Cushings disease
Frederic Castinetti*, Isabelle Morange, Bernard Conte-Devolx and Thierry Brue*
Abstract
Cushings disease, or ituitary ACT! deendent Cushings syndro"e, is a rare disease resonsible #or
increased "orbidity and "ortality$ %igns and sy"to"s o# hyercortisolis" are usually non seci#ic&
obesity, signs o# rotein 'asting, increased blood ressure, variable levels o# hirsutis"$ Diagnosis is
#re(uently di##icult, and re(uires a strict algorith"$ First-line treat"ent is based on transshenoidal
surgery, 'hich cures )*+ o# ACT!-secreting "icroadeno"as$ The rate o# re"ission is lo'er in
"acroadeno"as$ ,ther theraeutic "odalities including anticortisolic drugs, radiation techni(ues or
bilateral adrenalecto"y 'ill thus be necessary to avoid long-ter" ris-s ."etabolic syndro"e,
osteoorosis, cardiovascular disease/ o# hyercortisolis"$ This revie' su""ari0es otential
athohysiological "echanis"s, diagnostic aroaches, and theraies$
Disease na"e and synony"s
Cushings disease, corticotroh adeno"a, ituitary deendent Cushings syndro"e$ Chronic
glucocorticoid excess, or Cushings syndro"e, "ay be due to ACT!-deendent .)*+ cases/ or
indeendent .1*+ cases/ causes .Table 2/$ The latter are "ainly due to benign .3*+/ or "alignant .4*+/
adrenal tu"ors$ ACT! overroduction "ay be o# ituitary origin .)5+ cases/ or result #ro" ectoic tu"or
secretion .25+ cases/$ The ter" Cushings disease is seci#ically alied to ACT!-secreting ituitary
tu"ors$ Cushings disease, #irst described by !arvey Cushing in 2671, reresents the "ost #re(uent
cause o# Cushings syndro"e 829$ Cushings disease is de#ined by Adrenocorticotroin hor"one .ACT!/
hyersecretion, induced by a corticotroh adeno"a, and leading to cortisol hyersecretion .associated
'ith androgens hyersecretion/$
:ide"iology
The incidence o# Cushings syndro"e is esti"ated to be e(ual to 2;7 cases er "illion inhabitants er
year, 'hereas its revalence is close to 4* cases er "illion inhabitants$ ,# note, revalence o#
hyercortisolis" is thought to be e(ual to 1-5+ o# atients 'ith oorly controlled diabetes and
hyertension$ Fe"ale reonderance is generally assu"ed to be close to 7&2 819$ Cushings disease is an
extre"ely rare condition in children, 'ith a ea- in adults in the 7rd or 4th decade$ Cushings disease leads
to death i# untreated< it is resonsible #or increased "orbidity and "ortality, due to
cardiovascular co"lications, in#ections and sychiatric disturbances 87,49$
Clinical and biological characteristics
Clinical characteristics
!yercortisolic state "ay include several clinical signs 85,39
; ,besity& obesity 'ith centrietal #at deosition .#ace, suraclavicular and dorso-cervical #at ads/, #acial
lethora, rounded #ace, bu##alo-hu"
; %igns o# rotein 'asting& thin s-in, abdo"inal urle to red and 'ide cutaneous striae .abdo"en,
#lan-s,breasts, his, axillae/, easy bruising, slo' healing, "uscle 'asting .lo'er li"bs "uscle atrohy/
; Bone 'asting leading to osteoorosis .ossibly leading to #ractures/
; !igh blood ressure
; I"aired i""une de#ense "echanis"s 'ith increased rate o# in#ections
; =onadal dys#unction and hyerandrogenis"& hirsutis" ."ore #re(uently on the #ace/, "enstrual
irregularity .oligoa"enorrhea, a"enorrhea/
; Mild to severe sychic [Link], deression, irritability$ $ $/
The "ost #re(uent sign is obesity& abnor"al #at distribution is considered as the "ost sensitive sign 8>9$
:vidence o# rotein 'asting .osteoorosis, "yoathy/ is the "ost seci#ic sign$ Con?unction o# both
should theoretically allo' to distinguish bet'een hyercortisolis" and si"le obesity$ !o'ever, the
severity o# hyercortisolis" can be highly variable, 'hich #re(uently "a-es the diagnosis di##icult$
Moreover, hyersecretion ro#iles can be cyclical, leading to very "odest henotyic signs in so"e
atients .subclinical Cushings syndro"e/8)9$ In "ost cases, diagnosis deends on a high index o#
susicion, rather than a #lorid clinical henotye$ ,# note, none o# the signs can allo' to di##erentiate
