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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: v" p1 F" o! O1 S- s: A" W) TGONADOTROPIN. l% O) k+ B" L, M9 h4 U( I
RICHARD C. KLUGO* AND JOSEPH C. CERNY
1 @/ z& i7 }0 u4 ~$ a- @From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
. R+ a" f" P% L9 o! xABSTRACT/ ]/ y" {# o! \8 m7 G" B
Five patients were treated with gonadotropin and topical testosterone for micropenis associated3 \4 P0 v( X; @; n* J4 B! S) |
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-4 {7 e  C/ O7 M; u; w
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 o1 X( ?% Y/ D0 S5 l
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent$ J4 `. e6 F9 p' c. @; [
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent+ G, D. O# b; G: _5 M, I
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
$ A8 u! R, ?2 ?. O3 jincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ M; @7 u, S! o+ v1 K7 yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
  r) Z* V+ i3 L$ j% D1 F4 z7 D; y, K) fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ e9 E5 i# u) w- R3 d- g, ngrowth. The response appears to be greater in younger children, which is consistent with previ-2 P3 n( a0 _9 z$ Y- B" n
ously published studies of age-related 5 reductase activity.
: s5 M& n4 A% _* o  f9 UChildren with microphallus regardless of its etiology will! B' i. a# s1 E2 d; k' [. ]
require augmentation or consideration for alteration of exter-% a* h' Y/ }6 ?2 d( g& x
nal genitalia. In many instances urethroplasty for hypo-
7 r, Z5 r  D+ w  ospadias is easier with previous stimulation of phallic growth.
( q0 i- |5 s& X/ v0 MThe use of testosterone administered parenterally or topically5 X  i7 C% f. k) D- J- v0 z% `  g' s
has produced effective phallic growth. 1- 3 The mechanism of
9 q; L- i1 z% G$ {( Y* t" hresponse has been considered as local or systemic. With this) p0 p" f, W+ }: [7 A. J- }
in mind we studied 5 children with microphallus for response/ x: g; c4 @/ Y7 B9 R( i/ o$ ^) R
to gonadotropin and to topical testosterone independently.
1 S; o# h$ T( }MATERIALS AND METHODS3 h  G9 a; W" A( a
Five 46 XY male subjects between 3 and 17 years old were& Y$ M4 Z4 C% ~/ `, N9 X
evaluated for serum testosterone levels and hypothalamic
  @( r% Q5 h2 t, S  @function. Of these 5 boys 2 were considered to have Kallmann's
- V, ^& a' q7 r% H/ V% isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-- m' l; F( i; e
lamic deficiency. After evaluation of response to luteinizing
9 y3 I. B9 s9 |# W3 D! C+ v3 shormone-releasing hormone these patients were treated with
) o! h6 Y1 N! {; y1 h/ g* h" O" i1,000 units of gonadotropin weekly for 3 weeks. Six weeks8 b+ a0 h' p: `) U0 L/ d
after completion of gonadotropin therapy 10 per cent topical
7 P* u% s! Q* ]9 F  c2 n. C* `testosterone was applied to the phallus twice daily for 3 weeks.2 E( _' \( A5 b# ~6 p
Serum testosterone, luteinizing hormone and follicle-stimulat-/ Z& x* v# ^/ x
ing hormone were monitored before, during and after comple-$ `/ j' ~6 c* r+ P- e( A' P: t
tion of each phase of therapy. Penile stretch length was' c1 O6 D9 ?- X0 R# G0 [+ D" V) e
obtained by measuring from the symphysis pubis to the tip of
7 v. Z+ t+ Y7 ~) T2 Ethe glans. Penile circumferential (girth) measurements were8 d6 R) {) n  H: f+ r; G& c
