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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: ~ ^5 @2 J3 u% v# L) N- u6 AGONADOTROPIN& m! A3 |+ M+ F2 J: _1 |5 j
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 Q! U+ X- o" ^+ X
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 n) v# ^# e. }; S
ABSTRACT
- X8 P, f0 `2 B( Q- C/ h$ ]Five patients were treated with gonadotropin and topical testosterone for micropenis associated
7 {' v6 N/ V8 U8 ?( m, uwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ {" d+ K/ K5 e, | B2 D, M* Htropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 m% G& l2 O5 V+ X) bcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( h# Z% A) w: t b2 l0 R
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent, N. q3 u; P) Z. o% A* `9 E
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average- l# f# u7 A% J4 f+ o6 {0 _! B
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; Q. t; e K! j! A2 Y4 b$ g" Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
! S: c2 ^6 A1 \9 A5 k. kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 {3 Q: x/ W0 H$ E3 I5 [+ C
growth. The response appears to be greater in younger children, which is consistent with previ-
$ N9 Z+ O2 \* ^) p7 M8 ~ously published studies of age-related 5 reductase activity.9 C4 h6 Z5 p! S0 Q/ A, b
Children with microphallus regardless of its etiology will4 }3 W0 g7 d# o; w7 }* M1 A4 X
require augmentation or consideration for alteration of exter-" H: o X+ ]# @/ U0 q/ P
nal genitalia. In many instances urethroplasty for hypo-
1 {4 t9 x6 W& f& l& Ispadias is easier with previous stimulation of phallic growth.; J$ F( r; d8 d+ p5 r% t
The use of testosterone administered parenterally or topically
6 W- X F5 l3 A j _has produced effective phallic growth. 1- 3 The mechanism of
9 s8 n% \" R' a& \: J! ~ tresponse has been considered as local or systemic. With this
& F1 {$ N6 b# w9 {in mind we studied 5 children with microphallus for response
- q: z" ]) L3 U7 z2 sto gonadotropin and to topical testosterone independently.% t- m: b: G& X% B3 v [1 \
MATERIALS AND METHODS
* U( ~4 ]" C. |. ?- O) s* |# nFive 46 XY male subjects between 3 and 17 years old were
2 D- X- K0 I. j* N7 \3 D5 }evaluated for serum testosterone levels and hypothalamic
- i3 m; M6 |" T; O$ l2 Ffunction. Of these 5 boys 2 were considered to have Kallmann's9 _" O9 |2 B J8 v
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
4 [ @: f* k4 R3 C& p& Blamic deficiency. After evaluation of response to luteinizing: Y+ }/ A9 A# h- K6 Q+ y8 C
hormone-releasing hormone these patients were treated with: y! f& q, |" w% t, L1 q9 u
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ L0 t3 [$ g; W3 a; J* @" u1 L3 fafter completion of gonadotropin therapy 10 per cent topical
9 R9 _; C, H4 ^1 ytestosterone was applied to the phallus twice daily for 3 weeks.
' s' L8 S6 V( OSerum testosterone, luteinizing hormone and follicle-stimulat-
, o! Y9 s5 D8 ]% y; N; ]ing hormone were monitored before, during and after comple-
3 ^! }9 ^3 j2 o; otion of each phase of therapy. Penile stretch length was
8 M- I& T( j7 J' R0 Uobtained by measuring from the symphysis pubis to the tip of- d+ T. J' E# d
the glans. Penile circumferential (girth) measurements were
6 t+ F+ e) P7 O, U0 Zobtained using an orthopedic digital measuring device (see
8 J4 P; ?5 L: Ofigure).- d# h7 _$ `' z
RESULTS. M. P* y: \5 k7 P) }
Serum testosterone increased moderately to levels between. P R' F$ ~* R
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-+ a4 T/ e6 G9 g( J3 X
terone levels with topical testosterone remained near pre-3 C' t1 ]" G3 y, ~% @2 O
treatment levels (35 ng./dl.) or were elevated to similar levels
% R' T, ]( Y* g7 \6 |developed after gonadotropin therapy (96 ng./dl.). Higher( ]+ T& A o1 M5 O+ ^ j* L
serum levels were noted in older patients (12 and 17 years old),
- J, j) J4 {1 M+ w( nwhile lower levels persisted in younger patients (4, 8, and 10! [$ @3 T! {& B
years old) (see table). Despite absence of profound alterations8 M! h+ ?% F% I. D y# {" T
of serum testosterone the topical therapy provided a greater
8 h& z/ B! w# b. ]( ~0 F$ \3 V( IAccepted for publication July 1, 1977. · T1 b( Q9 u I/ b! t& j4 z( ?. n
Read at annual meeting of American Urological Association,
/ R# E* q9 M$ ?2 N1 F( r8 ZChicago, Illinois, April 24-28, 1977.0 {! [4 R! A& k, e: f6 ]5 H
