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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
) s. k, ?+ n# l  s$ KGONADOTROPIN
& a0 U/ V1 V9 y* C& ]RICHARD C. KLUGO* AND JOSEPH C. CERNY
7 {1 O2 `% m2 `7 x! h. pFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ P% a& G( y5 d9 c% n* V$ W
ABSTRACT
% R5 y; R& J% ?' _& R& `# lFive patients were treated with gonadotropin and topical testosterone for micropenis associated
, q0 F  ~1 L! X( u5 S7 [with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-% N  V7 U3 `2 ^+ }9 S' j" ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
7 E* G5 \' o7 J0 x9 v: Ycream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
0 I) j4 N" F8 m0 I* e0 X4 g( Wfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 x7 B) O: u2 j; v  A6 d3 c! Xincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 e# f* }' o# T; x. gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response1 \. n$ t  l& y3 S
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# O1 \) @) [1 [( l  v) Sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% g4 @0 s" F  f; ~, i" V7 V" \. Pgrowth. The response appears to be greater in younger children, which is consistent with previ-
5 K; W+ g  D6 Z( C7 m' o: Pously published studies of age-related 5 reductase activity.* ?+ j5 u5 Y8 _; Y7 g9 Q) x
Children with microphallus regardless of its etiology will
5 Y9 V: G2 o) O8 J7 t) j( B% @8 Z7 orequire augmentation or consideration for alteration of exter-  Q3 z1 b) V. ]' h
nal genitalia. In many instances urethroplasty for hypo-
3 G$ V* G2 k  Q% a- Rspadias is easier with previous stimulation of phallic growth.
: W9 a. ?7 H% \2 {) jThe use of testosterone administered parenterally or topically" P  b! k( w. W  O7 a
has produced effective phallic growth. 1- 3 The mechanism of
0 y. {7 F$ h( p$ i2 \0 A' lresponse has been considered as local or systemic. With this% i4 u$ s& q7 ?/ J' j
in mind we studied 5 children with microphallus for response
+ k) {- A3 K$ p" e* N0 nto gonadotropin and to topical testosterone independently.
8 u6 _& F7 [0 W$ E' }0 dMATERIALS AND METHODS! G8 M6 E- ?  P# D9 W  W
Five 46 XY male subjects between 3 and 17 years old were
2 l5 y; r; n' v4 K, [% hevaluated for serum testosterone levels and hypothalamic" f$ m: ]3 s9 y; _! R" h6 }# j
function. Of these 5 boys 2 were considered to have Kallmann's
# a6 D/ f9 K! k1 N; @3 J* vsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-( a+ \: n+ h7 @  ^( b
lamic deficiency. After evaluation of response to luteinizing. D! _  T* H( Y1 ~: [, T3 Q1 w
hormone-releasing hormone these patients were treated with* z7 k1 @- B7 P
1,000 units of gonadotropin weekly for 3 weeks. Six weeks1 j2 j- E+ z" ?! ]8 w% C
after completion of gonadotropin therapy 10 per cent topical
- e* D3 a% d' s4 m: e7 E8 }testosterone was applied to the phallus twice daily for 3 weeks.
6 \6 R( k1 v# \5 M3 O4 O+ L$ bSerum testosterone, luteinizing hormone and follicle-stimulat-8 J& z0 h3 s, E: t4 O. a- \) U
ing hormone were monitored before, during and after comple-# X  y, ~8 I5 ~3 J) `# d
tion of each phase of therapy. Penile stretch length was( l/ [2 o! v0 t, Q, q: g
obtained by measuring from the symphysis pubis to the tip of
- I6 }1 D/ |! N# Y+ ~+ o6 Hthe glans. Penile circumferential (girth) measurements were
2 R+ P+ \$ N9 L0 \9 Xobtained using an orthopedic digital measuring device (see
" b, R% d9 E+ Y1 m. I; B) Nfigure).
