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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
& R5 M9 B0 `: O2 g5 TGONADOTROPIN
+ m x$ X" c( ?# XRICHARD C. KLUGO* AND JOSEPH C. CERNY' p' M) A; W* v' _
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ e" q) K- t1 x9 k. U# h( S gABSTRACT
7 A" |7 G3 g) }0 Y" X, \/ ?, nFive patients were treated with gonadotropin and topical testosterone for micropenis associated g. Q; E: m" l* d8 h# W
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
1 w/ m+ g4 ?8 B5 C- r" g4 ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, E- W: h! L/ c/ E9 T: V4 d5 ~cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
# D/ C4 L3 S A9 `+ }) h1 J' v( _for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent+ Y& L: _9 Y [4 z
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: P: o6 S5 X V0 `0 @increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response, B% M: j( w2 f; v
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
$ Y( G$ S! c! N) i# n5 X, Gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
! x; h, W# X" |; m" n! q3 Y1 e/ tgrowth. The response appears to be greater in younger children, which is consistent with previ-
9 @* x) j% G( R& p& Aously published studies of age-related 5 reductase activity.7 F3 O: f1 G, D% E; J) C! u
Children with microphallus regardless of its etiology will
2 d& w. Z A/ L, B( [% R Grequire augmentation or consideration for alteration of exter-
: f- |. W0 ?% w; ^+ Ynal genitalia. In many instances urethroplasty for hypo-6 M7 \- w0 x4 {- p- V3 k5 u
spadias is easier with previous stimulation of phallic growth.
" u8 x$ Q. Q7 X) {0 w$ a8 iThe use of testosterone administered parenterally or topically6 x: }+ E* y9 t) N$ }# |0 W* i
has produced effective phallic growth. 1- 3 The mechanism of& s0 b# e1 p0 k
response has been considered as local or systemic. With this, T8 P& J+ t6 `; D+ s
in mind we studied 5 children with microphallus for response
8 I R+ ^$ x7 ?# Uto gonadotropin and to topical testosterone independently.; e; o$ s2 y0 H
MATERIALS AND METHODS
: k/ U/ e/ y) ]* K; t9 k/ xFive 46 XY male subjects between 3 and 17 years old were+ ]5 e6 R. K6 \/ S
evaluated for serum testosterone levels and hypothalamic+ d) ?2 l. {' X
function. Of these 5 boys 2 were considered to have Kallmann's1 y' n" l8 [" t
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-2 U9 P; J! E+ _) O ^$ t9 _' J
lamic deficiency. After evaluation of response to luteinizing9 J: e9 k' n# ]% C# Q6 j! r
hormone-releasing hormone these patients were treated with5 W( T4 k) l2 e0 o8 k! }7 g
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
9 n( X2 f; x' A+ L2 Hafter completion of gonadotropin therapy 10 per cent topical
1 S" }$ F2 s% r! C3 ftestosterone was applied to the phallus twice daily for 3 weeks.
5 O5 r8 }+ s9 ~ m9 ASerum testosterone, luteinizing hormone and follicle-stimulat-
; P* |: N$ f+ t& e# `( J! U _ing hormone were monitored before, during and after comple-# Q- D8 l" W9 S# \" _( t/ y, y
tion of each phase of therapy. Penile stretch length was
$ Y# o+ D( N i( ^. Z3 @obtained by measuring from the symphysis pubis to the tip of
- B) A2 D! ^. b6 s4 x+ ]) l1 wthe glans. Penile circumferential (girth) measurements were& S& O2 h' C! J# x
obtained using an orthopedic digital measuring device (see
4 I% ^% [5 I- J2 Q+ K( z8 Xfigure).
L. P4 V* n8 nRESULTS
5 Q4 O- O- Z: I+ SSerum testosterone increased moderately to levels between
9 i3 K5 c2 h- `# I% L/ N v50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 z9 E$ S2 z7 h4 B0 Z0 gterone levels with topical testosterone remained near pre-6 N8 H; v' M" v4 \1 W6 r
treatment levels (35 ng./dl.) or were elevated to similar levels
8 Y H- f, p4 R* u' X' g h; r* ?, Qdeveloped after gonadotropin therapy (96 ng./dl.). Higher
2 z* x+ n/ ~( a& ~, V( eserum levels were noted in older patients (12 and 17 years old),+ N ~% \1 I6 h# K5 Q8 d" D( T
while lower levels persisted in younger patients (4, 8, and 10, H2 G8 m( H; ?& l3 ^! Z
years old) (see table). Despite absence of profound alterations ]" q% n' E! t
of serum testosterone the topical therapy provided a greater
6 ?" _: f2 r- |5 N9 V* ^! ]Accepted for publication July 1, 1977. ·( B+ ]5 y* E# J! e$ J4 B
Read at annual meeting of American Urological Association,
. [" ] }- h& cChicago, Illinois, April 24-28, 1977.6 h U5 R. D/ ?& {5 ?
* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 j; L/ ~2 g3 \2799 W. Grand Blvd., Detroit, Michigan 48202.4 |3 f( w( P9 ^) F
improvement in phallic growth compared to gonadotropin.
; G5 F4 |/ V6 q% h3 k9 i; X5 d4 s- |Average phallic growth with gonadotropin was 14.3 per cent6 A% c4 g p! x: X/ n
increase in length and 5.0 per cent increase of girth. Topical& \% s Y0 g( ~3 f* }; n6 ?
testosterone produced a 60.0 per cent increase of phallic length
0 u6 G) ~+ D0 q2 Q- b0 p% `and 52.9 per cent increase of girth (circumference). The
7 i$ H, t, X3 U) A; y6 X. K5 \response to topical testosterone was greatest in children be-
( f5 o6 ~: {8 U# g4 @% g; z- `% Dtween 4 and 8 years old, with a gradual decrease to age 17; }2 P$ L; s9 o" z2 |
years (see table).
7 e7 j/ P6 s9 ZDISCUSSION
4 T7 b/ D: ^& a. lTopical testosterone has been used effectively by other
]+ }& f6 g" \1 P: mclinicians but its mode of action remains controversial. Im-
0 s1 B+ j3 B, z4 pmergut and associates reported an excellent growth response
5 l7 Z+ U2 f& H8 P2 Fto topical testosterone with low levels of serum testosterone,5 J- @! O0 L+ V- y# _
suggesting a local effect.1 Others have obtained growth re-, A& j8 J, [ s2 G% E" P2 s+ w
sponse with high. levels of serum testosterone after topical, n1 M6 ~) [8 h; j
administration, suggesting a systemic response. 3 The use of
' A, s* ]9 S8 {gonadotropin to obtain levels of serum testosterone compara-
/ |' E8 Q. l" V/ q, dble to levels obtained with topical testosterone would seem to5 h1 Z4 j( h" T. ~$ c
provide a means to compare the relative effectiveness of
3 ?, |5 x8 u. E% F. ]4 ^topical testosterone to systemic testosterone effect. It cer-
0 N/ \2 i8 r/ w% @( stainly has been established that gonadotropin as well as par-
! Y- a) B$ l3 o+ V3 u7 Q8 [enteral testosterone administration will produce genital
U2 [* [) O! O$ Tgrowth. Our report shows that the growth of the phallus was* H( D+ i. _5 C3 g
significantly greater with topical applications than with go-
/ [" o3 B* b7 C. p1 h* inadotropin, particularly in children less than 10 years old.5 k5 U6 @. @% s
The levels of serum testosterone remained similar or lower$ v! e$ P- h' u) l
than with gonadotropin during therapy, suggesting that topi-" H& ^; x$ |0 Q7 X5 ?
cal application produces genital growth by its local effect as
& V0 }; h/ T" h4 k4 I7 b+ ]well as its systemic effect.
