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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# Q9 h% l# {- z& e& ]
GONADOTROPIN2 ]* {3 p; E( h; t ?- _% x1 D
RICHARD C. KLUGO* AND JOSEPH C. CERNY8 Y% }7 i6 e1 E, i, \
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# }# z, K( {4 x/ p3 w* fABSTRACT- H$ O |" i9 B
Five patients were treated with gonadotropin and topical testosterone for micropenis associated+ t' B1 r2 |$ D4 n; i3 e3 M ]
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. U8 l4 N0 G& Ftropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! C" R1 n+ q7 J. O. ?1 ycream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 D+ P& B/ B9 K: ?
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent6 G5 L6 K3 l) B( L- g( e- t( O
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% w# a1 ^# j# L2 x/ a! n. l+ O+ {increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
) W' h0 m$ I! K7 V9 I) b n; boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
* J, T0 C/ X5 \4 A& Ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile# |% f- d! d: `7 Q ~% R M) p
growth. The response appears to be greater in younger children, which is consistent with previ-# e% u" C2 w2 R( W) Y
ously published studies of age-related 5 reductase activity.$ {+ k6 e; e2 V* H' ^/ J
Children with microphallus regardless of its etiology will
8 B' j# s- S0 A+ O$ ^require augmentation or consideration for alteration of exter-
l- r' p# T: W1 x3 |3 M& s. Tnal genitalia. In many instances urethroplasty for hypo-
) f/ ^" V7 f( Qspadias is easier with previous stimulation of phallic growth.% {' i0 H m; Z/ i
The use of testosterone administered parenterally or topically
" ?* K* N, d' V% Mhas produced effective phallic growth. 1- 3 The mechanism of
/ R, m" F; w* O$ ]# Vresponse has been considered as local or systemic. With this" H, q" {: f* P1 Z c
in mind we studied 5 children with microphallus for response
& w/ L& ?( w* Y1 d' r( bto gonadotropin and to topical testosterone independently.
2 x i! \8 @$ t7 M" t& T3 O$ vMATERIALS AND METHODS
3 j/ J* i D5 r* ], Z z1 pFive 46 XY male subjects between 3 and 17 years old were
{& v" i1 H, J" ~, ]$ devaluated for serum testosterone levels and hypothalamic9 R: ~/ e6 D+ S: T! V% ^1 u8 M5 @
function. Of these 5 boys 2 were considered to have Kallmann's- Z; J4 n" }5 P, G' n! B
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
y$ v# l# I3 n$ z; B( Flamic deficiency. After evaluation of response to luteinizing
% [9 l R9 d, P& t* l+ p: `hormone-releasing hormone these patients were treated with
9 G. ?8 M4 n. A8 M% B2 ^8 D1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 p4 _3 [$ [2 |' E/ q& B
after completion of gonadotropin therapy 10 per cent topical! E1 i3 h( J8 v" b1 c1 M
testosterone was applied to the phallus twice daily for 3 weeks.
% W5 F, a: V# xSerum testosterone, luteinizing hormone and follicle-stimulat-( V6 z4 J0 A1 C4 u+ [
ing hormone were monitored before, during and after comple-
+ Y! u2 E5 b9 ] |: Y" Z9 M5 ntion of each phase of therapy. Penile stretch length was/ ~ i9 ^( s: H% Q- N
obtained by measuring from the symphysis pubis to the tip of* x1 e! i8 a) [+ ?0 d7 |# ~
the glans. Penile circumferential (girth) measurements were
9 _- o& l' p: R1 N: c" @# W" Oobtained using an orthopedic digital measuring device (see8 ~- ~) c) X, |: S1 t" R$ @ c
figure).
7 T% r9 D6 F. T# iRESULTS' l# t+ f8 \& z2 R: H( h8 q
Serum testosterone increased moderately to levels between) x" e. h0 D0 _/ y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 Z1 ?2 y3 u2 D# T( cterone levels with topical testosterone remained near pre-+ D6 \) P' B. n! l
treatment levels (35 ng./dl.) or were elevated to similar levels7 i9 O$ q) g- `+ [$ L/ Y+ H0 H/ C3 I- s
developed after gonadotropin therapy (96 ng./dl.). Higher
/ l/ a8 B( k3 a4 A1 V+ S3 f4 [ Zserum levels were noted in older patients (12 and 17 years old),& g* W9 D7 ?/ V& Y
while lower levels persisted in younger patients (4, 8, and 10
& e5 M: G/ s$ Q0 \! Q$ T+ }( o8 Ryears old) (see table). Despite absence of profound alterations: s. t/ H& q# V: D( `1 ?
of serum testosterone the topical therapy provided a greater
, R+ |- U9 w* I( `+ }) gAccepted for publication July 1, 1977. ·
9 x r9 s/ |/ A( dRead at annual meeting of American Urological Association,2 c6 f: b, P6 }0 I
Chicago, Illinois, April 24-28, 1977.
