Lenvatinib in Advanced Radioiodine-refractory Thyroid Cancer: A Snapshot of Real-life Clinical Practice.

BACKGROUND: We retrospectively analyzed the efficacy and safety of lenvatinib in 12 patients with advanced radioiodine-refractory thyroid cancer in the setting of daily clinical practice. PATIENTS AND METHODS: The starting daily dose of lenvatinib was 24 mg, tapered in the case of adverse events. Disease status was periodically evaluated by a single radiologist and safety assessment was regularly performed. RESULTS: After a median follow-up of 13.3 months, 6- and 12-month progression-free survival rates were 63.6% and 54.6%, respectively. Overall survival at 6 and 12 months was 83.3% and 75.0%. Partial response was observed in five patients, while two showed stable disease as their best response. Conversely, progressive disease at first radiological assessment was detected in four patients. All patients experienced at least one adverse event, including systemic and gastrointestinal toxicity, high blood pressure and hand-foot syndrome. In order to manage toxicity, transient drug interruption and dose reduction were required in 10 and 9 cases, respectively. CONCLUSION: Our data confirm lenvatinib efficacy in patients with advanced thyroid cancer, despite an important toxic profile.

Tyrosine kinase inhibitors rechallenge in solid tumors: a review of literature and a case description with lenvatinib in thyroid cancer.

INTRODUCTION: In the last decade tyrosine kinase inhibitors (TKIs) have been employed for a wide range of hematological and solid tumors and today they represent a valid therapeutic option for different neoplasms. Among them, both sorafenib and lenvatinib were approved for the treatment of radioactive iodine (RAI) refractory differentiated thyroid carcinoma (DTC). Unfortunately, in some cases the efficacy of TKIs is limited by the onset of drug resistance after the initial response. Areas covered: We report the case of a patient with a RAI refractory advanced DTC, treated with lenvatinib after surgery, multiple RAI administrations, traditional chemotherapy, and sorafenib. During treatment with lenvatinib, a noticeable response was detected by sequential computed tomography scans but, after 27 months, tumor progression became evident and led to lenvatinib interruption. In absence of any active treatment, a further disease progression was documented, and lenvatinib was re-administered obtaining a new objective response. Starting from this case report, we review available reports about the rechallenge with TKIs in solid tumors, discussing the possible mechanisms underlying the efficacy of this approach. Expert commentary: Rechallenge with TKIs in solid tumors could be a therapeutic option in subjects with advanced and metastatic DTC who experience a progressive disease after initial response to lenvatinib.

Secondary Adrenal Insufficiency: Where Is It Hidden and What Does It Look Like?

Adrenal failure secondary to hypothalamic-pituitary disease is a common although underestimated and underdiagnosed condition, with serious consequences. Corticotropin deficiency can be isolated or more frequently occur in association with other pituitary hormones deficiencies. The most frequent endogenous cause of secondary adrenal insufficiency (SAI) is a tumor of the hypothalamic-pituitary region, usually associated with panhypopituitarism secondary to tumor growth or to its treatment with surgery or irradiation. Less commonly, SAI is due to nontumoral disorders including infiltrative lesions, infective processes, vascular alterations, traumatic brain injury, empty sella or genetic disorders. Finally, long-term administration of exogenous glucocorticoids can determine secondary and/or tertiary hypoadrenalism acting at the hypothalamic level and leading to prolonged suppression of the hypothalamic-pituitary-adrenal axis. It is essential to perform validated diagnostic procedures in order to promptly diagnose hypoadrenalism so as to prevent an adrenal crisis. At the same time, diagnosis is complex as no single test has sufficient sensitivity to identify all patients with SAI. Therefore, clinical judgment and follow-up are crucial for the assessment of corticotropin deficiency. Patients with persisting suggestive symptoms and/or a clinical history of higher risk for adrenal insufficiency deserve careful subsequent reassessments.

Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison's disease.

