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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# ?& ]& ~% I: Q; h- r& N( e5 `3 G
GONADOTROPIN% H$ E  j, J( \8 k  t
RICHARD C. KLUGO* AND JOSEPH C. CERNY
! _. j) z8 x1 \From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
; P6 v! i$ k8 ?; s& ^5 RABSTRACT
9 i0 k- h9 j" [- O: `3 Y* V& NFive patients were treated with gonadotropin and topical testosterone for micropenis associated
! ^( n& H: {% C; Ewith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
: G/ w+ t) T& O" f/ D( L; ~& Btropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
; ?9 Y- w: s, z; @" V, |+ h  ocream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 `% `5 V9 @  c" G3 X' L" k% l" D6 K
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ j4 Y" a3 B8 d& Aincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average* p# V9 Y; ~0 |/ }9 V/ @3 O
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
- v# W4 d. H/ x1 H6 d0 goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This' @% T$ A* {% p; O, m+ c
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 W, q. S' F( u& d* X+ s! j  ggrowth. The response appears to be greater in younger children, which is consistent with previ-6 z0 J: ]: T" u/ G' O" ^* V8 O
ously published studies of age-related 5 reductase activity.
1 Y/ u* a- ?( \5 r3 @8 x7 h8 V6 iChildren with microphallus regardless of its etiology will2 K2 X0 _" y  r- d) L, S0 T1 B4 j' f1 P, n
require augmentation or consideration for alteration of exter-( t( C: _' G3 Y4 @  x0 ?' u
nal genitalia. In many instances urethroplasty for hypo-
1 G( B2 I' t% k; yspadias is easier with previous stimulation of phallic growth." ]% F' H, A# z1 |0 P2 O/ y
The use of testosterone administered parenterally or topically5 w( J7 o% [: n  a" R- S  ^  q* A
has produced effective phallic growth. 1- 3 The mechanism of2 `5 G( v- _# I9 ^
response has been considered as local or systemic. With this
7 x9 D% I  r8 h/ min mind we studied 5 children with microphallus for response" u* a" Y5 }. ^' o3 v* R% H0 }4 m% ?
to gonadotropin and to topical testosterone independently.$ S6 {+ e& P! C+ s, {& A! ]2 R0 c
MATERIALS AND METHODS5 q' M( ]/ s) M2 l3 }5 O2 {
Five 46 XY male subjects between 3 and 17 years old were$ }+ p* _: n- ?6 f; _0 M- w
evaluated for serum testosterone levels and hypothalamic
. C; \+ l5 N/ d7 v( ^7 Mfunction. Of these 5 boys 2 were considered to have Kallmann's! [, F1 F/ ]) v1 u! ~" `& _
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-4 f# w: [+ T7 c
lamic deficiency. After evaluation of response to luteinizing
( O" Y- P: ?$ ^6 ~$ u) B2 R4 Bhormone-releasing hormone these patients were treated with
  S& }8 q$ b, k, ]7 Z& \1 `1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# ]1 \: W, l: ]* e" g) r" nafter completion of gonadotropin therapy 10 per cent topical
- Q1 P5 {/ \+ t3 T3 jtestosterone was applied to the phallus twice daily for 3 weeks., w( f* ~7 Z9 E1 a5 r0 A
Serum testosterone, luteinizing hormone and follicle-stimulat-
" c+ \9 q! D) Q& E4 g8 |5 _ing hormone were monitored before, during and after comple-8 H# }0 E# M/ P' g
tion of each phase of therapy. Penile stretch length was
+ f2 A8 m, I: e# R& i8 a* M) _obtained by measuring from the symphysis pubis to the tip of
% e! J/ F" ~& m3 Pthe glans. Penile circumferential (girth) measurements were
# ?& b# o8 Z. ^1 F9 pobtained using an orthopedic digital measuring device (see
& ^* }$ q( @3 Y' A9 j; xfigure).
% W( s& \$ W  C/ w* a  U+ _RESULTS: f: u$ i1 O# O, f/ f* e
Serum testosterone increased moderately to levels between
2 G/ ]2 d& F8 T- r( Z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' Z# ^) d+ {: |1 v9 S" xterone levels with topical testosterone remained near pre-
7 h& O0 X" D5 Z0 n7 N4 ~. `! H- ntreatment levels (35 ng./dl.) or were elevated to similar levels
% W( w7 ^1 p5 ]) I; d% p2 `developed after gonadotropin therapy (96 ng./dl.). Higher6 s: H  X4 Q/ m4 y
serum levels were noted in older patients (12 and 17 years old),
6 b% Z" b6 n, U' H% xwhile lower levels persisted in younger patients (4, 8, and 10
7 \4 _2 D: x0 J, V/ Cyears old) (see table). Despite absence of profound alterations3 W9 b& `# M7 G% i& i
of serum testosterone the topical therapy provided a greater
  \' {& O  Y. {, [Accepted for publication July 1, 1977. ·) U; J' T2 S* ~: n7 o& N2 r! `- H
Read at annual meeting of American Urological Association,
, h* m  e2 I+ vChicago, Illinois, April 24-28, 1977.
