- 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
! k3 C; H/ ^3 t" T5 YGONADOTROPIN
1 y: M- n1 T. l; r6 v. MRICHARD C. KLUGO* AND JOSEPH C. CERNY
4 g( ^& P2 k- z7 P% R! t. KFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan7 a6 l9 v7 W7 X, b0 M2 ?' s
ABSTRACT
" d6 ]# b$ ^. dFive patients were treated with gonadotropin and topical testosterone for micropenis associated
" m$ V' w" |4 F" e% Lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-, K- ~; J& W% z) E
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# g! e$ Q; _7 Y# M5 O
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, D& j; l4 w% b. B- Z" M; H
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 e2 r/ M/ D7 P5 l, _* C- b0 w( e* bincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average. R% h! t; |7 t" w, \+ n1 M
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 n7 P+ m2 |5 s
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
5 I# S7 R* X: i- e7 Astudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile: Z7 W4 R& |4 u5 l7 L1 X
growth. The response appears to be greater in younger children, which is consistent with previ-1 ]" a/ d. u1 X9 l
ously published studies of age-related 5 reductase activity.
9 I) o* Q3 N1 @9 k! ? S* CChildren with microphallus regardless of its etiology will8 P C* J8 [6 L% g! i) q. E" y
require augmentation or consideration for alteration of exter-! m/ L9 k. |! a1 R$ _) [4 b
nal genitalia. In many instances urethroplasty for hypo-. U' h6 S" I- Z0 p- @4 w! @
spadias is easier with previous stimulation of phallic growth.
/ X/ h, i5 e% b G# HThe use of testosterone administered parenterally or topically
" G4 y9 s: c4 t% H/ b1 ~# ?has produced effective phallic growth. 1- 3 The mechanism of6 S7 A, v* {( r9 {
response has been considered as local or systemic. With this
$ q4 S3 t9 v$ `4 v& B3 Jin mind we studied 5 children with microphallus for response
1 n9 ?6 a8 ~7 e _to gonadotropin and to topical testosterone independently.' ~- O9 y& D, r9 E
MATERIALS AND METHODS# X6 G1 V9 W0 C$ S' { O( d& K
Five 46 XY male subjects between 3 and 17 years old were7 I+ D9 x6 e' ~
evaluated for serum testosterone levels and hypothalamic4 P: r* q: M: @# B& L2 A5 p
function. Of these 5 boys 2 were considered to have Kallmann's; X# T* E. c9 F8 r) Z% |" A
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ X' B1 B0 }/ ?
lamic deficiency. After evaluation of response to luteinizing
- U1 q7 M) t9 i. U/ Ghormone-releasing hormone these patients were treated with' J! I5 u+ I( \( Q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& g! B& v: h8 {9 A: F0 ~& Xafter completion of gonadotropin therapy 10 per cent topical3 H9 W( ]8 O: b- y! @0 l# r
testosterone was applied to the phallus twice daily for 3 weeks.
8 F, j( p4 C9 B( I3 FSerum testosterone, luteinizing hormone and follicle-stimulat-
w& @1 b, f$ ?$ y) }$ p3 ding hormone were monitored before, during and after comple-
' |8 Z, Y& ?7 l+ @tion of each phase of therapy. Penile stretch length was9 X0 X- G' M2 |7 S, Y1 z6 W
obtained by measuring from the symphysis pubis to the tip of3 P( E4 x# B" u/ m0 _& \6 S$ D4 f
the glans. Penile circumferential (girth) measurements were
$ m$ I M5 L, k) t" iobtained using an orthopedic digital measuring device (see
) \) X8 e# k1 gfigure).: I# R+ T2 K; j" ^- [
RESULTS& @ d2 O- ?; L& J9 z0 L: T
Serum testosterone increased moderately to levels between
- R4 u: J0 J1 d* r# S50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 S# `. i2 T3 M$ R/ |1 a! j" d; uterone levels with topical testosterone remained near pre-# B! ~) k y" J) z" d. w
treatment levels (35 ng./dl.) or were elevated to similar levels
' q1 i8 \; J' j, d1 d% W* m5 c5 odeveloped after gonadotropin therapy (96 ng./dl.). Higher
8 K3 r& g; J/ W* \& J Jserum levels were noted in older patients (12 and 17 years old),2 p$ O0 k& x7 p
while lower levels persisted in younger patients (4, 8, and 10# T4 m6 t x/ e2 A) O( n7 @0 W7 V5 [
years old) (see table). Despite absence of profound alterations3 m' E8 r z" B1 Z) B/ B
of serum testosterone the topical therapy provided a greater$ [' o0 d3 e% j6 @6 ~, H; T; n( F
Accepted for publication July 1, 1977. ·
9 T; S3 n' t4 P1 L( {Read at annual meeting of American Urological Association,' Z% Y2 i0 N# o7 ?) }; m. M
Chicago, Illinois, April 24-28, 1977.3 K7 r) q# F5 [
* Requests for reprints: Division of Urology, Henry Ford Hospital,
& v6 M' H# b; @, `! M( d! N2799 W. Grand Blvd., Detroit, Michigan 48202.
