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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 k4 K2 C# w; k) I8 Y: V
GONADOTROPIN5 W0 D6 r' S- W9 R$ M$ o. g/ [' n
RICHARD C. KLUGO* AND JOSEPH C. CERNY
, Y0 S' x6 O: _  _# |9 |( |From the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 X. `8 K% @9 R# x% u# [. L
ABSTRACT
' \: {4 O) V3 F# YFive patients were treated with gonadotropin and topical testosterone for micropenis associated
# `0 \1 z! r/ I" K3 `with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
$ p( L7 o% m, `% T9 L0 H; Z; N$ r1 Ctropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ N: i, v; X# Hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 {7 J+ n( n" f, W: @- \! `. a2 N
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
6 f+ [( g6 Q+ M% T; |increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ Y) d1 |5 C& j2 ?  v, ~
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: R& ^( t* g' {: a$ U  T  K
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 E* g5 D+ g' y3 }. H4 j  i
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% X) u$ Z! q$ y/ W
growth. The response appears to be greater in younger children, which is consistent with previ-- I! ]& }3 \+ C& M# R9 q( z
ously published studies of age-related 5 reductase activity.
) f" o- c# B" x3 U) A/ M& GChildren with microphallus regardless of its etiology will( O. [' A8 L, s6 j1 A2 w
require augmentation or consideration for alteration of exter-
- X0 f9 v& v% ^9 @" y/ v/ y# J6 Vnal genitalia. In many instances urethroplasty for hypo-
) o% q3 U# K$ Bspadias is easier with previous stimulation of phallic growth.
9 l% r+ s, W0 }4 K0 h2 uThe use of testosterone administered parenterally or topically' {1 m* ]# h5 F% k0 p8 I5 X
has produced effective phallic growth. 1- 3 The mechanism of
0 I+ t. Y+ R  C9 B! k/ O, Iresponse has been considered as local or systemic. With this  T+ n! W- y6 k4 ~
in mind we studied 5 children with microphallus for response
" b: v1 |! v& z, c1 m4 fto gonadotropin and to topical testosterone independently.# N5 R' l8 ?: b; P7 @- P
MATERIALS AND METHODS- W* s7 m( R; O, I- I
Five 46 XY male subjects between 3 and 17 years old were
2 q4 }: V; k4 j$ ^9 x* sevaluated for serum testosterone levels and hypothalamic9 {. R, p/ r) U+ \, R
function. Of these 5 boys 2 were considered to have Kallmann's: J% N) u7 t& O! x) g+ [2 a
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 w% |% w2 G- x, x$ @
lamic deficiency. After evaluation of response to luteinizing2 y4 ], B' F' a
hormone-releasing hormone these patients were treated with
$ u5 B8 ]/ s( @$ s' O6 h3 V1,000 units of gonadotropin weekly for 3 weeks. Six weeks
; D( @. |6 l2 i- Cafter completion of gonadotropin therapy 10 per cent topical
1 P, N4 b$ `8 x: P4 D8 i! }testosterone was applied to the phallus twice daily for 3 weeks.
' I" f! Q8 [' d4 Y. E3 WSerum testosterone, luteinizing hormone and follicle-stimulat-" ~  T4 W7 q  U# o5 c# |
ing hormone were monitored before, during and after comple-2 X& N8 p, o+ ~+ x+ l
tion of each phase of therapy. Penile stretch length was$ x6 _+ b4 t3 p+ y; D) @$ h
obtained by measuring from the symphysis pubis to the tip of% }+ O2 p9 M9 J( ?
the glans. Penile circumferential (girth) measurements were
) r& u4 m% B/ M: ~& \5 T: ~obtained using an orthopedic digital measuring device (see
, C; d2 k" ?1 P1 }1 j4 h2 B; ^figure).; Y7 d  ]  m  s; @; _% n- Z5 d
RESULTS  w8 i: E+ q2 g$ O+ q& R; h
Serum testosterone increased moderately to levels between
. ]) }1 I* n5 n0 p) w3 |5 C6 h0 X6 B% ~9 J50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 b! k/ f# A! L3 L
terone levels with topical testosterone remained near pre-
" Q8 X  k# N0 w# I+ J, `treatment levels (35 ng./dl.) or were elevated to similar levels
  B% y" z" V% E' h2 kdeveloped after gonadotropin therapy (96 ng./dl.). Higher( S. z, G, C; c$ `
serum levels were noted in older patients (12 and 17 years old),6 A2 _, N9 r) Y) h" G
while lower levels persisted in younger patients (4, 8, and 10% F. g8 f# T: D5 `7 B
years old) (see table). Despite absence of profound alterations
* s" P. @# v: @of serum testosterone the topical therapy provided a greater) ~! e$ h  u" P. U) {( T
Accepted for publication July 1, 1977. ·
. J& w4 G6 H. ~7 B% |( z3 BRead at annual meeting of American Urological Association,
0 j6 z' k$ x" ]Chicago, Illinois, April 24-28, 1977.
