C la u d ia d e C a rva lh o R a m o s B o rto le tto , E d m u n d C h a d a B a ra ca t, W a g n e r Jo se G o n 9 a lve s, Jo a o N o rb e rto S ta va lle , G e ra ld o R o d rig u e s d e L im a , N e e l F e rre ira N o vo
T h e p ro g e s to g e n c h a lle n g e te s t in p o s tm e n o p a u s a l w o m e n :
C lin ic a l a n d m o rp h o lo g ic a s p e c ts
Discipline
of Gynecology, Escola Palliista de Medicina,
Universidade Federal de Silo Pallio - Silo Palllo, Brazil
T h e c lin ic a l a s p e c t s a n d a n a t o m o p a t h o lo g ic a l p a t t e r n s o f 1 5 0 p o s t m e n o p a u s a l w o m e n w e r e s t u d ie d u s in g t h e p r o g e s t o g e n c h a lle n g e t e s t . A n e n d o m e t r ia l b io p s y w a s o b t a in e d a n d s u b m it t e d t o t h e p r o g e s t o g e n t e s t . A h is t o p a t h o lo g ic a l a n a ly s is o f t h e u t e r in e m u c o s a f r o m w o m e n w it h a p o s it iv e p r o g e s t o g e n t e s t r e v e a le d t h a t t h e e n d o m e t r iu m w a s a c t iv e in 4 4 p e r c e n t o f c a s e s a n d a t r o p h ic o r in a c t iv e in 5 6 p e r c e n t . I n c o n t r a s t , a m o n g w o m e n w it h a n e g a t iv e r e s p o n s e , t h e e n d o m e t r iu m w a s a t r o p h ic in 9 4 p e r c e n t o f c a s e s a n d a c t iv e in 6 p e r c e n t . A n a ly s is o f c lin ic a l a s p e c t s d id n o t s h o w s ig n if ic a n t d if f e r e n c e s b e t w e e n g r o u p s in t e r m s o f a g e ; a g e a t m e n a r c h e a n d a t m e n o p a u s e ; f a s t in g b lo o d g lu c o s e le v e ls ; o r b o d y m a s s . H o w e v e r , p o s t m e n o p a u s a l t im e w a s s ig n if ic a n t ly s h o r t e r f o r w o m e n w it h a p o s it iv e t e s t , w it h a c o r r e la t io n b e t w e e n p o s t m e n o p a u s a l t im e o f o n e t o t w o y e a r s a n d t e s t p o s it iv it y . T h e p r o g e s t o g e n c h a lle n g e t e s t f o r t h e d e t e c t io n o f a t r o p h ic e n d o m e t r iu m p r e s e n t e d 7 8 . 5 7 p e r c e n t s e n s it iv it y , 7 7 . 0 5 p e r c e n t s p e c if ic it y , 4 4 p e r c e n t p o s it iv e p r e d ic t iv e v a lu e , a n d 9 4 p e r c e n t n e g a t iv e p r e d ic t iv e v a lu e . T h u s , w h e n n e g a t iv e , t h e t e s t is h ig h ly v a lu a b le , in d ic a t in g t h e p r e s e n c e o f a t r o p h ic e n d o m e t r iu m in 9 4 p e r c e n t o f c a s e s . F a ls e - n e g a t iv e r e s u lt s o c c u r r e d in o n ly 6 p e r c e n t o f t h e s u b je c t s , w it h n o c a s e o f h y p e r p la s ia d e t e c t e d . H o w e v e r , w h e n t h e r e s p o n s e t o t h e t e s t w a s p o s it iv e , t h e e n d o m e t r iu m w a s a t r o p h ic in 5 6 p e r c e n t o f t h e c a s e s . W e s u g g e s t t h a t , in o r d e r t o a v o id in v a s iv e p r o c e d u r e s , t h e p r o g e s t o g e n c h a lle n g e t e s t b e c o m b in e d w it h o t h e r m e t h o d s s u c h a s t r a n s v a g in a l u lt r a s o n o g r a p h y .
U N I T E R M S : E n d o m e t r iu m . P r o g e s t e r o n e . M e n o p a u s e .
I N T R O D U C T I O N
A
c c o r d i n gt h e c l i m a c t e r i ct o t h ei s d e f i n e dI n t e r n a t i o n a la s t h e t r a n s i t i o nM e n o p a u s e b e t w e e nS o c i e t y , t h e p e r i o d o f g r e a t e s t r e p r o d u c t i v e c a p a c i t y ( m e n a c m e ) a n d o l d a g e .1 .2W i t h i m p r o v e d s o c i o - e c o n o m i c c o n d i t i o n s w o r l d w i d e , a r e l a t e d i n c r e a s e i n p o p u l a t i o n l o n g e v i t y h a s o c c u r r e d . C o n s e q u e n t l y a g r e a t e r n u m b e r o f w o m e n h a v e r e a c h e d c l i m a c t e r i c . T h u s , 9 0 p e r c e n t o f t h e N o r t h A m e r i c a n f e m a l e p o p u l a t i o n n o w r e a c h e s m e n o p a u s e , w i t h a m e a n l i f e e x p e c t a n c y o f 8 0 y e a r s . T h e m e a n a g e a tA d d re s s fo r c o rre s p o n d e n c e :
C la u d ia d e C a rva lh o R a m o s B o rto le tto R u a H e n riq u e M a rtin s, 4 8 3 -Ja rd im P a u lista S a o P a u lo /S P - B ra sil - C E P 0 4 5 0 4 -0 0 0
o n s e t o f m e n o p a u s e i s 5 1 .4 y e a r s , i n d i c a t i n g t h a t w o m e n w i l l h a v e a p p r o x i m a t e l y 3 0 y e a r s o f l i f e a f t e r m e n o p a u s e .3
I f t h e t r e n d i s t h a t w o m e n w i l l s p e n d a p p r o x i m a t e l y 3 0 p e r c e n t o f t h e i r l i f e i n a p o s t m e n o p a u s a l c o n d i t i o n , o c c u r r e n c e s d u r i n g t h i s p e r i o d w i l l d i r e c t l y a f f e c t t h e i r q u a l i t y o f l i f e . W i t h f u r t h e r d e v e l o p m e n t s i n t h e f i e l d o f m e d i c i n e , t h e r e i s t h e p o s s i b i l i t y o f e n s u r i n g a b e t t e r q u a l i t y o f l i f e f o r p o s t m e n o p a u s a l w o m e n .
