- 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& ^! L; k( I* t% x, x$ y9 Q) ~: p
GONADOTROPIN" m8 O$ f0 b @* u& b0 o% P
RICHARD C. KLUGO* AND JOSEPH C. CERNY- C0 O7 ^$ R; G' x
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! c8 y0 R7 p, @/ ~: H5 J$ RABSTRACT
1 Z% G) q7 j$ q- DFive patients were treated with gonadotropin and topical testosterone for micropenis associated
* S7 r$ {. j2 E1 ~" m4 Y5 `/ i' n; zwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" k3 _' q6 w$ h9 S
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 V/ q) e( A/ s* K( ]) t0 n
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent7 A" ~) J* u9 f3 `, j
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
. V2 I4 l4 a" _: c, `* Qincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) a$ I) c, |, u, B' p! u& uincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 v8 }. B' c: g& a
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
. t9 v6 ~: c) L# _$ c: H5 P/ pstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 [ U* Q9 ~ h/ D% j
growth. The response appears to be greater in younger children, which is consistent with previ-5 }# _# M# g$ l8 _0 i1 h+ V
ously published studies of age-related 5 reductase activity.2 h8 `" p5 i( F: I B: h
Children with microphallus regardless of its etiology will
1 @2 f9 B8 A* zrequire augmentation or consideration for alteration of exter-9 M' X7 [, o) n1 H3 n
nal genitalia. In many instances urethroplasty for hypo-
- r% K! V0 p$ n1 p6 ispadias is easier with previous stimulation of phallic growth.
/ V5 e8 k% ]% b& R; {$ k6 E1 \The use of testosterone administered parenterally or topically5 y) {/ o4 F- A4 P% ^. T! o
has produced effective phallic growth. 1- 3 The mechanism of+ P% {% B1 I3 h% d
response has been considered as local or systemic. With this
9 t% F' D3 T. r2 l7 B/ H$ ain mind we studied 5 children with microphallus for response. G" Y; R( n" D9 p
to gonadotropin and to topical testosterone independently./ L! z5 D c u9 J: [0 n
MATERIALS AND METHODS& V' o" p9 _8 W+ j/ |4 [
Five 46 XY male subjects between 3 and 17 years old were( Q4 w# c- W: q8 s
evaluated for serum testosterone levels and hypothalamic
0 ^) m1 Z: j" V) Ufunction. Of these 5 boys 2 were considered to have Kallmann's
" H) F! F) w" Y" j( ^) @syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
: D" c' d, n- O, l g* Ulamic deficiency. After evaluation of response to luteinizing
9 @. ]: H, ^/ _" R: N5 Y8 o9 {hormone-releasing hormone these patients were treated with
1 F1 [5 B3 g5 N1 \; L% B1,000 units of gonadotropin weekly for 3 weeks. Six weeks; ]+ [9 y7 N! i$ s
after completion of gonadotropin therapy 10 per cent topical
$ `9 M$ U# P! ?# {! wtestosterone was applied to the phallus twice daily for 3 weeks.7 ^9 i; @( N3 g; ?4 x
Serum testosterone, luteinizing hormone and follicle-stimulat-9 ?1 i' R$ }; K6 x
ing hormone were monitored before, during and after comple-; A8 d' |( l" r, z
tion of each phase of therapy. Penile stretch length was" K8 z% ?0 R1 Y8 I' ]
obtained by measuring from the symphysis pubis to the tip of/ b7 X& _; i' N+ k/ G
the glans. Penile circumferential (girth) measurements were: W- j! p4 L" W" q, r a
obtained using an orthopedic digital measuring device (see. u5 B( E; U- n, s) h1 ]
figure).+ G L- T0 r' W b# d( ^3 `
RESULTS$ l6 J. m9 j, o/ |. t, n
Serum testosterone increased moderately to levels between
- K8 Z: G- ?0 X50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-; Z6 ~2 B* t; P" t( U/ `
terone levels with topical testosterone remained near pre-0 b: d# Y" u! ]: x# M
treatment levels (35 ng./dl.) or were elevated to similar levels
* S z' A( Z5 B5 l& cdeveloped after gonadotropin therapy (96 ng./dl.). Higher
5 a8 O2 x. o# e @$ J% j' pserum levels were noted in older patients (12 and 17 years old),: L/ ~! X- J. K, a
while lower levels persisted in younger patients (4, 8, and 10
' C6 u" f1 O+ J2 Q! y+ \) Q9 Oyears old) (see table). Despite absence of profound alterations
6 C# S- a# b3 W; H/ l a+ t% o& h3 Z$ Uof serum testosterone the topical therapy provided a greater9 Z2 m2 ?3 @) R& l% R3 c
Accepted for publication July 1, 1977. ·: m) j. w# i. P% s+ E
Read at annual meeting of American Urological Association,
# t8 C b+ ~+ m! _Chicago, Illinois, April 24-28, 1977.8 `4 \9 [" i2 z
* Requests for reprints: Division of Urology, Henry Ford Hospital,0 f8 }$ W0 q0 t3 j$ G
