- 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
- x r* t# H' A6 \$ gGONADOTROPIN# D, U* O+ w3 \. b# S3 V+ @
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 W R( u) N8 u9 `; c8 m$ z! HFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
7 c( I7 u3 f* Y# j0 EABSTRACT8 }9 r4 c1 j% y6 w) i) s& T
Five patients were treated with gonadotropin and topical testosterone for micropenis associated; x: _, J/ e1 z: B7 n0 b# M z
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# w x+ s" q) P/ |. btropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
* h) k u+ ~7 @9 xcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( `, Q( W4 o9 b1 t! {& T
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% i* Q: H/ ]# S2 a: l3 k- v X! d Dincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
. |: h7 U5 R* Y) k: rincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; x! u" j( f% B1 S* h; m
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
" {7 {8 G: v8 E8 m, z8 R+ H1 w# m: Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- A- `, S4 l7 j0 Cgrowth. The response appears to be greater in younger children, which is consistent with previ-
2 H# |7 \$ r H# Fously published studies of age-related 5 reductase activity.
! [% D# }5 k8 g0 GChildren with microphallus regardless of its etiology will( r8 M9 F: z- \# X8 p9 I6 P
require augmentation or consideration for alteration of exter-
. Q0 t, R. Z& H- I5 ?( C8 Jnal genitalia. In many instances urethroplasty for hypo-
# Q$ M8 a0 j/ ]' R8 Jspadias is easier with previous stimulation of phallic growth.9 p8 t+ l" u8 [. A8 z
The use of testosterone administered parenterally or topically
+ k& W# k. D- [$ v% l* j7 ^has produced effective phallic growth. 1- 3 The mechanism of6 \; S2 o) I* u) n- ~% y8 n
response has been considered as local or systemic. With this
+ X; O' ?9 I0 a* w) @1 m& o5 iin mind we studied 5 children with microphallus for response. F8 ~- W& Y% u7 t1 @. s
to gonadotropin and to topical testosterone independently.- f- N; E a# N2 D
MATERIALS AND METHODS
4 }% I' r! V/ v) y. B$ W- GFive 46 XY male subjects between 3 and 17 years old were
3 [0 y h H6 j7 ` Sevaluated for serum testosterone levels and hypothalamic$ o0 Q% K9 \& R: y
function. Of these 5 boys 2 were considered to have Kallmann's% J2 [4 v' ?! q, C8 F. B
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& S3 i8 b6 j: Y. V* X5 Klamic deficiency. After evaluation of response to luteinizing. `. u" w2 j1 g3 s7 [
hormone-releasing hormone these patients were treated with
5 i" c: S Z, }+ j1,000 units of gonadotropin weekly for 3 weeks. Six weeks
" C! t: c9 W" Lafter completion of gonadotropin therapy 10 per cent topical+ b' W) q0 }+ S0 S1 ~" p
testosterone was applied to the phallus twice daily for 3 weeks.2 g# T3 d! S, {0 _# \2 G T
Serum testosterone, luteinizing hormone and follicle-stimulat-- V" V7 B/ N' C# v% |
ing hormone were monitored before, during and after comple-
5 b6 }- C9 n u$ I, G2 z6 otion of each phase of therapy. Penile stretch length was
! j: \& f1 R* r- z5 Aobtained by measuring from the symphysis pubis to the tip of& j7 b! M7 c: C% `& y" s5 s9 G
the glans. Penile circumferential (girth) measurements were# @3 a. m- k I6 K6 b
obtained using an orthopedic digital measuring device (see
$ q3 m( a5 x* m! z. m2 b1 Ifigure).
5 c( f3 ^( j! A6 ]. \, \RESULTS. h1 c' F3 v; h3 w1 P% I: t. W
Serum testosterone increased moderately to levels between' e# H. ~8 y- ?8 Q/ b4 z' K
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' U8 `6 k$ @& u; r" i$ B+ o$ z
terone levels with topical testosterone remained near pre-
5 A; ~* {* N* @: x% {9 c' Xtreatment levels (35 ng./dl.) or were elevated to similar levels
2 e7 d* T5 v5 {, v9 ~* ?: ]developed after gonadotropin therapy (96 ng./dl.). Higher) I) }% v6 k0 H
serum levels were noted in older patients (12 and 17 years old),; ^4 V: Z4 P# {0 d
while lower levels persisted in younger patients (4, 8, and 105 V9 k! T" Y( M+ w
years old) (see table). Despite absence of profound alterations$ I1 y% V5 v& R' |- f7 `
of serum testosterone the topical therapy provided a greater8 ?1 k0 N$ M4 }9 X4 B
Accepted for publication July 1, 1977. ·
8 o6 f1 n- R ]$ X: L) [! S+ IRead at annual meeting of American Urological Association,
