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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND6 ]6 A* B0 V6 n; W" _! g. L
GONADOTROPIN9 {7 Q$ J2 m* R5 |; b2 ~! s
RICHARD C. KLUGO* AND JOSEPH C. CERNY' v% b. @# x6 i1 k, x
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 U3 \0 B0 H G. H- U0 w3 f( `
ABSTRACT: R7 g* G7 w: m
Five patients were treated with gonadotropin and topical testosterone for micropenis associated) }& D ^) W* c5 j/ F( Y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-# N6 z9 G" W- r0 ^
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 M A' z/ o$ l: A9 V3 D4 B. G1 G
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 d- j6 g4 O6 K w3 F5 v) bfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
# _0 z: ]; F7 v; _- Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 N+ i# K: x$ @5 _( J; C$ H, O2 }
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response0 V3 |' P2 ^* ?! E1 D
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 D4 _; j4 B7 q, |4 ?8 P: {study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile: v$ e {- @# q" d3 ]1 H
growth. The response appears to be greater in younger children, which is consistent with previ-
& b' _ G1 [+ x8 Z8 `& _ously published studies of age-related 5 reductase activity.
+ [' t n7 l8 G1 p2 K% {Children with microphallus regardless of its etiology will6 O5 @! M8 d4 x4 h: W9 l/ X
require augmentation or consideration for alteration of exter-5 y. v1 a' f6 {% ~
nal genitalia. In many instances urethroplasty for hypo-: p/ p I$ B5 w7 `, Y0 z2 {( \+ _; S
spadias is easier with previous stimulation of phallic growth.
1 d6 B) F Z+ A* TThe use of testosterone administered parenterally or topically6 ~( P# u. ^# y( `" l3 X* F
has produced effective phallic growth. 1- 3 The mechanism of3 b6 m- `' S: G1 l' ^8 N" g, z! {
response has been considered as local or systemic. With this
. J* [+ k5 O0 S: J) e$ \' Ein mind we studied 5 children with microphallus for response1 e7 k$ ]) E; W
to gonadotropin and to topical testosterone independently.) J0 Q: o0 x) X' ]4 Z t$ e
MATERIALS AND METHODS( ?# o! u6 F- E: n* _
Five 46 XY male subjects between 3 and 17 years old were
4 K1 I- C# c/ c5 mevaluated for serum testosterone levels and hypothalamic G K, G! Y8 g9 h' P+ H# e s; V: j
function. Of these 5 boys 2 were considered to have Kallmann's* A K. t$ d" K1 _. H# v# d- U
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 `0 K3 r; e! F! N5 _! e
lamic deficiency. After evaluation of response to luteinizing$ p0 N: n" D* q! ^0 M9 C% H. d4 U# h
hormone-releasing hormone these patients were treated with
& t0 U2 Q# V+ f, Z1,000 units of gonadotropin weekly for 3 weeks. Six weeks
7 E n4 k# e9 b7 F+ S1 \5 b2 Dafter completion of gonadotropin therapy 10 per cent topical/ ~; v; Y$ W3 N% Q' x* y3 h
testosterone was applied to the phallus twice daily for 3 weeks.
$ I8 a9 r+ I o- vSerum testosterone, luteinizing hormone and follicle-stimulat-( W) {5 U# s. j# v7 x$ r* O
ing hormone were monitored before, during and after comple-; Z$ O( u/ J6 i# M0 `% G1 N
tion of each phase of therapy. Penile stretch length was9 p+ A8 Z+ y1 S0 G* Q; S
obtained by measuring from the symphysis pubis to the tip of& J3 [3 u( H( f0 T; `
the glans. Penile circumferential (girth) measurements were! l9 s2 o& p& }) j2 K+ _& ^, F, @
obtained using an orthopedic digital measuring device (see
4 b' T* P3 @) R, _figure).
% Z- U9 x( n- r& qRESULTS
; S4 X' z- R/ z4 h- g5 a/ ~( XSerum testosterone increased moderately to levels between
3 {( C4 }0 B p8 K% ?, u50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
z! {( y" K( f9 r0 g6 r4 L" Tterone levels with topical testosterone remained near pre-
, L/ q- l: ~9 G, c: V- ctreatment levels (35 ng./dl.) or were elevated to similar levels3 }+ _% D1 X. e# r s0 u
developed after gonadotropin therapy (96 ng./dl.). Higher6 ]9 w2 W8 n; k0 U+ F4 v! h. P
serum levels were noted in older patients (12 and 17 years old),
% ?% g# K u$ h6 W- r8 \, M+ h8 Cwhile lower levels persisted in younger patients (4, 8, and 10
; Z$ P8 |" Z q/ a# }9 }; z: _years old) (see table). Despite absence of profound alterations5 k0 |0 p, y) B1 F2 F3 b
of serum testosterone the topical therapy provided a greater
4 K. l% o7 u9 H7 t$ K9 lAccepted for publication July 1, 1977. ·* v) L( v; \2 m6 q* O
Read at annual meeting of American Urological Association,3 n. G; U1 P9 e- {6 v5 ?
