High Plasma ACTH Research Articles

8356 Total Hypophysectomy in Cushing’s Disease: Results from a Terciary Center

Abstract Disclosure: M.V. Lopes: None. M.D. Severino: None. J. Rocha: None. C.R. Peixe: None. M.I. Alexandre: None. A. Gomes: None. M.J. Bugalho: None. Introduction: Transsphenoidal surgery (TSS) is the first line treatment for Cushing’s disease (CD), leading to remission in 70-80% of cases. Though selective adenomectomy is the preferred approach, total hypophysectomy may be needed. Objective: To describe 3 CD patients in which total hypophysectomy was performed. Clinical cases 1. A 58-year-old man with a history of type 2 diabetes (T2D) and obesity, was referred to the Endocrinology Clinic due to abdominal purple striae and facial plethora. Laboratory tests suggested ACTH dependent hypercortisolism, with normal serum ACTH, high 24h urinary cortisol and no cortisol suppression in the overnight 1mg dexamethasone suppression test (DST). The CRH test was suggestive of CD but no adenoma was found on pituitary MRI. Inferior petrosal sinus sampling (IPSS) was compatible with CD with right-sided lateralization. Right hypophysectomy was performed but no CD remission was achieved, so the patient underwent total hypophysectomy. Corticotroph hyperplasia was identified in histology. After 9 months of follow-up, he mantains CD remission. 2.A 37-year-old woman was diagnosed with ACTH dependent hypercortisolism after referral to the Endocrinology Clinic for alopecia, amenorrhea, hypertension and hirsutism. Laboratory tests showed severe hypokalemia, high plasma ACTH and 24h urinary cortisol and the MRI showed a right-sided macroadenoma. Nonetheless, considering the clinical severity, an IPSS was performed and definitely excluded an ectopic Cushing’s syndrome (CS) thus confirming the diagnosis of CD with right-sided lateralization. The patient underwent selective TSS, however, for lack of CD remission, total hypophysectomy was performed. Histology revealed an adenocorticotrophic adenoma. Yet, a year later, she maintains persistence of CD, although less severe, and is under treatment with metyrapone. 3.A 58-year-old woman with a history of T2D and class 3 obesity, was evaluated in our Endocrinology Clinic due to obesity. Her physical examination suggested CS, so this hypothesis was investigated. Laboratory tests suggested ACTH dependent hypercortisolism, with normal serum ACTH, elevated 24h urinary cortisol and no cortisol suppression in the overnight 1mg DST. The high dose DST was suggestive of CD but the pituitary MRI didn’t show an adenoma. IPSS was compatible with CD but it was not possible to determine lateralization. So, total hypophysectomy was performed. An adenocorticotrophic adenoma was identified in histology. Postoperative CD remission was achieved and persists 3 months later. Conclusions: These 3 cases highlight the challenge of treating CD and suggest that in certain cases total hypophysectomy may be the treatment of choice to cure or at least improve CD. Although it is associated with more complications than selective TSS, our patients had no complications, only developed panhypopituitarism and diabetes insipidus. Presentation: 6/1/2024