M a n y s t u d i e s h a v e b e e n c o n d u c t e d o n t h e a u x i l i a r y m e t h o d s o f t r e a t m e n t d u r i n g m e n o p a u s e , e s p e c i a l l y i n t e r m s o f t h e i n v e s t i g a t i o n o f t h e u t e r i n e m u c o s a , a n i m p o r t a n t s i t e o f p r e c a n c e r o u s a n d c a r c i n o m a t o u s l e s i o n s . R e g r e s s i v e h i s t o l o g i c a l p a t t e r n s a r e p r e p o n d e r a n t d u r i n g t h e p o s t m e n o p a u s a l p e r i o d a s a d i r e c t r e s u l t o f t h e f a l l i n e s t r o g e n l e v e l s ; 1 .4 c a n c e r o f t h e e n d o m e t r i u m i s c o n s i d e r e d t o b e a d i s e a s e p r e d o m i n e n t a m o n g p o s t m e n o p a u s a l w o m e n , w i t h a f r e q u e n c y o f 8 0 p e r c e n t d u r i n g t h i s p e r i o d .s
s a o P a u lo M e d ic a l J o u r n a l/ R P M 1 1 4 ( 3 ) : 1 1 6 6 - 1 1 7 2 , 1 9 9 6 B O R T O L E T I O , C . C . R . ; B A R A C A T , E . C . ; G O N < ; : : A L V E S , W . J . ; s T A v A L L E , J . N . ; L I M A , G . R .
M a n y p ro c e d u re s h a v e b e e n u se d to d e te rm in e th e
re a l sta tu s o f th e u te rin e m u c o sa in m e n o p a u sa l w o m e n .
D u rin g th e la st d e c a d e , th e e n d o m e tria l b io p sy h a s b e e n
re c o g n iz e d a s a u se fu l a n d e ffe c tiv e te c h n iq u e . A s it is
c a rrie d o u t in th e la b o ra to ry , c a u sin g little p a tie n t
d isc o m fo rt a n d o ffe rin g h ig h d ia g n o stic a c c u ra c y , th e
p ro c e d u re h a s p e rm itte d a d ra stic re d u c tio n in th e n u m b e r
o f c u re tta g e s a n d h a s o p tim iz e d g y n e c o lo g ic a l
a p p ro a c h e s. 6 .7
T h e c o st o f a n e n d o m e tria l b io p sy is a p p ro x im a te ly
1 0 tim e s le ss th a n th a t o f u te rin e c u re tta g e , a n d th e
p ro c e d u re in v o lv e s a lo w e r su rg ic a l risk a n d p ro v id e s
a c c u ra c y ra n g in g fro m 9 5 to 9 8 p e rc e n t w h e n c o m p a re d
to c u re tta g e o r o th e r su rg ic a l p ro c e d u re s. IIIA b io p sy ,
h o w e v e r, is still a n in v a siv e te c h n iq u e .
T h e re a re still o th e r n o n -in v a siv e m e th o d s th a t h a v e
b e e n u se d to stu d y th e u te rin e m u c o sa . A m o n g th e m is
th e p ro g e ste ro n e c h a lle n g e te st o r th e te st u sin g sy n th e tic
p ro g e sto g e n s. In 1 9 8 0 , G A M B R E L L e t a l. u tiliz e d a n d
d e fin ite ly sa n c tio n e d th e u se o f th e te st fo r m e n o p a u sa l
w o m e n . T h e y a p p lie d th e te st to 5 2 6 3 p o stm e n o p a u sa l
w o m e n in o rd e r to id e n tify p a tie n ts a t risk fo r d e v e lo p in g
h y p e rp la sia a n d c a rc in o m a o f th e e n d o m e triu m . W h e n
g e n ita l b le e d in g o c c u rre d , th e y re p e a te d th e p ro g e sto g e n
te st m o n th ly fo r a v a ry in g p e rio d o f tim e u n til th e te st
b e c a m e n e g a tiv e . A m o n g w o m e n n o t su b m itte d to
h o rm o n a l tre a tm e n t, a p p ro x im a te ly 3 5 p e rc e n t e x p e rie n c e d
b le e d in g in re sp o n se to th e te sty .lo
L a te r, H A N N A e t a l. (1 9 8 3 ) a d m in iste re d o ily
p ro g e ste ro n e in tra m u sc u la rly in 1 0 0 m g d o se s to 3 0
p o stm e n o p a u sa l a n d a sy m p to m a tic w o m e n , 1 0 o f w h o m
w e re u sin g e q u in e -c o n ju g a te d e stro g e n s. T h e y h a d
p re v io u sly o b ta in e d a n e n d o m e tria l b io p sy fro m e a c h
w o m a n fro m th e fo u r q u a d ra n ts u sin g a N o v a k c u re tte .
F iv e re sp o n d e d to th e te st w ith b le e d in g ; o f th e se p a tie n ts,
th re e p re se n te d e n d o m e tria l h y p e rp la sia (6 0 p e rc e n t) a n d
tw o a tro p h ic e n d o m e triu m (4 0 p e rc e n t). In th e se c o n d
g ro u p o f 1 0 w o m e n , k n o w n to h a v e a h y p e rp la stic u te rin e
m u c o sa , th e y o b ta in e d o n e fa lse -n e g a tiv e re su lt (1 0
p e rc e n t). T h e a u th o rs th e re fo re su g g e ste d th a t th e
p ro g e sto g e n c h a lle n g e te st b e a d d e d to th e m e d ic a l a rse n a l
fo r th e e v a lu a tio n o f c lim a c te ric w o m e n . I I
E R N Y e t a l. (1 9 8 6 ) la te r p e rfo rm e d th e p ro g e ste ro n e
te st 1 ,6 3 3 tim e s, w ith a 1 2 .8 p e rc e n t ra te o f p o sitiv e te sts.