* Requests for reprints: Division of Urology, Henry Ford Hospital,
# @( i* U9 ?1 R7 R2799 W. Grand Blvd., Detroit, Michigan 48202.
4 j! q1 c; b& Bimprovement in phallic growth compared to gonadotropin.
5 c6 n* M- I& L* D9 t9 r) x) jAverage phallic growth with gonadotropin was 14.3 per cent
3 S9 a) Y3 T4 c4 \5 O& t8 Qincrease in length and 5.0 per cent increase of girth. Topical
4 G6 M ^$ _7 }" x1 B* y: M9 |testosterone produced a 60.0 per cent increase of phallic length
1 _, n2 w, J: s2 R* Gand 52.9 per cent increase of girth (circumference). The
# U V4 b% f k5 t# Bresponse to topical testosterone was greatest in children be-
) J0 X: C8 _8 Ktween 4 and 8 years old, with a gradual decrease to age 17( v- |( x# a# j: l- W7 G! x
years (see table).
1 o* b& d- d( Z) G! [6 z, {) ~DISCUSSION
4 r1 {$ N, l* [8 D, sTopical testosterone has been used effectively by other! o; n& {- q. l$ L" S
clinicians but its mode of action remains controversial. Im-
* O" K z$ ~; smergut and associates reported an excellent growth response4 y! S3 `& F6 |! B0 C& \4 E9 y
to topical testosterone with low levels of serum testosterone,$ X: {: n, f$ Y2 z' f
suggesting a local effect.1 Others have obtained growth re-, F$ j. Z3 b5 p. M% ]$ W- M
sponse with high. levels of serum testosterone after topical% o: {; A# j4 Q' w
administration, suggesting a systemic response. 3 The use of
0 R0 e; \5 D8 g+ B' u* |gonadotropin to obtain levels of serum testosterone compara-
; a! g) Z* W9 z& g* z% n& c0 fble to levels obtained with topical testosterone would seem to: o- X; Z9 u, e% ~$ o4 T0 ]* [
provide a means to compare the relative effectiveness of$ I$ C2 y0 N) U9 b$ G- O+ T
topical testosterone to systemic testosterone effect. It cer-! }! q% t6 x; W- L, M. {
tainly has been established that gonadotropin as well as par-6 Q) s% a9 _, x
enteral testosterone administration will produce genital) B- }& X0 o/ h1 ^6 Z8 g
growth. Our report shows that the growth of the phallus was3 e# |0 @6 B0 `) F
significantly greater with topical applications than with go-. p6 a! Z& V+ X) i1 F* L
nadotropin, particularly in children less than 10 years old.( [% u8 I; t% Z* T7 A
The levels of serum testosterone remained similar or lower
4 g7 k+ k, \; hthan with gonadotropin during therapy, suggesting that topi-
# M' z" Z. p4 A' s' bcal application produces genital growth by its local effect as/ t- n; X$ S; v- L
well as its systemic effect.
5 u7 K; V/ o+ lReview of our patients and their growth response related to
6 m! V1 ? x) z: eage shows a greater growth response at an earlier age. This is' |$ N! E$ ?4 |# D* e+ a% A
consistent with the findings of Wilson and Walker, who ?9 J5 J' q1 n
reported an increased conversion of testosterone to dihydrotes-* O) F8 j8 A9 W8 J( h
tosterone in the foreskin of neonates and infants.4 This activ-
! ?% Z! K" d0 K9 L& M- hity gradually decreases with age until puberty when it ap-
" a" g9 l0 Q/ i3 n5 a3 F- l- aproaches the same level of activity as peripheral skin. It may
' F" u5 p0 L& u% ]: Twell be that absorption of testosterone is less when applied at
8 q% R, T I) ? Han earlier age as suggested by lower serum levels in children
; a1 [0 u* W) P: Q+ N; ^less than 10 years old. This fact may be explained by the
: ?7 R. `) W6 igreater ability of phallic skin to convert testosterone to dihy-& R. t8 R. Y% y* s, z n
drotestosterone at this age. Conversely, serum levels in older
5 L. ~/ F) p0 z; H" @/ u- }$ k5 f3 zpatients were higher, possibly because of decreased local
u% L& @3 ^! I; M& N' U, [667
8 ~: O: _; [3 n" z2 O) R# S668 KLUGO AND CERNY
; p# h* _3 }) {7 dPt. Age1 M& o! N+ Y. M
(yrs.)
