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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
# h' F" ]' k. g5 K1 T$ r) {GONADOTROPIN' k& G: C5 S3 j6 \5 U& k3 x
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 M7 c) `; _; j
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 k! z+ }; i4 {ABSTRACT& s" n$ i5 j# u
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
4 z& T3 c( _& P5 m7 Nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- G# f+ G. y7 k0 S& l1 G( c
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone5 V( _8 g1 J3 l: v! p
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: Q* b3 F, }& i, Z
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
: j1 J8 K8 V& w3 Z5 Mincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, o/ X9 u9 f3 X5 Aincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% ^- b/ Y% ]9 moccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This& }5 [, X6 i" d: o/ |( @. h
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
9 J& R4 [- g6 ?growth. The response appears to be greater in younger children, which is consistent with previ-, n' S4 o! ?6 a4 W5 U6 H' W* S% w
ously published studies of age-related 5 reductase activity.
2 [& S' R* [3 t- S5 ZChildren with microphallus regardless of its etiology will/ I3 s4 b( I& y! V3 X7 D
require augmentation or consideration for alteration of exter-+ g( z8 O" m$ M# N: w7 A
nal genitalia. In many instances urethroplasty for hypo-, t- g* ~7 f0 e. }- a. K
spadias is easier with previous stimulation of phallic growth.7 d1 y' I! b- C' C  e  ^7 E1 _
The use of testosterone administered parenterally or topically
: s- G# g& L1 g& khas produced effective phallic growth. 1- 3 The mechanism of! d! U! f/ \; K' d8 f: i1 K; I
response has been considered as local or systemic. With this2 ?0 K$ j0 ]$ R( w
in mind we studied 5 children with microphallus for response8 ~# |6 p+ A8 b5 J( \; ~, @! H' ~
to gonadotropin and to topical testosterone independently.
  z) x) z8 _) [6 F) D4 eMATERIALS AND METHODS
0 i6 e' X9 l, \/ T- d" o' rFive 46 XY male subjects between 3 and 17 years old were
0 w. p: G+ G7 Y6 Y* a! h) wevaluated for serum testosterone levels and hypothalamic3 e+ }% _+ o! [- }" t( o
function. Of these 5 boys 2 were considered to have Kallmann's
% L) Y, s" c6 S) z4 X) Ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 L( r4 G, ~$ ]" x- |lamic deficiency. After evaluation of response to luteinizing
8 s5 \4 R; q0 j* U' `hormone-releasing hormone these patients were treated with
( e  c: B3 m8 f0 n1,000 units of gonadotropin weekly for 3 weeks. Six weeks( w' V8 ^- L3 \, C: k1 z
after completion of gonadotropin therapy 10 per cent topical7 y) d4 D8 u! l$ K9 E
testosterone was applied to the phallus twice daily for 3 weeks.
  t8 W; L  v- G0 ySerum testosterone, luteinizing hormone and follicle-stimulat-
. I- s" z; _# C3 _4 ]ing hormone were monitored before, during and after comple-
1 j" Z5 P8 v& J# m( I/ F% gtion of each phase of therapy. Penile stretch length was5 I* a: c0 a+ r2 g
obtained by measuring from the symphysis pubis to the tip of
4 m8 ^% P& F5 a9 s8 cthe glans. Penile circumferential (girth) measurements were
8 I: S: G* j1 f# L* s& B  ^1 _5 M5 Jobtained using an orthopedic digital measuring device (see; K9 f, i' x5 s4 E! j
figure).
7 s& K6 q4 M7 Y; ?* F+ l& uRESULTS. X) m4 e! _$ Z
Serum testosterone increased moderately to levels between0 ?. i. g# ?( ?
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-& H. s% b" i! O2 ]4 n
terone levels with topical testosterone remained near pre-( s3 D2 t/ [: E& J! F1 L0 n
treatment levels (35 ng./dl.) or were elevated to similar levels
9 A& P, p5 u% q, K: X$ ~9 Ldeveloped after gonadotropin therapy (96 ng./dl.). Higher
0 s3 k5 T& y) i; K8 j% Yserum levels were noted in older patients (12 and 17 years old),
3 `) p- u4 \; B' D/ b3 g! xwhile lower levels persisted in younger patients (4, 8, and 10
( G/ t, ~' J' ?3 C* C+ v7 byears old) (see table). Despite absence of profound alterations
( a+ u; s) ^9 q4 Tof serum testosterone the topical therapy provided a greater
  G% W, }0 A3 M( a3 xAccepted for publication July 1, 1977. ·
8 K: Q; n9 V' A/ \) BRead at annual meeting of American Urological Association,
1 F' r7 G& c: V' T  _5 A* ?* `  u, lChicago, Illinois, April 24-28, 1977.6 _' e5 G* o, @2 D" Z; K5 l9 q; @
* Requests for reprints: Division of Urology, Henry Ford Hospital,
- b1 p. G+ J# K6 Z; a( u* _9 |2799 W. Grand Blvd., Detroit, Michigan 48202.
