Download - Effects of cyproterone acetate on reproductive functions in normal human males

C O N T R A C E ~ I O N

EFFE CTS OF CYPP/)~RONE ACETATE ON REPI~ODUCT~ FUNCTIONS IN NORMAL H~dAN M~ES

~ m n a t h Roy , M . B . B . S . , Ph . D. ~. tdha C h a t t e r j e e , P h . D ,

M. R . N . l ~ r a s a d *, P b . D . ~ y ~ r e ) , Ph . D. ( W i s c o n s i n ) A. ~ ~ d d a r , M.B. Bo S. (Cal~tta) , M. P.H. (North C a r o l i ~

D, C. l~ndey, M. ~

W i t h t e c h n i c a l a s s i s t a n c e of

H.C. ~ n d e y and Y.N. Jadhav

B i o m e d i c a l D i v i s i o n , N a t i o n a l I n s t i t u t e o f F a m i l y New D e l h i - 110016, I n d i a

* D e p a r t m e n t o f Z o o l o g y , U n i v e r s i t y of D e l h i , D e l h i - 1 1 0 0 0 7 , ~ i a

ABSTRACT

D a i l y a d m i n i s t r a t i o n of 5 o r 10 mg of c y p r o t e r o n e a ~ e t a t e to n o r m a l v o l u n t e e r s o v e r a p e r i o d of 20 w e ~ s c a u s e d a g r a d u a l d e c r e a s e in t he coun t and m o t i l i t y of s p g r m a t o z o a ~ c o n c u r r e n t l y w i th an i n c r e a s e in t he p e r c e n t a g e of n o n - m o t i l e a s w e l l a s abn<~rmal and immat~=~re s p e r m s . The a b i l i t y of m o t i l e s p e r m a t o z o a i n the e j a c u l a t e to p e n e t r a t e t h r o u g h t h e c e r v i c a l m u c u s ( K r e m e r ' s t e s t ) was mar l~ed ly i n h i b i t e d . T h e l e v e l s o f a c i d p h o s p h a t e , s i a l i c a c i d and g l y c e r y l p h o s p h o r y l c h o l i n e in t i le s e m e n d e c r e a s e d p r o g r e s s i v e l y p w h e r e a s t he l e v e l s o f f r u c t o s e d id no t show any s i g n i f i c a n t change . L i b i d o and p o t e n c y w e r e n o t s i g n i f i c a n t l y a l t e r e d . The l e v e l s o f SGOT, SGPT, s e r u m a l k a l i n e p n o s p h a t ~ s e , b lood u r e a ~ and h e m a t o c r i t v a l u e s w e r e n o t s ~ n i f i c a n t l y a l t e r e d . T h e p o s s i b l e s i t e s and m o d e of a c t i o n o f c y p r o t e r o n e a c e t a t e as w e l l a s i t s p o t e n t i a l a s a m a l e c o n t r a c e p t i v e a r e d i s c u s s e d .

Accepted for publication July 29, 1976

O C T O B E R 1976 VOL. 14 1",,/O. 403


INTRODUCTION

_ CyproteL-one a c e t a t e ( I , 2 ~ - m e t h y l e n e - 6 - c h l o r o p r e ~ - 4, 6-die~ue- 17 ~ - o l - 3 ~ 2 0 , d i o n e - 1 7 ~ - a c e t a t e ) , -which is p r o g e s t a U o ~ a s w e n as a n ~ - ~ d r o g e n i c , i n h i b i t s v a r i o u s a n d r o g e n - d e p e n d e n t o r a n d r o g e n - ind~aced b io log i ca l a c t i ons "(1-4) and p r e v e n t s the up t ake of r a d i o a c t i v e t e s t o s t e r o n e i n d i f f e r e n t t a r g e t t i s s u e s (5-8) . HAgh d o s e s o f c y p r o - t e r o n e a c e t a t e c a u s e r e c e s s i o n of s p e r m a ~ e n e s i s (9, 10} and r e d u c - t ion of f e r t i l i t y in m a l e r a t s ( 1 0 ) . C l i n i c ~ y , c y p r o t e r o n e a c e t a t e has b e e n u s e d e f f ec t ive ly to c o u n t e r a c t a n d r o g e n i c m a n i f e s ~ . t i o n s in h y p e r s e x u a ~ t y , h i r s u t i s m , s e x u a l p r e c o c i t y , and~be rdgnand m a l ~ a n t p r o s t a t i c g r o w t h s ( I1 -16) . In high d o s e s i t inhabits s p e m a t o g e n e s i s , l ib ido and po t ency in m e n ( 1 2 - 1 7 ] °

P r ~ a d et al. (18) r e p o r t e d t ~ t cont inuous r e l e a s e of m i c r o - q u a n t i t i e s o f c y ~ r o t e r o n e a c e t a t e f r o m s u b c u t a n e o u s l y i m p l a n t e d s i l ~ t i c c a p s u l e s at d o s e s too low to inhibi t t e s t i c u l a r and o t h e r a c c e s - s o r y g land funcUons , a l t e r e d e p i d i d y m ~ m i l i e u r e s u l t i n g in l o s s of m o t i l i t y and v i r i l i t y of the s p e r m a t o z o a . TbAs c a u s e d r e v e r s i b l e s t e r i l i t y in m a l e r a t s wi thou t a f f ec t ing m a t i n g b e h a v i o u r ; the s t r u c t u r a l and funcUorml J n t e g r i ~ of the a c r o s o m e s of the e p i d i ¢ / m a l s p e r m a t o z o a

m i n e w h e t h e r low d o s e s of c y p r o t e r o n e a c e t a t e would p r o d u c e s h - n ~ d i f f e r e n t ~ e f f e c t s in the Imman. The e f fec t s of t h e d r u g o n g e n e r a l h e a l t h , l i v e r and k idney func t ions and h_ematocri t v a l u e s w e r e ~ s o s t~adi~ .

