- Email: [email protected]
Plasma progesterone levels during infusion of prostaglandin F2α in the human
PROSTAGLANDINS
Abteitung fQP ktinische und expertmentette Endokrinotogte, Universit~ts-Frauenkttntk,
Hamburg, Germany
Plasma Progesterone Levels During
Infusion Of Prostaglandin F2c(
in The Human
F. Lehmann, F. Peters, M. Breckwoldt and G. Bettendorf
Supported by Deutsche Forschungsgemetnschaft ( S F B 34) Accepted April 23, 1972
APRIL 1972
VOL. 1 NO. 4
269
PROSTAGLANDINS
In 1923 L O E B r e p o r t e d t h a t the p r e s e n c e o f t h e u t e r u s w a s e s s e n t i a l f o r a n o r m a l o v a r i a n f u n c t i o n in g u i n e a pigs n o t i n g t h a t the l t f e s p a n o f the c o r p u s l u t e u m w a s m a r k e d l y e l o n g a t e d f o l l o w i n g hysterectomy. A persisting corpus luteum following hysterectomy w a s s u b s e q u e n t l y found in v a r i o u s o t h e r s p e c i e s such as sheep, p i g , h a m s t e r and r a t ( C A L D W E L L ) .
M a n y a t t e m p t s h a v e been m a d e
to c l a r i f y t h i s p h e n o m e n o n . T h e r e is a c c u m u l a t i n g e v i d e n c e t h a t the p e r s i s t i n g c o r p u s t u t e u m is due to the a b s e n c e o f u t e r i n e p r o s t a g t a n d t n s . T h e m e c h a n i s m o f a c t i o n o£ p r o s t a g t a n d t n s has not y e t been c l a r i f i e d . A c c o r d i n g to M c O R A C K E N et a t . p r o s t a g t a n d i n F2~ changes t h e o v a r i a n b l o o d f t o w d u r i n g t h e l u t e a t phase in sheep. A d e c r e a s e d b t o o d f l o w m a y be r e g a r d e d as t h e t u t e o t y t i c p r i n c i p l e , (Du C H A R M E
et a t . ,
PHARRIS
et a t . )
A s r e p o r t e d by M c C R A C K E N et a t . p r o s t a g t a n d i n F2c( caused a r e d u c t i o n o f p r o g e s t e r o n e s e c r e t i o n a s s o c i a t e d w i t h an i n c r e a s e of 20~-OH progesterone. PHARRIS
et a t . o b s e r v e d s i m i l a r changes
in the o v a r i a n s t e r o i d c o n c e n t r a t i o n s in r a t s .
T h i s p a p e r d e s c r i b e s the e f f e c t o f prostagteJndin F2oc ( P G F2~ ) on t h e p l a s m a p r o g e s t e r o n e l e v e l s in t h e h u m a n d u r i n g t h e t u t e a t phase and during
therapeutic abortion.
MATERIAL
AND
METHODS
A h e a l t h y 29 y e a r s o l d f e m a l e w i t h a nor-mat m e n s t r u a l c y c l e o f 28 days w a s s t u d i e d f o r 4 c o n s e c u t i v e c y c l e s . P l a s m a p r o g e s t e r o n e l e v e l s w e r e d e t e r m i n e d d a i l y a c c o r d i n g t o a m o d i f i c a t i o n o f the m e t h o d as d e s c r i b e d by J O H A N N S O N ,
T h e f i r s t c y c l e s e r v e d as c o n t r o l , in
the second c y c l e 1 mg PG F2E w a s i n f u s e d o v e r a p e r i o d o f 4 h o u r s on d a y 21. In t h e s u b s e q u e n t c y c l e 25 m g o f PG F2~ w e r e i n t r a v e n o u s l y
270
A P R I L 1972
VOL. 1 NO. 4
PROSTAGLANDINS
a d m i n i s t e r e d b y i n f u s i o n w i t h i n 5 h o u r s on the s a m e d a y o f the c y c l e , the 4th c y c l e s e r v e d again as c o n t r o l .
In 16 p a t i e n t s a d m i t t e d t o t h e h o s p i t a l f o r t h e r a p e u t i c a b o r t i o n (10th t o 26th w e e k o f g e s t a t i o n ) p l a s m a p r o g e s t e r o n e l e v e l s w e r e d e t e r m i n e d in 4 - 12 h o u r s i n t e r v a l s b e f o r e , d u r i n g and a f t e r the infusion of pg/min,
PG F2G. T h e i n f u s i o n r a t e r a n g e d between 5 0 and 2 0 0
until
abortion was completed. Side-effects
such as v o m i t i n g
and d i a r r h o e a
c o u l d be o v e r c o m e b y i n t r a v e n o u s a d m i n i s t r a t i o n o f x A t r o p i n ~ P a s p e r t i n R and 2 0 d r o p s o f a 1 % r n o r p h i n s o l u t i o n o r a l y .
