- 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
- s& @' Q; [7 CGONADOTROPIN
$ O+ r& V1 r) _1 I& B' p5 jRICHARD C. KLUGO* AND JOSEPH C. CERNY1 x: {1 c7 o! M# |7 ], g/ B5 N' J
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan; y# Y; b5 T1 W1 \5 x
ABSTRACT
. R/ {: Q, l/ \' Q; M4 e2 JFive patients were treated with gonadotropin and topical testosterone for micropenis associated" J% x% x8 j) Y9 U4 Q2 b M" E8 r
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; i0 }# l, Z* ]* Wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ E! t" v; R+ Z2 Z( i' N7 M! H+ Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent- J1 i# \3 v/ W/ _/ r5 h
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) v5 F5 \2 {6 m0 X6 D5 l
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average, ?9 z' U! P$ V0 a T, r
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response& j4 B; e5 Q( c9 t+ N, ?0 P8 p. X
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
/ K5 V6 p: I$ g8 G2 A/ X$ Q, tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
3 \& `; _3 U y, U# }% dgrowth. The response appears to be greater in younger children, which is consistent with previ-8 g1 T/ {$ k: I2 _$ G
ously published studies of age-related 5 reductase activity.: \7 R* D1 D3 F4 C$ L
Children with microphallus regardless of its etiology will
8 h6 ~8 l" Z" X8 p2 ?4 I. q1 ~7 ~require augmentation or consideration for alteration of exter-
* V5 i0 q- \* z' z0 D% Rnal genitalia. In many instances urethroplasty for hypo-
6 o: `( } k) [8 xspadias is easier with previous stimulation of phallic growth.
) p! X3 Z$ w7 @ [/ r+ z3 V* w) n( ]7 xThe use of testosterone administered parenterally or topically
; `! @) V3 o& p: E% R; }2 E- z ihas produced effective phallic growth. 1- 3 The mechanism of& `% W! I/ M3 G/ X r
response has been considered as local or systemic. With this! \# ^9 G: n" Q3 v4 ~
in mind we studied 5 children with microphallus for response- f! T) Z- e* F7 V
to gonadotropin and to topical testosterone independently.
1 R6 e# F' `$ @, s9 GMATERIALS AND METHODS# b" }% D; v: E( w) x4 E" @3 t
Five 46 XY male subjects between 3 and 17 years old were
: b- V& f, C, Y- R8 vevaluated for serum testosterone levels and hypothalamic! C+ {$ A7 Q3 w
function. Of these 5 boys 2 were considered to have Kallmann's5 a! O, \3 q* Q
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
$ W0 |. b- J, alamic deficiency. After evaluation of response to luteinizing
+ D% m c, w. dhormone-releasing hormone these patients were treated with% l( d: C, O8 t' t% |
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
' e: C$ B* }- N6 J- m+ |% F. w/ yafter completion of gonadotropin therapy 10 per cent topical7 N& L a! L6 q' ?9 z6 K. e+ p2 G- J
testosterone was applied to the phallus twice daily for 3 weeks.
6 v) n/ N4 A* m, B7 |Serum testosterone, luteinizing hormone and follicle-stimulat-( W# ]9 c+ a: p9 e- e" e
ing hormone were monitored before, during and after comple-$ T8 o5 s5 [# [. a6 n! F
tion of each phase of therapy. Penile stretch length was+ x& \ i3 T2 O3 r. J% {# ]
obtained by measuring from the symphysis pubis to the tip of8 R& n4 l5 H+ R
the glans. Penile circumferential (girth) measurements were
! B" @4 S4 P! s) k( S9 v& Kobtained using an orthopedic digital measuring device (see
- X1 Z# r# Y5 G% r" e4 i3 ]figure).
; L* N7 R& v! j9 SRESULTS2 q8 E* C3 n2 d1 C1 H: Q) V
Serum testosterone increased moderately to levels between: }8 A; i$ c% ?. B" _' V5 f
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! ~9 a$ ~2 y k5 |6 [8 c z# k
terone levels with topical testosterone remained near pre-
; I' _% Z g; w8 {( ~% f8 I5 Etreatment levels (35 ng./dl.) or were elevated to similar levels
]2 S3 d& T* Q d5 `5 e4 \developed after gonadotropin therapy (96 ng./dl.). Higher3 e8 S9 X% a; {; @& j
serum levels were noted in older patients (12 and 17 years old),7 I! C% o, e2 t. N' ^
while lower levels persisted in younger patients (4, 8, and 10
* p! ~: W! h; w% ^years old) (see table). Despite absence of profound alterations
; K8 S& T# A7 gof serum testosterone the topical therapy provided a greater5 M i, A5 N& s4 D1 m8 P
Accepted for publication July 1, 1977. ·- S! _- G+ X9 y
Read at annual meeting of American Urological Association,
- U" w. O% q: l9 \2 U" KChicago, Illinois, April 24-28, 1977.* _4 g2 \+ O5 B- o/ e
* Requests for reprints: Division of Urology, Henry Ford Hospital,
: b0 `% e/ {) s* T5 x2799 W. Grand Blvd., Detroit, Michigan 48202.
