- 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* k; Y7 w, A h% U/ e
GONADOTROPIN5 ^( D/ W. |/ Y
RICHARD C. KLUGO* AND JOSEPH C. CERNY- f3 @' Z) u8 {, K3 l" i- j7 b& y
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, g5 R# |- S7 v8 ~( h% UABSTRACT
9 M6 r6 O3 q3 m! w. O) vFive patients were treated with gonadotropin and topical testosterone for micropenis associated) O7 H7 f5 H. @! a
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
z$ f: g6 s7 b; O: b. xtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 H8 e& M7 e7 ]8 j$ e. R8 _5 E8 U/ gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! F4 b2 A+ ]7 ], B
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ G: I" ^+ E* X9 s4 x* xincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average# j! W, ?! ?8 x. M" Q
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 K4 h2 w E* T5 K8 P2 F1 yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This* M& R# }8 |4 v6 X! B9 U6 K% Y
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! X1 R/ r5 R- \# m# w8 h
growth. The response appears to be greater in younger children, which is consistent with previ-
3 B) Z4 f/ s" Q+ q6 Aously published studies of age-related 5 reductase activity.3 Y6 ]8 F6 I6 Y7 h% W0 K
Children with microphallus regardless of its etiology will
/ d6 Q# ? M) c2 s5 lrequire augmentation or consideration for alteration of exter-
6 f7 A/ a1 U7 Y. T2 N W2 f7 {( w inal genitalia. In many instances urethroplasty for hypo-; r+ |. e5 n& r% o5 F
spadias is easier with previous stimulation of phallic growth.
7 K2 U& g7 o( I2 Q: r& S2 nThe use of testosterone administered parenterally or topically0 Q+ W) u, ?$ ~3 ?
has produced effective phallic growth. 1- 3 The mechanism of
1 Y* k( h6 n5 C- l5 w+ s8 uresponse has been considered as local or systemic. With this& u( v$ S! ^! c }7 T& ~5 r+ \
in mind we studied 5 children with microphallus for response
D+ N. U/ B7 s: nto gonadotropin and to topical testosterone independently.
, t. ~+ N1 o' T# `& d' U6 |; sMATERIALS AND METHODS' v, Z0 B) Z7 Y
Five 46 XY male subjects between 3 and 17 years old were5 r4 G1 z1 [3 B4 O+ f7 i
evaluated for serum testosterone levels and hypothalamic8 _* d# C- R( ]' `, z
function. Of these 5 boys 2 were considered to have Kallmann's
4 L9 p. ]1 P. [5 A6 msyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-* |' T. F0 |" {9 t
lamic deficiency. After evaluation of response to luteinizing
1 b6 J5 m, d8 z! ]0 N' q* shormone-releasing hormone these patients were treated with
; j. u6 P, D- C. V5 b8 b+ u3 H% D1,000 units of gonadotropin weekly for 3 weeks. Six weeks, x- F7 w6 y5 o/ w8 J# O
after completion of gonadotropin therapy 10 per cent topical
& N$ l- ~) }5 h: ^6 N8 }- ytestosterone was applied to the phallus twice daily for 3 weeks.
+ Z, M3 T5 Y/ e9 {5 b9 bSerum testosterone, luteinizing hormone and follicle-stimulat-9 b5 n, H/ k2 M: W; i+ @9 J
ing hormone were monitored before, during and after comple-; {8 c3 |6 z1 P# l* ]
tion of each phase of therapy. Penile stretch length was% ?& i ~$ r) Y- S
obtained by measuring from the symphysis pubis to the tip of
# d7 u4 x1 U% k) fthe glans. Penile circumferential (girth) measurements were2 n1 Y( w# H4 R" H* W6 c
obtained using an orthopedic digital measuring device (see' K' t ~4 K6 M' |: ~" D d5 S
figure).
+ F2 v! ^7 L* m7 f. `* T6 ?( P+ wRESULTS
; e9 _, ]5 E4 Z7 @Serum testosterone increased moderately to levels between
+ I3 T3 W) s$ _50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: a! R- Q5 \0 J* D
terone levels with topical testosterone remained near pre-. M/ V% g3 \4 \6 v0 ~
treatment levels (35 ng./dl.) or were elevated to similar levels
% G% b% X7 G8 I' ?/ Vdeveloped after gonadotropin therapy (96 ng./dl.). Higher* G5 b: d9 g) n" c# M( h
serum levels were noted in older patients (12 and 17 years old),0 z4 s! W0 r( Z0 {
while lower levels persisted in younger patients (4, 8, and 10; N( {7 `, M5 @" R' t
years old) (see table). Despite absence of profound alterations7 p, w1 u' ^/ n. C) [. `
of serum testosterone the topical therapy provided a greater
b: e, H- H$ T1 h! `1 V$ fAccepted for publication July 1, 1977. ·( n4 ^! I- s3 R4 O, w
Read at annual meeting of American Urological Association,
0 X$ c! ?$ I+ n" @5 EChicago, Illinois, April 24-28, 1977.4 e: ?) Q' @1 y
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 N# i+ |% c* y2799 W. Grand Blvd., Detroit, Michigan 48202.
