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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 D2 F% K7 L& h; N, Y1 U
GONADOTROPIN
6 b) G8 y3 \ v( p, s7 ERICHARD C. KLUGO* AND JOSEPH C. CERNY( g: z$ v% ?9 l4 {
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan) [8 e6 [9 r+ S S; M9 Y
ABSTRACT
7 @+ S$ _+ O6 |, c) e: n# {Five patients were treated with gonadotropin and topical testosterone for micropenis associated: z1 H; Y# A4 G0 @* W8 l: h
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 N# f7 A% {# z0 Otropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone: f# L! f( j$ B& I, N: U% E
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! f+ e* u+ u) _2 `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 ~3 ] _& s3 ~% O( N/ P4 I. N( R
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average0 {' N' C, D) b6 j
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: H3 i9 V" [: n; ^3 Uoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
& e# j% q. f7 |- q0 `study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% h- D8 x7 I5 `
growth. The response appears to be greater in younger children, which is consistent with previ-0 G4 ]* k/ q1 E* O& |3 Q
ously published studies of age-related 5 reductase activity.. Q6 O# r' a' K v
Children with microphallus regardless of its etiology will
9 e+ x2 J2 J6 W; o- brequire augmentation or consideration for alteration of exter-7 M, s8 q+ q% d8 B m
nal genitalia. In many instances urethroplasty for hypo-
6 t4 w: X) o) P5 Y- Xspadias is easier with previous stimulation of phallic growth.
* }, I8 ^6 R3 ^4 r8 @The use of testosterone administered parenterally or topically E) r* m+ w6 _0 U: O" B2 U
has produced effective phallic growth. 1- 3 The mechanism of5 p, ~9 _& D+ b8 R$ a5 v6 C
response has been considered as local or systemic. With this/ R' ?" T6 C% A: @
in mind we studied 5 children with microphallus for response1 Y k/ h7 A, I$ T3 `/ ?# }4 w
to gonadotropin and to topical testosterone independently.$ }* _3 z/ H! C+ `/ ]# ?+ L
MATERIALS AND METHODS
) u* u; p* A- e6 M' n4 b8 {/ r! ]Five 46 XY male subjects between 3 and 17 years old were# T: V* H4 d# Z* {8 }2 ^0 n1 ~
evaluated for serum testosterone levels and hypothalamic
" {8 ^% h8 ~7 C/ zfunction. Of these 5 boys 2 were considered to have Kallmann's l3 f# ^+ y+ O X5 B
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
" f1 u3 }; J# u. I9 _+ g4 [( jlamic deficiency. After evaluation of response to luteinizing+ I+ r7 k6 ~7 [' ]. K: }% x
hormone-releasing hormone these patients were treated with
) |/ D4 q: m" a6 L; }1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ S' Z6 a6 ?, x4 w L
after completion of gonadotropin therapy 10 per cent topical( l- R2 f3 Y+ o2 j& M
testosterone was applied to the phallus twice daily for 3 weeks./ j3 p6 F% Z- [) m' K! Y
Serum testosterone, luteinizing hormone and follicle-stimulat-4 r- p* P4 D9 e+ Y
ing hormone were monitored before, during and after comple-
7 S% A( g2 t9 z: Ation of each phase of therapy. Penile stretch length was X M2 w: q, V( z# |% l9 w
obtained by measuring from the symphysis pubis to the tip of0 g/ S$ }0 M @4 X, @3 e
the glans. Penile circumferential (girth) measurements were
( t4 ~8 ~) q, d# v( A9 z6 q8 F: t* yobtained using an orthopedic digital measuring device (see s6 Z$ h$ J2 H" E; j" l, n) \
figure).
* T& O j7 E& t( E8 P N! H5 C0 wRESULTS
2 M- V9 J. m* v! L' B+ Z( M2 e3 xSerum testosterone increased moderately to levels between
% l V& [9 \* M+ n50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 l$ t) j) n B1 ]. D, V4 rterone levels with topical testosterone remained near pre-
, F. H) A0 t0 l! y& S' ltreatment levels (35 ng./dl.) or were elevated to similar levels5 f4 X& ^( o, M0 O
developed after gonadotropin therapy (96 ng./dl.). Higher
# x8 ^2 f% Q& Jserum levels were noted in older patients (12 and 17 years old),
4 Z$ W: M0 C+ ~ B) a; a5 d# pwhile lower levels persisted in younger patients (4, 8, and 10) P1 n6 t; t) [1 ~& n% h
years old) (see table). Despite absence of profound alterations
# w$ s& `8 D, l' i1 M8 ~3 J& mof serum testosterone the topical therapy provided a greater5 }( C3 m) `# T; G
Accepted for publication July 1, 1977. ·
4 X4 F1 ]4 K9 u( i# P$ O& \Read at annual meeting of American Urological Association,. T& y' W: e G/ p, @
Chicago, Illinois, April 24-28, 1977.% T. i* n4 Q6 A1 n
* Requests for reprints: Division of Urology, Henry Ford Hospital,# T0 G+ ^$ ~) @3 [6 U& Z' t
