Secretory Burst Half-duration Research Articles

Estimation of frequently sampled nocturnal melatonin production in humans by deconvolution analysis: evidence for episodic or ultradian secretion.

In order to investigate nocturnal melatonin production and clearance rates, we applied deconvolution analysis to plasma melatonin concentration time series obtained every 20 min for 12 hr from 20:00 h to 08:00 h in two groups of healthy subjects at rest (group 1, 12 male subjects, 22-26 yr; group 2, ten female subjects, 31-42 yr). The estimated melatonin production rate from group 1 (0.55 +/- 0.21 microg/kg/night) was significantly higher than that of group 2 (0.26 +/- 0.19 microg/kg/night), as well as the mass of melatonin released per burst (275 +/- 110 vs. 145 +/- 130 pg/mL for groups 1 and 2, respectively), the amplitude of secretory bursts (7.8 +/- 3.2 vs. 4.7 +/- 3.5 pg/mL/min), and the pulsatile melatonin production rate (2.76 +/- 1.14 vs. 1.27 +/- 0.97 ng/mL/night). These differences could reflect alterations related to age and or gender. No differences were observed between the two groups in the secretory burst half-duration and frequency and the interburst interval. Melatonin production rates, as estimated by deconvolution analysis, are in agreement with other independent estimates, especially the isotopic method, and disclose an ultradian rhythmicity.

Increased disorderliness and decreased mass and daily rate of endogenous growth hormone secretion in adult turner syndrome: the impact of body composition, maximal oxygen uptake and treatment with sex hormones

The objectives of this study were to (1) quantify pulsatility and orderliness of 24-h growth hormone (GH) secretion in adult Turner syndrome; (2) study the impact of sex steroid replacement therapy in adult Turner syndrome on these measures of GH secretion, and in addition examine the differential effect of oral vs transdermal estrogen administration on GH secretion patterns. To these ends, we used deconvolution analysis and approximate entropy (ApEn) to quantify GH release over 24 h in 21 patients with Turner syndrome before and during sex hormone substitution, compared to an age-matched control group. Deconvolution analysis revealed that the mass of GH secreted per burst and production rate was significantly lower in Turner patients compared to controls, resulting in a significantly lower integrated 24-h GH concentration. However, multiple stepwise regression revealed that lean body mass (LBM) and maximal oxygen uptake were significant discriminative variable, explaining a large part of the variation in mass secreted per burst (r = 0.72, P < 0.0005) and production rate (r = 0.73, P < 0.0005), while group (Turner or control) did not explain any of the difference. There was a significant difference in ApEn between Turner patients and controls, denoting more disorderly GH release in Turner syndrome. During administration of sex hormones, a significant increase was seen in basal secretion and GH secretory burst half-duration, as well as in integrated 24-h GH concentration. No change in ApEn was evident. We conclude that GH secretion in adult Turner syndrome is irregular, reduced in mass and production rate. The reduction in mass and production rate could be explained by differences in body composition and maximal oxygen uptake compared to relevant controls, while the irregularity of GH secretion was unexplained by the measured variables. We hypothesize that the increased irregularity could be attributable to low levels of circulating androgens or an increased biological age in the Turner patients.

Primary gonadal failure in men selectively amplifies the mass of follicle stimulating hormone (FSH) secreted per burst and increases the disorderliness of FSH release patterns: reversibility with testosterone replacement

