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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 m) h7 A; Z2 A* H8 @7 \  XGONADOTROPIN( l& g- C; Z# Y* F1 N5 f) a
RICHARD C. KLUGO* AND JOSEPH C. CERNY* z" S4 b/ p* t( p4 Y
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
. G8 D- [" \2 w; k2 T! qABSTRACT- O' S3 U+ b6 y: z) l8 h9 d4 r
Five patients were treated with gonadotropin and topical testosterone for micropenis associated6 |9 C+ l! N9 N/ e  }
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. I6 u. K6 ^% p9 o# g! d1 f- Q) ]tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 f) b2 G" a( E0 n; E( i0 [" Z8 `8 scream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" t1 ]# O  q% W8 Ifor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent; N+ y" T2 h7 x+ L3 x5 W
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
8 L: p, ?) u5 W" y7 C; D( [0 p/ r/ Pincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
! C# a9 F2 a( A# l4 doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' v: x1 B9 l* B  K$ }8 hstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 q6 |# @- m  ~+ e! f
growth. The response appears to be greater in younger children, which is consistent with previ-
1 M' ^% x0 Z9 @4 Hously published studies of age-related 5 reductase activity.
' a1 R$ X! Y2 z8 FChildren with microphallus regardless of its etiology will
4 }* I4 ?9 q) w1 f$ C7 p! G0 `require augmentation or consideration for alteration of exter-* B! D  ~7 C- o. y: m4 d
nal genitalia. In many instances urethroplasty for hypo-
9 t# B" M* e, P; i+ @+ u, c& v1 }spadias is easier with previous stimulation of phallic growth.
/ D- |5 s4 C5 J# d3 W+ i# ~The use of testosterone administered parenterally or topically9 G  u3 ~/ v( {! m
has produced effective phallic growth. 1- 3 The mechanism of& ^, M+ n8 D/ x$ Y: b* H3 N
response has been considered as local or systemic. With this  Q7 ~/ d: Z; I/ |9 P; z& m
in mind we studied 5 children with microphallus for response
! C9 o2 n- j& T  Jto gonadotropin and to topical testosterone independently.
- i  x7 U6 B3 M: CMATERIALS AND METHODS
) a2 h+ m% c1 O7 O9 VFive 46 XY male subjects between 3 and 17 years old were
: D. j0 S" J) {0 vevaluated for serum testosterone levels and hypothalamic
! K0 m! z5 f9 z1 G% Kfunction. Of these 5 boys 2 were considered to have Kallmann's
. p6 `9 x6 z/ f- @syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 r1 f2 W9 J" i8 h
lamic deficiency. After evaluation of response to luteinizing
8 j; A% U. h$ U) xhormone-releasing hormone these patients were treated with+ a5 F: S8 M: S4 Q: S7 Q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: R3 s+ v: _' Y- V" fafter completion of gonadotropin therapy 10 per cent topical
! \8 d% b6 U) u8 }* _. rtestosterone was applied to the phallus twice daily for 3 weeks.) Z3 q6 ?' j3 D; b. x1 o. y
Serum testosterone, luteinizing hormone and follicle-stimulat-4 y5 e( s& p1 \! F( E' k+ ~
ing hormone were monitored before, during and after comple-
* o, F2 H! E' V$ Htion of each phase of therapy. Penile stretch length was( [8 m' K+ q7 Z, ]
obtained by measuring from the symphysis pubis to the tip of# \: r9 e2 }0 @/ |' g# Z
the glans. Penile circumferential (girth) measurements were
' d9 c  G5 y: q! x0 k, {obtained using an orthopedic digital measuring device (see$ U7 _; X/ P4 k. z/ x1 |! {# k
figure).# v; C! W% G6 t; p( A/ ^
RESULTS
. C; j* p% Q9 C6 [Serum testosterone increased moderately to levels between
7 y/ e0 ^6 n% ]) z$ Z! ?9 J; x50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-. r& B; O5 {- E- `- l
terone levels with topical testosterone remained near pre-
' C' P8 q# j5 [$ e1 |: streatment levels (35 ng./dl.) or were elevated to similar levels
$ J5 b7 l( _( {) Fdeveloped after gonadotropin therapy (96 ng./dl.). Higher
! z' l; o  h! z+ z0 f) L( |# xserum levels were noted in older patients (12 and 17 years old),
: G( M# I" H  twhile lower levels persisted in younger patients (4, 8, and 10
. {; `: e6 e9 Y; g: j  Syears old) (see table). Despite absence of profound alterations
- g: u  u) V( P5 Y( Xof serum testosterone the topical therapy provided a greater* j7 N0 H- _% A. ^
Accepted for publication July 1, 1977. ·% f5 m+ q  e% ?% N, k. e2 S% U+ s9 {
Read at annual meeting of American Urological Association,& a3 j+ y7 i5 t
Chicago, Illinois, April 24-28, 1977.
