- 註冊時間
- 2023-5-6
- 精華
- 在線時間
- 小時
- 米币
-
- 最後登錄
- 1970-1-1
累計簽到:5 天 連續簽到:1 天
|
發表於 2025-1-4 03:09:28
|
顯示全部樓層
RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND3 V% ^. a1 h; n1 q% U
GONADOTROPIN$ C# ~" e& u8 ]+ _
RICHARD C. KLUGO* AND JOSEPH C. CERNY+ v+ W+ Y2 [ y4 [3 y, |& \
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 ~7 u0 K- X4 b6 T4 H7 `& W
ABSTRACT" D+ A7 `; n6 M. x* ~/ T. H
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' o" [3 U% a* j6 y9 F; k
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ K3 d1 |' j( N7 A& w% q1 h- mtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 I( A; g' w, {( o6 a. k. @cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 F& E2 I$ h# e7 d# q# Q$ e6 i0 sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 N1 j( @" `# iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
( ]- v* b; f" W& W0 W1 { @increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. k. W1 B* y/ `9 q @! roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
& `7 [1 m+ p; S- Q( pstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
4 ~9 Y! B* D. d. o+ [: n6 Egrowth. The response appears to be greater in younger children, which is consistent with previ-9 U! @- y( h3 S1 H q! z- K, c) F+ W1 A
ously published studies of age-related 5 reductase activity.
# T& o$ P& @7 S* r8 ~# |Children with microphallus regardless of its etiology will: ^. ?1 A! u U: U6 f5 A6 H
require augmentation or consideration for alteration of exter-! O$ a" L u! N( w3 A% i
nal genitalia. In many instances urethroplasty for hypo-
0 O+ D+ c" N! x5 x; q% a. {spadias is easier with previous stimulation of phallic growth.0 b& O# y0 ?! U% l# X M% N3 X
The use of testosterone administered parenterally or topically
) A j0 E2 P2 v( R$ G6 Z$ Shas produced effective phallic growth. 1- 3 The mechanism of
4 f3 Q9 C G! o% S6 b; Wresponse has been considered as local or systemic. With this& m$ D5 v2 X ~2 w; h9 ?$ l8 W
in mind we studied 5 children with microphallus for response' T# a% h' d. Q% t
to gonadotropin and to topical testosterone independently.9 U O9 r4 |4 d
MATERIALS AND METHODS" W8 Q) ^! w1 R4 o
Five 46 XY male subjects between 3 and 17 years old were
: `( O8 A/ V* V+ Revaluated for serum testosterone levels and hypothalamic: I6 u3 m2 n [
function. Of these 5 boys 2 were considered to have Kallmann's
& C, b+ k9 [! ?5 J+ q. ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
: V* n, {* B. I% ^6 r! d8 ]lamic deficiency. After evaluation of response to luteinizing
V# I$ V/ V1 D+ E* a. Nhormone-releasing hormone these patients were treated with
3 c I! i$ Y) b1,000 units of gonadotropin weekly for 3 weeks. Six weeks: h% R; l6 t u
after completion of gonadotropin therapy 10 per cent topical3 k( ]0 b5 c; a& D
testosterone was applied to the phallus twice daily for 3 weeks.# p/ v9 ?# ~7 p& n+ [' w' J8 Z q
Serum testosterone, luteinizing hormone and follicle-stimulat-
" S( ]# U, v8 l% jing hormone were monitored before, during and after comple-
, F$ [+ c( u% Btion of each phase of therapy. Penile stretch length was
, ^/ v& u; ^; ^% H' k& j0 ~obtained by measuring from the symphysis pubis to the tip of
* @# A/ y0 d0 n; P$ Z; f6 dthe glans. Penile circumferential (girth) measurements were
1 |* ?) {6 X3 \4 robtained using an orthopedic digital measuring device (see7 c# O( A1 C) x# V( P$ D# `
figure).& o1 [/ ^+ Q! v4 Y% @
RESULTS
% P; Y4 s+ ?2 n9 m# _Serum testosterone increased moderately to levels between$ _6 H7 ?2 P2 C* H
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' t D- w, _$ R& m/ r' z
terone levels with topical testosterone remained near pre-6 x; F8 Q# J. M+ V
treatment levels (35 ng./dl.) or were elevated to similar levels
/ t. k8 }1 \8 a) f" Q# Adeveloped after gonadotropin therapy (96 ng./dl.). Higher: P( ^% x% Z& `+ b
serum levels were noted in older patients (12 and 17 years old),! {" ~6 R4 u. C+ G; N; {
while lower levels persisted in younger patients (4, 8, and 10
6 f/ R }1 i7 o1 oyears old) (see table). Despite absence of profound alterations* m2 [1 y; A8 ?2 \, c8 s
of serum testosterone the topical therapy provided a greater' J0 w# z& |- u4 \5 O2 k9 i6 D
Accepted for publication July 1, 1977. ·
: ]+ x2 m: W1 \& mRead at annual meeting of American Urological Association,( ]% `* o9 y9 D7 ?& ?
