Relationship Between Gh Secretion And Sleep In Pathological States

In untreated acromegaly, studies that have examined the GH profile during poly-graphically recorded sleep have reported the absence of sleep-related GH pulses despite the presence of SW sleep (80,81). A few studies have examined nocturnal GH secretion in patients with obstructive apnea before and after treatment (82-84). As expected, nocturnal GH release is decreased in untreated apneic subjects. Because adult patients with this pathology are frequently obese, the low overnight GH levels could...

Introduction

In 1977, Bowers et al. observed that met-enkephalin analogs could stimulate secretion of growth hormone from pituitary cells (1). In 1981, Momany and Bowers (2) described additional work on the conformational analysis of small peptides that stimulate GH secretion (growth hormone releasing peptides, GHRPs), followed by their demonstration in 1984 that the hexapeptide His-DTrp-Ala-Trp-DPhe-Lys (GHRP-6) caused secretion of GH from the pituitary cells of several species, including the chick,...

Clock Time

Profiles of visually scored sleep stages (at 30-s intervals), delta power, plasma GH levels (sampled at 20-min intervals) and GH secretory rates from a typical normal young subject. Note that the profile of GH secretory rates clearly shows a rapid decrease in GH secretion coinciding with the end of the first period of increased delta wave activity and a re-initiation of secretion (reflected in a shoulder on the descending limb of the secretory pulse) at the beginning of the second...

Glucocorticoids

Glucocorticoids represent an enigmatic dilemma relative to their effects on GH secretion. In vitro data demonstrate glucocorticoids directly stimulate GH release from the anterior pituitary (68), and regulate pituitary GH gene expression by augmenting GH gene transcription and by an increase in GHRH receptor number (7). In vivo, glucocorticoids appear to blunt endogenous and stimulated GH secretion (68). The proposed mechanisms by which glucocorticoids effect this dual role in the regulation of...

Sleep Abnormalities in Conditions of Deficient or Excessive GH Secretion

A limited number of human studies, all originating from the same group of investigators, have examined sleep quality in subjects with congenital isolated GH-deficiency and in acromegalic patients before and after treatment (90). In GH-deficient adults, a decrease in duration of SW sleep and a significant suppression in delta power were observed but there were no significant differences in REM sleep (90,91). After six months of daily treatment with 2 IU m2 GH, the relative amount of REM sleep...

General Conclusion

The high and abnormal activity of the HPA axis, low levels of sex steroids, and attenuating GH secretion in abdominal obesity suggests a central neuroendocrine dysregulation in abdominal obesity. Whether this is of primary importance for the evolution of abdominal obesity or merely a secondary phenomenon to the obese condition remains to be elucidated. The finding that replacement with testosterone and GH to men with abdominal obesity are able to diminish the negative metabolic consequences of...

References

Herberg L, Bergmann M, Hennings U, Major E, Gries FA. Influence of diet of the metabolic syndrome of obesity. Isr J Med Sci 1972 8 822,823. 2. Haller H. Epidemiologie und assoziierte Risikofaktoren der Hyperlipoproteinamie. Ber Ges Inn Med 1978 32 124-128. 3. Reaven GH. Role of insulin resistance in human disease. Diabetes 1988 37 1595-1607. 4. Knospe S, Kohler E. Impaired hormonal regulation of adenosine 3', 5'-monophosphate release in adipose from hyperglycemic sand rats in vitro. Horm Metab...

Gh Secretion In Abdominal Obesity

With increased adiposity, GH secretion is blunted with a decrease in the mass of GH secreted per burst but without any major impact on GH secretory burst frequency (46). Moreover, the metabolic clearance rate of GH is accelerated (32). The serum insulin-like growth factor (IGF)-1 concentration is primarily GH dependent and influences GH secretion though a negative feed-back system (47). The serum levels of IGF-1 are inversely related to the percentage of body fat (46). In addition, the low...

Modulatory Effects Of Components Of The Somatotropic Axis On Sleep

Although the association between sleep and GH release has been well documented, there is also good evidence to indicate that components of the somatotropic axis are involved in regulating sleep quality. Although the roles of each hormone could not be identified, the findings of a recent study in transgenic mice with a deficiency in the somatotropic axis have been particularly convincing as a robust loss of non-REM sleep was demonstrated in these animals as compared to their wild-type...

