Excess Morbidity Persists in Patients With Cushing's Disease During Long-term Remission: A Swedish Nationwide Study.

CONTEXT: Whether multisystem morbidity in Cushing's disease (CD) remains elevated during long-term remission is still undetermined. OBJECTIVE: To investigate comorbidities in patients with CD. DESIGN, SETTING, AND PATIENTS: A retrospective, nationwide study of patients with CD identified in the Swedish National Patient Register between 1987 and 2013. Individual medical records were reviewed to verify diagnosis and remission status. MAIN OUTCOMES: Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by using the Swedish general population as reference. Comorbidities were investigated during three different time periods: (i) during the 3 years before diagnosis, (ii) from diagnosis to 1 year after remission, and (iii) during long-term remission. RESULTS: We included 502 patients with confirmed CD, of whom 419 were in remission for a median of 10 (interquartile range 4 to 21) years. SIRs (95% CI) for myocardial infarction (4.4; 1.2 to 11.4), fractures (4.9; 2.7 to 8.3), and deep vein thrombosis (13.8; 3.8 to 35.3) were increased during the 3-year period before diagnosis. From diagnosis until 1 year after remission, SIRs (95% CI were increased for thromboembolism (18.3; 7.9 to 36.0), stroke (4.9; 1.3 to 12.5), and sepsis (13.6; 3.7 to 34.8). SIRs for thromboembolism (4.9; 2.6 to 8.4), stroke (3.1; 1.8 to 4.9), and sepsis (6.0; 3.1 to 10.6) remained increased during long-term remission. CONCLUSION: Patients with CD have an increased incidence of stroke, thromboembolism, and sepsis even after remission, emphasizing the importance of early identification and management of risk factors for these comorbidities during long-term follow-up.

The incidence of Cushing's disease: a nationwide Swedish study.

BACKGROUND: Studies on the incidence of Cushing's disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden. METHODS: Patients registered with a diagnostic code for Cushing's syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data. RESULTS: Of 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4-1.8) cases per million. 1987-1995, 1996-2004, and 2005-2013, the mean annual incidence was 1.5 (1.1-1.8), 1.4 (1.0-1.7) and 2.0 (1.7-2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P < 0.05). CONCLUSION: The incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987-2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.

Overall and Disease-Specific Mortality in Patients With Cushing Disease: A Swedish Nationwide Study.

CONTEXT: Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable. OBJECTIVE: To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD. DESIGN, PATIENTS, AND METHODS: A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality. RESULTS: Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome. CONCLUSION: Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health.

Acylated ghrelin inhibits spontaneous luteinizing hormone pulsatility and responsiveness to naloxone but not that to gonadotropin-releasing hormone in young men: evidence for a central inhibitory action of ghrelin on the gonadal axis.

CONTEXT: Recent evidence suggests that ghrelin exerts a negative modulation on the gonadal axis. Ghrelin was reported to suppress LH secretion in both animal and human models. Moreover, acylated ghrelin (AG) also decreases the LH responsiveness to GnRH in vitro. OBJECTIVE: The objective of the study was to evaluate the effects of AG infusion on spontaneous and stimulated gonadotropin secretion. DESIGN, PARTICIPANTS, AND INTERVENTION: In seven young healthy male volunteers (age mean +/- sem 26.4 +/- 2.6 yr), we evaluated LH and FSH levels every 15 min during: 1) iv isotonic saline infusion; 2) iv saline followed by AG; LH and FSH response to GnRH (100 microg iv as a bolus), 3) alone and 4) during AG infusion; LH and FSH response to naloxone (0.1 mg/kg iv as a slow bolus), 5) alone and 6) during AG infusion. RESULTS: Significant LH but not FSH pulses were recorded in all subjects under saline infusion. AG infusion inhibited LH levels [area under the curve((240-480)): 415.8 +/- 69.7 mIU/ml.min during AG vs. 744.6 +/- 120.0 mIU/ml.min during saline, P < 0.02] and abolished LH pulsatility. No change in FSH secretion was recorded. The LH and FSH responses to GnRH during saline were not affected by AG administration. However, AG inhibited the LH response to naloxone [area under the curve ((120-210)): 229.9 +/- 39.3 mIU/ml.min during AG vs. 401.1 +/- 44.6 mIU/ml.min during saline, P < 0.01]. FSH levels were not modified by naloxone alone or in combination with AG. CONCLUSIONS: AG inhibits both spontaneous LH pulsatility and the LH response to naloxone. Because AG does not affect the LH response to GnRH, these findings indicate that the ghrelin system mediates central inhibition of the gonadal axis.

Growth hormone treatment in human ageing: benefits and risks.