. f3 y1 g: j( t' Q6 Dimprovement in phallic growth compared to gonadotropin.& r5 [; M% s, f
Average phallic growth with gonadotropin was 14.3 per cent' `# h. n: ~1 h/ r
increase in length and 5.0 per cent increase of girth. Topical
- n) e+ X/ m& p8 l e$ Ttestosterone produced a 60.0 per cent increase of phallic length% p7 h+ ~( p/ U; \7 b0 {: m
and 52.9 per cent increase of girth (circumference). The1 W! f# L/ f8 `* d2 h8 o7 n0 S( U
response to topical testosterone was greatest in children be-" a" y2 s0 Z- V
tween 4 and 8 years old, with a gradual decrease to age 17
B8 n1 ^0 l8 @, W$ r! t; R1 pyears (see table).
' b# D3 q H( H5 m9 UDISCUSSION+ l( T% G! c4 w+ ~7 U4 Q, m) h: @
Topical testosterone has been used effectively by other4 h# v. p: V& F
clinicians but its mode of action remains controversial. Im-, i6 H3 c1 `+ C9 }3 |! w& x
mergut and associates reported an excellent growth response+ E4 x. ^; ]5 \
to topical testosterone with low levels of serum testosterone,
& S0 g% @4 @4 }" |suggesting a local effect.1 Others have obtained growth re-
0 {; F1 g. l4 A' b3 @) Q. Esponse with high. levels of serum testosterone after topical& [; n! o, f, K
administration, suggesting a systemic response. 3 The use of
. {, t) c/ W$ H$ \6 s9 I4 bgonadotropin to obtain levels of serum testosterone compara-" e. S& o& h1 W* S$ `: }
ble to levels obtained with topical testosterone would seem to& z! M8 k, X9 f" X' n$ r, _$ g- z
provide a means to compare the relative effectiveness of
+ R+ t- S0 g% E: M$ O! b+ b' ]topical testosterone to systemic testosterone effect. It cer-
7 w! u+ ]6 f. l( h6 a6 V6 mtainly has been established that gonadotropin as well as par-: C" h4 f' t: R0 i$ X! [4 _0 g8 o
enteral testosterone administration will produce genital
: D2 Z* H. L/ g tgrowth. Our report shows that the growth of the phallus was1 l9 C( U! w I" l- l( |
significantly greater with topical applications than with go-
# B1 [+ P5 R7 B9 enadotropin, particularly in children less than 10 years old.1 l2 i. j) {1 I( _6 ^. v
The levels of serum testosterone remained similar or lower( `9 S4 h" u( M% I1 }7 p ]
than with gonadotropin during therapy, suggesting that topi-
: r7 P: a3 I2 T9 U! L8 ]. ^cal application produces genital growth by its local effect as+ W$ L1 R$ i j; X3 _
well as its systemic effect.
% a8 o9 [. Z3 C( n5 a' fReview of our patients and their growth response related to7 N/ N& \5 }6 o7 N( r: r S* K0 X
age shows a greater growth response at an earlier age. This is* e+ z) K1 g: _# T% I) S2 N/ e
consistent with the findings of Wilson and Walker, who
- H, T2 F4 b8 k1 \- X$ Nreported an increased conversion of testosterone to dihydrotes-' f! L; F0 d0 K5 ~8 E) n- g
tosterone in the foreskin of neonates and infants.4 This activ-) ~/ {5 t8 ]% K0 `2 q7 c/ \, j
ity gradually decreases with age until puberty when it ap-
{5 {7 Z r( Q( ~9 sproaches the same level of activity as peripheral skin. It may
% P1 \3 K: j& o. Ewell be that absorption of testosterone is less when applied at$ |+ |2 ~7 \+ l% Z
an earlier age as suggested by lower serum levels in children$ V$ u' T [% L) |* o2 ?8 h- D! P" v
less than 10 years old. This fact may be explained by the8 M9 T- Y0 L1 s3 v: o( R$ K* T. E* V
greater ability of phallic skin to convert testosterone to dihy-1 k z2 g0 |$ G: I1 _ R
drotestosterone at this age. Conversely, serum levels in older
& u0 ?/ O7 ]; E7 gpatients were higher, possibly because of decreased local. T( T% F2 F$ a% s
