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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

Sex-dependent alteration in cortisol response to endogenous adrenocorticotropin.

We have investigated ACTH and cortisol secretion patterns in two groups of five healthy adult male and female subjects. Plasma samples were obtained at 10-min intervals for 24 h, and pulsatile hormone release was analyzed by a multiparameter deconvolution technique. ACTH secretion was greater in male than female subjects; the production rate per 24 h was 139 +/- 7 pmol/L distribution volume in males, and 89 +/- 11 pmol/L distribution volume in females (P = 0.007). Cortisol secretion did not differ significantly between sexes; in males, the 24-h secretion rate was 2807 +/- 239 nmol/L distribution volume, and in females, it was 2970 +/- 411 nmol/L distribution volume (P = NS). The number of ACTH secretory pulses per 24 h, as determined by deconvolution analysis, was 16.2 +/- 1.4 in males and 19.6 +/- 2.0 in females (P = NS). There were no sex differences in the number of cortisol pulses or the calculated half-lives of ACTH and cortisol. ACTH and cortisol pulses were significantly concordant at a cortisol lag time of 10 min, as demonstrated by probability analysis and cross-correlation with auto-regressive modeling. Based on a significantly different regression intercept of cortisol pulse height on ACTH pulse height in women than in men (P < 0.001) and a higher ratio of cortisol to ACTH production rates in women than in men (P = 0.013), we suggest that the female adrenal cortex is more responsive to ACTH than its male counterpart in terms of glucocorticoid production. Consequently, equivalent daily cortisol secretion rates are attained in men and women at the expense of greater ACTH release in men.

Adrenocorticotropic Hormone↗
PubMed1995

Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay.

A chemiluminescence-based GH assay with 30- to 100-fold increased sensitivity recently disclosed combined basal and pulsatile GH secretion in men. However, how age, sex steroid hormones, and obesity singly and jointly influence the basal vs. pulsatile modes of GH release is not known. We used the foregoing assay (detection threshold, 0.002-0.005 microgram/L) and high sensitivity and specificity (> or = 90% each) deconvolution analysis to quantitate basal and pulsatile GH secretion from 24-h serum GH concentration profiles in 26 healthy lean and obese men, whose ages spanned 18-63 yr and whose percentage body fat ranged from 12-47%. Concentrations of serum insulin-like growth factor I (IGF-I), IGF-I-binding protein-1 (IGFBP-1), and IGFBP-3 were related to specific measures of basal or pulsatile GH release. We observed that mean (24-h) serum GH concentrations embraced a 140-fold range from 0.013-1.8 micrograms/L and were related negatively to age (r = -0.50; P < 0.01), percentage body fat (r = -0.620; P < 0.01), and their interaction (r = -0.610; P < 0.01). In contrast, testosterone was a robustly positive statistical determinant of mean serum GH values (r = 0.628; P = 0.0006). Stepwise multivariate regression analysis disclosed that percentage body fat alone and jointly with the serum testosterone concentration controlled, respectively, 38% and 50% of the total variability in GH levels (P = 0.0013 and P = 0.0008). As assessed by deconvolution analysis, GH secretory burst mass was negatively related to percentage body fat (r = -0.621; P < 0.01) and positively to serum testosterone (r = 0.529; P = 0.0054). The calculated half-life of GH correlated positively with serum estradiol (r = 0.447; P = 0.032), and negatively with percentage body fat (r = -0.437; P = 0.048). Basal GH secretion rates were negatively related to serum estradiol (r = -0.485; P = 0.016). In contrast, GH secretory burst frequency and duration were unrelated to age, percentage body fat, or sex steroids. The fraction of total GH secreted in bursts was negatively correlated with the body mass index (r = -0.540; P < 0.01). Serum IGF-I concentrations were positively related to total pulsatile GH secretion (r = 0.690; P = 0.0011) and negatively to age (r = -0.597; P = 0.007) and percentage body fat (r = -0.611; P = 0.009).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Dynamics of basal and gonadotropin-releasing hormone-releasable serum follicle-stimulating hormone charge isoform distribution throughout the human menstrual cycle.

In the present study we analyzed physiological changes in the relative distribution of FSH isoforms circulating under baseline conditions throughout the ovarian cycle as well as the forms discharged by GnRH stimulation from putative acutely releasable and reserve pituitary pools. Eight normally menstruating women underwent blood sampling on three occasions, once each during the presumptive early or midfollicular phase (FP), late follicular phase to midcycle (preovulatory phase; PO), and mid- to late luteal phase (LP) of the menstrual cycle. Blood samples were withdrawn at 10-min intervals for a total of 10 h before and after the iv administration of 10 and 90 micrograms GnRH. GnRH-stimulated FSH pulses were analyzed for secretory burst mass, secretory burst amplitude, integrated FSH concentrations, and endogenous FSH half-life by deconvolution. Serum FSH isoforms were separated by preparative chromatofocusing in 30 x 1-cm columns and identified by RIA of eluent fractions. The changes observed in serum FSH isoform distribution were then correlated with the corresponding secretory and clearance estimates of the released FSH molecules. In each phase of the menstrual cycle, a significant rise in serum FSH concentrations was observed after administration of the consecutive low and high dose GnRH pulses. The magnitude of the response in terms of secretory burst mass, secretory amplitude, and area of GnRH-induced FSH peaks was significantly higher during the PO. In all cycle phases, but particularly during the FP and PO, administration of the 90-micrograms GnRH dose elicited higher (1.4- to 1.7-fold) FSH secretory responses than the lower dose. Multiple parameter deconvolution of the GnRH-induced FSH pulses revealed that FSH molecules released in response to 10 micrograms GnRH at PO exhibited significantly (P < 0.01) shorter plasma half-lives (108 +/- 11 min) than those released during the follicular and luteal phases of the same menstrual cycles (apparent plasma half-life of FSH released at FP, 222 +/- 37 and 271 +/- 47 min for 10 and 90 micrograms GnRH-induced FSH pulses, respectively; LP, 244 +/- 41 and 198 +/- 40 min; P = NS, FP vs. LP) and in response to the high dose GnRH challenge at PO (276 +/- 40 min). Under all conditions studied, serum FSH charge isoforms were distributed along a pH range of 7.0 to less than 4.0.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1996

