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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
$ l( ?# a; R! m, P+ pGONADOTROPIN5 L& C) \) d7 e4 { b2 X: f# ]/ s
RICHARD C. KLUGO* AND JOSEPH C. CERNY7 c0 C7 d7 D% @$ Q% @ e
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& c0 O8 O$ z+ O) N4 n; r" t/ ~ABSTRACT
! @% d3 B# l" V. J3 QFive patients were treated with gonadotropin and topical testosterone for micropenis associated
( C1 c% J4 b. e' G/ _( nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
! n! u) e1 z9 C! M! Y! ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
3 a& T0 t$ y# R6 C7 A$ icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
$ }: H. } P# Z+ B3 Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. i! n9 Y K. w+ E/ @9 W/ k
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
" t% U8 s- S9 Y: A+ Uincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. _! G/ @0 ^1 Poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' u4 M4 p( p1 i) dstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
9 S4 e+ k' C5 t0 X1 l8 |growth. The response appears to be greater in younger children, which is consistent with previ-
/ B2 n& z+ p7 A, m* I7 M- q1 Gously published studies of age-related 5 reductase activity.
/ n4 \8 _7 }3 {! cChildren with microphallus regardless of its etiology will4 \/ U, I# S3 q- z: G! M
require augmentation or consideration for alteration of exter-0 X# m7 i: d6 G. c7 Z+ H
nal genitalia. In many instances urethroplasty for hypo-- b) d9 ^0 n7 L( l
spadias is easier with previous stimulation of phallic growth./ z5 J1 d+ E9 r
The use of testosterone administered parenterally or topically" I& h( H6 K9 k/ X
has produced effective phallic growth. 1- 3 The mechanism of' O k8 b) J; ?2 B, G8 p
response has been considered as local or systemic. With this9 E# _! P0 H. a! c4 f4 g! w) n2 M) a
in mind we studied 5 children with microphallus for response
" W; b+ o! b/ e& i' r, jto gonadotropin and to topical testosterone independently.- E% r- \9 R5 a
MATERIALS AND METHODS
/ i" r' H+ [! r. E7 JFive 46 XY male subjects between 3 and 17 years old were. E( b/ s: q4 D. H$ c, k% x
evaluated for serum testosterone levels and hypothalamic
8 `1 Q- c! q0 L9 q8 M6 d, g1 ffunction. Of these 5 boys 2 were considered to have Kallmann's
; |! z$ M& H4 e1 y* Q9 jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
1 U1 l& i7 o$ u. q* x5 E+ llamic deficiency. After evaluation of response to luteinizing
r/ ^' M& J: w' W# Xhormone-releasing hormone these patients were treated with6 Y5 A' y, I; D' y8 v0 ]7 D
1,000 units of gonadotropin weekly for 3 weeks. Six weeks( B. _' G' h' D' v
after completion of gonadotropin therapy 10 per cent topical: }& [/ F3 U. ]& {/ t% ^. {2 z
testosterone was applied to the phallus twice daily for 3 weeks.7 Q P9 M+ e5 p1 ]- T
Serum testosterone, luteinizing hormone and follicle-stimulat-
1 w& v0 Q7 x' a' Oing hormone were monitored before, during and after comple-5 t5 E0 D# x2 i# ~* H% @7 F
tion of each phase of therapy. Penile stretch length was. Q1 k- C6 H2 Q% g0 f7 c
obtained by measuring from the symphysis pubis to the tip of
+ E- ?" N7 i, v5 e% A$ s; b" othe glans. Penile circumferential (girth) measurements were0 N: h+ T1 m' S" {/ X4 ^8 K1 V
obtained using an orthopedic digital measuring device (see
7 H2 ^% W; x2 d$ }/ K0 [$ U! ] Hfigure).( E- F( f5 i7 X. X9 ]
RESULTS$ o- W3 M4 \$ D+ p- v6 L/ {* q/ P
Serum testosterone increased moderately to levels between0 c" _8 s- H* _2 m; v
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-& `7 A7 C4 U8 n2 t0 H/ V4 B
terone levels with topical testosterone remained near pre-
3 W% A6 U7 h& K! T) F$ E4 l3 M7 ktreatment levels (35 ng./dl.) or were elevated to similar levels" ]) N5 n5 l5 Q+ C) I7 h
developed after gonadotropin therapy (96 ng./dl.). Higher
g3 M( |6 k5 L& F, Xserum levels were noted in older patients (12 and 17 years old),
5 p _- e3 ?, C; [ z1 }while lower levels persisted in younger patients (4, 8, and 10
! n3 N y6 s- t0 v- ~8 C2 f- W- Y9 syears old) (see table). Despite absence of profound alterations
" }8 M2 E$ o' Rof serum testosterone the topical therapy provided a greater
`8 @. _) n* o* EAccepted for publication July 1, 1977. ·6 p0 i/ }, O1 V ~3 T
Read at annual meeting of American Urological Association,
! K, ^' u+ V" }5 n$ B0 mChicago, Illinois, April 24-28, 1977.
