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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 V; r5 H+ i& n0 d4 x5 X' c+ PGONADOTROPIN z/ ]0 m4 t2 l0 O7 {! r @
RICHARD C. KLUGO* AND JOSEPH C. CERNY
& H% O" E) C/ W( k( n! jFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
. c8 _+ S: F( C$ L$ l3 }" r8 F5 DABSTRACT
9 |, T* k. N* V: r: l6 Z! l7 K+ \Five patients were treated with gonadotropin and topical testosterone for micropenis associated- k# J# {% b1 M2 c+ }
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! J/ p0 Z. s5 C/ _
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! y8 O& r0 H- f0 y* N! v
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
+ y5 t, U4 J/ u9 Afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 \2 n4 K3 b8 \/ m. wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
& P e6 D% V6 O' M% o7 lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 l& g- j0 Z0 D: W+ t0 p3 n0 p% |) toccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This a D9 _7 ]% k/ v
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% G% j" D6 d+ [+ O; ]- @% p9 w" e8 kgrowth. The response appears to be greater in younger children, which is consistent with previ-
- ]' P9 i+ G( a) Zously published studies of age-related 5 reductase activity.2 H8 i% V5 V& ]; |) O" V
Children with microphallus regardless of its etiology will
9 z& c0 M- i: s0 [2 \1 |6 Vrequire augmentation or consideration for alteration of exter-
u6 t9 u3 C' B% E, ?7 N; n6 |- snal genitalia. In many instances urethroplasty for hypo-
$ ~' P9 s& Q5 Wspadias is easier with previous stimulation of phallic growth.7 E, z' f- @ x& N
The use of testosterone administered parenterally or topically
7 ~# u( I) l; H5 N uhas produced effective phallic growth. 1- 3 The mechanism of6 `7 a+ i! D* \
response has been considered as local or systemic. With this8 k/ Z& P5 d0 n" u5 Z
in mind we studied 5 children with microphallus for response
& M' y1 c3 g% B0 x$ `! qto gonadotropin and to topical testosterone independently.( A; h! m: r4 W
MATERIALS AND METHODS
$ f1 d" f% a& ~" ]3 y" o# x3 VFive 46 XY male subjects between 3 and 17 years old were( `) ?' J i1 n3 u0 A8 f. `8 |% {
evaluated for serum testosterone levels and hypothalamic
" U# f, s5 P3 b) gfunction. Of these 5 boys 2 were considered to have Kallmann's. p& @* q/ o+ p7 A' c x$ I- P
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 H" J" T3 Q7 \- [9 f3 E; Flamic deficiency. After evaluation of response to luteinizing
" m7 y. W5 x* F' p% ^hormone-releasing hormone these patients were treated with
/ r1 I# p- @: ]! w, H# i+ p. ?1,000 units of gonadotropin weekly for 3 weeks. Six weeks
$ V! d* q" _9 i9 Aafter completion of gonadotropin therapy 10 per cent topical: t# ?, z& r( w* w T, P4 I. c7 G4 W2 Y: Q
testosterone was applied to the phallus twice daily for 3 weeks.
% Q$ o8 M% J- C& m$ P+ U9 TSerum testosterone, luteinizing hormone and follicle-stimulat-
) r; T% l% x6 oing hormone were monitored before, during and after comple-
2 q1 o5 Q4 k) t8 O2 ~! ~$ Etion of each phase of therapy. Penile stretch length was; E6 p) G: U; s% p! I
obtained by measuring from the symphysis pubis to the tip of
! ~. r, l- _& U* |- ]4 v" [! fthe glans. Penile circumferential (girth) measurements were* D* D9 o, c: f y
obtained using an orthopedic digital measuring device (see
- p8 {9 P; b" Z/ ofigure).3 F, B3 m5 ] y' y; a4 U- q
RESULTS! @& l+ s1 h6 r9 [) _4 P
Serum testosterone increased moderately to levels between
9 ]3 H* R; _; I) ]50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
: ]0 ]; r, s; {1 |1 @terone levels with topical testosterone remained near pre-* h) ?: ~$ j2 x: V7 f. E" q/ B
treatment levels (35 ng./dl.) or were elevated to similar levels
! v C& K( ?) _% j& cdeveloped after gonadotropin therapy (96 ng./dl.). Higher
6 {% a+ L; n d7 dserum levels were noted in older patients (12 and 17 years old),
" N* `" f& B! S" @: I6 zwhile lower levels persisted in younger patients (4, 8, and 10
5 y4 f) G. Q' J& K1 Q; q4 n. tyears old) (see table). Despite absence of profound alterations7 y' d+ ]4 M, z- I
of serum testosterone the topical therapy provided a greater
/ V; y4 l2 V" F) ~Accepted for publication July 1, 1977. ·4 S' y4 L* S5 Y* o" S7 n ?+ V
Read at annual meeting of American Urological Association, z0 i. C& M8 Q |" K. Y# `7 d
Chicago, Illinois, April 24-28, 1977.
