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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
( u4 ?8 R4 u+ b2 `GONADOTROPIN
  h% U9 S1 E0 q8 J- {RICHARD C. KLUGO* AND JOSEPH C. CERNY- c( r  L2 H/ Y% @- e% F
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* D" T" i: [6 ZABSTRACT
# ^( s" c. k7 q  m0 m! GFive patients were treated with gonadotropin and topical testosterone for micropenis associated( I+ v8 u/ c" u  l) ]# ~% ~7 u
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-' p, D% d0 k; d8 K4 s- \
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ q- R* l# \% H
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 r2 [) p$ j( m  l; `for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ F2 q% ^( K# cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average: m# x1 j4 N$ E) b+ f, q6 P$ H
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
( F" j) A) M) y: m+ Xoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This' _; r& A  M) f* x6 e
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ g5 j- O5 B! Y% Y4 J/ K! v" @) Rgrowth. The response appears to be greater in younger children, which is consistent with previ-0 Q* Z' n" e1 i+ W* Y' z* {$ j3 U
ously published studies of age-related 5 reductase activity.7 q3 V: \" W2 j4 u
Children with microphallus regardless of its etiology will
1 M8 u8 C/ x9 O: L! zrequire augmentation or consideration for alteration of exter-
5 b+ L6 P/ l, z/ a$ e7 snal genitalia. In many instances urethroplasty for hypo-" [8 W' U( D6 J8 V# O8 P
spadias is easier with previous stimulation of phallic growth.$ T0 \: ]' v9 ?0 o& |
The use of testosterone administered parenterally or topically
; ^- v1 E' B+ X& o" C' shas produced effective phallic growth. 1- 3 The mechanism of$ i5 Z7 s8 j  @! P" {5 V4 G* M! G
response has been considered as local or systemic. With this' s: o# B9 M! V* c( O, [" i
in mind we studied 5 children with microphallus for response
  x4 m. v0 n' p1 N0 gto gonadotropin and to topical testosterone independently.
0 x+ C8 W9 O; sMATERIALS AND METHODS( g% t* V9 n/ k8 H& X4 Y
Five 46 XY male subjects between 3 and 17 years old were, X5 E) z0 P( ?8 |4 n! P
evaluated for serum testosterone levels and hypothalamic
$ x3 g; e6 F* A7 y9 E  Yfunction. Of these 5 boys 2 were considered to have Kallmann's
" M+ p$ P  e( O1 N7 Osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 V* s  |* G: ^9 m8 h8 l! P
lamic deficiency. After evaluation of response to luteinizing
+ ?* v4 ^' A# uhormone-releasing hormone these patients were treated with8 Y9 B5 F" q# s: a7 V0 x) s$ R
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
' v: i$ j7 q; Yafter completion of gonadotropin therapy 10 per cent topical
  L5 h# F0 R4 J; w' B7 `6 ?testosterone was applied to the phallus twice daily for 3 weeks.
, G4 A: L4 z) k0 s- j* y7 m6 oSerum testosterone, luteinizing hormone and follicle-stimulat-2 h/ G- L; n0 v, q% O
ing hormone were monitored before, during and after comple-
8 `4 N2 n; N2 E) g5 j! gtion of each phase of therapy. Penile stretch length was& S" w5 u, _8 K' L5 @5 N
obtained by measuring from the symphysis pubis to the tip of
2 ~# a" d# t# @/ X9 ^0 V/ bthe glans. Penile circumferential (girth) measurements were
0 Y3 D: ~8 c" l& P6 E5 F' f: Gobtained using an orthopedic digital measuring device (see
2 h. Z. \# i, l2 P$ x$ pfigure).
" s6 |- L8 p2 F3 {5 v  gRESULTS
' e$ T  t! P. t6 P6 g( _Serum testosterone increased moderately to levels between3 ~. i1 F: \, }
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-. Q6 l3 L6 {& g; G1 L+ B  s
terone levels with topical testosterone remained near pre-. b! k# q% F2 ]" }5 b, Y
treatment levels (35 ng./dl.) or were elevated to similar levels
7 j3 `  o+ `! Y8 ldeveloped after gonadotropin therapy (96 ng./dl.). Higher% W3 B' {: D1 \4 U5 x
serum levels were noted in older patients (12 and 17 years old),3 p: z+ m6 b0 n& @. `; ]
while lower levels persisted in younger patients (4, 8, and 10
' P9 J3 H( l( ]8 N2 a9 p$ q( a( B2 X* qyears old) (see table). Despite absence of profound alterations5 @$ _+ f. m( h1 J& z
of serum testosterone the topical therapy provided a greater
2 {5 w9 T2 m; W9 V( w6 I- f: LAccepted for publication July 1, 1977. ·
' _: F- X- C& P6 R5 x/ t, ~7 BRead at annual meeting of American Urological Association,
4 K& N2 c$ _4 k( C( l: p4 C6 V6 [& CChicago, Illinois, April 24-28, 1977.0 z% T. r4 M( c, W$ d" I8 s( c
* Requests for reprints: Division of Urology, Henry Ford Hospital,
3 z1 o" H- w8 A6 C" C, D2799 W. Grand Blvd., Detroit, Michigan 48202.. w/ H- O$ W1 K
improvement in phallic growth compared to gonadotropin.
