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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND( Z0 r7 u3 X" i( O' J/ w- `) h
GONADOTROPIN
5 V7 j& Z9 O$ i7 M0 T. hRICHARD C. KLUGO* AND JOSEPH C. CERNY7 q" ~- E4 q& I4 a% t! @
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* _5 m. F. Y6 T# OABSTRACT
$ z( G2 {8 v; i8 jFive patients were treated with gonadotropin and topical testosterone for micropenis associated1 z6 r- w: @1 A' u2 J0 n2 x
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ Y8 w4 N: X! a5 jtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* |& H; N' @2 d  Q
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 t- c7 d2 a/ r; m0 e) Q# qfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" i% E  U+ s$ X4 ?) d
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! }. K' P/ u/ F
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: }7 O9 D8 S6 R% n+ {
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# `: r+ y2 {% d: z$ s/ q% X+ Cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile: }4 v# u" c4 E( A5 w5 Y2 D8 q
growth. The response appears to be greater in younger children, which is consistent with previ-
) Z9 [. q( n3 j9 a2 t' Jously published studies of age-related 5 reductase activity.
0 f, H. V3 ~& J0 C4 WChildren with microphallus regardless of its etiology will; E# a% E4 h- h9 D6 E2 `
require augmentation or consideration for alteration of exter-( Y2 P  L1 y" N2 u' z
nal genitalia. In many instances urethroplasty for hypo-3 S% ~! ?7 @) R! @5 I
spadias is easier with previous stimulation of phallic growth.
; ^% r+ t9 c8 V+ j( I6 Z! ]( }The use of testosterone administered parenterally or topically
$ J' C. E7 y: {0 s& e* Bhas produced effective phallic growth. 1- 3 The mechanism of2 [# h+ ^+ K/ u6 i# m
response has been considered as local or systemic. With this
3 P( J2 ^4 d; m. v# n- Bin mind we studied 5 children with microphallus for response
& G: M- P) {" ?* H4 k: h8 Nto gonadotropin and to topical testosterone independently.
' ^/ E8 \' g1 H6 }  U" T0 y2 q2 M& GMATERIALS AND METHODS
0 N6 R  E, r- e1 `8 s2 DFive 46 XY male subjects between 3 and 17 years old were2 h/ ~+ Z6 h8 ]; E# A2 l% P$ q" N# K
evaluated for serum testosterone levels and hypothalamic, b* Q% m! ?8 ~& G% C# ^: E
function. Of these 5 boys 2 were considered to have Kallmann's
2 v( `7 `' P7 ]  b( _) ?0 ^syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
: V/ s9 x; ]1 F! d5 v7 r8 n, Z! Jlamic deficiency. After evaluation of response to luteinizing( o" a5 J2 O% V, h! a7 P
hormone-releasing hormone these patients were treated with
; j! z) y3 J! ^- Y" v  ]$ {1,000 units of gonadotropin weekly for 3 weeks. Six weeks
) ]( v/ K& c! D  Z( M7 k9 _; gafter completion of gonadotropin therapy 10 per cent topical7 W% t% n% @) L) U/ y8 P7 Q* O9 s
testosterone was applied to the phallus twice daily for 3 weeks.
# Q. d8 W) z  P' S1 {0 vSerum testosterone, luteinizing hormone and follicle-stimulat-  F5 X7 x  C0 R3 W+ ?4 U0 D
ing hormone were monitored before, during and after comple-
1 ~9 V- \# n% V& N- Y1 f& vtion of each phase of therapy. Penile stretch length was
' ^8 j0 o: \0 i+ y; iobtained by measuring from the symphysis pubis to the tip of
6 |  Z. c8 D. L) V$ x/ Zthe glans. Penile circumferential (girth) measurements were
" Q, g' n  u. m% W9 f' D  a2 ]" Robtained using an orthopedic digital measuring device (see1 e, }8 U! V7 ?. X
figure).* {$ q  y& W  ]3 }8 ?
