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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
! t# U0 n: }6 ~$ PGONADOTROPIN1 l7 }# F" q$ O; {
RICHARD C. KLUGO* AND JOSEPH C. CERNY
+ r6 g2 D! R7 T4 n1 |8 v, GFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 x/ W& _$ x' W% B# h8 c/ e- L& e( ?
ABSTRACT# |# K, T6 J8 r1 h, ~, M6 C7 W7 M
Five patients were treated with gonadotropin and topical testosterone for micropenis associated; c3 U# r- D% _
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. K5 q. O+ X5 c atropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
I8 k, s$ f& L( C9 y: ncream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent% D) i6 B2 k# ]2 N* k
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
U8 _" q" r, z5 B- Q* Qincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average' n$ |) q/ N8 T4 K1 t- P; G, _* Z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 j! _% P% @0 a! ^) n
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
" ]! O* b/ @/ M' ]9 qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
, V/ s; b6 `' u& Ugrowth. The response appears to be greater in younger children, which is consistent with previ-
% W9 ?" K8 r8 C Xously published studies of age-related 5 reductase activity.5 E$ \7 Q: z3 w0 z
Children with microphallus regardless of its etiology will
6 ?) V) \$ r) u! E$ r- g; Yrequire augmentation or consideration for alteration of exter-: j0 H$ C. W4 P4 u% r
nal genitalia. In many instances urethroplasty for hypo-
" w4 s$ V9 w1 p4 J% Bspadias is easier with previous stimulation of phallic growth.) `( d9 k0 {+ T8 Q- d0 l' _. O& H4 N
The use of testosterone administered parenterally or topically; k: k5 L4 N* [3 b3 m
has produced effective phallic growth. 1- 3 The mechanism of
& y" |) F/ E9 k+ U8 }! K1 d) W. Wresponse has been considered as local or systemic. With this
' n% l; U* s# n" _in mind we studied 5 children with microphallus for response; D' E5 s9 u+ b# p; T
to gonadotropin and to topical testosterone independently.2 O4 x) W* M- t
MATERIALS AND METHODS
% @6 P3 x2 a& Z" V: C, p0 hFive 46 XY male subjects between 3 and 17 years old were7 ?+ c! Y, T7 ~
evaluated for serum testosterone levels and hypothalamic5 K5 @! ]- X; f6 V, }
function. Of these 5 boys 2 were considered to have Kallmann's( t3 E6 y' u6 Z( q- L! I/ ^% \: N
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
# F3 p6 E7 R: h# V3 o& y% Tlamic deficiency. After evaluation of response to luteinizing# M& I& i* V* e. j* ^/ Z
hormone-releasing hormone these patients were treated with' m$ U0 Z; c7 m' v3 r/ t+ u9 F
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
$ I% J8 W, ~" |after completion of gonadotropin therapy 10 per cent topical
E+ f9 h4 g9 g$ u5 P, p& Dtestosterone was applied to the phallus twice daily for 3 weeks.& S" e/ W8 t; D2 V+ M! s& @
Serum testosterone, luteinizing hormone and follicle-stimulat-# S9 L0 F! n9 E8 z/ M1 D, v
ing hormone were monitored before, during and after comple-1 X8 J" O7 c3 L5 P
tion of each phase of therapy. Penile stretch length was5 W% F0 z: |( C" z- `
obtained by measuring from the symphysis pubis to the tip of1 V9 G# {' e1 G6 u! q$ M$ X) e
the glans. Penile circumferential (girth) measurements were
7 f9 C' U4 A% ]; @2 B# t4 gobtained using an orthopedic digital measuring device (see5 k2 K0 b8 \1 P& v- }
figure).
: ^0 I. G7 z2 u' GRESULTS) O% o) U+ h; f, ]' ^
Serum testosterone increased moderately to levels between9 q5 c# r+ b3 a" f: ?0 T( }$ P$ d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# N; R) D$ M( Kterone levels with topical testosterone remained near pre-
( @& s. m- \& v s1 E1 f0 \treatment levels (35 ng./dl.) or were elevated to similar levels4 {* H( b& R9 c
developed after gonadotropin therapy (96 ng./dl.). Higher
9 s2 i1 R( \; m2 oserum levels were noted in older patients (12 and 17 years old),
" E7 }5 `) f5 @* ?3 G1 n/ Jwhile lower levels persisted in younger patients (4, 8, and 10# R0 L' i' O" ~6 l: K( _
years old) (see table). Despite absence of profound alterations
" z, P$ u% _' Wof serum testosterone the topical therapy provided a greater& {0 v. @( k9 b K, ^
Accepted for publication July 1, 1977. ·$ A, r6 I7 ~0 B, Y- ?
