- 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# u( e9 f+ h4 K! A/ S: s# |/ x/ Z3 Z
GONADOTROPIN, G! Y6 N! ?8 U. j, U' j- B+ \/ @
RICHARD C. KLUGO* AND JOSEPH C. CERNY
9 h/ Y/ `- ~( j) p2 OFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: q. ], E8 v+ u1 yABSTRACT
8 u; M1 Z: a- j) w# Q2 aFive patients were treated with gonadotropin and topical testosterone for micropenis associated9 h, E1 o- R! L! h+ t# ?* {( U
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ h' \* O9 a5 X4 W. K( ?7 W
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone+ ?, o" O' E. L! `1 {
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( L; O! `# L* Q- I. kfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
- i% j# J. ? Z7 {/ X& ` V8 ]increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average2 n* e9 k' l6 d+ _
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 a ^- [/ B. \" a1 N f! e+ _occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; ]$ J5 d0 q! d7 a" v+ G
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# b6 _* Q H6 V. K- x( o5 B1 Vgrowth. The response appears to be greater in younger children, which is consistent with previ-+ U9 ~" q# c+ k0 k
ously published studies of age-related 5 reductase activity.
+ Z* @8 D- r& b' w4 C/ v7 P; J4 P+ j* rChildren with microphallus regardless of its etiology will
' m' v- n+ t% }7 {( G; \2 srequire augmentation or consideration for alteration of exter-
# ?, _ a9 q- J( h, Z Qnal genitalia. In many instances urethroplasty for hypo-
% r& ^! E0 Q5 m1 S9 p- Y1 ?# gspadias is easier with previous stimulation of phallic growth.0 {4 U; g/ K8 P. u1 l8 I' P% t; H
The use of testosterone administered parenterally or topically
' F0 Q0 \0 l5 g: ?has produced effective phallic growth. 1- 3 The mechanism of
: X4 v$ X, o. [- L4 X8 \% Wresponse has been considered as local or systemic. With this
( l- u# Q- V- }in mind we studied 5 children with microphallus for response
/ h: F6 K" x& E- v3 w4 c( [to gonadotropin and to topical testosterone independently.
3 R0 h* Z8 q3 ^- ~% ]MATERIALS AND METHODS
; r, [3 X1 X2 a" e) I1 g9 e/ tFive 46 XY male subjects between 3 and 17 years old were& G7 d) o0 \# J
evaluated for serum testosterone levels and hypothalamic
9 s0 L+ z+ v. a0 W" tfunction. Of these 5 boys 2 were considered to have Kallmann's
7 ^. \' n; c5 M2 b d( K3 G" ^syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-+ v7 f$ w/ d% Q/ |" K0 a9 f' H G; [
lamic deficiency. After evaluation of response to luteinizing
2 A$ y7 g9 z4 R/ j: `& F9 }hormone-releasing hormone these patients were treated with+ H9 ?2 n+ R) G) a1 [7 p- e+ d
1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ p" Y6 T5 ~( i' w1 @
after completion of gonadotropin therapy 10 per cent topical0 s$ P4 a E3 h% e5 {4 K
testosterone was applied to the phallus twice daily for 3 weeks.5 d1 j3 S ^. T1 [0 r& N
Serum testosterone, luteinizing hormone and follicle-stimulat-3 P, _8 R# @3 d6 M' v
ing hormone were monitored before, during and after comple-
) q8 k/ o- H+ H, V- gtion of each phase of therapy. Penile stretch length was( E' L/ l4 V4 U# i5 N4 p
obtained by measuring from the symphysis pubis to the tip of
2 @6 y9 H0 D( m# E. P! U6 f. R. t* @the glans. Penile circumferential (girth) measurements were
% L. q- o, z6 \ W% h- A- N/ |obtained using an orthopedic digital measuring device (see/ q7 O3 v7 N1 f- j) Q4 b
figure).
4 ~$ G! @/ v n* i4 x7 ERESULTS
+ [! ~" q9 V" I: c3 OSerum testosterone increased moderately to levels between
: a1 x5 z3 U: ?5 Y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! \- M9 @$ g* ^1 ^4 D
terone levels with topical testosterone remained near pre-1 e! V4 ~$ s* X! i% C( j
treatment levels (35 ng./dl.) or were elevated to similar levels4 A: r: Z& `3 l2 | Z
developed after gonadotropin therapy (96 ng./dl.). Higher
9 w q4 X% y, k# m oserum levels were noted in older patients (12 and 17 years old),
$ }& }2 w; s: ]6 L& q) K" iwhile lower levels persisted in younger patients (4, 8, and 107 ]0 q+ {( n9 M
years old) (see table). Despite absence of profound alterations
. y: t& K- D$ h3 [. w; M: A8 H7 ?of serum testosterone the topical therapy provided a greater
2 P% H% {$ M+ v- }- t m5 D qAccepted for publication July 1, 1977. ·
+ ]' j# x% M: b7 _4 N1 SRead at annual meeting of American Urological Association,
( h1 I9 w! V- y) RChicago, Illinois, April 24-28, 1977.
