Diabetes in Cushing Disease.

PURPOSE OF REVIEW: This review focuses on the pathophysiological and clinical aspects of diabetes mellitus occurring in patients with Cushing disease (CD). RECENT FINDINGS: Insulin resistance and impairment in insulin secretion are both involved in the pathogenesis of glucocorticoid-induced diabetes. Correction of glucocorticoid excess does not always resolve abnormalities of glucose homeostasis, and correction of hyperglycaemia is specifically required. In fact, insulin resistance may persist even after correction of glucocorticoid excess and diabetes needs to be treated for long term. On the other hand, emerging drugs used in the treatment of CD, such as the novel somatostatin analog pasireotide, may have direct effects on glucose homeostasis regardless of control of cortisol excess. Diabetes mellitus is a frequent and early complication of CD with important diagnostic, prognostic and therapeutic implications. Specifically, diagnosis of CD in patients with diabetes may be difficult due to potential misinterpretation of markers of cortisol hypersecretion. Moreover, diabetes mellitus is often difficult to be controlled in CD requiring a careful and dedicated therapeutic approach. Finally, the coexistence of diabetes may influence the therapeutic decision making in CD, since drugs used in this setting may variably influence glucose homeostasis regardless of control of hypercortisolism.

Biochemical evaluation of patients with active acromegaly and type 2 diabetes mellitus: efficacy and safety of the galanin test.

The oral glucose tolerance test, which is considered the gold standard for the diagnosis of active acromegaly, should not be performed in the presence of basal hyperglycemia. Moreover, false-positive responses may occur in patients with diabetes mellitus. Galanin has previously been demonstrated to induce paradoxical inhibition of growth hormone (GH) secretion in most patients with active acromegaly. In this study, we assessed GH response to galanin infusion in a series of 17 consecutive patients with active acromegaly, 7 of whom had coexistent type 2 diabetes mellitus and 10 were without either diabetes mellitus or impaired tolerance to glucose. 6 acromegalic patients with diabetes mellitus (85.7%) and 7 without diabetes (70.0%) showed a decrease in serum GH values during galanin infusion (chi2 0.9; p = 0.6). The GH nadir occurred at a comparable time in the two groups of acromegalic patients. Moreover, the two groups showed no significant difference (p = 0.45) in DeltaGH during galanin infusion. Galanin infusion did not induce any significant change in plasma glucose levels in both diabetic and non-diabetic patients with acromegaly. The results of our study provide evidence that the galanin test may be of value for the diagnosis of acromegaly in patients with type 2 diabetes mellitus.

Growth hormone deficiency in the adult.

Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD (AoGHD) usually results from damage to the pituitary gland or hypothalamus. GH is frequently undetectable in normal subjects and thus GHD cannot be distinguished from the normal state using a single random GH measurement. In general, a stimulation test is required to recognize GHD. Insulin tolerance test (ITT) has been considered the gold standard by the most important scientific societies, although alternative tests, in particular GHRH plus arginine have been proposed as valuable alternative to ITT. The clinical syndrome associated with AoGHD is characterized by a wide array of symptoms and important chronic complications, such as cardiovascular complications, which may be responsible for an increased mortality. The rationale for GH replacement in adults GHD patients is justified by the beneficial effects on some clinical end-points, such as quality of life (QoL) and cardiovascular risk factors, whereas the effects on mortality risk are still controversial. Over the recent years, guidelines on the use of rhGH as a substitution treatment in adult hypopituitarism have been issued by international (Growth hormone research society-GRS, Endocrine Society) and relevant national (National Institute of Clinical Excellence-UK, NICE) institutions. The aim of the paper is to review and discuss these guidelines.

New medical therapies of acromegaly.

Acromegaly is a rare disease associated with significant morbidity and increased mortality. Treatment of acromegaly aims at controlling growth hormone hypersecretion, improving patients' symptoms and comorbidities and normalizing mortality. The therapeutic options for acromegaly include surgery, medical therapies and radiotherapy. However, despite all these treatment options, approximately one-half of patients are not adequately controlled. Progress in molecular research has made possible to develop new therapeutic strategies to improve control of acromegaly. This article will review the new medical approaches to acromegaly which consist in evolution of traditional therapeutic protocols and development of new molecules with different profiles of activity.

High prevalence of radiological vertebral fractures in adult patients with Ehlers-Danlos syndrome.

