HO SEQUENTI
ON
FO
of
EPTI D
THE
. END
St.
and
Jean,
Gynecology
Brussels
of H a n R e p r o d u c t i o n, R e s e a r c h Univers ity of Louvain Belgium
A
B
TRIUM
+ D E R I C K , M. D. + BEE , M.D. + DE YL R, M . D . FERiN, M.D. ++
stetrlcs
Clinique + ~ Phy s i o 1 o gy
T
LAT!ONS
G. J. E J.
+ Department
C
S T
R A
C
Un i t
T
extensi endometrial study has been carried t on tee group s o f women r e c e i v in g c on t i n uou s o r d i s c on t i nu ou s s e quen t i a 1 o r al c o n t r a c e p t i v e f o r m u l a t i o n s. 1348 endometrial biopsies were taken fr 748 patients during 5173 cycles. A tendency t ards hyperplasla or an outs ken cystic hyperplasia appeared in 25 t o 48 % o f t h e c a s e s , a c c o r d i n g to e dosage progr used. Four cases of aden atous hyperplasia were found.
Mailing
Accepted
address
for
CEMBER
: J. F E R I N , M . D . University Hospital 3OOO LE N / BELGIUM
p u b l i c a t i , on S e p t e m b e r
1975
V O L . 12
. 6
24,
1975
655
CONTRACE
ION
I N
T
R
0
D
U
C
T
I
0
N
A relationship be een the occurrence of adenomatous hyperplasia and/or a d e n o - c a r c in a of the endometrium, and prolonged estrogenic trea ent in post-menopausal women is s t r o n g l y suggested by a nu er of set tions (1, 2, 3, 4, 5 ) . Similar lesions have been produced in young cycling w en recelving T E (6) a n d i n p a t i e n t s with Tu er's syndr e after stilbestroi therapy (7) . Attention has recently been focused on the development of endo trial carcinoma in y o u n g w en r e c e i v i n g an oral contraceptive in sequential fo ulation (8). Consequentiy, it w a s t h o u g h t interesting to report on the end etrial data obtained in a large group of young patients taking this klnd of oral contraceptive.
TE RI
D
THODS
The sequential for lations which have been used contained e th i ny 1 -e s t r a d i o i a s e s t r o g e n, a n d e i the r 6- d ehyd r o re t r op r o g e s t e t o n e (d y d r o g e s t e r o n e ) o r 6 - c h 1 o r o - 9 8 1 0 ~ - p r e g n a - 1 , 4 , 6 triene-3,20-dione, as p r o g e s t a t i o n a l agent This last compound, which is a derivative of dydrogesterone, seems to be more potent in animal experimentation (9), a s w e l l as i n t h e o v a r l e c t o m i z e d women (10). 748 cycling patients of proven fertility, seeking advice on contraception and considered to be "normal", were selected for th i s study Three dosage progr s were used : a) E t h i n y l .... e.s t r a d i o l O . i m g f o r 16 d a y s a n d O . i m g e t h l n y l estradiol with 5 mg dydrogesterone for 5 days. The treatment started on the fiZth day of e menstrual cycle and was interrupted cyclically for 7 days thereafter r ega rd i e s s o f the appe a r an c e o f men s t ru a t i on. T h i s r e g ime n was administered to 390 patients for a total of 2531 cycles. b) E t h i n y l - e s t r a d i o l O.i mg daily, from the first day of the first cycle, daily, was added f r o m d a y 24 o f e a c h c y c l e , for 5 days. This regimen was administered to 208 patients for a total of 1563 c les. c) E t h i n y i - e s t r a d i o l O.O8 mg daily, without interru io , from t h e f i r s t d a y o f t h e f i r s t c y c l e . ....................... 6 ....(. ~ regna1,4,6-triene-3,20-dione, 10 mg daily, was added f r o m d a y 21 of each cycle, for 8 days. This regimen was administered to 150 patients for a total of iO79 cycles. ....
