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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND [( r+ u. m$ B4 _/ I* U6 F. R
GONADOTROPIN& W. ~# i9 P! o% D0 W
RICHARD C. KLUGO* AND JOSEPH C. CERNY. C- l4 a7 R' A" {
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% K. c+ g/ X2 y9 o3 B6 D# F$ v( \: v1 k! SABSTRACT
0 |$ N8 i# `/ S1 [# h% S. O, PFive patients were treated with gonadotropin and topical testosterone for micropenis associated
) J# f% I7 d6 b8 W$ {with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-8 n* d+ K1 U, y9 _; k: g' V3 @
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' ]# B0 ]7 X' C( t6 f4 b5 S
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' x5 |4 \9 D% j n8 v; `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) l8 x0 { B5 ~3 Z
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average" Q( R; b3 m, _0 z/ `
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response* z7 M4 a) J9 I' W ~! s6 U$ [
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This+ k* n$ p2 d, Z1 m" I) ^5 o
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 {& K* e6 N2 o2 hgrowth. The response appears to be greater in younger children, which is consistent with previ-
" b# R! R! g$ N1 e# ~ously published studies of age-related 5 reductase activity.
+ U+ C1 C. \; q! Q$ [Children with microphallus regardless of its etiology will
, j5 s% k$ J8 V& U z. y9 ^require augmentation or consideration for alteration of exter-1 n# d* o( Q) h
nal genitalia. In many instances urethroplasty for hypo-
: E( e; \6 W4 q' ?: t5 jspadias is easier with previous stimulation of phallic growth.. A% B! B5 ^: t U9 v6 ]/ ?
The use of testosterone administered parenterally or topically
" ^, w) Y8 n' B, p6 H5 Jhas produced effective phallic growth. 1- 3 The mechanism of; P5 N$ Z' E. W; M) {( K9 c$ P2 X4 |: ^5 n
response has been considered as local or systemic. With this
9 M2 F- ]- P7 n5 M" B1 R% Kin mind we studied 5 children with microphallus for response
8 [; B" ^9 ^" b% H5 ~5 b& d& @4 Q7 Hto gonadotropin and to topical testosterone independently.6 l2 U0 B J5 _4 l+ \
MATERIALS AND METHODS# F" R. G3 z3 E- f3 M
Five 46 XY male subjects between 3 and 17 years old were& m0 }# ?# d' B- o5 h
evaluated for serum testosterone levels and hypothalamic9 T6 D7 I6 C" c" _1 j$ N+ _
function. Of these 5 boys 2 were considered to have Kallmann's
6 t# |& o7 u. u+ D& N: ~, Psyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-. b1 s% D9 i8 q: n0 V8 Q' |$ X
lamic deficiency. After evaluation of response to luteinizing
: n* b6 B8 E9 S: \; A0 d4 Chormone-releasing hormone these patients were treated with% X( D9 \( Q* F8 |0 ^! N
1,000 units of gonadotropin weekly for 3 weeks. Six weeks) D1 ]/ I9 |6 D' b" I& b
after completion of gonadotropin therapy 10 per cent topical
5 R: z% F7 n) U7 x, {! ~testosterone was applied to the phallus twice daily for 3 weeks.
/ I$ C# |6 @; |6 {Serum testosterone, luteinizing hormone and follicle-stimulat-; ~$ v, T' G3 j' o
ing hormone were monitored before, during and after comple-
) u' J2 l$ z& u! d7 Ytion of each phase of therapy. Penile stretch length was" f, a" \. i) W1 _' Y
obtained by measuring from the symphysis pubis to the tip of+ O# |) W( G% G: j& H3 Q2 ^
the glans. Penile circumferential (girth) measurements were: p1 W/ j! q- t
obtained using an orthopedic digital measuring device (see( [( X; O" s9 V0 P; @4 K9 r
figure).
7 ] C3 D; C! Y E3 O+ z! Q' _( G( ZRESULTS
, O- ]/ g' W3 R+ `Serum testosterone increased moderately to levels between
S, W0 w0 u2 V5 A! ~* s50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
. H' |5 `) ]9 M5 pterone levels with topical testosterone remained near pre-
( M2 o$ k: A$ w8 Z, m, V8 M! X' s$ _treatment levels (35 ng./dl.) or were elevated to similar levels! q2 d8 A5 z- o* z/ ?- Y3 }
developed after gonadotropin therapy (96 ng./dl.). Higher9 r0 Z# ]: F& q2 q ~0 t8 H* e
serum levels were noted in older patients (12 and 17 years old),( d0 d+ c! p7 V: @
while lower levels persisted in younger patients (4, 8, and 10
2 e3 y. ~) y8 Qyears old) (see table). Despite absence of profound alterations
9 H" S# H/ S3 S& V6 E$ cof serum testosterone the topical therapy provided a greater {1 @- k! |% x! u. o
Accepted for publication July 1, 1977. ·
0 G5 g% q1 L) I t+ I2 LRead at annual meeting of American Urological Association,
- ^) M' h; R/ M! N$ OChicago, Illinois, April 24-28, 1977.