RESU LTS
F i g . 1 i l l u s t r a t e s t h e e f f e c t o f PG F2~ on the f u n c t i o n o f the c o r p u s l u t e u m as f o l l o w e d b y the p l a s m a p r o g e s t e r o n e l e v e l s . 1 m g o f PG F2~ is w i t h o u t a n y s i g n i f i c a n t e f f e c t as c o m p a r e d t o the c o n t r o l c y c l e s . 48 h o u r s a f t e r the i n f u s i o n o f 25 m g PG F2~ a s h a r p d e c l i n e o f the p r o g e s t e r o n e l e v e l s in t h e p e r i p h e r a l b l o o d i s n o t e d . 72 h o u r s t a t e r p r o g e s t e r o n e l e v e l s a r e l e s s than 1 n g / m l and m e n s t r u a t i o n o c c u r s . T h e t u t e a l phase o f the f o l l o w i n g c o n t r o l c y c l e d i s p l a y s a g a i n the n o r m a l p a t t e r n .
Fig.
2 i t l u s t r a t e s the p l a s m a p r o g e s t e r o n e l e v e l s in 6 p a t i e n t s
d u r i n g t h e i n d u c t i o n o f t h e r a p e u t i c a b o r t i o n in the 12th-14th w e e k o f g e s t a t i o n . 2 7 . 5 - 120 m g PG F2~ w e r e infused at a f t o w r a t e o f 5 0 200 #g/min.
until complete abortion was achieved. The infusion-time
v a r i e d b e t w e e n 5 . 5 end 12 h o u r s . In a l l c a s e s p l a s m a p r o g e s t e r o n e l e v e l s d e c r e a s e d t o m o p e then 5 0 ~ w i t h i n 12 h o u r s , h o w e v e r the t i m e r e q u i r e d For c o m p l e t e a b o r t i o n d i s p l a y e d i n d i v i d u a l v a r i a t i o n s . If the a b o r t i o n c o u l d not be a c h i e v e d w i t h i n 10 h o u r s the i n f u s i o n w a s d i s c o n t i n u e d f o r 12 h o u r s and then r e s u m e d . F i g . 8 p r e s e n t s R:
2 - M e t h o x y - 4 - a m t n o - 5 - c h l o r b e n z o e s ~ u r e - N - ( 6 - N L d i ~ t h y l - a m ino -
~ t h y l ) - a m i d - m o n o - h y d r o c h l o r id.
APRIL 1972
VOL. 1 NO. 4
271
PROSTAGLANDINS
LUTEOLYSISWITH PGF2
i
,s
r///JVlllllll/~
~H/;N,'///#I
Fig, 1
Effect of PG F2 -inCusion on the corpus tuteum menstruationis
Therapeutic A b o l t i o n w i t h P G F 2 o(
RosmQ progestins ng/ml
12.-14.week of Gestation
pmgestin-tevetofter10hours:55
301
.......
20
~
10
Fig. 2
272
time "
20
30
40
50
%
of •
60 70 80 90 I~ou~ ~ e r 5tQrt
Therapeutic abortion with PG F2c(
•
i00
A b o r t i o n within 12 hours.
A P R I L 1972
VOL. 1 NO. 4
PROSTAGL&NDINS
Rasma ~st*r,s ~lr~
Therapeutic abortion with P G F 2 I0 ° 18 week of gestation ........ time of infusion i n f u s m n on two consecutive days, in one ca.~,e n o s~cces
~01
I~ogestln4ev~ after tOho=Jrs: 65=/, intermisc~on 12 t,ou~
0
10
cur~ta~
20
30
~,0
50
6C ?(' 8C hours Qfle¢ slart
~L
T h e r a p e u t i c a b o r t t o n w i t h PG F2~ A b o r t i o n w i t h i n 2 4 h o u r s , Fig. 3
t2 hours intermission~
in o n e c a s e n o r e s p o n s e .
Therapeutic A b o r t i o n @th week of g e ~ o n c ~ n p e t s i o n of the pre£estin- d c ~ e t i ~ Res~ mogest~ nglr~
PGF2 = ( 125m£ ;n 15 hours } cut.rage
~--~ 20
20
3O
~
~
6O
70
8O
90
I00 hoo,s
C o m p a r - t s o n o f p l a s m a p r o g e s t t n l e v e l s in t h e r a p e u t i c Fig, 4
abortion, *- . . . . . . . .
d i l a t a t i o n and c u r e t t a g e PG 2F(x i n d u c e d a b o r t i o n .
