Adverse effects of two nights of sleep restriction on the hypothalamic-pituitary-adrenal axis in healthy men.

CONTEXT: Insufficient sleep is associated with increased cardiometabolic risk. Alterations in hypothalamic-pituitary-adrenal axis may underlie this link. OBJECTIVE: Our objective was to examine the impact of restricted sleep on daytime profiles of ACTH and cortisol concentrations. METHODS: Thirteen subjects participated in 2 laboratory sessions (2 nights of 10 hours in bed versus 2 nights of 4 hours in bed) in a randomized crossover design. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 9:00 am to midnight to measure ACTH and total cortisol. Saliva was collected every 20 minutes from 2:00 pm to midnight to measure free cortisol. Perceived stress, hunger, and appetite were assessed at hourly intervals by validated scales. RESULTS: Sleep restriction was associated with a 19% increase in overall ACTH levels (P < .03) that was correlated with the individual amount of sleep loss (rSp = 0.63, P < .02). Overall total cortisol levels were also elevated (+21%; P = .10). Pulse frequency was unchanged for both ACTH and cortisol. Morning levels of ACTH were higher after sleep restriction (P < .04) without concomitant elevation of cortisol. In contrast, evening ACTH levels were unchanged while total and free cortisol increased by, respectively, 30% (P < .03) and 200% (P < .04). Thus, the amplitude of the circadian cortisol decline was dampened by sleep restriction (-21%; P < .05). Sleep restriction was not associated with higher perceived stress but resulted in an increase in appetite that was correlated with the increase in total cortisol. CONCLUSION: The impact of sleep loss on hypothalamic-pituitary-adrenal activity is dependent on time of day. Insufficient sleep dampens the circadian rhythm of cortisol, a major internal synchronizer of central and peripheral clocks.

Hypopituitarism (GHD) and neurodegenerative diseases.

Neurodegenerative diseases are a major focus of scientific and clinical interest because of their increasing medical and social importance. Due to the intimate connections between central nervous and endocrine systems, it is reasonable to suspect that important, and in some cases clinically relevant, endocrine modifications may accompany the progression of neurodegenerative diseases. Data on endocrine modifications in different neurodegenerative diseases have been reported, but results have often been non-conclusive, or conflicting. Accumulating evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism and in the regulation of muscle function. Dysfunctions in GH/IGF-I axis in most of neurodegenerative diseases are therefore reviewed. Alterations of this system could be actors in the complex network leading to (at least some) neurodegenerative diseases. A thorough effort in investigating every possible involvement is warranted, in the light of future therapeutic strategies.

Primary hyperparathyroidism is associated with marked impairment of GH response to acylated ghrelin.

BACKGROUND: Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level. OBJECTIVE: To evaluate secretory response of GH to ghrelin in PHP patients. PATIENTS: Fifteen patients [11 women/4 men, mean age 54 years, range 32-70 years, body mass index (BMI) 25.0 +/- 0.7 kg/m(2)] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35-68 years, BMI 24.1 +/- 1.1 kg/m(2)). METHODS: A measure of 1 microg/kg body weight i.v. acylated ghrelin or 1 microg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0.5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. RESULTS: Mean serum GH peak after GHRH + ARG was 32.6 +/- 7.8 and 17.4 +/- 4.0 microg/l, in controls and PHP patients, respectively (P < 0.05). Mean serum GH peak after ghrelin was 70.4 +/- 31.5 and 16.8 +/- 1.9 microg/l, in controls and PHP patients, respectively, (P < 0.001). Using ROC curves, a serum GH peak > 22 microg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations. CONCLUSIONS: The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.

Impairment of GH secretion in amyotrophic lateral sclerosis is not affected by riluzole treatment.

Amyotrophic lateral sclerosis (ALS), the most common motor neurone disorder in human adults, is characterized by selective and progressive degeneration of upper and lower motor neurones in the central nervous system. The main currently available drug for ALS treatment is riluzole, a compound that acts through inhibition of glutamate release, postsynaptic receptor activation, and voltage-sensitive channel inhibition. GH secretion, evaluated by GHRH+arginine (ARG) test, has recently been reported to be impaired in most untreated ALS patients. The aim of the present study was to evaluate whether riluzole administration could interfere with GH secretion and therefore with the diagnosis of adult GH deficiency. Ten patients (6 males, 4 females, mean age 59+/-11 yr) were studied performing GHRH+ARG test before and 3 months after starting riluzole treatment (100 mg/day). Blood samples for GH were collected at baseline, at 30 and 60 min. Both before and during riluzole treatment, 5 patients showed GH deficiency and 5 patients had a normal GH response according to body mass index (BMI). Mean peak GH levels were similar before and during riluzole treatment (13.4+/-10 vs 14.2+/-10.1 microg/l, p=ns). No significant correlation was observed between GH concentrations and age, BMI, disease duration, severity or clinical (bulbar/spinal) form. In conclusion, the present data confirm that GH secretion is impaired in a new series of ALS patients and indicate that riluzole treatment does not interfere with GH secretion. Thus, evaluation of GH secretion in ALS patients can also be performed without withdrawing riluzole treatment.

