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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 G# y3 x  x0 V* u0 }) UGONADOTROPIN. b8 L! t: H0 d) f; D, {
RICHARD C. KLUGO* AND JOSEPH C. CERNY
& C: |5 R5 A7 k. W; I! d) GFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan% Q' w8 u+ o0 ^" h( R* U
ABSTRACT
; ]9 X* r3 o( U' b( pFive patients were treated with gonadotropin and topical testosterone for micropenis associated
* |4 A( }. ~* d, j' Q0 p& zwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
6 y+ a+ ]& o5 ]" y1 Gtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) F/ ^' m' W% T1 gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* E1 R0 h! ?* ~% ~' |2 d, v8 W9 B
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ C+ W! ~" Y! I
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; l9 y4 L& x+ [  @( b  p8 tincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& P2 y  P( o- \. y, E1 O8 J) Koccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This" n* {( l- Q9 Q; p
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 S6 T$ s$ ^7 L  S* q: @- ]/ S( j+ w
growth. The response appears to be greater in younger children, which is consistent with previ-
; n  S7 W0 g0 d4 X' ?% eously published studies of age-related 5 reductase activity.: M' N9 t" s' |- g' I/ U1 \, U
Children with microphallus regardless of its etiology will7 Z& k0 P* ]9 l# q) E: n* C
require augmentation or consideration for alteration of exter-
; D) O7 }% s3 Y. B& x, Enal genitalia. In many instances urethroplasty for hypo-
3 b/ z5 i' f- G( c: Q: s( |9 U( `spadias is easier with previous stimulation of phallic growth.
" T1 M/ s$ M4 f0 n$ @# LThe use of testosterone administered parenterally or topically
0 y$ c" u' W7 o4 Uhas produced effective phallic growth. 1- 3 The mechanism of- e' u2 }: r# Z! ]6 i: }
response has been considered as local or systemic. With this+ s9 i& s  \1 l1 o) U
in mind we studied 5 children with microphallus for response
* Q' i0 h4 D  Rto gonadotropin and to topical testosterone independently.
. _: |! x& h6 F: iMATERIALS AND METHODS
+ S3 L  n2 v+ B4 W, U: t, z6 X* [# l4 m  VFive 46 XY male subjects between 3 and 17 years old were- b1 v% F3 ^6 [6 P8 }  d4 X
evaluated for serum testosterone levels and hypothalamic; A2 Q2 S$ j. D, r8 Y5 J3 q8 L
function. Of these 5 boys 2 were considered to have Kallmann's8 x( s* V. v% A6 `. L! ~
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
- ]4 Q0 J# u1 r5 d! ]5 M2 ulamic deficiency. After evaluation of response to luteinizing( r" {* @/ K/ J; U( r$ K
hormone-releasing hormone these patients were treated with
# ?/ I- ?* `  W5 A1,000 units of gonadotropin weekly for 3 weeks. Six weeks' z) t' h( H* K& C: `& A
after completion of gonadotropin therapy 10 per cent topical
  i7 o5 |2 f; C5 U- [2 X# \testosterone was applied to the phallus twice daily for 3 weeks.
( u9 N/ E1 C& E$ aSerum testosterone, luteinizing hormone and follicle-stimulat-
. W" ~& K) S& H7 r" M' m" x8 [  cing hormone were monitored before, during and after comple-* N9 g  S0 J9 G" ?) ?& E% y
tion of each phase of therapy. Penile stretch length was
$ u) b. u' ^/ `+ Kobtained by measuring from the symphysis pubis to the tip of
* Z9 Q6 _! w5 S0 @the glans. Penile circumferential (girth) measurements were0 u! Y. Z$ }4 w- v8 ]0 C
obtained using an orthopedic digital measuring device (see2 e: \" l5 c7 b: B# d9 S
figure).
! I* k+ W( o( Y4 T1 VRESULTS
$ k& D! l3 W; Y1 x! I, lSerum testosterone increased moderately to levels between
* K2 F& ]' Q/ X: |4 a$ X. h  M# a2 z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* X) H3 ?8 E6 L( e/ ]
terone levels with topical testosterone remained near pre-
% j1 N  n2 }$ q3 d9 jtreatment levels (35 ng./dl.) or were elevated to similar levels/ ^0 R' P! P5 e: k$ L# X+ \, g
developed after gonadotropin therapy (96 ng./dl.). Higher
! f& I5 q$ I- W$ ~+ @; dserum levels were noted in older patients (12 and 17 years old),
3 \' A* S& a: Q% Swhile lower levels persisted in younger patients (4, 8, and 10- _  R3 ^1 d1 E3 V, U& h
years old) (see table). Despite absence of profound alterations
* d8 [" h1 N/ X1 dof serum testosterone the topical therapy provided a greater( ~4 s0 l7 [$ k
Accepted for publication July 1, 1977. ·
+ e9 r& i; o$ U0 Y# XRead at annual meeting of American Urological Association,, {0 ?6 `% m6 z+ |
Chicago, Illinois, April 24-28, 1977.
