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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
( \9 a* [. w' G* IGONADOTROPIN
0 d' {1 y' O6 \2 eRICHARD C. KLUGO* AND JOSEPH C. CERNY8 i; {6 N$ }% H0 j
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, Y) e" b+ }' c) [; ^ABSTRACT1 H0 b' Y/ r1 a. ?# a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( V- ^& N& ~, M, _. n5 z. Q: c% p% Y( Bwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" m( W. q! e$ Q `2 [9 i, R! D
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 w4 r: K* {! \$ s q' J+ e
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent" o! Q. }* F' A' F* Q: f
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 B8 q& L; \. F. E! A/ aincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average" \) E/ G7 }; R5 P8 g* }
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response6 H: n2 ?( P# z
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
1 S, x; r- W8 O/ e6 a9 Ystudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 C" D% h0 y" W. ]3 t' d/ Ygrowth. The response appears to be greater in younger children, which is consistent with previ-, o& E6 x* j) P2 G4 z
ously published studies of age-related 5 reductase activity.9 ?: s- D0 H* e. I: i; E+ E8 C6 a. `
Children with microphallus regardless of its etiology will
2 @6 e7 {( g; y: A+ arequire augmentation or consideration for alteration of exter-
$ W: H1 N8 O0 O# T0 U8 _: dnal genitalia. In many instances urethroplasty for hypo-5 {1 ^5 j0 l# ]# ~% @
spadias is easier with previous stimulation of phallic growth.
& J8 s' H% P0 Y( y7 B/ R6 eThe use of testosterone administered parenterally or topically
9 O7 v, E9 W( t, |# L+ ~8 l- x# thas produced effective phallic growth. 1- 3 The mechanism of
3 C- y* e% F8 }1 presponse has been considered as local or systemic. With this
: V% J7 Z9 j1 }% p- P$ u) |# Rin mind we studied 5 children with microphallus for response. Q7 V# q6 S: A" {& w. n
to gonadotropin and to topical testosterone independently.
: l0 C7 @8 U# W0 P( p6 yMATERIALS AND METHODS- l, |* o! Q- q3 E
Five 46 XY male subjects between 3 and 17 years old were
3 u3 ?% v7 @. r' p+ ?evaluated for serum testosterone levels and hypothalamic0 K0 T3 Z, L9 m2 J, W" e1 q
function. Of these 5 boys 2 were considered to have Kallmann's
$ l: Z- B1 T% _: V) ?3 hsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
) ], S5 O: Q4 J9 ]0 [. T5 alamic deficiency. After evaluation of response to luteinizing! }8 a- B% d" k8 }& j- q0 j
hormone-releasing hormone these patients were treated with
) r8 E6 ~7 z* q6 p. b* O1,000 units of gonadotropin weekly for 3 weeks. Six weeks( e- t) p+ {0 B9 Q* ]
after completion of gonadotropin therapy 10 per cent topical& M+ O5 @1 C6 r- B) [8 q
testosterone was applied to the phallus twice daily for 3 weeks.# A. i5 p6 h( T4 W) K
Serum testosterone, luteinizing hormone and follicle-stimulat-! y# m' i' @( i5 ^
ing hormone were monitored before, during and after comple-+ J' s" }; j" g; B3 G
tion of each phase of therapy. Penile stretch length was4 {8 T0 X& }5 c2 P- A) e
obtained by measuring from the symphysis pubis to the tip of. F2 C5 C9 n- K$ z- o
the glans. Penile circumferential (girth) measurements were/ p; R0 d, I0 x2 {- [
obtained using an orthopedic digital measuring device (see
e" a- X( E% ~+ n# _# \5 h8 k' yfigure).
0 Q7 Q( v4 h5 [8 x3 TRESULTS
1 g# M) \! u( N# |Serum testosterone increased moderately to levels between& { y1 @ \1 Z8 |3 f i
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-, g* G; g3 Z. A) v0 q1 O
terone levels with topical testosterone remained near pre-3 C! R! }: |* P6 E7 Z2 |7 o
treatment levels (35 ng./dl.) or were elevated to similar levels q9 ]2 H: M& J8 a' \' M* y
developed after gonadotropin therapy (96 ng./dl.). Higher
! |7 O, h4 z2 J$ c9 dserum levels were noted in older patients (12 and 17 years old), t0 {( }, E6 F" U" N, j; C
while lower levels persisted in younger patients (4, 8, and 10
" j; X( Q* ^3 l1 \: c3 Jyears old) (see table). Despite absence of profound alterations
4 u' N/ Q4 T4 B8 D, Iof serum testosterone the topical therapy provided a greater Y+ f" z# X1 B
Accepted for publication July 1, 1977. ·
4 }# Q1 B* R* v# v+ {0 H& O' `Read at annual meeting of American Urological Association,
# j9 j' q: H! m2 dChicago, Illinois, April 24-28, 1977.9 U2 \5 |2 x+ b; O0 s0 S( s
* Requests for reprints: Division of Urology, Henry Ford Hospital,
, q, K" c8 z! m. D' K2799 W. Grand Blvd., Detroit, Michigan 48202.' ~* |* P) U7 M% M) @8 m* u
improvement in phallic growth compared to gonadotropin.