5 `* n. p* w' b% C0 c! L- Iimprovement in phallic growth compared to gonadotropin.
8 B% M: }4 p+ W7 [$ E1 ]/ uAverage phallic growth with gonadotropin was 14.3 per cent. H, q  T  ]2 @# O! h  c
increase in length and 5.0 per cent increase of girth. Topical5 a6 c: k  |+ ]2 O
testosterone produced a 60.0 per cent increase of phallic length
% ?. D" }7 e( l. g: Fand 52.9 per cent increase of girth (circumference). The  p3 l- o* N% h( `8 P
response to topical testosterone was greatest in children be-7 U% N3 p0 {2 |/ |! g( _4 B
tween 4 and 8 years old, with a gradual decrease to age 17/ ?4 B+ V; K$ ?
years (see table).4 i3 ?$ Z6 R9 L8 @# p* r; @
DISCUSSION
9 p& D1 ?0 x- v( _* _/ @" cTopical testosterone has been used effectively by other5 ^0 J3 T5 J$ r! w
clinicians but its mode of action remains controversial. Im-
6 i0 }1 R6 N1 H! P( {/ a+ Tmergut and associates reported an excellent growth response
* E; j3 i, x+ t2 v: ~- V  vto topical testosterone with low levels of serum testosterone,
2 k3 M5 S( X1 Ssuggesting a local effect.1 Others have obtained growth re-
( N. S. B  p- Y8 S) s7 B$ Osponse with high. levels of serum testosterone after topical
6 d/ u7 |* ?# Y) c* _% Dadministration, suggesting a systemic response. 3 The use of
/ p0 \2 ~  n$ E: H4 n0 d& c/ d8 M- T: Egonadotropin to obtain levels of serum testosterone compara-! u. H  L/ R1 t
ble to levels obtained with topical testosterone would seem to9 X/ @. T4 x2 ~% I0 b, X9 b
provide a means to compare the relative effectiveness of
4 J3 U3 k% `, K0 g3 c1 s# I) ^topical testosterone to systemic testosterone effect. It cer-6 O: A  ^3 X: \! `3 \
tainly has been established that gonadotropin as well as par-
' `% G8 M$ D! y8 Q$ p* ?enteral testosterone administration will produce genital
- Q# w% l; u* F- |9 |3 b  Agrowth. Our report shows that the growth of the phallus was( l) J2 q7 ?& \8 Z' Y8 e3 v  g
significantly greater with topical applications than with go-
' _9 D. M" k( P$ F. Wnadotropin, particularly in children less than 10 years old.
. I5 e) w4 k- C8 D( dThe levels of serum testosterone remained similar or lower2 k2 ]6 H) e: l4 E1 B0 q& p. {
than with gonadotropin during therapy, suggesting that topi-5 C9 Q% I& Q+ B+ u4 D
cal application produces genital growth by its local effect as
$ n2 l' p2 j+ T. pwell as its systemic effect.
( E/ l( e" A9 g% j7 VReview of our patients and their growth response related to
  n9 J* V& K! F  [( R3 ?age shows a greater growth response at an earlier age. This is
! B7 `. N% T7 f) z, u0 I: |consistent with the findings of Wilson and Walker, who
& k4 v5 @) n- l) f& l9 ureported an increased conversion of testosterone to dihydrotes-  F) F) b; S; d4 h/ |
tosterone in the foreskin of neonates and infants.4 This activ-
) Z) f- t7 Y2 u/ bity gradually decreases with age until puberty when it ap-
1 X' q0 |) I. a5 }- M6 tproaches the same level of activity as peripheral skin. It may
; a* z4 }' D3 t  U; Pwell be that absorption of testosterone is less when applied at  ~  i: s! p* i1 a1 K9 E
an earlier age as suggested by lower serum levels in children  O6 J1 Q( T; m; @8 j+ ?/ ^1 S+ w  {
less than 10 years old. This fact may be explained by the: @2 W% S* k# ^0 y% y% Q4 x
greater ability of phallic skin to convert testosterone to dihy-
0 K$ G/ v* h% D7 t. y4 M. Vdrotestosterone at this age. Conversely, serum levels in older) ~+ [! g* d% N
patients were higher, possibly because of decreased local
0 n; [# S( N+ |/ z" x  A667
* i, {9 [, R3 e) n668 KLUGO AND CERNY  u" B2 q* U$ |. A  s1 m
Pt. Age
5 ^6 o6 K8 v9 O$ o3 n! h(yrs.)