656
CEMBER
1975
V O L . 12 N O . 6
C O N T R A C E '~
ION
The n er of endometrial biopsies, taken during different cycles, a unted to 1348. The total nu er of cycles studle was 5173; 619 biopsies were taken fr women on Progr a) , 416 biopsies from those on progr b) , a n d 3 1 3 b i o p s l e s from o s e o n p r o g r a m c) . In m o s t o f t h e c a s e s , t h e b i sies were performed either t ard the end of the estrogenic phase or at the end of the co ined phase of the treatment. A i i t h e s .... l e s w e r e t a k e n with a Novak's curette, fixed in Bouin's fluid, e edded (Autotechnicon) and stained (H alun-Eosin) under standardizea condi tions. Aii histological evaluations were carried out by one person (J.F.) . Cys tic hype rpl a s i a and aden atous hype rplasia of the endometri are well kn n pathological entities. Tendency towards cystic hyperplasia can be easily characterized by a histometric m e t h o d ..(ll) .. . However, this method consumes too ch time and, therefore,~ the trend to hyperplasia has, in this study, been diagnosed on the basls of mor ological criteria: l) i r r e g u l a r i t y of the size of the glands,with diameters greater than usual, up to 150 microns; and 2) g l a n d u l a r w a l l s t h i c k e r t h a n u s u a l , w i t h m a r k e d D s e u d o ~ stratification of the nuclel. In t h e s t a t i s t i c a l analysis of our results, the distinction between cystic hyperplasia and the tendency towards ~stic hyperplasia h a s n o t b e e n m a d e .... T h e t w o c o n d i t i o n s are considered together as e n d o t r i a l h y p e r p l a s ia. en atous hyperplasia has been diagnosed on the basis of ~he following well-known cr teria : I) p r e s e n c e of itiple focal areas sh ing closely packed glanas with crowding of the intervening stroma; 2) c e n t r i f u g a l budding of the glands and, s crimes intra-luminal infolding in these areas; and 3) m a r k e d p s e u d o s t r a t i f i c a t i o n o f t h e n u c l e i in g l a n d u l a r walls t h ic k e r t h a n u s u a 1 ..... Pearl's index has been calculated taking into account patlent failures as w e l l a s m e t h o d failures.
R
E
S
U
~
T
S
Early secretory transfo ation was regularly found at the end of the c ined ase of each regimen. The differences be een the frequencies of end trial hyperplasia with each dose of estrogen r cycle are statistically ~ significant (p O0.OO~) (see Tables i, If, I l l a n d IV) .
DECEMBER
1975
V O L . 12 N O . 6
657
CONTRACE
Tab i e
X.
oyolo 1 2
-5
6
-
11-
ION
D i s tr ibut ion o f the du r i n g pro g r am a )
619
I TM" IE Eto !6 1 0o~ E E17 + !
endome
P
~21 I' intorval ~ days
taken
},
total
1
16
8
25
34
130
62
226
iO
|
13
35
39
87
15
J
18
20
17
55
16
-
20
28
40
17
85
21
-
25
36
29
12
77
26
-
30
19
19
li
49
31
-
33
6
6
Total
|
155
|
295
( E E = e t h i n y l ...e.s t r a d i o l O.i ~g daily; daily) . Program a) : 3 9 0 p a t l e n t s ,
658
t ri a i b lops ie s
....
I
3
169
i
15
|
619
P = dydrogesterone 2.531 cycles.
DECEMBER
1975
~OL. ~r
5
12
mg
. 6
C
Table
II.
Distribution take n du r in g
Day
Cycle
1
to EE
of the program
23
~ |
416 endometrial b )
Day
24 t o EE + P
28
TRACEPTION
blopsies
Total
3
I
7
!
10
!O 3
i
96
|
199 131
2
-
5
6
-
iO
61
|
70
I
11
15
32
i
2:0
i
5 2::
16
- 20
16
!
!
24
|
215
Total
(E~ ethinyl-estradiol 15 m g d a i l y ) . Program
Table
III.
8
Distribution t ak en du r i n g
Daylto20 EE
|
201
O.i mg daily; P = b) : 2 0 8 p a t i e n t s ,
of the p ro g r
J D
416
dydrogesterone 1.563 cycles.
313 endo~etrial c)
Cycle
I
1
I
2
!
3
!
5
- 5
!
40
!
1 IO
!
15o
-
|
36
I
100
|
136
2 ii
10
- 12
~o tal
I
8
I
86
i
21 tO EE + P
28
L. 12 NO. 6
Tot al
14
|
22
227
|
313
(EE e t h i n y I - e s t r a d I o i O. 0 8 ~ g d a i i y; P 9 8 -iO p r e g n a ~ i, 4 , 6 - t t i e n e - 3 , 2 0 - d i o n e ) . .... Program C) : 1 5 0 p a t l e n t s , 1.079 cycles.
D E C E M B E R 1975
}
biopsies
6 -ch 1 o Eo-
C
TRACE
ION
~j
~Q
O D
e ¸
~ O
~
~
0
~
~
O
-~
~
0
"~
0
0
O
~ 0
0
O~ ~ U
~
m
0
0
H
0
6
0
0
CEMBER
1975
V O L . 12 N O . 6
CONTRACE
ION
The trend t ards hyperp!asia can appear as early as the first cycle of the treatment. The frequency of this pattern seems not to be significantly modified with the length of the t r e a t m e n t e x c e p t in p r o g r a m b) , w h e n f r e q u e n c y increases slowly with time. The prolongation of the co ined trea ent together with a small reduction in the a nt of estrogen ( p r o g r a m c) s e e m s t o reduce the frequency of end e t r i a l h y p e r p l a s i a .... I n d e e d , of 8 6 biopsies taken during the estrogenic phase, 48.8 % sh ed vari le degrees of hyperplasia. On the other hand, of the 277 biopsies t a k e n d u r i n g t h e e s t r o ...p.r o g e s t o g e n i c phase, only 30.3 % revealed the same an ly. Endometrial hyperplasia, whatever its stage of development, always disappeared a f t e r t r e a t m e n t w a s s t o p p e d .... In t h e c a s e s w h i c h w e r e t r a n s f e r r e d to contraceptive co ined therapy, the usual endometrial pattern was found at the end of the second or e third course. In the others, a normal secretory endometrial pattern was obtained before the second or the third spontaneous menstruation. In t h e c a s e s w i t h a d e n o m a t o u s hyperplasia, treatment has been i ediately stopped and a p erful progestational drug (Lynestrenol 5 mg daily) was administered orally, for several nths, without interruption, in e a c h c a s e , t h e l e s i o n completely disappeared. Three of the four patients became pregnant after !ynestrenol was discontinued. Withdrawal bleeding occurred regularly, usually o to four d~ys after cessation of the progestogen. Hea menstrual !osses and/or a prolonged period lasting re than six days, as well as i n t e r m e n s t r u a l spotting, have been served in a few cases. No thr o-phl i tis was seen. In c o m p a r i s o n with the side effects co on to all types of oral contraception, the different sequential regimens used were relatively well accepted by the patients studied.
