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大家好心情
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND' j- q0 l- _9 l& ?8 R
GONADOTROPIN- V1 W$ p0 M- F
RICHARD C. KLUGO* AND JOSEPH C. CERNY
1 v" `4 Y) M+ t) @( ]# F: |% BFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan8 F* \' S' H- g% V
ABSTRACT3 O+ P7 f8 s4 f: _' j* S( r
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
4 r/ g1 R# \4 E: Xwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
4 N5 O" G! ~4 {& d9 ?( u5 ftropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) v& X. o! ?) o: x, X% A6 X6 ]
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
0 g$ e, @+ A1 rfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* P% t# `" B6 v& i* }+ c. |increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average, z* [2 Y* ?0 J! ^: r  i
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" M! B1 q9 p7 B6 r! joccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This% k/ T& G) a# o, |! Q( x* Y
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% S9 Q8 |2 s. s* z! ]growth. The response appears to be greater in younger children, which is consistent with previ-
; w2 Q# B5 M  t4 X; ^% nously published studies of age-related 5 reductase activity.+ E: ~0 Z4 S/ i: Y/ c
Children with microphallus regardless of its etiology will3 l- Z( w) M: k8 D( w1 B
require augmentation or consideration for alteration of exter-3 D- f& \/ w* R5 A
nal genitalia. In many instances urethroplasty for hypo-* c( z2 K3 ?9 ~
spadias is easier with previous stimulation of phallic growth.) t) Z) x) N3 e0 m' a2 @
The use of testosterone administered parenterally or topically2 O) ]/ M2 g! j1 M) z# i* t2 a
has produced effective phallic growth. 1- 3 The mechanism of
4 Q& q4 V0 d3 f6 X0 p# x! H% kresponse has been considered as local or systemic. With this
* f+ }! c3 [- Q2 _) U1 b4 q# tin mind we studied 5 children with microphallus for response
+ w! K' o% O  D* ~6 d* N/ G/ i6 W5 eto gonadotropin and to topical testosterone independently.5 x: P5 `! _# r! b+ a
MATERIALS AND METHODS
, s2 W/ B" h$ m& F, u5 A" ~/ F" Q/ FFive 46 XY male subjects between 3 and 17 years old were
0 c0 l4 {4 X' S8 @+ Nevaluated for serum testosterone levels and hypothalamic
/ |1 q7 m1 A) tfunction. Of these 5 boys 2 were considered to have Kallmann's
4 z% U7 j/ k$ r+ rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, g  v5 B. @, Q, R5 @, ]; T. ^5 _
lamic deficiency. After evaluation of response to luteinizing0 }$ W7 W  K. e4 [& H* i* ]3 f' @
hormone-releasing hormone these patients were treated with7 m9 _. z& G: Y+ e2 ?3 d( S
1,000 units of gonadotropin weekly for 3 weeks. Six weeks- Q( e0 }- x2 c5 A% c1 J
after completion of gonadotropin therapy 10 per cent topical
  s4 [. t$ z& E8 f/ y- mtestosterone was applied to the phallus twice daily for 3 weeks.
8 g' x. C5 `4 S1 U( o! ZSerum testosterone, luteinizing hormone and follicle-stimulat-# K9 R3 E& V/ S3 M. S. N2 c
ing hormone were monitored before, during and after comple-
4 i2 w2 c9 S/ p- I9 e& U1 S4 L& \tion of each phase of therapy. Penile stretch length was
. E* f+ t3 h6 Y; r4 h. c' ?) Bobtained by measuring from the symphysis pubis to the tip of
$ E0 E5 e# R& R, q" Hthe glans. Penile circumferential (girth) measurements were9 ~* }0 E2 @2 a( s" j" B- _
obtained using an orthopedic digital measuring device (see: N& y5 k7 W+ p; P' n2 e* I
figure).
- o6 A) }6 X8 ~* r" l: \0 LRESULTS# f1 R, f, p# N2 M+ n
Serum testosterone increased moderately to levels between/ {2 E- M) X8 f
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% b+ g* G  k& T/ _% pterone levels with topical testosterone remained near pre-" _* L# s# L% z  P- ^4 ^- |
treatment levels (35 ng./dl.) or were elevated to similar levels
$ j- \6 G" Z7 E- `developed after gonadotropin therapy (96 ng./dl.). Higher
/ [/ [. L6 k5 V; Qserum levels were noted in older patients (12 and 17 years old),( Y6 N7 M3 C# s
while lower levels persisted in younger patients (4, 8, and 106 D( j/ c. ~- ^$ S; N9 b
years old) (see table). Despite absence of profound alterations2 K0 g% ^6 v, x9 T% I5 T/ ?4 w
of serum testosterone the topical therapy provided a greater, `! N8 T& Q( g- O
Accepted for publication July 1, 1977. ·/ l+ m: u$ i; K  N
Read at annual meeting of American Urological Association,
& _; a) m8 y+ I& R9 G1 DChicago, Illinois, April 24-28, 1977.
