- 註冊時間
- 2023-5-6
- 精華
- 在線時間
- 小時
- 米币
-
- 最後登錄
- 1970-1-1
|
發表於 2025-1-4 03:09:28
|
顯示全部樓層
RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND Q' r3 l$ m! @9 b
GONADOTROPIN- {/ H0 Q2 Z- R9 v0 B
RICHARD C. KLUGO* AND JOSEPH C. CERNY* j9 W; b u6 Z
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan7 ?) C! t7 r# `3 v9 P3 ]
ABSTRACT
/ A7 R4 f7 T! t# Z; |' xFive patients were treated with gonadotropin and topical testosterone for micropenis associated
: n7 z3 ~) m: q0 J6 Z3 Cwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
p+ H' M; O) T( R7 x4 K/ Vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ p8 a! K+ _3 _% H3 u6 |2 F
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, I. `+ e& Y- I
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
. ?- \* }$ H ^( Nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 K1 r$ u5 O' L! N2 h/ H
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response) P& Z8 N1 ~( S. _
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 b% b9 U% v( U" V
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 D. v0 o* y. ?" Q b1 M
growth. The response appears to be greater in younger children, which is consistent with previ-4 z i/ x8 _9 E* j, E$ S9 v( z
ously published studies of age-related 5 reductase activity.% ~7 N( u; J6 O
Children with microphallus regardless of its etiology will
% k% q+ J& L2 Q# @% erequire augmentation or consideration for alteration of exter-4 S% U3 ]% n$ z$ n) Y- d
nal genitalia. In many instances urethroplasty for hypo-
6 `0 b; ]; n- K2 E7 P* rspadias is easier with previous stimulation of phallic growth.& @: o p: \' j; q' ]# I8 X& i
The use of testosterone administered parenterally or topically. x5 J( C& {' K% R+ }$ Z* Z
has produced effective phallic growth. 1- 3 The mechanism of
- Z% q5 ]% j2 V- i. uresponse has been considered as local or systemic. With this8 w0 ?7 x9 D H3 c
in mind we studied 5 children with microphallus for response
. d; k% o7 m/ qto gonadotropin and to topical testosterone independently.4 N* D1 h" q1 O6 r
MATERIALS AND METHODS0 S: C+ y9 L- k/ ?
Five 46 XY male subjects between 3 and 17 years old were
. Z% B' i+ s$ n) M& c0 p$ D) Eevaluated for serum testosterone levels and hypothalamic
) G% N- l" G+ p1 \# t& }& r. V: Kfunction. Of these 5 boys 2 were considered to have Kallmann's
) y( c( f+ G8 k& ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha- ^2 e% S2 r0 d; j6 [
lamic deficiency. After evaluation of response to luteinizing4 q3 D5 p$ y% a0 j$ U# y; P
hormone-releasing hormone these patients were treated with2 r; ]6 Y; m0 c8 d; @
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: n* m( g( z: h4 Yafter completion of gonadotropin therapy 10 per cent topical
- G0 [7 p* A4 H0 e) O3 q- btestosterone was applied to the phallus twice daily for 3 weeks.
/ |8 }8 z, Y' sSerum testosterone, luteinizing hormone and follicle-stimulat-
: u h* ^, x- ming hormone were monitored before, during and after comple-) Y4 X, C* m1 Y6 [
tion of each phase of therapy. Penile stretch length was. [) Q4 q+ K( n7 v
obtained by measuring from the symphysis pubis to the tip of+ u ^2 c# a6 ?8 d" ~) A' h& p+ F- {
the glans. Penile circumferential (girth) measurements were
6 i" e- j: J0 }3 C2 f( Zobtained using an orthopedic digital measuring device (see
" L* M' X9 Q3 x8 kfigure).# f5 ]' i T9 i- u0 U
RESULTS* k% X5 S3 G8 V) z4 w/ r) X
Serum testosterone increased moderately to levels between# _( L" m& O2 F& Z5 [; u8 ]
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 H+ e* K' x6 F. _6 i5 @6 dterone levels with topical testosterone remained near pre-3 o1 `) S0 |6 q( A" M
treatment levels (35 ng./dl.) or were elevated to similar levels
7 h$ H4 L3 I: H1 w' ldeveloped after gonadotropin therapy (96 ng./dl.). Higher
: i- i# o6 S' M2 q7 Z0 Qserum levels were noted in older patients (12 and 17 years old),8 L1 e. D @2 R1 ?- s7 M" r
while lower levels persisted in younger patients (4, 8, and 10
: L; [9 ^- ~" j. ?. t @years old) (see table). Despite absence of profound alterations: E; P2 D- [: P! q2 p
of serum testosterone the topical therapy provided a greater8 R8 v; X8 |7 d4 M% |3 T, v
Accepted for publication July 1, 1977. ·
5 g/ k3 `& \4 }0 b6 d' n3 p7 sRead at annual meeting of American Urological Association,
8 c Y/ h- \; a$ R" w. |Chicago, Illinois, April 24-28, 1977.4 X# D+ p% Q: Y# X& G/ a8 ?! i
* Requests for reprints: Division of Urology, Henry Ford Hospital,& ^3 f3 m6 h' h7 J
2799 W. Grand Blvd., Detroit, Michigan 48202.9 B7 t3 |$ r% j. x+ G
improvement in phallic growth compared to gonadotropin.
