Imaging findings in infants with recurrent vomiting after pyloromyotomy: a pictorial review.

Hypertrophic pyloric stenosis (HPS) is a common entity with an incidence of 2-4 per 1000 live births. Current definitive treatment is with pyloromyotomy, which is usually performed laparoscopically. The procedure is generally well tolerated with resolution of the patient's symptoms. In a small percentage of patients, however, there is recurrent vomiting which warrants further investigation. In this pictorial review, the expected post-operative appearance of the pylorus will be described, and the imaging findings and clinical course of two patients with recurrent vomiting after pyloromyotomy will be presented.

Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback.

OBJECTIVE: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. METHOD: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. RESULTS: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. CONCLUSION: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

GH deficiency in patients irradiated for acromegaly: significance of GH stimulatory tests in relation to the 24 h GH secretion.

BACKGROUND: Radiotherapy for pituitary adenomas frequently leads to GH deficiency (GHD). The characteristics of GH secretion in GHD induced by postoperative radiotherapy for acromegaly are not known. HYPOTHESIS: In the long term, stimulated and spontaneous GH release is not different between patients with GHD treated by postoperative radiotherapy for acromegaly or for other pituitary adenomas. DESIGN/SUBJECTS: We compared the characteristics of basal and stimulated GH secretion in patients with GHD, who had previously received adjunct radiotherapy after surgery for GH-producing adenomas (n=10) vs for other pituitary adenomas (n=10). All patients had a maximal GH concentration by insulin tolerance test (ITT) of 3 microg/l or less, compatible with severe GHD. Mean time after radiation was 17 and 18.7 years, respectively. Stimulated GH release was also evaluated by infusion of growth hormone-releasing hormone (GHRH), GHRH-arginine and arginine, and spontaneous GH by 10 min blood sampling for 24 h. Pulse analyses were performed by Cluster and approximate entropy. OUTCOMES: There were no differences between both patient groups in stimulated GH concentrations in any test. Spontaneous GH secretion was not different between both patient groups, including basal GH release, pulsatility and regularity. Pulsatile secretion was lost in two acromegalic and three non-acromegalic patients. Insulin-like growth factor-I (IGF-I) was below -2 s.d. score in nine patients in each group. CONCLUSION: Acromegalic patients treated by surgery and postoperative radiotherapy with an impaired response to the ITT do not differ, in the long term, in GH secretory characteristics from patients treated similarly for other pituitary tumors with an impaired response to the ITT. The ITT (or the GHRH-arginine test) is therefore reliable in establishing the diagnosis of GHD in patients treated for acromegaly by surgery and radiotherapy.

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.

Ultradian endocrine rhythms are altered by a circadian mutation in the Syrian hamster.

A single gene defect of the circadian clock (tau mutation) has recently been described that results in a shortening of the circadian activity cycle of the Syrian hamster. In the homozygous animal, free running activity is shortened by 4 h, resulting in a circadian period of approximately 20 h. Here, we examine the effect of the tau mutation on noncircadian oscillators by comparing the frequency of episodic secretion of LH and cortisol in normal period wild-type (approximately 24-h circadian rhythm) and tau mutant (approximately 20-h circadian rhythm) castrate females. Animals were ovariectomized at 14 weeks of age and maintained thereafter under conditions of constant illumination. Wheel-running records were obtained, and only those animals exhibiting clear single bouts of circadian activity were used in the experiment. Two days after intraatrial cannulation, blood samples were collected for a 5-h period every 5 min during the subjective day at the same relative phase of the circadian cycle. Deconvolution analysis revealed that LH pulse frequency was significantly reduced in the tau mutant females (33.3 +/- 2.25- and 28.7 +/- 2.0-min interpulse intervals for tau and normal period females, respectively). Cortisol pulse frequency also exhibited significant differences, with a reduced pulse frequency (32.8 +/- 3.6- and 27.8 +/- 1.4-min interpulse intervals for tau and wild-type females, respectively). There were no significant differences with respect to secretory pulse amplitude, hormone half-life or estimated burst amplitude, or mass of hormone secreted per burst for either hormone. We conclude that a genetic defect that affects the circadian clock located in the suprachiasmatic nucleus may have a more general effect on neural oscillators, including those controlling episodic hormone secretion.

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.

Low basal and persistent pulsatile growth hormone secretion are revealed in normal and hyposomatotropic men studied with a new ultrasensitive chemiluminescence assay.

