- 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 p; ?$ O. s9 \# J2 r+ p
GONADOTROPIN& s% X; x& V2 }! X$ e5 S0 Q' I1 q$ d
RICHARD C. KLUGO* AND JOSEPH C. CERNY
, u' `) [) X- O& B* Y# e: z* `From the Division of Urology, Henry Ford Hospital, Detroit, Michigan( B4 \8 U/ c; c8 P! p
ABSTRACT
& C" P+ E& k! A4 W1 x2 nFive patients were treated with gonadotropin and topical testosterone for micropenis associated: N% I0 n+ E I+ U2 U
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. W% |& w, R) a1 I# F) Ftropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
$ X7 | S H0 F/ s' o1 z" w mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* ?4 ]! U, v# Lfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 P. J/ U7 u4 x! L1 ^
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 ~" Q8 ]2 n: k( ^# U+ N. U; Pincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ O: r; y* j% A. I0 G
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This) y0 D5 d2 m( T# e) G' Y
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile1 s' U# d* Y, r$ A
growth. The response appears to be greater in younger children, which is consistent with previ-1 n) [8 m7 K0 I. E
ously published studies of age-related 5 reductase activity.
% A/ j. i T8 z g* r# x8 mChildren with microphallus regardless of its etiology will- @' {0 M3 q8 @- e3 R, q: U% `
require augmentation or consideration for alteration of exter-
9 Z2 l9 X; x; Z6 e* znal genitalia. In many instances urethroplasty for hypo-; Q) U' ]5 X: g: I& ^/ l5 h
spadias is easier with previous stimulation of phallic growth.
, _* ?# M# {- S# vThe use of testosterone administered parenterally or topically
3 j5 P% @ R9 p9 s) ihas produced effective phallic growth. 1- 3 The mechanism of: T3 n Q- F' w4 e# B- M
response has been considered as local or systemic. With this: Y' _9 h2 V/ P0 V8 Y; ~
in mind we studied 5 children with microphallus for response( W+ U* V0 ?: U+ `) I
to gonadotropin and to topical testosterone independently.2 q2 E+ @7 k" [/ c
MATERIALS AND METHODS
0 R% V& |5 y! h8 v; t# ]Five 46 XY male subjects between 3 and 17 years old were
, A8 k2 V; | ~5 Uevaluated for serum testosterone levels and hypothalamic( V* J; T7 e8 p Z
function. Of these 5 boys 2 were considered to have Kallmann's
4 Z7 a, L& s6 gsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 {8 y5 O2 r" ^/ @6 }lamic deficiency. After evaluation of response to luteinizing5 {8 Y0 b5 _: R! b
hormone-releasing hormone these patients were treated with+ _, w& [1 y' E
1,000 units of gonadotropin weekly for 3 weeks. Six weeks, W$ l w9 |! r( q+ K; i4 g
after completion of gonadotropin therapy 10 per cent topical
3 Y1 @8 @6 Q6 p) A0 I0 F R( Ktestosterone was applied to the phallus twice daily for 3 weeks.
0 `% T% ], U3 w: [6 h2 G, JSerum testosterone, luteinizing hormone and follicle-stimulat-
7 M; x; j! D" ?! U- c2 Hing hormone were monitored before, during and after comple-* w2 R6 p0 k$ a$ x( }
tion of each phase of therapy. Penile stretch length was
) D6 L' _3 c- v- l) t# Eobtained by measuring from the symphysis pubis to the tip of
' p9 p0 k' |9 z4 y3 Ethe glans. Penile circumferential (girth) measurements were
, b9 U& ^1 _2 _1 s, n5 {obtained using an orthopedic digital measuring device (see3 ?% h! m4 d% R! a; j
figure).1 D1 y' n8 n% p0 c7 W
RESULTS0 w/ L9 d0 F2 f1 G
Serum testosterone increased moderately to levels between
* R6 Y4 Z2 r0 v9 |: c& g* D& M* F50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ r; c! q( O( q! ^8 a
terone levels with topical testosterone remained near pre-# V6 Z. S4 M6 D& F1 C* v- y
treatment levels (35 ng./dl.) or were elevated to similar levels+ w3 y( Y; `: L9 P6 S! @; U# r
developed after gonadotropin therapy (96 ng./dl.). Higher
+ E/ `0 v0 t, [: r# u9 y Qserum levels were noted in older patients (12 and 17 years old),! |8 E- l* h+ e
while lower levels persisted in younger patients (4, 8, and 10/ c& e, F* [& G- m- }; |# A2 p
years old) (see table). Despite absence of profound alterations
' D( y* j, \- {3 ]2 Y) @of serum testosterone the topical therapy provided a greater
6 ]0 k3 @) d1 ~1 r+ i2 B; bAccepted for publication July 1, 1977. ·7 O# L& K: r( J: {3 p3 S
Read at annual meeting of American Urological Association,$ g9 U, |9 H9 P4 H; ]. I
Chicago, Illinois, April 24-28, 1977.
