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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
( p: e* }4 a) Q- x; q2 CGONADOTROPIN6 ?8 S) `  }0 q, \9 z$ l' Z
RICHARD C. KLUGO* AND JOSEPH C. CERNY3 ~/ Q$ o8 O! E9 @1 D  r. {
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan! [, ?/ a7 p9 |5 v; P" i6 b
ABSTRACT
& U' @# h1 R. @% t" |, KFive patients were treated with gonadotropin and topical testosterone for micropenis associated0 X. M/ d+ h& G% o9 V7 x. O2 ?
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ I. f! i/ D0 Y2 D7 c6 w0 stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 a/ T; C! q; B& T$ h7 ocream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 D; z9 W9 \# C" M6 pfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% Q& ?: P$ \  M8 ?increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; Y- k0 j# ~/ T7 h0 A+ ?5 Pincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# v8 L! N, u$ T: Q" A( u( Woccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 r8 q3 W  d; j
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, v2 h' c* y6 Q
growth. The response appears to be greater in younger children, which is consistent with previ-9 b$ V2 M' R  i' e2 Y
ously published studies of age-related 5 reductase activity.7 c. d# ~# X8 C  F; |) g0 G# L
Children with microphallus regardless of its etiology will( x5 o( I, k' U- c2 e  d
require augmentation or consideration for alteration of exter-0 ]3 A; k( z, ^1 z. ]0 J
nal genitalia. In many instances urethroplasty for hypo-5 y0 [- Q5 y# x' R! g
spadias is easier with previous stimulation of phallic growth./ o% r" U& b/ v
The use of testosterone administered parenterally or topically
/ l, K- j# p2 k% x' x. Z+ k: B$ zhas produced effective phallic growth. 1- 3 The mechanism of- P5 z7 r  w4 n+ R5 A: M# W
response has been considered as local or systemic. With this( e, `4 M# a4 v8 s
in mind we studied 5 children with microphallus for response
3 Z  X( h0 z8 p3 cto gonadotropin and to topical testosterone independently.: G; ]6 {7 j1 X1 D
MATERIALS AND METHODS
' ]0 p, h4 ]0 C: s5 Q8 _- NFive 46 XY male subjects between 3 and 17 years old were$ Z0 O* n2 N. S* \
evaluated for serum testosterone levels and hypothalamic
- U3 @- h4 a# |+ P9 M3 }2 rfunction. Of these 5 boys 2 were considered to have Kallmann's3 q+ V9 n# n) ]0 {5 w& V* G" K2 I* x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 Y  k0 n8 u7 {( `) r, Elamic deficiency. After evaluation of response to luteinizing
) h% K$ z% t8 W$ P9 u# _1 R+ S; ^' y  yhormone-releasing hormone these patients were treated with2 S3 v6 N3 X$ g( T0 i% \1 U
1,000 units of gonadotropin weekly for 3 weeks. Six weeks4 p  |0 J' [' r0 U
after completion of gonadotropin therapy 10 per cent topical
, ]0 u+ I. v) Y. L! o+ x- ~testosterone was applied to the phallus twice daily for 3 weeks.6 S& L0 S2 k; x5 D9 o; l6 P
Serum testosterone, luteinizing hormone and follicle-stimulat-: a# M3 \1 }8 G4 ^9 z
ing hormone were monitored before, during and after comple-0 Z* r/ z" h0 j& t, A
tion of each phase of therapy. Penile stretch length was% w1 O, j6 i1 n8 x( q3 q: A9 u
obtained by measuring from the symphysis pubis to the tip of4 [0 o1 Q* e: b2 b
the glans. Penile circumferential (girth) measurements were$ w" ^. y! S4 z6 n8 F
obtained using an orthopedic digital measuring device (see
" H5 ~3 @7 M& _; h' xfigure).7 z; ^, B4 H  o
RESULTS5 C6 r' s: B9 `3 j# e* b, |
Serum testosterone increased moderately to levels between
; M" P4 Q# j2 |0 ]) y2 k50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ I6 U6 n7 d6 f9 S( h" H# @7 Cterone levels with topical testosterone remained near pre-
5 ~+ A9 }" N" g+ E$ Ttreatment levels (35 ng./dl.) or were elevated to similar levels
' k  n( k4 Q6 e* Bdeveloped after gonadotropin therapy (96 ng./dl.). Higher; k- L- z: y* l/ t
serum levels were noted in older patients (12 and 17 years old),) I$ f$ G- x  ^
while lower levels persisted in younger patients (4, 8, and 10
- d$ k5 ]0 T; ~  ]4 v8 Hyears old) (see table). Despite absence of profound alterations
6 q5 L: j! q* U+ ]7 v% Sof serum testosterone the topical therapy provided a greater0 k4 j0 ~, }2 M) |$ F. Q* \7 }' R
Accepted for publication July 1, 1977. ·
3 U8 Z$ g& Z! i1 T: uRead at annual meeting of American Urological Association,
& ~% P# h( s; m! C7 ^- WChicago, Illinois, April 24-28, 1977.