Cushings disease #ro" any other etiology o# hyercortisolis", excet in case o# tu"or related sy"to"s
such as headaches or visual #ield de#ect .in "acroadeno"as/$
Biological characteristics
@on-seci#ic biological signs "ay include hyo-ale"ia and i"aired glucose tolerance or diabetes$ Blood
count "ay sho' increased he"oglobin, increased neutrohils and decreased ly"hocytes or eosinohils$
:tioathogenesis
Characteristics o# corticotroh adeno"as Cushings disease is #re(uently due to "onoclonal benign and
slo' gro'ing "icroadeno"as .less than 2* ""/ 86,2*9$ Alas"a ACT! .and cortisol/ classically lose their
hysiologic circadian eriodicity$ They are artially resistant to hysiologic sti"uli .i$e$, glucocorticoids/,
and do not resond to the nor"al #eedbac- negative loo$ In contrast, corticotroh adeno"as are
inaroriately sensitive to CB! and ACA$ Altered CB! secretion as 'ell as A,MC (ualitative changes
in gene exression 'ere also reorted to be involved in the athogenesis o# Cushings disease$ Cushings
disease can be "ore atyical& secretion ro#iles are so"eti"es cyclic, 'ith hyersecretion receding a
long eriod o# nor"al secretion8),229$ %o"e corticotroh adeno"as are called DsilentE as they are
clinically and biologically co"arable to non-secreting ituitary adeno"as& diagnosis is "ade by the
athologist 8219$ Finally, rare cases o# aggressive ituitary adeno"as or carcino"as have been
reorted8279$ Fhether hyerlasia o# corticotroh cells is or not a re(uired initial ste be#ore the genesis
o# corticotroh adeno"a re"ains a "atter o# debate$ The origin o# the disease, ri"ary ituitary condition
or secondary to an abnor"ality in the hyothala"us .chronic sti"ulation by CB! 8249/, re"ains a "atter
o# debate$ =enetic redisosition Cushings disease can be art o# Multile :ndocrine @eolasia Tye 2,
due to "utations o# the "enin gene$ It is a rare syndro"e, trans"itted in an autoso"al do"inant "anner,
'hich associates hyerarathyroidis", endocrine tu"ors, and ituitary adeno"as in 1*-5*+ cases$ Most
o# these are so"atotroh or lactotroh, but corticotroh adeno"as have been described in 5-2*+ o#
cases$ AIA .Aryl hydrocarbon recetor Interacting Arotein/ "utations have been reorted in #a"ilial
ituitary adeno"as& secretion ro#ile is usually so"atotroh or lactotroh, 'hereas very rare cases o# CD
have also beenreorted 8259$ Aotentially involved "olecular "echanis"s Triggering signals leading to
Cushings disease re"ain unclear$ ,ncogenes do not aear to be involved, as so"atic "utations are
usually not resent in corticotroh adeno"as cells$ Becent studies in "ice identi#ied a otential role o#
loss o# #unction o# Brg2 .brah"a-related gene 2/ and !DAC1 .!istone Deacetylase 1/ in the athogenesis
o# Cushings disease$ Both roteins #or" a co"lex 'ith the glucocorticoid recetor and the orhan
nuclear recetor nuclear gro'th #actor IB .@=FI-B/ to reress A,MC secretion$ Interestingly, about 5*+
o# corticotroh adeno"as do not exress these roteins any"ore$ The loss o# Brg2 could lead to
overexression o# cyclin :, leading to increased cell roli#eration and soradic hyerlasia or tu"ors$
Interestingly, tu"ors 'ith a loss o# nuclear locali0ation o# Brg2 see" to be "ore resonsive to
anticortisolic drugs in vitro co"ared to the ones 'ith a co"lete loss o# Brg2 oncogene 823,2>9$
Transcrition #actors involved in rogenitors roli#eration and di##erentiation during ituitary
e"bryogenesis could also be involved in ituitary tu"origenesis$ TAIT de#iciency is -no'n to result in
congenital isolated corticotroh de#iciency$ Aatients 'ith other ituitary transcrition #actors "utations
.AB,A2, G!H7, G!H4, !:%H2/ usually resent co"bined ituitary hor"one de#iciencies including
inconstant corticotroh de#iciency$ As so"e o# these #actors are still exressed at adult age, and their role
is not recisely -no'n, it could be te"ting to seculate on otential roles o# an overexression o# these
roteins in ituitary adeno"as ontogenesis$ !o'ever, to our -no'ledge, no "utation o# any locali0ation o#