7 m2 l2 K- Z" B, w% {5 V# f* Requests for reprints: Division of Urology, Henry Ford Hospital,6 j' y- l' R) @
2799 W. Grand Blvd., Detroit, Michigan 48202.+ @3 u! E0 w( h( x( p. m. B( I
improvement in phallic growth compared to gonadotropin.( d1 g j& w5 ~ M6 g. M$ W
Average phallic growth with gonadotropin was 14.3 per cent
$ f7 L2 T7 s5 ^; j- i) n, x b, A% Tincrease in length and 5.0 per cent increase of girth. Topical
" g/ F! t$ C/ | P9 {testosterone produced a 60.0 per cent increase of phallic length
" J* i9 d4 X" X8 nand 52.9 per cent increase of girth (circumference). The [3 o+ p9 N; e7 N
response to topical testosterone was greatest in children be-1 s7 h9 w; {- j, ?- @4 I5 \
tween 4 and 8 years old, with a gradual decrease to age 17
4 F1 `& X2 x" [, gyears (see table).& u- w( I8 n( n% K2 b/ M! U P7 ]
DISCUSSION
4 e) H; `9 S( F/ _8 G) A/ t2 X! fTopical testosterone has been used effectively by other- C/ u5 j3 z- O' x2 X9 K9 O
clinicians but its mode of action remains controversial. Im-
/ o- U6 G2 u9 K. @2 L1 ]' Hmergut and associates reported an excellent growth response
1 I k+ H8 b1 t2 J9 J, \$ y% v& S! Ito topical testosterone with low levels of serum testosterone,
0 a7 }3 I" y& B( g( fsuggesting a local effect.1 Others have obtained growth re-
3 l& P; H) f1 m% Vsponse with high. levels of serum testosterone after topical
' K1 B8 k: j* M% C, o' Nadministration, suggesting a systemic response. 3 The use of
5 k' `7 y0 `; K; L# [4 @gonadotropin to obtain levels of serum testosterone compara-
. U4 o- j$ e9 _! N1 }ble to levels obtained with topical testosterone would seem to; E$ m$ x8 W% S
provide a means to compare the relative effectiveness of
3 W a9 W3 V( X5 ?topical testosterone to systemic testosterone effect. It cer-& P E" s3 |' f
tainly has been established that gonadotropin as well as par-9 g9 i' w L) @8 \1 H
enteral testosterone administration will produce genital
% L( O2 k2 x! d( [+ o# `# ogrowth. Our report shows that the growth of the phallus was
1 L$ b: r! \8 e: |4 s' zsignificantly greater with topical applications than with go-2 J7 v& ^9 P3 U- m+ [ G
nadotropin, particularly in children less than 10 years old.
5 N7 I7 f5 m$ }/ W1 a6 E. U( JThe levels of serum testosterone remained similar or lower
& x$ Z/ B- n2 A1 G% L/ u" v9 Sthan with gonadotropin during therapy, suggesting that topi-
4 P9 A F. J, ^( ?8 wcal application produces genital growth by its local effect as: d8 W7 z6 r8 K
well as its systemic effect.2 g1 U E4 |: C+ R& j" \7 D
Review of our patients and their growth response related to
3 Y! W2 N+ q5 H" Jage shows a greater growth response at an earlier age. This is6 I1 \& Q! U# Z+ S$ A' n: F
consistent with the findings of Wilson and Walker, who
0 ]& q; P- j U) H9 S- g9 vreported an increased conversion of testosterone to dihydrotes-
0 a# k( W- u2 v. {tosterone in the foreskin of neonates and infants.4 This activ-
/ `6 k5 q4 W2 v# wity gradually decreases with age until puberty when it ap-
3 U5 @) I9 k7 b6 yproaches the same level of activity as peripheral skin. It may6 x0 F1 O* V7 j7 w/ K' D3 p0 C
well be that absorption of testosterone is less when applied at
, D* ?. P7 `, q, Lan earlier age as suggested by lower serum levels in children
% D" ~8 L- G5 h) f; l* R. `6 ~" z6 Mless than 10 years old. This fact may be explained by the
