Biomedical subjects

G Lizarralde

Publications and source records attributed to G Lizarralde.

At least 19 recordsLinked to original sources

PubMed1993

Amplitude suppression of the pulsatile mode of immunoradiometric luteinizing hormone release in fasting-induced hypoandrogenemia in normal men.

In the male rodent and primate, fasting or severe caloric restriction significantly decreases serum testosterone concentrations, putatively via inducing secondary hypogonadotrophism. To clarify this presumptive pathophysiology, we have used: 1) a high sensitivity immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay of LH; 2) blood sampling every 5 min for 24 h basally and every 10 min for 3 h after GnRH injection before and after a 5-day (water only) fast in eight healthy young men; and 3) deconvolution analysis to evaluate in vivo LH secretory burst frequency, amplitude, duration, and mass, and LH half-life simultaneously. We documented a 50% fall in serum total and free testosterone concentrations, and a 30% decrease in 24-h mean serum LH concentrations (viz., fed 3.0 +/- 0.47 vs. fasted 2.1 +/- 0.39 U/L, P = 0.043). Deconvolution analysis revealed preservation of LH secretory pulse frequency (fed 12.9 +/- 0.48 vs. fasted 12.6 +/- 0.78 secretory bursts/day, P = NS) during fasting-induced hypogonadotropism. The duration of computer-resolved LH secretory bursts, the interburst interval, and the calculated endogenous half-life of LH also did not change, whereas LH secretory burst mass declined significantly; viz. from 28 +/- 5 in the fed to 14 +/- 3.2 U/L of distribution volume/day in the fasted state (P = 0.034). In contrast, LH release after a 10 micrograms pulse of GnRH iv was enhanced during fasting in seven of the eight men. Fasting also decreased mean (24 h) serum TSH and PRL, increased cortisol, dehydroepiandrosterone sulfate and GH, and did not affect FSH concentrations or the radioiodinated albumen distribution space. In summary, in young men 5 days of nutrient deprivation selectively attenuates the mass of LH secreted per burst without altering LH secretory event frequency or LH half-life. We infer that decreased LH release per burst is due to decreased hypothalamic GnRH impulse strength, since LH release induced by a submaximally effective pulse of exogenous GnRH is amplified rather than attenuated.

Adult↗

PubMed1993

Evidence for attenuation of hypothalamic gonadotropin-releasing hormone (GnRH) impulse strength with preservation of GnRH pulse frequency in men with chronic renal failure.

To investigate the nature of putative disturbances in pulsatile gonadotropin (LH) secretion in men with chronic renal failure, we undertook blood sampling at 10-min intervals for 24 h in 9 hemodialysis-dependent uremic men and 16 community- and age-matched controls. Serum LH concentrations were measured in a 2-site immunoradiometric assay, which does not cross-react with free alpha or LH beta-subunit and correlates well with an in vitro Leydig cell bioassay. Deconvolution analysis was applied to calculate the number, amplitude, mass, and duration of spontaneous LH release episodes and simultaneously estimate the half-life of endogenous LH in each subject. We observed that: 1) the estimated half-life of immunoradiometric LH removal from plasma averaged 103 +/- 11 min in normal and 207 +/- 29 min in uremic men (P < 0.01); 2) the number of LH secretory bursts was slightly higher in uremic than healthy men (e.g. 20 +/- 2.2 vs. 15 +/- 1.0 secretory bursts/24 h, respectively; P = 0.05); 3) the mass of LH secreted per burst was approximately 50% lower in chronic renal failure than in health, namely 1.4 +/- 0.18 vs. 2.8 +/- 0.42 IU/L (P < 0.01); 4) the decrease in the mass of LH secreted per burst was not due to a decline in LH secretory burst amplitude, but rather an attenuation of LH secretory burst duration (4.8 +/- 0.35 min in uremic vs. 11 +/- 1.3 min in normal men; P < 0.001); 5) the mean 24-h serum immunoradiometric LH concentration was significantly higher in uremia at 5.7 +/- 0.68 vs. 3.6 +/- 0.41 IU/L in controls (P = 0.017); and 6) serum estradiol concentrations were increased in uremia, but total and free testosterone concentrations did not differ significantly between the two subject groups. In response to synthetic GnRH (10 micrograms, administered iv after the 24-h basal sampling period), the mean mass of immunoradiometric LH released within each calculated LH secretory burst was similar in uremic (n = 8) and normal (n = 21) individuals. We conclude that uremia is accompanied by a specific defect in the pulsatile mode of LH secretion, which is marked by an abbreviation of LH secretory burst duration and a consequent fall in the mass of LH secreted per spontaneous release episode. There is no overall decline in LH secretory pulse frequency or gonadotroph responsiveness to a submaximally effective dose of exogenous GnRH. Such findings are consistent with diminished hypothalamic GnRH impulse strength.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1993

