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Inhibition of spermatogenesis in men with monthly injections of medroxyprogesterone acetate and testosterone enanthate
CONT
S
SIS
Io
ION
WI
OF S S
J.F.
CE
S
d E.M.
C
ho
tern a d e CI r de O l e a par n t of ternal alth a Child Care F a c u l t y of dlc e, F e d e r a l e r s l t y of B a h i a Bahia Brazil
S
T
n ~ y .... f. e h e a l t h y m e n w e r e t r e a t e d w i t h m o n t h l y J e c t l o n s of I00 of dro progesterone acetate ) and 2 5 0 of t e s t o s t e r o n e e n t h a t e ( ) for p e r i s fr 4 to 16 nths. 24/25 sub~ects~ a r d drop spe co t o c c u r r e d b y 1-3 m o n t h s l o l l the f st c .... ed ject£ons of A and . E l e v e n s u b j e c t s out of 14 o C feted 9 nths of trea nt b e c azoospe Ic developed mar d ol~gozoospe ia. Of the 8 n treated for 12-16 ~onths, only one failed to re spo to t h e t r e a ent. subjects rep ted d e c r e a s e d ! Ido a potency; 4 jeers reported creased libido a potency, ere re n o c h a es t h e s i z e s c ....s l s t e n c y or s e n s i t ity of t h e t e s t i ~ cles or breasts, s ific t cha es o c -c u r r e d set trans a ses or al I e phosphatase d the trea t. With 2 possible e x c e p t l o n s ~ se t r i g l y c e r i d e s a l s o se ed to b e affected by treatnt. re no ch ges in b l o pressure, ight ga s c o
Accepted
E 1977
for
p
L. 115
llcation
. 6
Janua
20,
1977
CONT
CE
ION
I
DUCTION
dro p r o g e s t e r o n e a c e t a t e ( A) is a p o t e n t p r o g e s t ich has b e e n w i d e l y used as a long - a c t i n g c o n t r a c e p t i v e in w en (1,2). e d r u g r e d u c e s g o n a d o t r o p i n s e c r e t i o n ~ t h e r e b y s u p p r e s s i n g the m i d c y c l e p e a k and h i b i £ i n g o v u i a t i o n in w en for 6 m o n t h s or longer fol! ing a s i n g l e i n j e c t i o n of 4 0 0 m g A (3) e a g e n t w a s a l s o found £o r e d u c e spe 1 e is in m e n in i i ted c l i n i c a l t r i a l s (4) .... In the p r e ~ e n t study~ w e t e s t e d the a n t i s p e a t o g e n i c e f f e c t of in a g r o u p of f e r t i l e m e n w h o v o l u n t e e r e d for the c l i n i c a l trial. I n j e c t i o n s of t e s t o s t e r o n e e n a n t h a t e ( ) w e r e g i v e n cone itantly, in o~d~er to offset any e f f e c t s of d i m l n i s h e d e o g e n o u s t e s t o s t e r o n e r e s u l t i n g fr - i n d u c e d i n h i b i t i o n of g o n a d o t r o p i n r e l e a s e . It w a s also h o p e d that T E w o u l d e n h a n c e the i n h i b i t i o n of g o n a d o t r o p i n r e l e a s e , t h e r e b y incre a sing the an £ is pe a £ o g e n ic e f f ~ c t (4).
M ETHODS T enty-five tlealtlly volunteers, 21 to 41 years o f a ~ (a rage 3 I), were ac pted ~ r this study. ch subject had ~ t h e r e d at least 2 children. Tile subjects received i 00 mg reed roxyp gesterone acetate (150 g/!nI, Depo Pro ra, U p j o l m ) a n d 250 mg testosterone enanthate lalestryl, Squibb) in separate intra uscular injections at monthly intervals. Sper counts and otility were determined prior to initiation o f treat ent and b e f o ~ each pair o f monthly injections. Breasts and external ~ n i t a l s were e mined at each visit ....Subjects were questioned about coital quency, and changes ~ sexual desire and potency. Body weight and bMod p r e m u r e re determined. Serum ie is of aNaline phosphatase, transaminases (SGOT and SG ), and t rigiycerides were deter ined at regular intervals during t!le treatment ....
