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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
( M8 H: P5 r5 R- n5 }, P" M @8 HGONADOTROPIN0 Z7 p ~/ ]6 Q- p4 p
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 [* }, G t2 \' U7 z, R4 e5 uFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan" {! |& _) u( \3 V
ABSTRACT/ v5 `- ~6 o* Y+ p
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' w" S/ m r4 t/ g6 Q2 M' y; |
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 \. P" g; h. b! I7 U- L, Mtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 j; A0 F! R5 k9 Q* T" _
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent" v" y1 y- u. W. {
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: F5 s4 j' C5 N; y9 l6 E7 [2 o+ r
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average1 {5 L$ v2 K: b1 Z. ~& U( J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response( P# Q6 Z7 K. @5 G5 o! p" ^, [
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 l5 ?* n& Z/ j8 M3 u( o! Xstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
3 h, Q! K a3 B* T. S7 }: l, k& M* V1 f* lgrowth. The response appears to be greater in younger children, which is consistent with previ-
* f4 F5 I( H v9 @( nously published studies of age-related 5 reductase activity.4 F) q. I% T* T1 H5 m4 k
Children with microphallus regardless of its etiology will: K( L0 \) [/ k5 x5 m! h% P
require augmentation or consideration for alteration of exter-& o+ H) K8 e9 A6 V, H% }
nal genitalia. In many instances urethroplasty for hypo-7 u7 y* c: o& y
spadias is easier with previous stimulation of phallic growth.* Z) O) |& u) B/ u& G+ r
The use of testosterone administered parenterally or topically5 h( f' d; J; m. a o i
has produced effective phallic growth. 1- 3 The mechanism of
& u8 n! H% w- \7 @) m8 o. Z* {response has been considered as local or systemic. With this# u! Y- h: L; F8 } } _' Q
in mind we studied 5 children with microphallus for response
: P- W% Z5 X! w9 jto gonadotropin and to topical testosterone independently.
8 `7 r8 U% g4 L3 ? f: BMATERIALS AND METHODS8 X- T2 N6 o0 X/ f8 D! V- D
Five 46 XY male subjects between 3 and 17 years old were7 ]7 S! T, v8 R) w% t! ~
evaluated for serum testosterone levels and hypothalamic3 _' G8 C; F& ]: [- W+ n
function. Of these 5 boys 2 were considered to have Kallmann's- _( b/ y% e7 w0 g3 m3 a
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
% K M) M5 s8 u! |lamic deficiency. After evaluation of response to luteinizing
1 U- }& I0 F# R, }, }& r! Hhormone-releasing hormone these patients were treated with
3 ~2 A0 _9 b! m2 ^; F1,000 units of gonadotropin weekly for 3 weeks. Six weeks
; }: L( ~2 H# B/ y4 J8 {. i; P- _+ b$ mafter completion of gonadotropin therapy 10 per cent topical
n3 U2 w- H9 q& Ntestosterone was applied to the phallus twice daily for 3 weeks. G% u+ c" E% `/ A* k
Serum testosterone, luteinizing hormone and follicle-stimulat-
6 O3 U4 r! U, g& ^8 T! p5 o* z _ing hormone were monitored before, during and after comple-
8 }/ y$ d8 V4 K0 ytion of each phase of therapy. Penile stretch length was
/ I$ ~- z, h$ S0 x' {+ g! Xobtained by measuring from the symphysis pubis to the tip of+ `3 |, Z3 z$ B4 b. p6 [
the glans. Penile circumferential (girth) measurements were) U: }& C( h4 A# E6 ]3 v7 Q
obtained using an orthopedic digital measuring device (see- o' [2 z' X0 P. O7 w
figure).* u: N+ m: L* Q& P1 S5 `
RESULTS: f: n3 X- @! D7 I. M
Serum testosterone increased moderately to levels between# \8 `' R' i, k( D: F3 l" c
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# M7 p( E+ z/ r i1 G. rterone levels with topical testosterone remained near pre-( j- x( |8 N$ `+ K5 _2 {
treatment levels (35 ng./dl.) or were elevated to similar levels
# ?* o% M# a udeveloped after gonadotropin therapy (96 ng./dl.). Higher' `$ A" U: V1 N) R& B. a& _
serum levels were noted in older patients (12 and 17 years old),
6 ^9 b) g8 S1 _. j/ v3 W$ @4 l% z; c" ^while lower levels persisted in younger patients (4, 8, and 10
- O. Z4 w+ y- r. Myears old) (see table). Despite absence of profound alterations7 S6 a( a5 _3 j r7 M! V$ g
of serum testosterone the topical therapy provided a greater
5 G1 s, w) J7 G5 oAccepted for publication July 1, 1977. ·
" Y5 B4 d$ c6 l1 u7 l, Q& w3 FRead at annual meeting of American Urological Association,+ g4 i& F! ^$ H, [" n) ~6 I
Chicago, Illinois, April 24-28, 1977.
