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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND) A: J, ~6 _+ S" W: m4 {
GONADOTROPIN' U' ?6 }( [4 t4 r! C: y6 _
RICHARD C. KLUGO* AND JOSEPH C. CERNY
  K8 R. z' V- [' Y5 s( p1 ^* E; mFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% h! e/ |- H! e3 Y7 U& m) DABSTRACT
2 k3 K- ^5 l' p2 n7 nFive patients were treated with gonadotropin and topical testosterone for micropenis associated9 d& q- h: G+ N0 T6 c! t# T
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 L- Y0 Z, O% R6 Z: D( O, f
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( U+ f" k( [6 X; U' c# S7 lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( H( V* W; d/ L  o; cfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! f: {1 u+ n! c5 A
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average" _5 W# [" R! T- I# @7 m
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response1 G* H0 [6 T7 ~* R# v! Q7 v7 t1 q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This2 `. ]- ^8 a, g* U. r8 B/ W* d# t
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile: \! O' h3 f4 M- C$ ?2 O; o
growth. The response appears to be greater in younger children, which is consistent with previ-
7 A0 j0 C$ L1 iously published studies of age-related 5 reductase activity.
/ w* ~* j7 R3 Z, g+ U" Z& YChildren with microphallus regardless of its etiology will3 M& S# x' K% A1 y6 z/ ~% n4 C* J1 W
require augmentation or consideration for alteration of exter-9 b& [( `+ m/ ?& ]! e# m+ n
nal genitalia. In many instances urethroplasty for hypo-% l% x, V5 l2 t2 W8 T
spadias is easier with previous stimulation of phallic growth.
2 S0 v& G0 k  j" t- ?The use of testosterone administered parenterally or topically
* m: x" h( u6 j/ {- \" Xhas produced effective phallic growth. 1- 3 The mechanism of
" V" r& Q' u; i+ t+ ~/ ], sresponse has been considered as local or systemic. With this
5 e0 n. @* Z5 X7 d$ u6 e0 l1 f# W# X3 zin mind we studied 5 children with microphallus for response) i  ?: c1 [" q, i1 X! ?
to gonadotropin and to topical testosterone independently.
! x0 v) x5 l0 n8 t# W+ a$ sMATERIALS AND METHODS
* b' k  P6 Q5 u! B% w5 {Five 46 XY male subjects between 3 and 17 years old were+ ?9 g. H4 O! ]8 K4 m; B7 I/ G
evaluated for serum testosterone levels and hypothalamic
$ i$ r* E8 }% c% J1 wfunction. Of these 5 boys 2 were considered to have Kallmann's
4 f/ N( j: W5 N3 [! bsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 X4 |$ b! D, i
lamic deficiency. After evaluation of response to luteinizing
! }8 }! V" L# V9 ]% q/ H- Bhormone-releasing hormone these patients were treated with
+ l8 y1 J4 u% F* t' |5 u1 E1,000 units of gonadotropin weekly for 3 weeks. Six weeks. W: l7 x) ~6 l$ M5 y4 c( [
after completion of gonadotropin therapy 10 per cent topical
4 A; V' r: @- K: Wtestosterone was applied to the phallus twice daily for 3 weeks.' j2 {5 [8 ?) k/ u. B5 n+ K9 u
Serum testosterone, luteinizing hormone and follicle-stimulat-
4 L' s3 h* M7 j5 King hormone were monitored before, during and after comple-
- d: I( ]' W2 s7 I1 otion of each phase of therapy. Penile stretch length was8 ^+ r8 k) V1 b. v9 l1 d, s/ |, w
obtained by measuring from the symphysis pubis to the tip of( c6 N5 K) `6 H+ Y
the glans. Penile circumferential (girth) measurements were! @' S: O6 |6 c7 E7 r
obtained using an orthopedic digital measuring device (see
  c+ k0 H1 ^( M9 xfigure).
$ v" K  U! z. X7 J- b. NRESULTS  M3 j5 P, T& Y5 @6 r( t
Serum testosterone increased moderately to levels between
6 ]' e5 L% k) T50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% o1 O" v2 s( e: n! I4 C2 |' r) Lterone levels with topical testosterone remained near pre-
" t2 ~+ T) e9 e* q- \! a6 L3 jtreatment levels (35 ng./dl.) or were elevated to similar levels; F. d! _, E" a9 ~1 k4 @
developed after gonadotropin therapy (96 ng./dl.). Higher
6 {% k3 ^! I& K( yserum levels were noted in older patients (12 and 17 years old),* H6 p& I) Q& V- H0 [
while lower levels persisted in younger patients (4, 8, and 10
4 g! @6 |. D: O: [8 l8 Y( eyears old) (see table). Despite absence of profound alterations7 m4 F% l/ h. R9 j
of serum testosterone the topical therapy provided a greater
+ H7 m6 U" @* b, b4 CAccepted for publication July 1, 1977. ·
# |. X9 \. |# oRead at annual meeting of American Urological Association,8 E& o, }+ Q2 h9 F
Chicago, Illinois, April 24-28, 1977.
