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LITERATURE REVIEW

CUSHING s syndrome (CS) is caused by prolongedsupraphysiological levels of circulating cortisol.

Cushings disease (CD) is the most common etiolo-gy (70%80% of CS cases) of endogenous CS. It is causedby a pituitary adenoma that secretes adrenocorticotropichormone (ACTH), which stimulates secretion of cortisolby the adrenal glands. If not effectively treated, CD is as-sociated with hypertension, diabetes, obesity, osteoporo-sis, vascular disease, and shortened life span. Successfulresection of a CD-associated ACTH-secreting pituitaryadenoma results in immediate biochemical remission andpreservation of pituitary function. Early identi cation ofCD by clinical ndings, endocrinological evaluation, andimaging studies is critical for diagnosis and effective sur-gical management.

Endocrinological and Clinical FeaturesEndocrinological FeaturesNormal Physiology

Insight into the normal and pathophysiological mecha-nisms of control of the hypothalamicanterior pituitaryadrenal axis is critical to understanding the pathologic, di-

agnostic, and therapeutic features of CD (Fig. 1). 52 Undernormal physiological conditions (circadian rhythm, where

cortisol levels peak in early morning and nadir late at night),systemic in ammation (cytokine), or stress (physiologicalor psychological), corticotropin-releasing hormone (CRH; a41amino acid peptide) is released from the paraventricularhypothalamic nucleus via the median eminence. From themedian eminence, CRH is transported in the hypophysealportal venous system to the pituitary gland, where it bindsto the CRH receptor-1 (CRH-R1) on pituitary corticotrophcells. CRH binding to CRH-R1 receptors activates adenyl-ate cyclase and stimulates proopiomelanocortin ( POMC )gene expression in the corticotroph cells. 17,66 Proopiomela-nocortin preprohormone is processed into ACTH (a 39amino acid peptide) and b -lipotropin (a 93amino acidpeptide). Products of b -lipotropin include b -endorphin anda -lipotropin. ACTH is secreted into the systemic circula-tion and binds to receptors in the adrenal cortex, whereit stimulates production and secretion of glucocorticoids,including cortisol. 83 Under normal conditions, circulatingcortisol provides physiological control of this endocrineaxis by its negative feedback inhibition on hypothalamicCRH and pituitary ACTH secretion. 106

ABBREVIATIONS ATCH = adrenocorticotropic hormone; CD = Cushings disease; CRH = corticotropin-releasing hormone; CRH-R1 = CRH receptor-1; CS = Cushingssyndrome; IPSS = inferior petrosal sinus sampling; SPGR = spoiled gradient recalled; SRS = stereotactic radiosurgery.SUBMITTEDNovember 9, 2015. ACCEPTED January 18, 2016.INCLUDE WHEN CITINGPublished online April 22, 2016; DOI: 10.3171/2016.1.JNS152119.

Cushings disease: pathobiology, diagnosis, andmanagement

Russell R. Lonser, MD,1 Lynnette Nieman, MD,2 and Edward H. Oldfeld, MD 3

1Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio;2Program inReproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development,National Institutes of Health, Bethesda, Maryland; and3Department of Neurological Surgery, University of Virginia HealthSystem, Charlottesville, Virginia

Cushings disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonalpituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting insupraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hyperten-sion, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma isthe treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurateand early identi cation of CD is critical for effective surgical management and optimal prognosis. The authors review thecurrent pathophysiological principles, diagnostic methods, and management of CD.http://thejns.org/doi/abs/10.3171/2016.1.JNS152119KEY WORDSCushings disease; diagnosis; surgery; treatment; oncology

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R. R. Lonser, L. Nieman, and E. H. Oldfield

J Neurosurg April 22, 20162

CD PathophysiologyCD is caused by a benign monoclonal pituitary corti-

cotroph adenoma that secretes excessive ACTH, 39 whichcauses supraphysiological secretion of glucocorticoidsfrom the adrenal glands. The excess circulating cortisoldisrupts the normal physiological diurnal variation in cor-tisol levels and exerts negative feedback inhibition on CRHsecretion from the hypothalamus. However, the adenomaitself is relatively resistant to inhibition by endogenous cir-culating cortisol (Fig. 1). Consequently, CD is associatedwith suppressed secretion of CRH and elevated levels ofACTH in relation to the degree of cortisol production.