Assessment of stimulated and spontaneous adrenocorticotropin secretory dynamics identifies distinct components of cortisol feedback inhibition in healthy humans.

Corticosteroids inhibit ACTH secretion through diverse cellular mechanisms, including direct pituitary and indirect suprapituitary effects. Although exogenous CRH provides a useful assessment of corticotroph function, the suprapituitary component of ACTH regulation has been difficult to assess in humans. Naloxone (NAL) has been reported to stimulate ACTH secretion indirectly through the release of endogenous hypothalamic CRH, suggesting its potential application in the examination of suprapituitary regulation of ACTH secretory dynamics. We sought to examine the inhibitory effects of corticosteroids on kinetic parameters of ACTH secretion, assessed by a deconvolution method, in healthy human subjects. We also sought to directly compare the ACTH responses to serial administration of human CRH and NAL as well as spontaneously occurring ACTH pulses to distinguish pituitary and suprapituitary components of hypothalamic-pituitary-adrenal regulation. Normal healthy subjects (n = 11) received hCRH (0.4 microgram/kg) at 1800 h and then NAL (65 micrograms/kg) at 1930 h, respectively, on 3 separate study days: placebo pretreatment plus CRH/NAL stimulation, metyrapone (MET) pretreatment plus CRH/NAL, or MET alone. Plasma ACTH and serum cortisol were assessed at frequent (every 10 min) intervals during CRH/NAL or placebo infusions (1800-2100 h) on all 3 study days, and deconvolution analysis was performed to determine kinetic parameters of endogenous and stimulated ACTH secretion. Suppression of endogenous cortisol secretion with MET significantly increased both continuous (basal secretion rate) and pulsatile CRH- and NAL-stimulated ACTH bursts (P < 0.05). The increase in total ACTH secreted per burst was related to two distinct effects of cortisol regulating the amplitude (maximum secretion rate) and half-duration (P < 0.05) of secretory bursts. The ACTH responses to CRH and NAL for individual subjects were significantly and positively correlated in both placebo pretreatment plus CRH/NAL stimulation and MET pretreatment plus CRH/NAL studies (P < 0.01). MET administration disproportionately increased the ACTH response to NAL, producing a significant increase (P < 0.01) in the slope of the regression relating ACTH responses to CRH and NAL. The following conclusions were made: 1) endogenous cortisol secretion, even at levels associated with relatively low serum cortisol concentrations, exerts a significant negative feedback effect on both continuous and pulsatile ACTH secretion; 2) cortisol inhibits pulsatile ACTH secretion through distinct regulatory mechanisms that independently modulate both the mass and the duration of ACTH secretory bursts; 3) the differential sensitivity of the CRH- and NAL-stimulated ACTH responses to MET administration suggests that both pituitary and suprapituitary components of the hypothalmic-pituitary-adrenal axis are sensitive to negative regulation over a rapid or intermediate temporal domain. Endogenous cortisol modulates multiple components of dynamical ACTH secretion through composite effects that appear to be mediated through structurally and functionally distinct regulatory domains.

Adrenocorticotropic Hormone↗
PubMed1996

Mode of pulsatile follicle-stimulating hormone secretion in gonadal hormone-sufficient and -deficient women--a clinical research center study.

To test the hypothesis that FSH is secreted at least in part within discrete secretory bursts in women and that the characteristics of episodic FSH secretion are altered within differing gonadal hormone environments, we measured FSH by immunoradiometric assay every 10 min for 24 h in premenopausal women during the early follicular (EF), late follicular (LF), and midluteal (ML) phases of the menstrual cycle and in postmenopausal (PM) women (n = 8 in each group). Secretory events were evaluated using multiparameter deconvolution. FSH was secreted in an episodic manner, with the number of secretory bursts (per 24 h; mean +/- SEM) detected in LF (20 +/- 0.79) and PM (20 +/- 0.90) women being greater than that in EF (16 +/- 0.88) and ML (14 +/- 0.93) women. FSH secretory burst mass (milliinternational units per mL) was significantly higher in PM (12 +/- 1.6) than in EF (1.8 +/- 0.21), LF (3.1 +/- 1.3), or ML (0.8 +/- 0.11) women and primarily reflected a relative increase in the maximal secretory rate rather than increased burst half-duration. The estimated half-life (minutes) of endogenous FSH in LF women (155 +/- 18) was shorter than those calculated in EF (251 +/- 24), ML (277 +/- 38), and PM (231 +/- 18) women. Cross-correlation analysis showed strongly positive associations between successively paired serum FSH and LH concentrations in all four groups of women. Deconvolution of simultaneously obtained LH concentration-time series revealed statistically significant concordance (13-25%) between FSH and LH secretory episodes at a lag time of 0 min in EF, LF, and PM women and when LH secretory bursts led FSH secretory bursts by 10 min in ML phase women. However, as 75-87% of FSH and LH secretory pulses were discordant, we infer the operation of distinct control mechanisms in the generation of FSH and LH release episodes. In summary, these results suggest that FSH is secreted within discrete secretory bursts in women, that the mass and frequency of FSH secretory bursts differ in women exhibiting various gonadal hormone environments, and that FSH and LH secretory bursts occur coincidentally at a higher rate than expected on the basis of chance alone, but at such a low overall rate of concordance that distinct mechanisms probably operate to direct episodic FSH and LH secretory activity.

