Actualité des investigations biologiques pour le diagnostic du syndrome de Cushing

The demonstration of cortisol overproduction and the determination of its cause are still challenging in spite of the progress in imaging studies performances and in techniques for cortisol overproduction demonstration. The latter is established with the 24-hour urinary free cortisol determination, the best screening test when the threshold is settled at 180 μg/24 h. But, since cortisol overproduction is sometimes periodic in true Cushing's disease, two to three determinations might be necessary for the diagnosis. If 24-hour urine collection cannot be adequately obtained, measurement of salivary cortisol is a good alternative. Overnight dexamethasone test is a good screening test for the exclusion of Cushing's syndrome. Though, false negative and false positive results are frequent. Then, in many cases, the standard dexamethasone test is useful. When cortisol overproduction is established, ACTH determination and high dose dexamethasone test usually lead to the etiological diagnosis.     

Noninvasive methods to monitor the production of hormone]

Noninvasive method to screen for endogeneous hormone production is useful to diagnose hormone excess/deficiency, especially in children. There are currently some optimal test to diagnose, and these tests(for example, urinary GH, urinary cortisol, urinary cathecolamine...) has been widely used. Traditional 24-hour urine or midnight serum cortisol values may be difficult to obtain or elevated by venipuncture stress. Salivary cortisol measurement has been reported as a reliable way to screen for adrenocortical function. We tried to detect salivary cortisol level with drug loading test(Dexamethasone for Cushing syndrome, and ACTH for adrenal insufficiency) with time interval. Salivary cortisol measurement with drug loading test rules out both Cushing syndrome and adrenal insufficiency in nearly all cases. Salivary cortisol sampling is thus a simple, accurate way to screen for adrenocortical function.     

Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide

The effect of inhaled beclomethasone dipropionate and budesonide on the adrenal function was studied in 30 children (aged 7 to 15 years) with mild bronchial asthma. The trial was designed as a prospective double-blind parallel study of the effect of stepwise increase of either beclomethasone dipropionate or budesonide from 200 micrograms through 400 micrograms, to 800 micrograms daily in three consecutive periods of 4 weeks. At the end of each period, the adrenal stress response was evaluated by measurements of serum cortisol and androstenedione during a short adrenocorticotropic hormone test. The unstimulated diurnal production of glucocorticosteroids was assessed by measurements of free cortisol in 24-hour urine samples. Free cortisol in urine was found a valid measure of the total diurnal excretion of cortisol metabolites, since it exhibited a good correlation to the fractional cortisol metabolites measured by gas chromatography. The adrenal response to adrenocorticotropic hormone stimulation was unaffected by treatment or dose. The unstimulated diurnal production of glucocorticosteroids demonstrated a highly significant dose-related suppression in response to the inhaled steroids. No significant difference was found between the two topical steroids (probability value 5.3%), and yet the suppression was apparent in the group of children treated with beclomethasone dipropionate but not in the group of children treated with budesonide. Further studies are desirable in order to ascertain whether budesonide offers an improved ratio between beneficial anti-inflammatory effect and unwanted systemic activity.     

Problems of cortisol assay: confusion in the diagnosis of preclinical Cushing's syndorme

Cortisol assay is used for the diagnosis of hypothalamo-pituitary adrenal disorders. The Incidence of adrenal incidentaloma has been increasing with advances in imaging tools. The criteria for the diagnosis of preclinical Cushing's syndrome in Japan was made by the Nawata group supported by the Ministry of Health and Welfare in 1995. The presence of adrenal adenoma, a lack of overt signs of Cushing's syndrome and autonomic cortisol secretion are essential for the diagnosis of preclinical Cushing's syndrome. For the diagnosis of autonomy of cortisol secretion, cortisol should not be suppressed by either low dose dexamethasone (DEX) of 1 mg (cortisol > or =3 microg/dl) or high dose DEX of 8 mg (cortisol > or =1 microg/dl). We have reported that two doses of DEX suppression tests revealed a discrepancy in several cases of adrenal incidentaloma; therefore, we studied the cortisol values of DEX suppression tests in 47 cases with adrenal incidentaloma using four different cortisol kits (TFB, SPAC, TDX and TOSOH). Correlation between the kits was good; however, correlation coefficient in the low range (< or =5 microg/dl) among kits declined. In the inter assay, discrepant results of the cortisol level were seen in six cases after 1 mg of DEX and 18 cases after 8 mg of DEX. In the intra assay, discrepant results of cortisol after 1 mg of DEX and 8 mg of DEX were seen in 31 in TFB, 23 in SPAC, 24 in TDX and 25 in TOSOH. These results revealed that the clinical diagnosis varies according to the cortisol kit used. It is suggested that standardization of the cortisol assay is necessary for the accurate diagnosis of adrenal incidentaloma.     