2799 W. Grand Blvd., Detroit, Michigan 48202.
, r6 C5 R5 S0 J; m$ Z7 i6 uimprovement in phallic growth compared to gonadotropin. @8 ?2 ?2 l: K" B& M/ a
Average phallic growth with gonadotropin was 14.3 per cent
3 n. q, G# q @3 G. nincrease in length and 5.0 per cent increase of girth. Topical0 }& g7 C* R4 [( m. @3 K* z# `; Q
testosterone produced a 60.0 per cent increase of phallic length; Y7 Q5 f6 v1 A
and 52.9 per cent increase of girth (circumference). The a) u$ X, h9 C6 w. d
response to topical testosterone was greatest in children be-% _+ _5 E; y# x! N( @7 W2 e0 I# m
tween 4 and 8 years old, with a gradual decrease to age 17
$ w7 c8 s6 z, i. n4 }years (see table).. s0 }6 y* E8 E' S9 t
DISCUSSION7 s8 J2 R: r2 x
Topical testosterone has been used effectively by other7 }+ y% |# _. x
clinicians but its mode of action remains controversial. Im-: H5 }8 r, q5 b
mergut and associates reported an excellent growth response
% W2 [/ s2 Q6 f2 yto topical testosterone with low levels of serum testosterone,- X2 H! b- C4 P: l: D. x
suggesting a local effect.1 Others have obtained growth re-
. t( ]+ n! |& ^5 W& H$ osponse with high. levels of serum testosterone after topical3 b) _! C& k0 f9 ~6 ]: j7 X
administration, suggesting a systemic response. 3 The use of! }4 a2 _- j9 `8 ~- k- g
gonadotropin to obtain levels of serum testosterone compara-
, E0 e6 N- g" b: ]! H( |! B& i3 i5 Oble to levels obtained with topical testosterone would seem to
' G& l/ [/ k( Uprovide a means to compare the relative effectiveness of3 z0 ~6 _' u# n2 ?6 {. g' ~/ ]
topical testosterone to systemic testosterone effect. It cer-: L3 F) D1 o$ f/ Z* C, B4 G
tainly has been established that gonadotropin as well as par-& q9 ^4 E6 F, Q7 K) I7 m9 x: Z$ U" q
enteral testosterone administration will produce genital4 ]4 l0 E Z- x
growth. Our report shows that the growth of the phallus was
: w1 r$ l) i; X; l6 _" E4 _) \7 V8 gsignificantly greater with topical applications than with go-, i$ d& H' G( b/ F0 w
nadotropin, particularly in children less than 10 years old.
. `; R* ~* U9 F% e2 g. aThe levels of serum testosterone remained similar or lower5 @/ Y" r' `1 [; s
than with gonadotropin during therapy, suggesting that topi-! N; m& u3 w1 P' V3 W6 ~+ U8 S
cal application produces genital growth by its local effect as
. J9 n3 D; {& Y8 Z4 Gwell as its systemic effect.
( \, X t; e4 O2 m; t+ l# oReview of our patients and their growth response related to. S) N1 i( l5 \
age shows a greater growth response at an earlier age. This is
1 ^' ?7 X) e3 J& a' C0 tconsistent with the findings of Wilson and Walker, who
/ S3 \, G' ~, s# Treported an increased conversion of testosterone to dihydrotes-9 x6 P8 B2 [% t9 b) ]
tosterone in the foreskin of neonates and infants.4 This activ-& c- y: j' a7 s5 z
ity gradually decreases with age until puberty when it ap-
! h) l# G* }; B2 J- ~& tproaches the same level of activity as peripheral skin. It may( m6 o: g! v& U; a& f- f& ~ y
well be that absorption of testosterone is less when applied at
; p' ^& O, C9 I4 U7 I3 Qan earlier age as suggested by lower serum levels in children
( F+ @; [7 X( \- J& R Z, Dless than 10 years old. This fact may be explained by the) h$ X h% [! u. K0 L( P
greater ability of phallic skin to convert testosterone to dihy-8 c& D* i3 ^. K$ Z7 T4 X* L
drotestosterone at this age. Conversely, serum levels in older
& h- o$ p; L" [& I5 xpatients were higher, possibly because of decreased local) l& _ u0 r8 v4 X9 j
667
0 m& y) c; y3 F' H" K! M% b5 G668 KLUGO AND CERNY
3 q6 p5 Y- j& Y2 PPt. Age& `# Q; E: O4 C( v$ o7 c1 _
(yrs.)
