- 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
- k5 \6 P6 L$ o7 z! b! R2 v& R4 WGONADOTROPIN
& z' y. D* O9 r5 ^: N- }RICHARD C. KLUGO* AND JOSEPH C. CERNY
8 C: O7 C( w. DFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# O$ r( r/ r/ z( s" T" Z( IABSTRACT+ B: N' n9 u% a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated, j; x1 d- n6 {/ R! V% I5 u' }
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* |% D$ p" Q# P7 itropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 X- @5 R" `1 m" ]4 I1 {8 O: Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent1 L8 H- s3 P) x0 V5 d4 ^ K
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 B) n" Z! x4 f$ d# _increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average. k; e% p5 {$ l: n: O) M1 P
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 |6 M; C% {+ eoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, U V1 I$ a# C( Gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, J" K; L7 L" {
growth. The response appears to be greater in younger children, which is consistent with previ-
+ \* M4 J( t, C l K% Aously published studies of age-related 5 reductase activity.
" O0 t) i2 l/ H5 j# GChildren with microphallus regardless of its etiology will
; V( f. S9 }$ G; u/ L+ vrequire augmentation or consideration for alteration of exter-, w' p3 e* z; z' x; L$ c+ ?
nal genitalia. In many instances urethroplasty for hypo-, L) z& T6 A! I3 {; x9 j
spadias is easier with previous stimulation of phallic growth.4 G& h$ h$ d; E7 P! P) h
The use of testosterone administered parenterally or topically1 \5 z4 D* e! a; g/ |0 p- |
has produced effective phallic growth. 1- 3 The mechanism of: @+ H/ a9 |, q' P% W9 x) Z! Z
response has been considered as local or systemic. With this& a1 b4 S# a! Z" ~3 ]: W
in mind we studied 5 children with microphallus for response
& n# ]$ G0 c: L4 b. Q. O+ Vto gonadotropin and to topical testosterone independently./ _3 l1 k* s D
MATERIALS AND METHODS
- K6 p$ f9 Z% L# q I: mFive 46 XY male subjects between 3 and 17 years old were2 e% j& m& h+ P0 \& I# o. m3 c \, D
evaluated for serum testosterone levels and hypothalamic: D8 h( T4 G2 F4 @) M
function. Of these 5 boys 2 were considered to have Kallmann's
" a# p" A& D: a7 C& F" Asyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 l/ T- n. C1 Y) _0 ?% k
lamic deficiency. After evaluation of response to luteinizing
) y, p. M1 \) }% G7 [- p4 Vhormone-releasing hormone these patients were treated with2 @. @, Z* U; p. r
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
5 i+ `! r- k' c9 U- E8 s4 S# oafter completion of gonadotropin therapy 10 per cent topical
9 ]2 X, k% g/ ]testosterone was applied to the phallus twice daily for 3 weeks.7 E- M. Q& X/ |1 ^& c2 v& k" o, _
Serum testosterone, luteinizing hormone and follicle-stimulat-
/ n1 F" s# d# N6 Z3 _/ d" ]ing hormone were monitored before, during and after comple-/ h2 P: I6 n$ i0 \, ^' k, b+ C
tion of each phase of therapy. Penile stretch length was
0 D; `# Z6 j: M2 z# i6 Robtained by measuring from the symphysis pubis to the tip of
. }/ w( ^! x; h8 g! }; A# Sthe glans. Penile circumferential (girth) measurements were
9 E& a# v2 w' W3 G' T7 S* n* @: Eobtained using an orthopedic digital measuring device (see
3 q q9 ` }$ v2 K6 c0 ifigure).
" Z8 G& q5 X( `4 W; o; J+ G; eRESULTS- @6 G( ^8 p/ A; ^6 s
Serum testosterone increased moderately to levels between% {% g6 c" ~1 A' U: _5 z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ y- p% t: M1 Y' X z+ v" ]terone levels with topical testosterone remained near pre-# N4 i( m% g& K
treatment levels (35 ng./dl.) or were elevated to similar levels
3 {3 C- G5 o! E) b5 t5 B' k0 ^developed after gonadotropin therapy (96 ng./dl.). Higher& {; f# f' p/ I8 {% `' Y1 U' u
serum levels were noted in older patients (12 and 17 years old),
3 l$ L! t/ f( a! q/ [+ }4 K9 Rwhile lower levels persisted in younger patients (4, 8, and 106 x# b" A( C% ~7 u
years old) (see table). Despite absence of profound alterations4 ]2 s. T5 i% d4 ?. O
of serum testosterone the topical therapy provided a greater) `+ O! m8 |6 a5 f7 e2 |% B
Accepted for publication July 1, 1977. ·1 T- o' }0 B- s1 t
Read at annual meeting of American Urological Association,
8 v: M# q& H: \ N; X0 nChicago, Illinois, April 24-28, 1977.( \. l" @2 u0 W$ j" C% }( u
* Requests for reprints: Division of Urology, Henry Ford Hospital,
T* d$ g3 Q9 F, T1 o8 D4 O2799 W. Grand Blvd., Detroit, Michigan 48202. `7 I, K6 y6 c2 T
improvement in phallic growth compared to gonadotropin.
