- 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 AND9 v( O. n' t3 B* A, J- v' f
GONADOTROPIN
' ^( y2 A! A# B0 N0 nRICHARD C. KLUGO* AND JOSEPH C. CERNY6 |$ l5 n4 G4 f. X" ]( k
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
+ @6 B; l" {. QABSTRACT
q! T" u3 u& u( i: R9 b: FFive patients were treated with gonadotropin and topical testosterone for micropenis associated
+ V5 ]; N. ^0 `/ ^% jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-, o- L# M& G) l2 F7 t
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 d2 s$ Q' v: c- ucream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
+ Z l3 ]& r, m* o5 K3 Lfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
" K7 X# k1 ]( ?increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 n( r# ]" H- f- I. sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& x1 ^" X5 M0 joccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( S- t8 ^* S& |$ T: o* dstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; p/ v" B0 _: w" d ]! {growth. The response appears to be greater in younger children, which is consistent with previ-1 S( y- J5 |+ x! T6 x
ously published studies of age-related 5 reductase activity.( T/ N7 z1 M$ ~+ K9 C/ S
Children with microphallus regardless of its etiology will7 f* C* f& s0 q- Z
require augmentation or consideration for alteration of exter-
9 O- l& k) ~! t _nal genitalia. In many instances urethroplasty for hypo-3 n; J: N# }. j! H( C! i
spadias is easier with previous stimulation of phallic growth.; l3 C( x, \- `6 K* F! v* s1 t; }
The use of testosterone administered parenterally or topically4 i: K# ^9 L9 u1 l+ W! o
has produced effective phallic growth. 1- 3 The mechanism of% ?: v8 A4 b& S7 T' y7 U, {
response has been considered as local or systemic. With this- k- p+ h/ @$ f: e
in mind we studied 5 children with microphallus for response' @& O$ ?% `! C- {/ W
to gonadotropin and to topical testosterone independently.! H& z/ w) M% c3 p, z. _
MATERIALS AND METHODS
; c0 i n2 \% `5 D9 t4 JFive 46 XY male subjects between 3 and 17 years old were" U+ ]# W9 |$ |0 `7 ]1 U
evaluated for serum testosterone levels and hypothalamic
" f! L' \7 F+ bfunction. Of these 5 boys 2 were considered to have Kallmann's
: s! p# I3 p- \- @8 Rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-. K6 G9 T N) Y2 W& Z: S0 I. }
lamic deficiency. After evaluation of response to luteinizing. i8 X) [2 i# ?5 t+ \( m' o2 {
hormone-releasing hormone these patients were treated with
" O; l# O9 b2 b; j& b* @, N7 x7 U1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 b) v) d6 V! `1 E9 j
after completion of gonadotropin therapy 10 per cent topical8 l# v- ]2 z8 |7 t' Y4 _2 k
testosterone was applied to the phallus twice daily for 3 weeks.% U- w9 M- |1 G' u2 h
Serum testosterone, luteinizing hormone and follicle-stimulat-
& _. a' [, j1 C* U- C/ {ing hormone were monitored before, during and after comple-% L8 u# I) P; b" y
tion of each phase of therapy. Penile stretch length was) y9 ~$ w3 J$ S, k% A) d$ f, T
obtained by measuring from the symphysis pubis to the tip of3 X. i6 A6 w1 L; d; C( \* }2 w5 F
the glans. Penile circumferential (girth) measurements were
; g5 z6 o. T- L. W/ D8 ]. ^obtained using an orthopedic digital measuring device (see
; h: X$ p8 R- o9 @/ Bfigure).0 H9 n0 d% Y; C. p0 {+ a' K5 D
RESULTS( N+ u5 K% l; B. a3 z7 e: I
Serum testosterone increased moderately to levels between! B1 e0 |- A8 u
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
, d) {4 O+ L( G3 V }! C& f! z5 pterone levels with topical testosterone remained near pre-
& L/ E% i7 T; T, n0 F/ V$ ~8 Ctreatment levels (35 ng./dl.) or were elevated to similar levels+ v9 d. Q }6 e c3 @* ?
developed after gonadotropin therapy (96 ng./dl.). Higher. n4 J: A8 v; V5 i
serum levels were noted in older patients (12 and 17 years old),
8 u$ }2 P- X E8 Y. x3 i8 a. u* kwhile lower levels persisted in younger patients (4, 8, and 10 h7 O9 K& _" Z: `
years old) (see table). Despite absence of profound alterations+ Z I$ P7 p5 e6 T% U! X
of serum testosterone the topical therapy provided a greater7 ?/ h2 }& I* L% F: r0 I
Accepted for publication July 1, 1977. ·
$ v& e) O8 b1 G% q* _; aRead at annual meeting of American Urological Association,& L* z, j; F! I1 { K) |
Chicago, Illinois, April 24-28, 1977. D/ X5 H2 ~ f4 i8 U0 u
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 N& G- T5 [) i1 [: ^2799 W. Grand Blvd., Detroit, Michigan 48202.
