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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
2 l/ z0 X' k! {$ wGONADOTROPIN9 G- [$ ?# s9 l' C. e0 M5 B+ k
RICHARD C. KLUGO* AND JOSEPH C. CERNY1 \* T7 e/ t* U  s
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* N, X" n2 ~1 |; ?7 RABSTRACT
" e1 y$ L; N' Z; s) O% H) @3 W4 dFive patients were treated with gonadotropin and topical testosterone for micropenis associated
; R2 b0 q7 t; w; x! Z, rwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-. C8 z) s3 ^  ]  e8 i
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ t$ Q' D4 A& }, N( w0 _& Wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 w# ?! x: x, C6 p" x6 L
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* F, t# }5 K7 i  a& |, Eincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
  e6 \4 t) j. K" `$ l. fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 Y0 n6 ?4 _( ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- q# j+ y: F3 t9 f( d& C! Dstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile' T) ^1 d( m* c1 a
growth. The response appears to be greater in younger children, which is consistent with previ-4 i; i5 l- P1 k% P
ously published studies of age-related 5 reductase activity.- ?0 _& ]0 b$ `9 E6 y( G4 d3 N
Children with microphallus regardless of its etiology will1 m4 }% `/ Z  c. }3 k; O
require augmentation or consideration for alteration of exter-
3 _+ Y3 Y* G- L8 |# lnal genitalia. In many instances urethroplasty for hypo-7 z1 y& M  ?+ c. b( o" y3 c
spadias is easier with previous stimulation of phallic growth.
' ?: l3 M2 b  U) q2 s* @( `5 BThe use of testosterone administered parenterally or topically" q5 c% O' w* P5 y
has produced effective phallic growth. 1- 3 The mechanism of, N, {% Q' ^: q; x- }- y3 y& }
response has been considered as local or systemic. With this( h/ Q. z1 U4 }+ D! _
in mind we studied 5 children with microphallus for response0 m* k3 Z+ A5 B1 w! G( I# Q' G
to gonadotropin and to topical testosterone independently.
' ?: Y' E: O; ?MATERIALS AND METHODS
# I4 h" r- \' `) c( sFive 46 XY male subjects between 3 and 17 years old were7 ?) C: h9 h. p9 E( k
evaluated for serum testosterone levels and hypothalamic
* v& [9 M6 i7 ^+ I  Afunction. Of these 5 boys 2 were considered to have Kallmann's
9 d7 o" D6 o' Gsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' |" g9 D3 C/ c: t4 e' A( K  f+ U( t) ^
lamic deficiency. After evaluation of response to luteinizing5 J( A* \4 S  C+ A7 l" t' m" J
hormone-releasing hormone these patients were treated with
3 J: R4 q9 k  g+ T8 g( b. R' ]. ]1,000 units of gonadotropin weekly for 3 weeks. Six weeks2 J; p4 v9 m: Q, Z* h
after completion of gonadotropin therapy 10 per cent topical9 A( t; h* Y& W  _: J/ W
testosterone was applied to the phallus twice daily for 3 weeks.
- H' i7 u0 o; V' q3 I2 LSerum testosterone, luteinizing hormone and follicle-stimulat-
- R- Z" k  x4 P. Q, g# O1 ~ing hormone were monitored before, during and after comple-
$ x6 R1 S, g- e* m+ U/ I6 l4 Y/ Ftion of each phase of therapy. Penile stretch length was! M: e" V) S% U4 l, w
obtained by measuring from the symphysis pubis to the tip of
5 }- d! J* ^$ ~6 E5 Q. Qthe glans. Penile circumferential (girth) measurements were; e$ h' K# `/ w# d% u9 U
obtained using an orthopedic digital measuring device (see# V# E: T' @/ a
figure).' f: k2 u. [7 t# y  ]8 w
RESULTS
0 X7 X6 O1 n# VSerum testosterone increased moderately to levels between+ o, w0 V8 k8 ~) h( |5 w
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 q. e  w, m1 l' |
terone levels with topical testosterone remained near pre-
8 _+ f9 X7 l3 |/ Q4 m/ N5 a; Utreatment levels (35 ng./dl.) or were elevated to similar levels
8 n/ Q' H' i+ |developed after gonadotropin therapy (96 ng./dl.). Higher
" g* y9 i+ v3 P; |serum levels were noted in older patients (12 and 17 years old),/ R: q: k6 `  p  I4 l2 J
while lower levels persisted in younger patients (4, 8, and 10
7 K5 C) Q7 c* {9 fyears old) (see table). Despite absence of profound alterations
* P; }0 N) U. b' rof serum testosterone the topical therapy provided a greater1 K! y  ~+ c/ V6 T' F, K
Accepted for publication July 1, 1977. ·
. V+ e, E5 ~4 x& T+ [5 uRead at annual meeting of American Urological Association,
" C+ W- K+ G" G! N9 H# D' jChicago, Illinois, April 24-28, 1977.
