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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, B1 P  ^# }5 G# v
GONADOTROPIN
9 m9 H6 G+ a9 r0 c% c6 p. |, {RICHARD C. KLUGO* AND JOSEPH C. CERNY
* ]8 a$ |$ z9 y* a# ~9 ^From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
/ R$ k( U7 ^4 Q9 w3 ?# ^ABSTRACT
+ L* `  j' O+ w' S$ hFive patients were treated with gonadotropin and topical testosterone for micropenis associated% q! d, x3 r9 s1 ~
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
9 k+ C) u4 \% ntropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone" q0 W$ w  j; Y1 ~0 w( h% y* p1 }
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
  h+ @2 u4 u: Vfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
( E* [0 I- D) ?6 x" Lincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
8 w/ O. O  |. e0 q$ p0 r* dincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 L2 [$ ?. J" s' A7 @7 poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This, w+ Q/ s: v1 a/ I  S+ a( X
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" ~, L+ s4 Y, L% B( m* D
growth. The response appears to be greater in younger children, which is consistent with previ-
! h' U- s) v7 l  u" Yously published studies of age-related 5 reductase activity.0 V( G& H6 a4 O# }, |9 N5 O
Children with microphallus regardless of its etiology will
2 U' v+ f- N5 O. Brequire augmentation or consideration for alteration of exter-- ]! A* X* P9 I8 A8 T0 v; y
nal genitalia. In many instances urethroplasty for hypo-
; T/ ^- l" v& \; w- L" dspadias is easier with previous stimulation of phallic growth.- A9 n* h8 r# ?, b! [' e3 s, c
The use of testosterone administered parenterally or topically" _, R0 ~. d" f) u$ N& s
has produced effective phallic growth. 1- 3 The mechanism of
/ t2 Q& q$ R+ c& l# }" W& q; Yresponse has been considered as local or systemic. With this
2 v* p' c$ b! s2 ain mind we studied 5 children with microphallus for response* p' T/ D, X( P9 D
to gonadotropin and to topical testosterone independently.
$ l# z9 F2 ~0 g( y; vMATERIALS AND METHODS
! c' e2 g9 d/ \- [' OFive 46 XY male subjects between 3 and 17 years old were* D( ^5 R" H$ M
evaluated for serum testosterone levels and hypothalamic7 o" l7 {1 C% q6 D) N
function. Of these 5 boys 2 were considered to have Kallmann's/ e% A8 q- l! X5 d# C
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( f! w, c8 n7 o+ w2 L, P- wlamic deficiency. After evaluation of response to luteinizing/ q' o5 N5 W- V% g& d
hormone-releasing hormone these patients were treated with
$ ]6 m+ ^& J9 o- L! w+ U1,000 units of gonadotropin weekly for 3 weeks. Six weeks6 R/ u( f, i1 l
after completion of gonadotropin therapy 10 per cent topical. j$ y' @  @" V8 a% y( R6 G
testosterone was applied to the phallus twice daily for 3 weeks.
" {' B9 t  B' i% c& o" e7 E  zSerum testosterone, luteinizing hormone and follicle-stimulat-
1 W1 t% l5 T4 Ting hormone were monitored before, during and after comple-
' f& S. G8 M; Y5 p! j7 F  vtion of each phase of therapy. Penile stretch length was
- z  M0 n7 B4 n5 aobtained by measuring from the symphysis pubis to the tip of" j) y, Y; n# A2 p5 W
the glans. Penile circumferential (girth) measurements were
( b) R  ]1 K3 D4 X5 j7 {2 Eobtained using an orthopedic digital measuring device (see$ W2 U7 o& d$ u  c5 E
figure).
3 N) \5 a' j3 b5 JRESULTS* |; `: s. S1 ^4 p+ U  \( F
Serum testosterone increased moderately to levels between
3 A% I; z3 t3 Q, v+ G& S, \4 S50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! X  m1 N2 f4 F* H& l: ^8 h, n# C4 _
terone levels with topical testosterone remained near pre-
8 T! A6 q# Z  j' x2 Xtreatment levels (35 ng./dl.) or were elevated to similar levels
7 d+ o: M% {4 s" Z# [/ Bdeveloped after gonadotropin therapy (96 ng./dl.). Higher
  }+ ^' c& \6 f; M+ X- eserum levels were noted in older patients (12 and 17 years old),
* t; X% A# U" Q7 O% X" p( pwhile lower levels persisted in younger patients (4, 8, and 10
5 O  Z8 J& U' @. ]1 E$ kyears old) (see table). Despite absence of profound alterations
7 A, k+ c7 r( L- a6 m9 eof serum testosterone the topical therapy provided a greater' K' y2 |6 e6 F+ g" N
Accepted for publication July 1, 1977. ·
& z' _( z; @+ T! M7 Q2 I7 }. G4 kRead at annual meeting of American Urological Association,% B# w* Y$ H- |, n% z9 C4 x0 M
Chicago, Illinois, April 24-28, 1977.7 v1 e* Q3 }5 t4 h5 `+ j2 n
* Requests for reprints: Division of Urology, Henry Ford Hospital,
. c3 z: I: W8 }% P: d; R2799 W. Grand Blvd., Detroit, Michigan 48202.