3 T7 e B0 ~9 iimprovement in phallic growth compared to gonadotropin.
% T/ }7 m3 R9 K" W. ]Average phallic growth with gonadotropin was 14.3 per cent
! R% U% ?. I0 K, k8 z! Pincrease in length and 5.0 per cent increase of girth. Topical! s+ J' l0 ]+ E
testosterone produced a 60.0 per cent increase of phallic length1 H& I9 u3 M/ S! R- s: S9 {- _# i, r0 n! R
and 52.9 per cent increase of girth (circumference). The' F. B8 x- y; `5 b: j6 y" C/ ?
response to topical testosterone was greatest in children be-4 a' b& K5 M% b/ {6 s* A7 S
tween 4 and 8 years old, with a gradual decrease to age 17: ?, m) y, ]7 ]0 A3 I5 F' u
years (see table).
; t# ^8 J1 J9 L& U7 I7 j6 ^4 l- XDISCUSSION6 W% h. e3 R) H6 @# X' i' Y6 y
Topical testosterone has been used effectively by other7 `: y4 L# }7 s9 n/ O1 D
clinicians but its mode of action remains controversial. Im-7 J1 t/ d. M% X' \; g9 b/ j
mergut and associates reported an excellent growth response
$ @6 a2 r" t+ D9 H' T- ~; Gto topical testosterone with low levels of serum testosterone,
, q0 ]$ n- I w1 ~suggesting a local effect.1 Others have obtained growth re-
. d8 O3 \2 e. {" i& G% n9 Rsponse with high. levels of serum testosterone after topical
: S( O# X1 |. |/ P9 I2 A; A7 j8 ~administration, suggesting a systemic response. 3 The use of" W! \0 b2 _" a& _; i2 g* U7 s
gonadotropin to obtain levels of serum testosterone compara-
; }5 a: `- R' l6 Tble to levels obtained with topical testosterone would seem to
% B2 u, }8 ^ ^0 B7 [/ F! n, oprovide a means to compare the relative effectiveness of4 j8 N1 Z% c7 j* h" \5 k
topical testosterone to systemic testosterone effect. It cer-
1 }9 i( W; e/ U; m: p9 U' Ytainly has been established that gonadotropin as well as par-
8 q2 U# T7 b0 t% o1 A% n- ^& Qenteral testosterone administration will produce genital3 a) p& u/ r/ g% T, K7 j4 X3 F
growth. Our report shows that the growth of the phallus was+ v1 J' i. o# E) K5 U
significantly greater with topical applications than with go-( ?4 m1 g3 z2 \7 g2 c' b
nadotropin, particularly in children less than 10 years old.& o1 ~& q7 b; m+ L0 z# G6 \
The levels of serum testosterone remained similar or lower3 ~( e' d+ Y- k8 |
than with gonadotropin during therapy, suggesting that topi-
0 C! ~6 r7 O) q& E! |9 vcal application produces genital growth by its local effect as
0 e. ]5 s7 Y' _2 g4 r1 }' Twell as its systemic effect.* |. i; }& C, ~# I% k( t
Review of our patients and their growth response related to# v+ f5 [: v/ T3 J
age shows a greater growth response at an earlier age. This is ]5 |7 {$ ~5 X Y# p% u
consistent with the findings of Wilson and Walker, who1 s; \7 g% S0 S# g* K
reported an increased conversion of testosterone to dihydrotes-
# d1 B6 e% p6 c# I# u3 S9 k0 ltosterone in the foreskin of neonates and infants.4 This activ-( ~' U$ N+ z$ _ T
ity gradually decreases with age until puberty when it ap-) ]. H6 ]& O5 U' O2 D
proaches the same level of activity as peripheral skin. It may Z& R1 _8 Q+ f1 @
well be that absorption of testosterone is less when applied at" w8 m! K6 M+ @0 U
an earlier age as suggested by lower serum levels in children
- X4 n9 F l6 m9 h% G7 r9 pless than 10 years old. This fact may be explained by the
; Q, q# ]7 {2 Fgreater ability of phallic skin to convert testosterone to dihy-
% P0 G2 `* |/ bdrotestosterone at this age. Conversely, serum levels in older2 O7 l3 N* a# T% a& ?0 S& ]7 o7 g
patients were higher, possibly because of decreased local
' |2 H; w- X8 M' v9 a9 m5 v+ o667
, P% L. l5 Q+ u+ k& R$ v" E2 g8 j668 KLUGO AND CERNY3 A' V) N5 A2 X7 H6 w/ g
Pt. Age
8 z4 _( A/ U, @(yrs.)