5 X% A& k. _& Z7 i$ \5 C m) j" uAverage phallic growth with gonadotropin was 14.3 per cent
+ `! @' P8 V# n! z9 {7 @increase in length and 5.0 per cent increase of girth. Topical
& F1 ]( `' K( E; q% }0 Ftestosterone produced a 60.0 per cent increase of phallic length
; X9 y/ ], Y* Hand 52.9 per cent increase of girth (circumference). The' \, I" [ v5 c* m$ U! b# S
response to topical testosterone was greatest in children be-
( u6 ]) i% c' ztween 4 and 8 years old, with a gradual decrease to age 17$ E' Z, p$ Y# R( z# G, p
years (see table).0 U* W, t( L$ E9 w+ p8 X7 q
DISCUSSION
" t& d3 x! c0 p' T( I1 l& @Topical testosterone has been used effectively by other
8 x8 |& U P$ r- }# e' Xclinicians but its mode of action remains controversial. Im-% Y2 g8 T& _# e! p, x5 h7 U
mergut and associates reported an excellent growth response2 L7 u3 ]! p/ t) M, N; s& N
to topical testosterone with low levels of serum testosterone,
* ^6 t0 V6 I0 ^0 {0 K5 lsuggesting a local effect.1 Others have obtained growth re-8 n2 R* l2 c% o6 ?- G
sponse with high. levels of serum testosterone after topical
- h/ c1 H7 B8 g ]administration, suggesting a systemic response. 3 The use of6 V# X8 j' @4 K9 Y( n* |- D5 ] }
gonadotropin to obtain levels of serum testosterone compara-! d8 {8 @4 \$ y W) d$ o
ble to levels obtained with topical testosterone would seem to
' W2 O2 O* d, p+ Z; e+ q* aprovide a means to compare the relative effectiveness of: P6 Z& {5 o7 V4 |$ c1 F
topical testosterone to systemic testosterone effect. It cer- R3 F; Z# V* r( \6 y. ?
tainly has been established that gonadotropin as well as par- t( @6 N( B! Y) p: b1 C. W
enteral testosterone administration will produce genital
5 w! A% b( P# O' {) J8 Qgrowth. Our report shows that the growth of the phallus was! w2 x6 Q8 x9 J
significantly greater with topical applications than with go-* [! ]6 w; V6 U6 g
nadotropin, particularly in children less than 10 years old.
% `) Z- [6 O. [ ~ }: k; w1 d7 o( `. eThe levels of serum testosterone remained similar or lower; R0 c# C$ P& U* _9 R
than with gonadotropin during therapy, suggesting that topi-
- V |% Z' x3 e6 n: d) `2 Wcal application produces genital growth by its local effect as. a) f0 A. Y* F& T: R$ w* k
well as its systemic effect.3 h b3 i( `2 E6 V! O
Review of our patients and their growth response related to
, d! e6 W" b1 @age shows a greater growth response at an earlier age. This is3 T ]' r2 {2 o9 @
consistent with the findings of Wilson and Walker, who
, g/ A4 R# Z! nreported an increased conversion of testosterone to dihydrotes-
7 o% v' [) J2 T8 Z" w _3 C; k. Ctosterone in the foreskin of neonates and infants.4 This activ-
$ D% _! I3 _9 u' i7 q* Yity gradually decreases with age until puberty when it ap-
. g0 \5 M' E3 e( y6 vproaches the same level of activity as peripheral skin. It may
4 U V$ G+ z2 U: Kwell be that absorption of testosterone is less when applied at8 r: d( }7 |( G8 ~
an earlier age as suggested by lower serum levels in children
( ^1 g5 R, m% X T' v! Lless than 10 years old. This fact may be explained by the
- a' K% X" Y0 L2 K4 u- O4 Cgreater ability of phallic skin to convert testosterone to dihy-
) f$ W1 R a4 L& o4 ~. H! x; udrotestosterone at this age. Conversely, serum levels in older
* T$ g p8 O, a' A! n! _patients were higher, possibly because of decreased local
6 `9 ]* x6 s( z$ M6 R; f- ^667 h, F ]1 E+ u4 @# p* Q, L7 {4 ~! f
668 KLUGO AND CERNY
5 i- N/ j3 D3 O# [ i# ePt. Age
9 s% ~" |+ ^- Q& Q(yrs.)