5 P! K/ i! x# O) d7 R6 ?4 i* Requests for reprints: Division of Urology, Henry Ford Hospital,+ H$ z' C1 }$ a8 d3 P: I' p
2799 W. Grand Blvd., Detroit, Michigan 48202.
4 h/ ^ `7 B0 Q& i8 ?improvement in phallic growth compared to gonadotropin.+ m, ^& B+ B( s
Average phallic growth with gonadotropin was 14.3 per cent
: t9 a8 ~) o( t+ I$ eincrease in length and 5.0 per cent increase of girth. Topical2 B# {5 s U1 [( k/ H
testosterone produced a 60.0 per cent increase of phallic length! H2 f$ ~$ D( Z' b. c
and 52.9 per cent increase of girth (circumference). The
7 n& V3 U( ?0 ^! B3 ?# g, c/ ^response to topical testosterone was greatest in children be-* ]! W. O# c* L# z
tween 4 and 8 years old, with a gradual decrease to age 173 q3 _' K, R: ?9 f& j& C. `
years (see table).
1 d# N3 Q% Q5 B. Y2 K; q6 ]2 YDISCUSSION& E7 ~, {# @: b& i0 U
Topical testosterone has been used effectively by other
3 a Z* g# c) eclinicians but its mode of action remains controversial. Im-# m; s% O% q9 I
mergut and associates reported an excellent growth response1 d; K0 V3 Q1 p( {+ x
to topical testosterone with low levels of serum testosterone,# T2 |+ B% j5 E3 o( {, G0 q
suggesting a local effect.1 Others have obtained growth re-5 `6 k q2 K' s
sponse with high. levels of serum testosterone after topical
' X# ]! N) }" L+ R9 hadministration, suggesting a systemic response. 3 The use of
: h, _$ N: E' j6 i& v4 ]gonadotropin to obtain levels of serum testosterone compara-4 l3 h( a" M2 ?, h: l# m. y
ble to levels obtained with topical testosterone would seem to
+ | c" X5 ^% o& |; dprovide a means to compare the relative effectiveness of
8 j9 z2 v( r' o# z8 ^topical testosterone to systemic testosterone effect. It cer-
. Q, x; l0 x, s' o* d, y: ]tainly has been established that gonadotropin as well as par-
Z, a; h1 {6 A/ d# A* W3 `enteral testosterone administration will produce genital
& P b7 R" }/ Bgrowth. Our report shows that the growth of the phallus was p/ F1 M5 a- r
significantly greater with topical applications than with go-5 F7 n/ n4 B5 M) o0 ^+ k
nadotropin, particularly in children less than 10 years old.: ]9 {' j! I/ x
The levels of serum testosterone remained similar or lower
9 ~$ d( q; ]4 m6 zthan with gonadotropin during therapy, suggesting that topi-6 h T, A5 O8 ^$ l' j* M1 Z
cal application produces genital growth by its local effect as# [, G; @; s& P! T/ U: M7 B
well as its systemic effect.' j$ z8 O: @8 V2 y
Review of our patients and their growth response related to5 \( V4 z! S; Z l! w/ H
age shows a greater growth response at an earlier age. This is
9 |: p; Z6 z: b9 W. wconsistent with the findings of Wilson and Walker, who
2 z6 f7 q3 C+ t9 c! y, N: Freported an increased conversion of testosterone to dihydrotes-$ u$ d" F. R+ u1 x+ U" y: B- S( M
tosterone in the foreskin of neonates and infants.4 This activ-
& K* I% t' i* ~: c7 sity gradually decreases with age until puberty when it ap-
. y* B& p% h- q$ iproaches the same level of activity as peripheral skin. It may7 n# [1 ?" q6 i9 o/ t! I
