Comorbidities in Cushing's disease.

INTRODUCTION: Cushing's disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality. METHODS: Here we review the comorbidities associated with Cushing's disease and their impact on quality of life and mortality. RESULTS: Recent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition. In particular, increased cardiovascular risk may persist despite long-term remission of hypercortisolemia. This may be related to persistence of visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis and a procoagulant phenotype. Prior prolonged exposure to glucocorticoids also may have irreversible effects on the central nervous system, leading to persistent cognitive and mood alterations. Osteoporosis and fractures, especially vertebral fractures, can further add to morbidity and a poor quality of life. Normalization of cortisol levels leads to significant improvement in comorbidities but long-term data regarding complete resolution are lacking and need further study. CONCLUSION: Early diagnosis and treatment of hypercortisolemia, aggressive management of comorbidities along with long-term follow-up is crucial for the optimal recovery of these patients.

Is prolactin measurement of value during inferior petrosal sinus sampling in patients with adrenocorticotropic hormone-dependent Cushing's Syndrome?

Inferior petrosal sinus sampling (IPSS) is considered the gold standard test to distinguish between Cushing's disease (CD) and ectopic ACTH syndrome (EAS). Anomalous venous drainage, abnormal venous anatomy, and lack of expertise can lead to false-negative IPSS results and thereby misclassification of patients with ACTH-dependent Cushing's syndrome. Prolactin measurement during IPSS can improve diagnostic accuracy and decrease false negative results. A baseline prolactin inferior petrosal sinus to peripheral (IPS/P) ratio (ipsilateral to the dominant post-CRH ACTH IPS/P ratio) of 1.8 or more suggests successful catheterization during IPSS. Prolactin-normalized ACTH IPS/P ratios can then be used to differentiate between a pituitary and ectopic source of ACTH. Values ≤ 0.7 are suggestive of EAS and those ≥ 1.3 are indicative of CD, but the implication of values between 0.7 and 1.3 remains unclear and needs further investigation. Larger prospective studies are also needed for further evaluation of the role of contralateral prolactin IPS/P ratios, post- CRH prolactin values, and prolactin-adjusted ACTH inter-sinus ratios for tumor localization in CD.

Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion.

Spontaneous remission is rare in ectopic ACTH syndrome (EAS). We describe four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3-10 years in these patients was followed by a prolonged period of remission (15-60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h urinary free cortisol (UFC), and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity and case 3 has been in remission for ~5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.

Prolactin as a marker of successful catheterization during IPSS in patients with ACTH-dependent Cushing's syndrome.

CONTEXT: Anomalous venous drainage can lead to false-negative inferior petrosal sinus sampling (IPSS) results. Baseline inferior petrosal sinus to peripheral (IPS/P) prolactin ratio higher than 1.8 ipsilateral to the highest ACTH ratio has been proposed to verify successful catheterization. Prolactin-normalized ACTH IPS/P ratios may differentiate Cushing's disease (CD) from ectopic ACTH syndrome (EAS). OBJECTIVE: Our objective was to examine the utility of prolactin measurement during IPSS. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective analysis of prolactin levels in basal and CRH-stimulated IPSS samples in ACTH-dependent Cushing's syndrome (2007-2010). RESULTS: Twenty-five of 29 patients had a pathologically proven diagnosis (17 CD and eight EAS). IPSS results were partitioned into true positive for CD (n = 16), true negative (n = 7), false negative (n = 1), and false positive (n = 1). Prolactin IPS/P ratio suggested successful IPSS in eight of 11 with abnormal venograms. Baseline prolactin IPS/P ratio was helpful in two patients with abnormal venograms and false-negative (catheterization unsuccessful) or true-negative (catheterization successful) IPSS results; the normalized ratio correctly diagnosed their disease. Normalized ACTH IPS/P ratio was at least 1.3 in all with CD, but prolactin IPS/P ratios were misleadingly low in two. One patient with cyclic EAS had a false-positive IPSS when eucortisolemic (baseline prolactin IPS/P = 1.7; normalized ratio = 5.6). All other EAS patients had normalized ratios no higher than 0.7. CONCLUSION: Prolactin measurement and evaluation of the venogram can improve diagnostic accuracy when IPSS results suggest EAS but is not necessary with positive IPSS results. Confirmation of hypercortisolemia remains a prerequisite for IPSS. A normalized ratio of 0.7-1.3 was not diagnostic.