This paper will focus on the rationale of using Growth Hormone (GH) as an anti-ageing therapy in the healthy elderly with age-related decline in the activity of the GH/IGF-I axis, the so called "somatopause". Although the age-related decline in the activity of the GH/IGF-I axis is considered to contribute to age-related changes similar to those observed in Growth Hormone Deficient (GHD) adults, GH/IGF-I deficiency or resistance is also known to result in prolonged life expectancy, at least in animals. These data raise the question whether or not GH deficiency constitutes a beneficial adaptation to ageing and therefore requires no therapy. Moreover, although GH therapy has been shown to exert positive effects in GHD patients, its safety, efficacy and role in healthy elderly individuals is highly controversial. This review provides a comprehensive account of the implications of GH therapy in the ageing subject.

Corticotrope hypersecretion coupled with cortisol hypo-responsiveness to stimuli is present in patients with autoimmune endocrine diseases: evidence for subclinical primary hypoadrenalism?

OBJECTIVE: In autoimmune polyglandular syndrome types 1, 2, and 4 primary adrenal insufficiency is present, but its diagnosis is often late. We investigated the function of the hypothalamic-pituitary-adrenal axis in a group of patients with autoimmune diseases (AP) without any symptoms and signs of hypoadrenalism. DESIGN: In 10 AP and 12 normal subjects (NS), we studied cortisol (F), aldosterone (A), and DHEA responses to 0.06 microg adrenocorticotropin (ACTH) (1-24) followed by 250 microg, ACTH and F responses to human corticotropin-releasing hormone (hCRH; 100 microg) and insulin tolerance test (ITT) (0.1 UI/kg). RESULTS: Basal F, A, DHEA, as well as urinary free cortisol and plasma renin activity levels in AP and NS were similar, whereas ACTH levels in AP were higher (P<0.05) than in NS. NS showed F, A, and DHEA response to both consecutive ACTH doses. In AP, the F, A, and DHEA responses to 250 microg ACTH were similar to those in NS, whereas the 0.06 microg ACTH dose did not elicit any significant response. The ACTH responses to hCRH and ITT in AP were higher (P<0.05) than in NS. The F response to hCRH in AP was lower (P<0.05) than in NS, whereas the F response to ITT in AP did not significantly differ from NS. CONCLUSIONS: Enhancement of both basal and stimulated corticotrope secretion coupled with reduced adrenal sensitivity to low ACTH dose is present in AP patients without symptoms and signs of hypoadrenalism. This functional picture suggests that normal adrenal secretion is maintained due to corticotrope hyperfunction, suggesting the existence of some subclinical primary hypoadrenalism.

Neuroregulation of the hypothalamus-pituitary-adrenal (HPA) axis in humans: effects of GABA-, mineralocorticoid-, and GH-Secretagogue-receptor modulation.

The hypothalamus-pituitary-adrenal (HPA) axis exerts a variety of effects at both the central and peripheral level. Its activity is mainly regulated by CRH, AVP, and the glucocorticoid-mediated feedback action. Moreover, many neurotransmitters and neuropeptides influence HPA axis activity by acting at the hypothalamic and/or suprahypothalamic level. Among them, GABA and Growth Hormone Secretagogues (GHS)/GHS-receptor systems have been shown to exert a clear inhibitory and stimulatory effect, respectively, on corticotroph secretion. Alprazolam (ALP), a GABA-A receptor agonist, shows the most marked inhibitory effect on both spontaneous and stimulated HPA axis activity, in agreement with its peculiar efficacy in panic disorders and depression where an HPA axis hyperactivation is generally present. Ghrelin and synthetic GHS possess a marked ACTH/cortisol-releasing effect in humans and the ghrelin/GHS-R system is probably involved in the modulation of the HPA response to stress and nutritional/metabolic variations. The glucocorticoid-mediated negative feedback action is mediated by both glucocorticoid (GR) and mineralocorticoid (MR) receptors activation at the central level, mainly in the hippocampus. In agreement with animal studies, MRs seem to play a crucial role in the maintenance of the circadian ACTH and cortisol rhythm, through the modulation of CRH and AVP release. GABA agonists (mainly ALP), ghrelin, as well as MR agonists/antagonists, may represent good tools to explore the activity of the HPA axis in both physiological conditions and pathological states characterized by an impaired control of the corticotroph function.

The negative association between total ghrelin levels, body mass and insulin secretion is lost in hypercortisolemic patients with Cushing's disease.