A m o n g 1 5 6 w o m e n w ith a p o sitiv e te st su b m itte d to
c u re tta g e , th e a n a to m o p a th o lo g ic a l fin d in g s re v e a le d a n
a tro p h ic e n d o m e triu m in 7 9 (5 0 .6 p e rc e n t). In th e g ro u p
w ith n e g a tiv e te sts, o n e w o m a n h a d a d e n o c a rc in o m a o f
th e e n d o m e triu m Y O th e r re se a rc h e rs h a v e o b ta in e d 7 1 .4
p e rc e n t te st a c c u ra c y a n d re c o m m e n d e d th e u se o f th e te st
fo r a ll p o stm e n o p a u sa l w o m e n , a n d th e in v e stig a tio n o f
e n d o m e tria l h isto lo g y fo r th o se w ith a p o sitiv e re sp o n se .13
In a p io n e e rin g stu d y in B ra z il, W E H B A (1 9 8 8 )
c o m p a re d th e h isto p a th o lo g ic a l a n a ly sis o f th e
e n d o m e triu m o b ta in e d b y c u re tta g e fro m 5 0
p o stm e n o p a u sa l w o m e n w ith a p o sitiv e o r n e g a tiv e re su lt
o n th e p ro g e sto g e n c h a lle n g e te st, in o rd e r to stu d y th e
v a lu e o f th e te st in th e d e te c tio n o f h y p e rp la stic le sio n s o f
th e e n d o m e triu m . T h e a u th o r o b ta in e d 1 2 p o sitiv e re su lts
(2 4 p e rc e n t) a n d 3 8 n e g a tiv e re su lts (7 6 p e rc e n t). In th e
p o sitiv e te sts, th e e n d o m e triu m sh o w e d p ro life ra tiv e
a c tiv ity in a ll c a se s, a n d w a s h y p e rp la stic in 5 0 p e rc e n t.
W h e n th e te st w a s n e g a tiv e , th e e n d o m e triu m p re se n te d
e a rly p ro life ra tiv e a c tiv ity in o n ly 1 3 .2 p e rc e n t. In th e
re m a in in g p a tie n ts, a tro p h y w a s d e te c te d in 7 3 .7 p e rc e n t,
o r th e m a te ria l w a s c o n sid e re d in a d e q u a te in 1 3 .2 p e rc e n t.
T h is stu d y m a d e a d e c isiv e c o n trib u tio n to th e in tro d u c tio n
o f th e p ro g e sto g e n c h a lle n g e te st in B ra z il a s a ro u tin e
a p p ro a c h to th e m o n ito rin g o f p o stm e n o p a u sa l w o m e n .14
M A C IA e t a l. (1 9 9 3 ) la te r stu d ie d a sy m p to m a tic
p o stm e n o p a u sa l w o m e n n o t su b m itte d to h o rm o n a l
re p la c e m e n t. A c c o rd in g to th e se re se a rc h e rs, th e
p ro g e sto g e n c h a lle n g e te st p re se n te d 1 0 0 p e rc e n t
sp e c ific ity , a s it w a s n e g a tiv e in a ll p a tie n ts w ith a n a tro p h ic
e n d o m e triu m . In a d d itio n , se n sitiv ity w a s 7 6 p e rc e n t a s
a m o n g th e 8 9 w o m e n w ith a n e g a tiv e te st, a n d th e
e n d o m e triu m w a s p ro life ra tiv e o r h y p e rp la stic in th re e . IS
O th e rs a u th o rs o b se rv e d th a t 2 6 o f 1 8 7 a sy m p to m a tic
p o stm e n o p a u sa l w o m e n n o t su b m itte d to h o rm o n e th e ra p y
d id n o t p re se n t a tro p h y o f th e u te rin e m u c o sa . T h e te st
w a s p o sitiv e in 1 6 o f th e se p a tie n ts (6 1 .5 p e rc e n t), b u t
n e g a tiv e in 1 0 (3 8 .4 p e rc e n t). T h e se fin d in g s sh o w th a t
fa lse -p o sitiv e re su lts m a y b e o b ta in e d w ith th e p ro g e sto g e n
c h a lle n g e te st.16
H o w e v e r, fe w stu d ie s a re a v a ila b le th a t c o m p a re a
p o si ti v e o r n e g a ti v e re sp o n se to th e p ro g e sto g e n
c h a lle n g e te st w ith th e re sp e c tiv e h isto p a th o lo g ic a l
fin d in g s. T h u s, th e o b je c tiv e s o f th e p re se n t stu d y w e re
to e v a lu a te w o m e n w ith p o sitiv e a n d n e g a tiv e
p ro g e sto g e n c h a lle n g e te sts in te rm s o f a g e ; a g e a t
m e n a rc h e a n d m e n o p a u se ; d u ra tio n o f m e n o p a u se ; b o d y
m a ss in d e x ; fa stin g b lo o d g lu c o se le v e ls a n d e n d o m e tria l
h isto p a th o lo g y ; a n d to c a lc u la te th e se n sitiv ity a n d
sp e c ific ity , a s w e ll a s th e p o sitiv e a n d n e g a tiv e p re d ic tiv e
v a lu e s o f th e p ro g e sto g e n c h a lle n g e te st, w ith re sp e c t to
th e h isto lo g ic a l ty p e o f e n d o m e triu m .