Serum GH concentrations assessed by conventional RIA and immunoradiometric assay (IRMA) are often undetectable in healthy fed and awake humans. Serum GH concentrations are also low in obese, hypothyroid, middle-aged, and older individuals. Accordingly, to better investigate the pathophysiology of GH release in relatively hyposomatotropic states, we compared a new and putatively ultrasensitive GH chemiluminescence (CL) assay with a conventional IRMA. We report that the sensitivity of the CL assay is approximately 0.005 microgram/L, with a median intraassay coefficient of variation over more than 3 logarithms of serum GH concentrations of 5.2% (range, 3.6-8.3%). In each of 2 normal young men and 4 categories of hyposomatotropic adults studied (2 obese, 2 hypothyroid, 2 middle-aged, and 3 older men), we observed detectable serum GH concentrations by CL assay of all samples collected at 10-min intervals for 24 h. In the same sera analyzed by IRMA, 22-98% of the daytime sample values fell below IRMA sensitivity (0.10 microgram/L). Within the IRMA-detectable range, the correlation between the 2 assays ranged between r = 0.893 to 0.989 (P < 0.001 in each subject). In the CL assay, serum GH concentrations declined to 0.018-0.030 microgram/L, but were never undetectable during the awake fed state. Deconvolution analysis of 11 GH series assayed by CL disclosed basal GH release and superimposed GH secretory bursts. In the low GH series, there was a mean frequency of 12 +/- 1.4 secretory events/24 h, a mass of GH secreted per burst of 1.0 +/- 0.35 microgram/L, a secretory burst half-duration of 21 +/- 3.3 min, and an apparent endogenous GH half-life of 14 +/- 0.85 min. Compared to the GH IRMA, the CL assay detected approximately 50% more GH secretory events, and GH secretory burst frequency was increased significantly at night vs. the daytime. Cosinor analysis revealed significant 24-h serum GH concentration rhythms in both assays, but an earlier mean acrophase (time of maximum) and lower mesor (mean values) were estimated in the CL assay than the IRMA. We conclude that within the IRMA-detectable range, the correlation between serum GH concentrations measured by CL and IRMA techniques is high. However, unlike the IRMA, the GH CL assay can detect serum GH concentrations consistently in the awake and fed state not only in young individuals but also in subjects with obesity, hypothyroidism, and middle and older age.(ABSTRACT TRUNCATED AT 400 WORDS)

Disparate serum free testosterone concentrations and degrees of hypothalamo-pituitary-luteinizing hormone suppression are achieved by continuous versus pulsatile intravenous androgen replacement in men: a clinical experimental model of ketoconazole-induced reversible hypoandrogenemia with controlled testosterone add-back.

To investigate the neuroendocrine mechanisms underlying the negative feedback actions of testosterone on both the pulsatile mode of LH release and the entropy or disorderliness of the LH release process, we blocked testicular androgen biosynthesis using oral high dose ketoconazole treatment with concomitant low dose glucocorticoid replacement for 48 h in six healthy young men. Volunteers were then infused iv with saline or a total of 8.0 mg testosterone base over the second 24 h via either a continuous or a pulsatile (90-min boluses) delivery pattern. Discrete peak detection (Cluster analysis) was applied to obtain a model-independent estimate of the frequency of serum LH concentration peaks, maximal and incremental LH peak amplitudes, peak area, and interpeak nadir serum LH concentrations. Approximate entropy was used to quantify the relative orderliness/disorderliness of the LH release process over 24 h. Ketoconazole treatment markedly lowered 24-h mean serum total and free testosterone concentrations (by 17- and 9-fold respectively), and significantly increased LH pulse frequency, maximal LH peak height, and interpeak nadir serum LH concentrations. Continuous iv testosterone add-back increased 24-h pooled serum free testosterone concentrations 3-fold more and concomitantly reduced mean (24-h) serum LH concentrations by at least 2-fold more than pulsatile delivery of the same total daily amount of androgen. Both modes of testosterone infusion suppressed pulsatile LH release, but the effects were distinguishable; namely, treatment with continuous vs. intermittent androgen add-back, respectively, decreased LH pulse frequency and incremental LH pulse amplitude. Ketoconazole treatment alone also significantly increased approximate entropy values, indicating greater disorderliness of LH release during androgen removal. Approximate entropy/orderliness was restored to baseline by continuous, but not pulsatile, iv testosterone replacement. In conclusion, the present novel testosterone add-back clinical experimental paradigm indicates that 1) remarkably different 24-h mean serum free testosterone concentrations can result from continuous vs. pulsatile testosterone delivery into the bloodstream; 2) androgen negative feedback can exert frequency- as well as amplitude-dependent suppression of pulsatile LH release; and 3) testosterone is required to maintain an orderly 24-h LH release process in young men.

