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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND& i) J; l" ~% N( A3 V& }3 q
GONADOTROPIN  E" S  K- Q0 P( ~# A  p3 e5 _
RICHARD C. KLUGO* AND JOSEPH C. CERNY
! e5 E+ e* U2 h& {4 t7 EFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& e' B. Q6 \1 l. c5 M" VABSTRACT
! H; L8 k( f& k2 I# f3 ^- BFive patients were treated with gonadotropin and topical testosterone for micropenis associated) P! w2 f6 |8 L) T/ z
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
: w( K! k( r. U* N5 }: Atropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
. [$ @3 ]# j- t+ scream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
$ G5 Y& b. g& sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
( w1 S: ?! x5 Y: Y! s2 \0 Rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
0 k2 p) `% i- w* ?& `increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 a5 O$ B5 d( ?5 C. Yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
* _) @: d3 W, c1 j9 ~9 P! p, j; hstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ _: j$ m+ Z# Q  ~growth. The response appears to be greater in younger children, which is consistent with previ-2 E& |4 V( G1 V1 ]
ously published studies of age-related 5 reductase activity.
9 q3 F8 {& d' [! yChildren with microphallus regardless of its etiology will
3 w: S0 B- r4 F8 ]- ?1 e. mrequire augmentation or consideration for alteration of exter-8 H; \4 R! b* Z' ]
nal genitalia. In many instances urethroplasty for hypo-- J3 j) \7 N2 I' R, G1 \
spadias is easier with previous stimulation of phallic growth.
9 J- A! o+ }: ^; TThe use of testosterone administered parenterally or topically9 I+ G7 Y8 H8 T. K% r8 G
has produced effective phallic growth. 1- 3 The mechanism of
; @; G& l, A9 S. y8 U- V5 Gresponse has been considered as local or systemic. With this9 t" x( F" M2 e6 G/ Y% s& b
in mind we studied 5 children with microphallus for response
6 g' A8 A& w2 `# Vto gonadotropin and to topical testosterone independently.
& t4 Z6 s# ^9 BMATERIALS AND METHODS
) }3 X! A" _) rFive 46 XY male subjects between 3 and 17 years old were6 a4 T5 I0 A+ _3 C+ A
evaluated for serum testosterone levels and hypothalamic
- L6 W' q6 A& L! R6 h+ e8 ffunction. Of these 5 boys 2 were considered to have Kallmann's
% A0 l$ v) m, D. nsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; R6 u$ z7 {1 x  J
lamic deficiency. After evaluation of response to luteinizing$ P, e" ~( ~4 R$ m! L0 A, g
hormone-releasing hormone these patients were treated with: s7 Y9 N6 o# K0 G
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% Y, J: I! a7 R) _9 J) fafter completion of gonadotropin therapy 10 per cent topical
8 u$ h: P- S; d2 l. m* J. d+ {testosterone was applied to the phallus twice daily for 3 weeks.
) x& z1 n. |% `$ J! ZSerum testosterone, luteinizing hormone and follicle-stimulat-
4 w' k, o' {& ^4 y, fing hormone were monitored before, during and after comple-1 n) v8 S' W# E1 E: J0 R' J
tion of each phase of therapy. Penile stretch length was1 C: t6 V% L, u2 [( c4 y
obtained by measuring from the symphysis pubis to the tip of
/ T- {2 ?8 J; t$ v- p# B5 ]* g2 vthe glans. Penile circumferential (girth) measurements were$ ^7 b6 B3 }( ^3 s4 O
obtained using an orthopedic digital measuring device (see
2 {: `4 D: {0 \; G, Gfigure).0 n2 l# b+ D' R% A
RESULTS
5 v1 [2 `/ f" {3 o8 `- ISerum testosterone increased moderately to levels between9 a# h( d7 w/ ^
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* v0 A* J* I7 g, P3 Y* E, `3 e
terone levels with topical testosterone remained near pre-
1 Y/ w: ~! y) C2 r5 k" ltreatment levels (35 ng./dl.) or were elevated to similar levels
* K' u; P4 q* c$ Bdeveloped after gonadotropin therapy (96 ng./dl.). Higher
7 E$ m+ D8 b0 D' Userum levels were noted in older patients (12 and 17 years old),
0 G/ f; V( w9 l. g* {while lower levels persisted in younger patients (4, 8, and 109 N! ~. y7 P% G% `8 k$ ^
years old) (see table). Despite absence of profound alterations( G* A" F: C, T$ R
of serum testosterone the topical therapy provided a greater
% d2 s0 X% C% E8 p: `- b% L+ uAccepted for publication July 1, 1977. ·
# O( f, b* x6 ^& QRead at annual meeting of American Urological Association,7 j$ g6 I4 M' x- O- `& Q
Chicago, Illinois, April 24-28, 1977.; k; m; X' n$ V9 a
* Requests for reprints: Division of Urology, Henry Ford Hospital,5 C! m7 t# P% T
2799 W. Grand Blvd., Detroit, Michigan 48202.) Z4 x) g2 N3 m3 q. H  O
improvement in phallic growth compared to gonadotropin.
