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大家好心情
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ x$ ^, ~5 r6 r: n2 L
GONADOTROPIN
# R0 X  ]: v; w/ L; Y8 QRICHARD C. KLUGO* AND JOSEPH C. CERNY
) ~' E+ H' x% M$ Y' `From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& y  F. l# y+ Q
ABSTRACT. `, u5 v6 J" {+ c8 L1 F
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
- j4 y5 F, e0 F2 k. Z8 kwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
8 }* Q5 |, u( u% f9 N9 I; D$ `tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
; `) k2 {, R% \) jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* e! w: Q- b4 R' R8 S( H0 o& Yfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 z2 l( g6 G, E6 B2 A! Y* ?increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
. q: ~) Y6 j, `  ^& H6 Lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ \! E  y8 O$ Y% H0 P. H
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This  ]! G# a! ^$ R/ \2 p; T. |" p
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile- u2 H' H9 J; t' v2 _1 w
growth. The response appears to be greater in younger children, which is consistent with previ-
$ {2 n6 g! ^0 w7 Bously published studies of age-related 5 reductase activity.
! v9 e+ }8 x/ {/ t+ {& vChildren with microphallus regardless of its etiology will8 L5 C( F) V9 c: @
require augmentation or consideration for alteration of exter-
: P6 [+ E) p( q" f1 mnal genitalia. In many instances urethroplasty for hypo-2 b- F3 F0 s) ]! q: W3 p* y
spadias is easier with previous stimulation of phallic growth.! @3 M$ G# ~) v& \5 u+ D' T
The use of testosterone administered parenterally or topically% Q) F3 ~1 s/ i/ g% ^( G, V
has produced effective phallic growth. 1- 3 The mechanism of! T3 e- ~6 _& C! f
response has been considered as local or systemic. With this
$ ]$ }) d- q5 N* \8 C2 Ein mind we studied 5 children with microphallus for response
1 u7 u: E. S0 ?- Z! d+ g* Oto gonadotropin and to topical testosterone independently.) F7 y% Z% |# A+ u6 i& D
MATERIALS AND METHODS
$ }4 H$ P4 }4 v5 e, zFive 46 XY male subjects between 3 and 17 years old were
1 T* a$ g  C8 o! ]evaluated for serum testosterone levels and hypothalamic5 F5 J- Y+ H2 i4 a! c8 ?
function. Of these 5 boys 2 were considered to have Kallmann's, k) ]* w; A2 f( F( j% L6 P) j- C
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" a: H( g" ^$ X" e" m# t8 ?, L
lamic deficiency. After evaluation of response to luteinizing7 }: Y6 p: Q% a5 a& \1 [5 v
hormone-releasing hormone these patients were treated with
$ a; C: X, }% K: u# v1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 g1 l$ R& h( N4 I. G4 @after completion of gonadotropin therapy 10 per cent topical7 z* ?! {/ O: D. `: _
testosterone was applied to the phallus twice daily for 3 weeks.
9 G- |& }' _& ?2 U: G2 ?Serum testosterone, luteinizing hormone and follicle-stimulat-( `: X- ~7 O) r1 u! ~4 n! @
ing hormone were monitored before, during and after comple-
+ n+ s, K4 O- |4 n- }tion of each phase of therapy. Penile stretch length was
% ?5 C3 p( @4 p3 y7 D7 L' Hobtained by measuring from the symphysis pubis to the tip of) T  J0 W& L$ V2 ?) j3 Z4 r0 t& Z
the glans. Penile circumferential (girth) measurements were) |/ _7 r3 Z0 K2 P- ]( S
obtained using an orthopedic digital measuring device (see, ]: o! p/ {1 S: `8 C
figure).
+ D" o7 ~) I" k. ARESULTS
, [1 [7 |7 ~# h; y% ~9 ]& FSerum testosterone increased moderately to levels between. x7 K) E+ @2 q5 i
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) ]) j, |8 r$ X' H; ?9 X1 G# U+ F
terone levels with topical testosterone remained near pre-
; h" {* N2 U( d. U% ~treatment levels (35 ng./dl.) or were elevated to similar levels" K4 T" R- S# [* s
developed after gonadotropin therapy (96 ng./dl.). Higher, Z  V5 k+ V5 G
serum levels were noted in older patients (12 and 17 years old),
5 g9 Q5 g- O( n+ q$ _* Ywhile lower levels persisted in younger patients (4, 8, and 106 C: Q8 d  Z) {+ Q4 K
years old) (see table). Despite absence of profound alterations
. c0 F& E3 V. t. C( a1 @of serum testosterone the topical therapy provided a greater/ ~- o1 X% W" N8 c