2799 W. Grand Blvd., Detroit, Michigan 48202.
/ r; S# ^* L: q4 v) Nimprovement in phallic growth compared to gonadotropin.
/ m9 g( c# h- UAverage phallic growth with gonadotropin was 14.3 per cent
2 o7 a. ~: z: k2 h9 yincrease in length and 5.0 per cent increase of girth. Topical; B8 T7 X: C+ @/ ?: I* |
testosterone produced a 60.0 per cent increase of phallic length5 c5 ^; n3 x" Y: U- i2 T7 @
and 52.9 per cent increase of girth (circumference). The
+ O! n+ v3 i/ x" c& [4 Eresponse to topical testosterone was greatest in children be-
3 n; v, D% n6 p) x4 P# C6 atween 4 and 8 years old, with a gradual decrease to age 17
+ z9 N8 f1 K" K" n+ ^- K) p, iyears (see table).
+ g& i0 Y9 W4 B( g) ^; xDISCUSSION
/ S7 g2 r5 s. hTopical testosterone has been used effectively by other
f- Z# I8 F! P& kclinicians but its mode of action remains controversial. Im-
+ T9 T7 S$ _& d* H1 i0 {$ j9 u$ nmergut and associates reported an excellent growth response: x$ e" U+ W; |; G1 i
to topical testosterone with low levels of serum testosterone,
# P# F" H% N4 z3 ~; `suggesting a local effect.1 Others have obtained growth re-2 ?# D0 f! W+ ?* {0 {+ {
sponse with high. levels of serum testosterone after topical- H& @! H& ]" w# y# {8 p
administration, suggesting a systemic response. 3 The use of
( [) I& x# s+ i3 |5 agonadotropin to obtain levels of serum testosterone compara-3 U7 o# T( j: s1 a- v
ble to levels obtained with topical testosterone would seem to
$ \, i1 V" U4 N4 `4 ^$ R/ O* cprovide a means to compare the relative effectiveness of
" l8 z/ d2 D7 dtopical testosterone to systemic testosterone effect. It cer-
% ~8 S3 I; { p% z9 J: W) s! Mtainly has been established that gonadotropin as well as par-
) U# G1 T9 w1 D- o; g* M1 H! penteral testosterone administration will produce genital1 k: A4 d% }5 Q" P
growth. Our report shows that the growth of the phallus was
& _8 ]! j( Y0 C- N4 Zsignificantly greater with topical applications than with go-
4 E* b0 V& [1 z2 anadotropin, particularly in children less than 10 years old.
, D I* @3 u! BThe levels of serum testosterone remained similar or lower$ J/ L6 h. r' ?' r8 F
than with gonadotropin during therapy, suggesting that topi-% {; e x; J3 e0 F6 N& A# @
cal application produces genital growth by its local effect as
# _! w T/ {7 R8 ~well as its systemic effect.) d& |9 }, W3 G5 f0 Y6 X' `
Review of our patients and their growth response related to6 Q9 {0 v P8 Z* ?
