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The ACTH test in the diagnosis of hirsutism


Academic year: 2017

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M a rc o F á b io P ra ta L im a , M á rc ia G a s p a r N u n e s , C lá u d io E m ílio B o n d u k i, M a u ro A b i H a id a r, .G e ra ld o R o d rig u e s L im a , E d m u n d C h a d a B a ra c a t

The A CTH test in the diagnosis of hirsutism

Department ofGynecology - Escola Paulista de Medicina - Federal University of São Paulo - São Paulo Brazil

T h e A C T H te s t h a s b e e n u s e d to c o n firm th e d ia g n o s is o f a d re n a l in s u ffic ie n c y a n d th e c la s s ic a n d th e n o n c la s s ic a d re n a l h y p e rp la -s ia d u e to th e 3 -H S D , 2 1 O H e 1 1 O H d e fic ie n c ie -s . T h i-s a rtic le re v ie w -s th e h i-s to ric a l a -s p e c t-s o f th e u -s e o f A C T H in th e d ia g n o -s i-s o f h irs u tis m a n d p o in ts o u t its m a in s in d ic a tio n s . In s p ite o f n e w b io lo g ic a l m o le c u la r a d v a n c e s in th e d ia g n o s is o f a d re n a l e n z y m a tic d e fic ie n c ie s , th e u s e o f th e A C T H te s t c a n h e lp th e p h y s ic ia n to p re d ic t b o th g e n o th ip u s a n d fe n o th ip u s in p o p u la tio n s w ith h y p e ra n d ro g e n ic m a n ife s ta tio n s d u e to n o n -c 1 a s s ic a l o r la te -o n s e t c o n g e n ita l a d re n a l h y p e rp la s ia .

U N IT E R M S : A C T H , d ia g n o s is , h irs u tis m ,.a d re n a l h y p e rp la s ia


H is to ric a l a s p e c ts


ince the introductionof pituitary adrenocorticotropinof the test involvinghorm one (A C T H )infusion

in 1948, Iclinicians and gynecologists in general

have been using the m ethod to evaluate adrenal function

in patients suspected of having adrenal insufficiency or

congenital adrenal hyperplasia.

A s far as the gynecological aspects are concerned,

clinicians m ust be alert to the interpretation of the test;

recent publications point out that patients w ith congenital

adrenal hyperplasia in its late-onset or non-classical form

lnay present a clinicaI picture consisting of irregular

m enses, hirsutism and other hyperandrogenic


A C T H is a physiological agent that stim ulates the

biosynthesis of the adrenal cortex layers and is directly

A d d re s s fo r c o rre s p o n d e n c e : M a rc o F á b io P ra ta L im a . R u a S ã o S e b a s tiã o , 67 -C e n tro U b e ra b a lM G - B ra z il- C E P 3 8 0 1 0 -4 3 0 ,

stim ulated by the corticotropin releasing factor (C R F) of

hypothalalnic origino T hus, the adrenal cortex is evaluated

clinically on the basis of its response to A C T I-I

adm inistration.

A t first the test w as used only for patient~ w ith adrenal

insufficiency2 and w as considered to be costly and highly

com plexo W ith the advent of cosyntropin, a synthetic

A C T H derivative that reduced alIergic phenom ena, the

test. started to be used to diagnose late-onset synthesis

deficiencies, i .e., the non-classical cases suspected of

congenital adrenal hyperplasia.

M ost reports unanim ously state that after A C T H

stim ulation, there is an im portant increase of alm ast alI

androgen precursors; for this reason, the test m ay identify

patients w ith late-onset 21-0H (21-hydroxilasis) and

11-O H deficiency (11-hydroxilasis), as w elI as 3-H SD

(3-hydroxysteroid dehydrogenasis) deficiency.3

T hus, the test started to be em ployed m ore frequently

in the late 1960s, w ith different doses and routes being


.5 T oday, the test is perform ed by intravenous infusion

of 0.25 m g A C T H I.2, folIow ed by blood collection 30 to

60 m inutes Iater. T he test can determ ine w ith precision

the glandular adrenal reserve for each horm one separately.

B y studying the relationships betw een the horm ones and

their respecti ve precursors, it is possible to determ ine

diagnostic patterns for the deficiency of enzy.m es possibly

L IM A , M .F .P .; N U N E S , M .G .; B O N D U K I, C .E . e t a I. - T h e a c th te s t in th e d ia g n o s is o f h irs u tis m