APRIL 1972
¥ O L . 1 NO. 4
273
PROSTAGLANDINS
t h e p l a s m a p r o g e s t e r o n e v a l u e s in t h e s e c a s e s . A t the end o f the f i r s t i n f u s i o n p l a s m a p r o g e s t e r o n e l e v e l s had d r o p p e d to a b o u t 65 o f the o r i g i n a l v a l u e , In 4 c a s e s t h e p r o g e s t e r o n e l e v e l s w e r e c o n t i n u o u s l y f a i l i n g d u r i n g the i n t e r m i s s i o n t i m e .
In t w o cases the
d e c r e a s e w a s tess p r o n o u n c e d . In one case the p r o g e s t e r o n e l e v e l s r e m a i n e d c o n s t a n t , T h i s p a t i e n t d i d n o t r e s p o n d a t a l l , no u t e r i n e contractions were recorded. The
abortion was finally performed
by d i l a t a t i o n and c u r e t t a g e ,
F i g . 4 c o m p a r e s the p l a s m a p r o g e s t e r o n e l e v e l s o f 2 p a t i e n t s . In the f i r s t p a t i e n t t h e r a p e u t i c a b o r t i o n w a s a c h i e v e d by i n f u s i o n o f PG F2G. In the 2. p a t i e n t a b o r t i o n w a s induced and c o m p l e t e d by d i l a t a t i o n and c u r e t t a g e , T h e s l i g h t l y e l e v a t e d p r o g e s t e r o n e l e v e l s in t h e p a t i e n t t r e a t e d w i t h c u r e t t a g e m i g h t be due t o t h e f u n c t i o n o f the r e g r e s s i n g c o r p u s l u t e u m g r a v i d i t a t i s .
In t h e p a t i e n t t r e a t e d b y
p r o s t a g t a n d i n i n f u s i o n the d e c r e a s e o f the p l a s m a p r o g e s t e r o n e l e v e l s is m o r e p r o n o u n c e d . 72 h o u r s a f t e r the b e g i n n i n g o f t h e i n f u s i o n t h e l e v e l s o f t h i s p a t i e n t a r e l e s s than t n g / m l .
DISCUSSION
T h e data reported in this paper indicate that P G F2~ exerts a luteol y t i c e f f e c t on the n o r m a l c o r p u s l u t e u m m e n s t r u a t i o n s and g r a v i d i t a t i s in the h u m a n . L u t e o t y s i s a c h i e v e d by p r o s t a g l a n d i n s has been r e p o r t e d in o t h e r s p e c i e s ( P H A R R I S and VVYNGARDEN, K I R T O N et al., McORACKEN
et a t . ) . On the o t h e r hand p r o s t a g l a n d i n s have a
p r o n o u n c e d s t i m u l a t i n g e f f e c t on u t e r i n e c o n t r a c t i l i t y in v i v o K A R M I N et a t . and in v i t r o S A N D B E R G et a l . T h e i n d u c t i o n o f a b o r t i o n is the consequence o f s t i m u l a t e d u t e r i n e c o n t r a c t i l i t y . T h e r a p i d l y d e c r e a s i n g p l a s m a p r o g e s t e r o n e l e v e l s have to be c o n s i d e r e d as
274
A P R I L 1972
VOL. 1 NO. 4
PROSTAGLANDINS
a r ' e f t e c t i o n o f m e c h a n i c a l t e r a t i o n s on the p l a c e n t a , s i n c e the t i m e r e q u i r e d f o r i n d u c t i o n o f a b o r t i o n - i n a v e r a g e 10 h o u r s - i s r e l a t i v e l y s h o r t . In s u m m a r y w e m i g h t c o n c l u d e t h a t PG F2G e x h i b i t s in the h u m a n a l u t e o t y t i c e f f e c t and a s t i m u l a t i n g e f f e c t on t h e m y o m e t r i u m as w e l t . FoP c o m p l e t e l u t e o l y s i s o f the n o r m a l c o r p u s l u t e u m 72 h o u r s a r e r e q u i r e d in the h u m a n and a l s o in the sheep ( M c C R A O K E N et a t . ) and in the m o n k e y ( K I R T O N et a t . ) P r o g e s t e r o n e is shown to i n h i b i t m y o m e t r i a l r e s p o n s e t o PG F2G in t h e r a b b i t ( P O R T E R and B E H R M A N ) t h e r e f o r e a d i r e c t c o m p e t i t i o n o f PG F2~ and p r o g e s t e r o n e on the t a r g e t c e l t m a y be a s s u m e d . T h e a b o r t i f i c a n t e f f e c t o f PG F2G h o w e v e r s e e m s to be i n d e p e n d e n t o f the
plasma proges-
t e r o n e l e v e l s . T h e q u e s t i o n w h e t h e r PG i n t e r f e r e w i t h
the p r o g e s -
t e r o n e s y n t h e s i s i t s e l f cannot be a n s w e r e d b y o u r d a t a ,
ACKNOWLEDGEMENT We a r e i n d e b t e d to D r . B r u n n b e r g , Upjohn Co, g e r m a n b r a n c h f o r F u r n i s h i n g us w i t h the PG F2G s a m p l e s .