6 `& V2 E" Y4 Z2 Ggreater ability of phallic skin to convert testosterone to dihy-
2 Z2 X2 H. t( e8 n: D* S# `drotestosterone at this age. Conversely, serum levels in older, q2 ^' y- s; Z, P
patients were higher, possibly because of decreased local& ^" N# ^4 b* i7 V7 n/ X$ d* E
667
- a% u9 P' i% B. z& i6 s668 KLUGO AND CERNY( f/ b! |! a. c- I* l. z
Pt. Age& m$ m8 H2 b8 I0 y9 K
(yrs.), o& O7 Y# I, [( C) t3 e
Serum Testosterone Phallus (cm.) Change Length0 C9 U5 o, n8 {6 y5 B5 Y' b
(ng./dl.) Girth x Length (%)
- L4 Y1 }6 h4 O4
8 ~5 G" u, z* }- J4 e0 }: w5 A8
4 d3 ^9 X" ?1 V/ z t7 `10
+ S* J. B: [: l) ]: }3 L) E$ e; z124 v0 N' |" J2 ]" C& c9 o
17+ Y4 H' a6 d4 t7 b
Gonadotropin, E& N* Z5 e8 }, g& u/ m0 o; `" e" ]
71.6 2.0 X 3 16.6( C( `+ \5 Y$ v! R. W u
50.4 4.0 X 5.0 20.0
3 Y' W! V, ?5 b- Z, t22.0 4.5 X 4.0 25.0
, g6 {" y! J) M- s. V84.6 4.0 X 4.5 11.1
* A# b, \. R; L k+ Q( P2 D85.9 4.5 X 5.5 9.0& I9 j" M$ ~$ ~; ^* R+ h8 [
Av. 14.3
# G/ }1 a2 w ]& [: o1 j41 S% f# k8 w6 q$ J i& y3 k
8
; Y* n$ L; F1 X& G6 u: ~; |+ J10
4 F- \5 B8 l5 V12* _% @& K! }8 K( B2 ]4 n( }" a, S
17' c" Z0 { e- N. h( u
Topical testosterone
7 q+ U6 x( x# P4 L" L34.6 4.5 X 6.5 85
( I4 S+ _$ P5 ]3 Y38.8 6.0 X 8.5 70. \( z- l. Y% w0 T2 C. _. W- I! |
40.0 6.0 X 6.5 62.5) ^' J6 t1 s `2 @$ @! d
93.6 6.0 X 7.0 55.55 T% v/ ]8 s7 }3 p
95.0 6.5 X 7.0 27.2
' l% D0 _$ Y" G8 `3 kAv. 60.0$ q- H, a L0 z# f8 C, E3 D
available testosterone. Again, emphasis should be placed on# |" T3 o2 P% q
early therapy when lower levels of testosterone appear to* v* V+ M- W) |9 j6 Q" [
provide the best responses. The earlier therapy is instituted
1 Z2 v0 r( N+ Q) n6 a1 p, Cthe more likely there will be an excellent response with low
V) G" i( f( |serum levels. Response occurs throughout adolescence as
8 {5 H6 @: u+ Q7 `noted in nomograms of phallic growth. 7 The actual response* r. s- N+ B, H0 Z4 i7 Z6 N* N
to a given serum level of testosterone is much greater at birth
4 W" m# H. H: H9 L wand gradually decreases as boys reach puberty. This is most
4 B6 b. ?5 s _6 k' Zlikely related to the conversion of testosterone to dihydrotes-. P9 l" l3 y" [. N
tosterone and correlates well with the studies of testosterone
" m" l, p5 K! ^8 l+ J9 K% s cconversion in foreskin at various ages.
! s! e$ O; s W: y$ _The question arises regarding early treatment as to whether2 j# G* a+ m- ~" j9 L
one might sacrifice ultimate potential growth as with acceler-
! v$ |6 _) ?! Kated bone growth. The situation appears quite the reverse
( {. d4 N7 F" \; y& uwith phallic response. If the early growth period is not used
4 S- X8 I% M' V+ R1 wwhen 5a reductase activity is greatest then potential growth3 F8 H5 u: w7 o) C& v, c
may be lost. We have not observed any regression of growth7 L/ {" a: S; j' G' u
attained with topical or gonadotropin therapy. It may well
; }3 H9 j4 K' N) q! T/ ~+ Qbe that some patients will show little or no response to any- L+ Y6 q! E2 f4 m' M
form of therapy. This would suggest a defect in the ability to. k! ~! Q5 b/ o8 |3 v3 h6 |
convert testosterone to dihydrotestosterone and indicate that
1 z9 H- j" j. k+ Q0 z9 j6 M$ Jphallic and peripheral skin, and subcutaneous tissue should
- O2 J! K4 l; G! j0 nbe compared for 5a reductase activity.
