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good good support
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大家好心情
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" G0 D, J# ^# k) l. R9 Y7 t
GONADOTROPIN
7 k# B6 O% {. D0 O; X# G2 ~RICHARD C. KLUGO* AND JOSEPH C. CERNY5 |3 }5 C, z9 R6 p1 a
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
" ~9 s/ e* j' P7 M4 F$ x0 O7 M$ `' }ABSTRACT" q, }8 c8 ^4 ^  z7 g* [
Five patients were treated with gonadotropin and topical testosterone for micropenis associated/ z# L5 I1 j: A8 ~/ V' }) T6 e
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: U1 j; w; [# ]8 U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) i  [" G+ X9 `  R* U
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
- x$ {- _1 _( [3 |9 @" lfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. C7 t3 m: ?+ G
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ J# ]7 _. }6 M1 }! W; f4 T: f
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response0 Z/ D: |- u, }4 ~2 N
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This7 @7 x( t2 v6 x/ E
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile3 W, P* V: H6 v1 M7 c7 m( Y& w
growth. The response appears to be greater in younger children, which is consistent with previ-
. ~4 {4 r8 s8 ]7 i; ]9 t( oously published studies of age-related 5 reductase activity.7 x+ [6 P8 U5 f3 M; @/ i, U4 u
Children with microphallus regardless of its etiology will
4 `+ j7 M3 I2 W7 srequire augmentation or consideration for alteration of exter-
) C  d4 ]' ^( Q  }( Q8 h. Enal genitalia. In many instances urethroplasty for hypo-. G) }+ i" t4 B  h: H. M
spadias is easier with previous stimulation of phallic growth.
: ~) l- J) e' z, {' j  {# C0 cThe use of testosterone administered parenterally or topically7 }% i/ z, d5 I9 o
has produced effective phallic growth. 1- 3 The mechanism of
$ Z" p1 o% Y' b8 R, Qresponse has been considered as local or systemic. With this
. Z! i; e! a- h. [4 j5 C3 Fin mind we studied 5 children with microphallus for response
1 o, W/ J7 o) R7 m9 K) A3 l2 _# T% uto gonadotropin and to topical testosterone independently.
$ c7 b% R$ \6 |1 A# r5 UMATERIALS AND METHODS) l- f/ _' D3 w
Five 46 XY male subjects between 3 and 17 years old were
: ?: N8 ?1 l, ~! @+ G1 s; f, u6 ~evaluated for serum testosterone levels and hypothalamic
- u9 n( }. C/ k% c  Tfunction. Of these 5 boys 2 were considered to have Kallmann's, T) g' i2 w9 \" x- ?4 [
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 U6 m6 u( ~  ~( g8 z7 N/ \# Tlamic deficiency. After evaluation of response to luteinizing
7 ^6 }% ^# r# L$ \+ thormone-releasing hormone these patients were treated with; ?1 H9 y" b% H2 {" s+ [
1,000 units of gonadotropin weekly for 3 weeks. Six weeks. F' V( V5 c2 G+ n+ W
after completion of gonadotropin therapy 10 per cent topical
  P) ]2 {9 O0 ~6 y1 V9 g7 f* ~testosterone was applied to the phallus twice daily for 3 weeks.& O+ y- f( [$ o5 ?6 {  B) Z, Q
Serum testosterone, luteinizing hormone and follicle-stimulat-! E. F: H9 i# L+ q( d4 C
ing hormone were monitored before, during and after comple-: s% c% `; ]" n' q
tion of each phase of therapy. Penile stretch length was9 s0 _$ V9 n& M
obtained by measuring from the symphysis pubis to the tip of$ i% c- l5 [* l* R# ]+ l+ r
the glans. Penile circumferential (girth) measurements were
6 W3 v2 o+ n% y3 Jobtained using an orthopedic digital measuring device (see
- D' i6 G7 S6 a2 \figure)., S( J+ m. T$ k7 C3 x3 ]7 s+ o
RESULTS" R* t4 ]9 T9 g: r$ F
Serum testosterone increased moderately to levels between8 h( R9 V" ^; \4 s. K& N. f2 u, s
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# m" O. s; V4 i( B1 Q7 c+ gterone levels with topical testosterone remained near pre-- v# {1 w+ z$ b6 v
treatment levels (35 ng./dl.) or were elevated to similar levels
" I# f. W5 h) b( wdeveloped after gonadotropin therapy (96 ng./dl.). Higher/ H& F# K( _% {: M$ \
serum levels were noted in older patients (12 and 17 years old),9 N6 |9 h; y3 v5 K) \0 @2 x, B7 g
while lower levels persisted in younger patients (4, 8, and 10
8 @8 `7 Z3 z# I* v% p+ Oyears old) (see table). Despite absence of profound alterations8 o6 w8 D+ Q! G- `7 [. j- L
of serum testosterone the topical therapy provided a greater
- T$ p! I$ [8 o* d5 d. FAccepted for publication July 1, 1977. ·
4 Q9 ^6 j! t8 b0 W) \7 p) URead at annual meeting of American Urological Association,* |2 S7 c& l9 k' w2 m+ s
Chicago, Illinois, April 24-28, 1977.
