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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, F1 o+ z- `0 ]% [! @GONADOTROPIN9 e. C. Z8 [$ H9 Y4 |; G
RICHARD C. KLUGO* AND JOSEPH C. CERNY
7 v6 i* @' _4 T' Z7 i. ?0 HFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 j* k  H3 `, }ABSTRACT, l: H. l5 p8 J* y% y: ?
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
: s2 f  G/ }; d6 rwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 r6 N- w0 x2 c2 ^4 l  {tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( B/ Y& @& q1 w6 fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
9 g; R- l9 ~, h1 N- v" K: Lfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent- e4 ]! K! K% }. S/ r9 w/ K) F
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
8 _$ D5 |/ P' j% @. d0 Dincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response6 [+ J5 C, F) j, ^" j5 B
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 D+ _$ |2 ~: d; r; F; d
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! ?; z- D& y% H- R/ u6 c6 ^9 ^
growth. The response appears to be greater in younger children, which is consistent with previ-( e0 A& D: }# x$ ?/ _
ously published studies of age-related 5 reductase activity.
8 v4 `# t' ~8 ~" `Children with microphallus regardless of its etiology will
8 ?" U' V# F" S( yrequire augmentation or consideration for alteration of exter-
9 K* s' O% U2 ^nal genitalia. In many instances urethroplasty for hypo-
* g" {% M' G# b7 S% g. [/ X; Z+ rspadias is easier with previous stimulation of phallic growth.' H# J" ~0 o' V% n+ i
The use of testosterone administered parenterally or topically
0 `0 Y! H- p: ~5 E8 Q" Ghas produced effective phallic growth. 1- 3 The mechanism of
: m9 Y" ~( Y* _6 O$ A8 ]7 [response has been considered as local or systemic. With this
9 A/ }9 z/ U+ p& win mind we studied 5 children with microphallus for response
2 G$ i' D0 [5 y' w0 Uto gonadotropin and to topical testosterone independently.
) C0 J: g$ O7 K5 S0 ]MATERIALS AND METHODS4 _9 r0 Q# Q% P" M
Five 46 XY male subjects between 3 and 17 years old were
% ]5 B( D1 b1 I% m9 Jevaluated for serum testosterone levels and hypothalamic" K* @4 C/ p- o# T( C3 {1 r
function. Of these 5 boys 2 were considered to have Kallmann's
. m7 X0 t3 J0 M2 C" Ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 L& c0 q) @: Y/ olamic deficiency. After evaluation of response to luteinizing
8 Q8 {/ A0 Q1 X! s3 uhormone-releasing hormone these patients were treated with5 v% Q, E" @( o- U! c
1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 i4 a5 Z" H  T- e6 u& K; U
after completion of gonadotropin therapy 10 per cent topical
6 I9 @" r* m! q. Q, M( t! @testosterone was applied to the phallus twice daily for 3 weeks.+ T$ q6 _4 Y. Z. ]4 X
Serum testosterone, luteinizing hormone and follicle-stimulat-
; L/ m# D2 w( T! e3 K5 Ming hormone were monitored before, during and after comple-/ y+ U3 J4 u0 ]  K: n8 L8 {
tion of each phase of therapy. Penile stretch length was
% M( o0 e  U8 U6 C; O. A' x6 }obtained by measuring from the symphysis pubis to the tip of! v7 p( r- L% b0 ^* l7 B9 T. M
the glans. Penile circumferential (girth) measurements were
7 _  A% I- Y3 h0 @+ {5 kobtained using an orthopedic digital measuring device (see+ N1 p; v( ]7 J3 H
figure).
& H' ~9 \7 [$ a4 O$ H& j& O: ORESULTS
/ N' _9 n# s0 J9 J( k4 [, ]; o4 M# ySerum testosterone increased moderately to levels between
' V8 S& _7 L5 o- y( t. J+ S* T50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 L/ `$ u3 s3 p  D4 z6 H& p
terone levels with topical testosterone remained near pre-
, V' @0 |1 n# b; y- A/ Q% r7 Xtreatment levels (35 ng./dl.) or were elevated to similar levels9 A3 A% _% Z  t! a6 O
developed after gonadotropin therapy (96 ng./dl.). Higher$ ~0 d! s# T+ W* d
serum levels were noted in older patients (12 and 17 years old),# \3 z% D( b2 [. ~0 E
while lower levels persisted in younger patients (4, 8, and 104 L  Q, ?5 }3 J6 T% _
years old) (see table). Despite absence of profound alterations
0 S4 j( G' T& M! C  |2 l0 xof serum testosterone the topical therapy provided a greater. ]& l. [% a. f5 c7 |5 `9 s( t
Accepted for publication July 1, 1977. ·
8 {* @; M8 a' WRead at annual meeting of American Urological Association,
# ^! f8 G+ f! Q0 _& |. mChicago, Illinois, April 24-28, 1977.3 }) H5 a4 c; y6 ~5 J
* Requests for reprints: Division of Urology, Henry Ford Hospital,; {5 v. `- ?: S  a* n) ?1 L