M A T E R I A L S AND METHODS

E i g h t e e n hea l thy m a l e v o l u n t e e r s of p r o v e n f e r t i l i t y aged b e t w e e n 20 -40 y e a r s w e r e e n r o l l e d f o r th is s tudy at d i f f e r e n t p e r i o d s of t ime . The f ind ings on only s i x v o l u n t e e r s in each g roup who have c o m p l e t e d 20 w e e k s of d r u g t h e r a p y have been a n a l y s e d and a r e p r e s e n t e d in th is r e p o r t . A c a r e f u l h i s t o r y w a s ob ta ined and a tho rough phys i ca l e x a m i n a t i o n w a s done p r i o r to ep~rolm.ent. The v o l u n t e e r s w e r e d iv ided in to two g r o u p s , m a t c h i n g t h e i r age, b o d y w e i g h t and t h i c k n e s s of s u b - c u t a n e o u s fat. ~ Dr~ag t h e r a p y w a s in i t i a t ed fo l lowing a con t ro l p e r i o d o f 8 week~ and a p lacebo r e g i m e n o f 10 w e e k s , C y p r o t e r o n e a c e t a t e w a s a d m i n i s t e r e d o r a l l y , 10 m g p e r day t o G r o u p A ~nd 5 n lg to Group B. Sere en s a m p l e s w e r e obtained_ e v e r y fo r tn igh t wi th 3 d a y s a b s t i n e n c e b e f o r e e a c h s a m p l e , and b lood was co l l ec t ed e v e r y f o u r w e e k s . G e n e r a l w e l l - b e i n g , co i t a l f r e q u e n c y and s t a t u s of l ib ido w e r e r e c o r d e d e v e r y fn r t n igh t , mud p h y s i c a l c h e c k - u p s w e r e r e p e a t e d p e r i o d i c a l l y .

The v o l u m e of s e m e n , and the count , mo t i l i t y and m o r p h o l o g y of t he s p e r m a t o z o a w e r e s t ud i ed a c c o r d i n g to tne m e t h o d of K o l m e r et ai®

404 O C T O B E R 1976 VOL. 14 NO. a


(20). The l e v e l s of f r u c t o s e , s i a l i c a c i d , g l y c e ~ l p h o s p l ~ r y l c h o I h ~ , e (GPC) and a c i d p ~ s p h a t ~ e in the s e m e n w e r e d e t e r m i n e d ~ c o r d ~ g to the m e t h o d s o f : M a n n (21), W ~ r e n (22), Wrhite (23), and G u t m a n mud G u t m a n tga% , ' ,~spect ive ly , The l e v e l s of sex-am g l u t a m i c o x ~ t r a n s - a m i n a s e , s e ~ m g l u t a m i c p y r u v i c t r a n s a m i n a s e (SGPT),, a l k a - l i n e p ~ s p h a t ~ e and c h o l e s t e r o l w e r e s t u d i ~ i n b l o o d s m m p l e s a s i n d i c e s of l i v e r func t ion , and the l e v e l of u r e a w a s u s e d a s a n i n d e x of k i d n e y func t ion . The l e v e l s o f t h e s e c o n s t i t u e n ~ w e r e d e t e r m i n ~ a c c o r d i n g to the m e t b ~ of R e i t m a J , a n d FrarLke and A r m - s t r o n g (2 j, yon ~ e t z e l a e r a n d Zondag (27} :and r e s p e c - t i ve ly . The a b i l i t y of the s p e r m a t o z o a ~ p e n e t r a t e t ~ o ~ h c e r v i c a l m u c u s was t e s t e d in t h r e e c o n s e c u t i v e s e m e n sa_rn~es o f f o u r volun~ t e e r s i n e a c h g r o u p d u r i n g I6 th , 18th and 20 th w e e k s of d r a g t ~ r a p y by K r e / n e r ' s t e s t a s m o d ~ i e d b y Davajmn e t ~ . (29) . WI-~e s t a t i s ~ c a l ~ a / y s i s of the da t a w e r e c a r r i e d out u s i n g s t u d e n t ' s ' t ' ~ s t .

RESULTS

S p e r m Count,

In g roup A (Fig. 1), the m e a n s p e r m count s t a r t e d d e c r e a s i n g by the end of the f i r s t two w e e k s of d r u g t h e r a p y (P ~ 0 .05 ) , It was rechaced by about 60 p e r cen t be low the c o n t r o l l e v e l (P ~ 0 . 005) a t the end of s i x w e e k s of t h e r a p y and w a s m a i n t a i n e d at t h e s a m e l e v e l w i t h m i n o r f l u c t u a t i o n s up to the 12th week . D u r i n g the 14th to 20 th w e e k s , the m e a n s p e r m counts i n c r e a s e d g s w h i c h w e r e 35 to 40 p e r cen t l o w e r than the c o n t r o l 1 14 and 18 weeks}. C o n c u r r e n t w i th the drop in the s p e r m coun t s , t h e r e was a p r o g r e s s i v e i n c r e a s e in the p e r c e n t a g e of a b n o r m a l f o r m s ( P , ~ 0 . 0 0 1 at 8 th t o 2 0 t h weeks) , w h i c h i n c l u d e d v a r i o u s d e f o r m i t i e s s u c h a s doub le , g i a n t o r Din head, s w o l l e n neck , d o u b l e t a i l a s w e l l as s l o u g h e d o f f s p e r m a t i d s . 2"he p e r c e n t a g e of s p e r m a t o z o a showing good f o r w a r d move~nen t d e c r e a s e d p r o g r e s s i v e l y ( P , ~ 0 . 0 5 to ~: .0. 001} wi th the conti,-raation of the t r e a t m e n t , w h e r e a s the p e r c e n t a g e o f n o n - m o t i l e o r dead s p e r m s i n c r e a s e d p r o g r e s s i v e I y (P ,¢~ 0. 05 to ~ 0~ 001). The p e r - c e n t a g e of s l u g g i s h s p e r m a t o z o a did not s h o w any s i g n i f i c a n t c h a n g e th roughou t the t r e a t m e n t p e r i o d o f 20 w e e k s .