% c! z, @, |1 V0 z" XReview of our patients and their growth response related to
\% v7 R' `" ?, t, u& cage shows a greater growth response at an earlier age. This is/ k4 b) r8 R; u3 R6 j
consistent with the findings of Wilson and Walker, who) a" w8 u+ ^: @( I" `& E( h9 S
reported an increased conversion of testosterone to dihydrotes-) j! u) _4 F2 t5 y
tosterone in the foreskin of neonates and infants.4 This activ-1 E8 k$ ~' o7 T& _8 b" g. w, t1 d
ity gradually decreases with age until puberty when it ap-
, y2 ~. n* p1 z+ A" V0 jproaches the same level of activity as peripheral skin. It may/ ~8 q! |; T4 b; H4 A
well be that absorption of testosterone is less when applied at! B1 x1 u/ f0 p; W, @
an earlier age as suggested by lower serum levels in children
; r' d8 c6 ?$ [$ [/ Z0 s: Qless than 10 years old. This fact may be explained by the7 w4 `5 _$ z j0 G- t
greater ability of phallic skin to convert testosterone to dihy-& q- P' z* S( R7 K& V0 [5 x
drotestosterone at this age. Conversely, serum levels in older
8 g, K0 k. }) H* ipatients were higher, possibly because of decreased local
: M0 g G7 p, H* P6 K; c667$ a* e8 P# w4 L) C
668 KLUGO AND CERNY
! L' ]' _9 R* Y6 l# f+ ~$ L6 z/ qPt. Age3 O0 o" M% k) z; N4 z. W
(yrs.)/ ]9 X* i9 B6 N
Serum Testosterone Phallus (cm.) Change Length g1 f3 c6 w0 z+ g
(ng./dl.) Girth x Length (%)4 f* A8 P/ M8 ]- a
4" K3 p1 _* k) l& H: h
8+ s9 z$ ]( ~" n7 x
10
& l8 f+ Q. x5 M" Y12
8 L4 T! p" O" g175 `% K( v6 q8 q! [
Gonadotropin% |: \- q; A2 r) T
71.6 2.0 X 3 16.6
9 p$ E( e. W( \$ L7 C; M2 n50.4 4.0 X 5.0 20.0% `: e- l3 O2 Z! |9 \8 v- a$ u) m5 a
22.0 4.5 X 4.0 25.0
; g9 f9 v3 B; a6 F) ~; ]84.6 4.0 X 4.5 11.1
}" t2 y: S5 t& c/ V0 V1 A6 M85.9 4.5 X 5.5 9.09 G( u' Z0 F( K' h* P. Y/ @) v" K
Av. 14.33 |6 t5 z; l2 _
4
% a9 T4 G5 m5 ?! s0 [8: p5 s9 Q4 N" X' U4 l: k6 U
105 J6 O7 c0 R! E. c/ n% r
129 G, N& [8 ~* }8 v( s) N2 p
17
% p, S0 h: \+ ^5 jTopical testosterone5 j- H! `* l6 A, w
34.6 4.5 X 6.5 85( f( z0 y. I& _+ y
38.8 6.0 X 8.5 70) M9 I( ~, {3 A; o! T
40.0 6.0 X 6.5 62.5
% e. s Q0 ]1 B1 u93.6 6.0 X 7.0 55.5
5 |3 R0 g& Q+ h6 r9 o* }" ?# H, X95.0 6.5 X 7.0 27.2# W' P/ ]4 m; M
Av. 60.0
9 e! k1 P( x! D& l9 favailable testosterone. Again, emphasis should be placed on: @9 j* K9 V3 U1 q: O
early therapy when lower levels of testosterone appear to6 y' K D3 |8 f/ e
provide the best responses. The earlier therapy is instituted
( @) e( i5 B. Ethe more likely there will be an excellent response with low
1 X4 ^) ?: G' G) Eserum levels. Response occurs throughout adolescence as3 [8 z: B* V& U: z* n; }) A* k
noted in nomograms of phallic growth. 7 The actual response
6 q0 Y/ C3 [5 Q! g3 _4 X2 Lto a given serum level of testosterone is much greater at birth4 Z2 v9 r7 y& e. r1 }- G5 b
and gradually decreases as boys reach puberty. This is most8 I# p; T4 ~1 @" n |' ~5 F ^, X
likely related to the conversion of testosterone to dihydrotes-: @0 m8 ~ ~$ c* J
tosterone and correlates well with the studies of testosterone, T# h3 o, l' T
conversion in foreskin at various ages." a6 M1 E; X# l
The question arises regarding early treatment as to whether
8 t6 j7 X+ h6 G, B. W% ^one might sacrifice ultimate potential growth as with acceler-1 A, ^5 L9 V& i9 k0 L# L+ o" M
ated bone growth. The situation appears quite the reverse
2 U9 \7 n8 h2 J+ ~! x, D2 p( swith phallic response. If the early growth period is not used
2 [& l& E' w3 Y+ |+ E+ z' jwhen 5a reductase activity is greatest then potential growth7 E$ O( |. |4 K+ z
may be lost. We have not observed any regression of growth
X8 ~" S8 N; p9 kattained with topical or gonadotropin therapy. It may well6 o4 d" s& B( C# s) {
be that some patients will show little or no response to any9 y! A3 Z$ b4 p+ d0 n9 P
form of therapy. This would suggest a defect in the ability to
7 u b- {: i1 q2 gconvert testosterone to dihydrotestosterone and indicate that
- B1 x; O1 c7 S3 A# P1 h) ephallic and peripheral skin, and subcutaneous tissue should
" q/ V' b9 Y' L/ j* Jbe compared for 5a reductase activity.