' C# p$ Z2 l# P$ V% zAverage phallic growth with gonadotropin was 14.3 per cent
4 Z& A8 e+ u6 A' r0 p$ G# Aincrease in length and 5.0 per cent increase of girth. Topical
" R: ~( a$ o- m0 ^4 k' Otestosterone produced a 60.0 per cent increase of phallic length/ ?+ a$ d. S% I! K- X0 O/ @
and 52.9 per cent increase of girth (circumference). The
( ^* G0 m* ^) o8 jresponse to topical testosterone was greatest in children be-
& d" Q$ p$ u, r6 y" q. \' z6 _) [9 ttween 4 and 8 years old, with a gradual decrease to age 17
$ w$ @# H# J$ n9 r, Ryears (see table).
, A- M; b  E1 bDISCUSSION1 {- b2 C( v- ]  I( @) [
Topical testosterone has been used effectively by other
+ L. ~; G! K- |4 N4 e' Z3 W+ _; F; Wclinicians but its mode of action remains controversial. Im-) o# _- o7 {& |# f3 w7 f) K
mergut and associates reported an excellent growth response0 }; W3 o9 b* `% m% S7 _
to topical testosterone with low levels of serum testosterone,# h; |/ d+ r# X; C1 A
suggesting a local effect.1 Others have obtained growth re-
3 q. d9 `6 Z3 f$ _sponse with high. levels of serum testosterone after topical, F. o: |/ k' W' k
administration, suggesting a systemic response. 3 The use of% }, T+ U# z0 v. u
gonadotropin to obtain levels of serum testosterone compara-: z7 U* a( r& y$ X
ble to levels obtained with topical testosterone would seem to
3 H' A0 G, J, B& A+ fprovide a means to compare the relative effectiveness of
# @6 _) S+ ~) B7 w  Y& w* Ztopical testosterone to systemic testosterone effect. It cer-; M  I( y8 z* f. Z8 a# g
tainly has been established that gonadotropin as well as par-0 U* e" z; n* O  N) x7 N
enteral testosterone administration will produce genital% i$ U% U- N% ]4 M( ?' X6 a
growth. Our report shows that the growth of the phallus was
: y, B' @! i2 ]$ \8 osignificantly greater with topical applications than with go-& k; B: B! _" r
nadotropin, particularly in children less than 10 years old.' y! v: K2 D' y. N, S
The levels of serum testosterone remained similar or lower
: m, W) |( h3 Z1 N; ^+ c  u9 othan with gonadotropin during therapy, suggesting that topi-
+ x5 P: {7 |- \' ical application produces genital growth by its local effect as
( ]& N  G1 X# {  a  L* R9 y7 t- gwell as its systemic effect." U: u& B) O3 b3 K6 |0 C
Review of our patients and their growth response related to8 }! T& P5 [+ n/ A. ?
age shows a greater growth response at an earlier age. This is! J" O, X$ O- t' B1 r+ |2 u
consistent with the findings of Wilson and Walker, who. U. J" t0 l; ]$ M0 T. g8 W. [0 j
reported an increased conversion of testosterone to dihydrotes-6 B7 I5 W. ]* u9 E5 H
tosterone in the foreskin of neonates and infants.4 This activ-" Q0 q" I* D0 j/ p: ]1 ~- `
ity gradually decreases with age until puberty when it ap-
0 s  C& n# K0 v* k/ H4 Yproaches the same level of activity as peripheral skin. It may% M. k7 F9 ~0 [
well be that absorption of testosterone is less when applied at
( k  J/ {4 h6 e, F8 n, Uan earlier age as suggested by lower serum levels in children  |0 w) N" d) C9 J/ |! K$ _
less than 10 years old. This fact may be explained by the
! @- D( L8 c- G4 z% Y( t! Pgreater ability of phallic skin to convert testosterone to dihy-$ f# U# l9 ~' g% ~) M5 C# C! b1 G
drotestosterone at this age. Conversely, serum levels in older
2 g# _; h9 q! U+ x1 rpatients were higher, possibly because of decreased local
1 D: G! T2 P( ^667% `- L" O8 j* o8 O7 m5 @$ E$ i2 b
668 KLUGO AND CERNY8 ~( O) t) D# J1 l: v8 x6 a
Pt. Age
, I2 o, A: ^# l7 Y) a# d(yrs.)