Coordinate activation of the corticotropic axis by insulin-induced hypoglycemia: simultaneous estimates of beta-endorphin, adrenocorticotropin and cortisol secretion and disappearance in normal men.

In the present study, we investigated the coordinate kinetic response of the corticotropic axis to the acute metabolic stress of hypoglycemia by applying deconvolution analysis to adrenocorticotropin (ACTH), beta-endorphin and cortisol concentration-time series generated in seven normal men after intravenous administration of insulin. Hypoglycemic stress resulted in a 22-fold increase in the mean plasma concentration of ACTH to a maximum of 77 +/- 15 pmol/l, in conjunction with a 7.5-fold increase in the mean plasma beta-endorphin concentration, the maximal value of which was 96 +/- 11 pmol/l. Plasma cortisol concentrations increased by 2.6-fold with a mean value of 734 +/- 14 nmol/l. Maximal plasma ACTH and beta-endorphin concentrations were preceded by discrete secretory bursts with peak amplitudes of 10.5 +/- 2.7 and 10.6 +/- 2.0 pmol.l-1.min-1 (20-fold and ninefold increases compared to control), respectively. The mass of ACTH released was 114 +/- 20 pmol/l (3.4-fold increase), which corresponds to a total amount of 1.25 micrograms (50% of daily production and 0.5% of reported pituitary stores), assuming a distribution volume of 40 ml/kg. A total amount of 4.4 +/- 0.7 mg of cortisol was released after insulin-induced hypoglycemia, based on a mean cortisol secretory mass of 1088 +/- 137 nmol/l and a presumed 11.3-1 volume of distribution. Deconvolution-based estimates of the endogenous half-lives of ACTH, beta-endorphin and cortisol were 17 +/- 0.6, 22 +/- 1.7 and 65 +/- 5.3 min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1992

Divergent effects of short term glucocorticoid excess on the gonadotropic and somatotropic axes in normal men.

