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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; ?6 M! K* I$ \6 GGONADOTROPIN4 O6 P9 X8 E8 r+ D' l
RICHARD C. KLUGO* AND JOSEPH C. CERNY
! K% W, v) K$ _. v, C* S, xFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
0 x7 e3 l. V+ L( F2 j/ G  b3 ?ABSTRACT4 w1 M# ?! N/ E8 U3 z. q( K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated  o2 K1 q8 _; R. m
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 q3 ]! N5 }% k) b( Ytropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
. k8 E" S+ j+ lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ `; g+ K+ w9 i( m; Y1 u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
' q+ e: @8 i( }1 S7 u9 \/ ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average4 {3 l8 z7 f8 b/ @7 K4 G, J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
( B: V) J; B/ d2 @occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% Z% V/ {2 d# B) d; r& C  R" Lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% _6 |4 O/ z+ ]growth. The response appears to be greater in younger children, which is consistent with previ-3 M2 v9 L+ {3 ?9 ]
ously published studies of age-related 5 reductase activity.* ^1 j. e5 G. F
Children with microphallus regardless of its etiology will, c" y* J  g, T& u7 q- r" B2 {5 q
require augmentation or consideration for alteration of exter-
& C+ f- c' g% X0 m# ]nal genitalia. In many instances urethroplasty for hypo-8 G7 ^9 o. v: n' e
spadias is easier with previous stimulation of phallic growth.
& v4 O! M+ S0 e# [* \The use of testosterone administered parenterally or topically
8 T0 [( s, j1 q8 H1 rhas produced effective phallic growth. 1- 3 The mechanism of6 R7 P! k. H  u
response has been considered as local or systemic. With this
# L# s+ ^: U6 m1 w' Fin mind we studied 5 children with microphallus for response
4 D% n7 D. x, h) o+ u; Y& \$ h0 Cto gonadotropin and to topical testosterone independently.
2 @( }# `$ G& }8 s' x3 l8 T) RMATERIALS AND METHODS
* J0 K6 E! d1 d" z7 }Five 46 XY male subjects between 3 and 17 years old were8 H% A( a) Z2 I
evaluated for serum testosterone levels and hypothalamic
% [4 b3 _0 u6 b' P) afunction. Of these 5 boys 2 were considered to have Kallmann's
  `) m( l( o0 M; k4 i4 T4 Ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 ?4 Q0 H" @: c, t$ J- W$ o2 t
lamic deficiency. After evaluation of response to luteinizing
. j( {5 R& R- O6 [hormone-releasing hormone these patients were treated with
2 Q0 b* C7 L/ U$ I. l: A1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ K  ~) T, \' }9 Q- X) nafter completion of gonadotropin therapy 10 per cent topical
! C& f, n& W' Y# h7 x5 r7 `testosterone was applied to the phallus twice daily for 3 weeks.
1 T# j+ R- A; T$ e* {' q7 P) bSerum testosterone, luteinizing hormone and follicle-stimulat-9 n: P  C$ ]% S% h( W
ing hormone were monitored before, during and after comple-, `& s; E; e! l  W$ X5 k. Z
tion of each phase of therapy. Penile stretch length was
) ]# I2 g* z' i3 e, V8 T6 Dobtained by measuring from the symphysis pubis to the tip of& D: I# o* w/ k' Q" J+ g! A( p
the glans. Penile circumferential (girth) measurements were( R# o* |5 O9 f$ A! l- B" X6 b
obtained using an orthopedic digital measuring device (see
: F  v' @2 `1 Cfigure).
4 w( R7 T6 A2 J6 u5 n$ v# ARESULTS- y4 N( k- Z) b( V5 h9 t
Serum testosterone increased moderately to levels between
8 D% X2 Y% j0 S2 N  g. I+ H2 g50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
* c2 y/ O% u( j" c7 Fterone levels with topical testosterone remained near pre-3 G" @' D, u, u! Q
treatment levels (35 ng./dl.) or were elevated to similar levels: U* `* x4 h- }" X2 ^
developed after gonadotropin therapy (96 ng./dl.). Higher) n3 z: L; v  z2 z3 u: ~  ]: C4 h
serum levels were noted in older patients (12 and 17 years old),0 h* U/ Q: @' N  S  v0 Z  Z7 ?
while lower levels persisted in younger patients (4, 8, and 10
% P: a, L% O. }. v/ q3 nyears old) (see table). Despite absence of profound alterations, F$ ]4 k" J+ }- a0 }# Q/ t: I6 h
of serum testosterone the topical therapy provided a greater# r# p- F% D) n
Accepted for publication July 1, 1977. ·3 a0 ?; t- }0 _4 z- U
Read at annual meeting of American Urological Association,0 z1 q1 p% O: m1 {/ N. v$ ~+ }
Chicago, Illinois, April 24-28, 1977.
