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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" x; P) |/ v1 l5 Z! h
GONADOTROPIN+ D, P& e; x# G0 n/ {
RICHARD C. KLUGO* AND JOSEPH C. CERNY( \# M" P4 J# I# o8 o4 n
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan8 j) V5 b* t7 @! f! `! y/ N/ M
ABSTRACT
+ d; P( e6 X/ NFive patients were treated with gonadotropin and topical testosterone for micropenis associated
2 A2 o! [( I- r! _with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* F& ]* F, `; V; U; l Vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 j/ r# F+ G* ^' \' ?cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 C3 e& J3 e# s( L
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 v- p; z B, X: j2 X" d( L4 nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ T' e" f& |% L1 q9 r! Mincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ {6 [6 g0 s9 ?
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# i- G9 i2 L" @) _3 ?' W' ostudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile# e' l- ?: }3 V5 {0 Y0 |
growth. The response appears to be greater in younger children, which is consistent with previ-
& q: w1 s6 }8 X& B: W& v( |ously published studies of age-related 5 reductase activity.
: i' C1 i3 S: P6 f `8 A) YChildren with microphallus regardless of its etiology will( `; d7 Q( K$ H ]+ n1 v
require augmentation or consideration for alteration of exter-3 t( U8 E9 W9 c& [* j
nal genitalia. In many instances urethroplasty for hypo-
) l) @! w. }* x$ a6 ^: K! sspadias is easier with previous stimulation of phallic growth.
& C+ w' @0 L1 _ ~; RThe use of testosterone administered parenterally or topically! F: d- O% v. W. H) c: F
has produced effective phallic growth. 1- 3 The mechanism of1 V& h- s, w# i: a/ s* f
response has been considered as local or systemic. With this
' s) c+ x% I O/ z1 X, {in mind we studied 5 children with microphallus for response
$ ^9 T6 n- d- l# M: l, Qto gonadotropin and to topical testosterone independently.1 M) K" j( |! B( T
MATERIALS AND METHODS+ N# E# |. r' s
Five 46 XY male subjects between 3 and 17 years old were& A1 H6 j# Z/ {
evaluated for serum testosterone levels and hypothalamic- t" v* s5 W5 h
function. Of these 5 boys 2 were considered to have Kallmann's" L% g+ [# i! Z r9 N; d+ i7 e
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 U; S' \! N j, h3 J0 {
lamic deficiency. After evaluation of response to luteinizing2 z3 H% b# j0 Y
hormone-releasing hormone these patients were treated with
b, J' G5 @& d# p4 N* q& ~1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 g4 [" ?/ T- E, Q/ W5 g1 R
after completion of gonadotropin therapy 10 per cent topical
% \# H4 p2 v( E; |9 |! }1 C$ v0 j. w: mtestosterone was applied to the phallus twice daily for 3 weeks.
! V' p2 \! S/ X5 {Serum testosterone, luteinizing hormone and follicle-stimulat-
, a5 e4 o1 }! T9 ring hormone were monitored before, during and after comple-3 X) [' U9 r+ B$ x6 P. `
tion of each phase of therapy. Penile stretch length was
. s5 X4 L, U$ p& [obtained by measuring from the symphysis pubis to the tip of( |8 q$ f) ~7 l6 X
the glans. Penile circumferential (girth) measurements were
: m+ n8 A3 Y t0 N3 T3 Wobtained using an orthopedic digital measuring device (see6 p6 G9 e3 s" K5 T L
figure).7 f. Q, q8 X) b' H
RESULTS; s( u; h0 u F, H ?3 y: T
Serum testosterone increased moderately to levels between
6 [% m \, g- F7 `! B8 G50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
8 ^* {5 w1 s7 q/ h, P5 N8 e5 {! Z. I6 Nterone levels with topical testosterone remained near pre-% @$ p: ]) `8 H( e5 S' ?7 i$ q
treatment levels (35 ng./dl.) or were elevated to similar levels
( g! R+ u0 y) |( Z* W/ [7 ideveloped after gonadotropin therapy (96 ng./dl.). Higher( Q! `1 ^2 @* _$ p* ?! y
serum levels were noted in older patients (12 and 17 years old),- Q) u7 O& c( w' z
while lower levels persisted in younger patients (4, 8, and 103 o5 r3 t) x# N. x( ]
years old) (see table). Despite absence of profound alterations/ Q5 @1 X. N) X% j, ~1 u
of serum testosterone the topical therapy provided a greater' `" Z0 m" _7 o8 X; k$ y
Accepted for publication July 1, 1977. ·7 B" a K$ Y/ f
Read at annual meeting of American Urological Association,
1 o6 f3 A7 E" i- p$ d! DChicago, Illinois, April 24-28, 1977.# [( B- B$ y4 r2 B2 K: ^' ^1 q
* Requests for reprints: Division of Urology, Henry Ford Hospital,3 q: w% d4 w* \! S) o
2799 W. Grand Blvd., Detroit, Michigan 48202.$ F( J @; R6 H g
improvement in phallic growth compared to gonadotropin.