Previous studies have reported an increased prevalence of osteoporosis in Ehlers­Danlos syndrome (EDS), but these were limited by a small number of patients and lack of information on fragility fractures. In this crosssectional study, we evaluated the prevalence of radiological vertebral fractures (by quantitative morphometry) and bone mineral density (BMD, at lumbar spine, total hip and femoral neck by dual-energy X-ray absorptiometry) in 52 consecutive patientswith EDS (10 males, 42 females; median age 41 years, range: 21­71; 12with EDS classic type, 37 with EDS hypermobility type, 1 with classic vascular-like EDS, and 2 without specific classification) and 197 control subjects (163 females and 34 males; median age 49 years, range: 26­83) attending an outpatient bone clinic. EDS patients were also evaluated for back pain by numeric pain rating scale (NRS- 11).Vertebral fractures were significantly more prevalent in EDS as compared to the control subjects (38.5% vs. 5.1%; p b 0.001) without significant differences in BMD at either skeletal sites. In EDS patients, the prevalence of vertebral fractures was not significantly (p = 0.72) different between classic and hypermobility types. BMD was not significantly different between fractured and non-fractured EDS patients either at lumbar spine (p = 0.14), total hip (p=0.08), or femoral neck (p=0.21). Severe back pain(≥7 NRS)was more frequent in EDS patients with vertebral fractures as compared to thosewithout fractures (60% vs. 28%; p=0.04). Inconclusion, this is the first study showing high prevalence of vertebral fractures in a relatively large population of EDS patients. Vertebral fractures were associated with more severe back pain suggesting a potential involvement of skeletal fragility in determining poor quality of life. The lack of correlation between vertebral fractures and BMD is consistent with the hypothesis that bone quality may be impaired in EDS.

Galanin decreases circulating growth hormone levels in acromegaly.

Galanin is able to elicit GH secretion in normal man. In acromegaly, circulating GH levels are elevated, and GH secretory dynamics are usually abnormal. The aim of our study was to investigate the effects of galanin on GH secretion in acromegalic subjects. Six acromegalic patients (four males and two females) and seven healthy adult subjects (five males and two females) underwent in randomized order: 1) iv infusion of 100 mL saline from 0-45 min, and 2) iv infusion of synthetic porcine galanin (0.5 mg in 100 mL saline) from 0-45 min. In normal subjects, peak GH levels after porcine galanin administration (8.2 +/- 1.9 micrograms/L) were significantly higher than after saline infusion (1.3 +/- 0.1 micrograms/L; P less than 0.05). In acromegalic patients, GH values fell from baseline (32.5 +/- 12 micrograms/L) to a mean nadir of 24.5 +/- 12.7 micrograms/L after galanin infusion. The mean change in GH values from baseline after galanin treatment in these subjects significantly differed from that observed after saline infusion from 15-90 min. Serum PRL levels were not significantly affected by galanin in either normal or acromegalic patients. Our results give the first evidence that the same dose of galanin, acting as a GH secretagogue in normal man, is, on the contrary, able to significantly inhibit GH in acromegalic patients. The cause of this paradoxical GH fall after galanin treatment in acromegaly remains to be explained. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by GH-secreting adenomatous cells.

Pyridostigmine blocks the inhibitory effect of glucocorticoids on growth hormone-releasing hormone stimulated growth hormone secretion in normal man.

Glucocorticoids have been shown to inhibit GH secretion in normal man when acutely and chronically administered in pharmacological amounts. Pyridostigmine (PD), an acetylcholinesterase inhibitor, is able to elicit GH secretion when administered alone and to enhance the GH response to GHRH in normal subjects probably via a decrease in the hypothalamic release of somatostatin. The aim of the present study was to investigate the influence of glucocorticoids on the GH response to PD administered either alone or in combination with GHRH in normal adult subjects. Six healthy adult volunteers underwent six experimental protocols. They received 1) human (h) GHRH(1-29)NH2, 100 micrograms injected as an iv bolus; 2) cortisone acetate, 50 mg administered orally (po) 60 min before an hGHRH iv bolus injection; 3) PD, 120 mg administered po, 60 min before an hGHRH iv bolus injection; 4) PD and cortisone acetate, administered po 60 min before an hGHRH iv bolus injection; 5) PD, administered po 60 min before a saline iv bolus injection; 6) PD and cortisone acetate administered po 60 min before a saline iv bolus injection. Mean GH levels, peak GH levels, and GH area under the curves (AUCs) were significantly lower after GHRH + cortisone as compared to GHRH alone. However, these parameters were not significantly different after PD + GHRH + cortisone when compared to PD + GHRH and after PD + cortisone when compared to PD alone. We conclude that acute administration of pharmacological amounts of glucocorticoids cannot inhibit the GH response to PD alone or in combination with GHRH. Thus, we hypothesize that the inhibitory action of glucocorticoids on the GH response to GHRH in man may be mediated by an enhancement of either somatostatin release by the hypothalamus or somatostatin action on the pituitary.