* |( i7 G' x7 q5 }+ y* Requests for reprints: Division of Urology, Henry Ford Hospital,( c5 ?& W: E# O) {
2799 W. Grand Blvd., Detroit, Michigan 48202.6 E; h* {, G! ?7 f+ U7 ]7 C% K" Y, w
improvement in phallic growth compared to gonadotropin." K. M) ?9 o( Q5 K, M8 ^
Average phallic growth with gonadotropin was 14.3 per cent
1 Y) m+ |8 G* j. Yincrease in length and 5.0 per cent increase of girth. Topical
) ]$ J/ W, s) y8 B |testosterone produced a 60.0 per cent increase of phallic length( o+ B7 n" f( ^
and 52.9 per cent increase of girth (circumference). The) z1 t' Q) X0 M5 Q
response to topical testosterone was greatest in children be-
8 P- p Y0 H3 @* r" jtween 4 and 8 years old, with a gradual decrease to age 177 Y% O r- m. s) K' t! F+ r* h
years (see table).
9 j; X: y; t6 g7 VDISCUSSION [+ ?2 F( q3 D m
Topical testosterone has been used effectively by other( i% F- Y! [( [. g( t' T
clinicians but its mode of action remains controversial. Im-
& g* q' e9 b9 c6 _* G- [5 p3 F7 Jmergut and associates reported an excellent growth response
4 q! ^% C+ V- |to topical testosterone with low levels of serum testosterone,- g5 _0 M; q1 P/ F; W9 m3 A8 i7 ^
suggesting a local effect.1 Others have obtained growth re-
" V/ X* A; u P- osponse with high. levels of serum testosterone after topical% V/ a$ i# t& }3 x/ b
administration, suggesting a systemic response. 3 The use of
- A5 a% n3 h' G7 W6 o. [! v9 E4 o% Vgonadotropin to obtain levels of serum testosterone compara-* k$ n% H# W( L* p2 v0 Z
ble to levels obtained with topical testosterone would seem to' p+ W9 o$ b' { ^, z
provide a means to compare the relative effectiveness of, G, G9 o& \9 j* R
topical testosterone to systemic testosterone effect. It cer-
) d' c+ ~. _; W vtainly has been established that gonadotropin as well as par-
; l! q! Z& [+ i& a. D f: ~( xenteral testosterone administration will produce genital
! V1 U8 ^& C( k4 d+ ngrowth. Our report shows that the growth of the phallus was
9 x* C8 r5 h" [) s C; P [significantly greater with topical applications than with go-
' m- R* S% R. _! hnadotropin, particularly in children less than 10 years old.
B7 E/ j. n; y" U( S+ HThe levels of serum testosterone remained similar or lower3 U) S0 t. Z6 y' r
than with gonadotropin during therapy, suggesting that topi-( @+ c" V6 E! ^: |; T R9 G
cal application produces genital growth by its local effect as
- O) q4 n9 g: e7 o( {7 v) M7 cwell as its systemic effect.
/ O* U/ W" _) c( wReview of our patients and their growth response related to
' U7 k0 v6 O& {# _age shows a greater growth response at an earlier age. This is
! |' S! F# b! `; u6 i ]consistent with the findings of Wilson and Walker, who6 A, B3 d1 s5 y$ Y2 o" F8 M
reported an increased conversion of testosterone to dihydrotes-
; s9 [4 \' |: x2 m m7 b# ^; k- Rtosterone in the foreskin of neonates and infants.4 This activ-
- E0 a5 d& ~% x; |% kity gradually decreases with age until puberty when it ap-
. K) l+ ^2 O! R2 s+ Iproaches the same level of activity as peripheral skin. It may
4 \" [$ k& m/ r, v) h5 g. c/ dwell be that absorption of testosterone is less when applied at& I1 }! x3 c9 K. J4 ^9 }+ q
an earlier age as suggested by lower serum levels in children
! S+ d! F% z7 i( A( x- [4 kless than 10 years old. This fact may be explained by the
|/ P1 t9 y& j- Jgreater ability of phallic skin to convert testosterone to dihy-
, _; @# W/ E6 O6 D; M r1 A( Gdrotestosterone at this age. Conversely, serum levels in older
; v6 j5 b" e( Y4 Zpatients were higher, possibly because of decreased local
) e, x" o$ N3 Q8 H% b667
2 ?6 N3 E% c% G668 KLUGO AND CERNY. ^( O# T. G: B' ~+ P
Pt. Age! j4 G2 {6 W7 q; E7 m" W6 e3 H$ J& I
(yrs.)
