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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
. h. k# c6 {; N  eGONADOTROPIN6 U7 R$ ]- z0 `9 `' }1 x6 B( S
RICHARD C. KLUGO* AND JOSEPH C. CERNY: c! U0 p  `4 }4 u
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 H" l% Y+ L1 F- p* q0 m5 G" K  FABSTRACT
$ }6 g7 D8 u" H+ mFive patients were treated with gonadotropin and topical testosterone for micropenis associated8 v+ j" Z1 J; ?  \! x6 W
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-; C+ ^" O7 @5 G2 _
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone4 D5 g8 e1 O* b
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent- X$ W# }( d  J1 d' ^/ ^* g" D" p
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 ^0 D) a& |! @2 M+ b, mincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
  x: R, H$ o; @. w( x* Qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
6 l8 |7 J+ o; i6 T6 H4 Aoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
) ^$ p: I& G, _study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 ^4 z1 ]% C) n) H  @# Vgrowth. The response appears to be greater in younger children, which is consistent with previ-% @9 g# X! a9 r) [1 T4 F8 E- k
ously published studies of age-related 5 reductase activity.. R! `$ c7 U% Y9 S1 N
Children with microphallus regardless of its etiology will8 J4 g0 [$ o0 p, m9 R
require augmentation or consideration for alteration of exter-
$ W6 o, v: |# M% Mnal genitalia. In many instances urethroplasty for hypo-
1 [4 v+ F- o  {  L! T4 J: {1 ?) n0 Wspadias is easier with previous stimulation of phallic growth.
4 j, h) ^) w; X/ p+ l- ?6 l0 z7 p( ?The use of testosterone administered parenterally or topically
, Z7 P( J4 Q0 l, S7 q( M$ fhas produced effective phallic growth. 1- 3 The mechanism of; d5 o+ g) I$ _. ~) r6 r; n
response has been considered as local or systemic. With this. b$ u  I3 f; z9 H& D" a
in mind we studied 5 children with microphallus for response7 J2 O; B/ ], h) k% m
to gonadotropin and to topical testosterone independently.6 L) }0 @1 a3 I1 a0 G0 Q- S
MATERIALS AND METHODS
5 \1 R, _& ~' ]$ T& z' K& G& v: UFive 46 XY male subjects between 3 and 17 years old were7 u! T  N9 R6 j1 M; M
evaluated for serum testosterone levels and hypothalamic
8 n" \( r( }, vfunction. Of these 5 boys 2 were considered to have Kallmann's0 L9 a8 @1 H( y! K) C3 k) B
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 F9 q% j' j/ y5 {
lamic deficiency. After evaluation of response to luteinizing) q, [, T. m, q$ L1 P. d4 n
hormone-releasing hormone these patients were treated with
8 J$ U& Q* S5 q0 y& j3 |0 [, G) G1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ |8 I' t5 a3 w# I
after completion of gonadotropin therapy 10 per cent topical
; T. o/ }/ q2 O; ]* i% r' v) z5 \testosterone was applied to the phallus twice daily for 3 weeks.3 }% ^  j& G9 h9 O7 }
Serum testosterone, luteinizing hormone and follicle-stimulat-
/ }! n2 u+ r+ ?; H( E# v* n8 ping hormone were monitored before, during and after comple-
, U7 _) m1 O; b! Ktion of each phase of therapy. Penile stretch length was. l+ D6 J  z0 E" ~% Q+ l6 S( \
obtained by measuring from the symphysis pubis to the tip of# f) j' E2 M1 |
the glans. Penile circumferential (girth) measurements were. h4 f" g  x9 l( @5 `2 s
obtained using an orthopedic digital measuring device (see; P; b6 ~* S; K  A, y/ C& d+ L
figure).
  u6 L, b* s  }& fRESULTS
, z) e' v( B4 Y2 g1 ZSerum testosterone increased moderately to levels between
! a. R# a* i3 {$ O2 q50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 y9 K3 N$ d/ h; Y
terone levels with topical testosterone remained near pre-, E$ ?% I- m  V* w0 L
treatment levels (35 ng./dl.) or were elevated to similar levels
  M) d) X% L. |2 e6 n' ]1 z$ m) zdeveloped after gonadotropin therapy (96 ng./dl.). Higher, H! u$ P& w. V
serum levels were noted in older patients (12 and 17 years old),6 o/ a, M9 V4 P+ E5 p- g
while lower levels persisted in younger patients (4, 8, and 103 @2 ~. z& Q8 }' r
years old) (see table). Despite absence of profound alterations
, }1 e; p" w9 c7 c/ d0 rof serum testosterone the topical therapy provided a greater( y2 S' S% i0 Y( Q5 K* C- i; m
Accepted for publication July 1, 1977. ·- L) d1 g* v. z4 K; G! _3 M, S, T) j
Read at annual meeting of American Urological Association,, E+ C1 I7 M( Y7 Y% j& `
Chicago, Illinois, April 24-28, 1977.
