Alfonso Leal-Cerro

Prevalence of hypopituitarism and growth hormone deficiency in adults long‐term after severe traumatic brain injury

Objective Traumatic brain injury (TBI) has been associated with hypopituitarism and GH deficiency. However, TBI‐mediated hypopituitarism may be more frequent than previously thought. The present work, performed in patients with severe TBI at least 1 year before, had three aims: (i) to evaluate the prevalence of hypopituitarism, (ii) in particular to evaluate the prevalence of GH deficiency, and (iii) to compare three different tests of GH reserve in this cohort.

Influence of Cortisol Status on Leptin Secretion

The discovery of the adipocyte-produced hormone leptin has changed the field of obesity research and our understanding of energy homeostasis. It is now accepted that leptin is the afferent loop informing the hypothalamus about the states of fat stores, with hypothalamic efferents regulating appetite and energy expenditure. I addition, leptin has a role as a metabolic adaptator in overweight and fasting states. New and previously unsuspected neuroendocrine roles have emerged for leptin. Leptin participates in the expression of CRH in the hypothalamus, interacts at the adrenal level with ACTH, and is regulated by glucocorticoids. Since leptin and cortisol show an inverse circadian rhythm, it has suggested that a regulatory feedback is present. However glucocorticoids appears to play a modulatory, but not essential roles in generating leptin diurnal rhythm. Glucocortiocids act directly on the adipose tissue and increase leptin syntesis and secretion in humans. Leptin levels are markedly increased in Cushings syndrome patients and in others pseudo-Cushings syndrome states. Glucocorticoids appears to act as a key modulator of body weight and food intake, promoting leptin secretion by adipocytes, limiting central leptin induced effects and favoring those of the NPY. Furthermore the modulatory role of glucocorticoids could be altered in obesity, but the precise mode of action remains to be established. The relevance of this finding merits further studies.

Inhibition of growth hormone release after the combined administration of CHRH and GHRP‐6 in patients with Cushing's syndrome

OBJECTIVE In patients with Cushings syndrome there is a blunted OH response to all types of stimuli. Although Inferential data point towards a direct perturbation in the pituitary exerted by glucocorticoids, the bask mechanism is unknown. His‐d‐TRP‐ALA‐TRP‐d‐Phe‐Lys‐NH2 (GHRP‐6) is a synthetic hexapeptlde which releases GH by a direct pituitary effect through receptors other than GHRH receptors. Furthermore, the combined administration of GHRH and GHRP‐6 is able to induce a large OH discharge even in some pathological states such as obesity, associated with GH blockade.

Ghrelin Is No Longer Able to Stimulate Growth Hormone Secretion in Patients with Cushing’s Syndrome but Instead Induces Exaggerated Corticotropin and Cortisol Responses

Growth and growth hormone (GH) secretion are blunted or severely impeded in chronic hypercortisolism and in patients with Cushing’s syndrome. A mechanistic explanation for the effect however has yet to be provided. On the other hand, several properties of ghrelin, a new peptide recently identified as the endogenous ligand of the GH secretagogue receptor, are still largely unknown. The two aims of this study were to observe whether ghrelin-mediated GH secretion was altered, and to characterize the corticotropin (ACTH) and cortisol response to this new stimulus in patients with Cushing’s disease. Ten patients with active Cushing’s disease (6 harboring microadenomas and 4 with macroadenomas) and 10 sex- and age-matched controls were studied. Ghrelin was administered at a dose of 1 µg/kg i.v. and GH, ACTH and cortisol analyzed in duplicate. In control women, ghrelin induced GH secretion to levels of 74.4 ± 12.8 µg/l, while chronic hypercortisolism severely reduced the ghrelin-mediated GH release in all patients with Cushing’s disease (peak values 17.7 ± 5.2 µg/l). The slightly, but significantly higher adiposity of patients vs. controls may have contributed to the effect, since a significant negative correlation (r = 0.639) was found between the amplitude of the GH peak and body mass index. In control women, ghrelin increased ACTH and cortisol levels, with peaks at 57.4 ± 19.0 ng/l and 162 ± 16 µg/l, respectively. This secretion was enhanced in Cushing’s syndrome patients, with ACTH and cortisol values of 380.7 ± 109.8 ng/l and 338 ± 81 µg/l respectively, both significantly higher than in controls. In conclusion, ghrelin-induced GH secretion was severely blunted in patients with active Cushing’s syndrome, in addition to a remarkable hyper-response in ACTH and cortisol secretion. These findings could have implications for the understanding of the physiology and physiopathology of interactions between GH and ACTH regulation.

Marked GH secretion after ghrelin alone or combined with GH-releasing hormone (GHRH) in obese patients.

objectives  Ghrelin is a 28‐amino‐acid peptide, predominantly produced by the stomach. It displays a strong GH‐releasing activity mediated by the hypothalamus–pituitary GH secretagogue (GHS)‐receptor (GHS‐R). There are different studies that suggest the importance of ghrelin in feeding and weight homeostasis. In obesity there is a markedly decreased GH secretion. For both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli, including the response to GHRH. However, the response to the natural GH secretaogogue ghrelin is unclear at the present time. The aim of the present study was to evaluate the GH response to ghrelin alone or combined with GHRH in a group of obese patients, in order to further understand the deranged GH secretory mechanisms in obesity and to clarify the mechanism of action of ghrelin.