well be that absorption of testosterone is less when applied at
0 O: Z. M1 F8 p* ^5 Uan earlier age as suggested by lower serum levels in children
" J% L, c& m9 dless than 10 years old. This fact may be explained by the
0 G5 k2 `$ l2 R/ W7 `greater ability of phallic skin to convert testosterone to dihy-
9 e9 t$ L% P" b5 rdrotestosterone at this age. Conversely, serum levels in older
! N- |# V# K- n4 xpatients were higher, possibly because of decreased local
7 P( m) y8 e: v667, j! t; W/ }# h9 t! L) f$ _- u
668 KLUGO AND CERNY
( T, l+ C$ w$ l5 o. p5 g# a+ \Pt. Age
# k" J; P. q; I2 D0 k3 @2 H(yrs.)
' Z6 C2 p+ m+ P$ gSerum Testosterone Phallus (cm.) Change Length
+ W3 n& p; T; q(ng./dl.) Girth x Length (%)
6 x w3 L [- c2 c7 u6 I+ `+ `4
1 e5 V" d; o0 h- x) t8. ?8 s; J8 V; Z% A9 x
10
$ p, g9 N+ k) F& x% Q! u# m- Z+ W125 ]+ l7 U. v. d+ B# c
17
& s3 A; \7 W0 `( j1 z4 L+ VGonadotropin
8 B% R1 c# N: {) ]71.6 2.0 X 3 16.6
s# Z9 O) ^- Q$ A) }2 f4 I50.4 4.0 X 5.0 20.09 B1 |* C: S; A' E
22.0 4.5 X 4.0 25.0
; s0 L% w2 X# p% Y1 X84.6 4.0 X 4.5 11.1
# @5 h$ q/ s5 A- y! j# \85.9 4.5 X 5.5 9.0
7 |. u: Q e+ m' r+ i. E) T9 P( AAv. 14.3' d$ i% i. S: n
4" z9 J; c/ F5 F
8) V$ j6 O" K# s9 s" |9 C" t
10( A9 E+ i n3 E7 S3 L0 y
12
4 `+ ?' Z$ f, e1 U Y: |17
# ?( o* G* t* b( j9 L& ?) ?/ ZTopical testosterone
0 y) Q8 y9 a. d5 {3 a! Z b6 I7 t' G34.6 4.5 X 6.5 85
2 n8 e6 X8 V. b6 U4 _, n38.8 6.0 X 8.5 70- E: x' I1 L* a' w5 P
40.0 6.0 X 6.5 62.56 l s' G1 h$ \) Z7 R% t! |* @* T
93.6 6.0 X 7.0 55.5
4 W" ] \+ G% } y3 n0 h95.0 6.5 X 7.0 27.2
" z8 W- X% J1 l GAv. 60.0+ [( T( f8 _8 q7 J
available testosterone. Again, emphasis should be placed on
, H% e/ ^' v% @5 P# h0 ]7 z4 fearly therapy when lower levels of testosterone appear to
- Y. c. S& |! h5 E( g1 b4 `% v3 Wprovide the best responses. The earlier therapy is instituted! f/ O; ]3 z9 y9 H$ t( V" J
the more likely there will be an excellent response with low
7 n8 Q F N$ J; _. N8 H( zserum levels. Response occurs throughout adolescence as- r2 q4 ~1 {1 e+ ]! B
noted in nomograms of phallic growth. 7 The actual response
7 X8 e' a9 \- d9 kto a given serum level of testosterone is much greater at birth0 }. n3 m# R0 w9 `# U1 o* K8 V J* }2 w
and gradually decreases as boys reach puberty. This is most
. @/ D' A }; w* g/ X$ {likely related to the conversion of testosterone to dihydrotes-2 @5 V" W8 s7 b- s) |* P1 |
tosterone and correlates well with the studies of testosterone
4 d/ E3 j v% y* l; V3 Zconversion in foreskin at various ages.