Accepted for publication July 1, 1977. ·& Z/ Y: g/ V1 O4 h( h
Read at annual meeting of American Urological Association,* _! s4 D- A$ \( o
Chicago, Illinois, April 24-28, 1977.  Z! n5 ~3 J( }. P/ X* Z9 ~
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 f3 X3 x- Z! w
2799 W. Grand Blvd., Detroit, Michigan 48202.
/ n" B& W) j4 w" S- ?* V9 a# Dimprovement in phallic growth compared to gonadotropin.% A, }2 Q% o# S0 t" ^  f  j
Average phallic growth with gonadotropin was 14.3 per cent$ H1 s1 r2 t/ K4 r5 t0 }5 e6 T
increase in length and 5.0 per cent increase of girth. Topical
/ F& \6 V- u: Jtestosterone produced a 60.0 per cent increase of phallic length
+ [. {2 g( c  Z. J- o+ \and 52.9 per cent increase of girth (circumference). The4 S# v* b& x/ W3 L! W4 f+ A
response to topical testosterone was greatest in children be-
, z3 c/ C2 c/ |: _- l# q. r/ ttween 4 and 8 years old, with a gradual decrease to age 17
5 F$ Z; y2 z. a+ K6 g1 ^years (see table).
& D1 W/ y) [1 N" [" \' y5 VDISCUSSION
8 h, |; P2 ~+ ~0 |7 e1 [Topical testosterone has been used effectively by other" z' J2 K2 Q9 k8 g; ]- j. X% d- Y
clinicians but its mode of action remains controversial. Im-1 k& N2 c4 o2 X; D/ H! l1 v, S7 t
mergut and associates reported an excellent growth response9 l% E/ b1 Y! J9 [1 V, {+ ?
to topical testosterone with low levels of serum testosterone,
0 X5 H: _9 o* ?+ C3 \suggesting a local effect.1 Others have obtained growth re-
; F: Y! }. q5 O# P% H3 dsponse with high. levels of serum testosterone after topical7 x) @, j( u. g; T
administration, suggesting a systemic response. 3 The use of
) e% ^! F+ \+ U& @" bgonadotropin to obtain levels of serum testosterone compara-' U- _2 a4 P: Z& c/ k1 |9 H
ble to levels obtained with topical testosterone would seem to
; g7 X/ |9 D( m( G2 ~provide a means to compare the relative effectiveness of0 Y! q# ?' l, R8 E
topical testosterone to systemic testosterone effect. It cer-
/ }  M. t( D8 e/ itainly has been established that gonadotropin as well as par-
- |. _0 j/ M; M: Lenteral testosterone administration will produce genital5 H; U2 m6 T2 z
growth. Our report shows that the growth of the phallus was
  K/ W* ]" O  l1 r# `significantly greater with topical applications than with go-: n0 ^4 p, |2 u5 p
nadotropin, particularly in children less than 10 years old.
0 R9 n% U7 Y4 h3 W" C0 ?The levels of serum testosterone remained similar or lower8 z5 ~8 L+ G% g$ J" H
than with gonadotropin during therapy, suggesting that topi-
0 [0 o: J! G3 A. H( ]" j; hcal application produces genital growth by its local effect as- U7 H% Y$ e7 c( u4 y' ^; F( M4 N" g
well as its systemic effect.& D( C; p3 z, n# v1 L- m. Q
Review of our patients and their growth response related to
. H, y0 l6 ^) Q( z6 F( o9 ~' qage shows a greater growth response at an earlier age. This is
6 d* e5 F/ Q& V+ |+ [3 ]consistent with the findings of Wilson and Walker, who
1 }( t/ d. v; V3 x0 y$ Ureported an increased conversion of testosterone to dihydrotes-. k1 n  c6 b! }% t- @  E% k
tosterone in the foreskin of neonates and infants.4 This activ-" E2 }: F" j& X( @7 ^" b
ity gradually decreases with age until puberty when it ap-" V6 W0 i0 T/ ]1 g
proaches the same level of activity as peripheral skin. It may+ ~& e. B' f) k0 p+ H, M) F5 j' K
well be that absorption of testosterone is less when applied at4 N5 K' e: Z$ t) U7 U9 }% B6 x
