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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: v7 z4 e) g3 K! d/ L
GONADOTROPIN' i# N" I6 ~. B. X, T& C! k
RICHARD C. KLUGO* AND JOSEPH C. CERNY
7 U8 \. V1 v/ `: q6 Q0 ?* g0 zFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan( c# N: `1 J: Z  u- ~* i" f) X
ABSTRACT
, ~, w4 _( Y/ o9 W* b3 i! dFive patients were treated with gonadotropin and topical testosterone for micropenis associated
, b, ^# M4 I. s+ R( U) D  Iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-9 j% N7 t, L+ d; ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
" W& x* ~7 l2 [. \* i6 O0 \cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent" V  C8 g$ I5 L+ f, Z5 P( d
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) k+ S( M7 l+ g" K; Z, U
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average1 Z4 G. b/ r# L+ W( [$ z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 K$ ~5 u- u: J, U( F
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, |+ Y5 p! w  B' Ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
& F: _% Q: T$ P- v& P% d9 Rgrowth. The response appears to be greater in younger children, which is consistent with previ-7 O  t8 F$ r: g: e4 t0 O! j; V" {
ously published studies of age-related 5 reductase activity.& t; d$ O3 n* p7 M& [! z
Children with microphallus regardless of its etiology will& u8 j7 o/ x$ ?* e( b9 G2 H
require augmentation or consideration for alteration of exter-" f. n8 d- k+ e7 y, B
nal genitalia. In many instances urethroplasty for hypo-1 o8 R! G2 Z; c! T! q& S
spadias is easier with previous stimulation of phallic growth.+ @! i* [2 a4 F1 x- U: [( \
The use of testosterone administered parenterally or topically
1 e$ R' o& e" @% R$ c+ E( Uhas produced effective phallic growth. 1- 3 The mechanism of7 E; N  n% t) y9 {; ]" b8 p  C# b
response has been considered as local or systemic. With this/ r' U# Q+ p: {# ]8 L, m* j
in mind we studied 5 children with microphallus for response* R0 a& ^7 k, H% K- o# |' K# D- V, Z
to gonadotropin and to topical testosterone independently.
7 t% s1 Q9 |! u  w5 LMATERIALS AND METHODS( f6 Z/ W( n) |$ Y
Five 46 XY male subjects between 3 and 17 years old were
3 H! p6 I5 g; _+ Gevaluated for serum testosterone levels and hypothalamic
2 M& i) j" n0 N. t) Bfunction. Of these 5 boys 2 were considered to have Kallmann's& J( D% r) [  I
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-: |9 A0 p; p  D- g% i
lamic deficiency. After evaluation of response to luteinizing
  r$ _) G" S3 n6 s7 `hormone-releasing hormone these patients were treated with
8 i. \( p( [6 G( D3 G# c7 R1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: W( k3 o2 M) Y5 z4 z3 ?after completion of gonadotropin therapy 10 per cent topical  n  _: D. Z# u; b# B% ~! T
testosterone was applied to the phallus twice daily for 3 weeks.& j! K/ V  ], v4 n+ o/ g8 ]- H
Serum testosterone, luteinizing hormone and follicle-stimulat-
3 v  X/ k* E$ e; p- F4 ~) N! Zing hormone were monitored before, during and after comple-
) }/ h* p+ x3 W! x! o, Btion of each phase of therapy. Penile stretch length was% |( _. m1 Z/ i
obtained by measuring from the symphysis pubis to the tip of
. \: G4 C; A: ^0 v; \, ]the glans. Penile circumferential (girth) measurements were
3 `* u0 R0 g# p& b) uobtained using an orthopedic digital measuring device (see
9 z( A$ Z2 z* o: ~. o1 V/ bfigure).+ N* Q; _' W% C2 e2 P
RESULTS
( h, w: ]1 \: I- B! QSerum testosterone increased moderately to levels between  U$ a7 k4 z* \9 S8 I
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) d3 |: c5 s. {3 D2 o. `8 b, Y
terone levels with topical testosterone remained near pre-0 H' s0 L" \' w! w. E' z
treatment levels (35 ng./dl.) or were elevated to similar levels
5 y. A5 j# \2 W' W9 e* Edeveloped after gonadotropin therapy (96 ng./dl.). Higher. P9 _% l3 K9 z6 q' M+ E
serum levels were noted in older patients (12 and 17 years old),
4 A9 r0 ^& U9 q( cwhile lower levels persisted in younger patients (4, 8, and 10
; Z' Y! l  v) }2 Cyears old) (see table). Despite absence of profound alterations$ t' p- F' \- ]- R  R$ c- S
of serum testosterone the topical therapy provided a greater0 E! H% i; c( x/ t4 q
Accepted for publication July 1, 1977. ·
9 D' t) s7 X* BRead at annual meeting of American Urological Association,
# ~" w" t1 t3 r9 C. dChicago, Illinois, April 24-28, 1977.* e: Z( ?3 B; ~, O
* Requests for reprints: Division of Urology, Henry Ford Hospital,
" V  q. b: ?# r2 ?2799 W. Grand Blvd., Detroit, Michigan 48202.