age shows a greater growth response at an earlier age. This is
! M, r/ e y* }- `+ O* t) Xconsistent with the findings of Wilson and Walker, who2 q: t+ R4 r0 r
reported an increased conversion of testosterone to dihydrotes-( x* z0 v# m9 i7 n3 b. x* ~# H, p
tosterone in the foreskin of neonates and infants.4 This activ-
/ {- R, K$ G+ M( d/ N% S2 m5 z; @ity gradually decreases with age until puberty when it ap-
7 x! d9 f" p9 t# ]5 nproaches the same level of activity as peripheral skin. It may3 V, d$ X; v2 x! ]2 p0 ~
well be that absorption of testosterone is less when applied at
- G8 i6 u6 U' m3 f) van earlier age as suggested by lower serum levels in children3 z4 E" A9 T8 H& l8 w9 T; f6 q
less than 10 years old. This fact may be explained by the' A; ]9 I9 X& p3 y
greater ability of phallic skin to convert testosterone to dihy-
! n" _2 Z" p( R+ U7 }* gdrotestosterone at this age. Conversely, serum levels in older
, x- k# |! K- J6 k+ L8 dpatients were higher, possibly because of decreased local
. ~; i" P- E0 a, m) B2 ^) n667$ U5 @' `6 m9 m/ C, k
668 KLUGO AND CERNY# }4 ?; u/ f$ C
Pt. Age
. ]. T2 m% m+ z& g+ J' R(yrs.): R. | p# @9 {8 M8 P- n
Serum Testosterone Phallus (cm.) Change Length: t2 G2 r' m7 f1 k W8 g# J; Q
(ng./dl.) Girth x Length (%)6 L0 | r) e; w
4 C6 n5 T2 l2 A
8& D* z! P6 y' b% [4 J# ?. z5 E/ q
10
7 _# m' Z( E, A8 Q12
9 \3 ^$ O4 E' c+ n, \$ g17
: N) h) ?5 h1 a& E7 S% zGonadotropin
" Z+ m: l$ j! Y- e) {* _71.6 2.0 X 3 16.6
: U1 J, L% B0 d; i50.4 4.0 X 5.0 20.05 G, a) ?# h2 F) R6 T6 g" v+ L
22.0 4.5 X 4.0 25.0' ?+ ?; y6 |# x. I$ F
84.6 4.0 X 4.5 11.1
; z: k( u/ S; o% O85.9 4.5 X 5.5 9.0 n& P9 J5 M/ ^
Av. 14.38 Y1 ~' Q4 A5 A' T4 a& s
4
+ B' Y, X# Q, w4 s8
& A8 N/ F+ j* j; l4 @' R10
! U& C( C) C, g2 X1 @$ ]12$ Q; l0 M$ z% y( t4 P) @
17. |' y% H* J4 [) G/ w
Topical testosterone
( p, H, p: T; E6 U# @& U+ ^34.6 4.5 X 6.5 85
5 R/ C6 H& T/ w( T% R: t; I5 n. L38.8 6.0 X 8.5 70' n* {3 C6 B% _& b( b. U
40.0 6.0 X 6.5 62.55 u c+ w9 _0 a" F) Q: o0 a
93.6 6.0 X 7.0 55.53 M" D6 C& H2 o2 D9 w' z) P
95.0 6.5 X 7.0 27.2
, v* C& U7 ~. b6 gAv. 60.0
5 o7 N0 ]% u z2 z# L/ Havailable testosterone. Again, emphasis should be placed on7 a6 V G& F( d
early therapy when lower levels of testosterone appear to
- F$ I% w% c. x- i% L# m& A8 nprovide the best responses. The earlier therapy is instituted7 B3 y- w8 O1 S6 H) x: C$ k
the more likely there will be an excellent response with low
6 v& ?% V! F( B% _( A7 i) m. jserum levels. Response occurs throughout adolescence as
Q* m' B; ~3 I* a8 H3 J0 @noted in nomograms of phallic growth. 7 The actual response
/ Z3 b; l8 V K" {* ato a given serum level of testosterone is much greater at birth; p/ m3 ~( }0 D) e/ I
and gradually decreases as boys reach puberty. This is most
' U: Z& g, ?/ }7 u5 l& olikely related to the conversion of testosterone to dihydrotes-( q* ]% i8 M, m" a) s \
tosterone and correlates well with the studies of testosterone, ~8 _9 h( W+ S6 X0 ]0 v' i
conversion in foreskin at various ages./ d1 U7 w; y3 ^2 q
The question arises regarding early treatment as to whether& {+ G. V: b. N3 T6 I
one might sacrifice ultimate potential growth as with acceler-
N }; a1 [5 a5 l. U8 oated bone growth. The situation appears quite the reverse1 }4 A6 L3 i% \% h5 |
with phallic response. If the early growth period is not used
# `1 A. [6 f3 z6 |when 5a reductase activity is greatest then potential growth. c* W5 O+ o' |# r. v2 j
may be lost. We have not observed any regression of growth
2 q( J3 s# ~( G9 z% C. }# dattained with topical or gonadotropin therapy. It may well! M) w! }6 x/ ^7 e# ?! a
be that some patients will show little or no response to any
& x' S5 e/ p' Cform of therapy. This would suggest a defect in the ability to! E- E5 G# @# K1 j7 T0 j) {
convert testosterone to dihydrotestosterone and indicate that% g' Y3 O2 x9 {7 W3 V) j" N
phallic and peripheral skin, and subcutaneous tissue should. q' Z% E& C4 X1 {* w
be compared for 5a reductase activity., q% K1 x3 F+ _# s' ]/ \
A, loop enlarges to measure penile girth in millimeters. B,
% ~$ P4 m M0 E' U& _: x1 \) h3 `example of penile girth computed easily and accurately.