Growth Hormone

Consideration of GH feedback is relevant for understanding physiology in children. From a practical therapeutic point of view, exogenous GH readily increases growth velocity. GH is directly and indirectly involved in the feedback control of its own secretion as the hypothalamic neurons that generate the GH pulse are sensitive to the pattern of GH secretion they generate (93). Administration of exogenous GH results in a blunted GH response to clonidine and GHRH in short normal boys (94) and to...

Nutritional Dwarfing Anorexia Nervosa

Nutritional dwarfing, an entity characterized by nutritional deprivation, body weight below 90 of ideal, growth retardation and growth failure, is associated with increased serum GH and decreased IGF-1 concentrations. The dissociation between GH and IGF-1 suggests that impaired somatic growth is related to reduced IGF-1 synthesis or action, whereas GH may mediate the metabolic adaptation to starvation through its effects on hepatic glucose production, lipolysis, and nitrogen conservation (22)....

New Experimental Approaches To Study Gh Effects In The

An insight into many aspects of normal physiology has been obtained from the study of mutations in animals. Originally, such animal models were generated by recognizing spontaneous mutations, but the ability to manipulate the genome makes it possible to introduce specific genetic mutations to advance our understanding of the underlying mechanisms involving GH feedback in the CNS. There are various animal models of GH deficiency in rodents that can be used as an alternative to hypophysectomy to...

Srif Receptor Subtypes

SRIF induces its biological actions by interacting with membrane-associated receptors. A number of studies had suggested that subtypes of SRIF receptors are expressed in the body (1). Studies on the pancreas suggested that SRIF 28 was much more potent than SRIF in blocking insulin secretion, whereas the peptides had similar potencies in controlling glucagon release (2), indicating that different receptors may be involved in mediating SRIF peptide effects on pancreatic hormone secretions....

Pathogenic Mechanisms

The blood flow from visceral fat depot is drained via the portal vein to the liver, in contrast to other fat depots that are drained to the systemic circulation. Visceral adipose tissue has a higher turnover rate of fat, in both men and women, than other adipose tissue depots (11). Both lipid accumulation, by the action of lipoprotein lipase (LPL), and the lipolytic response to catecholamines are elevated (11-13). The increased lipolytic activity of visceral fat combined with its anatomical...

Effects of GHRH on Sleep Quality

A number of studies have demonstrated effects of GHRH on sleep quality and it has been suggested that GH secretion and sleep may share common regulatory mechanisms (98). In rodents, intracerebral as well as systemic injections of GHRH stimulate non-REM sleep, even in hypophysectomized animals (99-102). Systemic injections of GHRH also stimulate REM sleep in intact, but not in hypophysectomized rodents (101,102). Conversely, inhibition of endogenous GHRH using GHRH antagonists or antibodies to...

Diabetes Mellitus

Debate exists regarding the heights of children and adolescents with newly diagnosed Type 1 diabetes mellitus (IDDM) (32-34), however, it appears that growth deceleration may be seen prior to islet cell failure and overt symptoms of diabetes (35). Further, poor metabolic control of IDDM is associated with chronic elevation of serum GH concentration, growth retardation, and delayed sexual development (36,37). The metabolic effects of the elevated GH concentrations have been implicated as a...

Abstract

Somatostatin (SRIF) is a 14 amino-acid-containing peptide primarily expressed in the hypothalamus. It is a major physiological regulator of growth hormone (GH) secretion and is critical in maintaining the pulsatile release of GH. SRIF induces its biological effects by interacting with membrane-associated receptors, of which a family of five have recently been cloned. The cloned receptor subtype referred to as sstr2 may have an important role in mediating the inhibitory effects of SRIF on GH...

Adult Onset GHD and Osteoporosis

Studies of patients with adult-onset GHD have served to clarify the important role of GH in maintaining the skeleton once peak bone mass is reached. Such individuals have acquired hypothalamic or pituitary dysfunction in adult life, typically owing to neoplasms of the pituitary or adjacent structures. Compromise of secretory function may occur owing to mass effect of the lesion, or, as a result of surgical or radiation treatment. The best approach in diagnosing GHD in adults remains a major...

