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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- h O% F3 |$ {GONADOTROPIN3 Z4 r: I/ w- a& D
RICHARD C. KLUGO* AND JOSEPH C. CERNY, B4 E0 ]7 W0 m0 \6 ~) Y
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan0 a ~4 Q% \* p# j3 n8 c
ABSTRACT7 X) V9 A# z( B0 ]
Five patients were treated with gonadotropin and topical testosterone for micropenis associated: j0 g/ J: q% R K+ _0 k- Q* `
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-9 l( Q1 J0 U5 \+ Q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
1 A; m) O' j9 w% {cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' v9 n n9 S. D
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! `" W# a& K5 Z- ]) P
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: }' \! B1 ]8 Mincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 V! c8 K q$ ]# `' n7 I3 o% I
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This! x9 h. C; I5 T3 m
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( c( z, |. Q9 f& y5 X O8 agrowth. The response appears to be greater in younger children, which is consistent with previ-+ g* p. ?9 {* J/ L
ously published studies of age-related 5 reductase activity.' y" _' U' ]3 E# `+ Q, Z
Children with microphallus regardless of its etiology will3 ~1 v* ]2 i2 V0 ^5 K
require augmentation or consideration for alteration of exter-/ i! `: {9 P6 x) G$ n) S
nal genitalia. In many instances urethroplasty for hypo-
$ T$ [; M. {4 B- yspadias is easier with previous stimulation of phallic growth.& D, w" y. H( C
The use of testosterone administered parenterally or topically* U% R6 y/ r; b) k3 k+ u
has produced effective phallic growth. 1- 3 The mechanism of
. A. a, g; ?! Nresponse has been considered as local or systemic. With this
/ u% h( i- i" d \in mind we studied 5 children with microphallus for response0 b9 g _2 l4 I# f/ R
to gonadotropin and to topical testosterone independently.
* F3 F6 ]/ c' s/ x9 G$ BMATERIALS AND METHODS
+ \' A9 y+ ]7 gFive 46 XY male subjects between 3 and 17 years old were
$ v8 q; q# U$ J8 W9 fevaluated for serum testosterone levels and hypothalamic
1 {" R( |' w+ s4 Ffunction. Of these 5 boys 2 were considered to have Kallmann's4 e2 A2 R$ h& e" e* ?4 f4 X2 }1 e$ i
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 ^/ n: I- f- e2 m8 C( Qlamic deficiency. After evaluation of response to luteinizing! u1 M0 I% N1 A' \: F) Q" {
hormone-releasing hormone these patients were treated with& N0 W4 k L, P, V7 Z# {
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 D" \4 p. @* L+ J: T6 g6 q! yafter completion of gonadotropin therapy 10 per cent topical
! z, I+ R4 @. Q: u7 g% I7 `$ btestosterone was applied to the phallus twice daily for 3 weeks.0 d3 s% A% a3 b9 ~
Serum testosterone, luteinizing hormone and follicle-stimulat-
- V; H: ]9 i+ W+ B* U' ving hormone were monitored before, during and after comple-" H* E5 D4 K* K
tion of each phase of therapy. Penile stretch length was, N. z& `1 Z! h0 D, E2 l" l5 y
obtained by measuring from the symphysis pubis to the tip of3 {% V$ h. N. U- S: P
the glans. Penile circumferential (girth) measurements were8 e8 J1 y' K3 H! W5 ~& Y
obtained using an orthopedic digital measuring device (see3 w) F# Z9 X' m+ d. h, A
figure).: k6 D6 t' Y+ ?% ]( d# T9 D
RESULTS+ a9 k1 w, d+ x
Serum testosterone increased moderately to levels between
/ ]. B! |0 v! i5 G6 Q7 F- F( f$ f' h50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
8 u7 }9 T6 t* L. A7 B8 eterone levels with topical testosterone remained near pre-
0 L2 U- g( |* K3 F7 itreatment levels (35 ng./dl.) or were elevated to similar levels
# x: a0 z1 H* L( W) g! p1 {developed after gonadotropin therapy (96 ng./dl.). Higher
& ^1 g/ W# e8 Vserum levels were noted in older patients (12 and 17 years old),
( x( U1 c1 c d* e! }7 Pwhile lower levels persisted in younger patients (4, 8, and 10
& s* P6 \" l0 b5 m0 Zyears old) (see table). Despite absence of profound alterations: [" O3 W) s8 h2 M% m
of serum testosterone the topical therapy provided a greater
1 I$ c- [+ e- r" M8 |5 VAccepted for publication July 1, 1977. ·
( Q/ X0 \( o% w# Z Z RRead at annual meeting of American Urological Association,# D6 |% Z4 X/ C) U6 \
Chicago, Illinois, April 24-28, 1977.