6 z' Y8 t& U% Q* Requests for reprints: Division of Urology, Henry Ford Hospital,4 Z) j1 o# B# f6 w, T8 n2 _
2799 W. Grand Blvd., Detroit, Michigan 48202.
2 L( |$ T& p- Qimprovement in phallic growth compared to gonadotropin.
: e! O9 [, P0 {4 V8 w6 pAverage phallic growth with gonadotropin was 14.3 per cent
3 b* ^3 ]/ z- [- {/ vincrease in length and 5.0 per cent increase of girth. Topical
9 C" s% V1 w( v/ y: s$ ]testosterone produced a 60.0 per cent increase of phallic length" B! C; n! c3 ?
and 52.9 per cent increase of girth (circumference). The$ L0 ?- B8 b4 m' _8 n, Z- g1 H# w( C
response to topical testosterone was greatest in children be-
* y- Q+ P, b' ~% h$ \tween 4 and 8 years old, with a gradual decrease to age 17
. Q% z3 {8 I7 R" e- e' ]years (see table).
6 Z5 T4 t" a# |0 W0 `DISCUSSION
1 q$ \7 O' [+ v" [* b7 J) N6 KTopical testosterone has been used effectively by other
" o+ }! e1 \1 Pclinicians but its mode of action remains controversial. Im-
- x* |& ~, j! Hmergut and associates reported an excellent growth response
( _* J$ B) L8 A6 Jto topical testosterone with low levels of serum testosterone,3 z- C8 e: D! r2 a: v
suggesting a local effect.1 Others have obtained growth re-
2 N  B7 u; S2 m3 msponse with high. levels of serum testosterone after topical
; ]% L8 R9 d7 D0 I3 Radministration, suggesting a systemic response. 3 The use of( c- z1 R+ S' B& y; D/ h2 Y
gonadotropin to obtain levels of serum testosterone compara-
: s5 m  V8 B% G8 [$ C( hble to levels obtained with topical testosterone would seem to" G$ z6 n! Y9 p% o/ C; f1 @
provide a means to compare the relative effectiveness of* r8 }7 \& G' \  C8 _# N- {7 H
topical testosterone to systemic testosterone effect. It cer-
6 H1 ]5 O* u/ `4 [1 T$ E" `tainly has been established that gonadotropin as well as par-& T  x7 ]/ c4 `! \8 w
enteral testosterone administration will produce genital
- F0 o: g6 [5 Mgrowth. Our report shows that the growth of the phallus was
" {: N$ D/ o2 C+ N9 hsignificantly greater with topical applications than with go-
5 W7 H' T$ E8 c7 C; H- P# j/ Enadotropin, particularly in children less than 10 years old.2 ^  e& ]) ^5 X( [( w
The levels of serum testosterone remained similar or lower$ k0 W+ h2 Y' V% D' l1 r3 ]0 N
than with gonadotropin during therapy, suggesting that topi-
6 e4 m* y4 \$ y# |% F' P$ hcal application produces genital growth by its local effect as+ r- r! i  K7 f- ^6 h
well as its systemic effect.$ d' `4 ~4 g4 F2 Q
Review of our patients and their growth response related to
$ s6 G! {! H% l6 i8 ~age shows a greater growth response at an earlier age. This is+ t) I+ O: M) n( ^! L: k
consistent with the findings of Wilson and Walker, who
/ R6 e" {4 x% R1 A0 ]0 Qreported an increased conversion of testosterone to dihydrotes-; |$ K9 G" J( o" h) |9 l1 _1 Q
tosterone in the foreskin of neonates and infants.4 This activ-
6 ^# C5 q( I! I4 d/ aity gradually decreases with age until puberty when it ap-
! _; z/ X7 i( I  a! bproaches the same level of activity as peripheral skin. It may  L7 }% p0 f7 ?7 C8 a' \  _
well be that absorption of testosterone is less when applied at
5 s. t) \. l+ Y) T) k- X* wan earlier age as suggested by lower serum levels in children% e/ k' U1 t) Y( `' F' e
less than 10 years old. This fact may be explained by the- Q* Q& u* c) `" D* B4 K: ~. q
greater ability of phallic skin to convert testosterone to dihy-
