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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 ^" K4 l( Q0 U) _% W% Z: sGONADOTROPIN& n7 `  H' O8 L3 D! ^# C
RICHARD C. KLUGO* AND JOSEPH C. CERNY7 k/ y. Y$ `+ Y3 b9 z
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan# g1 B2 {3 }% ~: g
ABSTRACT
+ ?) H5 P' Z0 b0 g' {Five patients were treated with gonadotropin and topical testosterone for micropenis associated
) }' Y5 k$ e- f' t9 pwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-* f& T5 ?9 D1 w- ~
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
7 [7 M) B; o, F- L' v( Tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent6 O% v& r% l7 B/ i, l4 |3 r# i5 [. C
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) U  ]8 I5 _+ y$ z% I( [
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 {5 P! l" B( \- v: z. `. b
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: e. Y& p7 D2 _. N- n* t) u, {occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
! B7 Y3 D# Q' Ostudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 L7 X; N2 w7 y& s3 o3 n
growth. The response appears to be greater in younger children, which is consistent with previ-$ p% C6 D, g7 c( |" D
ously published studies of age-related 5 reductase activity.7 ]+ `% {5 l( L- o& i2 l
Children with microphallus regardless of its etiology will
6 b& V0 U* M$ \; p! N: T& jrequire augmentation or consideration for alteration of exter-
' S; }) D5 g4 J- d3 A% |nal genitalia. In many instances urethroplasty for hypo-
5 W! V% h/ Q9 ~# }spadias is easier with previous stimulation of phallic growth.& B. b$ T- k  z0 h
The use of testosterone administered parenterally or topically
/ e" q( n7 g( P5 S8 nhas produced effective phallic growth. 1- 3 The mechanism of
; x5 V3 h: A& c! R6 D6 u. d' B  gresponse has been considered as local or systemic. With this) u$ S/ o7 X8 v
in mind we studied 5 children with microphallus for response
& |8 w' W( }0 \6 Q( Hto gonadotropin and to topical testosterone independently.
/ x: G( U% ~* B! E% aMATERIALS AND METHODS
+ W/ V. M4 I( L, [Five 46 XY male subjects between 3 and 17 years old were, z: O2 F& J% c+ A4 O
evaluated for serum testosterone levels and hypothalamic/ {- Q: A- a9 F$ F
function. Of these 5 boys 2 were considered to have Kallmann's: u- V( [4 Q; x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
- t( K4 o: W6 T* I) l% Q' F4 b! I. ilamic deficiency. After evaluation of response to luteinizing
! K( r# B4 G- nhormone-releasing hormone these patients were treated with
) w2 {. h1 ^& g* b1 M" R/ {) U1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 M" \  K5 w) b4 b& N+ h/ l$ w: x
after completion of gonadotropin therapy 10 per cent topical  a; U1 i0 U, E7 }% y
testosterone was applied to the phallus twice daily for 3 weeks.0 ?$ @) R7 E. {; F( _. Z
Serum testosterone, luteinizing hormone and follicle-stimulat-1 I9 n; n7 v$ V
ing hormone were monitored before, during and after comple-8 p8 S2 H% h7 K2 C0 d
tion of each phase of therapy. Penile stretch length was
$ E" ?6 d% Z$ [, lobtained by measuring from the symphysis pubis to the tip of
+ k3 T5 j7 y' qthe glans. Penile circumferential (girth) measurements were
" B) c! y) s0 ^# n+ j5 Wobtained using an orthopedic digital measuring device (see3 |8 o( [& l7 t9 G8 f
figure).
. i/ L2 ]9 T- q. T2 M/ y" ^) DRESULTS0 P/ Z- b  g3 E
Serum testosterone increased moderately to levels between
- C$ o7 p/ x6 A& s; S% c3 I50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-3 N, O$ o- F( |7 H* P1 K
terone levels with topical testosterone remained near pre-
$ [4 r% l' a; P" G+ B3 `treatment levels (35 ng./dl.) or were elevated to similar levels8 }9 W7 G; L! t3 V
developed after gonadotropin therapy (96 ng./dl.). Higher
7 @6 q8 L' M# v* j; t: Nserum levels were noted in older patients (12 and 17 years old),
% I1 y8 b6 l1 U: [" K/ Twhile lower levels persisted in younger patients (4, 8, and 10
7 f! t6 {( g# g: x6 _years old) (see table). Despite absence of profound alterations
4 Y/ `" J" T1 s+ Z* v  gof serum testosterone the topical therapy provided a greater
* N+ h. ^- D. K# c* rAccepted for publication July 1, 1977. ·
& b, I% F* M6 ]  Q4 K4 ~/ FRead at annual meeting of American Urological Association,8 ^; i( \+ K7 \8 h
Chicago, Illinois, April 24-28, 1977., W; A' |! P+ m4 H* D# d- [" E  y% ]5 W" m
* Requests for reprints: Division of Urology, Henry Ford Hospital,
/ t. v" o3 N. S2799 W. Grand Blvd., Detroit, Michigan 48202.