667: W/ _& i+ e4 f }
668 KLUGO AND CERNY
* @' X) \- _7 VPt. Age
3 T# c3 z q9 }7 k# b2 d; H `(yrs.)
, G. O" e" C8 @ QSerum Testosterone Phallus (cm.) Change Length
$ B4 W& {+ ?' W8 a(ng./dl.) Girth x Length (%)& b' n" {* K9 k8 l; o- f
4
& `% N$ J$ R; W- y% t: v m8
% M1 [6 b! m: @% j2 A; C2 N10& h- z/ d- w4 A" C* E( Y
12% s" Y' I; @* }8 Y& _
17- B, r: k, C5 n' o6 G
Gonadotropin0 g- a, e3 z9 D. y2 O
71.6 2.0 X 3 16.6
$ D+ ?3 m- k6 L1 e1 L- y% q8 ~5 S50.4 4.0 X 5.0 20.0
( t# x0 j/ c; D9 b/ o3 Y( c22.0 4.5 X 4.0 25.0
4 k- d8 O% u8 o, L" e4 c8 I$ Q0 _84.6 4.0 X 4.5 11.1
/ {6 u4 d- j6 M85.9 4.5 X 5.5 9.0$ V# p6 m. n; }+ I- ~) O
Av. 14.3. u0 g' v1 d3 h" T& H1 J0 {
43 h1 o1 D" S5 h5 ?( X" ]
8
1 \* {4 H% `6 w6 a$ r8 O/ n0 I) @' K6 T: g10
0 @6 ^! `& g' D2 w$ v4 ?8 c12& m0 }" a/ g K$ ~2 f$ w5 n/ y" s6 a
17' B# y% d' e3 g7 P9 s1 W# G
Topical testosterone
. s0 p/ P3 D1 b34.6 4.5 X 6.5 85. h" E+ Q5 j# n0 G. {
38.8 6.0 X 8.5 70# d8 b4 \: N! S
40.0 6.0 X 6.5 62.5
+ ?% p& I) O2 |' G0 V0 A# Q; U8 G93.6 6.0 X 7.0 55.5
7 D& U6 Y6 c7 R& [: U95.0 6.5 X 7.0 27.2
. F. C; q0 z+ S* A: r- C3 rAv. 60.00 e$ ?: v5 @0 G* R5 d4 U* L. z
available testosterone. Again, emphasis should be placed on y! \' l; \' q! ~8 X. U a" p5 s4 i
early therapy when lower levels of testosterone appear to+ K& K0 e' F/ X% S3 v2 _ |
provide the best responses. The earlier therapy is instituted
" s& i5 u4 G4 p* gthe more likely there will be an excellent response with low4 _1 S4 S/ n# r
serum levels. Response occurs throughout adolescence as% U( H; k9 a2 g2 b. I
noted in nomograms of phallic growth. 7 The actual response8 O; u% I0 Z: j$ X- y* u
to a given serum level of testosterone is much greater at birth6 B2 p6 u( B6 N
and gradually decreases as boys reach puberty. This is most( L: s5 ^/ D( {1 m8 u
likely related to the conversion of testosterone to dihydrotes-
% F" h% H+ G* \& w$ k9 j% K" k5 s$ @tosterone and correlates well with the studies of testosterone! k5 ]' G7 b- J5 E1 D v
conversion in foreskin at various ages.$ n6 D1 i% q% e O% {) g* f
The question arises regarding early treatment as to whether7 ], e% K+ x9 Z5 w5 f9 G7 h
one might sacrifice ultimate potential growth as with acceler-
, i: V N7 J' `. k- oated bone growth. The situation appears quite the reverse
$ u$ d* Y4 I" ]4 S0 h: x* awith phallic response. If the early growth period is not used
- R ~. ]3 }9 Iwhen 5a reductase activity is greatest then potential growth ?& n2 \* Y. U9 c4 a' t
may be lost. We have not observed any regression of growth; }0 a% X; W* i" e/ c$ d* I
attained with topical or gonadotropin therapy. It may well
$ U; n9 l H* Q1 i, \7 k6 i5 M/ tbe that some patients will show little or no response to any
1 Q* s0 w3 x- \$ K& ?+ ? u- }form of therapy. This would suggest a defect in the ability to7 _4 w# I( X$ a
convert testosterone to dihydrotestosterone and indicate that6 F; |) D1 |7 v; E! K
phallic and peripheral skin, and subcutaneous tissue should9 n) p/ R5 l7 C
be compared for 5a reductase activity.