SU
S
In 2 4 / 2 5 s u b j e c t s , a ~ a r k e d d r o p in spe count a in spe m o t i l i t y o c c u r r e d b y 1-3 m o n t h s l o l l ing the f i r s t c ined jections of A a TE. A C the end of 4 m o n t h s of trea nt, 6 / 1 9 reel (31%) had r e a c h e d a z o o s p e ia or s e v e r e o l i g o z o o s p e ia (I m i l l i o n spe /mi or l e s s ) B y t s h m o n t h of trea nt, this n er had creased to !i/18 (61%). A f L e r 9 m o n t h s of = r e a r nt, 1 1 / 1 4 sub jeers (7 9 %) ~ had b e c azoospe ic or d e v e l o p e d m a r k e d o l l g o z o o s p e ia. Of the 8 n t r e a t e d for 12-16 ~ o n t h s , a l l b u r one s u b j e c t r e s p o n d e d to the trea ent. F i g u r e s 1-3 d e p i c t the t y p i c a l p a t t e r n of i n i t i a l d e c r e a s e spe coun=, t h e v a r i a t i o n s the e requ ed to a c h i e v e a ma ed d e c r e a s e , a the = e n d e n c y to m a t a l n this i 1 el w i t h cone ued = r e a en=. e spe c o u n t s for the u n r e s p o n s e subject are sh Fig. 4. not ....ly ~ a inta ed a h i g h spe count t h r o u g h o u t the t r e a en=, b u t d e v e l o p e d n o c h a n g e s in s p e tillty Ich w o u l d d l c a t e an a l t e r a t i o n in the f e r t i l i z g c a p a c i t y of the spe tozoa. T h i s s u b j e c t had no c l i n i c a l signs of e n d o c r opathy, and l i v e r f u n c t i o n tests r a ed at n o al levels t h r o u g h o u t t r e a t nt.
628
J
E i 977
L. 15 NO. 6
F~,I
F-
w
Z
m
0 J J
(.f)
-
6
8
Spe~ counts in men receiving monthly l~A a ~ ~ injections, Note that subject 20 took a ~ s t ~.~omonths longer than subjects 19 and 21 to reach azoospe~la.
4
22 o
20 • 21"
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COUNT- IN
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MILLIONS
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J U N E 1977 "VOL. 15 ]NO. 6
631
tal
F
w
4
6
8
I0
12
14
16 MONTHS
Spe~ count of a subject receiving ~nthly l~A and ~ Injections. Note that spe~ counts of this subject r~alned apparently unaffected by the monthly injections.
2
N~ 2 3 e
0 Z
CONTRACE
I
s u b ~ e c t s rep ted d e c r e a s e d l i b ~ o a pore y, a decked to dlscont ue t r e a nt for that reason. Four other n reported a t nsie decrease libido and p o t e n c y , but had rec ered by t next vlsit, 30 d a y s later. F e subjects reported c r e a s e d libido. Fo of these 5 a l s o r e p o r t e d c r e a s e d potency, ere r e no ¢ha es in the slze~ c o n s i s t e n c y or s e n s l t ity of the t e s t l c l e s or the breasts. derate ight g a l n oct crease w a s 2 kg one year. for one p a t nt one year. a
s
red e ere
most patlents. x ight re no c h a n g e s
The mean welght crease was kg blood press e
jeet.