, r) h! Z; e! a0 f& l [; ]' A3 ~% sSerum Testosterone Phallus (cm.) Change Length/ [; W' Q9 R& U: E( Q) Y% r
(ng./dl.) Girth x Length (%)
. s2 p' g2 X: S+ S4" f) Y9 c" s1 b3 X; t3 l' W( U
8 V2 V+ ]. k; k( F' q% ]: ]# C
10
7 N' ]) n: d% t. x; c126 V) I9 e9 w8 k# u. F {
17
7 {2 t& }: R$ aGonadotropin# ]( c8 u* h% {* o* s1 `- q5 c3 Q
71.6 2.0 X 3 16.6
1 V, J! Q" ^/ \50.4 4.0 X 5.0 20.0
, `( ^9 ~. n( u" g7 J2 y4 r22.0 4.5 X 4.0 25.0
7 o+ f2 U9 ^6 o2 H% q84.6 4.0 X 4.5 11.18 z8 T1 W e& G8 X; E
85.9 4.5 X 5.5 9.0 X1 F4 t. i1 z7 p2 S
Av. 14.38 p n% s( g/ e9 C* k2 i
4
4 y% t7 w; a/ v+ z! y* B; l3 J: x8/ r1 }6 v# I8 a5 b
10
5 [$ `$ U/ o7 I# C2 m* o; S128 ?3 i) T8 k/ C2 g- t2 [
17/ F# Y: a( M/ [: I0 n* t2 k' m5 W5 x* T
Topical testosterone: r% `3 U) q' e# t
34.6 4.5 X 6.5 85
$ l l- l. z0 `/ v( a38.8 6.0 X 8.5 70
$ P! T( Y' }+ X) Q4 h7 s4 H40.0 6.0 X 6.5 62.5
# N6 |( i6 w1 t8 Z% S93.6 6.0 X 7.0 55.5
/ Q; t4 X! s# B8 T95.0 6.5 X 7.0 27.2: [" Z1 i5 `0 G3 t9 s5 A' j8 p
Av. 60.0# ~4 [# `" k5 ]- s7 r
available testosterone. Again, emphasis should be placed on& z5 `" ~. j9 ?3 R8 T5 R4 M% K X
early therapy when lower levels of testosterone appear to
# h: {* n5 s# N9 j) Y7 A7 wprovide the best responses. The earlier therapy is instituted
, m2 [+ W* ?+ ]4 i: P# M' D# Tthe more likely there will be an excellent response with low
5 t3 U [% |! t; y; zserum levels. Response occurs throughout adolescence as
9 P' v4 @2 L Z/ ~! Onoted in nomograms of phallic growth. 7 The actual response
# d: V0 H* }# E. o( u2 O& yto a given serum level of testosterone is much greater at birth
9 w% Z7 \3 V6 wand gradually decreases as boys reach puberty. This is most% _+ c: p. I# ^% p3 }4 r" z
likely related to the conversion of testosterone to dihydrotes-
- ^& |2 O2 G# K( h, }8 utosterone and correlates well with the studies of testosterone, i6 Q8 v2 M: S! c7 v
conversion in foreskin at various ages.
: W- r8 |) J# b mThe question arises regarding early treatment as to whether# j9 A, _) }' t" t K. D$ z
one might sacrifice ultimate potential growth as with acceler-8 b% R6 M) Y; M, T
ated bone growth. The situation appears quite the reverse
6 w. f4 _3 i" p7 Uwith phallic response. If the early growth period is not used2 `3 h) j* Y+ _
when 5a reductase activity is greatest then potential growth
$ R* {0 h9 z. F: Tmay be lost. We have not observed any regression of growth
( K }$ u' w7 ^9 r) L# Gattained with topical or gonadotropin therapy. It may well
' V7 S# n" e/ w3 R( i# t6 I( Mbe that some patients will show little or no response to any
" b/ V, m+ t% a- G7 _/ @7 Eform of therapy. This would suggest a defect in the ability to
|, r' {0 i: u, f& x5 F& R8 wconvert testosterone to dihydrotestosterone and indicate that* N# E7 z$ v; H2 @9 j7 r
phallic and peripheral skin, and subcutaneous tissue should
' ~+ Q w. k9 Q( k( q8 mbe compared for 5a reductase activity. p2 L- y+ ^4 T, b/ r
A, loop enlarges to measure penile girth in millimeters. B,
9 f' R" Z! R/ t& q: cexample of penile girth computed easily and accurately.