1 r9 y0 t) g7 N+ B8 \2 u5 f9 [improvement in phallic growth compared to gonadotropin.1 t. f) q5 S" i- V
Average phallic growth with gonadotropin was 14.3 per cent
0 {9 T% Z% n2 jincrease in length and 5.0 per cent increase of girth. Topical' y- s. }! s( B3 ?& ~
testosterone produced a 60.0 per cent increase of phallic length
8 o9 R2 {+ ~$ M' F5 K3 Yand 52.9 per cent increase of girth (circumference). The
) w0 z6 F, {9 `response to topical testosterone was greatest in children be-; x* d5 F) M2 e! L9 k
tween 4 and 8 years old, with a gradual decrease to age 17
! C7 @$ X3 J5 @& Q; b/ h7 Qyears (see table).
' w6 v( W5 N5 ]+ v; L% @3 GDISCUSSION
; n8 v4 ?$ Z' zTopical testosterone has been used effectively by other) Z# @, O% ]3 C+ L* D# @( U
clinicians but its mode of action remains controversial. Im-
! H( C5 D6 ?# e+ x" A" c  d% `9 Qmergut and associates reported an excellent growth response
3 u* p1 P: n6 \" U! Gto topical testosterone with low levels of serum testosterone,' |4 H/ [7 M" a, K
suggesting a local effect.1 Others have obtained growth re-
  G9 f) G5 L! C+ E) ~1 A. qsponse with high. levels of serum testosterone after topical
! K; i! Z; w0 R, L# ]administration, suggesting a systemic response. 3 The use of  W+ a$ s& I- O: K2 t! M- Z
gonadotropin to obtain levels of serum testosterone compara-
! _& I, _% B! N" M, F4 t" eble to levels obtained with topical testosterone would seem to
+ n& W" K4 l* ?& \- d( x9 {- \provide a means to compare the relative effectiveness of% K% {% d0 S7 [) k# i* w6 E
topical testosterone to systemic testosterone effect. It cer-
* `! }5 w4 w; w, s% P: stainly has been established that gonadotropin as well as par-
: L. E' I5 `' T3 Eenteral testosterone administration will produce genital& h5 _4 R$ D- i# J/ q
growth. Our report shows that the growth of the phallus was/ a' z! S9 f$ k: ?
significantly greater with topical applications than with go-
8 t6 N# ], X$ a/ ~% Z" v: k& dnadotropin, particularly in children less than 10 years old.. @6 B( v: h. Z: W) z3 _. H3 W
The levels of serum testosterone remained similar or lower) T  v2 w4 w: Q3 X
than with gonadotropin during therapy, suggesting that topi-
& i2 I5 Q) ^* I8 d& V# \) ocal application produces genital growth by its local effect as