- v3 B6 w. S, k& y9 l" W' I* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 P+ i# G5 m8 W$ b  t2 {1 a2799 W. Grand Blvd., Detroit, Michigan 48202.
# v1 }( v/ j& I; L, w3 B4 ^' [improvement in phallic growth compared to gonadotropin.9 P3 S$ D+ k1 ]) f, C
Average phallic growth with gonadotropin was 14.3 per cent  L# v# f; i& T7 Y' a
increase in length and 5.0 per cent increase of girth. Topical
9 W3 Q# x& u! P4 \testosterone produced a 60.0 per cent increase of phallic length
$ O4 y: z3 H5 E1 J$ Band 52.9 per cent increase of girth (circumference). The
- y. w% a& K4 q) {$ Vresponse to topical testosterone was greatest in children be-$ y) u# X* J! ?- t# F1 W
tween 4 and 8 years old, with a gradual decrease to age 17
/ x9 u8 w. i7 @( z9 p7 Iyears (see table).
: C8 o; Q3 f, ?8 J7 }4 LDISCUSSION
: h$ t. Q$ W6 E  f4 E/ D9 z8 mTopical testosterone has been used effectively by other' Z: B- P. T; ?
clinicians but its mode of action remains controversial. Im-
9 W' z' L) X$ h1 q- omergut and associates reported an excellent growth response: c/ e. T2 O5 |; h
to topical testosterone with low levels of serum testosterone,3 y% P5 m( C* u4 f. i& o' z" Q, n
suggesting a local effect.1 Others have obtained growth re-
. X* f% ~* ]: b: d1 n( P7 Hsponse with high. levels of serum testosterone after topical. r- j7 l' M+ D% E% |; M
administration, suggesting a systemic response. 3 The use of/ t# @! @+ u4 ?3 L# }
gonadotropin to obtain levels of serum testosterone compara-+ }: J% I0 c: |/ K4 n9 S* h% K
ble to levels obtained with topical testosterone would seem to2 Y+ g3 E. ]; k$ L: A. I
provide a means to compare the relative effectiveness of
& \( W- b: i! B4 x7 V) Ltopical testosterone to systemic testosterone effect. It cer-
9 v, o" H" S: v2 P; p1 ctainly has been established that gonadotropin as well as par-
6 ]* @' Q9 V0 e' ^, [enteral testosterone administration will produce genital
$ V# M; d+ u, x2 Sgrowth. Our report shows that the growth of the phallus was2 e* [& `; @" J* b7 m7 P5 K2 {
significantly greater with topical applications than with go-3 ]  ^' q, L0 {$ J4 O
nadotropin, particularly in children less than 10 years old.
5 G3 m  c! S0 Q  X) M7 A9 s) zThe levels of serum testosterone remained similar or lower
& M" Q- }( }6 T( n7 Kthan with gonadotropin during therapy, suggesting that topi-
* o) l; K; Y' X% }6 z2 E: Y# x+ rcal application produces genital growth by its local effect as
. A, w; R( C4 T: \5 z/ m) Uwell as its systemic effect.7 g$ k! ~9 l" q4 h8 A
Review of our patients and their growth response related to) D6 i. d2 M, v- D+ v
age shows a greater growth response at an earlier age. This is
& P3 h$ s) M& l, v  L# f) q: [consistent with the findings of Wilson and Walker, who
6 m' u/ L& s+ Q- |- K0 a! N: n% ^* ]5 `reported an increased conversion of testosterone to dihydrotes-6 Z/ U8 j* x/ m% U7 p5 d
tosterone in the foreskin of neonates and infants.4 This activ-
9 a+ E1 A0 _- r1 d# Jity gradually decreases with age until puberty when it ap-% B) Z- N0 L/ ]  z
proaches the same level of activity as peripheral skin. It may! I+ ]6 V0 p& {+ y( G0 y
well be that absorption of testosterone is less when applied at& i+ v8 S$ M9 k! w# e8 G
an earlier age as suggested by lower serum levels in children& ]& E$ A" @& V. Q, P+ E" d9 f4 x) g
less than 10 years old. This fact may be explained by the  h3 ^7 p% t; s- N6 k
greater ability of phallic skin to convert testosterone to dihy-
  G/ `3 e; O) O$ p% e2 W9 Y) i4 `drotestosterone at this age. Conversely, serum levels in older
0 V& Z( Q* A: _5 e4 wpatients were higher, possibly because of decreased local
  O# R$ o( ~. S. q  `' @0 i5 c667/ B" i' `  Q2 M7 O( N# p8 C
668 KLUGO AND CERNY
; F: l4 S5 V7 W/ x/ ?( ^Pt. Age
2 b& P  G% ?8 e  U1 {$ l(yrs.)