P A TIE N TS A N D M E TH O D
T h e stu d y w a s c o n d u c te d o n 1 5 0 p o stm e n o p a u sa l
w o m e n se e n a t th e S e c to r o f E n d o c rin e G y n e c o lo g y a n d
B O R TO LE TTO , C .C .A .; B A R A C A T, E .C .; G O N Q A LV E S , W .J.; S TA vE LLE , J.N .; LIM A , G .R . & N O V O , N .F. - P rogestogen challenge test in postm enopausal w om en: C linical and aspects
C l i m a c t e r i c o f t h e D i s c i p l i n e o f G y n e c o l o g y , E s c o l a P a u l i s t a d e M e d i c i n a , f r o m S e p t e m b e r 1 9 9 2 t o N o v e m b e r 1 9 9 3 . A w o m a n w a s c o n s i d e r e d p o s t m e n o p a u s a l w h e n s h e w a s m o r e t h a n 4 0 y e a r s o l d , w i t h a t l e a s t o n e y e a r o f a m e n o r r h e a a n d h i g h l e v e l s o f f o l l i c l e s t i m u l a t i n g h o r m o n e ( F S H ) a n d l u t e i n i z i n g h o r m o n e ( L H ) . 1 . 1 4
T h e e x c l u s i o n c r i t e r i a w e r e a s f o l l o w s : n o n - s p o n t a n e o u s m e n o p a u s e ; p o s t m e n o p a u s a l g e n i t a l b l e e d i n g ; h o r m o n a l r e p l a c e m e n t t r e a t m e n t d u r i n g t h e c l i m a c t e r i c ; l i v e r , h e a r t , k i d n e y a n d t h y r o i d d i s e a s e ; c a n c e r o f t h e e n d o m e t r i u m o r o f t h e b r e a s t ; a n d c o n d i t i o n s t h a t w o u l d p r e v e n t t r a n s v a g i n a l u l t r a s o u n d e x a m i n a t i o n o r a n a t o m o p a t h o l o g i c a l s t u d y o f t h e e n d o m e t r i u m . E a c h p a t i e n t w a s s u b m i t t e d t o c l i n i c a l a n d h o r m o n a l e v a l u a t i o n a n d t o a n a n a t o m o p a t h o l o g i c a l e x a m i n a t i o n o f t h e e n d o m e t r i u m , a n d t h e f o l l o w i n g c l i n i c a l d a t a w a s r e c o r d e d : a g e , r a c e , m a r i t a l s t a t u s , a g e a t m e n a r c h e a n d a t m e n o p a u s e , d u r a t i o n o f m e n o p a u s e , w e i g h t , h e i g h t , a n d b o d y m a s s i n d e x . B o d y m a s s i n d e x w a s c a l c u l a t e d b y t h e w e i g h t / h e i g h t2 r a t i o .'7
E n d o m e t r i a l f r a g m e n t s w e r e o b t a i n e d w i t h a m o d i f i e d N o v a k c u r e t t e . T h e b i o p s y a l w a y s i n c l u d e d t h e a n t e r i o r , p o s t e r i o r a n d l a t e r a l w a l l s o f t h e u t e r i n e c a v i t y . T h e m a t e r i a l d e s t i n e d f o r h i s t o l o g i c a l s t u d y b y l i g h t m i c r o s c o p y w a s i m m e d i a t e l y p l a c e d i n 1 0 p e r c e n t f o r m a l i n a n d t h e n e m b e d d e d i n p a r a f f i n . B l o c k s w e r e c u t w i t h a m i c r o t o m e a d j u s t e d t o 5
/lm
t h i c k n e s s , a n d s l i d e s w e r e s t a i n e d w i t h h e m a t o x y l i n - e o s i n . T h e e n d o m e t r i u m w a s t h e n s t u d i e d m o r p h o l o g i c a l l y b y a s i n g l e e x a m i n e r .T h e m o r p h o l o g i c s t u d y w a s c a r r i e d o u t o n t h e e n t i r e e x t e n s i o n o f t h e h i s t o l o g i c a l s e c t i o n u s i n g a c o m m o n b i n o c u l a r Z e i s s m i c r o s c o p e w i t h a 1 0 x e y e p i e c e a n d o b j e c t i v e s w i t h 4 t o 1 0 0 x m a g n i f i c a t i o n .
T h e e n d o m e t r i u m w a s c l a s s i f i e d h i s t o l o g i c a l l y a s : 1 . i n a c t i v e : a t r o p h i c e n d o m e t r i u m .
2 . a c t i v e : a n y e n d o m e t r i a l p a t t e r n o t h e r t h a n a t r o p h y , i . e . , p r o l i f e r a t i v e , m i x e d , s e c r e t o r y , w i t h p o l y p s , a n d t y p i c a l o r a t y p i c a l h y p e r p l a s i a .
T h e p r o g e s t o g e n c h a l l e n g e t e s t w a s p e r f o r m e d a f t e r t h e e n d o m e t r i a l b i o p s y . M e d r o x y p r o g e s t e r o n e w a s a d m i n i s t e r e d b y t h e o r a l r o u t e a t t h e d o s e o f 1 0 m g / d a y f o r 1 0 c o n s e c u t i v e d a y s y . 1 5 . I RT h e t e s t w a s p e r f o r m e d o n l y s e v e n t o 1 0 d a y s a f t e r t h e u t e r i n e m u c o s a l b i o p s y i n o r d e r t o p r e v e n t a p o s s i b l e c o n f u s i o n b e t w e e n b l e e d i n g o c c u r r i n g n a t u r a l l y a f t e r t h e p r o c e d u r e , a n d a p o s i t i v e r e s p o n s e t o t h e t e s t . T h e t e s t w a s c o n s i d e r e d p o s i t i v e w h e n b l e e d i n g o c c u r r e d , a n d n e g a t i v e w h e n n o b l e e d i n g o c c u r r e d .
O n t h e b a s i s o f t h e p r o g e s t o g e n c h a l l e n g e t e s t , w e o b t a i n e d a g r o u p o f 5 0 w o m e n w i t h a p o s i t i v e r e s u l t ( G r o u p I ) , a n d a c o n t r o l g r o u p o f 1 0 0 w o m e n w i t h a n e g a t i v e r e s u l t
( G r o u p I I ) . T h e w o m e n w e r e a l s o c l a s s i f i e d i n t o f o u r g r o u p s a c c o r d i n g t o h o w l o n g t h e y h a d b e e n m e n o p a u s a l :
• G r o u p 1 , w o m e n w i t h a m e n o p a u s e d u r a t i o n o f o n e t o t w o y e a r s ;
• G r o u p 2 , w o m e n w i t h a d u r a t i o n o f t h r e e t o f i v e y e a r s ; • G r o u p 3 , w o m e n w i t h a d u r a t i o n o f s i x t o 1 0 y e a r s ; • G r o u p 4 , w o m e n w h o h a d b e e n m e n o p a u s a l f o r 1 1
o r m o r e y e a r s .