Adult↗
PubMed1999

Tripartite neuroendocrine activation of the human growth hormone (GH) axis in women by continuous 24-hour GH-releasing peptide infusion: pulsatile, entropic, and nyctohemeral mechanisms.

Despite the discovery of potent GH-releasing peptides (GHRPs) more than 15 yr ago and the recent cloning of human, rat, and pig GHRP receptors in the hypothalamus and pituitary gland, the neuroregulatory mechanisms of action of GHRP agonists on the human hypothalamo-somatotroph unit are not well delineated. To gain such clinical insights, we evaluated the ultradian (pulsatile), entropic (pattern orderliness), and nyctohemeral GH secretory responses during continuous 24-h i.v. infusion of saline vs. the most potent clinically available hexapeptide, GHRP-2 (1 microg/kg x h) in estrogen-unreplaced (mean serum estradiol, 12 +/- 2.4 pg/mL) postmenopausal women (n = 7) in a paired, randomized design. Blood was sampled every 10 min for 24 h during infusions and was assayed by ultrasensitive GH chemiluminescence assay. Pulsatile GH secretion was quantitated by deconvolution analysis, orderliness of GH release patterns by the approximate entropy statistic, and 24-h GH rhythmicity by cosinor analysis. Statistical analysis revealed that GHRP-2 elicited a 7.7-fold increase in (24-h) mean serum (+/-SEM) GH concentrations, viz. from 0.32 +/- 0.042 (saline) to 2.4 +/- 0.34 microg/L (GHRP-2; P = 0.0006). This occurred via markedly stimulated pulsatile GH release, namely a 7.1-fold augmentation of GH secretory burst mass: 0.87 +/- 0.18 (control) vs. 6.3 +/- 1.3 microg/L (GHRP-2; P = 0.0038). Enhanced GH pulse mass reflected a commensurate 10-fold (P = 0.023) rise in GH secretory burst amplitude [maximal GH secretory rate (micrograms per L/min) attained within a secretory pulse] with no prolongation in event duration. GH burst frequency, interpulse interval, and calculated GH half-life were all invariant of GHRP-2 treatment. Concurrently, as detected in the ultrasensitive GH assay, GHRP-2 augmented deconvolution-estimated interpulse (basal) GH secretion by 4.5-fold (P = 0.025). The approximate entropy of 24-h serum GH concentration profiles rose significantly during GHRP-2 infusion; i.e. from 0.592 +/- 0.073 (saline) to 0.824 +/- 0.074 (GHRP-2; P = 0.0011), signifying more irregular or disorderly GH release patterns during secretagogue stimulation. Cosinor analysis of 24-h GH rhythms disclosed a significantly earlier (daytime) acrophase at 2138 h (+/- 140 min) during GHRP-2 stimulation vs. 0457 h (+/-42 min) during saline infusion (P = 0.013). Concomitantly, the cosinor amplitude rose 6-fold (P = 0.018), and the mesor (cosine mean) rose 5-fold (P = 0.003). Fasting (0800 h) plasma insulin-like growth factor (IGF-I) concentrations rose by -11 +/- 12 microg/L during saline infusion and by 102 +/- 18 microg/L during GHRP-2 infusion (P = 0.0036). GHRP-2 infusion did not modify (24-h pooled) serum LH, FSH, or TSH concentrations and minimally increased serum (pooled) daily PRL (6.8 +/- 0.83 vs. 12 +/- 1.2 microg/L; P < 0.05) and cortisol (5.3 +/- 0.59 to 7.0 +/- 0.74; P < 0.05) concentrations. In summary, 24-h constant iv GHRP-2 infusion in the gonadoprival female neurophysiologically activates the GH-IGF-I axis by potentiating GH secretory burst mass and amplitude by 7- to 10-fold and augmenting the basal (nonpulsatile) GH secretion by 4.5-fold. GHRP-2 action is highly selective, as it does not alter GH secretory burst frequency, interpulse interval, event duration, or GH half-life. GHRP-2 effectively elevates IGF-I concentrations, unleashes greater disorderliness of GH release patterns, and heightens the 24-h rhythmicity of GH secretion. These tripartite features of GHRP-2's action in estrogen-withdrawn (postmenopausal) women also characterize normal human puberty and/or sex steroid regulation of the GH-IGF-I axis. However, how or whether GHRP-2 interacts further with sex hormone modulation of GH neurosecretory control in older women and men is not yet known.

