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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, c4 l( H9 L) ?/ U/ q& H# J4 x
GONADOTROPIN# }5 E! f% e7 v& ?7 ^
RICHARD C. KLUGO* AND JOSEPH C. CERNY
! E. M1 v8 n9 L; TFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan. Z0 ^& v; N" H& Y) K
ABSTRACT* r/ \6 V/ J1 n, I+ U8 T
Five patients were treated with gonadotropin and topical testosterone for micropenis associated, F6 o7 W1 @5 y! j' N! n9 @3 f
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
! B! H- p) V  A/ [( F" utropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
1 l1 F# u9 ~/ @8 C  R2 Gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: d5 N5 \, m- G! ?for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
, w+ e# A; _; x! s% d& n6 L! p& `# Sincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
! E0 w8 a/ T( g+ y/ t0 Kincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 N$ k5 d! }% G( d) `occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, r. G: J, X  k6 L" n" q4 ~# J. |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! {: l; w1 o# @" V6 Z( q$ u9 f" p6 K! O+ e
growth. The response appears to be greater in younger children, which is consistent with previ-
# B- o. e* [, ~9 l4 r- nously published studies of age-related 5 reductase activity.% W( L( x. \  G! k& B" X% c4 b
Children with microphallus regardless of its etiology will
6 `$ \+ g& ?! K! z( Z* R; `require augmentation or consideration for alteration of exter-/ O9 Z. a0 y+ J- P3 y5 b: o% O# H) H% o' V
nal genitalia. In many instances urethroplasty for hypo-
& o4 s7 {; E& S( S5 K; q& ]3 ospadias is easier with previous stimulation of phallic growth.4 c( q, U  v6 O( P' u4 {* ?4 [
The use of testosterone administered parenterally or topically" e" g+ m0 p* |: G. C
has produced effective phallic growth. 1- 3 The mechanism of3 m# W9 _- I3 m" Y
response has been considered as local or systemic. With this5 A- S' O. o5 b0 \) y0 j
in mind we studied 5 children with microphallus for response
* L0 B. o1 e' z/ g' d* B/ O! Pto gonadotropin and to topical testosterone independently.2 t' N1 @1 d' G, o2 ^+ M
MATERIALS AND METHODS* j4 N" I. l& h6 X; K) g
Five 46 XY male subjects between 3 and 17 years old were
! H* ?9 B& X& ]# Q; E, eevaluated for serum testosterone levels and hypothalamic6 n( T) x# w/ b2 g. B- {
function. Of these 5 boys 2 were considered to have Kallmann's7 b7 p; j; X; R' k7 M3 g# a$ |
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
4 x4 z2 f4 V* @- G  {7 e! nlamic deficiency. After evaluation of response to luteinizing
) l* [# i7 g9 P: H/ m2 zhormone-releasing hormone these patients were treated with
2 j3 v$ ~; E7 b5 q- a1,000 units of gonadotropin weekly for 3 weeks. Six weeks# j8 u  q; ~+ X/ ?( K( @
after completion of gonadotropin therapy 10 per cent topical
1 Y" K% b0 G0 W) b" S1 Ytestosterone was applied to the phallus twice daily for 3 weeks.
4 c( Y( [# d1 ]Serum testosterone, luteinizing hormone and follicle-stimulat-5 y: `' ^  A" U$ x
ing hormone were monitored before, during and after comple-- _( F2 O0 p, d5 A/ b) y! ^
tion of each phase of therapy. Penile stretch length was
% D* Y- ]. B( C* ~obtained by measuring from the symphysis pubis to the tip of3 G" Q( g5 ]0 K
the glans. Penile circumferential (girth) measurements were. u" M0 v* N4 Z
obtained using an orthopedic digital measuring device (see. z7 u% X- N! r4 z
figure).
6 a9 D8 q9 K0 \! j$ O. eRESULTS2 ^7 w# o+ R, B2 f1 U7 q2 n) l
Serum testosterone increased moderately to levels between" x8 C7 ^" D( j! Z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 R8 Q4 b+ N- w8 O5 R
terone levels with topical testosterone remained near pre-* y( D$ J8 I3 |) z
treatment levels (35 ng./dl.) or were elevated to similar levels
- w/ j( C2 c2 O. g0 Qdeveloped after gonadotropin therapy (96 ng./dl.). Higher/ n- C* g* ^; B+ e! o
serum levels were noted in older patients (12 and 17 years old),
$ ?4 g# r8 K) F* j+ A0 Y8 D4 N7 Bwhile lower levels persisted in younger patients (4, 8, and 10
& u9 x  L' u+ Wyears old) (see table). Despite absence of profound alterations
* B+ j: O. |# T5 @/ F5 |' Iof serum testosterone the topical therapy provided a greater
. o% m: ]+ d6 ^! Q" e/ ^Accepted for publication July 1, 1977. ·
9 [, j; t2 s$ A9 B- XRead at annual meeting of American Urological Association,
. n6 T- V* O* Z9 iChicago, Illinois, April 24-28, 1977.