3 C; m3 o$ V2 T* Requests for reprints: Division of Urology, Henry Ford Hospital,
: h8 _7 [. z8 d, I: f  @6 M7 k2799 W. Grand Blvd., Detroit, Michigan 48202.0 R9 ~8 Q) {+ N% f2 j2 f: d' K
improvement in phallic growth compared to gonadotropin.$ L! n" N% C) c1 |
Average phallic growth with gonadotropin was 14.3 per cent
: n& T- g7 s7 |$ h4 ~; R3 A* \increase in length and 5.0 per cent increase of girth. Topical
% J! j! z1 y4 `+ V0 otestosterone produced a 60.0 per cent increase of phallic length$ }; s% l2 g$ g5 x  Z: i# K# b
and 52.9 per cent increase of girth (circumference). The9 i/ C3 a0 D8 s- L' I' U$ U
response to topical testosterone was greatest in children be-
1 v" g, R8 B, G/ `( Q0 otween 4 and 8 years old, with a gradual decrease to age 17
. a; m7 f' o8 d" \1 W6 Zyears (see table).
0 D7 K9 t7 `/ P. YDISCUSSION
# C, j( z' J8 _2 ~2 c, bTopical testosterone has been used effectively by other
9 ~; l2 [7 _0 @& Qclinicians but its mode of action remains controversial. Im-: y7 {! C: D4 W3 ^0 t
mergut and associates reported an excellent growth response: s; P0 t) T: n. z) g
to topical testosterone with low levels of serum testosterone,
5 K9 Y4 E5 ^+ F6 [' i+ c% g- P# }suggesting a local effect.1 Others have obtained growth re-' L% Q2 m! d" H# X' ?3 N
sponse with high. levels of serum testosterone after topical" r; _5 m: P& e8 p9 z& S
administration, suggesting a systemic response. 3 The use of
! C/ b" _5 d- M' O: X. f+ u0 g3 Bgonadotropin to obtain levels of serum testosterone compara-
4 v7 ^3 a' |1 v2 S5 ^, _- Kble to levels obtained with topical testosterone would seem to: J+ i- U; }5 A! a/ ]' V  i4 m0 Y
provide a means to compare the relative effectiveness of7 Z# U$ q0 F* s' Z' d- C! b4 z# I, u
topical testosterone to systemic testosterone effect. It cer-
( I* R! J. a1 W9 ~8 \tainly has been established that gonadotropin as well as par-
) K7 X  h# k" yenteral testosterone administration will produce genital
+ ]9 G2 d' L7 g" @/ }, Ogrowth. Our report shows that the growth of the phallus was
- M+ A$ L6 j$ r- n+ ?- X; D4 C/ Tsignificantly greater with topical applications than with go-; ]) X$ {' ~  h$ F. `
nadotropin, particularly in children less than 10 years old.( i2 K/ Y/ ]+ `2 v7 i9 y
The levels of serum testosterone remained similar or lower
3 y2 J$ M: l9 ?than with gonadotropin during therapy, suggesting that topi-& y) U2 x, C$ m. R
cal application produces genital growth by its local effect as: O: F3 j$ q5 X' U
well as its systemic effect.' A+ D9 z3 X: ?  [0 {
Review of our patients and their growth response related to
- N- M9 b0 w6 S: W& {3 e3 u& Aage shows a greater growth response at an earlier age. This is
4 N. V/ j% L! l8 Qconsistent with the findings of Wilson and Walker, who3 w- [; ?! V, P5 Q" k" h3 j
reported an increased conversion of testosterone to dihydrotes-
" E4 W7 ^5 a1 ?4 Y' \tosterone in the foreskin of neonates and infants.4 This activ-
8 Z& y3 g; C- b* A  _8 jity gradually decreases with age until puberty when it ap-
7 F2 w* h, d: i0 \! D8 eproaches the same level of activity as peripheral skin. It may$ C! V3 w  [! N  \6 z
well be that absorption of testosterone is less when applied at
" h) H) Z: {! w% N% X0 `an earlier age as suggested by lower serum levels in children5 X. d: v& C- u  ~/ @. z
less than 10 years old. This fact may be explained by the3 v8 Y& d$ A7 z& H$ J( S