Clinical Presentation Of Ghad

Fetal growth is primarily driven by maternal and nutritional factors, rather than by GH action. Children with GHAD generally are born with normal appearances, birth weights only slightly below average, and birth lengths about one standard deviation below the normal mean (4). This may be related to the decreased GH receptor prevalence found in fetal tissues compared to the number found postnatally. It is likely that insulin and the insulinlike growth factors (IGFs) have a more major role than GH...

And Georges Copinschi MD PhD

In the Temporal Organization of Human GH Secretion Association Between Sleep Stages and Nocturnal GH Release Sleep-Related GH Secretion During Development and Aging Relationship Between GH Secretion and Sleep in Pathological States Modulatory Effects of Components of the Somatotropic Axis on Sleep Putative Mechanisms Underlying Interactions Between Somatotropic Axis and Sleep Conclusions Acknowledgments References

Ar Ar

Often temporary Complete GH-1 deletion Present Partial GH-1 deletions, GHRH receptor mutations Present Partial GH-1 mutations AR, Autosomal recessive AD, Autosomal dominant. Growth hormone releasing hormone Somatostatin Growth hormone secretagogue Pituitary *Growth hormone releasing hormone receptor *Pituitary transcription factors (Rpx, PROP, Pit-1) *Growth hormone Growth hormone secretagogue receptor Target tissues *Growth hormone receptor *Insulin-like growth factor 1 (IGF-1) *IGF-1 receptor...

Association Between GH Release and Sleep in Normal Adults

The fact that the secretion of growth hormone (GH) is markedly stimulated during sleep has been recognized for more than three decades. Early studies using the first available radioimmunoassays for GH demonstrated that the peripheral levels of this hormone increased rapidly following sleep onset (1-5). In normal adult subjects, the 24-h profile of plasma GH levels consists of stable low levels abruptly interrupted by bursts of secretion. The most reproducible pulse occurs shortly after sleep...

Cardiovascular System

Epidemiological data suggest that adults with hypopituitarism have reduced life expectancy compared with healthy controls, with a greater than twofold increase in mortality from cardiovascular disease (35,36). GH-deficiency has been proposed as the variable accounting for this increased mortality, and the hypothesis that long standing GH-deficiency predisposes to the development of premature atherosclerosis. The mecha nisms responsible for the increased cardiovascular mortality remain largely...

C

Hormone exocytosis, 129 Calcium fluctuations agonists, 129 Caloric supplementation, 286, 287 CAMP, 171 Camphorsulfonamide discovery of, 50, 51 GHS structure of, 50f structure-activity relationships, 5If GHD, 224. 225 Carpal tunnel compression GH replacement, 227 Catabolic states GHS, 326,327 Catecholamine regulation lipolytic process, 248 Cell culture studies MK-0677 as GHRP-6 mimetic, 59 Cellular effects GH, 234, 235 Central nervous system (CNS), 145 160 experimental approaches, 156, 157 GH...

Contemporary Endocrinology

Endocrine Oncology, edited by Stephen P. Ethier, 2000 24. Endocrinology of the Lung Development and Surfactant Synthesis, edited by Carole R. Mendelson, 2000 23. Sports Endocrinology, edited by Michelle P. Warren and Naama W. Constantini, 2000 22. Gene Engineering in Endocrinology, edited by Margaret A. Shupnik, 2000 21. Hormones and the Heart in Health and Disease, edited by Leonard Share, 1999 20. Endocrinology of Aging, edited by John E. Morleyand Lucretia van den Berg, 2000 19. Human...

D

Dawn phenomenon, 252 Deadly quartet, 247 Defective growth hormone (GH) action. See Growth hormone deficiency (GHD) GH secretion rates clock time, 269f plasma GH levels, 265f Depression GH peak detection program, 208 Devazepide sleep-related G M secretion, 269, 270 Diabetes GHS, 327 G H secretion, 194, 195 Dideoxyfingerprinting (ddF) GHAD, 183 Diencephalic syndrome, 195 Diet-induccd nitrogen wasting benzolactam secretagogues, 46-49 Down Syndrome GHS, 328 DTrp2, 17 DTrp2AlaLtrp4, 19 Dual-energy...

