148 PART II: PRIMARY CARE DISORDERS
Cushing’s Disease and Syndrome
General Characteristics
The adrenal glands are situated adjacent to the kidneys
andarecomprisedoftwotypesofhormone-secretingtis-
sue(Figure11–1).Thecoreistermedthe medulla. The
outerlayeristhecortex,whichisresponsibleforsecreting
three classes of steroid hormones: androgens, mineralo-
corticoids, and glucocorticoids. The glucocorticoid hor-
monesarethemostcommonclassofwhicheitherexcess
ordecienciesareencountered.Thedisorderofexcessis
termedCushing’s disease,andthe disorderof deciency
istermedAddison’sdisease(Figure 11–4).
29,30
Diseasesoftheadrenal glands,eitherexcessorinsuf-
ciency, are suspected based on patient symptoms and
physicalmanifestations.Rarely,adrenalmassesarefound
incidentallyonabdominalimagingstudiesperformedfor
unrelatedpurposes.Thewordsyndromeisutilizedprimar-
ilytodescribeacomplexofsymptomsthatissuggestive
ofaparticulardisease.ThetermCushing’ssyndromecan
beusedtorefertoaclinicalpresentationthatinvolvesa
numberofthesymptomslistedinTable 11–14.
31
Themost
commoncauseofCushing’ssyndromeisiatrogenicfrom
medically prescribed corticosteroids (i.e., prednisone)
requiredtocontrolsymptomsfromdiseasessuchasrheu-
matoidarthritis,lupus,severeasthma,orchronicobstruc-
tivepulmonarydisease.
31
Historically,thetermCushing’sdiseasehasbeenreserved
for cases that have been determined to be caused by the
pituitary producing excess adrenocorticotropic hormone
Table 11–14
Symptoms of Cushing’s Disease
Weakness with proximal myopathy and atrophy*
Facial plethora or rounding, called moon face*
Skin changes, including susceptibility to bruising,
abdominal red purple striae > 1 cm wide, acne/oily skin*
Weight gain with central adiposity and fat pad
at back of neck, called buffalo hump
Psychological symptoms ranging from loss of
emotional control, irritability, and depression to panic
attacks and paranoia; insomnia is also common
Blood clots
Glucose intolerance, polydipsia, polyuria
Menstrual irregularities (oligomenorrhea or amenorrhea)
Hirsutism
Impotence/hypogonadism
Bone loss (back ache, vertebral collapse, fractures)
Hypertension, ankle edema
* Indicates the most prominent symptoms
Source: Data from Biad SK, Rubino D, Sinaii N, Ramsey S, Frank A,
Nieman LK. Specicity of screening tests for Cushing’s syndrome in an
overweight and obese population. J Clin Endocrinol Metab.
2009;94:3857–3864.
Figure 11–4 Hypothalamus Pituitary Adrenal Axis.
Adrenocorticotropic hormone (ACTH), as its name implies, stimulates the adrenal cortex. More specically, it stimulates secretion of glucocorticoids, such as
cortisol, and has little control over secretion of aldosterone, the other major steroid hormone from the adrenal cortex. ACTH is secreted from the anterior
pituitary in response to corticotropin-releasing hormone (CRH) from the hypothalamus. CRH is secreted in response to many types of stress. CRH itself is
inhibited by glucocorticoids/cortisol, making it part of a classical negative feedback loop.
CORTISOL INHIBITS CRH
Chapter 11: Endocrine Disorders 149
(ACTH)(Figure11–4).Dr.HarveyCushingrstdescribeda
womanwithsignsandsymptomsofthisdiseasein1912.He
laterprovedthattheadrenaloverproductionofcortisolwas
causedbyanabnormalityinthepituitary(Figure 11–5).
32
The term Cushing’s disease has also been extended to
includeotherconditionsthathaveprimaryadrenaldisease
or an ectopic (nonpituitary) ACTH-secreting neoplasm.
29
Althoughitislesscommon,Cushing’ssyndromehasseveral
other possiblecauses,such as polycystic ovary syndrome
(androgenexcess fromthe ovaries),ovarian tumors, con-
genitaladrenalhyperplasia,ordinaryobesity,excessivealco-
holconsumption,orafamilytendencytohavearoundface
andabdomenwithhypertensionandhyperglycemia.
31
MostcasesofCushing’ssyndromeareduetoexogenous
glucocorticoids;noniatrogenicCushing’sdisorderisuncom-
mon.Theannualincidenceof endogenousCushing’ssyn-
dromeintheUnitedStatesrangesfrom5to25casesper
millionpeople.Ofthesecases,approximately70percentare
duetoCushing’sdisease(i.e.,apituitaryACTH-producing
tumor);15percenttoectopicACTH;and15percenttoa
primaryadrenaltumor.
29,31
PituitaryCushing’sdiseaseusu-
allypresentsafterpubertywithequaloccurrenceinmales
andfemales.Inadults,thefrequencyisgreaterinwomen
thanmen,withmostfoundfromages25to45years.
31
Estimatesof70percentandupto85percentofpatients
withendogenousCushing’sdiseasearefoundtohaveapitu-
itarytumorthatproducesexcessiveACTH.Mostpituitary
tumors are microadenomas.
31
In patients with adrenal
Cushing’sdisease,themajorityarefoundtohaveunilateral
adrenocorticalneoplasms. EctopicACTHproduction can
bearesultofanonadrenaltumor,mostofwhicharesmall-
cellcarcinomasofthelung.TheseleadtoexcessACTHand
cortisolproduction.Ectopiccorticotropin-releasingfactor
(CRF) is also a cause of Cushing’s syndrome. CRF is a
hypophysiotropic hormone that stimulates secretion of
ACTHfromthepituitarygland.
32
Signs, Symptoms, and Diagnosis
TherearefourfeaturesthataremostsuggestiveofCushing’s
disease:facialplethora(orround,red,andfullfacialfeatures,
calledmoonface),muscleweaknesswithproximalmyopa-
thyand atrophy,susceptibilitytobruising,andabdominal
redpurplestriaethataregreaterthan1cmwide.
2,3
The diagnosis of Cushing’s disease usually requires
three steps:
1. Thedisordermustbesuspectedonthebasisofthe
patient’ssymptomsandsigns.Exogenoussourcesof
cortisol mustberuledout.
2. Thepresenceofexcessiveendogenouscortisolmust
bedocumented:
a. Urine-freecortisol(atleasttwomeasurements)
b. Late-nightsalivarycortisol(twomeasurements)
c. One milligram overnight dexamethasone sup-
pressiontest(DST)
Figure 11–5 Anatomy of hypothalamus-pituitary adrenal axis.
Hypothalamus
CRH
Pituitary Glands
Adrenal Glands
Cortisol
ACTH

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