In patients with Addison's disease (AD), a dual-release preparation of hydrocortisone (Plenadren, PLEN) has been demonstrated to maintain cortisol levels in a more physiological range than conventional glucocorticoid therapy, and to exert positive effects. This study aimed to assess variations of anthropometric, metabolic, and hormonal parameters in patients with AD after switching from conventional hydrocortisone (HC) treatment to PLEN. In nineteen AD patients (15 F and 4 M, age 27-65 years) treated with HC 20 mg/day thrice daily, body weight, BMI, waist circumference, fasting glucose, HbA1c, serum lipids, plasma renin activity, electrolytes, and blood pressure were evaluated at baseline, and 1, 3, 6, and 12 months after switching from HC to PLEN. At baseline, and after 1 and 12 months of PLEN, blood ACTH and cortisol (at 0800 h at fasting, and 30, 60, 90, 120, and 240 min after drug ingestion), and health-related quality of life (HRQoL), using 30-AddiQoL questionnaire, were evaluated. During PLEN, waist and serum lipid progressively decreased. After 12 months of PLEN, a significant difference was observed in waist circumference (P = 0.007), HbA1c (P = 0.002), total and LDL-cholesterol levels (P < 0.05). ACTH levels at 240 min and the area under the curve (AUC) were lower (P < 0.05) during PLEN than HC, while cortisol peaks and AUC were similar. 30-AddiQoL total score also improved (P = 0.04) during PLEN. In AD patients, PLEN reduces central adiposity, and improves glucose and metabolism parameters and HRQoL.

Cushing's syndrome is associated with sleep alterations detected by wrist actigraphy.

BACKGROUND: The association between the hypothalamic-pituitary-adrenal (HPA) axis and sleep is well described. It is also known that HPA axis disturbances have an effect on sleep. In fact, patients affected by Cushing's syndrome (CS) often complain about poor sleep quality. Our aim was to evaluate objective sleep quality and duration in patients with Cushing's syndrome in active phase, using wrist actigraphy. PATIENTS AND METHODS: In 12 patients with active CS without ongoing specific therapy (11 F, 1 M; age 40.0 ± 10.9 years; BMI 28.4 ± 6.7 kg/m(2)) and 12 healthy control subjects (HS) (11 F, 1 M; age 44.0 ± 11.0 years; BMI 23.9 ± 4.2 kg/m(2)) an actigraphic evaluation was performed on 3 consecutive days under free living conditions. Objective measurement of sleep duration and quality was estimated by an actiwatch, which is a wristwatch-like device used to detect motor activity. RESULTS: In CS patients, wrist actigraphy showed higher fragmented sleep (fragmentation index CS 16.2 ± 4.2, HS 13.0 ± 3.6; p = 0.034) and increased nocturnal motor activity (total activity score CS 8318 ± 4308, HS 4971 ± 2372; p = 0.020; mean activity score CS 8.7 ± 4.2, HS 5.4 ± 2.2; p = 0.030; mean score in active time CS 104.8 ± 39.2, HS 74.8 ± 23.1; p = 0.030). On the contrary, actual sleep time resulted similar in CS and HS. No correlation was found between sleep alterations and urinary free cortisol in patients. CONCLUSIONS: The impaired actigraphic parameters described in our study suggest that hypercortisolism is associated with sleep alterations, which could contribute to the worsening of life quality and metabolic comorbidities associated with CS. These results have to be confirmed in a larger cohort of patients, using more accurate instruments for sleep assessment.

Enhanced oxidative stress and platelet activation in patients with Cushing's syndrome.

OBJECTIVE: Cushing Syndrome (CS) is implicated by increased cardiovascular risk (CVR) leading to increased morbidity and mortality. Oxidative stress (OS) and platelet activation (PA) are associated with increased CVR. However, scarce data of OS in CS exist. Our objective was to determine the oxidant-antioxidant balance in CS. DESIGN: Fourteen patients with CS at diagnosis and fourteen healthy subjects (NS) were evaluated OS by measuring plasma 15-F2t -Isoprostane (15-F2t -IsoP), PA by thromboxaneB2 levels (TXB2 ), and antioxidant reserve measuring total antioxidant capacity (TAC) and serum vitamin E. RESULTS: 15-F2t -IsoP and TXB2 levels were significantly higher (P < 0·01) in CS, while vitamin E levels were higher in NS (P < 0·03). 15-F2t -IsoP levels were significantly higher (P < 0·01) in complicated vs not-complicated CS and NS and significantly higher (P < 0·03) in CS not-complicated vs NS. TXB2 levels were significantly reduced (P < 0·03) in NS vs complicated and not-complicated CS. A negative correlation between Vitamin E and UFC was observed in CS (P < 0·05 r = -0·497). TXB2 correlated with glucose, HbA1c and T-score (P < 0·05 r = 0·512, P < 0·03 r = 0·527 and P < 0·01 r = 0·783, respectively) and HDL (P < 0·01 r = -0·651). 15-F2t -IsoP correlated with triglicerides, HbA1c and diastolic pressure (P < 0·01 r = 0·650, P < 0·03 r = 0·571 and P < 0·05 r = 0·498, respectively) and HDL (P < 0·03 r = -0·594). CONCLUSIONS: This study emphasizes the major role of OS in CS. As our findings demonstrated that enhanced OS and PA take place in this rare metabolic disorder which is associated with increased CVR, it could be suggested that these biochemical alterations can further contribute in the pathogenesis of atherosclerosis, increased CVR and mortality in CS.