W( j8 r5 @5 h& U8 t* Requests for reprints: Division of Urology, Henry Ford Hospital,/ w; H+ ? c6 F1 |/ O# z+ S, N
2799 W. Grand Blvd., Detroit, Michigan 48202.
7 `9 L/ o2 w1 m+ E& ^1 O: b5 [# }improvement in phallic growth compared to gonadotropin.
+ [$ n- @. k) MAverage phallic growth with gonadotropin was 14.3 per cent
" X: e! \& g! d& S; dincrease in length and 5.0 per cent increase of girth. Topical' B& u. W& q) @ V
testosterone produced a 60.0 per cent increase of phallic length& y- E; \- _3 m/ G7 V& g
and 52.9 per cent increase of girth (circumference). The0 b# D! r0 a* X p7 L
response to topical testosterone was greatest in children be-" x3 X8 b& S) T7 J8 ^/ e
tween 4 and 8 years old, with a gradual decrease to age 17
7 A; Y1 n& \. ^0 Y. m/ b) ]$ [ a6 o, zyears (see table).
5 I; G/ Z+ k, uDISCUSSION
( a" i- a9 E3 f; b, a; a& \Topical testosterone has been used effectively by other
- q; }+ l1 U$ y. _( Wclinicians but its mode of action remains controversial. Im-
0 t, r4 Y, x8 w7 b o A7 dmergut and associates reported an excellent growth response( z1 U- b% d& W0 N
to topical testosterone with low levels of serum testosterone,
. P; Z( Q2 @: v! Gsuggesting a local effect.1 Others have obtained growth re-
* z6 m3 D! i' ysponse with high. levels of serum testosterone after topical
9 f" W0 t8 h1 h$ C2 W/ radministration, suggesting a systemic response. 3 The use of2 p; C- D0 F; f8 y8 D& A, z
gonadotropin to obtain levels of serum testosterone compara-0 r! k" {, O7 t; w( @7 C/ G
ble to levels obtained with topical testosterone would seem to
- W- D6 J2 f" F$ N7 i9 jprovide a means to compare the relative effectiveness of" o8 n+ |/ _! r: D. M2 A( y4 ^. r
topical testosterone to systemic testosterone effect. It cer-
f* a$ s5 D- ~* ltainly has been established that gonadotropin as well as par-
- I+ L7 L+ R: ]enteral testosterone administration will produce genital
% v3 n& J0 U3 P8 x, r/ ogrowth. Our report shows that the growth of the phallus was
1 k; Z* _9 ?* n: Ysignificantly greater with topical applications than with go-; M3 F1 y: d% l! |! J- I, A" l
nadotropin, particularly in children less than 10 years old.
6 j' _9 k- P* ^- O7 V* u7 s2 [The levels of serum testosterone remained similar or lower
0 {5 }! V# x! vthan with gonadotropin during therapy, suggesting that topi-! `; Y: v7 h/ j4 j) \8 U# h
cal application produces genital growth by its local effect as
/ E4 v8 @* L( @well as its systemic effect.