- n: b4 {+ C8 V* Requests for reprints: Division of Urology, Henry Ford Hospital,( z4 j* t2 N6 E1 ~! s9 Q; K
2799 W. Grand Blvd., Detroit, Michigan 48202.
$ }7 k3 i4 r( k, p! Cimprovement in phallic growth compared to gonadotropin.! R, n" K+ ~: l' W% Q" K
Average phallic growth with gonadotropin was 14.3 per cent' q# _% v" f- P9 t
increase in length and 5.0 per cent increase of girth. Topical
$ r1 t& A$ D+ S$ v! u5 b! ~testosterone produced a 60.0 per cent increase of phallic length9 G, B& `6 D5 n- }3 e, g
and 52.9 per cent increase of girth (circumference). The8 n3 `# M& {0 l( p. y" {0 Y
response to topical testosterone was greatest in children be-6 q7 ~% N. s$ h+ l6 N- ^, t
tween 4 and 8 years old, with a gradual decrease to age 170 G4 ?8 i, S+ d; R# _- F! I, K( e
years (see table).: m" n! s& @) j, [5 V4 J
DISCUSSION  \: D( {/ ?# v4 U! p
Topical testosterone has been used effectively by other* N9 Q$ C4 G, g* o/ ~. V# K8 `
clinicians but its mode of action remains controversial. Im-
, z! T: p" H6 H+ _  qmergut and associates reported an excellent growth response  H' Y8 X# H# e  [% x5 e8 X
to topical testosterone with low levels of serum testosterone,# E1 D8 }  w# n( t- Z, c
suggesting a local effect.1 Others have obtained growth re-
) g7 c* w# Q" {sponse with high. levels of serum testosterone after topical- s4 B" P# j+ I$ k4 h
administration, suggesting a systemic response. 3 The use of
* z* D5 D! o0 egonadotropin to obtain levels of serum testosterone compara-
/ F9 a/ x3 `! I9 a6 c- r' yble to levels obtained with topical testosterone would seem to
: l3 [. `) j. @* v: j2 T* Cprovide a means to compare the relative effectiveness of
( O( Q' D4 d7 v! _4 \/ Jtopical testosterone to systemic testosterone effect. It cer-4 n( V; g( I+ E
tainly has been established that gonadotropin as well as par-
' n+ \) x3 q& s) D3 S3 K6 yenteral testosterone administration will produce genital
- p4 D& R- r6 W; }$ Ugrowth. Our report shows that the growth of the phallus was
1 f- ]# H: E( L* ?# t3 Lsignificantly greater with topical applications than with go-
7 s& u6 ~" J0 l& e" \) xnadotropin, particularly in children less than 10 years old.
4 V) l9 T; w4 ~% q. j- jThe levels of serum testosterone remained similar or lower& v; {$ X) f4 B' t; y. E' Q+ e
than with gonadotropin during therapy, suggesting that topi-
& p) t8 G4 E) n# S! o7 Q3 qcal application produces genital growth by its local effect as