: Z, C, U1 O' N: n1 B- r& ?9 d* Requests for reprints: Division of Urology, Henry Ford Hospital,2 R# p! w/ \# o; x0 ~" r
2799 W. Grand Blvd., Detroit, Michigan 48202.; O4 w3 [" c4 l7 x+ M6 n$ C
improvement in phallic growth compared to gonadotropin.
5 b5 k* b) _$ [% U+ MAverage phallic growth with gonadotropin was 14.3 per cent
* P0 ?3 k4 R0 v1 F. rincrease in length and 5.0 per cent increase of girth. Topical1 q; @% M8 @. t8 X7 J( E  R
testosterone produced a 60.0 per cent increase of phallic length, V( w, E: A; J9 |: l1 h* O; K& I& q
and 52.9 per cent increase of girth (circumference). The
. k0 Z) m& a4 ^: N0 {response to topical testosterone was greatest in children be-
3 u% Z9 h: N/ D, b# q; Stween 4 and 8 years old, with a gradual decrease to age 17- R% R) K2 i5 k% b  h0 {
years (see table).0 I$ j% {; C4 Y, ]
DISCUSSION
; c7 N2 z! R3 C. STopical testosterone has been used effectively by other
, R( g# N& W, a$ x! N$ {' Xclinicians but its mode of action remains controversial. Im-, {' c( g# I* M0 D- l2 _
mergut and associates reported an excellent growth response3 J2 ]( }2 O9 o4 e7 }
to topical testosterone with low levels of serum testosterone,. m7 {% ]7 w# _9 @
suggesting a local effect.1 Others have obtained growth re-( p8 m- T! z0 Y  }
sponse with high. levels of serum testosterone after topical
; W4 {2 Q0 F2 @, Nadministration, suggesting a systemic response. 3 The use of2 U' t  u, O- C
gonadotropin to obtain levels of serum testosterone compara-
. X% v- |7 A6 m5 c  Hble to levels obtained with topical testosterone would seem to
' D2 M& ^9 j* Y, Z% Z+ Oprovide a means to compare the relative effectiveness of# D. c5 M" f5 t1 I+ M
topical testosterone to systemic testosterone effect. It cer-; {9 J# U! N1 W# [$ _1 g
tainly has been established that gonadotropin as well as par-
& L5 f, H" v: K. M$ }' [enteral testosterone administration will produce genital
1 D% U6 F* F* G1 P& X/ zgrowth. Our report shows that the growth of the phallus was
$ O8 p: ~6 v' `6 Esignificantly greater with topical applications than with go-
9 \8 k4 N+ S7 x6 I0 z/ bnadotropin, particularly in children less than 10 years old.4 k8 Q3 u  h3 {6 V2 Q* Z. s/ w
The levels of serum testosterone remained similar or lower) d7 w) Y8 }+ Q3 {; v6 Z4 M& x( B5 C: b
than with gonadotropin during therapy, suggesting that topi-
: }0 k; k6 e4 r6 l, [; ]4 ucal application produces genital growth by its local effect as
; J  ]" s5 V( \/ ?+ Rwell as its systemic effect.
! {2 r1 _4 V* |5 {  F$ e" l. EReview of our patients and their growth response related to
# y* \1 I) c5 N( j- @age shows a greater growth response at an earlier age. This is# a( l5 P3 d7 K4 ?2 h0 Q* V2 C. M
consistent with the findings of Wilson and Walker, who9 \8 }0 i# s- C2 q  C9 Y! O- D
reported an increased conversion of testosterone to dihydrotes-3 T; a# c6 Q, Y3 e9 V8 B6 g7 O+ G
tosterone in the foreskin of neonates and infants.4 This activ-
+ _4 W; x) r, Pity gradually decreases with age until puberty when it ap-2 `' B5 d$ o; ?6 g4 i4 a% k
proaches the same level of activity as peripheral skin. It may
2 N! F! ^" K- }- Awell be that absorption of testosterone is less when applied at
0 n7 C* N6 q2 z- ~- P$ [! Xan earlier age as suggested by lower serum levels in children
! b( [/ G6 H: P, R: yless than 10 years old. This fact may be explained by the0 N% h" {- u2 j% t/ X, S
greater ability of phallic skin to convert testosterone to dihy-3 S& I8 L5 T( q) H& p, g
drotestosterone at this age. Conversely, serum levels in older
: U* P; _( R) a2 T7 ]patients were higher, possibly because of decreased local
- }+ ?6 D  `. l( Q3 K3 B9 T+ [667# ]6 o! c1 \" |0 [- c0 `, K
668 KLUGO AND CERNY
# R9 T* n9 y0 t' t3 yPt. Age+ h7 R* h! n5 F5 _1 P; A
(yrs.), [* |! Q8 \* d+ b
Serum Testosterone Phallus (cm.) Change Length5 t: y% E% n" x- k- J+ E0 T
(ng./dl.) Girth x Length (%)$ d$ V9 J4 P- I
4( a4 Y% b6 H5 Y3 A2 F* b2 C( u1 O
8
+ B$ D: f  Y& ?, G* S: z10
* `( }- D. b3 M12
, J% i0 p. x, y1 K17
3 t0 K0 |' M' F* u  S( H* oGonadotropin- A  r. U6 g+ _1 G6 \. n% I6 ?
