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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- u C" I; `! n0 u/ ZGONADOTROPIN
- D) ~( D2 j w* D% M& iRICHARD C. KLUGO* AND JOSEPH C. CERNY% u; M" H+ O! R% @& e u6 B
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan: q* D* @3 q' `, T/ }( t$ h8 X8 ?
ABSTRACT+ j8 [# W# x! n, T
Five patients were treated with gonadotropin and topical testosterone for micropenis associated* A, A* Q5 W5 ~. y D* L
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-1 k* x& t& c; E2 G! u
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 S% |- }" v5 H+ p# ?! g6 Z9 T/ t
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( }( R, U: H% f$ |2 m% x
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
# I9 q8 z3 [9 D: A. v) cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average4 Q1 B0 w" Y) s( I" x$ ^, K) r2 R
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
' r/ h" O0 r' ^( uoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
; i3 o$ {9 U/ _% m) E3 k0 F% sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
5 ^/ g, n }# z6 [1 m' l% h% @growth. The response appears to be greater in younger children, which is consistent with previ- f8 K% E" U S0 i8 s7 c7 I
ously published studies of age-related 5 reductase activity.% Q% D' m) }6 Y
Children with microphallus regardless of its etiology will m' o8 t) I1 `6 h3 N% T
require augmentation or consideration for alteration of exter-! c# Z* f+ P9 \. c4 X* k
nal genitalia. In many instances urethroplasty for hypo-
; Y3 p S2 g1 l3 gspadias is easier with previous stimulation of phallic growth.
( O# p1 S7 ]& G& ~1 zThe use of testosterone administered parenterally or topically
7 o: t& M" L/ \) x B1 z/ bhas produced effective phallic growth. 1- 3 The mechanism of
, y( h, A* v( H/ P& B4 W6 h2 Gresponse has been considered as local or systemic. With this
# v: m$ J( k. e1 Yin mind we studied 5 children with microphallus for response4 A7 z2 ]# B3 u% |5 G
to gonadotropin and to topical testosterone independently.
% {6 @$ ~- K+ }+ [: vMATERIALS AND METHODS0 \$ @& U, e; H
Five 46 XY male subjects between 3 and 17 years old were
0 c1 w2 T) N# B4 t0 revaluated for serum testosterone levels and hypothalamic
7 n6 K7 R: e ] M7 ~- mfunction. Of these 5 boys 2 were considered to have Kallmann's
; T3 _# y/ a% o* _" dsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-: c% `$ [2 a3 ^/ [" J9 u( j0 C
lamic deficiency. After evaluation of response to luteinizing
, R9 a* \7 p8 w1 R# K4 \* m6 ehormone-releasing hormone these patients were treated with
u* A, {( [+ i i7 A: U0 w1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% ~( N+ Y6 v$ s+ X- ~) a* {after completion of gonadotropin therapy 10 per cent topical& u/ b0 z! v4 K+ Q
testosterone was applied to the phallus twice daily for 3 weeks.
- A1 d( K" Y3 I# WSerum testosterone, luteinizing hormone and follicle-stimulat-
) R+ o( F$ E5 w. Y" e. ~ iing hormone were monitored before, during and after comple-
: Z& {* q7 H$ ^( P3 Ntion of each phase of therapy. Penile stretch length was
* N9 G& ^$ e$ `) l# g( Z2 \' x3 dobtained by measuring from the symphysis pubis to the tip of
0 p* [# d9 ~5 g8 r8 i1 x3 zthe glans. Penile circumferential (girth) measurements were" U+ T( m: L( j1 N
obtained using an orthopedic digital measuring device (see
0 W9 T# k- z" E- `$ {: o5 ^4 Yfigure).
" C3 I2 E0 J. m' Y; V+ G* ]RESULTS
4 E ^! q2 |( M- `: s hSerum testosterone increased moderately to levels between
/ n5 M9 n" f s5 V+ T50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! X* v. F4 p( X, Z
terone levels with topical testosterone remained near pre-
% T1 N) H+ _ C. d( ztreatment levels (35 ng./dl.) or were elevated to similar levels
% L9 X! C7 B9 Odeveloped after gonadotropin therapy (96 ng./dl.). Higher. H1 X7 b* o0 ~
serum levels were noted in older patients (12 and 17 years old),
9 y d, Y5 e. @0 @, Vwhile lower levels persisted in younger patients (4, 8, and 10. R( O. o: e+ r3 O# x. [
years old) (see table). Despite absence of profound alterations" `: |( q5 B" P9 }& q5 k/ L( R
of serum testosterone the topical therapy provided a greater
& r( y# B( D" I) PAccepted for publication July 1, 1977. ·4 W' e2 b, h+ ]% X( s
Read at annual meeting of American Urological Association,
5 d H4 q8 G0 x X7 _1 [7 p9 dChicago, Illinois, April 24-28, 1977.# R9 m( Q, G0 G5 h! B8 F; Y6 w
* Requests for reprints: Division of Urology, Henry Ford Hospital,( l" `# @3 O) L
2799 W. Grand Blvd., Detroit, Michigan 48202.- T7 ^9 c+ W% r& @4 ~! i
improvement in phallic growth compared to gonadotropin.