A Rare Case of Resistant Pigmentation

Introduction: Familial glucocorticoid deficiency (FGD) is characterised by ACTH resistance & isolated glucocorticoid deficiency, with typical biochemical findings of low serum cortisol & high plasma ACTH. Patients present with hyperpigmentation (due to stimulation of MC1R by POMC products) & hypoglycemia. Clinical presentation includes failure to thrive & susceptibility to infections. Case Report: A 14 year old girl presented to us with generalised hyperpigmentation of the skin and oral mucosa- it started when she was 4 years of age. There was history of recurrent respiratory infections around the same time the hyperpigmentation appeared - the patient required multiple hospitalisations for the same (she was admitted 3 times in 6 months). Her random serum cortisol was measured – it came out to be 8.27nmol/L. Her serum Na+ was 140 mEq/L & K+ was 3.5 mEq/L. She was also diagnosed with subclinical hypothyroidism at that time (TSH- 7.3 mIU/L, anti TPO antibodies positive). There was no history of alacrimia or achalasia. Her 17-OHP was 2.20 nmol/L. A probable diagnosis of autoimmune polyendocrine syndrome was made & oral hydrocortisone (@ 12 mg/m2) & levothyroxine (@25 mcg) was started. The patient was compliant with the treatment, but the mother complained that her hyperpigmentation improved only by 20–30 % despite continued treatment. There was no history of salt wasting crises or hospitalisations after the initiation of treatment. Her serum ACTH values were checked 2 times (2011 & 2015) and were > 2000 pg/ml on both the occasions. The hydrocortisone dose was increased to 20mg/m2 for 1 year in between, without any improvement in hyperpigmentation. Patient presented to us with persistent hyperpigmentation in 2019. She was a product of consanguineous marriage. Non-compliance was ruled out. She had attained menarche at the age of 12 years. There was history of delayed pubarche (started @ age of 13 years) & axillary hair was absent. Again, her serum ACTH was > 2000 pg/ml and electrolytes and BP were normal. In view of normal electrolytes with low cortisol at the time of diagnosis & persistent hyperpigmentation even on supraphysiological doses of hydrocortisone, Familial Glucocorticoid Deficiency was considered. Genetic analysis showed mutation in Thioredoxin Reductase (TXNRD2) Gene. This gene mutation has recently been reported in FGD. (Prasad R et al, JCEM Aug 2014.) Conclusion: In cases of primary adrenal insufficiency with normal electrolytes & resistant hyperpigmentation, familial glucocorticoid deficiency should be thought of. Treatment with standard glucocorticoid therapy should be given. Serum ACTH values should not be chased. The hyperpigmentation may not resolve completely. TXNRD2 deficiency leads to impaired redox homeostasis, highlights the important redox pathway in addition to defective ACTH signaling, giving us new insights in regard to steroidogenesis.

Deksametazon Süpresyon Testlerinin Hiperkortizolizm Ayırıcı Tanısında Kullanımı

Dexamethasone suppression tests (DST) are practical, cheap and safe tests which are used to evaluate endogenous hypercortisolism. They are based on the principle that glucocorticoids exogenously given at supraphysiological doses suppress the production of CRH, ACTH and cortisol by binding to central glucocorticoid receptors. Lack of suppression of cortisol production suggest endogenous hypercortisolism. Additionally, DST may be used in the diagnosis of glucocorticoid remediable hyperaldosteronism. Due to strong glucocorticoid activity, lack of mineralocorticoid activity and lack of cross-reaction with the measurement of cortisol, dexamethasone is the preferred drug for the tests. As a screening tool in endogenous hypercortisolism, overnight 1 mg DST is used. If screening test is negative, hypercortisolism is excluded; but if the test is positive, 2-day 2 mg DST should be performed to confirm the diagnosis of Cushing’s syndrome. If endogenous hypercortisolism is confirmed, plasma ACTH should be measured. Undetectable plasma ACTH level suggest ACTH-independent Cushing’s syndrome, but inappropriately normal or high plasma ACTH level suggest ACTH-dependent Cushing’s syndrome. High dose DST (overnight 8 mg or 2-day 8 mg) should be performed to discriminate pituitary or extra-pituitary cause in the patients with ACTH-dependent Cushing’s syndrome. In the presence of pituitary Cushing’s disease, because of relatively preserved negative feedback mechanism, high dose dexamethasone may suppress ACTH. In ectopic ACTH secretion, due to lack of a normal negative feedback mechanism, ACTH cannot be suppressed by high dose dexamethasone. Extraordinarily, ectopic ACTH production in some neuroendocrine tumors may be suppressed by high dose dexamethasone, but no suppression may be observed in some patients with pituitary Cushing’s disease. When applying DST, serum and plasma samples should be collected in appropriate route, and they should be transferred by true collection tubes and in right storage conditions.

Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels.

In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.

Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-diabetic gerbils (Gerbillus gerbillus).