D a t a w e r e a n a l y z e d s t a t i s t i c a l l y b y t h e f o l l o w i n g n o n p a r a m e t r i c t e s t s , t a k i n g i n t o c o n s i d e r a t i o n t h e n a t u r e o f t h e v a l u e s o f t h e v a r i a b l e s s t u d i e d : M a n n - W h i t n e y t e s t , c h i - s q u a r e t e s tl 9 ( p < 0 . 0 5 ) , t e s t o f s p e c i f i c i t y a n d s e n s i t i v i t y ,
a n d p o s i t i v e a n d n e g a t i v e p r e d i c t i v e v a l u e .2 0 T h e l e v e l o f
s i g n i f i c a n c e w a s s e t a t 5 p e r c e n t , a n d s i g n i f i c a n t v a l u e s a r e i n d i c a t e d b y a n a s t e r i s k .
R E S U LTS
T a b l e 1 l i s t s t h e d a t a p e r t a i n i n g t o t h e h i s t o l o g i c a l p a t t e r n o f t h e e n d o m e t r i u m o f w o m e n w i t h a p o s i t i v e a n d n e g a t i v e t e s t . A m o n g w o m e n w i t h a p o s i t i v e p r o g e s t o g e n c h a l l e n g e t e s t ( G r o u p I ) , a h i s t o p a t h o l o g i c a l a n a l y s i s o f t h e u t e r i n e m u c o s a r e v e a l e d a n a c t i v e e n d o m e t r i u m i n 4 4 p e r c e n t o f c a s e s , a n d a t r o p h i c o r i n a c t i v e e n d o m e t r i u m i n 5 6 p e r c e n t . I n t h e g r o u p w i t h a n a c t i v e e n d o m e t r i u m , t h e e n d o m e t r i u m w a s p r o l i f e r a t i v e i n 1 6 p e r c e n t o f c a s e s , s e c r e t o r y i n 1 0 p e r c e n t , w i t h t y p i c a l h y p e r p l a s i a i n 8
T a bl e 1
Th e hi s t opa t ho l ogi c a l pa t t e r n of t he e nd om e t r i um
of w om e n w i t h a po s i t i v e ( G r o up I ) a nd ne ga t i v e
( G r oup I I ) p r oge s t oge n c ha l l e nge t e s t .
H is to p a th o lo g y G ro u p I G ro u p II
N % N 0 /0
A tro p h ic (in a c tiv e ) 2 8 5 6 .0 9 4 9 4 .0
A c tiv e
P ro life ra tiv e 8 1 6 .0 2 2 .0
S e c re to ry 5 1 0 .0 2 2 .0
T y p ic a l h y p e rp la s ia 4 8 .0
M ix e d 2 4 .0 1 .0
P o p ly p 2 4 .0 1 .0
A ty p ic a l h y p e rp la s ia 2 .0
T o ta l 5 0 1 0 0 .0 1 0 0 1 0 0 .0
s a o P a u lo M e d ic a l J o u rn a l/R P M 1 1 4 (3 ): 1 1 6 6 -1 1 7 2 , 1 9 9 6
T ab le 2
T h e m ean s valu es o f ag e, ag e at m en arch e an d at m en o p au se, p o stm en o p au sal tim e, b o d y m ass in d ex (8M I) an d g lu co se levels
(mg/dl)
in w o m en w ith p o sitive (G ro u p I) an d n eg ative (G ro u p II) p ro g esto g en ch allen g e test.G roup
II
Age
54
55.1
Age at M enarche
13.1
13.3
Age at M enopause
48.1
47.8
Postm enopausal Tim e (Yr)
5.8*
7.2*
BM I
27.4
26.5
G lucose Levels
107.3
102.1
of individuals w ith an active
endom etrium w hen the test is positive,
w as
44
percent. The negativepredictive value w as 94 percent, i.e.,
w hen the test w as negati ve, the
endom etrium w as inactive in 94
percent of the cases.
D ISC U SSIO N
M an n -W h itn ey test (G ro u p I x G ro u p II)
zcritical = 1.96
A g e A g e at M en arch e A g e at M en o p au se
zcal
=
0.85 zcalc=
0.67 zcalc=
0.61percent, w ith a polyp in4percent, m ixed in4percent, and
w ith atypical hyperplasia in 2percent.
A m ong w om en w ith a negative response, the
endom etrium w as atrophic in 94 percent of cases and active in 6 percent. A m ong the latter cases, the
endom etrium w as secretory in 2 percent, proliferative
in 2 percent, m ixed in 1 percent, and w ith an
endom etrial polyp in 1 percent.
Table
2
lists data about w om en w ith a positive (G roupI) and negative (G roup II) test in term s of age, age at
m enarche and at m enopause, postm enopausal tim e period,
body m ass index, and fasting blood glucose levels. A fter
analysis by the M ann-W hitney test, only postm enopausal
tim e w as significantly shorter in w om en w ith a positive test,
w hile the rem aining param eters did not differ significantly
betw een groups. Thus, it w as dem onstrated that m enopausal
tim e w as significantly shorter in the group of w om en w ith a
positive progestogen challenge test (a m ean of 5.8 years for
G roup I and of 7.2 years for G roup II).
Table 3 show s the relationship betw een
postm enopausal tim e and response to the test. It w as
concluded that there w as a significant association betw een
a m enopausal tim e of 1to 2 years and a positive test.
The sensitivity, specificity, and positive and negative
predictive values of the test are listed in Table 4. Sensitivity,
defined as the ability of the test to detect individuals w ith
a non-atrophic endom etrium , w as 78.57 percent. Specificity, i.e., the ability of the test to select norm al
w om en w ith an atrophic endom etrium , w as 77.05 percent.
The positive predictive value, defined as the percentage
G lu co se L evels
zcalc = 0.98
P o stm en o p au salT im e
zcalc
=
2.33* G roup I<G roup II8M I
zcalc
=
1.11The endom etrium differs from
other hum an tissues m ainly by being
the target of fem ale sex steroids. Its
developm ent and regression cycles are
tied to the cyclic estroprogestative
oscillations. Thus, it represents a
horm one-dependent m ucosa that
reflects the endocrine activity of
hum an gonads.