1 ~ J3 K+ y/ U0 L3 d$ f; hAverage phallic growth with gonadotropin was 14.3 per cent
' ?: M. Q# B7 _% h/ K# ?8 `increase in length and 5.0 per cent increase of girth. Topical! G6 }1 }4 A, Q0 s0 w7 a/ K
testosterone produced a 60.0 per cent increase of phallic length
$ j# Z- j9 z/ D _and 52.9 per cent increase of girth (circumference). The+ D/ U' Y# B: z' I' K9 w
response to topical testosterone was greatest in children be-
: R: N# o* k. O# T u2 _6 Dtween 4 and 8 years old, with a gradual decrease to age 17& P& @8 T) r: q3 Z; m" i5 }/ T
years (see table).
. f$ G/ a5 N V+ |; C( HDISCUSSION- |' z! R3 V8 h# J2 r* [( q m2 y
Topical testosterone has been used effectively by other
7 {/ \, _( z3 G- m5 c7 ?7 @; wclinicians but its mode of action remains controversial. Im-0 c. V) w8 g' X/ P. w! t9 K' O# O
mergut and associates reported an excellent growth response
# U- D" P, c7 Q$ Z4 s3 Wto topical testosterone with low levels of serum testosterone,
) i! L0 x( s6 j* {5 u; Z tsuggesting a local effect.1 Others have obtained growth re-
4 {1 T( H5 p6 @- i1 D {sponse with high. levels of serum testosterone after topical
9 g* I' j9 d& \1 Y& `6 c4 iadministration, suggesting a systemic response. 3 The use of m6 c$ x [# o f6 ~
gonadotropin to obtain levels of serum testosterone compara-
- ^6 ^4 Q7 _: }. N) P+ g$ Xble to levels obtained with topical testosterone would seem to0 R3 p- _- S1 ~: r _3 J
provide a means to compare the relative effectiveness of
- y' U* w! U2 G( q6 T. etopical testosterone to systemic testosterone effect. It cer-0 W. [1 @8 b7 }8 F8 k% _
tainly has been established that gonadotropin as well as par-
* j B' H3 _0 m; G% q) n# ~enteral testosterone administration will produce genital; L8 K( u' f3 l' ^4 A
growth. Our report shows that the growth of the phallus was
: ]( v4 t e4 `. S0 {9 a) _significantly greater with topical applications than with go- K" E3 o! C9 `6 X# e' `
nadotropin, particularly in children less than 10 years old.( t# ]" w& v0 p2 ^5 A6 x1 I `* F
The levels of serum testosterone remained similar or lower
1 ^0 x) y. \9 A Athan with gonadotropin during therapy, suggesting that topi-, U+ M# b" w7 y$ A
cal application produces genital growth by its local effect as
0 Q! v4 ?( ^* q2 n- Owell as its systemic effect.
. F4 l1 S: l4 Y: \; AReview of our patients and their growth response related to4 e7 B. X( N, {
age shows a greater growth response at an earlier age. This is
. J) h* L( L. |* b; ?( gconsistent with the findings of Wilson and Walker, who
/ W4 r& q- D/ M( F8 ~/ yreported an increased conversion of testosterone to dihydrotes-
6 v, y) Z1 z9 S8 l/ `tosterone in the foreskin of neonates and infants.4 This activ-
+ e: |- J+ M6 f, b0 eity gradually decreases with age until puberty when it ap-
; y: Y7 t( @5 @) U7 nproaches the same level of activity as peripheral skin. It may7 r( k" D7 U2 D
well be that absorption of testosterone is less when applied at
8 P7 M) C' P2 h h) Ban earlier age as suggested by lower serum levels in children
7 i$ F9 F N4 `9 I4 M5 i" Bless than 10 years old. This fact may be explained by the
1 A: C; }; L" g+ J) b- Cgreater ability of phallic skin to convert testosterone to dihy-, W! L7 y, r9 b1 T* ^# i7 k i
drotestosterone at this age. Conversely, serum levels in older: P7 A5 y, v/ U+ C4 S3 V
patients were higher, possibly because of decreased local: u7 s, n7 I; M$ y7 t/ c
667
% \+ G$ H6 Z4 M2 Z5 m5 y668 KLUGO AND CERNY
: a$ a5 v. `3 h# L2 T; ~Pt. Age5 R! Z% C/ }& y9 M9 K
(yrs.)
