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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 F7 _8 d8 a% K  r  e, ?- gGONADOTROPIN. L/ T( v4 `5 X" P2 C
RICHARD C. KLUGO* AND JOSEPH C. CERNY
- ?5 c# B, I4 G4 G1 FFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan! F8 h9 F$ ]% v" l4 ^1 \7 E  X2 \9 v
ABSTRACT
+ T3 a9 R# r7 P5 r( v/ IFive patients were treated with gonadotropin and topical testosterone for micropenis associated: D% f. D; E& G( T
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# n7 V0 I3 I  P( Ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, F" l7 n2 c* R4 \2 k7 Fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" c. {6 s' C8 efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 h% j& A! _& w0 E6 J
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! O) ?. ]: Z. ]- p
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: C( {) ]+ ^% n: i  toccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This4 y% C4 s, I: ]( f
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 `6 G( {1 c. [# k+ j  fgrowth. The response appears to be greater in younger children, which is consistent with previ-
0 ?# B6 B3 \4 Mously published studies of age-related 5 reductase activity.0 C/ D9 Q! j% g# I' U3 j" [, _+ j
Children with microphallus regardless of its etiology will  o% J) ?# I; m9 M5 u  H
require augmentation or consideration for alteration of exter-
5 b$ a, p* T6 ?5 ~nal genitalia. In many instances urethroplasty for hypo-
& T( }! [* ~% o! @0 Y" l  Wspadias is easier with previous stimulation of phallic growth.! I5 h: ^: r8 s- }- p% a
The use of testosterone administered parenterally or topically: G* ]7 k  t- w  d$ G7 |4 y
has produced effective phallic growth. 1- 3 The mechanism of
* P# C/ \- r# Presponse has been considered as local or systemic. With this
% u3 j  G: c! d; P, }3 @in mind we studied 5 children with microphallus for response
- Q& k: ~+ r8 n  ito gonadotropin and to topical testosterone independently.
' E% Y2 b2 l4 J) U3 l( w+ ZMATERIALS AND METHODS
! W$ _: n* Z+ }4 sFive 46 XY male subjects between 3 and 17 years old were
7 s9 G: T8 A2 D4 Xevaluated for serum testosterone levels and hypothalamic
# \5 z- v: y8 l( ^1 q) [2 ?function. Of these 5 boys 2 were considered to have Kallmann's
! o/ [; D" j4 G6 A8 h6 m# _5 \syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-) }' P& e' w1 z4 w" T* p* e6 {' Q
lamic deficiency. After evaluation of response to luteinizing
7 [- o: S  G6 H. {; x9 vhormone-releasing hormone these patients were treated with
3 [% D; ]( g0 r9 i+ M7 S2 \1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 N: M% f& B8 @) U* Y- h4 u6 Bafter completion of gonadotropin therapy 10 per cent topical: o5 K# b( @. \2 C, m0 N% f
testosterone was applied to the phallus twice daily for 3 weeks.
# A! L, ~& P$ m! qSerum testosterone, luteinizing hormone and follicle-stimulat-9 k* y. V4 U9 b+ L' `% y. c
ing hormone were monitored before, during and after comple-
9 d! \7 `0 \* b7 S" @tion of each phase of therapy. Penile stretch length was
% Y$ G& \  b+ @/ Q! Tobtained by measuring from the symphysis pubis to the tip of: H! U, C5 g+ v( z
the glans. Penile circumferential (girth) measurements were6 V' I1 O5 W, I! J
obtained using an orthopedic digital measuring device (see
' h+ e' Y# a# |0 f# k6 Q9 Cfigure).
. Q7 }5 G9 P, M: H, d3 ^RESULTS( G) H3 x: U; g- F9 d
Serum testosterone increased moderately to levels between
9 ~% `7 k2 n4 E6 X50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  b& x& v. c* \& s1 Oterone levels with topical testosterone remained near pre-2 o! k1 r& x1 L1 Z* O
treatment levels (35 ng./dl.) or were elevated to similar levels
! c/ `) _8 S! S- a% E$ |" Ndeveloped after gonadotropin therapy (96 ng./dl.). Higher  O5 ]' L) L+ i
serum levels were noted in older patients (12 and 17 years old),3 _6 S+ {: b1 Q0 B1 q3 f
while lower levels persisted in younger patients (4, 8, and 109 A$ P2 K/ N) M" n4 ^  X4 {* |4 v8 D( X
years old) (see table). Despite absence of profound alterations
- i  k$ c) ^, Cof serum testosterone the topical therapy provided a greater5 a) p0 ]1 Q5 E/ |8 Y
Accepted for publication July 1, 1977. ·
7 e2 t; L( f0 ?: G2 [Read at annual meeting of American Urological Association,9 h; `& [( R* [8 ^0 ^$ V9 @
Chicago, Illinois, April 24-28, 1977.