6 d; R* v& ]/ t: w$ ?* Requests for reprints: Division of Urology, Henry Ford Hospital,$ p9 q1 D# P3 W6 f% s0 J' r
2799 W. Grand Blvd., Detroit, Michigan 48202.
% X) Q1 h. I; E$ Mimprovement in phallic growth compared to gonadotropin.% [! r9 A9 O! B. [& S6 `) \1 |; @/ p
Average phallic growth with gonadotropin was 14.3 per cent
7 w/ H1 [7 h6 @1 rincrease in length and 5.0 per cent increase of girth. Topical2 N0 X, z4 V0 K* ]- z& _& m
testosterone produced a 60.0 per cent increase of phallic length
; K/ @1 n' _9 B/ Eand 52.9 per cent increase of girth (circumference). The
: L M# ^. Z# R1 Lresponse to topical testosterone was greatest in children be-
% x( Y; W L; y1 e, Ltween 4 and 8 years old, with a gradual decrease to age 17
% i! B2 \- ?+ g& D1 D- i8 B* Eyears (see table).
M/ E9 l$ p0 X+ s }9 V T+ xDISCUSSION8 B3 D; h# a$ B4 o1 Z5 Y% j
Topical testosterone has been used effectively by other
$ k$ s7 r) h3 |2 }' v- s5 o Tclinicians but its mode of action remains controversial. Im-$ v0 D8 b% w- Z! O$ d V
mergut and associates reported an excellent growth response
9 |5 O$ U/ M+ D3 \. O# b% nto topical testosterone with low levels of serum testosterone,
0 Q4 W0 U0 v* W+ Usuggesting a local effect.1 Others have obtained growth re-
1 ?3 h; Z& l" v# v9 o/ W8 P$ Xsponse with high. levels of serum testosterone after topical
, J* D' e! F& I5 ~% D& \administration, suggesting a systemic response. 3 The use of! ^) n5 X9 k* l, O+ \ M$ i
gonadotropin to obtain levels of serum testosterone compara-7 b) Z% T% W% B+ {$ u- I6 {! e
ble to levels obtained with topical testosterone would seem to
. p1 Q6 ?; @ gprovide a means to compare the relative effectiveness of& _- d; {5 D7 U n6 f8 N5 d% c2 r
topical testosterone to systemic testosterone effect. It cer-
2 q! ~0 ?$ y/ u7 t" Gtainly has been established that gonadotropin as well as par-+ D; O/ ~4 }! C7 e* A$ W
enteral testosterone administration will produce genital
& I% ]; L+ L( a4 Q" I8 h' a: y# kgrowth. Our report shows that the growth of the phallus was
! s$ O, Z1 g! u4 |significantly greater with topical applications than with go-
! |- U- H4 @- D0 _# g' Y0 ^8 R: ]& Hnadotropin, particularly in children less than 10 years old.: T e1 _/ _2 P1 ?8 L& T( ?' q9 b
The levels of serum testosterone remained similar or lower
/ U: s) g) _6 q& K1 w% Ethan with gonadotropin during therapy, suggesting that topi-5 D ^0 H/ @; w: x
cal application produces genital growth by its local effect as: |# @0 e2 z$ W, [6 V' C
well as its systemic effect. {6 b4 Y* D5 n9 ^
Review of our patients and their growth response related to
+ o0 x2 x+ g; Q; g8 Zage shows a greater growth response at an earlier age. This is
) N0 e% c. }7 r/ R" @consistent with the findings of Wilson and Walker, who
/ X( E1 {, `3 R+ L5 w7 d, K) @( X4 Oreported an increased conversion of testosterone to dihydrotes-
" M9 e4 `7 i& F1 K3 O- dtosterone in the foreskin of neonates and infants.4 This activ-1 |1 R& v4 \0 c0 r! |
ity gradually decreases with age until puberty when it ap-
3 w) @! q: G. t4 Q/ g8 \proaches the same level of activity as peripheral skin. It may
" P3 ^: p. ?& i: a4 |well be that absorption of testosterone is less when applied at
% H6 v9 t% c% V2 oan earlier age as suggested by lower serum levels in children
9 S( p5 |" F* }0 j# G* Oless than 10 years old. This fact may be explained by the8 ?$ M- ^3 D, X) s1 `( Q8 |% l, u" V5 P
greater ability of phallic skin to convert testosterone to dihy-
5 g6 |8 r# m1 t' p1 wdrotestosterone at this age. Conversely, serum levels in older1 o$ L E* Q0 v% P4 v! n