Mechanisms subserving the physiological nocturnal relative hypoprolactinemia of healthy older men: dual decline in prolactin secretory burst mass and basal release with preservation of pulse duration, frequency, and interpulse interval--a General Clinical Research Center study.

Increasing age is accompanied by decrements in randomly obtained, fasting, or frequently sampled serum PRL concentrations. The precise neuroendocrine mechanisms underlying such relative hypoprolactinemia in aging are incompletely understood. In the present study, we sampled blood at 2.5-min intervals overnight in 11 young (aged 21-34 yr) and 8 older (aged 62-72 yr) healthy men for subsequent chemiluminescence-based assay of serum PRL concentrations. The mean (+/- SEM) serum PRL concentration was significantly reduced at 4.3 +/- 0.78 microg/L in older men compared with 9.5 +/- 1.2 microg/L in young volunteers (P = 0.0049). PRL concentrations correlated with serum testosterone (r = 0.473; P = 0.041), dehydroepiandrosteroen sulfate (r = +0.455, P = 0.05), and insulin-like growth factor I (r = 0.494; P = 0.032) levels. Deconvolution analysis was used to evaluate combined pulsatile and basal modes of PRL secretion. In older men, discrete PRL secretory bursts were marked by a significantly (2.4-fold) attenuated mass of hormone secreted per burst (amount of PRL secreted per unit distribution volume), viz. 1.6 +/- 0.23 (older) vs. 3.9 +/- 0.57 microg/L (young; P < 0.01). In contrast, PRL secretory burst frequency, interpulse interval, and pulse duration were invariant of age. Concomitantly, basal PRL secretion was reduced by 2-fold in older subjects, namely to 0.00030 +/- 0.00027 (older) vs. 0.00065 +/- 0.0002 microg/L/min (young; P < 0.01). The amount of total PRL secretion that was pulsatile averaged 82 +/- 5.3% in young and 99 +/- 0.13% in older men (P = 0.012), indicating preferential loss of the basal mode of PRL release in aging. Assuming that basal PRL secretion mirrors functional pituitary lactotroph cell secretory mass, whereas pulsatile PRL release reflects effective (net) intermittent hypothalamic drive to responsive lactotroph cells, then our results suggest both an attrition in lactotroph cell mass and an impoverishment of net positive hypothalamic (agonistic) input to lactotrophs in older men. Given the multiple roles of PRL reported in experimental animals (e.g. on the one hand to support immune function and adrenal androgen biosynthesis and on the other hand to activate intraprostatic growth factors), we suggest that the nocturnal relative hypoprolactinemia observed in healthy aging men may have both adaptive and maladaptive clinical implications to target tissues.

The orderliness of the growth hormone (GH) release process and the mean mass of GH secreted per burst are highly conserved in individual men on successive days.

Endocrine glands signal their remote target tissues via physiologically pulsatile release of regulatory molecules. A cardinal assumption of most pathophysiological experiments is that discrete attributes of pulsatile hormone secretion are stable over successive untreated observation intervals; i.e. repeated measurements show serial within-subject reproducibility. To test this hypothesis in the GH axis, we sampled blood every 10 min for 48 h in 14 healthy men (age range, 29-77 yr; body mass index, 21-51 kg/m2). The 2 consecutive 24-h serum profiles were subjected to ultrasensitive GH chemiluminescence assay (sensitivity, 0.002 micrograms/L) with a new dose-dependent variance model to estimate within-assay precision. We then applied deconvolution analysis to estimate the number, mass, amplitude, and duration of underlying GH secretory bursts as well as simultaneously calculate the apparent GH half-life and any concurrent basal hormone secretion. Test-retest consistency was assessed by the Pearson correlation coefficient, and differences were determined by paired nonparametric (Wilcoxon) testing. Comparing successive 24-h profiles, no significant differences existed in any of the foregoing secretion or half-life measures or in a novel estimate of the relative disorderliness of hormone release, namely approximate entropy. Correlation was minimal for secretory burst amplitude and half-duration. In contrast, the calculated mean mass of GH secreted per burst was highly conserved across sessions within subjects, with an r value of 0.932 (P < 10(-6). This correlation equaled or exceeded that of mean and integrated serum GH concentrations on consecutive days (r = 0.920; P = 0.00003). The calculated daily GH production rate was also strongly reproduced (r = 0.784; P = 0.0009). Moreover, the within-subject GH half-life and GH secretory burst frequency estimates were well correlated on successive days (P = 0.034-0.004; r = 0.568-0.711). Approximate entropy values were consistent at r = 0.837 (P = 0.0019). In addition, basal GH secretion rates correlated at r = 0.622 (P = 0.0176). We conclude that homeostatic control mechanisms within the GH-insulin-like growth factor I axis strongly preserve the day to day mean mass of GH secreted per burst and the serial orderliness of the GH release process in individual healthy men across a wide span of ages and body compositions.