APRIL 1972
VOL. 1 NO. 4
275
PROSTAGLANDINS
SUMMARY
T h e e f f e c t o f p r o s t a g l a n d i n F2G on t h e p l a s m a p r o g e s t e r o n e l e v e l s in t h e h u m a n d u r i n g t h e l u t e a l phase and d u r i n g t h e r a p e u t i c a b o r t i o n i s d e s c r i b e d in t h i s p a p e r . T h e i n f u s i o n o f 25 m g o f p r o s t a g l a n d i n F2G on d a y 21 o f a n o r m a l m e n s t r u a l c y c l e c a u s e d a p r o n o u n c e d d e c r e a s e o f the p l a s m a p r o g e s t e r o n e l e v e l s t o t e s s than 1 n g / m t w i t h i n 72 h o u r s .
F o r t h e i n d u c t i o n o f a b o r t i o n 2 7 . 5 t o 120 m g PG F2~ w e r e i n f u s e d i n t r a v e n e o u s l y a t a f t o w r a t e o f 5 0 t o 200 l l g / m i n u t e . W i t h i n 12 h o u r s p l a s m a p r o g e s t e r o n e l e v e l s d r o p p e d to m o r e t h a n 5 0 ~ in c a s e s w h e r e c o m p l e t e a b o r t i o n w a s a c h i e v e d w i t h i n 10 h o u r s . If c o m p l e t e a b o r t i o n c o u l d n o t be a c h i e v e d w i t h i n 10 h o u r s t h e p l a s m a p r o g e s t e r o n e l e v e l s had d r o p p e d o n l y t o a b o u t 65 ~ o f t h e o r i g i n a l v a l u e .
T h e d a t a o b t a i n e d in t h i s s t u d y i n d i c a t e t h a t p r o s t a g i a n d i n F2~ e x h i b i t s a l u t e o l y t i c e f f e c t on t h e h u m a n c o r p u s t u t e u m m e n s t r u a t i o n i s and g r a v i d i t a t i s and a s t i m u l a t i n g e f f e c t on t h e m y o m e t r t u m
276
A P R I L 1972
as w e l l .
VOL. 1 NO. 4
PROSTAGLANDINS
REFERENCES
1. DUCHARME, D.W. , and J . R . WEEKS, Nobel Symposton 2, 173 (1968)
2. DUCHARME, D . W . , J . R . WEEKS and R . G . MONTGOMERY: J. PhaPmacol. exp. theP. : 160, 1 (1968)
3. C A L D W E L L ,
B . V . : in Advances tn the Btosctences: 4,399
(1969) G. Raspe (editor') Pergamon Pr-ess, Vieweg
4. JOHANNSON, E . D . B . : Acta endocc. (Kbh): 61, 592 (1969)
5. KIRTON, K . T . ,
B . B . PHARRIS and A . D. FORBES: Proc.
soc. exp. b i o l . m e d . : 133,314 (1970)
6. LEHMANN, F . F . ,
F. P E T E R S , M. BRECKWOLDT and
G. BETTENDORF: Acta endocr-. (Kbh): Suppl. 159,61 (1972)
7. LOEB, L . : Pr'oc. soc. exp. b i o l . med. : 2 0 , 4 4 1 (1923)
8. McCRACKEN, J . A . ,
M . E . GLEW and R . J . S C R A M U Z Z h
J. c l i n . endocc, m e t a b . : 3 0 , 5 4 4 (1970)
9. PHARRtS, B . B . and L . J . VVYNGARDEN: P r o c . soc. exp. biol. reed. : 180, 92 (1969)
10. PORTER, D.G. and H . R . BEHRMANN: Natur'e, 232, 627 (1971)
11. SANDBERG, F . A . I N G E L M A N - S U N D B E R G and G. RYDEN: A c t a obstet, gynec, scand. : 44,585 (1966) APRIL
1972
VOL.