71.6 2.0 X 3 16.6/ b$ r# h' n. i
50.4 4.0 X 5.0 20.0
2 `3 `! L8 {8 }" M6 @! ?2 Z0 a) C  S22.0 4.5 X 4.0 25.0
, O/ q# d3 Q3 [5 H* [9 R% T/ E$ L84.6 4.0 X 4.5 11.1
$ z( g+ {$ H$ ]! p$ z- ^! }1 A! a85.9 4.5 X 5.5 9.0. a, b) J6 u" j8 r
Av. 14.31 v9 m2 Y% y+ t. _% _) S) K
4
# f. I, ^" N) Q( x81 M. a1 \2 I/ L8 o+ F6 Z; w1 _
10
+ s$ V6 E' n/ A6 c) E8 o& r' I12
- ]1 U' B4 |9 ?* v" g172 T" X4 t* k1 M3 G
Topical testosterone
+ T) ~' k" _1 `: G2 }34.6 4.5 X 6.5 85, V) j5 W" r9 ^- r/ ^" q
38.8 6.0 X 8.5 70
& W. j2 Y% P/ M0 H6 R4 \40.0 6.0 X 6.5 62.5
2 A' D. h0 R* @; j3 f' ?) \93.6 6.0 X 7.0 55.5
* h6 V; L, o+ x9 Q' d) z95.0 6.5 X 7.0 27.2, w# ~( B0 P0 Z9 Q9 n: h) K
Av. 60.0
* |- c8 v' z4 g4 Y+ Mavailable testosterone. Again, emphasis should be placed on
8 O& U' c, d2 M5 O" f  y" yearly therapy when lower levels of testosterone appear to4 `% ~+ f  M3 M" O. a% T- c$ R) M
provide the best responses. The earlier therapy is instituted
9 q1 W( C3 F! t0 z! Sthe more likely there will be an excellent response with low8 h/ r9 Y6 p! v3 l! R
serum levels. Response occurs throughout adolescence as6 r/ [+ [: a! G; d# x  O7 k6 X
noted in nomograms of phallic growth. 7 The actual response9 y2 c! r* y. i$ X% C4 l
to a given serum level of testosterone is much greater at birth3 S8 U, G& K( w  v8 R3 n4 }# P
and gradually decreases as boys reach puberty. This is most
. x! {/ ], E; U. T: `likely related to the conversion of testosterone to dihydrotes-
$ J/ i5 D, B: h1 l/ [, U% U4 Etosterone and correlates well with the studies of testosterone% C9 t" {( O9 g9 e0 ?" U  U; `
conversion in foreskin at various ages.' b) v- _3 r; `1 e' f/ i7 }
The question arises regarding early treatment as to whether9 K! t3 K  L. y
one might sacrifice ultimate potential growth as with acceler-
/ D4 c" z. q+ t% Aated bone growth. The situation appears quite the reverse, \; V2 v& Y+ b+ B9 F6 h6 h
with phallic response. If the early growth period is not used: S, I; ~% q% g& {) F" ~% T
when 5a reductase activity is greatest then potential growth. e8 A6 n$ R4 t0 m
may be lost. We have not observed any regression of growth. p+ B- Y2 [( q) }% a6 h6 U
attained with topical or gonadotropin therapy. It may well
3 t, Z4 X* u' @5 i- X: n7 Nbe that some patients will show little or no response to any
6 i0 v. I) s, |form of therapy. This would suggest a defect in the ability to
) k4 z% l/ s3 ~9 S. zconvert testosterone to dihydrotestosterone and indicate that
8 K' s7 J, y  ]' r3 m" Cphallic and peripheral skin, and subcutaneous tissue should: ^% E- [* z; k
be compared for 5a reductase activity.8 r7 m' C0 z2 {8 ?2 D$ x
A, loop enlarges to measure penile girth in millimeters. B,
; V3 r; @( \7 lexample of penile girth computed easily and accurately.