Chicago, Illinois, April 24-28, 1977.. i! O3 j2 h5 o i
* Requests for reprints: Division of Urology, Henry Ford Hospital,8 B2 A' K. ]$ n# P
2799 W. Grand Blvd., Detroit, Michigan 48202.% Q5 ]# V( p) h+ W7 @
improvement in phallic growth compared to gonadotropin.
( M3 u. B$ x2 c" @# r3 V: xAverage phallic growth with gonadotropin was 14.3 per cent) K; O4 h% W+ j' \. z0 c& M
increase in length and 5.0 per cent increase of girth. Topical
^) C7 l4 G; P7 c0 {testosterone produced a 60.0 per cent increase of phallic length
5 M+ _4 G/ y$ c6 k1 fand 52.9 per cent increase of girth (circumference). The9 u3 @, l h5 s8 o
response to topical testosterone was greatest in children be-; _( D- Q1 p( v+ C) y
tween 4 and 8 years old, with a gradual decrease to age 17* `! d6 t, x2 y) b4 s" ?) F( s( L* W! W
years (see table)., ]7 E- H0 y+ P( H: P$ }
DISCUSSION/ E7 k6 f j/ y+ X% r
Topical testosterone has been used effectively by other
/ E, u5 l* n& Kclinicians but its mode of action remains controversial. Im-
8 N% k0 g5 l0 g! K4 E0 m* J* @9 Ymergut and associates reported an excellent growth response; L3 O3 H5 J5 Q8 h" n% M3 l
to topical testosterone with low levels of serum testosterone,; b2 f+ s) d% t+ [( L+ Z9 I
suggesting a local effect.1 Others have obtained growth re-
! w c: N( r+ o1 z" Wsponse with high. levels of serum testosterone after topical) ~ ?( L- Z0 H5 F
administration, suggesting a systemic response. 3 The use of8 Q! E. L# q# Z. @+ ^
gonadotropin to obtain levels of serum testosterone compara-" X! L2 }" n/ z% z4 R
ble to levels obtained with topical testosterone would seem to, `% N* f" o# I0 d8 C' M
provide a means to compare the relative effectiveness of
! P+ {% w1 ?& S" H# Y- h0 ^topical testosterone to systemic testosterone effect. It cer-
7 T h9 J7 C. xtainly has been established that gonadotropin as well as par-, v- H/ w; s: d/ B2 r
enteral testosterone administration will produce genital8 p i, a! g' O( \) ^4 f
growth. Our report shows that the growth of the phallus was
2 t7 U# F3 i( Z2 e0 A2 ^significantly greater with topical applications than with go-
& I& P2 c1 I. ^* ~; B" L5 ~- @nadotropin, particularly in children less than 10 years old.% x0 B) u7 S! ^2 {$ t/ t/ l
The levels of serum testosterone remained similar or lower
, z( |2 E, [1 g, @; r# Tthan with gonadotropin during therapy, suggesting that topi-
I0 G2 T" Y& |, v! @cal application produces genital growth by its local effect as
! [. k% J) D$ q! {; A( K$ r' W/ Zwell as its systemic effect.
