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大家好心情
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND  n* O8 N) [: z1 y. k
GONADOTROPIN, ?, b1 t* `  C$ c5 y* I: T
RICHARD C. KLUGO* AND JOSEPH C. CERNY- X% F& ?% d2 b$ y' e, n4 m
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ [, G& Q8 l6 Q( ?6 u
ABSTRACT
8 X7 J: k+ {' a5 u7 I( QFive patients were treated with gonadotropin and topical testosterone for micropenis associated
; F. ~3 }; X4 Zwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-% K& V) g: T+ G/ D$ a* q3 f$ \
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone  T$ X" S: F( [/ l: u. g
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 C2 [- F  g  N. B
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 {, Q- p4 Q8 |! I1 c  X  @
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average8 r+ p' X# D  x* c( h: }6 n7 R
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; F" t9 Q# Z$ ^5 b. I. o
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This+ D! w/ h% u# h7 L& m5 l
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- P; W* F; Z% r9 ^) ~growth. The response appears to be greater in younger children, which is consistent with previ-
+ e" e& G5 o; r0 D! }9 x0 Xously published studies of age-related 5 reductase activity.3 c" `! ?9 `8 Q! j# N0 {  v& l
Children with microphallus regardless of its etiology will$ X# y+ I  z* _/ `
require augmentation or consideration for alteration of exter-; h( x3 Q- a1 Q/ i
nal genitalia. In many instances urethroplasty for hypo-, M8 u2 g6 w! t( J$ j$ a
spadias is easier with previous stimulation of phallic growth.
" j+ @. H) C; `6 W, v7 \! yThe use of testosterone administered parenterally or topically
4 ?5 p" t% c6 I0 [has produced effective phallic growth. 1- 3 The mechanism of1 u2 z# i+ R: _7 r& C9 M' J
response has been considered as local or systemic. With this+ f" O: U3 c8 @3 L
in mind we studied 5 children with microphallus for response2 Z2 v8 @' B2 i4 P; f6 |# t% @" a$ C
to gonadotropin and to topical testosterone independently.: k+ ~( Y  O; Z" c; m& i
MATERIALS AND METHODS/ l% {$ b* {( f3 t0 [' }
Five 46 XY male subjects between 3 and 17 years old were7 G2 J8 ]3 f1 O  R$ o, {- O5 T( O
evaluated for serum testosterone levels and hypothalamic8 l) B! a9 V* n# N5 z% p
function. Of these 5 boys 2 were considered to have Kallmann's
( g! L# o1 g7 i9 u" Msyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
9 z3 ?$ B1 ]9 W) x/ m8 ]3 Tlamic deficiency. After evaluation of response to luteinizing: q  X" d' ]+ Q0 }1 r
hormone-releasing hormone these patients were treated with* b4 {, X4 B$ s- D
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 p. m( f% d, N/ z& h: Q: uafter completion of gonadotropin therapy 10 per cent topical
0 g: h5 ~' [5 J  _testosterone was applied to the phallus twice daily for 3 weeks.
! a' B' Z+ P; G& ZSerum testosterone, luteinizing hormone and follicle-stimulat-
$ M+ t' s$ v2 C% G1 j# g1 Bing hormone were monitored before, during and after comple-
/ Z3 g+ ]+ i( C8 i2 {8 o6 L+ w+ f, @) ption of each phase of therapy. Penile stretch length was
0 c$ N) K. [* `* R- @* a$ E* bobtained by measuring from the symphysis pubis to the tip of
( j' ~3 L& S( zthe glans. Penile circumferential (girth) measurements were; K/ P3 W' [3 r$ n& s! x$ F6 a. G
obtained using an orthopedic digital measuring device (see
% ^* u( d/ K1 j+ @4 O6 ~* ~figure).' R, m& z: p( k) Y' `9 V! m
RESULTS4 H) ~; e, H4 u1 i
Serum testosterone increased moderately to levels between3 R. v1 j3 ?: M6 i) Z8 P: m
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) @- Z+ A4 z5 X. S) F) c4 l, e
terone levels with topical testosterone remained near pre-
" b! A5 d8 y( x9 H% I9 Z" E, q; ctreatment levels (35 ng./dl.) or were elevated to similar levels
% P* V0 q3 r2 g: B6 a+ l9 kdeveloped after gonadotropin therapy (96 ng./dl.). Higher- @4 p6 D1 p. q9 q4 K# ^
serum levels were noted in older patients (12 and 17 years old),
/ m# _+ t. Q3 R7 Qwhile lower levels persisted in younger patients (4, 8, and 10+ I4 j. u2 A/ h9 q
years old) (see table). Despite absence of profound alterations
! `1 C; V. l2 @- F* u: }of serum testosterone the topical therapy provided a greater' r- _3 z' B* d, g
Accepted for publication July 1, 1977. ·! R5 x2 O" q- \- [# N
Read at annual meeting of American Urological Association,9 l: w- |2 u* @& A2 u+ {) O
Chicago, Illinois, April 24-28, 1977.