$ o7 N3 ?- m& e5 y* Requests for reprints: Division of Urology, Henry Ford Hospital,( ]% ~# K$ m% T+ `0 g) v
2799 W. Grand Blvd., Detroit, Michigan 48202.* Y0 s% ]! d& ^
improvement in phallic growth compared to gonadotropin.
/ J. v1 x& J9 O! w5 ?Average phallic growth with gonadotropin was 14.3 per cent( B n- O* q+ M- J3 ?
increase in length and 5.0 per cent increase of girth. Topical
" ?, Q2 j; Y' ~7 Btestosterone produced a 60.0 per cent increase of phallic length7 T7 ~$ T( |1 g# ~5 N0 Q
and 52.9 per cent increase of girth (circumference). The1 R# l3 Q- n5 S! k% j6 A: J% A
response to topical testosterone was greatest in children be-8 a" C& H8 `# r
tween 4 and 8 years old, with a gradual decrease to age 17
! B$ i3 W7 @% w) K# k' a( vyears (see table).6 J9 j6 Q, x% c, d/ d1 }
DISCUSSION
! u; \4 u! ]- y; |9 eTopical testosterone has been used effectively by other" y9 V: m: z# l _7 A$ g
clinicians but its mode of action remains controversial. Im-
1 S; F! d- d' X" umergut and associates reported an excellent growth response: I# k# [& i9 v
to topical testosterone with low levels of serum testosterone,
2 C! v, \6 j9 Y& asuggesting a local effect.1 Others have obtained growth re-2 Z, u: t3 L, Z- r8 n
sponse with high. levels of serum testosterone after topical! y1 ^4 j4 P. h [" Z s
administration, suggesting a systemic response. 3 The use of
X9 W5 P) ^$ r: A$ a, C, pgonadotropin to obtain levels of serum testosterone compara-
% L$ z# N [ U: k# B" y; eble to levels obtained with topical testosterone would seem to- G* j- H! K5 x$ ^1 F5 ?4 o" e
provide a means to compare the relative effectiveness of
# X" I c$ O! d2 Otopical testosterone to systemic testosterone effect. It cer-! v7 e; x: x/ Y) |/ l5 ~. Y
tainly has been established that gonadotropin as well as par-
3 ?( O2 A0 V* |& Z( W% J, C8 Tenteral testosterone administration will produce genital) `6 J( H ~% U' i3 y9 G1 j
growth. Our report shows that the growth of the phallus was- k+ E" S7 I E4 H& A/ F1 [
significantly greater with topical applications than with go-$ G+ r! p) Q# C( \
nadotropin, particularly in children less than 10 years old.
8 S6 j/ q$ }6 R8 J9 @1 @9 k9 U& pThe levels of serum testosterone remained similar or lower
: o2 a u3 A) c5 w5 B8 k) A! sthan with gonadotropin during therapy, suggesting that topi-
4 R0 X0 K) O6 e0 X5 X0 [cal application produces genital growth by its local effect as
' j* [- S3 z" q7 @# n6 M# Mwell as its systemic effect.5 \$ {+ }3 j# m! X4 t3 _1 M. v
Review of our patients and their growth response related to
! W* D6 {8 U) {3 B5 M/ iage shows a greater growth response at an earlier age. This is( c1 f/ ~" q* i- \. {" Z) @
consistent with the findings of Wilson and Walker, who
7 D$ ]# ]! H( G* freported an increased conversion of testosterone to dihydrotes-: @6 b3 I! i3 X0 r& r: E- k
tosterone in the foreskin of neonates and infants.4 This activ-% l, w& b0 v# S- E! [& o% e, T, C
ity gradually decreases with age until puberty when it ap-
. ?) @- U, [% h1 D0 Z& y5 k7 Rproaches the same level of activity as peripheral skin. It may
1 r* }" p8 J2 U& }9 t: k9 Bwell be that absorption of testosterone is less when applied at2 L! _0 ? G* Q5 k" K- V
an earlier age as suggested by lower serum levels in children
# L$ u" b- a7 l4 T8 A+ b2 Vless than 10 years old. This fact may be explained by the
- `+ o6 ]: S8 n. l( @greater ability of phallic skin to convert testosterone to dihy-
! {- v4 l* d. Fdrotestosterone at this age. Conversely, serum levels in older
6 s: A' s! g0 Ypatients were higher, possibly because of decreased local
0 d- i' T# r! i; N667- \9 C3 B" {7 F% l0 f; _; ?