significant changes occurred S T, S ~, or a l k a l e phosphataSe levels ing the t r e a ent. all but 2 subjects3 no s l g n l f l c a n t changes o c c u r r e d . . . . ser trigiycerides dur g treat nt. In o s Ject~ t level of t r l g l y c e r i d e s r o s e fr 56 to 147 % and r ined at this h i g h e r 1 el thro bout the t r e a ent period, a n o t h e r subject, trig l y c e r i d e s r o s e fr a pre-trea t I el of 46 to 134 mg7~, and later d r o p p e d to I0i d i trea ent. H eve~ t h e s e h i g h e r le is r i d wlthln no I 1 Its. fo tlon is a v a i l a b l e r e t u r n to f e r t i l i t y one subject. His spe co t d r o p p e d fr 80 ~ i l l n/ml v i r t u a l l y to zero by the fo th m o n t h ; c o n t a c t w i t h the s j e c t was lost at the s th month. tee m o n t h s foll i t last j e c t l o n s ~ his w i f e b e c pregnant 3 a subse e n t l y gave b i r t h to an a p p a r fly n al son. Several nths a f t e r the birth (more t h a n one year foll Ing dlscont~ u a t l o n of trea t)3 the s ject pr ided a s en spec n in ich the spe nt s 105 m i l l l o n / m l .... tility s 80%, c ared w i t h the preea ent v a l u e of 607~o
DISCUSS
N
P r e v i o u s studies h e sh that it is p o s s i b l e to duce a z o o la men by it g adotropln secretion without a corresg suppressi of l i b i d o a p o t e n c y (5,6~7). Our trials w i t h c a t i o n trea ents of t e s t o s t one I ts a v a r i o u s i9-norsteroids leafed that a z o o s p e ia or s e v e r e o l l g o z o o s p e la c o u l d be ed d ta ed for s e v e r a l nths in y o u n g (7). Spe toge sis s restored wlth a f loll dlscont u a t i o n of trea
spe po
A jot pr 1 w i t h the v a r us 1 9 - n o r - s t e r o reg ns has b e e n the ed for fre t (weekly) a d m istrat of h i g h doses, ich y r e p r e s e n t an e r challe e to the 1 er. e present jeer!on trea ent g es sl r e l e a s e of e h o s, a r e d u c e s the total t of st o to h the I er is e osed at a n y p a r t i c u l a r t . dro progester a c e t a t e doses of 1 5 0 /3 ths and 400 /6 ~ o n t h s are c sidered non-toxic w n for long-te c tracept e u s e (i ~2,3). T doses of dro pr estro acetate d testosterone anthate used the p r e s e n t cl ical h e been il-toierated m t r e a t e d for as I as e year.
J
1977
1.,. i 5
.6
633
CONTRACE
pr press ion of peated spe the trea nt. an crease p g y, the long te spe S
ION
I s to be resolved are those associated w ~ h ¢ lete spe togenes is in s s jeers, and t need for counts as the o n l y y to ...evaluate . the e f f e c ~ e ss of Aith gh dlscont ati of trea ent is loll d by spe co and t h e r e one instance of a q stlon of full reversibJllt, in ail subjects after togenle supp=ese ion r s to be establ Ished.
is rk s erta s e a r c h progr sp s ed ittee for ...Contraception . York.
n as part of the e tracept e develo d coord ated by the Internatl a! search of e Population C nell
E
ent
ES
i
Cout s
2.
C
t i o, E . a Souza, j .C. Conceptlon control by nthly ~ectl s of ~ e d r o x y p r o g e s t e r e suspension and a long ...act . g oestrogen. J. prod. Fertil. 15:209-214 (i968).
3.
Gardner, and res ing
4
ho, E.M. Souza, J.C. a Csapo, A.I. ity uced by dro roEes tero ii. 17:26i-266 (1966).
vers ibie ions. Fert il.
J.M. and Mishell, D.R., . aiysls of bleedi part ns tlon of fertility follow g discont atl of a long jectabie c tracept e. Fert il Ster!~. 211286-291 (i970).
c , J., Agents Af fect ing Fert i I Ity (C. R. st try, i tots )~ urchll I ndon, 1965 ~ p. 93-122.
a
J. S.
5.
Frick, J. Control of spe togenesis in n by c strati of progest and a rogen. Contracept
6 ....
Pataneili, D.J., in Vol. V ( ie reproduce
7.
Coutl o, E.M. a io, 3.F. Successful inhlbitlon of spe in n without loss of l ~ i d o : A potential n approach to contraception. Contraception 8:207-217 (1973).
634
d a ini8:191-206 (1973).
book of slology, Section 7 ( e syst )~ 19 75~ p.245-258.
3
E 1977
oct
ology),
toge ie
L. 15 NO. 6
sis
S
SIS
Io
ION
WI
OF S S
J.F.
CE
S
d E.M.