D
I S C U
S S
I O N
it is w e l l k n n that treat nt with estrogen alone can induce endometrial cystic hyperp!asia and, also, adenomatous hyperplasia, which seems to be a pre li ant lesion (12) a t l e a s t i n 12 % o f the cases in a well controlled series (13) H ever, the role of estrogen in the develQ ent of endo trial carcinoma is ....n o t c o m p l e t e l y understood. ~ of ~5 patients treated ~U t wi massive doses of estrogens, in only one was there any suspicion of carcinoma (14) . additional individual predisposition seems to be required for the develo~ent o f c a r c i ~ t o m a (i2).
DECEMBER
1975
VOL. 12 N O . 6
1
CONTRACE
ION
Our observations have shown that dlscontlnuous or continuous estrogen therapy, wlth O.i mg ethinyl-estradlol daily, can induce endometrial hyperplasla, even of the adenomatous type, in y o u n g c y c l l n g w o m e n , d e s p i t e r e g u i a r a d d i t i o n o f a s h o r t c o u rs e o f p r o g e s t o q e n . Endometrlal hyperplasia occurs when menstrual desquamatlon is i n s u f f i c l e n t . Extension and depth of the endometrial shedding depends, first, on estrogenic priming; with a higher estrogenic d o s e t h e r e is l e s s s h e d d i n g . Endometrlal hyperplasia was not o b s e r v e d in p a t i e n t s r e c e i v i n g c o n t i n u o u s therapy with O.O5 mg ethinyl-es£radiol d a i l y (i5) . H o w e v e r , t h e n er o f e n d etrial e x p l o r a t i o n s w h i c h w e r e m a d e in t h i s s t u d y , is c l e a r l y t o o s m a l l . In nopausal or post-menopausal w en, e n d o m e t r i a i h y p e r p i a s i a h a s b e e n s e e n to o c c u r w i t h O . O 2 5 m g e t h i n y l - e s t r a d i o l d a i l y (5) . It c a n b e a r g u e d t h a t , w l t h age, t h e m e t a b o l i c c l e a r a n c e r a t e of ethinyl-estradiol might be 1 e r e d (16). H o w e v e r , t h e d o s e of 0.05 mg ethinyl-estradiol s e e m s to b e b i o c h e m i c a l i y a supraysiological oneo In d e e d , thls d o s e c a n i n c r e a s e t h e t r a n s c o r t l n b i n d i n g c a p a c i t y o f t h e p l a s m a to l e v e l s w h i c h c h a r a c t e r i z e late pregnancy (17) . E x t e n s i o n a n d d e p t h o f the e n d o m e t r i a l s h e d d i n g is a l s o i n f l u e n c e d b y the p r o g e s t a t i o n a l trea ent, its potency and more i m p o r t a n t l y its d u r a t l o n . With a longer progestational p h a s e as in p r o g r a m c ) , t h e f r e q u e n c y of h y p e r p l a s i a is s i g n i f i c a n t l y reduced, en, in a s e q u e n t i a l f o r lation, the progestational d r u g is l a r g e l y d o m l n a n t , t h e n e n d o trial hyperplasia is virtually excluded. N o t o n e c a s e o f h y p e r p l a s i a w a s f o u n d in 2 2 0 c o n s e c u t i v e e n d o m e t r i a l b i o p s i e s in 2 2 0 p a t i e n t s r e c e i v i n g the f o l l i n g r e g i m e n : O . O 8 m g m e s t r a n o l f r o m d a y 1 t o d a y 7, a n d 0 . 0 7 5 m g m e s t r a n o l p l u s 2.5 m g l y n e s t r e n o l f r o m d a y 8 t o d a y 22 ( R / O v a n o n , O r g a n o n ) . It s h o u l d b e e m p h i z e d t h a t f o r r e a s o n s as y e t u n k n n, in the majority of cases, endometrial hyperplasia remains asy tomatlc.
