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.

Clinical and diagnostic approach to patients with hypopituitarism due to traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and ischemic stroke (IS).

The hypothalamic-pituitary dysfunction attributable to traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH), and ischemic stroke (IS) has been lately highlighted. The diagnosis of TBI-induced-hypopituitarism, defined as a deficient secretion of one or more pituitary hormones, is made similarly to the diagnosis of classical hypopituitarism because of hypothalamic/pituitary diseases. Hypopituitarism is believed to contribute to TBI-associated morbidity and to functional and cognitive final outcome, and quality-of-life impairment. Each pituitary hormone must be tested separately, since there is a variable pattern of hormone deficiency among patients with TBI-induced-hypopituitarism. Similarly, the SAH and IS may lead to pituitary dysfunction although the literature in this field is limited. The drive to diagnose hypopituitarism is the suspect that the secretion of one/more pituitary hormone may be subnormal. This suspicion can be based upon the knowledge that the patient has an appropriate clinical context in which hypopituitarism can be present, or a symptom known as caused by hypopituitarism. Hypopituitarism should be diagnosed as a combination of low peripheral and inappropriately normal/low pituitary hormones although their basal evaluation may be not distinctive due to pulsatile, circadian, or situational secretion of some hormones. Evaluation of the somatotroph and corticotroph axes require dynamic stimulation test (ITT for both axes, GHRH + arginine test for somatotroph axis) in order to clearly separate normal from deficient responses.

Acylated ghrelin as provocative test for the diagnosis of ACTH deficiency in patients with hypothalamus-pituitary disease.

The insulin tolerance test (ITT) is the gold standard to evaluate adrenocorticotropic hormone (ACTH) insufficiency. However, alternative tests have been proposed such as metyrapone, glucagon, and ACTH stimulation test. We determined the diagnostic reliability of testing with ghrelin, the natural GH secretagogue that is a potent stimulus exploring the integrity of hypothalamic-pituitary-adrenal axis. We studied the ACTH and cortisol response to acylated ghrelin in 49 patients with history of pituitary disease. The best cortisol and ACTH cut offs to ghrelin test, defined as those with the best sensitivity (SE) and specificity (SP), were identified using the ROC analysis. We also compared accuracy of ghrelin test with that of a simple and cheap test like basal cortisol and ACTH levels. The best cortisol and ACTH cut offs to ghrelin test were ≤11.6 µg/dl (SE 86.4%, SP 77.8%) and ≤32.5 pg/ml (SE 72.7%, SP 51.9%), respectively; the best basal cortisol and ACTH cut offs were ≤10.7 µg/dl (SE 90.9%, SP 70.4%) and ≤25.0 pg/ml (SE 85%, SP 37%), respectively. The diagnostic accuracy was 81.6, 60.9, 79.6, and 57.4%, respectively. A comparison between ROC AUC showed a great diagnostic power for cortisol, both stimulated and basal, versus ACTH, both stimulated and basal, but no difference between stimulated and basal cortisol evaluation. Our data show that testing with acylated ghrelin is not a useful diagnostic tool for the diagnosis of central hypocortisolism; particularly ghrelin test adds no more information that basal cortisol evaluation in the diagnosis of ACTH deficiency in patients with hypothalamus-pituitary disease.

Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH--an update.

CONTEXT: GH deficiency (GHD) of the adult is a clinical condition characterized by the presence of several traditional and emerging cardiovascular risk factors that can significantly increase cardiovascular morbidity and mortality. It is still an open issue whether GH replacement is able not only to improve cardiovascular risk factors but also to decrease cardiovascular morbidity and mortality. EVIDENCE ACQUISITION: The major source of data acquisition included PubMed research strategies. Original articles, systematic reviews and meta-analyses, and included relevant citations were screened. EVIDENCE SYNTHESIS: In untreated GHD, cardiovascular risk is increased due to abnormal lipid profile (increased total and low-density lipoprotein cholesterol, increased triglycerides, and reduced high-density lipoprotein cholesterol) and impaired glucose metabolism. Emerging cardiovascular risk factors/markers such as proinflammatory cytokines, C-reactive protein, and adipokines are also increased in GHD patients. Increased cardiovascular morbidity and mortality have also been reported in GHD. GH treatment has been shown to improve both traditional and emerging cardiovascular risk factors and markers. However, evidence on the effects of GH replacement on cardiovascular events and mortality is limited. CONCLUSION: The GHD population may be considered at high cardiovascular risk, and GH substitution may be expected to bring an added value to patients with hypopituitarism in terms of cardiovascular protection. However, there is too limited evidence (rarely coming from randomized and controlled studies) to recommend GH treatment based on the cardiovascular status of the patients.

Octreotide for acromegaly treatment: a reappraisal.

INTRODUCTION: Acromegaly is a rare disorder characterized by excess secretion of growth hormone (GH) generally caused by a pituitary macroadenoma and associated with reduced life expectancy if the disease is untreated. This article covers the recent available evidences published on octreotide , the first somatostatin analog introduced into clinical practice for the medical treatment of acromegaly. AREAS COVERED: This article discusses i) pharmacology of somatostatin and octreotide; ii) biochemical effects of regular octreotide and long-acting repeatable formulation; iii) tumor shrinkage effects of octreotide in acromegaly; iv) impact of octreotide on acromegalic clinical manifestations and chronic complications; v) safety of octreotide and vi) place of octreotide in the guidelines for acromegaly treatment. Full-text articles in the English language were selected from a PubMed search spanning 1984 - 2013, for keywords including 'octreotide,' 'acromegaly,' 'GH,' 'IGF-I,' and 'tumor shrinkage.' Reference lists in selected papers were also used to broaden the search. EXPERT OPINION: Octreotide is a mature drug with a consolidated favorable benefit versus risks profile in the treatment of acromegaly.