4 a" ]4 v0 y% E d, A+ p2 n4 rAverage phallic growth with gonadotropin was 14.3 per cent# `; ]& J# G+ B9 [7 Y. k. g
increase in length and 5.0 per cent increase of girth. Topical' m: j& x6 h% z) U7 Q; L0 z# @
testosterone produced a 60.0 per cent increase of phallic length: m- G6 s' P! R" @9 k8 J
and 52.9 per cent increase of girth (circumference). The F3 ]: _) ? @3 u( q
response to topical testosterone was greatest in children be-
" J4 r! D' Q" s$ itween 4 and 8 years old, with a gradual decrease to age 17 Z6 S4 D' X/ q. h- o9 G
years (see table).
2 L# }* G u# _. d# ` [4 u9 j- bDISCUSSION
* [8 R4 o# D1 i4 tTopical testosterone has been used effectively by other m ?9 |: L/ b6 U7 Q2 ]
clinicians but its mode of action remains controversial. Im-3 W, j7 E; A$ { g4 a X, F+ f
mergut and associates reported an excellent growth response
4 f: g( x5 ^/ Y6 d2 L" i$ ?to topical testosterone with low levels of serum testosterone,
) l3 ]6 U2 `" T/ dsuggesting a local effect.1 Others have obtained growth re-$ u; R: O8 a" N& f6 g( T5 K7 \ e
sponse with high. levels of serum testosterone after topical4 a& p1 \ E1 B8 m) e
administration, suggesting a systemic response. 3 The use of5 Y4 o4 u- h5 u f
gonadotropin to obtain levels of serum testosterone compara-
% w, |7 P: u9 L0 Y8 ]! v, y1 Vble to levels obtained with topical testosterone would seem to
, N- Q$ _& {9 C% tprovide a means to compare the relative effectiveness of( g1 a9 w p# f& d
topical testosterone to systemic testosterone effect. It cer-# T7 y7 a2 }; [: w" j3 }
tainly has been established that gonadotropin as well as par-
d' Y5 W* K: Zenteral testosterone administration will produce genital
9 i) I8 z, ~7 m( L0 Y8 R% Pgrowth. Our report shows that the growth of the phallus was
$ G% W3 [7 h7 M! Dsignificantly greater with topical applications than with go-7 h9 S. F) A- t4 w) I/ M, K
nadotropin, particularly in children less than 10 years old.
+ {$ t5 ]" f1 Z0 kThe levels of serum testosterone remained similar or lower
* e2 U/ x0 ^3 n/ H* qthan with gonadotropin during therapy, suggesting that topi-
6 e3 L& C; k) Jcal application produces genital growth by its local effect as
: c6 }" O w; j0 u' W1 R; Ywell as its systemic effect.
