Macronodular adrenocortical hyperplasia in a postmenopausal woman.
This case report describes the diagnosis of Cushing's syndrome due to macronodular adrenal hyperplasia in an elderly woman who presented with fatigue, muscle weakness and oedema, and recent excessive bruising. Long-standing disease and comorbidity precluded adrenalectomy. Despite treatment with metyrapone and diuretics, the patient died after two months hospitalisation. Postmortal examination revealed overexpression of luteinising hormone (LH) receptors in the adrenal glands, suggesting that the postmenopausal rise in LH may have a role in adrenal hyperplasia and hypercortisolism. (+info)
Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion.
The hypothalamo-pituitary-adrenal axis is a stress-adaptive neuroendocrine ensemble, in which adrenocorticotropin (ACTH) drives cortisol secretion (feedforward) and cortisol restrains ACTH outflow (feedback). Quantifying direction- and pathway-specific adjustments within this and other interlinked systems by noninvasive means remains difficult. The present study tests the hypothesis that forward and reverse cross-approximate entropy (X-ApEn), a lag-, scale-, and model-independent measure of two-signal synchrony, would allow quantifiable discrimination of feedforward (ACTH --> cortisol) and feedback (cortisol --> ACTH) control. To this end, forward X-ApEn was defined by employing serial ACTH concentrations as a template to appraise pair-wise synchrony with cortisol secretion rates and vice versa for reverse X-ApEn. Coupled hormone profiles included normal ACTH-normal cortisol, high ACTH-high cortisol, and high ACTH-low cortisol concentrations in 35 healthy subjects, 21 patients with tumoral ACTH secretion, and 9 volunteers given placebo and a steroidogenic inhibitor, respectively. We used forward and reverse X-ApEn analyses to identify marked and equivalent losses of feedforward and feedback linkages (both P < 0.001) in patients with tumoral ACTH secretion. An identical analytical strategy revealed that ACTH --> cortisol feedforward synchrony decreases (P < 0.001), whereas cortisol --> ACTH feedback synchrony increases (P < 0.001), in response to hypocortisolemia. The collective outcomes establish precedence for pathway-specific adaptations in a major neurohormonal system. Thus quantification of directionally defined joint synchrony of biologically coupled signals offers a noninvasive strategy to dissect feedforward- and feedback-selective adaptations in an interactive axis. (+info)
Factors influencing cure by transsphenoidal selective adenomectomy in paediatric Cushing's disease.
OBJECTIVE: Early diagnosis and effective treatment of paediatric Cushing's disease (CD) is necessary to minimise associated morbidity. Accepted first-line treatment is selective transsphenoidal microadenomectomy (TSS), which can be technically difficult, and cure rates vary considerably between centres. In our paediatric CD patient group we have assessed the possible factors which may influence cure by TSS. SUBJECTS AND METHODS: From 1983-2004, 27 paediatric patients (16 males, 11 females; mean age+/-s.d., 13.1+/-3.2 yr; range, 6.4-17.8 yr) with CD were managed in our centre and underwent TSS. Sixteen patients (59%), seven males and nine females (mean age+/-s.d., 14.2+/-2.5 yr; range, 8.2-17.8 yr), were cured (post-operative serum cortisol < 50 nM). Eleven patients, nine males and two females (mean age+/-s.d., 11.5+/-3.6 yr; range, 6.4-17.8 yr) had post-operative cortisol levels above 50 nM (2-20 days), with mean serum cortisol levels at 09:00 h of 537 nM (range 269-900 nM) indicating a lack of cure. These 11 patients received external beam pituitary radiotherapy (RT). One patient with a pituitary macroadenoma had a post-operative cortisol level of < 50 nM but 0.8 yr later showed an elevated cortisol and residual disease. RESULTS: The patients cured by TSS alone were significantly older than those not cured (P = 0.038; Student's t test). All patients had CT/MRI pituitary imaging: 14 were reported to have microadenomas and one macroadenoma, while 12 were reported as normal. Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with i.v. corticotropin-releasing hormone (CRH) administration was introduced as a pre-operative investigation in 1986 and was performed in 21 patients (78%), on BSIPSS, 16 (76%) had evidence suggesting pituitary adrenocorticotropic hormone (ACTH) secretion (central to peripheral (IPS:P) ACTH ratio after CRH of > or = 3.0) and 16 (76%) showed lateralisation of ACTH secretion (IPSG of > or = 1.4). There was concordance between the BSIPSS finding and the position of the microadenoma at surgery in 17/21 (81%) patients. Of the 16 patients showing lateralisation of ACTH secretion, 12 (75%) were cured by TSS. Of the four without lateralisation of ACTH, suggesting a midline lesion, 3 (75%) were cured by TSS. Post-operative pituitary hormone deficiencies in the patients cured by TSS were: pan-hypopituitarism 1/16, isolated growth hormone deficiency (GHD) (peak GH on glucagon/ITT < 1-17.9 mU/l) 9/16 and diabetes insipidus 3/16. CONCLUSION: Over a 21-year period selective adenomectomy by TSS cured 59% of all paediatric CD patients, with higher age favouring cure. Introduction of BSIPSS resulted in the demonstration of a high rate of lateralisation of ACTH secretion consistent with the surgical identification of the adenoma, and therefore appears likely to have contributed to the higher surgical cure rate. (+info)
Periodic secretion of adrenocorticotropin in a patient with Cushing's disease manifested during pregnancy.