Pulsatile iv infusion of recombinant human LH in leuprolide-suppressed men unmasks impoverished Leydig-cell secretory responsiveness to midphysiological LH drive in the aging male.

The present investigation tests the clinical hypothesis that Leydig-cell responsiveness to pulsatile and midphysiological LH drive is impaired in older men. To this end, we implemented a novel clinical investigative paradigm consisting of preadministration of an LH-down-regulating dose (3.75 mg) of leuprolide acetate followed, 3-4 wk later, by controlled challenge of the testis, with pulsatile iv infusions of saline vs. recombinant human (rh) LH. Based on a preliminary dose-finding experiment, we evaluated LH action in 8 young (ages, 18-25 yr) and 7 older (ages, 60-85 yr) volunteers by infusing eight consecutive 6-min squarewave pulses of saline or 50 IU rhLH iv every 2 h. Analyses were carried out 48 or 72 h apart in a prospective, randomly assigned, double-blind, within-subject cross-over design. Serum concentrations of T (RIA) and LH (immunoradiometric assay) were measured in blood sampled every 10 min concurrently. Leuprolide injection suppressed pre-LH-infusion (0800 h baseline) serum T concentrations (pooled mean +/- SEM) markedly in both age groups (P < 10(-3)); namely, to 40 +/- 20 ng/dl (young) and 12 +/- 3.1 ng/dl (older; P < 0.05 vs. young) (to convert to nM, multiply by 0.0347). Successive iv pulses of rhLH stimulated T output, over time, to an asymptotic maximum of 166 +/- 42 ng/dl in young men (P = 0.0008 vs. saline) and 57 +/- 9.8 ng/dl in older subjects (P = NS vs. saline, and P < 0.05 vs. young). Further regression analyses identified significant reductions of both the initial rate and maximum of the time-dependent incremental rise in LH-driven serum T concentrations in older men. In contrast, infused serum LH concentrations, distribution volumes, and calculated LH half-lives were comparable in the two age cohorts. We conclude that older men manifest both a delayed initial and reduced maximal serum T concentration rise compared with young men exposed to identical controlled midphysiological pulsatile LH drive.

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.

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)

Older men manifest multifold synchrony disruption of reproductive neurohormone outflow.

