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大家好心情
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND! X. h3 ]7 K  c
GONADOTROPIN
" ]$ R: }2 N* k3 H6 ~  [% ?/ YRICHARD C. KLUGO* AND JOSEPH C. CERNY
4 F( M) K; X# ]4 e: Y0 FFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, Y* }# x4 W7 P1 p6 N  l& DABSTRACT+ A0 ]& H# m$ W% O9 c
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
/ U- f( `( K: l6 W' qwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 s6 A5 g) L7 e: _  }" H6 n
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone6 |# b' A4 _  K! B8 Z4 V
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* P$ ?2 o& j) F: Vfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* w. C/ G6 f1 u! P' Hincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average( m9 i) M8 u9 |: H3 l
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response( h5 i: a/ U* O- b. a5 D6 b
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
: [' G: H# v+ `% cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% S9 k/ v- A5 A8 R' h; m  ?8 o
growth. The response appears to be greater in younger children, which is consistent with previ-
" T5 J! y; k: ]/ S. Lously published studies of age-related 5 reductase activity.
, k$ I  ~" |* ?/ O% `Children with microphallus regardless of its etiology will; L  p% Z( p: f4 n8 E
require augmentation or consideration for alteration of exter-
+ |4 L0 N2 P9 J# ?. H3 ^6 [" {# wnal genitalia. In many instances urethroplasty for hypo-  |' c, t" V- d+ |
spadias is easier with previous stimulation of phallic growth.
& b# D6 c: `' [* rThe use of testosterone administered parenterally or topically
" T+ Y: G2 P+ B. O. T0 H6 D3 Yhas produced effective phallic growth. 1- 3 The mechanism of
- l* W, o0 V$ J% lresponse has been considered as local or systemic. With this$ l& i. \% x1 N$ O/ D/ E& D4 m8 ]
in mind we studied 5 children with microphallus for response0 |3 V0 h% c9 R* d
to gonadotropin and to topical testosterone independently.
6 r, O/ k; N* FMATERIALS AND METHODS
0 ^; J1 m" t/ }0 I7 r9 U/ rFive 46 XY male subjects between 3 and 17 years old were# H# ]9 \6 m7 L- e6 }2 A' N$ O
evaluated for serum testosterone levels and hypothalamic8 w/ c8 Q8 \. T& j/ i1 e
function. Of these 5 boys 2 were considered to have Kallmann's
8 h* H- C+ }( V* Y/ n8 tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 g0 |* p  ?0 B7 W1 {( z
lamic deficiency. After evaluation of response to luteinizing/ w& A! v0 v; s  Q2 F
hormone-releasing hormone these patients were treated with
/ @4 ^3 a# D/ h( I1 V3 |# S1,000 units of gonadotropin weekly for 3 weeks. Six weeks& h, Z/ h- A" Y5 c5 F4 z+ X
after completion of gonadotropin therapy 10 per cent topical
: m) m$ Y& e6 ?- N8 Ltestosterone was applied to the phallus twice daily for 3 weeks.9 W( ^# F0 k' [8 `. [" o
Serum testosterone, luteinizing hormone and follicle-stimulat-
  i0 I# \; R- M2 [" d; }ing hormone were monitored before, during and after comple-
8 h3 Y, K- o/ w1 t- ation of each phase of therapy. Penile stretch length was
* o0 q# W  {3 ~obtained by measuring from the symphysis pubis to the tip of
! v, x* a2 X( Qthe glans. Penile circumferential (girth) measurements were
: ?9 }$ Y* q9 S5 S9 ~- `. d: b/ Tobtained using an orthopedic digital measuring device (see  O+ F- g$ k4 k7 x4 H' ?* p
figure).
# F( Q- ?) U# D8 M- o3 @; fRESULTS: b0 i  h+ ?7 C# P
Serum testosterone increased moderately to levels between+ F; R9 N5 t- ?! ]' ~
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ |' I+ c" M4 u# rterone levels with topical testosterone remained near pre-6 ~0 o$ n1 f/ y4 m
treatment levels (35 ng./dl.) or were elevated to similar levels% k9 z9 X  R* p
developed after gonadotropin therapy (96 ng./dl.). Higher0 v  _8 |  V, g8 o: w. _8 G
serum levels were noted in older patients (12 and 17 years old),8 \- ]) D9 |; P& s  s4 N
while lower levels persisted in younger patients (4, 8, and 10
! K4 f* C$ O$ T8 q* Byears old) (see table). Despite absence of profound alterations2 n$ U) ~1 h* \/ l! t9 _
of serum testosterone the topical therapy provided a greater- m: I8 v5 I- L/ O6 W2 W+ [
Accepted for publication July 1, 1977. ·
. `: H$ t3 h3 L7 c+ o1 gRead at annual meeting of American Urological Association,
$ x9 O0 q9 V. WChicago, Illinois, April 24-28, 1977.! \7 w% l! E6 o" V  k! G
* Requests for reprints: Division of Urology, Henry Ford Hospital,
/ R) x+ a; K, @  h) H; Z! _4 @  b2799 W. Grand Blvd., Detroit, Michigan 48202.
