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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
0 |% F3 a4 U6 B( @: I9 }5 _. x! }GONADOTROPIN+ R0 ~" D+ t7 N) O3 m
RICHARD C. KLUGO* AND JOSEPH C. CERNY- ? G* y6 O& N3 A! Q# o1 p! X$ l$ x
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
( a, u) X- h% x- ~5 L2 i! gABSTRACT1 E# c5 A2 u7 X d1 z, T/ R% D8 A
Five patients were treated with gonadotropin and topical testosterone for micropenis associated9 l$ P& J% F) |, y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
7 r, i4 p1 V4 s0 Z8 M9 [1 e. @tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone5 i" i6 I3 m; p% Q
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent7 `# U; C/ X( A9 M
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent# e& j6 m! D2 v. P
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average$ R7 p( L! m7 |$ X
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 H8 ]0 L2 m- { m; l
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This9 t) C. R1 ^5 a/ @" T
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
& ?8 y/ k/ w' h; R; r# \growth. The response appears to be greater in younger children, which is consistent with previ-; J& {% a0 J U7 N
ously published studies of age-related 5 reductase activity.
- {+ t: k/ v# T" Y# GChildren with microphallus regardless of its etiology will; |. z: k, L3 P2 f" a
require augmentation or consideration for alteration of exter-
1 w3 W4 B6 o; D% C5 [9 S) Jnal genitalia. In many instances urethroplasty for hypo-* A' O0 `" `- ]6 D3 H X5 p6 L
spadias is easier with previous stimulation of phallic growth.
; G& K y7 f# w3 a _. s+ A5 RThe use of testosterone administered parenterally or topically/ r) {, _% w/ ] t
has produced effective phallic growth. 1- 3 The mechanism of
( i4 L7 D% p- q/ q% `0 Qresponse has been considered as local or systemic. With this5 |, N3 z* b& h+ }; q( w
in mind we studied 5 children with microphallus for response b) n4 f0 m4 }& l& m J0 U3 E
to gonadotropin and to topical testosterone independently.
4 _' V2 X9 K# I* Z$ E% BMATERIALS AND METHODS9 k5 |, {7 }/ `) k; x# ?
Five 46 XY male subjects between 3 and 17 years old were# ^8 ^2 R( X% |; e, w0 V2 n
evaluated for serum testosterone levels and hypothalamic& ]* ?( r5 E4 \: r0 m/ b
function. Of these 5 boys 2 were considered to have Kallmann's
- j' H, ~0 h1 `& isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-- ^' K- A" Z* p" w5 R# z
lamic deficiency. After evaluation of response to luteinizing
2 B/ k' W* S* [* ^* nhormone-releasing hormone these patients were treated with
2 p8 }% q; B9 L1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 G" l4 W7 t( @4 |5 O8 _
after completion of gonadotropin therapy 10 per cent topical
5 i8 a, L/ l, i/ r$ ~0 }9 Dtestosterone was applied to the phallus twice daily for 3 weeks.
: Z8 R" A8 y& ESerum testosterone, luteinizing hormone and follicle-stimulat-
% \- `" I& q9 z, f- Oing hormone were monitored before, during and after comple-" T- C4 g3 P3 W/ T, K. ?, {/ i! I
tion of each phase of therapy. Penile stretch length was$ ]! s4 R" X# l3 B# R: W$ P8 v
obtained by measuring from the symphysis pubis to the tip of
- Z& }& B6 a3 y0 s E; |: e4 pthe glans. Penile circumferential (girth) measurements were
# y7 I: C& E- M! r) Zobtained using an orthopedic digital measuring device (see
% o0 S, X6 g- k& s" Kfigure).