- y* l" B# X/ [! u! c) JAverage phallic growth with gonadotropin was 14.3 per cent
6 l1 o, w" W8 pincrease in length and 5.0 per cent increase of girth. Topical
' U, e2 Y5 Y' itestosterone produced a 60.0 per cent increase of phallic length% a+ {+ ^) T. w; U& f; O. r
and 52.9 per cent increase of girth (circumference). The
: X: X, V7 H) m1 Y: iresponse to topical testosterone was greatest in children be-$ x/ x' O) B: @! {
tween 4 and 8 years old, with a gradual decrease to age 17
3 V4 ~) T& y* o, }years (see table).
! g& F8 b0 b* c9 FDISCUSSION: `8 V: Q) y  @2 I5 i
Topical testosterone has been used effectively by other* ~( J6 u" q1 [; U' Y8 c1 g
clinicians but its mode of action remains controversial. Im-
# z* A$ a( ~% Y( n+ D) a2 x7 ^% n$ Xmergut and associates reported an excellent growth response
2 i& H+ I8 O1 W/ x0 Qto topical testosterone with low levels of serum testosterone,
# w/ S0 L0 V& a4 Z6 t- dsuggesting a local effect.1 Others have obtained growth re-
# S& w' F+ Q9 ?- W% C; [sponse with high. levels of serum testosterone after topical& z# A# l5 X4 E. Q" v* {
administration, suggesting a systemic response. 3 The use of
5 p! ]; H# o, {gonadotropin to obtain levels of serum testosterone compara-7 `; P7 \: \- Q2 _
ble to levels obtained with topical testosterone would seem to. c5 H; n, R" B4 _# ~; y' q; C
provide a means to compare the relative effectiveness of
5 X, H1 @0 h' y, Q6 G! L+ @! xtopical testosterone to systemic testosterone effect. It cer-
/ L! _4 Y4 H9 a$ q! l8 S5 rtainly has been established that gonadotropin as well as par-- L" b3 ]# ^4 p  L5 t
enteral testosterone administration will produce genital
& s4 _0 {3 c0 Ygrowth. Our report shows that the growth of the phallus was
( \. F" Y, B: _& tsignificantly greater with topical applications than with go-/ `) f2 V7 l4 v" l. m0 w% k
nadotropin, particularly in children less than 10 years old.9 m2 ?! ^0 x& M* A5 ?, m/ P
The levels of serum testosterone remained similar or lower
; H. r. @' r# X# T: v  _than with gonadotropin during therapy, suggesting that topi-1 k6 X# L- Y2 G! n9 v" Z
cal application produces genital growth by its local effect as$ T% S) ]; R/ `" F. c6 h. M3 @
well as its systemic effect.
$ S5 q' z' d+ zReview of our patients and their growth response related to  H" I$ @5 k: I: m! D
age shows a greater growth response at an earlier age. This is. Y8 S& V% z# ^3 q. }: ?
consistent with the findings of Wilson and Walker, who1 H  Z2 k. i& b; U' v& ~( v6 Z
reported an increased conversion of testosterone to dihydrotes-2 Z7 ?5 \) J* r0 C
tosterone in the foreskin of neonates and infants.4 This activ-
0 C& z0 W" {$ Yity gradually decreases with age until puberty when it ap-7 z3 m8 D3 Z6 l' h" q
proaches the same level of activity as peripheral skin. It may; u; h' T$ {; _6 E# R9 l; V
well be that absorption of testosterone is less when applied at9 y  T+ k4 s- a4 I; i) R! }
an earlier age as suggested by lower serum levels in children
4 ~, f) O+ e& c  c$ yless than 10 years old. This fact may be explained by the7 ?6 {$ ~; n* ]2 E6 k
greater ability of phallic skin to convert testosterone to dihy-& i7 G- t2 X4 A) I