C
ho
tern a d e CI r de O l e a par n t of ternal alth a Child Care F a c u l t y of dlc e, F e d e r a l e r s l t y of B a h i a Bahia Brazil
S
T
n ~ y .... f. e h e a l t h y m e n w e r e t r e a t e d w i t h m o n t h l y J e c t l o n s of I00 of dro progesterone acetate ) and 2 5 0 of t e s t o s t e r o n e e n t h a t e ( ) for p e r i s fr 4 to 16 nths. 24/25 sub~ects~ a r d drop spe co t o c c u r r e d b y 1-3 m o n t h s l o l l the f st c .... ed ject£ons of A and . E l e v e n s u b j e c t s out of 14 o C feted 9 nths of trea nt b e c azoospe Ic developed mar d ol~gozoospe ia. Of the 8 n treated for 12-16 ~onths, only one failed to re spo to t h e t r e a ent. subjects rep ted d e c r e a s e d ! Ido a potency; 4 jeers reported creased libido a potency, ere re n o c h a es t h e s i z e s c ....s l s t e n c y or s e n s i t ity of t h e t e s t i ~ cles or breasts, s ific t cha es o c -c u r r e d set trans a ses or al I e phosphatase d the trea t. With 2 possible e x c e p t l o n s ~ se t r i g l y c e r i d e s a l s o se ed to b e affected by treatnt. re no ch ges in b l o pressure, ight ga s c o
Accepted
E 1977
for
p
L. 115
llcation
. 6
Janua
20,
1977
CONT
CE
ION
I
DUCTION
dro p r o g e s t e r o n e a c e t a t e ( A) is a p o t e n t p r o g e s t ich has b e e n w i d e l y used as a long - a c t i n g c o n t r a c e p t i v e in w en (1,2). e d r u g r e d u c e s g o n a d o t r o p i n s e c r e t i o n ~ t h e r e b y s u p p r e s s i n g the m i d c y c l e p e a k and h i b i £ i n g o v u i a t i o n in w en for 6 m o n t h s or longer fol! ing a s i n g l e i n j e c t i o n of 4 0 0 m g A (3) e a g e n t w a s a l s o found £o r e d u c e spe 1 e is in m e n in i i ted c l i n i c a l t r i a l s (4) .... In the p r e ~ e n t study~ w e t e s t e d the a n t i s p e a t o g e n i c e f f e c t of in a g r o u p of f e r t i l e m e n w h o v o l u n t e e r e d for the c l i n i c a l trial. I n j e c t i o n s of t e s t o s t e r o n e e n a n t h a t e ( ) w e r e g i v e n cone itantly, in o~d~er to offset any e f f e c t s of d i m l n i s h e d e o g e n o u s t e s t o s t e r o n e r e s u l t i n g fr - i n d u c e d i n h i b i t i o n of g o n a d o t r o p i n r e l e a s e . It w a s also h o p e d that T E w o u l d e n h a n c e the i n h i b i t i o n of g o n a d o t r o p i n r e l e a s e , t h e r e b y incre a sing the an £ is pe a £ o g e n ic e f f ~ c t (4).
M ETHODS T enty-five tlealtlly volunteers, 21 to 41 years o f a ~ (a rage 3 I), were ac pted ~ r this study. ch subject had ~ t h e r e d at least 2 children. Tile subjects received i 00 mg reed roxyp gesterone acetate (150 g/!nI, Depo Pro ra, U p j o l m ) a n d 250 mg testosterone enanthate lalestryl, Squibb) in separate intra uscular injections at monthly intervals. Sper counts and otility were determined prior to initiation o f treat ent and b e f o ~ each pair o f monthly injections. Breasts and external ~ n i t a l s were e mined at each visit ....Subjects were questioned about coital quency, and changes ~ sexual desire and potency. Body weight and bMod p r e m u r e re determined. Serum ie is of aNaline phosphatase, transaminases (SGOT and SG ), and t rigiycerides were deter ined at regular intervals during t!le treatment ....