, X, \3 a; `% k' f( H8 i9 iSerum Testosterone Phallus (cm.) Change Length
1 P8 b* B- N) Q; N  d9 p' d(ng./dl.) Girth x Length (%)9 }# Y" e$ P8 b$ n8 n8 X
4
" j5 ?) ]3 w* n: t# A5 Y86 i# m* X# M. B
10
; p6 \3 ]4 {: q& }. u' B129 E/ L4 V: I& y6 k
174 ]5 L# |# K$ }  A$ ]
Gonadotropin, d- s0 u7 X/ a2 @, A  F8 |
71.6 2.0 X 3 16.6
/ L8 s( C: }5 o50.4 4.0 X 5.0 20.0
! N/ \6 c1 _/ S22.0 4.5 X 4.0 25.0
( ~0 ~. f- l4 m9 K* {# |- q: L84.6 4.0 X 4.5 11.1
$ m  ^, w' C- E85.9 4.5 X 5.5 9.0
% u+ C, o. u; |. [6 Q$ H1 I. S+ eAv. 14.3
" E. ]" f4 L0 A  o7 x" f; `4
9 u! I& }8 k7 q) ]8
' ?8 Y4 z/ ?0 S  j& n2 Q10$ E# A7 h+ `1 K- R$ p# P% w
12, p+ m# {& I$ q
179 V* N1 m; _/ m. Q
Topical testosterone
) V- U9 J; R* y5 f) V4 _34.6 4.5 X 6.5 851 x1 A0 ?! M9 S8 b# f/ D
38.8 6.0 X 8.5 70+ T  ~0 ]4 l( ?- W( H# I, v# R
40.0 6.0 X 6.5 62.5
! N- m' H" W7 d7 R93.6 6.0 X 7.0 55.5
* h! S% e6 r, k5 |! o  S95.0 6.5 X 7.0 27.28 k7 s& _6 F* V4 F; X& U5 l0 R
Av. 60.0, u' J' W# B# e" Q4 D/ V( T9 A3 t+ m
available testosterone. Again, emphasis should be placed on9 f. B# N5 ?& v: y8 o
early therapy when lower levels of testosterone appear to& H% ?( c0 R- J2 b* t9 Z$ k
provide the best responses. The earlier therapy is instituted% S$ I3 R% E9 m% x4 c) Y
the more likely there will be an excellent response with low% O  I3 x# |0 Z# L% T! I1 C' U4 R
serum levels. Response occurs throughout adolescence as' a( l$ |: C1 b- Y
noted in nomograms of phallic growth. 7 The actual response
3 h; B' u$ q/ Zto a given serum level of testosterone is much greater at birth
: f3 ~1 h: I) u8 D9 C" w$ W# |and gradually decreases as boys reach puberty. This is most5 J8 J) a3 G3 n2 ^+ ~
likely related to the conversion of testosterone to dihydrotes-
3 Z9 u+ m7 Y3 P$ W# utosterone and correlates well with the studies of testosterone: r. M* b  I! R2 ^0 t
conversion in foreskin at various ages.' T/ ^) n8 L* J9 |8 y( Q
The question arises regarding early treatment as to whether& W6 C+ _2 \5 [- l8 s0 S4 B
one might sacrifice ultimate potential growth as with acceler-
: N4 Q  D% W4 }; e  m- {ated bone growth. The situation appears quite the reverse% p0 K$ V8 [8 Y
with phallic response. If the early growth period is not used
  [% V0 Q1 s; Z9 dwhen 5a reductase activity is greatest then potential growth
$ t+ G, t! {9 i2 o) W  s0 o. \& Smay be lost. We have not observed any regression of growth' n4 m1 g" @' k
attained with topical or gonadotropin therapy. It may well" D) t) }& {% |3 s0 W
be that some patients will show little or no response to any
% X' a7 Z3 [, A6 w0 Pform of therapy. This would suggest a defect in the ability to) k' H# f$ P. w+ n5 z% `
convert testosterone to dihydrotestosterone and indicate that9 ^$ x, T0 G8 f. z
phallic and peripheral skin, and subcutaneous tissue should
: j) O; Y7 A& b1 `0 |# _be compared for 5a reductase activity.3 x& |2 [/ t$ f6 ]) p: s* g8 u
A, loop enlarges to measure penile girth in millimeters. B,
8 ?+ l  z/ z, M- F! Z, ]example of penile girth computed easily and accurately.
