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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
' T, U. s$ ]( B& A9 O1 ?4 L3 |GONADOTROPIN
: A( {! E! G) qRICHARD C. KLUGO* AND JOSEPH C. CERNY
6 X4 Q+ L- P8 U7 SFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
8 T8 a4 Q' Y: y7 |) N6 n- j8 v7 vABSTRACT
- t# \7 Q. i( }- T( V8 U- N* CFive patients were treated with gonadotropin and topical testosterone for micropenis associated- u3 J" f, c: ]1 v1 r3 h% `" j; W
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
& f e6 U- U) H" ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 ~" b3 L' Z2 w5 X% V( M9 Ccream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 M) a( m5 Q4 q' sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent6 v8 J6 x6 q* H1 C) i6 Y4 i9 f
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average# i1 s- e4 d" t0 @9 X+ _0 |# q
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response! l1 m5 x9 S- R$ ~
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
5 j7 Y0 w! V- p: S3 p. \) n1 S) rstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile- T/ b7 J5 h* g% h/ L$ I4 i
growth. The response appears to be greater in younger children, which is consistent with previ-7 @7 b; ]# o A" p) H8 o) R2 U) K
ously published studies of age-related 5 reductase activity.; O% B. |% K5 w4 _5 Q9 d6 E
Children with microphallus regardless of its etiology will
2 R4 Y. X3 X$ H4 v' Arequire augmentation or consideration for alteration of exter-# F; }/ y6 t) I' g0 g! P
nal genitalia. In many instances urethroplasty for hypo-) G, [) b! G5 u! M9 k4 i
spadias is easier with previous stimulation of phallic growth.
- m' [( f+ z9 a4 A) F" c; }; RThe use of testosterone administered parenterally or topically
2 B) L e) B* c. ohas produced effective phallic growth. 1- 3 The mechanism of
$ w0 `* v8 H) y2 F8 p; \, ~5 Iresponse has been considered as local or systemic. With this
! H+ R7 d- X: e4 _in mind we studied 5 children with microphallus for response
$ t( h" q$ P" hto gonadotropin and to topical testosterone independently.' ^6 G! i4 K* E8 ]6 d, u) h& G
MATERIALS AND METHODS1 H5 z2 b# w, c
Five 46 XY male subjects between 3 and 17 years old were
" n8 q# B( ^: f' V; |evaluated for serum testosterone levels and hypothalamic
! h! F) b0 x/ I4 [" Gfunction. Of these 5 boys 2 were considered to have Kallmann's
2 D7 [' w( y8 Isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha- R' w( _* ^+ ~3 V. g
lamic deficiency. After evaluation of response to luteinizing J# E- C' Z+ T; z
hormone-releasing hormone these patients were treated with% d* H1 w2 K4 O! b1 p/ G Y7 A
1,000 units of gonadotropin weekly for 3 weeks. Six weeks, X9 x* L5 e2 p+ B5 K( w* w
after completion of gonadotropin therapy 10 per cent topical0 j" x& ~$ _3 C* x( J4 `% s
testosterone was applied to the phallus twice daily for 3 weeks.
- y0 P' T3 ~, E- X9 |/ N6 jSerum testosterone, luteinizing hormone and follicle-stimulat-4 K" ]$ i8 N0 t
ing hormone were monitored before, during and after comple-
1 [6 C( z7 J$ y2 P* v3 x) q# Ation of each phase of therapy. Penile stretch length was( v1 w4 s# `* Q+ J7 U
obtained by measuring from the symphysis pubis to the tip of
4 j- I3 `, c$ ?. i/ [the glans. Penile circumferential (girth) measurements were
5 L7 I2 N, p1 _8 Hobtained using an orthopedic digital measuring device (see- x7 ]/ \7 |0 Z, Y
figure).$ C- z, ?, M: {
RESULTS
/ i) P, x8 P! z% v) YSerum testosterone increased moderately to levels between& y) t# l0 W6 _2 q! C$ B2 f9 Q, [
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 K9 q/ Z/ P; P; W8 i; }terone levels with topical testosterone remained near pre-
1 [* ^4 W$ }3 f1 _& G0 r6 Vtreatment levels (35 ng./dl.) or were elevated to similar levels
2 U; ~1 }' k& e* W' U! u4 Xdeveloped after gonadotropin therapy (96 ng./dl.). Higher6 `. W1 v* u( q" A' e; w
serum levels were noted in older patients (12 and 17 years old),
- `! f8 N. t7 m o4 V! z- awhile lower levels persisted in younger patients (4, 8, and 10$ O- i- M1 C% v% J
years old) (see table). Despite absence of profound alterations+ h8 |/ N9 e9 b! q) Z# q1 f
of serum testosterone the topical therapy provided a greater/ L% c4 d* ^/ `7 K7 W* ]0 F
Accepted for publication July 1, 1977. ·
" N% C; ?+ [: s- L6 b% Y- S; VRead at annual meeting of American Urological Association,
6 [- Q9 Q6 U8 B" Y' e( E; fChicago, Illinois, April 24-28, 1977.( T! |+ b, |) U$ R; _7 D
* Requests for reprints: Division of Urology, Henry Ford Hospital,' g, Y: ?2 |* [0 f6 T |8 l( D
2799 W. Grand Blvd., Detroit, Michigan 48202.- _1 o! L; y$ |8 E" w
improvement in phallic growth compared to gonadotropin.