Growth hormone (GH) responses to GH-releasing hormone alone or combined with arginine in patients with adrenal incidentaloma: evidence for enhanced somatostatinergic tone.

Spontaneous and stimulated GH secretion is blunted in hypercortisolemic states due to increased hypothalamic somatostatinergic tone. However, no data are available on the characteristics of GH secretion in patients with incidentally discovered adrenal adenomas. They represent an interesting model for studying GH secretion, as a slight degree of cortisol excess may frequently be observed in such patients who do not present with any clear Cushingoid sign. In the present study, 10 patients (3 men and 7 women, aged 48-63 yr) with an adrenal mass discovered serendipitously underwent, on separate occasions, a GHRH injection alone or combined with an infusion of the functional somatostatin antagonist, arginine. Thirteen age-matched healthy volunteers served as controls. Briefly, arginine (30 g) was infused from -30 to 0 min, and GHRH (100 microg) was injected as a bolus at 0 min, with measurement of serum GH [immunoradiometric assay (IRMA)] every 15 min for 150 min. Plasma IGF-I (RIA after acid-ethanol extraction) was measured in a morning sample. The diagnosis of cortical adenoma was based on computed tomography features and pattern of uptake on adrenal scintigraphy. Patients with obesity and/or diabetes were excluded. The study design included also an endocrine work-up aimed to study the hypothalamic-pituitary-adrenal axis [urinary free cortisol (UFC) excretion, serum cortisol at 0800 h, plasma ACTH at 0800 h, morning cortisol after overnight 1 mg dexamethasone]. Five of 10 patients showed abnormalities of the hypothalamic-pituitary-adrenal axis, including borderline or increased UFC excretion in 4 of them accompanied by blunted ACTH in 2 cases and failure of cortisol to suppress after dexamethasone in 1; the fifth patient displayed low ACTH and resistance to dexamethasone suppression. However, all patients had a unilateral uptake of the tracer on the side of the mass with suppression of the contralateral normal adrenal gland. As a group, the patients displayed greater UFC excretion and lower ACTH concentrations than the controls. GH release after GHRH treatment was blunted in patients bearing adrenal incidentaloma compared with controls (GH peak, 5.7 +/- 5.2 vs. 18.0 +/- 7.0 microg/L; P < 0.0001), whereas GHRH plus arginine was able to elicit a comparable response in the 2 groups (GH peak, 33.5 +/- 20.3 vs. 33.7 +/- 17.5 microg/L; P = NS). The ratio between GH peaks after GHRH plus arginine and after GHRH plus saline was significantly greater in patients than in controls (751 +/- 531% vs. 81 +/- 45%; P = 0.0001). Similar data were obtained when comparing GH area under the curve after GHRH plus saline or GHRH plus arginine between the 2 groups. In summary, the present data suggest that in patients with incidental adrenal adenomas the GH response to GHRH is blunted due to increased somatostatinergic tone, as it can be restored to normal by pretreatment with the functional somatostatin antagonist arginine. The blunted GH release to GHRH may be an early and long lasting sign of autonomous cortisol secretion by the adrenal adenoma.

Arginine blocks the inhibitory effect of hydrocortisone on circulating growth hormone levels in patients with acromegaly.

In patients with acromegaly, circulating growth hormone (GH) levels and GH responses to GH-releasing hormone (GHRH) are decreased by long-term administration of pharmacological doses of glucocorticoids. The aim of our study was to investigate the acute effects of intravenous (i.v.) infusion of hydrocortisone combined either with saline or arginine infusion on circulating GH levels in acromegaly. We studied five adult patients with acromegaly, two men and three women aged 54.6 +/- 4 years having a body mass index of 25.9 +/- 1.2 kg/m2. On two randomized occasions, patients underwent a bolus i.v. injection of 100 mg hydrocortisone succinate at time 0 followed by a 120-minute i.v. infusion of 250 mg hydrocortisone in 250 mL saline, combined with a 90-minute (from -15 to 75 minutes) i.v. infusion of (1) 60 g arginine hydrochloride in 200 mL saline, or (2) 200 mL saline. In all of the acromegalic patients during the infusion of hydrocortisone alone, serum GH levels clearly decreased (nadir range, 26.4% to 68.1%) with respect to GH levels before hydrocortisone administration (mean of time -15 and 0, basal level), with a nadir between 90 and 180 minutes after the beginning of the infusion. After arginine pretreatment, GH levels were significantly enhanced compared with levels attained with hydrocortisone saline, and they were also significantly increased (peak, 167.5% +/- 27.7%) with respect to basal levels. Our data show that arginine blocks the inhibitory effect of acute and sustained hypercortisolism on circulating GH levels in acromegaly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of glucocorticoids on the paradoxical growth hormone response to thyrotropin-releasing hormone in patients with acromegaly.

