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大家好心情
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# x% l8 P7 \3 c4 @: N% B9 l% Z  j) i& C
GONADOTROPIN
% [& E% _: t7 Z0 t# ]+ J6 `# XRICHARD C. KLUGO* AND JOSEPH C. CERNY
4 }* L+ @* u0 P# H7 P0 u) ^From the Division of Urology, Henry Ford Hospital, Detroit, Michigan. i% N( q: f& K
ABSTRACT* x2 X( t9 a% f$ L. z
Five patients were treated with gonadotropin and topical testosterone for micropenis associated% \5 ]# H  T- ~/ E
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 w; {/ j9 B$ v$ j
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 V/ q+ L7 X+ O/ V" @0 _5 C9 Rcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
0 x$ Z8 b0 F/ x1 r- V; Dfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 k" `5 S! ?& ]/ ?7 D" Iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: N" Q0 q8 L! p% q8 J& Gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
1 H7 U, r; J. q) C+ Loccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This2 e2 y. b: j$ E. u( o
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile& l+ \5 [" L" ^* @3 B
growth. The response appears to be greater in younger children, which is consistent with previ-
8 C8 L  n3 S1 R" a% o" Z  c1 L0 ~ously published studies of age-related 5 reductase activity.4 U+ P+ W7 p* n
Children with microphallus regardless of its etiology will) h) ?0 a/ p  k; Y
require augmentation or consideration for alteration of exter-
3 ]! A4 E  q% }! Nnal genitalia. In many instances urethroplasty for hypo-
7 I0 X+ w0 O4 N+ F: Vspadias is easier with previous stimulation of phallic growth.- l: u' P1 B* K
The use of testosterone administered parenterally or topically
+ {& J) r7 Z" ]: D5 ?has produced effective phallic growth. 1- 3 The mechanism of
# y* b" \6 ]+ H9 E) H- {response has been considered as local or systemic. With this
7 [( x5 l7 [2 V2 d/ Iin mind we studied 5 children with microphallus for response
" @* [# ]# x; Y& u0 T9 hto gonadotropin and to topical testosterone independently.; W: G6 f. V: o& p
MATERIALS AND METHODS! n4 X1 U' ], e+ K
Five 46 XY male subjects between 3 and 17 years old were( K7 S3 H9 e9 ~  _  \$ r6 d% E
evaluated for serum testosterone levels and hypothalamic
# g" K; T7 i# P) N- C6 b& xfunction. Of these 5 boys 2 were considered to have Kallmann's
! F- O7 U/ }! C/ q! W# B( O5 `syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
5 g" c( }4 M  ~lamic deficiency. After evaluation of response to luteinizing, O- |7 m& w4 o) ?2 W- G# O
hormone-releasing hormone these patients were treated with/ a2 u$ Y0 ?9 W5 @! O
1,000 units of gonadotropin weekly for 3 weeks. Six weeks2 @; S" X4 X/ W2 j# P, ]1 O3 _3 @
after completion of gonadotropin therapy 10 per cent topical
0 @5 E, N- z$ B* X8 z0 Itestosterone was applied to the phallus twice daily for 3 weeks.
2 \  }* C& ^2 g' _1 hSerum testosterone, luteinizing hormone and follicle-stimulat-& `! `3 u% Q  e- C! k, i: h
ing hormone were monitored before, during and after comple-7 U( x  s6 U  L( z! a
tion of each phase of therapy. Penile stretch length was. V8 j3 _" T# W, E7 b
obtained by measuring from the symphysis pubis to the tip of- o/ r% m% F  H) Z  m& o6 Q6 y9 M+ F
the glans. Penile circumferential (girth) measurements were
* T) E- V5 b+ z! y  \obtained using an orthopedic digital measuring device (see
; j; x. Q3 N4 h. y  g& z% r6 e; tfigure).0 ]' a+ q" v7 d& `, ^
RESULTS3 X+ T& L% ?% }$ K, g/ u
Serum testosterone increased moderately to levels between, E/ @: X* _& `9 k# j  @" a
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 M) ?- [* G% [4 k
terone levels with topical testosterone remained near pre-* r& N+ [4 n" i8 Z
treatment levels (35 ng./dl.) or were elevated to similar levels! o9 A5 I8 n6 y& c, z& _
developed after gonadotropin therapy (96 ng./dl.). Higher
, F$ U+ t- C2 G3 H& ?serum levels were noted in older patients (12 and 17 years old),
/ D. G0 ^6 ^1 w" m$ Y/ J( Qwhile lower levels persisted in younger patients (4, 8, and 10
- ~6 p$ T. Q* Z  D: {' q; x  i0 vyears old) (see table). Despite absence of profound alterations
4 V" A2 b5 c0 a5 q: Yof serum testosterone the topical therapy provided a greater
/ C( t" {( r1 `+ ZAccepted for publication July 1, 1977. ·
1 C  N( r2 e! t( b7 P% y5 fRead at annual meeting of American Urological Association,# B) |, L- K' C6 C
Chicago, Illinois, April 24-28, 1977.+ W& \% x1 l; x: p
* Requests for reprints: Division of Urology, Henry Ford Hospital,
6 ]+ V0 j. V' r, m# p( ~; `3 J# k2799 W. Grand Blvd., Detroit, Michigan 48202.
