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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 i4 u- M: |( zGONADOTROPIN
, v# N# |* p# [1 j: ?3 vRICHARD C. KLUGO* AND JOSEPH C. CERNY
# U$ ?- c1 H2 ~$ PFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
- [+ Q% t0 w: }8 s1 h: f1 gABSTRACT
2 K- W. V( }% h) f% {3 l* AFive patients were treated with gonadotropin and topical testosterone for micropenis associated: _# u" u4 K- ^
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 @( a# u- ]; M" [8 ?tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
8 W0 }. t1 l9 C( `" ocream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 F. E8 V& r) m# E9 }for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. d) y9 y7 P' c6 E! V1 F3 A$ I. i
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
y7 y0 p4 L7 c5 A, @, m" vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response/ V( x2 g% l, w/ D+ d
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
: `& o% g4 c% X! _% sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 {* a. G! g% s [- d" p3 Bgrowth. The response appears to be greater in younger children, which is consistent with previ-) I4 m% P$ |6 g9 W2 I, ?% T4 _3 x
ously published studies of age-related 5 reductase activity.
" {1 ]& H, G c$ rChildren with microphallus regardless of its etiology will
* |1 x4 m+ K' Q% ?require augmentation or consideration for alteration of exter-: F: t" y4 F* J, H" A7 L
nal genitalia. In many instances urethroplasty for hypo-" K% Z" q7 C) N) T; K" E4 K* m
spadias is easier with previous stimulation of phallic growth.
- N- v4 y- e( t4 s; [5 mThe use of testosterone administered parenterally or topically( }1 j6 j% _' I7 @2 e9 M
has produced effective phallic growth. 1- 3 The mechanism of
% Z1 l1 s M2 x; eresponse has been considered as local or systemic. With this
: f- j) S* P% I( D S1 T$ c( x' \in mind we studied 5 children with microphallus for response, @# H y+ c: L" z4 Q$ o: M
to gonadotropin and to topical testosterone independently.& l- M" v- Q ~& y6 \/ t
MATERIALS AND METHODS
. ~% l+ n- O* b3 l* \7 Q) Q5 DFive 46 XY male subjects between 3 and 17 years old were
2 {/ t: Y! e9 ?, cevaluated for serum testosterone levels and hypothalamic5 }) D E/ r1 I& ^$ B% i
function. Of these 5 boys 2 were considered to have Kallmann's
# v; z3 D7 N; G8 Dsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; J! o( | h% l: o3 M
lamic deficiency. After evaluation of response to luteinizing7 r2 d2 W5 ~; I% f6 x
hormone-releasing hormone these patients were treated with L; B& z9 e8 Q$ ]/ C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks& G* q* U! h/ Z) T; r
after completion of gonadotropin therapy 10 per cent topical
$ N( Y/ ?" r5 W! N! S8 o$ ]testosterone was applied to the phallus twice daily for 3 weeks.
7 z* @' a- a( w9 h3 Y5 M z* kSerum testosterone, luteinizing hormone and follicle-stimulat-5 `$ L) u! }$ C1 }
ing hormone were monitored before, during and after comple-4 e, N% X6 |8 [& E! ~
tion of each phase of therapy. Penile stretch length was2 D$ A: i v4 v; j' U3 N) H& T
obtained by measuring from the symphysis pubis to the tip of7 b& ^4 ?# s3 g1 O/ J
the glans. Penile circumferential (girth) measurements were
2 r q" I8 k; _& r( L3 k! n) Mobtained using an orthopedic digital measuring device (see
9 L; C Q: J! Efigure).) w1 B6 z. {9 t! _% I
RESULTS, `1 ?/ m* i( [2 e5 @1 P5 E9 x
Serum testosterone increased moderately to levels between
5 Z. B! A7 O" n7 `/ x2 R50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 H$ F; D' X" Q/ L9 V
terone levels with topical testosterone remained near pre-
/ y+ j) s& C" V; Q- j; @treatment levels (35 ng./dl.) or were elevated to similar levels+ D+ Z! R* Y0 S% H; e0 W
developed after gonadotropin therapy (96 ng./dl.). Higher
: {3 \( t- z$ \. h s5 Mserum levels were noted in older patients (12 and 17 years old),- r0 T/ {3 z$ a$ |
while lower levels persisted in younger patients (4, 8, and 10
' }: @! ~) x1 A1 k- F+ i. P' q5 eyears old) (see table). Despite absence of profound alterations: }0 W1 Z5 P6 h' F$ F
of serum testosterone the topical therapy provided a greater
1 r# C0 B2 x2 Z. K7 NAccepted for publication July 1, 1977. ·
1 M: j# a4 }. ?9 L9 V9 B+ { \Read at annual meeting of American Urological Association,
: F- w# i" p' Q& ?Chicago, Illinois, April 24-28, 1977., G+ i; f& _" J; a0 f2 I
* Requests for reprints: Division of Urology, Henry Ford Hospital,
# W% I! I {7 w" P |) n2799 W. Grand Blvd., Detroit, Michigan 48202.
0 y" V& r) R. e7 ]improvement in phallic growth compared to gonadotropin.