Diagnosis Of Gh Deficiency Classical Evaluation

Diagnosing GHD is not a simple process, but involves multiple laboratory and clinical criteria. Since the late 1950s, when it was first recognized that GH isolated from human pituitaries would stimulate growth in children with deficient GH secretion, clinicians and clinical scientists have been exploring ways of defining which children would benefit from available GH therapy. The introduction of expensive, commercial, recombinant DNA-derived hGH has only intensified the need to perfect...

End Organ Targets and Receptors

The GH receptor (GHR) gene has been isolated in humans to the proximal short arm of chromosome 5 (5p13.1-12) (96). The translated product is a 620 amino acid protein encoded by nine exons (numbered, interestingly, 2-10) for the secretion signal (exon 2), extracellular domain (exons 3-7), transmembrane domain (exon 8), and intracellular domain (exons 9-10) (97). The extracellular domain is also found in circulating serum as GH binding protein. The GHR has homology with the prolactin receptor,...

Endocrine Aberrations

During recent years of investigation abdominal visceral distribution of adipose tissue has been found to be associated with endocrine disturbances, confirming the original observation by Vague (6). These disturbances include an increased cortisol activity and a blunted secretion of growth hormone (GH) and sex steroids in both men and women (29-34). These endocrine perturbations can theoretically be a consequence of the obese condition but it has also been suggested that the endocrine...

Ethical Issues Regarding Treatment Of Shortstatured Children

There is agreement about the treatment of the short-statured GH deficient child. What is controversial is the use of recombinant hGH in the treatment of the non-GH deficient child. This discussion is separate from the problems inherent in diagnosing GH deficiency as previously reviewed in this chapter. In the United States, Food and Drug Administration-(FDA) approved indications for hGH treatment at the time of preparation of this chapter include GH deficiency, growth failure associated with...

General Structureactivity Relationships In Ghrh

It is clear from a comparison of GHRH with other members of the series that its active center comprises the N-terminal hexapeptide region. Early studies also quickly ascertained that the C-terminus could be shortened (2,12) only up to position 29 with retention of almost full potency. Reduction of chain length beyond Arg29 yields analogs with full intrinsic activity down to position 20 and full loss of activity beyond that point (31,32). Fig. 3. Chou-Fasman conformational analysis of...

GH Administration for Age Related Osteoporosis

Only a small number of studies have evaluated the effects of GH administration on bone density in women with postmenopausal osteoporosis and elderly men. The sample sizes of these studies have typically been small and overall fail to demonstrate a positive effect of GH on bone density. Aloia et al. (49) performed a series of three studies evaluating the effectiveness of GH in the treatment of post-menopausal osteoporosis. The first of these included eight patients who received pituitary-derived...

GH Administration in Adult Onset GHD

Demonstration of a positive effect of GH administration on bone density in adults with childhood-onset GHD cannot be assumed to be applicable to patients who acquired GH deficiency as adults. It is unknown whether the abnormal course of skeletal maturation and the potential failure to reach peak bone mass despite GH therapy in patients with childhood-onset GHD may enhance the subsequent response of such patients to GH administered in adulthood. Observations in patients with acromegaly, a...

GH Administration in Adults with Childhood Onset GHD

Before the introduction of recombinant human GH, provision of GH was limited in the clinical setting and largely in clinical research to children with GHD. Over the past 10 yr, the availability of virtually unlimited amounts of GH, has made possible the study of broader indications for its administration. One such area of research has been the administration of GH to adults with a history of childhood-onset GH deficiency, in whom GH therapy has generally been discontinued at the time of...

Ghd And Osteoporosis Childhood Onset GHD and Osteoporosis

The positive effects of GH on osteoblast proliferation and bone formation clearly manifest in humans. This has been illustrated by several studies of patients with GHD in whom the absence of GH is associated with diminished bone-density. A relative bone density deficit has been reported in children with GHD before the start of GH replacement therapy (17). However, these data are difficult to interpret because of the confounding variable of delayed skeletal maturation in such children. Studies...

