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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
2 `& u7 i0 ]) X7 t) IGONADOTROPIN% }: t- y" q) ~$ d2 s  ~3 C
RICHARD C. KLUGO* AND JOSEPH C. CERNY- G; B" y, h/ o2 x" O! f: E1 n
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' ?7 W( _$ ?' E- @" ?ABSTRACT
* h6 P3 a- b( v5 C& iFive patients were treated with gonadotropin and topical testosterone for micropenis associated" F7 R! q7 N7 {2 u2 G* K2 G
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-1 ?1 q( J1 H* w
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone  E$ I+ V0 v' t* O. ~& K
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent% S, b8 {9 `6 n, ~3 A6 e. k
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! N3 J7 `8 V3 N5 r8 j. Z
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average( a$ S0 I; V: w& D
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 f! f! P* p) h' h# [occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 c* k4 B/ U* M; ~( |  g* Rstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
8 A6 m$ R& Y1 g9 G2 B1 Y* pgrowth. The response appears to be greater in younger children, which is consistent with previ-
/ R9 K# O; Q* {, B6 A6 hously published studies of age-related 5 reductase activity.
( Z6 M6 b: i1 {) p& |3 K" f4 E1 CChildren with microphallus regardless of its etiology will7 M( y3 l% Y$ y' x
require augmentation or consideration for alteration of exter-
3 Q* W1 I6 O+ X* \  enal genitalia. In many instances urethroplasty for hypo-# q( K, _6 z# g
spadias is easier with previous stimulation of phallic growth.
- R: a. z* M0 n) k) vThe use of testosterone administered parenterally or topically
% F7 r1 d) X2 n5 X' ahas produced effective phallic growth. 1- 3 The mechanism of9 O7 F. n9 F3 p1 c1 ^
response has been considered as local or systemic. With this1 F# V) q0 o. K/ t
in mind we studied 5 children with microphallus for response: A2 a( H* u" D( {
to gonadotropin and to topical testosterone independently.
# {- j9 _% O0 f3 \- X( ^  h7 FMATERIALS AND METHODS
% M2 F2 i: ?  r8 kFive 46 XY male subjects between 3 and 17 years old were5 e  y) o  R9 H& a1 V
evaluated for serum testosterone levels and hypothalamic* }# U. r: \- b
function. Of these 5 boys 2 were considered to have Kallmann's6 r# r( y! U. T& G
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 T- _: V9 P9 W0 _' X5 v, _5 Z7 h# Clamic deficiency. After evaluation of response to luteinizing, b' t  l. }" o3 _: P
hormone-releasing hormone these patients were treated with
' V7 `! }! z+ @2 M4 |1,000 units of gonadotropin weekly for 3 weeks. Six weeks
, I% |( C- ]! Qafter completion of gonadotropin therapy 10 per cent topical! q: H( U# Q/ g4 z+ J6 o
testosterone was applied to the phallus twice daily for 3 weeks.
- j9 \! J# G& z" v9 `6 |Serum testosterone, luteinizing hormone and follicle-stimulat-
* k% _: o& v9 o6 J" ~) eing hormone were monitored before, during and after comple-# |# @# O9 `  ]' m, J1 Q
tion of each phase of therapy. Penile stretch length was
- L, z4 P0 E! L; B5 M; ~obtained by measuring from the symphysis pubis to the tip of
' w( q' z' v& `the glans. Penile circumferential (girth) measurements were
* ]& n. E+ B# q7 D) mobtained using an orthopedic digital measuring device (see0 @9 C2 d5 K0 O. R2 Q: W
figure).
  H) r! i! a  b7 DRESULTS
$ |( P' ~" P# V) W# o2 CSerum testosterone increased moderately to levels between
* i- k" N* v% v: E8 ^) H, }50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' }6 U" c0 A/ ~0 x& @$ i
terone levels with topical testosterone remained near pre-
; a9 V  H5 U) B( {6 t$ `6 itreatment levels (35 ng./dl.) or were elevated to similar levels  P. n. V% l7 m3 r/ ^% {' s9 S$ ]
developed after gonadotropin therapy (96 ng./dl.). Higher
) e  E/ {( B% k! r  T& F3 eserum levels were noted in older patients (12 and 17 years old),7 s. B" Y% I0 ?! k
while lower levels persisted in younger patients (4, 8, and 10  N7 I; D2 [9 q% W5 G
years old) (see table). Despite absence of profound alterations4 b1 y3 j0 m0 g0 c( R* W% \
of serum testosterone the topical therapy provided a greater
0 D/ l, l4 a; N, oAccepted for publication July 1, 1977. ·4 Q+ F* t; f  A
Read at annual meeting of American Urological Association,
) z3 g4 L2 b: \; v* sChicago, Illinois, April 24-28, 1977.