6 E& ^$ o& s* _% Y8 A6 awell as its systemic effect.6 x* r0 G, L. r8 R+ ?
Review of our patients and their growth response related to. _+ T3 p1 O$ X  |, a# N
age shows a greater growth response at an earlier age. This is
% i$ J  |! L+ z1 Bconsistent with the findings of Wilson and Walker, who+ B+ ^0 d, }  D8 l3 Z0 s- L7 s# o
reported an increased conversion of testosterone to dihydrotes-- `/ W3 z" b# K5 o( O) M9 a$ v
tosterone in the foreskin of neonates and infants.4 This activ-/ T9 x- `$ e( I8 x
ity gradually decreases with age until puberty when it ap-* W  w5 |+ q' q6 b5 I# ~
proaches the same level of activity as peripheral skin. It may3 _) l5 D5 K5 c; S* X! D- R7 M3 Q
well be that absorption of testosterone is less when applied at, S2 L) x4 g$ ^, k0 p
an earlier age as suggested by lower serum levels in children
' t; F* m& L# @less than 10 years old. This fact may be explained by the! y# B/ b0 C: t" E7 B
greater ability of phallic skin to convert testosterone to dihy-7 t4 Z4 U- U, Q  G7 \/ c% W0 ~
drotestosterone at this age. Conversely, serum levels in older1 g+ l& b7 D7 ^
patients were higher, possibly because of decreased local
8 G4 ]+ j- r! ]5 D0 m0 V: o/ U667
5 i9 O  C/ m2 N' F/ }1 @668 KLUGO AND CERNY
+ s7 V( y" q" b  j4 \# w6 |& cPt. Age
( E* r" i! s3 Y5 E8 V(yrs.)' A# ~( }% u7 f( T" n: f5 j
Serum Testosterone Phallus (cm.) Change Length" P. l: ^6 b, [
(ng./dl.) Girth x Length (%)& M1 k; X, k# n
4
2 g7 M. C% S; T) T  |82 E+ M* ?: ?5 I% i$ @
10" t. `: A  C% K1 M( B
12
" a+ M% c" {3 y17
- x' j3 ^5 f  t7 [Gonadotropin
: w# n1 _8 Y! d4 ]/ o8 M71.6 2.0 X 3 16.6
( S: Y- z6 V5 [6 @) v. v/ o& j50.4 4.0 X 5.0 20.01 c3 L9 C4 ]1 l3 a9 _% f. q
22.0 4.5 X 4.0 25.0
" k' j9 x; n$ [" b+ j7 p84.6 4.0 X 4.5 11.1
9 o# u) _& q7 c7 ]" x85.9 4.5 X 5.5 9.0
. }3 X* O! b  N9 |# wAv. 14.3
$ S$ U# D/ u1 ]% S1 h/ x$ S4; u! R6 [- m& q* s/ K! ~5 P$ g' h: R
8
" ^0 B9 z& ]; A; V109 F, f0 I* b) U3 C
12
# [0 K& q1 L% A7 k- K17) E- m+ A# X# x# M0 d% {! L
Topical testosterone# [1 [- h1 C, d$ A
34.6 4.5 X 6.5 859 N4 a" @7 l+ x, n3 O3 Y
38.8 6.0 X 8.5 709 f2 W0 Y1 f4 _8 Z# s" U" \5 r
40.0 6.0 X 6.5 62.52 R+ R' a, z' K" C" ?) R
93.6 6.0 X 7.0 55.5
6 Q5 v& _7 f5 E1 @& q" Q95.0 6.5 X 7.0 27.2
% n0 }8 y2 F+ i7 b' P0 @% p6 P% j7 rAv. 60.0
! G2 s- d: Y- D- @* q# L2 t% K4 qavailable testosterone. Again, emphasis should be placed on4 y) w/ g$ w2 ~
early therapy when lower levels of testosterone appear to1 H; }# a. c( e& `) I
provide the best responses. The earlier therapy is instituted
$ I% W0 _. R8 }the more likely there will be an excellent response with low
  O8 n( J  m# b9 V  dserum levels. Response occurs throughout adolescence as
8 L/ N7 k# K: Cnoted in nomograms of phallic growth. 7 The actual response
" k5 ^/ \/ a5 v0 v1 ^( N8 T" ato a given serum level of testosterone is much greater at birth
) ]. I3 o2 N+ r: d) A0 _& Fand gradually decreases as boys reach puberty. This is most
: Z4 y0 W. `+ T9 ?% ylikely related to the conversion of testosterone to dihydrotes-# j$ s0 ]; l3 o  Y$ u( d
tosterone and correlates well with the studies of testosterone
  D1 s3 ^% V2 c2 Aconversion in foreskin at various ages.
! l. X$ `. n" k- g. KThe question arises regarding early treatment as to whether+ D8 W$ t8 Z( K# ?- P4 U! T9 Q! J
one might sacrifice ultimate potential growth as with acceler-
) S4 T' q7 w! Y3 ?& R$ _9 p/ Iated bone growth. The situation appears quite the reverse, u  H7 V& @& P; ~
with phallic response. If the early growth period is not used
8 b1 {% b9 v+ L$ ^when 5a reductase activity is greatest then potential growth
# v3 C2 e7 k& Umay be lost. We have not observed any regression of growth! @3 Z/ u. T& ^8 ^+ _0 i3 d) m- q
attained with topical or gonadotropin therapy. It may well3 G$ _  H+ n$ }
be that some patients will show little or no response to any
. V- q- \) W# Jform of therapy. This would suggest a defect in the ability to
/ y8 V4 z( E5 d- `: xconvert testosterone to dihydrotestosterone and indicate that
" n0 g- C% v9 ?. hphallic and peripheral skin, and subcutaneous tissue should$ _* T4 Y4 J' O* j6 x. _
be compared for 5a reductase activity.
