ transients induced by rapid phenylephrine pulses (20-s interpulse interval) and continuous stimulation was similar (approximately 640 nM) but increased to approximately 1,000 nM as the interpulse interval was increased to 120 s. The same overall response was maintained despite a 13-fold reduction in average phenylephrine concentration. Some regimes of pulsed phenylephrine stimulation could give a higher frequency of pulsed phenylephrine stimulation could give a higher frequency of free calcium oscillations than continuous stimulation, or more rapid stimulation when some agonist pulses failed to elicit a free Ca2+ transient. For the same average phenylephrine concentration (0.3-0.6 microM), pulsed regimes could result in significantly higher frequencies and integrated responses than constant application. The lags between phenylephrine pulses and free Ca2+ transients reduced as the period between pulses increased. The amplitude and lag data are consistent with a refractory period of 18 s and a recovery phase with a time constant of approximately 100 s, perhaps corresponding to dephosphorylation of alpha 1-adrenoceptors phosphorylated by protein kinase C during each free Ca2+ transient.
Adrenergic alpha-Agonists↗
Evidence for P2-purinoceptors on human osteoblast-like cells.
ATP released from damaged cells or by controlled secretion could be an important factor in the formation or remodeling of bone. In a variety of other tissues ATP has been shown to control cellular processes by acting on P2-purinoceptors and activating the calcium signaling pathway. Here we demonstrate for the first time that extracellular ATP increases the intracellular free calcium [Ca2+]i concentration in normal human osteoblasts and in SaOS-2 cells, a human osteosarcoma-derived cell line, but not in ROS 17/2.8 cells. The ATP-induced increase in [Ca2+]i was dose dependent, and the concentrations of ATP required were similar to those reported to regulate cellular functions in other cell types. Although ATP is metabolized rapidly by bone cells, the effects on [Ca2+]i appeared to be mediated directly by ATP rather than one of its metabolites. Adenosine 3-thiotriphosphate, a nonhydrolyzable analog of ATP, induced similar changes in [Ca2+]i. This indicates that P2-purinoceptors are present on osteoblast-like cells and that extracellular ATP from various sources might be an important factor in the regulation of osteoblast functions.
Adenosine Triphosphate↗
Early adaptation of thyrotropin and thyroglobulin secretion to experimentally decreased iodine supply in man.
Five healthy male volunteers (aged 25 to 28 years) were studied both after 4 weeks of treatment with 200 micrograms iodine/d orally (PO) and following experimental iodine depletion by treatment with 3 x 300 mg perchlorate/d PO over a 4-week period, in an attempt to better define the early adaptive responses to an alteration in iodine supply in thyroid function. Intrathyroidal iodine, serum triiodothyronine (T3), free T3 (FT3), thyroxine (T4), free T4 (FT4), reverse T3 (rT3), thyroxine-binding globulin (TBG), thyroglobulin (Tg), and thyrotropin (TSH) levels (10-minute sampling over 24 hours) were measured at the end of iodine administration and at the end of perchlorate treatment. Thyroid volume was determined by sonography, and iodine content was determined by fluorescence scintigraphy. TSH pulses were analyzed by computer-assisted programs. Comparing both experimental situations, perchlorate treatment significantly reduced intrathyroidal iodine concentration (4.0 +/- 1.3 to 3.0 +/- 1.2 nmol/mL, P less than .05), but thyroid volume and total serum T4, T3, FT3, and TBG levels were not altered. Mean 24-hour serum TSH levels (1.8 +/- 0.3 to 1.0 +/- 0.3 mU/L, P less than .001), amount of TSH secreted/pulse (0.5 +/- 0.1 to 0.3 +/- 0.1 mU/L, P less than .001), and FT4 levels (15.7 +/- 1.7 to 14.3 +/- 1.4 pmol/L, P less than .005) were significantly diminished, whereas Tg levels (18.6 +/- 10.0 to 35.1 +/- 14.0 ng/mL, P less than .01) were significantly increased. Thyroid-specific antibodies were normal and were not altered by treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Classification of dynamical diseases by new mathematical tools: application of multi-dimensional phase space analyses to the pulsatile secretion of parathyroid hormone.
The biological importance of dynamic hormonal secretion has been demonstrated. There is good evidence from recent studies that parathyroid hormone (PTH) which plays an important role in bone physiology is secreted in a pulsatile manner. In this study we performed a classification of two 'dynamical diseases' namely osteoporosis and hyperparathyroidism by the visualization of dynamic PTH-secretion in multidimensional phase spaces.
Adult↗
The nude rat is established as a model for endocrine studies: regulation of thyroid function and xenotransplantation of a thyroid tumor cell line.
