The somatotroph pituitary gland function in high-aged multimorbid hospitalized patients with IGF-I deficiency.

PURPOSE: It is unclear whether the age-related decline in the somatotropic axis stems from a reduced growth hormone (GH) production in the pituitary gland, or from a peripheral origin akin to an acquired GH resistance. With the help of a GHRH/arginine test, high-aged multimorbid hospitalized patients with IGF-I deficiency are to be tested to determine whether there is primarily a pituitary GH deficiency in the sense of a somatopause. METHODS: Seventeen multimorbid patients (eleven men and six women) with a mean age of 82 years, with IGF-I concentrations below two standard deviations of 30-year-old men and women were identified. Patients suffered from a variety of common age-related stable diseases including coronary artery disease, chronic liver or kidney disease, chronic heart failure as well as acute conditions e.g., urosepsis or endocarditis. To assess the somatotropic axis they underwent a GHRH/arginine test. Results were evaluated using descriptive statistics. RESULTS: In average, the peak concentration of GH after stimulation was 14.8 µg/L with a range from 2.76 to 47.4 µg/L. Taking into account both, gender and BMI (with a mean of 26.5 kg/m²) for each participant, the pituitary gland was adequately stimulated in 16 out of the 17 patients. No patient reported common side effects related to the GHRH/arginine test. CONCLUSION: The somatotroph pituitary gland retains its secretory capacity in the advanced aged. Therefore, age does not seem to be the driving pacemaker for the functional decline of the somatotropic axis within the aged population.

Growth Hormone and Aging.

Growth hormone (GH) secretion declines with aging (somatopause). One of the most controversial issues in aging is GH treatment of older adults without evidence of pituitary pathology. Although some clinicians have proposed reversing the GH decline in the older population, most information comes from not placebo-controlled studies. Although most animal studies reported an association between decreased GH levels (or GH resistance) and increased lifespan, human models have shown contradictory reports on the consequences of GH deficiency (GHD) on longevity. Currently, GH treatment in adults is only indicated for individuals with childhood-onset GHD transitioning to adulthood or new-onset GHD due to hypothalamic or pituitary pathologic processes.

Musculoskeletal Effects of Altered GH Action.

Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws its name from its anabolic effects on muscle and bone but also has distinct metabolic effects in multiple tissues. In addition to its metabolic and musculoskeletal effects, GH is closely associated with aging, with levels declining as individuals age but GH action negatively correlating with lifespan. GH's effects have been studied in human conditions of GH alteration, such as acromegaly and Laron syndrome, and GH therapies have been suggested to combat aging-related musculoskeletal diseases, in part, because of the decline in GH levels with advanced age. While clinical data are inconclusive, animal models have been indispensable in understanding the underlying molecular mechanisms of GH action. This review will provide a brief overview of the musculoskeletal effects of GH, focusing on clinical and animal models.

Clinical relevance of insulin-like growth factor-1 to cardiovascular risk markers.

OBJECTIVE: Insulin-like growth factor-1 (IGF-1) is an anabolic hormone, the levels of which decline with age. The present study aimed to determine the impact of age-related declines in serum IGF-1 levels on various physiological processes. DESIGN: We retrospectively reviewed the medical records of patients whose serum IGF-1 levels were estimated in our department, and assessed the relationships between serum IGF-1 levels and various physiological parameters. RESULTS: A total of 427 patients with a mean (± standard deviation) age of 52.8 (± 17.1) years were included in the analysis. The levels of serum IGF-1 showed significant positive correlation with those of hemoglobin and hematocrit, and negative correlation with the presence of inflammatory and fibrin-related markers including C-reactive protein (CRP) and procalcitonin (PCT), and D-dimer and fibrin degradation products (FDP). These tendencies persisted after exclusion of patients with pituitary disease. CONCLUSIONS: In this study population of diverse diseases and backgrounds, a decline in serum IGF-1 levels with age was associated with an increase in inflammatory and fibrin-related markers. This may explain the correlation between low serum IGF-1 levels and an increased risk of cardiovascular events. Our findings suggest that serum IGF-1 is a clinically relevant marker of cardiovascular risk, particularly in males.