Clinical FeaturesEpidemiology

CD has a prevalence of 39.1 per million inhabitants (in-cidence 1.22.4 newly diagnosed cases per 1 million per-sons per year). 31,55 The average age at diagnosis for adultsis in the 4th decade (younger in females [mean 30.5 years]than males [mean 37.1 years]). The average age at diagno-sis in pediatric CD is approximately 13 years (symptomonset 10.6 years). 50,58,60 Symptom initiation to diagnosisaverages 23 years in pediatric and adult cases. 58,113 Be-fore puberty, the ratio of female-to-male cases is similar(1:1). 50,58 In adult CD patients, females are more frequentlyaffected than males (3:1 vs 5:1). 70,82,105,113

Clinical FindingsProlonged excessive cortisol exposure leads to multi-

system signs and symptoms. The most common clinicalfeatures in adults include obesity, diabetes, hypertension,moon facies, and facial plethora (Fig. 2). 70,82 While themost common ndings in prepubertal pediatric patientsinclude rapid weight gain, obesity, and decreased lineargrowth, the most common ndings in postpubertal pe -diatric patients are rapid weight gain, dorsal/subclavicu-lar fat pads, and amenorrhea. 50,58,60,100 Psychiatric de cits(depression, emotional liability, anxiety, psychosis, panicattacks, suicidal ideation, and paranoia) and neurocogni-

tive de cits (learning impairment and memory de cits)can also be associated with CD and may be the only sign/symptom in a subset of patients. 51,69

CD-Associated Morbidity and MortalityCD-associated morbidity includes cardiac and cere-

brovascular events, immunosuppression, osteoporosis,psychiatric disturbances, and diabetes. Untreated CD hasan estimated standardized mortality ratio (ratio of ob-served CD-related deaths to expected deaths in the gen-eral population) of 1.94.8. 21,31,40,55,111 CD-associated mor-bid risk factors are substantially reduced with successfultreatment, 21,42,102 but effectively treated patients may have

a higher frequency of diabetes, obesity, and dyslipidemia

FIG. 1. Hypothalamic-pituitary-adrenal axis in healthy individuals and CD patients. Left: Under normal physiological circum-stances, including circadian rhythm (diurnal secretion that peaks in early morning and nadirs near midnight) and stress (physiologi-cal and psychological), the paraventricular nucleus of the hypothalamus releases CRH (orange arrows), which the hypophysealportal venous system transports to the anterior pituitary gland. In the pituitary gland, CRH stimulates pituitary corticotroph cells(orange arrow ) by binding to CRH-R1 receptors to stimulate production and excretion of ACTH into the systemic circulation. ACTHthen stimulates the adrenal cortex (red arrow ) to synthesize and excrete glucocorticoids, including cortisol. Cortisol inhibits thisendocrine axis (blue arrows) at the hypothalamus and pituitary by binding to glucocorticoid receptors and reducing CRH and ACTH production/secretion, respectively. Right: Under the pathophysiological conditions associated with CD, a benign monoclo-nal basophilic adenoma of the anterior pituitary gland continuously (resulting in loss of normal diurnal secretory rhythm) secretesexcess levels of ACTH (large red arrow ). Circulating ACTH drives supraphysiological production and secretion of cortisol from theadrenal cortices (large blue arrows) that results in reduced CRH production/excretion by the hypothalamus. While the ACTH-se-creting adenomas in CD retain CRH-R1 and vasopressin receptors with their associated stimulatory capacity (adenomas secrete ACTH [large red arrow ] when stimulated by CRH or desmopressin [large blue arrows]), the cortisol-driven negative feedback onthe pituitary is significantly blunted. Nevertheless, very high levels of exogenous steroid (e.g., high-dose dexamethasone testresponse) suppress ACTH production by CD adenomas (small red arrow ) and downstream circulating cortisol levels (small blue arrows). Copyright OSU Health Sciences Library Medical Visuals. Published with permission.