! Z5 K9 l1 f" Y3 c" E; x* Requests for reprints: Division of Urology, Henry Ford Hospital,! D; L2 B; p" m- h
2799 W. Grand Blvd., Detroit, Michigan 48202.
) H% D" ^$ e" ^, d u r2 s. m' aimprovement in phallic growth compared to gonadotropin.% ? N$ y: U* y( s {, H
Average phallic growth with gonadotropin was 14.3 per cent
: G9 a5 r) i! B( C( S! q. Q( \0 Wincrease in length and 5.0 per cent increase of girth. Topical& Q! e+ f- x9 Z
testosterone produced a 60.0 per cent increase of phallic length
) P/ ?+ w; x' k1 a6 iand 52.9 per cent increase of girth (circumference). The( c' T4 h+ }/ x* n6 g& O
response to topical testosterone was greatest in children be-; ~8 H0 j( a: j/ m9 k% ?, d1 w w
tween 4 and 8 years old, with a gradual decrease to age 17( y: d w* I2 I
years (see table).
. z% @2 |, j8 p/ `DISCUSSION
& o: R; O6 g6 H4 t- VTopical testosterone has been used effectively by other
2 X+ W( C$ Z% c7 e, Uclinicians but its mode of action remains controversial. Im-
3 X, x9 X! \+ T+ o# `" }% omergut and associates reported an excellent growth response, D8 V' J& @4 u3 y$ T* ] d2 E5 r. B
to topical testosterone with low levels of serum testosterone,4 |+ A0 @. m4 J6 `2 r
suggesting a local effect.1 Others have obtained growth re-
4 [& l9 \: `" J3 n+ Fsponse with high. levels of serum testosterone after topical
$ A5 e) N6 _3 H/ r" `1 e. Sadministration, suggesting a systemic response. 3 The use of/ p9 O" @- v3 l5 G3 U7 @9 d* @. T
gonadotropin to obtain levels of serum testosterone compara-0 V4 i: v/ u3 S. D7 t9 t- ^
ble to levels obtained with topical testosterone would seem to
; S, _0 k: Y+ A& ?( x9 _provide a means to compare the relative effectiveness of0 [8 J) \3 J7 ^$ j7 x
topical testosterone to systemic testosterone effect. It cer-! f# f+ [5 P' g8 ?/ |- M5 u- A
tainly has been established that gonadotropin as well as par-
3 B4 u5 s( }9 I7 b# }0 M$ C/ Menteral testosterone administration will produce genital
3 k5 J5 D$ U3 i; R- Igrowth. Our report shows that the growth of the phallus was/ Z5 r' i& t4 _9 I9 v3 B) X
significantly greater with topical applications than with go-
+ k" F; J+ r9 V$ o$ y+ V, inadotropin, particularly in children less than 10 years old.5 q4 p% w. i: Y
The levels of serum testosterone remained similar or lower1 n5 W5 f3 g) j- Z
than with gonadotropin during therapy, suggesting that topi-% ~+ j. A! h2 w- X4 Y
cal application produces genital growth by its local effect as1 }7 c5 |# @. F( d
well as its systemic effect.. ?' j1 x h& o) u* ?
Review of our patients and their growth response related to# F$ T. N/ r& U( @9 d
age shows a greater growth response at an earlier age. This is% i+ {0 K% P# W+ O2 _
consistent with the findings of Wilson and Walker, who2 ^% D; i$ t/ s$ j; e& Y4 _. l" _
reported an increased conversion of testosterone to dihydrotes-9 V) {/ R5 L6 F* S0 ^3 R
tosterone in the foreskin of neonates and infants.4 This activ-/ f. S+ B1 M- m
ity gradually decreases with age until puberty when it ap-; V$ o( J* m/ S
proaches the same level of activity as peripheral skin. It may+ ]& Z+ [/ P' C! K8 M8 H0 R- b
well be that absorption of testosterone is less when applied at4 Y# U5 i- n" I, }( O2 v1 F+ P
an earlier age as suggested by lower serum levels in children# P: y+ w9 W8 ^9 K6 v+ U
less than 10 years old. This fact may be explained by the
4 f9 m$ o+ b1 y/ k1 p- ?+ [greater ability of phallic skin to convert testosterone to dihy-6 `1 O% D) x" E
drotestosterone at this age. Conversely, serum levels in older
; I+ t1 A3 o7 T, }5 z3 D) Epatients were higher, possibly because of decreased local4 s F( k8 D, D
667! G) ^8 b! a" h, B0 `4 p1 D9 L' x
668 KLUGO AND CERNY
5 Y$ y$ P1 t- l9 x) p1 ?' U1 aPt. Age/ a! k2 `$ v/ E" ]) ?9 H
(yrs.)