This study was designed to investigate the HPA-axis impairment in the streptozotocin (STZ)-diabetic gerbils (Gerbillus gerbillus). Twenty-six male gerbils (body weight ~27g) were divided into 3 groups: vehicle control (n=10), 2days of diabetes (n=09) and 30days of diabetes (n=07). The latter 2 groups received an intraperitoneal injection of STZ (150mg/kg of body weight). At 2 and 30days of diabetes, streptozotocin-diabetic gerbils underwent a retro-orbital puncture for assessment of biochemical and hormonal parameters. Subsequently the animals were decapitated and the adrenal glands were removed, weighed and processed for light microscopy and stereology. Nondiabetic control gerbils that had been injected with citrate buffer were examined as a comparison. At 2days of diabetes, STZ gerbils exhibited symptoms that are characteristic of human diabetes type 1. The adrenal gland showed significant increase in weight, associated with a larger cortex layer, hypertrophy of the fasciculate cells and a significant decrease in the nucleocytoplasmic index. These changes were associated with higher plasma ACTH and cortisol concentrations compared to nondiabetic controls. At 30days postdiabetes, ACTH levels remained elevated, whereas cortisol levels decreased compared to the early stage of diabetes. Histological analysis revealed the existence of a band of connective tissue (collagen) that separates the cortical and medullary zones and is not present in humans or laboratory rodents, which represents a striking change seen throughout the disease. STZ-induced diabetes mellitus in Gerbillus gerbillus resulted in hyperactivation of the HPA axis in the early stages of diabetes mellitus which did not persist into the final stages of the disease, suggesting a possible reduction in adrenocortical sensitivity over time.

Adrenocortical Stress Response during the Course of Critical Illness.

Critically ill patients have elevated plasma cortisol concentrations, in proportion to illness severity. This was traditionally attributed exclusively to a central activation of the hypothalamus-pituitary axis. However, low rather than high plasma ACTH concentrations have been reported in critically ill patients, with loss of diurnal ACTH and cortisol rhythm. Low ACTH together with high cortisol is referred to as "ACTH-cortisol dissociation." Although cortisol production is somewhat increased with inflammation, a reduced cortisol breakdown explains to a larger extent the hypercortisolism during critical illness. Inflammation-driven decrease in cortisol binding proteins further increase the active free cortisol fraction. Several drugs administered to ICU patients suppress plasma cortisol in a dose-dependent manner. Sustained low circulating ACTH might contribute to adrenal atrophy and dysfunction in the prolonged phase of critical illness. In the acute phase of sepsis or septic shock, a condition referred to as "relative adrenal insufficiency" has been suggested to ensue from glucocorticoid resistance and insufficiently elevated circulating cortisol to overcome such resistance, with pathological changes possibly occurring at every level of the HPA axis. However, it remains highly controversial whether tissue-specific glucocorticoid resistance is adaptive or maladaptive, how to diagnose "relative" adrenal insufficiency, and how it should be treated. Large RCTs, investigating the effect of 200 mg/d hydrocortisone treatment for sepsis or septic shock have shown conflicting, mainly negative, results. Not taking into account the reduced cortisol breakdown, which increases the risk of overdosing hydrocortisone, might have played a role. Further research on diagnostic, therapeutic and dosing aspects is urgently warranted. Compr Physiol 8:283-298, 2018.

Steroidogenic factor-1 inverse agonists as a treatment option for canine hypercortisolism: in vitro study

Hypercortisolism is one of the most commonly diagnosed endocrinopathies in dogs, and new targeted medical treatment options are desirable. Steroidogenic factor-1 (SF-1), an orphan nuclear hormone receptor, is a key regulator of adrenal steroidogenesis, development, and growth. In pituitary-dependent hypercortisolism (PDH), high plasma ACTH concentrations increase the transcriptional activity of SF-1. In adrenal-dependent hypercortisolism, SF-1 expression is significantly greater in dogs with recurrence after adrenalectomy than in those without recurrence. Inhibition of SF-1 could therefore be an interesting treatment option in canine spontaneous hypercortisolism. We determined the effects of 3 SF-1 inverse agonists, compounds IsoQ A, #31, and #32, on cortisol production, on the messenger RNA (mRNA) expression of steroidogenic enzymes and SFs, and on cell viability, in primary adrenocortical cell cultures of 8 normal adrenal glands and of 3 cortisol-secreting adrenocortical tumors (ATs). To mimic PDH, the normal adrenocortical cell cultures were stimulated with ACTH. The results show that only compound #31 inhibited cortisol production and SF-1 target gene expression in non–ACTH-stimulated and ACTH-stimulated normal adrenocortical cells but did not affect cell viability. In the AT cell cultures, the effects of #31 on cortisol production and target gene expression were variable, possibly caused by a difference in the SF-1 mRNA expressions of the primary tumors. In conclusion, inhibition of SF-1 activity shows much promise as a future treatment for canine hypercortisolism.