In group B {Fig. 2), the m e a n sperm count d e c l i n e d daring drug t h e r a p y , bu t the r a t e and ex ten t of d e c r e a s e w e r e not a s m u c h a s tha t

th we . . . . . . . . . .

w e r e 26 to 38 e x c e p t a t 6 w e r ing 12th t¢ p e r c en t be low t h e : c o n t r o l l e v e I ~ )1}. The p r o p o r t i o n s of a b n o r m a l s p e r m a t o z o a i n c r e a s e c i ve ty ( P ~ 0 . 0 5 t o < 0. 001 e x c e p t a t 4 w e e k s ) d a r i n g d r u g ther~4oy: The p e r c e n t a g e o f s p e r m a t o z o a

• I O B E R 1976 VOL. 14 PqO, 4 405

C O N T R A C E P T I O N

w i r e goo, m o v e m e n t d e c r e a s e d (P ~ 0, 005 to ~ 0. 00 I ) , w h e r e a s mtage of n o n - m o r S e o r dead s p e ~ a t o z o a i n c r e a s ~ p r 0 g r e s s i v e l y (P ~ 0 .0B to ~ 0 . 0 O I excep t a t 4 w e ~ s ) durhug the t r e a t m e n t p e r i o d .

The cP~a~uges in the v o l u m e and biocl '~emicat c o n s t i t u e n t s o~ the s e m e n a r e p r e s e n t e d i n F i g u r e s 3 ~ d 4, r e s p e c t i v e l y ,

T h e r e w a s no s i g n i f i c a n t change in s e m e n v o I u m e in e i t h e r ~ r o u ~ .

G n A ¢'- ...... o ~ r . B

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PERIOD IN FORTNIGHTS

3: M e a n s e m e n v o l u m e s w i t h S . E . i n v o l u n t e e r s r e c e i v i n g I0 m g dose (Group A~ and 5 m g dose (Group ]3) of c y p r o t e r o n e a c e t a t e d~]ring c o n t r o l and t r e a t m e n t p e r i o d . No s i g n i f i c a n t change w a s no ted in e i t h e r g roup .

In of a c i d p h o s p h a t a s e in the s e m e n d e c r e a s e d marked l~ le end of two w e e k s of d r u g t h e r a p y , and con t inued to d e c l i n e t h e r e a f t e r . T h e m e a n l e v e l of s i a l i c ?.cid d e c r e a s e d g r a d u a l l y 5 to ~ 0. 001 at 2 to 20 w e e k s ) . Tt-~ l e v e l of G P C d e c l i n e d s h a r u l v a t two w e e k s of t h e r a p y (P ~ 0.O5). a n d w a s

408 O C T O B E R 1976 VOL, 14 NO. 4

C O N T R _ A C E ~ I O N

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4: C h a n g e s :in tlle b i o c h e m i c a l c ~ s t k ~ e n t s o f s e m e n i n v o l u n t e e r s

response to androgen deprivation was noted in Lhe level of acid phosph~ttase, followed hl order by sialic acid and GPC. No sig~Aficant change wasnoted in the levels of fructose in either ~roup.

O C T O B E R 1976 VOL. 14 NO. 4 409

maint~n~ with minor ~uct~ations @ar~g the rest of the treatment period (P ~ O.O5 to~ 0.O25). :Semin~ f~ctose didnot show al~ s igni f icant c ~ r ~ e a t a ~ y t ime of d ~ g t.hera~t.

In B, the acid. phospha tase act ivi ty in the s e m e n d e c r e a s e d sha rp ly 0 .00 i} by the end of two w e e k s , ' and p r o g r e s s i v e l y t h e r e - a f t e r ~ The m e a n level of s ia l ic acid d e c l ~ e d slowly and P r o g r e s s i v e l y (P < O. 05 to ~.. 0 . 0 0 1 a t 6 t o 2 0 webks ) . The d e c r e a s e Jan t h e l e v e l s of GPC was l e s s m a r k e d (P ~-. 0 .05 to ~ 0. 005 a t 6 t o 2 0 weeks) than sialiC acid.

]Penetratio o f -Cerv ica l Mucus

four volunteers from each of the groups A andB, the penetrat- Lug abili~ of-the spermatozoa through the cervical mucuswas assessed during 16 to 20 weeks of drug adimh-~ls~ation. In-all-the ~cases, the penetrating ab~i~ ofChe spermatozoa through the cervical mucus w~ ~markedly decreased. They m,~rat~ only 10 to 20 prom into the mucus in 30 seconds and became immobile. On the other hand, spermatozoa from normal, untreated indivich~als penetrated more than 100 to 120 ~mm into the cervical mucus @.,ring thee same period.

Coital Frequency and Status of Libido:

The coital frequency (Table D and l~ido in both the ~roups r e m a i n e d u ~ t e r e d througlx)ut the t r e a t m e n t per iod , except for a t r ans i en t (for 2 to 3 w e ~ s ) d e c r e a s e in l ~ i d o in two v o l u n t e e r s of group A, f i r s t noted in the second week of t h e r a p y . In two o the r vo lun teers of group A, a t r ans i en t d e c r e a s e in c o i t a l was a t t r ibu ted by t h e m s e l v e s ¢o causes o the r than drug ac vo lun tee r in group B compla ined of d e c r e a s ~ libido ckzring the p lacebo per iod .

Liver Funct ion Tests:

There was no s ignif icant change in the l eve l s of S ~ T , SGlaT, s er~j.m a l k a l i n e p h o s p h a ~ s e and c h o l e s t e r o ! during dr~g t h e r a p y . The m ~ g ~ a ! increase noted in .the l eve l s Of alkaline phosph:~ase at c e r ~ i n p e r i o d s of t r e a t m e n t m A ( ~ b l e I~ , w ~ wel l w R ~ norm~ l ~ i t s -(3 ~ 13 ~ K~kU/IO0

Blood U r e a and Hematoc r i t :

No significant .ch~nge was noted, in the levels ofbl~d urea or in hema¢.ocrit walues in e i ther g r o u p ( T a b l e H}.'