We investigated the effects of short term glucocorticoid excess on the gonadotropic and somatotropic axes in healthy men. Subjects (n = 5) underwent blood sampling at 10-min intervals for 6 h before and on days 2, 5, and 8 of glucocorticoid treatment, and for 24 h (n = 6) to examine pulsatile LH and GH release before and during dexamethasone administration (1.5 mg orally twice daily for 1 week). In the time-course study, we found significant decreases on day 8 in serum concentrations of estradiol (from 144 +/- 18 to 99 +/- 18 pmol/L), free testosterone (from 105 +/- 10 to 87 +/- 10 pmol/L), and dehydroepiandrosterone sulfate (from 6.0 +/- 1.6 to 1.7 +/- 0.3 mumol/L; P less than 0.05). Mean serum LH concentrations did not change (baseline, 5.3 +/- 1.2 IU/L; glucocorticoid, 4.2 +/- 0.61 IU/L). The mean plasma somatomedin-C concentration rose from 0.74 +/- 0.08 to 2.0 +/- 0.35 U/mL (P less than 0.05), and the mean serum GH concentration increased from 1.2 +/- 0.90 micrograms/L (basal) to 4.2 +/- 1.5 micrograms/L (day 8 of dexamethasone; P less than 0.01). Deconvolution analysis of 24-h serum GH and LH concentration profiles revealed that the half-life of endogenous GH and the duration and amplitude (maximal rate of secretion) of computer-resolved GH secretory bursts were not influenced significantly by dexamethasone. The mass of GH secreted per burst rose 1.6-fold. Glucocorticoid treatment also increased detectable GH secretory burst frequency from 12 +/- 1.6 to 18 +/- 1.6 episodes/24 h, decreased the GH interburst interval from 127 +/- 23 to 79 +/- 5 min, and increased the daily GH secretion rate from 41 +/- 11 to 101 +/- 11 micrograms/L.day. These effects on the somatotropic axis were specific, since the half-life of LH; LH secretory burst frequency, amplitude, mass, and duration; and the total daily LH production rate (and LH secretion in response to exogenous GnRH) were not altered by dexamethasone administration. We conclude that short term moderate glucocorticoid excess augments pulsatile GH secretion without influencing the episodic release of LH in normal men.

Adult↗

PubMed1992

Robustness of the male lactotropic axis to the hyperprolactinemic stimulus of primary thyroidal failure.

Primary hypothyroidism is a presumptive proximate basis for increased serum PRL concentrations. However, most studies to date have been performed in females and do not address the possible effect of sex differences. In the present study we investigated the 24-h patterns of pulsatile PRL release in 10 hypothyroid men (24-h mean +/- SEM: total T4, 35 +/- 8 nmol/L; TSH, 55 +/- 10 mU/L) by sampling blood at 10-min intervals for 24 h. The study was repeated in 5 men, 5-7 months and again 14-36 months after treatment with levothyroxine. The control group consisted of 7 normal age-matched euthyroid men. The mean 24-h serum PRL concentration of 4.9 +/- 0.6 micrograms/L in 10 hypothyroid men was not significantly different from the value of 4.9 +/- 0.5 micrograms/L found in the normal group (P greater than 0.5). Pulsatile features of PRL release were evaluated by Cluster analysis, which revealed normal mean PRL peak frequency (12.6 +/- 0.7 vs 13.4 +/- 0.6 pulses/24 h; P greater than 0.5), maximal peak amplitude (6.1 +/- 0.7 vs. 6.7 +/- 0.6 micrograms/L; P greater than 0.5), peak increment (2.2 +/- 0.3 vs. 2.6 +/- 0.3 micrograms/L; P = 0.3), mean valley (4.2 +/- 0.6 vs. 4.4 +/- 0.4 micrograms/L; P greater than 0.5), and prepeak nadir (3.6 +/- 0.5 vs. 3.6 +/- 0.4 micrograms/L; P greater than 0.5) PRL concentrations. Five to 7 months of T4 therapy in 5 hypothyroid men caused significant decreases in the mean 24-h (2.9 +/- 0.5 vs. 6.1 +/- 1.2 micrograms/L; P less than 0.05), interpulse valley (2.5 +/- 0.4 vs. 5.2 +/- 1.1 micrograms/L; P less than 0.05), and prepeak nadir (2.3 +/- 0.3 vs. 4.6 +/- 1.0 micrograms/L; P less than 0.05) PRL concentrations. These values returned to normal after 14-36 months of treatment. Cosinor analysis revealed preserved circadian PRL rhythmicity during hypothyroidism, with a normal circadian mesor (mean), amplitude, and acrophase. In summary, we have demonstrated normal mean 24-h serum PRL concentrations as well as normal pulsatile and circadian patterns of PRL release in men with primary hypothyroidism. These results stand in contrast to previous reports of increased serum PRL concentrations observed predominantly in hypothyroid premenopausal women. The foregoing disparity suggests the possibility of a role for estrogen in enhancing the effect of hypothyroidism on PRL release.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1992

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.

