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This article reviews the attributes of the human surrogates most commonly used in injury biomechanics research. In particular, the merits of human cadavers, human volunteers, animals, dummies, and computational models are assessed relative to their ability to characterize the living human response and injury in an impact environment. Although data obtained from these surrogates have enabled biomechanical engineers and designers to develop effective injury countermeasures for occupants and pedestrians involved in crashes, the magnitude of the traffic safety problem necessitates expanded efforts in research and development. This article makes the case that while there are limitations and challenges associated with any particular surrogate, each provides a critical and necessary component in the continued quest to reduce crash-related injuries and fatalities.

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The nonlinear viscoelastic structural response of the major human knee ligaments when subjected to complex loading histories is investigated, with emphasis on the collateral ligaments. Bone-ligament-bone specimens are tested in knee distraction loading, where the ligaments are in the anatomical position corresponding to a fully extended knee. Temporal nonlinearities for time scales in the range of 1

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OBJECTIVE: Accidents involving pedestrians are very common, and often lead to severe injuries to the lower extremities. In a large portion of pedestrian-automobile collisions, knee ligament injuries are sustained. In this study, the viscoelastic properties of the four major human knee ligaments were investigated at loading rates representative for pedestrian-automobile collisions. METHODS: Bone-ligament-bone specimens were tested in knee distraction loading. The collateral ligaments and the separate functional bundles of the cruciate ligaments were tested in the anatomical position corresponding to a fully extended knee. A series of step-and-hold tests and ramp tests at different rates were conducted to characterize the time-dependent behavior of the knee ligaments for deformation rates associated with the pedestrian impact loading environment. The quasi linear viscoelastic (QLV) theory was used to describe the structural response of the knee ligaments and averaged parameters for this model were determined. RESULTS: The QLV theory was found to be applicable for the time range that is relevant for pedestrian-automobile collisions. The structural behavior of the knee ligaments was found to be particularly rate-sensitive for high elongation rates, as occur during these collisions. The ligament stiffness was found to increase with age for both the collateral ligaments and with weight for the medial collateral ligament. CONCLUSIONS: For the loading conditions that are relevant for pedestrian-automobile collisions, the use of the QLV model for the description of the mechanical behavior of knee ligaments is appropriate. The rate-sensitivity is particularly important for these extreme loading conditions. The relaxation behavior was found to be consistent between different ligament types and samples. Variations due to donor anthropometry were found predominantly for the instantaneous elastic behavior.

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The objective of this study was to provide data on the structural tolerance and material properties of the human femur in dynamic bending. Fifteen (15) isolated femurs from eight (8) males were tested in either posterior-to-anterior or lateral-to-medial three-point bending. The failure moment was 458 +/- 95 Nm and did not differ significantly with loading direction. A method was developed to estimate the elastic-plastic material properties of the bone using both force-deflection data and strain gauge measurements. The bone material appeared to yield at about one third of the ultimate strain level prior to fracture. It is hoped that these data will aid in the development of injury criteria and finite element models for predicting injuries to pedestrians and vehicle occupants.

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Activation of the gonadotropic and somatotropic axes in puberty is marked by striking amplification of pulsatile neurohormone secretion. In addition, each axis, as a whole, constitutes a regulated network whose feedback relationships are likely to manifest important changes at the time of puberty. Here, we use the regularity statistic, approximate entropy (ApEn), to assess feedback activity within the somatotropic (hypothalamo-pituitary/GH-insulin-like growth factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girls or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various stages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profiles is maximal in pre- and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P = 0.0008 by ANOVA). This indicates that marked disorderliness of the GH release process occurs in mid-late puberty at or near the time of peak growth velocity, with a return to maximal orderliness thereafter at reproductive maturity. Second, oral administration of ethinyl estradiol for 5 weeks to 7 prepubertal girls with Turner's syndrome also augmented ApEn significantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitutionally delayed puberty, im testosterone administration also significantly increased ApEn of 24-h GH time series (P = 0.0045). In counterpoint, 5 alpha-dihydrotestosterone, a nonaromatizable androgen, failed to produce a significant ApEn increase (P > 0.43). We conclude from these three distinct experimental contexts that aromatization of testosterone to estrogen in boys, or estrogen itself in girls, is likely the proximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathematical models that mechanistically link increased disorderliness (higher ApEn) to network changes, we suggest that sex-steroid hormones in normal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.