Aged↗
PubMed1999

Jointly amplified basal and pulsatile growth hormone (GH) secretion and increased process irregularity in women with anorexia nervosa: indirect evidence for disruption of feedback regulation within the GH-insulin-like growth factor I axis.

Anorexia nervosa (AN) is associated with multiple endocrine alterations. In the majority of AN patients, basal and GHRH-stimulated serum GH levels are increased. The metabolic effects of GH are known to be related to its pulsatile secretory pattern. The present study was performed to examine GH pulsatility in AN using the techniques of deconvolution analysis and approximate entropy, which quantify secretory activity and serial irregularity of underlying hormone release not reflected in peak occurrence or amplitudes. To this end, 24-h GH profiles were obtained by continuous blood sampling aliquoted at 20-min intervals in 8 nonfasting patients with AN [body mass index (BMI), 14.2 +/- 0.8 kg/m2; mean +/- SEM) and in 11 age-matched healthy women (BMI, 20.3 +/- 0.5 kg/m2). The deconvolution-estimated half-life of GH was not altered in the AN patients. The pituitary GH secretory burst frequency, burst mass, and burst duration were each significantly increased in women with AN compared to those in normal weight women. A 4-fold increase in daily pulsatile GH secretion was accompanied by a 20-fold increase in basal (nonpulsatile) GH secretion. There were significant negative correlations between BMI and the basal as well as pulsatile GH secretion rates. Moreover, AN patients exhibited significantly greater GH approximate entropy scores than the controls, denoting marked irregularity of the GH release process. In contrast to previous reports in healthy fasting subjects, cortisol levels in AN patients were positively correlated to GH secretion rates. Leptin levels were significantly inversely correlated to the pulsatile, but not the basal, GH secretion rate. The present data demonstrate augmented basal as well as pulsatile GH secretion with disruption of the orderliness of the GH release process in AN. Accordingly, GH secretion in AN probably reflects altered neuroendocrine feedback regulation, e.g. associated with increased hypothalamic GHRH discharge superimposed on reduced hypothalamic somatostatinergic tone.

Activity Cycles↗
PubMed1999

Time mode of growth hormone (GH) entry into the bloodstream and steady-state plasma GH concentrations, rather than sex, estradiol, or menstrual cycle stage, primarily determine the GH elimination rate in healthy young women and men.

We have investigated whether a reduced MCR of GH in women will account for their higher serum GH concentrations premenopausally compared with those in men. To this end, we directly compared the half-life (t 1/2) of GH and its volume of distribution (Vo) in 13 young men and 6 comparably aged women, each evaluated at three stages of the normal menstrual cycle (viz. the early follicular, late follicular, and midluteal phases). To estimate nonequilibrium GH kinetics, each subject received octreotide pretreatment to suppress endogenous GH release and then 3 randomly ordered iv bolus doses of recombinant human GH (1, 2, and 4 microg/kg). The resultant peak serum GH concentrations were 18 +/- 4, 36+/-8, and 70+/-9 microg/L in six women and 17+/-2, 30+/-4, and 84+/-25 microg/L in six men (P = NS, gender contrast). Corresponding Vo values were 66+/-1, 71+/-1, and 60+/-1 mL/kg in women and 69+/-1, 78+/-1, and 73+/-1 mL/kg in men (P = NS). Matching monoexponential GH t1/2 values were 7.6+/-0.3, 8.2+/-0.4, and 8.8+/-0.7 min in women and 9.8+/-0.8, 10+/-1, and 9.5+/-1 min in men (average 1.7 min longer in men). Regression analysis disclosed no relationship between serum estradiol concentrations and peak serum GH levels, GH t 1/2, or Vo. GH t 1/2 values were also invariant of menstrual cycle stage, e.g. t 1/2 values of 8.1+/-0.5, 9.1+/-1.0, and 8.1+/-0.4 min for the early follicular, late follicular, and midluteal phases, respectively. Corresponding normalized MCRs were 319+/-39 (early follicular), 340+/-48 (late follicular), and 340+/-71 (midluteal) L/m2 x day in women and 336+/-50 L/m2 x day in men (P = NS). In parallel equilibrium infusion studies in men, we administered GH by constant iv infusions for 240 min during octreotide suppression. At doses of 0.5, 1.5, and 4.5 microg/kg x min, steady state GH t 1/2 values were 9+/-1, 12+/-1, and 15+/-1 min (at respective steady state serum GH concentrations of 0.5+/-0.05, 2.1+/-0.2, and 7.5+/-0.5 microg/L). In a third analysis in the same volunteers, stopping the constant iv infusions revealed t 1/2 values of GH decay from equilibrium of 26+/-5 and 23+/-2.3 min for the two higher GH infusion rates. In a fourth paradigm, endogenous GH t 1/2 values, as assessed in the same individuals by deconvolution analysis of overnight (10-min sampled) serum GH concentration profiles, averaged 18+/-1.3 min. This value was intermediate between that of poststeady state decay and iv bolus elimination of GH. In summary, the foregoing clinical experiments in healthy men and women indicate that 1) the nonequilibrium GH t 1/2, (body surface area-normalized) Vo, and MCR are independent of GH dose, sex, menstrual cycle stage, and serum estradiol concentrations; 2) the GH t 1/2 calculated after iv bolus injection is significantly (50%) shorter than that assessed during or after steady-state GH infusions or endogenously (overnight) by deconvolution analysis; and 3) the descending rank order of GH t 1/2 values in healthy volunteers is approximately: decay from steady state (23+/-2.3 min) > endogenously secreted GH (18+/-1.3 min) > during equilibrium infusion (15+/-1 min) > after bolus infusion (9.8+/-0.8 min). We thus conclude that for any given body surface area, the elimination properties of GH in men and women reflect predominantly the time mode of hormone entry into the circulation, rather than gender, menstrual cycle stage, or prevailing serum estradiol concentration. Accordingly, differences in serum GH concentrations in premenopausal women compared to those in young men and across the normal menstrual cycle reflect commensurate differences in pituitary GH secretion rates.