$ h# W) u9 }* ?/ [8 N) kAverage phallic growth with gonadotropin was 14.3 per cent, \7 z8 A2 Q! a# v6 v# @
increase in length and 5.0 per cent increase of girth. Topical
( b# K7 Z0 j' stestosterone produced a 60.0 per cent increase of phallic length: w d$ o9 m2 J8 _, n
and 52.9 per cent increase of girth (circumference). The# w# D# h1 X3 n; l7 S6 T' n
response to topical testosterone was greatest in children be-# n$ h# n& E `! [( g
tween 4 and 8 years old, with a gradual decrease to age 17! g$ B4 \7 f7 t
years (see table).6 {( c( l/ C3 P/ J0 B# Q1 P
DISCUSSION
+ o# T% f; ?4 Y M TTopical testosterone has been used effectively by other7 \8 y; n& R/ R1 D9 T, E
clinicians but its mode of action remains controversial. Im-2 j+ v+ @ j, i: u: P j: [$ x: g# r
mergut and associates reported an excellent growth response
' s1 H8 O: T' I6 N1 Eto topical testosterone with low levels of serum testosterone,8 r! ]1 k/ m, c
suggesting a local effect.1 Others have obtained growth re-
% O8 T. z; h7 U9 Fsponse with high. levels of serum testosterone after topical' ?- W, J" C0 N; S$ J
administration, suggesting a systemic response. 3 The use of+ S- L2 O9 f& _% S- H
gonadotropin to obtain levels of serum testosterone compara-5 z% W2 H: T& v( Z
ble to levels obtained with topical testosterone would seem to, j7 v5 T! G- U6 w- [, b
provide a means to compare the relative effectiveness of
, w4 @% r2 a2 H' ^0 r) b7 A7 Stopical testosterone to systemic testosterone effect. It cer-$ G" g4 J: D8 m/ x6 U I$ B
tainly has been established that gonadotropin as well as par-
0 Y1 c% n1 X, X" B; Qenteral testosterone administration will produce genital( Q# g+ x" @, k/ f4 i8 Q2 Z: |
growth. Our report shows that the growth of the phallus was: e. [4 G) a' l0 z
significantly greater with topical applications than with go-
6 m" o% @ t! t4 l9 o. onadotropin, particularly in children less than 10 years old.
( L/ P( ?- g+ s; y* d2 k& e5 ?The levels of serum testosterone remained similar or lower
/ M/ o# T- |7 e# p9 d6 [( Uthan with gonadotropin during therapy, suggesting that topi-0 O; L. F+ |3 Q! \1 l. ]