- s4 e2 X- x6 A# [" T) N4 zRESULTS
% g5 b. X, ^7 K& S9 p( P+ n; N6 W( w0 xSerum testosterone increased moderately to levels between
, @& \ F5 Z1 L; J) g50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' g3 s& d" V0 S4 Z+ `
terone levels with topical testosterone remained near pre-
( G" L+ u1 e% c# ^& Z% _2 Wtreatment levels (35 ng./dl.) or were elevated to similar levels
' |9 v; A9 q8 k0 z% tdeveloped after gonadotropin therapy (96 ng./dl.). Higher6 @! S5 P; o J* }3 e6 y$ P u
serum levels were noted in older patients (12 and 17 years old),4 R; K [# K, A1 v- W
while lower levels persisted in younger patients (4, 8, and 10
+ s7 i. ?+ r, u) g {" Y- B) Qyears old) (see table). Despite absence of profound alterations" D5 v% o- K- i; i
of serum testosterone the topical therapy provided a greater: w' O; S2 @: a' ~* n( s& Q
Accepted for publication July 1, 1977. ·
; r9 ]7 J; J1 t% b% ERead at annual meeting of American Urological Association,) x F5 g; G) b8 N6 \) B/ u
Chicago, Illinois, April 24-28, 1977.+ n9 z7 q7 F u5 q) u# z
* Requests for reprints: Division of Urology, Henry Ford Hospital,
* A4 x: p; k9 Q+ J( g. @2799 W. Grand Blvd., Detroit, Michigan 48202.: M5 c1 @! e& P5 _; m
improvement in phallic growth compared to gonadotropin., _, M0 _! a* m, G0 g
Average phallic growth with gonadotropin was 14.3 per cent& J7 x `) J" R% x+ _
increase in length and 5.0 per cent increase of girth. Topical
6 A+ U' B' K' S+ itestosterone produced a 60.0 per cent increase of phallic length" \# r; q u. @- J- R0 F
and 52.9 per cent increase of girth (circumference). The
( \" m$ ]' A& ?9 g$ I7 tresponse to topical testosterone was greatest in children be-
9 C _$ L" O1 d; `; R. |' Ktween 4 and 8 years old, with a gradual decrease to age 17
* [! U9 O3 ?& ^- Myears (see table)." C* ^/ ]3 L6 O$ p6 y3 _
DISCUSSION2 b4 Q' r0 J& T N$ ]8 y
Topical testosterone has been used effectively by other
) y) R, S7 x* K; Pclinicians but its mode of action remains controversial. Im-
# }8 k+ A- G) }: J7 O( Ymergut and associates reported an excellent growth response
1 S$ n0 o [7 t) c; P6 i1 ^to topical testosterone with low levels of serum testosterone,
7 D( n+ Z9 c3 k! J. v! |suggesting a local effect.1 Others have obtained growth re- X1 {6 z2 @6 t0 X, e
sponse with high. levels of serum testosterone after topical0 i# `" V. S# w2 d
administration, suggesting a systemic response. 3 The use of3 N) y ]1 R6 q' k
gonadotropin to obtain levels of serum testosterone compara-
0 ~# j% x9 b$ |: M7 o, Wble to levels obtained with topical testosterone would seem to" N: B3 @. d% j) Z% ^% W7 N
provide a means to compare the relative effectiveness of
+ c' G/ C6 p# w5 l! Otopical testosterone to systemic testosterone effect. It cer-
9 _% L2 H, i' n# T0 T, T$ @7 X" _tainly has been established that gonadotropin as well as par-
' k% P& I: h9 M8 n9 Denteral testosterone administration will produce genital
9 Q% X; K/ S: ^8 S+ Ggrowth. Our report shows that the growth of the phallus was0 U( Y, p" _, ^) p( C
significantly greater with topical applications than with go-1 K1 z7 [* h: `* G+ o
nadotropin, particularly in children less than 10 years old.$ `: C: s. I- i
The levels of serum testosterone remained similar or lower
# ^" N/ f( q: Ethan with gonadotropin during therapy, suggesting that topi-
^+ Y* H% @2 J+ h' \* s: ^cal application produces genital growth by its local effect as
! }: R# Z8 y( K1 H3 R awell as its systemic effect.