Dual-release Hydrocortisone in Addison's Disease - A Review of the Literature.

In patients with adrenal insufficiency, glucocorticoids (GCs) are insufficiently secreted and GC replacement is essential for health and, indeed, life. Despite GC-replacement therapy, patients with adrenal insufficiency have a greater cardiovascular risk than the general population, and suffer from impaired health-related quality of life. Although the aim of the replacement GC therapy is to reproduce as much as possible the physiological pattern of cortisol secretion by the normal adrenal gland, the pharmacokinetics of available oral immediate-release hydrocortisone or cortisone make it impossible to fully mimic the cortisol rhythm. Therefore, there is an unmet clinical need for the development of novel pharmaceutical preparations of hydrocortisone, in order to guarantee a more physiological serum cortisol concentration time-profile, and to improve the long-term outcome in patients under GC substitution therapy.

The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic--pituitary--adrenal (HPA) axis in humans.

Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of hypothalamic-pituitary-adrenal (HPA)-axis, mediating the "proactive"-feedback of glucocorticoids. Fludrocortisone (FC), a potent MR agonist, has been shown to decrease HPA activity through a mechanism placed at hippocampal level. In order to clarify the effects of MR agonism on HPA function in humans, we studied the effects of FC, in a dose-related manner, on both basal and CRH-stimulated HPA axis during the quiescent phase. 8 young women were studied. ACTH, cortisol and aldosterone levels were evaluated every 15', from 1600 to 2000 hours, in randomized sessions: (1) placebo p.o. + placebo i.v., (2) 0.3 mg FC p.o. + placebo, (3) 0.1 mg FC. + placebo, (4) 0.075 mg FC + placebo, (5) 0.05 mg FC + placebo, (6) placebo + hCRH (2.0 µg/kg iv-bolus), (7) 0.3 mg FC + hCRH, (8) 0.1 mg FC + hCRH, (9) 0.075 mg FC + hCRH, (10) 0.05 mg FC + hCRH. FC induced a dose-related trend toward a further decrease of the ACTH and cortisol levels, while it showed a significant and dose-dependent inhibition of the hormonal response to hCRH (p < 0.05 for the doses of 0.3, 0.1 and 0.075 mg). Conversely, 0.05 mg FC did not modify the CRH-stimulatory effect on both ACTH and cortisol secretion. Aldosterone levels were not modified by FC administration. Fludrocortisone inhibits corticotrope and adrenal response to hCRH in humans, in a dose-dependent manner. The 0.075 mg FC seems the lowest active while 0.05 mg the first neutral dose on HPA activity. These data suggest a possible hypophysial MR-mediated inhibiting effect of FC, although its pituitary glucocorticoid-mediated effect cannot be excluded. The interplay between fludrocortisone and hypophysial glucocorticoid receptors needs to be clarified in order to define better the clinical consequences of the hormonal replacement therapy of patients with primary adrenal insufficiency.

Role of mineralocorticoid receptors on the hypothalamus-pituitary-adrenal axis in humans.