Abnormal pituitary function during melancholia: reduced alpha-melanocyte-stimulating hormone secretion and increased intact ACTH non-suppression.

In order to investigate pituitary alpha-melanocyte-stimulating hormone (alpha-MSH), intact (1-39 structure) adrenocorticotropic hormone (ACTH), and adrenal cortisol secretion, we measured 8 a.m. plasma levels of those hormones before and after administration of 1 mg dexamethasone in 39 depressed inpatients and 10 healthy controls. We found a significantly lower baseline alpha-MSH secretion in melancholic patients as opposed to healthy controls. There were no significant relations between alpha-MSH secretion on the one hand and ACTH or cortisol secretion on the other. Dexamethasone did not affect the 8 a.m. alpha-MSH circulating levels. The post-dexamethasone intact ACTH and cortisol values were significantly higher in melancholics as compared with healthy, minor and simple major depressed subjects. ACTH non-suppression was defined as post-dexamethasone intact ACTH greater than or equal to 12 pg/ml. ACTH non-suppression was found to be more sensitive (70%) and specific (100%) for melancholia than cortisol non-suppression. By means of pathway analysis we have established that cortisol non-suppression during a severe depression is completely determined by an augmented ACTH escape from suppression by dexamethasone. It is concluded that the assay of post-dexamethasone intact ACTH could, in the future, replace post-dexamethasone cortisol determination.     

Multiple pigmented adrenal cortical nodules associated with cushing's syndrome

Multiple pigmented adrenocortical nodules were found in a 25?year-old woman associated with Cushing's syndrome, whose laboratory data indicated that the adrenal cortex had been functioning autonomously and adrenocorticotropic hormone (ACTH) from the pituitary gland as suppressed. The surgically removed left adrenal gland disclosed multiple black nodules measuring up to 3 mm in diameter and histologically consisting of large “compact cells” which contained numerous yellow-brown pigments, but adjacent cortical cells were not atrophied. This kind of adrenal lesion is generally regarded as nodular hyperplasia of the cortex. The present case revealed scanty lipid and markedly increased activity of 3β-hydroxysteroid dehydrogenase (3β-HSD) and glucose?6?phosphate-dehydrogenase (G6PD). Ultrastructural study showed abundant cytoplasm with a large number of mitochondria, well-developed smooth-surfaced endoplasmic reticulum (SER), less rough-surfaced endoplasmic reticulum (RER), lysosomes, and numerous granules in cells of the nodules. Mitochondria varied in size and shape up to occasional giant mitochondria. SER was vesicular or tubular forming a network of anastomosing tubules. Granules varied greatly in size from 400 mm? to 6 m? in diameter, with diverse electron densities, mostly exhibiting the structural features of lipofuscin. The ultrastructural features resembled those in black adenoma associated with Cushing's syndrome ever reported. Concentration of cortisol was increased in the tissue where numerous black nodules were contained. Acta pathol. jpn. 34: 827 ～ 837, 1984.     