3 N4 |8 r8 g9 v, Cimprovement in phallic growth compared to gonadotropin.: N5 t3 P1 d: N3 W" T8 a
Average phallic growth with gonadotropin was 14.3 per cent
3 k3 ~2 R7 H. r* l4 Cincrease in length and 5.0 per cent increase of girth. Topical% \0 n8 y1 ]( x% f; r) O/ O
testosterone produced a 60.0 per cent increase of phallic length
; @# I, H( N* Y  M+ Tand 52.9 per cent increase of girth (circumference). The
: Z+ ?# T1 W4 ~3 R3 f+ jresponse to topical testosterone was greatest in children be-7 B& r. x% h4 R$ R: C
tween 4 and 8 years old, with a gradual decrease to age 17
' t" q$ c* u! A2 jyears (see table).
" z$ K9 V; a# hDISCUSSION
( L: B7 Q: W5 u8 O1 W& g! c5 n0 sTopical testosterone has been used effectively by other
6 B4 T7 V* o) j* D: Dclinicians but its mode of action remains controversial. Im-
- a! T7 D" V, D. smergut and associates reported an excellent growth response
  I. h% h/ I, i3 E+ n2 `to topical testosterone with low levels of serum testosterone,
4 t" K: P( {3 m/ a. |7 P* {. Hsuggesting a local effect.1 Others have obtained growth re-  G7 p3 J4 W1 m  N& h( H; h
sponse with high. levels of serum testosterone after topical
8 D* R4 `" y/ P" {7 V' O( S) Kadministration, suggesting a systemic response. 3 The use of
" e) O2 y/ w  P% z( C  y' hgonadotropin to obtain levels of serum testosterone compara-
0 S: o9 r$ i: V% }; n3 d6 Vble to levels obtained with topical testosterone would seem to
( q3 i! n* H! {0 w( d# ^provide a means to compare the relative effectiveness of$ A# ?5 l8 F$ p6 ^9 {
topical testosterone to systemic testosterone effect. It cer-
  @# j: @' C; x$ Y/ t, ^tainly has been established that gonadotropin as well as par-
% E2 x5 H- Z" oenteral testosterone administration will produce genital
' D4 p! I  a; ?$ \2 cgrowth. Our report shows that the growth of the phallus was8 B8 r, x/ A# n" M6 B
significantly greater with topical applications than with go-
  U  v2 Q( n- K4 Anadotropin, particularly in children less than 10 years old.
* Y. m3 X! Q4 yThe levels of serum testosterone remained similar or lower
; k, m0 k& n7 W9 J0 _$ athan with gonadotropin during therapy, suggesting that topi-7 C* h+ @- D2 T3 M. v5 z6 l0 U4 W
cal application produces genital growth by its local effect as! Z' F1 ~. {+ b7 G: ^7 ~  w
well as its systemic effect.3 F3 ~9 O/ F- w$ U
Review of our patients and their growth response related to8 y! m, b$ I4 X) G4 F
age shows a greater growth response at an earlier age. This is
: H/ t! U3 C: V% hconsistent with the findings of Wilson and Walker, who7 |' e; z* K+ k
reported an increased conversion of testosterone to dihydrotes-
  Q/ L! `- }5 \4 v2 U: Z! [tosterone in the foreskin of neonates and infants.4 This activ-. Q) [+ k- R+ l6 `) |" Y$ X; A* [9 _/ x
ity gradually decreases with age until puberty when it ap-- V1 d* Q/ A) g# z
proaches the same level of activity as peripheral skin. It may* r3 [: n( j0 A! K5 v- r
well be that absorption of testosterone is less when applied at" r5 F! M! i! K  ~  U8 \
an earlier age as suggested by lower serum levels in children0 H6 z- h+ k2 E1 s