SU
S
In 2 4 / 2 5 s u b j e c t s , a ~ a r k e d d r o p in spe count a in spe m o t i l i t y o c c u r r e d b y 1-3 m o n t h s l o l l ing the f i r s t c ined jections of A a TE. A C the end of 4 m o n t h s of trea nt, 6 / 1 9 reel (31%) had r e a c h e d a z o o s p e ia or s e v e r e o l i g o z o o s p e ia (I m i l l i o n spe /mi or l e s s ) B y t s h m o n t h of trea nt, this n er had creased to !i/18 (61%). A f L e r 9 m o n t h s of = r e a r nt, 1 1 / 1 4 sub jeers (7 9 %) ~ had b e c azoospe ic or d e v e l o p e d m a r k e d o l l g o z o o s p e ia. Of the 8 n t r e a t e d for 12-16 ~ o n t h s , a l l b u r one s u b j e c t r e s p o n d e d to the trea ent. F i g u r e s 1-3 d e p i c t the t y p i c a l p a t t e r n of i n i t i a l d e c r e a s e spe coun=, t h e v a r i a t i o n s the e requ ed to a c h i e v e a ma ed d e c r e a s e , a the = e n d e n c y to m a t a l n this i 1 el w i t h cone ued = r e a en=. e spe c o u n t s for the u n r e s p o n s e subject are sh Fig. 4. not ....ly ~ a inta ed a h i g h spe count t h r o u g h o u t the t r e a en=, b u t d e v e l o p e d n o c h a n g e s in s p e tillty Ich w o u l d d l c a t e an a l t e r a t i o n in the f e r t i l i z g c a p a c i t y of the spe tozoa. T h i s s u b j e c t had no c l i n i c a l signs of e n d o c r opathy, and l i v e r f u n c t i o n tests r a ed at n o al levels t h r o u g h o u t t r e a t nt.
628
J
E i 977
L. 15 NO. 6
F~,I
F-
w
Z
m
0 J J
(.f)
-
6
8
Spe~ counts in men receiving monthly l~A a ~ ~ injections, Note that subject 20 took a ~ s t ~.~omonths longer than subjects 19 and 21 to reach azoospe~la.
4
22 o
20 • 21"
ECTSN~- 19:
~q
9 "ON ~; I ""IOA LL6I ~IMI"If
SPERM o
COUNT- IN
0£9
MILLIONS
::I> 0 0
0
iv
o
it'
0") CZ
o
t'D
"---4 CO Z io
o l,-t
mm u)"o --'I 0 0 or) --I.- o
XJ r,o__ 0
0 tt
o
zm rn;~
I1) I::1 i.,1
rn z
.,!"
z
o
--!
212 r'o o
m
rt" i,.,i
0 Z ---t ! (./3
MOIX~3DVH~LMOD
I Z 0 °o~
W
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I
C
Z
~
Z W
~
~W Z~ 0
o N ~
a=oe
t~..J
0
~o
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7" O0
0
o~
~d
NI
J U N E 1977 "VOL. 15 ]NO. 6
631
tal
F
w
4
6
8
I0
12
14
16 MONTHS
Spe~ count of a subject receiving ~nthly l~A and ~ Injections. Note that spe~ counts of this subject r~alned apparently unaffected by the monthly injections.
2
N~ 2 3 e
0 Z
CONTRACE
I
s u b ~ e c t s rep ted d e c r e a s e d l i b ~ o a pore y, a decked to dlscont ue t r e a nt for that reason. Four other n reported a t nsie decrease libido and p o t e n c y , but had rec ered by t next vlsit, 30 d a y s later. F e subjects reported c r e a s e d libido. Fo of these 5 a l s o r e p o r t e d c r e a s e d potency, ere r e no ¢ha es in the slze~ c o n s i s t e n c y or s e n s l t ity of the t e s t l c l e s or the breasts. derate ight g a l n oct crease w a s 2 kg one year. for one p a t nt one year. a
s
red e ere
most patlents. x ight re no c h a n g e s
The mean welght crease was kg blood press e
jeet.
