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
IN T R O D U C T IO N
H is to ric a l a s p e c ts
S
ince the introductionof pituitary adrenocorticotropinof the test involvinghorm one (A C T H )infusionin 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
lnanifestations.
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
used.4
.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
1404
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
DIAGNOSTIC OF THE ENZIMATIC
DEFICIENCIES
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
patients.
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
used.14
CONCLUSIONS
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
repercussions.
1405
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o f h ir s u tis m