4 Z: z6 u$ j' J" }3 |+ \& WAverage phallic growth with gonadotropin was 14.3 per cent3 |, {: Y; i" A6 | _. d6 E! \
increase in length and 5.0 per cent increase of girth. Topical
; r/ o# M& k. y& x' ttestosterone produced a 60.0 per cent increase of phallic length
) d- ]- w( _/ G- @and 52.9 per cent increase of girth (circumference). The" \, u. C$ m$ O4 U9 E
response to topical testosterone was greatest in children be-
6 |- h& ^! Z& ]# \2 J9 s" @8 ltween 4 and 8 years old, with a gradual decrease to age 17' R4 w8 A7 f: f3 ]$ v! n* s
years (see table).5 o! j, w9 u* E9 u# i
DISCUSSION; `. |" ~% w. k; x; M8 D, A
Topical testosterone has been used effectively by other0 C7 w0 d9 \, J4 l, R/ [* p% U
clinicians but its mode of action remains controversial. Im-
1 m( j1 c2 y' o0 X) d+ i# nmergut and associates reported an excellent growth response6 r' s( L7 L+ R8 J7 j
to topical testosterone with low levels of serum testosterone,& m8 }' Z9 ~$ v) P" d5 X, I- C
suggesting a local effect.1 Others have obtained growth re-# d$ a0 F; C5 ~/ i
sponse with high. levels of serum testosterone after topical
9 a- P( ]4 `/ i' G* E Tadministration, suggesting a systemic response. 3 The use of9 e7 _8 w1 g, X$ X* \6 L! m5 f7 Y
gonadotropin to obtain levels of serum testosterone compara-1 Q5 c) S6 T& \' }4 f
ble to levels obtained with topical testosterone would seem to
[2 P, ?1 X) D2 y& v5 c; R uprovide a means to compare the relative effectiveness of# _2 V+ |! ]3 \2 x& B2 w2 ?9 D
topical testosterone to systemic testosterone effect. It cer-* ]) j5 g! @2 C6 b. @
tainly has been established that gonadotropin as well as par-
. e+ q$ S" C- ?enteral testosterone administration will produce genital, o% }3 K; s' ?, j& ]$ u9 X0 Q
growth. Our report shows that the growth of the phallus was
5 K! P, i7 v4 |, gsignificantly greater with topical applications than with go-
+ g6 `) @4 j/ z% j, u& ]' nnadotropin, particularly in children less than 10 years old.
3 ^7 X5 I2 w2 I! w* jThe levels of serum testosterone remained similar or lower0 J; Q7 s5 E/ X4 m( G ?