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Chronic stress leads to suppression of the hypothalamic-pituitary-gonadal (HPG) axis with decreased plasma LH concentrations. This is believed to be due to the influence of elevated levels of endogenous CRH mediated via the endogenous opiate peptide receptor. Efforts to reproduce this phenomenon with exogenous CRH have produced varied results depending on the dose and route of administration of CRH as well as on the species, gonadal state, and endogenous opiate peptide system tone of the experimental subjects. In humans, conflicting results for CRH-induced suppression of the HPG axis exist for women, and the issue has not been addressed sufficiently in men. We, therefore, studied the effects of a 4-h infusion of ovine CRH (oCRH) on LH secretion in 11 healthy, nonobese young adult men (age range, 20-33 yr). Subjects were admitted to the General Clinical Research Center on 4 occasions in randomized order. They underwent blood sampling for LH at 10-min intervals from 1800-0600 h. From 2200-0200 h, subjects received one of the following iv infusion protocols in blinded fashion: a normal saline (NS) bolus and NS infusion, a naloxone (NAL) bolus (4 mg) and NAL infusion (2 mg/h), a NS bolus and oCRH infusion (1 microgram/kg.h; maximum, 75 micrograms/h), and a NAL bolus and both NAL and oCRH infusions, using the above-mentioned doses. For each time point, serum LH values from the four experimental conditions were compared by one-way ANOVA with repeated measures; the paired t test was applied post-hoc. This experimental model is predicted to have a beta-error of less than 0.10 for identifying a 1.0 U/L change in LH levels. As expected, NAL was associated with a transient, but significant, rise in serum LH concentrations compared to those in the NS control. On the other hand, oCRH administration did not result in any significant alteration in either basal or NAL-stimulated LH levels. We conclude that exogenous oCRH administration does not significantly alter pituitary secretion of LH in healthy men. We speculate that any suppressive effect of CRH on the HPG axis occurs at the level of the hypothalamus.

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Gonadotropin subunit mRNA expression is differentially regulated during the 4-day estrous cycle in rats, with LH-beta and FSH-beta mRNA expression rapidly increasing on proestrus. Studies in an ovariectomized (OVX) GnRH-deficient female rat model have shown that GnRH pulses can increase alpha and FSH-beta mRNA concentrations, but LH-beta mRNA is unchanged. Thus, the factors required for physiologic regulation of the LH-beta gene are not fully understood. To determine whether or not the proestrous ovarian hormone environment is required to allow increased expression of the LH-beta gene, GnRH pulses were administered to GnRH-deficient (phenoxybenzamine-treated) intact female rats on proestrus. Both LH and FSH secretion and alpha and FSH-beta mRNA concentrations were increased, but LH-beta mRNA expression was unaltered. The effect of co-administration of GnRH and specific neurohormones (GnRH-associated peptide [GAP], galanin, neuropeptide-Y [NPY], and thyrotropin-releasing hormone [TRH] was also examined in OVX rats receiving estradiol (E2) and progesterone (P) replacement. Alpha and FSH-beta mRNA concentrations increased 2-fold in response to pulsatile GnRH, and no further increase was seen after the addition of GAP, galanin, or TRH. It was of interest that NPY blocked the GnRH-induced rise in alpha and FSH-beta mRNA. LH-beta mRNA expression was not increased by GnRH pulses alone or by addition of any of the neuropeptides. Further studies determined that continuous GnRH was no more effective than pulsatile GnRH in stimulating a rise in LH-beta mRNA. The results indicate that GnRH pulses are not sufficient to enhance LH-beta mRNA expression in the GnRH-deficient female rat.(ABSTRACT TRUNCATED AT 250 WORDS)