& m% I8 R" r( C: qRESULTS
. j% ]5 E# w: k+ l+ YSerum testosterone increased moderately to levels between  J& B3 _/ ]5 g8 q- a) x# {; c
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-  ]$ V: U! m+ X4 L' a* a/ b4 r
terone levels with topical testosterone remained near pre-
/ E, G, r) Y# Z& r: c" ^: qtreatment levels (35 ng./dl.) or were elevated to similar levels% N7 a# L8 g! t* B
developed after gonadotropin therapy (96 ng./dl.). Higher
0 i2 p6 E0 @4 q9 M% ]" Iserum levels were noted in older patients (12 and 17 years old),
2 [. f1 s6 @  @" W: bwhile lower levels persisted in younger patients (4, 8, and 10
  q$ w# h( ?: syears old) (see table). Despite absence of profound alterations
% N8 E. h* E: Wof serum testosterone the topical therapy provided a greater) H7 }9 `7 `% N# U
Accepted for publication July 1, 1977. ·, j0 y' Y$ t/ {. M
Read at annual meeting of American Urological Association,
! F8 B3 O! M) b2 b5 a4 BChicago, Illinois, April 24-28, 1977.  C! @$ z/ j/ X. N
* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 x. a/ A  |  O1 C2799 W. Grand Blvd., Detroit, Michigan 48202., J& v' Z+ V" l8 b
improvement in phallic growth compared to gonadotropin." y& T5 Q! _/ h* h& Q  g
Average phallic growth with gonadotropin was 14.3 per cent
$ ?3 D( y% z/ K- Vincrease in length and 5.0 per cent increase of girth. Topical- l. ?0 A+ g3 t4 b; J' F+ M
testosterone produced a 60.0 per cent increase of phallic length" l; d) T) R! ]( l. ?* N, W) I
and 52.9 per cent increase of girth (circumference). The
' s2 J3 l8 V$ T' }  ^& wresponse to topical testosterone was greatest in children be-
! O# z* F9 l. {' F) v" Q, h: T  stween 4 and 8 years old, with a gradual decrease to age 17
. ~2 k, Z) g! fyears (see table).
- H1 z( S! ^3 m# K2 [3 x7 XDISCUSSION! x; o$ Q3 I4 Z& K
Topical testosterone has been used effectively by other
0 G  ?3 S/ y) Kclinicians but its mode of action remains controversial. Im-! w- v; S, I% r) B3 A
mergut and associates reported an excellent growth response$ ^1 }) y; `4 l3 h! u
to topical testosterone with low levels of serum testosterone,
% S- D/ m9 x6 |, k6 tsuggesting a local effect.1 Others have obtained growth re-" g8 x% n" y: n7 D* [9 f$ z
sponse with high. levels of serum testosterone after topical, ~& j* ^; k7 K" G( D3 c
administration, suggesting a systemic response. 3 The use of
) S4 I+ c" Z. s) d) K8 o0 d( l6 C! Wgonadotropin to obtain levels of serum testosterone compara-  o1 ]# a5 h* r0 ]; C
ble to levels obtained with topical testosterone would seem to
  k. x) S2 d5 m# }4 L$ {provide a means to compare the relative effectiveness of
! `7 y' \/ `- J. k% O8 C5 itopical testosterone to systemic testosterone effect. It cer-8 ^6 o6 N- X" q. A; I
tainly has been established that gonadotropin as well as par-- d% ^! A4 N( A2 U5 G8 ?5 b. ^
enteral testosterone administration will produce genital
( U; I0 {( w" R  F. M) L2 Z& hgrowth. Our report shows that the growth of the phallus was2 u" Q7 `; R- ?# n2 t
significantly greater with topical applications than with go-  ~' S! [+ d1 ~& l6 r& l$ Z  N: t
nadotropin, particularly in children less than 10 years old.' B' b/ g% n" \, o( R; c0 e1 P
The levels of serum testosterone remained similar or lower
& D9 A0 J* e2 Z- T; Gthan with gonadotropin during therapy, suggesting that topi-6 D: d" Q% f7 p
cal application produces genital growth by its local effect as
" a! N% u1 d0 M4 Q/ \well as its systemic effect.
4 a' S) Y, R& p* \, h  WReview of our patients and their growth response related to( ]+ B) m$ {3 b5 O* T: f, c8 t
age shows a greater growth response at an earlier age. This is; ^& a* f* E2 y2 `/ I" U
consistent with the findings of Wilson and Walker, who. s, t3 G8 Y+ ?" A5 K3 E4 E
reported an increased conversion of testosterone to dihydrotes-- @2 G( r4 M: i) j
tosterone in the foreskin of neonates and infants.4 This activ-0 V# ]0 J$ I  G4 j% q- h
ity gradually decreases with age until puberty when it ap-
! X+ K, p# N# s2 E8 f- n+ X$ c8 s% }proaches the same level of activity as peripheral skin. It may1 r, [0 J% A( n. v! T
well be that absorption of testosterone is less when applied at" p3 m: R+ b% w5 O
an earlier age as suggested by lower serum levels in children
. q# X2 g6 s* _  u: K1 Fless than 10 years old. This fact may be explained by the
. q1 B+ P" S' L# Y3 Kgreater ability of phallic skin to convert testosterone to dihy-
9 S# p: t& @2 u7 P% {drotestosterone at this age. Conversely, serum levels in older, D0 t8 v$ a! X: j; E% M5 v
patients were higher, possibly because of decreased local
; j# I9 F# P0 A; m" |3 J% V6673 x2 M+ w3 y5 g
668 KLUGO AND CERNY! p+ |' c! O( }! V4 S" S8 W/ X# \
Pt. Age1 b, w4 a" |' [; h6 Y! W
(yrs.)