Combined aldosterone and cortisol secretion by adrenal incidentaloma

A 70-year-old woman was referred to the authors' unit following hospitalization for cardiac failure, high urinary free cortisol concentrations and severe hypokaliemia. A computed tomography scan of the abdomen showed an adrenal adenoma. The 24-hour urinary free cortisol values were high and plasma cortisol levels failed to suppress following 1 mg dexamethasone test. Aldosterone to plasma renin activity ratio was also pathologic, confirmed by saline load. She showed no symptoms of glucocorticoid excess. She was diagnosed with combined primary hyperaldosteronism and Cushing's syndrome. Cases of adrenal incidentalomas co-secreting cortisol and aldosterone are rare; they should be addressed in patients undergoing adrenal surgery for Conn's syndrome to avoid adrenal insufficiency after removal of the tumor.     

Hypothalamo–pituitary–adrenal axis,glucose metabolism and TNF‐α in narcolepsy

Narcolepsy with cataplexy is caused by a deficiency in the production of hypocretin/orexin, which regulates sleep and wakefulness, and also influences appetite, neuroendocrine functions and metabolism. In this case–control study, 11 patients with narcolepsy with cataplexy and 11 healthy adults underwent an oral glucose tolerance test, and dexamethasone suppression/corticotropin‐releasing hormone stimulation test. The average age of patients and controls was 35.1 ± 13.2 and 41.0 ± 2.9 years, respectively, body mass index was 28.1 ± 6.6 and 25.5 ± 4.7 kg m^?2. We did not find evidence of a significantly increased prevalence of disturbed glucose tolerance in patients with narcolepsy. After hypothalamo–pituitary–adrenal axis suppression, the number of non‐suppressors did not differ between the groups, indicating normal negative feedback sensitivity. The level of cortisol after dexamethasone suppression was significantly lower in patients with narcolepsy, suggesting a slight basal downregulation and/or a slightly increased negative feedback sensitivity of the major endocrine stress system in narcolepsy. Following corticotropin‐releasing hormone stimulation, there were no significant differences in levels of adrenocorticotropic hormone or cortisol, and in adrenocortical responsivity to adrenocorticotropic hormone. Finally, patients with narcolepsy displayed significantly higher plasma levels of tumour necrosis factor alpha, soluble tumour necrosis factor receptor p55, soluble tumour necrosis factor receptor p75 and interleukin 6 after adjustment for body mass index. The present study confirms that narcolepsy by itself is not associated with disturbances of glucose metabolism, but goes along with a subtle dysregulation of inflammatory cytokine production. We also found that dynamic hypothalamo–pituitary–adrenal system response is not altered, whereas negative feedback to dexamethasone might be slightly enhanced.     

MORPHOLOGICAL STUDIES OF HUMAN ADRENAL CORTEX UNDER PATHOLOGIC CONDITIONS*

The human adrenal cortex of 203 cases, surgically resected and obtained at autopsy, were investigated morphologically. As controls, 30 biopsy specimens were procured from the patients at operations for renal stones, tuberculosis, tumors and wandering kidneys. The structural alterations in the human adrenal cortex under physiologic and pathologic conditions related to the functional phase were discussed. Among hyperadrenocorticism the pathologic changes of the adrenal cortex in Cushing's syndrome and adrenogenital syndrome were considered to be circumstantial evidence in favor of the theory of “functional zonation”. On the other hand, tumorous alteration of the cortex, especially aldosteronoma, was difficult to assign an origin to the cells. It was reasonable to consider that “secretory cytology” plays an important role to explain the endocrinologic significance in these tumors. A morphologic comparison of nodular hyperplasia and adenoma in the adrenal cortex revealed that in some cases, these nodules preceded the development of cortical adenoma.     

Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder

Most prior studies in patients with premenstrual dysphoric disorder (PMDD) indicate a blunted hypothalamus–pituitary–adrenal axis function. However, the relationship between neuroactive progesterone metabolites, such as allopregnanolone, and hypothalamus–pituitary–adrenal (HPA) axis function in PMDD patients is relatively sparsely studied. The primary aims of this study were to assess diurnal variation in circulating cortisol and low-dose dexamethasone suppression in PMDD patients and healthy controls, and the relationship between these two HPA axis indices and allopregnanolone serum concentrations. Twenty-six women with prospectively defined PMDD and 30 healthy controls were recruited. Participants underwent diurnal sampling for cortisol serum concentrations and a low-dose dexamethasone suppression test. In addition, morning allopregnanolone serum concentrations were determined. There was no difference in diurnal secretion of cortisol and degree of dexamethasone suppression of cortisol between PMDD patients and healthy controls. However, PMDD patients with high allopregnanolone levels displayed blunted nocturnal cortisol levels in comparison with healthy controls who had low allopregnanolone serum concentrations. In women with PMDD, diurnal secretion of cortisol may be influenced by allopregnanolone levels of the luteal phase. This finding may be attributed to timing of blood sampling in the late luteal phase as well as the individual level of allopregnanolone but could potentially explain the discrepancies in results between studies examining HPA axis function in women with PMDD.     