8 a, c- n9 X: w( k1 J/ lSerum Testosterone Phallus (cm.) Change Length; h- q8 m2 n# |+ {+ U7 X/ A% x
(ng./dl.) Girth x Length (%)
8 L' V+ @) f7 _9 A9 t4 a4' f% X- L+ z- S/ J) F
8
( G# \6 n2 e9 K) v10
* |/ `+ J$ L5 m9 W! e* x12  E0 {: H) f: P. \
17% u5 L/ R3 J- h  W$ \, {
Gonadotropin# i, W0 ?/ F( K% {4 \$ R# r3 ]6 e
71.6 2.0 X 3 16.67 K3 x1 @+ h: [: X/ ?1 d1 Q
50.4 4.0 X 5.0 20.0' H& z4 B% @! D
22.0 4.5 X 4.0 25.0; Z: W# p7 H. H) v6 `9 H1 R
84.6 4.0 X 4.5 11.17 k) x- e7 s1 z3 `$ {  Z* B
85.9 4.5 X 5.5 9.0
# ^7 ^2 }9 T: `+ |Av. 14.3
( ^) F! |* R' s0 P: g4
  C- j; c- H% _8
6 z' x# W' z3 A( `106 |4 P, k# m3 @, j2 c/ w
12
+ B: O  G: y9 f  \) J5 \17
8 m" m) W3 G& H  k3 u. NTopical testosterone
. k$ ]5 c* z  ~* D9 a2 N/ l34.6 4.5 X 6.5 85
  d" G8 G9 L- w38.8 6.0 X 8.5 70( Z; P" L: k; Y6 |
40.0 6.0 X 6.5 62.50 S$ r' ]( u, H+ ?
93.6 6.0 X 7.0 55.5. Z; e1 k6 s2 l4 b; D& j- e
95.0 6.5 X 7.0 27.28 g6 Y& B# \+ V
Av. 60.0  d+ ]' T- K- A$ l
available testosterone. Again, emphasis should be placed on
* ^1 V9 P; P) C9 vearly therapy when lower levels of testosterone appear to0 w9 C% Y' ?% z
provide the best responses. The earlier therapy is instituted
) I9 f1 V" `6 U& c& gthe more likely there will be an excellent response with low( d3 [+ r2 O( H7 Z% t
serum levels. Response occurs throughout adolescence as
; ~7 b% D+ V, ~* g% Y! Tnoted in nomograms of phallic growth. 7 The actual response
! D* @! i* T( M' |3 {8 vto a given serum level of testosterone is much greater at birth$ H' P* _1 ^$ |3 U( ?
and gradually decreases as boys reach puberty. This is most, m5 T% Z- k5 r5 B( W9 }# b# _  F
likely related to the conversion of testosterone to dihydrotes-3 r9 Q% Q" F" h! L" c. r$ G
tosterone and correlates well with the studies of testosterone
2 t) O; q, a7 \" b& ^; D2 T$ gconversion in foreskin at various ages.
3 J- `5 f0 x* g* D  J$ \- TThe question arises regarding early treatment as to whether
) z3 ]0 a$ I1 V" N5 c% Jone might sacrifice ultimate potential growth as with acceler-5 j9 K! |  ^2 {2 X; s) R' ?( y
ated bone growth. The situation appears quite the reverse
; z* Q6 k$ T  jwith phallic response. If the early growth period is not used
. O% |- \' L1 b+ K( W+ }$ }4 G. wwhen 5a reductase activity is greatest then potential growth
0 }& z% ]1 E$ {1 Z# A3 h4 Gmay be lost. We have not observed any regression of growth
) w& ~/ r4 J2 |3 X1 P' q: l# cattained with topical or gonadotropin therapy. It may well
* D4 y; i$ e0 O0 X# L+ s" ^2 gbe that some patients will show little or no response to any
! H7 s: s  v6 N( Y& Zform of therapy. This would suggest a defect in the ability to
2 p" E& M" g7 w) s& k# y- E. \- Kconvert testosterone to dihydrotestosterone and indicate that
  [& L! S  f$ A8 L) Iphallic and peripheral skin, and subcutaneous tissue should% o4 a& F1 g4 z0 I7 @$ J6 J
be compared for 5a reductase activity.