Elemental Analysis of Aging Human Pituitary Glands Implicates Mercury as a Contributor to the Somatopause.

Background: Growth hormone levels often decline on aging, and this "somatopause" is associated with muscle and bone loss, visceral adiposity and impaired cardiovascular function. Mercury has been detected in human pituitary glands, so to see if mercury could play a part in the somatopause we measured the proportion of people at different ages who had mercury in their anterior pituitary cells. Materials and methods: Paraffin sections of pituitary glands taken at autopsy from 94 people between the ages of 2 and 99 years were stained for inorganic mercury using autometallography. Pituitary mercury content was classified as none, low (<30% of cells) or high (>30% of cells) in increasing two-decade age groups. Autometallography combined with immunohistochemistry determined which hormone-producing cells contained mercury. Laser ablation-inductively coupled plasma-mass spectrometry was used to confirm the presence of mercury. Results: The proportion of people with low-content pituitary mercury remained between 33 and 42% at all ages. The proportion of people with high-content mercury increased with increasing age, from 0% of people in the 2-20 year group to a peak of 50% of people in the 61-80 years group, followed by a fall to 35% of people in the 81-99 years group. Mercury, when present, was found always in somatotrophs, occasionally in corticotrophs, rarely in thyrotrophs and gonadotrophs, and never in lactotrophs. Laser ablation-inductively coupled plasma-mass spectrometry detected mercury in regions of pituitaries that stained with autometallography. Conclusions: The proportion of people with mercury in their anterior pituitary cells, mostly somatotrophs, increases with aging, suggesting that mercury toxicity could be one factor contributing to the decline in growth hormone levels found in advancing age.

A useful model to compare human and mouse growth hormone gene chromosomal structure, expression and regulation, and immune tolerance of human growth hormone analogues.

Human (h) pituitary growth hormone (GH) is both physiologically and clinically important. GH reaches its highest circulatory levels in puberty, where it contributes to energy homeostasis and somatogenic growth. GH also helps to maintain tissues and organs and, thus, health and homeostasis. A reduction in the rate of hGH production begins in middle age but if GH insufficiency occurs this may result in tissue degenerative and metabolic diseases. As a consequence, hGH is prescribed under conditions of GH deficiency and, because of its lipolytic activity, stimulation of hGH release has also been used to treat obesity. However, studies of normal GH production and particularly synthesis versus secretion are not feasible in humans as they require sampling normal pituitaries from living subjects. Furthermore, human (or primate) GH structure and, as such, regulation and potential function, is distinct from non-primate rodent GH. As a result, most information about hGH regulation comes from measurements of secreted levels of GH in humans. Thus, partially humanized hGH transgenic mice, generated containing fragments of human chromosome 17 that include the intact hGH gene locus and many thousands of flanking base pairs as well as the endogenous mouse (m) GH gene provide a potentially useful model. Here we review this mouse model in terms of its ability to allow comparison of hGH versus mGH gene expression, and specifically: (i) GH locus structure as well as regulated and rhythmic expression; (ii) their ability to model a clinical assessment of hGH production in response to overeating and hyperinsulinemia as well as a possible effect of exercise, and (iii) their hGH-related immune tolerance and thus potential for testing hGH-related analogue immunogenicity.

Somatopause, weaknesses of the therapeutic approaches and the cautious optimism based on experimental ageing studies with soy isoflavones.