This clinical review will summarize the available data regarding the role of mineralocorticoid receptors (MRs) on the hypothalamus-pituitary-adrenal (HPA) axis control in physiological and pathological conditions and in the memory processes involved in the control and appraisal of a stress event. MRs are predominantly expressed in the limbic structures, with the hippocampus being the main localization, although MRs are also found at the hypothalamic level. It is known that hyppocampal MRs control the proactive feedback involved in the maintenance of the basal HPA activity, mainly at the nadir of the circadian rhythm. In physiological conditions, the administration of pharmacological doses of both MR antagonists and agonists is able to interact with the HPA activity, modifying the quiescent phase-nadir of the circadian rhythm, although some data in the literature do not support these observations. Also, in a physiological condition such as aging, an enhanced HPA axis activity is found in the time window, when MRs are predominantly occupied by cortisol circulating levels, possibly reflecting an MR impairment in this period of life. In pathology, major depression has been correlated to MR qualitative-quantitative alterations which could reflect differences on psychological and physiological responses, possibly predicting psychopathologies. Most of the remarks reported in this review seem to indicate, in agreement with animal data, a role played by MRs in the delicate control of the HPA axis in humans and the possible predisposition to the development of pathologies in case of their alterations.

Acute administration of alprazolam, a benzodiazepine activating GABA receptors, inhibits cortisol secretion in patients with subclinical but not overt Cushing's syndrome.

The purpose of this study is to verify whether acute pre-treatment with alprazolam (ALP), a benzodiazepine that inhibits HPA secretion in normal subjects, could better characterize patients with subclinical Cushing's syndrome (SCS) than the 1-mg dexamethasone test (DST). In 22 patients with SCS, 10 with overt Cushing's syndrome (CS), 11 with non-functioning adrenal incidentalomas (NF) and 14 normal subjects (NS) we studied the effect of ALP (1 mg, p.o. at 2300 hours) on cortisol levels after 1-mg DST. Cortisol levels (mean ± SEM) after DST were lower (P = 0.012) in SCS (3.9 ± 0.3 µg/dl) than in overt CS (10.4 ± 1.9 µg/dl), while they were higher (P = 0.0005) than in NF (1.1 ± 0.1 µg/dl) and NS (1.5 ± 0.1 µg/dl). After ALP pre-treatment, cortisol levels further decreased (P = 0.004) in SCS (3.0 ± 0.3 µg/dl), but neither in CS (9.3 ± 1.3 µg/dl) nor in NF (1.3 ± 0.1 µg/dl) and in NS (1.3 ± 0.1 µg/dl). In SCS, cortisol levels after ALP + 1-mg DST persisted lower (P = 0.0005) than those in CS, but higher (P = 0.0005) than those in NF and NS. Considering individual cases, ALP pre-treatment reduced cortisol levels < 3 and < 1.8 µg/dl in 50 and 23 % of SCS patients, respectively. ALP amplifies the cortisol inhibition exerted by 1-mg DST in patients with SCS but not in those with CS. The clinical usefulness of ALP to increase the sensitivity of 1-mg DST to identify true autonomous cortisol release in patients with adrenal incidentalomas as well as to predict different clinical outcomes remains to be clarified.

BClI polymorphism of the glucocorticoid receptor gene is associated with increased obesity, impaired glucose metabolism and dyslipidaemia in patients with Addison's disease.

OBJECT: Although glucocorticoids are essential for health, several studies have shown that glucocorticoids replacement in Addison's disease might be involved in anthropometric and metabolic impairment, with increased cardiovascular risk, namely if conventional doses are used. As the effects of glucocorticoids are mediated by the glucocorticoid receptor, encoded by NR3C1 gene, different polymorphisms in the NR3C1 gene have been linked to altered glucocorticoid sensitivity in general population as well as in patients with obesity or metabolic syndrome. DESIGN: We investigated the impact of glucocorticoid receptor gene polymorphisms, including the BclI, N363S and ER22/23EK variants, on anthropometric parameters (BMI and waist circumference), metabolic profile (HOMA, OGTT and serum lipids) and ACTH levels in 50 patients with Addison's disease (34 women and 16 men, age 20-82 year) under glucocorticoids replacement. RESULTS: Neither N363S nor ER22/23EK variants were significantly associated with anthropometric, metabolic or hormonal parameters, while patients carrying the homozygous BclI polymorphism GG (n = 4) showed higher (P < 0·05) BMI, waist circumference, HOMA and 2-h glucose levels after OGTT, as well as total cholesterol and triglycerides than those with wild-type genotype CC (n = 28) or heterozygous CG (n = 18). The totality of GG patients was connoted by abdominal adiposity, impaired glucose tolerance/diabetes mellitus or dyslipidaemia, while a lower percentage of CC or CG patients showed some anthropometric and metabolic alterations. CONCLUSION: These results suggest that BclI polymorphism may influence the sensitivity to glucocorticoids in patients with Addison's disease and may contribute, along with other factors, to the increase in central adiposity, impaired glucose metabolism and dyslipidaemia.