: t" t7 ^) `; u- i8 Q7 Gimprovement in phallic growth compared to gonadotropin.
6 D* x$ p2 P6 e7 [3 d/ oAverage phallic growth with gonadotropin was 14.3 per cent
1 y' }! G1 Y2 \$ Mincrease in length and 5.0 per cent increase of girth. Topical/ T) w; U1 N% y1 P, f
testosterone produced a 60.0 per cent increase of phallic length* Y+ w$ Z0 ?, f4 r
and 52.9 per cent increase of girth (circumference). The1 G+ [! H9 ~/ i9 Y, R
response to topical testosterone was greatest in children be-' r0 L8 f% u! X# I4 v
tween 4 and 8 years old, with a gradual decrease to age 17
u, ?2 B# k6 L5 `- p5 iyears (see table).7 [9 S3 M) S) K, S* S; C
DISCUSSION2 v' H% i L b ]1 A6 `+ L
Topical testosterone has been used effectively by other
0 C: w( p$ c/ W7 p0 `$ ]7 v4 f+ [- u$ d5 xclinicians but its mode of action remains controversial. Im-1 A/ ^7 ^7 T# p0 ~# i' I
mergut and associates reported an excellent growth response' h: {4 Q% L# n# S
to topical testosterone with low levels of serum testosterone,2 O$ U. ~4 |0 t
suggesting a local effect.1 Others have obtained growth re-
; i8 v/ ]( Y$ A0 {" e# _- ysponse with high. levels of serum testosterone after topical
$ W3 j% o- ^& M# x/ @6 v' |8 ^administration, suggesting a systemic response. 3 The use of: ]* K1 L) w0 y9 ]
gonadotropin to obtain levels of serum testosterone compara-0 X0 \( m/ j8 S; {, u9 ~; P
ble to levels obtained with topical testosterone would seem to
+ C! E( u+ _4 B3 O2 D8 fprovide a means to compare the relative effectiveness of9 S- z2 Q$ s) F* q. z) q
topical testosterone to systemic testosterone effect. It cer-
4 |, N% ]2 f) L U& o, H! E+ E4 |/ itainly has been established that gonadotropin as well as par-
- P# h9 i' S6 D2 \% S( `: ?enteral testosterone administration will produce genital
$ M+ Q! C" n2 H4 {. tgrowth. Our report shows that the growth of the phallus was9 N# Q" z: X# x) L) E
significantly greater with topical applications than with go-
; w& u! i/ ], [: c j1 d- Wnadotropin, particularly in children less than 10 years old.
s& R5 [; r' t+ s! |% }The levels of serum testosterone remained similar or lower7 q6 A6 }- ` S* J
than with gonadotropin during therapy, suggesting that topi-
; l2 c% R+ F8 E+ L9 c! pcal application produces genital growth by its local effect as# @- E: \2 |! A! Z
well as its systemic effect.: g I* J* p4 k2 C
Review of our patients and their growth response related to
- z2 D+ f' \1 Z% x5 O% Bage shows a greater growth response at an earlier age. This is
/ f) u: j) w7 [! g L k, _consistent with the findings of Wilson and Walker, who4 G. B) b# M* M1 c
reported an increased conversion of testosterone to dihydrotes-
7 D6 P/ q) V& Q% H! ~7 qtosterone in the foreskin of neonates and infants.4 This activ-7 X: f9 F8 e. t6 j* \ r, s
ity gradually decreases with age until puberty when it ap-
+ h9 f# T2 a2 Qproaches the same level of activity as peripheral skin. It may, O I; \6 C& B! p4 O
well be that absorption of testosterone is less when applied at; n. U6 e/ V/ q/ p7 T
an earlier age as suggested by lower serum levels in children
7 D% w! |# d1 P, _less than 10 years old. This fact may be explained by the D' i% a7 @! E# }6 A3 R
greater ability of phallic skin to convert testosterone to dihy-$ C9 z) H- \% j$ L. L
drotestosterone at this age. Conversely, serum levels in older! N: x6 z0 _; ?: t8 K
patients were higher, possibly because of decreased local
2 A& Y" k; h1 g: T6671 m( Y* W' w3 h( y1 S
668 KLUGO AND CERNY
( F' ?1 g! W- e1 R$ i- m6 b' @% b ]Pt. Age: T4 `) `' \9 @$ V* l
(yrs.)