5 i" N" |9 c% Y+ y% i6 j* Requests for reprints: Division of Urology, Henry Ford Hospital,
) X, ^  l) _! R% ]- ^2799 W. Grand Blvd., Detroit, Michigan 48202.: D' K4 U0 ?7 W5 J8 E/ ^: H
improvement in phallic growth compared to gonadotropin.: R3 O& c% J5 O4 s7 b9 F% R
Average phallic growth with gonadotropin was 14.3 per cent
2 s( I6 b9 ?" E# c4 Iincrease in length and 5.0 per cent increase of girth. Topical
# m7 |- \/ `" l( w/ X  h, j4 [testosterone produced a 60.0 per cent increase of phallic length
+ F2 i% A8 v7 X- \and 52.9 per cent increase of girth (circumference). The, D. J0 ]! g* O0 K; |/ |
response to topical testosterone was greatest in children be-( A5 r  n# I, m- P, j# r& w
tween 4 and 8 years old, with a gradual decrease to age 17- P1 `' I- W& \" i; ?7 f6 @: _* C
years (see table).
$ b( U* [$ `3 P9 v9 C/ ADISCUSSION
' N5 D/ Z# J9 LTopical testosterone has been used effectively by other% U9 o, ^8 o1 K8 @3 Q6 O
clinicians but its mode of action remains controversial. Im-9 c; @* p% M" k4 R6 B
mergut and associates reported an excellent growth response  E5 X& r' i, O  e
to topical testosterone with low levels of serum testosterone,  D" p- A0 Q( C+ y( ^0 o1 j
suggesting a local effect.1 Others have obtained growth re-
/ z. |) n- {& D/ F6 G$ Xsponse with high. levels of serum testosterone after topical
8 C& s' e& ~% s4 }& P7 ^$ q" Ladministration, suggesting a systemic response. 3 The use of. {/ Q- d1 B* N% y, Q2 l
gonadotropin to obtain levels of serum testosterone compara-) Y  I  F" p, p5 Q) v  u( |/ L8 X
ble to levels obtained with topical testosterone would seem to
/ a/ b7 C4 U6 Z% }provide a means to compare the relative effectiveness of
3 e8 u- N  `2 w  Rtopical testosterone to systemic testosterone effect. It cer-- q! f' Y$ B$ R
tainly has been established that gonadotropin as well as par-, |3 l- e* V! Y
enteral testosterone administration will produce genital
7 z9 \3 H% L* f4 q7 Jgrowth. Our report shows that the growth of the phallus was+ X, r1 E8 y3 y
significantly greater with topical applications than with go-% l/ `6 F8 _" F/ y3 x
nadotropin, particularly in children less than 10 years old.
  ^" v* s. x/ aThe levels of serum testosterone remained similar or lower
2 g4 a- i6 s3 r: c% tthan with gonadotropin during therapy, suggesting that topi-) U- i4 ^2 \- n; z  K1 H+ |8 J
cal application produces genital growth by its local effect as
% J- W" C' B1 X) Jwell as its systemic effect.
1 @: z7 P; m+ E( q0 SReview of our patients and their growth response related to( C1 M- @& l8 f; n% K# ?