Read at annual meeting of American Urological Association,/ t* h: I4 f d8 d
Chicago, Illinois, April 24-28, 1977.6 ], h- ^2 U7 _- R# v0 z2 G! f
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 M+ S* v5 e" y7 D2799 W. Grand Blvd., Detroit, Michigan 48202.3 u2 f! y3 f* A8 }+ C
improvement in phallic growth compared to gonadotropin.6 y( m4 B& Z0 d+ Z# b
Average phallic growth with gonadotropin was 14.3 per cent w# [( I$ ^, A0 o
increase in length and 5.0 per cent increase of girth. Topical9 c( g6 K+ k- a0 q/ ]2 ?
testosterone produced a 60.0 per cent increase of phallic length
& |# S; \) z7 t' ?; sand 52.9 per cent increase of girth (circumference). The. I+ w& v3 ]/ z f0 v- g. u0 l1 d
response to topical testosterone was greatest in children be-* }2 v. b1 O! V* a! }( V% N) Q
tween 4 and 8 years old, with a gradual decrease to age 17; c, ]$ i6 x/ x% u0 C! h. s$ n
years (see table).
& i' @- R( l; P! ^6 u8 QDISCUSSION- Z3 e: `2 t4 f! x5 Q
Topical testosterone has been used effectively by other
! R& h3 ^& }4 e5 K& `clinicians but its mode of action remains controversial. Im-
' N) l9 B0 N; F9 m( Mmergut and associates reported an excellent growth response
6 {% c9 w! P9 [! fto topical testosterone with low levels of serum testosterone,6 A1 p; @+ a0 l" f: e9 B
suggesting a local effect.1 Others have obtained growth re-
& n$ i1 z0 J/ r% t, a! T6 \sponse with high. levels of serum testosterone after topical
! H$ H0 Q3 [2 l' {4 n; v8 uadministration, suggesting a systemic response. 3 The use of# b, C% N+ Z( T z
gonadotropin to obtain levels of serum testosterone compara-
) Y" Q! K, w+ O$ B) @ f$ u, jble to levels obtained with topical testosterone would seem to
( K& x' M' X! Rprovide a means to compare the relative effectiveness of+ E3 w+ G( j. v2 o& V) I
topical testosterone to systemic testosterone effect. It cer-
. k0 l" y2 E p# q1 D/ |6 ctainly has been established that gonadotropin as well as par-
2 D8 j4 E) `) T: c5 }enteral testosterone administration will produce genital
0 ~$ w* k5 h; b2 O& Kgrowth. Our report shows that the growth of the phallus was
9 v, |9 w: l* v3 x4 ksignificantly greater with topical applications than with go-
4 n' e% x! Z7 @nadotropin, particularly in children less than 10 years old.
p* z) L! k* tThe levels of serum testosterone remained similar or lower
% v6 R4 S! n- H! ?than with gonadotropin during therapy, suggesting that topi-5 C, y8 a7 O& o& g9 T" w4 W4 }
cal application produces genital growth by its local effect as
/ X7 h- o- \) i5 Nwell as its systemic effect.1 i, q* x4 l$ [" ?
