- 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 AND5 G* p, H) _& s
GONADOTROPIN" V, |4 l# C! @
RICHARD C. KLUGO* AND JOSEPH C. CERNY5 O5 G8 w ~6 @
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan( P2 [# T7 ?' P/ q
ABSTRACT
: n C% E4 [6 T' VFive patients were treated with gonadotropin and topical testosterone for micropenis associated
& w1 Z/ P+ F$ a# e* Nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-4 b! N. D/ Q# k+ F; I9 J. ^6 n
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
. p. a! y' n6 S' w/ X; Wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: u* }9 S" G! ^, P2 W4 m) j$ T6 f
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ l& R+ f9 K0 g0 o( x# i) ~3 rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average0 |" Q; ]( R1 H' ~) M
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ o& V0 h7 {; W! foccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
1 }, D! D0 C% n1 Jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile) j( B9 Q4 V' t0 B- E! u, g
growth. The response appears to be greater in younger children, which is consistent with previ-1 Q4 H' c. Z Z9 t; s9 e
ously published studies of age-related 5 reductase activity.! r. B7 M% [7 u8 x3 w
Children with microphallus regardless of its etiology will: W$ D& o) }# g& N: F7 ?
require augmentation or consideration for alteration of exter-! d: ?1 b* F* d# o+ t/ c
nal genitalia. In many instances urethroplasty for hypo-
3 i. r4 s8 j! |9 zspadias is easier with previous stimulation of phallic growth.
- j4 ?7 F% m( d0 z4 x b6 bThe use of testosterone administered parenterally or topically) Q% P2 |: r: |7 O# H8 `) i
has produced effective phallic growth. 1- 3 The mechanism of1 R4 w6 Y3 p% A" K8 U# r
response has been considered as local or systemic. With this- Y. \$ x- B J
in mind we studied 5 children with microphallus for response
+ o: n! w6 E: `' d4 {4 _: Ito gonadotropin and to topical testosterone independently.
. k L$ T( P3 e& B5 u) iMATERIALS AND METHODS0 _3 c8 A- t4 h$ x
Five 46 XY male subjects between 3 and 17 years old were! d1 G5 F# Y0 ]3 e5 u/ t& J2 F7 ^3 u0 A
evaluated for serum testosterone levels and hypothalamic
8 a0 u+ m- _ ~function. Of these 5 boys 2 were considered to have Kallmann's' p* G' d9 i; |' l5 P- }
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-- m% Q4 d/ m" F9 A7 [; a
lamic deficiency. After evaluation of response to luteinizing( L0 E( u5 ~/ e; B
hormone-releasing hormone these patients were treated with
) m3 e& U: f$ f3 B+ r3 d* k1,000 units of gonadotropin weekly for 3 weeks. Six weeks1 [3 M/ {+ ]3 k4 G I7 @
after completion of gonadotropin therapy 10 per cent topical/ d6 P4 I" }" l" n
testosterone was applied to the phallus twice daily for 3 weeks.3 }5 n! q# g6 {8 K/ P
Serum testosterone, luteinizing hormone and follicle-stimulat-
# q1 E7 t9 J8 T$ Ting hormone were monitored before, during and after comple-
@) Z$ i; I; f6 B6 O8 Ftion of each phase of therapy. Penile stretch length was# x) P; o( H5 s7 n2 b3 f% w
obtained by measuring from the symphysis pubis to the tip of! }6 L4 m) z+ Q/ R; G, ]& K0 W
the glans. Penile circumferential (girth) measurements were# _% `% S+ s% q4 P. d0 `7 K: H- u
obtained using an orthopedic digital measuring device (see' d7 X% T# s9 P
figure).+ }/ n/ K0 j0 C' ^9 ?& m
RESULTS1 R2 @# y3 B4 o ]" ?, Z h
Serum testosterone increased moderately to levels between) B! G7 l+ Q$ q0 s' Q- u6 Q6 P8 n/ E
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
& Z8 k# X0 l( L* Z ?' ^4 e) Gterone levels with topical testosterone remained near pre-/ e. r6 m! Y( A1 g& M
treatment levels (35 ng./dl.) or were elevated to similar levels
. q1 p% `! C& l% Y- i2 B* Odeveloped after gonadotropin therapy (96 ng./dl.). Higher2 o1 C9 J: O% d3 N9 K; F& a1 B6 [1 k5 l
serum levels were noted in older patients (12 and 17 years old),' [9 d: Z. G5 B
while lower levels persisted in younger patients (4, 8, and 10
% X$ _! a; w( z8 m' `1 hyears old) (see table). Despite absence of profound alterations
: A1 J0 @3 L: dof serum testosterone the topical therapy provided a greater2 m- p. I+ V" b; M, o6 M+ v8 e( i0 o
Accepted for publication July 1, 1977. ·
- X6 A3 p- N$ M8 u8 H" l+ R8 j! IRead at annual meeting of American Urological Association,
' P% T G* \7 y2 s; r0 VChicago, Illinois, April 24-28, 1977.! N9 G! D; d% G4 |( b( c
* Requests for reprints: Division of Urology, Henry Ford Hospital,2 F( }9 T2 L8 j8 F9 g