age shows a greater growth response at an earlier age. This is
2 A" {# a! s8 R/ K( ?consistent with the findings of Wilson and Walker, who; z, k5 d1 H' x3 u$ ?8 [
reported an increased conversion of testosterone to dihydrotes-# c/ N8 w* R) a
tosterone in the foreskin of neonates and infants.4 This activ-
4 L8 ]( b' f5 T/ ~# t( f+ S2 Kity gradually decreases with age until puberty when it ap-5 Q$ ~& ?7 ~7 S( t4 e9 g+ v; b
proaches the same level of activity as peripheral skin. It may- u( V6 C* W* z* i6 @7 n5 _
well be that absorption of testosterone is less when applied at
% \9 l( p1 @; A6 Y% Qan earlier age as suggested by lower serum levels in children* j/ X! D9 W8 p6 ~5 `7 B0 X
less than 10 years old. This fact may be explained by the  ~! i3 ?7 [+ v7 U7 Q1 ?5 }: q2 |
greater ability of phallic skin to convert testosterone to dihy-
/ u5 q" y  ^2 e! hdrotestosterone at this age. Conversely, serum levels in older+ y2 X$ K3 \3 s0 G. S9 r5 |# M
patients were higher, possibly because of decreased local
, n  k' x& ^* L3 P' I8 e% A667
. P. D! B$ V2 a668 KLUGO AND CERNY# X( R/ \3 i' M) I
Pt. Age$ A3 {; I4 c0 B* B& @* D9 e
(yrs.)9 M* Z0 Q4 a. g/ b1 |1 w
Serum Testosterone Phallus (cm.) Change Length
" @$ F9 g2 y* K2 v(ng./dl.) Girth x Length (%)
& h2 z  _( ~9 ]" L/ c) ^" H4
/ r( c- a, Q/ G% d4 G; t8+ c! e5 G' R) G: _, ?4 Z% Z
10
" A5 i/ t# ~9 d5 a0 u12
; U% ]/ S* z$ b$ }% i; M" D8 J17
) M5 G8 N# m" |2 ]Gonadotropin
# `/ C' e& A  R- F+ \9 X71.6 2.0 X 3 16.6/ d7 u* q" m( T8 S1 U0 \' W4 V
50.4 4.0 X 5.0 20.0
& j" h4 q; N3 J7 s9 g22.0 4.5 X 4.0 25.00 h4 F( @( U' s
84.6 4.0 X 4.5 11.16 a1 x2 x, u2 i. v
85.9 4.5 X 5.5 9.0! ^' C3 ~/ z* u7 X1 ^7 Y
Av. 14.3
# _# B: N' c+ ~2 d4
; ?: x7 R, z( `) K9 y2 S* u8/ L' C. n/ y# @
10
  q+ b7 j+ E7 |& u9 u12
3 d! n5 y& J/ S  `17
4 p# P! Q2 W' w4 T8 f, RTopical testosterone
: ^& I6 Y; p4 ?0 ?7 h34.6 4.5 X 6.5 851 ~; a  |9 D; f: }1 T2 q
38.8 6.0 X 8.5 70% j$ u; W! {6 S4 V
40.0 6.0 X 6.5 62.5
0 k( ?: l4 N& p3 m+ m$ }1 ^, `% U% `93.6 6.0 X 7.0 55.5
! s' t+ D$ d4 Z; ~95.0 6.5 X 7.0 27.2- _' P# @9 `6 l) }; Q
Av. 60.07 |, I* h  t* k% @
available testosterone. Again, emphasis should be placed on# T+ t8 ^! W7 x3 w: z) h0 G9 u+ m
early therapy when lower levels of testosterone appear to0 S5 I( G- W! t9 ^& Z+ h7 v
provide the best responses. The earlier therapy is instituted4 L- l) Q$ m5 v! T4 H1 s: c
the more likely there will be an excellent response with low
6 X! N4 \( O/ H: v- u' Zserum levels. Response occurs throughout adolescence as0 ?+ _; o8 S0 |8 V& j
noted in nomograms of phallic growth. 7 The actual response
  [& n+ N; s4 R8 r( U0 y! c  m8 J; s+ mto a given serum level of testosterone is much greater at birth; u* b9 z; x5 L  k% A+ ~' {6 A0 I
and gradually decreases as boys reach puberty. This is most
' R. D! \# B0 e) b4 Rlikely related to the conversion of testosterone to dihydrotes-( J- `, ~- U7 X6 X0 a7 O$ ?$ v
tosterone and correlates well with the studies of testosterone
( N( A8 X, R0 a2 @3 I" Y  T  ~conversion in foreskin at various ages.# n- }2 l3 w6 j" B  u
The question arises regarding early treatment as to whether
) D! e) r$ b) T# O7 h# D. C( Vone might sacrifice ultimate potential growth as with acceler-
4 k$ z% F: I6 _* O2 r, p9 cated bone growth. The situation appears quite the reverse
1 y/ P/ \& ^) u3 Dwith phallic response. If the early growth period is not used4 L' a' ^2 b- o
when 5a reductase activity is greatest then potential growth, P8 c' b5 Q0 K3 e
may be lost. We have not observed any regression of growth8 O, \- K3 q( R. b  W6 V
attained with topical or gonadotropin therapy. It may well
) X" i( S1 L; Y- g; f- gbe that some patients will show little or no response to any
' c1 q* D  |: {* {7 j/ qform of therapy. This would suggest a defect in the ability to
: C; m+ V4 c4 C1 ]& J" ]# Xconvert testosterone to dihydrotestosterone and indicate that1 A! S8 p* c: j3 b
phallic and peripheral skin, and subcutaneous tissue should