  ~! ]0 z& F7 ^% c2 econversion of testosterone to dihydrotestosterone. It is in this
. K2 F) j, J  r, c$ ?, |$ W3 |older group that others have noted high levels of serum& U. d1 \( M2 k+ S& ~+ V- a2 v9 V) r
testosterone with topical application. It would also appear
+ T, t6 z8 Y' S- Dthat phallic response during puberty is related directly to the
8 @0 H0 B# X- B. W. R$ Mserum testosterone level. There also is other evidence of local4 x7 x  X/ ?  @$ P! s
response to testosterone with hair growth and with spermato-
  n% o: g4 F* u' x5 p4 p% kgenesis. 5• 6
7 \0 s0 v5 e5 X4 w# ]5 e! u! IAdministration of larger doses of gonadotropin or systemic
. k4 M: D' S1 Ktestosterone, as well as topical applications that produce0 A0 d9 N! d; l5 b0 Z+ h
higher levels of serum testosterone (150 to 900 ng./dl.), will
9 v" N" o& R6 Nalso produce phallic growth but risks accelerated skeletal* i+ C8 V4 D3 S7 b3 K: L
maturation even after stopping treatment. It would appear, A. U5 V4 o: P4 y# y; ^2 n! e
that this may be avoided by topical applications of testosterone
! @3 v/ q- Y% n  fand monitoring of serum testosterone. Even with this control
9 y" O2 [7 V7 a) }$ w$ U1 u4 uthe duration of our therapy did not exceed 3 weeks at any7 l8 T, u6 v7 [  W
time. It is apparent that the prepuberal male subject may
5 N& L- t: T" t. Z" P9 msuffer accelerated bone growth with testosterone levels near
. r' i: ~* `. |- ?200 ng./dl. When skeletal maturation is complete the level of
3 Q2 U& N6 ^3 u3 j9 @$ vserum testosterone can be maintained in the 700 to 1,300 ng./
! L6 {* ], q8 l1 x: q, adl. range to stimulate phallic growth and secondary sexual: d  K' J/ f7 @
changes. Therefore, after skeletal maturation parenteral tes-' e% U5 ~: v% e, L  W
tosterone may be used to advantage. Before skeletal matura-9 A$ q8 _* j+ L% ~
tion care must be taken to avoid maintaining levels of serum
% W' F- z7 r# }! @" utestosterone more than 100 ng./dl. Low-dose gonadotropin- @/ o# V+ B  I% }' ]' g
depends upon intrinsic testicular activity and may require
5 b- L4 H- t9 {3 S" ~+ k8 M# wprolonged administration for any response.5 l; K+ `' `2 k- I
Alternately, topical testosterone does not depend upon tes-
( r5 x. t2 T, X) W3 d8 Hticular function and may provide a more constant level of
5 B" m0 P" @2 VREFERENCES
/ H! z! O8 f( ]1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,5 Z: a5 Y3 ~( m: x) O* I* w
R.: The local application of testosterone cream to the prepub-2 u$ u3 e$ X+ K5 S& V6 E
ertal phallus. J. Urol., 105: 905, 1971.
( E, a; ?; m7 f0 l/ a2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- |4 T& y* _2 Z0 d
treatment for micropenis during early childhood. J. Pediat.,
6 T" e& \3 S1 T3 }* `" M83: 247, 1973.
# b- S9 K$ J) J: e3 t. z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" M! f; s' j4 L2 G# j+ C  F- V8 tone therapy for penile growth. Urology, 6: 708, 1975.
- g0 `; o9 [3 D  G$ C7 O  T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 s3 T. q- B* a) W
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& T; g" _- V5 g( Yskin slices of man. J. Clin. Invest., 48: 371, 1969.% w: ]8 I/ K2 b. u
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth4 [2 g" `7 v8 z. B
by topical application of androgens. J.A.M.A., 191: 521, 1965.
4 w7 x8 V) L$ _- o6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- T' A; @' w+ f) i
androgenic effect of interstitial cell tumor of the testis. J.
8 \, p: [" N  j* J/ qUrol., 104: 774, 1970.
  E2 ]. Y) `! K2 ]- L' z9 b0 v7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
4 {3 b6 Y. M5 Otion in the male genitalia from birth to maturity. J. Urol., 48:
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