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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 l' |% t c; @' |& ^ GGONADOTROPIN4 e! @6 @- p8 X2 h* x- a4 b, y
RICHARD C. KLUGO* AND JOSEPH C. CERNY" _" n& ^4 H3 S! g' E
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan9 I9 i, O4 O/ z/ a Q" Q) ~! |4 M
ABSTRACT
' d9 q! U& n/ v; j: ~# pFive patients were treated with gonadotropin and topical testosterone for micropenis associated
3 w: K! |; m% I1 H! P7 mwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ G. g% }5 W9 D- a( U: ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 d* U! T1 X2 K) J) o& B$ g7 A" Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 D: P4 l( H8 S# ~* a% mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent( c* P' ~+ g$ l; R- d4 M* c
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: g& R" s- v3 C* r7 s0 `
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response/ \! \. f6 V* X3 B7 k
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ B8 {/ l9 W4 {9 W; I
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
3 i# v O+ V4 h a* q8 {growth. The response appears to be greater in younger children, which is consistent with previ-
# C! [7 Y( C% z# c6 rously published studies of age-related 5 reductase activity.) ^# e+ h" q; ~# U2 H
Children with microphallus regardless of its etiology will5 ]! `+ y( Z: t- A( e. Z+ {" B
require augmentation or consideration for alteration of exter-
; W( m# v! E. i1 pnal genitalia. In many instances urethroplasty for hypo-
; n# p( Z0 ~! f' C* `& F6 nspadias is easier with previous stimulation of phallic growth." l5 c( i- Z- c
The use of testosterone administered parenterally or topically' ~; x% P; w8 ~" W9 R4 D1 N& D9 z2 i
has produced effective phallic growth. 1- 3 The mechanism of3 a" _6 w' u, G
response has been considered as local or systemic. With this$ x' ?, n Y5 e& R2 p7 ? Z) b
in mind we studied 5 children with microphallus for response1 w& ?. x. U0 B
to gonadotropin and to topical testosterone independently.0 l/ j6 U2 U, X: U2 c! C, G5 @
MATERIALS AND METHODS
) j5 [, U7 a9 X2 q1 J3 q9 ?7 r& @; UFive 46 XY male subjects between 3 and 17 years old were
3 s& u% K# V2 d' H. P) qevaluated for serum testosterone levels and hypothalamic
& ?' b: j x) y5 F, M0 Jfunction. Of these 5 boys 2 were considered to have Kallmann's
. R3 h1 {) c; M- W( H& i; V Lsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
$ P8 Y9 y5 H* _+ Z& c) [. E) Dlamic deficiency. After evaluation of response to luteinizing9 V c+ m t: r' d2 ?3 _8 {! G
hormone-releasing hormone these patients were treated with
3 `9 W% U) L) X+ G% z% o ?5 F9 f1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 w: G. x% r2 D" _8 _5 K& [/ ?
after completion of gonadotropin therapy 10 per cent topical$ D7 ?+ ~( I) ?
testosterone was applied to the phallus twice daily for 3 weeks.
' O" S! ]8 P. s" t# h- KSerum testosterone, luteinizing hormone and follicle-stimulat-
2 T# h: h: t& o7 U4 H. Ting hormone were monitored before, during and after comple-+ A& L( B' k, q6 R( B( k
tion of each phase of therapy. Penile stretch length was
3 M) F0 b3 a; x3 \: gobtained by measuring from the symphysis pubis to the tip of
' }! P( b ?: }7 s/ P2 \9 C1 O1 sthe glans. Penile circumferential (girth) measurements were6 E9 F- X; S& P& E M. `3 M7 \8 |
obtained using an orthopedic digital measuring device (see1 z; f+ Q* T- ?2 Z
figure).
1 I8 @9 K& E' Q; ]RESULTS: W" K9 f/ i% d0 p8 Y% J1 O
Serum testosterone increased moderately to levels between
2 D! X @$ r3 N0 Y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
8 Y# V, ^4 ?1 |5 lterone levels with topical testosterone remained near pre-
* F* q& }' a/ A, e2 T1 N0 Ntreatment levels (35 ng./dl.) or were elevated to similar levels
/ m* d6 L H$ Ldeveloped after gonadotropin therapy (96 ng./dl.). Higher
6 H7 T8 a" c* o" U: z3 y: Xserum levels were noted in older patients (12 and 17 years old),
! s# E- v. k2 \- s' cwhile lower levels persisted in younger patients (4, 8, and 10
& q2 Z# U3 k0 W' q9 v& ?years old) (see table). Despite absence of profound alterations- _- h, e2 J2 o6 ?: z- ~
of serum testosterone the topical therapy provided a greater; r+ F8 h1 y( c, a6 O
Accepted for publication July 1, 1977. ·9 E9 U$ V) x" k8 S* H {6 q
Read at annual meeting of American Urological Association,
6 H" c! W6 _4 tChicago, Illinois, April 24-28, 1977., v( c2 s! E& ?: L V' x9 Q5 d
* Requests for reprints: Division of Urology, Henry Ford Hospital,
) R& x7 B& w# p; e2799 W. Grand Blvd., Detroit, Michigan 48202.