obtained using an orthopedic digital measuring device (see
* y2 x$ o6 ]  R# S# Efigure).% f7 C* M  s3 w+ Q$ N/ w# w
RESULTS
: V7 j  w$ b; n) jSerum testosterone increased moderately to levels between4 f: p$ ]0 Q% P& J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 s9 H% G# ]8 u! N5 u
terone levels with topical testosterone remained near pre-! K. `  |; m- ^
treatment levels (35 ng./dl.) or were elevated to similar levels
% l4 z' x4 ?6 s/ M" Jdeveloped after gonadotropin therapy (96 ng./dl.). Higher* F/ H; A$ a( Z& j
serum levels were noted in older patients (12 and 17 years old),' {& O& J+ ?9 k. z0 x
while lower levels persisted in younger patients (4, 8, and 10
9 k, B; s6 k$ I  K! Byears old) (see table). Despite absence of profound alterations
& d6 q. t  E; s/ N0 C" i; eof serum testosterone the topical therapy provided a greater$ ^1 C5 {/ L! r2 U7 F' X
Accepted for publication July 1, 1977. ·
* K1 L! k3 T  E/ Z# PRead at annual meeting of American Urological Association,
, k, i: |2 i2 U+ oChicago, Illinois, April 24-28, 1977.; [5 R- ^3 c0 s9 K
* Requests for reprints: Division of Urology, Henry Ford Hospital,3 \) {, A7 O/ D$ f, t  V
2799 W. Grand Blvd., Detroit, Michigan 48202.+ H, W( a7 ^3 {5 E+ m+ A0 g" c( h, _4 ^
improvement in phallic growth compared to gonadotropin." G: j; \) k6 y  k3 w
Average phallic growth with gonadotropin was 14.3 per cent  R* Z2 P8 Z) }( I. ^
increase in length and 5.0 per cent increase of girth. Topical
. Y5 z1 m6 E1 T; q2 W2 R* @) ?6 Atestosterone produced a 60.0 per cent increase of phallic length
5 c% \9 M5 S6 o0 xand 52.9 per cent increase of girth (circumference). The- }) k- s+ n, v  S3 p! L$ C
response to topical testosterone was greatest in children be-" U  T# T6 S' s, J1 b  L3 d- T
tween 4 and 8 years old, with a gradual decrease to age 17
- z. s3 i' e6 X4 }" L+ h- xyears (see table).8 s' m" t( A4 {' e6 b" R: e6 _
DISCUSSION1 a7 ?$ B  _( p' \+ j; u
Topical testosterone has been used effectively by other6 V4 n4 V2 k% V
clinicians but its mode of action remains controversial. Im-
0 P8 ^' O) c0 R3 i" |3 `0 R: z+ dmergut and associates reported an excellent growth response6 k9 |' `  t$ G" h+ I! r
to topical testosterone with low levels of serum testosterone,
, ]" y, y9 G* t4 t' [( Hsuggesting a local effect.1 Others have obtained growth re-
5 i4 K" N$ l/ P8 k: O4 s+ E- o3 jsponse with high. levels of serum testosterone after topical
! L2 [- M  r7 k9 p5 }8 {. V0 [administration, suggesting a systemic response. 3 The use of0 U* m' C/ T' U
gonadotropin to obtain levels of serum testosterone compara-7 r* T8 \; W' u/ k" s" ^# f2 V
ble to levels obtained with topical testosterone would seem to
9 i( {  q: x5 I: ]& Hprovide a means to compare the relative effectiveness of* j) ?$ i5 k7 ?
topical testosterone to systemic testosterone effect. It cer-4 W( N3 s% e9 a. @  |
tainly has been established that gonadotropin as well as par-8 s: C6 V4 z9 A: r- |
enteral testosterone administration will produce genital, ]+ Q$ s9 p+ L8 o3 {! u( R% x. r( {
growth. Our report shows that the growth of the phallus was3 M! f9 h5 `" u) h; A& u. V6 T
significantly greater with topical applications than with go-6 ^/ c2 {8 I8 B; r/ c
nadotropin, particularly in children less than 10 years old.