¸662¸
DECEMBER
1975
V O L . 12 N O . 6
O N ' I R"A C E P ' T IO N
C O N
C L U
S I O N
S
Oral contraception of a sequential type with a hi ly potent estrogen (ethinyl-estradioi, O.1 ~g or O.O8 mg daily) can very often induce endo trial hyperplasia, and, re rarely, adenomatous hyperplasia. It h a s n o t b e e n p r o v e d t h a t 1 ering the daily dose of ethinyl-estradiol to O.O5 mg, will reduce the risk. Long-term treatment with these sequential fo ulatlons has to b e admi n i s te red with c au t i on, t akin g i n t o a ccou n t the pos s ib i I i ty of end trial premali ant transfo ation. On the other hand, the prolongation of the estro-progestational phase beyond 8 days will undoubtedly reduce the incidence of cystic and aden at s hyperplasia. AC
EDGEMENTS
wish to thank Hoffmann-La Roche Labora Swltzerland) f o r s u p p l i e s o f m a t e r i a l ....
ties
(Basle,
R E F E R E N C E S i. G U S B E R G , S . B . Precursors adenomatous hyperplasia.
of
corpus J Obst
carcinoma estrogens G y n e c 54 : 9 O S - 9 2 7
d (1947)
2.
GUSBERG, S.B. and H L, R . E . Precursors of corpus cancer. IiI. e appearance of cancer of the endo trium in estrogenically conditloned patients. O b s t G y n e c 17 : 3 9 7 - 4 1 2 (196 i )
3.
GO , H. a n d endometrium.
HE !G, Clin
A.T. Premalignant st Gynec 5 : i148
lesions of the - 1 i 6 5 (1962)
4. D LENB~H-HELL G, G. Endometrium. Pathologische Histologie in D i a g n o s t i k und Forschung. Springe~ ~ rlag Berlin (1969) 5.
F E R I N , J. Effect of replacement erapy on endo t r i u m in post-menopausal ne in "The Menopausal Syndro " B Ed O R.B. Gre~blatt, V . B . M a h e s h a n d P .G. M c D o n o u g h , Medcom Press, N . Y . , 1 9 7 4 , p. 1 4 3 - 1 4 6 .
6.
KIS ER, R.W., o lation by
D
C E.
, C.J. and st Gynec 8
S E L L , H. : 399 - 404
7. W I L K I N S , E.J., IEDRICH, E.G., and CIS, J.C. Turner' s syndr carcinoma and stilbestrol thera . (! 973 )
DECEMBER
75
L. 12
. 6
Suppress ion (1956)
INGLY, R.F., e with endo trial st n e c 42 : 1 9 3
of
I, J . A . eno- 2
3
CONTRACE
8.
ION
glstry for contraceptive
endometrial carcinoma agents, items, er
in young women taking oral J Obst Gynec ll8 : 747
(19 7 4 ) 9.
HO f fman n-La n ic a t i on.
Ro c h e Lab or a to rie s
B a s i e,
S w i t z e r i a n d.
10.
FERIN, J. Orally active progestational compounds. Human studies : effects o n t h e u t e r o ...v.a g l n a l tract. I n " P h a .....a c o l ogy of the endocrine system and related drugs : progesterone, progestational druqs and antif~rtility agents ,Ed. M. Tausk, v o l . if, I n t e r n a t i o n a l Encyclopedia of Pharmacology and Th apeutics, Pergamon Press, N , Y o B !972 # p ~ 245-273 o
Ii.
DELFO E, J . P . and FERIN, J. A histometric study of estrogens : ethinyl-estradiol and its 3-methyl-ether ative (,,~estranol) ; t h e i r comparative effect upon the of the human endometrium. Contraception 1 : 5 7 - 72
12.
GUSBERG, S Obst Gynec
13.
GUSBE , SoB. and K L , A.L. Precursors of corpus cancer. IV. A d e n o m a t o u s hyperplasia as stage O carcin a of the endometrium J Obst Gynec 87 : 662 - 676 (19631
14.
K O L L E R t O. The risk of develo ent of u refine cancer patients with breast cancer after long-term treatment estrogen in massive doses. Acta Obst nec Stand 45 1 i 3 (1966 )
15.
16.
17.
6,
K S E , L. P e r s on a i co
HEBER, K.R. Contraception
B. 30
Hormone 257 -
A
flexible iO : 241
ependence 293 (1967)
-
of
endometrial
low dosage system 250 (i974)
of
oral
t der growth (1970)
cancer.
in with : lll
-
con~'~aceptlon.