9 C& P) G; F; ?The question arises regarding early treatment as to whether$ e% U E! u% f. t! G5 s0 A" B$ F
one might sacrifice ultimate potential growth as with acceler-
0 D+ W0 B A( ]3 g. v1 a3 Iated bone growth. The situation appears quite the reverse+ ^0 Q+ a* s2 L% a: E
with phallic response. If the early growth period is not used8 g; K# ^) M2 V3 F4 [& @& w- R
when 5a reductase activity is greatest then potential growth
8 T1 |9 b) u- d$ T, w& g" I5 o, ~may be lost. We have not observed any regression of growth
9 x1 h( e2 K: T( @: }, Battained with topical or gonadotropin therapy. It may well
1 s$ @2 k3 i: |be that some patients will show little or no response to any
- B1 R+ e; Q- G O" \$ iform of therapy. This would suggest a defect in the ability to
% m* H; l% O9 h. m3 {: F# `convert testosterone to dihydrotestosterone and indicate that
# t/ q' j! V* c$ Kphallic and peripheral skin, and subcutaneous tissue should
+ D9 g) X- U% b8 b2 Q7 nbe compared for 5a reductase activity.3 E% V7 z' G# J3 ~, e4 k
A, loop enlarges to measure penile girth in millimeters. B,
8 A6 ?# w- N+ g8 g( `5 ^example of penile girth computed easily and accurately., k" m) q% O( g/ R, R3 j
conversion of testosterone to dihydrotestosterone. It is in this
+ C, \9 ], w; m, eolder group that others have noted high levels of serum& g) M7 L& b6 Z9 o
testosterone with topical application. It would also appear: i% y2 c. B# y' G% c5 N9 |4 u
that phallic response during puberty is related directly to the
4 j/ m# s) t$ ?, r6 pserum testosterone level. There also is other evidence of local
) @0 |% M# b: R I" Mresponse to testosterone with hair growth and with spermato-5 u9 v9 I W r( H2 _
genesis. 5• 6
, ^! c. A; c( Q7 t5 rAdministration of larger doses of gonadotropin or systemic
; Z& c }; q( |testosterone, as well as topical applications that produce
; F% l. @0 k. Bhigher levels of serum testosterone (150 to 900 ng./dl.), will1 _0 O) T O( z( i4 s; j4 T
also produce phallic growth but risks accelerated skeletal: |( |7 X# H# \: A- m7 A
maturation even after stopping treatment. It would appear) G# c* t; S# u7 p$ ^" K, m# k
that this may be avoided by topical applications of testosterone) Q1 X4 o, A/ ]6 m
and monitoring of serum testosterone. Even with this control3 S2 p( c/ p7 e6 A7 d* K
the duration of our therapy did not exceed 3 weeks at any- v R s; x2 i X+ r. P. e% B
time. It is apparent that the prepuberal male subject may
, i" o' r0 ]4 m; C! R& Qsuffer accelerated bone growth with testosterone levels near' Y0 V' j; r# C! c! N' g( T
200 ng./dl. When skeletal maturation is complete the level of# \! ?. E) i- M
serum testosterone can be maintained in the 700 to 1,300 ng./
$ S A# [! a) _) k. gdl. range to stimulate phallic growth and secondary sexual. \1 s- `) ]: i X/ E- d
changes. Therefore, after skeletal maturation parenteral tes-( o% C9 D/ [1 ^2 s5 m7 J
tosterone may be used to advantage. Before skeletal matura-% ^/ q+ ^1 K' U( n! u) E: }: s- r/ L
tion care must be taken to avoid maintaining levels of serum7 U) W2 R; I4 W, q/ C
testosterone more than 100 ng./dl. Low-dose gonadotropin
, o" B/ v- E+ C( E8 N6 l$ b: Kdepends upon intrinsic testicular activity and may require, h! T% |# J2 x( \7 y: S, x
prolonged administration for any response.' e- F; }4 z. {' I5 r* h# }
Alternately, topical testosterone does not depend upon tes-
" { e# b- e8 O! ?ticular function and may provide a more constant level of
- r, B4 X I2 S- e& Q/ a% DREFERENCES0 g& ?( z9 w2 u' \8 B9 h/ l
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
! E& _- {" O4 V$ }R.: The local application of testosterone cream to the prepub-# m& |% N& B, [. W0 _; W4 e2 u7 l
ertal phallus. J. Urol., 105: 905, 1971.
) C0 i" L0 k* q" g9 e2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 _6 U2 c- B- y4 v% E; htreatment for micropenis during early childhood. J. Pediat.,# R' |3 [% w3 C6 ?+ u: y( r2 y' ]3 _
83: 247, 1973. a; I: r. o. {7 T/ ?( u& g' Y
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* S! ~" Q3 s1 x- Z* Y5 [9 Vone therapy for penile growth. Urology, 6: 708, 1975.
% _& O N7 N, b) ?4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: q( J* h. g% i- y7 r Q( Y) U' Vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by0 B. h# Q, u1 T! t4 \/ W. `1 _
skin slices of man. J. Clin. Invest., 48: 371, 1969.5 R" X4 [" h2 j9 C0 m; X4 I
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. z) E M; S! o" p) ]9 S3 nby topical application of androgens. J.A.M.A., 191: 521, 1965.
4 W( |9 }# P& T( F6 N8 t) x0 _6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
" ^& C; m8 s4 ]6 T. Y' Dandrogenic effect of interstitial cell tumor of the testis. J.
- k' M1 G1 h# B# j; {Urol., 104: 774, 1970.
4 K3 k2 L* \5 X, s m) h& S7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
: T0 e# G [3 ~7 Wtion in the male genitalia from birth to maturity. J. Urol., 48: |
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