drotestosterone at this age. Conversely, serum levels in older
( v" K# V& \) D  ypatients were higher, possibly because of decreased local
, a0 E) m4 G' S$ l/ d! O1 \667
# u/ Z0 ^; ~: o668 KLUGO AND CERNY
. h+ Y/ n7 S' d2 y. a2 ]0 m' yPt. Age
8 I4 [8 y& Y/ y4 y(yrs.)
  s$ _, g7 ]( TSerum Testosterone Phallus (cm.) Change Length
0 n8 i9 e6 k) I( g4 @  s(ng./dl.) Girth x Length (%)
6 `( p( d( b6 d47 O, X% [5 B5 k/ s
8
! S- ?6 E, }1 [* G6 O! {10
" y/ ~+ s- \) ]5 [; c12
0 }8 ~' S' ^" Q6 g! o/ x9 o. s# v17
- o% ]% o. Q& L9 H1 `9 g5 qGonadotropin
8 l3 e2 c0 G  V- }, T71.6 2.0 X 3 16.6
" {8 h4 p( ~1 g+ Y1 B( j/ P  D50.4 4.0 X 5.0 20.0
6 q0 l# j( Z! P+ a! d4 Q22.0 4.5 X 4.0 25.0# u) m' l& C7 f% L  Q. A
84.6 4.0 X 4.5 11.1
- F! W9 T" \! K* e1 l; O# a7 S6 R85.9 4.5 X 5.5 9.0
# T! |% V# B' N/ [/ DAv. 14.32 H0 }+ Y+ F8 S. z& j
4
5 {$ p9 \' G0 i7 p8
% `) @- \0 A! b9 u$ w& K1 W- W0 D10
( i1 L$ H3 w( S% X# Y, p12
5 S+ J" l" M: \; J; Y0 q177 B; a+ n. p; r
Topical testosterone
, d7 s! E% A5 n* g* W34.6 4.5 X 6.5 85
, c9 q! ^$ A. W2 u7 P& }' _38.8 6.0 X 8.5 70. v$ K4 K+ y4 d+ O! n9 a
40.0 6.0 X 6.5 62.5+ Y& P: ^% |& N0 b, ?
93.6 6.0 X 7.0 55.5, O) Y% D) _5 E% e2 c* T
95.0 6.5 X 7.0 27.2
+ A- ?1 `; }4 o1 ?9 \Av. 60.06 u* K) k) K0 _0 b: w
available testosterone. Again, emphasis should be placed on
% p' j1 W1 r8 N& {/ H4 G; k* L' K: Zearly therapy when lower levels of testosterone appear to: a, k, b, f( C
provide the best responses. The earlier therapy is instituted
# }2 L9 U2 u/ P$ x. V) X$ \6 othe more likely there will be an excellent response with low0 q6 Q. x- N! c
serum levels. Response occurs throughout adolescence as
0 c' c( A! [5 E  Q5 c% tnoted in nomograms of phallic growth. 7 The actual response3 f, O! ?$ e# U+ f3 B$ Q1 \& Y
to a given serum level of testosterone is much greater at birth0 |# e! C6 r7 M! U: q$ }
and gradually decreases as boys reach puberty. This is most
4 W4 E: N6 Y3 }. V7 c* plikely related to the conversion of testosterone to dihydrotes-  ?5 [# {3 ^2 x, G3 ?: H0 E7 ^
tosterone and correlates well with the studies of testosterone
# \, G" G6 n2 m$ Vconversion in foreskin at various ages.5 z. Z7 T: a; [  X1 l- a3 {
The question arises regarding early treatment as to whether
1 U: J9 d2 |* k2 {# |8 N3 Rone might sacrifice ultimate potential growth as with acceler-
- P3 M- _$ ^# D9 vated bone growth. The situation appears quite the reverse" a; S4 ?+ }5 h( p5 P/ c2 f
with phallic response. If the early growth period is not used# Q; z& k. l4 b/ _3 R  y  h
when 5a reductase activity is greatest then potential growth5 [5 u) W6 F' Z: o* a( b1 s
may be lost. We have not observed any regression of growth
$ ]: |& B: o8 Z- `attained with topical or gonadotropin therapy. It may well2 N. c+ ?- P7 E9 @: r2 r% i
be that some patients will show little or no response to any
( V& K- j- U/ H1 d: U4 D+ {form of therapy. This would suggest a defect in the ability to
" a1 D  ^( R7 n$ V% M) R& d+ i3 jconvert testosterone to dihydrotestosterone and indicate that
# X* N/ R+ X" C* {) ]% ephallic and peripheral skin, and subcutaneous tissue should
, I9 U& N" O- S5 @/ \. Y% Pbe compared for 5a reductase activity.8 b# n" G' z" O& s3 F
A, loop enlarges to measure penile girth in millimeters. B,
0 i; v+ X* z' B' Vexample of penile girth computed easily and accurately.+ }& M6 z( t* M) g) y# s: W; A7 z* j1 N
conversion of testosterone to dihydrotestosterone. It is in this
