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鄉下的妹子太便宜,一次四個都要了[12P]

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大家好心情
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 p. i8 X' b; Q" y! Q4 W  iGONADOTROPIN( W* X8 {4 w" `" w
RICHARD C. KLUGO* AND JOSEPH C. CERNY
/ B- a& A" i. [- O+ ZFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan6 d1 N* A, Y2 y) Z9 O- c
ABSTRACT; m- q8 f  @# K% a' C
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
) v0 ^5 k0 y3 W6 g; \1 f* f0 \( d  b0 Owith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-  i" Y& E, j/ k* d- j5 @
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 I9 @( B. h3 `
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
+ ~% }! d, F! ]5 f7 ?for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 V: d! ^. P% B6 T! x: ?+ {increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; V  a4 b4 t2 r+ F- P- m) aincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 m/ X6 G# y! U8 o' J# a
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 E7 I& k0 I$ S# E& ^( l5 i, V
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
7 g: J: G- Q( x! A' i9 s# a; Pgrowth. The response appears to be greater in younger children, which is consistent with previ-+ ~' F: s( `" m/ f# h1 b
ously published studies of age-related 5 reductase activity.
, \! U/ O  M& T" R; QChildren with microphallus regardless of its etiology will2 Y. l$ X; n4 f  x
require augmentation or consideration for alteration of exter-% V+ ^* y$ {5 b( Q1 \! x
nal genitalia. In many instances urethroplasty for hypo-
$ N( T5 `* \* Q2 M: T) A* |spadias is easier with previous stimulation of phallic growth.; z3 u2 ^' }" ^( P- A
The use of testosterone administered parenterally or topically' h9 ]8 M- U; R: C9 \  t5 q3 v
has produced effective phallic growth. 1- 3 The mechanism of8 h5 t7 v" ~" h6 c7 X& }
response has been considered as local or systemic. With this. X3 B1 S4 X1 K; A6 {
in mind we studied 5 children with microphallus for response' _  z2 P3 i# ]
to gonadotropin and to topical testosterone independently.
% n1 u9 _4 Y* [( W2 @1 RMATERIALS AND METHODS% S7 f6 S" E2 _+ T+ O$ t+ p2 \3 m4 w
Five 46 XY male subjects between 3 and 17 years old were
* d8 W. P7 ]' V* z0 D2 s7 I  ~evaluated for serum testosterone levels and hypothalamic  D) L7 }0 `# B9 b# K
function. Of these 5 boys 2 were considered to have Kallmann's
9 Y; U/ \5 i5 ^$ f' S0 rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-+ m3 R. z* A+ u( Y% n# P5 ^
lamic deficiency. After evaluation of response to luteinizing
$ y( a- D; O  }" b+ C# T$ ^hormone-releasing hormone these patients were treated with
7 E4 g, A) ~$ x% n1,000 units of gonadotropin weekly for 3 weeks. Six weeks  ?& l2 C6 S1 L
after completion of gonadotropin therapy 10 per cent topical
0 s$ L* B, p* ?testosterone was applied to the phallus twice daily for 3 weeks.
2 p; R9 w7 a# @7 B1 O) aSerum testosterone, luteinizing hormone and follicle-stimulat-
, R2 o% q: j: @4 Zing hormone were monitored before, during and after comple-2 W. [8 P- o8 i
tion of each phase of therapy. Penile stretch length was& P" u! D: |" D  k) P. Q$ t% E3 X
obtained by measuring from the symphysis pubis to the tip of! T6 K; j+ F  V4 b- y& T0 n
the glans. Penile circumferential (girth) measurements were
' M. b: T- m) m; aobtained using an orthopedic digital measuring device (see5 V2 g% m5 R' h
figure).
& S& y1 ^7 n6 f7 E" _RESULTS1 J. z: m- h" b
Serum testosterone increased moderately to levels between
  m0 h+ ?, }. w50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
8 N9 E8 b3 Z2 ]1 }terone levels with topical testosterone remained near pre-4 g) x: ]) V7 P7 g% j
treatment levels (35 ng./dl.) or were elevated to similar levels% K7 R0 v& D: N& r, {$ X
developed after gonadotropin therapy (96 ng./dl.). Higher
$ }/ |9 U* @) N/ p7 Eserum levels were noted in older patients (12 and 17 years old),
# N0 q' J& R  T1 n3 T( a! rwhile lower levels persisted in younger patients (4, 8, and 10
7 Q% ?4 {2 G# ~& t$ Qyears old) (see table). Despite absence of profound alterations
6 L/ \- V+ `) [" _" e* u0 n# Xof serum testosterone the topical therapy provided a greater7 Y2 Q" }' }2 x! O5 R
Accepted for publication July 1, 1977. ·# u' e5 V0 n) Q/ C+ g; W. b
Read at annual meeting of American Urological Association,5 Z/ i0 ~* c( p8 \9 o# D4 E
Chicago, Illinois, April 24-28, 1977., {6 o8 m" [8 ~4 y' z- e5 E, A7 l
* Requests for reprints: Division of Urology, Henry Ford Hospital,3 D# g' h6 d4 P5 a& d2 o6 O; h
