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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 y# s; q1 m+ X7 D( }. f/ v3 QGONADOTROPIN x9 z# X9 _0 u
RICHARD C. KLUGO* AND JOSEPH C. CERNY
P# i# A9 Z& [: H( q+ _1 L6 kFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
. v* d/ }* ?$ s$ V7 A( b" VABSTRACT
4 p l3 _* S8 vFive patients were treated with gonadotropin and topical testosterone for micropenis associated/ [% ~! ?% I) Q1 I: o( u1 I0 g
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-# ]: U+ R: E- F; U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. X1 @/ K) }2 B; k. r
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! m1 Q v7 x: Z) b4 T; V8 P, A
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent( f4 U3 k- s: b- g; K" M" X9 b
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average/ k* `( j7 A- B) N! ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; ]0 v0 Y1 D, I$ _2 }occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
) u3 o$ [( w* c! S. Q, Cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 J6 l' X8 \% I
growth. The response appears to be greater in younger children, which is consistent with previ-
* m! t1 H& K9 j, x; rously published studies of age-related 5 reductase activity.6 s9 G# U9 e: L* D2 s
Children with microphallus regardless of its etiology will" ] _, q" R$ R1 O2 Z- j
require augmentation or consideration for alteration of exter-
+ l9 _" p/ @+ C7 B2 u% _4 W- ^nal genitalia. In many instances urethroplasty for hypo-* F* i- I; M. U9 S7 E
spadias is easier with previous stimulation of phallic growth.
9 O! I9 x! ]/ t/ c, c' EThe use of testosterone administered parenterally or topically# M2 ?% u6 ^6 t5 {) j# ~: D
has produced effective phallic growth. 1- 3 The mechanism of
/ m6 I; B+ v |response has been considered as local or systemic. With this. X9 I: @! A- J% M5 J6 I! A
in mind we studied 5 children with microphallus for response
3 f" u! n4 g1 c# B! Y6 zto gonadotropin and to topical testosterone independently.) S( ` H3 q1 f) E, |
MATERIALS AND METHODS* n, q% p ]6 c$ C
Five 46 XY male subjects between 3 and 17 years old were* ]/ W9 u9 T2 W( Z3 L; ^, f! y
evaluated for serum testosterone levels and hypothalamic) s% N. D n: o
function. Of these 5 boys 2 were considered to have Kallmann's
W. j5 ]- O P& \syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
5 l3 s: v4 p2 w6 a/ elamic deficiency. After evaluation of response to luteinizing; O, G7 P" V' f' ]$ f
hormone-releasing hormone these patients were treated with0 d+ l3 x2 q! N1 Y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
9 U3 }: p _# [0 V2 `' I3 kafter completion of gonadotropin therapy 10 per cent topical
6 o& l" f& G- u0 atestosterone was applied to the phallus twice daily for 3 weeks.2 u5 K; T/ B. \0 v1 x* T
Serum testosterone, luteinizing hormone and follicle-stimulat-
6 z9 k# R; K3 W% {# v3 u0 `% v8 Ming hormone were monitored before, during and after comple-, k3 |% x) @, U: U2 ^4 \
tion of each phase of therapy. Penile stretch length was
" s" b* b: Y+ F7 ~7 ]! h& Gobtained by measuring from the symphysis pubis to the tip of1 v+ W3 e/ } \% R+ o. Q5 X, z
the glans. Penile circumferential (girth) measurements were
3 ^- j a, w: Bobtained using an orthopedic digital measuring device (see: C2 p& v2 _) {4 g5 b
figure).
n( u+ n! _$ ]7 b- ~6 h& V fRESULTS2 @" b% J1 U: M/ I6 c* q5 [" X
Serum testosterone increased moderately to levels between
/ Y7 y4 @8 L& n3 i3 q+ l& c# Y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-9 I8 n& G! u8 g1 x* h
terone levels with topical testosterone remained near pre-
) S& R" B4 C, Q( _2 s8 ~treatment levels (35 ng./dl.) or were elevated to similar levels- E& O; B7 x# L) z- v
developed after gonadotropin therapy (96 ng./dl.). Higher6 m: n) R2 Q/ W) c2 J( _6 v
serum levels were noted in older patients (12 and 17 years old)," k/ y" m& A% a. c( Q5 m5 D4 v' d
while lower levels persisted in younger patients (4, 8, and 10
$ L9 r* J) u, ?; B0 ]years old) (see table). Despite absence of profound alterations1 U5 q) A" s# f" j! a
of serum testosterone the topical therapy provided a greater
+ s) r o9 w) hAccepted for publication July 1, 1977. ·
$ z8 h3 r" E# K% k9 oRead at annual meeting of American Urological Association,
2 I7 h3 e& g W; u1 l% v7 |Chicago, Illinois, April 24-28, 1977.* J2 R2 G: C$ L) G. |. Q3 P* V
* Requests for reprints: Division of Urology, Henry Ford Hospital,
; d- N. T; a& m) Z3 p2799 W. Grand Blvd., Detroit, Michigan 48202.+ x0 R. @9 @" t; N2 f, }4 S$ [/ g
improvement in phallic growth compared to gonadotropin.