0 y/ W+ U: n; {1 uSerum Testosterone Phallus (cm.) Change Length% s- }& H8 i& ?) H9 R
(ng./dl.) Girth x Length (%)7 N$ E8 H V( x6 a; p
49 [) c' \3 ^% N, J. Q0 \1 i/ v0 O# D
89 ?1 \2 `( b+ E5 a8 {6 r
10# D* A1 F6 y0 A, Q" N" c" z
12
- b7 I' f0 \! y2 P: w17
! c2 h6 V0 J0 u6 IGonadotropin) M+ _* x" x/ ` m6 K
71.6 2.0 X 3 16.6/ H/ z# F1 P2 S8 @" J6 V. `3 D6 c
50.4 4.0 X 5.0 20.0
0 X$ m$ M" A6 j0 w# t3 N; e5 }22.0 4.5 X 4.0 25.0
0 X* h4 }4 k# g' F# t: T& _84.6 4.0 X 4.5 11.1$ t& S% l% Q |
85.9 4.5 X 5.5 9.0
9 R& {4 z `0 W5 [: gAv. 14.3: m* p0 s9 }5 D5 O2 k
4
9 u# s/ ?8 ?; E+ j. i7 w# r% k8
, [# g1 s8 \/ c7 x7 e; E10
( ?5 `( R! r4 j# O# W12
4 j2 S: R! e: M5 A9 m17
. L( e9 V" O: x; gTopical testosterone+ A. {$ A/ ^) L$ v3 h7 o5 z7 c
34.6 4.5 X 6.5 85
" i7 n; @6 C9 }: Z) [5 u c38.8 6.0 X 8.5 70
% B ]4 o5 i* U6 |, b3 `( a7 I40.0 6.0 X 6.5 62.5
8 b- e. ]8 }0 {2 B, u" X93.6 6.0 X 7.0 55.5
, p h% }$ \$ W% e1 s95.0 6.5 X 7.0 27.2
* K# w; _% t' a. h3 E1 J" dAv. 60.07 z, T' ]6 }$ A5 r8 M
available testosterone. Again, emphasis should be placed on
0 Q# |4 ~2 [- H6 L8 g* Aearly therapy when lower levels of testosterone appear to2 p; B- V4 @9 R
provide the best responses. The earlier therapy is instituted
: ?' u/ h* V1 s) C0 r0 L4 othe more likely there will be an excellent response with low: k# S! F3 ]3 A1 ~5 G" h5 @
serum levels. Response occurs throughout adolescence as
( w6 a4 T8 C4 onoted in nomograms of phallic growth. 7 The actual response) Q% R& j4 J: _4 S. d+ B) S
to a given serum level of testosterone is much greater at birth
: T& ~% }9 l& P- Band gradually decreases as boys reach puberty. This is most
: C- h2 x) I3 y/ }4 c4 Z& ilikely related to the conversion of testosterone to dihydrotes-
3 f/ w) S4 g; g F' b3 W3 Dtosterone and correlates well with the studies of testosterone. R" ] S; ~( d" `1 S- ^! U
conversion in foreskin at various ages.