The pathological phenomenon of somatopause, noticeable in hypogonadal ageing subjects, is based on the growth hormone (GH) production and secretion decrease along with the fall in GH binding protein and insulin-like growth factor 1 (IGF-1) levels, causing different musculoskeletal, metabolic and mental issues. From the perspective of safety and efficacy, GH treatment is considered to be highly controversial, while some other therapeutic approaches (application of IGF-1, GH secretagogues, gonadal steroids, cholinesterase-inhibitors or various combinations) exhibit more or less pronounced weaknesses in this respect. Soy isoflavones, phytochemicals that have already demonstrated the health benefits in treated elderly, at least experimentally reveal their potential for the somatopausal symptoms remediation. Namely, genistein enhanced GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells; refreshed and stimulated the somatotropic system (hypothalamic nuclei and pituitary GH cells) function in a rat model of the mild andropause, and stimulated the GH output in ovariectomized ewes as well as the amplitude of GH pulses in the rams. Daidzein, on the other hand, increased body mass, trabecular bone mass and decreased bone turnover in the animal model of severe andropause, while both isoflavones demonstrated blood cholesterol-lowering effect in the same model. These data, which necessarily need to be preclinically and clinically filtered, hint some cautious optimism and call for further innovative designing of balanced soy isoflavone-based therapeutics.

[Pituitary disorders in elderly patients].

The increase in life expectancy of about 30 years in the developed countries represents one of the most important achievements of the last hundred years. During aging, normal pituitary activity undergoes significant changes, reflecting the complex relationship between aging and endocrine systems. These alterations are postulated to be causally linked to human aging, possibly contributing to changes in body composition, bone structure, physical performance, cardiovascular system functions, and increased morbidity and mortality. Owing to age-dependent physiological changes in pituitary function, as well as coexistent chronic illness and polypharmacy, interpretation of pituitary function tests in older adults is more difficult than in the younger. As symptoms of pituitary disorders may overlap with what is considered to be ''normal aging,'' the presence of a pituitary disorder in the elderly may often go undiagnosed. Unrecognized and untreated pituitary disorders are associated with adverse outcomes that can be ameliorated or prevented by adequate therapy. This paper summarizes the present state of knowledge on the age-related changes in pituitary function, as well as discusses the etiology, clinical manifestation, diagnosis, and management of pituitary disorders in the elderly.

Growth hormone secretion in response to glucagon stimulation test in healthy middle-aged men / Secreção do hormônio do crescimento em resposta ao teste de estímulo com glucagon em homens saudáveis de meia-idade

OBJECTIVE: To investigate the growth hormone (GH) response to glucagon stimulation test (GST) in a population of healthy men over 50 years old in comparison to insulin tolerance test (ITT), analysis of the spontaneous 24-hour GH profile and insulin-like growth factor 1 (IGF-I). METHODS: 27 healthy men aged between 51 and 65 years were tested. RESULTS: Using non-parametric correlation analysis, a positive correlation between GH peak after GST and mean IGF-I (r = 0.528; p = 0.005) was found, as well with GH peak in 24-hour profile (r = 0.494; p = 0.009). No correlation was found comparing GH peak after ITT with the same parameters. Ten subjects presented GH peak of less than 3.0 μg/L after GST, none confirmed in ITT. CONCLUSIONS: GH peak response to GST was lower than ITT, but it showed a positive correlation with mean IGF-I and also with GH peak in 24-hour profile. However, GST should not be used to differentiate organic growth hormone deficiency (GDH) from the expected decline on GH secretion due to aging.