# n& ^0 [7 G% I6 \# J$ W7 molder group that others have noted high levels of serum
8 _/ E. y/ U# }) Mtestosterone with topical application. It would also appear' k, g% f0 b& j2 F& \, T
that phallic response during puberty is related directly to the
7 g7 j% X: F- \- ]) Wserum testosterone level. There also is other evidence of local
1 |6 U! c1 o( j" d+ {7 @response to testosterone with hair growth and with spermato-. D; \: _& L* C+ d. l, \4 \  `: z0 Q
genesis. 5• 6, V; ^4 c  o; y0 U- {  Z
Administration of larger doses of gonadotropin or systemic
/ c, C. N. F4 H/ |3 D+ _testosterone, as well as topical applications that produce
- }2 i8 h+ G2 Q3 Ahigher levels of serum testosterone (150 to 900 ng./dl.), will  v9 J9 ?2 t- |
also produce phallic growth but risks accelerated skeletal
& _3 c! B! U# s* u% Y( pmaturation even after stopping treatment. It would appear1 @2 J7 h9 p. R3 {. o" t& N
that this may be avoided by topical applications of testosterone7 Q# B9 {" e9 E* X/ K5 H' l0 A
and monitoring of serum testosterone. Even with this control9 Z+ z6 x3 s& Q( d3 E' v
the duration of our therapy did not exceed 3 weeks at any2 P- L  b( t* D/ @% [1 x; c) y
time. It is apparent that the prepuberal male subject may
6 p( N, y' Z6 m4 W+ d: Lsuffer accelerated bone growth with testosterone levels near* t' f3 |# X. M
200 ng./dl. When skeletal maturation is complete the level of
" b/ }' E  D# o2 r) w: \serum testosterone can be maintained in the 700 to 1,300 ng./9 ^- {. ^. ]3 T( g& o4 D9 N
dl. range to stimulate phallic growth and secondary sexual% i8 @/ Y: J: {  t; @# j
changes. Therefore, after skeletal maturation parenteral tes-8 ^/ _( V+ f! j8 ~8 M( E0 G( |: {
tosterone may be used to advantage. Before skeletal matura-
' P! J7 {  E/ O# h( ]tion care must be taken to avoid maintaining levels of serum
5 {3 f( Z4 ^# Wtestosterone more than 100 ng./dl. Low-dose gonadotropin
9 l' J8 b- {; Hdepends upon intrinsic testicular activity and may require
% }( Z$ e  a: C1 d* pprolonged administration for any response.6 R- |( @/ x1 ~8 D
Alternately, topical testosterone does not depend upon tes-: ]8 m) K' A! l! |
ticular function and may provide a more constant level of
8 |* n! \* S5 {2 VREFERENCES
& G# U3 J+ U- z3 A1 d, J# h1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,  O: K, Q- r* q
R.: The local application of testosterone cream to the prepub-
' a" z% ^- ]6 a1 P/ Mertal phallus. J. Urol., 105: 905, 1971., c+ y- F$ @1 L3 R8 }
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
/ h$ E0 J# m8 w  W3 F8 mtreatment for micropenis during early childhood. J. Pediat.,
# m/ W4 X' \. K83: 247, 1973.6 T& l4 x7 q6 {8 r
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 |0 p0 [0 l1 b$ bone therapy for penile growth. Urology, 6: 708, 1975.
% T3 C5 `/ {2 k4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; g8 s4 _3 q$ N/ g2 h* zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by2 a' I. U5 j# w- X
skin slices of man. J. Clin. Invest., 48: 371, 1969.* k  ~2 H) b/ q6 L
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
2 J9 `1 A+ _& X3 Oby topical application of androgens. J.A.M.A., 191: 521, 1965.
: _5 v3 N, G6 D/ y# t6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
- a$ ^  g+ L& D( x; ?androgenic effect of interstitial cell tumor of the testis. J.' d/ m$ o7 W2 a4 `
Urol., 104: 774, 1970.% O2 D- v- _0 Q4 N, }& S7 w
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
9 L+ I5 S# C: z4 a# ction in the male genitalia from birth to maturity. J. Urol., 48:
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