1 b3 Q5 U& t" P6 A6 q( NSerum Testosterone Phallus (cm.) Change Length% ]% C* ?4 Y0 j- ]# R
(ng./dl.) Girth x Length (%)) G, f4 V4 N+ ]9 j3 k
4* ^; D# E4 g ]+ a% |8 Q' `
8
" r. ?% O$ `% x& K5 L10/ x% |& h! t* f3 N1 U% V' t
12
" G% O& \( u0 i; z, R174 v2 _; P+ P2 x4 s; U* G0 T
Gonadotropin7 A: u% G: @+ v1 P6 _6 M7 w0 p
71.6 2.0 X 3 16.6
/ V5 l. n3 A6 Y; ^& u- `50.4 4.0 X 5.0 20.0* Z9 Q" |/ r9 e; Z- M3 U
22.0 4.5 X 4.0 25.0+ B8 R( `! E4 M+ @4 F. x+ I( p* r
84.6 4.0 X 4.5 11.1: R) J. a3 Q: c1 _8 b. k
85.9 4.5 X 5.5 9.0$ L& j, S" {) I+ T# ~
Av. 14.3
6 _6 ^0 a: e6 ?0 k4 D4. E- b+ a/ Z9 c
8
7 f# Y, D! D% A0 N: Y( W10
3 S# G+ M% ^+ {, L12" _% c3 E! X: s2 l, y
17) }$ Q0 ^1 c. t! s& `
Topical testosterone1 p. n8 d( s/ @2 h
34.6 4.5 X 6.5 856 C; P; H! ~' _4 B- g2 N
38.8 6.0 X 8.5 70% y( c' c: h& z1 [9 }" y
40.0 6.0 X 6.5 62.5
( ^5 y' y j9 u+ _- R5 A93.6 6.0 X 7.0 55.5! N4 Z; a4 G% V, o1 ]; n
95.0 6.5 X 7.0 27.2
7 H# V$ p/ Z ^Av. 60.0
, n8 w' j& ^9 w0 kavailable testosterone. Again, emphasis should be placed on8 v: F1 T, M, d. w! G, ^& S
early therapy when lower levels of testosterone appear to" W( z! F# i2 @9 K c
provide the best responses. The earlier therapy is instituted: U" W- L1 z# [
the more likely there will be an excellent response with low
' w2 t. |( v0 }1 {4 U. g% `1 @serum levels. Response occurs throughout adolescence as+ I* u0 i, r$ z8 O$ s- Z& _
noted in nomograms of phallic growth. 7 The actual response
% B) G% a' e& e- G0 Ato a given serum level of testosterone is much greater at birth) p6 ^* P. d0 m7 h5 h, I5 f+ y/ z
and gradually decreases as boys reach puberty. This is most" S( u8 i# a5 P% H7 ?
likely related to the conversion of testosterone to dihydrotes-% B# s) R+ N$ C) R0 c- u
tosterone and correlates well with the studies of testosterone: Q( z2 A7 R$ {/ j* s1 d
conversion in foreskin at various ages.- e; J9 l' i! q9 h
The question arises regarding early treatment as to whether" r' N1 U! w; k: k9 `
one might sacrifice ultimate potential growth as with acceler-
7 o- |( R9 m+ u m8 Wated bone growth. The situation appears quite the reverse
8 o7 h/ \! v' g) w' d4 cwith phallic response. If the early growth period is not used' R5 M, Y0 Z- w; ~3 B: r- R
when 5a reductase activity is greatest then potential growth$ o% D0 n9 r: e" L& ?