3 u- H$ t# U3 P( I$ }* Requests for reprints: Division of Urology, Henry Ford Hospital,
" x' b- f6 ^- G2 n0 [0 T2799 W. Grand Blvd., Detroit, Michigan 48202.  N( O( Z. d; f  n- Z" V
improvement in phallic growth compared to gonadotropin.
2 n# |5 b8 J, s% ]; cAverage phallic growth with gonadotropin was 14.3 per cent
# U$ e% ]  ~4 [6 l/ dincrease in length and 5.0 per cent increase of girth. Topical9 U( ~# M2 {3 B+ d% ~9 g
testosterone produced a 60.0 per cent increase of phallic length
% ?; [2 b# h7 |) w6 F% ?- [and 52.9 per cent increase of girth (circumference). The. Y$ u; V1 H( ?+ Z
response to topical testosterone was greatest in children be-9 |/ d4 N4 Z$ {- D: Y
tween 4 and 8 years old, with a gradual decrease to age 17
9 u/ N- _7 a1 X" cyears (see table).3 U: Z0 v+ q% j' k
DISCUSSION
5 c+ ^( s5 q/ d. r5 X! N4 ATopical testosterone has been used effectively by other
( g+ X/ P  Z' r3 Y% Rclinicians but its mode of action remains controversial. Im-
/ O( i: P. y6 T) |) imergut and associates reported an excellent growth response& w+ L2 v$ N5 W; l" r/ E9 h
to topical testosterone with low levels of serum testosterone,
' E2 C5 d7 D1 i( e6 @suggesting a local effect.1 Others have obtained growth re-0 t3 U( C% J' J; A
sponse with high. levels of serum testosterone after topical, ~5 j0 N& @% F* ]2 x/ H
administration, suggesting a systemic response. 3 The use of, R& t# X3 i$ [% ~5 S5 m% |
gonadotropin to obtain levels of serum testosterone compara-
' q" _$ \& U3 R7 Y, fble to levels obtained with topical testosterone would seem to
6 x+ b$ U( D$ }9 B! t0 Rprovide a means to compare the relative effectiveness of
8 {- H$ j. K$ r3 Etopical testosterone to systemic testosterone effect. It cer-5 w' x6 R6 o7 x' p' ~/ X9 z
tainly has been established that gonadotropin as well as par-
6 f: P9 g9 w, O# w" X" U8 Menteral testosterone administration will produce genital; v0 \& ^9 t  o$ F$ [1 W2 Y
growth. Our report shows that the growth of the phallus was
/ q% A: E* v8 t' B/ A; [' k! Xsignificantly greater with topical applications than with go-6 O+ J, s6 E1 m' R+ B
nadotropin, particularly in children less than 10 years old.2 Z: P9 j+ r' N! Y! e. D$ b
The levels of serum testosterone remained similar or lower: z2 Q$ C- F! n2 X& m. K- y( F9 p
than with gonadotropin during therapy, suggesting that topi-
( e9 T& K; w  ?: e: ]cal application produces genital growth by its local effect as
9 ~3 v: g( J# J6 w$ Z' Y& Awell as its systemic effect.
