Requirement for proximal putative Sp1 and AP-2 cis-deoxyribonucleic acid elements in mediating basal and luteinizing hormone- and insulin-dependent in vitro transcriptional activation of the CYP17 gene in porcine theca cells.

The cytochrome P450 17alpha-hydroxylase/C(17-20) lyase (CYP17) enzyme catalyzes the first committed step in androgen biosynthesis. In primary cultures of immature swine theca cells, LH and insulin induce CYP17 mRNA and incompletely processed heteronuclear RNA supraadditively over 2-6 h. To monitor in vitro transcriptional control by these two physiological signals, we cloned a -976 to +31-bp 5'-upstream region of the homologous CYP17 gene and fused it to a cytoplasmically targeted firefly luciferase minigene (CYP17/luc).

Involvement of Sp1 and SREBP-1a in transcriptional activation of the LDL receptor gene by insulin and LH in cultured porcine granulosa-luteal cells.

Luteinizing hormone (LH) and insulin stimulate transcriptional activity of the porcine low-density lipoprotein (LDL) receptor (LDLR) promoter supra-additively in primary cultures of granulosa-luteal cells. The mechanistic basis of this bihormonal interaction is unknown. The pig LDLR gene promoter includes three putative Sp1/Sp3-binding sites and one sterol response element (SRE) site 5' upstream to the transcriptional start site.

Putative GH pulse renewal: periventricular somatostatinergic control of an arcuate-nuclear somatostatin and GH-releasing hormone oscillator.

Growth hormone (GH) pulsatility requires periventricular-nuclear somatostatin(SRIF(PeV)), arcuate-nuclear (ArC) GH-releasing hormone (GHRH), and systemic GH autofeedback. However, no current formalism interlinks these regulatory loci in a manner that generates self-renewable GH dynamics. The latter must include in the adult rat 1) infrequent volleys of high-amplitude GH peaks in the male, 2) frequent discrete low-amplitude GH pulses in the female, 3) disruption of the male pattern by severing SRIF(PeV) outflow to ArC, 4) stimulation of GHRH and GH secretion by central nervous system delivery of SRIF, 5) inhibition of GH release by central exposure to GHRH, and 6) a reboundlike burst of GHRH secretion induced by stopping peripheral infusion of SRIF.

Insulin drives transcriptional activity of the CYP17 gene in primary cultures of swine theca cells.

Insulin stimulates androgen biosynthesis and the accumulation of CYP17 mRNA and heterogeneous nuclear (hn) RNA in primary cultures of immature swine theca cells. To further assess insulinomimetic transcriptional control, we subcloned 1.007 kilobases (kb) of the 5'-upstream region of the CYP17 gene (-976 to +31 base pairs [bp] to the transcriptional start site) into a firefly-luciferase reporter construct.

Contrasting negative-feedback control of endogenously driven and exercise-stimulated pulsatile growth hormone secretion in women and men.

GH represses its own secretion via rapid and reversible feedback exerted at key hypothalamic loci. The primary mechanisms include stimulation of somatostatin release and inhibition of GHRH outflow. Autoinhibition is prominent in the adult male rat but diminutive in the female animal.

Induction of beta-cell rest by a Kir6.2/SUR1-selective K(ATP)-channel opener preserves beta-cell insulin stores and insulin secretion in human islets cultured at high (11 mM) glucose.

In health, most insulin is secreted in pulses. Type 2 diabetes mellitus (TTDM) is characterized by impaired pulsatile insulin secretion with a defect in insulin pulse mass. It has been suggested that this defect is partly due to chronic overstimulation of beta-cells imposed by insulin resistance and hyperglycemia, which results in depletion of pancreatic insulin stores.

Exaggerated 17-hydroxyprogesterone response to intravenous infusions of recombinant human LH in women with polycystic ovary syndrome.

Studies using pharmacological gonadotropin stimulation suggest that ovarian steroidogenesis is abnormal in the polycystic ovary syndrome (PCOS). We assessed ovarian steroid secretion in response to near-physiological gonadotropin stimuli in 12 ovulatory controls and 7 women with PCOS. A gonadotropin-releasing hormone-receptor antagonist (ganirelix, 2 mg sc) was given to block endogenous LH secretion, followed by dexamethasone (0.

The insulin secretagogues glibenclamide and repaglinide do not influence growth hormone secretion in humans but stimulate glucagon secretion during profound insulin deficiency.