+ O# ?( g7 s, r* g8 c3 S* Requests for reprints: Division of Urology, Henry Ford Hospital,3 I! W& ^. U+ n2 C3 @
2799 W. Grand Blvd., Detroit, Michigan 48202.) e' B- u1 q( O4 p7 t5 c
improvement in phallic growth compared to gonadotropin.
( B% P0 q7 b/ d/ k. AAverage phallic growth with gonadotropin was 14.3 per cent
& N! i1 Q4 I2 i, G% r4 y+ s0 A5 bincrease in length and 5.0 per cent increase of girth. Topical
9 J6 |# e1 l1 B: p; l  n; F9 etestosterone produced a 60.0 per cent increase of phallic length3 g6 `" Z+ f9 g% `4 y  P
and 52.9 per cent increase of girth (circumference). The# C: E8 m; k+ T5 x$ n
response to topical testosterone was greatest in children be-0 |3 [4 C$ H$ X
tween 4 and 8 years old, with a gradual decrease to age 17
: A0 O4 t/ m% Hyears (see table).
! A$ |5 S  y9 ]+ s& x. z7 T7 Z6 ADISCUSSION5 H: }3 D3 u; T- k
Topical testosterone has been used effectively by other
# ?! @6 f+ u# nclinicians but its mode of action remains controversial. Im-
" Y" {. z# a% J7 ]mergut and associates reported an excellent growth response4 p3 b. K# Z, S- A% [3 q  i8 e# [
to topical testosterone with low levels of serum testosterone,2 j( H+ C1 T, N) _7 H# n
suggesting a local effect.1 Others have obtained growth re-+ f3 R, F; T' H& [5 C; g: i
sponse with high. levels of serum testosterone after topical
9 |- R6 W& u8 D6 S* L' y8 q* Aadministration, suggesting a systemic response. 3 The use of
- |4 E/ f, h4 P* [% A$ z! V$ N- dgonadotropin to obtain levels of serum testosterone compara-. S/ w( b8 A) @% L& H+ Z
ble to levels obtained with topical testosterone would seem to: j( [0 o/ A6 ~# l& J1 ]7 Q1 K
provide a means to compare the relative effectiveness of  q/ E2 [$ F) _( ^4 d
topical testosterone to systemic testosterone effect. It cer-( f6 L, A& L# t$ O: y+ ?5 C
tainly has been established that gonadotropin as well as par-0 ~( L% P+ M4 C0 ?1 o3 H) n9 p
enteral testosterone administration will produce genital) E. w6 ^# B0 }; {# S0 r3 P1 ~5 ^
growth. Our report shows that the growth of the phallus was: \, t% x" u6 z9 h# {
significantly greater with topical applications than with go-3 ^8 y; H: u5 {5 ?3 W; P# x
nadotropin, particularly in children less than 10 years old.
" n* L5 C6 Q' x0 M4 CThe levels of serum testosterone remained similar or lower; F7 Z/ s4 l7 h. w% q& C- W3 i8 J
than with gonadotropin during therapy, suggesting that topi-2 B! t, t- J/ K/ x4 g- C
cal application produces genital growth by its local effect as
( K, J, @# g- cwell as its systemic effect." q) n- k8 T8 b6 n, {
Review of our patients and their growth response related to+ H6 D7 U, ~6 e9 J: \
age shows a greater growth response at an earlier age. This is
5 v% R6 g8 s: J/ m: }" P0 e( Rconsistent with the findings of Wilson and Walker, who& }' u9 x. p) M7 |4 L( R/ u
reported an increased conversion of testosterone to dihydrotes-, ?! ~5 b( g* |4 Z- t
tosterone in the foreskin of neonates and infants.4 This activ-
+ e: S+ `: j( E: Y  l6 U5 D* Yity gradually decreases with age until puberty when it ap-
) I" @* ~; U& E5 t" g0 y8 Hproaches the same level of activity as peripheral skin. It may$ W/ N4 i# ]) o: M' G) b0 E
well be that absorption of testosterone is less when applied at/ l2 o& f4 G3 F3 P* T
an earlier age as suggested by lower serum levels in children. ?# Z& }; y- F8 |