LONGCOPE, C. Metabolic clearance of estrogens in post-menopausal w 778 - 781 (1971)
and blood production rates en. e~-J st ~ynec iiI
SCH R T Z , U. a n d H RSTEIN, J. various contraceptive steroids as on transcortin-binding capacity. (1974)
The estrogenic potency of dete ined b y t h e i r e f f e c t s Acta endocr 76 : 159 171
DECEMBER
179', 5
:
L. 12 N O . 6
ON
FO
of
EPTI D
THE
. END
St.
and
Jean,
Gynecology
Brussels
of H a n R e p r o d u c t i o n, R e s e a r c h Univers ity of Louvain Belgium
A
B
TRIUM
+ D E R I C K , M. D. + BEE , M.D. + DE YL R, M . D . FERiN, M.D. ++
stetrlcs
Clinique + ~ Phy s i o 1 o gy
T
LAT!ONS
G. J. E J.
+ Department
C
S T
R A
C
Un i t
T
extensi endometrial study has been carried t on tee group s o f women r e c e i v in g c on t i n uou s o r d i s c on t i nu ou s s e quen t i a 1 o r al c o n t r a c e p t i v e f o r m u l a t i o n s. 1348 endometrial biopsies were taken fr 748 patients during 5173 cycles. A tendency t ards hyperplasla or an outs ken cystic hyperplasia appeared in 25 t o 48 % o f t h e c a s e s , a c c o r d i n g to e dosage progr used. Four cases of aden atous hyperplasia were found.
Mailing
Accepted
address
for
CEMBER
: J. F E R I N , M . D . University Hospital 3OOO LE N / BELGIUM
p u b l i c a t i , on S e p t e m b e r
1975
V O L . 12
. 6
24,
1975
655
CONTRACE
ION
I N
T
R
0
D
U
C
T
I
0
N
A relationship be een the occurrence of adenomatous hyperplasia and/or a d e n o - c a r c in a of the endometrium, and prolonged estrogenic trea ent in post-menopausal women is s t r o n g l y suggested by a nu er of set tions (1, 2, 3, 4, 5 ) . Similar lesions have been produced in young cycling w en recelving T E (6) a n d i n p a t i e n t s with Tu er's syndr e after stilbestroi therapy (7) . Attention has recently been focused on the development of endo trial carcinoma in y o u n g w en r e c e i v i n g an oral contraceptive in sequential fo ulation (8). Consequentiy, it w a s t h o u g h t interesting to report on the end etrial data obtained in a large group of young patients taking this klnd of oral contraceptive.
TE RI
D
THODS
The sequential for lations which have been used contained e th i ny 1 -e s t r a d i o i a s e s t r o g e n, a n d e i the r 6- d ehyd r o re t r op r o g e s t e t o n e (d y d r o g e s t e r o n e ) o r 6 - c h 1 o r o - 9 8 1 0 ~ - p r e g n a - 1 , 4 , 6 triene-3,20-dione, as p r o g e s t a t i o n a l agent This last compound, which is a derivative of dydrogesterone, seems to be more potent in animal experimentation (9), a s w e l l as i n t h e o v a r l e c t o m i z e d women (10). 748 cycling patients of proven fertility, seeking advice on contraception and considered to be "normal", were selected for th i s study Three dosage progr s were used : a) E t h i n y l .... e.s t r a d i o l O . i m g f o r 16 d a y s a n d O . i m g e t h l n y l estradiol with 5 mg dydrogesterone for 5 days. The treatment started on the fiZth day of e menstrual cycle and was interrupted cyclically for 7 days thereafter r ega rd i e s s o f the appe a r an c e o f men s t ru a t i on. T h i s r e g ime n was administered to 390 patients for a total of 2531 cycles. b) E t h i n y l - e s t r a d i o l O.i mg daily, from the first day of the first cycle, daily, was added f r o m d a y 24 o f e a c h c y c l e , for 5 days. This regimen was administered to 208 patients for a total of 1563 c les. c) E t h i n y i - e s t r a d i o l O.O8 mg daily, without interru io , from t h e f i r s t d a y o f t h e f i r s t c y c l e . ....................... 6 ....(. ~ regna1,4,6-triene-3,20-dione, 10 mg daily, was added f r o m d a y 21 of each cycle, for 8 days. This regimen was administered to 150 patients for a total of iO79 cycles. ....