GHD in the Newborn Period

Hypopituitarism may present in the newborn in a nonspecific fashion. Signs and symptoms include apnea, cyanosis, pallor, lethargy, jitteriness, and seizures. The differential diagnosis of hypogylcemia includes GHD and hypopituitarism, which could include cortisol deficiency. Prolonged hyperbilirubinemia may be owing to TRH or TSH deficiency, causing hypothyroidism in a neonate with multiple hormone deficiency. Patients with congenital hypopituitarism may have a turbulent neonatal course,...

GHD Presenting During Childhood

GHD insufficiency and hypopituitarism can present in infancy and childhood in the following clinical settings hypoglycemia growth failure (< 7 cm yr prior to age 3 yr, < 4.5-5.0 cm yr from age 3 yr to puberty, < 5.5-6.0 cm yr during pubertal yr) diabetes insipidus disorders of pubertal development including micropenis and pubertal delay children with visual, neurological abnormalities and developmental defects characteristic truncal obesity. GHD insufficiency should be considered in...

Growth Hormone Deficiency

Early studies showed that a significant proportion of growth hormone deficient (GHD) children respond to the acute administration of GHRH with a rise in GH levels (20-22). These responses are lower on average than those of normal children or non-GH deficient children with short stature, but can overlap into the normal range (Fig. 4) (21). Depending upon the series, the fraction of patients who respond to GHRH ranges between 40 and 80 (23-25). Failure to respond to a first single bolus of GHRH...

I

Data from ref. 56. bUnpublished results. Data from ref. 56. bUnpublished results. Our initial approach involved introducing and derivatizing an aza group at the indane benzylic position. As summarized in Table 4, the unsubstituted spiroindoline derivative 32 raised rat pituitary cell potency slightly. However, the N-acetyl and N-methanesulfonyl derivatives 33 and 34 were markedly more potent (57). Other acyl and sulfonyl analogs are active at this position but attention focused on compound 34...

Inefficacy Of Caloric Supplementation

Simply increasing energy intake by oral, enteral, or parenteral routes does not consistently restore LBM in individuals with HIV infection. Failure to increase LBM was particularly evident in a group of patients with systemic infections, predominantly cytomegalovirus or M. avium complex, who were given total parenteral nutrition (TPN) (33). These individuals gained weight while receiving TPN, but they experienced no net increase in BCM, estimated by total body potassium counting. In contrast,...

Index

Abdominal obesity GH secretion, 249, 250 GH treatment, 252-255 Acquired growth hormone deficiency (GHD) causes, 206t Acromegalic patients, 273 Acromegaly, 250,299-301 GHRP-6, 32 Acute lymphoblastic leukemia (ALL), 196, 197 spontaneous pulsatile growth hormone secretion, 198f Adipose tissue, 248, 249 GH, 9 Adolescents. See Pediatrics Adrenocorticotropic hormone (ACTH) GHS pattern, 318, 319 Adult-onset GHD, 306,307 GH administration, 239, 240 osteoporosis, 235, 236 Adults osteoporosis, 235 GH...

Insulinlike Growth Factor1 Igf1

It is generally assumed that most, of not all, of the protein-anabolic effects of rhGH are mediated by IGF-1 (50). Indeed, as described earlier, significant increases in plasma levels of IGF-1 have been observed following rhGH administration to patients with HIV-associated wasting (30,39). However, the magnitude of these increases is less than that seen in HIV-negative controls. These observations have prompted speculation that there may be a degree of rhGH resistance in patients with...

Molecular Cellular And Histologic Effects Of Gh

The effects of GH on longitudinal bone growth at the cellular level are well-established. GH acts at the growth plate, where it binds to chondrocytes and promotes local synthesis of insulin-like growth factor (IGF-1) (3-5). GH stimulates the differentiation of growth-plate precursor cells and increases the responsiveness of these cells to IGF-1. Clonal expansion of differentiating chondrocytes, and thus longitudinal bone growth, is stimulated primarily by locally produced IGF-1, though GH and...