Neuropeptide Y and glucocorticoid secretion from guinea pig adrenal gland: an in vivo and in vitro study

The effects of neuropeptide Y (NPY) on adrenal glucocorticoid secretion are controversial, and we have investigated this issue in guinea pigs, where, like in humans and cows, the main glucocorticoid hormone is cortisol. In vivo experiments showed that prolonged NPY administration markedly lowered cortisol plasma concentration not only in normal guinea pigs, but also in animals whose hypothalamic-pituitary-adrenal axis and renin-angiotensin system had been pharmacologically interrupted by the simultaneous administration of dexamethasone and captopril. In vitro experiments ruled out the possibility that in vivo glucocorticoid anti-secretagogue action of NPY can ensue from a direct effect on the adrenal gland. In fact, NPY did not affect cortisol secretion from dispersed guinea pig inner adrenocortical cells. In contrast, NPY raised cortisol production from adrenal slices containing medullary tissue, and this effect was blocked by the beta-adrenoceptor antagonist l-alprenolol. This finding, coupled with the demonstration that NPY enhanced catecholamine release from guinea pigadrenomedullary tissue, strongly suggests that NPY may stimulate glucocorticoid secretion in this species through an indirect mechanism involving catecholamines, that in a paracrine manner promote the secretion of inner adrenocortical cells. In light of these observations, the conclusion is drawn that the in vivo effects of NPY are mediated by mechanism(s) independent of either the suppression of the main adrenal agonists ACTH and angiotensin-II or the direct inhibition of adrenal secretion. The possibility merits an investigation into whether NPY enhances the production of peptides, which, like leptin, inhibit adrenal glucocorticoid secretion acting as circulating hormones.     

Idiopathic hirsutism--an ovarian abnormality.

We investigated increased production of testosterone and androstenedione in 44 women with unexplained adult-onset hirsutism, 41 of whom had normal-sized ovaries. Twenty women in this group had at least 50 per cent suppression of plasma testosterone and androstenedione after four to five days of dexamethasone. Testosterone and androstenedione values in ovarian-vein effluents were higher than those of their adrenal veins. We calculated adrenal secretion rates of both androgens in each patient by relating the adrenal gradients to those of cortisol. In 42 of the hirsute women, including those whose androgens were suppressed after dexamethasone, the ovaries were the predominant source of androgen production. The women with dexamethasone suppression had milder degrees of virilism and lower production rates of testosterone and androstenedione. We conclude that the ovaries are the source of excessive androgens in most women with unexplained hirsutism, and that corticoid-suppressible patients have milder forms of ovarian hyperandrogenism.     

Cushing's syndrome and nocardiosis associated with a pulmonary carcinoid tumor: Report of a case and review of the literature

Ectopic hormone production is an uncommon complication of neoplastic lung disease. Rarely, patients may present with signs and symptoms of systemic endocrine dysfunction related to a hormone‐secreting tumor. Bronchopulmonary carcinoids are the most common neoplasm implicated in ectopic ACTH‐dependent Cushing's syndrome. Persistent hypercortisolism, such as that which occurs in Cushing's syndrome, causes immunosuppression and makes patients vulnerable to opportunistic infections. We present a case of a 42‐year‐old woman diagnosed with ACTH‐dependent Cushing's syndrome which was originally thought to stem from a pituitary lesion as interpreted on magnetic resonance imaging. Her symptoms persisted after undergoing hypophysectomy, and further work‐up involving a fine needle aspiration of the left lung revealed an ACTH‐producing carcinoid tumor. Before treatment could be administered, the patient developed several new suspicious nodules in the left lung that were shown by fine needle aspiration to be infectious in nature. A Gram stain revealed numerous Gram positive branching organisms, and culture of the specimen grew Nocardia asteroides. Her pulmonary infection was treated with antibiotics and she underwent successful ablation of the carcinoid tumor. Diagn. Cytopathol. 2011. © 2010 Wiley‐Liss, Inc.     