9 C3 c4 M2 H" H0 X+ Ximprovement in phallic growth compared to gonadotropin.; [9 t( I( c: M7 Q- ^5 ^1 f
Average phallic growth with gonadotropin was 14.3 per cent) r" L: \: {1 w+ b
increase in length and 5.0 per cent increase of girth. Topical) N/ P7 w: f8 s6 D8 t
testosterone produced a 60.0 per cent increase of phallic length
9 T+ r m# y: j6 d! Y2 n9 H, Gand 52.9 per cent increase of girth (circumference). The w% L9 W3 ?6 H( h' x
response to topical testosterone was greatest in children be-+ j- D/ I! u! [& ~+ l' M
tween 4 and 8 years old, with a gradual decrease to age 176 ]+ e- u/ u6 A4 N7 Q! a
years (see table).! z6 {( t) [8 Q4 |0 r) Y
DISCUSSION
$ U$ n- v6 v2 T3 ]9 OTopical testosterone has been used effectively by other
5 s6 q7 G0 u* g/ Z$ e/ K+ q. wclinicians but its mode of action remains controversial. Im-
: }2 W' i0 ^, C. E0 mmergut and associates reported an excellent growth response
, V$ j7 y7 H* l, B# Hto topical testosterone with low levels of serum testosterone,
5 i- o' j- e/ [, Xsuggesting a local effect.1 Others have obtained growth re-" M3 [! u. M# z2 u+ X
sponse with high. levels of serum testosterone after topical8 z6 G) M4 \1 Q( J
administration, suggesting a systemic response. 3 The use of
3 G o1 [: v$ n* O9 cgonadotropin to obtain levels of serum testosterone compara-; J( g& `" v: I& \
ble to levels obtained with topical testosterone would seem to/ w% q) H6 \5 i* E j4 [4 g2 F
provide a means to compare the relative effectiveness of; F% U# Y7 G* Q# n9 ?6 b0 H
topical testosterone to systemic testosterone effect. It cer-
: ^( `# S& I$ B% k5 Rtainly has been established that gonadotropin as well as par-7 O1 U- m7 M9 x2 d
enteral testosterone administration will produce genital j, h4 Q# e: p* ^1 n
growth. Our report shows that the growth of the phallus was6 J, |% [& B0 S- ]
significantly greater with topical applications than with go-
0 c4 n- `+ x% O( p5 ^' x2 d! O/ R" Lnadotropin, particularly in children less than 10 years old.
% n% ]( V: g6 }The levels of serum testosterone remained similar or lower6 B4 I% d& Q; O8 e
than with gonadotropin during therapy, suggesting that topi-
& O L3 q8 P- w# \cal application produces genital growth by its local effect as
0 m$ ]; e4 j9 u4 iwell as its systemic effect." V! v* e( h5 h5 k" ^' E
Review of our patients and their growth response related to4 y) p1 E( g( f/ m8 m( J( _* W
age shows a greater growth response at an earlier age. This is
. b3 B4 x( j, p0 U/ n; Zconsistent with the findings of Wilson and Walker, who
5 _: s+ m/ z2 m1 Z; H2 [reported an increased conversion of testosterone to dihydrotes-! H9 p4 ?8 J; e: M
tosterone in the foreskin of neonates and infants.4 This activ-. j% Y* I$ `6 Y
ity gradually decreases with age until puberty when it ap-
1 n, P! p8 {/ }9 s& t' q0 T& H7 B: wproaches the same level of activity as peripheral skin. It may/ i' F9 y; Q" }: z) d9 H