9 T N; y4 s! ~Average phallic growth with gonadotropin was 14.3 per cent
* P) @9 }( L s2 uincrease in length and 5.0 per cent increase of girth. Topical2 B- E6 U: `- l! `( R; t) M7 v
testosterone produced a 60.0 per cent increase of phallic length6 w0 {& z5 ?; \' G0 s. W9 W! B' s
and 52.9 per cent increase of girth (circumference). The
5 @ ^& u- Y/ y$ hresponse to topical testosterone was greatest in children be-" Y* {2 N0 Y! U0 N) q/ o
tween 4 and 8 years old, with a gradual decrease to age 17
8 z4 f9 U3 U# ?& Z, l* p; j0 Y$ myears (see table).
5 O6 j7 A/ J1 \- w! Z. w: z0 _3 n* KDISCUSSION" g2 z! v# X+ o0 c$ U
Topical testosterone has been used effectively by other- E8 s9 T/ Z$ G* n' U* ~" ]. K" H8 }
clinicians but its mode of action remains controversial. Im-
: r5 f" j0 |; L- g3 W% A9 Rmergut and associates reported an excellent growth response5 O. A# ?8 K8 t& x* j! {9 D n5 W) J
to topical testosterone with low levels of serum testosterone,$ }4 g1 U2 u% E3 i& L( h3 C
suggesting a local effect.1 Others have obtained growth re-
# ~. \* k& ~5 ?) lsponse with high. levels of serum testosterone after topical3 T9 V$ T- u, p9 @2 K# T. m4 |
administration, suggesting a systemic response. 3 The use of0 u) \" h" R3 e0 N
gonadotropin to obtain levels of serum testosterone compara-
0 U2 \8 }7 S2 G# o7 R2 g9 V+ z3 xble to levels obtained with topical testosterone would seem to4 m8 L: Y) [2 ^' U- \' b, _/ l
provide a means to compare the relative effectiveness of
) s: x) c8 `8 ztopical testosterone to systemic testosterone effect. It cer-
; [ a% p) M9 x3 z3 E! rtainly has been established that gonadotropin as well as par-# n; g$ B4 P4 b! [$ f& r# ~
enteral testosterone administration will produce genital
; F% I2 r5 d; lgrowth. Our report shows that the growth of the phallus was
/ b( d4 J( U0 y+ esignificantly greater with topical applications than with go-/ P* L3 x; i m& u% U
nadotropin, particularly in children less than 10 years old.
& @5 ?; n; A1 U: ~1 Q/ @The levels of serum testosterone remained similar or lower+ X. Z o M3 C) p, H4 e% Y* ]
than with gonadotropin during therapy, suggesting that topi-
9 i; A( _ y$ F# \6 J5 k' Rcal application produces genital growth by its local effect as7 N* m& }' [) x3 J
well as its systemic effect.