410 OCTOBER 1976 • VOL. 1 4 N O . 4

T A ~ I

COITAL FR~UENCY AT DIFFERENT PERIODS OF DRUG T ~ ~ (Me ±

T r e a t m e n t pe r iod Group A Group B ~in w e e k s (5)* (5)

Cont ro l 1 . 9 5 + 0 . 3 8 # 2 2 . 2 0 ¥ 0 . 47 4 3 . 2 o ~ z . 30 6 2~ 6 0 ¥ Oo 40 8 2 . 8 0 ~ 0 . 58

I0 2 :60 ~ 0 , 4 6 12 2 . 6 0 ~ 0 . 4 0 ~4 2. O0 ¥ O. 60 16 1 . 8 0 ~ O. 47 18 2. O0 ~0.31 20 2 . 2 0 V0.37

*Number of Individuals .

2 . 1 7 + 0.18 # L 5o ¥ o : 28 2. oo ~ O. O 0 2. oo ~ O, 40 2 . 2 0 ¥ O. 90 1 . 8 0 ~ 0 . 4 0 2. oo .'~ O. o0 2 . ~ 0 ~ 0 . 46, 2 . 2 0 ~"0:. 60 2 . 0 0 ¥ 0 . 25 2 . 2 0 ¥ O: 60

~Coi ta l f requency p e r wee~.

~ o u p A, one v o l u n t e e r r e p o r t e d g e n e r ~ w e t n e s s and ~ r ~ • headache during t~ placebo ~ ~. No one else l~md 2ny c~aint

during the study period, except one volunteer who compLained of a b d o m i n ~ ~ d i s c o m f o r t d u r i n g 16th t o 18th w e ~ of ~ e a t m e n t ~ :~ ~ ' e r was j u s t pa lpable : FollowL-lg c e s s a t i o n o f d rug the rapy fo r l0 ~ : / s , the t r e a t m e n t was Con t~ued wi thout f u r t h e r c o m p l a i n t s . : ~ l iver funct ion t e s t s w e r e a l s o w i t h i n n o r m a l l i m i t . In t h r e e vo lun tee r s the t e s t i s s ~ e m e d ~ ~be s l igh t ly s o f t on pa lpa t ion a t the 16th w e e k of d r u g theral~% but t h e r e w a s no s i ~ f f i c a n t t e n d e r n e s s .

I n ~ o ~ p B, t h e r e w ~ no p ~ s i c a l comp!a2nt ebazing t h e whole

n en tzoned .vo lun tee rs in bo th t h e g r o u p s - b e c a m e n o r m a l by/6 to 1 2 w e e k s a f t e r w i t h d r a w a l of: the d rug , Which WaS~ ~ m i n ~ t e r e d fo r 28 weeks .

The coup les w e r e a d v i s ~ t~ p r o t e c t t h e m s e l v e s wi th anoth~er methc~d of con t r acep t ion C~r~,g th~ ~ r ! o d of s H0wever , a n unplav~ued p r e l a c y in t h e w ~ e of o n e o f t h e v o l u n t e e r s ° ~ g roup A~

OCTOBER 1976 VOL. 1 4 NO. 4 411

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~,12 O C T O D E R 1 9 7 6 V O L . 1 4 N O . 4

C O N T R A C E I ) T ! O N

w h i c h w a s t e r m i n a t e d b y a d m i n i s t r a t i o n of p r o s t a g l a n d i n a t 16 w e e k s of g e s t a t i o n In a d i f f e r e n t t ' ~ s p i t a l , w a s b r o u g h t t o t h e n o t i c e o f t h e i n v e s ~ g a t o r s a t a l a t e r d a t e . A r e v i e w o f t he c a s e r e v e ~ e d t h a t c o n c e p t i o n p r o b a b l y o c c u r r e d s o m e t i m e d~arhng t h e 16 th o r 1V th w e e k of d ~ g a d m i n i s t r a t i o n . T h e m e a n s p e r r n co,ant o f t h i s v o l u n t e e r d u r i n g t h e c o n t r o l p e r i o d w ~ 124 m f l l i o n / m l w i t h a r a n g e o f 6 7 t o 170 m i l l i o n / m l . ~ r i n g 10 a n d 1 2 w e e k s o f d r~ jg a d m h u i s t r a t i o n , t h e s ~ r m c o u n t d e c r e a s e d t o 2 4 r a n d 22 m i U i o n / m l , r e s p e c t i v e l y , A b o u t t h e t i m e o f c o n c e p t i o n , i , e. ~ r i n g 14, 16 and 18 w e e k s o f t r e a t m e n t , s p e r m c o u n ~ o f 62~ 4 8 a n d 94 m i ~ i o n / m l w e r e r e c o r d e d , r e s p e c t i v e l y . The p o s s i b i l i ~ of i r r e g ~ l a r i n t ~ e o f t h e d ~ g d u r i n g t h i s p e r i o d c o u l d n o t b e r u l e d out , p a r t i c ~ a r l y s i n c e i n c r e ~ e d s p e r m c o u n t s w e r e r e c o r d e d .