Glucose metabolism in patients with subclinical Cushing's syndrome.

This clinical review will summarize the available data regarding the effect of either physiological or increased glucocorticoid concentrations on glucose metabolism and insulin-sensitivity, in order to clarify the role, if any, of subclinical Cushing's syndrome (SCS), a status of altered hypothalamic-pituitary-adrenal axis secretion in the absence of the classical signs or symptoms of overt cortisol excess, in patients with adrenal incidentalomas (AI) and diabetes mellitus type 2. Focusing on patients with SCS associated to AI, while there is convincing evidence in the literature that even a mild hyper cortisolemia is associated with alterations of glucose metabolism, evidence is insufficient to conclude that the simple correction of chronic, even mild, hypercortisolism can completely revert metabolic, mainly glycemic alterations. At the same time, considering the variability of the prevalence of Cushing's syndrome in patients with diabetes mellitus type 2 reported in the literature, no agreement does exist whether screening for CS can be useful and recommended in those patients.

Metabolic and cardiovascular outcomes in patients with Cushing's syndrome of different aetiologies during active disease and 1 year after remission.

OBJECTIVE: Cushing's syndrome is associated with several comorbidities responsible for the increased cardiovascular risk, not only during the active phase but also after disease remission. DESIGN: In 29 patients with Cushing's syndrome (14 Cushing's diseases and 15 adrenal adenomas), waist circumference, fasting and 2-h glucose after oral glucose tolerance test (OGTT), lipid profile and blood pressure were evaluated during the active disease and 1 year after remission and compared with those in 29 sex-, age- and BMI-matched controls. RESULTS: During the active disease, waist circumference, 2-h glucose after OGTT, total and LDL cholesterol were higher in patients with Cushing's syndrome than in controls (P < 0·001) but similar in Cushing's disease and adrenal adenomas. The prevalence of impaired glucose tolerance (IGT), diabetes mellitus, dyslipidaemia and hypertension was higher (P < 0·001) in patients with Cushing's syndrome (27%, 24%, 59% and 72%) than in controls (10%, 0%, 21% and 10%), with no significant difference between Cushing's disease and adrenal adenomas. One year following hormonal remission, waist circumference persisted higher than in controls (P < 0·05) in both Cushing's disease and adrenal adenomas. Metabolic and cardiovascular abnormalities were still present in both groups, although with a lower prevalence, as well as with a more marked decrease in adrenal adenomas (P < 0·05 vs active disease for IGT, dyslipidaemia and hypertension). CONCLUSIONS: These results show that chronic hypercortisolism, independently of its aetiology, contributes to metabolic impairment and increased cardiovascular risk, while these abnormalities mostly persist in patients with previous Cushing's disease after hormonal remission. Pituitary hormonal deficiencies, hormonal replacement treatments and/or incomplete cure from Cushing's disease may account for these findings.

Effects of cetrorelix, a GnRH-receptor antagonist, on gonadal axis in women with functional hypothalamic amenorrhea.