! Q3 g) d! t; s5 ]: t$ P: l* Requests for reprints: Division of Urology, Henry Ford Hospital,
- v$ I- c$ _# i! E( {0 Y# k2799 W. Grand Blvd., Detroit, Michigan 48202.
1 ]& ~! m: ~. O. x2 K% E& Timprovement in phallic growth compared to gonadotropin./ J' V9 Y0 x" N* C  y
Average phallic growth with gonadotropin was 14.3 per cent
. z7 r' Q0 z# b6 H! x1 {increase in length and 5.0 per cent increase of girth. Topical% L- K' I! D8 z/ I% g
testosterone produced a 60.0 per cent increase of phallic length  W6 @: J5 e: F$ L% W+ {7 w4 E9 C8 T$ |
and 52.9 per cent increase of girth (circumference). The
9 W, ]9 Q) X! f- L) Lresponse to topical testosterone was greatest in children be-
" c' O6 R% F  f+ e3 Btween 4 and 8 years old, with a gradual decrease to age 17! G; ]+ U. E2 \+ G5 O1 p
years (see table).! ^, E; L' n7 H2 N/ ?
DISCUSSION+ [" m5 o* p6 ~1 J$ T* m
Topical testosterone has been used effectively by other" {$ |' i$ T& O9 L9 r! v' |% ~$ T/ B
clinicians but its mode of action remains controversial. Im-
& s6 e+ g' p; N5 {9 T$ Zmergut and associates reported an excellent growth response: h# ~9 z) u/ W
to topical testosterone with low levels of serum testosterone,9 ~) C+ k; p2 u$ U- K, {
suggesting a local effect.1 Others have obtained growth re-/ N! u- p6 B& I7 X, f
sponse with high. levels of serum testosterone after topical' P- R, X7 s: c' W
administration, suggesting a systemic response. 3 The use of! f- G; u$ ^, G9 \
gonadotropin to obtain levels of serum testosterone compara-1 v( I$ R9 t, Q8 C( Z
ble to levels obtained with topical testosterone would seem to1 v, `9 }2 Y* X$ I
provide a means to compare the relative effectiveness of
4 i" b. P' i1 j1 L+ G) j' gtopical testosterone to systemic testosterone effect. It cer-; P# K; _' y# H) A
tainly has been established that gonadotropin as well as par-, H* v6 s% N4 a& O3 K: R9 l4 r8 g
enteral testosterone administration will produce genital
* L% `# I- y6 [! p5 Hgrowth. Our report shows that the growth of the phallus was
+ d0 O  I% V' Y" V0 C, S( r. psignificantly greater with topical applications than with go-1 d7 N$ t  ~% b7 S1 ^& t
nadotropin, particularly in children less than 10 years old.% v0 X! {2 T9 |  Q$ o1 m  S  l
The levels of serum testosterone remained similar or lower
# V# B# w' Q0 Q9 A  m" a5 N5 Kthan with gonadotropin during therapy, suggesting that topi-
( F+ g! r2 c, i) W# C6 {  v* Fcal application produces genital growth by its local effect as( w/ Q+ R; u0 u6 {* B6 T4 E
well as its systemic effect.' Z4 h% N4 Z/ ]$ i2 ~. a
Review of our patients and their growth response related to! {2 g, b* E0 z+ g& \
age shows a greater growth response at an earlier age. This is9 T+ I5 e7 r  n4 J: t3 i6 a
consistent with the findings of Wilson and Walker, who
9 J, J( }- v# `$ rreported an increased conversion of testosterone to dihydrotes-( y/ N3 t/ `. q" G1 _2 x! N
tosterone in the foreskin of neonates and infants.4 This activ-
8 P/ j, F1 S8 @' @1 \4 gity gradually decreases with age until puberty when it ap-
  e5 ]- p* E" o, Tproaches the same level of activity as peripheral skin. It may2 h8 H' N2 |) \4 X
well be that absorption of testosterone is less when applied at
( G& J; a; n6 q8 w  xan earlier age as suggested by lower serum levels in children2 t: D- ]  w! N# X& b
less than 10 years old. This fact may be explained by the  o% L6 w- T/ q# D
