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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 ?, o! j! n  l3 KGONADOTROPIN
' M9 c* O6 M& O7 ]  I! |1 LRICHARD C. KLUGO* AND JOSEPH C. CERNY
: V3 @6 A( I5 Y3 b7 IFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
" C( N5 u3 ]' f5 S& c; P1 ]ABSTRACT) R( K% W8 e+ y5 B+ ?9 ^- d
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
# b7 c, m- J0 Y# g' S2 C" i" Jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) t% m3 r3 H: dtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 @, K' a& y, h0 F0 N
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent- O' K  w5 Z2 w/ T  P  p! C
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent+ k! _! y9 k0 H6 p3 K# s+ u: n( F
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average$ H1 P3 u# |% L" J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
, d8 l5 D. V0 P1 S5 F* loccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
9 S6 o/ m( w3 ?0 }& A4 estudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile9 u( s0 W5 Z4 k+ `, _! Z1 d2 E
growth. The response appears to be greater in younger children, which is consistent with previ-
+ F. J; ^4 l% y# J1 C5 T$ _ously published studies of age-related 5 reductase activity.
. m  L* z1 n, O9 N& IChildren with microphallus regardless of its etiology will
3 J8 ^4 I. c/ p8 u! A* ^. vrequire augmentation or consideration for alteration of exter-
: @; P, k& i0 \8 a8 ]nal genitalia. In many instances urethroplasty for hypo-
+ }' L5 j0 T4 m8 N$ H4 G+ B; T) Wspadias is easier with previous stimulation of phallic growth.0 e; c- L6 t7 |
The use of testosterone administered parenterally or topically/ b7 P- o0 y( Q, K/ H( a& m
has produced effective phallic growth. 1- 3 The mechanism of9 N1 ^) a6 K! a; W0 F& }
response has been considered as local or systemic. With this
: ?" o! j- `: l4 ?in mind we studied 5 children with microphallus for response% ], `3 `. B- \$ f, V
to gonadotropin and to topical testosterone independently.
( |/ h  i; L- |" [MATERIALS AND METHODS$ b9 t6 j4 o! D0 ]3 T" W: Y
Five 46 XY male subjects between 3 and 17 years old were: H4 }* E$ o3 d
evaluated for serum testosterone levels and hypothalamic
! f0 A) ?( N& F$ D$ B8 E. {function. Of these 5 boys 2 were considered to have Kallmann's
9 H: {3 f( e1 g8 }5 rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
: M1 P; Z* r) L$ l1 ]( olamic deficiency. After evaluation of response to luteinizing2 z# M& Q* a+ ^% z, ^/ I0 K: ^6 J
hormone-releasing hormone these patients were treated with
2 E' @# K- H) l/ l( t! p3 s1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 R; {7 Q$ J, ?after completion of gonadotropin therapy 10 per cent topical
& c4 t# c8 o7 q: O9 U- otestosterone was applied to the phallus twice daily for 3 weeks.
- \$ S) m3 w6 n. b: }Serum testosterone, luteinizing hormone and follicle-stimulat-
. w7 W3 b6 e  H. r6 w1 z8 D: |ing hormone were monitored before, during and after comple-- [1 ^- C: j# z& Y
tion of each phase of therapy. Penile stretch length was, S0 N6 m1 Y( u
obtained by measuring from the symphysis pubis to the tip of/ @% y' T1 V" A) w& K' Y
the glans. Penile circumferential (girth) measurements were
! u# v8 n/ u$ [8 q2 h+ p; _obtained using an orthopedic digital measuring device (see
- f; j: _2 d7 a; G1 Kfigure).; T5 [& V, ^. j% `- R" r
RESULTS
9 d& y' E, S0 i- Y# j5 TSerum testosterone increased moderately to levels between
) G3 I; i" \( g3 ]) v9 I50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 }8 k7 o4 \2 F; H
terone levels with topical testosterone remained near pre-
; E: x9 H" t' M" q* }8 n' {treatment levels (35 ng./dl.) or were elevated to similar levels3 {/ r: c# R1 Z, ?4 S" [. o4 A
developed after gonadotropin therapy (96 ng./dl.). Higher
0 `+ p' v0 S! ]9 F( E( G' Sserum levels were noted in older patients (12 and 17 years old),
9 `. n4 l$ E8 n3 w8 H6 Bwhile lower levels persisted in younger patients (4, 8, and 10, ?$ O  G0 _$ T' L
years old) (see table). Despite absence of profound alterations1 B3 r9 w8 Z1 W4 ~# R; N
of serum testosterone the topical therapy provided a greater
5 Z& \) |2 Y$ @0 V7 e9 uAccepted for publication July 1, 1977. ·  |; \5 x3 K9 G7 c+ g
Read at annual meeting of American Urological Association,; M- U2 \6 W% Y9 x7 H, D1 `
Chicago, Illinois, April 24-28, 1977.