9 _7 \5 H5 \. D* Requests for reprints: Division of Urology, Henry Ford Hospital,! _+ z4 l" M5 N+ c; U2 v
2799 W. Grand Blvd., Detroit, Michigan 48202.( E0 Y" l2 a$ A% |+ ~- u
improvement in phallic growth compared to gonadotropin.
! K' \" a) i8 w8 p) k6 [, F8 ~Average phallic growth with gonadotropin was 14.3 per cent
# A. S+ ~1 t1 c% Gincrease in length and 5.0 per cent increase of girth. Topical
( x6 P% H N4 b& F0 T, {$ Mtestosterone produced a 60.0 per cent increase of phallic length b' Y" V/ i$ G4 U
and 52.9 per cent increase of girth (circumference). The. y @9 Y2 f4 x. A5 E1 N
response to topical testosterone was greatest in children be-
9 |3 T. n9 c7 A5 J2 u- d/ J/ l0 _4 Xtween 4 and 8 years old, with a gradual decrease to age 17, A* y- u9 W" e
years (see table).( o/ _" F8 X8 N0 b# I
DISCUSSION
3 J+ A b8 W6 f3 l, |( Z7 V: eTopical testosterone has been used effectively by other
: L2 t5 w+ a$ d3 e$ oclinicians but its mode of action remains controversial. Im-/ {6 d" U) U2 w+ L# |; z
mergut and associates reported an excellent growth response
# ]7 |+ G" V0 `* v+ `# H2 b' pto topical testosterone with low levels of serum testosterone,& N: e9 I+ c! R0 Y
suggesting a local effect.1 Others have obtained growth re-
: {$ i! ~ U2 wsponse with high. levels of serum testosterone after topical
+ D2 o5 h! u) \. G& f- a; sadministration, suggesting a systemic response. 3 The use of. R3 M. S( p) o3 E& Z
gonadotropin to obtain levels of serum testosterone compara-& }* j- N& T5 n0 e1 `. R) U+ V
ble to levels obtained with topical testosterone would seem to5 V8 k" `! F! ` {+ N# a# u
provide a means to compare the relative effectiveness of: @# q d, a& Y4 Q
topical testosterone to systemic testosterone effect. It cer-
6 J4 a" N. L: F3 L4 m& Htainly has been established that gonadotropin as well as par-
n: @! U. d, \2 O1 a8 |enteral testosterone administration will produce genital
% ?% [$ Y% l/ k, k: M3 ~4 _growth. Our report shows that the growth of the phallus was) I. z, B3 `8 }) v
significantly greater with topical applications than with go-7 C0 |: V, H" l: u/ j! U7 t' O
nadotropin, particularly in children less than 10 years old.& @! \+ l- Y1 e/ k9 V3 |0 t3 v
The levels of serum testosterone remained similar or lower
. w0 B; h* H5 V% c, ?3 K. lthan with gonadotropin during therapy, suggesting that topi-
6 {6 G7 t+ O6 t/ F/ S% rcal application produces genital growth by its local effect as