/ p( F8 i- _% g* FSerum Testosterone Phallus (cm.) Change Length" T8 ^- F; C2 R4 W* I
(ng./dl.) Girth x Length (%)
2 Q1 \0 W7 ~$ K4 H* n4
! D6 c6 G0 G# E( a89 a" u/ a9 h0 b8 F- M$ j
10( f/ R5 O5 S- Q. Q; m
12$ t0 g) [, D: o6 b Y
17
+ v& a( `. y$ D/ EGonadotropin
5 p$ K4 k5 c( v$ A F/ T71.6 2.0 X 3 16.6
; ?: |3 _) z; t2 Y50.4 4.0 X 5.0 20.0
8 Q p6 z$ V' {3 b22.0 4.5 X 4.0 25.05 r: A4 @; ~* G0 r: ?; Q
84.6 4.0 X 4.5 11.1" i9 ?% A5 q6 D( l0 P4 w
85.9 4.5 X 5.5 9.0
0 G- ?) M/ K. W. iAv. 14.3" Z3 g& L( _: o2 Q" F5 M! s
4. f& P, `" n! R) E3 o; ]7 q
81 e2 [' G7 E! X& s
10% \: |8 E- Q" p8 r$ S
12# S# c, y( }; [( d& I+ `. d
17
7 j5 _- U9 f' _. qTopical testosterone) D8 {# |2 S0 k; d
34.6 4.5 X 6.5 853 C2 |, X9 z$ P, E! h8 [
38.8 6.0 X 8.5 70
4 G, m1 {2 s8 j/ }# C40.0 6.0 X 6.5 62.56 Q% W; [: {1 @* x- K/ @
93.6 6.0 X 7.0 55.5
9 s, ^7 k! t$ }% a3 z8 B/ q% }6 {95.0 6.5 X 7.0 27.2
5 G! N) v7 A: G; @3 lAv. 60.0
4 @; @6 Q' u8 S9 L9 k @% wavailable testosterone. Again, emphasis should be placed on" @# _4 Z& \& X
early therapy when lower levels of testosterone appear to* r8 [( {+ q7 Q2 M) E, E
provide the best responses. The earlier therapy is instituted
+ [" v5 V1 c/ w0 Cthe more likely there will be an excellent response with low# X9 a" h; ]4 P& `
serum levels. Response occurs throughout adolescence as& `# m* W( O3 d0 \. n; L) V- ^8 }! O
noted in nomograms of phallic growth. 7 The actual response
* [; r+ \, P1 j" Q+ Dto a given serum level of testosterone is much greater at birth
) x% A6 g. Q7 B( d( ` O; Z! ^and gradually decreases as boys reach puberty. This is most. |" N( V) w/ h
likely related to the conversion of testosterone to dihydrotes-$ P' g% [" P# {
tosterone and correlates well with the studies of testosterone
$ ^) L$ i& G. I( G# O9 V8 Iconversion in foreskin at various ages.
+ h3 ~9 @! a1 uThe question arises regarding early treatment as to whether
* d1 e' \9 b# u- kone might sacrifice ultimate potential growth as with acceler-4 ]% \8 M5 \" A
ated bone growth. The situation appears quite the reverse
7 h, T' v/ e" F3 u( dwith phallic response. If the early growth period is not used
7 G+ p' U0 S3 T4 t* { swhen 5a reductase activity is greatest then potential growth
0 O4 I9 H* X2 u. d6 R# j+ |" P0 `may be lost. We have not observed any regression of growth" t4 V G* y4 V8 L. Y& _$ M M! y* A
attained with topical or gonadotropin therapy. It may well3 l; [: n1 a% w: ]0 m
be that some patients will show little or no response to any
( G& I2 v7 [1 y; hform of therapy. This would suggest a defect in the ability to/ Y& S- @; Q7 J/ }$ ^
convert testosterone to dihydrotestosterone and indicate that5 j3 n% T+ E( D. v+ u/ n: y
phallic and peripheral skin, and subcutaneous tissue should
5 w9 b5 c m% T5 y# A, e/ }be compared for 5a reductase activity.