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GnRH acts via a single cell surface receptor (GnRH-R), and the number of pituitary GnRH-R increases on proestrus, after gonadectomy, or in response to pulsatile GnRH in the rat. Estradiol (E2) is known to exert a transient positive action to increase GnRH-R number, and the rise in plasma E2 contributes to initiation of the midcycle LH surge. The present study was designed to determine the effect of GnRH pulse amplitude and frequency on GnRH-R messenger RNA (mRNA) levels and to assess the relative contributions of GnRH and gonadal steroids to increasing GnRH-R gene expression. These studies were conducted in vivo using previously characterized GnRH-deficient male (castrate testosterone-replaced) and ovariectomized phenoxybenzamine-treated female models. To investigate the effect of GnRH pulse amplitude, adult male and female rats received GnRH iv (5-250 ng/pulse at 30-min intervals; saline pulses to controls) for 12 or 24 h. In males, GnRH-R mRNA was increased by all pulse doses, with maximal effects (3-fold) at 5-25 ng/pulse. In contrast, only lower doses (5-10 ng/pulse) were effective in females (2-fold increase). In a subsequent study, GnRH pulses (25 ng for males; 10 ng for females) were given at 8-, 30-, or 240-min intervals for 12 or 24 h. Some animals received a continuous GnRH infusion (200 ng/h). In males, GnRH-R mRNA levels were stimulated by all GnRH pulse intervals (maximal after 30-min pulses), whereas continuous GnRH was ineffective. In females, only 30- and 240-min pulse intervals increased GnRH-R mRNA levels, with faster (8-min) pulses or continuous GnRH being ineffective. To determine the relative roles of ovarian steroids and GnRH, ovariectomized phenoxybenzamine-treated female animals received GnRH (10 ng/pulse, 30-min interval), E2 (via sc implants; plasma E2 levels, approximately 50 pg/ml), or their combination for 12-24 h (saline pulses to controls). In the absence of E2, GnRH-R concentrations fell by 70% between 12-24 h. E2 alone tended to increase GnRH-R mRNA at 12 h, with a 2-fold rise observed after 24 h. Pulsatile GnRH alone increased GnRH-R mRNA by 50% at 12 h (compared to saline-pulsed controls; P < 0.05) and by 6-fold after 24 h. When GnRH and E2 were combined, the magnitude of the increase (vs. saline controls) was greater than that seen for either GnRH or E2 alone.(ABSTRACT TRUNCATED AT 400 WORDS)

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The adolescent growth spurt is associated with a sex steroid hormone-dependent rise in GH production; both androgens and estrogens are implicated as positive regulators of the somatotropic axis during puberty. The issue is complicated by the fact that testosterone may act both directly via the androgen receptor and indirectly, after its aromatization to 17beta-estradiol, through the estrogen receptor. Recently, a number of investigators have studied the effects of the administration of androgen and estrogen receptor antagonists, as well as nonaromatizable androgens, on GH secretion. These reports suggest that estrogen receptor-dependent processes play a facilitatory role in the pubertyassociated rise in GH secretion. If androgen receptor-mediated events are involved in the control of the somatotropic axis, their role is likely inhibitory. A hypothalamic site of action of the sex steroids is postulated.

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The increase in GH production during the male adolescent growth spurt has been attributed to both androgen and estrogen receptor-mediated processes. To evaluate the role of endogenous estrogens in the control of GH secretion, we administered the estrogen receptor antagonist tamoxifen to 10 late pubertal males. Blood samples were obtained for GH determination at 10-min intervals on 2 occasions during the last 24 h of a 4-day course of either tamoxifen or placebo. Waveform-specific, multiple parameter deconvolution analysis was employed to assess GH secretory and elimination dynamics. Estrogen receptor blockade resulted in a significant (P < 0.05) diminution in mean 24-h serum GH concentrations, from 3.9 +/- 1.0 (placebo; mean +/- SEM) to 2.7 +/- 0.6 micrograms/L (tamoxifen). This was associated with a significant (P < 0.01) decline in the GH production rate [237 +/- 55 vs. 155 +/- 33 micrograms/L GH distribution volume (Lv).24 h]. Furthermore, this reduction in GH secretion was the result of significant decreases in both the maximal GH secretory rate (0.46 +/- 0.08 vs. 0.34 +/- 0.06 microgram/Lv.min; P < 0.01) and, to a smaller degree, GH secretory burst number (16 +/- 1 vs. 14 +/- 1/24 h; P < 0.05). There was also a trend toward reduced mass of GH secreted per burst (13.3 +/- 2.5 vs. 10.3 +/- 2.0 micrograms/Lv; P = 0.06). No significant alterations in either GH elimination t1/2 or GH secretory burst half-duration were observed during estrogen receptor antagonism. Tamoxifen treatment was associated with a significant (P < 0.05) decrease in plasma insulin-like growth factor-I concentrations. However, total and free testosterone, 17 beta-estradiol, insulin-like growth factor-binding protein-3, and pooled 24-h LH concentrations were not significantly changed by short term blockade of estrogen action. We postulate that endogenous estrogens play a facilitatory role in neuroendocrine control of the somatotropic axis during puberty in boys. Tamoxifen blocks this estrogen-dependent stimulation of GH secretion without altering the hormone elimination t1/2. Furthermore, we speculate that any stimulatory role of androgens on GH secretion is exerted primarily through the estrogen receptor after aromatization.