7 Y/ O! B: `/ ^$ wAverage phallic growth with gonadotropin was 14.3 per cent: Q0 |, v5 s6 y
increase in length and 5.0 per cent increase of girth. Topical/ U, {* Z, r. M3 m3 x6 }
testosterone produced a 60.0 per cent increase of phallic length; }' I9 N8 W4 F9 t( D( e$ l1 e
and 52.9 per cent increase of girth (circumference). The
j1 }) f3 |0 P7 Kresponse to topical testosterone was greatest in children be-
, K9 I2 A' Z9 xtween 4 and 8 years old, with a gradual decrease to age 17
- @ }) u! x# u/ ?years (see table).* [" U2 l( Z; R- }% }, I7 X% q
DISCUSSION0 @, O" ?" ]4 q1 k
Topical testosterone has been used effectively by other
5 y7 L! u1 K# i( u0 ]clinicians but its mode of action remains controversial. Im-
* \0 l& i* e. V( omergut and associates reported an excellent growth response+ V p/ R/ l- v- z" h y
to topical testosterone with low levels of serum testosterone,
( n) W+ \0 C4 J, f" ~4 Qsuggesting a local effect.1 Others have obtained growth re-
! \8 m( F: H. ~" M! `sponse with high. levels of serum testosterone after topical
5 ?0 J* C" |1 w8 o0 H' h% w! Z \administration, suggesting a systemic response. 3 The use of/ y+ y( k; v8 M% i
gonadotropin to obtain levels of serum testosterone compara-
8 s" Z8 q5 z' w5 Q& fble to levels obtained with topical testosterone would seem to
. |& w* G# t& L3 W+ fprovide a means to compare the relative effectiveness of
! O# w% w3 [& b' w: C& _topical testosterone to systemic testosterone effect. It cer-
& ~2 t9 R: j1 P! x( O) Q2 _% T otainly has been established that gonadotropin as well as par-, d+ ^2 M4 |1 L; E4 }0 v
enteral testosterone administration will produce genital
1 X+ O7 V6 H: e8 k, l! Z% p+ [0 Xgrowth. Our report shows that the growth of the phallus was5 N" H( _% u: x$ ^$ [
significantly greater with topical applications than with go-3 U( e$ g% Y3 T0 ]9 i+ v' K9 a+ j. t
nadotropin, particularly in children less than 10 years old.$ Q. G0 I6 ?, y" Q* h
The levels of serum testosterone remained similar or lower
. F# H+ p1 P- j0 Q3 t6 nthan with gonadotropin during therapy, suggesting that topi-. H4 f! K- t O
cal application produces genital growth by its local effect as
# x2 j; H4 o- l9 p7 y% X5 X% bwell as its systemic effect.- F" T5 M: W) y9 b* F4 g
Review of our patients and their growth response related to
4 M1 W- V L0 \$ X6 H- @# Y& i# Uage shows a greater growth response at an earlier age. This is
?) C' F% j/ h& A* Y2 tconsistent with the findings of Wilson and Walker, who
3 O; ]0 B+ D' G, P' k6 I" f, ]reported an increased conversion of testosterone to dihydrotes-
- O. {% v' b) R9 M3 n6 otosterone in the foreskin of neonates and infants.4 This activ-
6 \' _3 Y& A: Gity gradually decreases with age until puberty when it ap-5 u6 |8 y1 u. \, ?6 h2 J
proaches the same level of activity as peripheral skin. It may
: R# _7 ^5 e4 J. q% vwell be that absorption of testosterone is less when applied at) ?, r4 V: q0 }, z- j& U
an earlier age as suggested by lower serum levels in children
+ b5 l, i$ x Z/ \" H. J- lless than 10 years old. This fact may be explained by the% N1 |; u5 d, o" u# b; x/ Y
greater ability of phallic skin to convert testosterone to dihy-, u) r% e9 V! {' ^# \
drotestosterone at this age. Conversely, serum levels in older, ~* x, ^0 H n4 P8 b& Q/ D% R! D
patients were higher, possibly because of decreased local. Y- ]0 T0 R1 e
667
( }# K* ^/ C$ W# f* I s: U668 KLUGO AND CERNY' X4 c# w, F6 N, e. l! ^4 D3 p
Pt. Age7 e2 n; J" A0 s% J. g' U0 k% `
(yrs.)