O ur histopathological findings, listed in Tables
1
and 2, dem onstrate that an inactive endom etrium w as
detected in 94 percent of the w om en w ith a negative
progestogen challenge test, and in 56 percent of w om en
w ith a positive test. To determ ine the value of the test
by discrim inating betw een populations, especially w ith
respect to eventual risk factors for neoplasias of the
endom etrium , w e com pared som e variables betw een
G roups I (negative test) and II (positive test), listed in
Table 2. W e deduced that there w ere no significant
differences betw een w om en w ith a positive or negative
test in term s of age, age at m enarche, age at m enopause,
body m ass index, or fasting blood glucose levels. In our study, the m ean age of w om en w ith a positive
progestogen challenge test w as 54 years, and the m ean age of w om en w ith a negative test w as 55.1 years. A nalysis
of the literature did not reveal significant differences betw een the tw o groups in term s of age.13.14.21W e also
T ab le 3
P o stm en o p au sal tim e in.G roup I an d II.
Postm enopausal G roup I G roup II Total
tim e (years) N 0/0 N %
1-2 25 50.0 24 24.0 49
3-5 8 16.0 31 31.0 39
6 -10 8 16.0 23 23.0 31
11+ 9 18.0 22 22.0 31
BO R TO LETTO , C .C .R .; BAR AC AT, E.C .; G O N Q ALVES, W .J.; sTAvELLE, J.N .; LIM A, G .R .
& N O VO , N .F. - Progestogen challenge test in postm enopausal w om en: C linical and aspects
fo u n d n o d ifferen ces in term s o f ag e at m en arch e o r ag e at
m en o p au se. W E H B A (1 9 8 8 ) d etected a sig n ifican tly lo w er
ag e at m en arch e am o n g p atien ts w ith a p o sitiv e test, b u t
d id n o t o b serv e th e sam e p h en o m en o n w ith resp ect to ag e
at m en o p au se.1 4
A n o th er risk facto r fo r carcin o m a o f th e en d o m etriu m
co n sid ered in th e p resen t stu d y w as d iab etes m ellitu s. A
q u ite co n tro v ersial facto r, d iab etes m ellitu s h as b een
co n sid ered to resu lt fro m o th er v ariab les, esp ecially
o b esity .2 2 .2 3 In d eed , o b esity lead s to in creased estro g en
lev els in p o stm en o p au sal w o m en an d co n seq u en tly
rep resen ts an im p o rtan t risk facto r fo r en d o m etrial
carcin o m a.2 4
H E M P E L et al. (1 9 8 8 ) also ap p lied th e p ro g esto g en
ch allen g e test to g ro u p s o f d iab etic an d n o n -d iab etic
m en o p au sal w o m en . D esp ite m en tio n in g d iab etes m ellitu s
as a risk facto r fo r can cer o f th e en d o m etriu m , th e au th o rs
d id n o t rep o rt a sig n ifican tly h ig h er n u m b er o f p o sitiv e
tests in th e d iab etic g ro u p .2 4 S im ilarly , W E H B A (1 9 8 8 )
d id n o t d etect an asso ciatio n o f p o sitiv ity w ith fastin g b lo o d g lu co se lev els.'4
T h e literatu re h as n o t o b serv ed d ifferen ces in b o d y
m ass in d ex b etw een w o m en w ith p o sitiv e an d n eg ativ e
tests.1 4.2 1 O u r stu d y also sh o w ed n o sig n ifican t
d ifferen ces in fastin g b lo o d g lu ~ o se lev els an d b o d y
m ass in d ex b etw een th e g ro u p s w ith p o sitiv e an d
n eg ativ e tests (T ab le 2 ).
O n th e o th er h an d , p o stm en o p au sal tim e w as
sig n ifican tly lo n g er in w o m en w ith a n eg ativ e test (m ean ,
7 .2 y ears) co m p ared to w o m en w ith a p o sitiv e test (m ean ,
5 .8 y ears). ,W e fu rth er d iv id ed th e w o m en acco rd in g to
m en o p au sal tim e an d su b m itted th eir d ata to statistical
an aly sis (T ab le 3 ). T h e g ro u p o f w o m en w ith m en o p au sal
tim e o f o n e to tw o y ears p resen ted a sig n ifican t asso ciatio n
w ith a p o sitiv e p ro g esto g en ch allen g e test. T h ese fin d in g s
can b e ex p lain ed b y rem em b erin g th at circu latin g estro g en
lev els are in creased d u rin g p eri m en o p au se, w ith a slo w
d eclin e o ccu rrin g o v er su b seq u en t y ears.2 5 F u rth erm o re,
m etab o lic clearan ce an d p ro d u ctio n o f estro n e an d
estrad io l d ecrease w ith p assin g tim e.
T h u s, th e p ro liferativ e an d h y p erp lastic h isto lo g ical
p attern s o ccu rrin g d u rin g th e p o stm en o p au sal p erio d are
u su ally o b serv ed d u rin g th e first y ears after th e o n set o f
m en o p au se, w ith th e in cid en ce o f u terin e m u co sal atro p h y
in creasin g w ith p o stm en o p au sal tim e.1 6 T h u s, a g reater
p o sitiv ity o f th e test is to b e ex p ected d u rin g th e first y ears
after m en o p au se. V A L E N Z U E L A et al. (1 9 9 3 ) co n clu d ed
th at w o m en w ith a p o stm en o p au sal tim e o f fiv e y ears o r
m o re p resen t a lo w er risk o f p o sitiv ity to th e test.2 1
F ew au th o rs h av e related th e p ro g esto g en ch allen g e
test to th e h isto lo g ical in v estig atio n o f th e en d o m etriu m ,
Table 4
The sensitivity, specificity, positive and negative
predictive value ot' progestogen challenge
test in postmenopause.
P r o g e s to g e n te s t E n d o m e tr iu m T o ta l
A c tiv e In a c tiv e
P o s itiv e 2 2 2 8 5 0
N e g a tiv e 6 9 4 1 0 0
T o ta l 2 8 1 2 2 1 5 0
S e n s itiv ity = 7 8 .5 7 %
S p e c ific ity = 7 7 .0 5 %
P o s itiv e p r e d ic tiv e v a lu e
=
4 4 %N e g a tiv e p r e d ic tiv e v a lu e = 9 4 %
reg ard less o f th e resu lt. W h en th e resp o n se to th e test is
p o sitiv e, atro p h ic states o f th e u terin e m u co sa are d etected .