involved in the etiology of hyperandrogenism, especially

3-hydroxysteroid dehydrogenase (3-HSD, 21-hydroxylase

(21-0H) and ll-hydroxylase (ll-OH).ó

Despite the established use of the test, the literature

is not unanimous about its indication. CHETKOW ISKI et

aI., after evaluating patients with late-onset 21-0H

deficiency, concluded that the ACTH test does not

precisely identify these patients, in addition to being

excessively costly.7



In the detection of late-onset 21-0H deficiency,

measuring 17-0H-progesterone after stimulus provides an

important source of additional information.xThe diagnosis

of this deficiency is based on the evaluation of plasma

17-OH-progesterone leveIs; however, the literature has

reported different interpretations of the testo

AZZIZ & ZACUR consider women to be carriers

when their 17-0H-progesterone leveIs exceed 1200 ng/dl

after intravenous ACTH infusion.x In contrast,

DEW AILLY et aI. suggested that patients with

170H-progesterone leveIs exceeding SOOng/dl which are reduced

by dexamethasone should not be submitted to the ACTH

stimulation test as they would be considered to have

non-classical21-0H deficiency. W hen these values are between

200 and SOO ng/dl, the patient would be considered

borderline and should be submitted to the testo Those with

leveIs of less than 200 ng/dl would not be considered to

have late-onset 21-0H deficiencyY

In the Endocrine Gynecology Sector of the

Department of Gynecology, Escola Paulista de M edicina,

Federal Unjversity of São Paulo, we use the NEW

nomogram to evaluate these patients. W ith respect to

11-OH deficiency, which is much lnore rare, measurement of

compound S basely and after ACTH is also helpful for

diagnosis. There are no clear criteria to identify these


To evaluate 3-HSD activity, the diagnostic criteria

most frequently employed were those proposed by PANG

et aI., i.e.: 1. post-stimulus 17-0H-pregnenolone leveIs two

standard deviations above the leveIs detected in normal

women (S 170H-P>1639 ng/dl OI'49.2 nmol/I); 2.

post-stimulus DHEA leveIs two standard deviations above the leveIs observed in normal women (DHEA> 1818 ng/dl 01'

63.1 nmoll1); 3. 170H-pregnenolone/170H-progesterone

ratio two standard deviations above the values detected in

normal women C170H-progesterone>6.4); and 4.

170H-pregnenolone/cortisol ratio two standard deviations above

normal values (170H-pregnenolone/cortisol>S2).'o

Although these diagnostic criteria are widely

accepted, they are not unanilnously endorsed. GIBSON

et aI. used pregnenolone measurements,11 whereas LOBO

& GOEBELSM AN used a standardized DHEA-S

Ineasurelnent as a criterion.12 Other authors have

emphasized the DHEA/androstenedione ratio,5 whereas

REDM OND et aI. prefer the use of urinary Inetabolites.13

The tretacosatide depot (ACTH-depot) forms a

complex with zinc hydroxide when used in the

intramuscular form, with a slow and chronic .ACTH release

for a period of no less than 36 to 48 hours. Clinically, it is

used in situations in which it is desirable to increase seruln cortisollevels. Like intravenous ACTH, it cau also be used

to diagnose adrenal synthesis deficiencies due to the more

potent and prolonged stimulus it provides for the three

adrenal layers, chronically depleting their production.

PRATA LIM A, in a study of the effect of ACTH on

nonnal W Olnen and women with idiopathic hirsutisln,

suggested criteria for the diagnosis of 3-HSD deficiency

after detecting a considerable increase in the hormones of

the fasciculated Iayer and a significant elevation of

. peripheral androgens such as S-DHEA and testosterone,

a fact that is not observed when intravenous ACTH is



Today, some reports tend to disregard the ACTH testo

There are two reasons behind this attitude. The first has to

do with the fact that 21-0H deficiency, by being linked to

the HLA system, would not require the test but simply an

anaIysis ofthese histocompatibility antigens. However, the

cost of, and difficuIt access to this procedure are not taken

into consideration. BARNES et aI. stated that the excessive

number of patients with 3-HSD deficiency reported over

the last few years should be considered with some caution

since there may be other changes in steroid Inetabolism

that simulate this defect. 15However, the fact that an

HLA-Iinked antigen for the deficiency has not yet been identified

cannot ruIe out the testo

Thus, the test using ACTH stimuIation by the

conventional method OI' use of the ACTH-depot may be of heIp in the reproductive and endocrine function of

wOlnen in general with lnenstrual and aesthetic





1 . T h o m G W , F o rsh a m P H , P ru n ty F G . A te st fo r a d re n o c o rtic a l in su ffic ie n c y : T h e re sp o n se to p itu ita ry a d re n o c o rtic o tro p ic h o rm o n e . lA M A 1 9 4 8 ;1 3 7 :1 0 0 5 -9 .

2 . Ie n k in s D , F o rsh a m P H , L a id la w IE . U se o f A C T H in th e d ia g n o sis o f a d re n a l in su ffic ie n c y . A m I M e d 1 9 5 5 ; 1 8 :3 -1 4 . 3 . P a n g S , L e n o re L S , S to n e r E . N o n sa lt-Io sin g c o n g e n ita l

a d re n a l h y p e rp la sia d u e to 3 -H y d ro x y ste ro id d e h y d ro g e n a se d e fic ie n c -y w ith n o rm a l g lo m e ru lo sa fu n c tio n . I C lin E n d o c rin o l M e ta b 1 9 8 3 ;5 6 : 8 0 8 -1 8 .