656
CEMBER
1975
V O L . 12 N O . 6
C O N T R A C E '~
ION
The n er of endometrial biopsies, taken during different cycles, a unted to 1348. The total nu er of cycles studle was 5173; 619 biopsies were taken fr women on Progr a) , 416 biopsies from those on progr b) , a n d 3 1 3 b i o p s l e s from o s e o n p r o g r a m c) . In m o s t o f t h e c a s e s , t h e b i sies were performed either t ard the end of the estrogenic phase or at the end of the co ined phase of the treatment. A i i t h e s .... l e s w e r e t a k e n with a Novak's curette, fixed in Bouin's fluid, e edded (Autotechnicon) and stained (H alun-Eosin) under standardizea condi tions. Aii histological evaluations were carried out by one person (J.F.) . Cys tic hype rpl a s i a and aden atous hype rplasia of the endometri are well kn n pathological entities. Tendency towards cystic hyperplasia can be easily characterized by a histometric m e t h o d ..(ll) .. . However, this method consumes too ch time and, therefore,~ the trend to hyperplasia has, in this study, been diagnosed on the basls of mor ological criteria: l) i r r e g u l a r i t y of the size of the glands,with diameters greater than usual, up to 150 microns; and 2) g l a n d u l a r w a l l s t h i c k e r t h a n u s u a l , w i t h m a r k e d D s e u d o ~ stratification of the nuclel. In t h e s t a t i s t i c a l analysis of our results, the distinction between cystic hyperplasia and the tendency towards ~stic hyperplasia h a s n o t b e e n m a d e .... T h e t w o c o n d i t i o n s are considered together as e n d o t r i a l h y p e r p l a s ia. en atous hyperplasia has been diagnosed on the basis of ~he following well-known cr teria : I) p r e s e n c e of itiple focal areas sh ing closely packed glanas with crowding of the intervening stroma; 2) c e n t r i f u g a l budding of the glands and, s crimes intra-luminal infolding in these areas; and 3) m a r k e d p s e u d o s t r a t i f i c a t i o n o f t h e n u c l e i in g l a n d u l a r walls t h ic k e r t h a n u s u a 1 ..... Pearl's index has been calculated taking into account patlent failures as w e l l a s m e t h o d failures.
R
E
S
U
~
T
S
Early secretory transfo ation was regularly found at the end of the c ined ase of each regimen. The differences be een the frequencies of end trial hyperplasia with each dose of estrogen r cycle are statistically ~ significant (p O0.OO~) (see Tables i, If, I l l a n d IV) .
DECEMBER
1975
V O L . 12 N O . 6
657
CONTRACE
Tab i e
X.
oyolo 1 2
-5
6
-
11-
ION
D i s tr ibut ion o f the du r i n g pro g r am a )
619
I TM" IE Eto !6 1 0o~ E E17 + !
endome
P
~21 I' intorval ~ days
taken
},
total
1
16
8
25
34
130
62
226
iO
|
13
35
39
87
15
J
18
20
17
55
16
-
20
28
40
17
85
21
-
25
36
29
12
77
26
-
30
19
19
li
49
31
-
33
6
6
Total
|
155
|
295
( E E = e t h i n y l ...e.s t r a d i o l O.i ~g daily; daily) . Program a) : 3 9 0 p a t l e n t s ,
658
t ri a i b lops ie s
....
I
3
169
i
15
|
619
P = dydrogesterone 2.531 cycles.
DECEMBER
1975
~OL. ~r
5
12
mg
. 6
C
Table
II.
Distribution take n du r in g
Day
Cycle
1
to EE
of the program
23
~ |
416 endometrial b )
Day
24 t o EE + P
28
TRACEPTION
blopsies
Total
3
I
7
!
10
!O 3
i
96
|
199 131
2
-
5
6
-
iO
61
|
70
I
11
15
32
i
2:0
i
5 2::
16
- 20
16
!
!
24
|
215
Total
(E~ ethinyl-estradiol 15 m g d a i l y ) . Program
Table
III.
8
Distribution t ak en du r i n g
Daylto20 EE
|
201
O.i mg daily; P = b) : 2 0 8 p a t i e n t s ,
of the p ro g r
J D
416
dydrogesterone 1.563 cycles.
313 endo~etrial c)
Cycle
I
1
I
2
!
3
!
5
- 5
!
40
!
1 IO
!
15o
-
|
36
I
100
|
136
2 ii
10
- 12
~o tal
I
8
I
86
i
21 tO EE + P
28
L. 12 NO. 6
Tot al
14
|
22
227
|
313
(EE e t h i n y I - e s t r a d I o i O. 0 8 ~ g d a i i y; P 9 8 -iO p r e g n a ~ i, 4 , 6 - t t i e n e - 3 , 2 0 - d i o n e ) . .... Program C) : 1 5 0 p a t l e n t s , 1.079 cycles.
D E C E M B E R 1975
}
biopsies
6 -ch 1 o Eo-
C
TRACE
ION
~j
~Q
O D
e ¸
~ O
~
~
0
~
~
O
-~
~
0
"~
0
0
O
~ 0
0
O~ ~ U
~
m
0
0
H
0
6
0
0
CEMBER
1975
V O L . 12 N O . 6
CONTRACE
ION
The trend t ards hyperp!asia can appear as early as the first cycle of the treatment. The frequency of this pattern seems not to be significantly modified with the length of the t r e a t m e n t e x c e p t in p r o g r a m b) , w h e n f r e q u e n c y increases slowly with time. The prolongation of the co ined trea ent together with a small reduction in the a nt of estrogen ( p r o g r a m c) s e e m s t o reduce the frequency of end e t r i a l h y p e r p l a s i a .... I n d e e d , of 8 6 biopsies taken during the estrogenic phase, 48.8 % sh ed vari le degrees of hyperplasia. On the other hand, of the 277 biopsies t a k e n d u r i n g t h e e s t r o ...p.r o g e s t o g e n i c phase, only 30.3 % revealed the same an ly. Endometrial hyperplasia, whatever its stage of development, always disappeared a f t e r t r e a t m e n t w a s s t o p p e d .... In t h e c a s e s w h i c h w e r e t r a n s f e r r e d to contraceptive co ined therapy, the usual endometrial pattern was found at the end of the second or e third course. In the others, a normal secretory endometrial pattern was obtained before the second or the third spontaneous menstruation. In t h e c a s e s w i t h a d e n o m a t o u s hyperplasia, treatment has been i ediately stopped and a p erful progestational drug (Lynestrenol 5 mg daily) was administered orally, for several nths, without interruption, in e a c h c a s e , t h e l e s i o n completely disappeared. Three of the four patients became pregnant after !ynestrenol was discontinued. Withdrawal bleeding occurred regularly, usually o to four d~ys after cessation of the progestogen. Hea menstrual !osses and/or a prolonged period lasting re than six days, as well as i n t e r m e n s t r u a l spotting, have been served in a few cases. No thr o-phl i tis was seen. In c o m p a r i s o n with the side effects co on to all types of oral contraception, the different sequential regimens used were relatively well accepted by the patients studied.