% A- a! u3 h4 p" @8 m) l+ R! l* ^* Requests for reprints: Division of Urology, Henry Ford Hospital,- U* E& l& b; ~& \
2799 W. Grand Blvd., Detroit, Michigan 48202.2 E* l! b9 C3 o: ^) L0 D) F
improvement in phallic growth compared to gonadotropin.7 ^: b) c. [( j2 V5 A
Average phallic growth with gonadotropin was 14.3 per cent
# e4 H2 I% Y  ]% U. x! Rincrease in length and 5.0 per cent increase of girth. Topical
' j& E& j- B) O; E4 |testosterone produced a 60.0 per cent increase of phallic length
$ \3 C$ U* `5 V) e; h. H+ Wand 52.9 per cent increase of girth (circumference). The
* I. ]- ~' I9 B6 {$ Sresponse to topical testosterone was greatest in children be-% O, E! G3 t& J) X% H7 g) z
tween 4 and 8 years old, with a gradual decrease to age 17* R) D8 r/ |& E/ S
years (see table).3 A7 [5 r& b+ T3 l! k5 ?
DISCUSSION
& @# Q! ^- e" u* bTopical testosterone has been used effectively by other& g! |/ W- O9 k* p/ L) g
clinicians but its mode of action remains controversial. Im-: o  ^+ ?9 R, y) b9 c( g& E; d
mergut and associates reported an excellent growth response. ~% Q* l0 L: i- w2 x$ \; S8 `5 W
to topical testosterone with low levels of serum testosterone,
. N  E' w: p5 T$ Rsuggesting a local effect.1 Others have obtained growth re-
2 G. V" q* p( w5 m8 lsponse with high. levels of serum testosterone after topical
- w9 v* h' y4 e' X2 x/ c% cadministration, suggesting a systemic response. 3 The use of
- T4 S/ I" i# Y% g" egonadotropin to obtain levels of serum testosterone compara-3 y# J  ~  b2 [: |& z& }( \
ble to levels obtained with topical testosterone would seem to
* w* Z1 e) _% G8 j# nprovide a means to compare the relative effectiveness of* a! \8 |) w, V* P' @4 U; g  R2 p
topical testosterone to systemic testosterone effect. It cer-; X4 H( S: Q: j& u* r
tainly has been established that gonadotropin as well as par-
) [$ x( [# h% m2 t, d5 n& A' ^enteral testosterone administration will produce genital
6 m0 N5 e% |* G" Q* i/ rgrowth. Our report shows that the growth of the phallus was+ w9 t( t2 A) z3 @" y
significantly greater with topical applications than with go-' o. }6 x- J$ c5 u
nadotropin, particularly in children less than 10 years old.
, e* r8 R1 i; z7 KThe levels of serum testosterone remained similar or lower8 k( p9 G, d- ~7 T: h, U( z# c
than with gonadotropin during therapy, suggesting that topi-: o. H) J$ [0 d, ?; y% N( e! y, E' ]
cal application produces genital growth by its local effect as) R: a( R8 g7 w1 X' I  T
well as its systemic effect.  _* I) Z8 ^( w! X
Review of our patients and their growth response related to+ F! @, G+ E) J, d/ F8 q& D
age shows a greater growth response at an earlier age. This is
' ^. A5 h( \- W: z( aconsistent with the findings of Wilson and Walker, who0 g. i) K, y' ~) Y2 g& T1 t8 N% v
reported an increased conversion of testosterone to dihydrotes-, c% i; \6 Q  r- R
tosterone in the foreskin of neonates and infants.4 This activ-# j& i* h& T5 I; w6 J% K
ity gradually decreases with age until puberty when it ap-& m9 F2 r6 f$ W/ {) A. U8 k
proaches the same level of activity as peripheral skin. It may
1 q) Y+ \& \* I8 A2 S3 C* `well be that absorption of testosterone is less when applied at
' W3 l/ B1 _7 f$ M, ~an earlier age as suggested by lower serum levels in children1 d7 e9 W# A9 ^: N# [2 X* A
less than 10 years old. This fact may be explained by the2 \2 f/ X- Y9 |( F