Demonstration of pro-opiomelanocortin mRNA in pituitary adenomas and para-adenomatous gland in cushing's disease and Nelson's syndrome

Pro-opiomelanocortin (POMC) mRNA was demonstrated in pituitary adenomas from 16 patients with Cushing's disease and 10 with Nelson's syndrome. The intensity of signal was significantly greater in Nelson's syndrome than in Cushing's disease and there was a trend towards a greater proportion of positive cells. This probably reflects inhibition of POMC gene expression by the high circulating levels of cortisol in Cushing's disease. In the para-adenomatous gland, the intensity of signal was variable in cells showing Crooke's hyaline change, ranging from negative to strongly positive, in keeping with the functional heterogeneity of corticotrophs. In one case, junctional corticotrophs were present and these were more intensely stained than anterior lobe corticotrophs in the same gland. This supports the concept that these cells are subject to different regulatory influences from corticotrophs in the anterior lobe. Whether this is related to differences in embryological origins or to local factors is at present unclear.     

Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder

Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function – specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration – in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5 mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.     

Neuroendocrine evaluation in Kleine-Levin syndrome: evidence of reduced dopaminergic tone during periods of hypersomnolence.

A patient with Kleine-Levin syndrome had polysomnography and neuroendocrinological assays performed during asymptomatic (ASMP) and symptomatic (SMP) 24-hr periods. During the SMP, sleep data revealed poor nocturnal sleep efficiency, increased sleep fragmentation and reduced stages 3, 4 and rapid eye movement (REM). No sleep onset REM episodes were seen. Sleep staging in the ASMP was normal. Blood samples were obtained every 20 min and assayed for thyroid-stimulating hormone (TSH), cortisol (CORT), prolactin (PRL) and growth hormone (GH). Patterns of secretion, 24-hr mean and total integrated concentrations, and mean sleep period time values during the ASMP and SMP were compared. The mean 24-hr level of TSH was increased and GH decreased in the SMP. Comparing sleep period time in the SMP to the ASMP, values for TSH and PRL were increased and GH and CORT were reduced in the SMP. These hormone changes support the hypothesis that reduced hypothalamic dopaminergic tone is present in the SMP compared to the ASMP in Kleine-Levin patients.     

Duration of blood plasma cortisol suppression after a low-dose dexamethasone suppression test in dogs

The aim of this study was to determine the duration of the suppressive effect on the hypothalamus–pituitary–adrenocortical axis as measured by plasma cortisol concentration after injection of a low dosage of dexamethasone (0.01 mg/kg BW) used within the low-dose dexamethasone suppression test (LDDST). A LDDST was performed on ten clinically healthy dogs with unremarkable haematological and plasma biochemical profiles, abdominal X-ray, abdominal ultrasonography and fine needle aspiration cytology of the liver. Two of them were excluded from the analysis. Blood samples were collected at baseline, 4 and 8 h (standard protocol of a LDDST) and, additionally, at 24, 48, 72 and 96 h after the application of dexamethasone. Plasma cortisol concentrations <10 ng/ml were considered as suppressed. All eight dogs had suppressed plasma cortisol levels after 4 and 8 h. Three dogs still had suppressed plasma cortisol levels at 24 h after dexamethasone application, and one of them even had a suppressed level after 48 h. After 72 h, all dogs had plasma cortisol levels >10 ng/ml. The median 4, 8 and 24 h plasma cortisol concentrations were significantly lower than the median baseline plasma cortisol concentration, whereas at the remaining times no significant changes were seen compared to the median baseline value. The suppression of plasma cortisol induced by dexamethasone in a dosage of 0.01 mg/kg BW can last at least 48 h in individual dogs. Therefore, a repeated LDDST should be performed at the earliest 3 days after the prior test to prevent artificial results.     