  G1 A6 x+ R' I9 x- Z* Requests for reprints: Division of Urology, Henry Ford Hospital,' F' |$ Q7 }" s) @3 O8 Y
2799 W. Grand Blvd., Detroit, Michigan 48202.
0 c# z- i: \6 @. himprovement in phallic growth compared to gonadotropin.. W; [# D% L  r+ e
Average phallic growth with gonadotropin was 14.3 per cent
  }8 _/ |0 c8 I7 vincrease in length and 5.0 per cent increase of girth. Topical1 F6 G) Q. E, T/ Z% t1 j0 h; N8 k
testosterone produced a 60.0 per cent increase of phallic length
9 h( w, Y( s# s1 P& h! Uand 52.9 per cent increase of girth (circumference). The* H9 C9 C0 N- }( t6 h
response to topical testosterone was greatest in children be-* M- `% V- L) ]2 v
tween 4 and 8 years old, with a gradual decrease to age 173 i4 g" {; ^% Q* _6 e
years (see table).2 A4 A# a5 s* _4 R  Y
DISCUSSION
: x7 k3 R  p- I) w! p7 ]; TTopical testosterone has been used effectively by other
% s8 W* w/ S0 D& N4 B* B1 \clinicians but its mode of action remains controversial. Im-
% W" |- o0 j( U4 ~mergut and associates reported an excellent growth response
5 @8 |/ s2 x" yto topical testosterone with low levels of serum testosterone,3 X/ I9 V. h" U3 g- a  u7 O4 r
suggesting a local effect.1 Others have obtained growth re-
( g5 V( b5 P8 c7 S9 v! S6 bsponse with high. levels of serum testosterone after topical
. n+ z3 ?! B6 eadministration, suggesting a systemic response. 3 The use of
" V! P- r( c( H+ Y/ `9 n* y( I" Sgonadotropin to obtain levels of serum testosterone compara-9 j3 ]$ I2 j; n
ble to levels obtained with topical testosterone would seem to: i. M! b! i+ W& F$ S
provide a means to compare the relative effectiveness of0 A1 q  ^( `3 A/ I) d
topical testosterone to systemic testosterone effect. It cer-4 q3 ~0 N) D! F
tainly has been established that gonadotropin as well as par-! m4 U" X( |8 O3 f8 G
enteral testosterone administration will produce genital7 Q! u; B2 F1 l% B8 u
growth. Our report shows that the growth of the phallus was
5 q) R7 B6 f/ z" ]/ isignificantly greater with topical applications than with go-
. e5 N) F8 f- Unadotropin, particularly in children less than 10 years old." s. M- ~; c% z* S" h! d3 L6 j" {# ?
The levels of serum testosterone remained similar or lower
; B' g! u' |3 Z2 I- Ithan with gonadotropin during therapy, suggesting that topi-' ~+ Y3 x# i9 W% H* [) o+ V4 i, o
cal application produces genital growth by its local effect as: q% ]8 ]$ \8 x, s: ]
well as its systemic effect.
0 Q6 F8 L; i& V" R8 cReview of our patients and their growth response related to) _! s" ~1 J1 z0 M( X; e
age shows a greater growth response at an earlier age. This is. B) T# N( x7 U( h9 C  {1 T
consistent with the findings of Wilson and Walker, who& Y& M7 N; h6 L+ b3 L* I  M
reported an increased conversion of testosterone to dihydrotes-$ L0 v8 R- T9 j. K- V% k0 g
tosterone in the foreskin of neonates and infants.4 This activ-
; I6 j6 M2 r. d+ Y8 eity gradually decreases with age until puberty when it ap-
3 M6 g) m3 Q0 y9 Xproaches the same level of activity as peripheral skin. It may
- b6 c4 N+ {1 _; D* Y, A/ q/ Q% gwell be that absorption of testosterone is less when applied at( P& Z- Z/ ]( X8 g3 n2 o
an earlier age as suggested by lower serum levels in children' m. q+ k. _6 u
less than 10 years old. This fact may be explained by the' {- A7 }: ]* ?$ ]
greater ability of phallic skin to convert testosterone to dihy-
. M4 w3 n4 _9 J8 j* {drotestosterone at this age. Conversely, serum levels in older
9 W+ R: g1 h: [9 O6 W$ j* xpatients were higher, possibly because of decreased local/ n  S) }1 |- e( ^! g0 |
667  ^. v  [* Z: \( ?: c
668 KLUGO AND CERNY
1 L" i) F! {/ LPt. Age" o/ o1 D: Q( Y. B! t' h& K
(yrs.)