In vitro data have recently suggested that sulfonylureas (SUs) enhance GH secretion by modulating the effects of GHRH and somatostatin in pituitary cells. The present study was undertaken to explore in more detail a possible influence of a single dose of SU (glibenclamide) and a non-SU (repaglinide) insulin secretagogue on circulating GH dynamics. Ten C-peptide-negative type 1 diabetic individuals were examined on three occasions in random order.

Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive.

We postulated that short-term estradiol replacement in postmenopausal women may act, in part, by facilitating endogenous GHRH release or action. A prediction of this hypothesis is that estradiol repletion should enhance postsomatostatin rebound GH secretion, which appears to be driven by hypothalamic outflow of GHRH. To this end, we administered placebo and estradiol to eight healthy estrogen-withdrawn postmenopausal volunteers in a prospectively randomized, patient-blinded, within-subject crossover design for a total of 36 d.

Retention of estradiol negative feedback relationship to LH predicts ovulation in response to caloric restriction and weight loss in obese patients with polycystic ovary syndrome.

The present study tests the hypothesis that specific endocrine, metabolic, and anthropometric features distinguish obese women with polycystic ovary syndrome (PCOS) who resume ovulation in response to calorie restriction and weight loss from those who do not. Fifteen obese (body mass index 39 +/- 7 kg/m(2)) hyperandrogenemic oligoovulatory patients undertook a very low calorie diet (VLCD), wherein each lost > or =10% of body weight over a mean of 6.25 mo.

Beta1-adrenergic blockade augments pulsatile PTH secretion in humans.

Pulsatile peptide hormone secretion provides efficient control of specific end organ functions. To test the hypothesis that sympathetic neuronal activity drives synchronous pulsatile PTH release from the parathyroid glands, we investigated the acute effects of beta1-adrenergic receptor blockade on PTH secretion patterns in a single-blinded study in nine healthy adults. Plasma PTH levels were determined at 1-min intervals.

Sex-steroid modulation of growth hormone (GH) secretory control: three-peptide ensemble regulation under dual feedback restraint by GH and IGF-I.

Technical, genetic, and clinical developments have unveiled a burgeoning array of novel effectors of GH secretion. The present appraisal of central neuroregulatory components of the somatotropic axis highlights a simplifying concept of ensemble control by the final common peptides, GH-releasing hormone (GHRH), GH-releasing peptide(s) (GHRP, ghrelin), and somatostatin. These potent signals act individually, antagonistically, and synergistically to direct pulsatile GH secretion.

Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu.

To test the clinical hypothesis that an estrogen-enriched milieu enhances GHRH action, we administered placebo (Pl) and estradiol-17 beta (E(2)) orally for 23 d to six postmenopausal women in a prospectively randomized, double-masked, within-subject crossover design with 6 wk intervening. The GHRH stimulation protocol entailed consecutive i.v.

Divergent gonadotropin-gonadal dose-responsive coupling in healthy young and aging men.

The present study extends a recent composite model of in vivo interglandular signaling to assess the impact of age on 1) nonequilibrium exchange among diffusible and protein-bound testosterone (Te); 2) elimination of total and free Te; 3) basal and pulsatile Te secretion (sec); 4) the implicit feedforward function mediating luteinizing hormone (LH) concentration (con) drive of instantaneous Te sec; and 5) possible stochastic variability of the predicted LH con-Te sec dose-response linkage. To this end, we measured LH and Te con every 10 min for 24 h in healthy young (n = 13) and older men (n = 13). Statistical comparisons of analytic estimates revealed that elderly subjects manifest 1) reduced maximal burstlike LH-stimulated Te sec (impaired stimulus efficacy); 2) depressed half-maximally LH-stimulated Te sec (lower Leydig-cell responsivity); 3) decreased pulsatile and total Te sec; 4) elevated basal Te sec; 5) a prolonged half-life of total but not free Te con; and 6) delayed time evolution of LH and Te sec bursts.

Endocrine and metabolic effects of growth hormone (GH) compared with GH-releasing peptide, thyrotropin-releasing hormone, and insulin infusion in a rabbit model of prolonged critical illness.

Treatment with recombinant human GH (rhGH) increases the mortality of critical illness. We postulated that combined GH-releasing peptide-2 (GHRP-2), TRH, and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed, New Zealand White rabbits were randomized to receive 4-d treatment with saline (n=8); 60 microg/kg.

Control of LH secretory-burst frequency and interpulse-interval regularity in women.