well be that absorption of testosterone is less when applied at
7 G4 ^0 C6 ~8 G0 r! G; e7 n/ Dan earlier age as suggested by lower serum levels in children7 Q' T* J1 X# X7 }* _' M& ?
less than 10 years old. This fact may be explained by the0 I! Z3 A% |# J
greater ability of phallic skin to convert testosterone to dihy-
# }4 V' Z7 S7 U- edrotestosterone at this age. Conversely, serum levels in older
6 p" @! o+ m- B/ g4 I8 |4 apatients were higher, possibly because of decreased local m% x9 X: P- Y3 D1 h
667& o8 S% k8 Q/ m) @4 r0 h
668 KLUGO AND CERNY; k4 C4 N9 \ c4 A2 ^" T5 r- B
Pt. Age# b4 ^7 d5 l9 d* B
(yrs.)8 w5 Q2 o6 {' [
Serum Testosterone Phallus (cm.) Change Length
6 ?1 F( o: _/ I( [; W( t0 ^( _(ng./dl.) Girth x Length (%)2 x# q; {& \ t2 h. N& U$ O& L8 i) d
4
( e6 a0 ^$ F% [* h8
9 z& R2 J- C8 G1 ~9 J& {1 G* S7 A10+ }" d D! f# P+ R9 X7 j
12
% e! b, M: g$ l6 I17
0 s* P( p' X* J1 F% z7 nGonadotropin4 k* p& u6 Z* W3 I6 e* S) O# z
71.6 2.0 X 3 16.6
5 Y9 a' ~; K' m: H! d1 T: K5 b50.4 4.0 X 5.0 20.02 }3 q( }8 b3 u: a
22.0 4.5 X 4.0 25.0# M5 o: s6 e0 j p" M) S- N: U
84.6 4.0 X 4.5 11.1
/ |2 ~ e' r) Q) L0 r4 r85.9 4.5 X 5.5 9.0$ O% f8 M) K; _- b" p, K3 w
Av. 14.39 W. V; \0 I' y7 s) l" h. i
4' E: Z, H% _2 o8 U7 A) A
8
) E- E3 R0 p2 C7 F. ]% i10
; A& \7 S& g! z7 q5 r6 V' I12
7 V- w5 }$ G$ d5 a- f* w3 X17
# @1 b+ @1 d8 w: k) |Topical testosterone
8 \! m/ m( F$ t0 c9 j/ F34.6 4.5 X 6.5 85! q) w1 p O& ~# T5 z# @$ a6 k
38.8 6.0 X 8.5 70' X- J0 ^: H! i$ R6 W
40.0 6.0 X 6.5 62.5. ^) S0 u3 q- G
93.6 6.0 X 7.0 55.5$ b: k! @6 a9 A
95.0 6.5 X 7.0 27.2
+ ]" K1 j" Y- y# y# }' xAv. 60.0
" Y( d+ [5 O* G. `- e( xavailable testosterone. Again, emphasis should be placed on
2 J4 Q3 ]/ ?4 X' zearly therapy when lower levels of testosterone appear to O$ C! E& R' J( h+ w L! e/ t8 r
provide the best responses. The earlier therapy is instituted
! Q( Q1 Z8 q" ?+ p' Uthe more likely there will be an excellent response with low
/ ]+ ?5 \) P$ H0 wserum levels. Response occurs throughout adolescence as
1 E4 B O& m0 o7 \1 A }noted in nomograms of phallic growth. 7 The actual response1 v; o! G3 }4 c& t4 U* Y
to a given serum level of testosterone is much greater at birth
8 Y# ^; u1 p P' E }7 ]and gradually decreases as boys reach puberty. This is most
) W, [3 z$ F6 J$ blikely related to the conversion of testosterone to dihydrotes-
8 z% Y- ?3 K) |* _- ttosterone and correlates well with the studies of testosterone1 }2 P* L0 p- A
conversion in foreskin at various ages.
8 h2 U! x" W* ^- ^+ w+ I# fThe question arises regarding early treatment as to whether2 F" C# W% f' y5 m5 T9 y. e7 R
one might sacrifice ultimate potential growth as with acceler-
+ D" i6 K; i& @ Y* Yated bone growth. The situation appears quite the reverse2 J H5 s2 P2 N/ X. Q" M) q6 @
with phallic response. If the early growth period is not used5 A0 a* ?* @" h, b% r5 R
when 5a reductase activity is greatest then potential growth
+ o8 C9 h E* M) F6 amay be lost. We have not observed any regression of growth5 m/ @0 t0 |% C* J
attained with topical or gonadotropin therapy. It may well/ M6 [1 D+ k2 f6 R
be that some patients will show little or no response to any0 }; j( o4 F* t* ]
form of therapy. This would suggest a defect in the ability to
4 T% a, R2 D' B$ @convert testosterone to dihydrotestosterone and indicate that" G, k- w+ }4 R# A: s4 C
phallic and peripheral skin, and subcutaneous tissue should8 q; b5 @6 A: x; v2 B
be compared for 5a reductase activity.3 N, R* U( X! g# j' K
A, loop enlarges to measure penile girth in millimeters. B,, y2 S( Q# g& R5 \+ M
example of penile girth computed easily and accurately.