an earlier age as suggested by lower serum levels in children
& k- U: [2 x( ^& z8 r" K: \. Lless than 10 years old. This fact may be explained by the' s3 R9 h. Y+ N# l% y) r1 g; B
greater ability of phallic skin to convert testosterone to dihy-- |# p" f5 I2 ]+ ]
drotestosterone at this age. Conversely, serum levels in older
8 m( u: [) ~5 e1 Wpatients were higher, possibly because of decreased local' f% ?$ X1 S2 \7 k+ G3 M
6678 `& s) \( L( S
668 KLUGO AND CERNY" ~; V; I: l; H/ p+ }, @7 h8 Z0 ~- [
Pt. Age# b% Y3 y3 O3 f: h
(yrs.)8 V& q2 {0 ?. {6 F
Serum Testosterone Phallus (cm.) Change Length
( l: t7 b9 K1 L(ng./dl.) Girth x Length (%)
' I# G, d! @" U/ r9 x! `" u. X1 J41 B3 q! s& Y5 N& i
81 t6 u/ E- h: T. R6 _1 z
10% X7 Q' j9 p2 K  U
12
, r" y; q4 V7 t178 J3 r/ e% }3 Y* r) ~( U2 r) ~
Gonadotropin
/ x1 t. f( C% f- D' ]+ @71.6 2.0 X 3 16.6
4 z9 q) @1 I" g2 M4 ~! \50.4 4.0 X 5.0 20.0
7 F# Q0 e- F1 F$ h5 |8 z" g22.0 4.5 X 4.0 25.0* r" P5 P& P+ j" _- T
84.6 4.0 X 4.5 11.1' i1 V4 |4 z/ J
85.9 4.5 X 5.5 9.0. j! o( q3 x2 M- c
Av. 14.31 ?9 s) o& P3 r$ `: R5 j
4
( o  I3 \  P" P* `$ H8
$ d6 K6 S1 B/ A" w2 S7 h10# S: e  E3 S, T+ u3 }  H
12
' s' B: e4 c7 V( C* a4 [17
9 x0 U  G7 ~* S# I& \: nTopical testosterone  [; i8 R5 I. O! \
34.6 4.5 X 6.5 85
/ Z9 W+ C0 ?  j$ K9 z38.8 6.0 X 8.5 706 e- N# A: p% ]1 [( l
40.0 6.0 X 6.5 62.5) M$ Q. _( x% X! W' \+ \, o
93.6 6.0 X 7.0 55.5
) ~& c; d2 N- a5 T, s; ?% g- _4 K95.0 6.5 X 7.0 27.2# ^3 o; L* g2 k7 Q' f/ ?
Av. 60.02 ?! d4 w; }  y8 \4 K
available testosterone. Again, emphasis should be placed on- W) s! t7 x! k5 B' X
early therapy when lower levels of testosterone appear to
4 j2 h. z) _! Mprovide the best responses. The earlier therapy is instituted
. [6 @8 V+ C. f. X' k0 [the more likely there will be an excellent response with low
- |+ N; O9 k$ a$ z) @serum levels. Response occurs throughout adolescence as
' Q: h+ i- S6 ~5 W( qnoted in nomograms of phallic growth. 7 The actual response) w/ W5 `. j0 k0 h/ s" z  v
to a given serum level of testosterone is much greater at birth
, n" `. v! }+ \+ E0 Xand gradually decreases as boys reach puberty. This is most
: q& n0 I. T5 i1 d5 G+ {3 |likely related to the conversion of testosterone to dihydrotes-
" f1 R/ h' P& y! t/ x' z  Vtosterone and correlates well with the studies of testosterone
# X6 M" x' j$ @( h  Fconversion in foreskin at various ages.
/ x/ X/ r7 X6 H+ o+ H( r6 JThe question arises regarding early treatment as to whether
% @5 H& Q: @/ ~; none might sacrifice ultimate potential growth as with acceler-. m# g. D$ O% k
ated bone growth. The situation appears quite the reverse
3 O) w* @1 V9 d. L' twith phallic response. If the early growth period is not used
  J3 \6 A9 G' \- x9 r) Zwhen 5a reductase activity is greatest then potential growth! L% x* [' }+ s
may be lost. We have not observed any regression of growth
' G7 I/ a% v9 w: d& mattained with topical or gonadotropin therapy. It may well- H: H) E7 A2 T5 k$ |: g  ]  \
be that some patients will show little or no response to any
1 D8 R5 J2 k1 C0 h/ Z9 y3 Q9 o+ uform of therapy. This would suggest a defect in the ability to
1 L" c$ A3 q  L, h7 V6 Vconvert testosterone to dihydrotestosterone and indicate that6 y6 f: c* `$ Z$ H. I7 Y5 E( ^1 \2 m
phallic and peripheral skin, and subcutaneous tissue should
' }! g, R# |6 E: N. t* E; _be compared for 5a reductase activity.