OBJETIVO: Investigar a resposta do hormônio do crescimento (GH) ao teste de estímulo com glucagon (GST) numa população de homens saudáveis acima dos 50 anos de idade, em comparação ao teste de tolerância à insulina (ITT), além da análise do perfil de secreção espontânea de GH nas 24 horas e fator de crescimento semelhante à insulina (IGF-I) basal. MÉTODOS: 27 homens, com idades entre 51 e 65 anos, foram submetidos aos testes. RESULTADOS: Utilizando análise de correlação não paramétrica, encontrou-se correlação positiva entre o pico de GH pós-GST e a média de IGF-I (r = 0,528; p = 0,005), e também com o pico espontâneo do GH no perfil de 24 horas (r = 0,494; p = 0,009). Não houve correlação do pico de GH pós-ITT com os mesmos parâmetros. Dez indivíduos apresentaram pico de GH após GST inferior a 3,0 μg/L, sem confirmação no ITT. CONCLUSÕES: O pico de GH pós-GST foi menor do que o obtido pós-ITT, porém demonstrou correlação positiva com a média de IGF-I e o pico de GH na secreção espontânea de 24 horas. Entretanto, o GST não demonstrou ser um bom teste para distinguir entre deficiência de hormônio de crescimento (DGH) e somatopausa.

Effects of Growth Hormone Replacement Therapy on Quality of Life in Patients with Somatopause

OBJECTIVE: There is increasing interest in growth hormone (GH) replacement therapy to improve quality of life (QoL) of elderly with age-related decline in GH level (somatopause). The aim of this study was to evaluate the effect of GH replacement on the QoL in patients with somatopause. METHOD: A prospective study of 56 adults with somatopause was conducted. They were replaced with a GH over a 6-month period. QoL was assessed by using three self-rating questionnaires: the Nottingham Health Profile (NHP), the Psychological General Well-Being Index (PGWBI) and theAssessment of Growth Hormone Deficiency in Adults (AGHDA). RESULTS: Significant impairment in QoL as measured by NHP, PGWBI and AGHDA were noted in patients with somatopause compared with age and sex matched normal population (p<0.05). There was significant improvement in QoL after 6-month of GH replacement (p<0.05). CONCLUSION: Six months GH replacement induced an improvement in the QoL of patients with somatopause.

The Predictors of Growth Hormone Secretion after L-dopa Stimulation Test in Adults

BACKGROUND: Twenty four-hour GH secretion reaches a peak in puberty and declines by 14% every decade in adult life. By age 60, most adults have a total 24-hour secretion rate indistinguishable from those of hypopituitary patients with organic lesions in pituitary gland. We performed this study to know about the predictors of GH secretion after L-dopa stimulation test in adults. METHODS: One hundred and ninety eight patients over the age of 45, who visited the menopausal clinic from Oct. 2001 to May 2002, were studied. We compared the peak GH value after the administration of L-dopa 500 mg by gender and age groups. Also, we compared the GH deficiency group to normal by anthropometric and measured variables. RESULTS: The mean of the stimulated GH peak value and the prevalence rate of growth hormone deficiency were greater in women than in men. GH-AUC after L-dopa stimulation correlated well with all measurements of adiposity. In GH deficiency group, the mean values of measured variables about adiposity were greater than normal in statistical significance. Logistic regression test revealed sex and abdominal obesity contributed significantly to predict GH deficiency after L-dopa stimulation test. The odds ratio of GH deficiency were 3.0 in women compared to men with 2.9 in abdominal obesity. CONCLUSION: Gender and adiposity were the predictors of GH deficiency in adults after L-dopa stimulation test rather than age and IGF-1 values.

Aging and Hormone Replacement Therapy

Three hormonal systems show decreasing circulating hormone concentrations during normal aging : (1) estrogen(in menopause), and testosterone (in andropause), (2) dehydroepiandrosterone and its sulfate (in adrenopause), and (3) the growth hormone/insulin-like growth factor 1 axis (in somatopause). Throughout the adult life, all physiological functions gradually decline. There is a diminishing capacity for cellular protein synthesis, an decline in immune function, an increase in fat mass, a loss of muscle mass and strength, and a decrease in bone mineral density. Physical changes during aging have been considered physiologic, but there is evidence that some of these changes are related to the decline in the hormonal activity. Various hormonal replacement strategies have been developed, but many of their aspects remain controversial, and increased blood hormone levels in aging individuals to those found during the mid-adult life have not been uniformly proven to be safe and of benefit.