9 {9 m. M2 `. M4 X' B- X5 N* Requests for reprints: Division of Urology, Henry Ford Hospital,
3 I' s) t- y) v% w* a2799 W. Grand Blvd., Detroit, Michigan 48202.
( u/ `+ G! _' S8 eimprovement in phallic growth compared to gonadotropin.
) H( U6 e4 h$ R% r, f0 KAverage phallic growth with gonadotropin was 14.3 per cent. [. q/ {, v: |5 E  J0 L
increase in length and 5.0 per cent increase of girth. Topical
3 i1 M/ x: ^" n% g! wtestosterone produced a 60.0 per cent increase of phallic length
1 [/ w9 L( W; N8 g1 Eand 52.9 per cent increase of girth (circumference). The& I" }! p! m$ m+ D/ }
response to topical testosterone was greatest in children be-: H* Z: ]+ y* h- N5 Y0 y: u
tween 4 and 8 years old, with a gradual decrease to age 17
# K8 ^& e5 l0 o6 Q0 f. ]years (see table).$ ]4 T! U; W  i( B
DISCUSSION
# z% `" l/ e6 U+ U( FTopical testosterone has been used effectively by other7 ]( q2 |# ]* b3 ]$ X
clinicians but its mode of action remains controversial. Im-9 T% ~+ _% r% E  r) I% L( F# Q
mergut and associates reported an excellent growth response
8 J  e  d. |3 v( J8 P& zto topical testosterone with low levels of serum testosterone,
' `" C) w3 O% asuggesting a local effect.1 Others have obtained growth re-
1 M6 W$ \8 X- Q% Q- \/ e; gsponse with high. levels of serum testosterone after topical
# X  E" u- Q6 v; [$ z/ |5 [administration, suggesting a systemic response. 3 The use of$ {4 x# k/ [3 v1 p: q
gonadotropin to obtain levels of serum testosterone compara-
( Z- `  j9 t% W$ vble to levels obtained with topical testosterone would seem to& s1 m( F+ p4 C) b8 a- J$ i% R( G) U
provide a means to compare the relative effectiveness of
8 j+ W8 X: C' Wtopical testosterone to systemic testosterone effect. It cer-- G/ v# D+ N! p& z5 ^- {
tainly has been established that gonadotropin as well as par-
+ e0 a! r% e$ S4 [' Aenteral testosterone administration will produce genital, g4 g; k7 p0 ?9 `( n2 b
growth. Our report shows that the growth of the phallus was# \* M+ E. p4 f) k
significantly greater with topical applications than with go-3 u. b" l7 T4 x
nadotropin, particularly in children less than 10 years old.% [( h9 h; C; |4 \; ^  r% W8 o- G
The levels of serum testosterone remained similar or lower
4 k0 ?0 Z6 c+ Z3 e6 S: a9 w) ]: z; nthan with gonadotropin during therapy, suggesting that topi-
' C7 b9 I# G/ Y1 O. Xcal application produces genital growth by its local effect as
' F  W; R8 p) F9 f& {! v4 [well as its systemic effect.
: |4 \% @* ~2 e: p' H) I2 MReview of our patients and their growth response related to
/ Q6 \, X; K1 i' V9 Z4 oage shows a greater growth response at an earlier age. This is
6 D9 M$ E8 u7 n+ Uconsistent with the findings of Wilson and Walker, who/ z/ F2 T, k# a, r1 {
reported an increased conversion of testosterone to dihydrotes-
5 Y- C8 {; m( M, Z+ W/ etosterone in the foreskin of neonates and infants.4 This activ-7 d8 J2 U: u; K- i
ity gradually decreases with age until puberty when it ap-
. U, v$ n6 Z2 G. E4 Iproaches the same level of activity as peripheral skin. It may% e( g" Y0 F: s* D  o2 `6 Z
well be that absorption of testosterone is less when applied at( e1 D% S. c1 d  X" E
an earlier age as suggested by lower serum levels in children
$ \  [2 F  R. X4 ^- Jless than 10 years old. This fact may be explained by the$ t1 s* ]  f8 ]: x
greater ability of phallic skin to convert testosterone to dihy-
% o4 ]& |3 K( K, v# r$ i! V+ ~: n2 [drotestosterone at this age. Conversely, serum levels in older
3 O' P! y  y- C' p  Apatients were higher, possibly because of decreased local" l$ Z8 f7 Q/ M# z/ t
667
# a7 U5 S$ S& d668 KLUGO AND CERNY" s" b$ k& }3 r7 \
Pt. Age: Y; _* p+ r" ?
