- 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
) ?; _/ `' s2 e# G$ Z' ]0 {GONADOTROPIN" z' F8 `6 V Q' }" |' F
RICHARD C. KLUGO* AND JOSEPH C. CERNY
5 F8 B; r ?/ H ?/ y0 b! mFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan$ k& A$ j5 I. \
ABSTRACT
7 `' t0 g* ` A9 K$ qFive patients were treated with gonadotropin and topical testosterone for micropenis associated
+ r! [4 @7 }% Dwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' U+ V6 \0 B: }8 Otropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone, @: a7 R- ` R* Z- A
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& ~" N7 r3 S6 Z: ?9 c
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
. M" k H" v& _+ {7 T' @+ E% Qincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average2 J) K! u: s6 B/ M) N5 y: D
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" h: d5 m( F( m* ?# B" ?; doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This- n6 ~- c" _) g6 [
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
" x; }! u9 }' N6 X: |growth. The response appears to be greater in younger children, which is consistent with previ-
/ k$ c( A9 n+ d4 |+ i$ Q3 |ously published studies of age-related 5 reductase activity.
n+ ^3 X4 b6 B" t7 C( U, FChildren with microphallus regardless of its etiology will
# X' B6 z% y$ U' V5 h4 @require augmentation or consideration for alteration of exter-
- m7 l& E6 N/ C& k2 Cnal genitalia. In many instances urethroplasty for hypo-# r6 N6 q" I" @& s% e+ G
spadias is easier with previous stimulation of phallic growth.
. d& l3 X1 I3 v) ^The use of testosterone administered parenterally or topically
4 n2 \6 `5 {3 K5 ~1 }1 N- lhas produced effective phallic growth. 1- 3 The mechanism of$ [; [7 H8 a+ V8 U
response has been considered as local or systemic. With this
% {* T* x- ^+ K* w7 h5 Din mind we studied 5 children with microphallus for response1 p4 O: d6 p. ~
to gonadotropin and to topical testosterone independently.6 a6 x$ o8 A5 z0 f
MATERIALS AND METHODS5 L6 v8 V6 i0 h- \0 _" l. [7 n
Five 46 XY male subjects between 3 and 17 years old were
: X& W: I t5 T' [evaluated for serum testosterone levels and hypothalamic
% R# V$ o# `+ d# Rfunction. Of these 5 boys 2 were considered to have Kallmann's
# E, t/ _" s$ psyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-! ?3 d, J8 t% J- [
lamic deficiency. After evaluation of response to luteinizing. D0 X: n; d- t+ H9 A) \/ ?
hormone-releasing hormone these patients were treated with% G- m5 C+ A. \; k' x! |, @! U
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
5 ?7 ~ z# d) `4 f1 W3 A! H% Uafter completion of gonadotropin therapy 10 per cent topical+ T; ~; t/ \. P, F
testosterone was applied to the phallus twice daily for 3 weeks.
/ t3 J& L+ k' I& {% \Serum testosterone, luteinizing hormone and follicle-stimulat-
& i! |3 \* m, N! T5 s: f( ving hormone were monitored before, during and after comple-
: m, I! F" _" T% Qtion of each phase of therapy. Penile stretch length was7 I* [* K8 i" W" e
obtained by measuring from the symphysis pubis to the tip of( {6 I+ n2 S& |8 `2 K$ V% O
the glans. Penile circumferential (girth) measurements were4 G: Z5 O( [" R' Q9 ]
obtained using an orthopedic digital measuring device (see
n# V) v$ S, Q0 Zfigure).
% u! A( Y+ A3 W1 |* LRESULTS- T9 L% y# h; y( ?4 s
Serum testosterone increased moderately to levels between4 S3 Z. N4 z/ K, _* u _# d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% ^& N8 W/ J! p2 K3 B% q6 e+ c6 {terone levels with topical testosterone remained near pre-' {* R4 ^" g1 Q" ?8 U
treatment levels (35 ng./dl.) or were elevated to similar levels; r( Z* ~; l6 m t0 u- `# v
developed after gonadotropin therapy (96 ng./dl.). Higher, D4 ]" E8 i/ v: W7 g s( K" D
serum levels were noted in older patients (12 and 17 years old),
1 x- S8 X+ z- H+ ?6 cwhile lower levels persisted in younger patients (4, 8, and 101 b: O. E0 R* T3 N% N
years old) (see table). Despite absence of profound alterations2 [' d H5 R: M- w6 k$ U1 ?( z
of serum testosterone the topical therapy provided a greater) I6 _! O" L$ M- }* O
Accepted for publication July 1, 1977. ·; T/ \/ f& x) f: w* Q
Read at annual meeting of American Urological Association,
6 b. A" y: l% v- A }7 n5 R4 CChicago, Illinois, April 24-28, 1977.