?0 P+ b \% P$ u+ F6 h# X; |6 n# s" ySerum Testosterone Phallus (cm.) Change Length/ T0 {& O) K0 C8 _5 y) y( g
(ng./dl.) Girth x Length (%)
4 A5 X: j, J+ V! [& r4
6 e2 b; s- S# Y8 V83 V" p! p& {2 |3 h
100 @/ l2 Z9 g! K9 j
12
+ Q/ Y! W0 _( p$ j17% V" Q4 j) P% `: Q
Gonadotropin
( s2 ?+ S3 x( D& M71.6 2.0 X 3 16.6
! S7 y* M1 F3 g5 u7 S1 Y# X50.4 4.0 X 5.0 20.0
Y( F3 [1 m; y+ l22.0 4.5 X 4.0 25.0
; q+ R& b, ~- G& X84.6 4.0 X 4.5 11.1
, O( u: }0 m9 C* ^+ V# k" W85.9 4.5 X 5.5 9.09 M, L0 w7 K: r0 k% b$ l2 L4 g) @
Av. 14.3# P7 |4 q( d _+ I8 ]8 ~( |8 a: v" F' f4 t
42 k% N) @+ ~! M5 J& ?
88 J% b4 x: b4 B# G' v8 D
10- _; r' S. Q% b" H& m" Z* n& Q
12
) t3 j" [, t2 {5 x+ x: w17
9 J& u7 c) w' A, pTopical testosterone3 ]5 Q9 j$ @1 Y) A0 F* p% B
34.6 4.5 X 6.5 85
( `6 D% |+ T$ c' _' z; m& ^4 T38.8 6.0 X 8.5 70) M8 {$ G- A( {! Q$ F
40.0 6.0 X 6.5 62.5
: ^5 \3 |3 z) W0 e93.6 6.0 X 7.0 55.5
; E% m L& d& \8 p! |1 s% M95.0 6.5 X 7.0 27.2
2 O. B- f! W2 ~9 dAv. 60.0
' ^- e0 j1 Q" z+ M5 gavailable testosterone. Again, emphasis should be placed on. _" `( a) `5 B6 W& M9 L4 {
early therapy when lower levels of testosterone appear to6 M0 n; I: c6 r8 M2 {
provide the best responses. The earlier therapy is instituted
7 ^; O. Z+ ~, Q+ w0 q* l" w# Zthe more likely there will be an excellent response with low
, t r. Z6 [+ u" _+ s" m- Z# d8 Mserum levels. Response occurs throughout adolescence as( t1 q F% h6 g5 I* U: \* P
noted in nomograms of phallic growth. 7 The actual response
% C0 }# z+ L% {3 Tto a given serum level of testosterone is much greater at birth
9 J) Y& M; p3 n- [: b' i5 ^and gradually decreases as boys reach puberty. This is most
' M* K) j2 ?5 z8 t1 Tlikely related to the conversion of testosterone to dihydrotes-# i3 O! o4 g2 K+ Q' E
tosterone and correlates well with the studies of testosterone9 w/ T" [' C) V# n# H0 {
conversion in foreskin at various ages.* T6 G5 d0 }' H) `
The question arises regarding early treatment as to whether
7 q' V" n5 t7 D, i! J( Z5 lone might sacrifice ultimate potential growth as with acceler-; ^7 a, @" k! X0 H+ X. W# f9 E6 @8 S
ated bone growth. The situation appears quite the reverse( G; t3 @) w4 [: C, X8 V& P
with phallic response. If the early growth period is not used
7 x y3 B# z ?) m( ~4 ?6 Y9 i6 rwhen 5a reductase activity is greatest then potential growth+ L6 k+ r! z, u9 o3 Z
may be lost. We have not observed any regression of growth
% ]+ M' W4 i9 j$ w [, R2 v: Y3 nattained with topical or gonadotropin therapy. It may well
+ [$ T( c/ G% A* Lbe that some patients will show little or no response to any. O; S% q! \, M# E1 N# N! v* U; W
form of therapy. This would suggest a defect in the ability to& {5 ~1 v1 ~/ @/ a1 N
convert testosterone to dihydrotestosterone and indicate that5 q! }" U. s b! y" u0 m
phallic and peripheral skin, and subcutaneous tissue should
( f0 h) p+ X# |7 n. J" ?be compared for 5a reductase activity.