+ z* E+ K' P) g+ @0 y2 c D7 e5 MSerum Testosterone Phallus (cm.) Change Length
- K1 V2 \5 s6 E(ng./dl.) Girth x Length (%): `4 @$ I% J# s/ c0 T+ g1 k H
4, @# w# w% N0 e- S7 p; w7 t
83 g+ z: s+ ^6 y3 k1 B5 I4 n h/ A
10( {) v* i& Z. [! i2 `5 p. v
12/ E( `* B' x9 s* } E. p
17& Z; T2 B' k" i$ v
Gonadotropin
. x7 I8 ?: W2 Y- C71.6 2.0 X 3 16.6
2 d+ ]' c/ W5 q3 {8 G6 M50.4 4.0 X 5.0 20.0% j+ I$ [+ q8 Z: Z6 G
22.0 4.5 X 4.0 25.0: @: P9 }4 B4 Y7 {4 z) ]
84.6 4.0 X 4.5 11.1) @. d3 u. [) o
85.9 4.5 X 5.5 9.0
; U8 ?* c5 T. [Av. 14.3
\% E4 r) a+ h9 h9 _+ f4' r' p. U/ o# x9 K2 |
8
; e: n# D C( c10+ t2 n. F6 l3 K% o3 {) Q& p
12
* }3 b; m( { q. _3 X2 S2 d17
" X2 `+ ?$ z4 \% r& t, [5 XTopical testosterone
/ X0 y6 j7 i: I& a34.6 4.5 X 6.5 854 H. t$ v5 p1 P
38.8 6.0 X 8.5 70
' ^7 N" c% x( A9 B40.0 6.0 X 6.5 62.5; L- h) M, r u
93.6 6.0 X 7.0 55.5
], Q; m- s- v; B+ d* I95.0 6.5 X 7.0 27.2
% H1 ^. ]+ Y+ Y' H$ p) `Av. 60.0
7 k$ O' H+ j' {$ Y3 E$ f iavailable testosterone. Again, emphasis should be placed on
9 x) N6 m f3 J! H7 w, hearly therapy when lower levels of testosterone appear to
$ h$ I$ w" w' L: Q1 H; a( zprovide the best responses. The earlier therapy is instituted
) r1 p5 } k9 O# I& T: k# p! G+ w9 ?the more likely there will be an excellent response with low
; @. W& y9 S8 e1 N! lserum levels. Response occurs throughout adolescence as% `- [6 ]9 T7 K. d+ W
noted in nomograms of phallic growth. 7 The actual response
4 O& l( y0 h; U" W5 Rto a given serum level of testosterone is much greater at birth; ?2 N. ?& S# [
and gradually decreases as boys reach puberty. This is most
- E9 n8 A+ k8 k& J ^, a: Plikely related to the conversion of testosterone to dihydrotes-/ D% I Q* V5 P
tosterone and correlates well with the studies of testosterone
L P& w! P- C6 K1 J+ Jconversion in foreskin at various ages.