Under a working clinical hypothesis that aging putatively disrupts neuroendocrine control mechanisms, here we test a specific corollary notion that transitions in sleep stage, oscillations in nocturnal penile tumescence (NPT; a neurogenically organized signal), and the rates of instantaneous secretion of LH and/or testosterone are jointly synchronous in healthy young, but not older, men. To this end, we evaluated 10 young (aged 21-31 yr) and 8 older (aged 65-74 yr) men by intensive overnight multisite monitoring, viz. simultaneous electro-encephalogram and NPT recordings (every 30 s) and remote blood sampling (every 2.5 min) to quantitate LH and testosterone release. Waveform-independent deconvolution and cross-correlation analyses of these neurohormone outflow measures revealed that healthy young men sustain four salient physiological linkages overnight: 1) a strong inverse (confirmatory) relationship between sleep stage and NPT activity, such that deeper sleep is accompanied by suppression of NPT; 2) consistent coupling between NPT and testosterone secretion, wherein heightened NPT activity respectively precedes and follows increased testosterone secretion by 12.5-32.5 and 50-60 min; 3) evident synchrony between sleep stage and testosterone secretion, in which testosterone secretion increases over a 30-min window (-2.5 to 25 min) while sleep deepens; and 4) a close temporal linkage between instantaneous LH release and NPT oscillations, whereby LH secretion increases 55-62.5 min before and again 5-30 min after NPT declines. In contrast, older men manifested global loss of expected young adult synchrony; namely, 1) abolition of the inverse relationship between sleep stage and NPT, 2) decorrelation of NPT oscillations and testosterone secretion, 3) decoupling of testosterone release and deep sleep, and 4) abrogation of the linkage between LH secretion and penile detumescence. In summary, high intensity overnight monitoring of multiple reproductive neuroendocrine outflow measures simultaneously in young men delineates prominent neurophysiological coupling among sleep transitions and NPT activity, LH and testosterone secretion or NPT oscillations, and testosterone secretion and deepening sleep stage. In contrast, healthy older men exhibit near-universal disruption of physiological young adult synchronicity. Thus, we conclude that male reproductive aging is marked by erosion of coordinate regulation among sleep transitions, central nervous system-directed NPT activity, and hypothalamically driven episodic GnRH/LH (and thereby Leydig cell testosterone) secretion. Whether analogous multifold uncoupling of neurohormone signals emerges in the course of reproductive aging in women or in nonhuman species is not yet known.

Impact of age on cortisol secretory dynamics basally and as driven by nutrient-withdrawal stress.

The present study tests the clinical hypothesis that aging impairs homeostatic adaptations of cortisol secretion to stress. To this end, we implemented a short-term 3.5-day fast as an ethically acceptable metabolic stressor in eight young (ages 18-35 yr) and eight older (ages 60-72 yr) healthy men. Volunteers were studied in randomly ordered fed vs. fasting sessions. To capture the more complex dynamics of cortisol's feedback control, blood was sampled every 10 min for 24 h for later RIA of serum cortisol concentrations and quantitation of the pulsatile, entropic, and 24-h rhythmic modes of cortisol release using deconvolution analysis, the approximate entropy statistic, and cosine regression, respectively. The stress of fasting elevated the mean (24-h) serum cortisol concentration equivalently in the two age cohorts [i.e. from 7.2 +/- 0.35 to 11.6 +/- 0.71 microg/dL in young men and from 7.7 +/- 0.39 to 12.6 +/- 0.59 microg/dL in older individuals (P < 10(-7))]. The rise in integrated cortisol output was driven mechanistically by selective augmentation of cortisol secretory burst mass (P = 0.002). The resultant daily (pulsatile) cortisol secretion rate increased significantly but equally in young (from 94 +/- 6.3 to 151 +/- 15 microg/dL x day) and older (from 85 +/- 5.4 to 145 +/- 7.3 microg/dL x day) volunteers (P < 10(-4)). Nutrient restriction also prompted a marked reduction in the quantifiable regularity of (univariate) cortisol release patterns in both cohorts (P < 10(-4)). However, older men showed loss of joint synchrony of cortisol and LH secretion even in the fed state, which failed to change with metabolic stress (P < 10(-6)). In addition, older individuals maintained a premature (early-day) cortisol elevation in the fed state and unexpectedly evolved an anomalous further cortisol phase advance of 99 +/- 16 min during fasting (P < 10(-5)). Caloric deprivation in aging men also disproportionately elevated the mesor of 24-h rhythmic cortisol release (P = 10(-7)) and elicited a greater increment in the mean day-night variation in cortisol secretory-burst mass (P < 0.01 vs. young controls). Lastly, short-term caloric depletion in older subjects paradoxically normalized their age-associated suppression of the 24-h rhythm in cortisol interburst intervals. In summary, acute metabolic stress in healthy aging men (compared with young individuals) unmasks distinct, albeit complex, disruption of cortisol homeostasis. These dynamic anomalies impact the feedback-dependent and time-sensitive coupling of pulsatile and 24-h rhythmic cortisol secretion. Nutrient-withdrawal stress in the older male heightens the cortisol phase disparity already evident in fed elderly individuals. Conversely, the stress of fasting in young men paradoxically reproduces selected features of the aging unstressed (fed) cortisol axis; viz., abrogation of joint cortisol-LH synchrony and suppression of the normal diurnal variation in cortisol burst frequency. Whether fasting would unveil analogous disruption of feedback-dependent control of the corticotropic axis in healthy aging women is not yet known.

