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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 C3 N% k; h2 RGONADOTROPIN1 a* h' e1 | Y( H
RICHARD C. KLUGO* AND JOSEPH C. CERNY
# F6 p5 c A& ?4 z VFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan8 m7 a- ?( l, e6 o0 N+ U/ a: h( |' C
ABSTRACT
+ Y' ], ^4 S0 ?$ ?. x oFive patients were treated with gonadotropin and topical testosterone for micropenis associated
! @; K7 `% E: ?* V% C1 vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-$ I: b, ^: W: j t, Y
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 S \) b @/ s( A8 E% z. _cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' c9 O( Y5 ]$ T$ C' p: e3 a9 hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 ^/ A% @9 `9 C" `/ T1 v
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average2 l1 b" Y* m6 J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ P1 E, n2 Q# ?occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 k; H! L ]% gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ u4 I4 b/ o- o9 Z3 Q1 c9 p: t
growth. The response appears to be greater in younger children, which is consistent with previ-
& o& W( f3 |% I0 aously published studies of age-related 5 reductase activity.7 A' s; s% U2 ]. e& N
Children with microphallus regardless of its etiology will
; a) J) k4 ^ F- c5 L ]# jrequire augmentation or consideration for alteration of exter-
1 w! U" P$ \ l& H2 Enal genitalia. In many instances urethroplasty for hypo-
9 Q" H) M9 d1 jspadias is easier with previous stimulation of phallic growth.
5 R1 @. k7 Q- D( @# ^. l. N7 nThe use of testosterone administered parenterally or topically# [' V, A7 @ ^1 A' Z
has produced effective phallic growth. 1- 3 The mechanism of$ j0 q7 h7 S* \) ?5 l
response has been considered as local or systemic. With this) o+ H7 m$ k7 B0 r5 H$ a. b( P
in mind we studied 5 children with microphallus for response7 ~0 Z( t) V, [, {) H* s" Q5 {
to gonadotropin and to topical testosterone independently.* S8 Z/ t' e. q7 K; O: I: J) E
MATERIALS AND METHODS
2 B$ r1 {1 T7 c9 _) ?Five 46 XY male subjects between 3 and 17 years old were
( S! u0 J5 u$ v1 ~evaluated for serum testosterone levels and hypothalamic
J7 H3 y- k( c( L& g1 Gfunction. Of these 5 boys 2 were considered to have Kallmann's
8 F: I* G- w) Z) gsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, A" U% @# |6 V9 n' b I* r' Jlamic deficiency. After evaluation of response to luteinizing5 q2 f8 H1 _ P( O1 G
hormone-releasing hormone these patients were treated with) U: m+ `0 `7 R; A% d2 [
1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 j4 o) G% l4 { r. h
after completion of gonadotropin therapy 10 per cent topical; ] B- r2 @, n w* J
testosterone was applied to the phallus twice daily for 3 weeks.6 Z1 ]- H6 Y; ^1 Z
Serum testosterone, luteinizing hormone and follicle-stimulat-' b1 H' p$ ]# l1 f
ing hormone were monitored before, during and after comple-; p p p9 u' q
tion of each phase of therapy. Penile stretch length was% m# Z. G; ~ H5 e
obtained by measuring from the symphysis pubis to the tip of% M+ }+ P. i! w$ `$ {7 h2 Z& K; x& o
the glans. Penile circumferential (girth) measurements were
* k I8 j8 c% f8 X2 tobtained using an orthopedic digital measuring device (see
% M \, w$ W! \: J- A' D4 ^) mfigure).% Z0 I, \$ v: o3 u. V
RESULTS9 m" K O) U, @4 m3 [5 W* ^ `
Serum testosterone increased moderately to levels between; K$ M9 a Z' |$ H
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ v; x9 a6 ?6 K8 X0 Q% H; D7 xterone levels with topical testosterone remained near pre-
8 p! z6 Z# Y7 o) xtreatment levels (35 ng./dl.) or were elevated to similar levels. y: [4 ~' A4 @5 A( Q9 m/ g
developed after gonadotropin therapy (96 ng./dl.). Higher& M1 u# Z. R4 T0 C, \& b/ o) ^! a
serum levels were noted in older patients (12 and 17 years old),
3 C6 s u) N: H/ a, Fwhile lower levels persisted in younger patients (4, 8, and 10
$ A/ m9 U& M8 nyears old) (see table). Despite absence of profound alterations5 o' }" c" |( Y+ j
of serum testosterone the topical therapy provided a greater
9 b) o. S: b( W D" t: D9 q5 Z g! ^Accepted for publication July 1, 1977. ·6 U( z2 R7 R) v4 n
Read at annual meeting of American Urological Association,8 ?0 j7 y& u3 z+ p2 `1 Q: o3 m
Chicago, Illinois, April 24-28, 1977.6 h* d6 R: ?, _' @1 ^7 b
* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 `# q0 M/ x8 q( `9 b/ a2799 W. Grand Blvd., Detroit, Michigan 48202.