significant changes occurred S T, S ~, or a l k a l e phosphataSe levels ing the t r e a ent. all but 2 subjects3 no s l g n l f l c a n t changes o c c u r r e d . . . . ser trigiycerides dur g treat nt. In o s Ject~ t level of t r l g l y c e r i d e s r o s e fr 56 to 147 % and r ined at this h i g h e r 1 el thro bout the t r e a ent period, a n o t h e r subject, trig l y c e r i d e s r o s e fr a pre-trea t I el of 46 to 134 mg7~, and later d r o p p e d to I0i d i trea ent. H eve~ t h e s e h i g h e r le is r i d wlthln no I 1 Its. fo tlon is a v a i l a b l e r e t u r n to f e r t i l i t y one subject. His spe co t d r o p p e d fr 80 ~ i l l n/ml v i r t u a l l y to zero by the fo th m o n t h ; c o n t a c t w i t h the s j e c t was lost at the s th month. tee m o n t h s foll i t last j e c t l o n s ~ his w i f e b e c pregnant 3 a subse e n t l y gave b i r t h to an a p p a r fly n al son. Several nths a f t e r the birth (more t h a n one year foll Ing dlscont~ u a t l o n of trea t)3 the s ject pr ided a s en spec n in ich the spe nt s 105 m i l l l o n / m l .... tility s 80%, c ared w i t h the preea ent v a l u e of 607~o
DISCUSS
N
P r e v i o u s studies h e sh that it is p o s s i b l e to duce a z o o la men by it g adotropln secretion without a corresg suppressi of l i b i d o a p o t e n c y (5,6~7). Our trials w i t h c a t i o n trea ents of t e s t o s t one I ts a v a r i o u s i9-norsteroids leafed that a z o o s p e ia or s e v e r e o l l g o z o o s p e la c o u l d be ed d ta ed for s e v e r a l nths in y o u n g (7). Spe toge sis s restored wlth a f loll dlscont u a t i o n of trea
spe po
A jot pr 1 w i t h the v a r us 1 9 - n o r - s t e r o reg ns has b e e n the ed for fre t (weekly) a d m istrat of h i g h doses, ich y r e p r e s e n t an e r challe e to the 1 er. e present jeer!on trea ent g es sl r e l e a s e of e h o s, a r e d u c e s the total t of st o to h the I er is e osed at a n y p a r t i c u l a r t . dro progester a c e t a t e doses of 1 5 0 /3 ths and 400 /6 ~ o n t h s are c sidered non-toxic w n for long-te c tracept e u s e (i ~2,3). T doses of dro pr estro acetate d testosterone anthate used the p r e s e n t cl ical h e been il-toierated m t r e a t e d for as I as e year.
J
1977
1.,. i 5
.6
633
CONTRACE
pr press ion of peated spe the trea nt. an crease p g y, the long te spe S
ION
I s to be resolved are those associated w ~ h ¢ lete spe togenes is in s s jeers, and t need for counts as the o n l y y to ...evaluate . the e f f e c ~ e ss of Aith gh dlscont ati of trea ent is loll d by spe co and t h e r e one instance of a q stlon of full reversibJllt, in ail subjects after togenle supp=ese ion r s to be establ Ished.
is rk s erta s e a r c h progr sp s ed ittee for ...Contraception . York.
n as part of the e tracept e develo d coord ated by the Internatl a! search of e Population C nell
E
ent
ES
i
Cout s
2.
C
t i o, E . a Souza, j .C. Conceptlon control by nthly ~ectl s of ~ e d r o x y p r o g e s t e r e suspension and a long ...act . g oestrogen. J. prod. Fertil. 15:209-214 (i968).
3.
Gardner, and res ing
4
ho, E.M. Souza, J.C. a Csapo, A.I. ity uced by dro roEes tero ii. 17:26i-266 (1966).
vers ibie ions. Fert il.
J.M. and Mishell, D.R., . aiysls of bleedi part ns tlon of fertility follow g discont atl of a long jectabie c tracept e. Fert il Ster!~. 211286-291 (i970).
c , J., Agents Af fect ing Fert i I Ity (C. R. st try, i tots )~ urchll I ndon, 1965 ~ p. 93-122.
a
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6 ....
Pataneili, D.J., in Vol. V ( ie reproduce
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Coutl o, E.M. a io, 3.F. Successful inhlbitlon of spe in n without loss of l ~ i d o : A potential n approach to contraception. Contraception 8:207-217 (1973).
634
d a ini8:191-206 (1973).
book of slology, Section 7 ( e syst )~ 19 75~ p.245-258.
3
E 1977
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ology),
toge ie
L. 15 NO. 6
sis