1 NO. 4
277
Abteitung fQP ktinische und expertmentette Endokrinotogte, Universit~ts-Frauenkttntk,
Hamburg, Germany
Plasma Progesterone Levels During
Infusion Of Prostaglandin F2c(
in The Human
F. Lehmann, F. Peters, M. Breckwoldt and G. Bettendorf
Supported by Deutsche Forschungsgemetnschaft ( S F B 34) Accepted April 23, 1972
APRIL 1972
VOL. 1 NO. 4
269
PROSTAGLANDINS
In 1923 L O E B r e p o r t e d t h a t the p r e s e n c e o f t h e u t e r u s w a s e s s e n t i a l f o r a n o r m a l o v a r i a n f u n c t i o n in g u i n e a pigs n o t i n g t h a t the l t f e s p a n o f the c o r p u s l u t e u m w a s m a r k e d l y e l o n g a t e d f o l l o w i n g hysterectomy. A persisting corpus luteum following hysterectomy w a s s u b s e q u e n t l y found in v a r i o u s o t h e r s p e c i e s such as sheep, p i g , h a m s t e r and r a t ( C A L D W E L L ) .
M a n y a t t e m p t s h a v e been m a d e
to c l a r i f y t h i s p h e n o m e n o n . T h e r e is a c c u m u l a t i n g e v i d e n c e t h a t the p e r s i s t i n g c o r p u s t u t e u m is due to the a b s e n c e o f u t e r i n e p r o s t a g t a n d t n s . T h e m e c h a n i s m o f a c t i o n o£ p r o s t a g t a n d t n s has not y e t been c l a r i f i e d . A c c o r d i n g to M c O R A C K E N et a t . p r o s t a g t a n d i n F2~ changes t h e o v a r i a n b l o o d f t o w d u r i n g t h e l u t e a t phase in sheep. A d e c r e a s e d b t o o d f l o w m a y be r e g a r d e d as t h e t u t e o t y t i c p r i n c i p l e , (Du C H A R M E
et a t . ,
PHARRIS
et a t . )
A s r e p o r t e d by M c C R A C K E N et a t . p r o s t a g t a n d i n F2c( caused a r e d u c t i o n o f p r o g e s t e r o n e s e c r e t i o n a s s o c i a t e d w i t h an i n c r e a s e of 20~-OH progesterone. PHARRIS
et a t . o b s e r v e d s i m i l a r changes
in the o v a r i a n s t e r o i d c o n c e n t r a t i o n s in r a t s .
T h i s p a p e r d e s c r i b e s the e f f e c t o f prostagteJndin F2oc ( P G F2~ ) on t h e p l a s m a p r o g e s t e r o n e l e v e l s in t h e h u m a n d u r i n g t h e t u t e a t phase and during
therapeutic abortion.
MATERIAL
AND
METHODS
A h e a l t h y 29 y e a r s o l d f e m a l e w i t h a nor-mat m e n s t r u a l c y c l e o f 28 days w a s s t u d i e d f o r 4 c o n s e c u t i v e c y c l e s . P l a s m a p r o g e s t e r o n e l e v e l s w e r e d e t e r m i n e d d a i l y a c c o r d i n g t o a m o d i f i c a t i o n o f the m e t h o d as d e s c r i b e d by J O H A N N S O N ,
T h e f i r s t c y c l e s e r v e d as c o n t r o l , in
the second c y c l e 1 mg PG F2E w a s i n f u s e d o v e r a p e r i o d o f 4 h o u r s on d a y 21. In t h e s u b s e q u e n t c y c l e 25 m g o f PG F2~ w e r e i n t r a v e n o u s l y
270
A P R I L 1972
VOL. 1 NO. 4
PROSTAGLANDINS
a d m i n i s t e r e d b y i n f u s i o n w i t h i n 5 h o u r s on the s a m e d a y o f the c y c l e , the 4th c y c l e s e r v e d again as c o n t r o l .
In 16 p a t i e n t s a d m i t t e d t o t h e h o s p i t a l f o r t h e r a p e u t i c a b o r t i o n (10th t o 26th w e e k o f g e s t a t i o n ) p l a s m a p r o g e s t e r o n e l e v e l s w e r e d e t e r m i n e d in 4 - 12 h o u r s i n t e r v a l s b e f o r e , d u r i n g and a f t e r the infusion of pg/min,
PG F2G. T h e i n f u s i o n r a t e r a n g e d between 5 0 and 2 0 0
until
abortion was completed. Side-effects
such as v o m i t i n g
and d i a r r h o e a
c o u l d be o v e r c o m e b y i n t r a v e n o u s a d m i n i s t r a t i o n o f x A t r o p i n ~ P a s p e r t i n R and 2 0 d r o p s o f a 1 % r n o r p h i n s o l u t i o n o r a l y .