3 B3 `) W' p7 ~Chicago, Illinois, April 24-28, 1977.
" g3 C; ` k4 r% D5 z- U* Requests for reprints: Division of Urology, Henry Ford Hospital,; v( |9 U' Y5 i- K& h: c4 A f- h+ d
2799 W. Grand Blvd., Detroit, Michigan 48202.8 a! }1 B! ?0 n2 ?
improvement in phallic growth compared to gonadotropin./ D) N2 z( l/ q" U, n% h, H# u
Average phallic growth with gonadotropin was 14.3 per cent# s1 f! b- X7 u; X8 Q: z; U
increase in length and 5.0 per cent increase of girth. Topical* x5 I* K: V4 i6 U
testosterone produced a 60.0 per cent increase of phallic length
/ x5 E- b% k+ \5 Z* c, N! C1 nand 52.9 per cent increase of girth (circumference). The
, [3 _ f7 _. d* \" n6 qresponse to topical testosterone was greatest in children be-
0 A4 n7 ?1 z/ \1 N7 ?( b3 y9 xtween 4 and 8 years old, with a gradual decrease to age 17
; Z9 G ^. j) p" I6 e8 ]5 Qyears (see table).; e, G4 T4 b. j, _& t' N0 M1 t
DISCUSSION
2 [ J5 W0 a' k4 q, GTopical testosterone has been used effectively by other
8 e# c" `9 B- Rclinicians but its mode of action remains controversial. Im-4 ~* Q+ A/ l/ c8 K: q% N% a+ n
mergut and associates reported an excellent growth response! d6 {9 U, g# c1 B5 L
to topical testosterone with low levels of serum testosterone,5 x% {2 `- v1 L2 c$ ?, T4 K
suggesting a local effect.1 Others have obtained growth re-
# B6 w; {9 r4 I, p3 {, f, [# V" [6 {5 bsponse with high. levels of serum testosterone after topical
* i% L" w+ w; {administration, suggesting a systemic response. 3 The use of
1 u- y7 W1 L# u* `! B! cgonadotropin to obtain levels of serum testosterone compara-! C7 K5 _$ d* [, {" @2 P
ble to levels obtained with topical testosterone would seem to8 U& w/ z! F W
provide a means to compare the relative effectiveness of X( O5 a8 Y- i: V
topical testosterone to systemic testosterone effect. It cer-) T7 B# `! `/ j/ W
tainly has been established that gonadotropin as well as par-" o0 v: {2 z7 k( @5 R
enteral testosterone administration will produce genital, {0 u4 f+ Q! U( l8 y( F5 x
growth. Our report shows that the growth of the phallus was
, e: |- p! ^2 ^* p8 Rsignificantly greater with topical applications than with go-
/ G% S1 p, m+ [7 u/ l* W( onadotropin, particularly in children less than 10 years old.; n, h" ?3 {! V9 K2 |. B
The levels of serum testosterone remained similar or lower1 ]8 }7 i6 K% ]. h+ r+ E4 {
than with gonadotropin during therapy, suggesting that topi-( O6 C N& u; [( Q
cal application produces genital growth by its local effect as
6 @8 _' T1 n7 ~5 a5 hwell as its systemic effect.
