In an attempt to overcome ethnic and racial differences in skeletal maturation, the use of ethnic-specific standards has been suggested. Do we need such standards? Based on a fundamental understanding of phenotypic plasticity and an individual's ability to respond to environmental cues, the author argues that we do not need ethnic-specific standards for bone maturity. I suggest that we use a unified international standard of bone maturity for comparing the health, nutrition, and quality of life of all children, regardless of their race, nationality, and ethnicity.
This review attempts to use evolutionary life-history theory in understanding child growth in a broad evolutionary perspective. It uses the data and theory of evolutionary predictive adaptive strategies for transition from one life-history phase to the next, and the inherent adaptive plasticity in the timing of such transitions. Humans evolved to withstand energy crises by decreasing their body size, and evolutionary short-term adaptations to energy crises utilize a plasticity that modifies the timing of transition from infancy into childhood, culminating in short stature at the time of an energy crisis. Transition to juvenility is part of a strategy of conversion from a period of total dependence on the family and tribe for provision and security to self-supply, and a degree of adaptive plasticity is provided and determines body composition. Transition to adolescence entails plasticity in adapting to energy resources, other environmental cues, and the social needs of the maturing adolescent to determine lifespan and the period of fecundity and fertility.
Life-history transitions are the times when the child adaptively responds to environmental cues in order to enhance growth–body composition–lifespan–fecundity schedules and behavioral strategies that yield the highest fitness in a given environment.
Leah Even, Tarif Bader and Ze’ev Hochberg
Context: Circadian rhythms of plasma parathyroid hormone (PTH) show peak values at night, whereas serum calcium levels peak in the evening and display a nadir at night.
Hypotheses: Subclinical hypoparathyroidism (HPT) can be detected by utilizing the knowledge of diurnal variations. Thalassemia major (TM) may provide a model system of subclinical HPT.
Design: Nocturnal plasma PTH and serum calcium values were determined in 13 TM patients with normal morning serum calcium levels as compared with the corresponding values in eight healthy control subjects.
Results: Six patients with TM presented a nadir serum calcium level of 8.3 mg/dl or lower (hypoCa TM) at 0200 h, whereas the remaining seven showed nadir levels of 8.4 mg/dl or higher (normoCa TM). Patients with hypoCa TM displayed a drop between peak and nadir of 1.2 ± 0.5 mg/dl as compared with a considerably smaller fall of 0.3 ± 0.7 mg/dl in control subjects (P < 0.05). NormoCa TM patients experienced comparable nocturnal variation to that of control subjects. Patients from both the hypoCa and normoCa TM groups presented significantly lower nocturnal PTH levels than those of control subjects and lost the nocturnal PTH variation characteristic of healthy subjects. A plot of all serum calcium against plasma PTH levels provides a clear distinction of the three groups.
Conclusions: All 13 daytime normocalcemic TM patients presented a certain degree of HPT. The hypoCa TM group displayed a concealed HPT detected in all, except the morning sampling, whereas normoCa TM patients experienced sub clinical HPT observed in the absence of nocturnal HPT variation. Nocturnal measurements of serum minerals thus enhance the sensitivity of HPT diagnosis.
Gila Maor, Zeev Hochberg and Michael Silbermann
Abstract. This study used an organ culture system of neonatal condylar cartilage to study the in vitro effects of recombinant human growth hormone on the growth of cartilage and its inherent cell populations: progenitor cells, chondroblasts and early hypertrophic chondrocytes. Growth hormone at a dose of 2.5 nmol/l enhanced the overall growth of cartilage explant and stimulated the differentiation of its cells. Hence, growth hormonetreated explants revealed a substantial increase in the number of chondroblasts and young hypertrophic chondrocytes. Along with its effects upon cartilage the hormone also stimulated new bone formation adjacent to mineralized hypertrophic chondrocytes. These results provide support to the notion that growth hormone stimulates cartilage growth which in turn is followed by endochondral ossification. In spite of its in vitro effect it is not as yet clear whether the effect of growth hormone is indeed a direct one or is mediated via the local production of IGF-I.
Gila Maor, Zeev Hochberg and Michael Silbermann
The present study examined the effect of exogenous IGF-I on growth and development of neonatal cartilage of the mandible condyle. Condylar cartilage was cultured as organ culture. The explants were cultured on top of collagen sponges in medium containing 2% fetal calf serum and were treated with IGF-I at doses ranging from 3.25 to 26 nmol/l for up to six days. IGF-I was found to increase significantly the uptake of [3H]-thymidine and [35S]-sulfatein a dose-related manner. The enhanced cellular proliferation, along with the increased synthesis of proteoglycans, resulted in a substantially larger mass of tissue in the organ culture system. The nature of the IGF-I stimulative effect was further studied through the use of a tissue culture system whereby a separated chondroprogenitor zone is cultured under conditions which favor its development at first into cartilage and then into bone. Using this culture system, we could show that IGF-I induces merely the de novo chondrogenesis process. This was reflected in the appearance of relatively large amounts of cartilage specific antigens such as type II collagen, cartilage proteoglycans, chondrocalcin and 100 KDa protein. Yet, no bone specific antigens were significantly increased, as is the case with GH effects. These results indicate that IGF-I is a strong chondrogenetic agent. But, unlike growth hormone, it does not seem to stimulate bone formation.