`6 f! p6 u8 U3 }0 C: ^/ s0 JReview of our patients and their growth response related to ?2 T. T3 B. i. u e0 d
age shows a greater growth response at an earlier age. This is- h0 F- X0 d+ I/ ~) L# Z
consistent with the findings of Wilson and Walker, who6 n) v8 f" F# ^- I% z
reported an increased conversion of testosterone to dihydrotes-
# a, \' b! K& O. C! Ltosterone in the foreskin of neonates and infants.4 This activ-6 u% \4 B; o4 o3 j+ X0 V1 J
ity gradually decreases with age until puberty when it ap-
: b4 ]; b7 x$ iproaches the same level of activity as peripheral skin. It may7 E7 Q. [& C4 f' ?/ M S
well be that absorption of testosterone is less when applied at$ E2 i4 W' T" l& ?, v
an earlier age as suggested by lower serum levels in children
( ^0 G) t) n4 v9 |% f) hless than 10 years old. This fact may be explained by the- K) m! t+ T. \ j- R2 Y
greater ability of phallic skin to convert testosterone to dihy-' O% ]; e v+ x0 f# o
drotestosterone at this age. Conversely, serum levels in older
2 Z, J0 U; u2 W* |4 Ppatients were higher, possibly because of decreased local
, U2 o) X9 s( F5 z% q0 J1 f' @667 u5 l% g* d8 m f, r; `. y
668 KLUGO AND CERNY
3 r) M& M: R8 R/ tPt. Age
3 J4 i! [0 r5 r6 I [ r) p(yrs.)9 q7 L$ q9 Z- N, r p0 b. `7 y
Serum Testosterone Phallus (cm.) Change Length" H2 h2 B" r& d( b+ t- S" V3 `- |
(ng./dl.) Girth x Length (%)
) ^, d1 K) G& m8 J4/ D1 \7 W0 y8 C% j! G3 m5 _
8
% Q- b) ]( B5 m7 j6 \10
9 r1 j9 y3 w Q12
; L' e0 G; K3 \: D- g17
! D# Y5 ]9 ?/ ]" E2 {0 DGonadotropin- r5 E$ c" T* S% n/ G/ x2 ? ?
71.6 2.0 X 3 16.6
6 J& [" e: g8 h6 a7 b50.4 4.0 X 5.0 20.03 C$ h6 a) @4 c! Z) q* Q
22.0 4.5 X 4.0 25.0, A* p/ ~: P& D, ?5 d0 s2 R9 [% v
84.6 4.0 X 4.5 11.1
+ P/ E! r& X2 _' I& o5 ?85.9 4.5 X 5.5 9.0
" F8 M& B z6 R& l- A }. o* yAv. 14.3
, q# x2 b. K+ k. I6 R7 l4& Z- v# x: P; W( J' a, @( K. b
8
5 E: l7 H6 M' o% U, t" A, a10
; R9 ~. a; f6 e, e12
- q" Q$ h0 \7 R2 {: W4 ]! C; O17+ O( |' {" V* Q* V5 L. ~
Topical testosterone
( v. ^( F. M, i' d4 y' J34.6 4.5 X 6.5 85
2 I- }5 V) q/ a4 ^1 A" M5 H/ y38.8 6.0 X 8.5 70
* G( u0 S2 k; k$ C* u40.0 6.0 X 6.5 62.5/ q" P6 d9 u( n" _$ [
93.6 6.0 X 7.0 55.5
7 m* Z+ ]3 W3 n& q$ Z4 A$ O$ c3 \95.0 6.5 X 7.0 27.22 E% T; o2 C! G
Av. 60.07 p- s* N5 p: S
available testosterone. Again, emphasis should be placed on& X n; v) S+ v0 x. h
early therapy when lower levels of testosterone appear to
: e7 K9 t* Y0 jprovide the best responses. The earlier therapy is instituted
) D2 Z7 n! o8 v9 s" _the more likely there will be an excellent response with low: [6 d9 O. ]! N, B" A3 K
serum levels. Response occurs throughout adolescence as3 M0 u+ m( g: S, z" i6 N
noted in nomograms of phallic growth. 7 The actual response) w7 i: h# a/ y# ?" J1 O2 v& s
to a given serum level of testosterone is much greater at birth' O, a6 x7 J+ [7 e/ l v5 y8 h
and gradually decreases as boys reach puberty. This is most
( X3 B7 O8 @, \, Y! \( ^likely related to the conversion of testosterone to dihydrotes-$ r y( [$ N( j
tosterone and correlates well with the studies of testosterone
. S3 _4 M- o8 n9 Iconversion in foreskin at various ages.9 L- m) Y: i! d! o7 h$ H
The question arises regarding early treatment as to whether
9 t1 F( S8 Z; X; S5 @' L& T( D( C: G2 kone might sacrifice ultimate potential growth as with acceler-- A( G* q% i8 X# i6 X- T# C
ated bone growth. The situation appears quite the reverse- c/ b9 b& w/ k: d6 Z/ M7 n! ?