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To determine potential mechanisms by which androgens alter gonadotropin secretion and elimination in the pubertal male, we administered the potent nonsteroidal androgen receptor blocking agent, flutamide, to eight males with Tanner IV or V genital development. Venous blood samples were obtained every 10 min for 24 h and assayed for LH by a sensitive and high-precision fluorimmunoassay. Subjects were studied before and after the administration of flutamide. Deconvolution analysis was used to assess specific pulsatile LH secretory characteristics and estimate LH production and metabolic clearance rates quantitatively. After antagonism of endogenous androgen action, mean 24-h serum LH concentrations increased significantly. An increased mean 24-h LH production rate, without evident changes in serum LH half-life, accounted for the increase in average serum LH levels. The increased daily secretion rate of LH was in turn due to both an augmented mass of LH released per secretory episode and increased frequency of secretory events. There was no demonstrable change in the maximal rate of LH secretion attained within each secretory event. Serum concentrations of total testosterone, free-testosterone, and 17 beta-estradiol all increased during blockade of androgen action. Administration of the antiandrogen had no measurable effect on the pituitary response to a single maximally effective dose of exogenous gonadotropin releasing hormone (GnRH). These results indicate that, in the late pubertal male, endogenous androgen exerts negative feedback control of gonadotropin secretion primarily at a hypothalamic site reflected by regulation of the frequency of pulsatile LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

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Diminished concentrations of growth hormone (GH) have been observed in the male BB/Wor rat with diabetes mellitus (DM). The precise mechanism(s) responsible for the altered GH levels is not entirely understood. We have therefore employed independent techniques to investigate potential alterations in: 1) the peripheral metabolism of the hormone; 2) GH release by somatotropes; and 3) hypothalamic regulation of GH secretion. An extra group of insulin-untreated animals was included for the studies of acute DM. The results demonstrate diminished circulating mean concentrations of GH (35 +/- 4 vs. 16 +/- 4 micrograms/l; mean +/- SEM; control vs. animal with DM; P = 0.006) due to impaired GH secretion. In particular, there was a decrease in the mass of GH secreted per burst (230 +/- 22 vs. 136 +/- 34 micrograms/l; P = 0.04) and in the GH secretory rate (24 +/- 4 vs. 9 +/- 3 micrograms/l/min; P < 0.01). No differences in the secretory burst frequency, (5.3 +/- 0.3 vs. 5.2 +/- 0.5 #/8-h; P = 0.68), secretory half-duration (10 +/- 2 vs. 17 +/- 2 min; P = 0.09), or serum GH half-life (8 +/- 1 vs. 6 +/- 1 min; P = 0.13) were observed. In vitro studies of acutely dispersed somatotropes obtained from rats with DM demonstrated increased sensitivity to GHRH (1 nM), as detected by a greater mean hemolytic plaque area following exposure to an EC50 dose of the secretagogue (14.3 +/- 3.3 vs. 17.4 +/- 3.5 microns 2 x 10(3); P = 0.049), and diminished sensitivity to SRIH (1 nM) inhibition of GH release following exposure to an EC50 dose of the secretagogue (10.0 +/- 1.2 vs. 14.9 +/- 2.3 microns2 x 10(3); P = 0.026). The number of the pituitary cells (18.0 +/- 2.8 vs. 15.3 +/- 1.0 x 10(5) cells; P = 0.38) as well as the number of somatotropes (7.3 +/- 1.4 vs. 7.6 +/- 0.9 x 10(5) cells; P = 0.87) were indistinguishable between experimental groups. Hypothalamic gene transcript levels for GH-releasing hormone (GHRH) and somatotropin release-inhibiting hormone (SRIH) were evaluated by in situ hybridization histochemistry to assess cellular synthetic activity.(ABSTRACT TRUNCATED AT 400 WORDS)