) _, E6 ]: k" Y. F* Requests for reprints: Division of Urology, Henry Ford Hospital,6 o; _- d6 h* L" N( B- e
2799 W. Grand Blvd., Detroit, Michigan 48202.
% w( `' i" S0 y0 himprovement in phallic growth compared to gonadotropin.
4 u! i% p8 N/ d$ ]: z2 {Average phallic growth with gonadotropin was 14.3 per cent/ f9 Y( }% Q0 p3 b+ d5 b8 q
increase in length and 5.0 per cent increase of girth. Topical
: h$ d1 e2 B9 H9 b2 rtestosterone produced a 60.0 per cent increase of phallic length
7 u3 n" q. d" \# I6 vand 52.9 per cent increase of girth (circumference). The1 Q9 L& u# O6 W% l: P
response to topical testosterone was greatest in children be-
) ?+ Z# d) o; j; I$ p% Ptween 4 and 8 years old, with a gradual decrease to age 17; O: B* Z5 F, ]- l% v/ c
years (see table).
$ X8 \2 ~2 Z! M: WDISCUSSION
* D# L; B5 h$ `" w7 `0 g( TTopical testosterone has been used effectively by other! ~. Q  x7 C8 m& z2 M) @7 _
clinicians but its mode of action remains controversial. Im-+ T7 n0 D9 e. P5 _! ^, h
mergut and associates reported an excellent growth response
' U4 s% _, P+ W% \to topical testosterone with low levels of serum testosterone,
0 X8 c2 `$ p. ?0 p: r+ Isuggesting a local effect.1 Others have obtained growth re-5 D! J- q) W" Y% r" @* i
sponse with high. levels of serum testosterone after topical
  v( ~2 F$ M' w0 Aadministration, suggesting a systemic response. 3 The use of
3 N. M  ]$ e" r& Dgonadotropin to obtain levels of serum testosterone compara-
4 H" w* l8 V0 Q- A/ gble to levels obtained with topical testosterone would seem to
: ?6 ~: o" D! v8 p- [+ D# Oprovide a means to compare the relative effectiveness of
( W1 k2 l8 Y" E2 Qtopical testosterone to systemic testosterone effect. It cer-8 t' Q+ V3 E% \, b; c; E
tainly has been established that gonadotropin as well as par-6 J$ o' @* Q# s: R2 F
enteral testosterone administration will produce genital
( W4 i1 m/ q- Y# A/ H) r3 Kgrowth. Our report shows that the growth of the phallus was% Q# }# J9 [  R0 N! p
significantly greater with topical applications than with go-
. t) m. u  ^0 u6 i/ _" C# t0 I- unadotropin, particularly in children less than 10 years old.
9 R7 }) l; U) @/ M; U. @The levels of serum testosterone remained similar or lower! ~; z' {8 m2 c9 e6 L
than with gonadotropin during therapy, suggesting that topi-' T# [0 N3 v. z
cal application produces genital growth by its local effect as
) y' M/ b* H$ _/ Wwell as its systemic effect.
3 X9 A# `% U1 C6 i1 @Review of our patients and their growth response related to3 g" A) Z# Z, B3 F' m) _( `! A6 l
age shows a greater growth response at an earlier age. This is
) v: [1 I% k$ x+ Aconsistent with the findings of Wilson and Walker, who
" H- G, k+ x) z: mreported an increased conversion of testosterone to dihydrotes-
, y# @# k4 k, M6 g9 ~tosterone in the foreskin of neonates and infants.4 This activ-
- \4 ^9 x" S( ?ity gradually decreases with age until puberty when it ap-
* c3 I: s- Y, ?. _0 cproaches the same level of activity as peripheral skin. It may* q3 S. ^- P8 w4 {7 {3 }5 t
well be that absorption of testosterone is less when applied at& i% E0 Q: @; Z: c7 s/ |
an earlier age as suggested by lower serum levels in children# l+ M% Z; o8 R
less than 10 years old. This fact may be explained by the, f) s3 z: p0 B0 H& s& {
greater ability of phallic skin to convert testosterone to dihy-
) b) o% Z& T- q/ ~9 B' M7 Y7 Pdrotestosterone at this age. Conversely, serum levels in older
9 I1 n$ s/ P  n" s; F5 Q3 I) [patients were higher, possibly because of decreased local3 }! M8 n4 x  F$ s; Y! R
6678 y- K5 e; C$ i" E
668 KLUGO AND CERNY
% v2 m/ s$ T1 |. B  I% y: y6 d8 A; G2 ZPt. Age/ ?& Y2 o, t2 W  R" a
(yrs.)