RESU LTS
F i g . 1 i l l u s t r a t e s t h e e f f e c t o f PG F2~ on the f u n c t i o n o f the c o r p u s l u t e u m as f o l l o w e d b y the p l a s m a p r o g e s t e r o n e l e v e l s . 1 m g o f PG F2~ is w i t h o u t a n y s i g n i f i c a n t e f f e c t as c o m p a r e d t o the c o n t r o l c y c l e s . 48 h o u r s a f t e r the i n f u s i o n o f 25 m g PG F2~ a s h a r p d e c l i n e o f the p r o g e s t e r o n e l e v e l s in t h e p e r i p h e r a l b l o o d i s n o t e d . 72 h o u r s t a t e r p r o g e s t e r o n e l e v e l s a r e l e s s than 1 n g / m l and m e n s t r u a t i o n o c c u r s . T h e t u t e a l phase o f the f o l l o w i n g c o n t r o l c y c l e d i s p l a y s a g a i n the n o r m a l p a t t e r n .
Fig.
2 i t l u s t r a t e s the p l a s m a p r o g e s t e r o n e l e v e l s in 6 p a t i e n t s
d u r i n g t h e i n d u c t i o n o f t h e r a p e u t i c a b o r t i o n in the 12th-14th w e e k o f g e s t a t i o n . 2 7 . 5 - 120 m g PG F2~ w e r e infused at a f t o w r a t e o f 5 0 200 #g/min.
until complete abortion was achieved. The infusion-time
v a r i e d b e t w e e n 5 . 5 end 12 h o u r s . In a l l c a s e s p l a s m a p r o g e s t e r o n e l e v e l s d e c r e a s e d t o m o p e then 5 0 ~ w i t h i n 12 h o u r s , h o w e v e r the t i m e r e q u i r e d For c o m p l e t e a b o r t i o n d i s p l a y e d i n d i v i d u a l v a r i a t i o n s . If the a b o r t i o n c o u l d not be a c h i e v e d w i t h i n 10 h o u r s the i n f u s i o n w a s d i s c o n t i n u e d f o r 12 h o u r s and then r e s u m e d . F i g . 8 p r e s e n t s R:
2 - M e t h o x y - 4 - a m t n o - 5 - c h l o r b e n z o e s ~ u r e - N - ( 6 - N L d i ~ t h y l - a m ino -
~ t h y l ) - a m i d - m o n o - h y d r o c h l o r id.
APRIL 1972
VOL. 1 NO. 4
271
PROSTAGLANDINS
LUTEOLYSISWITH PGF2
i
,s
r///JVlllllll/~
~H/;N,'///#I
Fig, 1
Effect of PG F2 -inCusion on the corpus tuteum menstruationis
Therapeutic A b o l t i o n w i t h P G F 2 o(
RosmQ progestins ng/ml
12.-14.week of Gestation
pmgestin-tevetofter10hours:55
301
.......
20
~
10
Fig. 2
272
time "
20
30
40
50
%
of •
60 70 80 90 I~ou~ ~ e r 5tQrt
Therapeutic abortion with PG F2c(
•
i00
A b o r t i o n within 12 hours.
A P R I L 1972
VOL. 1 NO. 4
PROSTAGL&NDINS
Rasma ~st*r,s ~lr~
Therapeutic abortion with P G F 2 I0 ° 18 week of gestation ........ time of infusion i n f u s m n on two consecutive days, in one ca.~,e n o s~cces
~01
I~ogestln4ev~ after tOho=Jrs: 65=/, intermisc~on 12 t,ou~
0
10
cur~ta~
20
30
~,0
50
6C ?(' 8C hours Qfle¢ slart
~L
T h e r a p e u t i c a b o r t t o n w i t h PG F2~ A b o r t i o n w i t h i n 2 4 h o u r s , Fig. 3
t2 hours intermission~
in o n e c a s e n o r e s p o n s e .
Therapeutic A b o r t i o n @th week of g e ~ o n c ~ n p e t s i o n of the pre£estin- d c ~ e t i ~ Res~ mogest~ nglr~
PGF2 = ( 125m£ ;n 15 hours } cut.rage
~--~ 20
20
3O
~
~
6O
70
8O
90
I00 hoo,s
C o m p a r - t s o n o f p l a s m a p r o g e s t t n l e v e l s in t h e r a p e u t i c Fig, 4
abortion, *- . . . . . . . .
d i l a t a t i o n and c u r e t t a g e PG 2F(x i n d u c e d a b o r t i o n .