Adult↗
PubMed2000

Apparently complete restoration of normal daily adrenocorticotropin, cortisol, growth hormone, and prolactin secretory dynamics in adults with Cushing's disease after clinically successful transsphenoidal adenomectomy.

ACTH production in Cushing's disease is characterized by a markedly elevated rate of basal (nonpulsatile) secretion, an increased mass of ACTH released per burst and an unremarkable pulse frequency. In addition, the ACTH secretory process and that of GH and PRL exhibit profoundly disordered patterns. Whether some or all of these disturbances can be reversed or normalized by transsphenoidal microadenomectomy remains unknown. We therefore investigated the detailed dynamics of ACTH, GH, and PRL in eight patients (aged 38.9+/-4.2 yr) with pituitary-dependent Cushing's disease who were in long-term (8.2+/-1.7 yr) clinical remission following transsphenoidal surgery and eight controls matched for age, gender, and body mass index. To this end, blood was sampled at 10-min intervals for 24 h for the later assay of ACTH, cortisol, GH, and PRL. Secretory activity was quantitated by deconvolution methods, and the pattern orderliness (regularity) of hormone release was determined by the approximate entropy (ApEn) statistic. The joint synchrony of ACTH and cortisol secretion was monitored by the cognate bivariate statistic, cross-ApEn. Diurnal properties of the hormonal release were appraised by cosinor analysis. Based on deconvolution analysis, postsurgical patients exhibited a normal frequency, half-life, duration, and mass of ACTH and cortisol secretory bursts. Accordingly, the 24-h production rates of both ACTH (2.5+/-0.7 microg/L in patients vs. 2.9+/-0.7 microg/L in controls; P = 0.755) and cortisol (49+/-11 micromol/L in patients vs. 73+/-15 micromol/L in controls; P = 0.217) were normal also. The acrophase of the diurnal rhythm of ACTH (patients, 0817 h +/- 37 min; controls, 0850 h +/- 38 min; P = 0.629) and cortisol (patients, 1000 h +/- 24 min; controls, 0855 h +/- 30 min; P = 0.175) was also restored by surgery. ApEn values of ACTH (patients, 1.168 +/- 0.090; controls, 0.864+/-0.122; P = 0.133) and cross-ApEn of ACTH-cortisol (patients, 1.396+/-0.087; controls, 1.170+/-0.076; P = 0.140) secretion were both normal in this cohort, denoting restoration of the secretory process regularity. Cortisol ApEn was slightly higher in patients (patients, 1.034+/-0.084; controls, 0.831+/-0.038; P = 0.048). Both GH and PRL time series manifested full reconstitution of pulsatile, 24-h rhythmic, and entropic properties. In summary, clinically successful transsphenoidal microadenomectomy in adults with Cushing's disease can fully normalize virtually all quantitative features of regulated ACTH, cortisol, GH, and PRL secretion. Further studies will be needed to establish the consistency of these findings in larger cohorts of adults with Cushing's disease and in children with this disorder and to delineate the significance, if any, of a residual, minimally detectable disruption of orderly cortisol secretion in this patient population.

Adenoma↗
PubMed2000

Gender and sexual maturation-dependent contrasts in the neuroregulation of growth hormone secretion in prepubertal and late adolescent males and females--a general clinical research center-based study.