, H6 d) D n% P& b- M) U2 BSerum Testosterone Phallus (cm.) Change Length& @ J3 k) O/ f) a5 Z ^) _( L! w
(ng./dl.) Girth x Length (%)
) m" h( }! n1 L6 r: s45 K( {. W! w+ W. \3 a. K" _
86 j; |) G' l! c9 ]
10
5 E1 K f, w2 T0 s12
) O. \7 d5 L$ \" }8 k7 p. ]/ m17
$ O3 @* a* M ]# T3 m5 @2 z, r& U% {Gonadotropin
3 n- m) x+ a- m71.6 2.0 X 3 16.6: _( I! I C. ?2 E9 g- U m4 M: w
50.4 4.0 X 5.0 20.0. W9 f4 F& K8 n+ r# h9 [
22.0 4.5 X 4.0 25.0
8 I9 q8 U3 W% h3 k) j84.6 4.0 X 4.5 11.1
; a; E& G9 f; Y7 z) x+ p8 b85.9 4.5 X 5.5 9.0
3 k+ Y$ t q6 |( yAv. 14.34 a; x y# a8 o5 ~; E/ G
4
! v5 a! V, |4 r% ~( a {# S8, U3 K4 Q( e2 l8 @& u
10; y. ?1 A0 H$ |# p7 z" }. [
12' ?9 j+ M* S2 K" H) Y2 C0 e5 u+ E0 D
17' a+ ]6 v7 c. i5 i6 p9 \
Topical testosterone" Z% m/ m, Y! t9 u
34.6 4.5 X 6.5 858 x8 ~, c% u7 U* Z
38.8 6.0 X 8.5 70" S1 }! K$ `2 P4 |" i
40.0 6.0 X 6.5 62.5* ]7 l6 C) V, d
93.6 6.0 X 7.0 55.5
: b1 a8 n% X! ^95.0 6.5 X 7.0 27.2
" F" U, ], F, z& ^. N- u. e. t) h" ZAv. 60.08 O' M+ b2 q: ?, ]9 q$ ]
available testosterone. Again, emphasis should be placed on$ ?% |6 H, t4 M) J
early therapy when lower levels of testosterone appear to9 Z& O# p |" { R; C/ d4 d1 b
provide the best responses. The earlier therapy is instituted" l E$ N( ^% [8 a
the more likely there will be an excellent response with low/ e' m1 v. f8 l: E" c/ A" |
serum levels. Response occurs throughout adolescence as
6 Z- z, M# _! u5 {4 j; Knoted in nomograms of phallic growth. 7 The actual response; L$ N+ l# _# o0 f
to a given serum level of testosterone is much greater at birth# S! e2 s- h# X9 a; y- Z
and gradually decreases as boys reach puberty. This is most
( j4 `0 S6 y. {2 ?2 Ilikely related to the conversion of testosterone to dihydrotes-: m- i# q' B: t3 K. H. T
tosterone and correlates well with the studies of testosterone
: Q# A$ S, S% K) }0 ?conversion in foreskin at various ages.
* K7 x8 i( ?) p( TThe question arises regarding early treatment as to whether
* b' h; K9 C, E# E3 q9 R* S/ Zone might sacrifice ultimate potential growth as with acceler-2 c. x( Y U& Y
ated bone growth. The situation appears quite the reverse
5 n$ \# K8 O1 a7 Uwith phallic response. If the early growth period is not used5 o6 a! Y. j' X* r& F6 l' z
when 5a reductase activity is greatest then potential growth
1 J& n- S8 R3 Y6 kmay be lost. We have not observed any regression of growth
. ?% L! _6 l* R' {attained with topical or gonadotropin therapy. It may well- L& t. S- h2 J9 U" }! b5 l
be that some patients will show little or no response to any
) S8 U8 a7 j( f4 ^form of therapy. This would suggest a defect in the ability to5 j q) t. ?. b9 e2 ~0 \
convert testosterone to dihydrotestosterone and indicate that
" N' m+ [& \9 V" w+ Iphallic and peripheral skin, and subcutaneous tissue should
- Q! ?# p3 o* v9 Jbe compared for 5a reductase activity.