with phallic response. If the early growth period is not used) a X/ k% \* ~
when 5a reductase activity is greatest then potential growth; R" w4 y; {9 ^* H0 P9 G0 C
may be lost. We have not observed any regression of growth/ ]) A, n2 A$ b7 \% ?0 ]+ ]
attained with topical or gonadotropin therapy. It may well0 p* T" r" }) J( W; r2 E
be that some patients will show little or no response to any( c6 U" R8 b8 I. y$ s
form of therapy. This would suggest a defect in the ability to; l, H& G3 G# P+ Q: Y
convert testosterone to dihydrotestosterone and indicate that
. d3 R& U; I0 `# H5 ]phallic and peripheral skin, and subcutaneous tissue should- P$ M+ ]) A9 n" }) c( h* C& C
be compared for 5a reductase activity.0 n x1 K7 F$ W# J' D
A, loop enlarges to measure penile girth in millimeters. B,! }% u* d5 J: J4 F" h
example of penile girth computed easily and accurately.) R, L; x! i/ y! F6 |1 r& q! s' x
conversion of testosterone to dihydrotestosterone. It is in this
1 |9 C8 W4 L0 T' bolder group that others have noted high levels of serum
9 _9 n3 H+ `, D- j6 @6 ` {testosterone with topical application. It would also appear/ j' D6 {, f! s# i( Q4 y. h
that phallic response during puberty is related directly to the
D) |0 E8 m7 A0 s$ }$ f* m+ t/ Mserum testosterone level. There also is other evidence of local& h5 l* M$ @& i) ~$ P
response to testosterone with hair growth and with spermato-
# h9 ~! c+ N: Y+ egenesis. 5• 6/ q' d4 @+ [; g2 @( O
Administration of larger doses of gonadotropin or systemic- k; [7 |* J/ e f" k" q- _" V8 ]: e
testosterone, as well as topical applications that produce
X- m5 z3 T% r1 K1 xhigher levels of serum testosterone (150 to 900 ng./dl.), will
% l# Y9 H! u; C) z2 L' ^, Z6 {' Falso produce phallic growth but risks accelerated skeletal$ T" s1 e( T+ X0 |! I
maturation even after stopping treatment. It would appear
4 @7 F, S* P L# p2 V5 V1 a) Vthat this may be avoided by topical applications of testosterone
% b* X# ]% H( i4 G. band monitoring of serum testosterone. Even with this control
: V, t- e& u' {: ethe duration of our therapy did not exceed 3 weeks at any
. `# _# b( n8 x' t. Ktime. It is apparent that the prepuberal male subject may0 D! R1 }& h# ?. i' |. [: X+ X
suffer accelerated bone growth with testosterone levels near
8 [ o* U: X' H' V3 |) _" {! L/ a" D200 ng./dl. When skeletal maturation is complete the level of
$ F5 h! ?- m. Z& N+ C6 g3 Yserum testosterone can be maintained in the 700 to 1,300 ng./6 o0 Q8 A$ V0 L
dl. range to stimulate phallic growth and secondary sexual
$ E8 i6 j) ^% N2 I) q) ~* Nchanges. Therefore, after skeletal maturation parenteral tes-
: L% I0 q1 e; L0 itosterone may be used to advantage. Before skeletal matura-# O4 h- C% |1 M0 k; b: p2 M' S
tion care must be taken to avoid maintaining levels of serum! p1 j. A0 ~+ A8 o5 f3 {
testosterone more than 100 ng./dl. Low-dose gonadotropin
$ S& x' N. J: \& E& m2 D/ K( Ddepends upon intrinsic testicular activity and may require% n. I. b' j, H/ q# M' j( L, z* u
prolonged administration for any response.! w ]1 c$ W& N
Alternately, topical testosterone does not depend upon tes-
$ }% @2 D$ ^, e& F) Jticular function and may provide a more constant level of1 V" d# \2 w* G, w/ ^
REFERENCES
5 L/ J8 d' A' }% m c6 f( Y) b, \1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# J8 y& b% K4 F' ~" L y
R.: The local application of testosterone cream to the prepub-3 ^, ~) _4 M3 i4 e
ertal phallus. J. Urol., 105: 905, 1971.1 j8 _% |1 h A! |( C
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
d r7 U; T) G- ntreatment for micropenis during early childhood. J. Pediat.,
$ S0 P: ~; c% Y/ R83: 247, 1973.
# v# g7 w4 U& u y% ?8 u3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ |/ m e0 v8 ~one therapy for penile growth. Urology, 6: 708, 1975.. h& a# X- E( z- l! R
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone; T: z! W( \: f5 w3 f
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by1 s1 F9 ^2 r7 j* R$ g4 f6 ~9 I
skin slices of man. J. Clin. Invest., 48: 371, 1969., h5 {! X, q8 @$ T2 q: ^
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, _! D! A" g9 R5 qby topical application of androgens. J.A.M.A., 191: 521, 1965.1 ]' N: t8 V1 C# Z X. \) b5 o
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 A( a4 h U1 ?1 h6 vandrogenic effect of interstitial cell tumor of the testis. J.& c' h! z/ X$ j% i0 m! z" C- ~
Urol., 104: 774, 1970.
. B) `) ~, @6 O1 R7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-3 ?1 b! P U$ d
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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