& S1 W3 n2 z1 L$ V" ?: X5 f! }* Requests for reprints: Division of Urology, Henry Ford Hospital,+ `1 D7 k5 y: Q% k6 ?
2799 W. Grand Blvd., Detroit, Michigan 48202.# I" w  b1 o$ D
improvement in phallic growth compared to gonadotropin.
. y0 P9 ~' l! C. u0 F# CAverage phallic growth with gonadotropin was 14.3 per cent. u0 s# f# ]: j/ f3 C! U
increase in length and 5.0 per cent increase of girth. Topical
$ |- t  j' q1 ]9 [' z9 jtestosterone produced a 60.0 per cent increase of phallic length. k  A' [. V4 f
and 52.9 per cent increase of girth (circumference). The/ q' a$ w' C# P  d" A4 j
response to topical testosterone was greatest in children be-$ H6 m( Z, z, ]- z2 s/ }
tween 4 and 8 years old, with a gradual decrease to age 17
" c8 e0 i# I: }9 eyears (see table).
9 q3 q) W* g: A# _- x$ s( ZDISCUSSION
+ X  z% l0 X' G8 g. {/ ]- @Topical testosterone has been used effectively by other
0 @! K1 D. W0 D& G9 n, G7 f- ~clinicians but its mode of action remains controversial. Im-  v4 G6 z/ t% T8 T& p$ C
mergut and associates reported an excellent growth response
) v% E6 L( r& S# w, hto topical testosterone with low levels of serum testosterone,) O7 h0 D5 c, y% c: r3 q
suggesting a local effect.1 Others have obtained growth re-
' s( Z) q' m, e' A) xsponse with high. levels of serum testosterone after topical8 ]5 G0 G" Z6 g5 e4 L
administration, suggesting a systemic response. 3 The use of
  T# W& V, y; @/ C( W7 n8 t  N' Kgonadotropin to obtain levels of serum testosterone compara-) r) u7 B9 D+ {( u( U; e- O
ble to levels obtained with topical testosterone would seem to: c3 G9 j" D/ C# i2 x
provide a means to compare the relative effectiveness of
; H! T( m2 S$ F) x+ N+ Qtopical testosterone to systemic testosterone effect. It cer-0 p- G& n) V( `5 U1 b( n; j. L- `
tainly has been established that gonadotropin as well as par-
3 T0 z9 u1 c5 Q+ d' G- U+ denteral testosterone administration will produce genital
& @4 U1 M) w( Wgrowth. Our report shows that the growth of the phallus was7 o/ X0 e0 o7 I$ b5 `4 _: T
significantly greater with topical applications than with go-, `# d3 O$ Q7 F" x
nadotropin, particularly in children less than 10 years old.. [% ~2 U; P0 A8 N% o1 s; I
The levels of serum testosterone remained similar or lower' z1 {+ c4 m( J
than with gonadotropin during therapy, suggesting that topi-
. L3 e1 p! Q  E$ E: `cal application produces genital growth by its local effect as( l# U; O! @$ ?  T
well as its systemic effect.
. F! c8 q$ A0 q2 D' SReview of our patients and their growth response related to4 ~# h2 x4 D" x
age shows a greater growth response at an earlier age. This is+ H* Q) m& y5 ?! u2 A. j
consistent with the findings of Wilson and Walker, who* n- z' f- `0 o
reported an increased conversion of testosterone to dihydrotes-
2 r* }9 P- _4 ~  O; dtosterone in the foreskin of neonates and infants.4 This activ-
, Y, c7 A# ^( @, O1 Gity gradually decreases with age until puberty when it ap-0 J, N7 x% V1 E$ d
proaches the same level of activity as peripheral skin. It may/ P8 a) Z6 s% w& k) l, {0 o
well be that absorption of testosterone is less when applied at8 ^( f& r" C5 f( t4 n- `3 x
an earlier age as suggested by lower serum levels in children
8 t) b1 F- G( h" n8 w! K1 a9 Fless than 10 years old. This fact may be explained by the
4 q% w. ]. g6 |* ygreater ability of phallic skin to convert testosterone to dihy-
- T2 d" N/ w8 G& c/ K) V2 \drotestosterone at this age. Conversely, serum levels in older
5 |: N6 M+ `% `! u, B6 N0 T5 lpatients were higher, possibly because of decreased local
+ p+ @: L. {0 V+ Q+ p0 m; F% z667# b3 T+ B) s( C4 x, ?5 z
668 KLUGO AND CERNY
% r. @! f; l6 d. }6 BPt. Age3 a  G% t! W+ M! V( x' g
(yrs.)