less than 10 years old. This fact may be explained by the
' d3 o0 J; k' x' H: S7 ogreater ability of phallic skin to convert testosterone to dihy-
! h" b: U5 r# Q3 ^# {drotestosterone at this age. Conversely, serum levels in older0 u3 s! f- ~- f9 g
patients were higher, possibly because of decreased local* r& _( X6 G% e/ r, |7 c
667- X" R& ^0 K- m' ?- ~: J
668 KLUGO AND CERNY5 ]1 s* r, }5 U) w' U
Pt. Age6 w" o# @0 c( v
(yrs.)" K* v, B' G, {) {) k
Serum Testosterone Phallus (cm.) Change Length
' T& ~3 a* G& G) A+ q(ng./dl.) Girth x Length (%)
' [+ a: ]/ `& y) S3 o& {4
+ C  D3 W- \" ]  b. q  j2 \87 P9 R' Z6 O- Z7 ]) `) O* o) _3 G& a
10
. ?/ t, s5 Y% p2 j% |* Y: `12& r# m% \$ x! ?( s
17
7 E8 C4 v: _2 K* }/ p# a% x# HGonadotropin" B/ [- W1 @) n2 H
71.6 2.0 X 3 16.6; R& w0 o. ]/ a3 d$ s9 ~
50.4 4.0 X 5.0 20.0) [, ?9 J; _( w
22.0 4.5 X 4.0 25.09 f) J" R. d& H! ~9 n% B
84.6 4.0 X 4.5 11.1
& Q2 {/ V, ]7 N) v+ h" \85.9 4.5 X 5.5 9.0
+ v% R6 P  |: }( j8 m/ \Av. 14.3
; K- D* N* J8 u44 a' u+ `2 U& C, U7 p- r! o
8; g' T; P! G9 l, M4 G9 e0 m; L
106 `# Z+ D3 @% q8 A& T
12$ ]+ T# G" X+ Y. }
17
3 C$ c4 c# e0 STopical testosterone1 Y$ s5 Q8 s- E3 q/ O4 Z% [2 x) W9 m
34.6 4.5 X 6.5 85
; A! c6 x2 s  b6 J$ }2 W8 A2 Z38.8 6.0 X 8.5 70% Z& F4 b7 r: Z8 x, I
40.0 6.0 X 6.5 62.5
  B  h8 i; q) y8 m! ?93.6 6.0 X 7.0 55.5( y- j, A# w4 A/ u
95.0 6.5 X 7.0 27.27 V  `; U/ I6 y2 ^: p, O, L
Av. 60.04 r/ l8 ^1 J% C7 g( v  g$ i: L! I( ^
available testosterone. Again, emphasis should be placed on
' k  y+ {( p0 u$ ~4 tearly therapy when lower levels of testosterone appear to
2 k7 o: ]8 t5 o3 Z& ?5 Dprovide the best responses. The earlier therapy is instituted; v7 w8 _8 x! T3 u2 h, P
the more likely there will be an excellent response with low* F7 o+ R$ Y" I4 T! F+ Y: I
serum levels. Response occurs throughout adolescence as
7 a( w/ ~  ]' ?2 U% \noted in nomograms of phallic growth. 7 The actual response
- K9 @' ]3 V) t3 D  N- Pto a given serum level of testosterone is much greater at birth
  Q5 q: r: e& l7 A$ `% A1 y2 Zand gradually decreases as boys reach puberty. This is most; b' s. K% l" c# [- b6 x
likely related to the conversion of testosterone to dihydrotes-( R1 ^+ ~7 J1 k" D
tosterone and correlates well with the studies of testosterone
. o. s& m3 i3 R/ [conversion in foreskin at various ages.0 b6 e/ T7 K5 w2 U
The question arises regarding early treatment as to whether
5 Y  v6 ^  s  W+ Z+ X, Zone might sacrifice ultimate potential growth as with acceler-
7 {& S: O: \8 [9 Uated bone growth. The situation appears quite the reverse& s; c- L- c7 G* f* X2 m
with phallic response. If the early growth period is not used8 X. a) p# T; ?+ ~' i% m% _5 G
when 5a reductase activity is greatest then potential growth
( M8 {. c' u2 Dmay be lost. We have not observed any regression of growth
% q' f: a  ?$ N! I0 rattained with topical or gonadotropin therapy. It may well8 ]& o% C0 M" B
be that some patients will show little or no response to any! `2 ?9 t- X5 w
form of therapy. This would suggest a defect in the ability to. i+ A& X# e( u8 ]& L3 Y3 z) V7 e