* C4 ~+ \: o6 w$ LA, loop enlarges to measure penile girth in millimeters. B,
8 x' r4 c( c n/ `1 yexample of penile girth computed easily and accurately.
% ~6 U+ u1 G' S1 u- ?conversion of testosterone to dihydrotestosterone. It is in this
" m! d3 o6 F$ k0 p- b8 Oolder group that others have noted high levels of serum/ v j# C; f+ R8 f, l
testosterone with topical application. It would also appear
6 N1 W6 D2 h( f# F8 W3 fthat phallic response during puberty is related directly to the* Y+ N( @; n, A6 q9 f% p
serum testosterone level. There also is other evidence of local
4 S( T* O3 H3 ^$ S' W0 ^' oresponse to testosterone with hair growth and with spermato-
) Y! I8 k1 g! g" u+ V' Z( `. i5 |genesis. 5• 6& s! |5 y, M7 \# e/ p
Administration of larger doses of gonadotropin or systemic
$ C# Z2 U# |( W, ctestosterone, as well as topical applications that produce( r" y' P. ]9 t+ j+ W
higher levels of serum testosterone (150 to 900 ng./dl.), will
2 }& R) ?4 d! h4 Xalso produce phallic growth but risks accelerated skeletal) L1 k) a) I% } b
maturation even after stopping treatment. It would appear& f* T6 L5 G. @+ L8 E$ S
that this may be avoided by topical applications of testosterone M/ g* ^7 }8 f
and monitoring of serum testosterone. Even with this control
* k+ |, n" l& w) |4 Y* W: Xthe duration of our therapy did not exceed 3 weeks at any8 ]; ]3 l& E& B& E. o
time. It is apparent that the prepuberal male subject may
/ |9 `5 s+ \/ N% Gsuffer accelerated bone growth with testosterone levels near) a4 z3 n/ t( u8 A$ w) a. U' \
200 ng./dl. When skeletal maturation is complete the level of# o7 }* x1 }3 v
serum testosterone can be maintained in the 700 to 1,300 ng./$ r' s1 J6 u4 P$ f N
dl. range to stimulate phallic growth and secondary sexual
& Y: \ k( J3 Q: v' ichanges. Therefore, after skeletal maturation parenteral tes-# M+ u; \( o9 G9 h$ U! t
tosterone may be used to advantage. Before skeletal matura-+ a5 X- M0 w0 C. J7 e
tion care must be taken to avoid maintaining levels of serum; D% W3 K: A* n* { v
testosterone more than 100 ng./dl. Low-dose gonadotropin6 ]" ^- V& {" ~2 w" ?
depends upon intrinsic testicular activity and may require1 R8 b7 g. A" `0 q2 B6 j
prolonged administration for any response.) P( z$ p+ x& W
Alternately, topical testosterone does not depend upon tes-
3 G1 j* c' K& `% n6 ]( `ticular function and may provide a more constant level of
# _7 U$ A" O) Z3 s6 aREFERENCES: y9 S4 @7 Z) ` B
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 P2 D! ~2 h6 |2 Y' e8 y; UR.: The local application of testosterone cream to the prepub-1 z% C( Q }( o5 J! `" t C/ w
ertal phallus. J. Urol., 105: 905, 1971.
+ P' w( I/ [) Z; K6 ]9 }4 ]. x2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) e9 i& f/ W# D* Jtreatment for micropenis during early childhood. J. Pediat.,
, J/ ^( r% i7 I" @0 K! W7 ?' p83: 247, 1973.
# F% s2 K x: p( e. V3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( U$ F) a4 Y5 A8 t3 o) M4 N/ Zone therapy for penile growth. Urology, 6: 708, 1975.
8 |4 u9 m) ~: r4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' ~1 f u7 N8 X% V8 Q, A% O! Ato 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. f0 ~. n/ Q+ M) D5 a- Kskin slices of man. J. Clin. Invest., 48: 371, 1969.
7 N* r+ U9 I* x0 T. U# ^, l# p5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 e/ o, n _- i' t! w {$ |% eby topical application of androgens. J.A.M.A., 191: 521, 1965.
r3 F2 u7 y$ l$ o4 B2 u6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local' _1 z1 o h3 g/ j' e' q$ U
androgenic effect of interstitial cell tumor of the testis. J.! z- G3 \+ a5 |
Urol., 104: 774, 1970.
# J2 V& _% X- X; ?6 V7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' Y6 L0 ^$ c$ h' Xtion in the male genitalia from birth to maturity. J. Urol., 48: |
|