2 [4 |# M( N. b# @$ @+ [Serum Testosterone Phallus (cm.) Change Length
3 s! A% p! n- V9 I(ng./dl.) Girth x Length (%)" }) m+ t7 i) Z$ q1 h) Q
4
7 o( q+ ~+ Z" }' _: T2 [5 B8: \/ m% j6 m! i. }# [& w# U7 l
10
; Q3 @  s( K' k4 ]127 f$ b" p1 K, k# p6 `9 J5 z
17
' G+ [& n: r9 S' eGonadotropin
' u# t* F/ o8 R  x71.6 2.0 X 3 16.6
0 H& N  B9 G! j/ E/ k, Q50.4 4.0 X 5.0 20.00 R! a' ~/ }5 ?/ Y) D& z$ {# R+ m1 b
22.0 4.5 X 4.0 25.0
( y" O( f9 Z0 |( ^84.6 4.0 X 4.5 11.1
4 m) ~! U- [( m85.9 4.5 X 5.5 9.0$ Q: |' k& i7 G  ^- I
Av. 14.3& `0 j  m- J7 Q* o; V7 B  s
4
6 {9 i7 [; `/ C0 G& e# a8" }; \) q  E4 L" S
10
3 k" n$ V: Q" u" t" K$ C& A12
4 ]* E' L7 C" }1 b/ R0 }17% Y; ?1 Y% Y( U  z0 B, J* m
Topical testosterone
. A( e$ r8 v  M0 D34.6 4.5 X 6.5 85
5 j, v: T7 C/ `  H# m38.8 6.0 X 8.5 70
+ N+ f5 N3 {/ ^: V3 T/ ?7 `3 z40.0 6.0 X 6.5 62.5
/ d% D( {6 e, f& ^. N93.6 6.0 X 7.0 55.53 U3 Y; M) I" ^9 P0 v. r' d6 m
95.0 6.5 X 7.0 27.2
! h, j0 E4 {9 g8 E0 E5 x% p2 _Av. 60.0/ m. z1 W2 I+ p4 }
available testosterone. Again, emphasis should be placed on& V0 o* G0 N) ~  s) E  p! ?9 K2 B
early therapy when lower levels of testosterone appear to, l. c; f5 O' A2 z' f
provide the best responses. The earlier therapy is instituted
$ @/ l& p7 Z6 j9 w, dthe more likely there will be an excellent response with low  g: E  g. b* i. w9 W; L3 _0 f2 T
serum levels. Response occurs throughout adolescence as
# c6 q! R$ }# \7 v( lnoted in nomograms of phallic growth. 7 The actual response
# c2 s5 C0 n' i- d% [to a given serum level of testosterone is much greater at birth
" V2 C6 }' I% |0 T- O  Y/ e: xand gradually decreases as boys reach puberty. This is most
- l/ s$ f/ K8 r" Q; Dlikely related to the conversion of testosterone to dihydrotes-2 i3 A* I% X1 r5 E! x
tosterone and correlates well with the studies of testosterone
4 L& b% x' t6 Y/ {  jconversion in foreskin at various ages.6 P: n6 x& c: f+ `* F
The question arises regarding early treatment as to whether
4 |8 [6 q5 l; W" Y0 P' f7 A# Kone might sacrifice ultimate potential growth as with acceler-
! ]: D0 x4 L; M3 i! Vated bone growth. The situation appears quite the reverse4 }/ ~8 g' i5 h2 d4 R8 i+ L1 j% p
with phallic response. If the early growth period is not used
6 K/ W. ~: I+ x# x) v1 y5 R& J; Ewhen 5a reductase activity is greatest then potential growth4 h1 N+ P( K5 s, |- C# t! _/ O
may be lost. We have not observed any regression of growth
4 ~3 Y2 ]( A( \1 y; I; rattained with topical or gonadotropin therapy. It may well
: {8 u) D. W# ?7 w; wbe that some patients will show little or no response to any
( J' I3 ]/ b: a; S' t4 ]! Xform of therapy. This would suggest a defect in the ability to- n1 p' |$ B) r
convert testosterone to dihydrotestosterone and indicate that
# A# O0 l, Y- U* C. A- uphallic and peripheral skin, and subcutaneous tissue should
4 ^' d# E4 E7 x3 r0 T! [% n: X/ Ybe compared for 5a reductase activity./ n6 U% |5 X) Z& C# Z5 ^, [' s  K
A, loop enlarges to measure penile girth in millimeters. B,
% z( v- x6 C; Z3 A$ C/ U4 ~example of penile girth computed easily and accurately.
