We have been studying the endocrine system of elderly men with prostatic disorders, none of whom had any clinical or routine laboratory evidence of an endocrine disorder. The presence of prostate disease, so common in males over 60, may be an incidental finding, since we do not have data in age-matched controls. In 8 patients studied to date, 4 with prostate carcinoma and 4 with benign prostatic hypertrophy, decreased or absent pituitary luteinizing hormone (LH) reserve has been uniformly noted. No other abnormalities of pituitary function have been noted except that two patients had increased 24-h urinary total pituitary gonadotrophins, probably indicating primary testicular failure. Investigations included studies of growth hormone (GH) reserve by measurement of plasma GH levels following arginine stimulation (Merimee & Rabinowitz, 1969). Although 4 patients had Stage IV carcinoma of the prostate, none was cachectic and body weight in this group ranged from 2·5 to 16
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J. GELLER, AURORA BARON, and S. KLEINMAN
K. J. GURLING, MARION B. R. GORE, and D. N. BARON
2-Methyl-9α-fluorohydrocortisone has potent mineralocorticoid and adrenocortical-suppressing activity.
A single oral dose of 0·1 mg lowered the urinary Na/K ratio, causing Na retention and K loss. There was an eosinophilia and a fall in plasma 17-hydroxycorticoids and in urinary 17-oxosteroids and 17-hydroxycorticoids. These effects lasted 24–36 hr, after which time there was a Na diuresis and the values returned to normal.
Doses of 0·3 mg, repeated for 3 days, enhanced these effects, with accompanying oedema and hypokalaemia. No significant effects on carbohydrate or protein metabolism were observed.
The dangers and possible uses of the compound are discussed.
K. J. GURLING, D. N. BARON, and MARION B. R. GORE
1. 2-methyl-9α-fluorohydrocortisone was administered orally to two adrenalectomized patients in doses of from 0·025 to 0·1 mg daily.
2. Excessive sodium retention occurred with doses of 0·03–0·1 mg daily, and 0·025 mg sufficed for a positive sodium balance and maintenance of blood pressure.
3. Adrenocortical replacement did not seem to be physiological with this dose in spite of electrolyte control, and there was subjective improvement when cortisone was resumed.
DENIS ABELSON, D. N. BARON, and J. G. TOAKLEY
1. Cerebrospinal fluid (CSF), obtained in the course of routine air encephalography, was examined for the presence of adrenocortical steroids by the method of extraction followed by paper chromatography. Compounds provisionally identified as cortisone and hydrocortisone were found in approximate concentrations of 0·1–0·2 and 0·2–0·40·4μg/100 ml. respectively. Other uncharacterized compounds were also found.
2. After oral administration of either cortisone acetate or hydrocortisone the concentration in the CSF of the compound considered to be hydrocortisone was increased. This increase was greater after administration of hydrocortisone than after cortisone acetate and was maximal 4–4½ hr after the dose. No increase was detected in the concentration of cortisone.
3. The physiological and therapeutic implications of these results are discussed with special reference to the conversion in vivo of cortisone to hydrocortisone.
O Nilsson, V Abad, D Chrysis, EM Ritzen, L Savendahl, and J Baron
Estrogen regulates skeletal growth and promotes epiphyseal fusion. To explore the mechanisms underlying these effects we investigated the expression of estrogen receptor-alpha (ERalpha) and -beta (ERbeta) in rat and rabbit growth plates during postnatal development, using immunohistochemistry. Immunoreactivity for ERalpha and ERbeta was observed in resting zone and proliferative zone chondrocytes at all ages studied for both rat (7, 14, 28 and 70 days of age) and rabbit (1, 7, 28 and 120 days of age). In the rat distal humerus and the rabbit proximal tibia, expression of both receptors in the hypertrophic zone was minimal at early ages, increasing only at the last time point prior to epiphyseal fusion. Expression was rarely seen in the hypertrophic zone of the rat proximal tibia, a growth plate that does not fuse until late in life. Therefore, we conclude that ERalpha and ERbeta are both expressed in the mammalian growth plate. The temporal and anatomical pattern suggests that ER expression in the hypertrophic zone in particular may play a role in epiphyseal fusion.
David E Maridas, Victoria E DeMambro, Phuong T Le, Kenichi Nagano, Roland Baron, Subburaman Mohan, and Clifford J Rosen
Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro. Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4−/− mice. Both male and female adult Igfbp4−/− mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4−/− females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4−/− females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4−/− females. In contrast, Igfbp4−/− males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4−/− males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4−/− females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor.
E A Parker, A Hegde, M Buckley, K M Barnes, J Baron, and O Nilsson
Previous studies of the GH–IGF system gene expression in growth plate using immunohistochemistry and in situ hybridization have yielded conflicting results. We therefore studied the spatial and temporal patterns of mRNA expression of the GH–IGF system in the rat proximal tibial growth plate quantitatively. Growth plates were microdissected into individual zones. RNA was extracted, reverse transcribed and analyzed by real-time PCR. In 1-week-old animals, IGF-I mRNA expression was minimal in growth plate compared with perichondrium, metaphyseal bone, muscle, and liver (70-, 130-, 215-, and 400-fold less). In contrast, IGF-II mRNA was expressed at higher levels than in bone and liver (65- and 2-fold). IGF-II expression was higher in the proliferative and resting zones compared with the hypertrophic zone (P < 0.001). GH receptor and type 1 and 2 IGF receptors were expressed throughout the growth plate. Expression of IGF-binding proteins (IGFBPs)-1 through -6 mRNA was low throughout the growth plate compared with perichondrium and bone. With increasing age (3-, 6-, 9-, and 12-week castrated rats), IGF-I mRNA levels increased in the proliferative zone (PZ) but remained at least tenfold lower than levels in perichondrium and bone. IGF-II mRNA decreased dramatically in PZ (780-fold; P < 0.001) whereas, type 2 IGF receptor and IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4 increased significantly with age in growth plate and/or surrounding perichondrium and bone. These data suggest that IGF-I protein in the growth plate is not produced primarily by the chondrocytes themselves. Instead, it derives from surrounding perichondrium and bone. In addition, the decrease in growth velocity that occurs with age may be caused, in part, by decreasing expression of IGF-II and increasing expression of type 2 IGF receptor and multiple IGFBPs.