BACKGROUND: Gonadotropin Releasing Hormone (GnRH) antagonists (GnRHa) suppress gonadotropin and sex-steroid secretion. In normal women, acute GnRHa administration induces inhibitory effect on pituitary-gonadal axis, followed by Luteinizing Hormone (LH) rebound. Functional hypothalamic amenorrhea (HA) is characterised by impaired gonadotropin secretion and hypogonadism secondary to blunted GnRH pulsatility. METHODS: We studied the effects of a GnRHa, cetrorelix (CTX 3.0 mg), in six women with HA (age 30.7 ± 3.2 years; BMI 21.5 ± 1.7 kg/m(2)) and six control subjects (CS, 28.2 ± 0.6 years; 22.6 ± 0.9 kg/m(2)) on LH, Follicle-Stimulating Hormone (FSH) and oestradiol levels over 4 h (08.00-12.00 am) before, +24 h and +96 h after CTX; LH, FSH, and oestradiol were also evaluated at +6, +8, +12, +48, +72 h after CTX. RESULTS: CS: CTX reduced (p < 0.05) LH, FSH, and oestradiol (nadir at +12 h, +24 h, and +24 h); LH rebounded at +96 h, FSH and oestradiol recovered at +48 h and +72 h. The 4-h evaluation showed LH and FSH reduction (p < 0.05) at +24 h, with LH rebound at +96 h. HA: CTX reduced (p < 0.05) LH, FSH, and oestradiol, (nadir at +24 h, +48 h, and +48 h, recovery at +48 h, +72 h, and +96 h). The 4-h evaluation showed gonadotropin reduction (p < 0.05) 24 h after CTX, without any rebound effect. CONCLUSIONS: One single CTX dose still modulates gonadotropin secretion in HA. Its 'paradoxical' stimulatory effect on gonadotropins needs to be verified after prolonged administration.

Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamic-pituitary-adrenal axis in humans.

CONTEXT: Mineralocorticoid receptors (MRs) in the hippocampus display an important role in the control of the hypothalamic-pituitary-adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids, which maintains the basal HPA activity. The systemic administration of MR antagonists enhances spontaneous and CRH-stimulated ACTH, cortisol, and DHEA secretion, while the effects of chronic treatment with MR antagonists are scanty. Our study was performed in order to clarify this point. DESIGN: ACTH, cortisol, and DHEA levels were studied during the infusion of placebo, canrenoate, a MR antagonist (CAN, 200 mg i.v. bolus at 1600 h followed by 200 mg infused over 4 h), and human CRH (hCRH; 2.0 microg/kg i.v. bolus at 1800 h) before and during the last week of 28-day treatment with CAN (200 mg/day p.o.) in eight young women. RESULTS: Pre-treatment sessions: CAN and hCRH administration increased ACTH, cortisol, and DHEA levels versus placebo (P<0.05). Post-treatment sessions: during placebo infusion, cortisol and DHEA were significantly amplified versus pre-treatment session (P<0.05), while ACTH levels were not modified; CAN infusion, differently from pre-treatment session, was not able to significantly increase ACTH, cortisol, and DHEA levels; ACTH, cortisol, and DHEA responses to hCRH were amplified with respect to pre-treatment session, although statistical significance was obtained for cortisol and DHEA only. CONCLUSIONS: MR blockade by acute CAN administration significantly enhances the HPA activity in the afternoon, during the quiescent phase of the circadian rhythm. At the same period, prolonged treatment with CAN amplifies both spontaneous and CRH-stimulated activities of the HPA axis, while it blunts the HPA responsiveness to a further MR-mediated stimulation.

Neuroendocrine effects of citalopram infusion in anorexia nervosa.

Because of the role of serotonin (5HT) in regulating food intake and mood, several studies have focused their attention on the assessment of serotonergic activity in eating disorders, and in particular in anorexia nervosa, but the results have been inconsistent. Citalopram, a highly selective 5HT reuptake inhibitor, has been recently reported as a neuroendocrine probe to assess the serotonergic function in physiological and pathological conditions. We evaluated the adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL) and growth hormone (GH) secretion during placebo or citalopram IV infusion (20 mg over 120 min), in six women with anorexia nervosa restricter type, and in six healthy women, in order to test the hypothesis that this neurotransmitter system is abnormal in this group of patients. ACTH and PRL secretion was higher during citalopram infusion compared to placebo (p<0.05) in both groups, while cortisol secretion was higher during citalopram infusion only in healthy controls (p<0.05), but not in anorexic patients. GH levels were unaffected by citalopram in both groups. These results demonstrate that serotonergic activation by citalopram affects corticotroph and lactotroph but not somatotroph secretion in anorexic as well as in normal subjects. Our preliminary findings do not support the existence of remarkable alterations in the serotonergic control of anterior pituitary function in anorexia nervosa, while there seems to be an impairment of the adrenal function in this group of patients.

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.

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.