The neuroendocrine mechanisms by which primary gonadal failure in men increases mean serum FSH concentrations (castration-like response) are not known. To investigate the testosterone-dependent mechanisms of the FSH castration response: (i) blood was sampled at 10-min intervals for 24 h for later FSH assay in seven normal middle-aged men and in six patients with primary testicular failure, during testosterone withdrawal and after 6 weeks of parenteral testosterone replacement; (ii) using a specific two-site IRMA, serum FSH concentrations were measured, since this assay correlates well with an in-vitro Sertoli cell bioassay; (iii) multiparameter deconvolution analysis was then applied to estimate the frequency, amplitude, duration, and mass of underlying FSH secretory bursts, and the half-life of endogenous FSH, and (iv) approximate entropy was calculated to quantify the relative orderliness of FSH release over 24 h. Mean (+/- SEM) 24-h serum FSH concentrations were 3.9 +/- 0.8 IU/L in control subjects and 39 +/- 10 IU/L in unreplaced hypogonadal patients (p = 0.034). Deconvolution analysis revealed similar estimated mean FSH half-lives of 346 +/- 40 min (control) and 321 +/- 47 min (untreated patients), and indistinguishable FSH secretory burst frequencies, namely, 20 +/- 0.95 (normal) and 21 +/- 1.3 (patients) pulses per 24 h. In contrast, the daily production rate of FSH was markedly increased in testosterone-withdrawn hypogonadal men at 117 +/- 25 vs. 9.3 +/- 1.8 IU/L/day (control) (p < 0.01). This was due to a 10-fold higher calculated maximal rate (amplitude) of FSH secretion achieved within each FSH release episode (normal 0.078 +/- 0.02 vs. gonadal failure 0.74 +/- 0.087 IU/L/min, p < 0.01), yielding a 10-fold increase in the mass of FSH secreted per burst (control 0.53 +/- 0.06 vs. patients 5.3 +/- 0.81 IU/L, p < 0.01). In contrast, the mean half-duration of FSH secretory bursts was unaltered in unreplaced hypogonadal men at 8.2 +/- 2.2 min (control) vs. 7.0 +/- 1.0 min (patients). Approximate entropy (ApEn), a scale- and model-independent statistic designed to quantify the orderliness or regularity of hormone release, revealed greater irregularity of serum FSH concentrations in the hypoandrogenic state: ApEn = 1.8 +/- 0.025 (testosterone-withdrawn) vs. 1.6 +/- 0.037 (control) (p < 0.05). Parenteral testosterone replacement for 6 weeks significantly decreased mean serum FSH concentrations by reducing the daily FSH secretion rate and FSH secretory burst amplitude and mass, and concomitantly restored the orderliness of FSH release patterns. Testosterone treatment did not change FSH secretory burst half-duration, number, interburst interval, or half-life. It is concluded that primary gonadal failure in men evokes FSH hypersecretion which is marked by more disorderly FSH release patterns and a selectively amplified mass of FSH secreted per burst. These hypergonadotrophic mechanisms are, to a significant extent, testosterone-suppressible.

Estrogen receptor blockade with tamoxifen diminishes growth hormone secretion in boys: evidence for a stimulatory role of endogenous estrogens during male adolescence.

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.

QUANTITATION OF CORTISOL (F) PRODUCTION AND ELIMINATION RATES IN PREMATURE AND TERM NEONATES: EVIDENCE FOR PULSATILE SECRETION

Pulsatile secretion of cortisol has not been documented in the newborn infant. Using repeated blood sampling and deconvolution analysis, we investigated F secretory and elimination dynamics in a clinically stable group of 5 premature [gestational age (GA) 24-34 wk] and 5 term neonates. Blood samples were obtained through umbilical arterial cannulae at 15-min intervals for a 6-h period. All plasma F determinations were >55 nmol/L (2.0 μg/dL), and pulsatile F secretion was observed in all infants. On average, 4 ± 1 discrete F secretory episodes were detected during the study. No significant differences were noted between the 2 groups of subjects with regard to 6-h mean plasma F, plasma corticosteroid-binding globulin, F secretory burst frequency, mass of F secreted per burst, F production rate (FPR) or plasma F half-life. However, the premature infants had a significantly longer F secretory burst half-duration (p = 0.007) and a lower maximal F secretory rate (p = 0.018) than the term infants. The 2 most premature infants had significantly greater mean plasma F and FPR than the other 3 premature and all the term infants. Extrapolating to 24 h and correcting for distribution volume of F and for body surface area, we estimate FPR to be approximately 17-24 nmol/m2/24 h (6.6-8.8 mg/m2/24 h) for neonates of ≥34-wk GA. These values are consistent with estimates of FPR in older children and adults determined using either deconvolution analysis or stable isotope-dilution methods.

Altered growth hormone secretory dynamics in prepubertal males with constitutional delay of growth.

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)

Attenuation of luteinizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men.