APRIL 1972
¥ O L . 1 NO. 4
273
PROSTAGLANDINS
t h e p l a s m a p r o g e s t e r o n e v a l u e s in t h e s e c a s e s . A t the end o f the f i r s t i n f u s i o n p l a s m a p r o g e s t e r o n e l e v e l s had d r o p p e d to a b o u t 65 o f the o r i g i n a l v a l u e , In 4 c a s e s t h e p r o g e s t e r o n e l e v e l s w e r e c o n t i n u o u s l y f a i l i n g d u r i n g the i n t e r m i s s i o n t i m e .
In t w o cases the
d e c r e a s e w a s tess p r o n o u n c e d . In one case the p r o g e s t e r o n e l e v e l s r e m a i n e d c o n s t a n t , T h i s p a t i e n t d i d n o t r e s p o n d a t a l l , no u t e r i n e contractions were recorded. The
abortion was finally performed
by d i l a t a t i o n and c u r e t t a g e ,
F i g . 4 c o m p a r e s the p l a s m a p r o g e s t e r o n e l e v e l s o f 2 p a t i e n t s . In the f i r s t p a t i e n t t h e r a p e u t i c a b o r t i o n w a s a c h i e v e d by i n f u s i o n o f PG F2G. In the 2. p a t i e n t a b o r t i o n w a s induced and c o m p l e t e d by d i l a t a t i o n and c u r e t t a g e , T h e s l i g h t l y e l e v a t e d p r o g e s t e r o n e l e v e l s in t h e p a t i e n t t r e a t e d w i t h c u r e t t a g e m i g h t be due t o t h e f u n c t i o n o f the r e g r e s s i n g c o r p u s l u t e u m g r a v i d i t a t i s .
In t h e p a t i e n t t r e a t e d b y
p r o s t a g t a n d i n i n f u s i o n the d e c r e a s e o f the p l a s m a p r o g e s t e r o n e l e v e l s is m o r e p r o n o u n c e d . 72 h o u r s a f t e r the b e g i n n i n g o f t h e i n f u s i o n t h e l e v e l s o f t h i s p a t i e n t a r e l e s s than t n g / m l .
DISCUSSION
T h e data reported in this paper indicate that P G F2~ exerts a luteol y t i c e f f e c t on the n o r m a l c o r p u s l u t e u m m e n s t r u a t i o n s and g r a v i d i t a t i s in the h u m a n . L u t e o t y s i s a c h i e v e d by p r o s t a g l a n d i n s has been r e p o r t e d in o t h e r s p e c i e s ( P H A R R I S and VVYNGARDEN, K I R T O N et al., McORACKEN
et a t . ) . On the o t h e r hand p r o s t a g l a n d i n s have a
p r o n o u n c e d s t i m u l a t i n g e f f e c t on u t e r i n e c o n t r a c t i l i t y in v i v o K A R M I N et a t . and in v i t r o S A N D B E R G et a l . T h e i n d u c t i o n o f a b o r t i o n is the consequence o f s t i m u l a t e d u t e r i n e c o n t r a c t i l i t y . T h e r a p i d l y d e c r e a s i n g p l a s m a p r o g e s t e r o n e l e v e l s have to be c o n s i d e r e d as
274
A P R I L 1972
VOL. 1 NO. 4
PROSTAGLANDINS
a r ' e f t e c t i o n o f m e c h a n i c a l t e r a t i o n s on the p l a c e n t a , s i n c e the t i m e r e q u i r e d f o r i n d u c t i o n o f a b o r t i o n - i n a v e r a g e 10 h o u r s - i s r e l a t i v e l y s h o r t . In s u m m a r y w e m i g h t c o n c l u d e t h a t PG F2G e x h i b i t s in the h u m a n a l u t e o t y t i c e f f e c t and a s t i m u l a t i n g e f f e c t on t h e m y o m e t r i u m as w e l t . FoP c o m p l e t e l u t e o l y s i s o f the n o r m a l c o r p u s l u t e u m 72 h o u r s a r e r e q u i r e d in the h u m a n and a l s o in the sheep ( M c C R A O K E N et a t . ) and in the m o n k e y ( K I R T O N et a t . ) P r o g e s t e r o n e is shown to i n h i b i t m y o m e t r i a l r e s p o n s e t o PG F2G in t h e r a b b i t ( P O R T E R and B E H R M A N ) t h e r e f o r e a d i r e c t c o m p e t i t i o n o f PG F2~ and p r o g e s t e r o n e on the t a r g e t c e l t m a y be a s s u m e d . T h e a b o r t i f i c a n t e f f e c t o f PG F2G h o w e v e r s e e m s to be i n d e p e n d e n t o f the
plasma proges-
t e r o n e l e v e l s . T h e q u e s t i o n w h e t h e r PG i n t e r f e r e w i t h
the p r o g e s -
t e r o n e s y n t h e s i s i t s e l f cannot be a n s w e r e d b y o u r d a t a ,
ACKNOWLEDGEMENT We a r e i n d e b t e d to D r . B r u n n b e r g , Upjohn Co, g e r m a n b r a n c h f o r F u r n i s h i n g us w i t h the PG F2G s a m p l e s .
