- 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) h! @/ ]/ l) X& l$ `) q, M
GONADOTROPIN
. h' B* \2 k- }- a/ X0 ^ Y% p; gRICHARD C. KLUGO* AND JOSEPH C. CERNY
: p* {2 [8 P# T( b1 {+ bFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan ]0 f0 P+ R) w( T) |, Z1 v
ABSTRACT2 P4 a1 f, e) D6 \' K( t. w
Five patients were treated with gonadotropin and topical testosterone for micropenis associated: l" I" r& x% A: S
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* {& q7 n, |' v( ^/ v5 z8 itropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# R$ O8 k( ~+ Hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! `* g; q5 f3 T( |6 L$ [2 V1 hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
& V9 _" |2 E& f0 U; K5 P# b9 @increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average' X. B: A* q* ^, g$ @2 H2 N: A8 V2 U5 O
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response( }9 G7 |+ g- Z: q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This% Y5 | X! n# g! H' v, C. t, z3 C
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
: P7 E' w" T# T4 x bgrowth. The response appears to be greater in younger children, which is consistent with previ-; P# G, V! z) O' m- O% M
ously published studies of age-related 5 reductase activity.
' k+ o$ N9 `1 |+ I7 U: p% e, cChildren with microphallus regardless of its etiology will
$ G: O/ r7 K) D1 D. \require augmentation or consideration for alteration of exter-
! I( p6 g& j. v7 ?' Vnal genitalia. In many instances urethroplasty for hypo-
9 h/ R5 W9 \7 P$ k0 b6 t, Q" M+ vspadias is easier with previous stimulation of phallic growth.
7 Z; z8 z8 [# \9 q9 L, mThe use of testosterone administered parenterally or topically
* ~. l) M' T' z% Q$ H+ b: `, P* ghas produced effective phallic growth. 1- 3 The mechanism of4 o/ x2 z5 C6 W) [& p% X3 W: [
response has been considered as local or systemic. With this) V7 N H' a% J# @# {
in mind we studied 5 children with microphallus for response
( j+ `! ^; E2 ?- F" g$ M2 K9 P4 Nto gonadotropin and to topical testosterone independently.
- n4 p( ?$ y. R; B8 d7 a# ?MATERIALS AND METHODS5 l6 V2 |! q1 Q5 `! W" }2 w6 a' \; ^
Five 46 XY male subjects between 3 and 17 years old were- y1 d# h3 w/ _ L, W: b
evaluated for serum testosterone levels and hypothalamic
0 b2 G3 t4 M5 R1 v* l% Q5 zfunction. Of these 5 boys 2 were considered to have Kallmann's/ S7 o7 ^) e, t2 j5 e: m9 A
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 ^) _! Y4 C8 }
lamic deficiency. After evaluation of response to luteinizing
+ S4 @7 r/ a# [6 R3 }hormone-releasing hormone these patients were treated with
- V5 F) s- J' Q. R1,000 units of gonadotropin weekly for 3 weeks. Six weeks, m* }: B( O% d5 S; V
after completion of gonadotropin therapy 10 per cent topical. F; A6 R6 j! x
testosterone was applied to the phallus twice daily for 3 weeks.; f+ H2 V1 Y2 f& n$ ]
Serum testosterone, luteinizing hormone and follicle-stimulat-; G) c m& E7 H. E" ]* `7 A* g
ing hormone were monitored before, during and after comple-0 ^- [& J; F) B
tion of each phase of therapy. Penile stretch length was4 S8 @ R6 C7 i6 l, k6 {+ J, u
obtained by measuring from the symphysis pubis to the tip of
2 ]6 I! y( |. G7 O$ Wthe glans. Penile circumferential (girth) measurements were
& A" ?; w8 p7 g& p% ~' i( c |obtained using an orthopedic digital measuring device (see
! L' g$ |5 m- ?figure).9 T' D7 u0 S( w5 w4 M; d
RESULTS3 j$ @# g8 s$ o* V( ?) O/ f6 Z1 l9 g& z
Serum testosterone increased moderately to levels between
4 N0 d/ ]4 P. Y* ]9 v; U" N50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 n5 C; ?) A2 d' Q9 Hterone levels with topical testosterone remained near pre-3 E3 a' j% U! Z* G4 D8 ]' Z% C4 n3 h
treatment levels (35 ng./dl.) or were elevated to similar levels- |4 W* E8 ~ |, \7 ]5 ~7 j
developed after gonadotropin therapy (96 ng./dl.). Higher
& F! H4 V# G' Q% M) i! L1 t- Rserum levels were noted in older patients (12 and 17 years old),+ @2 Y0 |7 w. L: v) e3 A
while lower levels persisted in younger patients (4, 8, and 10
0 U) s& {3 m: K" n0 I: Uyears old) (see table). Despite absence of profound alterations
# Q: y- J4 E8 `7 }. b h( cof serum testosterone the topical therapy provided a greater
0 |+ g* N% b& m2 J- UAccepted for publication July 1, 1977. ·- F r. L& |, a x( U# t. _6 L
Read at annual meeting of American Urological Association,; v; K: g, b/ U5 J) `
Chicago, Illinois, April 24-28, 1977.1 i9 N5 A- c) Y" s5 X% U$ g
* Requests for reprints: Division of Urology, Henry Ford Hospital,
. W7 l) t; s7 q" G' c: Q2799 W. Grand Blvd., Detroit, Michigan 48202.