(yrs.)) e( G+ I/ c" U5 X; [1 o& e
Serum Testosterone Phallus (cm.) Change Length& F; O* X  d5 S$ G
(ng./dl.) Girth x Length (%)
7 G9 Y& B1 g7 _5 s2 y4+ C1 ?, V$ U/ b; b* A/ r
8* Q; j/ p) s/ D! P/ D1 I  C2 i2 B4 V# L
10
6 m0 p7 F5 p# T' U/ ]12
# {: p8 s) \4 S: i, \17
8 V! |4 Q- I7 BGonadotropin3 F) r* S' O/ |
71.6 2.0 X 3 16.6
1 m! u6 `) g) }. {8 L; [50.4 4.0 X 5.0 20.0) D: \+ e: `2 X0 S( t& z
22.0 4.5 X 4.0 25.0* B% {& |" V0 X
84.6 4.0 X 4.5 11.1
* F' U/ b% u; c# N/ z; F85.9 4.5 X 5.5 9.0; \' R( o( }; h4 `, R7 K
Av. 14.3
& s3 A1 h% E( h  i( S4! x( G) K0 S/ h4 B! H- U3 ]) k& W
8
% Z  Y+ F' h% y# \$ W10
  `8 F# X' K. e12, M6 X7 r3 Y; U. E' y
17. c' v# i3 _( A8 x
Topical testosterone
3 O+ P- s/ c, \7 ^2 V34.6 4.5 X 6.5 854 O  R# H) I; Z
38.8 6.0 X 8.5 703 T1 Y8 x5 R. m+ T' e
40.0 6.0 X 6.5 62.59 y  J7 q( ^/ G1 q' q6 l  T
93.6 6.0 X 7.0 55.5
+ T7 \' [6 O% A  G" {1 U. C: C/ a95.0 6.5 X 7.0 27.2
+ }. s! T# b/ [- h- YAv. 60.0
9 o0 i. G& W. ]; navailable testosterone. Again, emphasis should be placed on
+ {0 ?" ]6 j  f( ?; t  ~8 bearly therapy when lower levels of testosterone appear to
: W; z% C  A( x1 oprovide the best responses. The earlier therapy is instituted
  u- G; _* O! Kthe more likely there will be an excellent response with low8 y6 l  {' [7 ?' R: u. r3 [  W, V
serum levels. Response occurs throughout adolescence as2 b! {  Q8 {0 V4 n. v7 {4 @' U
noted in nomograms of phallic growth. 7 The actual response# }* t  w# o" k; @1 O. C
to a given serum level of testosterone is much greater at birth
+ `# A6 w# U( O  @7 ~! E+ Aand gradually decreases as boys reach puberty. This is most% B& p  i- W, @' m: [0 Q) e) B
likely related to the conversion of testosterone to dihydrotes-
% ^( x& x1 _# T) L( a& O+ Xtosterone and correlates well with the studies of testosterone3 [! x- ?6 H) Y4 }$ s
conversion in foreskin at various ages.# l; _5 D1 c8 x3 }0 T
The question arises regarding early treatment as to whether
" n" `& N: _, i8 V7 A7 r. z" oone might sacrifice ultimate potential growth as with acceler-
- e  A$ L" m9 r9 `ated bone growth. The situation appears quite the reverse# @3 G! i: t- J) I. x6 I2 T
with phallic response. If the early growth period is not used& g- E  E+ y- ?
when 5a reductase activity is greatest then potential growth
$ E  d3 E9 H, A8 w6 Hmay be lost. We have not observed any regression of growth
8 y7 s! O5 ~, t, z5 E+ P9 Fattained with topical or gonadotropin therapy. It may well
& y6 V$ }( |6 w* \' L9 J/ l! Y0 e% {be that some patients will show little or no response to any
. w1 x. e& [& ]) L  e' t' p$ ]% Rform of therapy. This would suggest a defect in the ability to
( }* N9 f$ J: ~( p; q# f: Lconvert testosterone to dihydrotestosterone and indicate that
8 c; I0 I, L1 ~0 v- Hphallic and peripheral skin, and subcutaneous tissue should* v+ Z. O6 a+ l
be compared for 5a reductase activity.