Brg2 see" to be "ore resonsive to anticortisolic drugs in vitro co"ared to the ones 'ith a co"lete
loss o# Brg2 oncogene 823,2>9$ Transcrition #actors involved in rogenitors roli#eration and
di##erentiation during ituitary e"bryogenesis could also be involved in ituitary tu"origenesis$ TAIT
de#iciency is -no'n to result in congenital isolated corticotroh de#iciency$ Aatients 'ith other ituitary
transcrition #actors "utations .AB,A2, G!H7, G!H4, !:%H2/ usually resent co"bined ituitary
hor"one de#iciencies including inconstant corticotroh de#iciency$ As so"e o# these #actors are still
exressed at adult age, and their role is not recisely -no'n, it could be te"ting to seculate on
otential roles o# an overexression o# these roteins in ituitary adeno"as ontogenesis$ !o'ever, to our
-no'ledge, no "utation o# anytranscrition #actor has ever been identi#ied in atients resenting 'ith
corticotroh adeno"as 82),269$
Diagnosis
Diagnosis o# Cushings disease is di##icult 81*9$ Clinical signs and sy"to"s are o#ten non-seci#ic< no
single biological test co"bines oti"al sensitivity and seci#icity #or the diagnosis o# hyercortisolis" and
#or the deter"ination o# its etiology 8129$ Moreover, ituitary and adrenal i"aging can so"eti"es be
con#using$ %everal stes are needed to #irst con#ir" the diagnosis o# hyercortisolis" and then deter"ine
its origin& the #irst 'ill be to con#ir" the lac- o# exosure to exogenous glucocorticoids that induces the
sa"e clinical characteristics as Cushings syndro"e and "a-es hyercortisolis" screening unavailable
8119$ In nor"al sub?ects, cortisol levels reach a ea- at early "orning and a nadir I5* n"olJl around
"idnight$ Aatients 'ith Cushings syndro"e lose this circadian rhyth"$ As a conse(uence, early "orning
ACT! and cortisol values are o# oor diagnostic value in the screening "ethods o# hyercortisolis"$ In
contrast a "idnight cortisol valueK1** n"olJl is strongly suggestive o# Cushings syndro"e 8179$
:valuation o# the circardian rhyth" o# cortisol is ho'ever not reco""ended as a #irst line screening
"ethod #or hyercortisolis"$ Fe 'ill not detail recisely all "ethods and tests roosed to con#ir" a
diagnosis o# hyercortisolis" .or Cushings syndro"e, C%/& these criteria have been 'idely described in
recent consensus con#erences83,149$ First line screening "ethods should include either ; 14-hour urinary
#ree cortisol, reeated at least t'ice< values should be above 11*;77* n"olJ14 h deending on the
assays, in Cushings syndro"e, -eeing in "ind that nor"al values can be seen in )-25+ o# atients 'ith
Cushings syndro"e 8159 ; cortisol resonse to 2 "g-overnight dexa"ethasone suression test& cortisol
valueI5* n"olJl .I 1 !gJdl/ excludes Cushings syndro"e 'ith high sensitivity .65+/ but lo' seci#icity
8139$ ; cortisol resonse to lo' dose dexa"ethasone suression test .*$5 "g dexa"ethasone every 3
hours during 4) hours/& cortisol valueI5* n"olJl .I 1 !gJdl/ excludes Cushings syndro"e 'ith a
sensitivity and seci#icity close to 2**+ 81>9$ ; or late night salivary cortisol 815,1),169 & a cortisol valueK1
ngJ"l .5$5 n"olJl/ has a 2**+ sensitivity and 63+ seci#icity #or Cushings syndro"e 87*9$ Aseudo
Cushings syndro"e is de#ined by the resence o# artial clinical signs o# hyercortisolis"$ It can be
induced by chronic alcohol consu"tion, deression and obesity$ Diagnosis bet'een Cushings
syndro"e and seudo Cushings syndro"e "ight be di##icult desite the use o# reviously described
screening "ethods 839$ CB! in?ection couled 'ith dexa"ethasone suression test, is in #avor o#
Cushings syndro"e 'ith 6*+ sensitivity and )4+ seci#icity in the resence o# ea- cortisol K5)* n"olJl
and ACT!K5* gJ"l 8729$ %tes #or ositive diagnosis o# Cushings syndro"e are su""ari0ed in Figure
2$Fhen the resence o# C% is con#ir"ed, diagnosis aroach 'ill deter"ine i# the secretion is ACT!-
deendent or not$ :arly "orning undetectable ACT! levels .I 2* gJ "l/ 'ill lead to a diagnosis o# ACT!
