Testosterone (T) levels in the plasma of male laboratory rats and mice were measured by radioimmunoassay. There was a striking individual variation with values ranging from less than 1 ng/ml to over 30 ng/ml in mice of the same age and strain housed under identical conditions. Using chronic indwelling catheters inserted into a jugular vein, blood was collected from adult conscious male rats every 24 hr for 4 or 8 days and every 30 min for 2 l / 2 or 8 hr. Considerable differences in plasma T levels were observed between different animals, and 2-to S-fold fluctuations of T concentrations in the plasma were detected between samples collected from the same animal at different times. These large and irregular changes in plasma levels of T are unlike the fairly stable levels observed in the human but bear certain resemblance to the pulsatile release of T described in bulls and rams and perhaps also to the social dominance related differences in plasma T levels in Rhesus monkeys. {Endocrinology 92: 1223, 1973

A total of 982 patients underwent 1,416 treatments with extracorporeal shock wave lithotripsy for upper urinary tract calculi between February 23 and December 17, 1984. A single treatment was performed in 90 per cent of the patients. Morbidity was extremely low and hospital stay was short (3.0 days). Adjunctive procedures were required in 13 per cent of the patients. Of the kidneys 72 per cent were free of stones at the 3-month followup, while 23 per cent contained small (less than 5 mm.), asymptomatic fragments believed to be passable spontaneously. Only 1 per cent of the patients required surgical removal of the calculi. Morbidity was related directly to stone burden, while results were inversely related to stone burden. Extracorporeal shock wave lithotripsy is the preferred form of management for symptomatic upper ureteral and renal calculi less than 2 cm. in diameter.

Two new therapies, percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy, are revolutionizing the treatment of upper urinary tract calculi. We report the success and morbidity rates in 110 patients undergoing percutaneous nephrostolithotomy and 982 patients treated with extracorporeal shock wave lithotripsy. Staghorn calculi were excluded from this series. The over-all success rate (free of stones plus small asymptomatic residual fragments) was comparable with both modalities (percutaneous nephrostolithotomy 98 per cent and extracorporeal shock wave lithotripsy 95 per cent), although the presence of residual fragments was more common in kidneys treated with extracorporeal shock wave lithotripsy (24 versus 7 per cent). Patient morbidity as measured by temperature elevation, length of postoperative stay, pain and blood loss was significantly less (p less than 0.05) with extracorporeal shock wave lithotripsy than with percutaneous nephrostolithotomy. Re-treatment rates were similar with both procedures, and tended to increase in relation to increasing stone size and stone number. Post-treatment ancillary procedures (cystoscopy and stone manipulation, and percutaneous nephrostomy) were used more frequently with extracorporeal shock wave lithotripsy. Because of its efficacy and low morbidity, we conclude that extracorporeal shock wave lithotripsy is the treatment of choice for upper urinary tract calculi less than 2 cm. in diameter. However, percutaneous nephrostolithotomy will continue to have a primary role in the management of larger stones and cystine stones, and it will be used as a secondary procedure after unsuccessful extracorporeal shock wave lithotripsy treatments. In addition, because of the complimentary nature of these 2 new technologies certain complex stones, such as staghorn calculi, may be handled best by a combination of the 2 techniques.

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A new class of potent, selective, nonsteroidal inhibitors of aromatase have been discovered. The most potent member of this series is fadrozole hydrochloride, CGS 16949 A, 4-(5,6,7,8-tetrahydroimidazo[1,5-alpha]pyridin-5-yl)benzonitrile monohydrochloride, 26a. In addition, the 6,7-dihydropyrrolo[1,2-c]imidazole (21a) and the 6,7,8,9-tetrahydroimidazo[1,5-alpha]azepine (21b) analogues were synthesized and evaluated. CGS 16949 A's ability to selectively inhibit aromatase (IC50 = 4.5 nM) over other cytochrome P-450 enzymes and suppress estrogen production when administered orally make it a suitable candidate to test the potential of an aromatase inhibitor in estrogen-dependent diseases including breast cancer.