Growth hormone secretion is impaired in amyotrophic lateral sclerosis.

OBJECTIVE: ALS is the most common motor neurone disorder in human adults. Scanty data on endocrine abnormalities have been reported. The aim of the present study was to investigate the GH-IGF-I axis in ALS patients. PATIENTS: Twenty-two ALS patients (12 men, 10 women), mean age 61 years, and 25 normal age- and sex-matched subjects. No patient was under riluzole therapy. MEASUREMENTS: Patients and controls underwent a GHRH plus arginine test. IGF-I was determined at baseline. A complete evaluation of pituitary function was also performed. RESULTS: Mean (+/- SD) basal GH levels were significantly reduced compared with normal controls (0.2 +/- 0.3 vs 1.6 +/- 1.8 ng/ml, P < 0.01), as well as peak GH concentrations after GHRH + arginine administration (12.6 +/- 8.9 vs 39.9 +/- 18.7 ng/ml, P < 0.001). Six (27%) patients showed a normal GH response to stimulus; 7 (32%) patients displayed a moderate GH deficiency; in 9 (40%) patients GH response was markedly deficient. IGF-I levels were normal in the majority of patients (mean +/- SD: 143.6 +/- 63.8 ng/ml). No significant correlation was observed between peak GH concentrations and age, BMI, disease duration, severity or clinical form. A higher incidence of GH deficiency was observed in male compared to female patients (83%vs 60%), with a peak GH response in males significantly lower than in females (8.9 +/- 6.6 vs 17 +/- 9.6 ng/ml, P = 0.03). Eighteen patients repeated the test after 5 months and similar results were obtained. CONCLUSIONS: The present data indicate a reduction of GH secretion in ALS patients.

Undetectable inferior petrosal sinus levels of PTH-related peptide (PTHrP) in patients with ACTH-dependent Cushing's disease.

PTH-related peptide (PTHrP), a member of the PTH family, is widely expressed in foetal and adult tissues, and it has been found in benign and malignant tumors, including GH and PRL-secreting adenomas. Conflicting data are reported in literature on serum PTHrP concentrations in patients with Cushing's disease. The aim of the present study was to further evaluate peripheral and inferior petrosal sinus (IPS) serum PTHrP concentrations before and after CRH, in a group of consecutive patients with ACTH-dependent Cushing's disease. Nine patients with active ACTH-dependent Cushing's disease (8 women and 1 man, age +/- SD 41 +/- 13 yr) were submitted to peripheral and IPS sampling under fluoroscopic control before and after iv administration of CRH. All patients were subsequently submitted to transsphenoidal surgery and an ACTH-secreting microadenoma was found in all cases. In all patients, serum IPS and peripheral ACTH measurement were in keeping with the diagnosis of ACTH-dependent Cushing's disease. Serum PTHrP concentrations before and after CRH stimulation were below the sensitivity limit of the assay in all samples, and no gradient between IPS and peripheral sampling was observed. Our data, combined with others reported in literature, indicate that PTHrP release by ACTH-secreting tumors is not a common occurrence. Therefore, we conclude that IPS and peripheral PTHrP are of little clinical usefulness.

Thyroid function differently affects serum cystatin C and creatinine concentrations.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p<0.05), and significantly decreased in short-term, long-term and mild hypothyroids (p<0.05, p<0.05, p<0.01, respectively). However, 36 (62%) hyperthyroid patients and 50 (76%) hypothyroid patients had normal serum Cys C values. In the prospective study, restoration of euthyroidism by either methimazole or L-T4 therapy was associated with normalization of mean serum Cys C concentrations. In conclusion, thyroid dysfunction affects serum Cys C concentration, possibly influencing the production rate of the protein. However, the observation that hyper- or hypothyroid patients have normal serum Cys C levels limits its use as a marker of peripheral thyroid hormone effect.