Obesity

The GH response to a variety of provocative stimuli (insulin-hypoglycemia, arginine, opiates, glucagon, levodopa and GHRH), is diminished in obese subjects (52). One study evaluating spontaneous GH secretory dynamics in obese men (body mass index BMI > 42) demonstrated a reduction in endogenous GH half-life relative to control subjects (BMI < 31), a daily production rate of GH 4.1-fold less compared with controls and a threefold decrease in GH secretory burst frequency despite preservation...

Other Action Of Gh In The

Although largely overlooked, GH has a number of neurotrophic actions (stimulating neuronal and glial proliferation, increasing myelination, and increasing brain size), whereas GH deficiency is associated with deficits in brain development (see ref. 1 for review). GH deficiency, and more especially GH treatment, are associated with a variety of changes in the major central neurotransmitters, their biosynthetic enzymes, or their receptors (102-106), but a physiological role for endogenous GH,...

Pharmacology Mechanism of Action

Physiologic secretion of GH is normally pulsatile, with the majority of secretion during the first few hours of sleep (13). Maintenance of this pattern is dependent upon the balance between stimulation by GHRH and inhibition by somatostatin, both secreted by the hypothalamus. However, the factor or factors responsible for regulating secretion of these hormones are unknown. The mechanism of GH release by the growth hormone secretagogues is complex and not completely understood. Both animal and...

Physiological Evidence In Support Of The Existence Of Multiple Gh Secretagogue Receptors Or Receptor Subtypes

To date, only one receptor for the GH secretagogues has been identified that is present at both pituitary and hypothalamic sites (8). With the large number of peptide and nonpeptide GH secretagogues now available for study, it is emerging that these compounds have subtle differences in action, raising the possibility that multiple GH secre-tagogue receptors or receptor subtypes may exist. The electrical activation of arcuate neurons by GHRP-6 has a number of distinctive characteristics most...

Potential Indications

A clear role for the growth hormone secretagogues has yet to be demonstrated. The secretagogues have both potential advantages and disadvantages compared to recombinant human GH. GH replacement therapy requires parenteral administration and results in a nonphysiologic serum GH profile with often supraphysiologic levels. Particularly in older individuals, these characteristics may contribute to the poor clinical tolerability that has been reported in several clinical trials (49-52). In contrast,...

Psychological Wellbeing And Quality Of Life

The psychological well-being and quality of life (QoL) of GH-deficient patients and the effects of GH replacement have been addressed in several studies. In the majority, self-perceived well-being, and QoL have been assessed using validated questionnaires, and comparisons have been made with healthy control subjects of similar age, sex and socioeconomic status. Although several instruments have been used in these trials the results have been remarkably consistent. Decreased psychological...

Preface

In Human Growth Hormone Research and Clinical Practice, we have been fortunate to be able to convince many of the leaders in the field to write about the recent developments in the understanding of basic and clinical research in the field of human growth hormone. During the last few years, there have been major advances in this field, one that has been dramatically enhanced by the discovery of the growth hormone-releasing peptide. This spawned much novel research, and ultimately led to the...

Putative Mechanisms Underlying Interactions Between Somatotropic Axis And Sleep

Based on the review of studies using various pharmacological agents, it may be concluded that sleep-onset GH secretion is regulated by GHRH stimulation occurring during a period of relative somatostatin withdrawal. Indeed, in humans, GH secretion during early sleep may be nearly totally suppressed by the administration of a specific GHRH antagonist, thus demonstrating an important role for GHRH in the control of sleep-related GH release (123). On the other hand, the late evening and nocturnal...

S

GH secretagogue-induced GH release, 92 Sarcopenia GHS, 326 Septo-optic dysplasia. 205 Serum insulin blood glucose glucose disappearance rate, 254f Serum prolactin. 209, 210 Serum triglycerides Syndrome X and GHD, 251 Sex steroids GH secretion, 202, 203 Sexual dimorphism GH secretion, 203 Short stature, 180 children GHS, 322 GH secretion, 201 Signal transduction GH receptor, 7, 8 Single-strand conformational polymorphism (SSCP) analysis GHAD, 183 Skeletal maintenance GH, 234 Skeletal muscle mass...