2799 W. Grand Blvd., Detroit, Michigan 48202.
* R% ^6 Z1 |# q, eimprovement in phallic growth compared to gonadotropin.) m# N) G2 b# ^9 n0 p9 q! w
Average phallic growth with gonadotropin was 14.3 per cent
1 q2 S( Y7 e- Cincrease in length and 5.0 per cent increase of girth. Topical
4 i* C& O: n' ?, K# mtestosterone produced a 60.0 per cent increase of phallic length
+ {8 w% \4 L7 Y/ @# `( cand 52.9 per cent increase of girth (circumference). The2 k2 f. @9 l% |8 @
response to topical testosterone was greatest in children be-
5 O7 w9 U7 G( O& [% L/ xtween 4 and 8 years old, with a gradual decrease to age 17
' ?( S$ r' x0 F6 ^years (see table).  K# M3 D$ I- P$ j/ y# c/ r
DISCUSSION
& t% I' w, x- FTopical testosterone has been used effectively by other
4 T" {6 Q9 D8 I7 S: hclinicians but its mode of action remains controversial. Im-
, e9 |4 Y4 b/ W3 c7 {  ^! zmergut and associates reported an excellent growth response
1 O. l8 J- i6 S9 Kto topical testosterone with low levels of serum testosterone,  k* r5 E/ I# [5 L" I% d
suggesting a local effect.1 Others have obtained growth re-
' I8 }! B; R  R! T1 }( Nsponse with high. levels of serum testosterone after topical
& v4 p% ^; g' U+ T7 i$ S! n& V3 Uadministration, suggesting a systemic response. 3 The use of
% G( r$ e6 @3 z) }$ r: W* g- `gonadotropin to obtain levels of serum testosterone compara-
1 t' d$ d( v- o2 f3 Tble to levels obtained with topical testosterone would seem to; n: Z1 p" M/ d4 l
provide a means to compare the relative effectiveness of
3 c  l" F' J7 z# @8 J) o2 ctopical testosterone to systemic testosterone effect. It cer-
7 C4 c5 V: x% O% V" n5 Mtainly has been established that gonadotropin as well as par-! T5 `* @; J( s, K* h
enteral testosterone administration will produce genital
9 h* a' i+ y- @9 ggrowth. Our report shows that the growth of the phallus was3 m4 d& K9 r; @+ T% z$ P2 I
significantly greater with topical applications than with go-
$ F0 e+ y2 k% [  [, E2 o. Xnadotropin, particularly in children less than 10 years old.
! d. I# J7 B( a2 s- p( e, RThe levels of serum testosterone remained similar or lower
: N" O+ l' j. G* T& xthan with gonadotropin during therapy, suggesting that topi-