9 ~/ L3 j. [5 V" e. cSerum Testosterone Phallus (cm.) Change Length- J; g0 E6 g/ u  Y2 ]# I$ l
(ng./dl.) Girth x Length (%)1 `7 ?" }; O0 ^5 D8 A& o8 v
40 m$ f  C, |& ^8 b+ a
8
. p7 X( }$ g7 [10
7 Y& s; z; R: ^  o, }, E12
) ^7 ?$ X# y" q6 s3 u& N& c: [. D17
. U4 a7 o; S, q/ @Gonadotropin2 g' {( M# j1 _+ A, d  i* ~7 C) U) l6 x
71.6 2.0 X 3 16.6
& p! z9 Q4 U  Q5 v% r% ^" _50.4 4.0 X 5.0 20.0
# L; [5 N& D, A7 h& ^22.0 4.5 X 4.0 25.0
, |( t1 Q4 z" H  F84.6 4.0 X 4.5 11.1* B  }6 d; V3 E$ ^6 K& ^
85.9 4.5 X 5.5 9.04 @9 o! \! v7 v
Av. 14.37 c7 l( g& ]+ T1 p# B$ |
4  p( S: R/ |7 F0 i5 b8 X% f1 j
8. u& h) u5 U9 j: ]2 O
10
" L8 f7 Y* R1 V, ~12
# k+ x! Q# C4 }. [! [) O6 C3 l" O17. o+ ]' I2 h( d+ B3 ?' B* k$ e
Topical testosterone
7 X4 z8 ^5 v' }- ~6 A8 c% e: w34.6 4.5 X 6.5 85* e/ `- Z3 ^1 v( @; g
38.8 6.0 X 8.5 70
& n& N4 }" W2 i; V40.0 6.0 X 6.5 62.51 s$ C  X* L$ j& `+ R
93.6 6.0 X 7.0 55.5
! M# \1 q; M4 H& o* b* Y  ~95.0 6.5 X 7.0 27.2# R  _( b/ e5 X8 D
Av. 60.0
1 V: a3 o; K* Wavailable testosterone. Again, emphasis should be placed on! a& I0 @# w' d. j  O2 N
early therapy when lower levels of testosterone appear to
7 |( q0 g; E0 Cprovide the best responses. The earlier therapy is instituted  [) n% Z* ?2 A5 @4 O
the more likely there will be an excellent response with low
; I' W' B. S8 Xserum levels. Response occurs throughout adolescence as8 K* B, A  Q6 b6 q- a! z' D  ^+ @
noted in nomograms of phallic growth. 7 The actual response- J: `; C5 z* z, A4 T7 f- z
to a given serum level of testosterone is much greater at birth, s2 P) u8 T  G$ u6 B
and gradually decreases as boys reach puberty. This is most
" @% X+ D; I+ c, u6 `/ r4 ^4 ilikely related to the conversion of testosterone to dihydrotes-
5 g2 F# [- U! A5 Q% I+ otosterone and correlates well with the studies of testosterone2 }% \  s5 J( t: Z( s5 q- K
conversion in foreskin at various ages.
* y! p9 a+ }" Y. t, dThe question arises regarding early treatment as to whether% t( ^" p% j) D0 h
one might sacrifice ultimate potential growth as with acceler-! Y  w8 B* Y7 l2 U( |$ I* p
ated bone growth. The situation appears quite the reverse- Z' \% \2 O! u: }
with phallic response. If the early growth period is not used
' n$ p/ R  ]; ?. Rwhen 5a reductase activity is greatest then potential growth
" T0 K  E+ X6 Imay be lost. We have not observed any regression of growth! u. N6 x9 [$ B4 u1 }
attained with topical or gonadotropin therapy. It may well; t$ f. s  [$ m7 Y- F0 c( {) y
be that some patients will show little or no response to any$ h! l8 P+ }( T6 ~4 v7 C6 R' d
form of therapy. This would suggest a defect in the ability to+ J1 C4 Y3 w: G9 k6 g
convert testosterone to dihydrotestosterone and indicate that4 T, z0 ~4 t/ z
phallic and peripheral skin, and subcutaneous tissue should
+ H% p8 N- p# i% Cbe compared for 5a reductase activity.
: p4 C0 c8 Z# V6 p6 V( e* JA, loop enlarges to measure penile girth in millimeters. B,5 s; h: V2 `8 b# w
example of penile girth computed easily and accurately.