The thyroid physiology of athymic nude rats, rnu/rnu, is characterized and established here as an animal model to study transplanted thyroid tumors. Male rats were catheterized 5 days before experiments were started. The mean thyroid-stimulating-hormone (TSH) plasma concentrations were 2.9 +/- 0.6 ng/ml during infusion of 0.25 ml/h of 0.9% NaCl (n = 12). T3 plasma concentrations were 2.6 +/- 0.4 ng/ml. T4 plasma levels were 22.0 +/- 5.6 micrograms/dl. A bolus of 0.1 mg thyrotropin-releasing hormone (TRH) significantly increased TSH plasma concentrations (P less than or equal to 0.001; from 2.9 +/- 0.6 to 7.8 +/- 1.1 ng/ml, n = 12). No pulsatile TSH secretion was observed in a 2-hour period with blood samples taken every 10 minutes (n = 12) and hourly sampling disclosed no circadian variation of TSH during a 24-hour period (n = 4). Successful xenografting was possible in 12 of 15 cases using a follicular thyroid carcinoma cell line (FTC 133). Measurement of human thyroglobulin (hTg) by a hTg IRMA revealed high levels in rats with functional FTC tumors, whereas no hTg was detected in untransplanted rats or animals with nonfunctional transplants.
Animals↗
[The osteoprotective effect of ovarian hormones].
Osteoporosis is regarded as a disease of the systems controlling bone evolution. Estrogen modulates such a control system; without estrogen 50% of bone is not formed to the peak bone mass or may be lost lateron. Substitution with estrogen can be interpreted as a natural right of the women in our society. Estrogen modulates by dynamic hormonal system the genexpression in bone and determines its three-dimensional architecture. Substitution with estrogen has to consider the individual genetic situation of each women and its biographic and health situation. Individual estrogen substitution is not fully realized yet but estrogen substitution prevents osteoporosis effectively. We question if senile osteoporosis exists at all if there were no estrogen deficiency.
Bone and Bones↗
Measurement of intracellular Ca2+ in single aequorin-injected and suspensions of fura-2-loaded ROS 17/2.8 cells and normal human osteoblasts. Effect of parathyroid hormone.
It is known that parathyroid hormone (PTH) activates the cyclic AMP (cAMP) signalling pathway in osteoblasts. In recent years it has been suggested that an elevation of the intracellular free Ca2+ concentration ([Ca2+]i) may also be involved in the regulation of osteoblast function by PTH. However, this remains controversial. Here we investigated the effect of PTH on the [Ca2+]i of ROS 17/2.8 cells and normal human osteoblasts. The [Ca2+]i was measured in single aequorin-injected cells and in suspensions of cells loaded with fura-2. Human PTH-(1-38)-peptide (1-300 nM) had no effect on the [Ca2+]i in single aequorin-injected ROS 17/2.8 cells (n = 17) measured at various times after injection (1-20 h), or in suspensions of fura-2-loaded ROS 17/2.8 cells (n = 9). Ionomycin (1 microM) increased the [Ca2+]i in fura-2-loaded and single aequorin-injected ROS 17/2.8 cells by 285 +/- 60 nM (n = 9) and 312 +/- 99 nM (n = 6) respectively, indicating that both methods detect changes in [Ca2+]i with equal sensitivity. In contrast, human PTH-(1-38) (10-100 nM) markedly stimulated cAMP accumulation in ROS 17/2.8 cells. In single aequorin-injected normal human osteoblasts there was no change in the [Ca2+]i in response to 100 nM human PTH-(1-38) or 100 nM bovine PTH-(1-84) (n = 18). In contrast, in suspensions of normal human osteoblasts loaded with fura-2, an increase in [Ca2+]i in response to human PTH-(1-38) (100 nM) was found (60 +/- 28 nM; n = 6). Considerable variation in the magnitude of the response was observed between individual preparations and donors. These data indicate that PTH activates cAMP accumulation without affecting [Ca2+]i in ROS 17/2.8 cells and that PTH causes a rise in [Ca2+]i only in a small subset of normal human osteoblasts. We suggest that the Ca2+ response to PTH in osteoblasts is limited by the state of differentiation of the cells, and may be due either to the presence of a distinct Ca2(+)-mobilizing receptor or to a cAMP-mediated Ca2+ response.
Aequorin↗
Classification of cell receptors.
This manuscript constitutes a first attempt to categorize the cell receptors. Based on evolutionary and biological characteristics, it is possible to classify ligand-receptor units into original families. Certain dynamic patterns that could not be classified previously lead us towards the ligand-receptor unit. Biological information is transformed at the receptor by cellular transduction and effector pathways. The dynamic code is compared with the genetic code. The dynamic code controls the biological information patterns necessary for the integral function and structure of cells, tissue, organs, and organisms. The genetic code controls the assembly and molecular structure of proteins. The original families can be assigned certain original functions. A coevolution of ligand-receptor and dynamic code is revealed. For the time being the most useful approach to receptor classification would seem to be based on the organization of the molecular and protein structure of receptors. Two classes of receptor can be described: receptors for cyclic hydrophobic compounds and membrane receptors. Until we know of the families of single membrane-spanning receptors, fourfold membrane-spanning receptors, sevenfold membrane-spanning receptors, fourfold membrane-spanning receptors. For the sevenfold membrane-spanning receptor the identity of conformation and dynamics of biological function has been established. Light and peptide ligands are used as examples. A systems theory for information transduction at receptors is introduced which can also describe the processes of sensitivity modulation.
Amino Acid Sequence↗
Biochemical characterization of cellular hormone receptors.
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Adenylyl Cyclases↗