" [: C- g" K7 a& J0 J" A& `& NReview of our patients and their growth response related to
( F; G+ H9 ^% N0 x' x6 \age shows a greater growth response at an earlier age. This is& I* p; r- x3 V4 n* J
consistent with the findings of Wilson and Walker, who* B! e2 c2 ?- m+ G' ^
reported an increased conversion of testosterone to dihydrotes-
& ^ {+ v6 b I$ ntosterone in the foreskin of neonates and infants.4 This activ-( J( j2 x& _9 v& z# r9 A; K
ity gradually decreases with age until puberty when it ap-
- I" b# d" u+ w8 k/ Y6 Lproaches the same level of activity as peripheral skin. It may
0 [& N% H3 Z/ y4 xwell be that absorption of testosterone is less when applied at6 n5 I4 T4 O# R/ T# x7 c/ o3 e
an earlier age as suggested by lower serum levels in children9 k( z, X0 O: z: B
less than 10 years old. This fact may be explained by the
* P% a: ?7 y& P$ ^: f1 Jgreater ability of phallic skin to convert testosterone to dihy-
* l- ]5 O5 r9 s! z( k o$ \+ \& edrotestosterone at this age. Conversely, serum levels in older( O9 x j4 f0 D' h; r$ o3 x2 _
patients were higher, possibly because of decreased local
6 j; v8 ?) A% k667' ~0 @& @3 O3 ]7 k7 t- V
668 KLUGO AND CERNY
5 ^- c8 r/ `/ w- Y. T! k& NPt. Age
& X* l2 c8 b$ s; y5 ](yrs.)2 A* ?3 i3 S& Z% N- {
Serum Testosterone Phallus (cm.) Change Length
5 o9 P6 ^. g) r( s(ng./dl.) Girth x Length (%)4 k# F ]8 f# }# q* Z0 |2 J, N/ d
4' B' q! z( W; l, @7 k, d$ G
8
3 }# H; j6 A! g1 l& S6 B! `10
. i; H- Y' h4 {0 ~+ |# b12
. o/ O0 ]; o0 Q17# @4 ^# [+ t2 s. q; S
Gonadotropin
$ |0 x. y0 d0 ^% O! c8 M H71.6 2.0 X 3 16.6
- @4 i O E* E% J* z. R, [50.4 4.0 X 5.0 20.0
" a, a& @! j0 q6 R4 ^22.0 4.5 X 4.0 25.0
5 |5 d, S& z9 ^! P8 b; _8 R84.6 4.0 X 4.5 11.15 }: z+ @2 P/ P4 j% m9 N
85.9 4.5 X 5.5 9.08 C3 b, P. M1 Q. C3 @
Av. 14.3" ~, z, I9 I$ n2 X7 m. z% R
46 @9 }+ M; D% S1 q/ x0 @/ q
8
2 ]% @9 H3 L! C& d; i! k6 t. B10
$ B9 S T8 g& N& A7 j ?& Q y12# x- Q; z- [, O( O5 \
17
3 ~/ ^; v. P) yTopical testosterone6 E4 u; X$ y W; w1 z& @) a: m
34.6 4.5 X 6.5 85
+ S5 `$ s: g7 [38.8 6.0 X 8.5 70+ e8 ?7 ?5 H4 ]4 S
40.0 6.0 X 6.5 62.51 S* u' @) A( Z7 u- y! a
93.6 6.0 X 7.0 55.5! i% T6 X, r+ t9 l
95.0 6.5 X 7.0 27.2
$ O- I/ O. T4 V5 Z( @. _. g4 vAv. 60.0
; b* |; ?/ d: ?7 t+ ]# u8 e7 ]8 Lavailable testosterone. Again, emphasis should be placed on
+ @& ?$ D8 v. }5 Iearly therapy when lower levels of testosterone appear to4 p8 K$ H5 C8 S
provide the best responses. The earlier therapy is instituted
% |* B# E% k; S. Y: u2 d/ gthe more likely there will be an excellent response with low% [6 v3 i. `: i% S
serum levels. Response occurs throughout adolescence as
9 ?" K9 D8 i1 O0 b8 y: _noted in nomograms of phallic growth. 7 The actual response9 \8 V) `# f4 W" N5 r( ^# i$ y
to a given serum level of testosterone is much greater at birth
% ~; B6 k7 g; c5 ]% B+ Vand gradually decreases as boys reach puberty. This is most
7 m! G0 [4 a; |& ~9 t; dlikely related to the conversion of testosterone to dihydrotes-; W! V. A! ?$ e
tosterone and correlates well with the studies of testosterone2 O6 m/ K, S0 h, D6 _1 N6 w3 ~
conversion in foreskin at various ages.
1 B. u* V( g' \) J* c2 Z% nThe question arises regarding early treatment as to whether
4 P: t2 d. q. ?2 o/ qone might sacrifice ultimate potential growth as with acceler-
* P( A9 C" q; \& \) a1 }ated bone growth. The situation appears quite the reverse) m) c7 [2 M; j9 w# n% `+ O8 G
with phallic response. If the early growth period is not used
: a; ^& H$ z9 { G( D1 u1 f! owhen 5a reductase activity is greatest then potential growth( w* p4 ^* C( y8 K `8 D3 g2 g& u
may be lost. We have not observed any regression of growth& Z$ } `# N( a4 v5 k- q/ G& u
attained with topical or gonadotropin therapy. It may well
2 ?3 k" ?; K; B0 ~be that some patients will show little or no response to any
& r# o: O* k5 _; X. @form of therapy. This would suggest a defect in the ability to4 T3 f% q7 K0 j# K8 a$ x( E
convert testosterone to dihydrotestosterone and indicate that
3 n# z/ g: ^# c) ?( Iphallic and peripheral skin, and subcutaneous tissue should6 f) z- j$ d$ i k/ t, z
be compared for 5a reductase activity.