To evaluate the impact of healthy aging on specific features of endogeneous LH secretion and clearance, we applied deconvolution analysis to 24-h serum immunoradiometric LH concentration series obtained in normal men whose ages ranged from 21-73 yr. Deconvolution analysis was employed to quantitate the number, amplitude, duration, and mass of individual LH secretory bursts underlying the serum LH concentration profiles, and simultaneously estimate the half-life of LH in individual men. Plasma total and free testosterone and estradiol concentrations and body mass index (a measure of relative adiposity) were studied as possible significant covariates of age and LH secretion. We found that age was a negative determinant of LH secretory burst amplitude (r = -0.519, P = 0.013), and a positive predictor of LH secretory burst frequency (r = +0.435, P = 0.043) and basal LH secretory rates (r = +0.486, P = 0.029). Increasing age also correlated positively with LH secretory burst half-duration (duration of the secretory event at half-maximal amplitude, r = +0.656, P less than 0.001). In contrast, age did not relate to daily pulsatile LH production rate, the mass of LH secreted per burst, or the mean (24-h) serum concentration of immunoradiometric LH. Age correlated negatively with serum free testosterone (r = -0.622, P = 0.0034) but not estradiol concentrations. The serum free testosterone concentration also declined significantly with increasing body mass index (r = -0.519, P = 0.023). Although there were strong combined effects of age, body mass index, and LH secretory burst amplitude on serum free testosterone concentrations (P = 0.0006, multi-r value 0.820), LH secretory burst amplitude was the most prominent single determinant of blood androgen concentrations.

Age and Relative Adiposity Are Specific Negative Determinants of the Frequency and Amplitude of Growth Hormone (GH) Secretory Bursts and the Half-Life of Endogenous GH in Healthy Men*

Mean plasma GH concentrations are controlled by the frequency, amplitude, and duration of underlying GH secretory bursts as well as by the half-life of endogenous GH. We investigated the specific mechanisms that subserve the clinically recognized negative effects of age and adiposity on mean serum GH concentrations. To this end, 21 healthy men, aged 21-71 yr, who were of nearly normal body weight underwent blood sampling at 10-min intervals for 24 h. Deconvolution analysis was used to estimate specific features of GH secretion and clearance. Compared to younger men, the older tertile of men had significant reductions in 1) GH secretory burst frequency, 2) the half-life of endogenous GH, and 3) the daily GH secretory rate, but not 4) GH secretory burst half-duration, amplitude, or mass. Linear regression analysis disclosed that age was a major negative statistical determinant of GH secretory burst frequency (r = -0.80; P = 0.005) and endogenous GH half-life (r = -0.70; P = 0.024). Body mass index, an indicator of relative obesity, was a significant negative correlate of GH half-life (P = 0.045) and GH secretory burst amplitude (P = 0.031). Age and body mass index each correlated negatively with the daily GH secretion rate (P = 0.0031 and P = 0.027, respectively), and together accounted for more than 60% of the variability in 24-h GH production rates (r = -0.78; P = 0.00056). On the average, for a normal body mass index, each decade of increasing age attenuated the GH production rate by 14% and the GH half-life by 6%. Conversely, each unit increase in body mass index, at a given age, reduced the daily GH secretion rate by 6%. We conclude that age and relative adiposity are distinct and specific correlates of individual attributes of GH secretion and clearance in men.

Decreased Metabolic Clearance of Endogenous Growth Hormone and Specific Alterations in the Pulsatile Mode of Growth Hormone Secretion Occur in Prepubertal Girls with Turner's Syndrome*

We have used deconvolution analysis to test the hypothesis that specific facets of GH secretion and clearance differ in young patients with Turner's syndrome and normal prepubertal girls. To this end, we sampled blood at 20-min intervals for 12 h overnight in 50 girls, 37 of whom had Turner's syndrome and 13 of whom were healthy Tanner stage I controls. Deconvolution analysis revealed that the half-life of endogenous GH in Turner's syndrome was significantly prolonged at 14 +/- 0.93 vs. 11 +/- 0.44 min in normal girls (P = 0.029). The number of significant GH secretory bursts was reduced in Turner's patients to 4.7 +/- 0.27 vs. 6.8 +/- 0.60 events/12 h in healthy girls (P less than 0.01). GH secretory burst half-duration was significantly prolonged in Turner's syndrome, viz. 23 +/- 1.3 vs. 15 +/- 0.87 min (controls; P less than 0.001). The changes in GH secretory burst frequency, duration, and half-life were specific, since neither the mass of GH secreted per burst nor the maximal rate of GH secretion attained per burst (amplitude of the secretion pulse) was significantly different in the 2 study groups. Thus, although 12-h GH secretion rates corrected for body weight were similar (3.9 +/- 0.76 in Turner's patients and 3.3 +/- 0.76 micrograms/L.kg/12 h in the control girls), equivalent GH production rates were achieved by different mechanisms in the 2 groups. We conclude that specific alterations in GH secretory burst frequency and duration and endogenous GH half-life can be documented in young girls with Turner's syndrome.