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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
4 X" t( K5 X/ X$ tGONADOTROPIN% T |" w3 [1 \2 z! |3 T
RICHARD C. KLUGO* AND JOSEPH C. CERNY0 g! N# e8 g& R8 _5 S
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 m- d0 \+ D9 l2 v$ A G4 gABSTRACT& W# V- l* `* L2 ?
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
& I$ o& }4 x0 ?9 i# Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
W+ j- Q* E+ _1 K2 ]7 {- v- Ntropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! A6 `! J9 _/ T' x; t9 ?
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 n/ z0 p+ a: `* B% W9 ]. m
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent% j% {+ V2 h/ h7 D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average- _" Q4 c9 U; m9 p! F( S7 ]
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
8 b- u* V0 V% uoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ R8 N/ Y ^! L, B; m) U, Hstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile4 p5 J+ f( x7 E4 y' @2 q
growth. The response appears to be greater in younger children, which is consistent with previ-
% z2 g( I9 H( l+ G# g+ Dously published studies of age-related 5 reductase activity.2 |1 @! a0 j" g/ w% y* J2 W
Children with microphallus regardless of its etiology will
6 I, i1 w( _ ~% o3 A qrequire augmentation or consideration for alteration of exter-
: W3 ~* u$ H" t1 s. f1 b& \nal genitalia. In many instances urethroplasty for hypo-
A3 R" ~- r6 {spadias is easier with previous stimulation of phallic growth.' q+ {1 [, I; `$ D4 y/ f
The use of testosterone administered parenterally or topically7 O- o3 v- u# N- F, ]8 Q8 P
has produced effective phallic growth. 1- 3 The mechanism of" B: p# T* I- ]
response has been considered as local or systemic. With this7 T/ u" v# M' F% T$ p; j6 e
in mind we studied 5 children with microphallus for response
6 r E3 b, p* M# [to gonadotropin and to topical testosterone independently.! i7 N. V4 N7 n" N$ J
MATERIALS AND METHODS# Q; A- Y1 H+ i5 T9 K5 S+ f+ j0 q
Five 46 XY male subjects between 3 and 17 years old were$ j, h1 P/ e* e9 q" B. ^
evaluated for serum testosterone levels and hypothalamic
# e2 w4 V2 R U4 ?- v( P+ O( rfunction. Of these 5 boys 2 were considered to have Kallmann's
- D4 n# x* { ~' I, K* h6 l2 qsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 A/ i' E2 F5 R# L. Z1 j
lamic deficiency. After evaluation of response to luteinizing
# b) t% x: e5 i% X9 ]# D7 H' rhormone-releasing hormone these patients were treated with6 ^& V, t) x$ a
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
, P Y E l1 p$ `0 N9 ?( kafter completion of gonadotropin therapy 10 per cent topical$ u) q% T3 F4 W
testosterone was applied to the phallus twice daily for 3 weeks.
+ m# `1 u! D: z1 {6 G2 FSerum testosterone, luteinizing hormone and follicle-stimulat-
! V( f$ U# o) _( p2 R5 T1 c: Ding hormone were monitored before, during and after comple-/ {* g+ c- q! S8 b; T V
tion of each phase of therapy. Penile stretch length was
, {8 g9 s# W* S5 K9 nobtained by measuring from the symphysis pubis to the tip of* m. d# L3 j& Y, @
the glans. Penile circumferential (girth) measurements were
/ B0 q0 r3 ?: K+ h6 P, Vobtained using an orthopedic digital measuring device (see1 H/ C! F, ~4 h
figure).
) \ |. a" D7 m8 uRESULTS0 u8 m# w0 j3 h6 G
Serum testosterone increased moderately to levels between8 n9 C, e/ G' V% U
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-9 E6 ?8 m$ Y/ N. p& j
terone levels with topical testosterone remained near pre-0 G+ Y; |9 O9 U5 W
treatment levels (35 ng./dl.) or were elevated to similar levels
# K/ b0 t$ F0 P% }- r0 @$ }developed after gonadotropin therapy (96 ng./dl.). Higher* o" z% V9 o. X' u- _
serum levels were noted in older patients (12 and 17 years old),0 L+ [5 p. V: Z5 o4 w
while lower levels persisted in younger patients (4, 8, and 10' u' O) P: F. r! v3 t
years old) (see table). Despite absence of profound alterations
) R0 i4 t- f: z; d8 H9 } r. dof serum testosterone the topical therapy provided a greater3 _/ i! c1 l7 f' t, d1 ~9 }
Accepted for publication July 1, 1977. ·
( H0 @, G& I' x' C( l& p+ }) G6 eRead at annual meeting of American Urological Association,
; |. e( o- x, e0 c, s" g- |$ W8 n6 YChicago, Illinois, April 24-28, 1977.