greater ability of phallic skin to convert testosterone to dihy-
. O: v+ x$ B. vdrotestosterone at this age. Conversely, serum levels in older
6 k% R) u' C/ z% p1 q5 Hpatients were higher, possibly because of decreased local& c* D; M5 u5 u( R  F; g4 h
667
) a# i9 v2 X7 V5 P- a668 KLUGO AND CERNY
9 B! q! l, z" ]6 X" j: u. @, JPt. Age
3 S1 \8 _" P& s9 Y' z5 k5 O8 y(yrs.)/ J- r9 G2 l  m9 n
Serum Testosterone Phallus (cm.) Change Length
# `( \- w0 O; t- F5 Z! t, D" L(ng./dl.) Girth x Length (%), B0 ?! y1 r' c8 ^
4
- H3 K4 ~# b; f8 k/ Q$ o3 D- K8 d8
# \" w% Z' r  ^+ W10
. h  E  _1 X- O7 y$ B9 R4 X12
" z& [% Q7 C9 T9 j4 b) L17
. b9 q- K6 E- z9 HGonadotropin
- j- Y5 `+ \9 z6 t/ W6 B& V3 R71.6 2.0 X 3 16.6
5 M/ w: k- S9 D3 O# P  }4 _, q50.4 4.0 X 5.0 20.0% d2 g7 l( R! p* o3 C
22.0 4.5 X 4.0 25.0
1 x" ^5 C9 B6 t  H7 z4 K84.6 4.0 X 4.5 11.1
% j# p/ @* s, V% Q" }85.9 4.5 X 5.5 9.0
; u! g3 D# H: n* FAv. 14.3
- C) w) Y' [8 S48 S4 h: r$ v9 l9 B1 a, z
84 n7 I( m6 @( m* e3 O
10/ \4 X- f- c  |
12' z+ ^# }  Z9 T; D* R- i( H
172 `5 C, l8 e6 J" T4 I( Z
Topical testosterone
* {  E: y0 z; n# l34.6 4.5 X 6.5 85% Z9 D+ r/ X0 _) l; u2 ?% z7 F- h
38.8 6.0 X 8.5 70; T$ H* y3 K4 w% g
40.0 6.0 X 6.5 62.5
* J8 T, v' q9 z" d/ _! G1 D93.6 6.0 X 7.0 55.5
' D. G+ O2 n( m7 v# ?8 }+ D95.0 6.5 X 7.0 27.24 z+ G1 M5 T3 I* F9 f
Av. 60.0
9 v/ |5 F- h' M# z* ?available testosterone. Again, emphasis should be placed on
- I8 I1 l9 a- Bearly therapy when lower levels of testosterone appear to, a0 p1 ^4 M# x+ ?; L
provide the best responses. The earlier therapy is instituted- g. a2 S9 U5 a: Q$ K7 }0 W
the more likely there will be an excellent response with low
8 k3 j$ c1 C9 M) Jserum levels. Response occurs throughout adolescence as' I0 o& q5 u# ?
noted in nomograms of phallic growth. 7 The actual response
9 I: D, T+ V- X2 _4 ito a given serum level of testosterone is much greater at birth
  y6 L: N$ Y( X' h% ?( {! }$ `and gradually decreases as boys reach puberty. This is most
$ s8 r8 V( h% d& Flikely related to the conversion of testosterone to dihydrotes-+ ~6 e# C* Z/ x* N% H/ n& L
tosterone and correlates well with the studies of testosterone% e3 s7 N! C; r: b! k) c9 N: [+ n
conversion in foreskin at various ages.
/ x9 M# d  D1 j3 f, Y8 _' ]The question arises regarding early treatment as to whether; S9 o- |0 \0 e' w- ~+ k
one might sacrifice ultimate potential growth as with acceler-# L2 C! a; q4 R; I- v6 a( T
ated bone growth. The situation appears quite the reverse
; m0 I& A& c# l& R, V* ?with phallic response. If the early growth period is not used1 |. R, k  T- c% h* _( R
when 5a reductase activity is greatest then potential growth
2 t* M0 H9 W  v2 S/ a$ rmay be lost. We have not observed any regression of growth6 H' V) ?, g8 l7 U+ h& m7 o8 R8 _
attained with topical or gonadotropin therapy. It may well
) r0 z1 k4 f+ V4 t5 ibe that some patients will show little or no response to any9 Y, H, W8 U6 k3 w7 C) d! p
form of therapy. This would suggest a defect in the ability to
! C# K# N* n' ^" U3 S8 Sconvert testosterone to dihydrotestosterone and indicate that# `9 V5 C9 a: K* Q, y' Y
phallic and peripheral skin, and subcutaneous tissue should
4 e: U. v- _5 _2 sbe compared for 5a reductase activity.7 {6 {6 W' L& N
A, loop enlarges to measure penile girth in millimeters. B,; Z- u+ \0 g  @  |# ]8 S1 X
example of penile girth computed easily and accurately.