7 y- ~0 z! t( k6 _6 y- S: \" lSerum Testosterone Phallus (cm.) Change Length
. g* l# @2 o2 U( F5 x(ng./dl.) Girth x Length (%)
5 r" u% x! t# ]& v4 x+ ~4
( ^' A. o1 i$ W4 m/ U# v( t85 y; X% m+ F+ b( a6 K9 Z! D$ w
10
9 ?/ q/ c; h: X  [12
0 X! U" O" @+ K+ W17
+ F8 V/ E6 H) z% }# YGonadotropin
" j4 n# p& Q" q4 V71.6 2.0 X 3 16.6- t  X+ R  {, Z% d: J
50.4 4.0 X 5.0 20.0
% u' l! Z/ ]5 n' q3 |22.0 4.5 X 4.0 25.09 r4 Y+ |1 M2 v( k% t. G0 V
84.6 4.0 X 4.5 11.1
& y7 T1 N4 ^+ L85.9 4.5 X 5.5 9.0
- Q* l4 E6 {3 H, KAv. 14.3
& |! r* e! X! @, J) ~3 P% e4+ t$ X" |( |( H# r2 r
8) I3 Y" H! K, k
10
( ~/ }" ?" Q! G9 e12
# f% v' }" g3 {17% f% ^" U5 |; |; W) S
Topical testosterone
1 A* H5 V% \6 R* c/ x* {34.6 4.5 X 6.5 85
% }0 k& R" a) l" E8 Q5 r; q38.8 6.0 X 8.5 70
( k  J3 h" G. ]" n40.0 6.0 X 6.5 62.54 N; W6 w' n6 k8 y
93.6 6.0 X 7.0 55.5
% ]' q$ b; L! V* ?$ d/ ?95.0 6.5 X 7.0 27.20 B" p8 ^2 f# E! d. \* g! p( [
Av. 60.01 I. r9 X4 W! v9 R
available testosterone. Again, emphasis should be placed on
* Q3 `: ^* o2 [( I# N. iearly therapy when lower levels of testosterone appear to
: W9 o5 a1 ?" K! ^) O& Tprovide the best responses. The earlier therapy is instituted% Q3 R% ^8 j0 E0 P0 h
the more likely there will be an excellent response with low
9 Y5 s* F. I6 \$ W1 Eserum levels. Response occurs throughout adolescence as" q) r. x( j' c7 s( h
noted in nomograms of phallic growth. 7 The actual response
0 \; W) g* X( L1 P9 ]to a given serum level of testosterone is much greater at birth
3 N8 a* F- V/ H, p8 y% `. u  rand gradually decreases as boys reach puberty. This is most) m6 k3 W% y2 {& [8 Z7 H7 ?( n
likely related to the conversion of testosterone to dihydrotes-
6 l5 a* P3 i5 S. G( btosterone and correlates well with the studies of testosterone
6 j+ h& c& _" {, J6 Iconversion in foreskin at various ages.