greater ability of phallic skin to convert testosterone to dihy-8 Q, ?1 }% I3 o2 x- C
drotestosterone at this age. Conversely, serum levels in older
& J- _) [: d/ @6 b% ?, y! hpatients were higher, possibly because of decreased local0 {2 J4 `+ e0 s
667; d1 g. M+ ^  h" {' L, @7 e
668 KLUGO AND CERNY
7 Q) j" u( n7 f* T8 @1 `Pt. Age5 P, b3 U) t( D! u6 [$ o8 `
(yrs.)7 h( p1 {/ S* B$ E1 [9 J" P3 Y, z( I
Serum Testosterone Phallus (cm.) Change Length2 Y1 S7 y9 L. Z$ {( ~
(ng./dl.) Girth x Length (%)
) K1 k9 }2 T3 p0 h* b' \4
9 c' ]4 b# ^  b: a8
2 B4 i7 y& E; g  Q, V" E10
. Q! X* q6 f, ~; a5 Y' t" R, `12
; k. t  V  P, _+ N! P) u- U9 S17
& m4 P1 D# A  Y0 x, ~Gonadotropin6 C/ A: y! v7 t! b4 U  S0 n" I& ]
71.6 2.0 X 3 16.62 q/ T$ J+ ~& Z& y: f
50.4 4.0 X 5.0 20.0" V: Z' @+ J  X* m/ F5 q
22.0 4.5 X 4.0 25.0, a  j7 Q: H6 F
84.6 4.0 X 4.5 11.1& X% Z0 O) [( M. G: ~0 ^8 Q
85.9 4.5 X 5.5 9.09 V5 {+ w/ H( k1 w
Av. 14.3( f4 A% j  U5 S! ?4 ^
48 d  l$ Z. b4 P* _+ D# c/ Y3 N
8
4 i0 u3 i; D# j8 J9 j3 f10
- @5 M, w! Y0 a) Q3 K! a12" p0 {# }1 R- }; U9 S4 q0 |
17
; C$ X; o" Z5 l9 s/ I, S* QTopical testosterone& l$ h! B+ _- m: F! r$ Y
34.6 4.5 X 6.5 85, `" h1 X2 S" g% E! u8 ?2 S1 ]
38.8 6.0 X 8.5 70
/ l& R! z! ^: H8 ?7 _4 J' P/ l40.0 6.0 X 6.5 62.5! K7 F0 y/ ^7 C" D$ C' u
93.6 6.0 X 7.0 55.5' f: K8 S5 s. R
95.0 6.5 X 7.0 27.26 \. k% @, r0 e' z+ V
Av. 60.0
' ]- m9 z6 A* I0 vavailable testosterone. Again, emphasis should be placed on
- @! }; Y2 K1 W1 Pearly therapy when lower levels of testosterone appear to
# k: N6 u) v+ Fprovide the best responses. The earlier therapy is instituted& u$ h( S7 m5 G6 t8 \, j" D
the more likely there will be an excellent response with low$ g" ]  `  c# H7 A
serum levels. Response occurs throughout adolescence as5 f' c) b- c  y
noted in nomograms of phallic growth. 7 The actual response
( O/ Y0 n! q9 z$ {6 S: c1 `to a given serum level of testosterone is much greater at birth2 K3 k, H3 A" u, n5 P; i
and gradually decreases as boys reach puberty. This is most3 {2 X( l- s3 c! F+ C, `% H
likely related to the conversion of testosterone to dihydrotes-% j2 ?4 z/ r# p
tosterone and correlates well with the studies of testosterone  M2 c" Q7 U8 c
conversion in foreskin at various ages.
# b- w4 ^$ m: oThe question arises regarding early treatment as to whether
; d3 g' T! F1 {$ c7 F+ G/ gone might sacrifice ultimate potential growth as with acceler-
- t  z% i) P" |8 Y/ J" Vated bone growth. The situation appears quite the reverse$ D. j2 b1 [6 N" ]4 B  \& ^
with phallic response. If the early growth period is not used
8 S8 R- A3 I& ?when 5a reductase activity is greatest then potential growth
/ r- C$ k) z; q; ]may be lost. We have not observed any regression of growth
1 y% L2 {; L3 J* R* C& `attained with topical or gonadotropin therapy. It may well: u( O4 s4 k9 o7 e& E
be that some patients will show little or no response to any
8 f  L6 B* t9 x, Kform of therapy. This would suggest a defect in the ability to
- j/ K$ W) W9 a1 M2 z* ?convert testosterone to dihydrotestosterone and indicate that: M; I- R  [3 a( r* p
phallic and peripheral skin, and subcutaneous tissue should7 [4 L  y" ^) {, N! i3 z
be compared for 5a reductase activity.3 L& W1 U3 e- V: ^4 k4 H
A, loop enlarges to measure penile girth in millimeters. B,
; s" n5 A2 f' l; n3 i& J5 C: k& Sexample of penile girth computed easily and accurately.