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Gonadotropin subunit gene transcription and messenger RNA (mRNA) levels are differentially regulated by GnRH pulse frequency and amplitude in the male rat. The rapid changes of subunit mRNA levels and LH and FSH secretion during the estrous cycle, particularly the rapid rise in LH-beta subunit mRNA on proestrus afternoon, suggest that physiological changes in the pattern of GnRH action may also be important in female rats. However, in the absence of a GnRH-deficient female model the role of varying GnRH stimulation remains to be determined. We have characterized a GnRH-deficient model by administering the alpha-adrenergic antagonist phenoxybenzamine (PBZ) to ovariectomized (OVX) rats. Initial experiments showed that PBZ given 24 h earlier abolished the afternoon LH surge in OVX estradiol (E2) replaced rats whereas LH responses to exogenous GnRH were preserved. A PBZ regimen of 15 mg/kg ip at OVX followed by 10 mg/kg at 24 h and 5 mg/kg at 48 h prevented the increase in alpha, LH-beta, and FSH-beta mRNAs and LH and FSH secretion for 72 h post-OVX. LH and FSH responses to GnRH pulses were preserved suggesting that PBZ blocked the post-OVX increase in hypothalamic GnRH secretion. The suppressive effect of PBZ appeared to be specific to the hypothalamic-pituitary-ovarian axis as plasma PRL, TSH, and corticosterone were not decreased compared to controls. We have used this GnRH-deficient OVX female model to investigate the effects of exogenous GnRH pulses on subunit mRNA expression. GnRH pulses (5-250 ng/30 min for 12-24 h) were administered via an intraatrial catheter beginning 24 h after OVX and the first PBZ injection (OVX+PBZ+saline pulses to controls). Expression of alpha and FSH-beta mRNAs and LH and FSH secretion were increased by GnRH pulse doses of 5-25 ng to values similar to or greater than those in OVX controls though the higher doses of GnRH/pulse did not increase FSH-beta mRNA or plasma FSH. However, LH-beta mRNA levels were not increased by GnRH pulses. GnRH pulses were also given to rats replaced with proestrus concentrations of estradiol alone or in combination with progesterone (P). Again, no demonstrable increases in LH-beta mRNA expression were observed. alpha-mRNA concentrations were further increased in the presence of E2 alone, and P in combination with E2, produced an augmented response of FSH-beta subunit mRNA. These data suggest that ovarian steroid hormones act directly on the gonadotrope to augment alpha and FSH-beta mRNA responses to GnRH.(ABSTRACT TRUNCATED AT 400 WORDS)

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Pulsatile secretion of cortisol (F) has not been documented in the newborn infant. Using repeated blood sampling and deconvolution analysis, we investigated F secretion and elimination dynamics in a group of five premature (gestational age, 24-34 weeks) and five term neonates. These infants had required placement of an umbilical arterial cannula for monitoring respiratory status, but were otherwise clinically stable. Blood samples were obtained at 15-min intervals for a 6-h period. All plasma F determinations were 58 nmol/L (2.1 micrograms/dL) or more, and pulsatile F secretion was observed in all infants. No significant differences were noted between the two groups with regard to 6-h mean plasma F concentration [350 +/- 129 (premature) vs. 277 +/- 54 nmol/L (term)], plasma corticosteroid-binding globulin (14 +/- 0 vs. 13 +/- 1 mg/L), F secretory burst frequency (4 +/- 0 vs. 5 +/- 1 bursts/6 h), mass of F secreted per burst [760 +/- 480 vs. 310 +/- 100 nmol/Lv [Lv, liter of F distribution volume)], F production rate (FPR; 2.7 +/- 1.4 vs. 1.1 +/- 0.2 mumol/Lv.6 h), or plasma F half-life (45 +/- 6 vs. 56 +/- 4 min). However, the premature infants had a significantly longer F secretory burst half-duration (63 +/- 18 vs. 6.7 +/- 4.0 min; P < 0.01) and a significantly lower maximal F secretory rate (9.4 +/- 3.4 vs. 100 +/- 26 nmol/Lv.min; P < 0.02) than the term infants. Body surface area and body weight were inversely correlated with F secretory burst half-duration (r = -0.74 and -0.75, respectively); both were also positively correlated with the maximal F secretory rate (r = 0.66 and 0.72). The two most premature infants had significantly greater mean plasma F and FPR than the other three premature and all of the term infants. Extrapolating to 24 h and correcting for the distribution volume of F and body surface area, we estimate FPR to be approximately 17-24 mumol/m2.24 h (6.6-8.8 mg/m2.24 h) for newborn infants of 34 weeks or more gestational age. These values are consistent with newer estimates of FPR in older children and adults determined using either deconvolution analysis or stable isotope dilution methods.