Evidence of Cognitive and Neurophysiological Impairment in Patients with Untreated Naive Acromegaly

CONTEXT Recent studies have suggested that long-term exposure to high levels of GH and IGF-I affect brain and cognitive functions. However, very few human studies have challenged this hypothesis. OBJECTIVE The aim of this study is to explore whether GH/IGF-I excess in naive patients with acromegaly alters cognitive functions, particularly memory, and whether these alterations are accompanied by neurophysiological correlates. DESIGN We conducted a comprehensive neuropsychological and neurophysiological exam on 16 naive acromegaly patients and 16 strictly matched healthy controls. Comparative analyses were carried out on major neurocognitive domains (executive functions, visual/verbal memory, attention, visuoconstructive abilities, and verbal fluency) and on quantitative electroencephalogram and low-resolution brain electromagnetic tomography sources. Results were correlated with GH and IGF-I hormone concentrations. RESULTS Short- and long-term memory were the most severely impaired cognitive functions. Moreover, memory performance correlated negatively with GH and IGF-I concentrations. No association was detected between depression and memory impairment, and only a marginal association was found with quality of life. Finally, acromegaly patients showed power attenuation in fast frequency electroencephalogram bands, as well as decreased activity in prefrontal and middle temporal cortices, that was associated to cognitive performance. CONCLUSIONS Results provide evidence of cognitive and neurophysiological impairment, characterized by moderate-to-severe memory impairment and decreased neural activity in specific brain areas. High levels of GH and IGF-I in acromegaly patients could be the basis for these findings.

Cognitive deterioration due to GH deficiency in patients with traumatic brain injury: A preliminary report

Primary objective: To determine whether cognitive and behavioural disorders observed in TBI patients are due to hormonal deficits or to the brain injury itself. Research design: Transversal, between-group design. Methods and procedures: Studied 22 severe TBI patients (GCS < 8): 11 had isolated GH deficiency and 11 did not. Prepared detailed clinical reports on patients and performed physical examinations, standard biochemical and full blood count analysis. Patients underwent neuropsychological assessment and hormonal evaluation 6 months after TBI diagnosis. Results: TBI patients with GH deficiency show greater deficits in attention, executive functioning, memory and emotion than those without GH deficiency. Conclusions: Results show GH-related cognitive impairment in patients who develop GH deficiency after TBI and suggest that treatment of GH deficiency would improve cognition. The clinical importance of these findings should be established to better understand the nature, magnitude and meaning of GH-related cognitive impairment in patients who develop GH deficiency after TBI.

A Cellular and Molecular Basis for the Selective Desmopressin-Induced ACTH Release in Cushing Disease Patients: Key Role of AVPR1b Receptor and Potential Therapeutic Implications

CONTEXT Desmopressin is a synthetic agonist of vasopressin receptors (AVPRs). The desmopressin stimulation test is used in the diagnosis and postsurgery prognosis of Cushing disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in patients with CD are poorly understood. OBJECTIVE The objectives of this study were to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release and to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD. DESIGN A total of 8 normal pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning pituitary adenomas, 17 somatotropinomas, and 3 prolactinomas were analyzed for AVPR expression by quantitative real-time RT-PCR. Primary cultures derived from corticotropinomas, nonfunctioning pituitary adenomas, somatotropinomas, prolactinomas, and NPs were treated with desmopressin, and ACTH secretion/expression, [Ca(2+)]i kinetics, and AVPR expression and/or proliferative response were evaluated. The relationship between AVPR expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin tests was assessed. RESULTS Desmopressin affects all functional parameters evaluated in corticotropinoma cells but not in NPs or other pituitary adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b antagonist completely blocked desmopressin stimulatory effects. Remarkably, only AVPR1b expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas. CONCLUSIONS The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and postsurgery prognosis of CD. Furthermore, our data indicate that AVPR1b is responsible for the direct/exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.

A clinical profile of memory impairment in humans due to endogenous glucocorticoid excess

Objective  Glucocorticoid excess is commonly related to neuropsychiatric and neurological disorders, with memory impairment typically found among these disorders. The objective of this study is to offer a clinical profile of memory deficits resulting from exposure to chronic stress‐level elevations of endogenous glucocorticoids in patients with Cushings Syndrome (CS).

Growth hormone releasing hormone priming increases growth hormone secretion in patients with Cushing's syndrome.

OBJECTIVE In patients with Cushings syndrome, decreased growth hormone (GH) secretion is observed though the basic mechanism is unknown. In states of chronic deficiency of hypothalamic growth hormone releasing hormone (GHRH) release, a blunted GH response to exogenous GHRH has been reported; such impairment can be partially normalized by repetitive GHRH administration (priming).