Zeev Hochberg, Ronnie J. Barkey, Lea Even, Israela Peleg, Moussa B. H. Youdim and Tamar Amit
Previous studies have described the close similarity of the GH binding protein to the liver membrane GH receptor. Since GH regulates its own liver receptors, we examined the effects of short- and long-term hGH therapy on GH binding protein in children with GH deficiency. Six GH-deficient children received their first hGH dose ever, and the pharmacodynamics of serum GH was followed for 12 h, along with measurements of GH binding protein activity. Over the first 6 h, serum GH and GH binding protein activity exhibited a parallel increase, followed by gradual decrease. At 8 h, some of the patients exhibited an apparent second peak in GH binding protein, despite the continuous decrease in serum hGH. During the period of hGH treatment, serum GH binding protein increased progressively over a period of 6 months. In a second uncontrolled group of 7 GH-deficient patients who had been treated with hGH for 30-36 months, GH binding protein activity was also significantly higher than pretreatment values. We suggest that the short-term pharmacodynamic changes probably represent the endogenous turnover of the GH receptor, whereas the elevated GH binding protein activity on hGH treatment may reflect up-regulation of the GH receptor.
Zeev Hochberg, Tamar Amit, Moussa B. H. Youdim and Jehuda A Bar-Maor
The effect of unilateral cryptorchidism on prolactin binding to the testes was studied in the rat. Cryptorchidism was rendered surgically for 3 weeks and 3, 6 and 9 weeks later prolactin binding was measured in testicular homogenates. Prolactin binding to the cryptorchid testes decreased significantly at 3 weeks with a further decrease at 6 and 9 weeks. Binding by the contralateral testes decreased at 3 weeks and increased at 6 and 9 weeks. To examine the possible mechanism of these changes one group of rats was treated for 5 weeks with testosterone and another with hCG. Testosterone treatment resulted in a significant fall in prolactin binding to normal, cryptorchid and contralateral testes. hCG also produced a slight but significant reduction in prolactin binding. To study the effect of surgical relocation of the testes into the scrotum, orchiopexy was performed in another group of rats. Orchiopexy increased prolactin binding only if performed 3 weeks after cryptorchidism. At 6 and 9 weeks after cryptorchidism orchiopexy did not increase prolactin binding. Treatment of cryptorchid rats with prolactin for 5 weeks induced an increase in prolactin binding to control, cryptorchid and contralateral testes. It is concluded that testicular atrophy follows upon placement of a testis within the peritoneal cavity. This atrophy lowers the total amount of prolactin binding and increases binding to the contralateral testes. Intratesticular concentration of testosterone may play a major role in the decrease of prolactin binding. Orchiopexy improves prolactin binding only if performed before 6 weeks of age. Administration of prolactin augments prolactin binding to the testes, irrespective of their location.
Eytan R. Barnea, Rina Perlman, Hassan Fakih, Tova Bick, Shahar Kol and Zeev Hochberg
The effects of physiological concentrations of the native catecholamines norepinephrine and epinephrine upon term placental hormonal function were examined by measuring estradiol and progesterone secretion by organ and cell culture systems. Results show that, in explants, both catecholamines caused a significant increase in the secretion of both sex steroids, p < 0.05. Estradiol secretion was blocked by the alpha and beta adrenergic receptors antagonists, phenoxybenzamine and propranolol, respectively, p < 0.05. Norepinephrine but not epinephrine dependent progesterone secretion was blocked by propranolol. In cells, epinephrine stimulated cyclic AMP generation and caused a 30% increase in estradiol secretion, p < 0.05. Both were abrogated by propranolol. Norepinephrine increased secretion by 25%, p < 0.05. This was inhibited by yohimbin and prazosin, alpha-1 and -2 receptors antagonists, respectively. In conclusion, the placenta in vitro is a target organ for catecholamines. The marked response of the explant system as compared with the marginal response of the cell culture system indicates that cell to cell contact/communication is required for full expression of catecholamine effect.
Dov Tiosano, Carlos Knopf, Ilana Koren, Nurit Levanon, Michaela F Hartmann, Ze'ev Hochberg and Stefan A Wudy
The CYP17A1 gene encodes many enzymatic reactions including 17α-hydroxylase and 17,20-lyase activities. Mutations that selectively ablate the 17,20-lyase activity, causing isolated 17,20-lyase deficiency, are exceedingly rare and may belong to the rarest of all disorders of steroidogenesis. We have previously reported an E305G mutation in the active site of CYP17A1 that apparently causes isolated 17,20-lyase deficiency. Expression studies suggested intact 17α-hydroxylase activity which was at odds with subnormal tetracosactrin stimulated cortisol in the patients.
To investigate the in vivo activity of the adrenal enzymes, we used the metabolomics approach with urinary steroid profiling by gas chromatography–mass spectrometry.
Of the 11 subjects investigated, 6 patients in the kindred were found to be homozygous, 4 members were asymptomatic heterozygous, and 1 was homozygous for the wild-type allele.
In the homozygous patients for E305G, both serum and urinary steroids showed a severe lack of androgens (C19-steroids) pointing to the absence of 17,20-lyase activities. Furthermore, precursor/product ratios of urinary steroid metabolites characterizing 17α-hydroxylase activity showed variable decreases in 17α-hydroxylase activities.
The results confirm the complete absence of 17,20-lyase activity in vivo, as in the in vitro expression studies. On the other hand, in vivo 17α-hydroxylase activity was partially impaired. Thus, the in vivo metabolic data seem to be more sensitive than the expression study and suggests that this mutation also impairs 17α-hydroxylase activity.