0 T2 Q7 U# ^ xwell as its systemic effect.
1 a# E0 _. O$ W E( r( D( ?Review of our patients and their growth response related to& e0 j; R7 p" b3 R$ t2 J3 R
age shows a greater growth response at an earlier age. This is, ], U; Z1 ?' J$ m M& l
consistent with the findings of Wilson and Walker, who
* e( o3 I. R+ A* `reported an increased conversion of testosterone to dihydrotes-
+ d2 a% J- T6 ]) C. X9 t+ atosterone in the foreskin of neonates and infants.4 This activ-
H9 c. W; {" M9 i( A. T' O4 lity gradually decreases with age until puberty when it ap-
4 Z0 a# s9 M- ]) b9 g* {proaches the same level of activity as peripheral skin. It may0 T( o1 \3 i0 k. g0 E; ]- O
well be that absorption of testosterone is less when applied at9 d( H# L& {4 t m
an earlier age as suggested by lower serum levels in children5 k# l% i/ |. Y) p( c6 l
less than 10 years old. This fact may be explained by the
2 Z+ D" O/ @8 L0 d7 X; P- j" ^8 h9 Bgreater ability of phallic skin to convert testosterone to dihy-
: `( ^7 t% C+ r: |6 d( E/ Ldrotestosterone at this age. Conversely, serum levels in older A- A: I! u! k+ j( n
patients were higher, possibly because of decreased local
3 [, c' r d, m( q6672 [' ^2 C' q( F+ r
668 KLUGO AND CERNY
+ \8 I& g9 t$ ?Pt. Age
0 O' |/ A8 ]" c2 ]* M1 C(yrs.)$ t) K9 Q( z+ t; E
Serum Testosterone Phallus (cm.) Change Length* T+ v8 J- e7 J* j
(ng./dl.) Girth x Length (%)
8 s9 o* ?- N: q4 E8 R6 X4# |. Q+ A' ^5 a& C
8 Q* A# K2 H. o( S/ O* p% T
10) p, [4 l! I1 X
12- L( M) v, L0 I* }. t6 F) j
17 e+ N4 L6 R5 A4 N
Gonadotropin& |% b4 L5 Q( f- Y! ]- X3 H1 V# v# ~
71.6 2.0 X 3 16.6( i4 {# H. y: r& Q; a$ u
50.4 4.0 X 5.0 20.0
. ~* Z4 p, ^3 [: B9 r( M3 N22.0 4.5 X 4.0 25.0
5 M6 a5 ]1 E ^0 u. K/ q) Z84.6 4.0 X 4.5 11.1
5 P2 S+ k$ L9 Y, y85.9 4.5 X 5.5 9.03 @$ C: C* N& H, t
Av. 14.36 Z; c' Q6 ^! ~: u% ~" r+ M# D
42 ?0 q9 k! j1 R; _( ^5 P2 N' x" k
8
3 H) n s% f0 i5 N10
% H8 n2 I! k, w: D126 k- T$ `. n* ~
17
4 }$ H( |8 d1 h2 n8 f KTopical testosterone
3 v: ]- u, G$ c; [* p9 t k8 ~34.6 4.5 X 6.5 855 ^) [( i, r. }4 p/ B+ c% T, }
38.8 6.0 X 8.5 700 V; ~0 R# s2 w9 P! P
40.0 6.0 X 6.5 62.5
, A/ X; p6 o4 |2 I& J4 p93.6 6.0 X 7.0 55.5$ ?. R, h* }9 O ^1 J. W
95.0 6.5 X 7.0 27.2
# C; M* c7 ` a+ e) @Av. 60.09 H( x0 k3 H6 y4 d
available testosterone. Again, emphasis should be placed on
! r# M S5 D4 a3 q e; q: yearly therapy when lower levels of testosterone appear to
" ?% E x) c6 Y3 _. Hprovide the best responses. The earlier therapy is instituted
& t0 b& Z' f; P5 M. I O: Cthe more likely there will be an excellent response with low
n* q0 H$ G* t' Y) Zserum levels. Response occurs throughout adolescence as
E) p& _6 U1 \$ o* U# F* Qnoted in nomograms of phallic growth. 7 The actual response$ J; `! U' L2 X$ n& _ s
to a given serum level of testosterone is much greater at birth
" P' W5 Y/ |. R2 dand gradually decreases as boys reach puberty. This is most6 o- `/ A* G; B3 K& W0 f
likely related to the conversion of testosterone to dihydrotes-$ T% O2 M; H& v! o1 ~4 P
tosterone and correlates well with the studies of testosterone
+ A+ @7 ^4 L( Y! N8 Yconversion in foreskin at various ages.
% K/ l: O% p3 E9 f* T6 fThe question arises regarding early treatment as to whether
% e- Q7 M6 W6 H1 [8 O2 e# O1 j/ rone might sacrifice ultimate potential growth as with acceler-% q2 I' K3 G! K8 q; p* |/ z
ated bone growth. The situation appears quite the reverse
6 p* h/ Y# I5 i1 }with phallic response. If the early growth period is not used
# m1 [: ^3 X' e& a* b4 Swhen 5a reductase activity is greatest then potential growth# d! `8 E7 m' u0 E
may be lost. We have not observed any regression of growth
& Y/ t+ n7 ~8 m8 p, X% Qattained with topical or gonadotropin therapy. It may well% \" o3 b- Z/ j0 a2 t2 O" x
be that some patients will show little or no response to any
3 g# n3 T! f8 f+ s, }, D/ Zform of therapy. This would suggest a defect in the ability to
) ^' J' c+ F9 Y- mconvert testosterone to dihydrotestosterone and indicate that
2 J0 C2 z5 }% o' x* bphallic and peripheral skin, and subcutaneous tissue should0 k" @: ^' f3 x3 Y1 Z! ]2 c
be compared for 5a reductase activity.! p& {2 _& |, |+ @' Z
A, loop enlarges to measure penile girth in millimeters. B,
) u+ i: n6 {. rexample of penile girth computed easily and accurately.
