- 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 AND0 a$ B; |1 q& z9 w$ V
GONADOTROPIN
4 K) J$ [7 r& GRICHARD C. KLUGO* AND JOSEPH C. CERNY8 \, m' _0 [4 @- V3 F7 m1 W
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan' D6 C* `6 A b) k+ j6 O4 L; Q
ABSTRACT S3 O! H# p5 M S8 ~) `
Five patients were treated with gonadotropin and topical testosterone for micropenis associated0 H/ K. G/ J: ~1 H8 A& H1 \* ~
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado- S0 k6 b+ ~3 l; }; @' z/ \
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# l$ u- k7 A! n/ _# J* e# B
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent+ v2 S& |- j9 c1 ^
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) |# @4 `- x- n" `5 _' }; _& j! q) m* u
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average$ c7 E) _- W; n# H2 k6 k5 S/ ^# v
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response4 q3 g2 { ?$ Q2 R
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ c+ \& @7 R7 B) X
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% D- Z% N" E" ~" K' }* _9 U0 Tgrowth. The response appears to be greater in younger children, which is consistent with previ-
5 j+ ~- z2 B7 n2 v" @ously published studies of age-related 5 reductase activity.5 X7 Q. Z. [0 w, `- U e8 c& }: e& C
Children with microphallus regardless of its etiology will$ \1 L" C0 }3 F/ L; \% Z
require augmentation or consideration for alteration of exter-5 O+ U) y9 x% {6 F; K& v* _6 _: }
nal genitalia. In many instances urethroplasty for hypo-
7 [& K2 }# c0 Kspadias is easier with previous stimulation of phallic growth. e, ]% p9 o6 i5 b4 O) [
The use of testosterone administered parenterally or topically
. N) w0 E! _ R+ h+ b3 N2 \; k( Lhas produced effective phallic growth. 1- 3 The mechanism of
* v, `- T7 e: ` _" S) Hresponse has been considered as local or systemic. With this
- d f4 W- i& O, y vin mind we studied 5 children with microphallus for response
' q w/ \0 `/ Z' C) q# Qto gonadotropin and to topical testosterone independently.8 |7 Q5 `7 \" X2 `6 V) _
MATERIALS AND METHODS( I' Q% P" Q, ]" N3 E0 L" k( I
Five 46 XY male subjects between 3 and 17 years old were5 _( j9 Z8 P, p8 {
evaluated for serum testosterone levels and hypothalamic3 s6 f i+ P8 v& w- u7 x; T
function. Of these 5 boys 2 were considered to have Kallmann's
3 d n+ e6 j' Z8 V) E2 K6 } Csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 q7 Y8 {' O- ~* V2 {2 ]lamic deficiency. After evaluation of response to luteinizing
& B$ V/ I/ M# B1 Z8 G \& v1 [: b& Xhormone-releasing hormone these patients were treated with! L6 H) M$ q2 k
1,000 units of gonadotropin weekly for 3 weeks. Six weeks. {- o3 u" `1 F% y3 ^
after completion of gonadotropin therapy 10 per cent topical" [- G8 w% L: A$ o9 B/ \, q
testosterone was applied to the phallus twice daily for 3 weeks.