  |$ C) ~) {/ t7 I8 I. Yconversion of testosterone to dihydrotestosterone. It is in this( X* K: x, F4 k) T
older group that others have noted high levels of serum! ?; p7 s) S6 O, E) H/ D* X
testosterone with topical application. It would also appear  q8 d, n) g, X! b. X; s
that phallic response during puberty is related directly to the2 \- |5 {) D0 g  q. X
serum testosterone level. There also is other evidence of local
1 l! I0 q. l6 _: R; W( Cresponse to testosterone with hair growth and with spermato-( A2 p& ~% o- o. O! J, O* O4 T
genesis. 5• 6
( o% {. R7 h% d5 [. FAdministration of larger doses of gonadotropin or systemic
. w$ h: P+ N* `! I: ttestosterone, as well as topical applications that produce
2 [' S" P2 k' A% nhigher levels of serum testosterone (150 to 900 ng./dl.), will; @1 j3 R# J7 L) N4 v1 Q8 o
also produce phallic growth but risks accelerated skeletal
6 b0 }/ T5 P2 g) k6 ^6 R9 P) lmaturation even after stopping treatment. It would appear0 j2 F% Q! x' m9 ^/ ~, T
that this may be avoided by topical applications of testosterone4 F0 J. F# U6 K( a  M2 \0 L9 P, T
and monitoring of serum testosterone. Even with this control
$ c# t- C  Y6 W+ D9 ^( athe duration of our therapy did not exceed 3 weeks at any, F* t7 V# O% z
time. It is apparent that the prepuberal male subject may! W! q( t2 l" Q9 x
suffer accelerated bone growth with testosterone levels near- S) u4 q) U: `2 ~! |1 L8 v
200 ng./dl. When skeletal maturation is complete the level of- l7 }( _1 ^! ]
serum testosterone can be maintained in the 700 to 1,300 ng./) ]0 v) P6 N, v" G
dl. range to stimulate phallic growth and secondary sexual" d. s3 I% b7 H; Q) [1 ?! T
changes. Therefore, after skeletal maturation parenteral tes-
  q) p5 p/ f7 i, x/ x6 Ytosterone may be used to advantage. Before skeletal matura-0 O' z7 S3 J1 s0 {- Q+ N8 B
tion care must be taken to avoid maintaining levels of serum
/ K: w/ L- Y& h) ~, n' a: H# G9 wtestosterone more than 100 ng./dl. Low-dose gonadotropin* z( g5 f! y6 ?# L7 v
depends upon intrinsic testicular activity and may require6 B' y% P. o/ |( h
prolonged administration for any response.* I0 j) F: c! ]' W. m6 Y
Alternately, topical testosterone does not depend upon tes-$ G  w6 W* g9 J0 }1 j5 y+ w
ticular function and may provide a more constant level of
3 _. o9 T3 c. S* B: u) X/ n/ jREFERENCES
7 ]; o1 Y; a8 @6 t) }& A1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( m+ w5 H$ c7 D. g/ `. a
R.: The local application of testosterone cream to the prepub-
1 j; w1 h. v4 Rertal phallus. J. Urol., 105: 905, 1971.$ {+ C, i7 {4 R$ m
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 B! I8 m$ }! G% U! h2 M/ T' @9 P
treatment for micropenis during early childhood. J. Pediat.,1 ^- u8 a( G" s
83: 247, 1973.
' y1 C. I' \5 I  T. b1 x3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* K0 X- i( {; |2 j  O) sone therapy for penile growth. Urology, 6: 708, 1975.
4 t/ H: Z* ^/ S2 N: Y4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- \* B0 j# X9 A1 f+ [8 Z9 p
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by  i# w2 _4 Y( b6 T* S7 T. C$ R. M$ t
skin slices of man. J. Clin. Invest., 48: 371, 1969.
8 L# w3 @% D8 ~# H/ L; w5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, ^( h% i  {% Y
by topical application of androgens. J.A.M.A., 191: 521, 1965.: b, F6 n5 ?+ [+ C" c  ?  |
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& K% N3 M$ `" _* W: e1 g
androgenic effect of interstitial cell tumor of the testis. J.
# l  Y1 j( U$ r  p, _! p. sUrol., 104: 774, 1970.
" Q7 F# ?& Y' i# c( Q+ d5 L+ D" q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 d$ y5 F. q+ e2 J3 N
tion in the male genitalia from birth to maturity. J. Urol., 48:
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