The steroid compound cyproterone acetate was identified in a high-throughput screen for glucocorticoid receptor (GR) binding compounds. Cyproterone (Schering AG) is clinically used as an antiandrogen for inoperable prostate cancer, virilizing syndromes in women, and the inhibition of sex drive in men. Despite its progestin properties, cyproterone shares a similar pharmacological profile with the antiprogestin mifepristone (RU486; Roussel Uclaf SA). The binding affinities of cyproterone and RU486 for the GR and progesterone receptor were similar (K d , 15-70 nM). Both compounds were characterized as competitive antagonists of dexamethasone without intrinsic transactivating properties in rat hepatocytes (K i , 10 -30 nM). In osteosarcoma cells, RU486 revealed a higher potency than cyproterone acetate to prevent responses to dexamethasoneinduced GR transactivation and NFB transrepression. Upon administration to Sprague-Dawley rats, both compounds were found to be orally bioavailable and to inhibit transactivation of liver GR. Molecular docking of cyproterone acetate and RU486 into the homology model for the GR ligand binding domain illustrated overlapping steroid scaffolds in the binding pocket. However, in contrast to RU486, cyproterone lacks a bulky side chain at position C11␤ that has been proposed to trigger active antagonism of nuclear receptors by displacing the C-terminal helix of the ligand-binding domain, thereby affecting activation function 2. Cyproterone may therefore inhibit transactivation of the GR by a molecular mechanism recently described as passive antagonism. New therapeutic profiles may result from compounds designed to selectively stabilize the inactive and active conformations of certain nuclear receptors.Glucocorticoids are steroid hormones that are essential for normal growth and development, for liver and immune functions, and for mediating the stress response. Synthetic derivatives of glucocorticoids, such as dexamethasone, have immunosuppressive, anti-inflammatory, osteocatalytic, proteolytic, and hyperglycemic activities and are used to treat various pathological conditions (Sapolsky et al., 2000). The GR is a ligand-activated intracellular transcriptional regulator that is a member of the nuclear receptor superfamily. In the absence of a ligand, the GR is retained in the cytoplasm by association with chaperone proteins. Upon ligand binding, the GR dissociates from chaperones, dimerizes, and translocates into the nucleus. In the nucleus, the hormone-bound GR can modulate transcription of target genes by direct interaction with specific DNA sequences, called glucocorticoid response elements (GRE) in GR responsive promoters (Karin, 1998). Alternatively, activated GR can interact with nuclear factor B (NF-B) or with activator protein 1 (AP-1) to repress gene expression induced by these proinflammatory transcription factors. The anti-inflammatory and immunesuppressive properties of glucocorticoids have been largely attributed to the transrepression of NF-B and AP-1 function, whereas...

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Treatment recommendations and results reported for the management of staghorn calculi are highly variable. In an attempt to provide a more objective means to compare treatment results for staghorn renal calculi, stone burden as measured by stone surface area was used. Stone surface area was determined by computer analysis. A total of 380 cases of staghorn calculi treated at the same institution was evaluated. Treatment consisted of initial percutaneous nephrostolithotomy with or without extracorporeal shock wave lithotripsy (ESWL*) in 298 cases and ESWL monotherapy in 82. When considered as a group, the overall stone-free rate for initial percutaneous nephrostolithotomy (mean surface area 1,378.3 mm.2) was 84.2% compared to 51.2% (p less than 0.0001) for ESWL monotherapy (mean surface area 693.4 mm.2). For staghorn calculi smaller than 500 mm.2 a stone-free rate of 94.4% was achieved in the percutaneous nephrostolithotomy with or without ESWL group compared to 63.2% for ESWL monotherapy (p = 0.0214). For calculi of 501 to 1,000 mm.2 the stone-free rates were 86% and 45.7%, respectively (p less than 0.0001). When stone surface area exceeded 1,000 mm.2 the stone-free rate for percutaneous nephrostolithotomy with or without ESWL was 82.4% but it was only 22.2% for ESWL monotherapy (p = 0.0002). Overall, when adjusted for stone surface area the odds of being stone-free were more than 8 times higher for initial percutaneous nephrostolithotomy versus ESWL monotherapy (odds ratio = 8.36, p less than 0.0001). While percutaneous nephrostolithotomy with or without ESWL appears to be the procedure of choice for most staghorn stones, ESWL monotherapy may have a role for some stones smaller than 500 mm.2. In 12 such cases associated with a nondilated renal collecting system (mean surface area 380.5 mm.2) a stone-free rate of 91.7% was achieved. The number of procedures required to complete therapy was higher in the initial percutaneous nephrostolithotomy group (2.8 versus 2.1, p less than 0.0001). Although complications were more common in the ESWL monotherapy group (manifested as obstruction in 30.5%), bleeding requiring blood transfusion was more frequent in the initial percutaneous nephrostolithotomy group (9.4%).