Chicago, Illinois, April 24-28, 1977.
/ i& F" s; B i# r/ q$ v7 G- X+ v& w* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 ^) u% M# N( b% D+ A7 i1 h6 H$ U7 ^2799 W. Grand Blvd., Detroit, Michigan 48202.
. v0 ^! p: s) K! |improvement in phallic growth compared to gonadotropin.0 u. q! w3 o7 g9 Y
Average phallic growth with gonadotropin was 14.3 per cent/ q' O# o# D1 e7 \' o
increase in length and 5.0 per cent increase of girth. Topical
/ Q9 g1 c& h/ e. N7 ztestosterone produced a 60.0 per cent increase of phallic length/ f3 y/ n- Z! J! R
and 52.9 per cent increase of girth (circumference). The
2 s) l0 ~. N; O9 Cresponse to topical testosterone was greatest in children be-
+ v7 g" }/ a: C2 r' _# mtween 4 and 8 years old, with a gradual decrease to age 17
% ?! a" |4 M0 }) D3 p: a) Iyears (see table).5 K1 e6 i: w: z( K. ]2 ?: P
DISCUSSION
9 {6 [) T% s+ q% G4 J. BTopical testosterone has been used effectively by other
9 r$ A4 }/ R/ ?; O/ Gclinicians but its mode of action remains controversial. Im-
! U/ U. i2 m/ i+ Q( C$ u+ Imergut and associates reported an excellent growth response0 @8 E% A& F" i4 C4 Q$ m% \
to topical testosterone with low levels of serum testosterone,2 ]+ X* A+ T: @6 a; s/ ]
suggesting a local effect.1 Others have obtained growth re-, c4 E! s9 p! c' F# _
sponse with high. levels of serum testosterone after topical/ |7 m. o$ x3 q
administration, suggesting a systemic response. 3 The use of
& X- ]- E0 O8 h& v3 S A! }gonadotropin to obtain levels of serum testosterone compara-' V" p, o- c7 P
ble to levels obtained with topical testosterone would seem to8 C }! n) s) A
provide a means to compare the relative effectiveness of
3 Z5 s4 i" x* R/ P% Itopical testosterone to systemic testosterone effect. It cer-
: C! L2 ^9 ]6 k: k! E4 T. F3 k# ^tainly has been established that gonadotropin as well as par-
/ Y, M4 B' H) w9 Y1 menteral testosterone administration will produce genital
# q3 q8 W& ]" h7 wgrowth. Our report shows that the growth of the phallus was' p! C; e C" g
significantly greater with topical applications than with go-% R2 u8 p3 }* o; z
nadotropin, particularly in children less than 10 years old.( f& |# o% g" ]3 V
The levels of serum testosterone remained similar or lower
( r5 H" L- `7 G0 r/ ?( Rthan with gonadotropin during therapy, suggesting that topi-
/ i5 X: n0 Z* Q: `. Q& r- qcal application produces genital growth by its local effect as
7 z$ o9 X& F. rwell as its systemic effect.
# j* A- c# k [' A$ _Review of our patients and their growth response related to$ d- N2 i& h4 w |
age shows a greater growth response at an earlier age. This is
1 l% E8 J9 X4 F& C2 _consistent with the findings of Wilson and Walker, who( r E( U/ `% n
reported an increased conversion of testosterone to dihydrotes-* e/ q0 _& M3 e8 Z) i
tosterone in the foreskin of neonates and infants.4 This activ-
# f' T0 \ l, \. Jity gradually decreases with age until puberty when it ap-
5 T+ h P) a" jproaches the same level of activity as peripheral skin. It may8 t" q1 {: {4 C ~& F7 H
well be that absorption of testosterone is less when applied at' w& S9 X a# V, F
an earlier age as suggested by lower serum levels in children
# _! A, S( Y1 |+ v! Gless than 10 years old. This fact may be explained by the! m( [+ ]0 T4 A" Z9 H/ r
greater ability of phallic skin to convert testosterone to dihy-
: a2 u) k# F% O5 rdrotestosterone at this age. Conversely, serum levels in older* ~( {( R: C4 H* J
patients were higher, possibly because of decreased local M; T3 R& P# K( A x
667# j. u: M; X$ M: S/ G, h' z
668 KLUGO AND CERNY
2 }' X$ ]9 D) H' z; @3 QPt. Age
0 ^2 x: H r1 T5 S5 Z9 Y(yrs.)