Primary adrenal insufficiency in adult population: a Portuguese Multicentre Study by the Adrenal Tumours Study Group.

IntroductionPrimary adrenal insufficiency (PAI) is a rare but severe and potentially life-threatening condition. No previous studies have characterized Portuguese patients with PAI.AimsTo characterize the clinical presentation, diagnostic workup, treatment and follow‐up of Portuguese patients with confirmed PAI.MethodsThis multicentre retrospective study examined PAI patients in 12 Portuguese hospitals.ResultsWe investigated 278 patients with PAI (55.8% were females), with a mean age of 33.6 ± 19.3 years at diagnosis. The most frequent presenting clinical features were asthenia (60.1%), mucocutaneous hyperpigmentation (55.0%) and weight loss (43.2%); 29.1% of the patients presented with adrenal crisis. Diagnosis was established by high plasma ACTH and low serum cortisol in most patients (43.9%). The most common aetiology of PAI was autoimmune adrenalitis (61.0%). There were 38 idiopathic cases. Autoimmune comorbidities were found in 70% of the patients, the most frequent being autoimmune thyroiditis (60.7%) and type 1 diabetes mellitus (17.3%). Seventy-nine percent were treated with hydrocortisone (mean dose 26.3 ± 8.3 mg/day) mostly in three (57.5%) or two (37.4%) daily doses. The remaining patients were treated with prednisolone (10.1%), dexamethasone (6.2%) and methylprednisolone (0.7%); 66.2% were also on fludrocortisone (median dose of 100 µg/day). Since diagnosis, 33.5% of patients were hospitalized for disease decompensation. In the last appointment, 17.2% of patients had complaints (7.6% asthenia and 6.5% depression) and 9.7% had electrolyte disturbances.ConclusionThis is the first multicentre Portuguese study regarding PAI. The results emphasize the need for standardization in diagnostic tests and etiological investigation and provide a framework for improving treatment.

An unusual case of Cushing's syndrome due to bihormonal ACTH–prolactin secreting pituitary macroadenoma with rapid response to cabergoline

A 23-year-old man presenting with florid Cushing's syndrome was found to have high plasma ACTH and very high serum prolactin. Pituitary MRI showed a large invasive macroadenoma. Low-dose cabergoline promptly...

X-Linked Adrenal Hypoplasia Congenita in a Boy due to a Novel Deletion of the Entire NR0B1 (DAX1) and MAGEB1-4 Genes.

X-linked Adrenal Hypoplasia Congenita (AHC) is caused by deletions or point mutations in the NR0B1 (DAX1) gene. We present a boy with AHC who came at the age of 25 days in a severe state due to prolonged vomiting and progressive dehydration. Laboratory studies showed prominent hyponatremia and hyperkaliemia but not hypoglycemia. Primary adrenal insufficiency was confirmed with low serum cortisol levels and high plasma ACTH levels. Hydrocortisone therapy combined with saline and glucose infusions was started immediately after blood collection. Two exons of the NR0B1 (DAX1) gene were impossible to amplify using the standard PCR method. Array CGH was used to confirm the putative copy-number variation of NR0B1 (DAX1) revealing a novel hemizygous deletion encompassing the entire NR0B1 (DAX1) gene together with the MAGEB genes. This genetic defect was also present in heterozygosity in the patient's mother. We show that NR0B1 (DAX1) gene analysis is important for confirmation of AHC diagnosis and highlights the role of genetic counseling in families with AHC patients, particularly those with X chromosome microdeletions, covering more than NR0B1 (DAX1) alone. We hope that further clinical follow-up of this patient and his family will shed a new light on the role of MAGEB genes.

