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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 M. \" `4 a$ S7 x
GONADOTROPIN- W0 m- z1 R/ b2 g& u
RICHARD C. KLUGO* AND JOSEPH C. CERNY
8 a9 k1 `, O5 b& B1 Q# oFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% r5 x9 ?# d: Q3 FABSTRACT0 n8 p2 U% k9 ^% z& f; n$ x8 q0 b8 ?
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
  N3 a' L9 \# ]# g* ]with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- A: b8 \; k" Y" r* `: V4 p9 |: t
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
  f- t# w) G8 s( \( l( z" v/ z# Zcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
- E1 O# c4 d& Q, Efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent# m( N" |5 x5 b; d
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
5 \3 P2 _9 |$ f) i. M: s8 Cincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response) ~  P: |) _- f6 E' b0 Y( _
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
: Q7 @/ P% W. c  {, R1 N8 ^+ J" Lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" H* F0 i/ n6 c- H4 P& _% C) |( F
growth. The response appears to be greater in younger children, which is consistent with previ-. p' o8 D! U3 r9 Y9 H4 G
ously published studies of age-related 5 reductase activity.
  |+ V! G, o/ I; [+ QChildren with microphallus regardless of its etiology will
3 o; x6 b/ `9 @; m. Drequire augmentation or consideration for alteration of exter-" ]/ V' o4 w: i. V
nal genitalia. In many instances urethroplasty for hypo-1 Y5 B4 g' }& S6 W% C% s% C4 `* n
spadias is easier with previous stimulation of phallic growth.0 w% W+ N; p  a) a- O
The use of testosterone administered parenterally or topically
& U0 @1 @( p+ g1 A4 Vhas produced effective phallic growth. 1- 3 The mechanism of0 J. e* G) U8 D6 c: H7 j
response has been considered as local or systemic. With this8 H- D- Y6 e  Z) w7 P
in mind we studied 5 children with microphallus for response# q7 x, `# d' M2 I9 m: X
to gonadotropin and to topical testosterone independently.
5 B$ a+ Z, y% F1 |MATERIALS AND METHODS
6 g& x  T5 g1 j8 A# [Five 46 XY male subjects between 3 and 17 years old were8 h" r. ]1 M( ]. Z0 ]
evaluated for serum testosterone levels and hypothalamic
4 ~" L( r, `* M4 x( sfunction. Of these 5 boys 2 were considered to have Kallmann's
, q5 T3 z5 d4 k9 o3 l- @% ^! s6 H1 wsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! \- T7 C/ p0 s, ~3 T2 Qlamic deficiency. After evaluation of response to luteinizing
+ b# Y0 O4 [! H# g6 Zhormone-releasing hormone these patients were treated with
& R  G6 K; M+ d3 D- ~1,000 units of gonadotropin weekly for 3 weeks. Six weeks4 r: C7 C9 w$ m$ [% Y! q
after completion of gonadotropin therapy 10 per cent topical# D) i, c/ L6 b/ X0 x
testosterone was applied to the phallus twice daily for 3 weeks., l1 F. ?' x4 ~0 L" f# z
Serum testosterone, luteinizing hormone and follicle-stimulat-/ V( A+ l. J) s
ing hormone were monitored before, during and after comple-. R! b7 j( i5 J# B3 u  _
tion of each phase of therapy. Penile stretch length was
- C3 l- S8 a/ Q8 Z" B  W9 lobtained by measuring from the symphysis pubis to the tip of! S, ]9 {7 V) f9 z, M* A. Y, h
the glans. Penile circumferential (girth) measurements were
# @) t) X, Y9 b5 z' l$ A; Gobtained using an orthopedic digital measuring device (see) D& x( O+ U# G9 P, V! r  `5 Q6 l$ H
figure).
' a6 n/ W0 `  B# y, _" e- q" ]* qRESULTS# [+ G- S6 Q1 v# X; s! c( f6 `! B
Serum testosterone increased moderately to levels between  I# q7 i" Y" x! z" ?. v9 W+ h7 B4 V
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 S* l; {& d- l# l
terone levels with topical testosterone remained near pre-) a9 ]; v( h4 J2 x& I
treatment levels (35 ng./dl.) or were elevated to similar levels
& b7 D* W, ]8 T2 \3 T4 \developed after gonadotropin therapy (96 ng./dl.). Higher" @3 L% N3 o. ?; m6 V
serum levels were noted in older patients (12 and 17 years old),4 @) v+ J  {( |( |0 |
while lower levels persisted in younger patients (4, 8, and 10$ h. J: f+ T' D# @" ^, ?0 c
years old) (see table). Despite absence of profound alterations
  J" l! C: s% |; Z6 m# y8 zof serum testosterone the topical therapy provided a greater
1 a' M% b; B) U% T' g9 hAccepted for publication July 1, 1977. ·" m4 R: a; c- r
Read at annual meeting of American Urological Association,/ r; V& o2 p0 T& N
Chicago, Illinois, April 24-28, 1977.