APRIL 1972
VOL. 1 NO. 4
275
PROSTAGLANDINS
SUMMARY
T h e e f f e c t o f p r o s t a g l a n d i n F2G on t h e p l a s m a p r o g e s t e r o n e l e v e l s in t h e h u m a n d u r i n g t h e l u t e a l phase and d u r i n g t h e r a p e u t i c a b o r t i o n i s d e s c r i b e d in t h i s p a p e r . T h e i n f u s i o n o f 25 m g o f p r o s t a g l a n d i n F2G on d a y 21 o f a n o r m a l m e n s t r u a l c y c l e c a u s e d a p r o n o u n c e d d e c r e a s e o f the p l a s m a p r o g e s t e r o n e l e v e l s t o t e s s than 1 n g / m t w i t h i n 72 h o u r s .
F o r t h e i n d u c t i o n o f a b o r t i o n 2 7 . 5 t o 120 m g PG F2~ w e r e i n f u s e d i n t r a v e n e o u s l y a t a f t o w r a t e o f 5 0 t o 200 l l g / m i n u t e . W i t h i n 12 h o u r s p l a s m a p r o g e s t e r o n e l e v e l s d r o p p e d to m o r e t h a n 5 0 ~ in c a s e s w h e r e c o m p l e t e a b o r t i o n w a s a c h i e v e d w i t h i n 10 h o u r s . If c o m p l e t e a b o r t i o n c o u l d n o t be a c h i e v e d w i t h i n 10 h o u r s t h e p l a s m a p r o g e s t e r o n e l e v e l s had d r o p p e d o n l y t o a b o u t 65 ~ o f t h e o r i g i n a l v a l u e .
T h e d a t a o b t a i n e d in t h i s s t u d y i n d i c a t e t h a t p r o s t a g i a n d i n F2~ e x h i b i t s a l u t e o l y t i c e f f e c t on t h e h u m a n c o r p u s t u t e u m m e n s t r u a t i o n i s and g r a v i d i t a t i s and a s t i m u l a t i n g e f f e c t on t h e m y o m e t r t u m
276
A P R I L 1972
as w e l l .
VOL. 1 NO. 4
PROSTAGLANDINS
REFERENCES
1. DUCHARME, D.W. , and J . R . WEEKS, Nobel Symposton 2, 173 (1968)
2. DUCHARME, D . W . , J . R . WEEKS and R . G . MONTGOMERY: J. PhaPmacol. exp. theP. : 160, 1 (1968)
3. C A L D W E L L ,
B . V . : in Advances tn the Btosctences: 4,399
(1969) G. Raspe (editor') Pergamon Pr-ess, Vieweg
4. JOHANNSON, E . D . B . : Acta endocc. (Kbh): 61, 592 (1969)
5. KIRTON, K . T . ,
B . B . PHARRIS and A . D. FORBES: Proc.
soc. exp. b i o l . m e d . : 133,314 (1970)
6. LEHMANN, F . F . ,
F. P E T E R S , M. BRECKWOLDT and
G. BETTENDORF: Acta endocr-. (Kbh): Suppl. 159,61 (1972)
7. LOEB, L . : Pr'oc. soc. exp. b i o l . med. : 2 0 , 4 4 1 (1923)
8. McCRACKEN, J . A . ,
M . E . GLEW and R . J . S C R A M U Z Z h
J. c l i n . endocc, m e t a b . : 3 0 , 5 4 4 (1970)
9. PHARRtS, B . B . and L . J . VVYNGARDEN: P r o c . soc. exp. biol. reed. : 180, 92 (1969)
10. PORTER, D.G. and H . R . BEHRMANN: Natur'e, 232, 627 (1971)
11. SANDBERG, F . A . I N G E L M A N - S U N D B E R G and G. RYDEN: A c t a obstet, gynec, scand. : 44,585 (1966) APRIL
1972
VOL.
1 NO. 4
277