Comparison of pulsatile luteinizing hormone secretion between prepubertal children and young adults: evidence for a mass/amplitude-dependent difference without gender or day/night contrasts.

The assessment of pulsatile GnRH activity in children has become possible since the introduction of the sensitive third generation immunochemiluminescent assays, permitting detection of previously unmeasurable levels of LH and FSH. Despite this, however, studies differ with regard to pulse frequency and the presence of a diurnal variation in LH secretion in clinically prepubertal children. Discrepancies may reflect the limitations of relatively long intersampling intervals, less sensitive LH assays such as RIAs, and the use of algorithms to analyze pulsatile LH secretion, which do not account for endogenous production rates and metabolic clearance. To address this, we studied LH secretion in 10 prepubertal children (4 boys and 6 girls, age 8.5-10.8 y) and 12 young adults (7 men and 5 women in the early follicular phase, age 18.6-32.8 y). Blood was sampled every 5 min from 2000 h to 0200 h (nighttime) and from 0800 h to 1400 h (daytime) for LH determination, using an immunochemiluminescent assay. Deconvolution analysis revealed no difference between daytime and nighttime LH secretion, including LH secretory amplitude and pulse frequency, within any of the 4 groups, permitting pooling of the data from the 2 sampling intervals for analysis. In addition, there was no difference in LH secretion or half-life between genders. Comparison of pulsatile LH secretion between children and adults revealed a marked increase in the mass and amplitude of LH secreted per burst. LH secretory burst mass rose 9.5-fold in females, increasing the mean LH concentration by nearly 13-fold and the production rate by nearly 9-fold. The trend in males was similar although less remarkable, with a 4.2-fold rise in LH secretory burst mass from childhood to adulthood. No differences in pulse frequency, interburst interval, half-life, or approximate entropy were found between prepubertal children and adults. We conclude that the maturational change in LH secretion occurs via a highly specific mass/amplitude-dependent mechanism without significant gender or day/night differences.

Amplified nocturnal luteinizing hormone (LH) secretory burst frequency with selective attenuation of pulsatile (but not basal) testosterone secretion in healthy aged men: possible Leydig cell desensitization to endogenous LH signaling--a clinical research center study.

The specific mechanisms underlying the relative hypogonadism of aging remain to be elucidated fully. We used frequent venous sampling (every 2.5 min), sensitive and specific LH and testosterone assays, and deconvolution analysis of the endocrine time series to delineate the differences between healthy young (n = 10, age 21-34 yr) and aged (n = 8, age 62-74 yr) men in the nocturnal secretion of LH and testosterone and their half-lives. We found that elderly men vs. young men had more frequent bursts of LH secretion (1.4 vs. 0.9/h, P = 0.003), less testosterone secreted per testosterone secretory burst (9.2 vs. 17.0 nmol/L, P = 0.021), and less testosterone secreted per hour (10.7 vs. 25.0 nmol/L.h, P = 0.05). As the frequency of nocturnal LH secretory bursts increased, the frequency of testosterone bursts decreased (r = -0.746, P = 0.034). We conclude that healthy aging is associated with diminished nocturnal testosterone production attributable to 1) a decrement in the mass of testosterone released per burst and 2) an inadequate response by the pituitary gland to enhance testosterone production via an accelerated LH secretory pulse frequency. We speculate that this may reflect a partial desensitization of Leydig cells to LH.

Pulsatile intravenous gonadotropin-releasing hormone administration averts fasting-induced hypogonadotropism and hypoandrogenemia in healthy, normal weight men.