Sex Steroids

Sexual dimorphism of GH secretion is well-recognized in the rat and characterized by high-amplitude GH pulses occurring at precise 3.3-h intervals and low or undetectable GH troughs in males, whereas females exhibit irregular, more frequent, low-amplitude GH pulses with elevated basal GH levels, no distinct troughs, and slower somatic growth relative to male animals (82). 17 -estradiol administration to gonadectomized and sham-operated adult male rats converts the typical male GH secretory...

The Privileged Structure Approach

The Spiroindanylpiperidine Lead From Screening The discovery of the benzolactams demonstrated that potent nonpeptide GH secreta-gogue agonists could be discovered in the 500-600 Kda molecular weight range. This was quite a breakthrough. Although there were many nonpeptide antagonists known at the time, the only precedent for non-peptide agonists were the opioid peptide mimetics including morphine and the analgesic benzodiazepine tifluadom. Compound screening continued after the benzolactam...

Use of GHRH in Diagnosis

Part of the challenge of considering treatment in a heterogeneous aging population is identifying those individuals with the most severe reductions in endogenous GH secretion before testing whether that process helps define who might most benefit from treatment. Measuring 24-h pulsatile or even mean GH levels is impractical for population screening, and thus there has been a search for simpler tests or markers, including GH responses to GHRH, which might correlate with reductions in endogenous...

Growth Hormone and Age Related Osteoporosis

Because both GHD and normal aging are associated with decreases in bone density, it has been hypothesized that reduced GH secretion may account in part for age-related loss of bone mass (24). However, a causal relationship between GHD and osteoporosis has not been established. Nocturnal serum GH peaks average 20 ng mL in 30-yr-old men, but this value declines steadily to 3 ng mL by age 80 (24). These values are reflected in the fall of IGF-1 levels, which also occurs with aging (24). Because...

Effects of Somatostatin on Sleep

Inconsistent data have been reported concerning the action of somatostatin on sleep. In the rodent, REM sleep was inhibited by immunoneutralization of endogenous soma-tostatin (111) and enhanced by intracerebroventricular administration of exogenous somatostatin (112), while non-REM sleep was inhibited by subcutaneous injections of a long-acting somatostatin analog (113). In humans, repeated intravenous injections or infusion of somatostatin did not influence sleep quality in normal young...

Gh Treatment Of Patients With Abdominal Obesity

Hormone Transition Photoshot

As GH promotes lipolysis low levels of GH has therefore been suggested to be of importance for the maintenance of the obese condition. The calorigenic effects of GH in obese subjects has also been known for many years (99). Some trials have therefore addressed the question of whether GH administration through its calorigenic and lipolytic action might enhance weight loss during dietary restriction in obese subjects. Both short-term (100) and several weeks of GH treatment (101,102) in...

Long vs Short Acting Compounds GH Secretory Pattern and Hormonal Specificity

Growth Hormone Adaptive Demands

In clinical studies, single doses of growth hormone secretagogues, given intravenously, intranasally, or orally have resulted in a dramatic elevation in serum GH levels (to approx 40-70 ng mL) (38-45) accompanied by modest post-dose increases in serum cortisol (mediated by ACTH) and prolactin (46,47). Since growth hormone and prolactin secreting cells are derived from the same embryonic lineage, stimulation of prolactin can Fig. 3. Serum samples were collected every 10 min from each of three...

Neurosecretory Dysfunction

The clinical evaluation of infants, children, and adolescents with growth disorders may include provocative tests of GH secretion and 24-h profiles of spontaneous GH release however, there is currently no gold standard laboratory test for the diagnosis of GH deficiency (121,122). A blunted GH response to known GH secretogogues may help to identify subjects suspected to be GH-deficient in the clinical setting of growth retardation (< 3rd percentile), diminished growth velocity, and delayed...

Discovery Of The Benzolactam Secretagogues

With the renewed interest in potential clinical applications of GH, Merck researchers in 1988 became interested in discovering an orally active nonpeptidyl mimic peptidomimetic of GHRP-6. Extensive structure-activity relationships for GHRP-6 had already been published 5,8,9 . Aromatic residues were favored at positions 2, 4, and 5 and a basic amino terminus was important for GH releasing activity. In addition, preliminary evidence at Merck suggested that the GHRP-6 receptor hereafter referred...