" @1 {2 k& e1 }+ O- x* Requests for reprints: Division of Urology, Henry Ford Hospital,0 t/ l& a3 K) V0 N
2799 W. Grand Blvd., Detroit, Michigan 48202.
" p* N4 V5 p7 N: L; E1 Pimprovement in phallic growth compared to gonadotropin.3 B9 N- a+ {. v! w
Average phallic growth with gonadotropin was 14.3 per cent: b! P0 s& ?; y( q
increase in length and 5.0 per cent increase of girth. Topical
# R* J2 x& [0 s+ a  Qtestosterone produced a 60.0 per cent increase of phallic length: X( n! o* i. T# t" g% g9 Z- h7 B( s1 M
and 52.9 per cent increase of girth (circumference). The
* y, Q% ]% K% Eresponse to topical testosterone was greatest in children be-
; p4 k( Y9 n1 ^tween 4 and 8 years old, with a gradual decrease to age 17
) ^  }0 _% P. u! Yyears (see table).$ }# D8 X9 F' n9 x4 m
DISCUSSION7 J# j) a3 U, L. }+ s
Topical testosterone has been used effectively by other$ x6 j. ~& c( _/ o# Q
clinicians but its mode of action remains controversial. Im-: z9 p- X- v! p) K2 G, N
mergut and associates reported an excellent growth response
0 W! a2 H/ n; w4 Tto topical testosterone with low levels of serum testosterone,
' [& C4 e4 L$ \" G" f# dsuggesting a local effect.1 Others have obtained growth re-" _6 b5 P6 u. M2 a: P
sponse with high. levels of serum testosterone after topical
7 M* N: g1 @" a* n) S6 }( madministration, suggesting a systemic response. 3 The use of
' v& A' [+ k7 U( v' v* vgonadotropin to obtain levels of serum testosterone compara-
! G2 G! q7 s1 h# G6 oble to levels obtained with topical testosterone would seem to+ t1 ~2 u! j& d: L% r3 e
provide a means to compare the relative effectiveness of) x$ N% T* D$ m* @1 n
topical testosterone to systemic testosterone effect. It cer-8 R' R7 z' L* l7 t7 ]
tainly has been established that gonadotropin as well as par-
4 I6 S: @0 Y! \$ I6 ]  Tenteral testosterone administration will produce genital
# N( m. |( B, J- b; z8 ]1 B. t  |growth. Our report shows that the growth of the phallus was8 T2 s) p( n5 Y& @
significantly greater with topical applications than with go-% I  W0 `1 Z0 X, ]
nadotropin, particularly in children less than 10 years old., u1 G7 ]3 r# ]; @# Y7 u/ W2 h9 q5 ^3 J
The levels of serum testosterone remained similar or lower2 w% k/ L# n8 t; o; D1 z( Y8 W
than with gonadotropin during therapy, suggesting that topi-
$ j* t) \/ [& c0 g/ mcal application produces genital growth by its local effect as
* k: `6 b) T' u1 O- }: i; \  hwell as its systemic effect.