convert testosterone to dihydrotestosterone and indicate that
1 S4 C8 N$ ]9 f* W, w* X+ @5 T# nphallic and peripheral skin, and subcutaneous tissue should' l7 x: f! B0 B/ A7 |
be compared for 5a reductase activity.# W4 w; x7 T' K: T
A, loop enlarges to measure penile girth in millimeters. B,
4 O8 |4 u$ O6 I" ?- gexample of penile girth computed easily and accurately.
) h4 L3 B7 ]6 l& Y  ~- }conversion of testosterone to dihydrotestosterone. It is in this
# Y: Z" @/ l( ^9 \older group that others have noted high levels of serum
; R- ]+ q  F% `8 X- }. N7 Ktestosterone with topical application. It would also appear
) y* c6 ^1 e! o: a# H5 L7 {" Wthat phallic response during puberty is related directly to the
9 R/ a; Z9 v' x5 gserum testosterone level. There also is other evidence of local
8 c+ u% O0 k6 C( Wresponse to testosterone with hair growth and with spermato-
2 q# N) N! ~  N/ \! d; fgenesis. 5• 6
4 ?7 O/ U5 A4 T" M. i* mAdministration of larger doses of gonadotropin or systemic
4 w3 ?( a% ^7 t, _0 K1 k1 Ltestosterone, as well as topical applications that produce
. U8 N+ j1 o  H. g2 n9 Xhigher levels of serum testosterone (150 to 900 ng./dl.), will
+ I; D8 v9 ^  N; P7 J& f7 malso produce phallic growth but risks accelerated skeletal. |) ^( @+ f( u0 |( ^: {+ ^% h0 |
maturation even after stopping treatment. It would appear
2 t; X, Z) c6 w* i3 e5 pthat this may be avoided by topical applications of testosterone6 i5 Y7 G  C9 P& \- i* _- M
and monitoring of serum testosterone. Even with this control: I% C" \1 `; g
the duration of our therapy did not exceed 3 weeks at any1 e5 C7 e8 m7 k* _: ?
time. It is apparent that the prepuberal male subject may
, |6 z  f( ?+ y9 ]8 P8 F( Psuffer accelerated bone growth with testosterone levels near
- r4 l: B' l& K5 s' g) B( Q: h200 ng./dl. When skeletal maturation is complete the level of3 o. I5 v% |% C: Q
serum testosterone can be maintained in the 700 to 1,300 ng./7 v7 |1 m+ \- ?$ B' b6 U
dl. range to stimulate phallic growth and secondary sexual
9 |0 J6 a2 D( u# q, x* echanges. Therefore, after skeletal maturation parenteral tes-2 f" l* B1 O4 B* W: f. j' _; V4 u5 d
tosterone may be used to advantage. Before skeletal matura-
+ y; T& a, T& Etion care must be taken to avoid maintaining levels of serum
+ _( D3 j: w/ U8 k  Btestosterone more than 100 ng./dl. Low-dose gonadotropin
& z# L) p. F0 M: L1 M7 jdepends upon intrinsic testicular activity and may require0 E+ G- F( Y+ |! A& e
prolonged administration for any response.
3 d0 Z1 k) x4 ?4 \5 K7 b# v) I* r6 w1 tAlternately, topical testosterone does not depend upon tes-. Z; t2 j9 K! `
ticular function and may provide a more constant level of
) _* K- f: \2 ]% IREFERENCES4 H) I0 b! Z5 p/ e2 W# {- M" w
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: ^! A5 H0 _" _" |$ g% O  P/ N" HR.: The local application of testosterone cream to the prepub-
* j, \( B4 v8 ?: O5 S5 o4 `7 H" yertal phallus. J. Urol., 105: 905, 1971.0 t3 B, h6 ~9 \+ `' A
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone; v7 ^0 `1 o; ^) O6 C8 ?( d
treatment for micropenis during early childhood. J. Pediat.,. \; {% y# l1 \5 g4 \
83: 247, 1973.' b$ Q3 S6 E7 ]1 s9 ?/ T
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ l% [) P5 e. ?* c( Hone therapy for penile growth. Urology, 6: 708, 1975.
1 P7 ~; X" U+ O; [# e# J  G4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone2 m) u- m* M' Q  l  ~/ J
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by7 g7 L  X. Y# l
skin slices of man. J. Clin. Invest., 48: 371, 1969.
- Z' F) a! [. P- R5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- P/ m3 Y* V% e1 v$ [by topical application of androgens. J.A.M.A., 191: 521, 1965.
# K# l1 G& H' r6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local2 G# N- j3 s( h: A
androgenic effect of interstitial cell tumor of the testis. J.# O! s1 O6 \0 l& H3 ~- Y
Urol., 104: 774, 1970.0 g% _) c  t( p6 f/ s+ l
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' M3 ]5 F0 p' ]9 X) o& y" A" g. xtion in the male genitalia from birth to maturity. J. Urol., 48:
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