668 KLUGO AND CERNY' C) J: { U2 M2 c; Q
Pt. Age
9 O# [( L5 ?4 q9 g(yrs.)
/ `0 l1 t" g9 h K& H, w3 ~Serum Testosterone Phallus (cm.) Change Length- A% _" E! g$ U5 x" a$ U
(ng./dl.) Girth x Length (%)3 o# u. J; u6 d* l6 i
4% S8 z* ?% E: {
8
9 B" c3 H% `/ |# }10; _; }" t' y$ ~% O3 q7 R
12
5 b, v0 _2 n0 z2 C! N17
& w8 k2 b" D- f+ Z2 OGonadotropin
) m4 b) n% c5 S* }) \71.6 2.0 X 3 16.6
* W5 ]& _9 t$ i5 ^50.4 4.0 X 5.0 20.0
! F6 S! k" q/ @* O22.0 4.5 X 4.0 25.0* D7 g8 A6 C6 Z; f& z/ b" N( T
84.6 4.0 X 4.5 11.1* z u, L; U- T# W
85.9 4.5 X 5.5 9.0
& {$ Z" L: B% ]* [; H4 VAv. 14.3* R2 L$ m5 k4 c3 W$ e; s
4
" u: e i6 w6 T8$ I+ C' Y* I6 _5 Y
10% \7 u% X7 j& K! ~+ ^; x
12% Q$ l4 A; ^; t J4 ^
170 K; Z+ t- I) d5 Q" w' [
Topical testosterone
- d2 ^. v0 {& B; ]4 n34.6 4.5 X 6.5 85 L1 a! E! J: p% ^8 d6 v
38.8 6.0 X 8.5 70+ t8 W7 G+ n" H
40.0 6.0 X 6.5 62.5
" J$ u3 |! ~, r6 o8 J93.6 6.0 X 7.0 55.5
; ^- `. w4 q$ N$ t! ~# q* w95.0 6.5 X 7.0 27.2- T' o4 y5 w% q
Av. 60.0
4 ~' W- R2 [+ x& b y1 Pavailable testosterone. Again, emphasis should be placed on
4 j/ A# V: A. [1 tearly therapy when lower levels of testosterone appear to* Q5 j4 N1 v7 d8 e2 w1 I" e# n
provide the best responses. The earlier therapy is instituted
, A- k/ n r* Y6 t- Pthe more likely there will be an excellent response with low
' j- s. [" H5 z" Sserum levels. Response occurs throughout adolescence as7 c9 \2 y( Z, S7 } @7 T, a0 w2 N
noted in nomograms of phallic growth. 7 The actual response
4 l- ^ F( F. `) ]3 Yto a given serum level of testosterone is much greater at birth
9 A; m8 E b) s f+ Aand gradually decreases as boys reach puberty. This is most; e* G9 q7 e" O
likely related to the conversion of testosterone to dihydrotes-
! b5 Y% ]0 W- d" R+ C8 y4 stosterone and correlates well with the studies of testosterone
5 J6 O$ q5 b6 K- B7 x: g' Oconversion in foreskin at various ages.
. l; f: I w6 o6 nThe question arises regarding early treatment as to whether
, |* P$ {7 O1 _( Sone might sacrifice ultimate potential growth as with acceler-" A4 l5 W# Y: h _3 C) U* J- S
ated bone growth. The situation appears quite the reverse
9 T/ x' z! l8 y7 x9 Ywith phallic response. If the early growth period is not used. e$ @8 j+ ^; f8 H* B/ @ l5 \7 ]
when 5a reductase activity is greatest then potential growth
9 O6 X0 j! ~/ Xmay be lost. We have not observed any regression of growth
4 p: d( \1 n' |$ O3 x5 v0 L# y$ c$ nattained with topical or gonadotropin therapy. It may well: \- B/ U/ j8 z! [: N
be that some patients will show little or no response to any, _) G! D* [" `- g
form of therapy. This would suggest a defect in the ability to
" v9 J4 h5 m2 ^ T/ D+ Z+ Aconvert testosterone to dihydrotestosterone and indicate that
9 P ]- b6 F* b' s# |7 B4 {* X. hphallic and peripheral skin, and subcutaneous tissue should
) a( b# W; L; n1 ybe compared for 5a reductase activity.