k# F! R# N+ K( @ S3 Y( hThe question arises regarding early treatment as to whether7 t( C2 v0 o: m9 a
one might sacrifice ultimate potential growth as with acceler-- r0 f0 }0 u8 J6 w9 [$ [8 V
ated bone growth. The situation appears quite the reverse
( }, }, p W6 R# H0 t+ Wwith phallic response. If the early growth period is not used
/ h g9 `/ b N# U: Fwhen 5a reductase activity is greatest then potential growth" F, H1 P4 |( f# S
may be lost. We have not observed any regression of growth
1 K- r+ q% E! a: c2 nattained with topical or gonadotropin therapy. It may well
% \/ I2 p$ m& J* g& J9 cbe that some patients will show little or no response to any
! J: ^% `- R$ n* d7 g/ _* zform of therapy. This would suggest a defect in the ability to
" O7 b$ W8 ]( _+ r: P7 n& Dconvert testosterone to dihydrotestosterone and indicate that: H% \1 [" t5 O: g* ?% j4 U
phallic and peripheral skin, and subcutaneous tissue should
8 p7 T2 ]. b4 e/ u7 qbe compared for 5a reductase activity.' J |9 i; t- p% R: P/ i3 v
A, loop enlarges to measure penile girth in millimeters. B,
9 F, l# T7 w$ B2 u+ kexample of penile girth computed easily and accurately.) B' Q0 p' c, h7 Q k6 n. H
conversion of testosterone to dihydrotestosterone. It is in this
2 `# o3 @" o7 d3 x$ ^3 tolder group that others have noted high levels of serum) j1 R+ G$ L y" z+ R
testosterone with topical application. It would also appear
; e& m: Y: v, G* dthat phallic response during puberty is related directly to the i$ p8 p/ a- n
serum testosterone level. There also is other evidence of local# ?% A j g- W
response to testosterone with hair growth and with spermato-
+ \% B+ r) K+ T( Hgenesis. 5• 6& D1 N- s/ A) c
Administration of larger doses of gonadotropin or systemic+ K- s4 d9 h' r8 ~" R
testosterone, as well as topical applications that produce
0 F3 ~9 w! G5 P3 E/ I/ Xhigher levels of serum testosterone (150 to 900 ng./dl.), will5 b/ q% {2 i! l! s. q( A
also produce phallic growth but risks accelerated skeletal
' F2 D, |$ G+ W& O0 u* Ematuration even after stopping treatment. It would appear
, y0 }: ^4 I& f* d( u+ Xthat this may be avoided by topical applications of testosterone# i6 M( Q% W$ L8 I1 S( c7 ?' a
and monitoring of serum testosterone. Even with this control, M# h" e2 V: H C
the duration of our therapy did not exceed 3 weeks at any7 [8 v8 G: H9 I8 y
time. It is apparent that the prepuberal male subject may
/ k, {7 z4 M# @7 S3 osuffer accelerated bone growth with testosterone levels near/ r% y: ~. G \! \% r
200 ng./dl. When skeletal maturation is complete the level of- S, A6 V7 I, s" z
serum testosterone can be maintained in the 700 to 1,300 ng./0 c1 B/ p, g/ W
dl. range to stimulate phallic growth and secondary sexual* ~9 v1 h: w3 G
changes. Therefore, after skeletal maturation parenteral tes-
" [. \* }& Z1 H! q4 x# Wtosterone may be used to advantage. Before skeletal matura-+ h/ i( p1 l2 {3 L3 O u! d/ M
tion care must be taken to avoid maintaining levels of serum
' ?9 m8 a: r( O. K. _1 \3 Gtestosterone more than 100 ng./dl. Low-dose gonadotropin
$ Y4 M( N( m# g. A# r Y) [: V! e! Wdepends upon intrinsic testicular activity and may require
* F8 S o$ L% l1 i yprolonged administration for any response. v+ b4 W$ o0 q# k+ f& V, s
Alternately, topical testosterone does not depend upon tes-) O7 H2 \6 m/ k
ticular function and may provide a more constant level of9 P; Z1 S& I& T* L! d) `2 I+ ?( M
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* z; [, J, R3 h/ P: v1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 ^+ [7 m! ?; \7 S* ^/ x% q
R.: The local application of testosterone cream to the prepub-
! `% W$ L/ S; e: x6 Xertal phallus. J. Urol., 105: 905, 1971.0 z4 G a) b# J% ~: C* d
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
; _1 S9 \5 _( x3 mtreatment for micropenis during early childhood. J. Pediat.,
. @+ o5 F& C: f5 @83: 247, 1973.& l# S! i) P K5 _ V9 B. g
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" v: W: P% f5 s: _one therapy for penile growth. Urology, 6: 708, 1975.
+ }, V, y$ }1 S+ k; a% G/ e4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; X* B9 r, ~1 i( rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by! G' ~: T3 A3 n' T, }) D& E$ r% U
skin slices of man. J. Clin. Invest., 48: 371, 1969.+ J, @4 S* \8 y6 Z8 Z" M) L8 A" Q
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
% Z8 K8 {' I0 Xby topical application of androgens. J.A.M.A., 191: 521, 1965.
! ^ m8 e4 y7 p3 a, B6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! k& P1 O+ a* k* K9 r- H1 y" landrogenic effect of interstitial cell tumor of the testis. J.
' l' e/ Y, E) {7 ]$ h. MUrol., 104: 774, 1970.. Z2 G# D& Z r2 `7 W
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia- k6 m' w8 [5 g, \, y, n; [
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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