% z! J: m; v* J8 w* Requests for reprints: Division of Urology, Henry Ford Hospital,7 w# @6 h" f. X  O/ C8 Z+ |. z
2799 W. Grand Blvd., Detroit, Michigan 48202.( A: V1 ]4 E6 S
improvement in phallic growth compared to gonadotropin.  k1 b$ Z4 [. z5 l
Average phallic growth with gonadotropin was 14.3 per cent
; _0 m2 n, c; l+ _( t& m- V$ Y, Aincrease in length and 5.0 per cent increase of girth. Topical: ]2 R# ^2 h- l
testosterone produced a 60.0 per cent increase of phallic length
" M4 S+ B8 x7 d+ C4 Fand 52.9 per cent increase of girth (circumference). The4 H6 x3 U" A( T! ]: h
response to topical testosterone was greatest in children be-
; c! Z8 j( n3 t3 A4 Utween 4 and 8 years old, with a gradual decrease to age 17
% A( O. V8 Y0 I4 G: lyears (see table)." f& `. B1 J# t  y( N$ A( q% |+ j
DISCUSSION
' O# n9 K; `& PTopical testosterone has been used effectively by other  H9 U2 @* ?+ X3 }# m6 i( b+ A
clinicians but its mode of action remains controversial. Im-) u2 T: k) a: s" W. M
mergut and associates reported an excellent growth response
$ W7 K  N# Z& Bto topical testosterone with low levels of serum testosterone,
# P. n/ t# v9 k  q8 O8 p7 v/ tsuggesting a local effect.1 Others have obtained growth re-3 Y+ U# |  X) t3 U1 `5 h3 T9 V
sponse with high. levels of serum testosterone after topical7 y4 {7 s  J' a4 K6 d$ y% \5 z7 y
administration, suggesting a systemic response. 3 The use of
: [+ ?. u0 f1 @, h# [1 _gonadotropin to obtain levels of serum testosterone compara-+ a" Y0 a: v6 E
ble to levels obtained with topical testosterone would seem to) H  Q) B. X( }% A
provide a means to compare the relative effectiveness of/ n1 l, _5 t5 X* i
topical testosterone to systemic testosterone effect. It cer-' M9 X, d" D. t1 P
tainly has been established that gonadotropin as well as par-  m( [, {" A" X
enteral testosterone administration will produce genital- I5 F$ U7 [! Q! P  B; O3 Y
growth. Our report shows that the growth of the phallus was
2 C7 u- ]* d! Y' `; Fsignificantly greater with topical applications than with go-
. K9 O" D# E& b" d1 e/ H& }+ vnadotropin, particularly in children less than 10 years old.0 C, d( J" C! D
The levels of serum testosterone remained similar or lower/ `7 f7 E! D% l1 l* m, C3 O
than with gonadotropin during therapy, suggesting that topi-& l7 G2 a. `" f% |
cal application produces genital growth by its local effect as% y. U+ E$ W9 O6 w$ A1 r/ k
well as its systemic effect.
2 w0 ^8 z% e& z; e/ [% K7 zReview of our patients and their growth response related to
9 Z8 L  `: z! f% N4 z) Kage shows a greater growth response at an earlier age. This is% X6 U6 v3 r1 y6 T+ {' t. R) }
consistent with the findings of Wilson and Walker, who8 N; H! o% S' G5 c( V3 I; n
reported an increased conversion of testosterone to dihydrotes-
  @$ w% ]" g2 W# X: z, mtosterone in the foreskin of neonates and infants.4 This activ-- b- ]& l$ }4 e5 \9 {$ h4 K
ity gradually decreases with age until puberty when it ap-
/ X' }( ], v) j, s( j2 L( ?' h' ?proaches the same level of activity as peripheral skin. It may! C7 J' b, J7 p* W; F
well be that absorption of testosterone is less when applied at2 ~, v0 F* N% z9 \
an earlier age as suggested by lower serum levels in children4 [! c7 b2 n; @3 e$ t
less than 10 years old. This fact may be explained by the
; S) r1 k: p9 q2 Zgreater ability of phallic skin to convert testosterone to dihy-5 A+ u9 @1 W% L; j. w
drotestosterone at this age. Conversely, serum levels in older
2 `0 [1 X( x/ Upatients were higher, possibly because of decreased local; H  g; V& ]" ]" c$ h1 F; q0 d- p