G441(P) Responding to hormone unresponsiveness

AimWe aim to raise awareness among Paediatricians to a group of conditions that are individually rare but collectively appear not to be so. Three cases were diagnosed in a medium...

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease

To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. Laboratory tests included morning and midnight serum cortisol levels, 24h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.

The comparative analysis of the results of clinical and hormonal investigations in the patients presenting with ACTH-producing neuroendocrine tumours

This study included the patients presenting with neuroendocrine tumours (NET) and the clinical picture of hypercoticism caused by excessive ACTH secretion from the tumour. The overwhelming majority of the patients (85%) suffered Cushing's disease (CD) associated with a pituitary tumour. The remaining 15% of the patients presented with ACTH-ectopic syndrome (ACTH-ES). The clinical picture of CD and ACTH-ES was very similar. The latter condition was associated with the higher plasma ACTH and cortisol levels as well as the free cortisol content in 24 hour urine and saliva samples collected in the evening compared with CD even though the differences were insignificant due to data scattering. Decompressin administration and catheterization of inferior petrosal sinuses caused a much greater enhancement of the ACTH level in the patients with CS in comparison with those suffering ASTH-ES.

Spontaneous remission of hypercortisolism presumed due to asymptomatic tumor apoplexy in ACTH-producing pituitary macroadenoma

Cushing's disease (CD) is usually caused by secretion of ACTH by a pituitary corticotroph microadenoma. Nevertheless, 7%-20% of patients present with ACTH-secreting macroadenomas. Our aim is to report a 36-year-old female patient with CD due to solid-cystic ACTH-macroadenoma followed up during 34 months. The patient presented spontaneous remission due to presumed asymptomatic tumor apoplexy. She showed typical signs and symptoms of Cushing's syndrome (CS). Initial tests were consistent with ACTH-dependent CS: elevated urinary free cortisol, abnormal serum cortisol after low dose dexamethasone suppression test, and elevated midnight salivary cortisol, associated with high plasma ACTH levels. Pituitary magnetic resonance imaging (MRI) showed a sellar mass of 1.2 x 0.8 x 0.8 cm of diameter with supra-sellar extension leading to slight chiasmatic impingement, and showing hyperintensity on T2-weighted imaging, suggesting a cystic component. She had no visual impairment. After two months, while waiting for pituitary surgery, she presented spontaneous resolution of CS. Tests were consistent with remission of hypercortisolism: normal 24-h total urinary cortisol and normal midnight salivary cortisol. Pituitary MRI showed shrinkage of the tumor with disappearance of the chiasmatic compression. She has been free from the disease for 28 months (without hypercortisolism or hypopituitarism). The hormonal and imaging data suggested that silent apoplexy of pituitary tumor led to spontaneous remission of CS. However, recurrence of CS was described in cases following pituitary apoplexy. Therefore, careful long-term follow-up is required.

Cardiovascular and cerebrovascular complications and clinical characteristics in patients with Cushing's syndrome of different aetiologies