3 ?2 v8 ]' Y2 Cimprovement in phallic growth compared to gonadotropin.
/ A: f& z) b; ]6 fAverage phallic growth with gonadotropin was 14.3 per cent
0 E: B7 H# R7 G2 Rincrease in length and 5.0 per cent increase of girth. Topical
& F( ^/ ?0 i, J! Htestosterone produced a 60.0 per cent increase of phallic length3 {8 @/ K2 I: k; j% L
and 52.9 per cent increase of girth (circumference). The/ R# T/ D5 J; @6 g* m+ q
response to topical testosterone was greatest in children be-
$ b# |( q$ |% atween 4 and 8 years old, with a gradual decrease to age 17" s- C* _- ~2 H( u/ A
years (see table)./ @1 n& H1 d* U. n- U
DISCUSSION3 A* d* x1 F6 R' z9 e; S2 u0 @
Topical testosterone has been used effectively by other8 o% d8 u2 j# ^* X; N
clinicians but its mode of action remains controversial. Im-
0 L$ h& I' F. e& N7 X+ p9 hmergut and associates reported an excellent growth response
" U  ]! \0 r1 v* [, Y) }to topical testosterone with low levels of serum testosterone,9 X8 ?/ _$ E* Y0 C1 O3 I
suggesting a local effect.1 Others have obtained growth re-4 v9 W. h$ _$ I2 c9 o& t4 D
sponse with high. levels of serum testosterone after topical" G' e+ x$ C4 p# D' s' t2 O
administration, suggesting a systemic response. 3 The use of
  R5 b: k' I  u1 N" L2 _3 h' F1 ogonadotropin to obtain levels of serum testosterone compara-+ [& F& ?; C9 b
ble to levels obtained with topical testosterone would seem to
1 w" K1 L: `/ z4 Wprovide a means to compare the relative effectiveness of
9 C, B4 r+ U6 E$ n, P; h' u! G- gtopical testosterone to systemic testosterone effect. It cer-
7 x; H: s( v, stainly has been established that gonadotropin as well as par-
  _: P! M5 u+ Menteral testosterone administration will produce genital
+ c) g5 C' [7 k9 R! y9 Agrowth. Our report shows that the growth of the phallus was
+ i0 }) f5 ~% w- dsignificantly greater with topical applications than with go-
- u# ]$ R* e# Dnadotropin, particularly in children less than 10 years old.
/ w& q; b2 ~% YThe levels of serum testosterone remained similar or lower
, N! ^2 l0 O5 K  K$ {4 t6 n3 \" ^& o7 mthan with gonadotropin during therapy, suggesting that topi-
1 C1 E7 l1 [4 J/ b, @8 w3 Zcal application produces genital growth by its local effect as
1 M* {- e# I2 v' S7 lwell as its systemic effect.# w1 d3 G0 z+ V" S8 c! E; l& Y
Review of our patients and their growth response related to: m0 S" J: D! T5 }
age shows a greater growth response at an earlier age. This is& G) \% f' O$ Z4 C, |  s! x
consistent with the findings of Wilson and Walker, who% X- x, D$ L4 B4 ?+ H
reported an increased conversion of testosterone to dihydrotes-+ S- y# H" ~0 U& P, ~5 d
tosterone in the foreskin of neonates and infants.4 This activ-$ o& t0 L% @2 L9 M1 v1 m. u, _& R' @% b
ity gradually decreases with age until puberty when it ap-
" w  y% {  Q+ [+ uproaches the same level of activity as peripheral skin. It may
, u0 C4 |9 Y+ {) ewell be that absorption of testosterone is less when applied at
3 T  }) v, d$ t! g* {an earlier age as suggested by lower serum levels in children
" r9 p) S/ c8 \7 f( I) ~) B% B8 ~less than 10 years old. This fact may be explained by the
# S7 W5 ]& P% ]3 y9 ugreater ability of phallic skin to convert testosterone to dihy-
* m( F& d1 G+ a3 M- ~drotestosterone at this age. Conversely, serum levels in older
. t" d7 h# y: L6 H1 Cpatients were higher, possibly because of decreased local
9 T/ ~$ z) |  ~' A5 c9 v6676 k% c+ E. D. ^
668 KLUGO AND CERNY3 T' U& V9 ?! n' ^
Pt. Age# d% Y* Q7 d! h2 A6 d8 x/ d
(yrs.)