$ G( W! K0 l1 HReview of our patients and their growth response related to) {! J j/ s0 T( r0 x+ r2 \% J
age shows a greater growth response at an earlier age. This is0 L0 X! z7 Q9 q$ U
consistent with the findings of Wilson and Walker, who
1 V1 z4 O( M7 M% m2 M/ y7 @1 Xreported an increased conversion of testosterone to dihydrotes-
' F3 _4 L! U% Z O- [; Z" Btosterone in the foreskin of neonates and infants.4 This activ-
2 v: V2 e+ n6 A1 J& wity gradually decreases with age until puberty when it ap-1 c. b8 n! ^7 E ?; x: x& A
proaches the same level of activity as peripheral skin. It may1 O/ f. b: D+ E
well be that absorption of testosterone is less when applied at. G0 b9 Q) Y, ~) s; {& O+ D6 Z
an earlier age as suggested by lower serum levels in children+ a D; A" d; F2 h* j3 r: d5 W
less than 10 years old. This fact may be explained by the1 q: j. y* {- A6 b, `- o: ~
greater ability of phallic skin to convert testosterone to dihy-2 ^/ l7 R0 |; ^- t+ L
drotestosterone at this age. Conversely, serum levels in older) ~( W3 T: O" Q' r
patients were higher, possibly because of decreased local& a$ \3 V0 [. J' D! L+ E% f
6672 s- A! E* B* Q
668 KLUGO AND CERNY8 C4 E* K7 m) Q: {# h) B7 P
Pt. Age7 s, a8 s% B- [: h* [7 D v
(yrs.)( g+ L; _* d3 z' [7 j/ ~) q( u
Serum Testosterone Phallus (cm.) Change Length
7 P" g) C% `' \8 J(ng./dl.) Girth x Length (%)2 a1 V& ?! V. T+ e) D/ d5 ]
4
; [! d: B1 b3 y' Q9 b% r8) g7 I, i' I* e. z. r
10
: e; W# K5 r" x* i% w12
. f6 j! M1 T. x4 G( U17% j" D/ a7 i6 | n
Gonadotropin% F8 ]. q& f9 p' E8 C
71.6 2.0 X 3 16.6
8 \% o) |( J8 e! E k$ Y A& l- k50.4 4.0 X 5.0 20.0
5 ~ S! R3 z5 t" c) f. _22.0 4.5 X 4.0 25.0
; H$ Y: N4 v: F$ g) @84.6 4.0 X 4.5 11.1
% Z- G; i" t# r# ^' }85.9 4.5 X 5.5 9.0
' k+ I/ f1 X: X8 p9 JAv. 14.3
7 d( x. v9 k5 q6 X/ ]0 F0 U1 g+ t4. o/ o$ B8 h0 E
81 W+ w% d S5 l
10
) r2 ]0 g K; P4 c1 x2 E% z120 j8 x- O* X& k" J! `5 }5 b: x2 q0 W E
17' p- i0 ~( Q( n4 d' S4 j
Topical testosterone$ [$ y9 i* J0 K/ ?1 j- K
34.6 4.5 X 6.5 85/ |& I. k' H! ]/ A. K) F3 G3 U
38.8 6.0 X 8.5 702 @! n/ K. c) y( Y
40.0 6.0 X 6.5 62.5
2 d! ~; k7 h" Q) N, U. d0 _) T93.6 6.0 X 7.0 55.5% x$ z, H/ W/ k6 C5 ]5 u. q, e
95.0 6.5 X 7.0 27.2) i$ L4 I$ v! A0 X F2 B
Av. 60.0
( n+ v0 u9 w( n! ?9 ?! Cavailable testosterone. Again, emphasis should be placed on
/ X$ ~" |& i7 z, T$ Jearly therapy when lower levels of testosterone appear to
, F2 J2 c: [% aprovide the best responses. The earlier therapy is instituted
" j: I& c5 k3 v6 n3 ~/ r8 Kthe more likely there will be an excellent response with low1 l! R+ u# p! y; M |
serum levels. Response occurs throughout adolescence as0 r& b* i! X Y% c: d
noted in nomograms of phallic growth. 7 The actual response( A0 F3 p8 E/ b* |3 n
to a given serum level of testosterone is much greater at birth
. Z/ E' `& |7 {; ^9 Uand gradually decreases as boys reach puberty. This is most
" G: A+ {. l, m0 F6 M" D. O. p9 s# glikely related to the conversion of testosterone to dihydrotes-
9 m; }" d1 I- r# Htosterone and correlates well with the studies of testosterone
$ g, L) R! B+ \0 X4 v' Aconversion in foreskin at various ages.. Z4 d, R8 a* a; o' h+ U
The question arises regarding early treatment as to whether
3 ~' B; j/ a" A- w- w$ p; gone might sacrifice ultimate potential growth as with acceler-
8 ]: A" L) r. p- h/ Y( rated bone growth. The situation appears quite the reverse, Q' Y+ h/ C; m' e# {
with phallic response. If the early growth period is not used
* w6 _7 Y* S3 gwhen 5a reductase activity is greatest then potential growth
/ U1 t" _% R) w& X5 ~( B |may be lost. We have not observed any regression of growth
d0 ^1 b6 K" R+ R2 r% wattained with topical or gonadotropin therapy. It may well( v' E2 \% p- W! }, {" B
be that some patients will show little or no response to any* F4 o2 F, O6 W' U- l' u
form of therapy. This would suggest a defect in the ability to( {0 w q4 w0 F6 e
convert testosterone to dihydrotestosterone and indicate that, ]+ b: n1 d9 h w! Q6 t7 T; ~
phallic and peripheral skin, and subcutaneous tissue should
7 |. {9 u ?+ F- w0 j& n) d$ s4 ^+ `be compared for 5a reductase activity./ }0 A# c/ m2 [ F, Q& g
A, loop enlarges to measure penile girth in millimeters. B,5 }9 \+ {1 B4 g9 [: ^) S: X
example of penile girth computed easily and accurately.