Adult↗

PubMed1992

Rhythmic and nonrhythmic modes of anterior pituitary gland secretion.

Because of confounding effects of subject-specific and hormone-specific metabolic clearance, the nature of anterior pituitary secretory events in vivo is difficult to ascertain. We review an approach to this problem, in which deconvolution analysis is used to dissect the underlying secretory behavior of an endocrine gland quantitatively from available serial plasma hormone concentration measurements assuming one- or two-compartment elimination kinetics. This analytical tool allows one to ask the following physiological questions: (a) does the anterior pituitary gland secrete exclusively in randomly dispersed bursts, and/or does a tonic (constitutive) mode of interburst hormone secretion exist? and (b) what secretory mechanisms generate the circadian or nyctohemeral rhythms in blood concentrations of pituitary hormones?(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Nature of altered growth hormone secretion in hyperthyroidism.

Hyperthyroidism is accompanied by various neuroendocrine regulatory disturbances that affect not only the thyrotropic, but also the gonadotropic, corticotropic, and somatotropic axes. To examine the nature of alterations in neuroendocrine control mechanisms that direct the somatotropic axis in hyperthyroidism, we have applied a novel deconvolution technique designed to estimate the number, amplitude, and mass of significant underlying GH secretory events after the influence of GH metabolic clearance has been removed mathematically. To this end, blood was sampled at 10-min intervals for 24 h in seven hyperthyroid and seven age-matched euthyroid men. The subsequent GH time series were assayed by immunoradiometric assay (sensitivity, 0.08 ng/mL) and submitted to quantitative deconvolution analysis. We found that hyperthyroid compared to euthyroid men 1) had significantly more GH secretory bursts per 24 h (viz. 15 +/- 1.0 vs. 10 +/- 1.1; P = 0.017); 2) secreted 3 times as much GH per burst (3.7 +/- 0.80 vs. 1.3 +/- 0.42 ng/mL distribution vol; P = 0.013); 3) achieved a maximal rate of GH secretion in each burst 2.3-fold higher than that in control men (0.14 +/- 0.028 vs. 0.060 +/- 0.015 ng/mL.min; P = 0.017); and 4) had 3.7-fold higher 24-h endogenous GH production rates (P less than 0.01). Neither hyperthyroid nor euthyroid men had significant interburst (tonic) GH secretion. We conclude that the somatotropic axis in hyperthyroid men is marked by a higher frequency of spontaneous GH secretory bursts, a higher rate of maximal GH secretion attained per burst, and a larger mass of GH released per burst. These neuroregulatory disturbances result in a nearly 4-fold increase in the 24-h production rate of GH in thyrotoxicosis.

Adult↗

PubMed1991

Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man.

We have examined the mechanisms underlying reduced circulating GH concentrations in the obese human. Computer-assisted (deconvolution) analysis was used to determine endogenous GH secretory and clearance rates quantitatively from entire 24-h plasma GH concentration profiles. These analyses revealed that the half-life (t 1/2) of endogenous GH was significantly shorter in obese (11.7 +/- 1.6 min) than in normal weight subjects (15.5 +/- 0.81 min; P less than 0.01). The accelerated blood disposal rate of GH was not due to decreased circulating concentrations of GH-binding protein, since the latter were similar in obese (25 +/- 1.0%) and normal weight (24 +/- 2.3%) men. However, obese men had significantly fewer GH secretory bursts (3.2 +/- 0.53 vs. 9.7 +/- 0.67/day; P less than 0.01). Among the rare GH secretory bursts that occurred in obese subjects, there were significantly prolonged mean intersecretory burst intervals (282 +/- 65 vs. 131 +/- 11 min; P less than 0.05). The resultant daily GH production rate in obese men was reduced to one fourth that in normal weight individuals. Both GH secretion rate and burst frequency were negatively correlated with the degree of obesity (ponderal index). The decreases in GH burst frequency and half-life were specific, since GH secretory pulse amplitude (maximal rate of GH release), the mass of GH released per burst, and the duration of computer-resolved GH secretory bursts were not different in obese and normal weight men. We conclude that obese men harbor a double defect in GH dynamics involving both GH secretion and clearance, and that the severity of the GH secretory deficiency is proportionate to the degree of obesity.