T h u s, an an ato m o p ath o lo g ical stu d y o f th e en d o m etriu m
o f w o m en w ith a p o sitiv e test rev ealed atro p h y in 3 6 .9 to
5 0 .6 p ercen t.1 3 .1 8 .2 6 -2 H
O u r resu lts sh o w ed en d o m etrial atro p h y in5 6 p ercen t
o f th e w o m en w ith a p o sitiv e test, in ag reem en t w ith
reco rd ed v alu es. T h is b leed in g o f th e atro p h ic
en d o m etriu m d u rin g th e p o stm en o p au sal p erio d m ay b e
d u e to sclero tic d eg en eratio n o f th e en d o m etrial v ein s, o r
to lo cal o r sy stem ic h y p erten sio n , esp ecially in w o m en
w ith sen ile arterio sclero sis an d en d o m etritis.2 fi A lso , it 'is
p o ssib le th at b leed in g after th e u se o f p ro g esto g en is d u e
to m in u te fo ci o f activ e en d o m etriu m in tersp ersed
th ro u g h o u t an alm o st co m p letely atro p h ied m u co saY
H o w ev er, a n eg ativ e test u su ally reflects en d o m etrial
in activ ity . A n activ e en d o m etriu m is d etected in 3 .4 to 1 0
p ercen t o f th e w o m en w ith a n eg ativ e test.I1 .1 5 .2 7 .2 9
In o u r series, w e o b tain ed a 6 p ercen t rate o f
false-n eg ativ e resu lts, i.e., six cases o f activ e
en d o m etriu m in w o m en w ith a n eg ativ e p ro g esto g en
ch allen g e test (T ab le 2 ) . N o h y p erp lasia w as o b serv ed
am o n g w o m en w ith a n eg ativ e p ro g esto g en ch allen g e
test. T h u s, w e m ay co n clu d e th at th e p ro g esto g en
ch allen g e test is o f p aram o u n t im p o rtan ce w h en its
resu lt is n eg ativ e, w ith a n eg ativ e p red ictiv e v alu e o f
9 4 p ercen t. H o w ev er, w h en th e resp o n se to th e test is
p o sitiv e, reg ressiv e states o f th e u terin e m u co sa are
d etected , as em p h asized b y sev eral in v estig ato rs.IH .2 1 .2 7 .2 9
T h ese d ata sh o w th at th e sen sitiv ity o f th e p ro g esto g en
ch allen g e test in d etectin g en d o m etrial alteratio n s w as 7 8 .5 7
p ercen t an d its sp ecificity (th e ab ility to id en tify w o m en
w ith an atro p h ic en d o m etriu m ) w as 7 7 .0 5 p ercen t. T h e
p o sitiv e p red ictiv e v alu e o f th e test w as calcu lated at 4 4
s a o P a u lo M e d ic a l J o u r n a l/R P M 1 1 4 ( 3 ) : 1 1 6 6 - 1 1 7 2 , 1 9 9 6 B O R T O L E T IO , C .C .A .; B A R A C A T , E .C .; G O N < ;A L V E S , w 'J .;s T A v A L L E , J .N .; L IM A , G .R .
p ercen t, in d icatin g th at, w h en th e test is p o sitiv e, en d o m etrial
activ ity is p resen t in 4 4 p ercen t o f cases.
O n th is b asis, in th e ev alu atio n o f th e u terin e m u co sa
d u rin g th e p o stm en o p au sal p erio d , w e b eliev e th at th e
p ro g esto g en ch allen g e test, w h en n eg ativ e, is reassu rin g
to th e p h y sician . H o w ev er, w h en th e test is p o sitiv e, o th er
m eth o d s, su ch as tran sv ag in al u ltraso n o g rap h y sh o u ld b e
asso ciated w ith it. In th is w ay , cu rettag e can b e av o id ed
fro m th e start, b ecau se in m o re th an 5 0 p ercen t o f cases in
w h ich th e test is p o sitiv e, th e en d o m etriu m is atro p h ic.
T h erefo re, w e b eliev e th at th e p ro g esto g en ch allen g e test
an d tran sv ag in al u ltraso n o g rap h y , p erfo rm ed o n
p o stm en o p au sal w o m en , can d eterm in e th o se req u irin g
o th er ex am s, su ch as h y stero sco p y o r cu rettag e.
REFERENCES
I. B a ra c a t E C . A sp e c to s m o rfo lo g ic o s e m o rfo m e tric o s d o
e n d o m e trio h u m a n o n a p o s-m e n o p a u sa a n te s e a p o s
e stro g e n io te ra p ia o ra l e tra n sd e rm ic a . S a o P a u lo , 1 9 9 1 .
(C o n c u rso D o c e n te -L i v re - E sc o la P a u lista d e
M e d ic in a ).
2 . U tia n W H o O v e rv ie w o n m e n o p a u se . A m J O b ste t G y n e c o l
1 9 8 7 ; 1 5 6 : 1 2 8 0 -3 .
3 . A m e ric a n C o lle g e o f O b ste tric ia n s a n d G y n e c o lo g ists.
C a rc in o m a o f E n d o m e triu m . In t J G y n e c o l O b ste t
1 9 9 3 ;4 0 :2 5 5 -6 1 .
4 . M o re JA R . T h e n o rm a l h u m a n e n d o m e triu m . In : F o x H ,
e d . H a in e s a n d T a y lo r O b ste tric a l a n d G y n a e c o lo g ic a l
P a th o lo g y , 3 rd .e d . E d in b u rg : C h u rc h ill L iv in g sto n e ,
1 9 8 7 :3 0 2 -1 9 .
5 . A m e ric a n C o lle g e o f O b ste tric ia n s a n d G y n e c o lo g ists. H o rm o n e re p la c e m e n t th e ra p y . In t J G y n e c o l. O b ste t
1 9 9 3 ;4 1 : 1 9 4 -2 0 2 .
6 . F o th e rg ill D J, B ro w n V A , H ill A S . H isto lo g ic a l sa m p lin g
o f th e e n d o m e triu m : a c o m p a riso n b e tw e e n fo rm a l c u re tta g e
a n d th e P ip e lle sa m p le r. B r J O b ste t G y n a e c o l 1 9 9 2 ;9 9 :7 7 9
-8 0 .