greater ability of phallic skin to convert testosterone to dihy-4 W4 y% f" @+ B! F# B9 A$ g
drotestosterone at this age. Conversely, serum levels in older
) t0 S" A! e; K/ j/ d$ Opatients were higher, possibly because of decreased local+ [3 q6 U% u1 f
667' N6 j/ S4 O2 V/ K$ T- L# z( p. i
668 KLUGO AND CERNY
& c3 I3 i- Y% R  mPt. Age* u; q0 ]: h1 g" U7 Z
(yrs.)/ M0 g7 i9 ~5 U8 _0 ?- c
Serum Testosterone Phallus (cm.) Change Length
% G0 q& V" I. F! k4 g9 c# I(ng./dl.) Girth x Length (%)
3 g5 {& z0 [4 J& D  r$ d  `4
) }* n# [: L/ F0 @8. o/ F( ^. O. X3 c- K
10) M: `. _' |7 z+ E1 Z8 s2 K( z; u
127 W: z7 b; T+ i1 g/ K, y
174 s& R$ l; U' }( q
Gonadotropin
% R( U4 i  I3 Q/ _71.6 2.0 X 3 16.6
6 M" A& g. l( ]50.4 4.0 X 5.0 20.0) `0 N, p; I6 Z. H0 ^" M' h6 a, e% m1 U
22.0 4.5 X 4.0 25.0, a6 n# }: P9 M! [# b2 t) @
84.6 4.0 X 4.5 11.10 u6 X+ w, k6 h
85.9 4.5 X 5.5 9.0
% c& _, C, a* `  X% O* aAv. 14.3+ M) o. q0 P& v0 A
4  o( s5 g" a3 C: r, @
83 L( n0 V7 T+ @( w- i+ q
105 d( `, c0 N! c% [
12
/ q0 |4 V# k& v17
0 [5 M$ w6 s! ]! XTopical testosterone
9 I8 x* Z1 M6 l% a/ ~+ m34.6 4.5 X 6.5 85
4 E2 ?# O( r% b  j2 M' @  |0 t38.8 6.0 X 8.5 70
3 E4 B+ [1 `9 K5 U$ _  C9 @40.0 6.0 X 6.5 62.5
) [3 n5 ^8 p1 |) b93.6 6.0 X 7.0 55.5, Y0 j# \  G- Y$ ^0 y/ X" G5 p3 e
95.0 6.5 X 7.0 27.2: e' g* G& T2 ~( _+ q
Av. 60.0# A% ?* H5 R% e' `" e- S+ t
available testosterone. Again, emphasis should be placed on
1 p$ v+ v( ?+ w7 Kearly therapy when lower levels of testosterone appear to
) a0 b# M0 f; C! {  uprovide the best responses. The earlier therapy is instituted2 ~" i, B, e. P" r9 v( A, H4 S' O
the more likely there will be an excellent response with low
6 i. V, n$ R# G) U# E9 C6 N. Lserum levels. Response occurs throughout adolescence as* o. P5 m* K5 I- `  B- m
noted in nomograms of phallic growth. 7 The actual response' d0 D: ^# E* v% Y
to a given serum level of testosterone is much greater at birth
' S' Q: }0 d% ^1 ]and gradually decreases as boys reach puberty. This is most
+ V$ Z& ?2 d/ G( O  N7 a' Nlikely related to the conversion of testosterone to dihydrotes-3 i0 E0 N5 s: x* v) g) I5 h0 T2 f
tosterone and correlates well with the studies of testosterone( R% P, b. o% J
conversion in foreskin at various ages.
3 r) R. C0 J3 t0 j" U# \9 IThe question arises regarding early treatment as to whether9 {) b8 p" c/ w% b: t- m
one might sacrifice ultimate potential growth as with acceler-& q0 S4 |: i' p: {/ k
ated bone growth. The situation appears quite the reverse
" `( F4 f. C  C7 hwith phallic response. If the early growth period is not used
, d+ i1 M; @# E' O3 O" V1 _when 5a reductase activity is greatest then potential growth
* [3 n# K* ]" o# P- c; U& p' |4 ~may be lost. We have not observed any regression of growth
. `0 X- K( |. _attained with topical or gonadotropin therapy. It may well
4 z4 ^( ^" g& i% y% Zbe that some patients will show little or no response to any
: Z6 q( k) k% Tform of therapy. This would suggest a defect in the ability to: F' X" U1 X7 P; [! R
convert testosterone to dihydrotestosterone and indicate that8 X3 n9 o+ g9 r) n, D) k  l
phallic and peripheral skin, and subcutaneous tissue should+ w% I) D/ S0 b3 A% u) y3 I3 k
be compared for 5a reductase activity.! U1 p0 X' l- |
A, loop enlarges to measure penile girth in millimeters. B,
7 v5 h4 F& {0 [$ V5 j) Qexample of penile girth computed easily and accurately.