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To investigate daily cortisol production and clearance rates in a group (n = 18) of normal unstressed pubertal males, we applied deconvolution analysis to serum cortisol concentrations obtained every 20 min for 24 h. Subject-specific characterization of adrenocortical secretory episodes, cortisol production rate, and serum hormone half-life for nine early pubertal (Tanner I or II; early) and nine late pubertal (Tanner IV or V; late) subjects was undertaken to assess potential roles of sexual maturation and changing gonadal steroid hormone concentrations on glucocorticoid physiology. The estimated cortisol production rate for the early group [16.8 +/- 1.3 mumol/m2 x day (6.1 +/- 0.4 mg/m2 x day)] was indistinguishable from that of the late subjects [14.8 +/- 1.4 mumol/m2 x day (5.3 +/- 0.5 mg/m2 x day)]. No differences were observed between the two pubertal groups in the secretory burst frequency and half-duration, mass of cortisol released per secretory episode, average maximal rate of hormone secretion, and serum cortisol half-life. A significant diurnal pattern of cortisol secretion was observed for all subjects manifest by nyctohemeral variations in the frequency of adrenocortical secretory bursts, the amplitude (maximal rate of cortisol secretion) and the mass of cortisol released per secretory episode. Maximum serum hormone concentrations occurred between 0706 and 1114 h. We conclude that in normal pubertal males: 1) cortisol production rates as estimated by deconvolution analysis are in agreement with other recent independent isotopic estimates, but are lower than many previous estimates; 2) the rise in serum gonadal steroid hormone levels is unassociated with alterations in the production rate or metabolic clearance of cortisol; and 3) increased secretory burst frequency, increased amplitude (maximal rate of cortisol secretion attained within each secretory event), and increased mass of cortisol released per adrenocortical secretory episode give rise to the normal diurnal rhythm of circulating cortisol.

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Chronic renal insufficiency (CRI) is associated with growth failure in children and laboratory rats and is considered to be due, in part, to co-existent malnutrition. Alterations in hypothalamic control of growth hormone (GH) secretion have been suggested in uremic patients. We sought to determine whether factors unique to CRI play a role in this disturbance of GH regulation. Using in situ hybridization histochemistry, we compared messenger RNA (mRNA) levels for the hypothalamic neurohormones GH-releasing hormone (GHRH) and somatostatin (SRIH) in three groups: rats with CRI induced by 5/6 nephrectomy (NPX, N = 4); sham-operated, ad libitum fed rats (SAL, N = 5); and sham-operated, pair-fed rats (SPF, N = 5). We also measured plasma GH at 10 minute intervals for a six hour period via intra-atrial cannulae. The NPX group had significantly lower hypothalamic GHRH mRNA concentrations than both other groups; in addition, these levels were significantly lower in the SPF than in the SAL group. Concentrations of hypothalamic SRIH mRNA did not differ significantly among the three experimental groups. Six-hour mean plasma GH concentrations were significantly lower in the SPF (18.3 +/- 1.8 micrograms/liter) than in either the SAL (27.0 +/- 3.3 micrograms/liter) or the NPX groups (36.8 +/- 7.2 micrograms/liter); the difference in the mean plasma GH levels in the NPX vs. the SAL group did not attain statistical significance. This study provides evidence for an effect of CRI on the neuroendocrine control of GH secretion not related to caloric intake.(ABSTRACT TRUNCATED AT 250 WORDS)