may be lost. We have not observed any regression of growth( _$ X. i3 C7 m. B5 O
attained with topical or gonadotropin therapy. It may well
2 v* }. q7 X# f( ~( i: a% Rbe that some patients will show little or no response to any( c9 D' a7 b( m/ k" ^: _" J* H/ V- h
form of therapy. This would suggest a defect in the ability to
* I: _+ E( @" x7 n+ yconvert testosterone to dihydrotestosterone and indicate that [* Z5 p7 X! L/ s" i' s
phallic and peripheral skin, and subcutaneous tissue should: w* Y5 d/ ^* C9 r$ Q: S
be compared for 5a reductase activity.$ O; v; n. @% P/ X% C$ H, ]
A, loop enlarges to measure penile girth in millimeters. B,( L @# }, I% y
example of penile girth computed easily and accurately.* a; [6 L& A) y) C/ z. Y
conversion of testosterone to dihydrotestosterone. It is in this7 S8 Z# Y* V' Y c# r4 F
older group that others have noted high levels of serum
# b+ Z* k1 m, Itestosterone with topical application. It would also appear
4 e, C. G' _2 v) m& G! S& hthat phallic response during puberty is related directly to the1 [/ [8 |, `2 q: E4 O& T
serum testosterone level. There also is other evidence of local8 ^: r. k0 E, X4 { |3 q' ], ~/ H
response to testosterone with hair growth and with spermato-; I( e( i1 L4 U) h6 _0 \
genesis. 5• 6
3 t# a! ]# A$ R! N' J# p. F @Administration of larger doses of gonadotropin or systemic
1 g' `$ m9 O6 [! z% ctestosterone, as well as topical applications that produce
/ {2 q1 d9 w" `higher levels of serum testosterone (150 to 900 ng./dl.), will/ Q% q7 b) p& u+ u. s( ]; a3 p
also produce phallic growth but risks accelerated skeletal
0 m" ?7 Z/ B+ V4 K0 C2 v8 ?maturation even after stopping treatment. It would appear
" B, S3 G% D' D, G4 k6 bthat this may be avoided by topical applications of testosterone* u4 y) h+ B* W2 x* n, q
and monitoring of serum testosterone. Even with this control
8 K2 Z) |. F) J, Ythe duration of our therapy did not exceed 3 weeks at any
- ^8 m7 D+ v6 r5 c+ n! O- b' d2 `* xtime. It is apparent that the prepuberal male subject may
7 N( b2 Y' r6 `$ d' ]+ ]suffer accelerated bone growth with testosterone levels near
1 @& K' _+ q) Y F: k( u- ?! g200 ng./dl. When skeletal maturation is complete the level of
! x7 E) U+ W& I* [+ X+ b; eserum testosterone can be maintained in the 700 to 1,300 ng./- h; M- h: J6 p: r$ f! y, {
dl. range to stimulate phallic growth and secondary sexual) ?/ E; ^6 \1 ~$ s
changes. Therefore, after skeletal maturation parenteral tes-
) T# W$ v1 ^3 jtosterone may be used to advantage. Before skeletal matura-% d$ p1 ?: y! x& i
tion care must be taken to avoid maintaining levels of serum
3 |6 v/ A9 s) E! `- atestosterone more than 100 ng./dl. Low-dose gonadotropin5 c( I: W* c" x
depends upon intrinsic testicular activity and may require* W9 [6 c) {& m5 v& v! j
prolonged administration for any response.
0 g- x/ p* x% j4 YAlternately, topical testosterone does not depend upon tes-3 \ n- [( C+ H% M2 l1 C2 s
ticular function and may provide a more constant level of' R t/ q# i' m' X
REFERENCES
' _+ e3 o2 W2 c) l. E% q9 u1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ l" x7 G9 e/ ^R.: The local application of testosterone cream to the prepub-
- C' z0 z3 u8 o2 I5 Hertal phallus. J. Urol., 105: 905, 1971., L3 e. D: ]( C7 f ]
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# t. W7 q( P$ F9 a. L: ~2 `' J
treatment for micropenis during early childhood. J. Pediat.,$ A5 H6 M i H+ F, Y' v _
83: 247, 1973./ ?# {/ L1 L& [& R, M$ ] \4 c$ k
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-- X% L+ J% v. }9 N8 C( y9 m y
one therapy for penile growth. Urology, 6: 708, 1975.
5 \* Q( D7 O+ `) @6 t% a+ K. `/ ~4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ J% D/ x8 J$ H& {0 a: l) f
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by }5 }5 L+ E( Z' F+ D/ N7 i
skin slices of man. J. Clin. Invest., 48: 371, 1969.+ C; C& c6 v* i U8 g1 t, ^4 Q
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ G" x h/ d4 o
by topical application of androgens. J.A.M.A., 191: 521, 1965.
/ a8 J# N+ X! R6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 M6 ~; W+ \! r) z5 z* g! g8 D
androgenic effect of interstitial cell tumor of the testis. J.
0 z! k. a0 j! J/ N2 j* |: uUrol., 104: 774, 1970.+ `2 ~0 i: o0 G2 j& w& }2 ?6 X0 k
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 d! l1 @5 I: Y5 B& d) W; [
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|