less than 10 years old. This fact may be explained by the; H8 R" c8 G; `8 O% A; @
greater ability of phallic skin to convert testosterone to dihy-
( Y* _( _5 U# y& B- ~6 p* J/ ?/ {drotestosterone at this age. Conversely, serum levels in older$ X5 v9 J9 R( C! B" H$ X$ m4 t
patients were higher, possibly because of decreased local2 c& g  O' g# O( k. {
667
% Z; J4 N  p8 c! g4 `: `668 KLUGO AND CERNY
1 n* v4 O4 X* j9 f: u+ S3 G- EPt. Age7 A  \# K- D' ^
(yrs.)* _$ Q0 e! m* F/ u6 g
Serum Testosterone Phallus (cm.) Change Length
0 ^. Y9 Z, J" F2 {! ?7 A" |, l9 h(ng./dl.) Girth x Length (%)
3 B* t' {. m" G8 u( b4/ S. T. n, ~  f& F5 _0 S9 B8 k
8& `- \) F5 }! M6 |! |1 X; M
10
: L/ O  G- t$ B8 D: g12
- i! ~( M" z, A3 K5 P, ~17# H6 D% j. h  T( g: [" m3 o
Gonadotropin
7 L+ G4 o  O$ e" x9 w7 @. p9 M71.6 2.0 X 3 16.6
% I% v# U  S: t. z50.4 4.0 X 5.0 20.0
$ G* F3 v0 T# ?  N9 h% h% l22.0 4.5 X 4.0 25.0( h( f+ Z+ Q9 d
84.6 4.0 X 4.5 11.1
/ z; }1 J# n3 c* e( K  r85.9 4.5 X 5.5 9.00 H& `& k3 B2 w; w& F1 }
Av. 14.3* Q) P$ Z% L$ f4 G$ ?5 P* P
4! ^5 a" L  ?$ D5 J- k1 P; |6 t  L
88 S& [  E1 v- Z
101 G# S; @" _7 {% `1 {
129 n* R6 B3 `3 C/ n
17
( y1 ?0 R+ P# j/ a& |2 ]Topical testosterone
- Y$ X+ v8 C1 o" k8 _4 w/ l34.6 4.5 X 6.5 85# `4 I. V1 X3 m$ u; P" ^9 `+ L
38.8 6.0 X 8.5 70
9 c4 [. P+ _! t& Y40.0 6.0 X 6.5 62.5
$ m$ b: r: {5 ^( H9 p9 Q93.6 6.0 X 7.0 55.5* z/ E. T7 d2 [" v) U
95.0 6.5 X 7.0 27.2/ @6 a- \; n2 V5 h! \
Av. 60.06 j  L, v0 a& X  ~
available testosterone. Again, emphasis should be placed on! h( x' T6 V. e; u6 l
early therapy when lower levels of testosterone appear to
. i. R/ @5 f2 w% h( w7 j4 o( Aprovide the best responses. The earlier therapy is instituted
% L: |9 N8 Q2 v: x; ithe more likely there will be an excellent response with low0 E6 q3 S1 R) U
serum levels. Response occurs throughout adolescence as+ \; I) t2 x" v. ]  P: b  I$ a  o
noted in nomograms of phallic growth. 7 The actual response
, |# a: \9 M5 H! m7 vto a given serum level of testosterone is much greater at birth
, ~; A, O" W! H! z( r) kand gradually decreases as boys reach puberty. This is most1 k- G5 E9 Y6 Z
likely related to the conversion of testosterone to dihydrotes-- d7 I8 z1 Z  l5 Q- w+ M' C
tosterone and correlates well with the studies of testosterone; F5 v# c4 T7 @* P% y
conversion in foreskin at various ages.
  ]) {- _: T* \* g2 s* w! IThe question arises regarding early treatment as to whether
& l& [) L! B+ _0 m. oone might sacrifice ultimate potential growth as with acceler-
8 p& X4 m5 @1 Z) H, wated bone growth. The situation appears quite the reverse
- d4 G5 W/ n% ?5 n8 P* Iwith phallic response. If the early growth period is not used
* Q; _6 f) t* j2 N$ G% kwhen 5a reductase activity is greatest then potential growth
& c5 u  ?5 U& y( w6 G  j7 \6 hmay be lost. We have not observed any regression of growth$ G; ^7 N: A0 Z6 ^9 M3 y
attained with topical or gonadotropin therapy. It may well6 Z- T" K1 z1 j; A
be that some patients will show little or no response to any! ~% t% n) F$ K2 C; a
form of therapy. This would suggest a defect in the ability to: h) ]  {9 [3 e
convert testosterone to dihydrotestosterone and indicate that
8 n! b* R8 q7 e, y/ m. Tphallic and peripheral skin, and subcutaneous tissue should. c% ?2 H' E9 @
be compared for 5a reductase activity.