patients were higher, possibly because of decreased local
; G' H) r% {- ?& D( [667
q1 V+ X4 D' m, [668 KLUGO AND CERNY
8 A2 ^9 d" s) c3 X* E9 Z/ {Pt. Age
8 W6 z0 c. d. _8 K' z0 `(yrs.)
6 |; U* |; s9 y. ^' jSerum Testosterone Phallus (cm.) Change Length6 N; u2 |7 p9 D- [
(ng./dl.) Girth x Length (%)$ _8 Q; H0 F0 B- l' ?9 [ Y
4+ t. z- r/ f: ?1 U S8 S6 y8 d
8
' q. }2 D% |) O. G$ N0 d* k10
" }. j" Q4 \1 J' t' N4 Y- F2 U9 \! x2 {12: X( g& {* m% E8 b( f% m/ d" V
17+ [# A8 Y# D* i6 n% n
Gonadotropin
9 |1 h6 u h1 g; h71.6 2.0 X 3 16.6
* ~3 Z c: C- F! C50.4 4.0 X 5.0 20.0& K; X p8 S! v
22.0 4.5 X 4.0 25.0 i2 C- v6 Q4 O% X
84.6 4.0 X 4.5 11.1& u: ]- }( n" B
85.9 4.5 X 5.5 9.0
. u1 f& f8 y; C+ D3 w6 Y8 HAv. 14.3% A0 i; ?+ c7 a- E1 D" |- u
4
5 I6 ]: n) |4 J% |8# _2 D4 Q7 o8 W/ N k
10- T, |+ H/ V8 Z& D' K7 `! Z
124 e3 k: h+ o( h* l% {( a
17
7 l# U& i8 J$ J/ M0 H5 \ UTopical testosterone
\( Z3 I0 a! y: [: |34.6 4.5 X 6.5 85
K( E. H! x8 F38.8 6.0 X 8.5 70
, x5 O- ?6 {+ E$ ]8 ^8 G! ?40.0 6.0 X 6.5 62.5
- }! ?4 W+ ]: d93.6 6.0 X 7.0 55.5
+ G# u+ ?0 D. e L, e& S% T8 W95.0 6.5 X 7.0 27.2
% k. H0 B5 g5 \4 \$ D9 eAv. 60.0
- R8 Z1 A! H3 M3 E5 Tavailable testosterone. Again, emphasis should be placed on9 ]6 q" U( J% F9 W! G+ U
early therapy when lower levels of testosterone appear to ]+ x/ y; u5 S8 X4 _% R9 w# j
provide the best responses. The earlier therapy is instituted- F/ i2 E2 |: |3 w
the more likely there will be an excellent response with low" C8 U1 g- r) ]" R. N6 Q
serum levels. Response occurs throughout adolescence as9 z% V2 n0 `& w7 b6 d- |
noted in nomograms of phallic growth. 7 The actual response6 q$ L ]# _; \; y2 d4 \4 j
to a given serum level of testosterone is much greater at birth$ q2 o' M, T5 [+ E7 ]( D, W9 P
and gradually decreases as boys reach puberty. This is most' x( e* x3 ?2 d2 f: k! W W$ R
likely related to the conversion of testosterone to dihydrotes-7 t2 E- y* [/ v$ R1 s
tosterone and correlates well with the studies of testosterone/ b0 a. v3 `- h( U& W
conversion in foreskin at various ages." }, H0 Z( h7 m- h2 r; d: W5 x
The question arises regarding early treatment as to whether% N3 O; P$ b4 s( E
one might sacrifice ultimate potential growth as with acceler-
1 ~; Q. b; w" Fated bone growth. The situation appears quite the reverse3 I% |/ k7 b: s1 W/ q# T$ v
with phallic response. If the early growth period is not used2 i1 s! N' P( [4 F! z7 H
when 5a reductase activity is greatest then potential growth J. @/ n- c5 }" y( f1 l
may be lost. We have not observed any regression of growth
+ q1 O9 ]) ]: b$ Y3 k2 p nattained with topical or gonadotropin therapy. It may well6 i9 C0 B, t3 K' Y2 M( U( G% l
be that some patients will show little or no response to any
* o3 j: A/ G" Z, [! N7 u* vform of therapy. This would suggest a defect in the ability to* k4 a- ]. z, M6 J5 b f
convert testosterone to dihydrotestosterone and indicate that: \9 J+ |% U1 j7 N. E9 ~
phallic and peripheral skin, and subcutaneous tissue should
! l) R0 u% ?$ Qbe compared for 5a reductase activity.