, V, \# W& j' h4 E+ I5 aconversion of testosterone to dihydrotestosterone. It is in this
& V m& t! D# Golder group that others have noted high levels of serum
|) a: [9 ?6 \( J9 F" x( utestosterone with topical application. It would also appear8 H% b8 O0 I2 i* p9 b5 k
that phallic response during puberty is related directly to the L# ]4 r, a) w3 w4 U9 Z
serum testosterone level. There also is other evidence of local% q6 y3 L3 |: K3 z- ?
response to testosterone with hair growth and with spermato-
2 u1 O5 \+ k! Egenesis. 5• 6
2 R2 m# t+ d$ rAdministration of larger doses of gonadotropin or systemic1 J/ v) ]0 x3 q7 _
testosterone, as well as topical applications that produce
/ |! W! t3 o! G+ K# p+ ahigher levels of serum testosterone (150 to 900 ng./dl.), will9 `5 X& [1 H& V6 f) S. G1 D+ c; D
also produce phallic growth but risks accelerated skeletal
y1 j4 o6 Q# mmaturation even after stopping treatment. It would appear
A0 A- L! G1 othat this may be avoided by topical applications of testosterone4 V r" H& X) R* @6 r) b7 u: w
and monitoring of serum testosterone. Even with this control3 v( m* S. g# Q, x7 s
the duration of our therapy did not exceed 3 weeks at any
" o3 N' g7 f7 h2 ^time. It is apparent that the prepuberal male subject may$ C5 W! s- o7 k7 q# x+ g% C
suffer accelerated bone growth with testosterone levels near
; U9 J4 Y* z$ w3 Q200 ng./dl. When skeletal maturation is complete the level of
0 X R( |! g6 _( m" Wserum testosterone can be maintained in the 700 to 1,300 ng./# c x% w2 A B
dl. range to stimulate phallic growth and secondary sexual' g4 g: B0 B. o$ [
changes. Therefore, after skeletal maturation parenteral tes-% e6 w# J) N1 I* z, `, V
tosterone may be used to advantage. Before skeletal matura-
7 W# s1 P o- k! {. Vtion care must be taken to avoid maintaining levels of serum. b9 y% H! u1 |! L# O
testosterone more than 100 ng./dl. Low-dose gonadotropin4 R' ?9 `8 ^6 i/ ?5 V2 s6 i: t7 |
depends upon intrinsic testicular activity and may require5 W5 W- b3 q* e0 M& I! d6 Z
prolonged administration for any response.3 @. ` @9 Y( W
Alternately, topical testosterone does not depend upon tes-5 ?: K* Y* n% u4 R& ^$ U: ~
ticular function and may provide a more constant level of4 H) @+ D# Z+ h- P, {
REFERENCES
* l1 P2 x2 G* a2 |- E( [5 Z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,. ^* Y' K7 T) a! c
R.: The local application of testosterone cream to the prepub-, X; c' l- c6 Y
ertal phallus. J. Urol., 105: 905, 1971.% ^# _3 ~& s/ a! a
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone! ^# ]( ~5 G- \5 j( ~( f6 v- X
treatment for micropenis during early childhood. J. Pediat.,5 D4 m4 H' _9 i M& [; H
83: 247, 1973.
# n& c5 r( y1 Y( k) v7 D+ D/ g0 n3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-" k; w, h7 ]* x8 Z
one therapy for penile growth. Urology, 6: 708, 1975.
& a& o V! |2 }3 O( Y c( m4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' D; N- p8 ?$ s* f# }5 A# lto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' ` U% G7 ]8 C! Oskin slices of man. J. Clin. Invest., 48: 371, 1969." r& `3 c3 n; p- B0 ^" Q
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ V/ d4 q- w' v1 t
by topical application of androgens. J.A.M.A., 191: 521, 1965.
* w6 }! @8 J% l1 D+ H6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 k. t$ q" U6 V8 h" r; v
androgenic effect of interstitial cell tumor of the testis. J.
! U1 E4 _* j0 Q4 W3 u- JUrol., 104: 774, 1970.
& K6 S/ ~; i/ k' y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-6 i z( g8 P) M! {
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|