( n, G% [; E& N6 z% zimprovement in phallic growth compared to gonadotropin.$ v' R; S6 e4 Y9 z3 a
Average phallic growth with gonadotropin was 14.3 per cent+ K$ q% k2 X9 ?$ v* ?% _
increase in length and 5.0 per cent increase of girth. Topical+ g7 r% m2 {6 t8 k6 _) m" q
testosterone produced a 60.0 per cent increase of phallic length  M+ n0 y/ y2 X& D
and 52.9 per cent increase of girth (circumference). The( m6 |4 _% h2 E
response to topical testosterone was greatest in children be-' ^# m9 k8 d0 p. v- x5 d) e! C) B
tween 4 and 8 years old, with a gradual decrease to age 17, x+ u$ A1 z5 I" `: K1 I
years (see table).
7 a% D$ P5 ]6 t& X% u# ~- f5 V6 SDISCUSSION
0 s, Z5 Q+ T5 Y8 wTopical testosterone has been used effectively by other0 U; o. t; P; z
clinicians but its mode of action remains controversial. Im-
8 T8 D, m' F8 E, {6 Gmergut and associates reported an excellent growth response
; M) T9 b7 w+ c8 d& E% zto topical testosterone with low levels of serum testosterone,9 T3 T4 W# t/ Y2 i9 H3 v
suggesting a local effect.1 Others have obtained growth re-
) Y. T2 x1 E3 a5 I( fsponse with high. levels of serum testosterone after topical
- h4 B- S1 A/ o7 D1 B+ j9 X1 K/ C  B! eadministration, suggesting a systemic response. 3 The use of7 ]" J; B$ P2 D3 Y
gonadotropin to obtain levels of serum testosterone compara-
( |- s& l: u8 P  m) fble to levels obtained with topical testosterone would seem to7 ^7 y6 W8 t# H+ Y
provide a means to compare the relative effectiveness of4 K* g) `: m$ p
topical testosterone to systemic testosterone effect. It cer-2 J: \8 y  ?, J5 n( U
tainly has been established that gonadotropin as well as par-9 }2 n/ c* J' e! b% h/ P4 E& _
enteral testosterone administration will produce genital; j0 p5 C% m7 E9 u
growth. Our report shows that the growth of the phallus was  i6 r7 b) l; q; C4 P0 k( n
significantly greater with topical applications than with go-  x8 `3 W8 x% j* g) H2 t% @
nadotropin, particularly in children less than 10 years old.8 Y3 h$ n  K+ L, \2 E* U# s8 }
The levels of serum testosterone remained similar or lower
7 \0 C! e/ g4 D& V- h  @  Qthan with gonadotropin during therapy, suggesting that topi-
6 Y  R. R+ S; d1 Qcal application produces genital growth by its local effect as
& R+ ?# `0 Q; p$ ^3 |% S4 _well as its systemic effect.5 @# m" [; i  G; Z4 d2 X( U! i5 y
Review of our patients and their growth response related to
+ f, A  }3 r; S) Dage shows a greater growth response at an earlier age. This is
; \7 o3 Z! F, g3 ]consistent with the findings of Wilson and Walker, who* u8 W+ a7 ~4 E+ Y8 k
reported an increased conversion of testosterone to dihydrotes-2 O( \6 y* H8 x- A! w' z! P
tosterone in the foreskin of neonates and infants.4 This activ-
4 h: i- s4 q4 zity gradually decreases with age until puberty when it ap-5 \. W. B. b4 ^% a! ^( e& t4 T
proaches the same level of activity as peripheral skin. It may
3 m, H  |# Y. c; [$ L$ qwell be that absorption of testosterone is less when applied at
  G0 s  x# Q3 k, I# ?an earlier age as suggested by lower serum levels in children- F* S: U9 [$ _
less than 10 years old. This fact may be explained by the1 I% g$ b) _3 V+ V% O
greater ability of phallic skin to convert testosterone to dihy-8 F# I0 U2 A: N4 p) `
drotestosterone at this age. Conversely, serum levels in older7 f  S$ ]6 b; S