Adult↗

PubMed1991

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.

Adult↗

PubMed1990

Temporal structure of in vivo adrenal secretory activity estimated by deconvolution analysis.

Circadian and ultradian rhythms of plasma cortisol concentrations have been documented under physiological conditions in diverse animal species. Using a novel, biophysical convolution model to remove subject-specific metabolic clearance rates, we have now estimated spontaneous adrenal secretory events in vivo. The latter were characterized by prominent ultradian rhythms of discrete secretory bursts with periodicities averaging 32, 46, 76, and 130 min. These ultradian cortisol secretory rhythms represented a 17- to 240-fold larger fraction of circadian secretory variations than did cortisol concentration rhythms. We conclude that deconvolution analysis can unmask underlying ultradian rhythms in adrenal secretory activity in vivo.

Activity Cycles↗

PubMed1990

Dynamics of 24-hour endogenous cortisol secretion and clearance in primary hypothyroidism assessed before and after partial thyroid hormone replacement.

Although various abnormalities of hypothalamic pituitary adrenal function have been reported in primary hypothyroidism, neither 24-h patterns of pulsatile cortisol release nor estimation of its endogenous secretion and clearance rates have been fully investigated in this clinical setting. We studied pulsatile and circadian patterns of cortisol secretion in six hypothyroid men [mean free T4 index, 0.59 +/- 0.22 (+/- SE); mean TSH, greater than 50 mU/L] by sampling blood at 20-min intervals for 24 h before (unreplaced) and then after 5-7 months of partial replacement treatment with levo-T4. Compared to a normal group, hypothyroid men had significantly elevated 24-h mean serum concentrations of cortisol (419 vs. 254 nmol/L; P less than 0.001), with no change in serum cortisol-binding globulin concentrations. Cluster analysis of cortisol time series revealed a normal pulse frequency, with significant increases in mean peak amplitude (527 vs. 331 nmol/L; P = 0.001), mean interpulse valley concentrations (384 vs. 204 nmol/L; P less than 0.05), and mean prepeak nadir concentrations (298 vs. 166 nmol/L; P less than 0.05). Cosinor analysis showed preserved circadian rhythmicity (i.e. normal mean circadian amplitude of cortisol release) in hypothyroidism, with a significant delay in the timing of circadian acrophases and an increase in the mesor (mean). Analysis of data by a multiple parameter deconvolution method demonstrated a normal 24-h endogenous cortisol production rate in the presence of significantly prolonged subject-specific half-life of cortisol disappearance (155 vs. 73 min; P less than 0.05). Partial replacement therapy with levo-T4 caused significant decreases in 1) mean 24-h serum cortisol concentrations (419 vs. 323 nmol/L; P less than 0.05); 2) mean cortisol peak amplitudes (527 vs. 375 nmol/L; P less than 0.05); 3) mean prepeak nadir concentrations (298 vs. 221 nmol/L; P less than 0.05); and 4) mean half-life of cortisol disappearance (155 vs. 112 min; P less than 0.0019). In summary, the present study of cortisol secretory dynamics in hypothyroid men has shown elevated mean 24-h serum concentrations of cortisol with preserved circadian rhymicity and normal endogenous production rates, but prolonged half-lives of cortisol disappearance. In conjunction with normal serum cortisol-binding globulin concentrations, these largely reversible findings suggest that significant hypercortisolemia in primary hypothyroidism is primarily due to decreased metabolic clearance of cortisol and a presumptive decrease in the negative feedback effect of cortisol on the hypothalamo-pituitary axis.

Adult↗

PubMed1990

Attenuated pulsatile release of prolactin in men with insulin-dependent diabetes mellitus.