2799 W. Grand Blvd., Detroit, Michigan 48202.
2 r' ^ d2 U0 V& {# Limprovement in phallic growth compared to gonadotropin.% Q) p4 y# q- y0 q4 a- f
Average phallic growth with gonadotropin was 14.3 per cent
. p, F' m2 h% t$ P: F9 uincrease in length and 5.0 per cent increase of girth. Topical
" Y; L F7 R3 h( gtestosterone produced a 60.0 per cent increase of phallic length
* k' R, C! f5 \+ }9 land 52.9 per cent increase of girth (circumference). The
3 g* _/ j8 i/ e. ?response to topical testosterone was greatest in children be-
+ B- L1 w1 h, G( n3 h+ H& B& U- otween 4 and 8 years old, with a gradual decrease to age 17- b, `+ H: y& R5 o8 O' X) {6 j U
years (see table).! X5 ~9 `9 n. V: t8 m" h6 ^
DISCUSSION
% S, G; \4 d# T, \" fTopical testosterone has been used effectively by other9 q* J/ }+ [4 Z' e8 J' R% G5 W% B
clinicians but its mode of action remains controversial. Im-
/ B" P; J- r1 V% a1 ]0 Bmergut and associates reported an excellent growth response5 ]( U$ Q/ p8 _3 j4 a; g
to topical testosterone with low levels of serum testosterone,0 ]. b: g" ?! J7 P) D
suggesting a local effect.1 Others have obtained growth re-& O( w2 t+ B0 M1 y$ C1 ~, |
sponse with high. levels of serum testosterone after topical9 h6 e8 L6 v5 o" F" h
administration, suggesting a systemic response. 3 The use of
. X4 z! m6 g! agonadotropin to obtain levels of serum testosterone compara-
( p9 O8 J i5 B }2 u" s' Q; Z J5 Lble to levels obtained with topical testosterone would seem to
0 z# m; [0 `" k+ N; \provide a means to compare the relative effectiveness of
7 ~9 F+ A- i7 w/ D+ Btopical testosterone to systemic testosterone effect. It cer-
; `9 }5 z: v) m$ Xtainly has been established that gonadotropin as well as par-
' a: f: C t! Q6 a$ Uenteral testosterone administration will produce genital4 p3 v( p4 A! |- D9 F
growth. Our report shows that the growth of the phallus was: t4 l. @" d( E6 r
significantly greater with topical applications than with go-
1 h. {3 X$ `4 a0 Pnadotropin, particularly in children less than 10 years old.; O5 B/ y) D( ?! M: r' v5 a
The levels of serum testosterone remained similar or lower
: S: l/ c) F0 T7 c% U6 R/ _$ b( ~than with gonadotropin during therapy, suggesting that topi-
/ V% z" ^0 @* U& o9 Vcal application produces genital growth by its local effect as
( M, N) {* ~* c, ~well as its systemic effect.