5 R( \& _. |* v$ h- _conversion of testosterone to dihydrotestosterone. It is in this
7 P+ s6 h" z9 Q& Z: M; g" J- }) iolder group that others have noted high levels of serum
' e9 [& P; Z/ n: Z: a: mtestosterone with topical application. It would also appear9 k. _ h/ ~! ]# D* i. j3 @- A2 _0 o/ z% m
that phallic response during puberty is related directly to the# I9 \8 _5 a2 Y* U5 W
serum testosterone level. There also is other evidence of local/ a- H+ V, q; D
response to testosterone with hair growth and with spermato-
" `' r$ P0 N$ {' q& ugenesis. 5• 6
5 j7 y6 \8 b2 {2 OAdministration of larger doses of gonadotropin or systemic" `% r4 i; t- X
testosterone, as well as topical applications that produce
7 k S1 n* D# F6 u. Thigher levels of serum testosterone (150 to 900 ng./dl.), will
1 X) w2 N! t# h' walso produce phallic growth but risks accelerated skeletal
# I0 f, }6 N0 b; ]& H5 c2 d# W' Umaturation even after stopping treatment. It would appear
* B7 C+ M( }' m: v: cthat this may be avoided by topical applications of testosterone N! _, k) r- D2 \
and monitoring of serum testosterone. Even with this control9 B; k0 y( ~4 ^& B4 i1 U% `& W
the duration of our therapy did not exceed 3 weeks at any
. a, E' z9 F9 l) L- Ktime. It is apparent that the prepuberal male subject may
* Q2 M" L e0 j1 d3 S3 l: Hsuffer accelerated bone growth with testosterone levels near
( J- v' j5 W0 Y8 p' r, ?200 ng./dl. When skeletal maturation is complete the level of
/ g7 ?# P0 W j- fserum testosterone can be maintained in the 700 to 1,300 ng./
* [# i: O" u- s4 o! ddl. range to stimulate phallic growth and secondary sexual9 g) _) _. e3 n7 U: u0 \7 y4 G
changes. Therefore, after skeletal maturation parenteral tes-
3 `! s# |) K6 }4 k. S4 jtosterone may be used to advantage. Before skeletal matura-
; o# W; p( C, m- J' ]+ s& Qtion care must be taken to avoid maintaining levels of serum
! _/ v5 l n, L9 [6 X; C- e' v; m9 Otestosterone more than 100 ng./dl. Low-dose gonadotropin
, ?4 ~. @; f+ w' x6 }9 jdepends upon intrinsic testicular activity and may require4 l6 K8 k, h" g) R, J& S% G
prolonged administration for any response.
/ }% V2 ]1 G7 c1 u' jAlternately, topical testosterone does not depend upon tes-
8 T* i* t8 h, h, Fticular function and may provide a more constant level of$ B; b$ f4 l" O
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1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,+ `' l- k& L2 } O I
R.: The local application of testosterone cream to the prepub- z {$ a7 {$ d7 w: z9 F
ertal phallus. J. Urol., 105: 905, 1971.9 T/ Y- U/ B5 t7 ]
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
9 I7 f/ F7 q' Utreatment for micropenis during early childhood. J. Pediat.,
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3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-" ?; J0 _5 ^. t
one therapy for penile growth. Urology, 6: 708, 1975.
0 ~! f3 c" E( U9 k/ {7 b; [4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' j# r2 ~0 C- x7 s; T# ]to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by& p* L; f" {( i- s9 Y1 C
skin slices of man. J. Clin. Invest., 48: 371, 1969.
1 H7 J& ~; M( J# L5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ s7 \( T f# J; ]3 `1 ^8 N
by topical application of androgens. J.A.M.A., 191: 521, 1965.$ U9 c5 U% F3 h7 `, b
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- H/ Z5 L3 S" @
androgenic effect of interstitial cell tumor of the testis. J.
0 l( U l+ K. c( X2 p6 EUrol., 104: 774, 1970.$ n3 Y' \% y, ~5 v+ V- ]# g8 T
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 A: G9 l$ }8 L- F( Vtion in the male genitalia from birth to maturity. J. Urol., 48: |
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