$ P% x' T6 e f+ V. L& u% ?! pimprovement in phallic growth compared to gonadotropin.7 V4 \8 R3 M1 ?
Average phallic growth with gonadotropin was 14.3 per cent+ G( `4 D# l1 c& b; i' s5 j
increase in length and 5.0 per cent increase of girth. Topical
1 x P3 P0 v) e, Q" K* Xtestosterone produced a 60.0 per cent increase of phallic length
! A# p# {- B$ W7 gand 52.9 per cent increase of girth (circumference). The) P0 ?) j6 x ~; \) f
response to topical testosterone was greatest in children be-
0 c1 d/ O* W5 S* `" G7 ?; Ntween 4 and 8 years old, with a gradual decrease to age 17% Y: A, b- o6 ?9 t7 z& t
years (see table).
( R g) y: ?3 X" r2 r- Q. |DISCUSSION& T- m3 J7 R8 j& z. H6 \% ^
Topical testosterone has been used effectively by other& U1 k4 s2 b( p5 A$ y
clinicians but its mode of action remains controversial. Im-
1 X7 c3 W! S) H0 U; |mergut and associates reported an excellent growth response
9 H6 j5 c e" h. lto topical testosterone with low levels of serum testosterone,
- H* ]9 y9 B5 K2 a& g; W2 _, Msuggesting a local effect.1 Others have obtained growth re-
! q& E5 f# c R/ p4 q1 R& J5 Asponse with high. levels of serum testosterone after topical! v5 q E& ~6 Z3 `" X' ]: w
administration, suggesting a systemic response. 3 The use of$ J- ~3 u$ \* r# g) \" s
gonadotropin to obtain levels of serum testosterone compara-
2 I/ `- p) q# U" h( Dble to levels obtained with topical testosterone would seem to; P8 g% }/ F% L2 q) x6 w
provide a means to compare the relative effectiveness of2 v8 p! R$ J9 \8 e
topical testosterone to systemic testosterone effect. It cer-
* O9 l. U! O! g) M utainly has been established that gonadotropin as well as par-0 u: o8 B( T! j, k, k5 ?( d
enteral testosterone administration will produce genital
) Z+ X6 u1 [0 O4 `growth. Our report shows that the growth of the phallus was) h" z% u1 Q$ Z; }% c+ A& d1 V
significantly greater with topical applications than with go-& K$ [) L$ X2 s! ^" \
nadotropin, particularly in children less than 10 years old. c2 L+ P2 o( V/ C" \ h% \
The levels of serum testosterone remained similar or lower
+ F" c0 H$ j# N& [/ }& Gthan with gonadotropin during therapy, suggesting that topi-
" n8 r: A. G# e9 m2 vcal application produces genital growth by its local effect as( ~) ~8 z+ m# ~7 |; j. g: \1 e
well as its systemic effect.6 q" V, t5 G E3 r' v7 M4 T6 F2 E
Review of our patients and their growth response related to
3 n& x: g7 T- c/ t: e2 @" kage shows a greater growth response at an earlier age. This is' c! @0 r! Y, S& O+ U; Y' i, P
consistent with the findings of Wilson and Walker, who
5 ~& O) Z) M: ~5 E3 }reported an increased conversion of testosterone to dihydrotes-# Y' P8 a& _0 K4 F1 O0 j6 P
tosterone in the foreskin of neonates and infants.4 This activ-% a2 M- P7 |' ?! l
ity gradually decreases with age until puberty when it ap-, G# P& g, p+ l D. v: }" R
proaches the same level of activity as peripheral skin. It may
1 ~) S/ {" W/ f8 e/ E0 vwell be that absorption of testosterone is less when applied at
0 l+ z# T+ D) ^an earlier age as suggested by lower serum levels in children+ N# R5 G: n! @4 B7 a
less than 10 years old. This fact may be explained by the
+ e' h, f% H5 y# Vgreater ability of phallic skin to convert testosterone to dihy-
% s2 W/ r- p8 b6 A4 fdrotestosterone at this age. Conversely, serum levels in older
* p3 I! t9 |0 Hpatients were higher, possibly because of decreased local
* F; }7 g3 d0 B- s6 u/ Z667 M& k4 A/ {) \( U' O
668 KLUGO AND CERNY! j$ A& K1 ^" z! f8 [3 ~ \
Pt. Age- v( @9 n& s( ~ C4 ~) g5 J$ h. C
(yrs.)