We report the case of 19-year-old woman with cyclical Cushing's disease, in whom plasma adrenocorticotropin (ACTH) was secreted periodically after her first pregnancy. Since the 33rd week of pregnancy, hypertension and proteinuria became clinically remarkable. She gave normal birth at 36th week of pregnancy; however she continued to gain body weight even after delivery and developed typical Cushingoid features. Her ACTH secretion lacked normal daily fluctuation but exhibited periodic change during 1-year observation, showing 119 pg/ml, 34.6 pg/ml and 115 pg/ml at the 4th, 7th and 13th months after delivery. Plasma ACTH levels were increased by corticotropin releasing hormone and metyrapone, while low-dose dexamethasone suppressed cortisol secretion. Gel filtration analysis of the patient's plasma detected big ACTH molecules being eluted with a peak of authentic 1-39 ACTH. Cranial magnetic resonance imaging revealed a 1-cm pituitary mass in right cavernous sinus. The pituitary tumor was removed by transsphenoidal surgery at 13th month after delivery and was pathologically compatible with ACTH-producing pituitary adenoma by immunohistochemistry. This case includes clinically rare subsets of Cushing's syndrome showing periodic ACTH secretion and aberrant ACTH molecules. (+info)
Corticotroph adenoma of the pituitary in a patient with X-linked adrenal hypoplasia congenita due to a novel mutation of the DAX-1 gene.
OBJECTIVE: Mutations in the DAX-1 gene result in X-linked congenital adrenal hypoplasia. The classic clinical presentation is primary adrenal insufficiency in early life and hypogonadotropic hypogonadism at the time of expected puberty, but recent data have expanded the phenotypic spectrum of DAX-1 mutations. We report the occurrence of an ACTH-secreting adenoma in a patient with X-linked congenital adrenal hypoplasia. DESIGN AND METHODS: Detailed clinical, radiological and pathological investigation of the pituitary adenoma. Genomic analysis of the DAX-1 gene in the patient and his mother. RESULTS: In this patient, primary adrenal failure had been diagnosed at 3 years of age and, despite replacement therapy, at 30 years of age progressive pigmentation developed and impairment of the visual field followed. ACTH was 24 980 pg/ml and nuclear magnetic resonance disclosed a huge pituitary adenoma. Three transsphenoidal operations and radiotherapy were necessary to remove the tumor mass and control ACTH secretion. Histologically, the adenoma was composed of chromophobic and basophilic neoplastic cells with positive immunostaining for ACTH. Moreover, a novel mutation was found both in the patient and his mother: a 4 bp insertion (AGCG) at nucleotide 259, in exon 1 resulting in a frame shift and premature termination. CONCLUSIONS: This case suggests that in adrenal hypoplasia congenita the development of a pituitary adenoma should be considered when a sudden rise of ACTH occurs despite adequate steroid substitution. (+info)
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. (+info)
Adrenal pathophysiology: lessons from the Carney complex.
The Carney complex (CNC) is a dominantly inherited syndrome responsible mainly for spotty skin pigmentation (lentiginosis), endocrine overactivity, and cardiac myxomas. Adrenocorticotropic hormone independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is a main characteristic of CNC. PPNAD is a very rare cause of Cushing's syndrome due to a primary bilateral adrenal defect that can be also observed in some patients without other CNC manifestations nor familial history. One of the putative CNC genes, located on 17q22-24, has been identified as the regulatory subunit R1A of protein kinase A (PRKAR1A). Heterozygous inactivating mutations of PRKAR1A have been reported initially in about 45% of the CNC index cases and could be found in about 80% of the CNC families presenting mainly with Cushing's syndrome. PRKAR1A is a key component of the cyclic AMP signaling pathway that has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. Interestingly, patients with isolated PPNAD and no familial history of CNC can also present a germline de novo mutation of PRKAR1A. Somatic mutations of PRKAR1A have been found in PPNAD as a mechanism of inactivation of the wild-type allele, in a patient already presenting a germline mutation, and in a subset of sporadic secreting adrenocortical adenomas with clinical, hormonal, and pathological features quite similar to PPNAD. This review will summarize the recent findings on CNC from the perspective of the pathophysiology of adrenal Cushing's syndrome and PPNAD. (+info)
Diagnosis and management of pituitary tumours in the elderly: a review based on personal experience and evidence of literature.
An increasing proportion of pituitary adenomas are recognized in the elderly, raising the question of their optimal diagnosis and management. Age-related endocrine changes and associated diseases may significantly modify the clinical presentation and hormonal evaluation of these patients. About 80% of pituitary adenomas in this age group are non-secreting, requiring careful differential diagnosis with non-adenomatous sellar lesions. In this group, visual deterioration and hypopituitarism remain the leading symptoms. Recognized secreting tumours are mainly GH-secreting, most of them intrasellar, followed by prolactinomas, which present as clinically non-secreting and are usually invasive. Cushing's disease appears as a very rare eventuality in the elderly. Optimal therapeutic management should aim to control the disease while preserving or improving patient's quality of life. Transsphenoidal surgery has proved to be an efficient and well-tolerated option for non-secreting adenomas with visual defects and intrasellar GH-secreting adenomas, being able to improve metabolic and cardiovascular complications of acromegaly even in this age group. In contrast, dopamine-agonist drugs can be proposed as a primary therapy for prolactinomas even in the presence of severe neurological complications. Because the use of radiotherapy is hampered by its delay of action and potential neurological side effects, its indications should be better defined in this age group. The clinical importance of hypopituitarism should not be underestimated, and thyroid- and adrenal-replacement therapy are mandatory in the presence of documented hormone deficiency, carefully avoiding overtreatment in order to limit possible side effects on the cardiovascular system and bone mineralization. Indications for GH- and sex steroid-replacement therapy still await age-specific guidelines. (+info)