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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
( K2 c& T1 W; F; u2 h, EGONADOTROPIN& g" B: U; ~/ ^2 u. J3 s  B4 K( C
RICHARD C. KLUGO* AND JOSEPH C. CERNY' b6 @' j- @8 o6 E9 ^% U, p7 O$ G
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan4 [/ E# ~9 z1 I  J! U: f
ABSTRACT
) H  M3 B* e& ?  I/ A2 z  O4 H0 k: OFive patients were treated with gonadotropin and topical testosterone for micropenis associated: u7 o* s: d, {7 b0 E
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
7 y0 \1 z( @/ m/ }7 G7 Vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 q& H& ]5 r% h& A
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 f# M' T/ ]" m+ u3 n& nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 ?0 ?$ S( w3 m* m' m
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average. F9 K; R. a9 @9 }) W6 x
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 Q  \4 W9 y( v3 ^8 `* v, R: Z% Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
1 _$ x. f3 W0 ]7 Z- sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ [. o8 L8 w9 ~growth. The response appears to be greater in younger children, which is consistent with previ-
$ T6 a! t" ]6 Z, j% Wously published studies of age-related 5 reductase activity.
3 o8 S; h3 x. X5 D* m0 G! SChildren with microphallus regardless of its etiology will$ O, E( q- a% ]8 h1 {
require augmentation or consideration for alteration of exter-: s8 X' K1 R: N+ }+ e: m; y
nal genitalia. In many instances urethroplasty for hypo-1 M- H! v1 a# z  G4 M
spadias is easier with previous stimulation of phallic growth.$ I9 Y' t, o6 I7 A+ g2 K9 I6 l! t
The use of testosterone administered parenterally or topically1 l$ F: e8 k9 a5 i- {
has produced effective phallic growth. 1- 3 The mechanism of. Z8 `2 |' ~  u! H% n
response has been considered as local or systemic. With this
+ F8 F+ l( ]. pin mind we studied 5 children with microphallus for response  E; \- c5 H: W/ X; z; V
to gonadotropin and to topical testosterone independently.6 ~& ]" Q/ o9 g& {5 q  z  }
MATERIALS AND METHODS
, h0 I! F" |- N& F8 Y5 ]3 SFive 46 XY male subjects between 3 and 17 years old were' z; a/ W1 y) R( g0 `0 z7 E
evaluated for serum testosterone levels and hypothalamic' p6 D% M. J1 M# w$ e7 W9 i8 r
function. Of these 5 boys 2 were considered to have Kallmann's
) F" _9 X! C  \  F/ Osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 K( s0 v8 b+ W* \5 p& E* [: flamic deficiency. After evaluation of response to luteinizing
0 a) P1 f4 x% g0 ohormone-releasing hormone these patients were treated with
' c8 k# K% K. u$ V5 C6 Y+ {( n1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* I# d9 l1 O" S; F# Eafter completion of gonadotropin therapy 10 per cent topical
* z! a- ^1 f8 f) T0 t0 K9 btestosterone was applied to the phallus twice daily for 3 weeks.% W. |5 h( X4 j2 G% h: g% {
Serum testosterone, luteinizing hormone and follicle-stimulat-
/ s! M- }3 }! o/ n* Qing hormone were monitored before, during and after comple-
  V3 a; C- ?9 g6 k# Ftion of each phase of therapy. Penile stretch length was# L9 M0 y  B8 E. Q+ S' e1 a) R
obtained by measuring from the symphysis pubis to the tip of
' H4 y1 z4 x. d/ Y8 Mthe glans. Penile circumferential (girth) measurements were
. A2 g; l, O3 U7 V8 k" Nobtained using an orthopedic digital measuring device (see
) Y2 i6 [7 R; _4 ]% u% R5 a- I1 Z" cfigure).
1 x9 ?7 @: z) ]! J# v6 u( @RESULTS
; Q" {2 }7 G$ O) i% FSerum testosterone increased moderately to levels between; y) a% ~0 n" D* K7 k1 w9 Z3 S
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' p/ S1 L1 \6 \. s' b. B8 X
terone levels with topical testosterone remained near pre-
" ^6 `* i% v' [, M4 [treatment levels (35 ng./dl.) or were elevated to similar levels+ j+ }2 t( @! k0 A) G6 j
developed after gonadotropin therapy (96 ng./dl.). Higher
7 R5 B, K+ c6 \+ M+ z9 U& Aserum levels were noted in older patients (12 and 17 years old),4 A& P- c6 m! O3 u
while lower levels persisted in younger patients (4, 8, and 103 y8 R+ H; H, p, Q. V
years old) (see table). Despite absence of profound alterations2 h. e; |- L6 @8 Q3 d" k  v$ ~7 ?( g
of serum testosterone the topical therapy provided a greater
- F9 o$ J7 ~. d) x" v2 R$ DAccepted for publication July 1, 1977. ·& m$ A. D# v9 U
Read at annual meeting of American Urological Association,
" d4 r- y: E6 z) V7 a8 I9 [5 T/ NChicago, Illinois, April 24-28, 1977.  V" I5 h% W* W1 |! ]9 q- C: ^
* Requests for reprints: Division of Urology, Henry Ford Hospital,; z$ z  `- {) k+ l' I/ c