RESULTS
5 ^0 m7 ^. V  ]/ `4 zSerum testosterone increased moderately to levels between
( P8 M5 q2 {3 a# I* E' J50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 _7 T$ ?  m, o( ^+ b# ^  I9 x3 p
terone levels with topical testosterone remained near pre-, R8 K# P/ h# [6 O+ a/ I  G7 O
treatment levels (35 ng./dl.) or were elevated to similar levels
  `  T4 o, G& }" R/ J. ~6 bdeveloped after gonadotropin therapy (96 ng./dl.). Higher* }& p: u& g7 [& r6 ]- c
serum levels were noted in older patients (12 and 17 years old),3 m; F6 O5 e; e( ], M0 F% O
while lower levels persisted in younger patients (4, 8, and 10
  M" I9 J4 K$ H, L- K3 R  Myears old) (see table). Despite absence of profound alterations
( d0 p) C  {% k, A6 b/ Kof serum testosterone the topical therapy provided a greater
' K$ y" E( [1 L% x, mAccepted for publication July 1, 1977. ·
: C$ _% Q" x* h! p* [Read at annual meeting of American Urological Association,
8 w& C9 g/ N: m+ B% ?! cChicago, Illinois, April 24-28, 1977.  }4 W% X, U- q+ x4 E5 r& A: X
* Requests for reprints: Division of Urology, Henry Ford Hospital,/ u2 m+ B' i; {/ k- @- q" x5 _: |
2799 W. Grand Blvd., Detroit, Michigan 48202.
0 x" l" ?! [5 m8 x" e. I! R3 @improvement in phallic growth compared to gonadotropin.
% x' q* H2 M9 J* {Average phallic growth with gonadotropin was 14.3 per cent
8 t" t' b. A! V# _# \- @# b8 g6 Pincrease in length and 5.0 per cent increase of girth. Topical* y4 D. b' [" e% b+ {
testosterone produced a 60.0 per cent increase of phallic length; P% @* t$ @' @6 B
and 52.9 per cent increase of girth (circumference). The. F9 `6 B8 {1 o7 o
response to topical testosterone was greatest in children be-% K6 B7 s3 G3 M% v0 ]) y
tween 4 and 8 years old, with a gradual decrease to age 17
6 Y% v1 _5 R: X+ U4 X' myears (see table).
' ~3 j9 }# t8 J. m% p$ [5 zDISCUSSION
/ h$ _) e/ s8 n0 B: |Topical testosterone has been used effectively by other
9 q3 d' k8 V3 f9 c( h* V8 Oclinicians but its mode of action remains controversial. Im-
% S5 V" i9 o" U2 U1 r+ ^8 @mergut and associates reported an excellent growth response
3 q  O* y/ l) a! j' eto topical testosterone with low levels of serum testosterone,8 U3 L+ m. m; \# G
suggesting a local effect.1 Others have obtained growth re-
7 l- ]! {5 I% W' \0 _8 asponse with high. levels of serum testosterone after topical
# i: w8 B: C- x4 `administration, suggesting a systemic response. 3 The use of
/ a* _6 F- U& A; I& Qgonadotropin to obtain levels of serum testosterone compara-0 r7 O& N* P2 B" ]* u5 C" Z
ble to levels obtained with topical testosterone would seem to
& X; d8 t- i4 Dprovide a means to compare the relative effectiveness of
3 k, m$ z1 ]4 I4 ctopical testosterone to systemic testosterone effect. It cer-
) _* T1 M" o2 w2 y3 C7 G6 wtainly has been established that gonadotropin as well as par-8 _3 b3 [7 z/ }8 E4 _
enteral testosterone administration will produce genital1 }6 d- h! J0 z
growth. Our report shows that the growth of the phallus was
8 f2 ^( R; l& J1 S% q  msignificantly greater with topical applications than with go-
. f8 o3 B9 X. z6 A/ ~nadotropin, particularly in children less than 10 years old.
+ n6 P9 \3 i$ e+ x) o- CThe levels of serum testosterone remained similar or lower0 _6 d/ C4 c  m3 v, m8 H* T
than with gonadotropin during therapy, suggesting that topi-
+ T1 o" T4 H: V; pcal application produces genital growth by its local effect as3 b; W/ x+ c1 {+ Q8 B
well as its systemic effect.