/ k8 l( W( K" Ical application produces genital growth by its local effect as
3 F5 |( h+ j4 v% twell as its systemic effect.
+ ?) _. g/ n4 {( _# [& tReview of our patients and their growth response related to
4 z4 z' |1 {( t2 page shows a greater growth response at an earlier age. This is
7 X. Z" M7 B" U% {1 P" Mconsistent with the findings of Wilson and Walker, who
/ _  Z1 p4 K! B" a8 kreported an increased conversion of testosterone to dihydrotes-
( z  Y$ K3 a! g8 f* jtosterone in the foreskin of neonates and infants.4 This activ-
/ `# ]0 o% ]6 q. D" K4 Aity gradually decreases with age until puberty when it ap-8 j5 C, k3 u! H% d% X
proaches the same level of activity as peripheral skin. It may
" w; f0 l" J0 U: swell be that absorption of testosterone is less when applied at
" N% [# b# x4 o# _  Oan earlier age as suggested by lower serum levels in children
( N) g* k+ J: E4 A7 Aless than 10 years old. This fact may be explained by the" }2 y0 j. i7 i6 ~* o
greater ability of phallic skin to convert testosterone to dihy-
) ?5 v. a) Q, ?; B' V; wdrotestosterone at this age. Conversely, serum levels in older2 e% u3 B. C' R: u' T6 m, v
patients were higher, possibly because of decreased local) W6 G0 H9 o  T* F2 p. i0 l6 ^' j+ s
667
0 q! x$ M% K" l* ?; _' C: ?668 KLUGO AND CERNY
) L2 {% D: Q6 e. g" i3 Y4 U' @Pt. Age
& }0 L4 h4 _) c8 r* h8 I(yrs.)4 Z4 k3 Z1 S0 w$ K* a; Z# @
Serum Testosterone Phallus (cm.) Change Length; ~" Q- ]! d4 t0 n) f) x
(ng./dl.) Girth x Length (%): @& T, M/ Q# L2 o" C( B8 U+ U) c
4- H1 M: C; l% ~( R0 `( h
8
+ X4 q; o! W9 i3 k2 U0 |  {( N10
. B8 f6 p  @0 h; K4 g2 ~# u( f12
  ^8 f. y( B8 l17& @" J. Y; u  \1 z, V
Gonadotropin" E8 c* n7 r$ @/ a9 ^
71.6 2.0 X 3 16.6. L: S; h- T2 Q- Q( ~
50.4 4.0 X 5.0 20.0( `6 N7 N! b8 P" \; O( b- H8 O
22.0 4.5 X 4.0 25.0
$ a$ U/ J% X* X7 p8 Y  Y84.6 4.0 X 4.5 11.1! ]3 Z: y$ u9 u# y
85.9 4.5 X 5.5 9.0
) c3 [, p" @# k$ w1 IAv. 14.3
% h2 q2 B0 t: Z6 a5 j3 W, ?4
' c7 r7 ^2 {, Z, c6 K3 a8( b; d5 e+ d+ P# F' \: d
106 C4 H' e8 w% L% F
12
& T. e( c) ], \; o6 S* b4 S7 i17+ }9 z1 O3 o2 t3 p& Z2 w
Topical testosterone8 y/ k% ~" @7 I9 g0 _7 L) F3 A& h
34.6 4.5 X 6.5 85
7 R; T2 {8 R; n38.8 6.0 X 8.5 70
( H3 i2 S8 v- _40.0 6.0 X 6.5 62.5% B& {9 v9 B( C) ?
93.6 6.0 X 7.0 55.5
( @! o0 l$ {  z# w9 C. j8 S; o95.0 6.5 X 7.0 27.2$ p, W9 C4 U, b; }8 e: r1 R
Av. 60.0- ?) U. L' f! e0 t/ t2 M4 x
available testosterone. Again, emphasis should be placed on
" o7 e& n5 Q! N* J5 x0 ^, @early therapy when lower levels of testosterone appear to
6 x; J- b( [7 c  Kprovide the best responses. The earlier therapy is instituted
: D0 Q( N: w+ o- othe more likely there will be an excellent response with low4 b( ~) y$ X6 e4 ~6 v! a* ^
serum levels. Response occurs throughout adolescence as9 p3 Z5 C; z8 _8 a6 s' \. n
noted in nomograms of phallic growth. 7 The actual response
" E6 }4 j$ c  ?' _to a given serum level of testosterone is much greater at birth
; t0 R. H4 v3 h3 I' D1 Gand gradually decreases as boys reach puberty. This is most
9 d4 ^! {( f/ R/ V0 {" Glikely related to the conversion of testosterone to dihydrotes-) q, M$ H1 S9 H; [: P0 K
tosterone and correlates well with the studies of testosterone
' r0 ]" B) |& a( b& L: U, Fconversion in foreskin at various ages.7 u1 v4 {# [1 Z# M8 y
The question arises regarding early treatment as to whether
; S6 [4 B7 Y7 f: vone might sacrifice ultimate potential growth as with acceler-% }: [; S: {  G6 f! X9 f
ated bone growth. The situation appears quite the reverse( }3 L& {9 a4 s! U
with phallic response. If the early growth period is not used4 l- U. Q2 E) _+ u. a4 w
when 5a reductase activity is greatest then potential growth
! e, j2 X2 A4 O8 Bmay be lost. We have not observed any regression of growth. t8 F; d) p7 F2 u/ F3 ^  Q
attained with topical or gonadotropin therapy. It may well
% M* i" m7 ?. _0 ]be that some patients will show little or no response to any
, c/ m  P1 T, C8 X1 v# M6 w6 fform of therapy. This would suggest a defect in the ability to; i" D$ s& ~! a7 d4 S0 n
convert testosterone to dihydrotestosterone and indicate that
" a5 ~+ q% Z" e9 r4 c, Jphallic and peripheral skin, and subcutaneous tissue should( l) x. P- y* w9 O0 |
be compared for 5a reductase activity.! C, {3 [6 K) d, P. U
A, loop enlarges to measure penile girth in millimeters. B,) ~' a5 |* k/ Z' d3 J
example of penile girth computed easily and accurately.