9 f2 M% C" s& ~5 V2 e4 f3 f# ]! F9 gA, loop enlarges to measure penile girth in millimeters. B,: a8 N& A5 O4 r+ Y1 x
example of penile girth computed easily and accurately.7 u- r8 O1 v5 J' z& y, b
conversion of testosterone to dihydrotestosterone. It is in this9 q# R/ `9 o% z9 l
older group that others have noted high levels of serum/ K% V8 S- h7 R9 r4 J" @
testosterone with topical application. It would also appear
% c3 X& N4 `( A7 W" L, K) t0 l( pthat phallic response during puberty is related directly to the
1 ?# ~- P- ]& Z @" y: D6 e# [8 Jserum testosterone level. There also is other evidence of local- b1 O9 k7 g9 y
response to testosterone with hair growth and with spermato-
& f# }! N- p, v6 F B/ Igenesis. 5• 60 V3 T7 e, k3 |2 l8 Q, K, K
Administration of larger doses of gonadotropin or systemic- l, z: }8 P4 N" }, |3 Z2 L c
testosterone, as well as topical applications that produce
0 |, @5 s& Y; I/ shigher levels of serum testosterone (150 to 900 ng./dl.), will$ b) O. c7 \ z8 ]2 t% b2 N
also produce phallic growth but risks accelerated skeletal
# h: N& C0 t0 v" H9 smaturation even after stopping treatment. It would appear) B' K8 J* T+ I4 y0 J
that this may be avoided by topical applications of testosterone
5 w1 [, @ ]) e7 [' y: Qand monitoring of serum testosterone. Even with this control
9 W2 U$ U/ X1 r; K, fthe duration of our therapy did not exceed 3 weeks at any
8 C! ]" S9 N+ f5 A# ?time. It is apparent that the prepuberal male subject may
$ g+ x5 M1 D; i5 D( E) |suffer accelerated bone growth with testosterone levels near
7 o) x4 ^, G0 M3 j200 ng./dl. When skeletal maturation is complete the level of
' [( e9 D; v* Rserum testosterone can be maintained in the 700 to 1,300 ng./
+ L& {! u/ x2 y& d- xdl. range to stimulate phallic growth and secondary sexual
4 }# G: P7 t& {7 `changes. Therefore, after skeletal maturation parenteral tes-
: ]5 A3 \& @/ A& [9 e6 `tosterone may be used to advantage. Before skeletal matura-% ~6 |9 f ?' X
tion care must be taken to avoid maintaining levels of serum. D* o3 M0 W" U m2 H g
testosterone more than 100 ng./dl. Low-dose gonadotropin3 K- [5 G) ^6 U+ o7 u
depends upon intrinsic testicular activity and may require% ?" k+ q! \9 p0 U
prolonged administration for any response.- A1 I+ b" @& w6 [# [% u0 l
Alternately, topical testosterone does not depend upon tes-% `, ~' H( x' A. W
ticular function and may provide a more constant level of2 [# T1 ]( E5 E
REFERENCES3 M, z9 t* @0 M) e: [
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; d6 ^) G2 e: O( `7 NR.: The local application of testosterone cream to the prepub-
" a8 Z& o% j U, [ertal phallus. J. Urol., 105: 905, 1971.
% R3 x$ w/ `; n( Z5 S2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
d& a) v- O4 E/ c7 D4 d3 y' I2 itreatment for micropenis during early childhood. J. Pediat.,2 L' V/ p2 T5 K/ Z' k
83: 247, 1973.
8 ]; z/ F- s- `: u9 T9 O9 C) }. m3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 l- v2 b- Z$ }! [. @0 j1 mone therapy for penile growth. Urology, 6: 708, 1975.
( V7 {7 N# b+ O6 H/ f5 N/ g4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ v- W' o4 ]5 V; e
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
1 a- e' |2 N1 n1 |' t5 T) Zskin slices of man. J. Clin. Invest., 48: 371, 1969.
8 S" U+ {0 N5 U, p7 D5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) M0 q3 o' [% W b5 r
by topical application of androgens. J.A.M.A., 191: 521, 1965.; Z' j& f( K Z! x2 }% J+ t6 W
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
( S( V H) @0 z8 sandrogenic effect of interstitial cell tumor of the testis. J.
. h ?1 q% t& g2 YUrol., 104: 774, 1970.! e7 r2 G. U, G% C/ J' d+ j0 v5 [
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 K% V. k9 @3 N# K" H8 s, dtion in the male genitalia from birth to maturity. J. Urol., 48: |
|