7 O" l: | `* H- N0 x+ u9 QThe question arises regarding early treatment as to whether
- L7 Q t2 k D# p- \one might sacrifice ultimate potential growth as with acceler-- a$ J5 g8 M' N% o2 U
ated bone growth. The situation appears quite the reverse" l* s; f' ?1 O& \, a# U
with phallic response. If the early growth period is not used7 @ C0 ~, W, v$ I" L x
when 5a reductase activity is greatest then potential growth
5 |4 J' A7 ?4 b9 _9 k) g* b% W/ m( {may be lost. We have not observed any regression of growth
; ?* H& Y$ L" s7 P$ G0 m; wattained with topical or gonadotropin therapy. It may well- {% B2 L2 ?( m! C: f- z
be that some patients will show little or no response to any
* R, \- G+ Y) R. Y9 v6 Iform of therapy. This would suggest a defect in the ability to8 R% g: q G- Z/ f9 S* l
convert testosterone to dihydrotestosterone and indicate that
2 q }& _/ W5 y; l3 V! A5 @phallic and peripheral skin, and subcutaneous tissue should, b H1 Y a' y# o4 B" g( G
be compared for 5a reductase activity.3 J% @' k( D1 F' F! t
A, loop enlarges to measure penile girth in millimeters. B,
/ v0 ~, q: S1 N qexample of penile girth computed easily and accurately.' ~% g- w( k* ^2 b
conversion of testosterone to dihydrotestosterone. It is in this
# f# e7 F/ W7 R0 L( Solder group that others have noted high levels of serum
% t/ e# V/ R! [4 S8 }; ktestosterone with topical application. It would also appear
4 r) l5 M2 e9 U$ e) u; \that phallic response during puberty is related directly to the
: A" m% b. |5 _. Tserum testosterone level. There also is other evidence of local( P0 Z9 o7 W) J; V0 X$ K
response to testosterone with hair growth and with spermato-6 {0 z; Z1 l- |" D7 G: ^2 G
genesis. 5• 6
' t2 ^( v3 i% y5 W$ N, }Administration of larger doses of gonadotropin or systemic
& r: I0 B, j `7 @2 Vtestosterone, as well as topical applications that produce7 u2 O" @8 G" n6 Q
higher levels of serum testosterone (150 to 900 ng./dl.), will+ l6 ^4 [9 W- ]5 ]& r
also produce phallic growth but risks accelerated skeletal
0 @4 Z, b/ D7 W7 \3 S" N/ h8 `) `maturation even after stopping treatment. It would appear8 R. U: f. A' ?) A c* a+ d
that this may be avoided by topical applications of testosterone ^( j( L' x" Q$ ]% N
and monitoring of serum testosterone. Even with this control
$ ^3 `( R I/ j0 C5 Ythe duration of our therapy did not exceed 3 weeks at any
, E: m. U% A1 ]' |. t3 }4 T6 ktime. It is apparent that the prepuberal male subject may, c: ~8 F% V# L% f# o6 M. y
suffer accelerated bone growth with testosterone levels near8 Z! K4 v. u2 i7 A7 Y' l
200 ng./dl. When skeletal maturation is complete the level of
' t o, [9 e' {0 H6 i5 M% lserum testosterone can be maintained in the 700 to 1,300 ng./6 d! x+ C: t! d9 y" T8 j5 h& \- _
dl. range to stimulate phallic growth and secondary sexual) F4 C, b5 Q( ]" c
changes. Therefore, after skeletal maturation parenteral tes-
) a& V) O+ N6 ]- X3 M# w7 _* mtosterone may be used to advantage. Before skeletal matura-
- G; @- H. z. i% T3 M! R: gtion care must be taken to avoid maintaining levels of serum
7 r4 y0 W% f2 j" V" X* Ytestosterone more than 100 ng./dl. Low-dose gonadotropin, n7 P1 G( {) d# \$ ^" I
depends upon intrinsic testicular activity and may require1 [0 ]) {* j& q+ R- q% l; Z. V8 Z
prolonged administration for any response.4 ^4 Q! H4 ~! q% H) A7 F. o, ?
Alternately, topical testosterone does not depend upon tes-! |& O. _+ |; p8 \4 B
ticular function and may provide a more constant level of
3 i" q. t$ z1 hREFERENCES
5 S1 U3 L. n0 }! S5 K9 F" |1 ^1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: ]% L% B5 o9 F6 ]R.: The local application of testosterone cream to the prepub-
2 T( d/ b' [: |0 ]0 uertal phallus. J. Urol., 105: 905, 1971.
5 z" V$ t+ ]& S0 N" K- b! U! A2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone: K8 t% Y" m( v9 V7 W
treatment for micropenis during early childhood. J. Pediat.,
+ _6 s) Y% f; x+ d# P7 c$ q83: 247, 1973.
4 Z& V6 ^1 ~0 q9 A4 m# e/ `- s3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% B: P( `# o9 X3 g3 s0 g" g e, V
one therapy for penile growth. Urology, 6: 708, 1975.* S: P$ ]! l( b: U6 R' K/ \0 y
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone8 I# b# ]! i8 y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by4 z9 K- N; U8 x" B, B; Y) ?
skin slices of man. J. Clin. Invest., 48: 371, 1969.
8 g: a9 q, a {7 `' l- S5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth* B! K/ ^/ W% ~$ M. r: t* `. m
by topical application of androgens. J.A.M.A., 191: 521, 1965.6 e& S1 A& r7 \( S$ {& ]6 Q
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! [ J' K* B! l/ B j2 Xandrogenic effect of interstitial cell tumor of the testis. J.
/ d' A4 I% r9 B. j' X2 GUrol., 104: 774, 1970.
$ V- v, H6 r) s( |- P% p9 h+ F7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
3 ]9 ^7 x8 o- {$ ztion in the male genitalia from birth to maturity. J. Urol., 48: |
|