6 u) \& K0 n5 x; x3 M1 |. FA, loop enlarges to measure penile girth in millimeters. B,/ G* @6 m7 j- _! N( G2 Z S
example of penile girth computed easily and accurately.6 h8 G- I' W- |( `
conversion of testosterone to dihydrotestosterone. It is in this
; U0 @- J4 W- ~# Jolder group that others have noted high levels of serum$ H: e8 E6 p9 Q i% q: O! C: Y
testosterone with topical application. It would also appear( y* A' w+ t0 v4 [. O4 H6 O
that phallic response during puberty is related directly to the. ?2 u) V, G3 X5 _) [$ O' p3 K+ x
serum testosterone level. There also is other evidence of local
; v2 X& _, ?) J& x, ~response to testosterone with hair growth and with spermato-
+ j5 N, [; x, e7 E. F/ k; pgenesis. 5• 6
& v5 p% O0 b# Q" }" V1 h/ D5 GAdministration of larger doses of gonadotropin or systemic
9 Y4 c$ w3 a8 ~7 j ]2 ?testosterone, as well as topical applications that produce# M" ?- P2 g( l; ?7 d5 @7 q
higher levels of serum testosterone (150 to 900 ng./dl.), will
' k. I4 D B) ]" Z$ Lalso produce phallic growth but risks accelerated skeletal5 s, |8 r2 B7 @3 p) E9 B, i5 g/ B
maturation even after stopping treatment. It would appear; z# t' c% @" O- h7 W
that this may be avoided by topical applications of testosterone s' U, W: J3 u+ A4 n
and monitoring of serum testosterone. Even with this control" W+ v# W. T' k E1 r( R
the duration of our therapy did not exceed 3 weeks at any/ y5 Q1 w" {6 P h' Y
time. It is apparent that the prepuberal male subject may
+ `6 U% _# t& bsuffer accelerated bone growth with testosterone levels near F* m5 H O$ \$ h. a+ m7 n
200 ng./dl. When skeletal maturation is complete the level of4 i6 r/ e5 [) a# `5 K/ C
serum testosterone can be maintained in the 700 to 1,300 ng./
0 t6 B1 l# @$ p4 q4 i9 I8 ]& A qdl. range to stimulate phallic growth and secondary sexual! s+ Z5 E k( C3 r- G
changes. Therefore, after skeletal maturation parenteral tes-
4 u- C+ E W% O8 c& x+ Q2 J' itosterone may be used to advantage. Before skeletal matura-
5 Y6 j4 U2 @& g. d$ }* d2 ztion care must be taken to avoid maintaining levels of serum% V/ O& X) w# O. M: c q+ U6 i. U' r
testosterone more than 100 ng./dl. Low-dose gonadotropin( B- k x* Z$ Z' ]" t1 q
depends upon intrinsic testicular activity and may require
7 Q# t. E5 a" U: l+ U4 g4 Sprolonged administration for any response.
0 K4 l8 E+ X. a( \3 L1 cAlternately, topical testosterone does not depend upon tes-0 [ B2 }. @, o% Q* Z9 l+ R
ticular function and may provide a more constant level of
1 G. N3 ^$ y3 U0 Y# KREFERENCES
* k6 z' o$ f1 I. R9 P1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- D% G( |& J* L4 Y/ p
R.: The local application of testosterone cream to the prepub-
- q7 X2 u( i: Z/ |# z4 |9 Certal phallus. J. Urol., 105: 905, 1971.1 w: `5 d& X& O9 Q. k( L+ e
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 ?$ ]) n4 v$ d* W
treatment for micropenis during early childhood. J. Pediat.,
8 U, M$ }8 U: S U |8 q2 h& C) M% t83: 247, 1973.$ v; ^0 J% {% I4 o0 a
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-$ U2 O, _$ m5 W0 w
one therapy for penile growth. Urology, 6: 708, 1975.7 B, {7 j. y C4 Y
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
6 _5 B z) w r/ Vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, u( [6 m& f9 D4 g0 K* f5 w
skin slices of man. J. Clin. Invest., 48: 371, 1969.) f( T& Q3 m5 ~+ A
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 M8 m% o1 C$ Sby topical application of androgens. J.A.M.A., 191: 521, 1965.
. O2 \3 ~; b5 k2 D5 M% K6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
" h P; ?: ~9 F2 b+ C! T9 tandrogenic effect of interstitial cell tumor of the testis. J.8 ?7 ]5 M. w$ C6 Y3 j+ f
Urol., 104: 774, 1970.6 i- ^+ P# S7 m7 ~3 }5 a1 v6 ]
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ _6 O* \; k6 w! ^# w2 v0 U5 x
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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