Although numerous studies have delineated an impact of gender on the neuroendocrine control of GH secretion in the adult, few investigations have defined the nature and extent of sex differences before puberty. This deficit reflects jointly the sensitivity limitations of earlier GH assays and the paucity of intensive sampling protocols in healthy children. Here we have applied a chemiluminescence-based GH assay (sensitivity, 0.005 microg/L) to study GH release in blood sampled every 10 min for 12 h from 1800-0600 h in 58 healthy children. Males and females were evaluated in prepuberty (n = 17 boys; n = 11 girls) and late adolescence (n = 13 males; n = 17 females). We quantitated the principal regulated facets of GH release by 1) deconvolution analysis to assess basal vs. pulsatile GH secretion, 2) approximate entropy to compute the regularity of GH release patterns, and 3) cosine regression analysis to evaluate the overnight rhythmic release of GH. Gender by maturation analysis of variance revealed a mean 2.3-fold increase in the integrated serum GH concentration between prepuberty and late adolescence (P < 10(-6)). Deconvolution analysis disclosed that 91-97% of total GH secretion was pulsatile. Pulsatile, but not basal, GH release showed marked sexual maturation dependence (P < 10(-5)). Pulsatile GH release rose in adolescents due to a 2.25-fold greater GH secretory burst mass (P = 0.00011), which reflected joint 1.5-fold increases in GH secretory pulse amplitude and duration (P < 0.01). Pulse-mass enhancement across puberty was gender independent, but mechanistically specific, as GH pulse frequency, intersecretory burst interval, and half-life were invariant of pubertal status. The approximate entropy statistic identified more disorderly GH secretion patterns in adolescent females compared with prepubertal children and adolescent males (P = 0.00074). Cosinor analysis unmasked elevated overnight rhythms in GH secretory burst mass and interburst intervals in late adolescents of both genders compared with prepubertal boys (for burst mass) or girls (for interburst intervals). Linear regression analysis disclosed strong correlations among 1) the plasma insulin-like growth factor I concentration and GH secretory burst mass (P < 10(-3)), 2) the GH pulse mass and the serum testosterone concentration (P = 10(-3)), 3) the irregularity (entropy) of GH secretory patterns and the serum estradiol concentration (P < 10(-4)), and 4) the basal GH secretion rate and the serum estradiol concentration (P = 10(-2)). In summary, healthy prepubertal children and late adolescent boys and girls manifest distinctive mechanisms controlling GH release, as appraised for all three of the pulsatile, entropic, and 12-h rhythmic modes of GH neuroregulation. The major maturational contrast in the pulsatile mode of GH secretion is amplified secretory burst mass in adolescents due to jointly heightened GH pulse amplitude and duration. The dominant gender distinction lies in the reduced orderliness of GH release patterns in late adolescent girls. Overnight rhythms in GH secretory burst mass and interburst intervals enlarge in both sexes at adolescence, thus signaling enhanced coupling between the rhythmic and pulsatile control of GH release at this time. At the extrema of pubertal development, sex steroid hormones are associated differentially with specific facets of GH release, e.g. an elevated basal GH secretion rate (estrogen), greater irregularity of GH release patterns (estrogen), and amplified GH secretory burst mass and higher plasma insulin-like growth factor I concentrations (testosterone). Accordingly, we postulate that sex steroids supervise selectively each of the dominant facets of GH neurosecretory control across human puberty.

Adolescent↗
PubMed2001

Basal, pulsatile, entropic, and 24-hour rhythmic features of secondary hyperprolactinemia due to functional pituitary stalk disconnection mimic tumoral (primary) hyperprolactinemia.

Under physiological conditions, PRL secretion is regulated precisely by various stimulating and inhibiting factors. Hyperprolactinemia may arise as a primary consequence of a PRL-secreting pituitary adenoma. Secondary hyperprolactinemia (SH) may emerge in patients with hypothalamic disease, hypophyseal stalk compression, or suprasellar extension of a (nonlactotrope) pituitary adenoma. The latter may reflect diminished delivery of dopamine or other inhibitory factors to normal lactotropes. We hypothesized that diurnal and ultradian rhythms of PRL secretion would differ in secondary (e.g. hypothalamic) and primary (e.g. tumoral states) hyperprolactinemia (PH), assuming that the underlying pathophysiologies differ. To test this clinical postulate, we investigated the patterns of 24-h PRL release in eight patients with SH associated with functional hypothalamo-pituitary disconnection and in eight patients with PH attributable to microprolactinoma. Data in each group were compared with values in healthy gender-matched controls. PRL time series were obtained by repetitive 10-min blood sampling, followed by high- precision immunofluorometric assay. PRL concentration profiles were analyzed by the complementary tools of model-free discrete peak detection, waveform-independent deconvolution analysis, cosinor regression, and the approximate entropy metric to quantitate pulsatile, basal, 24-h rhythmic, and pattern-dependent (entropic) PRL secretion. Patients with tumoral hyperprolactinemia (PH) showed a 2-fold higher 24-h mean serum PRL concentration than patients with SH (62 +/- 13 microg /L vs. 30 +/- 6.9 microg/L, respectively, P = 0.029). Estimated PRL pulse frequency (events/24 h) was similar in the two patient groups (18.5 +/- 0.7 vs. 17.6 +/- 0.8; P = 0.395) but elevated over that in euprolactinemic controls (P < 0.0001 for both). Deconvolution analysis disclosed a mean daily PRL secretion rate of 790 +/- 170 microg in PH patients vs. 380 +/- 85 microg in SH patients (P = 0.030). Nonpulsatile PRL secretion comprised nearly 70% of total secretion in both patient groups and 50% in controls (P < 0.0001). Cosinor analysis revealed similar acrophases in all three study cohorts. The mean skewness of the statistical distribution of the individual PRL sample secretory rates was reduced, compared with controls (P < 10 (-5) for each), but equivalent in SH and PH patients (0.83 +/- 0.12 vs. 0.78 +/- 0.08, respectively), denoting a loss of the normal spectrum of low- and higher-amplitude secretion rates. Approximate entropy, a regularity statistic, was markedly elevated in both patient groups over controls (P < 10 (-6) for each) and was slightly higher in PH patients than in SH patients (1.639 +/- 0.029 vs. 1.482 +/- 0.067, P = 0.048). In summary, patterns of PRL secretion in PH and SH states exhibit an equivalently increased frequency of PRL pulses, a comparably marked rise in nonpulsatile (basal) PRL secretion. Despite overlap, the regularity of PRL release patterns is disrupted even more profoundly in PH (tumoral), compared with SH. Assuming that the orderliness of serial PRL output monitors normal integration within a feedback-controlled neurohormone axis, then the more disorderly patterns of tumoral PRL secretion point to greater regulatory disruption in PH. The latter may reflect abnormal secretory behavior associated with lactotrope neoplastic transformation and/or isolation of the tumor cell mass from normal hypothalamic controls.