667+ l& [! U; ]$ k" E( k
668 KLUGO AND CERNY; s2 ]$ ?2 p1 ^" }# B
Pt. Age
9 F3 n" E- x$ d% G& N& \9 @(yrs.)
$ r; P1 R& u2 gSerum Testosterone Phallus (cm.) Change Length
  q7 W! K4 O5 |(ng./dl.) Girth x Length (%)
) O4 V1 R2 n- q; ?7 _+ G) a4: p# l( m) t# f+ {. s% [4 e
8
5 m' ^& I  {( c" ?108 _, M, ]0 v% x
12
1 ^& v4 ^7 q) T6 L3 k- n17# }5 H' x% k; w/ S: J
Gonadotropin1 \5 F, n, }2 a2 x$ [+ j1 n: k
71.6 2.0 X 3 16.6
+ c8 ^# r" v) B! U  x50.4 4.0 X 5.0 20.0
. Y/ y5 A  O/ _+ G3 d# ]; C2 X0 A22.0 4.5 X 4.0 25.0
( W2 Z2 E$ f1 ~84.6 4.0 X 4.5 11.1
& g& L5 Y$ w3 R" M: m85.9 4.5 X 5.5 9.0
; U$ T7 Y6 P- v& h- D2 b$ F6 zAv. 14.3
' W7 Y* R2 L) a) ~1 k" o4
; J5 Q/ \; h' D& M( y# G/ j& E) A* b8
2 s: E& P9 {+ J+ i! c6 y5 E108 q2 Y, C& X0 ^+ i: u  \
12
! u& n: s/ k  c17! b! f( p0 K+ \/ p: s; ~6 M
Topical testosterone
, R; l# Y4 T+ ]- {34.6 4.5 X 6.5 85% z2 ]$ J* x; H6 Q8 s- T# l. K# x
38.8 6.0 X 8.5 70
+ A( Z7 k/ y; L% \  v8 w! u  G  Y40.0 6.0 X 6.5 62.5, G# x3 [$ N# g$ f
93.6 6.0 X 7.0 55.52 j/ h: n4 B" E/ q" @+ z2 f
95.0 6.5 X 7.0 27.2
: I: w# V1 `# i6 V% v3 aAv. 60.0
. q5 ~6 I+ ^( T8 [# B" `available testosterone. Again, emphasis should be placed on
6 S6 B/ [/ z7 j8 [. ~early therapy when lower levels of testosterone appear to
  r6 [6 d  R9 K; }7 ]. Hprovide the best responses. The earlier therapy is instituted+ n* j7 v5 H; s. z3 Z
the more likely there will be an excellent response with low
, R; t9 |) h/ B' d+ q1 q" h- a( Lserum levels. Response occurs throughout adolescence as
$ v8 v9 {5 k$ j3 Snoted in nomograms of phallic growth. 7 The actual response( d& d1 J4 _0 s8 Z2 h3 O
to a given serum level of testosterone is much greater at birth
2 |0 \* l, f8 r4 R- |and gradually decreases as boys reach puberty. This is most
& H# S$ z8 B2 N4 J" I" ulikely related to the conversion of testosterone to dihydrotes-4 h* C, n: P" g" _4 i/ }
tosterone and correlates well with the studies of testosterone
" D7 T, i1 U" E& ?6 N  j# @/ Econversion in foreskin at various ages.
. W" w3 O4 X! cThe question arises regarding early treatment as to whether
: d$ _# o) _3 f" Sone might sacrifice ultimate potential growth as with acceler-' `, V! o( }2 w! h
ated bone growth. The situation appears quite the reverse
) P$ U1 n0 s$ G& H5 L6 z- ]) ], xwith phallic response. If the early growth period is not used' @: r4 c; w% R8 E7 e2 q
when 5a reductase activity is greatest then potential growth( [2 n( m; l4 P% [
may be lost. We have not observed any regression of growth- x. S) _' `9 }1 j% G- q$ Y
attained with topical or gonadotropin therapy. It may well# T( _8 F* B4 Y: o5 s7 e
be that some patients will show little or no response to any
2 x# K. `& G4 L6 |7 Rform of therapy. This would suggest a defect in the ability to' u! A& ~+ C% \) M; H3 q4 w
convert testosterone to dihydrotestosterone and indicate that
: I" t3 b3 I* R+ ~- Lphallic and peripheral skin, and subcutaneous tissue should+ W3 X+ ~/ i/ F6 z5 H. w
be compared for 5a reductase activity.