6 ~. @! X5 D( [( _* Requests for reprints: Division of Urology, Henry Ford Hospital,
w( ~$ d6 @" @% e. N/ E2799 W. Grand Blvd., Detroit, Michigan 48202.% L0 p T8 N; Q1 D6 S4 z; t
improvement in phallic growth compared to gonadotropin.
* ]- W3 x0 G [' F+ d/ s; s( {Average phallic growth with gonadotropin was 14.3 per cent! L# K' O m/ a! g
increase in length and 5.0 per cent increase of girth. Topical
' {' O% ?/ f8 a/ {" n& g/ L( l. Qtestosterone produced a 60.0 per cent increase of phallic length& ?7 F+ ~3 s1 J# ]' H: a$ q
and 52.9 per cent increase of girth (circumference). The
& u' K/ {; s0 [9 k) X y* }# _6 jresponse to topical testosterone was greatest in children be-1 G( {% i3 A% t, i3 j) \
tween 4 and 8 years old, with a gradual decrease to age 177 O4 r' m F ]9 i' o
years (see table).
$ Y3 z* F) n) w$ {* b9 Y1 v6 P' PDISCUSSION
% @; q* ^, S1 \! y* r8 r2 z3 mTopical testosterone has been used effectively by other, v# P" h# E1 i6 B& v- H
clinicians but its mode of action remains controversial. Im-0 l( A" \4 \+ C+ g
mergut and associates reported an excellent growth response! ^% }& z7 J, U' q
to topical testosterone with low levels of serum testosterone,; S' i# N3 W4 L$ h' y4 a/ k. m q
suggesting a local effect.1 Others have obtained growth re-
) ^7 d- S9 ?; c$ B _5 V6 ~. H. i9 Nsponse with high. levels of serum testosterone after topical/ s2 ~( @" u' t* N
administration, suggesting a systemic response. 3 The use of
0 D0 C) m' c8 c" u S& `6 `gonadotropin to obtain levels of serum testosterone compara-' g% b9 M# A! ^& {
ble to levels obtained with topical testosterone would seem to: s( L* e* S0 H# ] z4 T; G6 v
provide a means to compare the relative effectiveness of! q- Y9 M* `1 ?- m% K( i
topical testosterone to systemic testosterone effect. It cer-
4 m+ [7 Q! F$ A4 J$ M* {/ q3 g, rtainly has been established that gonadotropin as well as par-) e0 ]; Z1 z. I# R0 }7 e
enteral testosterone administration will produce genital
# t8 R' k$ W. x+ w2 `( xgrowth. Our report shows that the growth of the phallus was6 R3 ?4 z. I; _" W* Q( d
significantly greater with topical applications than with go-2 Z' y: \" ?2 Y, K. @
nadotropin, particularly in children less than 10 years old.
1 F- |* d$ K: I' c' M6 P8 [* sThe levels of serum testosterone remained similar or lower. T2 Z$ t% z4 k/ W2 z& ?8 L
than with gonadotropin during therapy, suggesting that topi-7 r; c* @' G( c, b$ J. C3 _
cal application produces genital growth by its local effect as. l0 [3 l. o. i; }7 d
well as its systemic effect.1 i' ]) Z* Y! Y# G2 y- N2 X2 w
Review of our patients and their growth response related to
V5 r0 Q5 ]8 r3 y# A. D7 }! ^age shows a greater growth response at an earlier age. This is8 b0 g* D9 z( r- ~0 D h
consistent with the findings of Wilson and Walker, who2 m: x+ A! K: u9 O( b- v