2 C; e" g+ G! g1 `conversion of testosterone to dihydrotestosterone. It is in this
" C) X0 n" U* _older group that others have noted high levels of serum6 F% C5 k8 P1 z& n: _+ q/ z0 [' _) Q
testosterone with topical application. It would also appear: y' H" h6 A0 _/ p8 e
that phallic response during puberty is related directly to the, x% C; o2 B- Z! Q$ M0 y5 A" {
serum testosterone level. There also is other evidence of local4 L( g& w. P R
response to testosterone with hair growth and with spermato-
6 w- t* D0 W/ x5 H0 k4 _genesis. 5• 6! z. P: _# s: @$ n3 H
Administration of larger doses of gonadotropin or systemic
- I X5 R/ b5 _* D2 r( _testosterone, as well as topical applications that produce
/ p$ {! ]1 o" e; [( Q- Zhigher levels of serum testosterone (150 to 900 ng./dl.), will |- v9 ?/ [* k, F# Z
also produce phallic growth but risks accelerated skeletal
- S# j0 _5 h, o: Z% m5 N& Jmaturation even after stopping treatment. It would appear) Q- Y, U3 N! W2 j
that this may be avoided by topical applications of testosterone$ {- d& }$ r5 \- p. h
and monitoring of serum testosterone. Even with this control
$ c H" \( y/ O- S Gthe duration of our therapy did not exceed 3 weeks at any+ k% Z6 M ?4 n% D/ D! o
time. It is apparent that the prepuberal male subject may$ F: M3 U, U! p
suffer accelerated bone growth with testosterone levels near
" m# Y l& J- _2 v7 D( _200 ng./dl. When skeletal maturation is complete the level of' g6 a7 k3 \3 e8 R
serum testosterone can be maintained in the 700 to 1,300 ng./
" b* ~( k# ^- n* H/ `/ ydl. range to stimulate phallic growth and secondary sexual
; X% G4 [% f- r z& K" E& M) mchanges. Therefore, after skeletal maturation parenteral tes-7 M x' }% q( x5 d3 w) o/ v4 Q
tosterone may be used to advantage. Before skeletal matura-
$ G8 ?0 U& Z- a( T) ^3 qtion care must be taken to avoid maintaining levels of serum4 d+ ^: a& y9 ^4 X
testosterone more than 100 ng./dl. Low-dose gonadotropin6 D0 r4 g/ \- y# l D8 ]
depends upon intrinsic testicular activity and may require8 f! E' h4 Y8 w$ r
prolonged administration for any response.' ^, v; `0 i. F$ V2 Y
Alternately, topical testosterone does not depend upon tes-) k4 F p6 n c1 I+ b
ticular function and may provide a more constant level of w6 i( t; w2 x/ C# W' K3 ]+ W
REFERENCES
: b* \2 \" E! |- g7 k1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 m- d9 R$ R# a0 ]R.: The local application of testosterone cream to the prepub-, F% [. W+ ?" l
ertal phallus. J. Urol., 105: 905, 1971. {$ @0 Q2 ^; e, E, D
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 p# D y0 P; s4 X% @- ^& ltreatment for micropenis during early childhood. J. Pediat.,, i$ E+ f! c5 F, t3 M) h2 W8 b
83: 247, 1973./ A3 |: ~5 s. F0 y
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
$ `' w+ u! S; e6 _0 V! `one therapy for penile growth. Urology, 6: 708, 1975.
7 a8 l5 F3 d/ \0 y) {, B! |4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone8 M' W) C0 k: F; q! u
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 I( m0 @. J: Sskin slices of man. J. Clin. Invest., 48: 371, 1969.' r6 J5 M) ^' [* t
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- z- e9 y1 ~& Vby topical application of androgens. J.A.M.A., 191: 521, 1965.
$ @6 ]( F& e. u* [# b+ ^. e6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
' L, J6 D. w9 r$ h! xandrogenic effect of interstitial cell tumor of the testis. J.
; [, D9 U% h/ e# h: K2 j1 uUrol., 104: 774, 1970.* X% P6 a. i l+ L. P
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( m) z9 e0 i* y$ ~; j4 m: N0 ftion in the male genitalia from birth to maturity. J. Urol., 48: |
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