7 b4 `3 v1 ]9 k/ I( j9 `Review of our patients and their growth response related to6 ^& q3 a! k+ w) j! ]
age shows a greater growth response at an earlier age. This is
1 X3 P# D* l/ O0 d6 D) dconsistent with the findings of Wilson and Walker, who7 @" U4 j; R# [; t( {1 `
reported an increased conversion of testosterone to dihydrotes-; k N# \- \ v0 q3 G7 V
tosterone in the foreskin of neonates and infants.4 This activ-1 k. J) q$ b' V2 {6 t: i; @
ity gradually decreases with age until puberty when it ap-
, R3 q8 K$ P, R8 {0 h6 t4 mproaches the same level of activity as peripheral skin. It may
6 z3 }0 I, W' ewell be that absorption of testosterone is less when applied at
8 k( t3 P, ?' p; G$ o. R* k& r& San earlier age as suggested by lower serum levels in children
! e, E+ j/ E: ~6 L1 [$ Rless than 10 years old. This fact may be explained by the
9 `, Z h( C/ M$ i) H, Dgreater ability of phallic skin to convert testosterone to dihy-
( F1 v P8 w( x7 Ddrotestosterone at this age. Conversely, serum levels in older
2 X1 k8 r* M9 Lpatients were higher, possibly because of decreased local/ [( O8 t. h8 N/ b
667
9 f# ~9 q' ?0 J7 A8 N9 o4 f: N668 KLUGO AND CERNY! |$ B* g# i/ [! [
Pt. Age1 C% G" n! L! R
(yrs.) I _2 D2 K1 q! [( F1 m
Serum Testosterone Phallus (cm.) Change Length0 [' A# f6 a0 P0 z" L( { E
(ng./dl.) Girth x Length (%)
3 a% ~5 W# N# E* V% i$ K/ Q% c" F4
4 e" u; j v* n) ?! V H' i. c: o8
# y$ U$ U* F# h0 m10
. W- L$ B' w* Y5 d! ~2 m+ k- I/ j, |12
) G. A+ O5 e! b+ r8 L5 y& s17
3 L( C+ k" R" {) L( m1 M' k) aGonadotropin6 C) ~/ O( y: G5 l( X" O. y( Q
71.6 2.0 X 3 16.6
4 K# ]+ F! e! ~' T4 D! w: T50.4 4.0 X 5.0 20.0
: U# c5 X% E$ Z: A) X) ^& `( ^22.0 4.5 X 4.0 25.0
3 @6 l& `: k: Y+ Q: D5 {84.6 4.0 X 4.5 11.1
; f* S7 I& j) L( z( U0 E85.9 4.5 X 5.5 9.08 f( J- p( k% ]) B9 B" _- Q$ Q
Av. 14.3
% j* g- X; q- |9 e40 M, K3 w' p. s( q) y
8
& W% l* X7 s: m5 a$ e10
! g3 o" D& ~+ [' Z3 [( I$ H12
- V/ S7 w+ V, N17
1 Z8 z4 l7 @7 g0 v- y! tTopical testosterone# _3 }" F( g/ x) P5 N
34.6 4.5 X 6.5 85/ W; g7 d3 c7 p
38.8 6.0 X 8.5 70( F. B1 c& u y
40.0 6.0 X 6.5 62.54 H3 y3 g' v! Z- J5 v
93.6 6.0 X 7.0 55.5
^0 K8 @2 e& l% a+ F95.0 6.5 X 7.0 27.26 j J' ~% c) {2 z7 {
Av. 60.0
3 Y) d5 O5 p( A8 y$ v8 O2 Ravailable testosterone. Again, emphasis should be placed on
& N. k/ q# X- P! n! `early therapy when lower levels of testosterone appear to# f# r) C' g% w& ~* [
provide the best responses. The earlier therapy is instituted m, N' v; E, }1 g4 v" V7 ~6 [
the more likely there will be an excellent response with low0 x; A1 A6 g7 X7 g" _$ u
serum levels. Response occurs throughout adolescence as
% o$ V$ `* i& r8 [$ w- Znoted in nomograms of phallic growth. 7 The actual response
! ~# b( i+ Z: |" lto a given serum level of testosterone is much greater at birth* F! c" _5 v6 F- r" v7 B/ ?
and gradually decreases as boys reach puberty. This is most. a! Y N% g" @. X- _' J
likely related to the conversion of testosterone to dihydrotes-1 @" k% L. Q/ Y$ v
tosterone and correlates well with the studies of testosterone
/ [8 ^) h+ G9 S5 \5 W* rconversion in foreskin at various ages.5 j" x9 h; @/ v4 ~) u1 D6 q0 Y2 L% [
The question arises regarding early treatment as to whether$ _( X& G$ Y; l' g) E
one might sacrifice ultimate potential growth as with acceler-& ]% u, `; m. e. {- d- K
ated bone growth. The situation appears quite the reverse/ @$ w. U( K: E) O* p) s
with phallic response. If the early growth period is not used! n& O) h7 l' W. }7 A
when 5a reductase activity is greatest then potential growth1 e- ?' h% c' f ?* F" p" t
may be lost. We have not observed any regression of growth! ~6 E) n p0 v2 p w, M0 V) Z; t% w
attained with topical or gonadotropin therapy. It may well. F$ `* O$ E4 b
be that some patients will show little or no response to any$ m! o* u6 `4 O
form of therapy. This would suggest a defect in the ability to
/ D# h4 Q# r( F, mconvert testosterone to dihydrotestosterone and indicate that. [7 L2 A- ]4 v; w4 |. M: ]% U
phallic and peripheral skin, and subcutaneous tissue should
) j6 q7 q d* x/ Obe compared for 5a reductase activity.