2799 W. Grand Blvd., Detroit, Michigan 48202.
6 e8 W" r0 s' @improvement in phallic growth compared to gonadotropin.1 p( i' s) B; B2 i# L9 P, S
Average phallic growth with gonadotropin was 14.3 per cent
& j9 @  U1 ~* @* ^3 V2 H, K+ [6 O8 wincrease in length and 5.0 per cent increase of girth. Topical' O4 i( t  {+ }3 H
testosterone produced a 60.0 per cent increase of phallic length
2 u; c) S; C% Z  E: Eand 52.9 per cent increase of girth (circumference). The
: X; r9 ]' K" i# j8 H' x( ^response to topical testosterone was greatest in children be-
% r8 d4 X9 g6 ]tween 4 and 8 years old, with a gradual decrease to age 17# z" l3 e  M& S2 D7 W+ _0 i# _
years (see table).
; H. T, U  i  _- T+ d  l# ADISCUSSION
: L1 n: L8 r1 r4 l* m& b; ]' vTopical testosterone has been used effectively by other2 n$ [" ]! b: s4 t6 [/ V
clinicians but its mode of action remains controversial. Im-
9 B/ S! T4 b8 I+ I5 j1 l: V1 ?! smergut and associates reported an excellent growth response
9 I$ n, A% x7 e+ u: g! Cto topical testosterone with low levels of serum testosterone,
7 _) ^  {* y3 `7 p+ N. g! S! e& z5 Wsuggesting a local effect.1 Others have obtained growth re-4 D) I$ Q9 o% e: v0 k
sponse with high. levels of serum testosterone after topical; V+ K! x% Z$ l) ^  Y6 q' k( M3 ]& N
administration, suggesting a systemic response. 3 The use of
2 w; Y; p4 H" z, q+ X- @" Ygonadotropin to obtain levels of serum testosterone compara-
8 @7 I+ \6 K3 {$ e1 S& jble to levels obtained with topical testosterone would seem to% k$ F: N  P! C4 X3 K
provide a means to compare the relative effectiveness of
& c7 d! {+ |5 ?  l& H" R' \topical testosterone to systemic testosterone effect. It cer-5 I) I# Q1 Z/ a+ B/ Y+ l/ a
tainly has been established that gonadotropin as well as par-% X8 N! a" @( A  q/ [% J# Y! U
enteral testosterone administration will produce genital2 X% o$ b2 J- ~
growth. Our report shows that the growth of the phallus was) L) Y8 [" u( p1 a5 s% `6 m
significantly greater with topical applications than with go-
2 ^7 d& B3 ~3 u  fnadotropin, particularly in children less than 10 years old.
' e, R, k  I$ y1 C8 r& u0 cThe levels of serum testosterone remained similar or lower# D  j/ i* I. n7 I
than with gonadotropin during therapy, suggesting that topi-
& d4 }; ]$ ~9 X* gcal application produces genital growth by its local effect as
/ @/ Q, L2 A' |' swell as its systemic effect.% N) j$ d( k2 _0 i
Review of our patients and their growth response related to( f, H$ M0 }& `6 c% n
age shows a greater growth response at an earlier age. This is5 }3 q: I: _  G
consistent with the findings of Wilson and Walker, who
6 G- J9 ?; Q) ~2 c) N. U6 I3 \9 k* b( |9 greported an increased conversion of testosterone to dihydrotes-
5 \4 G0 i8 r0 l1 R9 H# Ytosterone in the foreskin of neonates and infants.4 This activ-# V3 \+ V  c, [8 C
ity gradually decreases with age until puberty when it ap-
. X8 M; z5 Y- D% T/ i& {proaches the same level of activity as peripheral skin. It may1 A( u, V6 A% ]8 z9 l# ^( z
well be that absorption of testosterone is less when applied at
$ b' P5 c0 ]: e+ X# ?an earlier age as suggested by lower serum levels in children' M  I1 K# [# a, N0 @" y
less than 10 years old. This fact may be explained by the
' A- n" I0 Z3 jgreater ability of phallic skin to convert testosterone to dihy-
. d  K9 h5 a/ `+ D# l- Y% W4 m3 K' _5 }drotestosterone at this age. Conversely, serum levels in older
) y: C4 a  d  K* k, K$ V& Apatients were higher, possibly because of decreased local0 s, R" V8 F$ P& S; m
667
' g$ C* h0 h% B7 |  m668 KLUGO AND CERNY
% V: @# N; L( u1 x1 c4 B9 P0 a" \Pt. Age# B7 R" P' {  P; i
(yrs.)8 v! J* f$ E6 c5 V  }( D* G
Serum Testosterone Phallus (cm.) Change Length
& n, n; e7 S4 f  Q* r0 r(ng./dl.) Girth x Length (%)' m. }7 ~* |0 O  ^! R
4
7 r! ]8 A9 _% j+ w/ l8 W# U9 ?2 G8- D/ a& C, r/ s& d" _0 ?