+ h/ m6 o5 R5 y8 h$ V4 S2 i' U  bconversion of testosterone to dihydrotestosterone. It is in this5 I' I& Y' I$ _& d
older group that others have noted high levels of serum
; ^" q0 y& N  O" s- _% t; ptestosterone with topical application. It would also appear! p& M7 C/ D6 E3 u$ I+ b
that phallic response during puberty is related directly to the$ z4 N1 b+ @4 ]# Q7 u! [) q( @
serum testosterone level. There also is other evidence of local' M8 z# A) ^* |2 X! d
response to testosterone with hair growth and with spermato-
2 V8 F# W% X3 A" F5 I# Igenesis. 5• 61 V4 B# [6 q3 [) }9 K* j
Administration of larger doses of gonadotropin or systemic2 D. x  j$ n, Y: C
testosterone, as well as topical applications that produce
7 v6 g) w: p* A  [" Xhigher levels of serum testosterone (150 to 900 ng./dl.), will/ q1 O% m9 K" ]
also produce phallic growth but risks accelerated skeletal! i, m$ ~6 u0 K& R3 b4 F# B5 _
maturation even after stopping treatment. It would appear, ~% J( }# u! }, O; G
that this may be avoided by topical applications of testosterone! I% g6 [8 G, I
and monitoring of serum testosterone. Even with this control0 q- E1 ^) u) x+ b$ g
the duration of our therapy did not exceed 3 weeks at any+ {$ s. T3 I9 A* H7 P0 l, ~* N5 D
time. It is apparent that the prepuberal male subject may
2 S, f  Z, \) i' [) a/ ?suffer accelerated bone growth with testosterone levels near5 K1 X7 a9 V; F  y) X0 J4 t
200 ng./dl. When skeletal maturation is complete the level of+ G# p, z, S" {
serum testosterone can be maintained in the 700 to 1,300 ng./0 [2 y* A' c# q/ v2 r6 p* o
dl. range to stimulate phallic growth and secondary sexual
7 F9 W1 e8 w: }, |changes. Therefore, after skeletal maturation parenteral tes-& O6 \2 g- ~' E5 S' B3 C
tosterone may be used to advantage. Before skeletal matura-
8 k! m: J1 ^  K4 U% ntion care must be taken to avoid maintaining levels of serum
/ P: a' b2 ]) etestosterone more than 100 ng./dl. Low-dose gonadotropin
2 \" F6 \$ L) q9 f' s% \depends upon intrinsic testicular activity and may require
7 n( v( g" `& |prolonged administration for any response.( s; ]3 ^' Q6 t
Alternately, topical testosterone does not depend upon tes-" k% O$ h9 r$ N# |. k, A0 Q
ticular function and may provide a more constant level of* f/ [! z3 J& B. @6 |
REFERENCES, [6 U6 R5 j" W5 s/ v' X" p
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 Z' S# L- F( O" V$ TR.: The local application of testosterone cream to the prepub-
* R0 f; Y5 F# M0 j. A6 ~ertal phallus. J. Urol., 105: 905, 1971.( {1 C0 m' n& E, M
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone) S9 N/ w9 ~" l9 N, M: e
treatment for micropenis during early childhood. J. Pediat.,4 m9 `( K7 N0 ^# g$ s. c4 y" m
83: 247, 1973.
6 C! {& j1 a7 M% _7 z. W; E3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-  g5 ^: a) [" e% a' o* K5 H
one therapy for penile growth. Urology, 6: 708, 1975.
$ i( W2 v; B; J4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone: a* q3 B" W$ M' F. j- h0 a
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
) E# H5 z# o5 d2 h7 O% Askin slices of man. J. Clin. Invest., 48: 371, 1969.3 S$ [( v! p8 ~+ M% N& ^+ ?
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 q. ]" D$ s( T* g( @7 X, g
by topical application of androgens. J.A.M.A., 191: 521, 1965.
6 d/ |/ ]. Q( z9 N& y6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local7 b/ y* f+ R4 U; t( g2 z$ S" f
androgenic effect of interstitial cell tumor of the testis. J.
2 M+ g: x( D9 \; I6 B: \Urol., 104: 774, 1970.
/ x" X; L5 ^; B9 _0 Z! a5 c7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. B& o5 q" y7 c7 O$ ution in the male genitalia from birth to maturity. J. Urol., 48:
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