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Exogenous and endogenous sex steroid hormones influence GH secretion. To test the relative importance of androgens in the enhancement of GH secretion, we administered flutamide (a potent androgen receptor blocker) to six late pubertal males. Blood samples for GH (and LH) were obtained at 10-min intervals for 24-h periods after 3 days of flutamide and during the untreated state. Waveform-specific, multiple-parameter deconvolution analysis was employed to assess secretory and elimination dynamics for GH. Androgen receptor blockade was confirmed by significant increases in 24-h mean LH concentrations and in total 17 beta-estradiol and free testosterone levels in the serum. Mean serum GH concentrations (24-h) also increased (P < 0.001) during androgen receptor blockade (mean +/- SEM, 2.9 +/- 0.3 vs. 1.8 +/- 0.3 micrograms/L); this was associated with an increased (P < 0.001) GH production rate [152 +/- 15 vs. 93 +/- 16 micrograms/liter of distribution volume (Lv)/24 h]. The enhanced GH secretion during flutamide administration was a result of both increased mass of GH released per secretory burst (12.0 +/- 1.4 vs. 8.4 +/- 1.0 micrograms/Lv; P < 0.005) and increased maximal rate of GH secretion (0.39 +/- 0.04 vs. 0.30 +/- 0.03 micrograms/Lv/min; P < 0.05), as well as a small increase in the number of detectable secretory bursts (12 +/- 1 vs. 10 +/- 1/24 h; P < 0.05). There was no significant change in either the serum half-life of GH or in the half-duration of GH secretory bursts during androgen receptor blockade. We speculate that the augmentation of GH secretion observed during antagonism of androgen action in late pubertal males is a result of increased stimulation of estrogen receptor-mediated pathways. Alternatively, androgens may exert a tonic inhibition of GH secretion which can be abolished by androgen receptor blockade.

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We have used the technique of deconvolution analysis to determine if abnormalities in growth hormone (GH) secretion or metabolic clearance underlie the observed alterations in circulating hormone concentrations in a group of seven prepubertal males with constitutional delay of growth (SHORT-DBA). The results were compared with data obtained from 13 healthy, short prepubertal males (SHORT) and 11 healthy prepubertal male subjects of normal stature (NORMAL). Although the mean 12-h overnight GH production rates were invariant among the groups (8.0 +/- 1.0 versus 7.3 +/- 0.7 versus 6.7 +/- 1.2 micrograms/L, NORMAL versus SHORT versus SHORT-DBA for all comparisons), different secretory mechanisms were operative. The secretory burst half-duration (time interval of the secretory event at half-maximal amplitude) of the SHORT-DBA subjects (26 +/- 1 min) was greater (p = 0.02) than that of the SHORT group (20 +/- 1 min); values for both the SHORT and SHORT-DBA subjects were indistinguishable from that of NORMAL controls (22 +/- 2). Both the mass of GH released per secretory episode and the maximal rate of hormone secretion were less (p < or = 0.02 and the p < 0.01, respectively) for the SHORT-DBA subjects [16 +/- 2 micrograms/unit of body distribution volume (Lv) and 0.6 +/- 0.1 microgram/Lv/min, respectively] compared with those of the NORMAL (26 +/- 2 micrograms/L, and 1.1 +/- 0.1 micrograms/Lv/min, respectively) and SHORT (28 +/- 4 micrograms/Lv and 1.3 +/- 0.2 micrograms/Lv/min, respectively) groups; values for the latter two groups were indistinguishable.(ABSTRACT TRUNCATED AT 250 WORDS)

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To investigate possible mechanisms whereby the augmentation of hypothalamic proopiomelanocortin (POMC) messenger ribonucleic acid (mRNA) levels occurs with pubertal development, we employed the techniques of testosterone administration and in situ hybridization histochemistry in sexually immature male rats. Six animals from each of the following groups were studied: (1) untreated controls (CTRL); (2) empty capsule (SHAM); (3) testosterone capsule (TEST), and (4) untreated adults (ADLT). Capsules were implanted at 21 days of age. Groups 1-3 were sacrificed at 35 days of life; group 4 at 55 days. Ventral prostate and seminal vesicle weights were obtained to assess the biologic effect of testosterone. Hybridizations were performed on coronal brain slices through the region of the arcuate nucleus using a 35S-labeled oligonucleotide probe complementary to a 30-base sequence within POMC mRNA. Anatomically matched tissue sections (11 per animal, from the retrochiasmatic region rostrally to the premammillary nucleus caudally) were exposed to x-ray film, followed by densitometric analysis. The mean serum testosterone concentration of the TEST group was significantly greater than that of the ADLT animals; values for the CTRL and SHAM rats were undetectable. The accessory sex organ weights of the ADLT animals were greater than those of the TEST rats; both values were greater than those of the CTRL and SHAM groups which were indistinguishable. Increased levels of hypothalamic POMC mRNA were observed in the male rat after pubertal development.(ABSTRACT TRUNCATED AT 250 WORDS)

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