! t, K  {5 k4 X7 v' B" n, xconversion of testosterone to dihydrotestosterone. It is in this6 t7 W: S+ z- {0 B* O& R. i0 I6 [3 W
older group that others have noted high levels of serum$ I5 @3 V# [& q
testosterone with topical application. It would also appear1 Z- S- z5 a9 I8 w/ ]
that phallic response during puberty is related directly to the! f4 C" e3 i' M6 s- A" |% k# Q
serum testosterone level. There also is other evidence of local: o9 ~" x9 ]$ f5 ]% G& s4 F* |- |
response to testosterone with hair growth and with spermato-
' W, m# @+ s  q8 [genesis. 5• 6/ T  C: s: x! w) s2 ^
Administration of larger doses of gonadotropin or systemic
" b8 E# \% \0 ^; S) l' [testosterone, as well as topical applications that produce$ u2 _  \+ `7 ^* d" F% H* x- P
higher levels of serum testosterone (150 to 900 ng./dl.), will( v  d8 y/ r+ k' B
also produce phallic growth but risks accelerated skeletal) S7 w; G4 D+ U# T0 \
maturation even after stopping treatment. It would appear
- w3 c2 B; b9 b  r0 ~that this may be avoided by topical applications of testosterone5 k0 w! h/ s* O$ l8 l
and monitoring of serum testosterone. Even with this control
9 Z5 _% }+ o. Q- k4 N7 Sthe duration of our therapy did not exceed 3 weeks at any
$ E) X; D# i2 Z" h5 {2 stime. It is apparent that the prepuberal male subject may+ I" E% h2 X; J2 `
suffer accelerated bone growth with testosterone levels near
, e, y: F$ U5 W7 U) b2 ~200 ng./dl. When skeletal maturation is complete the level of* @. r, c! U$ W0 [( v2 b1 `% `2 m
serum testosterone can be maintained in the 700 to 1,300 ng./* ]. z9 r* ~9 A/ L& P- X0 N% }
dl. range to stimulate phallic growth and secondary sexual5 [- i, G' z+ [6 _
changes. Therefore, after skeletal maturation parenteral tes-
+ B6 u4 W3 q$ mtosterone may be used to advantage. Before skeletal matura-3 _( ^1 N' y* h  |, u, c; H& G
tion care must be taken to avoid maintaining levels of serum
# ]! t$ C5 j- K/ Jtestosterone more than 100 ng./dl. Low-dose gonadotropin$ V9 l' A, x/ M( K/ o6 Y+ o; D$ [
depends upon intrinsic testicular activity and may require- V" m5 m4 Z, n# H, C
prolonged administration for any response.- ^' Z  V' ?( y" ?, Z
Alternately, topical testosterone does not depend upon tes-
' B' h/ Y9 g0 e2 U4 Zticular function and may provide a more constant level of
0 M* z8 v  j1 `REFERENCES* k" r* z8 B) f+ N1 ]/ D* V
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ G0 ~6 u% `  L2 e/ b: A! F
R.: The local application of testosterone cream to the prepub-
$ r0 _7 S6 ?2 yertal phallus. J. Urol., 105: 905, 1971.2 }: L, ~9 \5 q5 V" g& C; n
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" S* [3 q0 ~0 c8 h- y- F8 F
treatment for micropenis during early childhood. J. Pediat.,
9 O4 ]  i0 h8 F* C6 M83: 247, 1973.
) t  W( e/ K! W: B3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-! n* t5 g# f1 W4 m- g) {9 \
one therapy for penile growth. Urology, 6: 708, 1975.
) Y9 l0 E- M' }6 D2 G! R4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 T; }0 k4 f% x! ^& W8 A
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 n: j, Q5 h4 p0 }6 mskin slices of man. J. Clin. Invest., 48: 371, 1969.7 ]& c" f3 j+ N4 s
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth  g$ B+ r1 K% I/ O
by topical application of androgens. J.A.M.A., 191: 521, 1965.
6 K5 `( j6 m* R$ O6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 o1 {3 b/ b; q2 ]: z6 h
androgenic effect of interstitial cell tumor of the testis. J.
/ u+ t. w+ C+ h2 D5 A* G0 vUrol., 104: 774, 1970.
# J( W( r5 s1 Y1 u3 A& v& r: a7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; F% d; S+ \3 c3 `; y8 j
tion in the male genitalia from birth to maturity. J. Urol., 48:
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