, r u& g' Z% n1 ^. z( ?Average phallic growth with gonadotropin was 14.3 per cent
+ J8 a" X6 [8 H fincrease in length and 5.0 per cent increase of girth. Topical
" e# Q5 a+ Z0 e1 D" p; O7 Etestosterone produced a 60.0 per cent increase of phallic length4 n: H/ D' K" i; T+ L
and 52.9 per cent increase of girth (circumference). The
: T4 h# K( U- ~" H( a, sresponse to topical testosterone was greatest in children be-
) P, q8 d2 J8 D- |$ Ptween 4 and 8 years old, with a gradual decrease to age 17
8 q2 \) i* k' f, qyears (see table).
! e% D) q1 B( q9 ?8 X6 RDISCUSSION8 i+ ? ~% r) U9 Z5 p9 y
Topical testosterone has been used effectively by other* A- ~- | a9 Z/ M% C1 H
clinicians but its mode of action remains controversial. Im-
, z8 J" u# j: Q0 smergut and associates reported an excellent growth response/ a2 X A! ^$ y0 s
to topical testosterone with low levels of serum testosterone,# D) ?( L2 E: }& i, f+ R% Y- U
suggesting a local effect.1 Others have obtained growth re-0 j L1 S+ V4 J3 }' n
sponse with high. levels of serum testosterone after topical
9 e5 A) \/ E1 H/ \administration, suggesting a systemic response. 3 The use of
1 Y& e2 J6 T$ K$ h4 Zgonadotropin to obtain levels of serum testosterone compara-
& v- s( o7 b5 @% _, nble to levels obtained with topical testosterone would seem to; X) _" H7 Q: v; _6 Q
provide a means to compare the relative effectiveness of" ]! ?& R& |! n
topical testosterone to systemic testosterone effect. It cer-. s! r- E) V( g3 b' C% y0 Y# T
tainly has been established that gonadotropin as well as par-$ p; y' F, R% e4 J5 \, U! Z
enteral testosterone administration will produce genital
. T9 j+ q& v/ r( Vgrowth. Our report shows that the growth of the phallus was
! T( Q0 i+ I% K. ]4 m) qsignificantly greater with topical applications than with go-
8 [0 a, ]- @! n1 b, }: {nadotropin, particularly in children less than 10 years old.3 P1 d' J# h1 t
The levels of serum testosterone remained similar or lower3 x% t/ N% H3 F* X
than with gonadotropin during therapy, suggesting that topi-
o) L# |4 U; X8 {4 bcal application produces genital growth by its local effect as
4 o" f5 o+ K$ r4 Y( r- ?well as its systemic effect.
5 T) |0 S% W; T; h7 W. ~4 A" bReview of our patients and their growth response related to
0 K& a7 v1 ^! b: cage shows a greater growth response at an earlier age. This is/ I, h; e/ y! z3 y& {
consistent with the findings of Wilson and Walker, who5 x( l: F ^! ^0 p4 [
reported an increased conversion of testosterone to dihydrotes-7 E# l& I# `3 ]* n6 }5 Y. F/ `
tosterone in the foreskin of neonates and infants.4 This activ-
0 T2 \, E% M6 w$ ~$ _ity gradually decreases with age until puberty when it ap-
* k0 y; f* A( G+ H3 C% [2 Jproaches the same level of activity as peripheral skin. It may3 b/ b5 d/ } {- a
well be that absorption of testosterone is less when applied at3 `5 H* z# g5 t% h$ P1 ?+ L
an earlier age as suggested by lower serum levels in children
7 s" Y7 t- i! l$ Jless than 10 years old. This fact may be explained by the
1 a. q) ^9 L0 {' q. r8 F" |greater ability of phallic skin to convert testosterone to dihy-
+ n$ `7 e& z( E) A) ]/ Gdrotestosterone at this age. Conversely, serum levels in older+ ?# t6 U0 z8 |, i# u1 p2 G
patients were higher, possibly because of decreased local$ h1 f/ T3 ?3 T. H8 v, V
667 s! p* Y# d8 B6 ^) G, x! |
668 KLUGO AND CERNY
9 C8 Q) D* d7 ^3 I' z( ~; Z! H+ _) {1 lPt. Age, i4 v; f$ K4 l2 Y3 X
(yrs.)