DISC

T h e r e s u l t s s h o w t h a t a d m i n i s t r a t i o n of low d o s e s (5 m g a n d 10 m g da i ly ) o f c y p r o t e r o n e a c e t a t e to n o r m a l h u m a n m a l e s c a u s e d a s i g n i f i - c a n t d e c r e a s e h-l the c o u n t mud m o t i l i t y o f s p e r m a t o z o a . The s p e r m d e n s i t y d e c r e a s e d b e g i n n i n g two w e e k s a f t e r t h e i n i t i a t i o n of d r u g t h e r a p y ~ c o n c u r r e n t l y w i t h al l i n c r e a s e in t h e p e r c e n t a g e o f n o n - m o t i l e s p e r m a t o z o a a s w e l l a s a b n o r m a l and i m m a t u r e f o r m s . T h e a b i l i t y o f t h e m o t i l e s p e r m a t o z o a to p e n e t r a t e t h r o u g h t h e c e r v i c a l m u c u s , t e s t e d in ~some c a s e s d u r i n g t he 16th to 20Lh w e e k s o f t h e r a p y , w a s m a r k e d l y i n h i b i t e d . The l e v e l s o f a c i d p h o s p h a t a s e , s i a l i c a c i d a n d G P C i n the s e m e n d e c r e a s e d s i g n i f i c a n t l y , w h e r e a s t h e r e w a s no s i g n i f i c a n t c h a n g e in t h e l e v e l s o f f r u c t o s e , o f s e m e n a l s o w a s no t a l t e r e d . L i b i d o a n d t h e f r e q u e n c y o "e no t s i g n i f i c a n t l y a l t e r e d e x c e p t f o r t r a n s i e n t c h a n g e s n o t e d in two v o l u n t e e r s in t h e 10 m g d o s e g r o u p . The l e v e l s of ~ T , S G P T , and s e r u m a l k a l i n e p h o s p h a t a s e a n d c h o l e s t e r o l w e r e n~t s i g n i f i c a n t l y a l t e r e d . _The m a r g i n a l e l e v a t i o n s I n :~er~'n a l k a l i n e p h o s p h a t a s e n o t e d a t s o m e p e r i o d s o f d r u g t h e r a p y w e r e

~.I1 w i t h i n n o r m a l l i m i t s . T h e o n e v o l u n t e e r , w h o c o m p l a i n e d o f ~<~orn ina l d i s c o m f o r t and w h o s e l i v e r w a s j u s t p a l p a b l e a t 16 to 18 w e e k s of d r u g therapy- , g a v e a p a s t h i s t o r y of a m o e b i a s i s . F o l l o w i n g d i scon t inu tLt ion o f d r u g t h e r a p y ' f o r t en d a y s , h i s t r e a t m e n t w a s c o n - t i n u e d w i t h o u t f u r t h e r c o m p l a i n t s . H i s l i v e r f u n c t i o n t e s t s w e r e w i t h i n n o r m a l r a n g e t h r o u g h o u t the S tudy p e r i o d . A f t e r c a r e f u l l y r e v i e w i n g t h e c a s e i t i s c o n c l u d e d t h a t no a d v e r s e e f f e c t o f t h e d r u g on h e p a t i c f u n c t i o n w a s e v i d e n t . T h e b l o o d u r e a a n d t h e ~ h e m a t o c r i t v a l u e s w e r e n o t s ~ n i f i c a n t l y a l t e r e d i n e i t h e r g r o u p .

Us ing tg d a i l y d o s e s o f c y p r o t e r o n e a c e t a t e , K o c h a n d c o w o r k e r s I a r a p i d d e c r e a s e h-l s p e r m c o u n t a l o n g w i t h a n i n c r e a s e i n t h e n o n L m o t i l e a s w e l l a s a b n o r m a l a n d i ~ m a t u r e s p e r m s , S e m h l a l a c i d p h o s p h a t a s e l e v e l w a s d e c r e a s e d , w h e r e a s a l k a l i n e p h o s p h a t a s e w a s e l e v a t e d . " T h e l e v e I of s i a l i c a c i d w a s e l e v a t e d a n d t h a t of f r u c t o s e w a s n o t a l t e r e d ~ b u t t h e r a t e of

V O L , , 1 4 ]NO. 4 413


f r u c t o l y s i s w a s d e c r e a s e d . T h e l e v e l o f p l a s m a t e s t o s t e r o n e d e c r e ed , w h i l e t h e l e v e l s o f F S H a I , H r e m a i n e d u n a l t e r e d . T h e e~:~.~culate vo l e w a s n o t c h a n g e d a n d t r a n s i e n t low e r i n g of l i b i d o w a s n o t e d i n s o m e v o l u n t e e r s . O n t he o t h e r h a , h i g h d o s e s ~(100 to 200 m g d a i l y ) o f c y p r o t e r o n e e t a t e s u p p r e s s s p e ~ a t o g e n e s i s w en. libi (12, 17).

C y p r o t e r o n e a c e t a t e in d o s e s o f 100 to 250 m g d a i l y c a u s e d a r a p i d d e c r e e ~ in t h e l e v e l o f p l m a t e s t o s t e r o n e (16, 3 3 , 34) ; l-e.owever, ~: there , , v ~ .r~ c o n e o m i t ~ t d e c r e a s e in t h e . l e v e l o f p l ~ m a o r u r i n a i 5, L H (17, 3 5 , 36) . T h e d e c r e a s e in P l a s m a t e s t o s t e r o n e l e v e l m a y b e d u e to a d i r e c t , i n h i b i t i o n of i t s b i o s y n t h e s i s in ~ t h e t e s t i s (34_). C y p r o t e r o n e a c e t a t e c a u s e d no c h a n g e (12, 17, 36 , 37) o r a d e c r e a s e in the l e v e l of F S H (35, 38) . T h o u g h w e d id no t m e a s u r e , t h e l e v e l s of p l a s m a F S H d LH, i t i s l i k e l y t h a t t h e y m n o t b e a l t e r s i n c e m u c h s m a l l e r d o s of p r o t e r o n e a c e t a t e w e r e u s t n in t h e s t u d i e s c i t e d o r e .

C y p r o t e r o n e a c e t a t e c a u s e s r o g e n d e p r i v a t i o n in ~ t a r g e t t i s s u e s in o w s . I t d e c r e a s e s t h e s e c r e t i o n of t e s t o s t e r o n e f r o ~ t h e t e s t i s d a l s o c o u n t e r a c t s t h e t i o n of d r o g e n p r o b l y b y c o m p e t i t h , - e in i t i o n a t t h e t ~ g e t d s s u e l e v e l (1).