* @. ?! k& T! U. }: Z6 oA, loop enlarges to measure penile girth in millimeters. B,
9 S7 o: l- e) g/ y) `example of penile girth computed easily and accurately.
4 v" z! ~( _% fconversion of testosterone to dihydrotestosterone. It is in this6 L$ T8 ^2 @+ D5 m. E
older group that others have noted high levels of serum) V0 \* n9 o" R, |% C
testosterone with topical application. It would also appear$ v! D5 t# H [. S3 P
that phallic response during puberty is related directly to the0 L$ W( }8 R1 X
serum testosterone level. There also is other evidence of local
' w8 q2 K* T3 n# D* Z( fresponse to testosterone with hair growth and with spermato-
0 r5 @4 c9 }1 n4 i" D4 `genesis. 5• 6
; L1 t M% E: q& U2 T/ p6 Z. GAdministration of larger doses of gonadotropin or systemic S3 t3 ~" u" Z) j1 \+ F" H
testosterone, as well as topical applications that produce" H: D, {- t& e% L* u
higher levels of serum testosterone (150 to 900 ng./dl.), will9 f, j N% y# ~0 `0 r7 e
also produce phallic growth but risks accelerated skeletal4 V m: I5 h U% ~9 @
maturation even after stopping treatment. It would appear5 [! u( e; @3 r, g* J: \" m
that this may be avoided by topical applications of testosterone* {) y3 E* u2 E+ O
and monitoring of serum testosterone. Even with this control
! w6 Z# C6 L1 M/ p$ Y$ Bthe duration of our therapy did not exceed 3 weeks at any% C! q" D7 ?+ z: r1 g8 p
time. It is apparent that the prepuberal male subject may6 ]4 W1 t) U1 x( T; \0 a+ ~/ F
suffer accelerated bone growth with testosterone levels near
1 E t2 z0 u7 m3 K. c4 H* U200 ng./dl. When skeletal maturation is complete the level of* y- q) W( _9 k5 d4 d" M- w
serum testosterone can be maintained in the 700 to 1,300 ng./$ e9 n) f) v: K% @. g4 n
dl. range to stimulate phallic growth and secondary sexual" O4 l4 r, z. g* r
changes. Therefore, after skeletal maturation parenteral tes-
" F( T. ~6 R3 K/ |0 {; n; |tosterone may be used to advantage. Before skeletal matura-
* ^" Q! N s% {; G4 M. \; Ition care must be taken to avoid maintaining levels of serum
) _ m2 F; R! `5 R5 itestosterone more than 100 ng./dl. Low-dose gonadotropin3 T7 B% `" q0 }1 j0 k
depends upon intrinsic testicular activity and may require
( o. B9 G" x- F0 L' Xprolonged administration for any response.
, A" n9 P6 F& c6 _3 vAlternately, topical testosterone does not depend upon tes-6 ^( N: I4 j' g7 M, O( M( P
ticular function and may provide a more constant level of
; u' T$ m; n3 r/ TREFERENCES
; ~' p; u/ d1 x( _1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
) I& y& h9 f' x4 A uR.: The local application of testosterone cream to the prepub-
. H2 Y( r. e! Bertal phallus. J. Urol., 105: 905, 1971.' L/ x. {: M& X" m. d7 S! s& q
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 L1 T! d& W" ^3 S3 f1 Rtreatment for micropenis during early childhood. J. Pediat.,5 m" b/ Y' Y O+ D" {, T
83: 247, 1973.
0 l* W# S, A$ s4 X; ]" I6 R1 N3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* |* M* i/ Y6 [ K$ d7 u
one therapy for penile growth. Urology, 6: 708, 1975.
/ A; S7 \' p4 o9 Y$ L4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* ?% v7 w: C3 a2 o8 y" L0 ]
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, A! Q3 F# D/ m; nskin slices of man. J. Clin. Invest., 48: 371, 1969.- w- s7 z6 f0 p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
1 y1 e( ?+ T6 t5 G# a, J( Vby topical application of androgens. J.A.M.A., 191: 521, 1965.
) I% Y( U( j& Z: I' w6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# V% q9 } q* V" m6 n% o% qandrogenic effect of interstitial cell tumor of the testis. J., p% I- j4 Q+ e3 h2 I- n- T2 I
Urol., 104: 774, 1970.9 T8 N) {8 x7 M. R# \9 X4 S
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
" W8 \1 c2 `- ?7 k1 j6 K% m! Ftion in the male genitalia from birth to maturity. J. Urol., 48: |
|