+ w  r* h! X4 jReview of our patients and their growth response related to
9 r) X+ j0 E6 _. page shows a greater growth response at an earlier age. This is! E& C! I6 J* G. s7 {
consistent with the findings of Wilson and Walker, who
9 W9 u, e/ }, E, f0 ereported an increased conversion of testosterone to dihydrotes-
' k* _/ O% m5 Ptosterone in the foreskin of neonates and infants.4 This activ-
8 O' G& G! \+ z* e; o1 i. oity gradually decreases with age until puberty when it ap-- t0 G+ R9 v1 g0 S
proaches the same level of activity as peripheral skin. It may6 M  Y# V( s# w" a3 z
well be that absorption of testosterone is less when applied at; z6 v) [( `1 a$ f4 A+ p% g
an earlier age as suggested by lower serum levels in children
  H$ v- q. M7 Iless than 10 years old. This fact may be explained by the
$ ?- N8 Y$ T$ _5 b3 Rgreater ability of phallic skin to convert testosterone to dihy-; Z. E( [" \9 F
drotestosterone at this age. Conversely, serum levels in older: e5 P+ X# |4 x- N+ P5 A
patients were higher, possibly because of decreased local* B1 a6 y) j/ S9 I
667
) V2 U, @+ \! t% Q* E668 KLUGO AND CERNY
& {- I  Y4 y2 jPt. Age
. O& s- q4 E9 e, o' c(yrs.), B  e- g/ u" j" \7 A2 I+ K! u
Serum Testosterone Phallus (cm.) Change Length
+ X1 C7 o2 V1 b# l(ng./dl.) Girth x Length (%)- z0 p7 j! @5 `  W: U6 K& S* m
46 l' k/ c, ^* F
8# ?( E. ?+ y1 J
10- H) v( m1 [& u: {3 O* K
12% i  q8 ], i7 A
17
0 x% g" X& f. {1 J5 u6 o; ?) _' o% wGonadotropin
8 n/ ?9 ~6 V: @& g9 |/ g  Q, k71.6 2.0 X 3 16.6" f% T* w% Z" {* r) E: t; N3 x5 i' [
50.4 4.0 X 5.0 20.0' u- n; d/ g- H/ f) H+ Z7 U0 T- Q
22.0 4.5 X 4.0 25.0+ u: h* `: S& k7 d$ ^8 i( C
84.6 4.0 X 4.5 11.1
6 W  Y. b8 l& l8 q85.9 4.5 X 5.5 9.0- }0 \5 a9 h- Y% \
Av. 14.3
4 Q) Q; h0 ]) t% d4
% m( K3 ?) L" D1 N) q# k8
+ A) D9 g+ A; v/ g4 ]4 v+ J1 ^10' A% o6 c* ?1 F; l  J2 c
128 W' ~; s3 F: y- Q( m; K
17, K5 y0 a  [: ?5 d8 N( N4 s" Z
Topical testosterone
0 k9 i) Y; s/ P+ s: i! A4 Q34.6 4.5 X 6.5 856 c+ k+ p" d6 F1 y% n% ?/ K; D
38.8 6.0 X 8.5 70( R4 q" C" j5 ]' J3 A7 ^
40.0 6.0 X 6.5 62.5
3 i+ {5 ?; S1 I93.6 6.0 X 7.0 55.51 _/ ~, `& [7 O7 f% X, p
95.0 6.5 X 7.0 27.2  I. j- m- o: M2 y" Y' c: M
Av. 60.0
! O. X( C. v/ ^/ Wavailable testosterone. Again, emphasis should be placed on3 g8 m0 w# w3 q4 v( s5 y
early therapy when lower levels of testosterone appear to! f* o+ ~! P$ i; U% n" ~
provide the best responses. The earlier therapy is instituted( c8 q( i% N1 u1 Q3 ?  m
the more likely there will be an excellent response with low1 s/ F) k) X- H/ `
serum levels. Response occurs throughout adolescence as. a! [: t+ h$ N# k% s6 K( }. H0 I
noted in nomograms of phallic growth. 7 The actual response
, o* i" |0 v5 U9 J+ S0 C0 Zto a given serum level of testosterone is much greater at birth2 A4 J1 e6 V/ C. T
and gradually decreases as boys reach puberty. This is most
9 v& D+ J  O7 ]3 hlikely related to the conversion of testosterone to dihydrotes-+ Q7 h: @% S  T" o
tosterone and correlates well with the studies of testosterone" g) M- |9 f4 @4 h
conversion in foreskin at various ages.$ z0 O3 |, _% s0 _
The question arises regarding early treatment as to whether
* C& z, u+ t3 l6 I2 r6 o5 X% Lone might sacrifice ultimate potential growth as with acceler-3 m  Q7 S9 R3 e2 n1 y3 ~: X6 F9 K
ated bone growth. The situation appears quite the reverse3 M; s) c7 X# J3 M9 w
with phallic response. If the early growth period is not used2 Y: o* R2 o8 i" v5 x$ i' F
when 5a reductase activity is greatest then potential growth9 J; c. n1 y; U/ j
may be lost. We have not observed any regression of growth7 I: M2 |5 z1 H
attained with topical or gonadotropin therapy. It may well
- G' i5 B+ r" o8 T8 o$ O! `. ube that some patients will show little or no response to any
6 n1 n* k+ U( `+ b! Qform of therapy. This would suggest a defect in the ability to3 c* y+ d; \' R7 K6 k' L; p4 C! }( O
convert testosterone to dihydrotestosterone and indicate that
+ E4 Y, N8 T2 c+ |9 @# S$ r3 mphallic and peripheral skin, and subcutaneous tissue should
- X3 p% z8 z# V7 }1 zbe compared for 5a reductase activity.