2 P) u* f- e! N5 @1 r4 o( {$ ?drotestosterone at this age. Conversely, serum levels in older
7 F) v. u& @2 `. J& Rpatients were higher, possibly because of decreased local
* U! R% B# k5 V" d  A! j667
* q& F6 F, a0 V) I& c5 R6 U668 KLUGO AND CERNY
( Y3 W) {; ~& F$ Z* GPt. Age% ~) h: G# @( K9 t
(yrs.)( m7 C) U- _0 l9 V$ @
Serum Testosterone Phallus (cm.) Change Length$ k/ G! K7 R' V9 j
(ng./dl.) Girth x Length (%)* s- [6 i! h, @
4
; A# Q8 b4 h) E" a8 n7 _7 n8
- G  o+ n; L3 G0 }* [+ s/ H# N10
9 e3 h( Q( l1 C: o! Y! g8 Y8 o8 s12$ D) J1 d/ e  u* f
17) h3 L4 x! o/ Y: L; g" h
Gonadotropin
5 C+ }2 h1 {" Z6 [& j( ^: B71.6 2.0 X 3 16.6
& U9 t9 X+ ~" T$ o$ [" r0 @( j50.4 4.0 X 5.0 20.0
, c3 L& L; B5 I$ w3 G# `22.0 4.5 X 4.0 25.0
3 }/ Y5 [* }/ w, u9 c5 {& @84.6 4.0 X 4.5 11.11 ]% Q& R) v* C; Z4 d9 r" [) n
85.9 4.5 X 5.5 9.09 V3 Z7 d  x1 c8 e  j
Av. 14.3+ R, k$ `) ~# D  O' ^, y( x, V
46 ?8 I/ e$ g+ x
8; G# j/ r$ o* Z. ~
10* j! Y! |3 o& m4 p0 H
12) o) `9 A- c: y( l
17* @- }7 U6 _6 s% \
Topical testosterone
2 m4 Y$ \$ a2 |/ g7 e- p34.6 4.5 X 6.5 85
) w; G5 d' ?) E3 R# E38.8 6.0 X 8.5 704 r" U% n& V) G
40.0 6.0 X 6.5 62.5
% F( ?; `$ A# J9 a) L0 ?93.6 6.0 X 7.0 55.5
  z2 x. H* ~7 M7 Q; x2 |! y! g95.0 6.5 X 7.0 27.2
8 l3 D4 ]( A7 mAv. 60.0- E; Z2 |8 b2 j' b/ O2 M
available testosterone. Again, emphasis should be placed on
9 _) B$ j8 Q0 L' h* d/ W. @early therapy when lower levels of testosterone appear to& @5 O( a! T4 w1 k/ [' w6 D) u
provide the best responses. The earlier therapy is instituted
4 @/ j$ p9 K; [" J- ?7 q1 Uthe more likely there will be an excellent response with low0 ^; ]; a. P# b  P
serum levels. Response occurs throughout adolescence as
' L9 \# ~; F9 i5 v5 ~, ^noted in nomograms of phallic growth. 7 The actual response
$ I  R4 q" K$ V+ }! ^to a given serum level of testosterone is much greater at birth: H! H' f6 a% K8 L, E
and gradually decreases as boys reach puberty. This is most
/ R. n0 P+ d' d& @2 T" `- K7 alikely related to the conversion of testosterone to dihydrotes-
# [* H! M3 O% t2 L! Ctosterone and correlates well with the studies of testosterone# B% T. W8 V6 u7 z% J! V0 `& w
conversion in foreskin at various ages.
  x- w  Z2 d5 I6 K  Q: j1 a3 PThe question arises regarding early treatment as to whether
# O5 o$ S! W9 {, L( D+ v% [9 _one might sacrifice ultimate potential growth as with acceler-+ |9 Y! y& V8 {0 ?: {4 w  g6 b
ated bone growth. The situation appears quite the reverse; ?. [. b7 i0 s$ L: d) Q: E9 R
with phallic response. If the early growth period is not used; D; U( v8 c2 s' F$ f, E
when 5a reductase activity is greatest then potential growth$ h% g: K! P: ^# Q. V; U8 m1 @
may be lost. We have not observed any regression of growth
$ s; o) y3 m6 }' |attained with topical or gonadotropin therapy. It may well
: G9 O& ]5 V! z7 ?+ y0 g& ibe that some patients will show little or no response to any
/ c1 l% ]+ z) [7 Rform of therapy. This would suggest a defect in the ability to
9 H* T; b" X" y) aconvert testosterone to dihydrotestosterone and indicate that, j8 m  C: n' Y& `1 w; d1 L% c
phallic and peripheral skin, and subcutaneous tissue should5 w; g7 _/ r) R/ ?1 ?8 N, J9 G
be compared for 5a reductase activity.! ?5 V$ L3 w4 t# Q. L: E3 ]- g
A, loop enlarges to measure penile girth in millimeters. B,
& F6 Y* b( r: o/ M6 K# bexample of penile girth computed easily and accurately.