/ `' B1 C/ t, f# VThe levels of serum testosterone remained similar or lower9 B( y7 I7 d4 {9 g/ Y! i
than with gonadotropin during therapy, suggesting that topi-
2 b1 t) i9 ~" `/ t* zcal application produces genital growth by its local effect as. p% S9 ^5 j! {5 R
well as its systemic effect.7 V6 k4 V: V9 \, \# w$ S
Review of our patients and their growth response related to& D/ l; M& S4 J. O
age shows a greater growth response at an earlier age. This is
7 s! q3 n- V" f4 P0 Q( [$ econsistent with the findings of Wilson and Walker, who
+ p+ z3 t. I; Areported an increased conversion of testosterone to dihydrotes-1 }) r. A1 k& t1 W) U
tosterone in the foreskin of neonates and infants.4 This activ-
+ @* ]( C* g' H* vity gradually decreases with age until puberty when it ap-3 _/ S7 [0 t/ `* J2 x; V
proaches the same level of activity as peripheral skin. It may
, J/ c' O7 o- ?" ^. @well be that absorption of testosterone is less when applied at
# w) x- k8 ]; T2 a2 ^! y* fan earlier age as suggested by lower serum levels in children
( s# X+ j6 c: y% G7 ]less than 10 years old. This fact may be explained by the7 W3 c: R( n3 f" Q/ N! e
greater ability of phallic skin to convert testosterone to dihy-) v7 a" P1 }: g. L7 b2 |6 f
drotestosterone at this age. Conversely, serum levels in older
9 r. l+ K/ T9 N( Y4 G1 fpatients were higher, possibly because of decreased local
9 S. }( N' M# I. _667
+ X& g  R0 @. |, b- x668 KLUGO AND CERNY" a6 Z( y4 n; E. k% B: p: J
Pt. Age3 b* X. U& L9 G& {& O1 r8 U* r
(yrs.)+ T# ]/ R5 A1 Q" L( @# H
Serum Testosterone Phallus (cm.) Change Length) E5 P( ?* b, o
(ng./dl.) Girth x Length (%)
6 N, v4 ?, _% ^) M. E46 M3 _$ H* X: Q# k# A1 z; O
8
) V) T( O* k2 h$ f10
8 J) a3 t$ R5 C. R( |7 y) j12
- H" p1 @3 A, `% X17
* P  k* m3 ^3 }) x, XGonadotropin
3 j8 D5 T. L- Y, {! p( m0 u71.6 2.0 X 3 16.68 S. F: B. J2 A! ?, f
50.4 4.0 X 5.0 20.0; C3 \, m- f+ D
22.0 4.5 X 4.0 25.08 v. M: ]+ U% a4 Z
84.6 4.0 X 4.5 11.19 g" P0 q9 N, L" S
85.9 4.5 X 5.5 9.0, C" N7 q9 U" v0 P( r2 I4 a8 I
Av. 14.3
8 R8 _8 g8 S, h" I7 C& w4
/ i( L/ }" }7 o  g& m  c8+ u8 y, b/ y& f
10
3 O& V( n7 K/ P120 e1 K4 n4 `2 Q
17; x: E6 o1 s1 f! }! t; e' \/ N8 Q
Topical testosterone3 G* u$ Y3 K1 n" Z$ B# w3 T
34.6 4.5 X 6.5 85
4 z5 Q0 l! V, C2 V, O1 ?38.8 6.0 X 8.5 709 F6 E! J0 b+ J# }6 W9 |2 `3 z3 c
40.0 6.0 X 6.5 62.57 G' \+ I2 z" ?) a
93.6 6.0 X 7.0 55.51 N  s/ x% G' i% N0 J2 t& O
95.0 6.5 X 7.0 27.2& t- i+ h7 c# k& o1 c1 `
Av. 60.0# ^1 m- h4 W% P% Y/ G/ |% ]
available testosterone. Again, emphasis should be placed on7 s! o3 e. j7 t  @. o
early therapy when lower levels of testosterone appear to
# O* n; ]: L4 L/ c! T! u6 ^provide the best responses. The earlier therapy is instituted  o& S( B  ]$ ?7 [! Y$ v- j# i
the more likely there will be an excellent response with low, `! A" Z" P& G
serum levels. Response occurs throughout adolescence as
& ^) B7 F; a8 ^  P  Z% t) Mnoted in nomograms of phallic growth. 7 The actual response
" b! o+ n  }$ X' d$ ?' Yto a given serum level of testosterone is much greater at birth
* W6 M1 f2 r: @+ i4 [and gradually decreases as boys reach puberty. This is most* m, {6 |$ `& R
likely related to the conversion of testosterone to dihydrotes-! ~- v5 b- k5 ]6 S' O( L7 T) [
tosterone and correlates well with the studies of testosterone' w: @$ e$ G0 r/ W7 C' b
conversion in foreskin at various ages.