Objective To compare the cardiovascular and cerebrovascular complications and clinical characteristics in patients with Cushing's syndrome of various aetiologies.Methods Two hundred and eighty-four consecutive patients with Cushing's syndrome were included and divided into three groups according to aetiologies:Cushing's disease group (CD),adrenal adenoma group (AA),ectopic ACTH syndrome group (EAS).Results (1) Of the 284 patients,the mean age was(37.7 ± 12.3) years(16-76 years),while in EAS group it was(45.1 ±16.4) years (16-68 years,P ＜0.05).Patients in EAS group had shorter duration of illness (1-3 months).Hypokalemia was present in 44.9％,32.3％,100％ of patients in CD group,AA group,and EAS group respectively.(2) Patients in EAS group were more susceptible to alkalosis and edema of lower limbs,and had lower prevalence of striae (P＜0.05) ; AA group had lower prevalence of pigmentation and acne(P＜0.01).(3) Patients in EAS group had significantly higher baseline plasma ACTH,cortisol,and 24 h urine free cortisol levels than those in CD group and AA group.(4) Patients in EAS group and CD group had similar prevalences of overall vascular complications(68.8％ vs 59.2％,P＞0.05),which were significantly higher than that in AA group(43.4％,P＜0.05).Compared with AA group,patients in CD group had higher prevalence of cardiovascular complications (43.8％ vs 31.3％) and cerebrovascular complications (13.1％ vs 6.1％,P＜0.05),manifesting as cardiac arrhythmia(33.7％ vs 22.2％) and cerebral infarction (13.1％ vs 5.1％,P ＜0.05).No significant difference in the prevalence of impaired renal function in three groups was found (P ＞ 0.05).Multivariate logistic regression analysis revealed that the incidence of hypokalemia was positively correlated with vascular complication in group CD,but serum potassium level was negatively correlated with vascular complication.Conclusion Patients in EAS group were older and had shorter duration of illness,and higher levels of hormone,and were more susceptible to hypokalemia,alkalosis edema of lower limbs,and pigmentation.Patients in CD group had higher prevalence of cardiovascular and cerebrovascular complications than that in AA group,especially arrhythmias and cerebral infarction.No significant difference in the incidence of impaired renal function was found among three groups.Hypokalemia might be the independent risk factor of vascular complications in CD group. Key words: Cushing's syndrome; Hypokalemia; Vascular complications; Different aetiologies

Ectopic Cushing's syndrome caused by a pulmonary ACTH-secreting tumor in a patient treated with octreotide

Ectopic ACTH syndrome is a rare disease often associated with severe hypercortisolism. When feasible, optimal management is surgical excision of the tumor. A 33-year-old male patient was admitted to the hospital in 1993 with clinical manifestations suggestive of Cushing's syndrome. He presented high plasma ACTH and markedly elevated urinary free cortisol excretion that was not suppressed with high-dose dexamethasone administration. Pituitary MRI scan was normal. No central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. Thoracic CT scan showed a 1.7 cm nodule at the left lung. Pulmonary fine needle cytology and immunocytochemical and ultrastructural studies, together with the presence of bone metastases, led to the diagnosis of an ACTH-producing neuroendocrine carcinoma. He was initially submitted to chemotherapy and has been on treatment with octreotide LAR since 1998, having shown a favorable clinical, biochemical and imaging response. We highlight the excellent long-term response to medical therapy with octreotide LAR, without tachyphylaxis, probably due to its antiproliferative effect.

Testicular Adrenal Rest Tumors in Patients With Congenital Adrenal Hyperplasia

Testicular adrenal rest tumors have been described in patients with congenital adrenal hyperplasia (CAH). The aim of this work was to (1) evaluate the prevalence of testicular adrenal rest tumors in patients with CAH; (2) study the hormonal profile; (3) define the sonographic features; (4) assess the seminal profile; and (5) initiate a longitudinal study on the possible role of corticotropin (ACTH) plasma levels in the induction and persistence of testicular adrenal rest tumors. Eighteen patients affected by CAH, aged 21 to 41 years, were studied. These were all patients referred to our endocrinology unit for the first time to undergo a clinical evaluation. All of the patients were taking long-term cortisone acetate and fludrocortisone replacement therapy. The study included (1) a physical examination, (2) testis sonography, (3) a hormonal profile, (4) semen analysis. Sonography showed testicular adrenal rest tumors in 11 patients (61.1%); of these, 9 cases (50.0%) were bilateral, and 2 (11.1%) were unilateral. The diameter ranged from 4 to 38 mm. In 9 patients, the lesions were hypoechoic, whereas in 2, they were hyperechoic. High plasma ACTH levels were detected in all of the patients with tumors despite long-term therapy. Semen analysis found 2 cases of azoospermia and 6 cases of oligoasthenoteratozoospermia; the 3 remaining patients were normospermic. The preliminary longitudinal study has shown 3 patients with a disappearance or reduction of the tumors after 6 months of modified treatment. This study confirms the high prevalence of testicular adrenal rest tumors in patients with CAH and the major role played in its pathogenesis by high plasma ACTH levels.