$ c: @0 [. b6 E4 q/ ^Serum Testosterone Phallus (cm.) Change Length3 `1 a: f. X; R9 }7 Z% _
(ng./dl.) Girth x Length (%)8 }: O! ?) {2 F4 s; V9 H7 e
4
9 Z6 f1 a# H9 c) I) J* s83 @  e1 a* r2 U# K
109 o; B4 }1 Z2 }; u
120 @! n, m5 s" U: f+ v8 K
17
: `) s0 C2 x2 W) o4 T& Y8 hGonadotropin
' E& s6 L$ C2 ^/ J  X$ ~8 D" @71.6 2.0 X 3 16.6
* @2 S2 z% i# w! e! Y1 l: d50.4 4.0 X 5.0 20.0
1 d* O4 m, q4 j$ |4 ^, W22.0 4.5 X 4.0 25.0
9 {6 V% {& E8 z! Q$ K84.6 4.0 X 4.5 11.1/ p8 d  @) Y0 k9 J  f
85.9 4.5 X 5.5 9.07 s3 Q' z7 b: Q4 b! b+ n7 K
Av. 14.3/ \6 ~0 s2 w' G' H2 O
4$ ^' W; k' c: w: v* [+ z$ A# n% x
8
" x! f& p" P* w/ b4 v  c100 X7 i6 ^6 r8 |0 U8 L$ \4 K
12
! [2 w& z6 F& a5 B179 X9 t, h/ L: p) t% [& ?2 u
Topical testosterone
9 }# k0 u5 G' f. [9 K. [. b34.6 4.5 X 6.5 85
/ y+ \& @8 K) l3 s% U38.8 6.0 X 8.5 70$ G& X2 C, l2 m, U& b7 U
40.0 6.0 X 6.5 62.5
! \; h) f% h1 ]- X' ^0 ?93.6 6.0 X 7.0 55.5
8 v) X3 o+ A, R! t95.0 6.5 X 7.0 27.2+ J! j0 U/ h+ A
Av. 60.0
3 A5 ?/ a( C: S9 g* _* K; C) x% f! Pavailable testosterone. Again, emphasis should be placed on+ A0 @( H5 _: B* Y& Q+ A3 I. V
early therapy when lower levels of testosterone appear to
" r; ^' O4 Z" L& W6 @0 P& b( P: ]1 I: z+ Wprovide the best responses. The earlier therapy is instituted# p! \- S# k! J" x% J% i
the more likely there will be an excellent response with low' R* w: x/ ?) |0 g, m
serum levels. Response occurs throughout adolescence as! b7 P* S' F4 ~  x5 [/ w( ]
noted in nomograms of phallic growth. 7 The actual response
9 B+ W8 i$ g) s3 J# vto a given serum level of testosterone is much greater at birth
# Q$ P$ @9 ?6 t# H. o5 F5 g# y* Dand gradually decreases as boys reach puberty. This is most
4 h. F5 e% W4 B' G! T( p5 Qlikely related to the conversion of testosterone to dihydrotes-
9 h0 _6 J- b' I, Z; l% R6 ztosterone and correlates well with the studies of testosterone5 c& [. L/ t) ?1 w( K) C
conversion in foreskin at various ages.
) f/ e4 n1 W& y8 aThe question arises regarding early treatment as to whether- A0 V; ~1 X; Z- N2 _/ V
one might sacrifice ultimate potential growth as with acceler-
4 O& d. f* u( U6 Y% c" K& `ated bone growth. The situation appears quite the reverse* R" n3 Y, X& z9 Z. ?  M
with phallic response. If the early growth period is not used+ }( @8 O. W( K7 P
when 5a reductase activity is greatest then potential growth& E" L. y! D1 W+ t* \
may be lost. We have not observed any regression of growth
1 ?9 E3 ~% p& Gattained with topical or gonadotropin therapy. It may well
, G/ p, b  p! u9 ?# C  J3 e7 Ebe that some patients will show little or no response to any
0 ]6 k: r$ z- Q4 g4 iform of therapy. This would suggest a defect in the ability to
$ U3 `9 m3 x( ?4 r7 dconvert testosterone to dihydrotestosterone and indicate that  V3 @! w! w5 ^; u! C
phallic and peripheral skin, and subcutaneous tissue should6 E/ R! ], N% w/ v9 ?+ X) |
be compared for 5a reductase activity.