1 }/ f0 ^& L: |# e/ Rconversion of testosterone to dihydrotestosterone. It is in this
, G' [/ [# _' N$ Bolder group that others have noted high levels of serum5 i& ?1 g9 |1 c
testosterone with topical application. It would also appear
5 ]9 O) U' P/ _; G# j* c& d Dthat phallic response during puberty is related directly to the
( s1 _4 L2 g. M0 m! e" }* nserum testosterone level. There also is other evidence of local9 e% P/ C/ }9 E2 }. P
response to testosterone with hair growth and with spermato-! B! f4 ]+ c$ L0 F, | o; N* R
genesis. 5• 61 y Q5 ^% ~% a6 {5 t
Administration of larger doses of gonadotropin or systemic
, w8 e: g2 b( i$ M# _testosterone, as well as topical applications that produce3 V' `' m/ K" m1 V5 @( _
higher levels of serum testosterone (150 to 900 ng./dl.), will
- I; h6 S3 P) H! N9 Ralso produce phallic growth but risks accelerated skeletal
, @- d& p9 o7 g% ]2 f4 nmaturation even after stopping treatment. It would appear
3 U- i8 V( E& ythat this may be avoided by topical applications of testosterone
2 c! Y+ X6 k9 J5 S2 X4 i3 Fand monitoring of serum testosterone. Even with this control
5 f6 ^5 x5 N- _ wthe duration of our therapy did not exceed 3 weeks at any
# V' g4 v: F$ e) C$ ~; rtime. It is apparent that the prepuberal male subject may/ `2 n9 x/ y. A9 Q
suffer accelerated bone growth with testosterone levels near& M6 u; K" u$ F7 @
200 ng./dl. When skeletal maturation is complete the level of
0 f# {5 B3 I3 d& X- sserum testosterone can be maintained in the 700 to 1,300 ng./
8 `& N2 f5 [" d( |+ P1 Vdl. range to stimulate phallic growth and secondary sexual# L9 j9 ~1 P! C
changes. Therefore, after skeletal maturation parenteral tes-$ e- n( M$ B& a. k B( \
tosterone may be used to advantage. Before skeletal matura-
6 G* E" D* M8 a5 t+ L9 }4 Ntion care must be taken to avoid maintaining levels of serum" B' q- }3 E' ^3 n
testosterone more than 100 ng./dl. Low-dose gonadotropin
0 S) s/ i' b: @0 ]4 mdepends upon intrinsic testicular activity and may require
. c1 H, _1 [# |& k7 ~: e' m0 iprolonged administration for any response.
' K R! z5 |' @7 U& c# E% BAlternately, topical testosterone does not depend upon tes-8 f6 N4 a$ r, j4 D# {9 ?# ?
ticular function and may provide a more constant level of
8 C7 b6 o) e9 K) K/ qREFERENCES, Y6 Y5 |$ X# s8 f3 u! N" y5 t
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( X3 r* e7 z$ E0 z9 \# U' v) n: F4 E
R.: The local application of testosterone cream to the prepub-3 {2 d' U1 `. L* P& q. [
ertal phallus. J. Urol., 105: 905, 1971.
' K% U$ B3 T: B0 K/ f2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( M& z% P0 J0 S. c& l
treatment for micropenis during early childhood. J. Pediat.,9 |7 d( w4 [* n+ V5 j, h
83: 247, 1973.* E, e: S0 X7 f
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( _/ o9 f! h; N! H
one therapy for penile growth. Urology, 6: 708, 1975.
( f4 M3 z/ ~+ C% ?# M; r7 Y4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, m. c; M% H+ v* r8 i# Z- }" uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
) v2 S1 Q" @+ P9 K. l, F% Xskin slices of man. J. Clin. Invest., 48: 371, 1969.- [& ?" R$ x& A }( k9 L
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth( K7 j- y, V' p4 P# o: r
by topical application of androgens. J.A.M.A., 191: 521, 1965., u) V- F- e. C2 y e: H
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# s: I8 h: @1 z5 pandrogenic effect of interstitial cell tumor of the testis. J.
% w8 q- Q4 }0 G+ nUrol., 104: 774, 1970.
3 a4 D9 y1 D, {+ Q7 R7 p7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" @7 X( F6 j+ p& T+ P6 q2 u- h& y
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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