Review of our patients and their growth response related to
v" [3 E# C, y1 Y, N: Y- Hage shows a greater growth response at an earlier age. This is
' w0 i% C3 ^4 _: Nconsistent with the findings of Wilson and Walker, who
6 E4 D6 y; o/ `+ N$ breported an increased conversion of testosterone to dihydrotes-
9 U# s2 c$ E# ]2 |; H+ etosterone in the foreskin of neonates and infants.4 This activ-, u2 v; c. x# V! ^$ ?% O% U
ity gradually decreases with age until puberty when it ap-. T6 T& d) R" V3 S+ O. m
proaches the same level of activity as peripheral skin. It may, k$ D" f5 A' _. r3 j& c! \3 I/ ]
well be that absorption of testosterone is less when applied at
' e9 F8 L' x# }4 lan earlier age as suggested by lower serum levels in children7 ^8 N& b, @. f
less than 10 years old. This fact may be explained by the# n- ], H' \. ^; m
greater ability of phallic skin to convert testosterone to dihy-* r' T& {: J M2 F* V5 M
drotestosterone at this age. Conversely, serum levels in older% ]1 l2 [! d) O5 K
patients were higher, possibly because of decreased local) d- z& g* C6 O1 O% ^1 A1 E
667
. J# n, d- ~/ q& D668 KLUGO AND CERNY
# I; E& |6 e) ~3 S' }Pt. Age5 T% R3 ?# v3 G5 Q7 i. p! Q/ p
(yrs.)$ _2 _6 {* U: W a3 A' L% a% q
Serum Testosterone Phallus (cm.) Change Length% E/ d8 ?. Z1 b6 d: P4 \
(ng./dl.) Girth x Length (%); b) C3 l) B& A4 K2 H: m
4
0 w$ _1 _. s/ m5 j7 W( g4 Y) |0 h8
. W* V% B4 o0 p2 o3 k10& J% R M; X1 c; @0 E1 n
12, _. C$ t7 r+ e9 M/ ~) v( K
17
1 f1 R+ P: f" o: Y* g4 n" HGonadotropin/ U' z9 O* f: P, Z$ |% k6 d
71.6 2.0 X 3 16.6
( U3 l" r) Y9 r4 V( }1 v50.4 4.0 X 5.0 20.0# s- B8 l' \. Q% `4 V+ g
22.0 4.5 X 4.0 25.04 _1 n! ]! k0 ?4 n3 q( @& F
84.6 4.0 X 4.5 11.1. l$ @1 Q; U# m, |8 S
85.9 4.5 X 5.5 9.03 x/ ^# E/ d7 \% |( m
Av. 14.3
9 y* E0 o% d& y& [6 j: k4
9 m4 @& `9 p+ `1 m8
5 G8 a' O5 p9 c( ^3 E4 s, q10
+ `, g. h9 E: L; O2 ]12
- b0 @0 H( H2 E/ Z4 N( s17) M2 |) m; z9 l$ h
Topical testosterone7 i1 n- v8 R0 x, ~1 S0 b, s
34.6 4.5 X 6.5 85; b* @2 c! B" H7 Q" B& g
38.8 6.0 X 8.5 70, h5 f1 A7 C J6 W7 ?- K( k
40.0 6.0 X 6.5 62.59 N! x. r: U/ s% |5 f5 _2 I3 c
93.6 6.0 X 7.0 55.5
# }7 d/ p* y/ j% ]- h95.0 6.5 X 7.0 27.2
& X# B% F% v* X+ }! g( hAv. 60.0" I, {9 o& }) [0 x- M
available testosterone. Again, emphasis should be placed on1 L; j/ J5 h J) F g' C4 p: _8 L
early therapy when lower levels of testosterone appear to- d8 o) X' `+ \1 H" v3 r( k5 O
provide the best responses. The earlier therapy is instituted+ E% _( Z) w% \8 ?6 q/ p6 t
the more likely there will be an excellent response with low& C# |! C/ e$ q/ N! E- K# U
serum levels. Response occurs throughout adolescence as5 {) S2 T3 i7 v9 t! ^7 T
noted in nomograms of phallic growth. 7 The actual response
' I& O2 ]- P- B( g. R4 ?; ]0 Fto a given serum level of testosterone is much greater at birth
2 T- n K3 V/ P8 D; z, f. b/ q( Nand gradually decreases as boys reach puberty. This is most* X1 t/ |" d. ], B6 M- e+ Q8 P
likely related to the conversion of testosterone to dihydrotes-
$ M( @. Q/ f2 A/ U2 l6 Ftosterone and correlates well with the studies of testosterone6 u9 r8 x! l U+ I
conversion in foreskin at various ages.