, L! I  Y* k8 _6 qconversion of testosterone to dihydrotestosterone. It is in this+ |3 r8 o, `* E1 A- w+ U
older group that others have noted high levels of serum
" T5 K- b5 y; S, d8 G+ stestosterone with topical application. It would also appear
4 }* h) n; l; m6 W5 D' r( L8 uthat phallic response during puberty is related directly to the
, ]' b7 u& A2 a( J" u* f: ?! ~6 fserum testosterone level. There also is other evidence of local
6 s" H* q) I" z. t. A5 _9 @0 dresponse to testosterone with hair growth and with spermato-
" C3 g# p+ A) c; r- Z: \genesis. 5• 6$ J& o/ M1 M$ A) T
Administration of larger doses of gonadotropin or systemic
+ j1 c# w* d' y* A3 Ftestosterone, as well as topical applications that produce; P7 ~/ k1 L" W4 c. P6 }
higher levels of serum testosterone (150 to 900 ng./dl.), will
- q6 \: T, x: s+ g1 a/ Z- Yalso produce phallic growth but risks accelerated skeletal
- |& v, g6 ]0 }; V1 L& L! X; vmaturation even after stopping treatment. It would appear( _0 g8 h( \1 X% P: ]3 C$ ]- V
that this may be avoided by topical applications of testosterone
/ Q6 e8 m& m1 aand monitoring of serum testosterone. Even with this control
, h5 n' c9 I* m2 Lthe duration of our therapy did not exceed 3 weeks at any
' G- X& ?* F" X3 w5 Itime. It is apparent that the prepuberal male subject may& U4 h$ o4 C' g/ }2 q
suffer accelerated bone growth with testosterone levels near. H1 r; z1 M6 O: e) x- y
200 ng./dl. When skeletal maturation is complete the level of  @. l: f9 N: `) \% \5 z
serum testosterone can be maintained in the 700 to 1,300 ng./
& D& r9 v+ x! E) k9 l5 bdl. range to stimulate phallic growth and secondary sexual% H& z, ^/ i9 Q. ]8 z; i) u3 R
changes. Therefore, after skeletal maturation parenteral tes-
- Z+ }6 R2 r  X) ?8 N6 ]tosterone may be used to advantage. Before skeletal matura-! f5 s% R2 N  C3 G+ d
tion care must be taken to avoid maintaining levels of serum+ p7 t. ~/ ^/ i0 K7 T
testosterone more than 100 ng./dl. Low-dose gonadotropin
; J0 f; v2 m) D/ ydepends upon intrinsic testicular activity and may require" P  \% A; g! q( l: L
prolonged administration for any response.
9 Q& F; @% K6 tAlternately, topical testosterone does not depend upon tes-  |  x) H( V. Q
ticular function and may provide a more constant level of
2 [( ]" o9 h4 H/ `, cREFERENCES5 X" }0 q- z; i3 E9 L! O
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 i7 x% k4 \* M8 }2 r( K8 E
R.: The local application of testosterone cream to the prepub-
- L: z5 f$ ~1 G* }0 rertal phallus. J. Urol., 105: 905, 1971./ ]( I* b1 y: P8 e* _
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% i9 k% M! E+ B3 M
treatment for micropenis during early childhood. J. Pediat.,
. K/ i1 R. @, Z6 [1 {83: 247, 1973., r( Z& B+ L. X5 M) p
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( A" Q% x8 V7 n' A6 P  j' None therapy for penile growth. Urology, 6: 708, 1975.
: i! K1 r/ i# |- h6 d* B4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 m0 W4 q( _' h+ G* S' ~6 l
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
5 H* F0 t5 E0 N( b7 [4 |skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 `# U0 O# ~. G* J6 R7 @2 \5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth& H  o) D  a+ C  `# o/ M$ n+ W
by topical application of androgens. J.A.M.A., 191: 521, 1965.
- f; S( L" L# y! @0 U% P6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ N. u/ H- f# P- g) D' W$ B
androgenic effect of interstitial cell tumor of the testis. J.8 |0 B, K! w1 O
Urol., 104: 774, 1970.6 V( r  |# u& D
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-! M9 ], h! `! D: K: r, v
tion in the male genitalia from birth to maturity. J. Urol., 48:
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