* H' r. q) v5 T+ U4 ?Serum Testosterone Phallus (cm.) Change Length
8 z8 ?" D' U; s: b3 d4 Q(ng./dl.) Girth x Length (%)
2 ^, [( k0 \( n2 l4. H5 s% }" X4 c& H$ o4 N% {
8
$ A6 }/ @9 ]: o10
( O3 v$ o {2 i% Y) g125 H% S/ b* E- A
17" F) K1 _8 B) N' u" p
Gonadotropin* b% [' `9 I. ?& \
71.6 2.0 X 3 16.69 r0 ?' G5 u S5 N. K$ [# p
50.4 4.0 X 5.0 20.0$ F2 J2 W+ p* f5 F
22.0 4.5 X 4.0 25.0: h4 e1 V& H$ E+ M! }+ ^4 Z8 u
84.6 4.0 X 4.5 11.1
, u" Z* x" M# w85.9 4.5 X 5.5 9.00 w" J# i% f. k1 K1 v4 G7 r7 ~& h
Av. 14.36 D: e! h: h% T k& q; Z
4
# Y) k: J6 b$ s8
/ e( T/ y0 n# I" J8 V7 F, J2 m' W6 l6 Y10
3 m' T9 C# }9 ]2 }7 K12) x, L; A5 j' b1 y: N
17/ E% @* N+ A" ~' R
Topical testosterone7 ~# E$ S( z R) r6 v5 r1 z
34.6 4.5 X 6.5 85& a, f/ ?5 Q2 I/ G0 F) y; d
38.8 6.0 X 8.5 703 h* i# M: O8 C: a5 R7 k
40.0 6.0 X 6.5 62.5& Y' `2 e4 }' Z" l8 y
93.6 6.0 X 7.0 55.5
# S$ C- E, H4 K8 o; I4 [0 V$ g95.0 6.5 X 7.0 27.2
, a- F2 r0 B/ p& y6 F6 EAv. 60.0
/ h) Q8 C9 }& Y# M' b3 ~, v \# @8 Z; f) a. Uavailable testosterone. Again, emphasis should be placed on& o7 F- a) r6 v( o) R& S
early therapy when lower levels of testosterone appear to( j; d4 w6 @0 v1 T# n6 I9 ]8 _6 Z7 ~. G5 C
provide the best responses. The earlier therapy is instituted2 p; A% O3 X( L; a" q
the more likely there will be an excellent response with low$ L+ Z/ O. {5 {7 s L. D
serum levels. Response occurs throughout adolescence as
, D( t2 X7 [2 C$ z. L5 Tnoted in nomograms of phallic growth. 7 The actual response
! K. y' e8 k6 ]& _7 F) T hto a given serum level of testosterone is much greater at birth
/ i, u+ M7 k! Vand gradually decreases as boys reach puberty. This is most7 b( M4 e4 P( W* u7 c5 r
likely related to the conversion of testosterone to dihydrotes-
, h6 q9 U6 g+ q. [tosterone and correlates well with the studies of testosterone" E9 `- X: ?$ Q3 B* b
conversion in foreskin at various ages.* P7 Q- s' B2 i
The question arises regarding early treatment as to whether
( _3 p: K6 ]' G- Xone might sacrifice ultimate potential growth as with acceler-
2 ~0 t' J- z8 `- G) N/ r2 fated bone growth. The situation appears quite the reverse) T+ P+ S8 i, N9 k& @6 q
with phallic response. If the early growth period is not used# j6 h& C, N8 l5 T
when 5a reductase activity is greatest then potential growth8 f8 ]4 s: w4 c5 E+ P
may be lost. We have not observed any regression of growth
3 |9 m) ~* d( p2 Y* Vattained with topical or gonadotropin therapy. It may well
: {4 R. W3 u& F% w8 `! b5 T% Ibe that some patients will show little or no response to any5 o+ F f7 V q6 L7 F/ g: T
form of therapy. This would suggest a defect in the ability to
0 w; F! _! I7 D. V, [2 X. uconvert testosterone to dihydrotestosterone and indicate that
$ u- b+ t: ]- }0 }phallic and peripheral skin, and subcutaneous tissue should
7 v3 i- ]$ h! h; Gbe compared for 5a reductase activity.% O- w& B5 o, p+ Q
A, loop enlarges to measure penile girth in millimeters. B,) K* G% b( |8 v0 f: y7 r9 w0 z
example of penile girth computed easily and accurately.: j4 B8 K0 z- N/ `2 }8 C5 n. l# f
conversion of testosterone to dihydrotestosterone. It is in this
- S/ J$ K) I0 I! ~9 Z& Lolder group that others have noted high levels of serum
. s( m8 V. F. {& z; N' stestosterone with topical application. It would also appear; t' z3 T1 \( X
that phallic response during puberty is related directly to the