! e6 Z$ _! Q" i0 F8 d6 `& @A, loop enlarges to measure penile girth in millimeters. B,
0 p$ s2 U* L) Z; A, h4 y# Texample of penile girth computed easily and accurately.# R: X+ S( s) Z, Z
conversion of testosterone to dihydrotestosterone. It is in this# b# W$ O$ E% b  X0 P
older group that others have noted high levels of serum
. e2 l( q$ N9 t% R9 V% {6 Rtestosterone with topical application. It would also appear
0 L' ]6 F% P4 G9 O0 Lthat phallic response during puberty is related directly to the- Q8 m6 q% A2 x( d/ j) v
serum testosterone level. There also is other evidence of local! b- R$ W  Z9 X
response to testosterone with hair growth and with spermato-- w( \( D& \& D: S; Y
genesis. 5• 6
% B! i8 d/ m  I/ d2 f5 tAdministration of larger doses of gonadotropin or systemic3 C) {6 I# V0 i" ]; t
testosterone, as well as topical applications that produce7 m. T- T8 t' W: O4 V& A# b# I
higher levels of serum testosterone (150 to 900 ng./dl.), will# z/ v& X/ |! T) ]$ _
also produce phallic growth but risks accelerated skeletal
& ^( J0 P- b! [8 Q  qmaturation even after stopping treatment. It would appear
/ z3 e' b: b; l; y8 Q" uthat this may be avoided by topical applications of testosterone
: g4 g' a" b- v7 u3 Iand monitoring of serum testosterone. Even with this control3 Z% Q% f, l1 H# x
the duration of our therapy did not exceed 3 weeks at any
" |0 M$ G* Q5 V4 m" F4 E$ S4 Gtime. It is apparent that the prepuberal male subject may% m+ o( W0 N& J8 P
suffer accelerated bone growth with testosterone levels near- z# `  b& l5 H4 @$ }
200 ng./dl. When skeletal maturation is complete the level of
, l% V0 y6 d$ M7 u( Q+ V% eserum testosterone can be maintained in the 700 to 1,300 ng./
1 f9 f  N: S% W  ^, n8 Z, Tdl. range to stimulate phallic growth and secondary sexual
# D+ [- v, F. X; x) r+ vchanges. Therefore, after skeletal maturation parenteral tes-! r1 Y5 a8 o* T" M
tosterone may be used to advantage. Before skeletal matura-
% @7 N2 L0 [3 w3 H3 Ption care must be taken to avoid maintaining levels of serum
1 E: h4 ?5 V$ e+ N+ f6 Ttestosterone more than 100 ng./dl. Low-dose gonadotropin! [( {( W8 a* G& r; e* T
depends upon intrinsic testicular activity and may require
9 I  N- H+ x, G% J7 d/ qprolonged administration for any response.  ]3 h# |  r- [/ r6 y; A
Alternately, topical testosterone does not depend upon tes-
2 J9 S5 P$ ^& K9 c+ u, w+ pticular function and may provide a more constant level of
$ I5 r* P) [( _) H2 S. XREFERENCES
0 F) o; Q7 u6 |( j% G1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ _* B+ b1 C5 J; ~R.: The local application of testosterone cream to the prepub-
. K8 r& t; N$ |7 j4 }( Iertal phallus. J. Urol., 105: 905, 1971.
9 k) y5 I- c9 j. N# u! Q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- Z0 T: }; Z; s) Y* Y" f4 n# d
treatment for micropenis during early childhood. J. Pediat.,
) D7 j" k% W8 I9 P& n7 n83: 247, 1973.+ O8 S1 B+ ?8 v) B7 }( I
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& y3 x4 N+ u' x1 I  a" a
one therapy for penile growth. Urology, 6: 708, 1975.7 y4 V) N3 R( I
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
2 k: X1 J: y( O# ~5 {to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, A% Y' m1 S+ r0 k9 Q1 q
skin slices of man. J. Clin. Invest., 48: 371, 1969.9 R& O8 h' ?5 y. s7 ^, o, W
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 A- o% o/ c  E" U- P
by topical application of androgens. J.A.M.A., 191: 521, 1965.
8 S- L3 A! W% @- O! v, L; H6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local( b2 j% I+ ]3 S  A
androgenic effect of interstitial cell tumor of the testis. J.( u4 ]# u( R; ?- K, R
Urol., 104: 774, 1970.
- C& V. B, h# E( _7 J7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 h3 l0 [8 M; ~1 k! C5 }4 x, k
tion in the male genitalia from birth to maturity. J. Urol., 48:
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