Pituitary ACTH-dependent Cushing's Syndrome Research Articles

A commentary on Diagnosing Cushing's disease in the context of renal failure.

The diagnosis of endogenous hypercortisolism (Cushing's syndrome) is extremely challenging. Chronic kidney disease (CKD) increases the activity of the hypothalamic-pituitary-adrenal axis making the diagnosis of Cushing's syndrome even more challenging. This is particularly so since urine free cortisol (UFC) testing is not useful in CKD. The case report by Stroud et al. in this issue of the European Journal of Endocrinology highlights this problem by finding normal UFC in a patient with pituitary ACTH-dependent Cushing's syndrome. Elevated late-night salivary cortisol (LNSC) testing was diagnostic and pituitary adenomectomy was curative. LNSC measurement is the diagnostic test of choice in patients with suspected Cushing's syndrome, particularly in the presence of CKD..

Inferior petrosal sinus ACTH and prolactin responses to CRH in ACTH-dependent Cushing’s syndrome: a single centre experience from the United Kingdom

Inferior petrosal sinus sampling (IPSS) of ACTH with CRH stimulation helps distinguish pituitary ACTH-dependent Cushing's syndrome from the ectopic ACTH syndrome (EAS). The usefulness of the paradoxical response of other pituitary hormones including prolactin to CRH remains controversial. Data from 33 IPSS procedures carried out at the Walton Centre for Neurology and Neurosurgery in Liverpool were analyzed. Patients were selected for this procedure if they had been diagnosed with ACTH dependent Cushing's syndrome and the majority had no obvious pituitary adenoma on Magnetic Resonance Imaging. Satisfactory simultaneous bilateral catheterization was accomplished in 23/33 (success rate 70%). The diagnostic sensitivity of a basal central/peripheral ACTH ratio >2.0 and >3 post-CRH was 94%. In two patients with subsequently confirmed EAS the maximal central/peripheral ACTH ratio was <2.0 on basal samples and did not change following CRH. The maximal central/peripheral prolactin ratio was noted at 5 min post-CRH, coinciding with the maximal central/peripheral ACTH ratio. The intersinus gradient (ISG) of ACTH was paralleled by a consistent ISG of prolactin and in 7 out of 9 patients (with successful bilateral IPSS and unilateral adenomas) the ISG of prolactin correctly lateralized the microadenoma whereas the ISG of ACTH correctly lateralized in 8 out of 9 patients. Neither of the patients with EAS achieved a central/peripheral prolactin ratio >2 in the basal state and >3 post-CRH. Bilateral catheterization of inferior petrosal sinuses can be successful in up to 70% of cases. Prolactin measurements do not have superior lateralizing capability compared with ACTH but may be useful in the differential diagnosis of pituitary-driven from EAS.

Location of ectopic adrenocortical hormone‐secreting tumors causing Cushing's syndrome in the paranasal sinuses

The majority of ectopic adrenocorticotropic hormone (ACTH)-secreting tumors are localized in the chest or abdomen. Occasionally, these tumors are found in the paranasal sinuses. We present 2 unusual cases of ectopic ACTH syndrome whose ACTH-secreting tumors were localized in the paranasal sinuses and describe their biochemical and radiological presentation. The first patient had an ACTH-secreting olphactory neuroblastoma originating in the ethmoid sinuses. The second patient had a clinical course and biochemical findings indistinguishable from pituitary ACTH-dependent Cushing's syndrome, except for negative petrosal sinus sampling. Head imaging showed a "polyp" in the left maxillary sinus-secreting ACTH. Both patients went into remission following surgical resection and recovered normal pituitary-adrenal axis function. Ectopic ACTH secretion may originate from lesions in the paranasal sinuses. This accessible location allows for direct immunohistochemical diagnosis with ACTH staining. Surgical resection/radiation therapy can result in complete remission of the disease and restoration of normal pituitary-adrenal function.

Clinical manifestations and hormonal profile of two women with Cushing’s disease and mild deficiency of 21-hydroxylase

The development of Cushing's disease among patients with deficiency of 21-hydroxylase has not been observed to date. The clinical manifestations and the hormonal profile of this exceptional association are herein described through the study of two cases. The first one was a 39-yr-old woman who had undergone non-curative transsphenoidal surgery for a pituitary-dependent Cushing's syndrome 12 yr before. She showed hypertension, central obesity, severe hirsutism, alopecia and hyperpigmentation. Urinary excretion of cortisol was normal, but ACTH levels were very high and hormonal dynamic studies (cortisol circadian rhythm, insulin-induced hypoglycemia and dexamethasone suppression tests) revealed the qualitative disturbances that characterize Cushing's disease. Serum concentrations of androstenedione, free testosterone and 17-hydroxyprogesterone were clearly increased. Reexamination of the tissue samples from previous surgery confirmed the presence of an ACTH-producing pituitary adenoma. CYP21 gene analysis found the splicing 655G mutation at intron 2 and the V281L mutation at exon 7. The second case was a 21-yr-old woman who was diagnosed with pituitary ACTH-dependent Cushing's syndrome according to unequivocal clinical and laboratory findings. However, hirsutism was particularly severe and both serum androgens and 17-hydroxyprogesterone were elevated. The patient was heterozygote for a large conversion of CYP21 gene. In these cases, the clinical and biochemical expression of Cushing's syndrome was determined by the different severity of 21-hydroxylase deficiency and the subsequent residual ability of adrenal cortex to synthesize cortisol.

A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome.

The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

Metyrapone Is Useful Only as Adjunctive Therapy in Cushing's Disease

Editorials1 July 1978Metyrapone Is Useful Only as Adjunctive Therapy in Cushing's DiseaseDAVID N. ORTH, MD., F.A.C.P.DAVID N. ORTH, MD., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-89-1-128 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptA recent paper in theBritish Medical Journal(1) has recommended the use of metyrapone (Metopirone®; 2-methyl-1,2-bis(3-pyridyl)-1-propanone) for long-term treatment of patients with pituitary ACTH-dependent Cushing's syndrome (bilateral adrenal hyperplasia). Metyrapone inhibits the final step in adrenal steroid biosynthesis—the conversion of biologically inactive 11-deoxycortisol to cortisol (2). Metyrapone and aminoglutethimide (Elipten®; α-ethyl-α-p-aminophenylglutarimide), an agent that blocks the first step in steroid biosynthesis (3), have long been used to reduce hypercortisolism associated with adrenocortical tumors or ectopic ACTH syndrome (4-6); the only novelty in the British report lies in the use of such agents in Cushing's disease. What is the pathophysiology...