2 Q3 ]6 ?0 D: v8 ?well as its systemic effect.
6 ~- Q  A: N& r% {Review of our patients and their growth response related to
4 ]7 t& y. A  `2 {  v4 bage shows a greater growth response at an earlier age. This is
4 n7 C2 K; Y. ~5 D9 W: H: I& ^- qconsistent with the findings of Wilson and Walker, who
' V% h4 A& K' [# O2 A. Nreported an increased conversion of testosterone to dihydrotes-
; ]' _+ |; s! l* U4 g4 [' Ktosterone in the foreskin of neonates and infants.4 This activ-- Y7 n  J9 _: A5 _. g& u* L$ e) @
ity gradually decreases with age until puberty when it ap-/ P# [+ i6 ]; G- x
proaches the same level of activity as peripheral skin. It may
0 r, B; K* o5 |  R$ q' fwell be that absorption of testosterone is less when applied at7 B- P+ I( O3 n8 q+ V! |, b
an earlier age as suggested by lower serum levels in children
1 J: l3 E5 I6 Dless than 10 years old. This fact may be explained by the
7 U( J- ^0 w2 r6 Ggreater ability of phallic skin to convert testosterone to dihy-
0 p9 ~' p/ f7 A5 C7 G& a; f% cdrotestosterone at this age. Conversely, serum levels in older
8 S+ E% S* s1 x7 ]. E- s$ L8 ~$ tpatients were higher, possibly because of decreased local
+ M; l/ o  J3 x$ }) S; Q667
( I6 t# _4 X, X+ _/ |668 KLUGO AND CERNY
- W& e8 L4 b8 Y3 tPt. Age
5 A+ A+ G' v8 m/ v; ]/ N- X(yrs.); }$ ]% S9 V, \  Q6 d" x2 P
Serum Testosterone Phallus (cm.) Change Length
0 X2 E* y6 O4 P1 k( H, v+ B( B& v% s(ng./dl.) Girth x Length (%)! K! j4 ]8 [$ h5 ~$ i
4
/ ?1 I  F4 ^/ k# X/ D. @8
+ O- v- h  O4 T" @( |# V# W10" q* t7 \: Y+ I0 _( b0 L+ ^3 ]; Q
12
. b9 q2 z# f) x4 o17
& s, ]6 v0 f& \( Z: `4 z! WGonadotropin% G+ U6 T% i( s8 z+ I
71.6 2.0 X 3 16.6' p( |1 M% y, Q+ g
50.4 4.0 X 5.0 20.0) x6 U% ?3 f3 ^. |& [! b
22.0 4.5 X 4.0 25.0
; i6 t2 g& M- W9 |5 R84.6 4.0 X 4.5 11.1
( E! c. J% v. z, i3 X  R85.9 4.5 X 5.5 9.0
) p* O; T" ?7 e# [Av. 14.3
4 y* @) w+ e3 o( ], J4  ~+ w1 {, D  ~) [* F2 L( h
8
( O( \! @/ ^! j# o* M/ P10) \( F6 l& u: d$ A' |
12% e( Y. H: m5 Z: k
17  E8 }+ M$ x; x+ W9 }1 m9 G; H: X
Topical testosterone4 M0 U4 f( V& t. f  A; b2 _
34.6 4.5 X 6.5 856 ^0 h! x/ C% Q4 ~. B9 A
38.8 6.0 X 8.5 70  P$ [9 X5 N9 D
40.0 6.0 X 6.5 62.5
" s5 v$ }0 j1 R: ]5 P$ \. M93.6 6.0 X 7.0 55.5
# R. Q9 U; S0 J; x" P95.0 6.5 X 7.0 27.2# B- b8 _5 z8 r3 N$ @
Av. 60.0
" A, y. j6 h9 F4 g+ }available testosterone. Again, emphasis should be placed on1 d8 |  Z) |  v2 x, Y3 o, z
early therapy when lower levels of testosterone appear to
0 H3 D' R1 @; P3 e% ~, |provide the best responses. The earlier therapy is instituted9 L& N) J7 L* b! w' ~
the more likely there will be an excellent response with low
# V; H8 m# n' _4 d2 L' d0 A& userum levels. Response occurs throughout adolescence as9 R/ p6 ~1 z/ s/ k, S
noted in nomograms of phallic growth. 7 The actual response- D- Z2 _9 I7 A  }4 H( s
to a given serum level of testosterone is much greater at birth, P! j6 n: N2 a% K8 O$ }
and gradually decreases as boys reach puberty. This is most& \' U% g# l, G: N$ c( F; [- v
likely related to the conversion of testosterone to dihydrotes-' @8 @$ n0 l7 y- b( w9 E( O
tosterone and correlates well with the studies of testosterone
; O0 M0 [+ S3 |- _! Mconversion in foreskin at various ages.
: n& _* U0 R! vThe question arises regarding early treatment as to whether& [, A/ ]1 q  l, W' ^
one might sacrifice ultimate potential growth as with acceler-) h( m3 W7 P: M- C& A
ated bone growth. The situation appears quite the reverse3 S4 t. L! Z# M3 T& ~3 q
with phallic response. If the early growth period is not used
4 U9 Y! }5 `0 ^& A+ {) d2 [/ P7 Mwhen 5a reductase activity is greatest then potential growth
* P* i+ `9 Y: l/ n! G+ ^may be lost. We have not observed any regression of growth% }& f" d8 e" l3 A  h& X! s' F
attained with topical or gonadotropin therapy. It may well
+ n; }8 q0 w4 N3 R+ T+ p$ wbe that some patients will show little or no response to any
5 _. ~9 @+ `; }' w& K; rform of therapy. This would suggest a defect in the ability to
) r7 k  q& x! Q; v# `convert testosterone to dihydrotestosterone and indicate that3 r6 s/ v8 b7 l. ~
phallic and peripheral skin, and subcutaneous tissue should- I' n6 l/ B9 f. L  {! c# P8 }5 ]
be compared for 5a reductase activity.