than with gonadotropin during therapy, suggesting that topi-
: W9 d$ D( U+ E8 l# G0 ]& j- {' Jcal application produces genital growth by its local effect as9 S6 _8 Z5 a. r" k1 l- X
well as its systemic effect.: C# ?- R# J3 K& n! N# x, E
Review of our patients and their growth response related to
. x+ E( |: j6 `+ o5 [, Vage shows a greater growth response at an earlier age. This is
H8 r h" L. Q+ g4 O1 h" Fconsistent with the findings of Wilson and Walker, who2 p2 ^" H& d O% C7 D; Y0 D
reported an increased conversion of testosterone to dihydrotes-
. x, {: q6 g1 Z7 L& K* N0 R3 Xtosterone in the foreskin of neonates and infants.4 This activ-
, E; m" l- t+ }/ Y- q) D, Gity gradually decreases with age until puberty when it ap-& @/ n% E. a8 U
proaches the same level of activity as peripheral skin. It may* O& s! ], }2 w0 i4 j2 ?& q6 _3 w
well be that absorption of testosterone is less when applied at
4 ]4 T: E- g, y! k9 k2 j6 man earlier age as suggested by lower serum levels in children
7 H4 L2 D+ F1 n5 O% Y/ w; h2 qless than 10 years old. This fact may be explained by the% N) P4 r6 H! B+ q
greater ability of phallic skin to convert testosterone to dihy-
n1 ?7 Y* }4 t% a& Fdrotestosterone at this age. Conversely, serum levels in older
) Q4 F6 J' M6 v1 lpatients were higher, possibly because of decreased local, x" c; O* @ R6 c
667
& R, o1 q; T# h- ?4 g: A3 {' i668 KLUGO AND CERNY c$ U9 o. M% W' L9 A
Pt. Age- {( e+ w/ Y' V5 \
(yrs.)7 d7 ~( K2 w# E2 o. J& p& Y+ e
Serum Testosterone Phallus (cm.) Change Length
8 `) k; f0 I; q; M, B# _0 f G(ng./dl.) Girth x Length (%)
- d/ N+ ?. h$ N- D6 S4
5 H1 T. |8 ? n1 t2 x2 r8. i% |0 u! B, U' Q s- A
10) C* s( ~3 y. _# {9 @1 Y7 q
12( A( j/ _0 f3 K" N, G! `
17. b- o, O+ g+ [3 k
Gonadotropin
Q* r- h- U+ z# e& H/ b71.6 2.0 X 3 16.6
# G0 u+ [8 @# k5 j50.4 4.0 X 5.0 20.0
U! @& B% t. u) q8 R! ~22.0 4.5 X 4.0 25.0( R% E; {& x2 G+ t5 I0 q/ e
84.6 4.0 X 4.5 11.1+ i$ Z# D0 j. Q+ x
85.9 4.5 X 5.5 9.00 E, N1 U7 x! _0 ]# l2 L
Av. 14.3
( U8 C! |, u1 M5 L5 c6 B2 B+ U4
S& \# d: h1 c' i# w8
' C& J+ z( Z" U8 I& N1 a! b10
x8 H- h# m1 R5 k8 P/ e) ^12
& R5 C0 h9 U9 y& J5 L- i- B17
1 H0 L; w' x% D3 u r2 pTopical testosterone
. P2 Z. Q- Q9 x, m5 D2 G34.6 4.5 X 6.5 85
/ h: x! \, g l( o0 p) I38.8 6.0 X 8.5 705 M4 k+ {$ g* Y, O3 q+ n& i6 O, x! ^
40.0 6.0 X 6.5 62.5* t2 b7 R1 F1 u9 d1 L% T
93.6 6.0 X 7.0 55.5 S. C/ X0 c5 R! B) ]6 {4 x
95.0 6.5 X 7.0 27.23 w4 x/ I- ?) ?3 u
Av. 60.0 v$ m- j* w& c
available testosterone. Again, emphasis should be placed on
- B2 a* p. @; x, s9 Xearly therapy when lower levels of testosterone appear to: Y% i1 t5 @8 w2 ]4 k
provide the best responses. The earlier therapy is instituted
) G! G* P& ~! R" x6 uthe more likely there will be an excellent response with low! i* f# y) ^7 y9 g
serum levels. Response occurs throughout adolescence as
, F5 M+ s6 {& n# c6 qnoted in nomograms of phallic growth. 7 The actual response: |/ H3 T8 G# d' P8 z B' O2 X
to a given serum level of testosterone is much greater at birth
8 K# q E2 _6 [0 wand gradually decreases as boys reach puberty. This is most
. G2 h. p% s: O# J' U4 y" u6 Zlikely related to the conversion of testosterone to dihydrotes-
& _# c& z' \1 g3 |$ Dtosterone and correlates well with the studies of testosterone
: X0 _+ W6 l& C) econversion in foreskin at various ages.% s# s% u, J" {: X% c, b
The question arises regarding early treatment as to whether
' K# w( k4 q' V0 e t0 \one might sacrifice ultimate potential growth as with acceler-
( Y- O3 K/ g. Oated bone growth. The situation appears quite the reverse- ^3 ^! w5 B3 \2 d1 Z: o
with phallic response. If the early growth period is not used
) ?( h& g; b7 vwhen 5a reductase activity is greatest then potential growth4 W' e: t6 n% N$ n. V# j, I' Q& h
may be lost. We have not observed any regression of growth$ t% l0 ]" j- J% S& o
attained with topical or gonadotropin therapy. It may well
8 Q* |4 Y# K, K) U# M0 f. p0 Mbe that some patients will show little or no response to any
0 N+ O: [1 |7 e9 g1 @$ sform of therapy. This would suggest a defect in the ability to
/ U/ |0 L: S9 ~6 uconvert testosterone to dihydrotestosterone and indicate that
; v. m4 |+ \, L+ V Z1 g# j/ J* Ophallic and peripheral skin, and subcutaneous tissue should$ Y: M( t: y) Q5 Z3 N