  A% U( @( A2 i$ k. g7 U) }Serum Testosterone Phallus (cm.) Change Length( f  u1 m! j7 z# \7 T- K6 ~/ z2 Q
(ng./dl.) Girth x Length (%)
) {9 v6 U( r; Q! [! `% E+ \& D4/ v) d/ N% a2 ]' r
8+ r+ Q2 l9 D+ |9 E+ g
10
: [) A9 J/ Z) A9 C* e9 G12
% S6 J* w5 }0 F/ z% T" F2 f17
2 K! \  a1 u: B; ~) eGonadotropin: O9 n% ^* C- N% V0 V
71.6 2.0 X 3 16.6
" P. e& g0 v, w. m4 m3 N; w50.4 4.0 X 5.0 20.0
1 E* Q8 j: p( R" c0 i1 ]" x2 E22.0 4.5 X 4.0 25.0
* l4 l( e5 ?9 \84.6 4.0 X 4.5 11.1! W  \8 w! H3 ^
85.9 4.5 X 5.5 9.0" v8 g1 D2 N, c" Y' ~1 r8 y
Av. 14.3
$ C, T* E, m. Y8 Q& j( F7 Z* u: }' r4; Z5 R9 Q/ ?- ]% H8 l& `
89 B8 e$ n6 K/ {& P
10
; c$ s7 V+ p, E) b5 G7 d4 y) y12
( i" c% y. x$ P" ^17% B) N/ t0 [! F$ h
Topical testosterone
. O4 Y0 `  A( b* R34.6 4.5 X 6.5 85
4 ^* Q8 x. k3 o5 {* h5 [38.8 6.0 X 8.5 70
, ]% R8 G" f2 E5 ]' _( G40.0 6.0 X 6.5 62.5
$ Z, X5 w% b; s9 v93.6 6.0 X 7.0 55.5( M$ V& V6 o% m2 Y3 G. A
95.0 6.5 X 7.0 27.26 N6 I% ^2 H/ I. g: D, l0 d
Av. 60.0: I; ]2 c; [3 R1 `
available testosterone. Again, emphasis should be placed on( Z& j  b4 B( |( j& {. O  O) ^5 g5 `
early therapy when lower levels of testosterone appear to
$ n8 X, K" {; D1 o  wprovide the best responses. The earlier therapy is instituted9 k# p6 u# s; J, F0 i+ z6 O
the more likely there will be an excellent response with low& x+ `- l( u1 r8 I
serum levels. Response occurs throughout adolescence as9 ]$ E) B" u. J, c( M  J
noted in nomograms of phallic growth. 7 The actual response8 o' D+ S; I3 t8 @
to a given serum level of testosterone is much greater at birth
& C+ t, G$ e2 q# `6 wand gradually decreases as boys reach puberty. This is most
6 ~- f5 I1 X# i; ]4 Tlikely related to the conversion of testosterone to dihydrotes-
' i' N# |6 D# D( ]! A& L6 R6 Y) ftosterone and correlates well with the studies of testosterone# u* D% I7 Y0 {
conversion in foreskin at various ages.
" W1 k" e, `3 K+ y' J" \# fThe question arises regarding early treatment as to whether1 O  s' j  l$ M5 \/ d
one might sacrifice ultimate potential growth as with acceler-/ n* V) _% T7 h3 x/ L1 R
ated bone growth. The situation appears quite the reverse
* n7 R% j6 m& u' N; u  xwith phallic response. If the early growth period is not used- S/ ^/ i" q& M! N6 e! t, Q5 C8 u
when 5a reductase activity is greatest then potential growth, x  }) W- b4 h% m$ o- k6 K4 p3 i8 ^
may be lost. We have not observed any regression of growth0 T& `% m9 f- ?5 y" N
attained with topical or gonadotropin therapy. It may well
( Y3 r# W& d! q2 W7 Z" abe that some patients will show little or no response to any
, o$ N0 H( f" R; s6 K: Cform of therapy. This would suggest a defect in the ability to0 Z+ v8 T0 c. X* ?8 d# R4 J4 ?