( r% V4 }' Z& ^+ t6 qA, loop enlarges to measure penile girth in millimeters. B,
# Y% ~, U9 B* L$ R- h$ |: yexample of penile girth computed easily and accurately.
5 j# N7 Z4 i0 uconversion of testosterone to dihydrotestosterone. It is in this
/ e1 p$ G& R0 m" x+ rolder group that others have noted high levels of serum
5 L. a% ?. X% r6 Ntestosterone with topical application. It would also appear, l' H, j$ m/ A- {6 d' d
that phallic response during puberty is related directly to the
; J/ D* W; {2 Bserum testosterone level. There also is other evidence of local. N) d! y3 @& z: q
response to testosterone with hair growth and with spermato-
% J0 j2 o* t: B  agenesis. 5• 6
, [' Z5 `8 Y) u! RAdministration of larger doses of gonadotropin or systemic5 D  u1 h! h1 N' Y) C2 y* v' g
testosterone, as well as topical applications that produce
, A! D( Z' G* }7 B1 ~8 G1 z7 whigher levels of serum testosterone (150 to 900 ng./dl.), will6 ~6 @" @4 y. i
also produce phallic growth but risks accelerated skeletal
% l3 g( F3 U! ^+ ^maturation even after stopping treatment. It would appear$ X* j% \$ B; N/ u
that this may be avoided by topical applications of testosterone1 ]- B  ?. a% R- j6 `
and monitoring of serum testosterone. Even with this control
. s+ F/ X- C2 z; athe duration of our therapy did not exceed 3 weeks at any" [0 Y9 |4 q8 N5 }! Z
time. It is apparent that the prepuberal male subject may2 J  ]" U. z! o% j" x1 |! F
suffer accelerated bone growth with testosterone levels near8 X. U9 q  J0 X  C( {) t
200 ng./dl. When skeletal maturation is complete the level of) f) t9 o9 P- J; f. V+ ^
serum testosterone can be maintained in the 700 to 1,300 ng./
3 h$ j1 w$ M0 y* ^2 ndl. range to stimulate phallic growth and secondary sexual6 V2 Z' s4 X9 p! w8 p
changes. Therefore, after skeletal maturation parenteral tes-
* W; m$ P; P2 r4 ^0 e4 _tosterone may be used to advantage. Before skeletal matura-1 U5 }+ A, k1 Q! t
tion care must be taken to avoid maintaining levels of serum- T9 q' v: C4 q7 T& {9 S8 S) ^: |
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ G, [' _1 e# E" g( Jdepends upon intrinsic testicular activity and may require# o( }3 ~2 y" ^8 n0 F
prolonged administration for any response.# p, M: E' J) l) x
Alternately, topical testosterone does not depend upon tes-
( \. a4 j$ n& `ticular function and may provide a more constant level of
( w! A6 v* o6 NREFERENCES+ S4 g( P( j, T$ R9 H
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ [, @& b1 F& u
R.: The local application of testosterone cream to the prepub-
& v3 `. o3 |% eertal phallus. J. Urol., 105: 905, 1971.$ W5 l  u* H% Z8 ^; ]+ q# E+ E2 \
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' m" [  D4 Q$ Xtreatment for micropenis during early childhood. J. Pediat.,2 X# F% d8 w( S% I
83: 247, 1973.
7 f- X4 l6 E# c# y3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# w' E; q/ q; ^" m
one therapy for penile growth. Urology, 6: 708, 1975.
# \) t& j' S: Y. e4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( A5 g% t" v/ c9 n& d. r0 Dto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 H- \8 d5 ^' f( \skin slices of man. J. Clin. Invest., 48: 371, 1969.) {5 C" i$ [/ L/ \2 p& g
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 m* [) Z3 ?3 ~+ e: t+ \by topical application of androgens. J.A.M.A., 191: 521, 1965.
" @* y" g0 q9 r6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
) P6 k& s  D  P) E$ aandrogenic effect of interstitial cell tumor of the testis. J.& p8 d" U- H6 C
Urol., 104: 774, 1970.. L* R- m* _# Q7 C8 I6 r
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
  `& z5 n8 [; p/ M1 M& ption in the male genitalia from birth to maturity. J. Urol., 48:
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