% t; N9 e; C3 ^6 X5 RReview of our patients and their growth response related to
: b# P$ B3 g  Hage shows a greater growth response at an earlier age. This is
) l2 Z4 n4 D' E, R& ?consistent with the findings of Wilson and Walker, who6 j" O- `" C. }0 `
reported an increased conversion of testosterone to dihydrotes-* o( w5 n+ T* q+ K6 k. Y1 i
tosterone in the foreskin of neonates and infants.4 This activ-
" X$ z3 Z6 ~) D5 a2 W+ kity gradually decreases with age until puberty when it ap-% f( x: ]* m+ a8 i1 V
proaches the same level of activity as peripheral skin. It may
0 U  o5 {' {; j6 \& _: twell be that absorption of testosterone is less when applied at
+ M. W. b% I! w* B# han earlier age as suggested by lower serum levels in children# O$ D) A% J  c- U1 Y
less than 10 years old. This fact may be explained by the. Y7 U9 F' g& n) Z' B* ^
greater ability of phallic skin to convert testosterone to dihy-' |4 Z; D; h9 J4 z. I% a& }
drotestosterone at this age. Conversely, serum levels in older9 [) g$ X9 ?+ A+ Z- s
patients were higher, possibly because of decreased local
  h) y9 }+ r) [& ^2 j% n* _0 O667
, C  ?$ `) `* L: a! E0 v) }( ^668 KLUGO AND CERNY
5 l" V% h! N; dPt. Age" \. y$ `0 @! J" Q5 ~
(yrs.)# ^: G; [. L% S/ `7 @3 L
Serum Testosterone Phallus (cm.) Change Length
! }$ f( \3 S1 C. \" Y(ng./dl.) Girth x Length (%). }6 O7 q' f1 i4 B* B
4! B! B- s& o5 G( B
8
8 M1 v4 s- V: v4 c, d$ m* g10
; K4 r: u6 P; K128 Q% n9 z! K* X+ d: T' H
17
4 I* _9 [# F( k+ j; Z$ w0 ]Gonadotropin
* I, e8 g! g# S/ y% o' [71.6 2.0 X 3 16.6# Y7 J0 H$ ^; x
50.4 4.0 X 5.0 20.0- D1 l; R( `; S* `2 x7 s
22.0 4.5 X 4.0 25.0+ }% P0 ]7 l9 q7 b' d$ H; u
84.6 4.0 X 4.5 11.1
) ], A3 N. y6 l- H" C: D85.9 4.5 X 5.5 9.0
" w" S1 k! y8 g2 L7 IAv. 14.3
+ V& ]) f& T3 x" A/ g3 T6 R3 V& S4
$ B1 p" R# H( P2 K8
; ]; L8 z+ e: I# q$ @5 p10: S" y3 \( Q; f
12  a; D' P) S# x) Y  {, L
17
8 i' M" J- `1 V# b2 [Topical testosterone/ K; J8 \* e- m, J& A
34.6 4.5 X 6.5 85
  M. a$ ]# L( X3 R38.8 6.0 X 8.5 70+ m6 ]' l* S1 z! g4 B0 }2 J9 j
40.0 6.0 X 6.5 62.5/ x; D# N; {. N, P
93.6 6.0 X 7.0 55.50 \8 ?% {1 _% {$ m1 Q  \
95.0 6.5 X 7.0 27.29 ~8 l* [6 w# I+ f- r, v/ W
Av. 60.0
5 `( }8 I1 k% Aavailable testosterone. Again, emphasis should be placed on) h* {. [  O* E, H% g: }
early therapy when lower levels of testosterone appear to
- x  d. x9 C% cprovide the best responses. The earlier therapy is instituted
  f' ^* l2 C7 h/ Y: [; [4 sthe more likely there will be an excellent response with low) o. P/ ?2 \1 X. x, X
serum levels. Response occurs throughout adolescence as2 d& d* p! r# P* P
noted in nomograms of phallic growth. 7 The actual response) ^3 z0 l% S  T# ^' |
to a given serum level of testosterone is much greater at birth- c7 g; @- p- A" p9 {+ S' J) H
and gradually decreases as boys reach puberty. This is most
" B  v3 J, O3 p& zlikely related to the conversion of testosterone to dihydrotes-$ Q5 m6 A- \. c
tosterone and correlates well with the studies of testosterone
; K, |. y& N, l3 B0 q) n- \: Rconversion in foreskin at various ages.
' \" @0 O3 I9 _5 r& a4 K, @2 Z) @The question arises regarding early treatment as to whether3 y/ w& V2 i1 B" g7 i: n
one might sacrifice ultimate potential growth as with acceler-$ E5 z+ G" I+ D2 q( R& I
ated bone growth. The situation appears quite the reverse9 r+ R( T& e( \; Y
with phallic response. If the early growth period is not used- `& c6 [# J  P  S
when 5a reductase activity is greatest then potential growth
6 k% t6 z/ i* @6 e/ q' Vmay be lost. We have not observed any regression of growth
( Z" n# H2 p5 [+ |( kattained with topical or gonadotropin therapy. It may well- y3 j; G. g* w$ b$ a
be that some patients will show little or no response to any
9 d, s* U3 _4 X/ Mform of therapy. This would suggest a defect in the ability to
- N7 R/ _. H3 F3 t+ iconvert testosterone to dihydrotestosterone and indicate that" T- m, Q7 U; L( g
phallic and peripheral skin, and subcutaneous tissue should
4 Y% ]8 N. o1 S( ]" r5 L+ \be compared for 5a reductase activity.
5 G8 e  Y8 }( x. x: |, r3 jA, loop enlarges to measure penile girth in millimeters. B,
6 [9 z. b4 g7 f8 K) o( Fexample of penile girth computed easily and accurately.