D
I S C U
S S
I O N
it is w e l l k n n that treat nt with estrogen alone can induce endometrial cystic hyperp!asia and, also, adenomatous hyperplasia, which seems to be a pre li ant lesion (12) a t l e a s t i n 12 % o f the cases in a well controlled series (13) H ever, the role of estrogen in the develQ ent of endo trial carcinoma is ....n o t c o m p l e t e l y understood. ~ of ~5 patients treated ~U t wi massive doses of estrogens, in only one was there any suspicion of carcinoma (14) . additional individual predisposition seems to be required for the develo~ent o f c a r c i ~ t o m a (i2).
DECEMBER
1975
VOL. 12 N O . 6
1
CONTRACE
ION
Our observations have shown that dlscontlnuous or continuous estrogen therapy, wlth O.i mg ethinyl-estradlol daily, can induce endometrial hyperplasla, even of the adenomatous type, in y o u n g c y c l l n g w o m e n , d e s p i t e r e g u i a r a d d i t i o n o f a s h o r t c o u rs e o f p r o g e s t o q e n . Endometrlal hyperplasia occurs when menstrual desquamatlon is i n s u f f i c l e n t . Extension and depth of the endometrial shedding depends, first, on estrogenic priming; with a higher estrogenic d o s e t h e r e is l e s s s h e d d i n g . Endometrlal hyperplasia was not o b s e r v e d in p a t i e n t s r e c e i v i n g c o n t i n u o u s therapy with O.O5 mg ethinyl-es£radiol d a i l y (i5) . H o w e v e r , t h e n er o f e n d etrial e x p l o r a t i o n s w h i c h w e r e m a d e in t h i s s t u d y , is c l e a r l y t o o s m a l l . In nopausal or post-menopausal w en, e n d o m e t r i a i h y p e r p i a s i a h a s b e e n s e e n to o c c u r w i t h O . O 2 5 m g e t h i n y l - e s t r a d i o l d a i l y (5) . It c a n b e a r g u e d t h a t , w l t h age, t h e m e t a b o l i c c l e a r a n c e r a t e of ethinyl-estradiol might be 1 e r e d (16). H o w e v e r , t h e d o s e of 0.05 mg ethinyl-estradiol s e e m s to b e b i o c h e m i c a l i y a supraysiological oneo In d e e d , thls d o s e c a n i n c r e a s e t h e t r a n s c o r t l n b i n d i n g c a p a c i t y o f t h e p l a s m a to l e v e l s w h i c h c h a r a c t e r i z e late pregnancy (17) . E x t e n s i o n a n d d e p t h o f the e n d o m e t r i a l s h e d d i n g is a l s o i n f l u e n c e d b y the p r o g e s t a t i o n a l trea ent, its potency and more i m p o r t a n t l y its d u r a t l o n . With a longer progestational p h a s e as in p r o g r a m c ) , t h e f r e q u e n c y of h y p e r p l a s i a is s i g n i f i c a n t l y reduced, en, in a s e q u e n t i a l f o r lation, the progestational d r u g is l a r g e l y d o m l n a n t , t h e n e n d o trial hyperplasia is virtually excluded. N o t o n e c a s e o f h y p e r p l a s i a w a s f o u n d in 2 2 0 c o n s e c u t i v e e n d o m e t r i a l b i o p s i e s in 2 2 0 p a t i e n t s r e c e i v i n g the f o l l i n g r e g i m e n : O . O 8 m g m e s t r a n o l f r o m d a y 1 t o d a y 7, a n d 0 . 0 7 5 m g m e s t r a n o l p l u s 2.5 m g l y n e s t r e n o l f r o m d a y 8 t o d a y 22 ( R / O v a n o n , O r g a n o n ) . It s h o u l d b e e m p h i z e d t h a t f o r r e a s o n s as y e t u n k n n, in the majority of cases, endometrial hyperplasia remains asy tomatlc.