# g2 ^& n- K D/ C3 d" LReview of our patients and their growth response related to, z. j' z: \7 F0 f) ~* X, @7 ^ W
age shows a greater growth response at an earlier age. This is( `# r3 R$ ^8 c# s2 ~ y
consistent with the findings of Wilson and Walker, who) w. U8 ^- u. h& D
reported an increased conversion of testosterone to dihydrotes-
2 m( d+ |2 s/ K9 k9 ktosterone in the foreskin of neonates and infants.4 This activ-' ^% O1 |% K. R
ity gradually decreases with age until puberty when it ap-
3 a5 A3 L2 \- Q5 S3 |0 mproaches the same level of activity as peripheral skin. It may% @; `- Y5 Z9 n1 C% W/ g" |0 J
well be that absorption of testosterone is less when applied at
4 b7 i! n, `& t' zan earlier age as suggested by lower serum levels in children# m6 c) L8 h( D* c4 a( l
less than 10 years old. This fact may be explained by the: K# i/ d! R- T: b& `8 g; D/ D
greater ability of phallic skin to convert testosterone to dihy-
6 [6 E9 L6 c2 J' w- K q2 l1 I# E9 Odrotestosterone at this age. Conversely, serum levels in older
2 G" q; Y* |0 d; V# F0 Xpatients were higher, possibly because of decreased local, x- ^- [, G/ |+ B* M( A$ v
667
" ~4 x' p% L$ c$ G" g668 KLUGO AND CERNY
3 F2 M; g( z6 j+ s4 ?Pt. Age) l0 N' v! l/ R$ g7 a1 g- w5 a
(yrs.)' t0 ~) N. ^ S; a3 |0 U5 c
Serum Testosterone Phallus (cm.) Change Length
! J l1 ^2 x8 i" p(ng./dl.) Girth x Length (%)! w" J: i. e" L0 i! E) h0 U
4
; p& a! a( K" j' {( ^) V8
}3 C, T' N& e, ]) Q( b10; A8 i0 X) }7 j- a4 L K
124 r s; R" ^" b) D
17
8 R* q7 u+ ~ D6 C# ~$ k) h! FGonadotropin% a: H9 K: M5 d$ B: \* C
71.6 2.0 X 3 16.6
- V u3 S+ `0 L6 {" B$ @50.4 4.0 X 5.0 20.0
! m+ G8 i. V% ]' U. ?22.0 4.5 X 4.0 25.0
0 O" U: {! ^2 G8 }9 k, i* m* v84.6 4.0 X 4.5 11.1/ `. j0 A3 g9 G0 q1 o
85.9 4.5 X 5.5 9.0) `5 I& b9 J( _; [) J" p/ v
Av. 14.3; j o; s1 N) g3 z' f# ]
4, o R3 H+ z: V4 a# M3 f
8$ T6 q% G( H9 S6 A! B& q8 g
10! |5 ?0 W7 q+ E+ T) ?$ z. D
12$ ~% M+ S: \' B! x0 c3 o
17
; k& t* P! s# U; ITopical testosterone
. z1 d( ^& v' T1 `34.6 4.5 X 6.5 85
3 ?- l7 d. X3 _% F38.8 6.0 X 8.5 70* j/ d0 F+ \4 ]: R5 L
40.0 6.0 X 6.5 62.5
' b4 v% m1 a8 q/ d0 O2 Z/ `93.6 6.0 X 7.0 55.5
- S) i% ~( c( [4 p7 h$ \95.0 6.5 X 7.0 27.2% S- a# W1 a: x' c- o
Av. 60.0
- k8 e$ ?2 ]( a8 Davailable testosterone. Again, emphasis should be placed on% P) E0 D0 J1 m2 b+ L4 _
early therapy when lower levels of testosterone appear to
. r$ `' V7 y9 } h/ M2 k Vprovide the best responses. The earlier therapy is instituted
9 ?2 I) s6 E# K0 d& c$ ~; Nthe more likely there will be an excellent response with low
# o1 z# w% M& K) J' o/ {) M: f. hserum levels. Response occurs throughout adolescence as
9 S( X' Q) ^6 `6 pnoted in nomograms of phallic growth. 7 The actual response* h: M5 v0 B; ]% T; N* i
to a given serum level of testosterone is much greater at birth3 u2 B- q( N4 e3 W, X
and gradually decreases as boys reach puberty. This is most- f& F3 ]6 I% S) \6 m& G& t
likely related to the conversion of testosterone to dihydrotes-
% j: ]/ T, ?/ V, v1 s$ |tosterone and correlates well with the studies of testosterone
2 h; P, B S6 Sconversion in foreskin at various ages.8 i. [8 ?: p: n+ ]9 @6 S, s
The question arises regarding early treatment as to whether
2 i3 a& X7 a1 M3 g- m9 i- oone might sacrifice ultimate potential growth as with acceler-6 ` D9 ]! i+ W/ x$ V
ated bone growth. The situation appears quite the reverse; Z& l2 P9 S w/ E5 y" r+ t
with phallic response. If the early growth period is not used
" B- U X6 M$ F+ w0 G* Y+ O; Vwhen 5a reductase activity is greatest then potential growth, x" U+ E2 n& j
may be lost. We have not observed any regression of growth
4 V* f. X- R! ?' T4 z/ |3 X9 k8 jattained with topical or gonadotropin therapy. It may well; e, i$ {. k8 C
be that some patients will show little or no response to any
+ J4 N) a) T# S) P2 s) N1 G8 gform of therapy. This would suggest a defect in the ability to3 W Z: f! I& i7 W# E- V0 A# d0 [/ I
convert testosterone to dihydrotestosterone and indicate that