9 B; c( I9 u1 A: k7 p+ v) Nimprovement in phallic growth compared to gonadotropin.
: B, ?$ z' M0 m$ pAverage phallic growth with gonadotropin was 14.3 per cent
5 L, d7 D. x r3 \# U4 Sincrease in length and 5.0 per cent increase of girth. Topical
) L5 W$ {# V9 t" j) Z$ z: {2 Z% ctestosterone produced a 60.0 per cent increase of phallic length
$ x0 ^6 H m8 Wand 52.9 per cent increase of girth (circumference). The3 G; N; [# s" y1 o( d# g g
response to topical testosterone was greatest in children be-
9 [& P- Z! l/ Z. S. V1 ktween 4 and 8 years old, with a gradual decrease to age 17
' l4 W( x1 k' a( Myears (see table).
3 s3 N E# a! `: M/ rDISCUSSION, H7 ?3 r' h; \0 R5 c2 w
Topical testosterone has been used effectively by other5 ~. l1 @8 N& m
clinicians but its mode of action remains controversial. Im-! v, N0 t* |* ?. {3 P2 ~
mergut and associates reported an excellent growth response
q! y; y8 M" D6 F! v$ O+ _3 g# \to topical testosterone with low levels of serum testosterone,
2 X0 \; \; P, h5 \1 b7 l hsuggesting a local effect.1 Others have obtained growth re-
8 U" p" Y3 x8 K0 Q/ I8 _/ r- Fsponse with high. levels of serum testosterone after topical# ?' w; ]4 e% z; V1 N2 `
administration, suggesting a systemic response. 3 The use of
`3 \ h, I$ m2 m$ R+ Egonadotropin to obtain levels of serum testosterone compara-6 ?: H1 m4 G7 c4 |: Q4 g
ble to levels obtained with topical testosterone would seem to
4 ~9 h( H+ [- E( u8 o) `4 kprovide a means to compare the relative effectiveness of0 b# T+ }0 y0 i9 ?# B+ {0 m, h/ h
topical testosterone to systemic testosterone effect. It cer-
$ @; D- s, {9 y `& C# S2 p% ztainly has been established that gonadotropin as well as par-) c. @ z+ A2 H1 Q" x) E' W
enteral testosterone administration will produce genital
4 K8 p2 j2 X' D" U: qgrowth. Our report shows that the growth of the phallus was
9 H. B4 H) Y/ ]1 }1 ^significantly greater with topical applications than with go-
; z, y, B+ p6 Dnadotropin, particularly in children less than 10 years old." Q0 _9 D4 T" @5 l! K* f5 U9 ~
The levels of serum testosterone remained similar or lower% q6 P: M" {% i2 }- \5 }7 _
than with gonadotropin during therapy, suggesting that topi-
* \- [+ X. P+ ]7 Z" } D |9 M- }cal application produces genital growth by its local effect as. }& R4 _! H" z" t$ q
well as its systemic effect.8 c7 D; B' V5 M1 |; Z9 j
Review of our patients and their growth response related to
& h$ ~$ ]& g1 K! X+ y; mage shows a greater growth response at an earlier age. This is$ T* R* z# O# e2 R3 X4 ]
consistent with the findings of Wilson and Walker, who" e R1 r0 |0 |4 k. }! n! z
reported an increased conversion of testosterone to dihydrotes-
8 r) m4 y, i! r# j! w% qtosterone in the foreskin of neonates and infants.4 This activ-
1 p# k" X; ?4 K6 Nity gradually decreases with age until puberty when it ap-4 K) o* @0 Q0 v, q& [2 c4 S
proaches the same level of activity as peripheral skin. It may
# I* \3 @, _& v- B* z1 X5 z4 s" iwell be that absorption of testosterone is less when applied at
. h! F" {8 D0 K/ d& g8 \an earlier age as suggested by lower serum levels in children& J' I# B1 a* R# G$ y
less than 10 years old. This fact may be explained by the3 c' O" N; F( Q" V