2 X0 h/ k, u7 P: {2 Q: yA, loop enlarges to measure penile girth in millimeters. B,# v$ u8 Q1 {( q/ l
example of penile girth computed easily and accurately.1 |* j; f6 s3 \$ L# D) p
conversion of testosterone to dihydrotestosterone. It is in this
* |8 B: R' Q" a) s. ~older group that others have noted high levels of serum
# ^# V+ n8 ^* ^. F7 Wtestosterone with topical application. It would also appear
& H0 V1 d2 v# Q& @3 U+ Gthat phallic response during puberty is related directly to the
7 c4 |) y" @2 R2 nserum testosterone level. There also is other evidence of local
5 w K5 _7 d: _0 i+ r) [response to testosterone with hair growth and with spermato-
$ E7 [1 g [1 C$ m7 K$ s9 F! F0 `genesis. 5• 67 V- n6 D: c. ]$ ] K; n5 B
Administration of larger doses of gonadotropin or systemic' Y6 [) V% c. ]' a5 \1 ^% A
testosterone, as well as topical applications that produce
7 T _- X% ?5 I" g5 uhigher levels of serum testosterone (150 to 900 ng./dl.), will
; X7 R' k0 J& _3 W7 B j) Yalso produce phallic growth but risks accelerated skeletal
; X& ?7 k" Z; x8 H$ E7 s& Imaturation even after stopping treatment. It would appear$ Q( E4 u) p9 S
that this may be avoided by topical applications of testosterone
3 {- {+ p7 e' Z% J& Y6 T1 Q) R$ }and monitoring of serum testosterone. Even with this control
: }3 X. ]0 e6 y% z& M1 Z; _9 } ]the duration of our therapy did not exceed 3 weeks at any, h$ H4 `& K" R9 R* ~+ Z* v; Q, |
time. It is apparent that the prepuberal male subject may0 V! X0 R5 `( Y: |' F
suffer accelerated bone growth with testosterone levels near
) b4 C( n# z4 w0 f200 ng./dl. When skeletal maturation is complete the level of8 |4 E3 @- x! S3 A5 |& ~
serum testosterone can be maintained in the 700 to 1,300 ng./9 a7 y) |, L0 {) Y
dl. range to stimulate phallic growth and secondary sexual7 W: I6 B: Q/ m1 ] p
changes. Therefore, after skeletal maturation parenteral tes- h" E( S7 ]1 b- T l y
tosterone may be used to advantage. Before skeletal matura-
6 c o# x+ V+ X3 o6 ttion care must be taken to avoid maintaining levels of serum
3 Q- d( c' F/ H, Z2 itestosterone more than 100 ng./dl. Low-dose gonadotropin. G7 m1 w8 K; A1 I5 D
depends upon intrinsic testicular activity and may require
6 Z8 Q9 o A! Y9 a5 D# _% q; Dprolonged administration for any response.: h* {/ i+ [" _6 k7 t! l
Alternately, topical testosterone does not depend upon tes-
( Y2 Z: g1 j3 ]6 R- B" \ticular function and may provide a more constant level of# Z1 {: {1 R0 Y8 l3 ?' A
REFERENCES
# K9 Q0 m) H b1 m1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- T Y) W7 U# }- a. ~
R.: The local application of testosterone cream to the prepub-
5 x8 m9 N. f2 f% Mertal phallus. J. Urol., 105: 905, 1971.& M! z7 E$ [- p% P
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone9 B$ }1 V2 E5 E, r; I
treatment for micropenis during early childhood. J. Pediat.,- z" d: Z6 f9 P0 c/ r% m1 y
83: 247, 1973.
9 C$ W' n ?3 S* Z. v& s3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ `% Z! u- n; _; g; kone therapy for penile growth. Urology, 6: 708, 1975.
1 l" z) ^* l0 \ c& ?4 z$ g0 B# ?4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 P8 @1 Z- I* q( g& y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
) j. b) T2 {+ Q# Z; M5 Cskin slices of man. J. Clin. Invest., 48: 371, 1969.
8 Y7 I" F9 D' y Y5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
7 o! u2 v! C' {: K4 k; aby topical application of androgens. J.A.M.A., 191: 521, 1965.
: x W2 S1 V8 t$ S3 |# m0 {6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: @" |: a% \" t
androgenic effect of interstitial cell tumor of the testis. J.3 y: n( h' J! r1 g9 P& R
Urol., 104: 774, 1970.
0 [( c* j0 w" }3 A7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia- I& G4 N8 n) Q) E# y3 f0 G
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|