reported an increased conversion of testosterone to dihydrotes-
~1 R- W" h* R) q. w& Vtosterone in the foreskin of neonates and infants.4 This activ-6 H- X. s: \) ~, o
ity gradually decreases with age until puberty when it ap-) G9 M" ~: G: V7 d i( T
proaches the same level of activity as peripheral skin. It may
1 M# D) }+ D$ [. r! ~6 uwell be that absorption of testosterone is less when applied at
& |: O, ]# ^' |$ N, nan earlier age as suggested by lower serum levels in children, v, j+ v' G* U" D+ a
less than 10 years old. This fact may be explained by the
- V3 i+ Q; O' c2 igreater ability of phallic skin to convert testosterone to dihy-
8 N. t' \* L8 U' \5 tdrotestosterone at this age. Conversely, serum levels in older
8 {* C$ b5 Y3 y# T; ]$ A5 y7 B1 epatients were higher, possibly because of decreased local5 E& f* c; r! k' O$ T0 @
667% E$ g) a( c- ?5 F
668 KLUGO AND CERNY, F0 r/ C, @2 E; C
Pt. Age
( m! x/ @; I" J0 }% P0 i(yrs.): X: L7 ?5 A3 m t @1 y" }* o
Serum Testosterone Phallus (cm.) Change Length
! _, d- f+ P x1 O(ng./dl.) Girth x Length (%); @( t+ u4 D% E8 v/ G
4
# J. z# V7 v# I8& ^" u. Q1 a b3 o0 X q
10# p/ e( a& w1 n6 g; m
128 e3 y# a% e( j @
17
% J1 \$ f; l" K; z! |Gonadotropin
/ X/ V% D2 g5 t! @71.6 2.0 X 3 16.60 \8 ], O& c- f% O, W
50.4 4.0 X 5.0 20.0! `/ c6 v) E7 f2 [% Q# \
22.0 4.5 X 4.0 25.0
7 N/ e' `5 \) _84.6 4.0 X 4.5 11.1* T2 `! {& `8 k" T
85.9 4.5 X 5.5 9.0
/ V8 w* x# O5 v$ ^4 M2 FAv. 14.3
g+ B: k; X8 O5 k6 Y+ C4: x3 [5 J4 Y. d# [; R. }
8
" X4 Z% d8 Z6 @5 l5 r: y103 ]$ H) d( Y; ]; l/ H* F0 H% d
12% a N: m# A3 j! D
17
% G- f; y8 f+ g' c% T) NTopical testosterone9 y- _! S+ Q8 z7 J9 A$ j
34.6 4.5 X 6.5 85
2 R8 r1 R: X% Z* m38.8 6.0 X 8.5 70, t8 P% p; J: W% d
40.0 6.0 X 6.5 62.5( ]; q- n- \! j3 w
93.6 6.0 X 7.0 55.5
; U; g* g0 o# t+ W9 V/ _% }95.0 6.5 X 7.0 27.2
; c& e; r/ V7 O& n. ?Av. 60.0
4 ~% H- K, l7 u8 T' k) ^available testosterone. Again, emphasis should be placed on2 D, [) `9 Y) R$ W+ W. o4 l7 r
early therapy when lower levels of testosterone appear to2 N8 G+ O Q+ h9 |2 ^
provide the best responses. The earlier therapy is instituted- G3 O. X0 Z9 U. Q* |
the more likely there will be an excellent response with low
0 Y2 g+ A: [- \' `& }3 iserum levels. Response occurs throughout adolescence as; m6 P5 L R3 N+ U* x" H- l
noted in nomograms of phallic growth. 7 The actual response0 M9 f. P! W+ G1 e4 P* e: ~
to a given serum level of testosterone is much greater at birth- Z5 `% a& t% P+ e8 s+ `
and gradually decreases as boys reach puberty. This is most( o2 q E/ @! ?, ^. b+ m* D0 o' N
likely related to the conversion of testosterone to dihydrotes-
% B) Y v3 B& b; stosterone and correlates well with the studies of testosterone
/ _2 Y/ b i G. }conversion in foreskin at various ages.