1 e. A t. k! Y2 X2 o( XSerum Testosterone Phallus (cm.) Change Length
! q3 g* [5 ]2 X0 \; T(ng./dl.) Girth x Length (%) d, o! |0 J$ Z+ S. T# o
4
' w0 F8 A6 A% @) R84 \4 x7 x$ q, \( l/ A
10, O+ d; N$ @* U2 p6 T
12
% C: O. P4 V0 S. i X) w0 ?& F8 }17' V, L/ k) d* m4 l( d6 D% Y" a& S
Gonadotropin. v5 V; E+ W9 X9 F* f
71.6 2.0 X 3 16.6
0 ^) u" Y( c. g6 g) X8 P50.4 4.0 X 5.0 20.0
s2 k7 K( ~7 F {22.0 4.5 X 4.0 25.07 @* q6 {1 v8 O9 N
84.6 4.0 X 4.5 11.1: @3 `! N J: X
85.9 4.5 X 5.5 9.01 S! @. A0 E% b
Av. 14.3
8 r7 r0 h9 ?8 S4 s: d3 R* `4# w0 \! ?7 f! D1 w/ r+ ~6 f: {( k
8
/ ?1 W- {( E2 ]10
) H5 J0 M0 f/ S0 J12
; ]2 K) p" w+ O( u( ^" q7 R17
2 g6 J8 _- H. w% q+ TTopical testosterone
3 S/ ?3 T1 |+ S2 O34.6 4.5 X 6.5 85
* a9 C& h T/ Q* |38.8 6.0 X 8.5 70
1 O5 P- W6 P& @' Q8 `40.0 6.0 X 6.5 62.5
; {* _" _1 Q, u! d- A93.6 6.0 X 7.0 55.5$ Z4 H, C$ w4 a
95.0 6.5 X 7.0 27.21 q3 i8 Q7 |) b: [- ~/ z
Av. 60.0
, N5 v6 v& k( r% x& L/ D, O+ yavailable testosterone. Again, emphasis should be placed on
3 r6 z3 \) b0 F4 n0 Oearly therapy when lower levels of testosterone appear to
d* r X+ |- ]. O! h' @) u/ Zprovide the best responses. The earlier therapy is instituted
, w9 s: q# ?0 K9 R: p0 d' O0 [' athe more likely there will be an excellent response with low$ c2 V$ e* ?! c7 P
serum levels. Response occurs throughout adolescence as3 j% |: T d/ N: o
noted in nomograms of phallic growth. 7 The actual response5 [0 Z! F, b5 \
to a given serum level of testosterone is much greater at birth# x! S5 d0 ~5 l$ v7 @
and gradually decreases as boys reach puberty. This is most2 L8 D) ?: N& l; C" q [
likely related to the conversion of testosterone to dihydrotes-; I8 `+ O& O. ?" r; c
tosterone and correlates well with the studies of testosterone* P% D8 Y& ? T
conversion in foreskin at various ages.2 C9 u" ~" k' d4 y$ M; Q
The question arises regarding early treatment as to whether
. m. ~/ u" j3 @$ s4 U8 P# L2 Tone might sacrifice ultimate potential growth as with acceler-
" |: A7 R6 E( d) Y% Gated bone growth. The situation appears quite the reverse% [4 g9 \( F S4 F" F& f6 n* }
with phallic response. If the early growth period is not used
+ C2 \' D' |( I- B" y5 `$ N1 ^* swhen 5a reductase activity is greatest then potential growth# Q1 e9 ?# C7 y9 F. ?& f
may be lost. We have not observed any regression of growth
5 Q! O& H* `9 ^; z. H! s: zattained with topical or gonadotropin therapy. It may well$ K a; @+ Q# I1 c! O
be that some patients will show little or no response to any! M. v9 i2 v) j/ r. c7 d: C
form of therapy. This would suggest a defect in the ability to
7 m3 i1 W/ z3 d/ }, Fconvert testosterone to dihydrotestosterone and indicate that
' R- @( D( t# \: b# Gphallic and peripheral skin, and subcutaneous tissue should
/ H, Z* g) q' y7 d) k* qbe compared for 5a reductase activity.