9 J; @, i+ X' x, d" o" Jconversion of testosterone to dihydrotestosterone. It is in this+ n! ~& w$ U. M
older group that others have noted high levels of serum
( {6 a, d; j4 t5 f. N# ntestosterone with topical application. It would also appear
) B- U. o6 T1 X3 o' Qthat phallic response during puberty is related directly to the
/ k' A4 T9 p. O4 v2 k/ R0 k6 jserum testosterone level. There also is other evidence of local! A" ^( Q0 M1 t$ g$ K
response to testosterone with hair growth and with spermato-, o4 `5 i) F7 }+ u7 }/ [
genesis. 5• 6
& G* ^7 H- c, Y0 K+ ?- C8 CAdministration of larger doses of gonadotropin or systemic
: m" L4 P9 r7 R7 L, Dtestosterone, as well as topical applications that produce
1 t( P7 C; l& k1 M: G1 X: |higher levels of serum testosterone (150 to 900 ng./dl.), will9 }/ a7 Q( Z0 e3 |, A2 D
also produce phallic growth but risks accelerated skeletal
0 p4 G2 i' g: S7 A$ Lmaturation even after stopping treatment. It would appear
4 o; I5 |+ ?! i( ~3 cthat this may be avoided by topical applications of testosterone
" H+ d! N9 a+ o  b' @! Nand monitoring of serum testosterone. Even with this control3 N+ \5 ?$ C7 l" x
the duration of our therapy did not exceed 3 weeks at any, K4 X9 t3 W/ `& d
time. It is apparent that the prepuberal male subject may
5 ]: ?& U9 U' g$ l4 P# V# u7 Y+ N* Ssuffer accelerated bone growth with testosterone levels near
' l- c0 X1 U' O5 q* p$ l! y200 ng./dl. When skeletal maturation is complete the level of9 o* w* a! @0 R* t: Y3 y4 t
serum testosterone can be maintained in the 700 to 1,300 ng./6 q, g* t! u0 q4 ~
dl. range to stimulate phallic growth and secondary sexual
- G$ D8 L; {. m$ S  K0 a; W5 \changes. Therefore, after skeletal maturation parenteral tes-# f; `; ]9 n+ E1 r  J
tosterone may be used to advantage. Before skeletal matura-( Q3 k  H% R7 k0 f, H
tion care must be taken to avoid maintaining levels of serum
# M) ~; k3 n1 @- itestosterone more than 100 ng./dl. Low-dose gonadotropin7 f! G) P7 j1 f. Y5 j
depends upon intrinsic testicular activity and may require# m$ w2 m: G9 q, r1 `
prolonged administration for any response.+ n' I/ K- Q) }; M' C6 S
Alternately, topical testosterone does not depend upon tes-
/ Z1 s  }& l8 m, gticular function and may provide a more constant level of: ~0 i( V3 f' G3 B" i
REFERENCES
0 ~/ S' H4 e+ h' ^" @  D/ U9 Z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,3 z/ C/ Y# y, e& n7 [
R.: The local application of testosterone cream to the prepub-
; h- f" m% _3 s: Yertal phallus. J. Urol., 105: 905, 1971.
' C4 p) Q4 g2 a) X( _' f2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 H; T# @( k8 ptreatment for micropenis during early childhood. J. Pediat.,* o9 v2 ~0 u9 C
83: 247, 1973.; ]( p0 E0 ]( f+ s) a: j7 Z( b7 {
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-+ B% l) x- r& m! ]4 e5 R4 \3 i
one therapy for penile growth. Urology, 6: 708, 1975.: T7 k3 G& y9 A" s- ~3 S5 ?# N
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone% w" Z4 n/ c6 s+ h+ Y& c! f. G
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( V" s: m1 ^8 K2 x" E( d
skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 o. l# E# ~3 r, V! T. z5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 i; }7 {" o' h6 d* |
by topical application of androgens. J.A.M.A., 191: 521, 1965.4 P* H) }+ |3 \$ f6 e0 b6 A8 H+ f
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! e9 |& x) n! Y* fandrogenic effect of interstitial cell tumor of the testis. J.
; E/ S7 F' h1 k5 VUrol., 104: 774, 1970.
4 {9 O" |5 y, k; g( Q- Q) v1 A5 M7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. h+ R& g. a/ O" b
tion in the male genitalia from birth to maturity. J. Urol., 48:
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