# t* p6 M: D6 a) R( ?2 n0 ~) V# n3 Z7 D) mA, loop enlarges to measure penile girth in millimeters. B,  M7 ~! s, c5 {7 c# E9 _0 J8 ], Q
example of penile girth computed easily and accurately.
( ^" c8 |7 c8 T' p" P5 t9 Pconversion of testosterone to dihydrotestosterone. It is in this5 Z; V9 r5 J8 o/ _! ^
older group that others have noted high levels of serum
8 \' i# Y8 `, Dtestosterone with topical application. It would also appear
4 B. J: h/ v9 @: \3 X9 Rthat phallic response during puberty is related directly to the2 A* X5 Q* ^1 E* p
serum testosterone level. There also is other evidence of local
6 g2 \9 a( u1 V5 n% |response to testosterone with hair growth and with spermato-- Q/ S' h( N/ ~2 P. _
genesis. 5• 6
! d/ K6 [" [  ?- i$ p- eAdministration of larger doses of gonadotropin or systemic
; A; r& t  z0 Q; {) W6 rtestosterone, as well as topical applications that produce
, d/ l+ |) R5 |9 Q' qhigher levels of serum testosterone (150 to 900 ng./dl.), will8 V$ L( d- q' F& w
also produce phallic growth but risks accelerated skeletal
, \  H2 A4 ^- |% h, ~maturation even after stopping treatment. It would appear8 z+ E9 }9 g3 k5 s# X) @( ?
that this may be avoided by topical applications of testosterone
5 w8 k9 Z% l) K0 W4 {and monitoring of serum testosterone. Even with this control  f. u# w6 n1 O
the duration of our therapy did not exceed 3 weeks at any; Q5 I7 V. O( v& H
time. It is apparent that the prepuberal male subject may
6 x8 I4 i. Y. s3 `* l. wsuffer accelerated bone growth with testosterone levels near) h) q0 g. l+ s: n- M$ y9 D- k
200 ng./dl. When skeletal maturation is complete the level of: Y9 e5 I) @: s" q0 \- r. Q
serum testosterone can be maintained in the 700 to 1,300 ng./
/ m4 G. z$ b7 z4 odl. range to stimulate phallic growth and secondary sexual
3 a3 ?  O+ P( y7 K5 _6 \' u6 Schanges. Therefore, after skeletal maturation parenteral tes-6 A2 K3 s) \8 _, T9 q
tosterone may be used to advantage. Before skeletal matura-7 i: }/ {" |. \5 a' v
tion care must be taken to avoid maintaining levels of serum5 v3 Q1 ]2 i, ]; B4 i; I
testosterone more than 100 ng./dl. Low-dose gonadotropin0 z# Q2 E9 E% X! B. Z5 [
depends upon intrinsic testicular activity and may require, Q9 r; b4 O3 d$ I/ t7 {; e8 g# a
prolonged administration for any response.
  z. Y+ ~7 F. [6 LAlternately, topical testosterone does not depend upon tes-9 {' K  i7 ^+ n& e
ticular function and may provide a more constant level of
" Z" x7 W$ |& f1 n8 @" l/ p# xREFERENCES% G0 V1 k) u. i3 z7 x
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# C$ t" x* v. r) W& ^) C! J
R.: The local application of testosterone cream to the prepub-
3 m/ w; K/ a* A3 U% f$ ]3 I! g9 Kertal phallus. J. Urol., 105: 905, 1971.
/ I, s1 b: F3 n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 X- P5 L, V/ E" W4 |. Jtreatment for micropenis during early childhood. J. Pediat.," E! w: X% `1 q9 M+ B0 ]# {
83: 247, 1973.4 |9 i: T8 J2 ?
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 K5 j: y: K! K: ~( O" Mone therapy for penile growth. Urology, 6: 708, 1975.8 ^2 Y# r7 b) Y3 i6 w- I3 n
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& @" d$ U6 v- _' Oto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
! w- Z6 X2 ^- R1 q  Fskin slices of man. J. Clin. Invest., 48: 371, 1969.
- N) Y$ ?0 C5 \6 `" O$ c5 x$ F* P9 ]5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth; _) ]' j& S4 K" z( b) a9 s
by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ ]+ `; o2 A) `/ L0 }0 }6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
: {) L4 \0 @- handrogenic effect of interstitial cell tumor of the testis. J.$ u* x6 {& ?. R
Urol., 104: 774, 1970.8 }# ~) a, B( p0 S6 g% X, t4 i0 G
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
) k8 i  B% u+ Q1 {tion in the male genitalia from birth to maturity. J. Urol., 48:
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