Low Growth Hormone Levels Research Articles

Opposing Roles of Peroxisome Proliferator-activated Receptor α and Growth Hormone in the Regulation of CYP4A11 Expression in a Transgenic Mouse Model

CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for omega-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2-3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor alpha (PPARalpha) null mice. Dietary administration of either of the PPARalpha agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2-3-fold, and these responses were also abrogated in PPARalpha null mice. Basal liver CYP4A11 levels are reduced differentially in PPARalpha-/- females (>95%) and males (<50%) compared with PPARalpha-/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARalpha-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARalpha-/- CYP4A11 Tg male mice to levels similar to that of female PPARalpha-deficient mice. These results suggest that PPARalpha contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.

Hemangiopericytoma-associated hypoglycemia improved by glucocorticoid therapy: a case report

A 59-year-old man was admitted because of recurrent, severe hypoglycemia. He had multiple metastases from a meningeal hemangiopericytoma, which had been operated on 12 years earlier. The results of laboratory testing at the time of hypoglycemia showed very low serum levels of insulin, C-peptide, and growth hormone, with slightly high levels of insulin-like growth factor-II, and a normal level of insulin-like growth factor-I. The diagnosis of hemangiopericytoma-associated hypoglycemia was proposed. The patient was given corticosteroid therapy, which ameliorated symptoms of hypoglycemia.

Les récepteurs centraux de l’IGF-1 contrôlent la longévité chez la souris

Using a mouse model relevant for humans, lifespan can be prolonged by reducing IGF-I signaling selectively in the central nervous system. This effect occurred through changes in specific neuroendocrine pathways. Investigating the pathophysiological mechanism, we found that IGF receptors in the brain steered the development of the somatotropic axis, which in turn altered the individual growth trajectory and lifespan. Our work is experimental proof that chronically low IGF-I and low growth hormone (GH) levels favor long lifespan and postpone age-related mortality. Our results, together with other recent reports, challenge the notion that GH can slow down or prevent human aging. This is important because growth hormone is sometimes proposed to elderly people as a substitutive treatment in order to compensate the negative effects of aging.

Traumatic Brain Injury Causes Long-Term Reduction in Serum Growth Hormone and Persistent Astrocytosis in the Cortico-Hypothalamo-Pituitary Axis of Adult Male Rats

In humans, traumatic brain injury (TBI) causes pathological changes in the hypothalamus (HT) and the pituitary. One consequence of TBI is hypopituitarism, with deficiency of single or multiple hormones of the anterior pituitary (AP), including growth hormone (GH). At present no animal model of TBI with ensuing hypopituitarism has been demonstrated. The main objective of this study was to investigate whether cortical contusion injury (CCI) could induce long-term reduction of serum GH in rats. We also tested the hypothesis that TBI to the medial frontal cortex (MFC) would induce inflammatory changes in the HT and AP. Nine young adult male rats were given sham surgery (n = 4) or controlled impact contusions (n = 5) of the MFC. Two months post-injury they were killed, trunk blood collected and their brains and AP harvested. GH was measured in serum and AP using ELISA and Western blot respectively. Interleukin-1beta (IL-1beta) and glial fibrillary acidic protein (GFAP) were measured in the cortex (Cx), HT, and AP by Western blot. Lesion rats had significantly (p < 0.05) lower levels of GH in the AP and serum, unaltered serum IGF-1, and significantly (p < 0.05) higher levels of IL-1beta in the Cx and HT and GFAP in the Cx, HT, and AP compared to that of shams. CCI leads to a long-term depletion of serum GH in male rats. This chronic change in GH post-TBI is probably the result of systemic and persistent inflammatory changes observed at the level of HT and AP, the mechanism of which is not yet known.

Predicting behavioral problems in craniopharyngioma survivors after conformal radiation therapy

Although radiation therapy is a primary treatment for craniopharyngioma, it can exacerbate existing problems related to the tumor and pre-irradiation management. Survival is often marked by neurologic deficits, panhypopituitarism, diabetes insipidus, cognitive deficiencies, and behavioral and social problems. The Achenbach Child Behavior Checklist (CBCL) was used to evaluate behavioral and social problems during the first 5 years of follow-up in 27 patients with craniopharyngioma treated with conformal radiation therapy. All group averages for the CBCL scales were within the age-typical range at pre-irradiation baseline. Extent of surgical resection was implicated in baseline differences for the internalizing, externalizing, behavior problem and social scores. Significant longitudinal changes were found in internalizing, externalizing, behavior problem and school scores that correlated with tumor and treatment-related factors. The most common variables implicated in post-irradiation behavioral and social problems were CSF shunting, presence of an Ommaya reservoir, diabetes insipidus, and low pre-irradiation growth hormone levels.