102 v- p$ p3 }" `
12
2 {6 G' t) [, {4 V$ j" K17; k2 y  K+ G% l4 y
Gonadotropin
1 ^9 d( x2 F9 W% G% C# m; |& Z71.6 2.0 X 3 16.6' `5 a+ Z+ E4 M7 I3 h1 m
50.4 4.0 X 5.0 20.0
! Q) M1 q# ]) q8 h3 ]22.0 4.5 X 4.0 25.0
( d3 k. n# [" \* D84.6 4.0 X 4.5 11.1$ s7 p) m+ a! o
85.9 4.5 X 5.5 9.0
' v$ i- `( `  z% x6 YAv. 14.3
7 E8 j2 u. Z6 d3 p# P, k9 I4) U% b5 g6 L# E+ o5 P. E% {
8
# Q# K$ l% z6 ^8 U10
0 n1 B% [* n6 s# U12, ]2 u; B$ G" C( X! X
17! H& z9 S) s8 T1 a! p
Topical testosterone
$ k; N. g4 Q* ?& H34.6 4.5 X 6.5 85' V2 p$ L% Y$ h, R' l4 g  Z. D
38.8 6.0 X 8.5 702 ^' l9 x$ c: ^- {' t' [; M0 y8 W2 l- B
40.0 6.0 X 6.5 62.5
7 n& L7 i! i5 ]% M9 V93.6 6.0 X 7.0 55.5, X& j5 M$ N! @1 v! b; f" [1 l
95.0 6.5 X 7.0 27.2
1 E! T) K) j* _2 x- }0 D  B5 ~& B: ?Av. 60.04 w) o( d" N4 A4 e7 h! p* l
available testosterone. Again, emphasis should be placed on
& X% E; ]5 b6 O; ~- |early therapy when lower levels of testosterone appear to
% N) W1 e  g! W3 Oprovide the best responses. The earlier therapy is instituted' m( c+ ^0 U5 R/ I& _
the more likely there will be an excellent response with low/ s0 a+ ]$ c/ O/ Y5 W
serum levels. Response occurs throughout adolescence as9 W5 O& Y; ]0 \% E7 c( t
noted in nomograms of phallic growth. 7 The actual response
8 \5 o6 ]/ i- xto a given serum level of testosterone is much greater at birth" J3 j3 ]" j+ f
and gradually decreases as boys reach puberty. This is most2 N) V, i8 u* ?$ n
likely related to the conversion of testosterone to dihydrotes-
: w* y! C9 j1 Ktosterone and correlates well with the studies of testosterone* [2 z9 p1 J1 b2 Q
conversion in foreskin at various ages., l4 `+ l4 L% M+ Y- s$ `
The question arises regarding early treatment as to whether7 f3 G/ E( G( B: o
one might sacrifice ultimate potential growth as with acceler-: v0 ?- D: P; e- j
ated bone growth. The situation appears quite the reverse' U0 h" o7 ^- E8 o
with phallic response. If the early growth period is not used
6 v7 M$ q# E$ K% G- {0 G/ Y9 cwhen 5a reductase activity is greatest then potential growth
9 e* ~' O; c5 M* U9 {( qmay be lost. We have not observed any regression of growth& Q+ D: Z% q# T+ W' f2 K% z
attained with topical or gonadotropin therapy. It may well
% _  J" z9 W0 o. O$ p$ Rbe that some patients will show little or no response to any
" q  M* L- H9 k4 e6 L! Uform of therapy. This would suggest a defect in the ability to
& L5 F: w+ s1 x. W% Iconvert testosterone to dihydrotestosterone and indicate that
3 N4 T, U. U( D# K) I; R2 Qphallic and peripheral skin, and subcutaneous tissue should
# Q5 L# W4 u" p  d7 Tbe compared for 5a reductase activity.& B! W. @; o3 K( i
A, loop enlarges to measure penile girth in millimeters. B,. k4 u( |  h/ h
example of penile girth computed easily and accurately.+ E4 _/ Q6 l) ~$ z  N2 N
conversion of testosterone to dihydrotestosterone. It is in this
% p3 M+ I2 M! @+ G; Q! r% iolder group that others have noted high levels of serum1 m2 W+ r! l# G* ?: H% T
testosterone with topical application. It would also appear! F( R* t# B2 m* k
that phallic response during puberty is related directly to the! q. d' p' H- ^  B0 i7 ?