6 x. G J" s3 u5 R* xserum testosterone level. There also is other evidence of local
2 h/ z, t I% O2 Bresponse to testosterone with hair growth and with spermato-6 N0 p2 c$ V0 c6 O6 L+ x
genesis. 5• 6- _" e" r! X5 y5 a/ q# X5 F2 O. [
Administration of larger doses of gonadotropin or systemic& I# c5 q, W2 I. g( E# Z: \
testosterone, as well as topical applications that produce
7 g: ~# m8 z0 Y' C/ a& X( Jhigher levels of serum testosterone (150 to 900 ng./dl.), will/ H4 X' R: N4 v" E: p. Z
also produce phallic growth but risks accelerated skeletal7 d4 W' z7 ]5 K2 c3 |( ?# P
maturation even after stopping treatment. It would appear( R0 [ o& i- \' ~3 c
that this may be avoided by topical applications of testosterone
% B! C( S) P, p' Q2 Q! @* [and monitoring of serum testosterone. Even with this control
; Y3 Z! C _ g9 z2 {the duration of our therapy did not exceed 3 weeks at any
1 k+ Y0 L8 y+ ]2 T4 q' H. \1 S+ }time. It is apparent that the prepuberal male subject may
% a( e/ r3 U! @1 ^& T% @7 Z& msuffer accelerated bone growth with testosterone levels near; U" q3 c3 F% K% z" X2 f
200 ng./dl. When skeletal maturation is complete the level of) J" b) R- |8 i: _1 ?+ ]1 z# e3 J
serum testosterone can be maintained in the 700 to 1,300 ng./
, }, ^$ r: g- b5 F- jdl. range to stimulate phallic growth and secondary sexual5 i' J3 H" O9 t0 H5 @- A
changes. Therefore, after skeletal maturation parenteral tes-$ j$ q9 ~0 ^9 x5 G; o1 I2 Y7 a6 Y
tosterone may be used to advantage. Before skeletal matura-3 C2 u% R( q' Y
tion care must be taken to avoid maintaining levels of serum# Z s: W7 S, ]% S
testosterone more than 100 ng./dl. Low-dose gonadotropin5 @- c i: k, s+ q% u+ i
depends upon intrinsic testicular activity and may require
+ l, j9 `9 T g, d2 `prolonged administration for any response.- g' `7 H' J o4 K N8 ~5 V8 E
Alternately, topical testosterone does not depend upon tes-/ ]8 K: z% R& Q7 L9 `# K9 d T% S
ticular function and may provide a more constant level of- Q) O e4 B8 p2 m! T1 i3 O1 D I H* @
REFERENCES- L ]8 j1 x" y# }/ B- R
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# f8 Q" ], k" N
R.: The local application of testosterone cream to the prepub-
% \, x* X* b4 Certal phallus. J. Urol., 105: 905, 1971.
; @$ V# o2 _ N6 V# n( s9 L2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone0 l$ H) f8 G, h9 b, t! O2 `1 m
treatment for micropenis during early childhood. J. Pediat.,
; F5 {6 b M$ S9 N' P8 \83: 247, 1973.! o8 `. h7 W9 z! f: `
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-! \, W e& _. r2 t4 E( E" W
one therapy for penile growth. Urology, 6: 708, 1975.$ T8 P; p- f: M2 \4 D! K7 w. G) ?
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 I z7 ^: X# [6 m" ]8 `, p" P. a# P5 u
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ X7 ^% F( b3 @5 `$ I- N' v9 [
skin slices of man. J. Clin. Invest., 48: 371, 1969.0 r u" |1 b( a7 L8 u
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: }' S8 x' Y( x9 ~( e6 {1 {
by topical application of androgens. J.A.M.A., 191: 521, 1965.8 n- T% m- P- C* K
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ N7 k: h( G# O, bandrogenic effect of interstitial cell tumor of the testis. J.
: ~4 Q4 g' C( U& |/ F' L% ?& S- N! aUrol., 104: 774, 1970.2 y; V% _% m; l, S* V0 k1 W# w
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& h" a) U3 X6 ttion in the male genitalia from birth to maturity. J. Urol., 48: |
|