: x) T( ]% g7 j3 @* T3 x$ PA, loop enlarges to measure penile girth in millimeters. B,8 `* q: @( W; @6 c
example of penile girth computed easily and accurately.
1 m+ T% b# R+ W& c* ?1 Mconversion of testosterone to dihydrotestosterone. It is in this0 \1 Z4 d- c9 e
older group that others have noted high levels of serum
# H9 i/ @5 T" g5 ~' M+ W/ Qtestosterone with topical application. It would also appear4 g! ?7 A+ p0 J# {6 h6 P$ u
that phallic response during puberty is related directly to the* V( x3 Z: F2 a) x, r. \0 Z+ p
serum testosterone level. There also is other evidence of local
: O. s! y/ z% O, m- i* Iresponse to testosterone with hair growth and with spermato-! I( Q+ I8 J# e. P* N' X0 f
genesis. 5• 6
# z4 O. {: V3 z' r0 oAdministration of larger doses of gonadotropin or systemic& _! j! j: |, T
testosterone, as well as topical applications that produce
6 {/ F' ?9 s) L& c  U' xhigher levels of serum testosterone (150 to 900 ng./dl.), will- Q8 s& Z5 |! G- r
also produce phallic growth but risks accelerated skeletal
0 c2 n7 Q) R! J/ P1 z" x4 xmaturation even after stopping treatment. It would appear2 D) L. X. X, U5 K& _0 S
that this may be avoided by topical applications of testosterone3 d* x) X  j. f* x9 O9 c7 B* p8 S
and monitoring of serum testosterone. Even with this control/ n6 P5 [# L- s, I8 h9 ?# ^' V$ c
the duration of our therapy did not exceed 3 weeks at any6 ?# q" \5 D% u7 b" y2 v% {$ @7 r
time. It is apparent that the prepuberal male subject may* X, S9 q3 \& j
suffer accelerated bone growth with testosterone levels near
% u' P* N# k4 \/ p. ]: U+ W, s200 ng./dl. When skeletal maturation is complete the level of
$ S1 k( ~2 E& ]; ]serum testosterone can be maintained in the 700 to 1,300 ng./
' @5 b4 X( z2 i3 ^, vdl. range to stimulate phallic growth and secondary sexual5 D5 K. r0 m8 a2 ~* u% U
changes. Therefore, after skeletal maturation parenteral tes-
- g% g+ k- o4 Q" ^! q% gtosterone may be used to advantage. Before skeletal matura-
7 r* G) q; d% [4 B$ |7 u4 ?tion care must be taken to avoid maintaining levels of serum% K) w- d7 B' r: B2 Z$ \. I  w
testosterone more than 100 ng./dl. Low-dose gonadotropin
; o; [4 v6 D- a- p  Edepends upon intrinsic testicular activity and may require3 y) @/ D  }5 s5 M- ~
prolonged administration for any response.) K) }$ n) _2 D& }1 z, W5 H! t
Alternately, topical testosterone does not depend upon tes-, C" w& a; C; K6 W+ }) k5 l; Q
ticular function and may provide a more constant level of
% b1 y; U  o) T+ JREFERENCES  k4 I, b5 i8 Q% A+ n
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; {8 C' \! D5 vR.: The local application of testosterone cream to the prepub-- P- _! |/ F( k* k# G9 `
ertal phallus. J. Urol., 105: 905, 1971.
& a1 U( p4 n" x6 h: ]2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, m1 m! n$ ^9 Y# @1 N8 y
treatment for micropenis during early childhood. J. Pediat.,
+ T0 D6 y- Y( K' N83: 247, 1973.' j$ |8 X- W% O6 p( A- W* ?
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' O9 Z0 E) X( G0 b: U# G( Bone therapy for penile growth. Urology, 6: 708, 1975.
& z! I- o3 ^& o. a6 m4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, a: k8 b6 s/ Sto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: Z4 T/ r+ i+ u9 W$ |: iskin slices of man. J. Clin. Invest., 48: 371, 1969.9 D/ P7 r9 o( T  N" @# M: `
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth0 ^$ k1 e+ W( y$ |  A4 I6 g' G
by topical application of androgens. J.A.M.A., 191: 521, 1965.& Z; {! \! H; C, M4 b" J7 o
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 \2 J% W/ Y/ o8 N" Z
androgenic effect of interstitial cell tumor of the testis. J.3 M& ]4 z6 ]3 h" w( d9 g9 T
Urol., 104: 774, 1970." t8 ^+ E) b' x5 Z& W
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( N; ^% w, ]. j
tion in the male genitalia from birth to maturity. J. Urol., 48:
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