It has been hypothesized that in acromegalic patients, as well as in normal subjects, acute increases in serum cortisol levels may cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid-mediated growth hormone (GH) inhibition. The aim of this study was to investigate short-term effects of an intravenous (i.v.) infusion of hydrocortisone on the GH response to thyrotropin-releasing hormone (TRH) in acromegaly. We studied six adult patients with active acromegaly. The group was composed of four women and two men with a mean age of 55.8 +/- 6.4 years (range, 27 to 68) and a mean body mass index of 26.7 +/- 1 kg/m2 (range, 23.3 to 30). All patients underwent the following treatments: (1) hydrocortisone alone: a bolus i.v. injection of hydrocortisone succinate 100 mg in 2 mL saline at time -60 minutes, followed by a 120-minute i.v. infusion of hydrocortisone succinate 250 mg in 250 mL saline from -60 to 60 minutes; (2) TRH+hydrocortisone: a bolus i.v. injection of TRH 200 micrograms 60 minutes after initiation of a 2-hour hydrocortisone infusion; (3) TRH alone: a bolus i.v. injection of TRH at time 0, 60 minutes after initiation of a 2-hour saline infusion. In all six patients, TRH induced large GH increases (absolute peak GH level, 58.1 +/- 23.2 micrograms/L; maximum % GH change with respect to baseline, 1,397.8% +/- 807.8%; range, 205% +/- 5,219%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of galanin on the growth hormone response to growth hormone-releasing hormone in acromegaly.

Galanin enhances growth hormone (GH)-releasing hormone (GHRH)-stimulated GH secretion in normal man. In acromegaly, circulating GH levels are increased and the GH response to GHRH may be exaggerated. Galanin has been recently shown to decrease circulating GH levels in acromegaly. The aim of our study was to investigate the effects of galanin on the GH response to GHRH in acromegalic subjects. Five acromegalic patients (three men and two women) and seven healthy adult subjects (five men and two women) were studied. GHRH-induced GH secretion was evaluated during a 40-minute intravenous (IV) infusion of saline (100 mL) or porcine galanin (12.5 micrograms/min in 100 mL saline). In normal subjects, delta GH levels after GHRH+porcine galanin administration (47 +/- 7.5 micrograms/L) were significantly higher in comparison to levels obtained with GHRH+saline (21.7 +/- 3.5 micrograms/L, P < .05). In acromegalic patients, GH responses to GHRH (delta GH, 18.8 +/- 8.6 micrograms/L) were not altered by galanin infusion (delta GH, 17.6 +/- 5 micrograms/L). Our results give the first evidence that the same dose of galanin that induces a significant enhancement of the GH response to GHRH in normal subjects has no effect on the GH response to GHRH in acromegalic patients. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by somatotropes independent of GHRH. Failure of galanin to enhance GH response to GHRH in acromegalic patients could be due to a change in function of the galanin receptor on GH-secreting adenomatous cells.

Exercise-induced microalbuminuria in patients with active acromegaly: acute effects of slow-release lanreotide, a long-acting somatostatin analog.