% [0 u% A) z6 t5 o! G, eimprovement in phallic growth compared to gonadotropin.8 S5 l) i8 _5 }2 x' b
Average phallic growth with gonadotropin was 14.3 per cent. N+ Z7 }2 m2 U/ h
increase in length and 5.0 per cent increase of girth. Topical
7 R$ \, `. e2 ^. k, [' k& Y5 f7 Y) {; ~; ltestosterone produced a 60.0 per cent increase of phallic length
2 B$ ~  d7 t3 D( @+ Aand 52.9 per cent increase of girth (circumference). The
" _1 M, B9 j" J3 Q" _$ V- Nresponse to topical testosterone was greatest in children be-6 }4 _0 A/ _9 y" o, X
tween 4 and 8 years old, with a gradual decrease to age 17
; P0 a) f+ n: b/ f( U& Xyears (see table).
( v8 E4 x/ ]; n3 K0 a; [DISCUSSION
: m" F5 D& |& X+ ^0 w$ G) MTopical testosterone has been used effectively by other
+ }+ k4 b2 j+ \( |- Rclinicians but its mode of action remains controversial. Im-# P2 L; I+ e+ O  Y2 f: K0 a: z
mergut and associates reported an excellent growth response
! s* [4 Q2 _$ y. W  vto topical testosterone with low levels of serum testosterone,
- |' |7 ~+ w; m' o5 x8 Hsuggesting a local effect.1 Others have obtained growth re-5 g* m/ t5 |. ^/ J" v1 E4 N! _
sponse with high. levels of serum testosterone after topical( q! L, {5 t% L* w0 G5 j& B
administration, suggesting a systemic response. 3 The use of
; r* U9 }+ A2 d0 s7 P$ Igonadotropin to obtain levels of serum testosterone compara-2 [4 J# A3 u$ w. b) ]7 s3 f1 r3 C: E
ble to levels obtained with topical testosterone would seem to2 y5 y" D% F: X/ ^- @, g) c0 N  G4 G
provide a means to compare the relative effectiveness of, s. H( j) D2 O6 ~6 c
topical testosterone to systemic testosterone effect. It cer-
9 s+ Q- a, Y6 E# ?0 P& H7 ktainly has been established that gonadotropin as well as par-7 F0 f$ S7 y" D: o, v
enteral testosterone administration will produce genital: U8 ?5 Y8 f3 w' Y& B2 N4 v& E. N
growth. Our report shows that the growth of the phallus was+ |$ L, \5 ?' N& l+ \) _
significantly greater with topical applications than with go-  s) S' K; }( o0 A+ ?
nadotropin, particularly in children less than 10 years old.+ Q7 y. a9 N( L& Q/ w
The levels of serum testosterone remained similar or lower- l6 v3 J3 @' u& ^! q9 }1 m- d- p
than with gonadotropin during therapy, suggesting that topi-( b3 |9 z( a! t/ e7 \8 l7 b
cal application produces genital growth by its local effect as5 b4 m! p& d8 a$ V; |5 k% Y: C
well as its systemic effect.
) L$ ^+ r) n5 }2 c: r7 _+ BReview of our patients and their growth response related to
1 p4 K2 u% X0 A+ Q2 y0 |+ qage shows a greater growth response at an earlier age. This is
( v3 C9 D5 \1 Dconsistent with the findings of Wilson and Walker, who4 ]5 w: m+ [7 t; U% e/ w
reported an increased conversion of testosterone to dihydrotes-
7 v, x# X( ^+ L/ m6 M# U. ltosterone in the foreskin of neonates and infants.4 This activ-8 [3 Q9 C0 X7 N( h
ity gradually decreases with age until puberty when it ap-; Z" F6 ?" F- r
proaches the same level of activity as peripheral skin. It may
. M, i8 M+ @4 Twell be that absorption of testosterone is less when applied at: p# s5 B' Y1 T2 v- C/ V: b0 C
an earlier age as suggested by lower serum levels in children& E+ d9 `8 z  h; a8 D
less than 10 years old. This fact may be explained by the
; _0 g+ h# G( q& D, `greater ability of phallic skin to convert testosterone to dihy-, \) Y3 J' `5 B6 \; y0 r$ n
drotestosterone at this age. Conversely, serum levels in older
5 G9 x1 U4 z( v7 a9 Gpatients were higher, possibly because of decreased local
7 l% ^& L7 Y3 M0 {! Z* [667# S* w5 C8 Z; ]. a% y
668 KLUGO AND CERNY4 [& J4 r0 W& P" [# Z/ n. i
Pt. Age
+ u( _8 \1 S. ?4 k  G: G(yrs.)