indeendent hyercortisolis" .autono"ous adrenal hyersecretion/, 'hereas inaroriately nor"al or
increased levels .K 2* gJ"l/ 'ill be in #avor o# an ACT!-deendent hyercortisolis"$ ACT! deendent
C% includes Cushings disease .CD/ and, "ore rarely, ectoic ACT! secretion .:A%/ 8719$ Distinction
bet'een both is di##icult, and #re(uently re(uires the use o# several diagnostic "ethods 8779&
; high dose dexa"ethasone suression test .) "gJday during 1 days/& a decrease o# "ore than 5*+
urinarycortisol level is observed in 6*+ o# atients 'ith CD,co"ared 'ith less than 5*+ o# those 'ith
:A%$ ,# note, "ore than 6*+ suression o# urinary cortisol has 2**+ seci#icity in the diagnosis o#
Cushingsdisease 819$
; CB! test .2** !g intra-venously/& "ore than 5*+ ACT! and 1*+ cortisol increase is in #avor o#
Cushings disease$ %ensitivity and seci#icity are close to 6*+ 8749$
; Des"oressin test .2* !g intravenously/, ACT! and cortisol increases si"ilar to those observed 'ith
the
CB! test are in #avor o# CD 'ith >*+ sensitivity and )5+ seci#icity 81*,759 Concordant resonses to at
least 1J7 o# these tests should lead to the diagnosis o# Cushings disease, and ituitary MBI$ !o'ever, the
sensitivity o# MBI in CD is hardly greater than 3*->*+ and seci#icity close to )5+, as "ost corticotroh
adeno"as are "icroadeno"as$ In one study, 2*+ o# the general oulation resented MBI ituitary
i"ages o# less than 5 "" that "ight be considered as adeno"as 8739$ Cushings disease diagnosis is
hus con#ir"ed in the resence o# an adeno"aK3 "" and concordant resonses to tests$ In the lac- o# an
i"age suggesting a ituitary adeno"aon MBI desite dyna"ic tests in #avor o# CD, or in case o#
discordant tests, bilateral intra-etrosal sinus sa"ling .sti"ulated by CB! or des"oressin/ should be
er#or"ed& it 'ill give a de#inite ans'er to con#ir" the etiology o# ACT! deendent C%$ The rincile is to
"easure a ratio de#ined by central ACT!Jeriheral ACT!$ A central to eriheral las"a ACT! ratio
exceeding 1 .or 7 a#ter sti"ulation by CB!/ is in #avor o# Cushings disease87>-4*9 $In case o# ACT!
deendent hyercortisolis", i# the initial etiologic 'or-u is not in #avor o# a ituitary origin,
co"le"entary "orhologic investigation including to"odensito"etric 'hole body exa"ination should be
er#or"ed$ %o"e tea"s re#er to er#or" syste"atically a thoraco;abdo"ino-elvic scan in each atient
'ith ACT! deendent Cushings syndro"e, 'hatever the status o# tests and MBI$ The li"it o# this
aroach is identical to the one reorted 'ith ituitary MBI, as so"e atients "ight have bronchial
incidentalo"as not resonsible #or ectoic ACT! secretion, and leading to a "isdiagnosis 8779$ %tes
necessary #or the etiological diagnosis o# ACT! deendent Cusgings syndro"e are su""ari0ed in
Figure 1$
Di##erential diagnosis
; Chronic exogenous ad"inistration o#glucocorticoids
; Aseudo-Cushing states as described reviously
; ACT! deendent Cushings syndro"e& :ctoic ACT! secretion .see above/
; ACT! indeendent Cushings syndro"e 'ill be ruled out by inaroriately nor"al or increased ACT!
levels$
; Functional hyercortisolis" during regnancy
Clinical "anage"ent Transshenoidal surgery is the #irst line treat"ent o# Cushings disease842,419$ It
allo's re"ission in 3* 6*+