- U" e- q4 X2 e, z: ?conversion of testosterone to dihydrotestosterone. It is in this
6 G. q, u/ A/ L A( g0 Holder group that others have noted high levels of serum
b* @. c% O* n/ S0 ]testosterone with topical application. It would also appear' u! q: G' a1 c+ e$ j$ n% m
that phallic response during puberty is related directly to the
5 l @* c5 o+ S8 r4 Fserum testosterone level. There also is other evidence of local
4 L# s7 S0 r& a0 d W0 c, L* `response to testosterone with hair growth and with spermato-- v8 W' k5 j7 i' z
genesis. 5• 62 o' {5 r R0 g) H" I2 T/ Y1 D* p
Administration of larger doses of gonadotropin or systemic
2 D5 q, u0 e; K* e1 S8 Htestosterone, as well as topical applications that produce
0 l# p" w, c7 o% t# r6 j. v9 Dhigher levels of serum testosterone (150 to 900 ng./dl.), will( @6 x% {+ J/ e) a! Q
also produce phallic growth but risks accelerated skeletal1 C0 N4 u5 y& H
maturation even after stopping treatment. It would appear O$ k' Y7 s1 ?* @
that this may be avoided by topical applications of testosterone
$ l; y( P: [, d+ land monitoring of serum testosterone. Even with this control
& o- p7 O7 ]+ l1 Pthe duration of our therapy did not exceed 3 weeks at any
& T, \5 c7 e7 k! N1 ctime. It is apparent that the prepuberal male subject may
. i( r- V* Z" R$ @2 N4 W7 tsuffer accelerated bone growth with testosterone levels near
$ ]$ E9 e, u4 e' R' T; H200 ng./dl. When skeletal maturation is complete the level of
7 S' Z1 d+ k* I3 z6 v5 w( X. lserum testosterone can be maintained in the 700 to 1,300 ng./
/ v; g. }7 k$ y, }& jdl. range to stimulate phallic growth and secondary sexual
& T: y; A/ `8 Q! p5 s h7 d. y& A, vchanges. Therefore, after skeletal maturation parenteral tes-
! k$ H- s5 j! p: Xtosterone may be used to advantage. Before skeletal matura-
8 i) |3 |( @. D, u" z3 Xtion care must be taken to avoid maintaining levels of serum
4 J" ^% V3 W/ @4 T9 C5 g/ Q8 Mtestosterone more than 100 ng./dl. Low-dose gonadotropin+ T, U3 F/ x# s0 p' \
depends upon intrinsic testicular activity and may require
% J6 n: U; {/ \" e( H/ b/ G" @prolonged administration for any response.. z! T, b- R8 B" f3 q5 }5 I" P7 u
Alternately, topical testosterone does not depend upon tes-
) P( I- m# S# ^! iticular function and may provide a more constant level of* D( @ s9 w1 X3 e% N; S8 G
REFERENCES4 u! E' F# \ y. H3 b' y
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,1 |! X) m+ u$ Y
R.: The local application of testosterone cream to the prepub-
! i7 J! p7 Z! ~" G- L5 K( j2 h3 Kertal phallus. J. Urol., 105: 905, 1971.( A/ R& v1 v/ A7 E5 n j
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone9 l0 S) w) }" C+ d' l0 J T0 g6 _
treatment for micropenis during early childhood. J. Pediat.,
8 k& c- M0 [& Q! i3 R8 L: R3 \83: 247, 1973.2 s! E8 q0 i. T( A! ^- {; U9 v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% y @+ J& v. i$ |) c
one therapy for penile growth. Urology, 6: 708, 1975.
; H$ U: L/ J" `; ?' Y8 S6 p1 G9 b6 [4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 j9 U2 a) _, ?: u8 c) K, i: p) y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 V1 N- t: S, P7 k% a6 ^skin slices of man. J. Clin. Invest., 48: 371, 1969.: P2 O0 Q7 j4 X2 {1 g
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
0 n0 u1 @: ?+ ^ m( S% F0 Pby topical application of androgens. J.A.M.A., 191: 521, 1965.
* Z/ O0 c& Q; q8 k$ d6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- S0 n0 E* V# A
androgenic effect of interstitial cell tumor of the testis. J.
/ H% U2 T0 t9 v) a0 |Urol., 104: 774, 1970.
6 D9 t1 q3 [4 W7 M5 i* F4 z7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& Q7 o$ F5 ?4 t& L% n; Q0 X" Xtion in the male genitalia from birth to maturity. J. Urol., 48: |
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