greater ability of phallic skin to convert testosterone to dihy-
: |5 i/ T" _; A* k9 z0 `# x- Wdrotestosterone at this age. Conversely, serum levels in older
2 J% X* Q7 v$ `; ~! ~' o- Zpatients were higher, possibly because of decreased local' {1 P' d: o. _. ~
667
* `0 ?$ Q4 k. k& i668 KLUGO AND CERNY
& m' @% ^0 \ d8 b$ w% FPt. Age2 V9 z7 E3 L) t) n
(yrs.). |6 B$ u7 t" L
Serum Testosterone Phallus (cm.) Change Length
. C% m9 r, R5 D i5 J& Y0 i(ng./dl.) Girth x Length (%)9 b/ }3 _9 I& ?( g
4
5 I6 g9 ^3 |; ?$ {6 c' O3 G8' _ v# D H& q- n( q9 A: |
10
% U5 [( G) V) c12% |) V* \. P) A
17
& b# D, B$ }: J4 N9 O# `Gonadotropin4 L1 `2 s8 K7 \- I
71.6 2.0 X 3 16.63 L" p# J5 [: s. G- n; B) @
50.4 4.0 X 5.0 20.0$ @# k: r5 a; B" E/ Q
22.0 4.5 X 4.0 25.06 ~/ x: z. o+ Z' m5 `) h$ m+ {
84.6 4.0 X 4.5 11.1# e! d3 h$ A) e/ h8 b; D3 j4 |" w- C
85.9 4.5 X 5.5 9.02 u+ D; w) \0 h9 ]! ]: j/ c
Av. 14.3& B/ @5 Z; f) k1 r: {8 ^7 A! {3 U
4
; |. r* `5 s5 p: s/ u8
" x0 O6 W: ^& L; D/ p$ R B10
0 V9 W# Q6 c+ x" `# Q( q, k: F12
) X% X+ C/ }6 q* {! n17
7 @0 p4 \( y" C4 \! ~( H1 }Topical testosterone. }& c7 I) y$ `
34.6 4.5 X 6.5 85
6 K3 P, A) d) Z8 b38.8 6.0 X 8.5 70
0 R5 u* }- M' F" V9 R( v6 g7 t# }40.0 6.0 X 6.5 62.5! H$ _$ y; J+ q) a' y
93.6 6.0 X 7.0 55.56 @; m2 h. p, z- i; S3 M
95.0 6.5 X 7.0 27.2
$ m- O6 p& d; @ I3 VAv. 60.02 J, C( g, ]1 k; R* ]9 S' m8 Y
available testosterone. Again, emphasis should be placed on
1 W3 Q$ y3 h; }) `early therapy when lower levels of testosterone appear to
6 d: G0 q: X ^6 W# M: O9 m4 o3 Eprovide the best responses. The earlier therapy is instituted5 W1 \% n$ F* u' o
the more likely there will be an excellent response with low8 W% W6 I, X" n' j7 m, R+ o
serum levels. Response occurs throughout adolescence as; k/ D# `1 o C5 _6 U! c
noted in nomograms of phallic growth. 7 The actual response8 v1 i+ a# {9 A- l! C- B: f' ~
to a given serum level of testosterone is much greater at birth$ t$ V) u6 K2 ^- z* H1 X; ]
and gradually decreases as boys reach puberty. This is most t5 c2 Z2 N- K' f" w$ a
likely related to the conversion of testosterone to dihydrotes-8 _: \1 {! U* h6 h; x
tosterone and correlates well with the studies of testosterone5 Q# k5 g5 Q i' A _
conversion in foreskin at various ages.
/ s, R& b3 o2 x! pThe question arises regarding early treatment as to whether- [& \% z" G! X! I
one might sacrifice ultimate potential growth as with acceler-
* J3 y! b& w3 K+ p( G0 U, u# Eated bone growth. The situation appears quite the reverse
c9 Y% }& V* A5 g9 jwith phallic response. If the early growth period is not used
) y8 O) `8 a/ Z$ Zwhen 5a reductase activity is greatest then potential growth$ d6 t" h5 J4 E. e* e
may be lost. We have not observed any regression of growth. u; c8 W+ w- W' ^# ]- _
attained with topical or gonadotropin therapy. It may well4 p0 @) J8 X9 U; c- Q
be that some patients will show little or no response to any
' E+ P1 _1 `2 Wform of therapy. This would suggest a defect in the ability to
( Q+ }5 A5 p3 K- T) }1 Cconvert testosterone to dihydrotestosterone and indicate that
- l* u5 p5 F+ v$ ?; ~& W6 @phallic and peripheral skin, and subcutaneous tissue should; H* ?: }$ V6 u5 v; d5 \# g
be compared for 5a reductase activity.