serum testosterone level. There also is other evidence of local
9 D+ X; ?0 x! f% m$ z* Mresponse to testosterone with hair growth and with spermato-7 k9 J+ V% O* ?9 Q# W% G
genesis. 5• 6
9 v7 M% O! _2 B2 M/ `2 E# D" ~; WAdministration of larger doses of gonadotropin or systemic; x! z# X4 C; d6 P" y
testosterone, as well as topical applications that produce
$ p6 k/ C" L/ ^+ O9 E, Dhigher levels of serum testosterone (150 to 900 ng./dl.), will# l- N; D$ Z: w( w
also produce phallic growth but risks accelerated skeletal5 W0 j: _. S* ~$ _% b1 M: [3 i8 D
maturation even after stopping treatment. It would appear
: p7 I1 k4 ~' L. N8 R# F3 O0 dthat this may be avoided by topical applications of testosterone
$ y$ A2 }4 z" a' H6 e4 land monitoring of serum testosterone. Even with this control" G# T$ @. n, s3 u* o
the duration of our therapy did not exceed 3 weeks at any
) }  k6 b! w1 h7 n3 w6 Vtime. It is apparent that the prepuberal male subject may
. \3 n+ g- q: p: S0 s1 J0 |suffer accelerated bone growth with testosterone levels near
; O9 i/ O2 x; ~" l7 L200 ng./dl. When skeletal maturation is complete the level of
, b) y1 j# [! I+ _6 lserum testosterone can be maintained in the 700 to 1,300 ng./) C9 [" N, ^1 ~, G5 x$ y
dl. range to stimulate phallic growth and secondary sexual9 M% Q* g) D7 l0 j
changes. Therefore, after skeletal maturation parenteral tes-
2 Z/ M/ w  T0 m+ D; f) rtosterone may be used to advantage. Before skeletal matura-
5 i3 }3 m% x: q: w6 j" \tion care must be taken to avoid maintaining levels of serum
+ P% T: d( h/ @& H. w$ a  V- Atestosterone more than 100 ng./dl. Low-dose gonadotropin
% c# v0 K' w  d& s" Q! ^$ jdepends upon intrinsic testicular activity and may require+ t  ?2 ^: b, J# c# W
prolonged administration for any response.
0 o9 }1 T$ g! P3 ]3 QAlternately, topical testosterone does not depend upon tes-7 k9 g) |8 j5 p. j
ticular function and may provide a more constant level of. W" G2 C/ @- h$ w* G; k
REFERENCES. D/ e+ m, l! r& B0 Q
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% t2 V8 {- p* W  c
R.: The local application of testosterone cream to the prepub-# y5 k. ]7 v8 G' Z" [. [% j! ?
ertal phallus. J. Urol., 105: 905, 1971.
/ O( u. i- X8 l8 T3 n7 |2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 B$ p) x8 D5 P# W( B
treatment for micropenis during early childhood. J. Pediat.,
" E, S! n. S) E9 ~83: 247, 1973.! v* u% x' e& C- u& F% ~2 \
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 Q) I* c" e/ C2 x
one therapy for penile growth. Urology, 6: 708, 1975.
. A$ ]" p) S+ [, K; v: a; H4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: C2 p  |, M6 @  i( sto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
  [) d4 |' D8 z5 |) r" dskin slices of man. J. Clin. Invest., 48: 371, 1969.
) \& _3 L. U2 H+ {* K3 k, }: R- Q5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
6 T0 ]$ J% [: T6 q' hby topical application of androgens. J.A.M.A., 191: 521, 1965.' _8 k# Y2 E$ x& r: h7 U' U
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
1 G% j+ M* V7 H; i8 B, iandrogenic effect of interstitial cell tumor of the testis. J.
# a6 S1 y0 o9 ^& X2 |, f7 P) i( aUrol., 104: 774, 1970.
. V! ?# h. k' d! e7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-- s; d, @4 T8 }9 v
tion in the male genitalia from birth to maturity. J. Urol., 48:
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