# b  b" ^) ]! W$ H2 c" S* Requests for reprints: Division of Urology, Henry Ford Hospital,% w3 Y+ l! }3 f0 ~1 Q& @0 X! {4 f
2799 W. Grand Blvd., Detroit, Michigan 48202.
) ^) s( I* v. y. o1 j- qimprovement in phallic growth compared to gonadotropin., _4 B* t2 j3 ~- Y4 b3 S; q% M
Average phallic growth with gonadotropin was 14.3 per cent: C: n* [; R2 a
increase in length and 5.0 per cent increase of girth. Topical
+ s6 h9 I3 \# U$ ]testosterone produced a 60.0 per cent increase of phallic length
$ \! `9 D2 Y5 G8 Z" wand 52.9 per cent increase of girth (circumference). The. B6 c5 V% J! Z& |) y# B  W
response to topical testosterone was greatest in children be-+ K* L1 ^- v9 F! C% _
tween 4 and 8 years old, with a gradual decrease to age 17
9 j% @% c8 ~  Q# Cyears (see table).
& C+ ~8 B3 \4 n# g# MDISCUSSION! K; y7 j+ H5 ?
Topical testosterone has been used effectively by other
3 j' e+ u3 j- d7 Q; l" H- G& {clinicians but its mode of action remains controversial. Im-
$ k/ [# Z' E7 j2 V$ c$ j/ Emergut and associates reported an excellent growth response
. o- Y2 O' f/ T0 K9 N) Ito topical testosterone with low levels of serum testosterone,3 V' u/ S! `0 z- m
suggesting a local effect.1 Others have obtained growth re-- |& L1 ]! I6 |1 O2 _
sponse with high. levels of serum testosterone after topical
7 W  y) Y8 P. `; }administration, suggesting a systemic response. 3 The use of* {0 ]' L, {+ m( U
gonadotropin to obtain levels of serum testosterone compara-; c: X& k5 b2 {! M& b' L# q0 s
ble to levels obtained with topical testosterone would seem to: b4 l  B. {- ^2 R7 V2 L2 A- ~
provide a means to compare the relative effectiveness of
# j5 p" `7 M: `& d# o6 K' btopical testosterone to systemic testosterone effect. It cer-
- P  _) Y7 P  V* k/ Ftainly has been established that gonadotropin as well as par-
, L- v; c) I2 S' R  s. z& Wenteral testosterone administration will produce genital- ^( K9 r, s1 b1 L5 J  L
growth. Our report shows that the growth of the phallus was2 K- ]7 \* @9 x& E
significantly greater with topical applications than with go-. e8 A; ]" u% F) H9 c# Z
nadotropin, particularly in children less than 10 years old.
, A$ V( u6 W0 r7 c% [7 P0 A' G" DThe levels of serum testosterone remained similar or lower
# o  f) d* M. \1 D) t2 Xthan with gonadotropin during therapy, suggesting that topi-
! ~0 T. X2 N* b7 Bcal application produces genital growth by its local effect as4 Q3 q- i4 y; w4 I. |; F7 [$ ~9 D
well as its systemic effect.' P. A/ |# z7 k7 H% O2 k" }5 s
Review of our patients and their growth response related to# g; X$ Y& x5 v1 F# y" C  c$ s
age shows a greater growth response at an earlier age. This is( A: i! d* Z$ Q8 b' z% m' J! A" G
consistent with the findings of Wilson and Walker, who4 @+ B; |5 b5 E
reported an increased conversion of testosterone to dihydrotes-: D6 q' V$ m  w
tosterone in the foreskin of neonates and infants.4 This activ-4 z, z" O% F6 C( C% g
ity gradually decreases with age until puberty when it ap-; L: n, u  g+ x6 J. X& m9 {8 M: b
proaches the same level of activity as peripheral skin. It may  E& V" M* P2 p: b9 s3 `3 a; h/ J
well be that absorption of testosterone is less when applied at) s- T& A9 a- q  U
an earlier age as suggested by lower serum levels in children
% x6 z1 w/ x% X) V, r$ Tless than 10 years old. This fact may be explained by the
+ f, [0 R1 o. Agreater ability of phallic skin to convert testosterone to dihy-- x7 j: m$ x# Z
drotestosterone at this age. Conversely, serum levels in older, c0 p& I5 h' z" a5 {7 W6 u
patients were higher, possibly because of decreased local
$ i* q% f4 }0 P667
# `6 O' j9 l9 G) c, K; X668 KLUGO AND CERNY: Q4 r0 ?9 Q8 @  ]
Pt. Age
7 _, Z2 \. d1 L(yrs.)