Adult↗
PubMed2002

Pulsatile insulin secretion by human pancreatic islets.

Insulin is secreted in discrete bursts. These pulses are also present when individual or groups of islets are perifused. Interpretation of the measured frequency and magnitude of pulsatile hormone secretion requires an examination of the sensitivity and specificity of the methods for pulse detection and validation of these for the experimental apparatus and hormone assay in which they are applied. In the present study we achieve these aims for a perfusion method for measurement of pulsatile insulin release by human islets. A deconvolution technique previously developed for measurement of pulsatile hormone secretion in vivo was specifically validated for in vitro pulse detection in the present study. Deconvolution analysis reliably (>90%) detected insulin pulses with an amplitude 20% or more above baseline and recovered quantitatively the insulin secretion profile, insulin secretion rate, and insulin pulse mass from single as well as multiple perifused islets. Cluster analysis was less sensitive, but was able to detect most (>80%) pulses with an amplitude of 40% or more above baseline. With this limitation, cluster analysis is potentially useful for groups, but not single perifused human islets. Analysis of single human islets showed that enhanced insulin secretion by increased glucose concentrations in the perfusate is achieved by enhancing insulin pulse mass with no change in pulse frequency. Perfused single or groups of human islets exhibited an interpulse interval ( approximately 6-8 min) comparable to that observed in humans in vivo. Dynamic in vitro perifusion should facilitate studies of the mechanisms driving pulsatile insulin secretion.

Cluster Analysis↗
PubMed2002

GH secretion is impaired in patients with primary hyperparathyroidism.

The activity of the GH/IGF-I axis as a function of parathyroid activity and calcium metabolism in humans has never been assessed. To address this issue, we studied 18 patients (5 men, 13 women; age range, 23-76 yr; mean, 61 yr) with primary hyperparathyroidism (PHP) due to solitary parathyroid adenoma. GH secretion was evaluated by serum IGF-I levels, spontaneous mean GH secretion over two morning hours, and GH response to arginine (ARG) alone or combined with GHRH. In five patients, serum GH concentrations were measured every 20 min for 24 h, and deconvolution analysis was performed. A group of 35 age- and sex-matched normal subjects served as controls. Mean serum IGF-I levels in PHP were lower than in normal controls, and in six PHP patients individual serum IGF-I levels were below the age-related normal range. The mean (+/-SE) peak GH response to ARG alone in PHP patients was significantly lower than in normal subjects (4.0 +/- 1.0 vs. 22.0 +/- 1.3 microg/liter; P < 0.001). Likewise, the mean (+/-SE) peak GH response to ARG plus GHRH was reduced in PHP patients (9.9 +/- 0.9 vs. 38.0 +/- 3.5 microg/liter; P < 0.001). The mean GH concentration over two morning hours in PHP was lower (0.20 +/- 0.05 vs. 1.34 +/- 0.31 microg/liter; P < 0.001). The mean GH concentration over 24 h in five PHP patients was lower than in six normal controls (0.3 +/- 0.1 vs. 0.7+/- 0.1 microg/liter; P < 0.05); the deconvolution analysis showed that 24-h GH production rate (3.0 +/- 1.7 vs. 28.2 +/- 4.7 microg/liter.d; P < 0.05) and mean secretory burst mass (1.2 +/- 0.7 vs. 10.5 +/- 2.6 microg/liter; P < 0.05), but not pulse frequency, were lower in PHP patients than in normal controls. GH half-life and approximate entropy values of 24-h GH profiles were similar in PHP patients and normal controls. No correlation was found between serum-ionized calcium or PTH levels and spontaneous or stimulated GH levels in PHP patients. In conclusion, this study demonstrates that PHP patients have a reduction in both spontaneous and stimulated GH secretion. Accordingly, PHP should be mentioned as a further example of a metabolic condition in which GH secretion in adults is reduced.

Adult↗
PubMed2002

Increased orderliness of growth hormone (GH) secretion in GH-deficient adults with low serum insulin-like growth factor I.