  T. Q( T$ K  o: ]conversion of testosterone to dihydrotestosterone. It is in this
: A. l2 z! W! |* N5 f' o# U* @: ~older group that others have noted high levels of serum0 E! C4 \  Z% D/ i, b' B' O
testosterone with topical application. It would also appear
  L# e5 X- |8 |6 C/ o/ [3 [8 E; Athat phallic response during puberty is related directly to the" _( x6 ]/ `/ ]4 u  L" k: x
serum testosterone level. There also is other evidence of local3 ~  E' Y2 v6 c" j# b# d( ]' ?
response to testosterone with hair growth and with spermato-% l; G' T: q0 ?$ o
genesis. 5• 6( j8 q# o: B  X4 k
Administration of larger doses of gonadotropin or systemic1 o5 U/ r! ]. L% r
testosterone, as well as topical applications that produce
: ?6 C; [/ a' g; a1 U( R" `) O; J2 V4 C. xhigher levels of serum testosterone (150 to 900 ng./dl.), will
! j3 l& K7 }3 Aalso produce phallic growth but risks accelerated skeletal
* f- F* a+ U$ H  _3 [4 P* V0 Cmaturation even after stopping treatment. It would appear" k; z2 x) N) s9 b7 [& j7 o2 [! X
that this may be avoided by topical applications of testosterone3 H  P5 |& T9 _0 H
and monitoring of serum testosterone. Even with this control5 h3 G, O6 e- ~
the duration of our therapy did not exceed 3 weeks at any! A5 t3 f8 m" c
time. It is apparent that the prepuberal male subject may6 M6 d; V; g0 E  h
suffer accelerated bone growth with testosterone levels near% c6 O- S- ~1 @' p1 i; K1 w& t* ^
200 ng./dl. When skeletal maturation is complete the level of
' [2 w& C# o# xserum testosterone can be maintained in the 700 to 1,300 ng./
* ~, ~! i' }0 `- t% w  l  Bdl. range to stimulate phallic growth and secondary sexual
8 u: ~) W* B+ D" E: Vchanges. Therefore, after skeletal maturation parenteral tes-
& F3 s% u7 D* i# @: U8 d, P3 {7 xtosterone may be used to advantage. Before skeletal matura-
, U) f* {: j( F: J% U9 j, ption care must be taken to avoid maintaining levels of serum9 X1 z' ^, f. ?* _
testosterone more than 100 ng./dl. Low-dose gonadotropin
- d3 F; O- B; b& odepends upon intrinsic testicular activity and may require6 H% X" J5 C9 q  }/ n
prolonged administration for any response.9 a$ e$ _# A2 R9 Z8 S  ~+ b
Alternately, topical testosterone does not depend upon tes-) I+ T) m' M- x
ticular function and may provide a more constant level of. d: T2 M+ k/ s' f- q
REFERENCES  _9 M" j2 m! y6 j0 M# R& p
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,0 y$ }" v0 Q0 v* E1 T- U, z2 d
R.: The local application of testosterone cream to the prepub-
/ r  X6 g0 W+ s3 N- l% l9 Iertal phallus. J. Urol., 105: 905, 1971.) j% P" M! C( v- e0 \" I0 h& ]/ G# h
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
* Q5 |, k5 `% ]7 g) M2 ytreatment for micropenis during early childhood. J. Pediat.,
* i" E. A/ k$ F4 r  d6 m83: 247, 1973.: W/ ^8 D% _8 S% g* m6 E% L
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( V4 W5 D9 r5 B& i- U! n4 s8 |, Uone therapy for penile growth. Urology, 6: 708, 1975.
% a) O$ [2 ]/ j( L! d: Z( d4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- L/ L3 H% B8 b! ]
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 m+ ?3 }& a) T3 W: d5 h
skin slices of man. J. Clin. Invest., 48: 371, 1969.
' T* X0 }* {. F3 h5 O5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ U+ x% d  o6 Cby topical application of androgens. J.A.M.A., 191: 521, 1965.3 `, t; }- f+ e) b
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& b& G/ o3 F  Y% G* z- G' \5 x9 ]
androgenic effect of interstitial cell tumor of the testis. J.
1 i3 U, Q9 ^- W  W' B- k, Q& qUrol., 104: 774, 1970.! ]1 l; P: t  z/ s+ k: W' U6 \: t9 p
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 D$ s; h% p- j! d
tion in the male genitalia from birth to maturity. J. Urol., 48:
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