Pulsatile and circadian patterns of PRL release were studied in 11 insulin-dependent diabetic men by sampling blood every 10 min for 24 h and comparing the results to those obtained in 12 normal nondiabetic men. The diabetic men had a mean (+/- SE) 24-h serum PRL concentration of 5.5 +/- 0.42 micrograms/L, which was significantly lower than that in the nondiabetic men (9.3 +/- 0.86; P = 0.0008). Quantitative Cluster analysis of pulsatile PRL time series revealed a normal pulse frequency, but decreased maximal peak amplitude (6.6 +/- 0.5 vs. 11.8 +/- 1.1 micrograms/L; P = 0.0009), peak increment (2.6 +/- 0.24 vs. 4.0 +/- 0.3 micrograms/L; P = 0.009), peak area (126 +/- 15 vs. 192 +/- 19 micrograms/L.min; P = 0.03), and interpulse valley mean concentration (4.8 +/- 0.4 vs. 8.6 +/- 1.2 micrograms/L; P = 0.0007). PRL pulse incremental amplitude correlated significantly (r2 = 0.577; P = 0.007) and negatively with duration of disease. Fourier analysis disclosed a normal circadian rhythm of PRL release in diabetic men, with a mean circadian amplitude of 1.5 micrograms/L +/- 0.31, which peaked at 0201 h +/- 89 min (+/- SE). In summary, we have demonstrated significantly reduced mean 24-h serum PRL concentrations in men with poorly controlled insulin-dependent diabetes mellitus. The concomitant suppression of spontaneous PRL pulse amplitude, peak increment, and interpulse valley mean concentrations in the presence of normal pulse frequency is consistent with a reduced mass of PRL secreted per burst and/or accelerated metabolic clearance of PRL in men with type I diabetes mellitus.

Adult↗

PubMed1990

Amplitude, but not frequency, modulation of adrenocorticotropin secretory bursts gives rise to the nyctohemeral rhythm of the corticotropic axis in man.

The ACTH-adrenal axis is a critical stress-responsive system with prominent circadian rhythmicity. To test the basis for the circadian ACTH physiology, we have used 1) a sensitive and specific two-site immunoradiometric assay to estimate plasma ACTH-(1-39) concentrations during intensive (every 10 min) and extended (24-h) blood sampling to capture complete diurnal ACTH profiles in eight normal men, and 2) a novel deconvolution model designed to resolve the number, amplitude, and duration of ACTH secretory bursts and simultaneously estimate subject-specific ACTH half-lives under physiological conditions in vivo. Deconvolution revealed 40 +/- 1.5 significant ACTH secretory bursts/24 h, with a mean interburst interval of 39 +/- 2.3 min. ACTH secretory bursts were discrete punctuated events arising without tonic interpulse secretion and had a half-duration (duration at half-maximal amplitude) of 19 +/- 2 min. The estimated half-life of endogenous ACTH was 15 +/- 1.2 min, and its daily production rate was 0.96 +/- 0.16 ng/mL (0.21 +/- 0.035 nmol/L) distribution volume. Cosinor analysis revealed a significant (3.8-fold) 24-h rhythm in the mass (or rate) of ACTH secreted per burst (maximal at 0818 h), but no nyctohemeral variation in ACTH secretory pulse frequency. The validity of ACTH pulse analysis was supported by the significantly nonrandom associations among ACTH, beta-endorphin, and cortisol peaks in the same subjects. Specifically, we found that ACTH and beta-endorphin bursts occurred simultaneously (P less than 10(-4)) and were both followed in 10 min by a cortisol pulse (P less than 10(-4)). We conclude that 1) selective amplitude control of a punctuated burst-like mode of ACTH secretion can give rise to the nyctohemeral corticotropic rhythm without the need to postulate any tonic (or interpulse basal) component of ACTH release; and 2) there is exquisite 3-fold temporal synchrony among bursts of ACTH, beta-endorphin, and cortisol release in normal men.