Poor Specificity of Low Growth Hormone and Cortisol Levels During Fasting Hypoglycemia for the Diagnoses of Growth Hormone Deficiency and Adrenal Insufficiency

Fasting tests are used to identify the cause of hypoglycemia in children. The purposes of this study were to (1) determine whether growth hormone and cortisol levels obtained at the time of hypoglycemia in such tests can identify children with growth hormone and/or cortisol deficiency and (2) identify potential clinical factors that influence growth hormone and cortisol responses to hypoglycemia. The design consisted of chart review of all diagnostic fasting tests conducted over a 3-year period (n = 151). A normal growth hormone level was defined as >/=7.5 ng/mL, and a normal cortisol level was defined as >/=18 mug/dL. During the fasting tests, 84 children (median age: 1.3 years [2 days to 14.3 years]), became hypoglycemic, with blood glucose </=50 mg/dL. Diagnoses included normal, ketotic hypoglycemia, hyperinsulinism, fatty acid-oxidation defects, glycogen-storage disease, and late dumping hypoglycemia. A total of 70% had growth hormone and cortisol levels less than the "normal" thresholds regardless of diagnosis. Of various factors (age, diagnosis, fast duration, duration blood glucose level of <60 mg/dL, and blood glucose nadir), only age was positively associated with cortisol, and none were consistently related to growth hormone. A singe low growth hormone or cortisol value at the time of fasting hypoglycemia has poor specificity for the respective diagnoses of growth hormone deficiency and adrenal insufficiency.

Somatostatin: The beginnings, 1972

Somatostatin: The beginnings, 1972

Sleep-disordered breathing and hypoventilation with a large right-side pleura-based mass

We report the case of a 56-year-old female patient with daytime sleepiness, snoring, dyspnea to exertion and hypoglycemia. During the previous months, she had noticed the enlargement of the tongue and the facial characteristics and also development of head lesions. Upon admission, hypoventilation was confirmed ( P aO 2 61.5 mmHg, Pa CO 2 50 mmHg). The chest X-ray showed right-side opacity and CT scan presented an intrathoracic, extrapulmonary lesion. Obstructive sleep apnea–hypopnea with severe desaturation episodes was revealed by a sleep study. It was suspected that all the manifestations were due to substances produced by the tumor, and laboratory test showed low levels of insulin, growth hormone and insulin-like growth factor I. Surgical resection of the mass was performed and the diagnosis of solitary fibrous tumor of the pleura (SFTP) was confirmed. We present the case of a patient with SFTP associated with multiple paraneoplastic manifestations.

Serum Insulin-like Growth Factor-I (IGF-I), IGF-Binding Protein-3, and Growth Hormone Levels in Collodion Babies: A Case-Control Study

Because growth failure occurs in many collodion babies, we investigated serum growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels in collodion babies admitted to Gevher Nesibe Hospital, Kayseri, Turkey between 1999 and 2006. The newborns diagnosed clinically as 'collodion baby' were included in the study group (group 1). Because collodion babies are usually born small for gestational age (SGA) and/or premature, a control group (group 2) was formed by selecting the first infant admitted immediately after each study infant who matched for gestational age (+/- 7 days) and birth weight (+/- 100 g). All infants' blood samples were collected within the first 2 h of life for measurements of serum GH, IGFBP-3 and IGF-I levels. Group 1 consisted of 23 collodion babies (13 males and 10 females) with gestational ages ranging from 32 to 42 weeks, and birth weights ranging from 1,300 to 3,600 g. Ten were born premature and 16 were SGA. Serum IGF-I and IGFBP-3 levels were lower but serum GH levels were higher in collodion babies than in controls. Birth weight was positively correlated with serum IGF-I (r = 0.310, p = 0.046) and IGFBP-3 (r = 0.389, p = 0.011) levels. Serum GH level was negatively correlated with birth weight (r = -0.376, p = 0.014), serum IGF-I (r = -0.567, p <0.001) and IGFBP-3 (r = -0.444, p = 0.003). Collodion babies had lower serum IGF-I and IGFBP-3 levels but higher serum GH levels than controls in the present case-control study. The underlying mechanism needs to be explored.