3 N' H* n n! ~. k) c) U5 WA, loop enlarges to measure penile girth in millimeters. B, F3 f1 Q8 G9 ]8 K2 \
example of penile girth computed easily and accurately.8 B. ]: R: s* s3 P2 E
conversion of testosterone to dihydrotestosterone. It is in this& U- D# R) W; u; r. J7 s) P/ R) P
older group that others have noted high levels of serum" N- u% _5 J2 U
testosterone with topical application. It would also appear8 T ]8 v+ S d; m8 e
that phallic response during puberty is related directly to the
9 x5 ~' K1 l2 r' p1 yserum testosterone level. There also is other evidence of local+ r4 g9 [8 c" V' z, V) j
response to testosterone with hair growth and with spermato-
9 {* S- A) V' K/ G( xgenesis. 5• 64 t3 m/ D; q# j4 P
Administration of larger doses of gonadotropin or systemic5 u4 E0 o( M( {5 N* E$ E; c
testosterone, as well as topical applications that produce, I& W( l& q, s
higher levels of serum testosterone (150 to 900 ng./dl.), will
9 h' w" J% E) Z5 palso produce phallic growth but risks accelerated skeletal' e5 U: X3 g# J3 s( B7 t& J
maturation even after stopping treatment. It would appear- k3 _6 s: Q/ I0 ]+ f1 U
that this may be avoided by topical applications of testosterone
' y D1 o7 t' E9 J( G3 Y* l3 \5 ]and monitoring of serum testosterone. Even with this control
; b, ^6 ?5 t G$ |" T, fthe duration of our therapy did not exceed 3 weeks at any
1 P( W- c4 p# o0 @time. It is apparent that the prepuberal male subject may
0 L5 D4 t* [# G0 q7 }) l. \8 vsuffer accelerated bone growth with testosterone levels near
4 h3 |% ^: V8 Y0 X8 Q) d% u200 ng./dl. When skeletal maturation is complete the level of
$ p2 W* R: J; S& g* C8 Qserum testosterone can be maintained in the 700 to 1,300 ng./' r6 J8 t2 d2 t9 e$ N
dl. range to stimulate phallic growth and secondary sexual g0 N* O( B; ?2 ]7 }$ |
changes. Therefore, after skeletal maturation parenteral tes-( ?- H# J/ c! V* }5 a- @
tosterone may be used to advantage. Before skeletal matura-
0 N( ]6 h# B; E" B7 _tion care must be taken to avoid maintaining levels of serum
6 M6 c! r+ w3 ?2 B) |- vtestosterone more than 100 ng./dl. Low-dose gonadotropin
& F. M' D3 a( u( Idepends upon intrinsic testicular activity and may require7 b+ ]$ \8 A1 f ~# Z% ?7 o
prolonged administration for any response.
2 n, w& X1 P# B7 s/ {) j: nAlternately, topical testosterone does not depend upon tes-, q0 C1 @9 a/ }
ticular function and may provide a more constant level of
* J" V3 E* w* O' w/ ]9 x3 A' \$ QREFERENCES* X( N8 O1 }3 x. r# V) A
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ l' i9 A- y2 e1 \, @
R.: The local application of testosterone cream to the prepub-
0 b' O* O' n5 p9 mertal phallus. J. Urol., 105: 905, 1971.
2 m- u* k/ s& D7 T2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, }4 M* a& B& N' xtreatment for micropenis during early childhood. J. Pediat.,9 _* B5 p2 E2 j9 {* m0 ^8 d
83: 247, 1973.
1 a- J/ |- t; O* W; ^2 ^9 C9 C/ i3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 |4 Y6 G3 p( S5 j% w4 r6 }
one therapy for penile growth. Urology, 6: 708, 1975.
- e1 s8 p7 s' ]1 G4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone, q6 t# k# a4 }
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 h9 t* |) _# _3 u7 N+ M! m3 Yskin slices of man. J. Clin. Invest., 48: 371, 1969.3 L8 H8 U" p' B1 b
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ ]# v; g2 Q/ i8 c# O& sby topical application of androgens. J.A.M.A., 191: 521, 1965.& @. U. M- i! r
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. A2 {& a9 F7 t$ L
androgenic effect of interstitial cell tumor of the testis. J.
1 m( ]) K0 _$ Z1 ` jUrol., 104: 774, 1970.
' _1 B7 w8 K) X- F, O( h. I! q' H! A7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-+ U6 v5 ^1 }2 M6 {5 s/ R$ u3 N
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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