A t b o t h t h e d o s e s u s e d , c y p r 0 t e r o n e a c e t a t e c a u s e d a : p a r t i a l s u p p r e s s i o n of s p e r m a t o g e n e s i s , a s e v i d e n c e d by a- d e c r e a s e . i n s p e r ~ d e n s i ~ / a n d a n i n c r e a s e in t h e p e r c e n t a g e o f a b n o r m a l mnd~ i m m a t u r e s p e r m a t o z o a in t he e j a c u l a t e . T h e hu~man t e s t i s a p p e a r s to be, s e n s i t i v e to t h e a c t i o n o f m n t i - a n d r o n; ,,the d e g r e e o f s p e r r n a t o - g e ~ i c s u r e s s i o n i s a p p a r e n t l y r e l a t e d to th~ d e g r e e of i n h i b i t i o n o f t h e a c t i o n o f r en , vch ich a r e r u i r f o r t he m a i n t e n ~ c e o f s p e r m a t o g e n e s i s . T h e s e - e f f e c t s r e s u l t p a r t l y f r o m a - d e c r e e ~ i n d r o g e n p r e t i o n , , an_d m a y a l s o b e m e d i a t e d t h r o u g h a l o e a I a n d r o g e n d e p r h r a t - i o n e f f e c t e a u s by c o m p e t i t i v e . i nh ib i n o f p r e s t e r o n e d r o g e n r e c e p t o r s in. t h e n o n - f i e I l a t e ~ g e r m c e l l s (39) a n d / o r , b y e h ~ g e s - . p r e e d ~ . t h e S e r t o l i .~ e e I I s " ( 4 0 ) -

T h e i n c r e a s e in t he p e r c e n t a g e o f n o n - m o t i l e s p e r m a t o z o a , a d e c r e ~ e in t h e a b i l i t y o f e j a c u l a t e d m o t i l e s p e r m a t o z o a t o m i g r a t e t h r o u g h t h e c e r v i c a l . . . m u c u s , " a n d ~ t h e d e c r e a s e , in t h e - l e v e l o f GPC,, i n t h e s ~ m e n m a y b e d u e t o a n d r o g e n d e p r i v a t i o n o f t h e e p i d i d ~ u n is a f f e c t ~ n 3 i t s i n t e r m i l i e u . Lt i s l~<ely t h a t t h e a c t i o n of t h e d r u g o n t h e v d e f e r e ~ m a y a l s o b e p a r t l y r e s p o n s i b l e f o r t h e ch g e s in ~ o t i l d t h e impaired ability of s p e r m a t o z o a : t o p e n e t r a t e t h e c e r v i c a l m u c u s . . ~~The,.~decre e - in~the,~levels~of a c i d s p h a t a s e ~ , ~ d s i a l i c a c i d in t h e s e m e n i n d i c a t e s an. i n h i b i t i o n of t h e / s e c r e t o r y a c i t y h n t h e c e s s o r y ~ g l ~ d s . w e r , t h e v o ! u m e of t h e ej a c ~ l a t e a n d s e c r e t i o n o f f r ~ a c t o s e w e r e n o t a f f e c t e d . I n a n

414 O C T O B E R 1976 VOL. -~ 14 N O 4


s e m e n the ac id p h o s p h a t a s e - i s c o n t r i b u t e d m a i n l y ~ . t h e p r o s t a t e , . .

f r u c t o s e by s e m l n a I v e s i c l e s , and s i a l i c .a~id b y both p r o s t a t e a n d s e m i n a l v e s i c l e s (41) , A . s r n a l l p a r t of tim s t a l i c a c i d i s c o n t r i b u t e d by the e p i d i d y m i s (42). The GPC is m a i n l y c o n t r i b u t e d by t h e e p i d i d y m i s (21 , 43). O u r " r e s u l t s i n d i c a t e ~ tlmt. the ack l p h o s p l m t a s e is m o s t s e n s i t i v e to ~androgen d e p r i v a t i o n , ~ f o l l o w e d i n o r d e r : b y s i a l i c acid. and G P C . . L e v e l s of f r u c t o s e do no t show ~ anY change" Roy e_tt al_. ( 4 4 ) f o u n d tha t a c i d p h o s p h a t a s e - i n h u m a n s e m e n w a s m o s t s e n s i t i v e to s t i m u l a t i o n by a n d r o g e n fo l lowed in o r d e r by sialic~, a c id m~d f r u c t o s e . • It .is~likely tha t in t he h u m a n , ~ s e c r e t o r y ~ac t i v i t yo f t h e . p r o s t a t e i s a f f e c t e d by a n d r o g e n d e p r i v a t i o n e a r l i e r thanthat of t h e ep id idymis .

O u r r e s u l t s on the l e v e l . o f s i a l i c ac id i n the s e m e n do n o t - a g r e e with t h o s e of Kmch (45),. who .found an increm,~e in t h e . - l e v e l o f s i a l i c ac id in t h e s e m e n of hu a n v o l u n t e e r s t r e a t e d dai ly w i th 10 o r 20"rag/ of c ~ p r o t e r o n e a c e t a t e .