cal application produces genital growth by its local effect as
6 S) S3 i" h$ q0 Q1 @% _well as its systemic effect.
7 J3 y0 }( n& W+ c$ pReview of our patients and their growth response related to* X$ c! H' H) h$ x- }$ D3 [
age shows a greater growth response at an earlier age. This is
9 o6 C& P, X# s* ?2 Cconsistent with the findings of Wilson and Walker, who
8 X# l i( O9 A4 \1 Yreported an increased conversion of testosterone to dihydrotes-
# ~" X: b4 v2 |/ U' ctosterone in the foreskin of neonates and infants.4 This activ-
4 Y/ D: l+ Y% D) N2 b, V2 O2 Tity gradually decreases with age until puberty when it ap-' b Z, r9 Z& N1 b
proaches the same level of activity as peripheral skin. It may
6 Y6 T; b/ }& ]" p6 `! x' ~well be that absorption of testosterone is less when applied at, T7 V, Z! s7 U
an earlier age as suggested by lower serum levels in children, a2 p8 |, X" F/ h o5 }# h
less than 10 years old. This fact may be explained by the
$ K7 `# P. X$ sgreater ability of phallic skin to convert testosterone to dihy-
% C. o* u) x* [8 L, L/ H0 `drotestosterone at this age. Conversely, serum levels in older
. A a6 O& n* Y3 z7 J% v" zpatients were higher, possibly because of decreased local
d4 s! w$ a) R, F1 y667
0 u% C" Q: w4 y) v1 q5 w: |& |668 KLUGO AND CERNY+ s9 Q9 H, q5 N7 ~
Pt. Age
( f1 j# V8 S5 v3 y4 n(yrs.)" n( F, ~( d( _7 a6 i5 n1 a
Serum Testosterone Phallus (cm.) Change Length
' ?, O; x1 _$ x! x& q(ng./dl.) Girth x Length (%)
% g7 n8 M9 \ j! D! A3 J# P8 b E4
* X2 E; _% d/ t5 B# W8) C# C. u- S( D. D* R/ y
10* o/ W+ _0 p6 s
12( t8 d, S$ e0 W
17
: u8 H* F7 O9 b, b/ s, D( DGonadotropin
5 Y$ h; p" @! M, `& ^7 Z- j; L71.6 2.0 X 3 16.6
* F: C# |9 [9 a0 }50.4 4.0 X 5.0 20.0
' }- C$ ]5 K6 H: X E22.0 4.5 X 4.0 25.01 U$ X! D$ o g# ] Y8 u1 G
84.6 4.0 X 4.5 11.1
* t" \. i% z- E' k P85.9 4.5 X 5.5 9.03 M% Q( |# Q: ~6 t" b, _' r, \
Av. 14.3
/ t& ~0 G1 A+ E- J; h6 y4 D# K4 p4
. H' C' A/ P5 t8 q3 y8
r# x' W& f" X8 }/ o, N' Z10
0 ]- g6 O+ p# n3 K$ g% u$ N12. W% ], t& @! q0 ~/ `; P( F p9 H
17% u, |' _% [* v) b& F+ C2 D8 R
Topical testosterone) P" @6 w5 b! w, g$ k& Z+ b& m
34.6 4.5 X 6.5 85
2 F) E% x. p8 W z# h; {38.8 6.0 X 8.5 700 a# f8 d, C& h) ?: ]
40.0 6.0 X 6.5 62.55 s) q; q% Z$ g0 ]
93.6 6.0 X 7.0 55.5: D2 l" Q/ E- I1 |3 b" G
95.0 6.5 X 7.0 27.22 y& H1 w6 x4 a) k# C
Av. 60.0. n, ?7 H' l, o% I6 e
available testosterone. Again, emphasis should be placed on( B, x9 K7 ]; j/ s, s$ R, z
early therapy when lower levels of testosterone appear to+ _0 c7 @' m0 j
provide the best responses. The earlier therapy is instituted* N6 c) @# A- A2 X$ L3 {
the more likely there will be an excellent response with low
# J2 j& _ `* h7 k, nserum levels. Response occurs throughout adolescence as
K) R# X B/ j9 M! inoted in nomograms of phallic growth. 7 The actual response
% ~; M! o5 h' V3 k: T* [to a given serum level of testosterone is much greater at birth' K0 P% J6 ~: K
and gradually decreases as boys reach puberty. This is most: h& d. r. B2 S4 u4 \
likely related to the conversion of testosterone to dihydrotes-
; q5 t* c7 q- G# Y* S! }* Mtosterone and correlates well with the studies of testosterone
' s3 w% p; X' }conversion in foreskin at various ages.