( G" c0 j2 v/ ~Serum Testosterone Phallus (cm.) Change Length
. {& F* v5 |6 w* b+ _ W( \(ng./dl.) Girth x Length (%)3 [/ M+ D0 b" g6 C, ?! i
40 X4 {- l, L# k( G9 J8 I
8
' R3 q: f# S6 x0 a" ~" K+ R% A0 ^; p5 P10, n) z6 k5 @& p/ s1 r
12
, [2 e; z& M$ o17
! ?7 s) `- A* H9 o7 E2 @# w( t1 G0 sGonadotropin' ^% ~2 @- G9 p" [
71.6 2.0 X 3 16.6; s7 R" |- {, {. x0 t' O* j: v
50.4 4.0 X 5.0 20.0
1 [3 P. i* [; c0 L: h1 \22.0 4.5 X 4.0 25.0
, B& B# t8 i. v8 I: B6 _7 c( a84.6 4.0 X 4.5 11.1
; t( c1 A' B1 n' [85.9 4.5 X 5.5 9.0$ U+ F/ v$ y+ v, F; B5 i9 |& v
Av. 14.3; ~' S, I0 `& B! I, c: ]7 y+ _
4# [6 r6 G6 F+ J9 _; r: P
8
/ N# Q" d# }8 J6 R% w10
& }% Y f" q6 y0 R12
9 t; }, K8 i+ G' O) F177 q: T' s* v5 A2 L
Topical testosterone5 c) A- O( v7 f
34.6 4.5 X 6.5 850 | O/ G* U3 P4 }5 V
38.8 6.0 X 8.5 700 O7 j' n/ B7 o7 d# e! m: D
40.0 6.0 X 6.5 62.5
- O9 r9 F+ r N4 H" y! N93.6 6.0 X 7.0 55.5
; K- N* b" ~6 R0 _5 _# D95.0 6.5 X 7.0 27.2
. C1 n+ x% y' W5 x NAv. 60.0
. |7 `+ k+ U3 n, {* J& t. W5 bavailable testosterone. Again, emphasis should be placed on
# | @, f6 o' Aearly therapy when lower levels of testosterone appear to
a3 v& d7 Q) y6 `3 `: aprovide the best responses. The earlier therapy is instituted2 {/ |* X2 y1 [& F* k
the more likely there will be an excellent response with low
. F) q1 s, X4 W: F% Userum levels. Response occurs throughout adolescence as
3 L" M& c1 q. _noted in nomograms of phallic growth. 7 The actual response8 h; O; m8 P e! q1 w% W7 U
to a given serum level of testosterone is much greater at birth
9 X7 l3 Z, }# ~ k' `5 mand gradually decreases as boys reach puberty. This is most
/ Z( Z8 k5 {( p- [) E5 f, t- Ulikely related to the conversion of testosterone to dihydrotes-- U6 j% e+ r0 N, h
tosterone and correlates well with the studies of testosterone' k" J$ A8 s* J* n) P, L
conversion in foreskin at various ages.
7 O% S/ E0 o2 OThe question arises regarding early treatment as to whether9 Y4 Q1 M9 G" x# F: z+ ~! y2 v
one might sacrifice ultimate potential growth as with acceler-
1 d U& c7 x4 B3 uated bone growth. The situation appears quite the reverse
3 h5 I- s' o3 X) ^; x$ Cwith phallic response. If the early growth period is not used) S6 l _ D8 N$ ]
when 5a reductase activity is greatest then potential growth
& X( ^( z3 _$ c& }may be lost. We have not observed any regression of growth/ E8 Z0 K7 t; W1 n; }- Z+ ~
attained with topical or gonadotropin therapy. It may well6 o/ |6 g' N" k: ]1 h/ P( O
be that some patients will show little or no response to any) _, \8 y( R+ B3 t/ ?0 ~
form of therapy. This would suggest a defect in the ability to
; l' V2 ~" `* ~convert testosterone to dihydrotestosterone and indicate that9 u8 E- h& V9 t
phallic and peripheral skin, and subcutaneous tissue should" `: e8 ?. ?5 X
be compared for 5a reductase activity.3 ?; _! q6 {, G T7 Q X1 z* M
A, loop enlarges to measure penile girth in millimeters. B,$ M; I4 E. _; E: a0 v) a+ r
example of penile girth computed easily and accurately.