$ i7 v' u$ R# [- ?  u0 wconversion of testosterone to dihydrotestosterone. It is in this
% p' W) G4 |. y7 ?8 Uolder group that others have noted high levels of serum! y. w/ x5 ]% D4 A  M# V  Q$ ]0 w
testosterone with topical application. It would also appear
2 r9 ]4 P# u4 I  w* X! nthat phallic response during puberty is related directly to the
: |" T9 A; ?4 E5 d, Z0 e$ Lserum testosterone level. There also is other evidence of local
4 n. L8 m4 e3 m3 `: S8 c: Y4 Qresponse to testosterone with hair growth and with spermato-
! Q* q& L8 @3 p7 ?3 ggenesis. 5• 6
( x9 P" p3 {9 w: D- G( k) m( \/ J, |Administration of larger doses of gonadotropin or systemic5 s2 @+ D5 T# N# o) m, E# V, P
testosterone, as well as topical applications that produce- _2 Z! }. ^( r8 P7 m8 {
higher levels of serum testosterone (150 to 900 ng./dl.), will# q' B& v; G3 c* t
also produce phallic growth but risks accelerated skeletal
3 T! `2 C3 E8 x! O# @maturation even after stopping treatment. It would appear
5 e, R3 g. @# L, Z9 r! i  W+ gthat this may be avoided by topical applications of testosterone
8 P# B3 M2 Z; F7 cand monitoring of serum testosterone. Even with this control9 \& Z' H& P3 L# \4 g- l
the duration of our therapy did not exceed 3 weeks at any# l8 w% y9 J. U- U/ ]) r
time. It is apparent that the prepuberal male subject may  ^* E" [. P# s. y$ p- l9 @1 b0 }
suffer accelerated bone growth with testosterone levels near
" Y. E. a, u+ y5 Z7 C% j200 ng./dl. When skeletal maturation is complete the level of# Z; O9 |# Z3 G1 K
serum testosterone can be maintained in the 700 to 1,300 ng./0 H5 c/ ]0 ?3 E$ }' `# H
dl. range to stimulate phallic growth and secondary sexual+ h& ~% Q! l) L! h+ S2 j1 T
changes. Therefore, after skeletal maturation parenteral tes-
9 V3 O; X9 `6 X) B% Q1 J' ztosterone may be used to advantage. Before skeletal matura-" w. I2 g( v( ^- B; z$ S% G
tion care must be taken to avoid maintaining levels of serum! K) Q0 `3 r3 E6 F+ S5 U" G! B
testosterone more than 100 ng./dl. Low-dose gonadotropin
; C$ H" O5 c* @& s0 udepends upon intrinsic testicular activity and may require
0 _0 n* s" M! H7 E7 s" i! {prolonged administration for any response.
$ e, S; j* o$ ~Alternately, topical testosterone does not depend upon tes-0 }! t, N2 I  ^0 C- {* I, }
ticular function and may provide a more constant level of3 u, L1 W: A7 w" n& p6 g
REFERENCES. E# m! @& l% a
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 |3 d$ e) A; u+ e4 uR.: The local application of testosterone cream to the prepub-
( X! H$ K) I( H  s8 A% ^2 Zertal phallus. J. Urol., 105: 905, 1971.
3 t% I, u; ^4 [% G( z0 h2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 n7 I. m* n) Z1 w0 N) g7 `  H1 R
treatment for micropenis during early childhood. J. Pediat.,1 H4 H) o) p  I% d- m# n
83: 247, 1973.! H+ N) d4 k; n; W; @- e
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
- c( t0 F; P" _1 N: E" ^- g+ ?one therapy for penile growth. Urology, 6: 708, 1975.+ \3 }' ~% s8 ~. Z$ `# r# g
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ ]4 B- \2 [: w; @! n. X$ cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by' @- c9 I8 n0 U
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 W5 L, C6 p. r1 h8 k5 ?5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
& L3 k: h5 B0 u! i! cby topical application of androgens. J.A.M.A., 191: 521, 1965.
* z7 Q; Q# ^" |( {8 T* K( s6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local1 n' Y; G9 ?3 E
androgenic effect of interstitial cell tumor of the testis. J.
  {: d& y3 ^/ i6 m" v3 eUrol., 104: 774, 1970.
) }$ o# X! r8 y* K! u" n. a7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-: {) i% N2 D8 `0 k! [
tion in the male genitalia from birth to maturity. J. Urol., 48:
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