4 H. a5 _. J( X- m, BThe question arises regarding early treatment as to whether
: h% E/ I4 [# Lone might sacrifice ultimate potential growth as with acceler-4 V' q/ R% A7 e7 c2 b
ated bone growth. The situation appears quite the reverse Q7 ]/ ]& g8 ]! M- z
with phallic response. If the early growth period is not used _" b9 k6 e) F9 [: s3 H& D' G* y
when 5a reductase activity is greatest then potential growth5 B. I1 c6 O0 q8 }9 q k$ P' a n5 ~
may be lost. We have not observed any regression of growth
6 b. l/ M: V6 h4 Y& j( E; dattained with topical or gonadotropin therapy. It may well
- q" h, ? B) g5 I) Mbe that some patients will show little or no response to any
, j* W" e0 @8 M' Yform of therapy. This would suggest a defect in the ability to; H: v7 I+ w6 ^. ^; f. z) L! R
convert testosterone to dihydrotestosterone and indicate that: z5 e% _/ r L" k# o7 b3 I
phallic and peripheral skin, and subcutaneous tissue should
8 a. `- s8 f/ i" I, w0 ybe compared for 5a reductase activity." |# l1 ~4 E* X, l1 |
A, loop enlarges to measure penile girth in millimeters. B,
& \; R' q; ~+ f, O' V# Z, l/ m6 ]example of penile girth computed easily and accurately.. ?/ [ d7 ~* c! S( T
conversion of testosterone to dihydrotestosterone. It is in this
# s3 ]: S9 ]5 W3 b7 E2 Zolder group that others have noted high levels of serum
( F' O, [( N3 stestosterone with topical application. It would also appear
) U% W8 ^- j$ athat phallic response during puberty is related directly to the: B& ` Z% p) N& t3 Y' j( o
serum testosterone level. There also is other evidence of local) D' f) X& ~3 K
response to testosterone with hair growth and with spermato-
# O& N7 s7 W$ h5 J8 [genesis. 5• 62 E) z! N3 E) o% n% C0 s
Administration of larger doses of gonadotropin or systemic R! }/ ]" [2 P& W' X1 y
testosterone, as well as topical applications that produce& { p3 n+ Y5 ]( B, j( F4 W
higher levels of serum testosterone (150 to 900 ng./dl.), will8 d, `! ~" ^" n0 V4 K8 L
also produce phallic growth but risks accelerated skeletal f: ]/ K+ I; ]; U9 n$ ^
maturation even after stopping treatment. It would appear( w o/ ^# V W9 I1 P5 J
that this may be avoided by topical applications of testosterone
+ W7 _3 a4 a" U" b% V1 X- eand monitoring of serum testosterone. Even with this control0 L0 f% l3 R1 G! Q$ ^
the duration of our therapy did not exceed 3 weeks at any( x, j1 J7 y- T4 K+ ^' L8 X
time. It is apparent that the prepuberal male subject may, B; P) D! ^4 J+ u9 [5 m- Y7 L
suffer accelerated bone growth with testosterone levels near6 k* Q: d6 T" L! [; y1 r
200 ng./dl. When skeletal maturation is complete the level of
2 G: X# N+ K8 _/ Pserum testosterone can be maintained in the 700 to 1,300 ng./ Z3 | Y1 s; F6 O3 w
dl. range to stimulate phallic growth and secondary sexual" x/ F" u/ v$ \2 E
changes. Therefore, after skeletal maturation parenteral tes-
# M7 G& v5 J: o% w3 n) itosterone may be used to advantage. Before skeletal matura-
* V/ ^, Y2 q% vtion care must be taken to avoid maintaining levels of serum
0 n0 I( ` R( y4 s, h& y$ y( L" htestosterone more than 100 ng./dl. Low-dose gonadotropin4 z* g) W4 Y# `! }4 ]
depends upon intrinsic testicular activity and may require# N% A: x& a8 `+ h; A
prolonged administration for any response.
+ c4 L: t& H" v% x) F3 T0 J* NAlternately, topical testosterone does not depend upon tes-3 [! I% U. A! S0 {
ticular function and may provide a more constant level of8 \: V& U' J" x, C$ ` p- h' [
REFERENCES& Y. j) R9 O9 N/ c1 a
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
/ O9 s: }7 {0 @6 j( ER.: The local application of testosterone cream to the prepub-
8 |8 A) Y3 D9 N/ ^' }ertal phallus. J. Urol., 105: 905, 1971.1 T; z! E/ T) {- ~% q6 C
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
9 H# y' g; t6 T- ^treatment for micropenis during early childhood. J. Pediat.,
( g0 I" p- t7 I8 M$ M1 J83: 247, 1973.# G8 M g9 X2 ?$ p' V0 h3 A
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-! R" W7 b! [6 i
one therapy for penile growth. Urology, 6: 708, 1975.
, m: f7 R! x! ^, x4 }4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
5 X) \) ?5 J- K- y" H# e# |to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by# h* M+ H7 W2 a: J+ W+ @5 d2 {
skin slices of man. J. Clin. Invest., 48: 371, 1969.3 n# x9 p8 C5 {* ~ ]/ D
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: [5 j% ^! P8 T. ]* c6 t
by topical application of androgens. J.A.M.A., 191: 521, 1965./ x! [0 r0 U' R# ]3 u0 L8 t& ?- h
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
' k/ v' \ j+ v( Z+ T; }3 ]5 ~androgenic effect of interstitial cell tumor of the testis. J.
3 Q7 x; M% U2 h3 {/ xUrol., 104: 774, 1970.
6 t0 H2 u0 `9 M7 r: X7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 H2 W# R9 {& u M, q$ @
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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