Fasting or severe caloric restriction in the human or experimental animal suppresses serum LH and sex steroid concentrations. In healthy men undergoing prolonged (5-day) nutrient deprivation, the daily LH secretion rate, the mass of LH secreted per burst, and the serum testosterone concentration fall markedly, with no decrease in responsiveness to a single bolus of GnRH. Here we test the hypothesis that the hypogonadotropic hypoandrogenemia accompanying fasting reflects decreased endogenous GnRH release. To this end, six healthy young men were studied on a fed day and during two 83-h fasting sessions with concurrent saline or pulsatile GnRH administration (100 ng/kg, i.v., every 90 min for 24 h) followed by a single bolus of 10 microg GnRH, i.v., to evaluate pituitary responsiveness. We employed a highly sensitive LH immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay, and deconvolution analysis to calculate in vivo LH secretory burst frequency, amplitude, duration, mass, and LH half-life. Fasting resulted in 30-50% declines in serum total and free testosterone and LH concentrations, and a 3-fold decrease in the calculated 24-h LH secretion rate (fed, 42 +/- 12; fasting, 14 +/- 1.9 U/L distribution volume x day; mean +/- SEM; P < 0.05, by ANOVA). Reduced LH secretion was accounted for by dual mechanisms, viz. a fall in both the apparent number of computer-resolved LH secretory bursts per 24 h (fed, 16 +/- 1.1; fasting, 10 +/- 1.2; P < 0.01) and the mass of LH secreted per burst (fed, 2.5 +/- 0.5; fasting, 1.5 +/- 0.1 U/L; P < 0.05). Fasting also decreased the mean value of the 24-h (nyctohemeral) rhythm in serum LH concentrations and reduced the approximate entropy (disorderliness) of LH release. Exogenous pulsatile GnRH injections prevented both the reduction in the calculated daily LH secretion rate (fed, 42 +/- 12; fasting plus GnRH, 64 +/- 16 IU/L; P = NS) and the decline in serum testosterone concentrations (fed, 556 +/- 71 ng/dL; fasting, 391 +/- 41; fasting plus GnRH, 859 +/- 65). Pulsatile GnRH treatment also restored the nyctohemeral mesor of serum LH concentrations and the approximate entropy value to baseline. Administration of a submaximal dose of exogenous GnRH (10 microg, i.v.) at the end of the fasting interval revealed statistically identical LH release in the three study groups, suggesting that pituitary responsiveness to GnRH was unchanged in this paradigm. In summary, a pulsatile iv GnRH infusion in young men averts completely the fasting-induced decline in LH secretory burst mass/amplitude and frequency, reinstates serum total and free testosterone concentrations, and restores the mesor of LH's nyctohemeral rhythmicity and the approximate entropy of LH release. Rescue of hypogonadism by pulsatile GnRH stimuli supports the thesis that nutrient withdrawal decreases the output of the human hypothalamic GnRH burst generator.

Differential sex steroid negative feedback regulation of pulsatile follicle-stimulating hormone secretion in healthy older men: deconvolution analysis and steady-state sex-steroid hormone infusions in frequently sampled healthy older individuals.

The healthy aging male reproductive axis tends to exhibit a progressive decline in serum concentrations of biologically available testosterone with gradual concomitant reciprocal increases in both LH and FSH concentrations. However, relatively little is known about the sex steroid-mediated negative feedback regulation of physiologically pulsatile gonadotropin release in general, and episodic FSH release in particular, in older males. To examine the steroid hormone negative feedback control of pulsatile FSH secretion in healthy older men, we applied multiparameter deconvolution analysis to serum FSH (immunoradiometric assay) profiles obtained by sampling every 10 min over 24 h during steady state (4.5-day) infusions of estradiol (E2; 48 micrograms/day), 5 alpha-dihydrotestosterone (DHT; 7.0 mg/day), or 5% dextrose in water in five healthy older men, aged 60-73 yr. We observed the following principal responses: 1) both E2 and DHT significantly suppressed mean and 24-h integrated serum FSH concentrations (P < 0.032); 2) the calculated daily secretion rate of FSH fell significantly in all five individuals during DHT infusion; 3) the apparent half-life of FSH decreased during E2 (but not DHT) infusion; 4) DHT infusion reduced the mass and frequency of FSH secretory bursts significantly; 5) neither E2 nor DHT treatment significantly attenuated the release of FSH stimulated by consecutive iv injections of GnRH (10 and 100 micrograms); and 6) integrated 24-h serum LH (immunoradiometric assay) concentrations decreased significantly during both DHT and E2 infusions, whereas mean LH release after the serial GnRH injections was not altered. Compared to younger men studied earlier in an identical fashion, older men had significantly reduced FSH intersecretory burst intervals, reflecting a higher FSH pulse frequency at baseline and during the steroid infusions and a significantly lower mass of FSH secreted per burst during E2 infusion. We conclude that healthy older men maintain intact negative feedback responsiveness of the hypothalamo-pituitary gonadotroph unit to exogenously delivered sex steroid hormones, and that individual sex steroid hormones differentially regulate specific features of pulsatile FSH release and half-life in older men.

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.