$ v$ q; m( _' A4 xconversion of testosterone to dihydrotestosterone. It is in this
+ f- _! }" @& N+ w2 Solder group that others have noted high levels of serum
  r1 X1 l. F' q; f0 R1 g2 B+ Y6 Vtestosterone with topical application. It would also appear" O2 `* k+ b# n- F, l
that phallic response during puberty is related directly to the
) ^1 K: z$ w4 w; Wserum testosterone level. There also is other evidence of local
! k4 `& K; d. r  ^- _  `) j& gresponse to testosterone with hair growth and with spermato-
0 R3 u8 l* q- J% k' s5 v* _& Dgenesis. 5• 6
  f) k# y  D: C  |- C) [3 `Administration of larger doses of gonadotropin or systemic
; s, k- P- `+ v( T) B5 D/ vtestosterone, as well as topical applications that produce3 j" z4 |* J0 S$ O' N% j% C
higher levels of serum testosterone (150 to 900 ng./dl.), will
: v/ i* s: x4 }+ _: `7 _! [9 t7 i1 |also produce phallic growth but risks accelerated skeletal% @: ^% K$ O* X3 d2 f# ]
maturation even after stopping treatment. It would appear8 s0 n6 l& ^/ w3 d1 p! r
that this may be avoided by topical applications of testosterone# ]6 g) s* y3 s! w3 k, p% z9 b  ^6 ]
and monitoring of serum testosterone. Even with this control& b, u% D* f$ [3 F
the duration of our therapy did not exceed 3 weeks at any2 n; [, k$ V- G8 q: ^! }
time. It is apparent that the prepuberal male subject may
* S( o3 F3 X0 M- Ysuffer accelerated bone growth with testosterone levels near+ d5 w+ v5 M+ y2 t/ S' p7 ]9 G
200 ng./dl. When skeletal maturation is complete the level of
" O8 v- s/ h4 ^' n# U5 Nserum testosterone can be maintained in the 700 to 1,300 ng./; ?3 `1 }$ n; ?. M& e3 X& ]( ?
dl. range to stimulate phallic growth and secondary sexual( b; }: |% s9 e) a8 b
changes. Therefore, after skeletal maturation parenteral tes-
6 Y# |# m7 v$ gtosterone may be used to advantage. Before skeletal matura-
5 M: j& ]3 Y+ Ytion care must be taken to avoid maintaining levels of serum
2 X1 r; Y3 m$ C: {, ^% B" s7 i6 Qtestosterone more than 100 ng./dl. Low-dose gonadotropin" H- T  T+ C% P: H: ^' x! h
depends upon intrinsic testicular activity and may require8 `* c) J. K7 _$ f0 h+ d; F
prolonged administration for any response.
& V; a8 I  H+ L9 p  SAlternately, topical testosterone does not depend upon tes-) R0 @" o  n/ m8 }. x
ticular function and may provide a more constant level of  g/ H0 P  C/ D- Y4 Q5 ]6 d
REFERENCES
7 \2 R6 A1 s7 @& D1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
9 a& p8 o" p# A" X4 {* J+ T/ wR.: The local application of testosterone cream to the prepub-
, A) M% l6 T  N$ uertal phallus. J. Urol., 105: 905, 1971.
$ O1 Q, P' e3 m2 m8 c; @0 w, o2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone6 ^1 I& v8 w7 T
treatment for micropenis during early childhood. J. Pediat.,0 k* I) X! ~9 E/ q! Y( x" Z9 S9 |
83: 247, 1973.
/ ]1 b  f+ h/ W! P" c. @  {. \3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
  H: _$ b0 M" V4 w& @( R2 ?one therapy for penile growth. Urology, 6: 708, 1975.
, g/ ]7 S/ |% U& J: E3 V5 U4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
$ \& _3 |6 K- Oto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: R4 g' Q; \0 Y6 eskin slices of man. J. Clin. Invest., 48: 371, 1969.
& _$ i8 B, B( n3 R# z$ P' t- H5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
& V, \/ Z5 y/ A' h1 D4 A) vby topical application of androgens. J.A.M.A., 191: 521, 1965.& A& J( X: E1 Z8 @
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& I0 a) {( T& R7 K" F. V9 _
androgenic effect of interstitial cell tumor of the testis. J.
9 Q% @) r! u9 c1 hUrol., 104: 774, 1970.
6 ^+ Q! y& V. {7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. {2 X4 v/ P3 e$ ?- y1 s& _+ L) ktion in the male genitalia from birth to maturity. J. Urol., 48:
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