Hypothalamic neurons generate discrete bursts of gonadotropin-releasing hormone (GnRH) and thereby pulses of luteinizing hormone (LH) at randomly timed intervals centered on a probabilistic mean frequency. We tested the hypothesis that physiological mechanisms govern not only the number but also the stochastic dispersion of the GnRH/LH pulse-renewal process in humans; for example, in young women in the early (EF) and late (LF) follicular and midluteal (ML) phases of the menstrual cycle (n = 18) and in postmenopausal individuals (PM, n = 16). To this end, we quantify stochastic interpulse variability by way of the order-independent, two-parameter Weibull renewal process (Keenan DM and Veldhuis J.

Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly.

Octreotide is a potent somatostatin analog that inhibits growth hormone (GH) release and restricts somatotrope cell growth. The long-acting octreotide formulation Sandostatin LAR is effective clinically in approximately 60% of patients with acromegaly. Tumoral GH secretion in this disorder is characterized by increases in pulse amplitude and frequency, nonpulsatile (basal) release, and irregularity.

A tripeptidyl ensemble perspective of interactive control of growth hormone secretion.

Current investigational tools in molecular biology, biochemistry and integrative physiology have revealed an increasing array of signals that influence growth hormone (GH) secretion. The present perspective combines these factors under a simplified final-common pathway model of threefold joint control by GH-releasing hormone, GH-releasing peptide/ghrelin and somatostatin. This concept is highlighted from the viewpoint of sex steroid- and age-dependent modulation of the peptide trilogy listed above.

Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion.

Growth hormone (GH) secretion is vividly pulsatile in all mammalian species studied. In a simplified model, self-renewable GH pulsatility can be reproduced by assuming individual, reversible, time-delayed, and threshold-sensitive hypothalamic outflow of GH-releasing hormone (GHRH) and GH release-inhibiting hormone (somatostatin; SRIF). However, this basic concept fails to explicate an array of new experimental observations.

Diazoxide attenuates glucose-induced defects in first-phase insulin release and pulsatile insulin secretion in human islets.

Humans with type-2 diabetes mellitus (TTDM) have hyperglycemia ( approximately 11 mM) and impaired glucose-mediated insulin secretion characterized by impaired first-phase insulin release (FPIR) and pulsatile insulin release. Culture of islets from nondiabetic humans in very high glucose concentrations ( approximately 20-30 mM) for 96 h causes impaired FPIR. We sought to determine 1).

Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency, and mass in a dual-waveform construct: time of day-dependent regulation.

Quantification of in vivo pituitary hormone secretion requires simultaneous appraisal of implicit 1) secretory-burst waveform, mass, and stochastic pulse timing; 2) basal secretion; 3) biexponential elimination kinetics; and 4) random experimental error (Keenan DM, Licinio J, and Veldhuis JD. Proc Natl Acad Sci USA 98: 4028-4033, 2001). The present study extends this analytic formalism to allow for time of day-dependent waveform adaptation (burst-shape change) at statistically determinable boundary times.

Neuroendocrine facets of human puberty.

The unfolding of pubertal growth and maturation entails multisystem collaboration. Most notably, the outflow of gonadotropins and growth hormone (GH) proceeds both independently and jointly. The current update highlights this unique dependency in the human.

Three-peptide control of pulsatile and entropic feedback-sensitive modes of growth hormone secretion: modulation by estrogen and aromatizable androgen.

The present review highlights a simplified perspective of growth hormone (GH) secretory control, which incorporates the individual and joint effects of final-common signals that converge on somatotrope cells. Critical peptidyl effectors are GH-releasing hormone (GHRH), GH-releasing peptide (GHRP, ghrelin), and somatostatin. The latter three-peptide ensemble mediates stimulation, inhibition, and feedback suppression of GH secretion via homologous and heterologous interactions.

Physiological control of pituitary hormone secretory-burst mass, frequency, and waveform: a statistical formulation and analysis.

The present study investigates the time-varying control of pituitary hormone secretion over the day and night (D/N). To this end, we implemented an analytical platform designed to reconstruct simultaneously 1) basal (nonpulsatile) secretion, 2) single or dual secretory-burst waveforms, 3) random effects on burst amplitude, 4) stochastic pulse-renewal properties, 5) biexponential elimination kinetics, and 6) experimental uncertainty. The statistical solution is conditioned on a priori pulse-onset times, which are estimated in the first stage.

Neuroendocrine adaptations in renal disease.

Chronic renal failure (CRF) disrupts the time-dependent secretion of multiple hormones. The present review focuses on altered pulsatile release of peptide hormones. CRF is marked by impaired tissue actions, disorderly release patterns, and relative [growth hormone (GH)] or absolute [luteinizing hormone (LH)] deficiency of secretion.