P r a s a d and c o w o r k e r s ( see 46 fo r r e v i e w ) have no ted ithat t h e t h r e s hold r e q u i r e m e n t of a n d r o g e n s to m a i n t a i n the s t r u c t u r a l - a n d func t iona l i n t e g r i t y of the e p i d i d y m i s in t h e r a t , h a m s t e r and m o n k e y is m u c h . h i g h e r than. t lmt needed. 1~ the . a c c e s s o r y . g landse ... B a s e d on • th i s c o n c e p t o f . h i g h e r t h r e s h o l d r e q u i r e m e n t o f - a n d r o g e n f o r the m a i n t e n a n c e of e p i d i d y m a l f u n c t i o n , P r a s a d et a l . - . (18) i n d u c e d r ~ , - e r s i - b le f u n c t i o n a l s t e r i l i t y in r a t s w i th microdose--s o-'f - cyp ro t e rone a c e t a t e by s e l e c t i v e inh ib i t ion of e p i d i d y m a l funct ion . A d m L , ~ s t r a t i o n o f c y p r o t e r o n e a c e t a t e t h r o u g h s u b c u t a n e o u s l y ~ p l a n t e d s i l a s t i c c a ! ~ u l e s ' in r h e s u s m o n k e y s r e s u l t s in s u p p r e s s i o n of s p e r m a t o g e n e s i s , , d e c r e a s e i n s p e r m coun ts .in s e m e n w i t h o u t a n y change in t he l e v e l s of s e m ~ m t e s t o s t e r o n e and se Lual f r u c t o s e , , v o l u m e of.-the e j a c u l a t e a n d . b i o ' c~ ,emis t ry of the a c c e s s o r y g l a n d s ( 4 7 ) . / A p e r u s a l of t h e t i m e s e q u e n c e .:::. the c h a n g e s in t he coun t a n d m o t i l i t y o f s p e r r n a t o z o a a n d t h e b i o - ci~emical . c o n s t i t u e n t s o f s e m e n i n t h e : p r e s e n t s tudy ;shows ~that a c t i o n s of c :ypro te rone a c e t a t e h l t h e Ira.man a r e m a n i f e s t e d s 'm~ul taneous ly at

• mu_ltiple s i t e s . T h e d i f f e r e n c e s in t h e r e s p o n s e e l i c i f ~ d : in thei:-human ~, and , the a n i m a l s b y - c y p r o ~ r o n e " a c e t a t e m a y be"due"to ~ s p e c i e s d i f f e r e n c e s . ..

O u r r e s u l t s s h o w t h a t a t low d o s e s of c y p r o t e r o n e a c e t a t e t h e r a p y , l ib ido ' and p o t e n t i a a r e - n o t a d v e r s e l y affected;~/ the-sperm." p r o d u c t i o n is d e c r e a s e d , 5 0 to 8 0 p e r c e n t o f t h e : s p e r m a t o z o a s ~ l l r e m a i n ~ .~in the. ej a c u l a t e i a r e n o n - m o t i l e m-ld the-~ ab i l i ty , of ::the motilell s p e r m a t o . ~ o a t o p e n e t r a t e :t h r o u g h t h e c e r v i c a l m u c u s ~ : i s d e c r e a s e d . : ~ a r t h e r c l i n i ca l s tudies : need ~ t o b e ~, car r ied : j out-: t o d e t e r m i n e ~ w h e t h e r s u c h spe rmatozoa : : a r e u n a b l e to m i g r a t e : i n : v i v o : t h r o u g h . t h e c e r v l c a l l m u c - ~ in to the. u t e r u s a n d f a l l o p i a n tube,/an--d whe'-----ther:-: they h a v e . : a l s o : i o s t t h e i r . f e r t i l i z ing ' :ability. F r o m . o u r / r e s u l t s it: a p p e a r s t ha t

O C T O B E R 1976 V O L . 1 4 N O . 4 415

C O N T R d k C E ~ I O N

a d m i n i s t r a t i o n of low d o s e s o f cypro te r<)ne a c e t a t e m a y ~ v e ~ t a g e s o v e r o t h e r m e t h o d s o f u s e o f c o m b i n a t i o n s o f p r o g e s t ~ e n s a n d a n d r o g e ~ f o r t he c o n t r ~ of f e r t t l i ~ i n the m a l e .

A C I ~ q O W L E ~ E M E N T

T h ~ s ~ lms b e e n s u p p o r t e d b y a r e s e a r c h g r a n t f r ~ t h e W° H. O. T a ~ F o r c e on M e t h o d s f o r i o n of M a l e F e ~ U i t y . T h e a u t h o r s w i s h to thank Dr . R , ~ S a n y ~ , f o y e r ~ r e c t o r of the N a t i o n a l L n s t i ~ t e of F a m i l y P l a n n i n g , f o r h i s k e e n L , ~ r e s t .

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G e l l e r , J . , v a n D.amme, O . , G a r a b i e t a , G° , L o h , A.~ R e t t u r a , J , and S i e f t e r , E . . E f f e c t o f c y p r o t e r o n e a c e t a t e on H - t e s t o s - t e r o n e u p t a k e and e r ~ e p r o s t a t e of t h e r a t . E n d o c r i n o l . 84,

B a l h a m , J . E . and N e a l , G, E . : T e s t o s t e r o n e a c t i o n in the v e n t r a l p r o s t a t e . The e f f e c t s of d i e t h y l s t i l b e s t r o l a m c y p r o t e r o n e a c e - t~te on the m e t a b o l i s m of 3 H - t e s t o s t e r o n e and t h e r e t e n t i o n of l a b e l l e d rn e t abo l i t e i p r o s t a t e in v ivo and i n v i t r o . B i o c h e m , J . : 125, ~ .

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10.

11.

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420 O C T O B E R 1976 VOL. 14 NO. 4


RNA METABOLISM OF'THE NORMAL AND THE COPPER TREATED

HUMAN ENDO~TRIUM*

Omar Hern~ndez P~rez

Ram6nAznar

Luz Ma~ Ballesteros

J~ Dom~ngo M~ndez

Adolfo Rosado

Secci6n de B ioqu~mica de.la Reproducci6n Departamento de !nvestigaci6n en Medicina Experimental ~ InstitUt0 Mexicano del Segu~ ~ Social, Apartado Postal 12L184~ M~×ico 12, D. F.