: H; F1 G: V# m& D* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 Z @ }& u, o. a9 }2799 W. Grand Blvd., Detroit, Michigan 48202.! O7 \# V$ R7 G" a$ i I! [
improvement in phallic growth compared to gonadotropin.0 E5 q# T( F! F% v, I! P% _1 ?
Average phallic growth with gonadotropin was 14.3 per cent2 i' m3 S+ g+ g# v1 h
increase in length and 5.0 per cent increase of girth. Topical
' g( T% z" w3 q% }) Z# P3 g- ?testosterone produced a 60.0 per cent increase of phallic length
% l2 v/ m/ X. X: R) W6 Dand 52.9 per cent increase of girth (circumference). The
' W% q4 H$ n% P1 Z" Xresponse to topical testosterone was greatest in children be-+ h- p; c1 m1 G! ^1 n: _
tween 4 and 8 years old, with a gradual decrease to age 171 C8 s. Y5 y- G8 \- k& w/ v
years (see table).
L5 u8 Q" t2 K0 `DISCUSSION
8 T# b" y- F# a% E- bTopical testosterone has been used effectively by other
- [) c5 u' `5 V9 {clinicians but its mode of action remains controversial. Im-
. H4 E2 P+ k. cmergut and associates reported an excellent growth response
j5 g8 ~, w5 k. M: {to topical testosterone with low levels of serum testosterone,
' J& J+ p! q) q2 P+ R+ _7 H' Tsuggesting a local effect.1 Others have obtained growth re-% f1 M7 o5 F. _' ]( A/ C
sponse with high. levels of serum testosterone after topical; N, e. }8 l/ X) |1 G% v& X, i
administration, suggesting a systemic response. 3 The use of
$ U5 P) O3 q6 Jgonadotropin to obtain levels of serum testosterone compara-! P/ n- c3 ~( u# U- P3 u0 L+ N
ble to levels obtained with topical testosterone would seem to1 X2 n! g- O6 M* e
provide a means to compare the relative effectiveness of
% {6 d" D1 U" r* J" vtopical testosterone to systemic testosterone effect. It cer-3 N P/ k v8 w: W" I1 ^. j
tainly has been established that gonadotropin as well as par-
3 F7 J2 N) z0 a) T8 z' benteral testosterone administration will produce genital2 {2 a m2 u5 `+ _3 M- J, G6 ~" `) M. m
growth. Our report shows that the growth of the phallus was
0 _0 y( G9 G3 ]4 g# [7 m/ T) l csignificantly greater with topical applications than with go-" t8 Q0 E! T* d0 g
nadotropin, particularly in children less than 10 years old.
! t( n6 X2 V* g7 UThe levels of serum testosterone remained similar or lower
# ^1 n1 S1 ]6 @, y# _than with gonadotropin during therapy, suggesting that topi-2 L6 g7 [% ]/ R! R( w
cal application produces genital growth by its local effect as
4 p- ]; J m4 I- f# Fwell as its systemic effect.