2799 W. Grand Blvd., Detroit, Michigan 48202.
& h0 c  z0 B' e7 A; Timprovement in phallic growth compared to gonadotropin.8 ]- E/ h: o$ W& a$ R3 q( Y
Average phallic growth with gonadotropin was 14.3 per cent! d% [+ B" g( k9 ?9 y% c: n
increase in length and 5.0 per cent increase of girth. Topical
$ n- I! l4 Q( a! y& g4 Ktestosterone produced a 60.0 per cent increase of phallic length
: T$ c/ Q- [# i0 t( ^and 52.9 per cent increase of girth (circumference). The
$ z- |: w% X8 l' Q& H3 R+ gresponse to topical testosterone was greatest in children be-
0 ]: y( e! k  P5 Stween 4 and 8 years old, with a gradual decrease to age 17
" ^( f( Y; I' n  X: J4 c" H1 ^! ^years (see table).8 K7 W( E% ]3 A$ r8 F6 [% {
DISCUSSION1 I  `" G! a! A! y- v4 K
Topical testosterone has been used effectively by other
: o! o. e* ]- Y: H+ z8 ?4 Tclinicians but its mode of action remains controversial. Im-3 l6 _' m' A% e+ _1 a& ]& F
mergut and associates reported an excellent growth response
" S# V3 e  i# L" f: |to topical testosterone with low levels of serum testosterone,- y9 Q0 Y& |! R& Z: l2 o
suggesting a local effect.1 Others have obtained growth re-
# t! Y8 Q! W1 ]$ X7 N- }; Osponse with high. levels of serum testosterone after topical
& v* q+ L! a! k9 [! X6 Oadministration, suggesting a systemic response. 3 The use of- {7 J/ ?( \% s  j9 m  ]
gonadotropin to obtain levels of serum testosterone compara-3 m! R& j/ }) }5 g: ]
ble to levels obtained with topical testosterone would seem to
! ]' D6 b4 m7 J1 v5 N. ~provide a means to compare the relative effectiveness of
6 @1 l/ V, z% }! htopical testosterone to systemic testosterone effect. It cer-) d5 g6 W. U. R1 }
tainly has been established that gonadotropin as well as par-+ x  @" w) {# D6 v
enteral testosterone administration will produce genital4 h' w* w4 q( U
growth. Our report shows that the growth of the phallus was
* _$ S( w/ p' H& Q0 Z8 f8 c# }4 w# Vsignificantly greater with topical applications than with go-  S+ ^* `# R' q* `% N( Y3 p
nadotropin, particularly in children less than 10 years old.
9 D7 {6 `) Y% G% G4 j. K7 W8 ^$ _4 wThe levels of serum testosterone remained similar or lower
( H) z& w2 M; j8 ^: S5 H$ athan with gonadotropin during therapy, suggesting that topi-
9 g' h5 _8 {: {; |. Jcal application produces genital growth by its local effect as5 m: q9 S& O$ @) M
well as its systemic effect.: f, x/ v8 r1 k5 N/ X0 K
Review of our patients and their growth response related to
5 b4 R% y9 |0 A8 Z- G& u! {4 \age shows a greater growth response at an earlier age. This is* T& O; s  C3 h* D2 A
consistent with the findings of Wilson and Walker, who
3 L5 B# t% V, k; j6 Ereported an increased conversion of testosterone to dihydrotes-8 D# i: [' _  p6 b+ |6 k/ y
tosterone in the foreskin of neonates and infants.4 This activ-8 R, S. G  J2 }; D
ity gradually decreases with age until puberty when it ap-/ W' D8 L* Q/ k% s7 b' j8 ?
proaches the same level of activity as peripheral skin. It may
2 c: o0 K- \8 V# y1 H8 ?well be that absorption of testosterone is less when applied at' O2 M# N0 q* o5 J7 S+ I
an earlier age as suggested by lower serum levels in children
4 o4 L3 Q' [5 G  o/ M4 Iless than 10 years old. This fact may be explained by the
7 M) R8 v% j8 |; x5 ~, j* Pgreater ability of phallic skin to convert testosterone to dihy-) U$ D$ f) Y0 q" [! {! o+ ]# t* t
drotestosterone at this age. Conversely, serum levels in older
: ~& J! \) @( w+ B9 P8 Ppatients were higher, possibly because of decreased local' q/ M0 D2 }  Y/ T  d
667: A) p4 ^3 }' Y6 M3 V0 ]- u5 m) v
668 KLUGO AND CERNY: }; x- F$ O$ z: B9 K
Pt. Age
6 @( `: ]( k+ v8 V$ \& l(yrs.)