Does acromegaly enhance mortality?

The increased mortality associated with acromegaly was first demonstrated in early epidemiological studies. Since the seminal paper by Wright et al. in 1970, nearly 20 studies have analyzed mortality rates in over 5,000 patients with acromegaly. Overall standardized mortality rates are approximately two times higher than in the general population, relating to an average reduction in life expectancy of around 10 years. The excess deaths are due predominantly to cardiovascular, cerebrovascular and respiratory disease. Malignancy deaths have been high in some studies but not others; in the largest series looking at cancer mortality in acromegaly, overall cancer deaths were not increased, but colon cancer mortality was higher than expected. In 1993, Bates et al. first demonstrated that outcome was related to the latest measurable growth hormone (GH), and treatment to reduce GH levels led to improved outcomes. Other factors predicting poor outcome include the presence of hypertension and diabetes. On the basis of current evidence, a latest GH of less than 2-2.5 mug/L is a better predictor of good outcome than a normal insulin-like growth factor-1 (IGF-1), possibly due to discrepancy between GH and IGF-1 at low GH levels. There is some evidence to suggest a more stringent GH cut-off (less than 1 mug/L) may yield additional benefit but further studies are required to investigate any added risk of increased mortality from hypopituitarism. Radiotherapy has been linked specifically to cerebrovascular mortality and its use in patients with acromegaly must involve a careful risk-benefit analysis in each case.

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

Neuroendocrine dysfunction after traumatic brain injury (TBI) is under-diagnosed, under-treated, and may adversely affect the rate of recovery. Single or multiple pituitary-target hormone disruption occurs in up to two-thirds of persons with TBI, most commonly affecting the gonadal and growth hormone axes. The time course of decline in and recovery of pituitary function in relation to cognitive dysfunction and rehabilitation progress are not well described. This article reviews the clinical spectrum of neuroendocrine deficits after TBI and their underlying mechanisms. Future studies of the effects of hormonal replacement on recovery are recommended.

Endochondral gigantism: A newly recognized skeletal dysplasia with pre‐ and postnatal overgrowth and endocrine abnormalities

We report on a 3-year-old male, born at 34 weeks of gestation, with marked pre- and postnatal overgrowth, birth weight of 6,600 g, length of 61 cm, and head circumference of 38.5 cm. A striking phenotype was recorded at birth, which became more evident during the follow-up period. He had macrobrachycephaly, facial abnormalities, small thoracic cage, long trunk, deformed spine, rhizomelia, large hands and feets, absent subcutaneous fat, small umbilical hernia, inguinal hernias, and large joints with mild contractures. Hypoglycemic episodes and obstructive apnea complicated the neonatal period. During follow-up, overgrowth continued with a height of 146 cm (+11.65 SDS) and a weight of 39 kg (BMI 18.3 kg/m(2)) at 3.5 years. Endocrinological work-up disclosed extremely low levels of growth hormone, insulin-like growth factors, and insulin. What makes our patient unique is the association of marked prenatal overgrowth; unusual phenotype; skeletal dysplasia caused by accelerated endochondral ossification resulting in cartilage hyperplasia of the skull base and spine, and postnatal gigantism; and complete absence of subcutaneous fat. Other well-known overgrowth syndromes were excluded. We hypothesize that autocrine/paracrine growth factors could be the cause of excessive endochondral ossification. Alternately, activating mutations in transcription factors involved in both growth and endocrine/metabolic homeostasis could be responsible for this unusual phenotype.