* `+ \& |, G& r9 rimprovement in phallic growth compared to gonadotropin.8 _0 V3 h5 \& a
Average phallic growth with gonadotropin was 14.3 per cent
4 F3 z3 A2 ?6 a7 D& q+ Rincrease in length and 5.0 per cent increase of girth. Topical' q7 I9 p" I. O
testosterone produced a 60.0 per cent increase of phallic length/ w3 ~3 w2 S! H: i: J# N! a
and 52.9 per cent increase of girth (circumference). The, B4 _+ B$ Z! n
response to topical testosterone was greatest in children be-: ~2 O Q9 w8 } u. g. E
tween 4 and 8 years old, with a gradual decrease to age 17
0 w' u `& U- z* h% s4 Zyears (see table).
$ v. e0 o4 k, B5 S T7 rDISCUSSION
' A! G" N* F _Topical testosterone has been used effectively by other
1 |6 a/ `, K: O+ J$ Q2 D; I' {, wclinicians but its mode of action remains controversial. Im-
/ t8 }( c1 |. f; n+ `9 X. zmergut and associates reported an excellent growth response
4 V8 f+ ~/ n2 @/ v4 M4 B0 Uto topical testosterone with low levels of serum testosterone,
8 t; ^" d( T5 i6 F* H7 osuggesting a local effect.1 Others have obtained growth re-) h, h/ `1 a) f. c) ~& H
sponse with high. levels of serum testosterone after topical/ Q3 ^+ P# @, F/ i* z0 G% u5 p- }. c
administration, suggesting a systemic response. 3 The use of
1 Z# O( F; p5 B+ fgonadotropin to obtain levels of serum testosterone compara-
% i. M: f& M% u7 Q% y9 a0 L8 {( uble to levels obtained with topical testosterone would seem to+ v0 N3 a: d$ D- \; w+ T9 g
provide a means to compare the relative effectiveness of, v O3 \) K; ~* P
topical testosterone to systemic testosterone effect. It cer-( e% w K7 o# F0 I* q0 J6 N; x
tainly has been established that gonadotropin as well as par-. i! W2 _: b8 | r1 _0 @; F U
enteral testosterone administration will produce genital0 @( r3 |+ o1 _' | Y: }' B
growth. Our report shows that the growth of the phallus was
$ [1 T [+ W* p. c* nsignificantly greater with topical applications than with go-, _# m3 F. B" S" p" e2 o% z! d0 U$ J
nadotropin, particularly in children less than 10 years old.
$ L6 `- }, _. O5 n, oThe levels of serum testosterone remained similar or lower' _/ s7 V3 C# }: N' [
than with gonadotropin during therapy, suggesting that topi-
( @' h( K p8 ]0 ?) u: v, A8 Jcal application produces genital growth by its local effect as
( J1 O3 D7 H7 A7 x, J' e0 Twell as its systemic effect.% {( i7 Z4 _+ m1 r$ }
Review of our patients and their growth response related to
7 }9 w" g+ p/ q: Lage shows a greater growth response at an earlier age. This is1 t7 i1 M4 H+ [! h0 f1 w9 c
consistent with the findings of Wilson and Walker, who
1 j# B/ U9 ?" B9 [5 D1 r4 wreported an increased conversion of testosterone to dihydrotes-
" X6 \, k- E" G- `; D- n+ i: }tosterone in the foreskin of neonates and infants.4 This activ-
; M( ?( n0 Y- l% H$ L2 `9 hity gradually decreases with age until puberty when it ap-
3 a3 l. D7 @' s# s, vproaches the same level of activity as peripheral skin. It may1 a7 i4 _3 A" [' n) Y1 I& k
well be that absorption of testosterone is less when applied at L/ N4 o" n* }( Q, r
an earlier age as suggested by lower serum levels in children; D4 w6 z( r+ \1 E5 }1 `( C% u
less than 10 years old. This fact may be explained by the
3 v6 C# M! I! r1 i, f6 M5 Q' _greater ability of phallic skin to convert testosterone to dihy-5 ~$ x! Z- K- M2 |: X: m
drotestosterone at this age. Conversely, serum levels in older
+ P& ^8 ?$ C* X0 d: g9 j: U, ypatients were higher, possibly because of decreased local
2 B* n; a, p7 Q, K( s# [4 O$ |6678 d/ R1 x) r* P
668 KLUGO AND CERNY
4 c# @" N# A4 o8 `Pt. Age$ j; E |& U3 `, ?) }5 N' T
(yrs.)