- X) s: v5 r3 C6 E. _Review of our patients and their growth response related to7 v8 f9 {" L% x+ ?1 j
age shows a greater growth response at an earlier age. This is
+ o2 ]! } t2 v( Hconsistent with the findings of Wilson and Walker, who; E7 T. J. X8 z! Y5 E0 Y
reported an increased conversion of testosterone to dihydrotes-
$ @' }% V5 D( A, U: ~tosterone in the foreskin of neonates and infants.4 This activ-8 M( K% E3 ]% v$ C/ r
ity gradually decreases with age until puberty when it ap-
9 l; u. k6 k; Y& |; C2 K. \proaches the same level of activity as peripheral skin. It may' ~3 |2 H7 T- E. S7 g6 c
well be that absorption of testosterone is less when applied at
* } Q& P8 Q. P4 p* p, Xan earlier age as suggested by lower serum levels in children
# Z N3 L2 B0 }less than 10 years old. This fact may be explained by the
' K+ ]' m" a+ f% t9 bgreater ability of phallic skin to convert testosterone to dihy-( n$ l! H" f4 X
drotestosterone at this age. Conversely, serum levels in older
$ Q' {% z8 L' y1 f( vpatients were higher, possibly because of decreased local
5 T! J6 f& b8 U R: N. O667
! Q8 R# G. g7 _7 r668 KLUGO AND CERNY
L' H5 ^/ i# p RPt. Age8 G+ c4 c, n. B
(yrs.)% V* {9 E" m7 H& U- M8 F
Serum Testosterone Phallus (cm.) Change Length
. I8 A: x" Z$ ^/ x! z(ng./dl.) Girth x Length (%)
) B: |9 Y Y) Q4) Z4 C9 u; O8 a
8$ m" r2 ~, z; S: U
10
% h3 I, b; {4 b% M12
4 [: b, G3 B( D8 L) M" K4 J17
# H; M* l, }6 _2 i% K3 |* O+ uGonadotropin1 G, I- w: c# Q+ T
71.6 2.0 X 3 16.6* W+ H- b0 \ u$ {! Z |
50.4 4.0 X 5.0 20.0
4 f# g; h, ~& |! y' ~! I22.0 4.5 X 4.0 25.0, v; j; r( i0 }9 V
84.6 4.0 X 4.5 11.18 y+ @+ T6 j. F9 M/ H# Q" V7 p) {
85.9 4.5 X 5.5 9.0% X$ Q1 b* S6 T& O
Av. 14.3
! [. Z& Q% r4 e9 S- X5 @* G4, c R% ~4 R* G3 _" @
8* ?" s; j/ G: X |( h$ ^
104 b) E$ v( c/ ?8 F# M% G9 [
12" R. P1 Y6 E" X1 O- a) s
17
4 x/ t: M9 v8 K+ s d X. TTopical testosterone5 m1 H: k- x' f0 M3 d) u9 F/ J
34.6 4.5 X 6.5 85
/ B4 K# z W" m. q5 g/ d- V, z38.8 6.0 X 8.5 70, b g& P7 {2 f( i: h8 R) W& W
40.0 6.0 X 6.5 62.5/ m9 Z6 @, O+ t9 ?; y$ u* ]
93.6 6.0 X 7.0 55.5) d% t5 i7 p# ?, B
95.0 6.5 X 7.0 27.2
: m* }' ?+ W6 N2 t, lAv. 60.0
* S& x2 t% A( javailable testosterone. Again, emphasis should be placed on
. I3 M5 R2 N0 U" [' r; Cearly therapy when lower levels of testosterone appear to+ o @& M& g! Q* g; D
provide the best responses. The earlier therapy is instituted
J! o; Q2 F, ?4 ]: b# \5 tthe more likely there will be an excellent response with low
) v e, D$ H9 f& H" t% S- Pserum levels. Response occurs throughout adolescence as
5 q+ f: S1 m fnoted in nomograms of phallic growth. 7 The actual response
* g# ~1 u: ^ m1 uto a given serum level of testosterone is much greater at birth
2 o2 a; ]/ ~ w, d [. J" J& _and gradually decreases as boys reach puberty. This is most
+ n& O$ |& Z0 D& ~8 g/ m" X" W P. olikely related to the conversion of testosterone to dihydrotes-3 c& _3 C) D4 o: X1 r! [
tosterone and correlates well with the studies of testosterone
) ]) z. _7 M$ K3 g0 b/ q5 t. n( w8 [conversion in foreskin at various ages.
- M) T% A4 m: X) u0 L& p q5 D: RThe question arises regarding early treatment as to whether
5 X& l# X2 w- O8 z; |( p& `( none might sacrifice ultimate potential growth as with acceler-0 `- ]( h9 K* x& T& y8 f
ated bone growth. The situation appears quite the reverse
; {2 `( t; o6 O7 a# {* f+ q8 I9 {with phallic response. If the early growth period is not used
- q1 Q% {' o: h0 k' |& Nwhen 5a reductase activity is greatest then potential growth1 U2 L7 U4 Z% L, l
may be lost. We have not observed any regression of growth5 m/ ]% D! b" p, w3 {3 H
attained with topical or gonadotropin therapy. It may well( d1 N3 Q+ g5 _' o) P0 C& [
be that some patients will show little or no response to any
% g8 w; h5 I+ G1 s4 C" tform of therapy. This would suggest a defect in the ability to
, l4 S' y `9 `. hconvert testosterone to dihydrotestosterone and indicate that- E' f% e/ u i2 k, ^% V
phallic and peripheral skin, and subcutaneous tissue should
, i! o6 A# \) w; mbe compared for 5a reductase activity.
( K) b" M3 n# F. H$ TA, loop enlarges to measure penile girth in millimeters. B,
, |8 Y9 H9 y' @5 V8 Nexample of penile girth computed easily and accurately.