Familial Glucocorticoid Deficiency with a Point Mutation in the ACTH Receptor: A Case Report

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by severe glucocorticoid deficiency associated with failure of adrenal responsiveness to ACTH but no mineralocorticoid deficiency. We report a 2 month-old boy of nonconsanguineous parents, presented with hyperpigmentation. Physical examination showed diffuse dark skin of body including, oral mucosa, gum, hands, nails and scrotum. Laboratory evaluation revealed low serum cortisol (0.3 µg/dL), with very high plasma ACTH level (18,000 pg/mL), and serum cortisol level did not increase after ACTH stimulation test. Serum sodium, potassium, plasma renin activity, aldosterone and 17-hydroxyprogesterone were normal. Sequence analysis of the ACTH receptor (MC2R) gene showed a homozygous mutation of D103N. Diagnosis of FGD was made and treatment started with oral hydrocortisone.

Differential development of stress system (re)activity at weaning dependent on time of disruption of maternal care

Maternal deprivation, a separation of mother and pups for 24 h in the first weeks of life has long-lasting consequences for the glucocorticoid stress system in rats. We examined in male CD1 mice whether the postnatal day (pnd) of deprivation determines the (re)activity of the stress system at weaning under basal and novelty stress conditions. Maternal deprivation was only effective when applied within the stress hypo-responsive period (SHRP) between pnds 1 and 12, but not on pnd 13. Maternal deprivation (i) early in the SHRP (pnd 3) resulted in lower hippocampal GR mRNA expression together with a prolonged corticosterone response to stress; while (ii) late in the SHRP (pnd 8) the amplitude of the ACTH response to stress was enhanced. (iii) Strikingly, the effects of the double deprivation (pnds 3 and 8) were not additive: sustained, stress non-responsive high plasma ACTH concentrations with corticosterone indistinguishable from control animals coincided with a lower expression of hippocampal MR and GR mRNA. These results present species-specific effects (mouse versus rat) of an adverse early life event on HPA axis regulation at weaning. A subsequent deprivation experience interferes with the effects of earlier deprivation. We conclude that the developmental stage of the organism determines the vulnerability for the detrimental effects of maternal deprivation and the organization of the stress system in adolescence.

Adrenalectomy enhances endotoxemia-induced hypophagia: higher activation of corticotrophin-releasing-factor and proopiomelanocortin hypothalamic neurons

Inflammatory and infectious processes evoke neuroendocrine and behavioral changes known as acute-phase response that includes activation of the hypothalamo-pituitary-adrenal (HPA) axis and reduction of food intake. Besides its action as the most important ACTH secretagogue, corticotrophin-releasing factor (CRF), synthesized in the paraventricular nucleus (PVN), is also involved in the control of food intake. Alpha-melanocyte stimulating hormone (α-MSH) in the arcuate nucleus also plays a role in the energy homeostasis, possessing anorexigenic effects. To investigate the participation of neuropeptides involved in the regulation of food intake during endotoxemia, we administrated lipopolysaccharide (LPS) in sham-operated and adrenalectomized (ADX) male Wistar rats to evaluate food intake, hormone responses and Fos-CRF and Fos-α-MSH immunoreactivity in the PVN and arcuate nucleus, as well as CRF and POMC mRNA expression in these hypothalamic nuclei. In sham-operated rats, treatment with LPS (100 µg/kg) showed lower food intake, higher plasma ACTH and corticosterone levels, as well as an increase in Fos-CRF double labeled neurons and CRF mRNA expression in the PVN, with no changes in Fos-α-MSH immunoreactivity and POMC mRNA expression in the arcuate nucleus, compared to saline treated rats. After LPS treatment, ADX rats showed further increase in plasma ACTH levels, marked decrease of food intake, higher Fos-CRF immunoreactive neurons in the PVN and CRF mRNA expression, as well as an increase in Fos-α-MSH immunoreactivity and POMC mRNA expression in the arcuate nucleus, compared to sham-operated rats treated with LPS. In conclusion, the present data indicate that the marked hypophagia during endotoxemia following ADX is associated with an increased activation of CRF and POMC neurons in the hypothalamus and an increased mRNA expression of these neuropeptides.