1 H) Z6 {+ J d) HSerum Testosterone Phallus (cm.) Change Length9 L) h: f# j1 F N: `
(ng./dl.) Girth x Length (%)
+ i" P3 O) m; L1 Y4 d4
4 B4 o8 k2 Z5 f/ Z% u2 N8
6 n+ }) H, B6 z g- r' x7 ~10
8 v; b7 X) m4 D% q: \3 `3 N1 }12
' ?8 h' E, \9 |# y; y6 p17
, k. M8 \. u& a% h! nGonadotropin
8 G$ R: a1 h/ R3 {4 y# h u71.6 2.0 X 3 16.6
: v7 ?. S* P) k! E! S- p) E6 b50.4 4.0 X 5.0 20.0
' Q0 Z$ F. A/ {' K, c* O7 S& Y g) N22.0 4.5 X 4.0 25.0$ S! {: e. d9 x8 ^* N0 `
84.6 4.0 X 4.5 11.1
2 X9 w/ C0 Z1 Z2 Y3 u3 o0 B, K85.9 4.5 X 5.5 9.0) i x* m. k, M0 I8 @3 K
Av. 14.3
@8 c1 ^. x1 ?! I' l- ~4
. e, p% Z4 }0 L. o' Z; ]& _8$ {0 `( d( v& _' h
10/ y$ `* p8 K/ `' Z! ?
12
9 R' D9 m7 M2 o, R17
6 u8 U& |2 I4 F7 G, C' G' X2 d' UTopical testosterone7 ~6 L0 r) ]6 K' a3 R
34.6 4.5 X 6.5 857 w8 l i2 E/ P! i# p" u
38.8 6.0 X 8.5 70, ?+ K0 z7 y2 T$ Z0 U( @
40.0 6.0 X 6.5 62.5 a8 L% I0 N) s
93.6 6.0 X 7.0 55.5' X5 @2 f4 W6 W) a0 S) e: Z1 n; w7 g) D
95.0 6.5 X 7.0 27.2
8 g! `/ q5 P* l5 k1 @; v6 u5 \Av. 60.0
, K/ n) |7 i) R# l+ {available testosterone. Again, emphasis should be placed on( ^- A3 Z( }' r! P# {+ d2 D' }
early therapy when lower levels of testosterone appear to# I& F( [4 H1 A6 j3 I' g
provide the best responses. The earlier therapy is instituted% S4 D6 u( S& R1 ?/ t) n
the more likely there will be an excellent response with low( J# C8 N3 F, G" U, n2 h
serum levels. Response occurs throughout adolescence as: K t5 I! K v8 m& i
noted in nomograms of phallic growth. 7 The actual response0 O! Y$ t( G5 _: J& Z) k+ u2 s9 _. J
to a given serum level of testosterone is much greater at birth+ o# W, J/ t9 s
and gradually decreases as boys reach puberty. This is most
3 H: P: W3 d9 [likely related to the conversion of testosterone to dihydrotes-
9 R1 c) a4 `" c1 o) Ntosterone and correlates well with the studies of testosterone
, y; D0 y6 m( I" \9 d" iconversion in foreskin at various ages.
( G f) J2 @) y' y; y+ sThe question arises regarding early treatment as to whether
; P+ }, }$ U7 y1 S9 ~' z* n/ Y8 hone might sacrifice ultimate potential growth as with acceler-
8 f! n/ `$ r7 x9 U0 @/ o, U! Y: Sated bone growth. The situation appears quite the reverse
# x. ~. m5 y- X# {# |with phallic response. If the early growth period is not used
" G6 x/ u5 c( i6 m! Uwhen 5a reductase activity is greatest then potential growth# M/ I$ x% B; F/ f
may be lost. We have not observed any regression of growth7 t, z2 f- b/ x, ]' e$ q# I8 J7 t0 l
attained with topical or gonadotropin therapy. It may well
5 d3 H8 E4 Y/ Ebe that some patients will show little or no response to any4 ^; U `/ v6 ]/ b# ?( b
form of therapy. This would suggest a defect in the ability to
, u9 q/ F5 w8 _" n4 s8 [" g7 Kconvert testosterone to dihydrotestosterone and indicate that
: x- G$ W5 c! f, l, K' Yphallic and peripheral skin, and subcutaneous tissue should
( `; T5 X8 u+ P0 d9 gbe compared for 5a reductase activity.# M* f& L) f8 T' Y$ O
A, loop enlarges to measure penile girth in millimeters. B,
7 n2 e7 I4 `+ b! F1 ?; Xexample of penile girth computed easily and accurately.