ABSTRACT

Using the techn~q~le of affinity chromatography in poly (U) •sepharose, we have studied the relative• concentration of total, messenger, ribosomal and transfer ~/WA in the normal and the Copper trea~ed human endometri~, at" tempting •to further elucidate the mechanism of the •Cu- T200 intrauterine device. The transition fZom the proliferative to the secretory endometri~ in normal women was found(to be accompanied by s!gnifioative increases in total RNA (from 5.19 • O. 7 ~ ~to 7.9 • 0.7 :~ mg/g.w,w. ), in mRNA (frOm 0.22 ~ 0~026 to 0.34 ~-+ 0.04) and in r~A ~from 3.52 ~-+ 0.45 to 6.68 -~ 0.85). The relative pro i>~'rtions of bound and free m~/q~ were also ~modlfied by endometrial maturation changing from 70% bound mi~l~A!n the proliferative to 83% in the secretory phasel Intra- uterine ~COp~r r e!eaie seems to particularly affect/I~NA

Accepted for publication August 9, 1976

This womkwas suppopted inpart by a grant from theFomd FoundaTion.

O C T O B E R 1976 VOL. t4 NO. 4 4.21


I NTROI~UCTION

intrauterine copper has been shown to inhibit the syn, thesls of DNA in the endometrium of t.he rat~ (I) as well.as the incorporation of 35S into endometrial muco- proteins (2). It.h@s also been shown that the presence of an intrauterine device (IUD),. of either the inert or the medicated type, induces a significant decrease in theconcentration of endometrial RNA (3, 4, 5). However, Grundsell and Hakansson (6) have shown that the presence of.copper, ~ u/~. does not Interfere with the incor - poratlon of uridine into RNA by the rat endometrium.

Recently,~Hern~ndez et 0~£. (7) have shown that in U.6t%oad- ditions of copper in concentrations as low~as 0.15mM produce a significant decrease in ~he amount of~ polysome aggregates~that may be recovered- from thehuman endome - trium. In addition, ~qnen the obtained p01ysomes are analyzed in a sucrose gradient, it was found that-pre- incubation in the presence of increasing concentrations of copper induced a progressive shift of the polysome pattern towards the predominance of the lighter components

I n v i v o studies of the same parameters in endometrial biopsies~obtained from women users of copper-T200 intrauterine devices (Cu-T200~IUD) (5) showed that the concentrations of ribonucZeoprotein particles were sig nificantly lower than the concentrations observed in control women. In addition, the Cu-T 2 ....... ed a decrease in the heavy components of the pattern with a concomitant increase~in the lighter componentsl

The previously mentioned facts seem to indicate that one of the possible mechanisms ofaction of the intrauterine copper may be interfering with the ~normal ribosomal cycle (8). ~inhlbitin~g-the initial binding of mPe~ ~to the 40 S subunit~ Lack of b!nding~of miRNA to rlbosomes will produce ~an increase in the latent RNase activity of ~ these organelles (9) with a~concomitant increase in ERNA cata- bolism;: secondarily the unbounded~A will ~isoibe hy- drolyzed (i0).

Taking advantage of the occurrence :o~ poly (A) secants in m_wlqA molecules of~eukariotic animals; (Ill ;12; 13).and using the ~technZ~le of af finity~ chromatography oin ~ poly (U) sepharose (14, 115) ; we have studied the relative concentrations of total ~/~A, ~mRNA; rRNA, and tRNA in. the normal and ~the copper treated h~_-man secretory endometrlum, attempting to further~elucidate ~ the : mechanism of.i. action : of cu-T200

422 O C T O B E R 19"6 V O L . 14 NO. 4

R A C E P T I O N

MATERIAL AND t~THODS

Endometrial biopsies were takenas previously described (3) from 10 apparently healthy, n0rmal, ~regularly menstruating women with proven fertility and ~from 8 other women who had been wearing an intrauterlne device of theTcopper releasing type (Cu-T200) ~ for 6-8 months. In both groups, the;women were of similar age (25-35 years old). All the biopsies were:taken flrst during the~secretory.~half of the menstrual cycle (20 ± 1 day) and then in.the same w~men during the~proliferative phase (i0 ~ 1 day)~ of the next menstrual cycle. In all cases the time~ 0f the~ mens£ruai cycle was checked by histological datlng-of a slmultaneously taken specimen.

The endometrial biopsy was ,taken and washed in 0..25 M sucrose containing ~200 ~g/ml of:heparln as ~ase inhibitor (16). Wet weight of~ the s~mples was quantified aspre- viously described (5);

To insure adequate homogenlzatlon, the samples were briefly exposed (60 sec) and homogenized ~ -- using, a tightly fitting glass to glass Potter-Elvehjem homoge - nizer -- in 2 vol~es of ice cold distilled water containing 200 ~g/ml of heparin. The homogenate~was then quickly mixed with i vol%hme 0f~;solutlon prepared in ~ such/& way as tO obtain the following final concentrations in the mixture: NaCI 0.14 M, Tris-HCl ~.010 M," MgCI 2 0.0015 M, KCI 0.005 M, heparin 200 Dg/mlt ~all at final pH of 7.8.

DNA, P~NA and proteins were measured in an aliquot of this homogenate after mixing I:I with 10% perchloric acfd as has been previously described (5) . The ~ rest ~ ~ of the: homogenate was centrifuged for i0 min at 15,000 revs/min ~ (Sorvall ~ rotor SS34): to obtain the . post-mitochondrial: su - pernatant: fluid ~. : T o t a l : ribonucleoproteinS (RNP) ~ were isolated, -rinsed and purified from this supernatant by centr~fuga~tion for 120 rain a~t 150,000 ~ g in a Beckman L-4 ultrac, adding deoxycholate as~as been prevlol _ (7).

The el&fir iedi~ :r ibonucleopro~e in par ticles were:-.dlssoclated by the addition• of 0,03 M:EDTA and/ !% sarcosyl( (Lauryl~ • sarcosine) (flnal~<concentrations) which pre-~iously has bee~_sho~ to release polys0mal B/~A ~ from:pr0£eins :(17).

EDTA 0. 010 M; pH ' 7 ~.5,;prepared .in~:; 25 %J~!formamide;, ~-~ buffer" PUS I) and applied:to a-poly. (U) sepharose: (Pharmacia Fine

O C T O B E R 1976 ~¢OL. 14 570. 4 423

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