% v  h% r# F. B9 E5 j/ b7 c- kA, loop enlarges to measure penile girth in millimeters. B,
  f9 I( d& u& {) ~: N7 R( wexample of penile girth computed easily and accurately.
" P  G$ ^; k/ l8 j" p* ]0 _conversion of testosterone to dihydrotestosterone. It is in this
) x8 R, x+ a- _0 h  c+ F  Xolder group that others have noted high levels of serum
8 m) [$ U- B' U2 ^" Etestosterone with topical application. It would also appear' q- z& N5 U! L1 a7 M
that phallic response during puberty is related directly to the
1 ~) A; c6 |$ `( U* t* j( y7 vserum testosterone level. There also is other evidence of local
+ ~  W3 G9 {1 F6 Z0 I* xresponse to testosterone with hair growth and with spermato-
5 l+ e5 |6 D" c  z- kgenesis. 5• 6
0 g' \0 n5 l: p- {5 t! B6 `Administration of larger doses of gonadotropin or systemic
: k% d! v/ `( ktestosterone, as well as topical applications that produce! P4 {$ w2 U2 e% C( e+ \
higher levels of serum testosterone (150 to 900 ng./dl.), will
5 s, ]+ J/ Q( @also produce phallic growth but risks accelerated skeletal  X) U7 @# G5 z8 s0 z, {
maturation even after stopping treatment. It would appear( {4 ^  u, a3 z! o' O
that this may be avoided by topical applications of testosterone1 W6 H+ o3 P# s+ q/ F
and monitoring of serum testosterone. Even with this control: c; J9 }( V- e' S% o
the duration of our therapy did not exceed 3 weeks at any
' A$ b+ {7 U$ G3 a% qtime. It is apparent that the prepuberal male subject may
7 p' y4 w' D5 A# E* r. Tsuffer accelerated bone growth with testosterone levels near  K$ `4 ?& N- B# x/ @6 q4 _
200 ng./dl. When skeletal maturation is complete the level of
2 X" |1 l# q* ^: Z/ Q- N. bserum testosterone can be maintained in the 700 to 1,300 ng.// u' Q( f. X, t. f/ K6 y$ t
dl. range to stimulate phallic growth and secondary sexual% V- C$ L7 S0 r/ w0 \4 h: B% n
changes. Therefore, after skeletal maturation parenteral tes-
" N2 T9 W- N' q0 G& t' Y: Rtosterone may be used to advantage. Before skeletal matura-
- n- z2 z( X1 c# q9 Htion care must be taken to avoid maintaining levels of serum
) P* l0 w7 G" A7 [/ @testosterone more than 100 ng./dl. Low-dose gonadotropin# ~1 S, Y1 i# O8 J' W4 g
depends upon intrinsic testicular activity and may require7 H: S" \4 T! |: S, l$ a( t2 j
prolonged administration for any response./ ~: s* n& p" ]! _/ e  z
Alternately, topical testosterone does not depend upon tes-
' K, [; {4 ~* Q  X& B6 vticular function and may provide a more constant level of1 A* P) M0 e+ M
REFERENCES& B7 t4 v  m/ s/ c/ X; M. k7 M" B
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 _. ?2 e( K5 O* q/ m; k& e6 K  J
R.: The local application of testosterone cream to the prepub-2 q0 b6 ?3 D7 q. l
ertal phallus. J. Urol., 105: 905, 1971.
' y4 l  U1 M" v; n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone: @* \. l" k! R7 c0 C) D
treatment for micropenis during early childhood. J. Pediat.,+ I0 r" R4 R5 o% ?
83: 247, 1973.% c: L  F3 x+ d" K8 Y8 N3 F
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( a& K: N, T3 m3 x! {# [one therapy for penile growth. Urology, 6: 708, 1975.2 s: J* [7 t- j1 b- K/ D7 T! x
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone. m6 ?4 ?* P3 V$ H
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 P, Z9 a8 g1 b* Z- uskin slices of man. J. Clin. Invest., 48: 371, 1969.
  L7 O3 t$ Z$ j0 I( P5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- U; p0 J# _, V3 z! O1 iby topical application of androgens. J.A.M.A., 191: 521, 1965.
+ w  M; @& P2 m- s) T( \6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, V/ Q/ A+ y& p
androgenic effect of interstitial cell tumor of the testis. J.) w, P8 A* M# |0 q- M4 W
Urol., 104: 774, 1970.
' {, G5 \; ?3 v' ?6 q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" G' X% `! x: `6 q# m3 a. l& t
tion in the male genitalia from birth to maturity. J. Urol., 48:
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