' M; k. O1 |* ]4 l8 ~& [/ V1 w# L$ Econversion of testosterone to dihydrotestosterone. It is in this
! T) L2 s5 g: d, Eolder group that others have noted high levels of serum
j4 p7 n5 ]8 U4 q7 K0 rtestosterone with topical application. It would also appear3 V5 A. Q1 p3 ~: u
that phallic response during puberty is related directly to the7 O' R# | @: p
serum testosterone level. There also is other evidence of local
9 K( \5 i) e" b+ z6 S! r; vresponse to testosterone with hair growth and with spermato-
) ]" C) w" f& g0 k9 v) Hgenesis. 5• 6& S8 f0 u- Y$ ?7 ^* M+ D& z' }
Administration of larger doses of gonadotropin or systemic, [0 V1 ^* ]! }/ p( _
testosterone, as well as topical applications that produce( E9 U% O. Q( W2 N! h- N
higher levels of serum testosterone (150 to 900 ng./dl.), will
5 k# u0 ?" w& ^also produce phallic growth but risks accelerated skeletal3 ~, F3 ~$ L( w4 }4 f: F
maturation even after stopping treatment. It would appear
' X8 B- R) A' Lthat this may be avoided by topical applications of testosterone
6 \) ?( B5 \$ N Dand monitoring of serum testosterone. Even with this control9 J4 P8 Z. r4 B a! O
the duration of our therapy did not exceed 3 weeks at any
9 @- z, ~% s; g1 _& @! e0 O, O1 ntime. It is apparent that the prepuberal male subject may: K; b- w& p8 t3 F1 t# X3 J1 J
suffer accelerated bone growth with testosterone levels near
: c% ~* g& Z9 d200 ng./dl. When skeletal maturation is complete the level of
2 ~. P4 Z5 Z& ~! tserum testosterone can be maintained in the 700 to 1,300 ng./
: D; y+ K; E( G% h! N8 c/ Y8 Sdl. range to stimulate phallic growth and secondary sexual
1 j8 ^& M8 i# N, G5 g. s$ r) Tchanges. Therefore, after skeletal maturation parenteral tes-6 e) w. ?( a- A9 B/ N* U% d9 L
tosterone may be used to advantage. Before skeletal matura-% P } [! ]3 t6 Q: n }
tion care must be taken to avoid maintaining levels of serum6 T' d% B7 l/ x( x7 Z/ K- }
testosterone more than 100 ng./dl. Low-dose gonadotropin6 a* z- h$ z7 K9 e) ~
depends upon intrinsic testicular activity and may require/ S7 ]9 O( V5 H7 E! X
prolonged administration for any response.
# u: ?8 ^3 o# {Alternately, topical testosterone does not depend upon tes-
* L: V9 D" I/ g) r8 l6 a: F, g& eticular function and may provide a more constant level of
# R$ B0 J- L9 GREFERENCES. j5 C4 y b) X! L5 e" z; R% e
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
( a2 n3 K$ N+ V8 H8 O3 z1 u. iR.: The local application of testosterone cream to the prepub-( u; A% h* C) o1 l5 ^, M, q2 {
ertal phallus. J. Urol., 105: 905, 1971.. @6 j9 N. M/ }. g, c+ f$ v _
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' b' ^0 O, |1 K* atreatment for micropenis during early childhood. J. Pediat.,
9 c, E0 {) N0 I83: 247, 1973.
2 S" A' m9 J' O9 H8 W/ K$ T3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, z/ D& b3 z" b9 Pone therapy for penile growth. Urology, 6: 708, 1975.
( a+ @& _7 x6 x; W" f. v) g0 A, ]4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) r* z3 ^& s+ g) W( z
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. g5 O' H/ o+ u3 @skin slices of man. J. Clin. Invest., 48: 371, 1969.6 R, y/ ?" J. C: m* K! c! G
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' \. o$ t, Q) v4 m7 J) A
by topical application of androgens. J.A.M.A., 191: 521, 1965.
. s$ I# k0 J& ~1 l" D" W6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 ?9 M; K) j6 v% O5 vandrogenic effect of interstitial cell tumor of the testis. J.
4 g: K& D. G2 l. hUrol., 104: 774, 1970.
" E3 c# ]' ~/ j& e) V7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. e4 S. s, t" f4 c3 q+ E/ A0 U; R
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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