Adrenocorticotropic Hormone↗

PubMed1990

Intensive venous sampling paradigms disclose high frequency adrenocorticotropin release episodes in normal men.

Recent studies in the rat and rhesus monkey have disclosed apparently high frequency in vivo ACTH release episodes. While the circadian pattern of plasma ACTH concentrations has been known for many years, the exact frequency of ultradian pulsatile ACTH release in man is not clear, due in part to variable intensities of blood-sampling schedules and the limited availability of sensitive ACTH assays. In this study we used a new sensitive and specific immunoradiometric assay to measure plasma ACTH concentrations in blood sampled at 1) 2-min intervals for 3 h, followed by 4-min intervals for 4 more h in six men; and 2) 10-min intervals for 24 h in eight other men. An objective peak detection algorithm (Cluster) and cosinor analyses were used to assess the episodic pulsatility and circadian rhythmicity of ACTH. Comparisons were made among the 2 min (3 h), 4, 8, and 12 min (7 h), and 10 min (24 h) time series. Mean ACTH interpulse intervals were significantly different among the five sampling groups (P less than 0.00001). Sampling every 2 min yielded a mean ACTH interpulse interval of 18 min, which was significantly shorter than the mean interpulse intervals of 35, 53, 52, and 73 min resulting, respectively, from sampling every 4, 8, 10, and 12 min (P less than 0.05). In contrast, maximal peak ACTH amplitudes (picomoles per L or percent increase) did not vary as a function of sampling frequency. The 24-h plasma ACTH concentration time series showed significant diurnal variation, with a mean circadian amplitude of 0.95 +/- 0.15 pmol/L occurring at 1008 h (+/- 25 min). Cosinor analysis of various ACTH pulse parameters deduced from the 24-h time series revealed significant circadian rhythmicity in the ACTH peak maxima (P less than 0.05), peak increments (P less than 0.05), and prepeak nadir (P less than 0.05) concentrations, but not in ACTH interpulse intervals. We conclude that in men, 1) intensive sampling at 2-min intervals unmasks high frequency ACTH release episodes that cannot be detected at conventional sampling rates; and 2) ACTH peak amplitude, but not frequency, varies significantly during the course of circadian changes in the plasma ACTH concentrations.

Adrenocorticotropic Hormone↗

PubMed1990

Twenty-four-hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts.

To evaluate the nature of anterior pituitary secretory events in vivo, we have applied a novel waveform-independent deconvolution technique that dissects the underlying secretory behavior of endocrine glands quantitatively from available serial plasma hormone concentration measurements assuming one- or two-compartment elimination kinetics. We used this new tool to ask the following physiological questions. 1) Does the pituitary gland secrete exclusively in randomly dispersed bursts, and/or does a tonic (constitutive) mode of interburst hormone secretion exist? 2) What secretory mechanisms generate the nyctohemeral rhythms in plasma hormone concentrations? Analysis of 24-h plasma concentration profiles of GH, LH, FSH, PRL, TSH, ACTH, and beta-endorphin (n = 6-8 men/group) revealed that 1) pituitary secretion in vivo occurs in an exclusively burst-like mode for all hormones except TSH and PRL (for the latter two, a mixed burst and constitutive mode pertained); 2) significant nyctohemeral regulation of secretory burst frequency alone was not demonstrated for any hormone; 3) prominent 24-h variations in secretory burst amplitude alone were delineated for ACTH and LH; 4) TSH, GH, and beta-endorphin were both frequency and amplitude controlled; 5) no significant diurnal variations in FSH secretory parameters occurred; and 6) a fixed hormone half-life yielded fits of the 24-h data series with a normalized residual variance of less than 8%. We conclude that the normal human anterior pituitary gland releases its multiple (glyco)protein hormones via punctuated secretory episodes unassociated with tonic basal (constitutive) hormone secretion, except in the case of TSH and PRL. Hormone-specific amplitude and/or frequency control of secretory burst activity over 24 h provides the mechanistic basis for the classically recognized 24-h rhythms in plasma concentrations of adenohypophyseal hormones in men.