6 c% s" L5 {' J8 A2 cA, loop enlarges to measure penile girth in millimeters. B,. O1 ^. x, _" d; `5 Q$ Q$ C( G! w! d
example of penile girth computed easily and accurately.0 K* D1 e. p% D2 `' c. h3 P
conversion of testosterone to dihydrotestosterone. It is in this
8 ?' \5 _) u! y5 Q2 volder group that others have noted high levels of serum* k$ H6 @2 b; S7 `. y3 j) g
testosterone with topical application. It would also appear
R" y6 h1 ?! n6 u, k$ \$ d- Gthat phallic response during puberty is related directly to the
+ b3 k6 ]9 L! V3 lserum testosterone level. There also is other evidence of local9 F+ O; c. Z: q! ?5 V, P
response to testosterone with hair growth and with spermato-* b& ~) I9 b$ G& d. A5 I4 U3 H
genesis. 5• 6; ~. G2 u* @1 H# p
Administration of larger doses of gonadotropin or systemic. V: c: m0 w4 M
testosterone, as well as topical applications that produce
( X+ L, b- v7 ]higher levels of serum testosterone (150 to 900 ng./dl.), will3 Z2 I# B$ F T6 F
also produce phallic growth but risks accelerated skeletal
; c l( l" T# v4 h% e( z& k& Y2 kmaturation even after stopping treatment. It would appear
3 h: E$ y$ u+ _5 othat this may be avoided by topical applications of testosterone
- `1 c2 \$ `4 ]* A3 I8 I6 b2 yand monitoring of serum testosterone. Even with this control
& q; x4 `5 ~, _, G2 @6 dthe duration of our therapy did not exceed 3 weeks at any" Z- e7 i& D$ C# j
time. It is apparent that the prepuberal male subject may, Q& `- m# e( Z3 c9 O+ z2 z; @
suffer accelerated bone growth with testosterone levels near) `" l' p0 a6 o9 l
200 ng./dl. When skeletal maturation is complete the level of
' L+ \& D8 `8 a; Y) e: Jserum testosterone can be maintained in the 700 to 1,300 ng./
3 ?/ @1 [0 I w# o& r9 vdl. range to stimulate phallic growth and secondary sexual
# n, A0 P5 [3 Z3 |changes. Therefore, after skeletal maturation parenteral tes-
) G7 ~2 N) d# r6 a7 P' x) vtosterone may be used to advantage. Before skeletal matura-8 N: Y8 L) n* f" s9 G
tion care must be taken to avoid maintaining levels of serum6 R; H) \" G2 y- W, \# [
testosterone more than 100 ng./dl. Low-dose gonadotropin
) N) ]+ j' A ^, a( Gdepends upon intrinsic testicular activity and may require
! C5 K7 ?! N! D! B# Aprolonged administration for any response.
% r6 ]& T+ [9 t/ T$ D# J, uAlternately, topical testosterone does not depend upon tes-
$ E" b# F7 v7 c; m8 N7 }4 G4 s7 q0 d; Pticular function and may provide a more constant level of3 y0 y2 \+ s' l& B
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( v9 P2 j6 J+ dR.: The local application of testosterone cream to the prepub-
6 |$ N6 h) o0 t; ^( m" Wertal phallus. J. Urol., 105: 905, 1971.
3 h, T J+ M8 I' v' k! |+ p2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. ^+ i8 b/ J' p
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$ F% N9 z4 s7 ^4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
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4 b: Z7 X: A3 B9 E4 f( g9 g) TUrol., 104: 774, 1970.
# x8 J6 _' g1 E" u0 z5 U# m7 s* x7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ ]. ?! K6 j, \7 S7 b* l* N: Ttion in the male genitalia from birth to maturity. J. Urol., 48: |
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