( S: |! s( u& Z6 U! G1 {Serum Testosterone Phallus (cm.) Change Length( v+ y! N) Q: ~
(ng./dl.) Girth x Length (%)
- I& W% b. d/ b8 P& N8 }! U! |4
1 r K* h' x8 O8
, |" b8 E; @& S9 c8 U' k* |10
; P8 k2 n' [/ {. K/ S& H. N# V12
: X* r( s+ v3 W) N1 A- Y/ k17$ q( E4 x3 z3 t. M. m' J# b) i: f
Gonadotropin5 Q" f3 H9 M- G4 Y; r! U& n: n* G
71.6 2.0 X 3 16.67 s+ z8 ?6 m: |& _% G
50.4 4.0 X 5.0 20.0/ i- c/ T9 p4 ?4 F6 i4 A4 n
22.0 4.5 X 4.0 25.08 n6 Q" L, H( _( C
84.6 4.0 X 4.5 11.1
6 N' S+ B$ U9 v! Q9 C85.9 4.5 X 5.5 9.0
& G4 |6 D Y: G- y4 O# @# G4 W5 BAv. 14.3
7 U2 t) j6 ]6 V3 J" E% Q4
& b# R, B( V8 s/ P. F" k8) W& s* ?. d+ E: b
10
Y* c& z( i4 k4 ~& r) u! m12, ~+ N' A9 K% h: d5 D7 |
17
7 S4 `: s9 e5 sTopical testosterone
) [5 G$ G/ l) H' s( |+ z* n34.6 4.5 X 6.5 85
1 B6 m& X& s/ ? f6 J K38.8 6.0 X 8.5 707 |0 A. e* g' z" O
40.0 6.0 X 6.5 62.5
' ]/ f9 r8 r) F6 A# a5 a93.6 6.0 X 7.0 55.5$ R& J, ^6 u0 W7 k% }1 A
95.0 6.5 X 7.0 27.2
* s) c g! V/ t3 `# Z9 QAv. 60.0
$ D& F1 N1 @4 {* ?9 D9 lavailable testosterone. Again, emphasis should be placed on
, o) y* f& X1 E( ?+ k" ~8 ]early therapy when lower levels of testosterone appear to. ?4 z. c5 Q- ?8 X( o
provide the best responses. The earlier therapy is instituted) e' ]) k: E: k) P b
the more likely there will be an excellent response with low3 M' C' T# u& h7 q5 Z# \; M" _
serum levels. Response occurs throughout adolescence as
; M4 M7 c' X1 E& q! [noted in nomograms of phallic growth. 7 The actual response7 I+ e/ t0 D; E; b1 H v7 }
to a given serum level of testosterone is much greater at birth) V5 B# u0 F' ~. l% ^& Q
and gradually decreases as boys reach puberty. This is most8 [" o$ V# x6 I
likely related to the conversion of testosterone to dihydrotes-" i/ r. W2 }0 u
tosterone and correlates well with the studies of testosterone
+ E2 k/ c) `9 C" L7 [( Oconversion in foreskin at various ages.: l3 \2 O {1 s" [! [4 e8 z
The question arises regarding early treatment as to whether% e( ~9 s( R, }% e3 }. {* E
one might sacrifice ultimate potential growth as with acceler-
# Q1 }+ {4 `( `3 [# Nated bone growth. The situation appears quite the reverse
- W* C2 @8 g' H: m b* X/ lwith phallic response. If the early growth period is not used
" c( P( z( g& U5 L- f7 Gwhen 5a reductase activity is greatest then potential growth
3 j" f7 q5 r: S6 y; Y* j) ~% [! Smay be lost. We have not observed any regression of growth
F( O9 q6 j$ m9 Vattained with topical or gonadotropin therapy. It may well3 I% S3 e% f* L
be that some patients will show little or no response to any8 K* m- ]9 p) N w( N6 T& d
form of therapy. This would suggest a defect in the ability to9 e1 B) D, X* M+ B1 Q
convert testosterone to dihydrotestosterone and indicate that! e, X3 p( }! S) _9 E- A
phallic and peripheral skin, and subcutaneous tissue should; x" c4 N5 B& G R
be compared for 5a reductase activity./ U3 a8 v$ J9 a$ E- o: }2 z/ F7 m
A, loop enlarges to measure penile girth in millimeters. B,
6 \+ j6 Z8 ?7 l6 n5 Gexample of penile girth computed easily and accurately.