' A$ V7 R1 O, H7 D6 e0 TSerum Testosterone Phallus (cm.) Change Length/ k% i. Z. Q0 U6 q5 N! l
(ng./dl.) Girth x Length (%)
  D: A/ o# U, u4! d4 H3 J- U0 `: d! l( W
8/ Q( x+ D' m6 C% }! D0 k
10
' L5 Y" U' ~/ `3 {) l4 F9 m; l& r7 b12. ~6 g2 g1 i- V2 m* S& g
17. _8 ]* K! F- p& H4 f" @' h
Gonadotropin+ o! y5 d+ A9 e: ]$ o
71.6 2.0 X 3 16.6
( S& [: z, {9 D50.4 4.0 X 5.0 20.0' |" `5 n; i' c' i5 G9 k6 |! y$ U
22.0 4.5 X 4.0 25.0: a) m. n5 o1 b# W- ?1 I" H3 H9 n/ ^' ]
84.6 4.0 X 4.5 11.1" ]! B1 z9 B0 t& N
85.9 4.5 X 5.5 9.0
- w* W2 d* S4 q8 j7 i! `Av. 14.3
( q/ ?3 v9 P# u0 s2 d4
7 M. E, z- T6 s7 N8* n! e* D& \* Q7 w0 J
10' E$ K. m: i& f) ]* t. _. K
12
5 f+ D8 i& ^% R, L177 J( C  ?) ^& `) G6 m, L1 L
Topical testosterone1 s: l; M, c$ J1 O6 A% Q7 b
34.6 4.5 X 6.5 85
' A% ]$ T5 ]) i" d" q6 d5 ]38.8 6.0 X 8.5 70
3 X2 d: L& j) a40.0 6.0 X 6.5 62.51 h. ^1 O: H" C# a
93.6 6.0 X 7.0 55.5& o" y! U3 j, Q8 I  b0 e6 g
95.0 6.5 X 7.0 27.2/ M& K  b7 j# Q& F5 y
Av. 60.0
/ L( H% i5 A9 @" ]  O# F6 Y& Pavailable testosterone. Again, emphasis should be placed on  X6 R; Q% E; z: ^. V5 c( }
early therapy when lower levels of testosterone appear to
- T6 w  f: O4 m9 n0 ~& ?5 T! sprovide the best responses. The earlier therapy is instituted# p8 m+ ?$ R: H/ b
the more likely there will be an excellent response with low
& _( r7 _/ ^& ^  J* yserum levels. Response occurs throughout adolescence as
$ R6 v) C; w0 u1 q8 \noted in nomograms of phallic growth. 7 The actual response. f7 e8 m5 r$ I' r& x% w
to a given serum level of testosterone is much greater at birth
0 A9 C1 H2 o8 A7 ^and gradually decreases as boys reach puberty. This is most3 ~; B: K% E5 t
likely related to the conversion of testosterone to dihydrotes-
: Y2 r8 h1 y  J1 o/ Etosterone and correlates well with the studies of testosterone8 D" [" W) ^, E4 h4 ~
conversion in foreskin at various ages.) [% H- T( ]# ~, z- h' h8 f7 U7 V
The question arises regarding early treatment as to whether
( G4 }/ s% C4 V0 j+ i: oone might sacrifice ultimate potential growth as with acceler-% W  Y1 K1 d; k( O; N4 m( S& U
ated bone growth. The situation appears quite the reverse9 D' U+ v# ^% c, Z
with phallic response. If the early growth period is not used3 T* H1 U# m- J1 \2 l# [
when 5a reductase activity is greatest then potential growth1 y5 M; x% F+ M/ ^5 d
may be lost. We have not observed any regression of growth3 u  x5 t1 }* W+ C& \4 x" J
attained with topical or gonadotropin therapy. It may well( R1 @6 }, q2 Y. `
be that some patients will show little or no response to any
, A% Z$ [. _! F8 ]* Y3 S8 K# s% Sform of therapy. This would suggest a defect in the ability to8 V; z% i, A: K( B6 }
convert testosterone to dihydrotestosterone and indicate that! R" S; k. p3 o
phallic and peripheral skin, and subcutaneous tissue should
( A6 s- A3 [* K' h4 U- Obe compared for 5a reductase activity.