% l: [; F! B# P5 A* G- H7 O  xReview of our patients and their growth response related to
- v% h5 X4 [# f% Yage shows a greater growth response at an earlier age. This is8 N) \5 s& o( L' d2 Z6 `
consistent with the findings of Wilson and Walker, who; ^6 D: }- P5 Y5 M0 c; W7 d
reported an increased conversion of testosterone to dihydrotes-8 A' Z6 T6 y: r; _; F: C* X6 a
tosterone in the foreskin of neonates and infants.4 This activ-6 O# k* x) L$ X- b" N  \+ b
ity gradually decreases with age until puberty when it ap-
% U: x1 k6 W. @- M& qproaches the same level of activity as peripheral skin. It may/ }& o. }* N0 c: Y
well be that absorption of testosterone is less when applied at  k9 W! u6 r, A, U  b% I" a
an earlier age as suggested by lower serum levels in children
' s  n, P0 l6 S/ U9 a& C9 g, mless than 10 years old. This fact may be explained by the
$ B7 [% y5 d+ x- L! V0 Mgreater ability of phallic skin to convert testosterone to dihy-
  W0 x' I0 ~. ^3 n8 r# e) }drotestosterone at this age. Conversely, serum levels in older
2 E- o$ R7 \( @- F) Xpatients were higher, possibly because of decreased local. V% F) I1 E2 v# s5 a
667
4 B& {$ z6 u8 x! @& e668 KLUGO AND CERNY
" C  }, B3 M) |. I- v" R9 \' i) J8 [- HPt. Age! @3 s* w( q; P) D9 S2 f# N* Q
(yrs.)+ L2 i. `; C' d6 O. L
Serum Testosterone Phallus (cm.) Change Length
; t, C/ U% \0 d7 C(ng./dl.) Girth x Length (%)! K8 S% V. _6 i: v8 a9 x, A5 L6 j
4
( ~" v  M: T' L# z1 t8
/ |/ l, K6 O' i6 M6 z10, o& I! A) G7 u2 T
12; k8 I4 \! a- N
170 |0 I2 v9 B1 B# E7 v6 K! f
Gonadotropin! }8 `3 ^' I. q5 {. V* z  d. S2 H
71.6 2.0 X 3 16.6
6 `: P! U4 z9 w0 f2 Y5 U4 |50.4 4.0 X 5.0 20.06 k4 |4 {5 s5 N$ o" U' l6 R5 d
22.0 4.5 X 4.0 25.0
7 R0 c( o% H* \7 E84.6 4.0 X 4.5 11.1
1 I7 w5 P, G  o; j5 r85.9 4.5 X 5.5 9.0
2 Y! p: u0 d( b6 w2 A. v  @Av. 14.3- u0 M6 V: ^/ J% F: T. x0 q
4
! e$ r4 f$ f  V: x) B8. R, n* i5 t& m5 R1 }
10
  k4 i( N5 z9 z, D" L12* S% J$ e9 N) ~0 P3 ^0 C
17; f4 o8 b9 `( x
Topical testosterone
9 }; B/ O+ D- e8 L* e1 k34.6 4.5 X 6.5 852 j! K9 l0 D: ?$ J2 B
38.8 6.0 X 8.5 704 `/ G% e# b/ U
40.0 6.0 X 6.5 62.5
1 C5 o' C3 O" U6 P; E93.6 6.0 X 7.0 55.5
0 n5 |9 B4 A" V( y, W95.0 6.5 X 7.0 27.2
3 O* s: t# K+ CAv. 60.0" z* M4 O, j# o
available testosterone. Again, emphasis should be placed on1 G4 J# g' q% k4 S" `: b
early therapy when lower levels of testosterone appear to! i1 l, A( c( j1 Z% k0 o
provide the best responses. The earlier therapy is instituted
9 A& ^! _1 t6 R  _the more likely there will be an excellent response with low+ [2 f, {! M& J
serum levels. Response occurs throughout adolescence as/ P9 s1 v! ]9 Z) ]1 C
noted in nomograms of phallic growth. 7 The actual response
4 S0 S4 ?. B7 T5 l9 Bto a given serum level of testosterone is much greater at birth" D0 s# d5 H: h) d3 G# G
and gradually decreases as boys reach puberty. This is most
4 H* ~. C4 _! v, M: Rlikely related to the conversion of testosterone to dihydrotes-
- x& G+ \. g: `tosterone and correlates well with the studies of testosterone
; ]$ n& K; \* L# c( H7 `2 Lconversion in foreskin at various ages.
. _: \) X: f7 b5 i) w& CThe question arises regarding early treatment as to whether& P5 f. K8 H* c. F% ?* m: K* G# k
one might sacrifice ultimate potential growth as with acceler-8 Y& H# ]1 }- [: V; O7 a( h1 M
ated bone growth. The situation appears quite the reverse* [% [9 P; [7 P4 g2 {
with phallic response. If the early growth period is not used
+ Q( {* i* {0 b( I  m+ Iwhen 5a reductase activity is greatest then potential growth# n( q" ^' d  m: A" \) O% `$ N
may be lost. We have not observed any regression of growth
; q( H( z/ r7 }, ^' a* kattained with topical or gonadotropin therapy. It may well
# ]# l4 r2 R! C2 r2 K) Y. kbe that some patients will show little or no response to any
4 ?0 {3 a& g" @5 o; z! S+ iform of therapy. This would suggest a defect in the ability to( A  R0 _4 ]$ S  J! r- w
convert testosterone to dihydrotestosterone and indicate that
: y* ]9 U* C9 D. K- _phallic and peripheral skin, and subcutaneous tissue should& i& e6 u7 _& L3 o! @1 u
be compared for 5a reductase activity.