7 . G ro n ro o s M , S a lm i T A , V u e n to M H , e t a t. M a ss sc re e n in g
fo r e n d o m e tria l c a n c e r d ire c te d in risk g ro u p s o f p a tie n ts
w ith d ia b e te s a n d p a tie n ts w ith h y p e rte n sio n . C a n c e r
1 9 9 3 ;7 1 : 1 2 7 9 -8 2 .
8 . L u tz M H , U n d e rw o o d P B , K re u tn e r A , M itc h e ll K S .
V a c u u m a sp ira to r: a n e ffic ie n t o u tp a tie n t sc re e n in g
te c h n iq u e fo r e n d o m e tria l d ise a se . S o u th M e d J
1 9 7 7 ;7 0 :3 9 3 -5 .
9 . G a m b re ll Jr R D , M a sse y F M , C a sta n e d a T A , U g e n a s A J,
R ic c i C A , W rig h t JM . U se o f th e p ro g e sto g e n c h a lle n g e
te st to re d u c e th e risk o f e n d o m e tria l c a n c e r. O b ste t G y n e c o l
1 9 8 0 ;5 5 :7 3 2 -8 .
1 0 . G a m b re ll JR R D . P ro g e sto g e n c h a lle n g e te st. O b ste t
G y n e c o l 1 9 8 1 ;5 7 :2 6 8 .
II. H a n n a JH , B ra d y W K , H ill JM , P h illip s G L . D e te c tio n o f
p o stm e n o p a u sa l w o m e n a t risk fo r e n d o m e tria l c a rc in o m a
b y a p ro g e ste ro n e c h a lle n g e te st. A m J O b ste t G y n e c o l
1 9 8 3 ; 1 4 7 :8 7 2 -5 .
1 2 . E rn y R , Isn a rd S , B o u b li L . T e sts a u x p ro g e sta tifs a p re s la
m e n o p a u se . R e v F r G y n e c o l O b ste t 1 9 8 6 ;8 1 : 1 9 5 -8 .
BORTOLETTO, C.C.A.; BARACAT, E.C.; GON<;ALVES, W.J.; sTAvELLE, J.N.; LIMA, G.A. & NOVO, N.F. - Progestogen challenge test in postmenopausal women: Clinical and aspects
13. T oppozada M K , Ism ail A A A , H am ed R S M , S id-A hm ed
K , E I-F aras A . P rogesterone challenge test .and estrogen
assays in m enopausal w om en w ith endom etrial
adenom atous hyperplasia. Int 1 G ynecol O bstet 1988;26: 115-9.
14. W ehba S . T este da progesterona para detecc;ao de lesoes
hiperplasicas do endom etrio em m ulheres na
p6s-m enopausa. S ao P aulo, 1988. (D issertation, E scola P aulista
de M edicina).29.B ortoletto C C R , G onc;alves W l, B aracat
E C , L im a, G R . T he use of progestogen challenge test,
transvaginal ultrasonography and endom etrium biopsy in
postm enopause. Int 1 G ynecol O bstet 1994;46( 1):76.
15. M acfa M , N ovo A , C es 1, G onzales M , Q uintana S ,
C odesido 1. P rogesterone challenge test for the assessm ent
of endom etrial pathology in asym ptom atic m enopausal w om en. IntJ G ynecol O bstet 1993;40: 145-9.
16. G onc;alves W l, S im oes R D , S tavale lN , B aracat E C . E studo
histol6gico do endom etrio em m ulheres na p6s-m enopausa.
In: lornada P aulista D e O bstetrfcia E G inecologia, 2, G uaruja, S ao P aulo, 1993:42.
17. K eys A , F idanza F , K arvonen M l, K im ura N , T aylor H L .
Indices of relati ve w eight and obesity. 1 C hron D is
1972;25:329-43.
18. P ansini F , D e P aoli D , S erra M M , C am pobasso C , L evato
F , G iulini D . C om bined use of progesterone challenge test
and endom etrium thickness evaluated by transvaginal
ultrasonography in the preventive m anagem ent of
postm enopausal w om en. G ynecol O bstet Invest 1992;34:237-9.
19. S iegel S . E stadistica no param etrica. M exico: T rillas,
1975:346.
20. G allen R S , G am bino R . B eyond norm ality: the predictive
value and efficiency of m edical diagnoses. N ew Y ork: 10hn
W iley & S ons, 1975.
21. V alenzuela P , S abatel R M , V alls V , N ieto A , G
onzalez-G om ez F . P rogestin challenge test in postm enopausal
patients. Int 1 G ynecol O bstet 1993;43:313-6.
22. K neale B L G , G iles GG. E ndom etrial cancer: trends in incidence and survival: a preventable disease? A ust N Z J
O bstet G ynaecol 1993;33: 1-7.
23. P arazzini F , L a V ecchia C , B occiolone L , F ranceschi S . T he
epidem iology of endom etrial cancer. G ynecol O ncol
1991;41: 1-16.
24. L evi F , L a V echchia C , N egri E , P arazzini F , F ranceschi S .
B ody m ass at different ages and subsequent endom etrial
cancer risk. Int 1 C ancer 1992;50:67-71.
26. D allenbach-H ellw eg G . T he endom etrium in the
c!im ateric and after m enopause. In: D allenbach-H ellw eg
G - H istopathology of the endom etrium , 4th ed. N ew
Y ork: S pringer-V erlag, 1987:86-92.
25. S herm ann B M , W est lH , K orenm an S G . A nalysis of L H ,
F S H , estradiol and progesterone concentrations during
m enstrual cycles of older w om en. 1 C lin E ndocr M etabol
1976;42:629-36.
27. E rny R , S erradim igni F . D epistage des hyperplasies et des
cancers de I'endom etre. R ev F r. G ynecol O bstet 1984;79:91-6.
28. H em pel V E , N oschel H , E ichhorn K H , R asch A , F ranke
D . V ergleich von progesterntest and uterussonographie als
screening-verfahren zur erkennung von risikopatientinnen
hinsichtlich endom etrium karzinom . Z entralblatt G ynakol.
1988; 110:597-602.