9 h8 N. O0 } G: d+ f" W: AA, loop enlarges to measure penile girth in millimeters. B,' p8 N; w" a! j; k& ^7 d
example of penile girth computed easily and accurately.
' S6 s- Y. w# U8 ? V* Wconversion of testosterone to dihydrotestosterone. It is in this
( G; l" S( o7 N: v9 T/ folder group that others have noted high levels of serum, M( t9 Q7 n) [1 g2 A) I' m
testosterone with topical application. It would also appear
{: m; M; j( |6 u8 L+ | L3 W( bthat phallic response during puberty is related directly to the) z+ W. E) y# A) i
serum testosterone level. There also is other evidence of local2 a) A1 a# ?: B) A9 @
response to testosterone with hair growth and with spermato-
7 V7 p* \3 A* r( g4 [& t! v8 ~genesis. 5• 6: k L/ U. |5 r/ b
Administration of larger doses of gonadotropin or systemic& R* S2 l1 G' X' M. r7 P
testosterone, as well as topical applications that produce
+ E1 N" j; O$ W( p. J7 Q' Thigher levels of serum testosterone (150 to 900 ng./dl.), will$ z2 u" K# k9 X" G! j$ F! d c
also produce phallic growth but risks accelerated skeletal, b7 q. C' g0 ~/ L1 e+ n
maturation even after stopping treatment. It would appear
T* Z `6 L. c# y# B9 mthat this may be avoided by topical applications of testosterone4 R! r! F+ k( z6 K) p8 @
and monitoring of serum testosterone. Even with this control+ b# u* A+ r- S/ ~* j$ |5 w' b3 s) _
the duration of our therapy did not exceed 3 weeks at any
; K6 y1 A- z, h$ m* Qtime. It is apparent that the prepuberal male subject may
% n, B7 }& @3 l( Dsuffer accelerated bone growth with testosterone levels near
: k. ~; F- K! @200 ng./dl. When skeletal maturation is complete the level of
. [: |/ N3 f0 ?% t! B' b5 w& kserum testosterone can be maintained in the 700 to 1,300 ng./
* M- G, W4 c" s: Sdl. range to stimulate phallic growth and secondary sexual
( d2 S* p$ }" K9 l3 p6 h5 ychanges. Therefore, after skeletal maturation parenteral tes-
5 [$ |8 O3 x8 [# H; M, Y. ^tosterone may be used to advantage. Before skeletal matura-
$ P4 E9 ?5 h5 P) _tion care must be taken to avoid maintaining levels of serum1 h1 n8 \7 d5 q+ {# H2 u
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ b) P) j1 V' b; w0 Adepends upon intrinsic testicular activity and may require; @6 w9 n- `9 N% Z3 I1 W9 \0 x
prolonged administration for any response.- E0 U+ Q. h4 W3 K: C$ i6 E
Alternately, topical testosterone does not depend upon tes-. r5 Z. o' Z# `
ticular function and may provide a more constant level of) D1 S, f3 B' G% d! z% X$ @! ~4 q& P
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( R7 Y6 C2 P: ~/ z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
% j i9 r/ D% g0 rR.: The local application of testosterone cream to the prepub-$ H. ]% R2 o5 }. T, ^, i
ertal phallus. J. Urol., 105: 905, 1971.
; `. z& e- q, z ~2 y2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone: S! B; Q1 n" ^: e& S( n
treatment for micropenis during early childhood. J. Pediat.,
4 d( H& P, v, n83: 247, 1973.
. \7 V4 L- l4 H" z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
2 E6 B& B! _* e! Pone therapy for penile growth. Urology, 6: 708, 1975.
# X. J/ _! t" v6 F# x2 u) S4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* q$ y1 D1 _' }" x, i- W
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
2 r4 }! i# X9 |skin slices of man. J. Clin. Invest., 48: 371, 1969.0 j$ Z: ~. ]% n% r$ e$ h, E5 F
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
/ S- d* |. k0 n. W+ Rby topical application of androgens. J.A.M.A., 191: 521, 1965. Z" N M. s9 Z' C- R4 f
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, r* ?0 z& ~6 ?, J- i0 l2 Qandrogenic effect of interstitial cell tumor of the testis. J.
4 l' d9 r n5 y1 o0 {& H( y2 OUrol., 104: 774, 1970.
+ T. o- ^' ?: i b4 @3 |7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-+ e! Q. B" ]+ M4 S s& k
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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