Healthy Aging Is Associated with Unaltered Production of Immunoreactive Growth Hormone but Impaired Neuroimmunomodulation

Background: Both endocrine and immune systems are continuously remodeled during aging. Objective: Here, we investigated to what extent adrenal and somatosenescence are associated reciprocal changes in the immune system during strictly healthy aging. Methods: Forty-six elderly subjects and 33 young adults were recruited according to the health criteria of the SENIEUR protocol. Peripheral blood mononuclear cells were isolated and stimulated in vitro with lipopolysaccharide or phytohemagglutinin to assess the production of immunoreactive growth hormone (GH). Peripheral sensitivity to steroids was assessed in vitroby dexamethasone-, cortisol- or dehydroepiandrosterone (DHEA)-induced inhibition of T-cell proliferation. DHEA and GH levels were measured by radioimmunoassays. Results: Healthy elderly had lower salivary DHEA and serum GH levels (somatosenescence). They presented reduced T-cell sensitivity to dexamethasone but similar cellular sensitivities to cortisol and DHEA. Their cells produced similar levels of immunoreactive GH compared to the cells of young adults. Conclusions: These data indicate that healthy aging is associated with adrenal and somatosenescence as well as impaired neuroendocrine immunoregulation at the level of the lymphocyte. In addition, somatosenescence may not be associated with a reciprocal decline in immunoreactive GH.

Is further evaluation for growth hormone (GH) deficiency necessary in fibromyalgia patients with low serum insulin-like growth factor (IGF)-I levels?

Objective Fibromyalgia (FM) is characterized by diffuse pain, fatigue, and sleep disturbances; symptoms that resemble the adult growth hormone (GH) deficiency syndrome. Many FM patients have low serum GH levels, with a hypothesized aetiology of dysregulated GH/insulin-like growth factor (IGF)-I axis. The aim of this study was to assess the GH reserve in FM patients with low serum IGF-I levels using the GH-releasing hormone (GHRH)-arginine test. Design We retrospectively reviewed the GHRH-arginine data of 77 FM patients with low serum IGF-I levels referred to our tertiary unit over a 4-year period. Results Of the 77 FM patients, 13 patients (17%) failed the GHRH-arginine test. Further evaluation with pituitary imaging revealed normal pituitary glands ( n = 7), coincident microadenomas ( n = 4), empty sella ( n = 1) and pituitary cyst ( n = 1), and relevant medical histories such as previous head injury ( n = 4), Sheehan’s syndrome ( n = 1), and whiplash injury ( n = 1). In contrast, the remaining 64 patients (83%) that responded to the GHRH-arginine test demonstrated higher peak GH levels compared to age and BMI-matched controls ( n = 24). Conclusion Our data shows that a subpopulation of FM patients with low serum IGF-I levels will fail the GHRH-arginine test. We, thus, recommend that the GH reserve of these patients should be evaluated further, as GH replacement may potentially improve the symptomatology of those with true GH deficiency. Additionally, the increased GH response rates to GHRH-arginine stimulation in the majority of FM patients with low serum IGF-I levels further supports the hypothesis of a dysregulated GH/IGF-I axis in the pathophysiology of FM.

Risk of Insulin Resistance induced by Growth Hormone

It is interesting to know if there is a threshold for growth hormone (GH) serum level above which GH increases insulin resistance and bellow which the inhibitory agents used in acromegaly like somatostatin analogs (octreotid) do not produce diabetes mellitus through their well-known insulin lowering actions. This threshold for GH serum levels, calculated by us to be 2 μg/L (6 mU/L) (1), could be a useful indicator for radical therapies efficacy in acromegaly due to GH secreting pituitary tumors. However, this cut-off level has a low specificity but GH levels over 8.3 mg/L predict insulin resistance with over 74% specificity.

Age‐related changes in growth hormone‐immunoreactive cells in the anterior pituitary gland of Jcl: Wistar‐TgN (ARGHGEN) 1Nts rats (Mini rats)

Rats of the Jcl: Wistar-TgN (ARGHGEN) 1Nts strain (Mini rats) are transgenic animals carrying an antisense RNA transgene for rat growth hormone (GH); they show poor somatic growth and a low blood GH level compared to age-matched wild-type Wistar (non-Mini) rats. The purpose of the present study was to investigate age-related changes in growth hormone-immunoreactive (GH-IR) cells in the anterior pituitary gland (AP) of Mini rats at four, six, and eight weeks of age. The body weight and size of the GH-IR cells of Mini rats was significantly lower than that of non-Mini rats at six and eight weeks of age; however, this difference was not observed at four weeks of age. The AP volume and the number of GH-IR cells in Mini rats were significantly smaller than those of the age-matched non-Mini rats at the three ages. These results suggest that the abnormal development of GH-IR cells in the AP induced by the GH antisense RNA transgene is responsible for the poor somatic growth and the low blood GH levels in Mini rats.