1 M$ }" i: G6 ]" a9 L! `7 Q0 @conversion of testosterone to dihydrotestosterone. It is in this
; A0 n: g: Q, ^( r. W& J! _older group that others have noted high levels of serum; _% B" X+ M) f# [: F2 d
testosterone with topical application. It would also appear
' B4 V6 n B1 _ P" v6 n0 Q* Lthat phallic response during puberty is related directly to the
( d$ I* E6 h+ Z2 O& B5 Tserum testosterone level. There also is other evidence of local
& d( f- d4 _# Y. ~response to testosterone with hair growth and with spermato-
& w9 m2 W9 O7 |# O, H4 ~genesis. 5• 61 r( t4 G& x; d/ q" J& y! c+ b2 F
Administration of larger doses of gonadotropin or systemic
1 L1 B N% Z" A2 Ntestosterone, as well as topical applications that produce
+ g X* y5 i# R+ _6 t2 ghigher levels of serum testosterone (150 to 900 ng./dl.), will E, d- M$ A. ] K; Y6 G2 ~! [
also produce phallic growth but risks accelerated skeletal# u4 L: ]2 a: G- |: c
maturation even after stopping treatment. It would appear# v; N y3 b" J2 _# J2 ?: t
that this may be avoided by topical applications of testosterone
, U- i- S" }. T0 V3 Uand monitoring of serum testosterone. Even with this control: d, `! m* M. k& n' n1 N
the duration of our therapy did not exceed 3 weeks at any
9 p3 V. @4 u4 _2 L9 |) }& B8 W3 f. ztime. It is apparent that the prepuberal male subject may
2 e" Q4 s: ?7 N8 zsuffer accelerated bone growth with testosterone levels near
- M# Q/ N8 S9 r3 [( O9 j+ x3 a200 ng./dl. When skeletal maturation is complete the level of" s6 V+ N, Y2 T7 X9 I3 X
serum testosterone can be maintained in the 700 to 1,300 ng./# Q+ Z& E4 w s% X. [
dl. range to stimulate phallic growth and secondary sexual
8 \$ O, b1 x: S1 g( t4 achanges. Therefore, after skeletal maturation parenteral tes-% W1 h8 s; d( S# }4 D0 Q
tosterone may be used to advantage. Before skeletal matura-" b* j7 m' m6 t1 _
tion care must be taken to avoid maintaining levels of serum4 G" |% Y3 C8 B
testosterone more than 100 ng./dl. Low-dose gonadotropin
) n; r1 E0 R( @. N& t9 mdepends upon intrinsic testicular activity and may require3 z6 W6 h* t/ x, ], E/ n
prolonged administration for any response.5 |! x1 [& t2 i1 E: m
Alternately, topical testosterone does not depend upon tes-
( E. B& j/ {" M+ N1 kticular function and may provide a more constant level of5 @5 F, d# D2 z4 M1 m
REFERENCES
8 e/ a' t" Q/ n( m6 ], a1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
6 D0 j/ b% d$ Y+ T8 E5 R' _R.: The local application of testosterone cream to the prepub-
' e J; G0 N3 f' x* v5 m: ?( S" kertal phallus. J. Urol., 105: 905, 1971.1 k9 K1 u) {. t1 }& h- a
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( E$ j' A( ~: }, [8 k
treatment for micropenis during early childhood. J. Pediat.,% U* [ j3 _: ~" V* q; B6 i3 u
83: 247, 1973.
' a; w' Y4 V4 K5 [3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; ^6 C& p v* Z. \% i2 Q/ \3 l
one therapy for penile growth. Urology, 6: 708, 1975.! Y3 T, n( W) `; U7 f
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 J* l+ S7 V- Ato 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ S3 r7 ~! v4 |8 X: I2 o) N
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ Q4 Z h9 l/ {7 r9 R z8 r& ]# J
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
" Q9 w. x5 j1 M: u& eby topical application of androgens. J.A.M.A., 191: 521, 1965., _* p% P' ~6 \; Q- b$ b1 x- n
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. U T" O& f$ I8 {/ f# Xandrogenic effect of interstitial cell tumor of the testis. J.9 |4 V+ I% ]2 }& X# }5 @& m c
Urol., 104: 774, 1970.& g% r- }' N" u! B. A% F$ f, H C
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; W# x% Y# f. \! I
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|