* _! }5 y* S: I0 o& g% s+ y9 `Serum Testosterone Phallus (cm.) Change Length
6 S; G; O" U; S8 Z' \) q3 g(ng./dl.) Girth x Length (%)! K& d" s7 B+ o0 p9 P
46 _- q5 C# T* W
8
& F% ]* i* M% b! k' S' N& h10
% R, l/ b9 Y0 ~7 q7 X/ v8 Y  |& V- U# c. S12- M$ o; z% X* O9 G3 g% I8 p
17
5 a/ Z+ O* p% \  ]8 o+ yGonadotropin$ d7 j0 ~" u7 u+ G& z( x
71.6 2.0 X 3 16.6
% b; l, ~6 K1 x# q  E+ @50.4 4.0 X 5.0 20.0; z3 m2 b8 f0 U2 ~* n/ t3 D4 f
22.0 4.5 X 4.0 25.0
8 j( l; F$ C2 m+ x" v4 |1 G84.6 4.0 X 4.5 11.1' D+ E1 \: P& ]4 I
85.9 4.5 X 5.5 9.0' p) P" l1 q  ^9 z+ A; w6 c- F2 E
Av. 14.3
: j2 t" [2 l1 _. [5 D, I4& S# b' |2 ], t/ l# R, E; n/ k
8
2 E  G& {6 f/ v* k  l# x+ t# Q10  R0 |/ l, Y/ T
128 W- E- P8 v* q% d/ M# Z
17
6 g3 Y0 D( R& s* s: W. ?4 lTopical testosterone
! L2 ]- o4 q0 m1 C& X34.6 4.5 X 6.5 85
1 `3 J1 W& `4 f38.8 6.0 X 8.5 70
' j# r, ~$ {$ h+ H7 ~40.0 6.0 X 6.5 62.5& H7 _" r; {- \" K0 }( k3 H$ x
93.6 6.0 X 7.0 55.5# P2 T2 ]( y6 r( q& B# B
95.0 6.5 X 7.0 27.2, o! ^" Z( c) ~' W
Av. 60.01 c5 ~" @! e* j; f0 e# p4 K. I- x
available testosterone. Again, emphasis should be placed on
+ o- @1 w* a7 yearly therapy when lower levels of testosterone appear to
9 _# C; k9 q" S' ^- S# |provide the best responses. The earlier therapy is instituted
! g* W4 @) I) sthe more likely there will be an excellent response with low
' H) s1 ?; F& q# l1 F5 kserum levels. Response occurs throughout adolescence as( p0 v6 g  J0 m8 M
noted in nomograms of phallic growth. 7 The actual response4 H- j0 v# I( F* }8 T# u5 X8 H9 _
to a given serum level of testosterone is much greater at birth
1 }+ g; b$ e2 [: uand gradually decreases as boys reach puberty. This is most0 [; i  `. I. ^5 l7 F0 ?
likely related to the conversion of testosterone to dihydrotes-
4 k% k6 y/ k( I4 R/ rtosterone and correlates well with the studies of testosterone
; P9 ]5 W- C9 \( C3 @conversion in foreskin at various ages.
) p1 I+ q+ Q1 }2 ]) A2 b. G$ G5 Q0 JThe question arises regarding early treatment as to whether
' C: K! {. [3 h0 @' d4 wone might sacrifice ultimate potential growth as with acceler-; L$ M1 D8 Y0 v* P
ated bone growth. The situation appears quite the reverse; E' |: ]/ S) a% I* K
with phallic response. If the early growth period is not used2 _+ |- t/ R+ L& l
when 5a reductase activity is greatest then potential growth
5 M( c/ \1 T2 z: Mmay be lost. We have not observed any regression of growth
: k% F  S8 ^% x! Kattained with topical or gonadotropin therapy. It may well
$ i& _- D! a% H* u8 L% p/ Fbe that some patients will show little or no response to any2 T+ P4 x" H; C( o. V) H/ i( u, w
form of therapy. This would suggest a defect in the ability to" c% b' J% n0 U; p$ k
convert testosterone to dihydrotestosterone and indicate that* N) Y% H4 {- Z- M0 g2 i
phallic and peripheral skin, and subcutaneous tissue should9 C& L8 G2 y; H% l/ H7 `% D1 ], D
be compared for 5a reductase activity.