8 ?, G* \3 s4 R% {7 d8 q/ j( {+ P& vA, loop enlarges to measure penile girth in millimeters. B,
& W: z* N8 S" a1 Hexample of penile girth computed easily and accurately.
0 z. c+ Z* K7 J, E$ Rconversion of testosterone to dihydrotestosterone. It is in this
0 S- h8 R0 F5 _8 ~7 Q8 u* uolder group that others have noted high levels of serum- Q- _3 O' K6 T' _
testosterone with topical application. It would also appear3 |4 H- Q! H4 m
that phallic response during puberty is related directly to the0 H- F' k% }9 D: u. v( `
serum testosterone level. There also is other evidence of local3 g# c4 l2 N& `' |
response to testosterone with hair growth and with spermato-" e, e* [7 Y8 |* d3 r
genesis. 5• 6
3 z- v/ ]0 r4 \0 R7 g' C( @Administration of larger doses of gonadotropin or systemic) j" M2 [* C3 j
testosterone, as well as topical applications that produce% D  M1 y3 O; o
higher levels of serum testosterone (150 to 900 ng./dl.), will# P2 s/ t; W. e7 o, O. O
also produce phallic growth but risks accelerated skeletal# C) Q5 h8 z( G5 [
maturation even after stopping treatment. It would appear
  x& _4 M+ w2 M) |( Z# v8 H+ c$ \that this may be avoided by topical applications of testosterone* |/ J3 ^' \4 O9 G" V; L
and monitoring of serum testosterone. Even with this control0 V. L( I. K" v. N
the duration of our therapy did not exceed 3 weeks at any
6 ?' g2 c0 z% D0 J( S1 w; V+ Gtime. It is apparent that the prepuberal male subject may' t+ n" q. u2 t; l4 I+ k' w
suffer accelerated bone growth with testosterone levels near6 Y& w9 N. u; u5 Q
200 ng./dl. When skeletal maturation is complete the level of
: l2 W  }% G: k0 d8 Tserum testosterone can be maintained in the 700 to 1,300 ng./
' T8 I( e) b  [' ~5 idl. range to stimulate phallic growth and secondary sexual
; P+ \6 F- x& g- ^4 w7 \" Z! bchanges. Therefore, after skeletal maturation parenteral tes-
. a5 L) s4 f$ R) K, ^tosterone may be used to advantage. Before skeletal matura-5 q5 H- b+ k* M* G/ e4 N
tion care must be taken to avoid maintaining levels of serum- x& e& H$ ^/ h7 m
testosterone more than 100 ng./dl. Low-dose gonadotropin
3 c( @# |& x4 _1 r1 \* hdepends upon intrinsic testicular activity and may require
( A' U2 d) e; b: tprolonged administration for any response.
- Z) F3 i4 A) k( sAlternately, topical testosterone does not depend upon tes-
& J0 }: y+ ~/ [5 G2 p, n6 Nticular function and may provide a more constant level of
# W2 ^  p* e3 h0 i: z0 ?( |9 q9 eREFERENCES
3 k1 P' H- {4 k1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
7 ]  b5 v+ R8 VR.: The local application of testosterone cream to the prepub-
/ S  y5 P! q3 H* W, o& }  Fertal phallus. J. Urol., 105: 905, 1971.* e" [% }+ @2 K7 s
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 I4 e  ^/ U" }) G. ?7 G( M( H4 \4 w) G* q
treatment for micropenis during early childhood. J. Pediat.,  U3 z8 B# \# a9 N0 F
83: 247, 1973.
. N) s( }. v- d8 t# s7 \3 d3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-1 P* _1 H: i4 O/ m8 U0 {
one therapy for penile growth. Urology, 6: 708, 1975.- ?+ u; t) [9 I' k6 U3 j, c) h
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& M( ]  D' i5 C# }6 fto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by! V% v! e; a) I! _  D
skin slices of man. J. Clin. Invest., 48: 371, 1969.( ?' W+ j9 P: b; I$ R. @& g
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# W0 O+ k( F0 c$ S) i! `1 F0 }+ |
by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ r, }" f' A+ e+ m. t6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 j, z1 Z! B3 @0 T# j0 Handrogenic effect of interstitial cell tumor of the testis. J.  I1 I4 Y9 _3 ?9 |" n  p9 x
Urol., 104: 774, 1970.  l% u) o. X) z: Z7 D$ a
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 }3 T2 {; B0 v( m4 Z: dtion in the male genitalia from birth to maturity. J. Urol., 48:
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