Effect of theophylline on cortisol secretion

Theophylline is thought to improve asthma by increasing intracellular cyclic adenosine 3'-5'-monophosphate (cAMP) levels. It has been demonstrated in experimental animals that elevation of intracellular cAMP in the adrenal cortex causes an increased secretion of cortisol. We studied whether therapeutic doses of theophylline given intravenously and orally to human subjects over 3 days would increase cortisol secretion. A single-blind, 6-day protocol was employed in five normal and five asthmatic volunteers. Adrenal function was monitored by 8 A.M. and 4 P.M. serum cortisol and adrenocorticotropic hormone (ACTH) levels; daily 24-hr urine for urinary-free cortisol (UFF), 17-hydroxysteroids (17-OH), and 17-ketosteroids (17-KS); and alternate-day cortisol secretory rates (FSR) measured by isotope dilution after intravenous 14C-cortisol. Serum theophylline concentration also was monitored. Results in normal and asthmatic subjects were similar. Theophylline caused a significant but transient increase in UFF and 17-OH excretion. Urine volumes also increased significantly, suggesting that the renal effect of theophylline accounted for the increased UFF and 17-OH excretion. FSR increased during the first 24 hr after theophylline in eight of nine cases (p < 0.05 by sign test), mean values increasing from 14.2 to 19.3 mg, but this effect had dissipated by day 3 of theophylline administration. In contrast to these findings, theophylline had no effect on serum cortisol or ACTH or urinary 17-KS. It is likely that serum cortisol and ACTH remained unchanged because the increase in cortisol secretion was offset by a concomitant increase in cortisol clearance. It is concluded that theophylline produces a small, transient increase in cortisol secretion and clearance, and this effect is similar in asthmatic and normal subjects.     

Bilateral primary pigmented nodular adrenocortical disease--a case of report describing a rare cause of Cushing's syndrome.

A case of Cushing''s syndrome due to bilateral pigmented nodular adrenal disease in a 35-year-old male is presented. The adrenals showed multiple, black, variable sized nodules. Histologically the cells contained lipofuscin and either had a clear cytoplasm or an eosinophilic cytoplasm with a prominent nucleus. Lymphocytic infiltration and fatty metaplasia within the nodules are two of the prominent histological features. There is extreme internodular atrophy which suggests that primary pigmented nodular adrenocortical disease is a non-adrenocorticotropic hormone dependent condition. Since the disorder appears to involve primarily the cortex of both adrenals, the treatment of choice is bilateral adrenalectomy followed by steroid replacement. The characteristic clinicopathological manifestations that separate this diagnosis from other types of adrenal disease are also discussed. This is the first reported case in Korea to be documented with the pertinent clinicopathological findings.     

Cortisol measures in primary major depressive disorder with hypersomnia or appetite increase

Morning plasma cortisol response to the 1 mg dexamethasone suppression test along with cortisol levels in blood, cerebrospinal fluid (CSF), and urine were measured in hospitalized male and female patients with primary major depressive disorder who reported hypersomnia (n = 23), or increase in appetite (n = 22). Comparisons were drawn to cortisol levels in patients with primary major depressive disorder who did not report hypersomnia or appetite increase (n = 23) and to normal controls (n = 23), all age- and sex-matched. Depressives with hypersomnia or increased appetite showed higher than normal 24-h urinary free cortisol concentrations. Depressed patients without hypersomnia or appetite increase had in addition to elevated free urinary cortisol concentrations higher than normal morning plasma cortisol levels before and after dexamethasone administration and a higher incidence of cortisol non-suppression after dexamethasone compared to normal subjects. The findings provide preliminary evidence that HPA activation in depression is diminished in the presence of hypersomnia and/or an increased appetite. Studies of the hypothalamic-pituitary-adrenal axis may be useful for differentiating subtypes of depression characterized by hypersomnia or enhanced appetite.