5 S" |, N% @2 ?3 rA, loop enlarges to measure penile girth in millimeters. B,8 d" H+ @- \# F
example of penile girth computed easily and accurately.
$ K! ]. E3 o- m5 q3 ?* b2 yconversion of testosterone to dihydrotestosterone. It is in this, r0 h) y' p+ c1 r: [& R
older group that others have noted high levels of serum
' D3 d- ]* U* i& U- ]! Utestosterone with topical application. It would also appear) }- Y X+ x7 ~
that phallic response during puberty is related directly to the
$ v9 a, t/ H6 a1 J$ t- J* mserum testosterone level. There also is other evidence of local
2 @ i" u) _2 x! v' Wresponse to testosterone with hair growth and with spermato-% U/ `* C" m, Q. ?5 H2 n8 B$ }
genesis. 5• 6
3 A8 j3 z: P. T- t: [; eAdministration of larger doses of gonadotropin or systemic
$ A8 o# [9 X; I# vtestosterone, as well as topical applications that produce, J6 v3 [: N/ O. b, x/ R( i
higher levels of serum testosterone (150 to 900 ng./dl.), will
# O( S( `3 H# |also produce phallic growth but risks accelerated skeletal
, O& y1 O; ~% e: wmaturation even after stopping treatment. It would appear
8 j# D+ C8 Q0 K" ~7 |9 }7 othat this may be avoided by topical applications of testosterone! I' t6 |6 H) y
and monitoring of serum testosterone. Even with this control, H+ ?1 E7 D8 g/ f6 N
the duration of our therapy did not exceed 3 weeks at any
$ }" I9 t! G" d- M3 a% c0 Q* Ytime. It is apparent that the prepuberal male subject may
; f- |0 f$ ~; l: f/ C8 q7 ~9 Gsuffer accelerated bone growth with testosterone levels near
: ]0 S2 H* w3 }% U& H200 ng./dl. When skeletal maturation is complete the level of
L3 W( o3 u& o; [, B) Z' Tserum testosterone can be maintained in the 700 to 1,300 ng./2 A* k5 W, I6 r
dl. range to stimulate phallic growth and secondary sexual4 a2 V7 I$ ~, w4 C- |) C
changes. Therefore, after skeletal maturation parenteral tes-
; n0 b# Q( m9 B9 ^. ]" v: H% A0 Jtosterone may be used to advantage. Before skeletal matura-( W) W) m4 J7 f; M5 r% \3 {
tion care must be taken to avoid maintaining levels of serum
! r5 C# ^3 S. J; Xtestosterone more than 100 ng./dl. Low-dose gonadotropin
# o! T& [( t7 _depends upon intrinsic testicular activity and may require
. |/ o0 Q; j, l% w: _! J8 X% l6 V& {prolonged administration for any response.0 K3 v6 ^8 S3 S) n, O# @
Alternately, topical testosterone does not depend upon tes-
+ K, u! I" D! w2 P% C& Xticular function and may provide a more constant level of1 z b+ K# V) [
REFERENCES
) B. Q2 H1 C; R0 s( q5 E; X0 F0 a" y1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; @7 d b8 Y- B9 g- J3 R6 a; }7 s8 A
R.: The local application of testosterone cream to the prepub-
$ }: A2 v$ H4 D6 tertal phallus. J. Urol., 105: 905, 1971.
/ I, ^( f/ H# S6 y. v2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone) E" R8 N. S" q* \9 P8 l) M
treatment for micropenis during early childhood. J. Pediat.,0 O* H$ X* q% `) y, _! @/ |
83: 247, 1973.9 M. F+ w- W# E* y D
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
% R& F; g6 ]$ l% eone therapy for penile growth. Urology, 6: 708, 1975.
: c g+ g" {( H& ^4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' Z$ L- V, ]; @4 ^; P! h. ]
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, o( l5 @2 {& M7 Oskin slices of man. J. Clin. Invest., 48: 371, 1969.$ V F$ L8 o6 v2 l8 K
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ g' a( h1 r. Z2 C$ G/ T1 l
by topical application of androgens. J.A.M.A., 191: 521, 1965.7 o' |" l- R0 D$ Z- d
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
- O f! x$ \: p: L% c& dandrogenic effect of interstitial cell tumor of the testis. J.
4 O/ e6 Y* T/ Y6 R B! S; [Urol., 104: 774, 1970.
% P) m5 W% {/ x: \7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 t) c- C% V9 f* C# d
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|