be compared for 5a reductase activity., Q* X9 o4 v' E. F+ U% b
A, loop enlarges to measure penile girth in millimeters. B,
7 A* I) i; r; pexample of penile girth computed easily and accurately.
1 j, J M% g j7 ~conversion of testosterone to dihydrotestosterone. It is in this
6 r: K+ h7 a3 k3 Eolder group that others have noted high levels of serum
( U, w$ v* n# Q4 J3 _* U$ xtestosterone with topical application. It would also appear
, o0 f' Q- R9 bthat phallic response during puberty is related directly to the
' M, {7 F) H$ userum testosterone level. There also is other evidence of local
& ]$ j3 \0 w* H _# n& Aresponse to testosterone with hair growth and with spermato-0 M+ z+ \3 Q# F: ]& W7 H
genesis. 5• 6
9 Z* k/ B% j, E8 S0 p* fAdministration of larger doses of gonadotropin or systemic
' Y8 }( s4 r6 C. E: v$ Htestosterone, as well as topical applications that produce
" d" `9 k4 E6 {; n! w# `higher levels of serum testosterone (150 to 900 ng./dl.), will4 \ ~: w4 l! j" u M( W4 {; W
also produce phallic growth but risks accelerated skeletal
% h+ h& [1 [9 H; G" Hmaturation even after stopping treatment. It would appear
* G* V+ r: B; L v% ^8 Ythat this may be avoided by topical applications of testosterone
: r B- u& V6 {6 |: {' H0 v1 B6 jand monitoring of serum testosterone. Even with this control1 W' O% a2 Q5 ?
the duration of our therapy did not exceed 3 weeks at any
# P7 k2 O) B/ H wtime. It is apparent that the prepuberal male subject may: H6 ?- q- }; z. e ?& \. R, K
suffer accelerated bone growth with testosterone levels near
* M$ j6 m1 A; c% f& `8 J200 ng./dl. When skeletal maturation is complete the level of: n, Y9 V: D8 x( W
serum testosterone can be maintained in the 700 to 1,300 ng./
( {3 I s4 |9 [. p, E, ndl. range to stimulate phallic growth and secondary sexual" M4 W: X( t8 K6 `/ i; F
changes. Therefore, after skeletal maturation parenteral tes-
; s7 T6 ^" y* w# t" wtosterone may be used to advantage. Before skeletal matura-" L2 a: p: P3 R ]4 Y3 n+ `3 A
tion care must be taken to avoid maintaining levels of serum
* c6 ]3 [) [) u7 Y! Z' d+ rtestosterone more than 100 ng./dl. Low-dose gonadotropin
! z( f& v3 ]" s- [8 P" i- [depends upon intrinsic testicular activity and may require3 ]8 S# G# u& z- X5 A
prolonged administration for any response.9 Y' D* O! c: G1 u; G8 }! t& G: @
Alternately, topical testosterone does not depend upon tes-
5 h* v6 u1 S3 j/ `5 E, B7 S, s! sticular function and may provide a more constant level of
' m9 J. {, K3 XREFERENCES: C! K) a+ c1 p1 d$ k
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 z* O* z l) ?. S. M8 j
R.: The local application of testosterone cream to the prepub-
2 R# m! U9 C k, M0 ~ertal phallus. J. Urol., 105: 905, 1971.. K: Z/ v2 M6 X& Y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 M6 k" I% [8 x
treatment for micropenis during early childhood. J. Pediat.,
# c X: `" T& i, B4 }, c8 T83: 247, 1973.7 _4 c# E- n& H
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-1 S/ ^" ~+ K1 N
one therapy for penile growth. Urology, 6: 708, 1975.# S/ W$ `# W1 f+ F. h' e# O4 L4 m
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 U& [. }" r. P6 U8 ? Oto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
) P* I! ^2 h$ z& I- G9 C$ tskin slices of man. J. Clin. Invest., 48: 371, 1969. x0 V+ l# ?9 U. W: u7 l7 _
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
: C6 n5 O; I! w& W4 e$ o8 Jby topical application of androgens. J.A.M.A., 191: 521, 1965.
- a R7 \6 Y0 f; p* ]! ]# |6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 W. \9 g1 o/ F1 \7 S7 L: r' ?
androgenic effect of interstitial cell tumor of the testis. J.) \ l& e" l2 O6 j) V
Urol., 104: 774, 1970.4 V) z; J7 U- f9 x; u
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 H, r5 s* Z2 Y0 P& v$ s' }( t, L: |
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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