¸662¸
DECEMBER
1975
V O L . 12 N O . 6
O N ' I R"A C E P ' T IO N
C O N
C L U
S I O N
S
Oral contraception of a sequential type with a hi ly potent estrogen (ethinyl-estradioi, O.1 ~g or O.O8 mg daily) can very often induce endo trial hyperplasia, and, re rarely, adenomatous hyperplasia. It h a s n o t b e e n p r o v e d t h a t 1 ering the daily dose of ethinyl-estradiol to O.O5 mg, will reduce the risk. Long-term treatment with these sequential fo ulatlons has to b e admi n i s te red with c au t i on, t akin g i n t o a ccou n t the pos s ib i I i ty of end trial premali ant transfo ation. On the other hand, the prolongation of the estro-progestational phase beyond 8 days will undoubtedly reduce the incidence of cystic and aden at s hyperplasia. AC
EDGEMENTS
wish to thank Hoffmann-La Roche Labora Swltzerland) f o r s u p p l i e s o f m a t e r i a l ....
ties
(Basle,
R E F E R E N C E S i. G U S B E R G , S . B . Precursors adenomatous hyperplasia.
of
corpus J Obst
carcinoma estrogens G y n e c 54 : 9 O S - 9 2 7
d (1947)
2.
GUSBERG, S.B. and H L, R . E . Precursors of corpus cancer. IiI. e appearance of cancer of the endo trium in estrogenically conditloned patients. O b s t G y n e c 17 : 3 9 7 - 4 1 2 (196 i )
3.
GO , H. a n d endometrium.
HE !G, Clin
A.T. Premalignant st Gynec 5 : i148
lesions of the - 1 i 6 5 (1962)
4. D LENB~H-HELL G, G. Endometrium. Pathologische Histologie in D i a g n o s t i k und Forschung. Springe~ ~ rlag Berlin (1969) 5.
F E R I N , J. Effect of replacement erapy on endo t r i u m in post-menopausal ne in "The Menopausal Syndro " B Ed O R.B. Gre~blatt, V . B . M a h e s h a n d P .G. M c D o n o u g h , Medcom Press, N . Y . , 1 9 7 4 , p. 1 4 3 - 1 4 6 .
6.
KIS ER, R.W., o lation by
D
C E.
, C.J. and st Gynec 8
S E L L , H. : 399 - 404
7. W I L K I N S , E.J., IEDRICH, E.G., and CIS, J.C. Turner' s syndr carcinoma and stilbestrol thera . (! 973 )
DECEMBER
75
L. 12
. 6
Suppress ion (1956)
INGLY, R.F., e with endo trial st n e c 42 : 1 9 3
of
I, J . A . eno- 2
3
CONTRACE
8.
ION
glstry for contraceptive
endometrial carcinoma agents, items, er
in young women taking oral J Obst Gynec ll8 : 747
(19 7 4 ) 9.
HO f fman n-La n ic a t i on.
Ro c h e Lab or a to rie s
B a s i e,
S w i t z e r i a n d.
10.
FERIN, J. Orally active progestational compounds. Human studies : effects o n t h e u t e r o ...v.a g l n a l tract. I n " P h a .....a c o l ogy of the endocrine system and related drugs : progesterone, progestational druqs and antif~rtility agents ,Ed. M. Tausk, v o l . if, I n t e r n a t i o n a l Encyclopedia of Pharmacology and Th apeutics, Pergamon Press, N , Y o B !972 # p ~ 245-273 o
Ii.
DELFO E, J . P . and FERIN, J. A histometric study of estrogens : ethinyl-estradiol and its 3-methyl-ether ative (,,~estranol) ; t h e i r comparative effect upon the of the human endometrium. Contraception 1 : 5 7 - 72
12.
GUSBERG, S Obst Gynec
13.
GUSBE , SoB. and K L , A.L. Precursors of corpus cancer. IV. A d e n o m a t o u s hyperplasia as stage O carcin a of the endometrium J Obst Gynec 87 : 662 - 676 (19631
14.
K O L L E R t O. The risk of develo ent of u refine cancer patients with breast cancer after long-term treatment estrogen in massive doses. Acta Obst nec Stand 45 1 i 3 (1966 )
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16.
17.
6,
K S E , L. P e r s on a i co
HEBER, K.R. Contraception
B. 30
Hormone 257 -
A
flexible iO : 241
ependence 293 (1967)
-
of
endometrial
low dosage system 250 (i974)
of
oral
t der growth (1970)
cancer.
in with : lll
-
con~'~aceptlon.
LONGCOPE, C. Metabolic clearance of estrogens in post-menopausal w 778 - 781 (1971)
and blood production rates en. e~-J st ~ynec iiI
SCH R T Z , U. a n d H RSTEIN, J. various contraceptive steroids as on transcortin-binding capacity. (1974)
The estrogenic potency of dete ined b y t h e i r e f f e c t s Acta endocr 76 : 159 171
DECEMBER
179', 5
:
L. 12 N O . 6