Available studies suggest that a proportion of GH-deficient (GHD) adults maintain serum IGF-I concentrations within the age- and sex-matched normal range. The basis for this distinction is not known. In this study 24-h GH profiles (sampling every 30 min) were appraised in five GHD adults with low serum IGF-I concentrations (<2 SD of the age- and sex-matched normal range), five GHD adults with normal serum IGF-I levels (within +/-2 SD), and five healthy subjects. Serial GH concentrations, measured using a chemiluminescence assay, were analyzed by deconvolution and approximate entropy (ApEn; regularity) analyses. The apparent half-duration of GH secretory bursts was longer in both GHD groups than in the healthy controls, as determined by deconvolution analysis (P < 0.05 each). The GH burst frequency was higher, the interburst interval was shorter, and the GH burst amplitude was lower in GHD adults with normal serum IGF-I than in healthy controls (P < 0.05, P < 0.05, and P < 0.01, respectively). The percentage of total daily GH secretion that was pulsatile was also reduced in the GHD adults with normal serum IGF-I compared with the other two groups (P < 0.05 and P < 0.05, respectively). In contrast, ApEn ratios were lower in the GHD adults with low serum IGF-I than in the GHD adults with normal IGF-I and controls (P < 0.01 and P < 0.05, respectively). Serum IGF-I concentrations correlated positively with ApEn ratios in the total study population (n = 15) and in the GHD adults (n = 10). In conclusion, 24-h patterns of GH release differed in GHD adults with low vs. normal serum IGF-I concentrations. GHD adults with low IGF-I levels maintain low ApEn ratios (denoting greater relative orderliness of GH secretion), whereas GHD patients with normal IGF-I values generate a high frequency, low amplitude GH output. The foregoing contrasts point to distinct neuroendocrine features of the GH-deficient state of adults, which can be related to concurrent IGF-I production.

Adult↗
PubMed2000

In-vitro in-vivo correlation models for glibenclamide after administration of metformin/glibenclamide tablets to healthy human volunteers.

In this study, level C and A in-vitro in-vivo correlation (IVIVC) models were developed for glibenclamide. In-vitro dissolution data were collected for the glibenclamide component of three metformin/glibenclamide tablets using a USP Type II apparatus. In-vivo plasma concentration data were obtained after administration of the prototype formulations to 24 healthy volunteers and subject to deconvolution analysis to obtain percentage in-vivo absorbed profiles. Multiple linear level C models were developed for CMAX and AUC(0-48) using percentage in-vitro dissolved data at 10, 45 and 120 min. Initially, the level A model was constructed for the first 2 h only, based on availability of in-vitro data. Another level A model was attempted using a time-scaled approach, with percentage in-vivo absorbed at time t and percentage in-vitro dissolved at time t/I as the correlating data. Internal predictability was evaluated for the level C and time-scaled level A models. For all level C approaches, linear regression models with r2 > 0.99 were determined. The prediction errors (% PE) for Cmax and AUC(0-48) were less than 1% for all formulations at all three chosen time points. The deconvolution analysis indicated biphasic absorption for glibenclamide, with one phase occurring at 2-3h and another at 6-12h after dose administration. The level A model using 2-h data was not unique for all formulations and was therefore not developed. The time-scaling factor I correlated highly (r2 = 0.99) with in vitro mean dissolution time (MDT). A linear regression time scaled model (r2 = 0.97) was successfully developed using in-vitro and in-vivo data from all 3 formulations. However, the internal predictability of the time-scaled model was poor, with % PE values for Cmax and AUC(0-48) being as much as 30.5% and 18.7%, respectively. The results indicate that level C models have good internal predictability. Though a time-scaled level A IVIVC model was successfully developed, the model was found to have poor internal predictability.

Adult↗
PubMed1992

Brain and cerebrospinal fluid distributions of metoprolol in rats.

The distribution of metoprolol tartrate (MPL) into the brain and cerebrospinal fluid (CSF) from plasma was determined at 2 different steady-state plasma concentrations (2 and 20 nmol/ml) and following intravenous bolus administration (100 nmol/kg) in rats. Under steady-state condition, no difference in the brain and CSF distributions of MPL was observed between 2 different plasma MPL concentrations, and the value of brain- or CSF-to-plasma partition coefficients were 5.7 and 1.5, respectively. Following intravenous administration, MPL distributed into CSF very rapidly and its initial uptake phase was not detected. On the other hand, MPL distribution into the brain was relatively slow with the uptake phase. Thus, the brain uptake of MPL from the plasma was pharmacokinetically analyzed using a modified 2-compartment model and deconvolution method, whereas the CSF distribution of MPL was not adequate for kinetic analysis because of the lack of uptake phase. The analysis of brain uptake of MPL by both compartment model and deconvolution gave the same results and the calculated brain Kp value of MPL was almost comparable with that of observed Kp value under steady-state plasma concentration. The distribution of MPL into CSF was considered mainly depending on the pH difference between the plasma and CSF, and the mutual transfer of MPL between CSF and the brain tissue was considered to be negligible from an in vitro study.

Animals↗
PubMed2002

Noniterative blind data restoration by use of an extracted filter function.

A signal-processing algorithm has been developed where a filter function is extracted from degraded data through mathematical operations. The filter function can then be used to restore much of the degraded content of the data through use of a deconvolution algorithm. This process can be performed without prior knowledge of the detection system, a technique known as blind deconvolution. The extraction process, designated self-deconvolving data reconstruction algorithm, has been used successfully to restore digitized photographs, digitized acoustic waveforms, and other forms of data. The process is noniterative, computationally efficient, and requires little user input. Implementation is straightforward, allowing inclusion into many types of signal-processing software and hardware. The novelty of the invention is the application of a power law and smoothing function to the degraded data in frequency space. Two methods for determining the value of the power law are discussed. The first method assumes the power law is frequency dependent. The function derived comparing the frequency spectrum of the degraded data with the spectrum of a signal with the desired frequency response. The second method assumes this function is a constant of frequency. This approach requires little knowledge of the original data or the degradation.

Journal Article↗