# z5 P4 X/ i# a4 [9 @Review of our patients and their growth response related to7 z5 Y6 C; |- D s- G
age shows a greater growth response at an earlier age. This is
! ?% D6 W; h X: rconsistent with the findings of Wilson and Walker, who
( a5 {3 L0 ]: G# S B+ H8 O* Sreported an increased conversion of testosterone to dihydrotes-
7 e" P7 o/ E( c3 H3 |' Jtosterone in the foreskin of neonates and infants.4 This activ-3 t6 P0 W9 f% L& U* K
ity gradually decreases with age until puberty when it ap-. y. e) N9 W+ A3 J) @- p" D
proaches the same level of activity as peripheral skin. It may8 M J7 V1 x5 l2 b0 f; V. c
well be that absorption of testosterone is less when applied at
9 u7 `+ F3 J* h/ L( p3 X% Nan earlier age as suggested by lower serum levels in children
7 z- s8 z) |* b r oless than 10 years old. This fact may be explained by the
& [& l: x$ w# D; V& l0 Hgreater ability of phallic skin to convert testosterone to dihy-
) W3 H3 w0 M0 z) ^drotestosterone at this age. Conversely, serum levels in older
- `; e' h) R; t1 D- i% ]patients were higher, possibly because of decreased local
9 c! v6 @. {, p667
@5 @5 }6 u' ~- |668 KLUGO AND CERNY, g. C' o3 j+ b# G4 ?! z
Pt. Age6 [$ _$ ^4 ?0 B) b4 k
(yrs.)
/ J' B$ _( t0 _0 k* `Serum Testosterone Phallus (cm.) Change Length
6 R2 F. \6 K8 _( \% U% L2 m9 p(ng./dl.) Girth x Length (%)
% r5 u, `# u) p4! F. S" H0 H4 Y% u4 @' T
8
& e% r$ e* b* _10
# [' H% N' q. |/ J* Q# k9 U5 P12
" L- }$ B g4 x' p17
7 @, @ p4 I0 K' D( v1 |Gonadotropin& u/ @. [) d0 j+ d
71.6 2.0 X 3 16.6) q7 Y% Q) V0 Z9 P$ b
50.4 4.0 X 5.0 20.01 N# G% P* m9 \* k
22.0 4.5 X 4.0 25.0
; I7 P4 d" p1 k* ^- Y84.6 4.0 X 4.5 11.1, Z1 [; Z8 H. X0 W1 t
85.9 4.5 X 5.5 9.0
8 d, v2 `5 T$ n, GAv. 14.3
- G4 K+ t! H, ~, q# Q' p4
+ ^1 W9 Q- I- @1 [8
; V' {6 m# ^! `" E. h10
: m" a6 G! N/ k, W12) D& d/ a0 O$ b. ? Q1 t* ?+ A/ o
176 D4 p. T. C; [. Q; f* O2 ^
Topical testosterone
# ^6 _% j/ p% N, }2 R34.6 4.5 X 6.5 85, x) _+ `0 f2 P, m$ J r1 Y
38.8 6.0 X 8.5 70
# ]6 `1 p) w) c2 i5 [! z m40.0 6.0 X 6.5 62.52 U; ?" {. r' \$ J/ A5 l( E5 c
93.6 6.0 X 7.0 55.5. ?8 b/ K4 F& V: E5 T; @
95.0 6.5 X 7.0 27.2' ]9 i3 X/ N# q0 M/ s3 w# Z
Av. 60.0
- z. L. D+ J9 s/ S6 [available testosterone. Again, emphasis should be placed on( P8 o: K" B' F# w# _ r! J" q4 c
early therapy when lower levels of testosterone appear to
9 V/ ^$ T% S. A+ l( i8 m# D/ n; wprovide the best responses. The earlier therapy is instituted1 J5 C/ \4 D" Q
the more likely there will be an excellent response with low5 s, o$ q7 r9 `* m+ w( ^, g- ~/ |
serum levels. Response occurs throughout adolescence as
4 ~3 R2 [, v3 {! unoted in nomograms of phallic growth. 7 The actual response0 ~. h5 v& H; r! Z
to a given serum level of testosterone is much greater at birth" F6 M7 v# F' z! c. j* y# f/ f" \
and gradually decreases as boys reach puberty. This is most1 ?" q' Z% |' S: z5 Q; V- d
likely related to the conversion of testosterone to dihydrotes-. c l- `- r$ {' k' Y7 A4 N$ |
tosterone and correlates well with the studies of testosterone& V+ x/ q- n7 \! A! ~, f
conversion in foreskin at various ages.% B8 p/ w; G6 w) j5 ^! E0 n7 C
The question arises regarding early treatment as to whether
' n0 r& p/ Y+ A5 f9 Z% G1 F [one might sacrifice ultimate potential growth as with acceler-
2 j5 c% M' `/ X% ]2 p" sated bone growth. The situation appears quite the reverse1 d% G) t; Y7 C* g6 k
with phallic response. If the early growth period is not used/ T9 E m3 E5 I' k
when 5a reductase activity is greatest then potential growth
) K3 m9 d$ {* z# T+ rmay be lost. We have not observed any regression of growth
& z0 X5 h4 I, tattained with topical or gonadotropin therapy. It may well
4 x2 z; I. _% y/ M. z6 Jbe that some patients will show little or no response to any
# G9 u5 |5 o- [/ T# P& {form of therapy. This would suggest a defect in the ability to
' Y9 ^ c7 g# D2 B" M8 E0 econvert testosterone to dihydrotestosterone and indicate that9 s% v: _6 ]* l
phallic and peripheral skin, and subcutaneous tissue should
& C1 a, H; Y/ q- \be compared for 5a reductase activity.