; m0 ~; K% U! s4 L& f5 S. q$ I8 dA, loop enlarges to measure penile girth in millimeters. B,
! m5 h: P" H" G" ]. g+ ^example of penile girth computed easily and accurately.$ {+ ]1 a5 M$ J' q% c
conversion of testosterone to dihydrotestosterone. It is in this
5 M+ H3 l1 V; @& z( b% k: Oolder group that others have noted high levels of serum
/ x; I) ^& D" O7 D; u0 x4 ktestosterone with topical application. It would also appear) K1 p* U$ D2 C, {  z0 m7 w; _( h
that phallic response during puberty is related directly to the
, b  E8 M/ d. y' }* t# x' eserum testosterone level. There also is other evidence of local
! l5 |" f6 T% O5 B4 J4 n# kresponse to testosterone with hair growth and with spermato-
6 z8 O, N1 N2 l  j3 Dgenesis. 5• 6  X1 k: B4 P/ c: l, `! X
Administration of larger doses of gonadotropin or systemic
$ |0 ?+ e* p1 o# u# q- Ftestosterone, as well as topical applications that produce
) O# a  l! \% s% ?' m! qhigher levels of serum testosterone (150 to 900 ng./dl.), will$ l, R. n- d8 t* D# x
also produce phallic growth but risks accelerated skeletal
- Q- `! s. w. j; q8 e% {$ ymaturation even after stopping treatment. It would appear
$ K" B) I# N5 }( ethat this may be avoided by topical applications of testosterone2 ]4 b' ~+ p: p1 p- f( i9 }
and monitoring of serum testosterone. Even with this control
; S- t. D: m8 i6 L. rthe duration of our therapy did not exceed 3 weeks at any
4 k6 Y4 n7 e9 u. otime. It is apparent that the prepuberal male subject may+ l% I' f8 p0 h9 C$ ?
suffer accelerated bone growth with testosterone levels near+ x: r* `* D; z  W; j
200 ng./dl. When skeletal maturation is complete the level of
' C! a% w6 ]9 G: B" y" e$ j/ Rserum testosterone can be maintained in the 700 to 1,300 ng./
* Z; p& O3 \  v" p0 `2 pdl. range to stimulate phallic growth and secondary sexual
3 I3 m# R$ b, `; F' @# Z0 Zchanges. Therefore, after skeletal maturation parenteral tes-
4 `$ J/ O, E5 ~. B# F4 C* U7 Etosterone may be used to advantage. Before skeletal matura-% U8 {- N6 `- s6 I$ |7 T
tion care must be taken to avoid maintaining levels of serum3 _2 B5 F$ M6 o  W% T  W
testosterone more than 100 ng./dl. Low-dose gonadotropin) D  `6 a# Q, u: B% F$ W* s2 |5 ?
depends upon intrinsic testicular activity and may require$ \9 I5 L1 B: `8 Q0 e7 Q
prolonged administration for any response.! X  ~5 T: C8 a2 I3 A, ]
Alternately, topical testosterone does not depend upon tes-% y2 R8 a/ h0 Y! A
ticular function and may provide a more constant level of
) r9 l/ I$ B; r, K7 D2 z3 f/ s. aREFERENCES
& E4 D! @1 g7 ]  ~' L/ U" [$ Y1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
' O% ~' l* K8 t. P! m& _  V: iR.: The local application of testosterone cream to the prepub-, C3 @$ a; b0 K6 I; {# w5 _& p/ w
ertal phallus. J. Urol., 105: 905, 1971.
' [1 T% J9 S8 E2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- U- B( r  |. w4 h$ L5 B* x% z- T; G
treatment for micropenis during early childhood. J. Pediat.,  j+ n! u  N% n# N/ N
83: 247, 1973.
/ k/ r- ~% V( x* Q3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; t1 n$ M& r$ F" _5 c( z: J5 ~; t. Z
one therapy for penile growth. Urology, 6: 708, 1975.
  ~8 _" o& f+ I' |4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' }- c- ?5 J. B/ `: x# [: G7 ]: Vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ x  i& n% n  }4 \
skin slices of man. J. Clin. Invest., 48: 371, 1969.
8 e$ |+ _# D. O7 L& _5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth( S' U9 o# j, R
by topical application of androgens. J.A.M.A., 191: 521, 1965.
: e8 |$ e& m6 w! g, L. X6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
5 k  |$ |! }9 F! a* u/ n0 q! Y  Tandrogenic effect of interstitial cell tumor of the testis. J.
: ^3 d/ }* F4 M" P- E5 e' EUrol., 104: 774, 1970.
) {4 o% W( Y, j( i" b7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 W/ e% @' @9 w
tion in the male genitalia from birth to maturity. J. Urol., 48:
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