$ c$ G/ _, ]0 C: z) @9 g9 A' k, b0 GA, loop enlarges to measure penile girth in millimeters. B,
8 u( D$ j- f; `( b/ L: P/ mexample of penile girth computed easily and accurately.6 X! H- h1 s U- F
conversion of testosterone to dihydrotestosterone. It is in this3 K; h5 F. X" H; ~
older group that others have noted high levels of serum. d3 q5 H% ~! Z8 w
testosterone with topical application. It would also appear, D+ q% {% p" @, L! q/ o" `
that phallic response during puberty is related directly to the: }% N% h4 K5 \& B$ @
serum testosterone level. There also is other evidence of local6 J% o9 k6 \4 @6 z+ G3 [
response to testosterone with hair growth and with spermato-
+ ~6 ^4 V$ O0 X% u$ j6 O4 jgenesis. 5• 6
1 z3 G4 g% c& N: `% x( G7 rAdministration of larger doses of gonadotropin or systemic* _+ }; B; Z/ R& X1 i$ h$ m
testosterone, as well as topical applications that produce
# `! _1 V+ @1 K5 i3 V% O! q: U4 Rhigher levels of serum testosterone (150 to 900 ng./dl.), will! G! j7 I+ s+ u; `5 M
also produce phallic growth but risks accelerated skeletal
0 |/ F( @* g E! Zmaturation even after stopping treatment. It would appear
* H# _' k% m* P1 W6 {% N1 Qthat this may be avoided by topical applications of testosterone" N! ^. V i) R' H E8 p! C
and monitoring of serum testosterone. Even with this control
; i# E8 c& z6 T8 Q: H( ]: Ithe duration of our therapy did not exceed 3 weeks at any
; U" g! [6 N2 r- ~time. It is apparent that the prepuberal male subject may4 j& T/ ]" S! q+ A1 {3 q) r
suffer accelerated bone growth with testosterone levels near
9 N+ p5 s( v; i# ^9 @200 ng./dl. When skeletal maturation is complete the level of$ B' p. R' P( p( ?) q4 U
serum testosterone can be maintained in the 700 to 1,300 ng./6 i9 X# S4 j, ]" N' y6 D
dl. range to stimulate phallic growth and secondary sexual
; u; s. r' L; echanges. Therefore, after skeletal maturation parenteral tes-1 Q5 ?; S* n, g9 j, }2 ]% I
tosterone may be used to advantage. Before skeletal matura-" X, v: P5 J* A4 o$ L
tion care must be taken to avoid maintaining levels of serum
( J L& c5 i, xtestosterone more than 100 ng./dl. Low-dose gonadotropin# d* p B7 l0 k* e& O& \' H
depends upon intrinsic testicular activity and may require8 F% p6 Q7 @. i4 x
prolonged administration for any response.( a; g$ M& B. g4 g
Alternately, topical testosterone does not depend upon tes-
1 |9 x- i; r3 S6 F; l* xticular function and may provide a more constant level of
2 y. D9 X. F, k9 CREFERENCES* Y' a* Q: s/ Y/ `& o
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,. h* u4 u9 _3 b! g! R( w
R.: The local application of testosterone cream to the prepub-
" w V, S, C% [ertal phallus. J. Urol., 105: 905, 1971.
* V0 q2 }. g9 [: q; S0 L2 s2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone' z) d# A* u+ n8 L( V$ F! d, d5 m5 g+ I
treatment for micropenis during early childhood. J. Pediat.,
$ F z# S, q+ z/ z6 j$ y8 }83: 247, 1973.
) c* O" c- q) g) R0 g5 h; r6 v) ?$ J3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-+ `- O" Y) W% p# @% i' H
one therapy for penile growth. Urology, 6: 708, 1975.! N8 _; u$ X" ^+ L; s
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' J2 @/ A f% k7 H( H6 {: k1 Y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' n3 V. b1 {* c8 eskin slices of man. J. Clin. Invest., 48: 371, 1969.7 e9 C, [; T* t4 v# y/ Y
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 c% W! x3 e! ~2 T2 qby topical application of androgens. J.A.M.A., 191: 521, 1965.
5 h3 a0 P& x: t4 K6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 v# ^, J' h4 E8 ~. Mandrogenic effect of interstitial cell tumor of the testis. J.
; h( D6 ` _ j! iUrol., 104: 774, 1970.& U) H' F6 g4 l; N8 X; g
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 _( ` n% m8 M. E$ j3 r* f4 }tion in the male genitalia from birth to maturity. J. Urol., 48: |
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