Potential role for retinoic acid in patients with Cushing's disease.

CONTEXT: Cushing's disease, i.e. cortisol excess due to an ACTH-secreting pituitary adenoma, is a rare disorder with considerable morbidity and mortality but no satisfactory medical treatment as yet. Experimental data have recently shown that retinoic acid restrains ACTH secretion by tumoral corticotropes. OBJECTIVE: Our objective was to evaluate the efficacy and safety profile of retinoic acid treatment in patients with Cushing's disease. DESIGN: This is a prospective, multicenter study. Seven patients with Cushing's disease (three men, four postmenopausal women) were started on 10 mg retinoic acid daily and dosage increased up to 80 mg daily for 6-12 months. ACTH, urinary free cortisol (UFC), and serum cortisol as well as clinical features of hypercortisolism and possible side effects of retinoic acid were evaluated at baseline, during retinoic acid administration, and after drug withdrawal. RESULTS: A marked decrease in UFC levels was observed in five patients; mean UFC levels on retinoic acid were 22-73% of baseline values and normalization in UFC was achieved in three patients. Plasma ACTH decreased in the first month of treatment and then returned to pretreatment levels in responsive patients whereas no clear-cut pattern could be detected for serum cortisol. Blood pressure, glycemia, and signs of hypercortisolism, e.g. body weight and facial plethora, were ameliorated to a variable extent on treatment. Patients reported only mild adverse effects, e.g. xerophthalmia and arthralgias. CONCLUSIONS: Long-term treatment with retinoic acid proved beneficial and well tolerated in five of seven patients with Cushing's disease. This represents a novel, promising approach to medical treatment in Cushing's disease.

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.

Isoprostane as a marker of oxidative stress in chronic heroin users: correlation with duration of heroin use or concomitant hepatitis C infection.

BACKGROUND: Although chronic heroin abuse has been extensively linked to oxidative stress, and while plasma 15-F(2t)-IsoP is considered a good indicator of oxidative stress, there remain few references in the literature about the plasma concentration of this marker in heroin dependent subjects. OBJECTIVES: To determine plasma 15-F(2t)-IsoP, as a marker of oxidative stress, in chronic heroin users, and to examine whether the values of this marker correlate with the duration of heroin use or with the presence of anti-HCV antibodies. METHODS: Forty-two chronic heroin users and twenty two healthy control subjects were recruited for this study. An enzyme-immunoassay method was used for the determination of 15-F(2t)-IsoP in plasma. RESULTS: Plasma 15-F(2t)-IsoP values were significantly higher in chronic heroin users compared to healthy controls. No correlation was found between the values of plasma 15-F(2t)-IsoP and the duration of heroin use. Heroin dependent subjects positive for anti-HCV antibodies had significantly lower values of plasma 15-F(2t)-IsoP as compared to those without a history of HCV infection. CONCLUSIONS: The elevated plasma 15-F(2t)-IsoP values in heroin dependent subjects, compared to healthy individuals, indicate a shift of the balance between oxidants and antioxidants towards the former and suggest that heroin dependent subjects could benefit from an antioxidant therapy.

Enhanced oxidative stress with a gradient between plasma and muscle interstitial fluid in patients with end stage renal failure on hemodialysis.

OBJECTIVE: The concentration of 8-iso-prostaglandin-F2 alpha (8-iso-PGF2 alpha in biological fluids has been considered as the most reliable biochemical index of the lipid peroxidation and oxidative stress in patients with several pathological conditions including end stage renal failure. However, there is no reference regarding the influence of Hemodialysis (HD) on the values of 8-iso-PGF2 alpha in the muscle Interstitial Fluid (IF) of patients with end stage renal failure. The aim of our study was to determine 8-iso-PGF2 alpha concentration in the IF during hemodialysis and the gradient between plasma and IF in patients with end stage renal failure. DESIGN: In this study, two microdialysis probes were inserted into the vastus lateralis muscle of the right leg of six male patients with end stage renal failure who were on hemodialysis, and in six healthy males (controls). The samples of IF (12 dialysate fluids) were collected after an equilibration of 30 min: a) during the 1st hour preceding hemodialysis (group CRF0), b) during the 1st, 2nd, 3rd and 4th hour while on hemodialysis (groups CRF1, CRF2, CRF3 and CRF4) and c) during the 1st hour following hemodialysis (group CRF5). At the end of the above periods and simultaneously, blood samples were drawn from the arteriovenous fistula. In the controls, the IF samples (twelve dialysate fluids) were collected during a period of one hour and the blood samples at the end of this period. The levels of 8-iso-PGF2 alpha were measured with an enzyme-immunoassay method. Statistical evaluation was carried out with the statistical program NCSS 2000 and the ANOVA test. RESULTS: Plasma and IF levels of 8-iso-PGF2 alpha in the patients were significantly higher than in controls at base line. During hemodialysis, the 8-iso-PGF2 alpha rose progressively both in plasma and IF but remained higher in plasma than in IF. CONCLUSIONS: Lipid peroxidation is higher in patients on hemodialysis than in controls but it is lower in the IF compared to plasma. The mechanism for this gradient is speculative.