/ o I2 m: z/ J I* r: JA, loop enlarges to measure penile girth in millimeters. B,9 f0 L4 W- r4 A# b5 k2 N
example of penile girth computed easily and accurately.+ R" L1 `( a" F9 J$ Y( E
conversion of testosterone to dihydrotestosterone. It is in this
' J/ e3 q2 \/ M0 tolder group that others have noted high levels of serum
! _3 \3 K% s' s" }testosterone with topical application. It would also appear8 S! ?$ I: W& T. Y! \, Y/ _
that phallic response during puberty is related directly to the
/ e& w+ A/ ~5 s0 rserum testosterone level. There also is other evidence of local
7 s$ G& T& j3 R0 ~2 t+ t& f) @response to testosterone with hair growth and with spermato-
' o4 L/ d/ o# _genesis. 5• 6
6 ` { C" }* L% Y7 S. [Administration of larger doses of gonadotropin or systemic+ Q+ Z$ N1 G' b6 Y3 L
testosterone, as well as topical applications that produce
1 e" ^( @( s+ o& |5 K6 Chigher levels of serum testosterone (150 to 900 ng./dl.), will
; U1 b, }/ J: F zalso produce phallic growth but risks accelerated skeletal
: ]1 V2 P0 N! X% P2 wmaturation even after stopping treatment. It would appear& v6 u# Z8 V# h+ S& Q9 _! B
that this may be avoided by topical applications of testosterone/ W* K% I/ a7 a5 y C4 q1 k1 u; z- Q
and monitoring of serum testosterone. Even with this control2 D+ w' l! m6 t* V; h+ U0 k1 `2 E
the duration of our therapy did not exceed 3 weeks at any8 V3 ?4 L+ ^0 @. D7 E( f1 F4 `" u
time. It is apparent that the prepuberal male subject may8 j0 @8 d: ]% R
suffer accelerated bone growth with testosterone levels near
3 E( Q& c" }) @. I+ ]4 s" ]* ]200 ng./dl. When skeletal maturation is complete the level of
; Q5 r1 Y* Z3 e9 F# l4 o3 N/ z2 Qserum testosterone can be maintained in the 700 to 1,300 ng./5 u0 K6 _5 m/ n- m
dl. range to stimulate phallic growth and secondary sexual
, I+ r+ |# U# P9 n" Lchanges. Therefore, after skeletal maturation parenteral tes-
" J3 a! Z5 y2 z6 _tosterone may be used to advantage. Before skeletal matura-
. F4 x+ n8 U8 @( Xtion care must be taken to avoid maintaining levels of serum2 E- ^/ K, H+ p
testosterone more than 100 ng./dl. Low-dose gonadotropin
8 D( O( U2 j Wdepends upon intrinsic testicular activity and may require
/ u+ N! n& A2 L2 h9 R/ i3 Iprolonged administration for any response.8 K4 v# W" u* w/ u- n/ H5 N
Alternately, topical testosterone does not depend upon tes-* O$ c( X- K& N" r- B! l
ticular function and may provide a more constant level of
, ^. E. T0 S0 ]; r3 QREFERENCES
4 Q& P% @) e3 r# k/ x7 G1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,9 h' q1 K# u# w, L2 \
R.: The local application of testosterone cream to the prepub-
: D3 s: z( {4 A2 g+ _ertal phallus. J. Urol., 105: 905, 1971.
6 `8 a. R3 O5 z2 Y0 N' U2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
* `" L; o+ P0 V9 E( v/ G( Wtreatment for micropenis during early childhood. J. Pediat.,# R" s$ p' j0 t2 Y7 M" M l
83: 247, 1973.! A2 s$ k, R) ?/ }% Z9 W, K
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
- k: E/ p' i& v: n. V, Ione therapy for penile growth. Urology, 6: 708, 1975.
0 e! C# c% W4 C5 m/ r" r+ L$ m4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; h% [, r1 z( x( ]4 }$ ~4 i3 jto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* [1 e3 N/ h! m! t! Uskin slices of man. J. Clin. Invest., 48: 371, 1969.
! X2 n2 W5 C: Z' f$ p! B g5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth9 {, | |& r4 G% a P! L; v
by topical application of androgens. J.A.M.A., 191: 521, 1965.0 p, i& Z. @( j x. ^1 U# r" W
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local% V1 B+ z' K) l9 e( O( F0 P1 s1 q7 o
androgenic effect of interstitial cell tumor of the testis. J./ W/ ]! b1 i- C/ O3 N. |
Urol., 104: 774, 1970.
2 y" G+ B3 R* |7 X( y& U/ i* I3 g7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-# c7 ]$ _9 t% Y% n; {+ n- e
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|