+ o+ w1 g# x" \' YThe question arises regarding early treatment as to whether
; b3 U3 o: ^- P# ?9 ]9 ?one might sacrifice ultimate potential growth as with acceler-
2 p0 e, X3 ~# k1 H/ q+ yated bone growth. The situation appears quite the reverse( w |0 E5 R# ?/ u( u2 i# I7 ~
with phallic response. If the early growth period is not used
$ [; f' u% U6 u. K7 gwhen 5a reductase activity is greatest then potential growth3 r( g8 U' ?2 M0 a
may be lost. We have not observed any regression of growth
2 q( j' z+ ?1 }3 p9 `! Uattained with topical or gonadotropin therapy. It may well3 |8 C& ~5 L7 E+ b1 i; J9 b
be that some patients will show little or no response to any% T; ?. s2 t r# G- E: M
form of therapy. This would suggest a defect in the ability to
' ?7 {0 H6 j5 w8 F" t! }8 M3 Sconvert testosterone to dihydrotestosterone and indicate that! W1 `0 i+ M5 t% B6 ?" j' }" B
phallic and peripheral skin, and subcutaneous tissue should/ _7 B' N; A" T g d
be compared for 5a reductase activity.* G7 Y% E P8 K1 c9 S, }1 }. g
A, loop enlarges to measure penile girth in millimeters. B,3 C% [4 X& _' ~ c0 k7 ^( ?- I
example of penile girth computed easily and accurately.- c- g7 o2 @' k% B( N
conversion of testosterone to dihydrotestosterone. It is in this" w# g X# I& b1 T/ x
older group that others have noted high levels of serum
7 s6 |5 x1 @) S& p+ B- ~testosterone with topical application. It would also appear4 P( y z) N% f
that phallic response during puberty is related directly to the5 u% R2 M% G: W+ g2 ?' D0 _3 }: a
serum testosterone level. There also is other evidence of local
6 X7 I0 n% @( r% hresponse to testosterone with hair growth and with spermato-
/ F) t( {3 S: ~# qgenesis. 5• 6$ f9 N( _0 p! Y, M/ W
Administration of larger doses of gonadotropin or systemic
2 s" q/ J6 U6 Mtestosterone, as well as topical applications that produce
' W3 }; Q# b5 E, |4 O' g7 ahigher levels of serum testosterone (150 to 900 ng./dl.), will5 @$ W/ [, O+ Q. k
also produce phallic growth but risks accelerated skeletal; j( t2 d& f2 S
maturation even after stopping treatment. It would appear1 p# Y% m) Q( H0 e( d* j5 M3 `
that this may be avoided by topical applications of testosterone
4 g' ^5 G% p: O' L0 a2 `' ^and monitoring of serum testosterone. Even with this control. A l' B, |9 x E7 ~$ n: T: R
the duration of our therapy did not exceed 3 weeks at any
6 O6 E9 {/ u7 h) _4 itime. It is apparent that the prepuberal male subject may: X8 ^( K! [7 N) H/ |6 h
suffer accelerated bone growth with testosterone levels near
* q6 I0 h* R) E2 X6 f, x200 ng./dl. When skeletal maturation is complete the level of+ {: O# o; S( {. E% a
serum testosterone can be maintained in the 700 to 1,300 ng./
9 }) w, z+ O3 ~4 `dl. range to stimulate phallic growth and secondary sexual
) _; ~6 F6 |3 D8 Z2 Fchanges. Therefore, after skeletal maturation parenteral tes-
% d3 f" ~: ]5 S3 mtosterone may be used to advantage. Before skeletal matura-$ r9 p9 Z: B& Q o6 f8 ?4 s
tion care must be taken to avoid maintaining levels of serum
% Y' H/ {5 |/ W: k; A/ itestosterone more than 100 ng./dl. Low-dose gonadotropin7 T: D1 n, E! z& w" k
depends upon intrinsic testicular activity and may require
) c/ _( ]0 ^ S5 H! Z. bprolonged administration for any response.
* p/ M6 F# w7 P' O# {, _$ uAlternately, topical testosterone does not depend upon tes-
1 N1 ^) i) B! E3 b: qticular function and may provide a more constant level of* u0 v: b& o6 T) B' w7 Z5 e, Q
REFERENCES
; {" R3 O& w" h& j9 J, i1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
! b6 X& a7 d @) `R.: The local application of testosterone cream to the prepub- s: J) ~$ E, W6 O' t; F/ I
ertal phallus. J. Urol., 105: 905, 1971.4 T0 K' A. c! g$ j' w1 s( P
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
* @" s+ V& |! J4 ltreatment for micropenis during early childhood. J. Pediat.,
9 F5 f9 p) T9 h6 F& E3 e83: 247, 1973.' d g1 o1 U4 f% s
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-2 g9 c: [" r3 O$ X a( F( ?
one therapy for penile growth. Urology, 6: 708, 1975.8 F# [" ~8 T8 J/ V! C0 n' F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 B$ n' e1 R! z, W" n& k! q5 L. v$ E4 Nto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 ]1 l& y0 Q' r" R2 F c2 ]8 [
skin slices of man. J. Clin. Invest., 48: 371, 1969.8 h) S) Y u) p X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# T/ J9 w8 g1 e3 x* _! o2 Tby topical application of androgens. J.A.M.A., 191: 521, 1965.
, R) b4 g3 s7 C x6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 [" H# {8 S3 v7 T
androgenic effect of interstitial cell tumor of the testis. J. i* Z9 l0 j+ {+ h9 a( l
Urol., 104: 774, 1970.& ^4 [, V5 a& ~) K! c# m
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. [& k+ i w3 ?
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|