2 P6 {+ {- [9 ^; O. \Serum Testosterone Phallus (cm.) Change Length
) ?* d$ @5 ?$ Z; p& E(ng./dl.) Girth x Length (%)
9 T" K$ ?/ ~$ G3 }4
7 x7 V3 V& K/ T7 b1 Y1 u' q0 w$ D89 \  I1 r! N3 _* H/ P# o- U- ^9 U! B% z
10  o% Q& q( [- L7 K' Q4 q! S0 P
127 k5 v! w1 ^5 T4 Y1 h5 E
17
+ S" p; m# ?  ?$ W9 g; e! f& qGonadotropin2 h" X0 q$ N, z% F- {. n
71.6 2.0 X 3 16.6
$ c+ [5 b( C' v) T8 [* g# X4 b50.4 4.0 X 5.0 20.0
0 G6 \, H1 c3 I" g3 z& R+ e! c22.0 4.5 X 4.0 25.0
$ }3 O8 f; _* V" U3 `8 {84.6 4.0 X 4.5 11.1' y# j! B( B/ X3 C0 K
85.9 4.5 X 5.5 9.0
1 l& N; F' J: k# RAv. 14.3, s( C2 Z3 V$ N  K6 X) X. @
44 c6 j: L. Z! Z) y
8
& l( Z) }5 q$ {% e4 N" J& f1 Q& g7 r% ?104 [4 X* Y; T5 ~2 w1 s: `
12
; ?/ Z4 w, u! f+ c* `17$ y5 e  ]' W( K
Topical testosterone, u8 L# E5 P( B  q" j
34.6 4.5 X 6.5 855 t& X0 Y8 g5 p/ j
38.8 6.0 X 8.5 70  r' u" K0 G8 S1 j
40.0 6.0 X 6.5 62.57 h0 h& ^8 B$ E, z3 V8 ?
93.6 6.0 X 7.0 55.5
4 t; C7 I4 E, M4 a+ @95.0 6.5 X 7.0 27.23 s! y7 w! u* `
Av. 60.0) y; m3 \1 \+ A
available testosterone. Again, emphasis should be placed on
6 m8 Q  o. F: H& G8 [( F4 Cearly therapy when lower levels of testosterone appear to
0 r# }. p# o7 a8 L% }! zprovide the best responses. The earlier therapy is instituted9 l% N. z% }( ?4 o
the more likely there will be an excellent response with low
/ d, S+ p8 m, o, Bserum levels. Response occurs throughout adolescence as2 M7 p- g1 R0 y9 w
noted in nomograms of phallic growth. 7 The actual response0 U# J4 `5 b. A9 j* N, K! e& f
to a given serum level of testosterone is much greater at birth
/ l* }+ V' n% Mand gradually decreases as boys reach puberty. This is most* Y0 P$ `8 e  u$ U" k4 U2 J
likely related to the conversion of testosterone to dihydrotes-, T8 l% i+ Q. t, A( ?! |
tosterone and correlates well with the studies of testosterone
: C; Y- P- ]( A2 p1 U3 y# L# \conversion in foreskin at various ages./ O3 s5 ~+ e/ u' |- f4 y
The question arises regarding early treatment as to whether
2 O9 U8 ~7 A1 l$ P: yone might sacrifice ultimate potential growth as with acceler-: I& |. O- B. a) z. z1 N9 u
ated bone growth. The situation appears quite the reverse& D2 y2 u% Q: j& W- Y
with phallic response. If the early growth period is not used# Y1 J2 b3 u3 \. Z- k4 m
when 5a reductase activity is greatest then potential growth- s' W0 B3 E; ]& D
may be lost. We have not observed any regression of growth
7 [; T$ U7 ^3 k! v0 H' fattained with topical or gonadotropin therapy. It may well
$ g' ?3 V" O* Zbe that some patients will show little or no response to any9 g. W: x( c# a; `$ P4 w) ~
form of therapy. This would suggest a defect in the ability to6 J. K6 D: Z" F( D! T4 \! o
convert testosterone to dihydrotestosterone and indicate that
4 Y0 N9 o; V+ A6 aphallic and peripheral skin, and subcutaneous tissue should* ^4 X7 z/ \6 z% Q) n4 F/ ]" O* F* {1 c
be compared for 5a reductase activity.