2 s8 W8 N0 k9 Z4 T5 y* \A, loop enlarges to measure penile girth in millimeters. B,
/ k4 j* N0 j- w! p4 l5 o! S- uexample of penile girth computed easily and accurately., D& Z" |6 a3 ?
conversion of testosterone to dihydrotestosterone. It is in this
' m) N% B5 G$ a) @" l6 Yolder group that others have noted high levels of serum* \, s1 \5 |! g4 s: r3 R
testosterone with topical application. It would also appear* c) T, D2 U( N+ R
that phallic response during puberty is related directly to the
# k) o* h! x1 ~' F& k9 E8 I- Bserum testosterone level. There also is other evidence of local
8 Z# ]: |, a9 w* `4 hresponse to testosterone with hair growth and with spermato-
6 @' v) m8 N, W5 k5 Y# Cgenesis. 5• 6
]8 }# I5 ]) w& \, W) N1 IAdministration of larger doses of gonadotropin or systemic1 D4 G1 k* I, T
testosterone, as well as topical applications that produce
B- f* S: ^" E2 Q% O) M1 ghigher levels of serum testosterone (150 to 900 ng./dl.), will
' ]( y O' B& w0 o; salso produce phallic growth but risks accelerated skeletal9 Q- d: M4 j9 b4 x9 Y6 z) B- S
maturation even after stopping treatment. It would appear" f0 R% H, A6 b, {5 l3 o
that this may be avoided by topical applications of testosterone
6 s2 f; c5 |# ~ ~4 Z1 C: T4 Sand monitoring of serum testosterone. Even with this control6 ~1 d) m2 E2 l' p- j4 E( `
the duration of our therapy did not exceed 3 weeks at any
0 U2 h; t* s! T# }$ K3 J- Q8 |time. It is apparent that the prepuberal male subject may8 e1 L" w' I9 p1 E* M% V6 Z
suffer accelerated bone growth with testosterone levels near
$ Y5 ^1 g: x+ Y9 ]6 M! i200 ng./dl. When skeletal maturation is complete the level of9 q) h( G; p5 ~& u' ]. I
serum testosterone can be maintained in the 700 to 1,300 ng./
4 V# N, f a: V: C; |dl. range to stimulate phallic growth and secondary sexual9 G9 V2 O' V2 x4 X; T
changes. Therefore, after skeletal maturation parenteral tes-
2 c% a. _7 c. E4 utosterone may be used to advantage. Before skeletal matura-
& w5 G+ I2 H9 i$ f9 A. c2 E- Ption care must be taken to avoid maintaining levels of serum
: l- N! ^/ u4 W2 ]7 `* G& ]testosterone more than 100 ng./dl. Low-dose gonadotropin I8 ]4 n% ]5 b5 K- |: x
depends upon intrinsic testicular activity and may require
( X |+ u @0 V7 |4 b1 t" ]prolonged administration for any response.
% H$ G9 k& a! K( ^' C$ r+ VAlternately, topical testosterone does not depend upon tes-
$ c5 Q( w0 Z5 ~ticular function and may provide a more constant level of# m7 ^* e: @" c# [2 v$ u6 L7 a0 d
REFERENCES
! s" \" x0 Y( {2 B1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# E0 u# V& [5 p |! G8 h
R.: The local application of testosterone cream to the prepub-
. u) M7 q* @* l, mertal phallus. J. Urol., 105: 905, 1971.
! K x# x& K% Q0 e! X# n3 V/ R+ |2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% x% C5 B" y& w$ a0 K: D
treatment for micropenis during early childhood. J. Pediat.,
# A/ R9 ]" D) p* x. v/ O% \7 i; B, ~83: 247, 1973.
- |% C( o; X1 o' f3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% R7 E6 o" @+ b/ C' l8 z
one therapy for penile growth. Urology, 6: 708, 1975.& }. ~+ Z- v, h+ y1 B
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
9 \6 R: e. G" p( ?" M# _to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ c$ q; u" n/ C4 b- r
skin slices of man. J. Clin. Invest., 48: 371, 1969.
% n8 Z/ f/ @) O, A& t8 g5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 \. n( s8 ~+ h( i$ M9 D* F" K- n
by topical application of androgens. J.A.M.A., 191: 521, 1965.9 N4 \; R/ [! L0 |2 r/ q! @
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
9 t2 g) l& j9 x3 s+ w; _androgenic effect of interstitial cell tumor of the testis. J.
7 K: Q$ F( D8 K4 k7 i$ v' ?Urol., 104: 774, 1970.
- h2 W5 G4 S: P: }3 y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. y: X" j) J) i9 p( j! S) |5 Y
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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