' B1 n, d f h$ Z& yA, loop enlarges to measure penile girth in millimeters. B,
/ X M2 Y" r, b! ~7 H. c7 D" Cexample of penile girth computed easily and accurately.
# U2 X7 K" r9 l5 ]; Fconversion of testosterone to dihydrotestosterone. It is in this3 ?" g% g) d/ c. U( W V
older group that others have noted high levels of serum
0 |8 l* M6 i* K! z( qtestosterone with topical application. It would also appear0 M+ `+ P# O7 {; o* t g6 j7 R
that phallic response during puberty is related directly to the; @6 n% P- w/ x# k0 e
serum testosterone level. There also is other evidence of local
( P" J* i# d* `. hresponse to testosterone with hair growth and with spermato-
) `7 P3 U, Y& f3 rgenesis. 5• 6! q( H8 ]4 ~2 r/ s- W
Administration of larger doses of gonadotropin or systemic
6 Q }8 V6 |# o5 S) Ntestosterone, as well as topical applications that produce
/ T; v, D! `6 u6 {% s4 F7 J, w6 \higher levels of serum testosterone (150 to 900 ng./dl.), will
$ s: D9 a1 m2 p, |- Salso produce phallic growth but risks accelerated skeletal N" R6 H: v X5 S/ y8 B' S/ l3 t
maturation even after stopping treatment. It would appear- n% ]( q2 z. o# h
that this may be avoided by topical applications of testosterone
1 f& ]5 s. w, r, O0 v- w. ~and monitoring of serum testosterone. Even with this control- H9 N% h \: u) o1 r8 |/ x
the duration of our therapy did not exceed 3 weeks at any. r$ |( m) h0 Z6 n6 r5 E$ T! ~# r
time. It is apparent that the prepuberal male subject may
% i# F% P: w% V ^# Rsuffer accelerated bone growth with testosterone levels near
6 `$ i* P" C5 s200 ng./dl. When skeletal maturation is complete the level of
2 k+ q4 O( `& C# t# ^serum testosterone can be maintained in the 700 to 1,300 ng./
" e( ]' s- n3 Q! \- T# [dl. range to stimulate phallic growth and secondary sexual
; `; a& r4 K" Hchanges. Therefore, after skeletal maturation parenteral tes-
5 ]( K7 K4 }" V2 l& Ztosterone may be used to advantage. Before skeletal matura-
! \' P) ^5 Q" Z: [: _tion care must be taken to avoid maintaining levels of serum2 Q+ }% F* U; k8 q. O$ t
testosterone more than 100 ng./dl. Low-dose gonadotropin8 V4 H$ Z/ J7 t/ ~+ {9 |- G9 `- Q
depends upon intrinsic testicular activity and may require
# C. T9 ~# a1 P2 ?1 q7 O$ [ Sprolonged administration for any response.& W3 C: R6 z. R7 A
Alternately, topical testosterone does not depend upon tes-
( O- j6 ]% y% ^7 D5 _ E1 j& zticular function and may provide a more constant level of$ A' g+ P: R& Y
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" l+ h7 h0 D9 y# Z9 I, Y- U7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-! i1 u* o: y" ~ q# Q2 @9 h! n
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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