Role of ghrelin in growth hormone-deficient patients

Ghrelin is the endogenous ligand for the growth hormone (GH) secretagog receptor and exogenous ghrelin is a strong stimulator of GH secretion. Whether endogenous ghrelin is a major regulator of GH release remains dubious, but there is increasing evidence to suggest that ghrelin exhibits direct effects on appetite regulation. Systemic ghrelin levels in patients with GH deficiency (GHD) are normal, whereas GH substitution moderately suppresses ghrelin. Certain subgroups of GHD do respond to ghrelin with significant GH release, but the clinical implications are uncertain. Administration of ghrelin or a synthetic GH secretagog in other conditions with low GH levels, such as obesity and aging, has also been performed in controlled trials and has been shown to translate into insulin-like growth factor-I stimulation and changes in body composition; however, long-term data are not available. Even though ghrelin does not seem to be abnormal in patients with classic GHD, these patients constitute an interesting model for studying GH- and adrenocorticotropic hormone-independent effects of ghrelin.

Effect of obesity and morbid obesity on the growth hormone (GH) secretion elicited by the combined GHRH + GHRP‐6 test

Obesity is characterized by low basal levels of growth hormone (GH) and impeded GH release. However, the main problem arises in the diagnosis of GH deficiency in adults, as all accepted cut-offs in the diagnostic tests of GH reserve are no longer valid in obese subjects. In this work, the role of obesity in the GH response elicited by the GHRH + GHRP-6 test was assessed in a large population of obese and nonobese subjects. GHRH + GHRP-6-induced GH peaks were evaluated in 542 subjects. One hundred and five were healthy obese, 50 were morbid obese, and 261 were nonobese (both normal weight and overweight). One hundred and seventy-six GH-deficient patients (obese and nonobese) were also studied. A regression analysis of the 366 subjects with normal pituitary function indicated that adiposity had a negative effect on the elicited GH peak (r = -0.503, P < 0.0001). A receiver operating characteristic (ROC) curve analysis showed that in subjects with a BMI < or =35, the currently accepted cut-offs of the GHRH + GHRP-6 test (GH peaks > or =20 microg/l: normal secretion; GH peaks < or =10 microg/l: GH deficiency), were fully operative. However, in subjects with a BMI > 35, normality was indicated by GH peaks > or =15 microg/l and GH deficiency by peaks < or =5 microg/l (1 microg/l = 2.6 mU/l). This study confirms: (a) that the combined provocative test is adequate to separate normal and GH-deficient subjects; (b) the negative effect of obesity on GH secretion; (c) that obesity accounts for 25% of the reduction of GH release; and (d) that present cut-off values are applicable to normal weight, overweight and grade I obesity subjects, whereas in obese subjects with a BMI exceeding 35, all the normative limits of the GHRH-GHRP +6 test must be reduced by 5 microg/l.

Somatropin Therapy and Cognitive Function in Adults with Growth Hormone Deficiency

Both growth hormone (GH) and insulin-like growth factor (IGF)-I have receptors in the brain, in particular in areas that are involved in cognitive function. Therefore, it has been hypothesized that GH deficiency can lead to cognitive dysfunction, and that somatropin replacement therapy may have beneficial effects on cognitive function in GH-deficient patients. In this review, an overview is given regarding the possible effects of decreased activity of the GH/IGF-I axis and somatropin therapy in GH deficiency in relation to cognitive function. The available data regarding cognitive function in GH-deficient patients are limited, but suggest that this condition can lead to specific cognitive changes, in particular attentional deficits and altered processing speed. The underlying mechanisms and the effects of somatropin treatment on cognitive function in GH deficiency are still unclear. Similar studies to those performed in patients with GH deficiency have been performed regarding the cognitive changes in elderly patients with relatively low GH and/or IGF-I levels. Large controlled studies regarding the effects and safety of somatropin treatment in healthy elderly patients have not been performed.