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Cushings disease

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compared with controls. While many studies indicate thatCD-associated mortality is returned to general popula-tion rates after biochemical remission, 21,42,102 other studieshave shown an elevated cardiovascular risk of death up to5 years after successful biochemical remission. Psychiat-ric and neurocognitive disturbances can persistent in somepatients after successful treatment. 4,23,37,69,87 Patients withpersistent CD after treatment suffer increased morbidityand mortality. 42,103

DiagnosisBiochemical DiagnosisDiagnosis of CS

After exogenous sources are ruled out, clinical suspi-

cion of CS leads to laboratory assessment to con rm thepresence of endogenous hypercortisolism (Fig. 3). Estab-lished guidelines for the diagnosis of CS recommend veri-cation of hypercortisolism by 2 screening tests. Screen -ing tests include late night salivary cortisol, 24-hour urinefree cortisol, or low-dose dexamethasone suppression (1

mg overnight or 2 mg over 48 hours) testing.72

Establishing the Cause of HypercortisolismAfter the diagnosis of CS is established, its cause is

sought. Endogenous hypercortisolism can be caused byeither an ACTH-dependent (pituitary adenoma or ecto-pic tumor) or independent (adrenal tumor) mechanism(Fig. 3). 6,70 Plasma ACTH levels are obtained to assess forACTH dependency as the cause of hypercortisolism. Inap-propriately elevated ACTH levels in a hypercortisolemicstate (i.e., greater than 10 pg/ml) are consistent with anACTH-dependent cause (Fig. 3).

After the isolation, sequencing, and synthesis of CRHby Vale and colleagues in 1983, 106 CRH stimulation wasintroduced as a diagnostic test for the differential diagnosisof ACTH-dependent causes of CS (Fig. 1). 19,43,70,73,78 Thisstrategy was based on the assumption that CD is caused bywell-differentiated adenomas derived from pituitary corti-cotrophs and that these adenomas should have receptors forCRH and the cellular constituents necessary to respond toCRH stimulation (a positive response is set arbitrarily at a50% or more increase in ACTH and 20% or more increasein cortisol). Alternatively, ectopic ACTH-secreting tumorsare derived from nonpituitary tissues and generally do notrespond to CRH. However, there is an approximately 10%incidence of false-negative and false-positive results in ec-topic tumors with CRH stimulation testing. 43,73

High-dose dexamethasone suppression testing also canbe used to distinguish between ACTH-dependent causesof CS. 19,43,54,70,73 Similar to the biological basis for CRHstimulation testing, dexamethasone suppression testingtakes advantage of the presence of cellular constituentsnecessary to respond to dexamethasone (suppression) inthe pituitary adenoma corticotroph cells and the lack ofthe negative feedback response in ectopic nonpituitarytumors that secrete ACTH (Fig. 1). In this manner, highdoses (8 mg) of dexamethasone can suppress cortisol (i.e.,a 50% or more decrease) secretion in approximately 80%of CD patients but the majority of ectopic ACTH-secret-ing tumors typically do not respond. However, a signi -cant overlap in responses of pituitary and ectopic tumorsto high-dose dexamethasone suppression testing compro-mise the diagnostic accuracy of this test. 34,43,73

MR ImagingBecause of their potent biological/clinical effects, CD-

associated pituitary adenomas are often discovered whenthey are small. Data from large surgical series indicatethat over 90% of ACTH-adenomas are microadenomas (