patients were higher, possibly because of decreased local
" R, h& j* m) r2 l% _- W6674 Y0 J6 O4 q2 @" B) |
668 KLUGO AND CERNY
5 K( K/ ^$ d7 B+ z% c% ~$ nPt. Age
$ S! z+ x( R# g* i(yrs.)" X" U( |  \; f/ p. z) m" ^
Serum Testosterone Phallus (cm.) Change Length; S; b; K/ ?; ~* l6 {
(ng./dl.) Girth x Length (%)! Q& |& [0 R- A8 s
4
" }1 B+ Z5 c: M3 k, @$ p2 H8$ \% ]# c) d7 o/ |# g3 R4 p3 c& e
10
) p5 z, G5 h7 i3 w3 K! @) b* U126 O. S4 x+ ~/ p5 |/ M, u6 c5 s# j
17
4 y: c# d& R) C) b  B+ J, lGonadotropin; e4 J5 n, g1 Y+ `; Z& \% o  h9 g
71.6 2.0 X 3 16.6
' x! [: a, u) M8 r! A50.4 4.0 X 5.0 20.0
/ i9 G( q% t8 m9 l. ?7 r* k6 W, G22.0 4.5 X 4.0 25.0
& l1 S" w( M7 }6 z84.6 4.0 X 4.5 11.11 d, M+ e" i9 P& [
85.9 4.5 X 5.5 9.0% h6 ~) e( H$ S2 E
Av. 14.33 {/ E: _+ w4 r9 G0 B& r
4/ N7 m1 c5 ]# ]0 `2 b* r
8. b  @) b2 c% g% n& s6 p% ?
10
8 D& z) m2 F3 x9 I& G8 U  _3 ?12/ U) a: V+ v& H5 ^( r
17
2 g! \) n* X3 C/ g4 ~) J  A$ D' wTopical testosterone5 W7 x' h( d  A: ?) F4 t3 g8 g
34.6 4.5 X 6.5 85  u# `8 `! n/ g7 h; Y! f" L
38.8 6.0 X 8.5 70
1 }/ E1 C6 T/ p+ E40.0 6.0 X 6.5 62.52 {  [/ _% y/ D! V0 [5 ~
93.6 6.0 X 7.0 55.5( J+ Z$ b' t# W
95.0 6.5 X 7.0 27.2
5 \& h6 ^$ C" `9 w  T9 iAv. 60.0
6 y$ A, |. ]7 G6 L& zavailable testosterone. Again, emphasis should be placed on
; F( _# ]$ F$ q5 A* j$ s7 h! `# v4 hearly therapy when lower levels of testosterone appear to7 I3 L, C) y5 q) v' k3 l
provide the best responses. The earlier therapy is instituted4 x2 D7 o; b  x& U$ e
the more likely there will be an excellent response with low4 G( u8 h! r' x% C8 B+ ?
serum levels. Response occurs throughout adolescence as6 i' i1 k# C! ?' i
noted in nomograms of phallic growth. 7 The actual response! [* Z' e& ]7 u/ J6 X! e) y
to a given serum level of testosterone is much greater at birth% b( k& J4 y$ V- q) A# t7 e& Y% L3 s
and gradually decreases as boys reach puberty. This is most: c: E% |9 g) @, Y* h' u& o
likely related to the conversion of testosterone to dihydrotes-
0 v1 ?. H6 R& y2 f8 u; ~tosterone and correlates well with the studies of testosterone( m- Y$ w1 L6 m" ?
conversion in foreskin at various ages.) X/ {& n) W0 {1 ~3 n
The question arises regarding early treatment as to whether
* ~8 E* O$ B4 ?! K; A9 w- X$ L: c8 H$ fone might sacrifice ultimate potential growth as with acceler-7 E) L! U+ l; u" c) Z
ated bone growth. The situation appears quite the reverse
! H- w' M) B. A& ^  qwith phallic response. If the early growth period is not used+ C. o4 V: d; Y" f5 C6 ]+ a/ K
when 5a reductase activity is greatest then potential growth* v* G3 Y5 ]- r" R! ^
may be lost. We have not observed any regression of growth
8 l' a) Z& j6 e4 m+ Nattained with topical or gonadotropin therapy. It may well7 g& |$ d0 }& @( Y3 R9 \2 m  T
be that some patients will show little or no response to any
- \* N) q! V8 p+ i% f& aform of therapy. This would suggest a defect in the ability to
: F( {$ Q: U" V: ?8 rconvert testosterone to dihydrotestosterone and indicate that, ]- F$ W- T& e# m& {8 u5 x5 Y
phallic and peripheral skin, and subcutaneous tissue should
# R, o0 B, j5 _' p8 _be compared for 5a reductase activity.
/ {, z1 K9 Y# O/ {A, loop enlarges to measure penile girth in millimeters. B,
+ i; J, e& `0 I- _example of penile girth computed easily and accurately.