6 W  \1 T2 H( U  J; m4 G7 |conversion of testosterone to dihydrotestosterone. It is in this
' z- U1 c! E6 u5 X) }; M' Molder group that others have noted high levels of serum3 f3 e7 `* a  q/ R- `
testosterone with topical application. It would also appear6 Y, V( u5 P) @& p% I; R# [
that phallic response during puberty is related directly to the
$ E- U; S. J2 I+ N+ S9 P& Mserum testosterone level. There also is other evidence of local
  w- k5 w2 S: c) K3 K; m2 qresponse to testosterone with hair growth and with spermato-  `3 O9 J8 K" }2 d4 H
genesis. 5• 6
! [5 }* \0 Q* oAdministration of larger doses of gonadotropin or systemic0 N5 M. {, b) u3 _" C# V3 ~  z
testosterone, as well as topical applications that produce# ^- n* e7 k2 I% ~1 o5 O7 |
higher levels of serum testosterone (150 to 900 ng./dl.), will
) o# ?* ^) m- malso produce phallic growth but risks accelerated skeletal
8 \! j1 n+ Z" g: cmaturation even after stopping treatment. It would appear3 I2 X; L  S$ W4 E
that this may be avoided by topical applications of testosterone
2 ~6 y- T. ~' E$ rand monitoring of serum testosterone. Even with this control
+ g' V) U- K' ?  @' C3 Kthe duration of our therapy did not exceed 3 weeks at any
8 z  ?0 O4 D0 f2 I, N% vtime. It is apparent that the prepuberal male subject may
' o4 p7 n! N; \7 w$ Fsuffer accelerated bone growth with testosterone levels near
; h6 b$ a$ J+ K$ g: U8 l; j" ^200 ng./dl. When skeletal maturation is complete the level of
# D2 A! D7 A+ C5 k3 Iserum testosterone can be maintained in the 700 to 1,300 ng./3 r, I, {' i7 {' V$ T
dl. range to stimulate phallic growth and secondary sexual- p4 V! r3 F( g
changes. Therefore, after skeletal maturation parenteral tes-+ m" t6 X0 [" v+ h
tosterone may be used to advantage. Before skeletal matura-
  |" e# p* M9 otion care must be taken to avoid maintaining levels of serum! v; H* H3 ^$ U! U( H, |$ u* w- m
testosterone more than 100 ng./dl. Low-dose gonadotropin( v9 s5 F* `+ c: f; O3 o
depends upon intrinsic testicular activity and may require1 S4 p) I9 w3 E  S' o
prolonged administration for any response.$ O  m) l. h( `: q/ ~+ F
Alternately, topical testosterone does not depend upon tes-# D) T( s- N1 t9 K8 \3 j
ticular function and may provide a more constant level of
* R7 N/ k. z5 IREFERENCES6 o  C: [0 r, V& _6 I' M/ t+ ~
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,* s6 o5 e4 J1 q  v
R.: The local application of testosterone cream to the prepub-1 M$ C, o& L' [- B4 |
ertal phallus. J. Urol., 105: 905, 1971.
+ ?$ L$ z7 Z+ ?) G3 p2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone; K, T  o) A* w) r' K' `
treatment for micropenis during early childhood. J. Pediat.,  d/ e2 h3 z' k0 f
83: 247, 1973.
' I5 ]0 R& @5 L; y( {  {: P3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( s- J* ~* R5 `
one therapy for penile growth. Urology, 6: 708, 1975.
6 C& l4 D) j6 N8 h$ }& g2 A7 p4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
9 @  t8 o3 p+ P/ N4 Dto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( ]$ r: G+ G$ P$ ^) R9 F
skin slices of man. J. Clin. Invest., 48: 371, 1969.
( Z& f0 K9 w* c6 A! d, {$ I5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
' ~9 P3 k: `0 o# i0 A* b5 }by topical application of androgens. J.A.M.A., 191: 521, 1965.
1 ]* `3 a  m8 F% w  B5 d8 e6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local% u% W: |# S0 u2 c: ^0 E
androgenic effect of interstitial cell tumor of the testis. J.+ H; T6 {7 j9 u4 d' x  Z' h
Urol., 104: 774, 1970.! r2 A. {/ D5 ~  }  D8 d$ l: @8 a8 k3 b
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-# w3 C+ _7 w1 c9 _
tion in the male genitalia from birth to maturity. J. Urol., 48:
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