- F# E4 s6 D( B( W# B- JSerum Testosterone Phallus (cm.) Change Length
9 g9 }% o0 E3 K(ng./dl.) Girth x Length (%)0 u# {2 D$ u4 [+ d5 y
4
5 ~$ S: w1 d6 w1 s- V3 \8
. f5 r3 ~1 @( W \5 g8 E, f% ]" F a10
3 ~- o' q% K2 B& a1 A+ h2 j12( }; ]# D0 r- a$ a2 w/ X2 {( z: h
17
T. y* @2 V# S$ \Gonadotropin+ \6 P/ h# T, O
71.6 2.0 X 3 16.6
8 q9 Q! S. Z, [' b' X% U M50.4 4.0 X 5.0 20.0
5 a9 R* G( D+ |. A- ?! s22.0 4.5 X 4.0 25.0
3 L# Z5 A) h6 r, r, ?/ C3 U84.6 4.0 X 4.5 11.1
* t/ G# f9 R+ }* @" u85.9 4.5 X 5.5 9.0
I( r: I7 `/ KAv. 14.3: w3 `4 j) t4 f% X7 @: H* l
4
1 g" L" p0 }0 y7 e& F8 [) G+ ]80 B$ [. a9 L0 z7 }8 C
10! P- K* d5 S6 F# z; _7 B
126 x# f `4 r, {2 w
17
) W' c% o+ W7 O {( t5 X8 @Topical testosterone2 j A( A" ]2 f- G
34.6 4.5 X 6.5 85' G% h; g' {: x9 a. {6 @3 ]9 s! g
38.8 6.0 X 8.5 70
, k5 x' T1 S. s: n8 W. Q40.0 6.0 X 6.5 62.5: Y4 k0 R" C3 k* N$ J9 k
93.6 6.0 X 7.0 55.5
7 C& R% F; ]$ f ?6 ^+ d& @95.0 6.5 X 7.0 27.2& C3 Q& I7 `0 W7 X
Av. 60.0
4 K# j2 B- I6 M% k" Wavailable testosterone. Again, emphasis should be placed on
" P$ C9 G4 K- T# N. mearly therapy when lower levels of testosterone appear to. F. }0 x' F$ _6 p
provide the best responses. The earlier therapy is instituted
p A- b+ {$ V) @ ~6 \# H( w6 a# \the more likely there will be an excellent response with low
$ A( s0 x9 v3 }7 D3 userum levels. Response occurs throughout adolescence as
" s) n4 h- z/ n' ^; G; dnoted in nomograms of phallic growth. 7 The actual response, Y5 L) I5 z" s' }
to a given serum level of testosterone is much greater at birth1 x( v R1 X8 U, e0 x
and gradually decreases as boys reach puberty. This is most
3 R8 w' f- T6 W3 Dlikely related to the conversion of testosterone to dihydrotes-
: m% H& J9 p* g# C, Xtosterone and correlates well with the studies of testosterone
' b" Y) q) I% Z# ?3 g3 wconversion in foreskin at various ages.
1 [+ w+ P( {- ]- T" |The question arises regarding early treatment as to whether
2 W$ h5 p Q# X+ |one might sacrifice ultimate potential growth as with acceler-
& X% ^% [$ ]2 X3 R3 a& nated bone growth. The situation appears quite the reverse! F+ b7 p* v2 L0 b) [+ W! A
with phallic response. If the early growth period is not used' h2 h0 X. ~1 B# z! c# k8 y
when 5a reductase activity is greatest then potential growth7 }! ^8 T6 r" Q4 M
may be lost. We have not observed any regression of growth
H. s Q+ p1 J7 sattained with topical or gonadotropin therapy. It may well6 [2 {3 p, x4 {2 g! E/ E
be that some patients will show little or no response to any( u) e% B, k/ S2 y
form of therapy. This would suggest a defect in the ability to
/ ^/ p: x2 _: _, ^; m0 nconvert testosterone to dihydrotestosterone and indicate that7 D7 v. k. V% S6 F8 g
phallic and peripheral skin, and subcutaneous tissue should# z e8 _) Q R9 V7 Q2 X1 `
be compared for 5a reductase activity.+ {8 p' n( C5 x3 Q
A, loop enlarges to measure penile girth in millimeters. B,6 L5 d( M; ?7 D2 h; n
example of penile girth computed easily and accurately.5 F1 Y" L" u+ w) r6 B! ?