3 V& a/ b, B3 \3 ]  U% ISerum Testosterone Phallus (cm.) Change Length3 `0 ]( q3 q' T& K& ~3 K
(ng./dl.) Girth x Length (%)
$ m, r; D% @: x9 b, |4 s4
; u* Y; }1 {& o" {& o88 l+ ^: b# r. [/ z
100 @& ^9 }: ?/ {* |5 Q: F
12
1 C" k( @! t9 b0 w17
" v  C& _0 v2 T0 p# AGonadotropin
, W, n% ]6 d8 P+ e6 X/ e71.6 2.0 X 3 16.6
$ K7 X  r9 ^8 f& N, h5 h+ N50.4 4.0 X 5.0 20.0) t0 ]5 N+ B" V* E
22.0 4.5 X 4.0 25.0
# t' @9 ~) D3 W84.6 4.0 X 4.5 11.1
* ]5 M8 }8 K2 p85.9 4.5 X 5.5 9.08 [# I( e4 r- M  A/ n% ~
Av. 14.36 O4 b) w) q* z3 @  X* a$ S# }
4! i8 l1 [6 R; \5 i8 m
8; r' }) A4 H* N8 h% R: k4 ]# o5 Y' p
10
; P3 T/ u# Y6 p  X2 H- \12
: M+ f6 t8 P% l1 Y+ j2 p" u17  ^) V- @$ G7 y  l1 O' u* y
Topical testosterone; j: N1 e+ M; R9 O5 C% X9 Q
34.6 4.5 X 6.5 859 C2 _; T; ]& S
38.8 6.0 X 8.5 70
! ~- G2 C: b+ q+ e1 a+ h40.0 6.0 X 6.5 62.5
& Q4 Q: m5 o/ E" b* ^93.6 6.0 X 7.0 55.5; ^0 u6 B* m; b2 b3 O/ ^
95.0 6.5 X 7.0 27.2
, y$ t4 {, w" e: \$ H$ }' ?Av. 60.0
6 z; ]8 Q# P  n* Y* q6 vavailable testosterone. Again, emphasis should be placed on6 c# S! `' J; U5 g& t
early therapy when lower levels of testosterone appear to
, d: G. n7 m5 H- W! Vprovide the best responses. The earlier therapy is instituted
5 d7 R1 V. ~: y+ x/ ~3 q3 X9 [5 Ithe more likely there will be an excellent response with low7 N# a) {$ d' a
serum levels. Response occurs throughout adolescence as
7 X* ]0 \6 }; ~7 wnoted in nomograms of phallic growth. 7 The actual response
+ r" g) ~% W7 G0 c8 {) ]to a given serum level of testosterone is much greater at birth) D; O1 k% ~9 x. @
and gradually decreases as boys reach puberty. This is most4 {; _. L3 g& Z$ M7 J: x
likely related to the conversion of testosterone to dihydrotes-
2 n! m+ t$ i! atosterone and correlates well with the studies of testosterone
; D6 Y8 @* g. B5 v- I8 r. Uconversion in foreskin at various ages.
* r3 Q& s' _: t% a+ aThe question arises regarding early treatment as to whether
( u7 w5 ]' X8 ?# i+ tone might sacrifice ultimate potential growth as with acceler-8 `6 I& b5 ]9 _4 ^
ated bone growth. The situation appears quite the reverse
5 g6 O) n( r6 xwith phallic response. If the early growth period is not used% p) i2 w+ A+ M; C$ E6 n: `
when 5a reductase activity is greatest then potential growth
. g- f, ^, v$ x8 z' f( Amay be lost. We have not observed any regression of growth+ n; ^6 w& F! u4 R
attained with topical or gonadotropin therapy. It may well& [/ a0 C3 K9 L% W) w5 Q
be that some patients will show little or no response to any
' m# f7 i$ q: V* T. t* q+ x1 d, iform of therapy. This would suggest a defect in the ability to
8 \0 N0 Q8 X$ d* {+ [# ^0 B, c) k) fconvert testosterone to dihydrotestosterone and indicate that
, W! s7 c" X' rphallic and peripheral skin, and subcutaneous tissue should
( h0 d, O. U  _. ^1 l. t; Fbe compared for 5a reductase activity.