; @) @( S  S5 S7 B# Mconversion of testosterone to dihydrotestosterone. It is in this
& a- [, I0 Z( M; }" Y5 n, l5 uolder group that others have noted high levels of serum: \  G  L5 D; H" U5 e
testosterone with topical application. It would also appear  d- z9 X2 V- O- \( f7 q3 x
that phallic response during puberty is related directly to the. ~4 `+ ?5 w5 P' `3 K6 F
serum testosterone level. There also is other evidence of local
& n* C4 S7 H1 C, q3 zresponse to testosterone with hair growth and with spermato-
3 f  K7 d! ~+ j) c. ggenesis. 5• 63 `9 C1 |4 W8 [
Administration of larger doses of gonadotropin or systemic) J* y! |$ x1 h0 L- `$ A% o
testosterone, as well as topical applications that produce
" L0 K+ e" i7 G8 w2 W  yhigher levels of serum testosterone (150 to 900 ng./dl.), will- y6 T* l9 d" z" O$ D3 z
also produce phallic growth but risks accelerated skeletal" n5 {! n( ]! g2 v# ]) S; b
maturation even after stopping treatment. It would appear2 ]9 f' k2 G7 x. d
that this may be avoided by topical applications of testosterone( R8 ^, p/ Z$ T8 U" q+ v" b  v! i
and monitoring of serum testosterone. Even with this control+ g- K+ @- p, X- _( {; ^8 B
the duration of our therapy did not exceed 3 weeks at any" G/ d! R2 S, K
time. It is apparent that the prepuberal male subject may4 ^7 G' Q/ Q$ r9 |8 J2 y+ z
suffer accelerated bone growth with testosterone levels near* l5 Q! Y  }7 }8 s
200 ng./dl. When skeletal maturation is complete the level of2 W# a+ J7 P; b7 l6 w& e! E
serum testosterone can be maintained in the 700 to 1,300 ng./; A' n8 O3 s( b; a9 I
dl. range to stimulate phallic growth and secondary sexual
& P" Z( c1 ~1 l  ychanges. Therefore, after skeletal maturation parenteral tes-
' d4 J& i) [0 Y: xtosterone may be used to advantage. Before skeletal matura-
3 u7 \0 R, d: w3 w) ution care must be taken to avoid maintaining levels of serum
3 y* j3 K1 Q% O1 ?% W4 Ztestosterone more than 100 ng./dl. Low-dose gonadotropin: F. S* \! k& ?1 Y* G% s
depends upon intrinsic testicular activity and may require
1 G2 t0 M: k! O% X  V$ ?/ \% L9 ?prolonged administration for any response.
' F; Z7 m% E8 y1 X! Q$ ZAlternately, topical testosterone does not depend upon tes-
/ F! O6 Z; |1 E. a5 ^/ \ticular function and may provide a more constant level of
$ s) u2 h+ S3 Q; iREFERENCES* I  X1 z! T* `
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 \: s7 _% e! E) J7 s( ?( H) lR.: The local application of testosterone cream to the prepub-
, ?1 e% f( \' E) l; Q: vertal phallus. J. Urol., 105: 905, 1971.% |3 \' A2 f- e  H4 U6 b5 w8 _
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone6 C" @# ^  e3 |$ X" q$ S! K4 p+ k# M9 k
treatment for micropenis during early childhood. J. Pediat.,9 e9 i6 D" P3 ~9 P! E$ e" O
83: 247, 1973.4 i, V" P( c5 v) t2 D, @' K
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-3 [$ h1 w8 k0 @
one therapy for penile growth. Urology, 6: 708, 1975.  V/ ?: `  Z3 q; `$ t- K* ?' R
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) {* _# \2 r  H- a$ u" yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 X- P' p4 Y0 A9 y- J/ W
skin slices of man. J. Clin. Invest., 48: 371, 1969.% A: S+ s9 f6 C  B1 X2 v
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
6 r0 x4 I. w& F4 ^! s) k& Uby topical application of androgens. J.A.M.A., 191: 521, 1965.
# h) E) q5 j+ z0 V6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. e* u6 C+ U/ H) u. a) c7 G
androgenic effect of interstitial cell tumor of the testis. J.
, d( ~6 Q- M0 S+ \! o. HUrol., 104: 774, 1970.
5 p0 b8 W* [8 G7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* \/ q$ n7 I0 E9 I2 Q
tion in the male genitalia from birth to maturity. J. Urol., 48:
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