Recent clinical studies have demonstrated an increase of urinary albumin excretion (UAE) at rest in acromegalic patients and, on the other hand, a reduced UAE in patients with growth hormone (GH) deficiency. Physical exercise is known to induce abnormal UAE in patients with diabetes, probably unmasking early glomerular alterations. The effect of exercise on UAE in acromegaly is not known. Moreover, the effect of acute but sustained GH inhibition in acromegaly on UAE at rest and after exercise has never been studied. The aim of our study was to evaluate the acute short-term effects of slow-release lanreotide (SR-L), a long-acting somatostatin analog, on UAE and alpha1-microglobulinuria (A-1-M), a marker of renal tubular damage, at rest and after exercise in 7 normotensive patients with active acromegaly and normal renal function (4 males and 3 females; mean age, 53 +/- 3.1 years; body mass index [BMI], 27.3 +/- 1.1 kg/m2) at baseline and 7 and 14 days after SR-L injection (30 mg). Two of the acromegalic patients were microalbuminuric at rest, and in other 3 cases, UAE was in the borderline range (10 to 20 microg/min). At baseline in the acromegalic subjects, we found a significant increase in UAE at rest with respect to 7 normal subjects considered as a control group. GH and insulin-like growth factor-1 (IGF-1) were also reduced compared with baseline 7 and 14 days after SR-L injection (GH, 13.4 +/- 7.3 and 13.61 +/- 7 v 18.5 +/- 9.3 microg/L, P < .05; IGF-1, 230 +/- 53 and 255 +/- 54 v 275 +/- 64 microg/L). Concomitantly, we observed a significant decrease of UAE at rest and after exercise and 7 and 14 days after SR-L injection as compared with baseline values (27.3 +/- 20.5 and 18.2 +/- 13.7 v 35.3 +/- 12.8 microg/min, P < .05; exercise, 48.5 +/- 24.1 and 18.6 +/- 6.8 v68.3 +/- 39.7 microg/min, P < .05). A-1-M always remained in the normal range (< 12 mg/L) both at rest and after exercise. We can thus conclude that in acromegaly, submaximal exercise induces abnormal increases in microalbuminuria. We hypothesize that this phenomenon may be due to the functional glomeruler involvement. SR-L can significantly reduce UAE at rest and after exercise in the short-term in acromegaly, probably via a decrease in circulating GH levels.

The role of cholinergic tone in modulating the growth hormone response to growth hormone-releasing hormone in normal man.

Growth hormone-releasing hormone (GHRH) increases serum GH levels in a dose-dependent manner. Pyridostigmine (PD), an acetylcholinesterase inhibitor, is able to elicit GH secretion when administered alone and to enhance the GH response to GHRH in normal subjects, probably via a decrease in the hypothalamic release of somatostatin. The aim of the present study was to investigate if an enhancement of the cholinergic tone was able to influence the dose-response relationship between GHRH and GH in normal adult subjects. Six healthy adult volunteers underwent 10 experimental protocols. They were: human GHRH (1-29)NH2, 1 micrograms/kg injected as an intravenous (IV) bolus 60 minutes after (a) PD, 120 mg administered orally, or (b) placebo, two tablets administered orally; GHRH, 0.3 micrograms/kg injected as an IV bolus 60 minutes after (c) PD or (d) placebo; GHRH, 0.1 micrograms/kg injected as an IV bolus 60 minutes after (e) PD or (f) placebo; GHRH, 0.01 micrograms/kg injected as an IV bolus 60 minutes after (g) PD or (h) placebo; saline, 1 mL injected as an IV bolus 60 minutes after (i) PD or (l) placebo. The GH response in placebo-treated subjects was similar after 1 microgram/kg and 0.3 microgram/kg GHRH, while the 0.1 microgram/kg dose elicited a lower response. The 0.01 microgram/kg dose of GHRH did not significantly increase GH levels as compared with saline. After PD, the GH responses to GHRH were greatly enhanced at all doses tested: 1.0, 0.3, and 0.1 microgram/kg GHRH all elicited similar GH responses; the GH response to 0.01 microgram/kg GHRH was lower, but was still higher than that observed after saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome of glucose homeostasis in patients with glucocorticoid-induced osteoporosis undergoing treatment with bone active-drugs.

Over the last few years, there has been experimental evidence for the existence of cross-talking between bone remodeling and glucose metabolism. Whether this experimental model can be translated to humans is still debated, and it is also unclear whether the modulation of bone turnover by anti-osteoporotic drugs may lead to changes in glucose metabolism. The aim of this 12-month prospective study was to investigate whether treatment of glucocorticoid-induced osteoporosis (GIO) with bipshosphonates or teriparatide may influence serum glycated hemoglobin (HbA1c) and fasting plasma glucose. One-hundred-eleven patients (70 F, 41 M, median age 70, range: 55-89) chronically treated with glucocorticoids were evaluated for changes in serum HbA1c and fasting plasma glucose during treatment with bisphosphonates (45 cases) or teriparatide (33 cases) as compared to those occurring during treatment with calcium and vitamin D alone (33 cases). In patients treated with teriparatide, but not in those treated with bisphosphonates or calcium and vitamin D alone, a statistically significant (p=0.01) decrease in serum HbA1c was observed during the follow-up, the change being greater (p=0.01) in patients with diabetes as compared to those without diabetes. In most cases, the decrease of serum HbA1c was relatively limited and in some patients the improvement of glucose homeostasis was concomitant with implementation of anti-diabetic treatments. Fasting plasma glucose did not change significantly during either bisphosphonates or teriparatide treatments. In conclusion, currently used bone active drugs may produce limited effects on glucose metabolism in patients with GIO. Interestingly, the bone anabolic drug teriparatide was shown to be associated with some improvement in serum HbA1c in this clinical context.

