On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis

Darmon, Patrice; Dadoun, F.; Frachebois, C; Velut, JG; Boullu, S.; Dutour, A.; Oliver, Charles; Grino, Michel

doi:10.1530/eje.0.1400051

Cited by 30 publications

(26 citation statements)

References 24 publications

(20 reference statements)

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“…[41][42][43]. Comparison of plasma cortisol levels between young and old subjects showed that greater plasma cortisol levels were achieved as a result of the cortisol infusion in old subjects than in young subjects and that women achieved consistently higher plasma cortisol levels than men (Fig.…”

Section: Resultsmentioning

confidence: 92%

Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study

Wilkinson

Petrie

Murray

et al. 2001

Journal of Clinical Endocrinology & Metabolism

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We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20 -35 yr, n ϭ 22) and old (Ͼ65 yr, n ϭ 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids. (J Clin Endocrinol Metab 86: [545][546][547][548][549][550] 2001) A GING IN RODENTS has been found to result in prolonged glucocorticoid responses to stress and impaired feedback inhibition of ACTH secretion by glucocorticoids (1-3). These age-related modifications of hypothalamicpituitary-adrenal (HPA) function have been linked to deficits in learning and memory (4 -6). Until recently, it has not been clear whether similar changes occur in the human HPA axis during aging. Several groups have reported age-associated increases in resting cortisol levels, especially near the nadir of the cortisol circadian rhythm (7-16). The magnitude of pituitary-adrenal responses to ovine corticotropin-releasing factor (CRF) has generally not been found to change with aging in humans (17, 18). However, when human CRF has been used to provoke the HPA axis, greater ACTH and cortisol responses have been found in older individuals (19,20), both with and without concurrent administration of arginine vasopressin (19).Impairment of glucocorticoid feedback inhibition of ACTH secretion, one of the primary age-related changes in HPA function reported in animal studies, has been supported by some, but not all, human studies. Pavlov et al. (17) concluded that the finding of a trend toward increased ovine CRF-stimulated levels of plasma ACTH and cortisol in older subjects in the face of age-related increases in resting cortisol was "consistent with the hypothesis that aging is associated with decreased pituitary sensitivity to negative feedback regulation by glucocorticoids."Studies of age-related changes in feedback inhibition using dexamethasone have reported age-related impairments (11, 20 -26) or no change (18,(27)(28)(29). In these studies, dexamethason...

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Section: Resultsmentioning

confidence: 92%

Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study

Wilkinson

Petrie

Murray

et al. 2001

Journal of Clinical Endocrinology & Metabolism

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“…In studies of the peak cortisol response to 1 μ g Synacthen in healthy subjects, means between 466 and 600 nmol/L have been reported [32–34] with peak levels of >400 nmol/L considered as within normal range. Based on these results, none of the subjects displayed signs of adrenal insufficiency; peak cortisol levels ranged from 460 to 764 nmol/L.…”

Section: Discussionmentioning

confidence: 99%

Improved Insulin Sensitivity during Pioglitazone Treatment Is Associated with Changes in IGF-I and Cortisol Secretion in Type 2 Diabetes and Impaired Glucose Tolerance

et al. 2013

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Background. Hypercortisolism and type 2 diabetes (T2D) share clinical characteristics. We examined pioglitazone's effects on the GH-IGF-I and HPA axes in men with varying glucose intolerance. Methods. 10 men with T2D and 10 with IGT received pioglitazone 30–45 mg for 12 weeks. OGTT with microdialysis in subcutaneous adipose tissue and 1 μg ACTH-stimulation test were performed before and after. Glucose, insulin, IGF-I, IGFBP1, and interstitial measurements were analyzed during the OGTT. Insulin sensitivity was estimated using HOMA-IR. Results. HOMA-IR improved in both groups. IGF-I was initially lower in T2D subjects (P = 0.004) and increased during treatment (−1.4 ± 0.5 to −0.5 ± 0.4 SD; P = 0.007); no change was seen in IGT (0.4 ± 39 SD before and during treatment). Fasting glycerol decreased in T2D (P = 0.038), indicating reduced lipolysis. Fasting cortisol decreased in T2D (400 ± 30 to 312 ± 25 nmol/L; P = 0.041) but increased in IGT (402 ± 21 to 461 ± 35 nmol/L; P = 0.044). Peak cortisol was lower in T2D during treatment (599 ± 32 to 511 ± 43, versus 643 ± 0.3 to 713 ± 37 nmol/L in IGT; P = 0.007). Conclusions. Pioglitazone improved adipose tissue and liver insulin sensitivity in both groups. This may explain increased IGF-I in T2D. Pioglitazone affected cortisol levels in both groups but differently, suggesting different mechanisms for improving insulin sensitivity between T2D and IGT.

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“…The low dose cosyntropin stimulation test is established to have higher sensitivity and specificity compared to the standard dose cosyntropin stimulation test in making the diagnosis of secondary or relative adrenal insufficiency [4,5,8,9]. It is suggested that 250 µg cosyntropin is a powerful adrenal stimulus at supraphysiological, but not physiological doses [14].…”

Section: Discussionmentioning

confidence: 99%

“…It is suggested that the standard cosyntropin stimulation test, as well as urine findings and physical examinations, is crucial to make an accurate diagnosis of Addison's disease [3], while several cases with primary adrenal insufficiency had an adequate response to 250 µg cosyntropin [6,7]. The validity of low dose cosyntropin stimulation test is reported only in making diagnosis of secondary or relative adrenal insufficiency [4,5,8,9], but not primary adrenal insufficiency.…”

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confidence: 99%

A Case of Addison's Disease Confirmed with Low Dose Cosyntropin Stimulation Test

et al. 2007

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Abstract. An eighty-year-old man who had complained of skin pigmentation and weight loss was referred to our hospital. Upon physical examination, marked hyperpigmentation was found on the whole body including oral mucosa, tongue and fingernails. Endocrinological findings showed increased ACTH (126 pg/ml) and normal serum cortisol (15.4 µg/dl). First, we used a 250 µg cosyntropin stimulation test which is valid to diagnose Addison's disease, resulting in an adequate cortisol response. Second, we performed 1 µg cosyntropin stimulation test, and the cortisol response was blunted. Since the diagnosis of Addison's disease was fairly certain, he was treated with hydrocortisone 15 mg/day, and improvement of his skin pigmentation and an increase in body weight were observed. To our knowledge, this is the first report that 1 µg cosyntropin stimulation test was helpful to make diagnosis as having Addison's disease rather than the 250 µg cosyntropin stimulation test, although it is established that the 1 µg cosyntropin stimulation test is useful in secondary or relative adrenal insufficiency.

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On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis

Cited by 30 publications

References 24 publications

Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study

Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study

Improved Insulin Sensitivity during Pioglitazone Treatment Is Associated with Changes in IGF-I and Cortisol Secretion in Type 2 Diabetes and Impaired Glucose Tolerance

A Case of Addison's Disease Confirmed with Low Dose Cosyntropin Stimulation Test

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