3 i7 U( E- \$ @% |, b$ v1 Rbe compared for 5a reductase activity.5 Q5 ~- X+ C3 P
A, loop enlarges to measure penile girth in millimeters. B,
( c; t2 \& f0 v# d" k+ a! H4 Dexample of penile girth computed easily and accurately.  T4 K# K2 M  A) R/ r
conversion of testosterone to dihydrotestosterone. It is in this# _7 d% W5 \- z
older group that others have noted high levels of serum
) c8 ?: G* v' k& R' r1 i! r, Rtestosterone with topical application. It would also appear
) w4 w" y( O$ ?& x7 ethat phallic response during puberty is related directly to the7 U/ A  e* d  x! F. A
serum testosterone level. There also is other evidence of local
2 z+ h/ X- m+ {3 q9 [response to testosterone with hair growth and with spermato-
/ |% B* i% R1 F. U( G8 }genesis. 5• 6
& N5 R  f+ Y* z& B! n9 TAdministration of larger doses of gonadotropin or systemic6 @( }* C# k% D0 q! l) q7 d
testosterone, as well as topical applications that produce/ @  z( O2 ~3 _
higher levels of serum testosterone (150 to 900 ng./dl.), will3 z: r2 }' a' {/ ?, i
also produce phallic growth but risks accelerated skeletal6 L  A! M# A7 _. `3 N6 a  [
maturation even after stopping treatment. It would appear" Q7 t: C! w  S
that this may be avoided by topical applications of testosterone2 O- m+ G% Z( t0 a1 h( L
and monitoring of serum testosterone. Even with this control' Y3 S# ?. B- e3 Z  Q( O
the duration of our therapy did not exceed 3 weeks at any7 C% L: w' _- w9 ^/ V% Z/ k; f3 {
time. It is apparent that the prepuberal male subject may
* H0 o3 T, o& c- o3 P# Ysuffer accelerated bone growth with testosterone levels near
6 T& x( f% B) [. s" \) P200 ng./dl. When skeletal maturation is complete the level of7 ?1 H3 B4 K7 F' |; V" y
serum testosterone can be maintained in the 700 to 1,300 ng./
% ?! t7 ^4 Z1 P3 O$ B0 Bdl. range to stimulate phallic growth and secondary sexual2 k+ h) P! ]0 N6 W% d' C( c8 k
changes. Therefore, after skeletal maturation parenteral tes-* j5 f: C4 W7 s# t6 u* F* x
tosterone may be used to advantage. Before skeletal matura-
* \$ q) q! L. k- g0 a  ^tion care must be taken to avoid maintaining levels of serum
+ E9 a: j3 {( g3 ^" K1 T# mtestosterone more than 100 ng./dl. Low-dose gonadotropin
6 @) `3 X) v. t( jdepends upon intrinsic testicular activity and may require0 \  ], j7 G+ M$ o& b/ I  Q3 _6 w
prolonged administration for any response.
$ S. c1 A# f, o* HAlternately, topical testosterone does not depend upon tes-# F, R) D( m# h3 Y, R2 ?; f
ticular function and may provide a more constant level of
+ \4 x2 Z5 H  `( c7 p: t. o- b" c- IREFERENCES* ?, @0 M2 N( T" k3 p2 v
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,0 `/ c1 _+ I) D* [6 L% j
R.: The local application of testosterone cream to the prepub-6 b- V6 N' K( D; r. C( \
ertal phallus. J. Urol., 105: 905, 1971.
8 N& \5 l' N6 P( G2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( ^" x- x' z4 e8 y! R( [* btreatment for micropenis during early childhood. J. Pediat.,
5 b6 E$ [6 U  L0 o7 b! F/ ]3 r8 a83: 247, 1973.
3 E' P2 q2 d3 M( K3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
! T* u' q" j/ j+ none therapy for penile growth. Urology, 6: 708, 1975.
3 z6 ^# F. \& j: j( {4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- X( `1 B. H5 ^$ ~" rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
/ |; E$ K1 u+ ], q* |. Eskin slices of man. J. Clin. Invest., 48: 371, 1969.9 q, }+ |& k2 x* z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' P0 v( f6 B4 \# h. ~: B( t
by topical application of androgens. J.A.M.A., 191: 521, 1965.' k. k6 |' S0 t8 u
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 [8 c: b/ Q( v8 l0 `
androgenic effect of interstitial cell tumor of the testis. J.  h" r! A  y  H6 g% b6 m$ m. L  Z
Urol., 104: 774, 1970.
5 [4 G" P2 L2 j* d7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& O! A* U# A! r7 z! l3 l5 \* Stion in the male genitalia from birth to maturity. J. Urol., 48:
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