( O3 C7 p  q8 q3 X: r4 VA, loop enlarges to measure penile girth in millimeters. B,
6 F7 @2 t  |5 n) V. \: N- A& c: |example of penile girth computed easily and accurately.
. y+ e2 o9 ~4 s6 qconversion of testosterone to dihydrotestosterone. It is in this4 z/ H, |) ]! T$ s; ~5 [
older group that others have noted high levels of serum
# {4 w; V9 Z% D. r/ ]testosterone with topical application. It would also appear
, O2 M, s8 X2 l# x  B1 vthat phallic response during puberty is related directly to the3 G! d, l. W9 @" F- j$ V0 ~. Q& l- Q) O
serum testosterone level. There also is other evidence of local
! R! f1 {; l# \1 Oresponse to testosterone with hair growth and with spermato-
* d1 @' i8 }4 s' Z2 X- Wgenesis. 5• 6
5 Q% W  P. ^/ I4 ?" y% g6 dAdministration of larger doses of gonadotropin or systemic& [# ]) T  z7 d8 O
testosterone, as well as topical applications that produce* P0 @+ Q9 S5 B/ E
higher levels of serum testosterone (150 to 900 ng./dl.), will" N+ w" V# m) p+ {$ }! ]7 f6 t
also produce phallic growth but risks accelerated skeletal
( C  m! c6 s! d2 gmaturation even after stopping treatment. It would appear8 O3 q( W. y. k: f$ S6 k# Z$ r2 q
that this may be avoided by topical applications of testosterone% L" m$ O  W3 z6 G' T$ p
and monitoring of serum testosterone. Even with this control$ R! j8 r# g4 C; y# S
the duration of our therapy did not exceed 3 weeks at any
, t: p  ]; f$ m7 L+ Qtime. It is apparent that the prepuberal male subject may
& I( \9 \4 S9 e! _* J7 L+ W% K9 ysuffer accelerated bone growth with testosterone levels near
8 }. A  m: {$ U/ s; C: B200 ng./dl. When skeletal maturation is complete the level of
9 c" M# b8 ~' j6 i7 c! L5 U7 e7 K% Yserum testosterone can be maintained in the 700 to 1,300 ng./8 h+ A$ K3 y- Q1 y
dl. range to stimulate phallic growth and secondary sexual
: w, j) R8 J  M' c8 nchanges. Therefore, after skeletal maturation parenteral tes-, \6 G8 U! i& Z) V" f7 t# `, U
tosterone may be used to advantage. Before skeletal matura-$ O  ]/ t" D* w1 \
tion care must be taken to avoid maintaining levels of serum
  l, o, r3 C! ^, w2 Z# I% t9 F" wtestosterone more than 100 ng./dl. Low-dose gonadotropin
% U: N- G5 [; N3 H3 L* t4 C  hdepends upon intrinsic testicular activity and may require8 s* W5 J" V4 y5 L% q
prolonged administration for any response.: s+ U/ J1 }) V* w6 P
Alternately, topical testosterone does not depend upon tes-! I  R) K: a" E. k4 K+ D1 \( p
ticular function and may provide a more constant level of
! m! P( \' M( s: _4 O; `REFERENCES
# D( H/ L/ t2 C. G' w8 s; c! _: w9 J3 ^1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 ^3 B: N5 q1 F! i' B6 F  |+ F
R.: The local application of testosterone cream to the prepub-1 s- k* z1 j  n2 A9 ?* M6 @8 t+ Y
ertal phallus. J. Urol., 105: 905, 1971.* `$ e: d2 a+ g; Q: j
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 r" ~# g, N7 @! _: v) `% _treatment for micropenis during early childhood. J. Pediat.,
  Y7 [1 {, M; o& u+ j83: 247, 1973.. I- u# j: J: @  i1 J3 b- E! m
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
  G: r4 a: q0 x# Q3 kone therapy for penile growth. Urology, 6: 708, 1975.
5 ?9 q' ?  G% T4 _) N+ B4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& U' A& `1 w  w+ |* {: {# `
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 o- t  p, }' }/ c' w
skin slices of man. J. Clin. Invest., 48: 371, 1969.  H9 C, J( R2 o% |4 s
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 L( v) l0 Q. @: [- e
by topical application of androgens. J.A.M.A., 191: 521, 1965.# d9 Y# B' x0 n4 P+ u- x  n! T
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
5 Z/ _8 w0 L: y5 iandrogenic effect of interstitial cell tumor of the testis. J.
4 J8 h& ^- ^' r) j5 Q) qUrol., 104: 774, 1970.0 e3 @( b# M/ p
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. z6 H1 ?6 P4 Q  i
tion in the male genitalia from birth to maturity. J. Urol., 48:
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