$ Y) N3 ?) N9 }4 G R; p& h7 @' Zphallic and peripheral skin, and subcutaneous tissue should# Z3 Q8 y( \# l
be compared for 5a reductase activity.6 G" ?" L2 m8 Y+ q; k# C' V
A, loop enlarges to measure penile girth in millimeters. B,$ ^' Y6 L' g9 ~2 h1 X
example of penile girth computed easily and accurately.1 C ~) y4 ]9 x" n( N
conversion of testosterone to dihydrotestosterone. It is in this
# T# y( Y0 k# l: C0 z- ?older group that others have noted high levels of serum
0 h! C1 o, T# z$ c) Itestosterone with topical application. It would also appear4 @+ |& t o& J, n5 i+ g
that phallic response during puberty is related directly to the! W2 W$ h" F# |6 s$ M, u+ R9 U
serum testosterone level. There also is other evidence of local8 l* `8 U: @1 d0 S0 `; @0 d3 S1 ~- n
response to testosterone with hair growth and with spermato-
0 r8 d w- L6 Z( V( C6 m. C% z9 Agenesis. 5• 6
1 w' I8 s$ @6 @) f/ dAdministration of larger doses of gonadotropin or systemic
% C4 X7 x) T: atestosterone, as well as topical applications that produce4 m/ a. ~: F4 |5 D8 ^5 l
higher levels of serum testosterone (150 to 900 ng./dl.), will; n: X: [! g/ T. a1 ~8 e/ M6 y
also produce phallic growth but risks accelerated skeletal
- ?" F( X2 V( T) k$ Z5 U' bmaturation even after stopping treatment. It would appear
7 g+ l m/ @+ V9 } athat this may be avoided by topical applications of testosterone
2 [, _: k& X3 X e2 Kand monitoring of serum testosterone. Even with this control
s" D7 L7 K5 z o; d/ Rthe duration of our therapy did not exceed 3 weeks at any j) S' Q- c+ s X( w' r+ K
time. It is apparent that the prepuberal male subject may
! L7 ^9 P" M- Fsuffer accelerated bone growth with testosterone levels near
/ F0 G X& N2 z5 C200 ng./dl. When skeletal maturation is complete the level of
4 ~& s5 U+ d2 A! d" ^1 X- c7 z0 Z% Gserum testosterone can be maintained in the 700 to 1,300 ng./! z" F4 f9 r. `8 R
dl. range to stimulate phallic growth and secondary sexual
( ?. i$ p6 T8 M5 E4 u+ nchanges. Therefore, after skeletal maturation parenteral tes-
, {) u3 v5 `. J) L8 `% C; ltosterone may be used to advantage. Before skeletal matura-( Y. P$ N+ @' U0 B6 h, o
tion care must be taken to avoid maintaining levels of serum
+ z) }0 _$ C' B# {7 [testosterone more than 100 ng./dl. Low-dose gonadotropin
$ U4 Z9 e% O( ^$ u3 Cdepends upon intrinsic testicular activity and may require
8 Z9 N3 m: ]1 o/ ~2 F2 K/ Bprolonged administration for any response.1 M8 \7 V0 T/ P/ \1 y
Alternately, topical testosterone does not depend upon tes-6 n, E) K' Q! o& k; _8 z7 R
ticular function and may provide a more constant level of
- J0 U; y& j- {% z; _ oREFERENCES" G( Y [4 G- A! E$ Q$ s7 \
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% g3 b/ L' t9 b3 C: F
R.: The local application of testosterone cream to the prepub-
, |9 A$ }2 w4 K" } i" Certal phallus. J. Urol., 105: 905, 1971.) {$ Q$ \. o. X% `6 M) d: u* r
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- L/ r+ p( w {3 u- n
treatment for micropenis during early childhood. J. Pediat.,' m+ w6 {/ Q1 M5 ?$ V! m
83: 247, 1973.. ?: c& `# ?& L0 @! Q
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
! ~$ H& `4 }9 z- sone therapy for penile growth. Urology, 6: 708, 1975.6 c! Z: }. ?: t5 q
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
F- `5 F+ J/ k' g- u8 v$ wto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 U3 ?1 k( [7 g3 |. s; g) nskin slices of man. J. Clin. Invest., 48: 371, 1969.
8 @: S7 j5 G% r5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' B6 z+ X7 q, l% W% x! g( G6 ?" N
by topical application of androgens. J.A.M.A., 191: 521, 1965.; l& I% J6 R( g {" a3 t2 I- H4 ?) k
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 a' t' \: e9 k- N4 P7 ^androgenic effect of interstitial cell tumor of the testis. J.
) G4 m: i' _/ r; Q u% I7 o, [Urol., 104: 774, 1970." d3 ]' X, @, Q+ K1 d' W4 R6 b9 v
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; Z& T' Y5 U$ i: R$ V
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|