OBJECTIVE: Ghrelin exerts a wide spectrum of endocrine and non-endocrine actions. The stomach is the major source of circulating ghrelin levels that are negatively associated with body mass, insulin and glucose levels. The role of glucocorticoids in ghrelin secretion and action is still unclear. DESIGN: In 8 patients with Cushing's disease (CD, BMI 29.8 +/- 1.6 kg/m(2)), 7 normal (NS) and 6 obese subjects (OB, BMI 32.9 +/- 1.1 kg/m(2)) we studied: a) total ghrelin levels (every 15 min over 3 h) and their correlation with BMI, insulin, glucose, homeostatic model assessment (HOMA) index, ACTH and cortisol levels; b) GH, ACTH, cortisol, insulin and glucose responses to acylated ghrelin administration (1.0 mug/kg i.v. at 0 min). RESULTS: CD patients had BMI, insulin and glucose levels as well as HOMA index higher than those in NS (P < 0.05) but similar to those in OB. Despite this, total ghrelin levels in CD were similar to those in NS and both were higher (P < 0.05) than those in OB. No correlation was found among total ghrelin and BMI, insulin, glucose, ACTH and cortisol levels in CD patients. The GH responses to ghrelin in CD and OB were similar and both were lower (P < 0.002) than those in NS. In CD ghrelin induced exaggerated ACTH and cortisol responses clearly higher (P < 0.005) than in OB and NS. Ghrelin administration increased glucose in all groups; insulin levels showed slight decrease that was significant (P < 0.05) in OB only. CONCLUSIONS: Hypercortisolism in humans is associated with impaired ghrelin secretion and action. In fact, total ghrelin secretion in CD is not reduced despite increased BMI, insulin and glucose levels, while the GH and ACTH responses to acylated ghrelin are clearly reduced and enhanced, respectively.

Hypothalamus-pituitary-adrenal hyperactivity in human aging is partially refractory to stimulation by mineralocorticoid receptor blockade.

CONTEXT: The hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by CRH, arginine vasopressin, and glucocorticoid feedback. Hippocampal mineralocorticoid receptors mediate proactive glucocorticoid feedback and mineralocorticoid antagonists, accordingly, stimulate HPA axis. Age-related HPA hyperactivity reflects impaired glucocorticoid feedback at the suprapituitary level. DESIGN: ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion were studied in eight healthy elderly (75.1 +/- 3.2 yr) and eight young (25.0 +/- 4.6 yr) subjects during placebo or canrenoate (CAN) administration (200 mg i.v. bolus followed by 200 mg infused over 4 h). RESULTS: During placebo administration, ACTH and cortisol areas under the curve (AUCs) in elderly subjects were higher than in young subjects (P < or = 0.01); conversely, DHEA AUCs in elderly subjects were lower than in young subjects (P = 0.002). CAN increased ACTH, cortisol, and DHEA levels in both groups. In young subjects, ACTH, cortisol, and DHEA levels at the end of CAN infusion were higher (P < or = 0.05) than after placebo. In elderly subjects, at the end of CAN infusion, ACTH, cortisol, and DHEA levels were higher (P = 0.01) than after placebo. Under CAN, ACTH and cortisol AUCs were persistently higher (P < or = 0.01) and DHEA AUCs lower (P = 0.006) in elderly than in young subjects. Cortisol AUCs after CAN in young subjects did not become significantly different from those in elderly subjects after placebo. CONCLUSIONS: 1) Evening-time ACTH and cortisol secretion in elderly subjects is higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by CAN but less than that in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in mineralocorticoid receptors function at the hippocampal level.

Ghrelin, hypothalamus-pituitary-adrenal (HPA) axis and Cushing's syndrome.

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS. Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts pleiotropic actions that are explained by the widespread distribution of ghrelin and GHS-R expression. Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a. However, GHS-R subtypes are likely to exist; they also bind unacylated ghrelin that is, in fact, the most abundant circulating form and exerts some biological actions. Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction. The role of glucocorticoids on ghrelin synthesis and secretion is still unclear although morning ghrelin levels have been found reduced in some patients with Cushing's syndrome; this, however, would simply reflect its negative association to body mass. Ghrelin, like synthetic GHS, stimulates ACTH and cortisol secretion in normal subjects and this effect is generally sensitive to the negative glucocorticoid feedback. It is remarkable that, despite hypercortisolism, ghrelin as well as synthetic GHS display marked increase in their stimulatory effect on ACTH and cortisol secretion in patients with Cushing's disease. This is even more intriguing considering that the GH response to ghrelin and GHS is markedly reduced by glucocorticoid excess. It has been demonstrated that the ACTH-releasing effect of ghrelin and GHS is purely mediated at the central level in physiological conditions; its enhancement in the presence of ACTH-secreting tumours is, instead, likely to reflect direct action on GHS receptors present on the neoplastic tissues. In fact, peculiar ACTH hyperresponsiveness to ghrelin and GHS has been observed also in ectopic ACTH-secreting tumours.