6 R, E* T7 y. r' G/ |- L+ y; pA, loop enlarges to measure penile girth in millimeters. B,
. Q5 ?" |3 V- O1 U2 Nexample of penile girth computed easily and accurately.+ w. m& j/ w$ c
conversion of testosterone to dihydrotestosterone. It is in this
: b) R; B+ Y  Y. `7 j9 `older group that others have noted high levels of serum+ t8 t+ H1 m" O& V. P, D: y, ]
testosterone with topical application. It would also appear
0 c) o* u# ?1 g) X2 Q9 e, z* b( P% Uthat phallic response during puberty is related directly to the# M, p) J2 e9 U8 r  O# {. l) @
serum testosterone level. There also is other evidence of local2 ]7 i8 ^) h" E6 B& F% @3 p- P% J
response to testosterone with hair growth and with spermato-# N+ V/ x! p% Z+ o, ]4 D& K
genesis. 5• 6' z% p4 k/ ]" d! m* Y* y8 i
Administration of larger doses of gonadotropin or systemic
& V1 T' N# B1 [/ |/ G# {. gtestosterone, as well as topical applications that produce
& y6 |$ H; Z* @2 Nhigher levels of serum testosterone (150 to 900 ng./dl.), will3 c0 W# X4 O( D8 V$ ~1 L2 {
also produce phallic growth but risks accelerated skeletal' J/ Z2 q4 \; M2 Y
maturation even after stopping treatment. It would appear" X' q. G# Y; @' g2 \
that this may be avoided by topical applications of testosterone: m! q& p0 }% T+ v: q( i
and monitoring of serum testosterone. Even with this control: \$ B, n; K; `$ q: N6 `
the duration of our therapy did not exceed 3 weeks at any1 v4 x+ R8 P+ L( A- C
time. It is apparent that the prepuberal male subject may+ b- Z7 ]7 o5 r* I
suffer accelerated bone growth with testosterone levels near
% w1 W  c, e1 t/ [5 g200 ng./dl. When skeletal maturation is complete the level of/ u( o  A0 H  V5 i2 l
serum testosterone can be maintained in the 700 to 1,300 ng./+ r$ w8 `9 w5 K
dl. range to stimulate phallic growth and secondary sexual
6 A( q; p( {4 G- ^+ `changes. Therefore, after skeletal maturation parenteral tes-7 U  O+ A; H/ f7 d; p7 f6 b1 E" a/ B
tosterone may be used to advantage. Before skeletal matura-% @8 p# Q" Y1 h4 o
tion care must be taken to avoid maintaining levels of serum' N. v  ^6 o& P( `# |2 u
testosterone more than 100 ng./dl. Low-dose gonadotropin
  I; \5 L5 s# g' _3 F& Gdepends upon intrinsic testicular activity and may require
6 h0 R6 X8 Y4 W0 J# c* yprolonged administration for any response.. Z$ i2 B( `) M
Alternately, topical testosterone does not depend upon tes-: j% ~1 O: \% \; e" Y1 A
ticular function and may provide a more constant level of
$ w+ E. U) m+ ^; a* M( WREFERENCES2 m2 ~6 c& M  H" E9 \
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
5 D( H# B; d! T6 ]5 G) y0 KR.: The local application of testosterone cream to the prepub-
& ]9 O, F0 o/ C; F0 Pertal phallus. J. Urol., 105: 905, 1971.
* a& N8 y2 r( p1 w3 `  ^2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 r& s) |! N" X3 k. U2 U  v2 z
treatment for micropenis during early childhood. J. Pediat.,8 z8 `- n% `% b9 h3 @
83: 247, 1973.
3 `  N0 ^) Q5 p9 s0 |  Q3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-) B' X* A* e6 `2 \) k* O
one therapy for penile growth. Urology, 6: 708, 1975.7 Y5 s7 C; C' ^
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone/ e- |# u2 K/ _! s6 U9 i5 n
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by' T2 B6 G2 v3 e8 ]; B+ k" w8 h
skin slices of man. J. Clin. Invest., 48: 371, 1969.
; ^- t! s) j- S, b. z; T5 G5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
7 [; I; F8 r+ I% i- z9 N/ W2 xby topical application of androgens. J.A.M.A., 191: 521, 1965.3 x) W, l0 [+ Z# g& u' e
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
- Y  P8 Y9 r6 T5 u* Qandrogenic effect of interstitial cell tumor of the testis. J.
+ L% k+ @4 s) S8 GUrol., 104: 774, 1970.
! x) r1 D- Z- ~5 a1 K! W/ ]' U, V7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
- _1 T0 E/ n9 g4 {tion in the male genitalia from birth to maturity. J. Urol., 48:
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