" Z( l8 Q7 M- n. a: n; \$ gA, loop enlarges to measure penile girth in millimeters. B,
+ a$ q0 [9 V- i9 L9 o; l  u4 w! Aexample of penile girth computed easily and accurately.4 a, M8 `" \9 j3 e) M0 D5 j
conversion of testosterone to dihydrotestosterone. It is in this/ F* R/ E5 @3 M- s7 @2 v
older group that others have noted high levels of serum
4 Z7 }. T' |$ xtestosterone with topical application. It would also appear
( Y/ s6 i" x/ R) B& F& t$ ]that phallic response during puberty is related directly to the. |& r" u! P6 M/ b: d
serum testosterone level. There also is other evidence of local5 w& x# \# _) {& N; ]; |# d& U
response to testosterone with hair growth and with spermato-
# j9 R$ R/ n1 u: v) f4 q  ugenesis. 5• 6& L3 d$ E, ~- t* G" }# o
Administration of larger doses of gonadotropin or systemic
/ N" Z6 V) R% E8 S9 Dtestosterone, as well as topical applications that produce
" }2 V8 |- C. G' A! Q3 |; N+ |" _higher levels of serum testosterone (150 to 900 ng./dl.), will
  [' A0 Q, O4 z3 V3 ]# V3 ?also produce phallic growth but risks accelerated skeletal" L( N: l, X2 V# u, N& ~0 S: R& Q
maturation even after stopping treatment. It would appear% O( X; Q6 h4 Z2 X$ o/ Q$ C- L
that this may be avoided by topical applications of testosterone
+ H" x6 F8 u$ Gand monitoring of serum testosterone. Even with this control
: e1 V3 D7 J/ W) ]3 ?% Z. q  V2 v3 othe duration of our therapy did not exceed 3 weeks at any
3 Z$ f& ^) U9 t6 Gtime. It is apparent that the prepuberal male subject may
! m: X4 Z! @; \. Y8 G& x' @: V# Qsuffer accelerated bone growth with testosterone levels near; x& K5 v/ ?8 }/ g8 m$ r: \
200 ng./dl. When skeletal maturation is complete the level of
& I& K) m- B. p; zserum testosterone can be maintained in the 700 to 1,300 ng./
, ?4 x0 s! }- j6 O' X0 I8 wdl. range to stimulate phallic growth and secondary sexual
6 c% c1 e9 _5 [% K1 d, j- S8 T* E2 |changes. Therefore, after skeletal maturation parenteral tes-# A1 M3 V5 Y  o3 b  |- d# k4 c2 Y
tosterone may be used to advantage. Before skeletal matura-
' e: F/ l5 E% S! z; v" A( ption care must be taken to avoid maintaining levels of serum; E, c8 ]6 v. ?/ L, l
testosterone more than 100 ng./dl. Low-dose gonadotropin& z! x, W$ Y- V8 e+ z  V
depends upon intrinsic testicular activity and may require6 B6 K' z& R0 F6 @, A
prolonged administration for any response.
, h, @2 z+ [0 C# l. nAlternately, topical testosterone does not depend upon tes-
) F: ?1 ^" p! Y% ]# d$ Fticular function and may provide a more constant level of
7 S, I) x' N5 ?REFERENCES4 t3 X% ~% i' O& c
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,. w, m$ q% c2 P5 h
R.: The local application of testosterone cream to the prepub-, \' k2 U) h4 \: `2 u
ertal phallus. J. Urol., 105: 905, 1971.
3 s8 @! N. f( I' h4 Q  o8 g3 R2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
$ F( Z' e, O( Y# H0 V* Ntreatment for micropenis during early childhood. J. Pediat.,$ p8 }1 Y  ~; t' U
83: 247, 1973.
5 C6 `% [8 B5 |& v# O' g3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 K" d  \6 j+ D9 N" q1 Rone therapy for penile growth. Urology, 6: 708, 1975.
9 r( z4 q  l( a0 o) V4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone( t& F" I7 N: C) a/ g+ h0 H9 j. v
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' h4 b6 H$ w5 b6 Cskin slices of man. J. Clin. Invest., 48: 371, 1969.% `. P) u  {$ T9 \
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth( y; H  ^" @1 J: M; G% N
by topical application of androgens. J.A.M.A., 191: 521, 1965.) Y! N( c5 k: @& @' Q9 j1 W
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
  {/ B  l; w* R; tandrogenic effect of interstitial cell tumor of the testis. J.
0 Q2 s) r/ ]. i' z8 EUrol., 104: 774, 1970.
2 v( |+ C. C$ H0 G7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" ^' v# q5 k2 n. {' @! V0 t9 Y* V
tion in the male genitalia from birth to maturity. J. Urol., 48:
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