8 e3 e% A$ B5 v( nconversion of testosterone to dihydrotestosterone. It is in this
6 P* |! J" F! ?% Q, U" R; z yolder group that others have noted high levels of serum7 w) S2 b9 o' ?5 J% P
testosterone with topical application. It would also appear" Z# p: c. T% D" y3 Y/ q/ t
that phallic response during puberty is related directly to the7 R% R2 Z; \( _9 g2 [2 @
serum testosterone level. There also is other evidence of local* ^1 t/ s2 P8 Z0 D0 l* K5 F
response to testosterone with hair growth and with spermato-& y* x5 }& I* U/ \8 V
genesis. 5• 64 [& l4 x! V% Z* u( U' p. C+ J, D
Administration of larger doses of gonadotropin or systemic
' }" A5 e c1 m' `/ i( c' l% E Y. n0 ~testosterone, as well as topical applications that produce' @% @ B+ O0 [( H
higher levels of serum testosterone (150 to 900 ng./dl.), will6 l, c& s$ ?7 ~: x' z. e
also produce phallic growth but risks accelerated skeletal
: ~ j+ y& Y: w. ]" J! {1 @maturation even after stopping treatment. It would appear
$ L$ v; S6 r/ o [3 xthat this may be avoided by topical applications of testosterone
7 D% \, t/ f) T0 v$ c) sand monitoring of serum testosterone. Even with this control
; p) S. F' J+ |7 `3 cthe duration of our therapy did not exceed 3 weeks at any, H" @+ E4 ^5 }. y( A% L6 f
time. It is apparent that the prepuberal male subject may1 H5 u% I' v" L7 m' E2 n
suffer accelerated bone growth with testosterone levels near
8 \$ t9 \' v+ q% E1 Z4 w200 ng./dl. When skeletal maturation is complete the level of
# N% J( i- U5 @9 x$ c* Sserum testosterone can be maintained in the 700 to 1,300 ng./
4 {9 x# `3 i' J" @. f2 A1 }dl. range to stimulate phallic growth and secondary sexual
! n4 C. E0 X4 m: Z) l/ ]3 `changes. Therefore, after skeletal maturation parenteral tes-: J8 b5 w; C) C( ^5 q2 T. T6 d
tosterone may be used to advantage. Before skeletal matura-
2 L5 w1 o. @: X% f7 `4 gtion care must be taken to avoid maintaining levels of serum
7 G- F/ P& C9 E" Ntestosterone more than 100 ng./dl. Low-dose gonadotropin
% l# f+ q" M$ \$ R' {depends upon intrinsic testicular activity and may require
4 D( I9 a, j- k8 s7 A6 t9 Cprolonged administration for any response.: r5 H, X% o6 Q9 y0 U4 m
Alternately, topical testosterone does not depend upon tes-
0 ~6 p2 p$ h; O7 q$ dticular function and may provide a more constant level of% \( `8 o) u) W
REFERENCES
4 N. B4 n3 I J4 Q/ u/ Z# P1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( n/ f* U$ n' Y: ~/ Q) b( }
R.: The local application of testosterone cream to the prepub-
5 Z z' _4 U# L7 z+ l' C& a, u9 _ertal phallus. J. Urol., 105: 905, 1971.: \) q9 v t& X0 [- \+ V" G/ I3 }
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" X) ^. w q9 x% z, t+ I* x; n
treatment for micropenis during early childhood. J. Pediat.,* S* n) N6 U& s7 l2 `3 j
83: 247, 1973.
8 t; c2 j4 R6 _' f2 ?3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-+ u8 X8 |: b5 t
one therapy for penile growth. Urology, 6: 708, 1975.4 C. P: o' x0 I! M' `
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
# w$ ~, a) u9 o% K' v7 xto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by/ [% G. \ P' W- ~, H
skin slices of man. J. Clin. Invest., 48: 371, 1969.2 |8 _7 ~5 W7 x! [$ Y/ @
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth& U% X! |3 {& v! U) b! D* A& C
by topical application of androgens. J.A.M.A., 191: 521, 1965.2 Y5 ~8 \6 h5 X9 a, \
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ T7 e! a6 c# y5 x
androgenic effect of interstitial cell tumor of the testis. J.
7 j" s6 U! ~- r- P: C' ^" sUrol., 104: 774, 1970.
, D5 Z2 G# v( T: U0 J6 U# A7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 |9 F" D% l& t
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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