4 . Y a m a ji T , Ib a y a sh i H . P la sm a d e h y d ro e p ia n d ro ste ro n e su lfa te in n o rm a l a n d p a th o lo g ic a l c o n d itio n s. I C lin E n d o c r 1 9 6 9 ;2 9 :2 7 3 -7 8 .

5 . G rifftin g G T , A lle n I, P r':ltt H , M e lb y IC . D isc o rd a n c e o f p la sm a D H E A -S ,D H E A , a n d c o rtiso l re sp o n se s w ith v a rio u s A C T H re g im e n s. M e ta b o lism 1 9 8 5 ;3 4 :6 3 1 -3 6 .

6 . E ld a r-G e v a T , H u rw itz A , V e c se i P , M ilw id sk y A , R o sle r A . S e c o n d a ry b io sy n th e tic d e fe c ts in w o m e n w ith la te -o n se t c o n g e n ita l a d re n a l h y p e rp la sia . N E n g l I M e d 1 9 9 0 ;3 2 3 :8 5 5 -6 3 .

7 . C h e tk o w isk i R I, D e fa z io I, S h a m o n k i I, Iu d d H L , C h a n g I. T h e in c id e n c e o f la te -o n se t c o n g e n ita l a d re n a l h y p e rp la sia d u e to 2 1 -h y d ro x y la se d e fic ie n c y a m o n g h irsu te w o m e n . I C lin E n d o c r M e ta b 1 9 8 4 ;5 8 :5 9 5 -9 8 .

8 . A z z iz R , Z a c u r H A . 2 1 -h id ro x y la se d e fic ie n c y in fe m a le h y p e ra n d ro g e n ism : S c re e n in g a n d d ia g n o sis. I C lin E n d o c rin o l M e ta b 1 9 8 9 ;6 9 :5 7 7 -8 4 .

9 . D e w a illy D , V a n ty g h e m -H a u d iq u e t M c , S a in sa rd C . C lin ic a I a n d b io lo g ic a l p h e n o ty p e s in la te -o n se t 2 1 -h id ro x y la se d e fic ie n c y . I C lin E n d o c rin o l M e ta b 1 9 8 6 ;6 3 :4 1 8 -2 3 . 1 0 . P a n g S , L e rn e r A I, S to rn e r E . L a te o n se t a d re n a l ste ro id 3

-h y d ro x y ste ro id d e h y d ro g e n a se d e fic ie n c y . A c a u se o f h irsu tism in p u n e rta l a n d n o n -p u b e rta l w o m e n . I C lin E n d o c rin o l M e ta b 1 9 8 5 ;6 0 :4 2 8 -3 9 .

Il. G ib so n M , L ,a c k ritz R , S c h iff I, T u lc h in sk y D . A b n o rm a l a d re n a l re sp o n se s to a d re n o c o rtic o tro p ic h o rm o n e in h y p e ra n d ro g e n ic w o m e n . F e rtil S te ril 1 9 8 0 ;3 3 :4 3 -4 9 . 1 2 . L o b o R A , G o e b e lsm a n n U . E v id e n c e fo r .re d u c e d 3 0 1

-h y d ro y ste ro id d e sid ro g e n a se a c tiv ity in so m e w o m e n th o u g h t to h a v e p o ly c y stic o v a ry sy n d ro m e . I C lin E n d o c rin o l M e ta b

1 9 8 1 ;5 3 :3 9 4 -4 0 0 .

1 3 . R e d m o n d G .P , B e d o c s N , S k ib in sk i C . A tte n u a te d a d re n a l h y p e rp la sia a n d o th e r a b n o rm a litie s o f ste ro id m e ta b o lism in w o m e n w ith a n d ro g e n d iso rd e rs. P ro g A b st, 7 0 th A n n u a l M e e tin g o f E n d o c rin e S o c ie ty , Iu n e , 1 9 8 8 :7 4 0 -4 5 .

1 4 . P ra ta L im a M F . A v a lia ç ã o d a a tiv id a d e d a 3 -h id ro x ie ste ró id e d e sid ro g e n a se e m m u lh e re s h irsu ta s a p ó s e stím u lo c o m A C T H -d e p o t. T e se m e stra d o - E sc o la P a u lista d e M e d ic in a -1 9 9 4 .

1 5 . B a rn e s R B , E h rm a n n D A , B rig e ll D F , R o se n fie ld R L . O v a ria n ste ro id o g e n ic re sp o n se s to g o n a d o tro p in -re le a sin g h o rm o n e a g o n ist te stin g w ith n a fa re lin in h irsu te w o m e n w ith a d re n a l re sp o n se s to a d re n o c o rtic o tro p in h o rm o n e su g g e stiv e o f 3 -h y d ro x y -5 -ste ro id d e h y d ro g e n a se d e fic ie n c y . I C lin E n d o c rin o l M e ta b 1 9 9 3 ;7 6 :4 5 0 -5 5 .

L IM A , M .F .P .; N U N E S , M .G .; B O N D U K I, C .E . e t a I. - T h e a c th te s t in th e d ia g n o s is

o f h ir s u tis m


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