Prevalence of thoracic vertebral fractures in hospitalized elderly patients with heart failure.

OBJECTIVE: Heart failure (HF) has been associated with increased risk of fragility fractures. Indeed, most literature data on fractures were based on an historical and clinical approach focused on the identification of peripheral fractures, whereas the risk of vertebral fractures in this clinical setting is still unclear. DESIGN: Cross-sectional study. AIM: To evaluate the prevalence and determinants of radiological thoracic vertebral fractures in patients with HF. METHODS: The study includes 1031 elderly hospitalized patients (491 females and 540 males; median age, 75 years; range, 65-90; 430 patients with HF) who were evaluated for the presence of thoracic vertebral fractures by quantitative morphometric analysis, using chest X-ray routinely performed in the diagnostic work-up of HF. RESULTS: Vertebral fractures were found in 166 patients (16.1%), the prevalence being significantly higher in patients with HF as compared with those without HF, both in females (30.9 vs 15.8%; P<0.001) and in males (16.4 vs 7.4%; P=0.001). The association between HF and vertebral fractures remained statistically significant (odds ratio, 2.14; 95% CI, 1.25-3.66; P=0.01) even after adjustment for age, sex, loop diuretic therapy, anticoagulant therapy, proton pump therapy, coexistent chronic obstructive pulmonary disease, diabetes mellitus, renal insufficiency, and chronic liver diseases. In patients with HF, vertebral fractures were positively correlated with female sex, duration of HF, ischemic heart disease, cigarette smoking, and treatment with anti-osteoporotic drugs, and inversely correlated with left ventricular ejection fraction. CONCLUSIONS: Hospitalized patients suffering from HF are at higher risk of vertebral fractures than patients without HF in the same clinical context.

Prevention and treatment of glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis with fractures occurring in as many as 30-50% of patients receiving chronic glucocorticoid therapy. Calcium and vitamin D are important measures in the primary prevention of GIO. However, vitamin D and calcium alone do not allow to prevent fractures. Estrogens and androgens should be used in patients with documented hypogonadism. Bisphosphonates are the most effective of the various therapies that have been assessed for the management of GIO. These drugs need to be started early in order to correct the increase in bone resorption occurring in the first weeks of glucocorticoid treatment. Anabolic therapeutic strategies are under investigation. Teriparatide seems to be also efficacious for the treatment of patients with GIO.

Diagnosis and treatment of acromegaly and its complications: consensus guidelines.

In February 1999, May 2000 and April 2002, three workshops were held in Cortina, Montecarlo and Versailles, respectively, to develop a consensus defining the diagnosis and treatment of acromegaly and its complications. The workshops were sponsored by the Pituitary Society and European Neuroendocrine Association. Invited international participants included endocrinologists, neurosurgeons and radiotherapists skilled in the management of acromegaly. This review paper summarizes the main points of the three consensus statements published following these three workshops.

Cardiovascular risk in aging and obesity: is there a role for GH.

GH has significant impact in adults. In fact, patients with the GH deficiency (GHD) syndrome are now recognized as having an increased cardiovascular risk. The effects of human aging on GH secretion have been evaluated by a number of researchers. Studies of 24 h secretion of GH have shown variable reductions in most 24-h GH secretory parameters in middle-aged and in older men and women, resulting in a decrease in plasma levels of its anabolic mediator IGF-I. Obesity is also associated with several endocrine and metabolic abnormalities. These include decreased serum GH concentrations, reduced GH half-life, frequency of GH secretory episodes and daily GH production rate. The mechanism of the low GH in obesity is not completely understood nor is it clear whether its relationship with visceral adiposity is causal. The aim of this article will be to review the available clinical data concerning the potential involvement of "subclinical" or perhaps better "functional" GHD, which is observed in aging and obesity, in the increase in cardiovascular risk which characterizes these two conditions.