$ p8 c# S+ Z- }! F& q3 ^The question arises regarding early treatment as to whether2 @, H. U- S) ?$ x: T/ h: X. s3 g
one might sacrifice ultimate potential growth as with acceler-
( Z- Z# |& M: Mated bone growth. The situation appears quite the reverse4 j6 \+ Y# p/ f& {, \% b
with phallic response. If the early growth period is not used, X/ N/ C) V% L9 P3 j
when 5a reductase activity is greatest then potential growth
, e7 u8 U4 C; U0 a% Smay be lost. We have not observed any regression of growth
2 z! q6 e! t: G8 ]0 g) Aattained with topical or gonadotropin therapy. It may well, z# V! U6 {4 s) [4 }
be that some patients will show little or no response to any5 ^4 e: R; D& e' w+ w- A) ?% K
form of therapy. This would suggest a defect in the ability to4 q/ @9 o: e% m5 ?# Z( n
convert testosterone to dihydrotestosterone and indicate that
+ t# h! |  R# g8 Sphallic and peripheral skin, and subcutaneous tissue should* |0 G5 u# I; Y
be compared for 5a reductase activity.5 ~& w7 R. V& k0 v2 i
A, loop enlarges to measure penile girth in millimeters. B,
8 D5 i: o0 V6 X- K2 B1 hexample of penile girth computed easily and accurately./ Y! v. \; B2 e6 c3 Z
conversion of testosterone to dihydrotestosterone. It is in this
2 u( V  |# [2 x& U" |- g6 x# solder group that others have noted high levels of serum6 @% I1 W  V" \6 p( {) T/ ^% ~  r
testosterone with topical application. It would also appear
; H! ~+ f; I" [. b! wthat phallic response during puberty is related directly to the; m0 _5 L# O7 C2 W3 p" F
serum testosterone level. There also is other evidence of local! F) w' r$ m* e0 u
response to testosterone with hair growth and with spermato-
9 o4 O1 a- ^: o+ F8 A' _: w: zgenesis. 5• 6
9 V; a& M* T) [- C: z/ QAdministration of larger doses of gonadotropin or systemic
) v! }" G% ?4 E9 j, L# U1 F, `testosterone, as well as topical applications that produce$ L. `9 [4 c: O, W6 p9 a
higher levels of serum testosterone (150 to 900 ng./dl.), will
3 F; U9 w; i- W, z8 a( nalso produce phallic growth but risks accelerated skeletal
7 S: A7 V, [3 l8 {9 Ymaturation even after stopping treatment. It would appear7 X* h# a$ c! U8 o" L
that this may be avoided by topical applications of testosterone$ A, {; N2 ~' ~8 P
and monitoring of serum testosterone. Even with this control
  ?. ?$ E7 c% j/ A, Ethe duration of our therapy did not exceed 3 weeks at any
) C# ^! {2 Z  [  E8 ?5 `time. It is apparent that the prepuberal male subject may3 o4 R1 i7 C' y. i
suffer accelerated bone growth with testosterone levels near
' J' a1 F6 r8 y  E200 ng./dl. When skeletal maturation is complete the level of- n" a2 S5 S' r7 N) r% Y
serum testosterone can be maintained in the 700 to 1,300 ng./: m+ y1 x# r$ L: }
dl. range to stimulate phallic growth and secondary sexual
6 m! A# ^# K7 D, n/ W9 S2 m% ochanges. Therefore, after skeletal maturation parenteral tes-$ `' C9 c, A* _3 d) W! J% S% P7 |
tosterone may be used to advantage. Before skeletal matura-
2 j# _, }+ R7 stion care must be taken to avoid maintaining levels of serum
$ L( P0 e0 U* a. J8 Q) etestosterone more than 100 ng./dl. Low-dose gonadotropin( `5 f! o7 I+ N$ x" n5 \5 R6 v. P
depends upon intrinsic testicular activity and may require: O# Q7 G7 B. U$ r4 h/ l: J( z' I
prolonged administration for any response.  |9 o8 d3 |7 Z+ G# k6 e: ], s
Alternately, topical testosterone does not depend upon tes-
- g: @0 f; a+ U7 d* d0 y7 W& aticular function and may provide a more constant level of
' |# p. h1 O' B  B3 T0 |" _REFERENCES1 K0 w, X$ u6 g) b& k  f
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& o7 Q# Y/ C4 G* F; e# T! m
R.: The local application of testosterone cream to the prepub-
* p& k5 K% d1 O1 |, Mertal phallus. J. Urol., 105: 905, 1971.
- m. B8 {4 u8 S& d2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone' _. T. a, X9 M* U( w9 O, j
treatment for micropenis during early childhood. J. Pediat.,
& q- b' R( L& s# z; y5 t1 Y83: 247, 1973.' K7 _, F/ g5 H0 g* }
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 U' B3 [8 |: s) _' e  Lone therapy for penile growth. Urology, 6: 708, 1975.
8 j! F; W. q1 ~  X+ i/ e" e7 [4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* p: h# q1 }( P' m: B) w, Zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by0 f; `# D5 ~- O8 @. ]" Z
skin slices of man. J. Clin. Invest., 48: 371, 1969.& c5 k4 J# |* s* K; ~$ a! \
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth" ~; {% z+ v& [' J; h
by topical application of androgens. J.A.M.A., 191: 521, 1965.
# H& m' O, k: U6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! k' m! D% R: t, Z) M2 v9 Landrogenic effect of interstitial cell tumor of the testis. J.
: O- i4 o2 C( P/ ~) a1 dUrol., 104: 774, 1970.. e, r! j2 j8 b, |2 y7 ~& ~6 ]/ ~
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( e/ k: m# g7 h3 [1 w7 K
tion in the male genitalia from birth to maturity. J. Urol., 48:
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