  O9 V0 a& Z& D% T/ mA, loop enlarges to measure penile girth in millimeters. B,
) N$ ?8 E% k# ?6 b& _' Jexample of penile girth computed easily and accurately.7 r: F$ W9 L% K' V8 k
conversion of testosterone to dihydrotestosterone. It is in this1 L  A5 J: [0 ?6 D! A( X: B$ K
older group that others have noted high levels of serum- X( `: U& C; p/ y
testosterone with topical application. It would also appear
4 J4 L9 Y( m9 R2 qthat phallic response during puberty is related directly to the
+ l7 Z$ N: F- w; @: f. S4 V9 _serum testosterone level. There also is other evidence of local% T% L  x; q# L$ Z% f1 Z
response to testosterone with hair growth and with spermato-# k% k* e! ~' d" I
genesis. 5• 6
  ]6 v5 j6 X* ~, L, ^+ UAdministration of larger doses of gonadotropin or systemic3 z& G9 E6 X6 x0 H" j0 ]( o2 A% z% J$ D
testosterone, as well as topical applications that produce5 \! l+ i' a( ]; l
higher levels of serum testosterone (150 to 900 ng./dl.), will
$ c+ `2 n. C/ malso produce phallic growth but risks accelerated skeletal
, b7 D* E0 G6 a7 D( s6 ?0 i" ]8 gmaturation even after stopping treatment. It would appear+ Y: ^( v) O& b( i+ o! f0 y0 O
that this may be avoided by topical applications of testosterone
8 H0 M: V; \1 M- T  O7 v9 [and monitoring of serum testosterone. Even with this control5 n) l+ X# X. D* t1 ~5 N$ K6 m! ~& A
the duration of our therapy did not exceed 3 weeks at any7 A" s5 J1 ?: [% Q" L/ J, R1 @+ R
time. It is apparent that the prepuberal male subject may
1 B% B; x6 T3 w$ u7 J4 `. a7 W- Z3 [+ d5 }suffer accelerated bone growth with testosterone levels near8 u4 B7 i1 @( ~& v0 ^! @
200 ng./dl. When skeletal maturation is complete the level of: Q, b" C- o+ `9 p7 H* {7 `
serum testosterone can be maintained in the 700 to 1,300 ng./: a" Q. q  f, ~1 ~  l% `! v
dl. range to stimulate phallic growth and secondary sexual
1 z( Q% Q- S) s/ ]) D- Xchanges. Therefore, after skeletal maturation parenteral tes-
; E. @. v+ M- s3 ctosterone may be used to advantage. Before skeletal matura-
4 g5 E1 R8 D3 Rtion care must be taken to avoid maintaining levels of serum
( _# O5 J$ q5 r* {testosterone more than 100 ng./dl. Low-dose gonadotropin* T! B5 I4 M- g4 V/ d  {
depends upon intrinsic testicular activity and may require
3 p! [- K% n, W% L' N( Q: `  m7 Oprolonged administration for any response.- h) v2 |4 ~. y$ v
Alternately, topical testosterone does not depend upon tes-( S' _3 U, ?/ _8 \& _1 L
ticular function and may provide a more constant level of
6 }, k* U! L7 p  I" VREFERENCES
/ B  p7 L7 U! |- E: G4 h1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
5 v7 ~) [2 e3 R* |1 c$ s$ \0 zR.: The local application of testosterone cream to the prepub-- D6 I# n0 {" i. Y& \
ertal phallus. J. Urol., 105: 905, 1971.+ k+ ~3 J# P6 R
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% i( m, f, ~- V( A; n, y" {  ]8 I
treatment for micropenis during early childhood. J. Pediat.,/ V/ U1 }4 i7 d0 X0 {
83: 247, 1973.7 i  s2 B4 R, w* m8 M3 n
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
& ~9 m, e) e3 `one therapy for penile growth. Urology, 6: 708, 1975.
$ C% ]; d8 x9 ]5 B2 t. T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 z2 r& t0 W( |( bto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ S" A, b% Z$ b3 c/ X7 t4 H1 k8 X
skin slices of man. J. Clin. Invest., 48: 371, 1969.0 s: ~  F0 R$ p6 K
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# p* A1 m4 w2 lby topical application of androgens. J.A.M.A., 191: 521, 1965.
3 s/ p+ [, u) c8 H$ b6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
9 u. B7 A/ K4 w, landrogenic effect of interstitial cell tumor of the testis. J.
/ f/ \) y3 v% ?/ b$ c7 N& u0 d& i! M: WUrol., 104: 774, 1970.8 N# e$ I* w2 W0 D! N
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 ?6 W5 c9 q6 ztion in the male genitalia from birth to maturity. J. Urol., 48:
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