) j0 ]9 V& X& aA, loop enlarges to measure penile girth in millimeters. B,2 r3 B; b$ ]. m3 ?4 V- b5 g
example of penile girth computed easily and accurately.
% E4 d  R6 z, t/ m$ x+ r9 cconversion of testosterone to dihydrotestosterone. It is in this
3 N+ s: t& B; a% volder group that others have noted high levels of serum* h0 O; t+ M! o) t2 @$ i; _' B6 y$ c
testosterone with topical application. It would also appear
  g! \1 z- X8 R! h$ T; i' ?1 e5 W5 nthat phallic response during puberty is related directly to the' f) m' x2 D0 m1 f# t' h1 V: q- @
serum testosterone level. There also is other evidence of local
* ]( d% F3 p  W+ s, C$ z" ^response to testosterone with hair growth and with spermato-! J' m( D. s' q7 ?2 w6 S7 `
genesis. 5• 6" m' w9 D  @7 A' D$ T; N. x
Administration of larger doses of gonadotropin or systemic
2 g5 \8 D' D& j, V; {$ M3 Ytestosterone, as well as topical applications that produce
; Z2 s5 G! O# _higher levels of serum testosterone (150 to 900 ng./dl.), will3 T1 W8 `7 |2 o, x- G* j0 J
also produce phallic growth but risks accelerated skeletal0 X6 R0 p0 _$ U
maturation even after stopping treatment. It would appear
: M+ M6 u5 z# h- N+ |1 Y4 q# Athat this may be avoided by topical applications of testosterone
0 |6 h; D8 @! x* M* _1 ?4 Fand monitoring of serum testosterone. Even with this control
$ |) x) `4 N6 {) {  O8 H8 e/ I, hthe duration of our therapy did not exceed 3 weeks at any( ?  \  @% T/ F- A* M! s' C
time. It is apparent that the prepuberal male subject may9 Y' ^" _/ r. @$ _; H
suffer accelerated bone growth with testosterone levels near' V3 Z$ |# k% m
200 ng./dl. When skeletal maturation is complete the level of
+ e* F( D4 a8 @$ ^; ]2 g" R& z* yserum testosterone can be maintained in the 700 to 1,300 ng./
2 [$ D! X: C" l+ {/ {dl. range to stimulate phallic growth and secondary sexual
3 H2 v2 z; z! S. M# e# Achanges. Therefore, after skeletal maturation parenteral tes-+ N- Y/ O* `8 \
tosterone may be used to advantage. Before skeletal matura-
; L, R$ A( |) ]9 M6 Etion care must be taken to avoid maintaining levels of serum7 |; `9 T" Z8 i5 j8 `
testosterone more than 100 ng./dl. Low-dose gonadotropin; Y4 W0 {2 w8 Y: F% n- q6 S- E4 g
depends upon intrinsic testicular activity and may require( R, b( H+ q( h
prolonged administration for any response.- p4 l, r# h* }# M2 H; M3 h
Alternately, topical testosterone does not depend upon tes-8 Q8 l6 }2 ^6 s( g
ticular function and may provide a more constant level of
6 b+ y* m( O; X4 V; e5 j* o+ cREFERENCES. d% `! V2 v: t
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- t  `% f6 i+ w3 `3 }8 C
R.: The local application of testosterone cream to the prepub-# l' P! U0 P+ g6 X/ x& H0 j
ertal phallus. J. Urol., 105: 905, 1971.
! @8 g* V+ q: T* R0 |1 @* w2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 q/ O5 k- U8 k$ O$ Ftreatment for micropenis during early childhood. J. Pediat.,$ ]5 h" w7 g. l
83: 247, 1973.* f) P5 D. B8 w* A. D+ M! s) ~
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-" Q$ k) Y4 T8 r5 b
one therapy for penile growth. Urology, 6: 708, 1975.
3 g& g( F* m' c+ `) b# v( `+ Z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 U! |; l! b6 `" s3 _5 F
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by7 M2 L6 P* [0 h% E4 |
skin slices of man. J. Clin. Invest., 48: 371, 1969.; h: m3 h; M9 u, }- F2 I) s( T0 [
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 O0 s/ S4 G& G) `2 n
by topical application of androgens. J.A.M.A., 191: 521, 1965.; B1 |; c5 a1 m6 k4 }4 l
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. @, P8 G. v+ }2 f9 A
androgenic effect of interstitial cell tumor of the testis. J.; _" r$ C0 w4 m- v8 h
Urol., 104: 774, 1970.. W" j8 y- x  t
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, P* l2 P. i4 {. e% }' t; L1 l
tion in the male genitalia from birth to maturity. J. Urol., 48:
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