Adrenocorticotropic Hormone↗

PubMed1989

Amplitude modulation of a burstlike mode of cortisol secretion subserves the circadian glucocorticoid rhythm.

We have examined the mechanism subserving the in vivo circadian rhythm of cortisol in men. To this end, blood samples were withdrawn at 10-min intervals for 24 h in each of six men to yield well-defined profiles of episodic cortisol release. A novel multiple-parameter deconvolution model was applied to discriminate the number, amplitudes, and durations of all statistically significant underlying cortisol secretory bursts from the plasma hormone concentrations and simultaneously estimate the endogenous half-life of cortisol disappearance in each subject. These experiments disclosed randomly occurring cortisol secretory bursts at a mean frequency of 19 +/- 0.82 events per day (interpulse interval 77 +/- 4.0 min). Secretory bursts exhibited a mean half-duration (duration at half-maximal amplitude) of only 16 +/- 0.61 min indicating that 95% of daily cortisol secretion occurred in 8.2 h. Cortisol secretory burst frequency varied 2.2-fold over 24 h, whereas cortisol secretory burst amplitude varied 6.6-fold. We conclude that the nyctohemeral pattern of cortisol variation in vivo can be accounted for by an amplitude-modulated, random burstlike mode of cortisol secretion without the need to postulate a tonic mode of cortisol release.

Adult↗

PubMed1989

Circadian, ultradian, and episodic release of beta-endorphin in men, and its temporal coupling with cortisol.

beta-Endorphin and ACTH derive from a common peptide precursor. Although much is known about the physiological patterns of ACTH release, neither the minute to minute regulation of beta-endorphin secretion nor its temporal relationship to cortisol has been characterized. As an initial step to defining the regulation of beta-endorphin release in man, we studied the circadian periodicity, ultradian rhythmicity, and episodic pulsatility of serum beta-endorphin concentrations in seven normal men. Blood sampling was conducted at 10-min intervals for 24 h, and the subsequent serum samples were assayed by a two-site immunoradiometric assay. Computerized analysis of the subsequent beta-endorphin time series revealed a mean beta-endorphin pulse frequency of 13 +/- 1 (+/- SE) peaks/24 h, corresponding to an interpulse interval of 100 +/- 7 min. The mean maximal peak height of beta-endorphin pulses was 31 +/- 3 pg/mL (9.0 +/- 0.8 pmol/L), which represented an incremental increase of 11 +/- 1 pg/mL 3.2 +/- 0.4 pmol/L; 63 +/- 13%) above the preceding nadir. The average beta-endorphin peak exhibited a duration of 68 +/- 6 min. Fourier analysis revealed a significant circadian amplitude of 6 +/- 1 pg/mL (1.6 +/- 0.4 pmol/L; 23% of the 24-h mean concentration), with an acrophase (time of maximum value) at 1043 h (+/- 40 min). Spectral analysis also disclosed beta-endorphin rhythms with mean periodicities of 29 +/- 4, 42 +/- 4, and 61 +/- 5 min. Gel filtration chromatography confirmed that serum beta-endorphin peaks contained significantly more immunoactive beta-endorphin [62 pg/mL (18 pmol/L)] than did the flanking nadirs [16 and 18 pg/mL (4.6 and 5.2 pmol/L)]. Auto- and cross-correlation analyses of serum beta-endorphin and cortisol concentrations followed by autoregressive modeling disclosed that all seven men had significant positive cross-correlations between serum beta-endorphin and cortisol considered simultaneously or when cortisol lagged beta-endorphin by 10 min. A negative cross-correlation was found in five of the seven men when cortisol was considered to lead beta-endorphin by 20 or 30 minutes. We conclude that beta-endorphin is released physiologically in a pulsatile manner with circadian and ultradian rhythmicity and a close temporal coupling to cortisol.

Adult↗