+ V4 v3 ]3 S( W5 M) @( S) x7 iThe question arises regarding early treatment as to whether
$ N3 m! l/ N- ?$ N8 P7 D% ^one might sacrifice ultimate potential growth as with acceler-
& o% ^' L! j( z7 e1 Lated bone growth. The situation appears quite the reverse/ f1 }. ]" a4 I' E3 @
with phallic response. If the early growth period is not used) n" F0 e; A: D) \, \) x& T
when 5a reductase activity is greatest then potential growth. [8 x8 [0 L) S
may be lost. We have not observed any regression of growth  \  ?+ M9 R9 ]% `2 R' x  y
attained with topical or gonadotropin therapy. It may well
2 r1 C; p& E4 o6 ?) H) Zbe that some patients will show little or no response to any0 d/ z4 x! D& m! x$ B- K
form of therapy. This would suggest a defect in the ability to
6 X' `' ~6 o; [$ h  Fconvert testosterone to dihydrotestosterone and indicate that& [- X/ B" B- r  [
phallic and peripheral skin, and subcutaneous tissue should
, Y. H1 x! y' y0 |1 ]& {& Ebe compared for 5a reductase activity.9 o  @. \7 U  r$ s, o
A, loop enlarges to measure penile girth in millimeters. B,
7 W( {8 m; f- R6 u4 J% Gexample of penile girth computed easily and accurately.& J- a3 z$ e8 `3 s/ `
conversion of testosterone to dihydrotestosterone. It is in this  D7 ~* J$ A9 z2 U, ]# z) }* H9 {
older group that others have noted high levels of serum6 ?# D" D' T3 S. R0 q6 k5 A
testosterone with topical application. It would also appear8 q* ~0 W6 y! c" C5 N3 z' l
that phallic response during puberty is related directly to the
1 r+ y& _7 L9 @; f/ w; fserum testosterone level. There also is other evidence of local
* [1 R  T' B0 V# d# i9 ]! Presponse to testosterone with hair growth and with spermato-+ Y0 K$ J: B! A4 ^
genesis. 5• 6- o) o$ V' n, W* |% H: w% ]! ^4 }- J
Administration of larger doses of gonadotropin or systemic, ~) R2 _8 y, c' @! H
testosterone, as well as topical applications that produce9 {8 N/ v9 B9 \8 O, {
higher levels of serum testosterone (150 to 900 ng./dl.), will* x$ s- s; K: Y" q! m! l" o# i
also produce phallic growth but risks accelerated skeletal
3 e1 G3 y# q8 w3 C8 mmaturation even after stopping treatment. It would appear$ n/ p1 d2 |5 w2 V8 Y
that this may be avoided by topical applications of testosterone9 F% |# ?) c/ r. J; D
and monitoring of serum testosterone. Even with this control
( {  `2 p2 v, V4 ithe duration of our therapy did not exceed 3 weeks at any4 j- S% q3 M% x' `# p6 w
time. It is apparent that the prepuberal male subject may
$ q3 A0 {. P' j( r9 h$ dsuffer accelerated bone growth with testosterone levels near
% Q  p0 W- v$ G( b200 ng./dl. When skeletal maturation is complete the level of% |0 \1 _* a2 c
serum testosterone can be maintained in the 700 to 1,300 ng./- \) ]0 a( W  ?0 h6 \4 h  X
dl. range to stimulate phallic growth and secondary sexual
0 v+ A. Y1 T/ ?& _  }1 ~# ichanges. Therefore, after skeletal maturation parenteral tes-$ E! Y1 K+ E& f+ X7 a" e
tosterone may be used to advantage. Before skeletal matura-
& O6 B( Y2 H" c. |tion care must be taken to avoid maintaining levels of serum
2 m. b: {5 d, `) @testosterone more than 100 ng./dl. Low-dose gonadotropin( H$ O; d1 z* c  C4 `& C0 M- s- C7 w
depends upon intrinsic testicular activity and may require6 X* e9 {# @% k+ A; M4 V; O2 k7 w
prolonged administration for any response.
. L; f' I& a+ P5 G4 g4 tAlternately, topical testosterone does not depend upon tes-
$ M% j, c9 G0 P* a+ q0 cticular function and may provide a more constant level of
& L5 X+ Q% u/ _! T" w8 N( O. jREFERENCES6 Z1 A" e) V- I8 [# C$ _
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; A2 X- _4 X% V6 }  ER.: The local application of testosterone cream to the prepub-
# e. Z5 G+ b2 ]# Y; ^  m) E, Tertal phallus. J. Urol., 105: 905, 1971.7 z& ?! l4 c7 A7 z/ P# j
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( g; L# b, p) o" E, s4 p- _0 T2 k# @+ m8 @treatment for micropenis during early childhood. J. Pediat.,
+ ~$ V8 c+ a1 X, o2 G! w* s9 R83: 247, 1973.
" d1 B& K  @3 |/ W$ t* s) W' F3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-8 Y5 ?6 x& \( [" L0 t* a
one therapy for penile growth. Urology, 6: 708, 1975.( V6 P- o" u8 {: o
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, ^- d- L: e/ j/ F/ C5 cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 ?, R( `. j' s$ ?! p$ yskin slices of man. J. Clin. Invest., 48: 371, 1969." Y1 w0 W- s+ g% r, T, q2 q, K
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% R" d( r7 M2 K; k( f. V! ?
by topical application of androgens. J.A.M.A., 191: 521, 1965.
# R! @" K# ], s+ m. R2 X" a7 {6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
- U' Y/ ^8 ^" Zandrogenic effect of interstitial cell tumor of the testis. J.
* G( y/ x' s: T" c: n" ZUrol., 104: 774, 1970.0 d( L, O# X5 K8 Y% p' M' O+ B
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 K7 I3 {$ V$ M( x; w
tion in the male genitalia from birth to maturity. J. Urol., 48:
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