convert testosterone to dihydrotestosterone and indicate that8 F  E, F* s# M/ f
phallic and peripheral skin, and subcutaneous tissue should1 h4 W+ I$ `2 b$ T/ i# K* I( b
be compared for 5a reductase activity.6 x: t- j  m4 v" d
A, loop enlarges to measure penile girth in millimeters. B,  {6 d+ T) b8 j
example of penile girth computed easily and accurately.7 i% ?6 ~. t. s$ u9 o
conversion of testosterone to dihydrotestosterone. It is in this
3 }2 |) \! \3 J. N9 ]7 solder group that others have noted high levels of serum
# N1 b. E# t/ N# o8 @5 B) Stestosterone with topical application. It would also appear
- x* O+ `& Y* }* l% }9 ~  U! v  othat phallic response during puberty is related directly to the0 H2 j% D- c3 c: }+ G
serum testosterone level. There also is other evidence of local
& G8 H  r) D3 ]3 Q# o$ h7 Cresponse to testosterone with hair growth and with spermato-
' N+ N! r; R. ^3 M) m7 |; \genesis. 5• 61 I8 }% j0 A9 i
Administration of larger doses of gonadotropin or systemic
2 x7 C8 r6 o% z. Z7 s) v4 f" Ltestosterone, as well as topical applications that produce+ ?, N5 T% U" z. A: c# v' |/ g
higher levels of serum testosterone (150 to 900 ng./dl.), will3 `9 {% ^3 E7 U0 K" c7 j
also produce phallic growth but risks accelerated skeletal
) H# {) @, R7 @" a* I; G$ w7 I+ O# E; n1 ymaturation even after stopping treatment. It would appear
) z# F4 V& ]$ U; r# R- p1 zthat this may be avoided by topical applications of testosterone) u9 [, ?' |6 `' c  Z3 }0 m
and monitoring of serum testosterone. Even with this control
7 C1 I. ^) [9 x5 f" j7 hthe duration of our therapy did not exceed 3 weeks at any) a- _+ [; R/ N
time. It is apparent that the prepuberal male subject may0 w5 D: `$ d% u; f+ q- w
suffer accelerated bone growth with testosterone levels near
8 ^& q' j1 |, D; g# ?200 ng./dl. When skeletal maturation is complete the level of
9 e0 d* W' n. K( M+ y8 _serum testosterone can be maintained in the 700 to 1,300 ng./7 t* I, i! ~" O+ x" |
dl. range to stimulate phallic growth and secondary sexual
$ [0 c$ ]: Z$ v0 [, e! echanges. Therefore, after skeletal maturation parenteral tes-
4 a/ P7 y* j8 ctosterone may be used to advantage. Before skeletal matura-, E  k% [" i- O/ p$ d  B) D
tion care must be taken to avoid maintaining levels of serum. b& u5 A6 @+ M6 h' |* o4 k
testosterone more than 100 ng./dl. Low-dose gonadotropin' ?  w3 u2 L9 l1 S7 b) U
depends upon intrinsic testicular activity and may require8 H) u) V/ `* N6 w5 C
prolonged administration for any response.& a8 p9 g5 |  h' W+ ?) P
Alternately, topical testosterone does not depend upon tes-. i; b  W1 p% C& e! B- k$ h1 N/ Q( }
ticular function and may provide a more constant level of6 M4 B3 w, h: T: e/ Q; ]* K/ m
REFERENCES  R, C/ l4 |+ J, W/ v# [
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
2 }+ R" P0 D  i) ~" ]$ _R.: The local application of testosterone cream to the prepub-0 g4 @0 N' _5 G' i
ertal phallus. J. Urol., 105: 905, 1971.! h) w+ i/ Z; q+ a1 T- ~* c
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, V: M# M- [' }& _+ Z
treatment for micropenis during early childhood. J. Pediat.,
- g: u3 n' q8 ^0 r8 N& e+ ?# ?83: 247, 1973.
+ U  j; K) N& R0 N! M6 n3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* }. v  x- v4 C7 z* i
one therapy for penile growth. Urology, 6: 708, 1975.
3 S  {+ a1 j9 t6 s3 Z( G% @. y7 B4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) [  |; O0 @4 k2 H1 uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, d! z7 R) Z0 Z2 S# fskin slices of man. J. Clin. Invest., 48: 371, 1969.; w3 H5 }0 K- M' z! K1 L5 a+ i
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
9 q; d4 D: P: C- e9 o- j0 h* Eby topical application of androgens. J.A.M.A., 191: 521, 1965.! ~/ H' \$ `4 k5 u1 h7 t
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 [- G& d. G3 f1 ?5 q6 e
androgenic effect of interstitial cell tumor of the testis. J.
. H% R! L& W7 }: xUrol., 104: 774, 1970.
4 s: W" {$ E( m7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
9 U6 ?% B; o+ y, h+ p# `* w; Jtion in the male genitalia from birth to maturity. J. Urol., 48:
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