conversion of testosterone to dihydrotestosterone. It is in this
6 I9 b* S! ]/ J# ?: ]+ p+ rolder group that others have noted high levels of serum
& a: [ L7 r* {$ h- \' Otestosterone with topical application. It would also appear# H C( A1 S9 s* F( R
that phallic response during puberty is related directly to the
# S& E- D/ h9 q- f; vserum testosterone level. There also is other evidence of local6 d" r' e; z6 o! ], T4 L; O3 \
response to testosterone with hair growth and with spermato-
" a8 E/ x) i4 j4 d* _+ Ugenesis. 5• 6, P, s+ o, t. ]4 A& L. h! b5 b& |
Administration of larger doses of gonadotropin or systemic. r# ]/ J. P4 k! s7 Y( a: n
testosterone, as well as topical applications that produce
1 p! P1 _3 e/ Q# m" A# T2 Q: b: H: _higher levels of serum testosterone (150 to 900 ng./dl.), will
) Y" V" E6 o- C3 _+ qalso produce phallic growth but risks accelerated skeletal
2 V* ^" t3 U: J: W" E, B ymaturation even after stopping treatment. It would appear
: q* x& f0 n( S1 pthat this may be avoided by topical applications of testosterone
6 `- y) m; K r0 ], i( m3 w6 E7 Q# Iand monitoring of serum testosterone. Even with this control
! W& z, o0 N9 U% Pthe duration of our therapy did not exceed 3 weeks at any
$ `0 ]) \/ L' ?& x" _* N- `time. It is apparent that the prepuberal male subject may
& i/ Z" [! ~" |! m( t8 Vsuffer accelerated bone growth with testosterone levels near& L6 l7 @. ] q
200 ng./dl. When skeletal maturation is complete the level of
, V, |# p: s | R* S6 e( {. b. M2 Wserum testosterone can be maintained in the 700 to 1,300 ng./2 W3 F& w) g) S: l& x
dl. range to stimulate phallic growth and secondary sexual
0 K, u) j. P l" pchanges. Therefore, after skeletal maturation parenteral tes-
. i& E& J1 F4 l8 o" X3 Z3 }tosterone may be used to advantage. Before skeletal matura-
1 ?5 u, c1 c2 G/ {tion care must be taken to avoid maintaining levels of serum
9 s. J( ~/ k+ T2 s$ M) W& jtestosterone more than 100 ng./dl. Low-dose gonadotropin
9 _# |- \( V9 N3 H% udepends upon intrinsic testicular activity and may require
M2 D% F9 S8 P/ b+ [: `prolonged administration for any response.& @$ K4 X7 J4 p' ~3 s8 m3 Y" z ~
Alternately, topical testosterone does not depend upon tes-
; m, j2 m4 y. @# m- E Q {. Iticular function and may provide a more constant level of
* @: F- x4 z" a0 P' D& c: ]REFERENCES
1 g7 q% E4 F( p4 D1 X4 ~9 d1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; C9 l* e: h( _R.: The local application of testosterone cream to the prepub-
! X% x {/ K; R3 @# tertal phallus. J. Urol., 105: 905, 1971.8 w5 G% ?' O+ y) M( b
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone/ B; r2 `' |; k3 T1 Y
treatment for micropenis during early childhood. J. Pediat.,
0 |$ N F7 W$ }; }83: 247, 1973.
1 G0 M/ s2 z* Q3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' ^# Z: d* C0 L; [6 L4 }one therapy for penile growth. Urology, 6: 708, 1975.8 B0 v7 R; ]: t: Q* v8 Y
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
6 _3 z' q3 W I8 Zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* W8 |4 z m- T: @
skin slices of man. J. Clin. Invest., 48: 371, 1969.# U: ~" q, f, `8 {+ u
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 Q- @% y/ t. F5 N$ y5 ?
by topical application of androgens. J.A.M.A., 191: 521, 1965.6 E% n: n# I" b/ K( y1 f) t
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: b" Z2 { p! |7 B) @5 v. ~; X
androgenic effect of interstitial cell tumor of the testis. J.8 F- W; ^+ U' B6 O) D2 O
Urol., 104: 774, 1970.2 t6 d& q6 \; l7 K: f
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
# P! o0 x1 y- E* A' K; Btion in the male genitalia from birth to maturity. J. Urol., 48: |
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