3 S, H8 c* x( P s$ ~Review of our patients and their growth response related to7 F* @: p) M4 ~/ @5 t& f/ Z/ C
age shows a greater growth response at an earlier age. This is) L f- { S1 L& d1 B( H6 c: z" f
consistent with the findings of Wilson and Walker, who8 c' U8 a! `7 X/ l& F R' A. \
reported an increased conversion of testosterone to dihydrotes-
3 u7 L1 s1 k2 z: k" j" y: ctosterone in the foreskin of neonates and infants.4 This activ-% p2 \& T9 S" F( h0 q( C0 `
ity gradually decreases with age until puberty when it ap-
$ k6 E* Z+ I2 I; D; gproaches the same level of activity as peripheral skin. It may
& Y) [: x) |4 bwell be that absorption of testosterone is less when applied at" K( _& E9 l* ^! R7 C
an earlier age as suggested by lower serum levels in children
4 [( u8 K% P, g$ D- mless than 10 years old. This fact may be explained by the/ ?8 y7 J+ w% p1 U$ _/ B9 D
greater ability of phallic skin to convert testosterone to dihy-/ X) q a+ Y q/ ]) d3 X
drotestosterone at this age. Conversely, serum levels in older7 ^! `+ }" P5 T! w% x
patients were higher, possibly because of decreased local& [+ A; W3 {- L+ }. ^; d
667- v& {- _* L% Y9 _, u+ k( |
668 KLUGO AND CERNY9 Q" K6 d3 F1 h7 ]% o2 n
Pt. Age$ _8 a* R F" E1 a
(yrs.)4 |3 j, L/ p _5 A: u8 W
Serum Testosterone Phallus (cm.) Change Length
. [% E$ p; z1 B(ng./dl.) Girth x Length (%)7 Z! j. m8 ~7 P4 [2 r. A
4
7 T1 R) |7 I6 u7 B& o% I8
! W# q+ B H' Y10
- n0 }3 L' Q! I* r" M! q0 [# F2 q12' D! X/ C6 w {( z
17( F/ s1 G/ g1 }) K
Gonadotropin8 | m& H0 w3 x
71.6 2.0 X 3 16.62 s. i, w4 E4 H3 `6 h0 R1 a
50.4 4.0 X 5.0 20.0
, ]5 P8 S) z0 t8 U+ z) @22.0 4.5 X 4.0 25.07 ^2 y& l7 S- A( s8 v& r# a1 M5 B
84.6 4.0 X 4.5 11.12 ~4 @ l9 F) ~- s
85.9 4.5 X 5.5 9.05 Z0 j! t: r4 {" D3 J
Av. 14.3! o8 H- k2 o2 L. G8 g
4
0 D# P% U m: j) H2 n5 D5 z8
! R) Z7 o2 A, d( r5 y10
7 N, a* E( B( X" }' ^/ s126 y& }+ u4 {+ h) N; c/ t) F: b' b6 K
17; b; B9 ~# }/ T7 r0 E7 @& I
Topical testosterone5 c' |6 W0 J: H+ v2 a( L& L3 y5 h/ t
34.6 4.5 X 6.5 85
) j) c% z' g! d! H, t# q38.8 6.0 X 8.5 70
" Z7 F* g/ A& e$ `3 p8 y; k40.0 6.0 X 6.5 62.5
2 B6 m/ U1 b/ }1 z2 T2 P93.6 6.0 X 7.0 55.5
; C' K" f0 k s! o& W9 {95.0 6.5 X 7.0 27.2) C7 F( c* d! Z/ i( I
Av. 60.0
+ ]5 M. N2 d, @2 davailable testosterone. Again, emphasis should be placed on! a! a: A7 g3 c2 [2 v6 |) C
early therapy when lower levels of testosterone appear to
' W- l' d+ K! x5 S; V# ^ r- eprovide the best responses. The earlier therapy is instituted
5 I3 a) ~/ w% D; H* [the more likely there will be an excellent response with low
( w( Y V4 O8 @/ K* Q) }serum levels. Response occurs throughout adolescence as8 o, x' a3 ] f: Q
noted in nomograms of phallic growth. 7 The actual response
/ S- a- `: p9 U3 a) s4 J- E7 cto a given serum level of testosterone is much greater at birth
( B) |. h( K M2 G. ~9 M3 Wand gradually decreases as boys reach puberty. This is most
% L" n' A# Z$ X* F/ Ulikely related to the conversion of testosterone to dihydrotes-
* r1 r1 L9 K4 L0 x' \# o7 Xtosterone and correlates well with the studies of testosterone* C+ {$ ~$ t9 @ w$ V9 S5 u( p& |
conversion in foreskin at various ages.
7 R& o$ {# W" O6 g: @6 y3 \7 nThe question arises regarding early treatment as to whether- [' T3 a/ Z" `, O
one might sacrifice ultimate potential growth as with acceler-; @6 }$ c* B. I! a5 E* _. C) @
ated bone growth. The situation appears quite the reverse
# Y+ }* H! B5 b r6 ewith phallic response. If the early growth period is not used
5 B) w# j# H1 m3 H, _2 [when 5a reductase activity is greatest then potential growth2 l6 P, s( Y; a7 q1 a! o% i9 _
may be lost. We have not observed any regression of growth
$ R1 {# Y5 `& f+ f4 u6 z+ iattained with topical or gonadotropin therapy. It may well
" d/ {# }! v+ pbe that some patients will show little or no response to any- Z( E% a. G3 p9 |% A/ X
form of therapy. This would suggest a defect in the ability to0 C( u S. @: G+ ~+ g) ]
convert testosterone to dihydrotestosterone and indicate that% |- N! f+ c2 o% w: f
phallic and peripheral skin, and subcutaneous tissue should" g7 z+ N2 ?; W( A: l
be compared for 5a reductase activity.