: u" h; u- H) ~* O; Q8 [3 n, ^7 UThe question arises regarding early treatment as to whether
& r/ K' }+ F. V" ]one might sacrifice ultimate potential growth as with acceler- f8 `. ~& z' y: A
ated bone growth. The situation appears quite the reverse+ N' y/ P6 i0 |+ x
with phallic response. If the early growth period is not used
9 u( T% ] \8 n: h4 [7 fwhen 5a reductase activity is greatest then potential growth
1 h9 I- @7 ?. Q1 Xmay be lost. We have not observed any regression of growth7 V0 x' b6 T# h6 t+ y
attained with topical or gonadotropin therapy. It may well
* V/ c9 r$ I8 w/ ibe that some patients will show little or no response to any C( q* N/ S8 a3 E1 n: D1 ?! A5 K
form of therapy. This would suggest a defect in the ability to6 R" }( J) E+ a1 p8 h% q& o
convert testosterone to dihydrotestosterone and indicate that
5 q. v s' C7 xphallic and peripheral skin, and subcutaneous tissue should
3 r. Q0 o: a! Dbe compared for 5a reductase activity.% h! U! W+ i0 L- E7 a1 | Q
A, loop enlarges to measure penile girth in millimeters. B,
$ L) S4 i! R- y7 b3 L0 `8 o. Uexample of penile girth computed easily and accurately.! B' Y% k) ]; S( m" P8 z
conversion of testosterone to dihydrotestosterone. It is in this
: o# F& j6 R: F$ B( l+ ^older group that others have noted high levels of serum
7 t" b/ D8 u ~testosterone with topical application. It would also appear2 N( c" J V' t! F
that phallic response during puberty is related directly to the
2 R: S/ M$ {8 W6 Iserum testosterone level. There also is other evidence of local8 B7 S1 t: n! z9 S3 _
response to testosterone with hair growth and with spermato-; x; e: y; ^4 E: B' q# H& ~
genesis. 5• 6
/ `* U2 c/ ?% O9 r( S5 Z! jAdministration of larger doses of gonadotropin or systemic
1 D2 g6 w, U! ktestosterone, as well as topical applications that produce3 l3 D- Z3 r6 S) @4 {/ b& O
higher levels of serum testosterone (150 to 900 ng./dl.), will! x5 x! ?9 w$ D" `! q2 C, ~
also produce phallic growth but risks accelerated skeletal1 N- G! V2 l! L
maturation even after stopping treatment. It would appear
% b* I5 e. x2 Athat this may be avoided by topical applications of testosterone, F9 S4 s* Q/ z0 i2 m, O
and monitoring of serum testosterone. Even with this control$ q" Z0 V; E& S
the duration of our therapy did not exceed 3 weeks at any
2 M4 }; [/ \# \ k7 w2 Q# n. f9 f9 Ttime. It is apparent that the prepuberal male subject may
) ^+ `& W6 ^. Lsuffer accelerated bone growth with testosterone levels near
/ M7 `7 n+ w$ b& Q7 D/ Z200 ng./dl. When skeletal maturation is complete the level of
) E$ v% D* }3 c5 v1 x* userum testosterone can be maintained in the 700 to 1,300 ng./
2 Q, \5 {& U* J: Vdl. range to stimulate phallic growth and secondary sexual9 U3 g+ v A2 i2 w) l$ v) E; I
changes. Therefore, after skeletal maturation parenteral tes-
( v. P# O0 @; ~3 Q8 M; Z9 htosterone may be used to advantage. Before skeletal matura-- I* V- V+ R6 l9 F- W
tion care must be taken to avoid maintaining levels of serum) \. E+ t4 K+ q, p/ x) S( L
testosterone more than 100 ng./dl. Low-dose gonadotropin
* l& U O- w) {8 mdepends upon intrinsic testicular activity and may require
% e7 M1 Y% s- Z4 u+ oprolonged administration for any response.
! g0 x% t( K3 xAlternately, topical testosterone does not depend upon tes-
' r) _8 D: Y. ]- X2 Pticular function and may provide a more constant level of; J( a4 A; ~) T
REFERENCES2 J% ~8 X% J: `1 D
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
* }, A) M e/ M& @7 C; n4 h wR.: The local application of testosterone cream to the prepub-
- h& {2 T8 l* x$ n. x4 @ertal phallus. J. Urol., 105: 905, 1971.
# c7 o; z4 r# \ R! j" v2 R2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 `" h* O1 Z& z* rtreatment for micropenis during early childhood. J. Pediat.,
, f# q# Y. }+ N& I83: 247, 1973.
: B2 C& j! c* X5 G; W; }3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
$ d; H% x$ h: x* {" ^: s* b b* r6 vone therapy for penile growth. Urology, 6: 708, 1975.- D5 T, R+ n9 U9 p+ e
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 W& h; `! H; O. Y8 S! B
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- i8 c: s8 C& c }' uskin slices of man. J. Clin. Invest., 48: 371, 1969.* o# Q8 T! e; n' K7 J9 u4 w' G, {
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 {( O* L& x; ^4 I
by topical application of androgens. J.A.M.A., 191: 521, 1965.9 u: F# g5 U7 F4 J, P& H" G, M
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local1 _) a: M' R% |; S5 P9 ?- C
androgenic effect of interstitial cell tumor of the testis. J.6 P) a- ?8 A3 G1 l6 q% P
Urol., 104: 774, 1970.
; Q- K2 W1 ~. E! ~, y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
Z! j. I5 y6 q8 Ntion in the male genitalia from birth to maturity. J. Urol., 48: |
|