9 @0 K& M+ Z+ U6 c. c, e, AA, loop enlarges to measure penile girth in millimeters. B,: u: D1 e# V* q1 j. W, ~( p: ~9 |
example of penile girth computed easily and accurately., I" l5 g  q/ F, ?' ]6 T
conversion of testosterone to dihydrotestosterone. It is in this
$ r" x# Q* P4 i1 f. eolder group that others have noted high levels of serum3 W. q6 }0 M  f' f, j  D$ t
testosterone with topical application. It would also appear2 z* Q& x5 d, E
that phallic response during puberty is related directly to the
  h0 [) a0 L$ L$ v2 T0 fserum testosterone level. There also is other evidence of local
8 E" d* R4 s& ~& {+ a4 hresponse to testosterone with hair growth and with spermato-8 S7 z: k) [5 D' G" |* R3 q0 B
genesis. 5• 69 e. w- j7 l! R& _# t, T& ^
Administration of larger doses of gonadotropin or systemic
& T  T  [2 j; O0 V4 @testosterone, as well as topical applications that produce
; y0 O, _5 w" e& Mhigher levels of serum testosterone (150 to 900 ng./dl.), will
- _7 B- h4 h; a" a3 w+ |# Halso produce phallic growth but risks accelerated skeletal. ~9 p- R8 }5 w' `/ ]) b
maturation even after stopping treatment. It would appear  M2 I' z. V7 l; n8 n$ U: `
that this may be avoided by topical applications of testosterone
" H; k+ s& z* M1 B! u# s3 nand monitoring of serum testosterone. Even with this control* ]0 m% ^9 h% V) g3 s% {  m
the duration of our therapy did not exceed 3 weeks at any3 |0 R7 m5 ^  ~6 X# |' Y" g
time. It is apparent that the prepuberal male subject may/ C6 c* D7 h3 u- C" |9 O
suffer accelerated bone growth with testosterone levels near
* P3 p$ j* e) n! z9 H200 ng./dl. When skeletal maturation is complete the level of0 S6 J! P' X" ]( L0 t" y: a8 f( t
serum testosterone can be maintained in the 700 to 1,300 ng./
) z. P& a: ]$ A, }! M) M! M2 idl. range to stimulate phallic growth and secondary sexual* o. I: g4 s8 \- A0 J- q
changes. Therefore, after skeletal maturation parenteral tes-
: B# K. @; H# {& v9 ^; }tosterone may be used to advantage. Before skeletal matura-: N8 o; X8 ?6 _9 P. K2 E
tion care must be taken to avoid maintaining levels of serum
, q1 L$ V8 e; V+ M6 B: _  ytestosterone more than 100 ng./dl. Low-dose gonadotropin
6 e& B7 J9 X# F' [4 `1 H# Q/ cdepends upon intrinsic testicular activity and may require
4 V: |6 z5 @, {  y# R9 d8 f. rprolonged administration for any response.
, |( r* P! N. n  @7 I% @Alternately, topical testosterone does not depend upon tes-
# O3 v$ H! |& jticular function and may provide a more constant level of
; ], ^. u& J5 BREFERENCES5 b0 n) k9 x0 s8 t8 N" |! \$ _
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
' n9 e% Z& H5 j9 V( E( WR.: The local application of testosterone cream to the prepub-% c+ ~) j4 }7 o) k
ertal phallus. J. Urol., 105: 905, 1971.- W8 \" \. l7 }9 Q# W8 F
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone! q: c5 Y; a$ Y$ V0 E
treatment for micropenis during early childhood. J. Pediat.,
; ^5 I- L; A: g' H' Y0 P5 L83: 247, 1973.0 h# o. K+ }" N& X
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; Z, Z: E2 A+ y8 m9 X/ c8 cone therapy for penile growth. Urology, 6: 708, 1975.
( D( ^5 [% Y- h4 v# k4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* M9 u. N& o0 E6 _
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* P8 G1 ?( ?9 h
skin slices of man. J. Clin. Invest., 48: 371, 1969.! Z( z' ^3 H6 X- n0 N
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 g: F4 [# S0 E3 K) z8 [8 Z, J
by topical application of androgens. J.A.M.A., 191: 521, 1965.! K) I0 \/ p5 q. G( K3 k/ r
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: x( u: }1 D) m; y, T8 ?
androgenic effect of interstitial cell tumor of the testis. J.+ ^& v! T0 X5 [; l4 H) N
Urol., 104: 774, 1970.; W( _3 X+ `; @- e. ?! o; `6 A
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 f0 p& }/ E  C) _  ~' l0 F
tion in the male genitalia from birth to maturity. J. Urol., 48:
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