# h* g; m& J9 w6 d4 Y" Tconversion of testosterone to dihydrotestosterone. It is in this- y. D2 n: @* `4 _4 t. x5 N# G: V
older group that others have noted high levels of serum! R, Q |/ a8 N8 U7 n: y) R
testosterone with topical application. It would also appear
1 |2 ?9 c. w* O: \5 M* c/ {9 Tthat phallic response during puberty is related directly to the
0 \" J: C3 u/ }/ O1 O) P; Y/ xserum testosterone level. There also is other evidence of local
& \2 i% t6 E% n7 A1 Hresponse to testosterone with hair growth and with spermato-
7 {7 n6 C& V7 vgenesis. 5• 67 c4 o3 R$ b6 Z7 Y$ ^ p' _
Administration of larger doses of gonadotropin or systemic5 n8 N( y. z4 B2 Q$ _: M4 K
testosterone, as well as topical applications that produce
1 @% Z3 y6 H* a2 T7 D7 Y/ qhigher levels of serum testosterone (150 to 900 ng./dl.), will( T% @3 O2 c7 P# f+ O
also produce phallic growth but risks accelerated skeletal# ?$ _- e! y8 Q5 ^( v: h6 r3 A# a* k
maturation even after stopping treatment. It would appear
, S5 _5 `7 o' g. i5 d1 M4 `* y4 Ithat this may be avoided by topical applications of testosterone, P1 k4 R% ]: I# y( V% l
and monitoring of serum testosterone. Even with this control. O4 q+ Y) Z- u! q5 T4 c, {
the duration of our therapy did not exceed 3 weeks at any3 P) f: |4 a5 y5 D* @$ ?) @( J0 T
time. It is apparent that the prepuberal male subject may
4 B( v S6 L _suffer accelerated bone growth with testosterone levels near
0 s+ Y6 _" @) L4 I8 E5 v200 ng./dl. When skeletal maturation is complete the level of+ q0 Q9 x; H/ a5 d
serum testosterone can be maintained in the 700 to 1,300 ng./' r# [/ q# c8 X' ^
dl. range to stimulate phallic growth and secondary sexual
- C2 J; v7 E7 H- d7 A, v+ wchanges. Therefore, after skeletal maturation parenteral tes-: B: S. u& `+ x) E4 s; m3 R4 ]
tosterone may be used to advantage. Before skeletal matura-; { ^1 N1 w' `2 Y3 u1 O* z
tion care must be taken to avoid maintaining levels of serum& F, K1 o, N c# i5 Y( m$ R
testosterone more than 100 ng./dl. Low-dose gonadotropin( ]# y# ^$ u* f5 u. _$ {" h& ~
depends upon intrinsic testicular activity and may require ~5 K9 T2 b8 _: |1 G0 r
prolonged administration for any response.' f) l# w" I- ]' k6 w1 E
Alternately, topical testosterone does not depend upon tes-
; q2 f2 D. }0 w# v! ~3 @# uticular function and may provide a more constant level of Q% \* z9 K7 e+ s, O3 I1 W
REFERENCES
3 i4 A* F6 Z2 r" s1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
7 b O( o: p( K* `' T: WR.: The local application of testosterone cream to the prepub-
; Z$ g4 c" h4 B. i9 ~ertal phallus. J. Urol., 105: 905, 1971.
/ P" R% O& O( M& M# n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 o; @3 Q- ~* P+ ]
treatment for micropenis during early childhood. J. Pediat.,+ Y5 ^9 a3 m2 Y! P6 t1 e- T
83: 247, 1973.
! a/ e/ O9 Q! X8 C8 v( O3 D$ ]6 Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 @) V" u0 G' I5 m; ~+ Lone therapy for penile growth. Urology, 6: 708, 1975.3 o5 J/ ]7 |' p+ W2 G& f& N# x
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: Q0 Q4 P9 N' b Kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
8 j6 d6 a# [5 i; R2 m: _' s( u. X$ rskin slices of man. J. Clin. Invest., 48: 371, 1969.
# ?; F9 J/ Q5 w3 D8 s2 O( B5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
( h0 D2 q6 E0 o" Y' d4 a7 tby topical application of androgens. J.A.M.A., 191: 521, 1965.. Q* I8 s- x+ j: K
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
" X- l! D1 G4 J$ l0 a6 Dandrogenic effect of interstitial cell tumor of the testis. J.
& e; l3 ^ s8 N0 dUrol., 104: 774, 1970.
. s( b4 R0 M9 I0 d' J7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& S, S& t L3 y' k; r9 `tion in the male genitalia from birth to maturity. J. Urol., 48: |
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