( E; }1 Y4 c) {7 _A, loop enlarges to measure penile girth in millimeters. B,( N* n# {$ @3 Z7 X+ l  S# V
example of penile girth computed easily and accurately.
3 U* \3 r" x8 K0 h4 kconversion of testosterone to dihydrotestosterone. It is in this
5 X" J3 o# j$ ^! w- c, molder group that others have noted high levels of serum
3 R# }; V- n8 f7 ^8 J% Rtestosterone with topical application. It would also appear/ [, x$ N  B6 D& c/ p0 h+ m
that phallic response during puberty is related directly to the
' [3 s, B) Z# V1 Gserum testosterone level. There also is other evidence of local
2 A9 n; F0 g% Qresponse to testosterone with hair growth and with spermato-
# _$ S: I0 _  I2 i1 T- ^2 C" _genesis. 5• 60 b# V" R1 q. L+ a# l
Administration of larger doses of gonadotropin or systemic
% [: c# \& R7 h* U1 {testosterone, as well as topical applications that produce
2 T5 \) h) O3 r/ d) dhigher levels of serum testosterone (150 to 900 ng./dl.), will& F: a/ q$ A) _5 T
also produce phallic growth but risks accelerated skeletal
( D( N5 w* V5 w. @! ]# N& F* Amaturation even after stopping treatment. It would appear
8 W  k0 |4 b/ ]1 o6 P4 b9 u  |that this may be avoided by topical applications of testosterone
2 w' o+ ?: H3 Q2 K- Kand monitoring of serum testosterone. Even with this control
& z# q0 _: Z) n6 d( w% d2 Uthe duration of our therapy did not exceed 3 weeks at any
2 K) |& V! ?) e; U  v' N7 G% B$ Stime. It is apparent that the prepuberal male subject may
: Z+ S5 o, N2 N) d( T: N; {7 `suffer accelerated bone growth with testosterone levels near2 _& J; o6 w  T. \* E' A
200 ng./dl. When skeletal maturation is complete the level of
  C- R* s7 W/ @' y2 Hserum testosterone can be maintained in the 700 to 1,300 ng.// t- S- H# \$ h
dl. range to stimulate phallic growth and secondary sexual# u5 }( S: J/ J. u2 N) Z
changes. Therefore, after skeletal maturation parenteral tes-
+ y  S7 q1 _1 t' @7 g( gtosterone may be used to advantage. Before skeletal matura-
+ L# K1 L+ i3 _8 K" mtion care must be taken to avoid maintaining levels of serum# w4 w0 {( @7 ^+ q! c7 h$ g
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ @" ]& p  u" o* ^! ~) Wdepends upon intrinsic testicular activity and may require
; D6 D& L9 e) r! g, ]( ^' Q8 l+ H5 dprolonged administration for any response.( ~' W: U, f7 d1 m- X! t9 I
Alternately, topical testosterone does not depend upon tes-
+ A. B8 ?+ M, S8 _ticular function and may provide a more constant level of' x6 d1 ~9 l  p, x' E0 u0 b
REFERENCES
9 T% d1 Y# h9 j& _1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,) q& r) s- Y( Q1 c
R.: The local application of testosterone cream to the prepub-
$ I8 C' @' A! w) Y( _# {* z8 Tertal phallus. J. Urol., 105: 905, 1971.
' G# P' v+ z0 V2 k8 T0 r2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 M0 {8 D5 n/ X7 T
treatment for micropenis during early childhood. J. Pediat.,
# Z. ]/ O9 M/ ?: @0 L83: 247, 1973.
7 m) G# d6 `5 ~& c) a3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 Y7 R* P- n, G( P& C* K8 fone therapy for penile growth. Urology, 6: 708, 1975." {, P# {  K9 e9 {/ \
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( l' S8 |% j! w- Ato 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
5 `) s( x3 x3 Z! N! pskin slices of man. J. Clin. Invest., 48: 371, 1969.$ y& k2 S8 s1 s! E  Z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
6 @* V2 H8 ~2 i2 k) Uby topical application of androgens. J.A.M.A., 191: 521, 1965.
: }$ ^/ k1 A& |; Z4 f: u6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local3 m( n$ P% p1 o# F4 H9 d& B
androgenic effect of interstitial cell tumor of the testis. J./ }9 f& t, A, L7 D4 S) N
Urol., 104: 774, 1970.; x' ?7 o3 T, J& B: ^) D3 y
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-0 d2 Y7 \$ W% M2 P- Q
tion in the male genitalia from birth to maturity. J. Urol., 48:
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