- x7 ]! N& Y$ i4 X; F0 KA, loop enlarges to measure penile girth in millimeters. B,
: ^( Y1 P, C$ v* [- o$ cexample of penile girth computed easily and accurately.9 f4 u, z6 k+ v- ]( f7 b& r
conversion of testosterone to dihydrotestosterone. It is in this
% z- X$ c+ Z. `5 G1 ~older group that others have noted high levels of serum
6 o' F6 i% z' Q; Ztestosterone with topical application. It would also appear
$ y5 r! x% K$ J( E& b1 Qthat phallic response during puberty is related directly to the9 A" h3 P7 j6 J) k! l8 Y
serum testosterone level. There also is other evidence of local
' z/ v) Q3 \: G% L4 q1 O# w$ P uresponse to testosterone with hair growth and with spermato-3 c. T/ F- a0 }$ D
genesis. 5• 6$ O" ^3 o6 A3 V8 J7 P2 E0 O
Administration of larger doses of gonadotropin or systemic3 T7 |7 [5 D. Y% s( T. }
testosterone, as well as topical applications that produce
4 _% s2 N9 W3 V+ _0 O$ |higher levels of serum testosterone (150 to 900 ng./dl.), will# j' Y$ z+ `$ w
also produce phallic growth but risks accelerated skeletal
- c: ^) J0 M1 g/ h1 D, _maturation even after stopping treatment. It would appear5 }: ?7 l, d. d7 g" |* |: T/ B
that this may be avoided by topical applications of testosterone
) M2 J2 p9 o* c4 A2 i. Z" Jand monitoring of serum testosterone. Even with this control- L0 |1 ?( n g$ [, V% h: X
the duration of our therapy did not exceed 3 weeks at any
5 [8 ?- r1 }2 w1 X2 {8 I- ltime. It is apparent that the prepuberal male subject may% O* M; }: @+ A" B Z% b
suffer accelerated bone growth with testosterone levels near" h# Z& {& L& u- {& R$ w
200 ng./dl. When skeletal maturation is complete the level of
) S1 q D7 y `3 @- ]. X! bserum testosterone can be maintained in the 700 to 1,300 ng./
$ d! q9 U, p) n9 \5 _dl. range to stimulate phallic growth and secondary sexual
3 F. s6 b5 n* j: g" Uchanges. Therefore, after skeletal maturation parenteral tes-
! A6 ?7 A1 _2 X! ?4 m0 N; h4 Xtosterone may be used to advantage. Before skeletal matura-. y7 t r1 h% g; ] e* C6 Q
tion care must be taken to avoid maintaining levels of serum
- q- x+ \ |5 `, Z( [testosterone more than 100 ng./dl. Low-dose gonadotropin3 @) U" m8 E" s
depends upon intrinsic testicular activity and may require% z$ D! B$ l1 c1 I2 `) V2 {, I
prolonged administration for any response.8 d( ~. Q# { s
Alternately, topical testosterone does not depend upon tes- N& ^9 ^/ [: l; T t5 N
ticular function and may provide a more constant level of# ]5 A% u. d8 w3 J6 t# f* w
REFERENCES: `5 ]: r, d" }8 r2 z
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,3 C% K' ?% y. _) J# Z
R.: The local application of testosterone cream to the prepub-0 I8 u2 @4 d6 u+ i2 A9 E- n
ertal phallus. J. Urol., 105: 905, 1971.5 E( ]+ t" o* l4 x) u4 T2 I \
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( I2 O2 Z* A xtreatment for micropenis during early childhood. J. Pediat.,
1 L. T. a/ a" n83: 247, 1973.
1 J! `# y' z8 w3 U* Q0 V' `3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ i: r7 M- J. K8 S7 }8 y$ ione therapy for penile growth. Urology, 6: 708, 1975.
# R4 Z3 R9 g9 I5 z% t4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
. N* m7 H2 l+ Z) c+ g4 Oto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
5 j d1 x3 z+ |) eskin slices of man. J. Clin. Invest., 48: 371, 1969.$ h4 @0 d- X6 _4 U- i. n) K v' |
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 V# R1 n5 }: @! {, \! D- R
by topical application of androgens. J.A.M.A., 191: 521, 1965.
9 l& C, ~; n- ^5 G/ |# @6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local3 P( K+ S& I% K# @/ v
androgenic effect of interstitial cell tumor of the testis. J.
, t& v0 t- {8 bUrol., 104: 774, 1970.
" @7 ^5 o k6 y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 |& A& @1 ?% i7 r: d5 d/ J
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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