# J" j0 F$ K* @/ OSerum testosterone, luteinizing hormone and follicle-stimulat-
* o8 T4 f3 B3 m( |+ i( ling hormone were monitored before, during and after comple-/ I4 t2 v' ~: U% n l' a% J
tion of each phase of therapy. Penile stretch length was7 z% E# F7 V% T# Z8 U
obtained by measuring from the symphysis pubis to the tip of
' z6 K% C3 [) F" Vthe glans. Penile circumferential (girth) measurements were
' B: `- c% ~, D2 D a& kobtained using an orthopedic digital measuring device (see
2 O% c' i" p; w9 ofigure).' r. k" C. O' b& Q
RESULTS
9 W+ n! u- b- W" P' D+ `0 lSerum testosterone increased moderately to levels between- g" F+ R" _8 k
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 E/ _5 s* {; ?terone levels with topical testosterone remained near pre-- D# G' L, x0 Q$ b \4 ^- N
treatment levels (35 ng./dl.) or were elevated to similar levels
% A' k# ^4 \ y0 J. e2 @. Gdeveloped after gonadotropin therapy (96 ng./dl.). Higher8 h" f% d6 \/ Z
serum levels were noted in older patients (12 and 17 years old),4 U6 d3 r& b8 g
while lower levels persisted in younger patients (4, 8, and 100 {& y7 O. i6 u2 S" [; F% m" b& a0 l* Z
years old) (see table). Despite absence of profound alterations% A( i# A* n! U5 Z7 `6 J, F
of serum testosterone the topical therapy provided a greater
5 x8 Z" H9 A5 u( Y4 W: l0 yAccepted for publication July 1, 1977. ·' g2 K5 f# |+ L* ?! D0 j- N
Read at annual meeting of American Urological Association,
6 y/ R$ L) {9 A! ?- V! Y8 ]8 oChicago, Illinois, April 24-28, 1977.# h2 k% H- K2 O2 k' d B
* Requests for reprints: Division of Urology, Henry Ford Hospital,' g. o. b- R! q( O: d
2799 W. Grand Blvd., Detroit, Michigan 48202.1 E+ L9 |) `& W; S6 i, Q; z& n
improvement in phallic growth compared to gonadotropin.
* g% S+ V6 q) S: Z9 V2 _9 @8 hAverage phallic growth with gonadotropin was 14.3 per cent
1 {6 e1 r: h# Z8 }8 g Qincrease in length and 5.0 per cent increase of girth. Topical
; T3 N' v8 y; X+ {" k# a3 rtestosterone produced a 60.0 per cent increase of phallic length/ u+ P h' i- D/ o
and 52.9 per cent increase of girth (circumference). The
7 l1 A; b) c3 g4 [! zresponse to topical testosterone was greatest in children be-
2 q. k/ i8 w: f3 g4 m5 stween 4 and 8 years old, with a gradual decrease to age 17. V4 I1 `4 } C2 p
years (see table).
% o q' n/ h- }9 QDISCUSSION
3 K) s' {5 R' w, A' PTopical testosterone has been used effectively by other
) ~& x2 C1 z- ? j( zclinicians but its mode of action remains controversial. Im-/ q$ h/ d* R$ F4 d, u6 t
mergut and associates reported an excellent growth response" r/ ^; t [ I* v
to topical testosterone with low levels of serum testosterone,6 y7 W; O& A3 W
suggesting a local effect.1 Others have obtained growth re-
* c. b) v4 M4 b; f0 J$ O8 [# w Tsponse with high. levels of serum testosterone after topical$ v# v4 D9 V& O7 K& T' X1 u8 x
administration, suggesting a systemic response. 3 The use of2 A; T! Y/ R- {2 P( q% G! _
gonadotropin to obtain levels of serum testosterone compara-- y7 j% [0 C$ p- H
ble to levels obtained with topical testosterone would seem to% B/ `! t4 ?) Q6 l T* C
provide a means to compare the relative effectiveness of
; Z& I' \2 M7 Z+ N* y# mtopical testosterone to systemic testosterone effect. It cer-
0 F% K, ]3 G- c+ `" U8 `( ttainly has been established that gonadotropin as well as par-
$ v; g# l" C0 [3 F$ A9 N. qenteral testosterone administration will produce genital1 G7 U8 O* e$ k7 [3 A% `
growth. Our report shows that the growth of the phallus was
: s& E' ~6 d8 W# Osignificantly greater with topical applications than with go-5 X$ E$ U1 E W5 O0 V. ~$ ~( e0 }
nadotropin, particularly in children less than 10 years old.3 \& Q+ t8 r" a3 E4 F9 S3 Z4 W2 w6 R
The levels of serum testosterone remained similar or lower
& r& D u1 v! h. lthan with gonadotropin during therapy, suggesting that topi-
( q4 L/ l7 r! R/ S; Ccal application produces genital growth by its local effect as2 I R( E1 p& `* Q1 ~: K7 C
well as its systemic effect.
' _3 M5 w `" |' ] |3 }9 {, k2 wReview of our patients and their growth response related to6 p. S A5 I( t# |+ U; i6 _
age shows a greater growth response at an earlier age. This is
% C4 K2 V7 W7 r8 S& |& oconsistent with the findings of Wilson and Walker, who+ i" V u, K6 N& r3 T' c
reported an increased conversion of testosterone to dihydrotes-+ Q+ s. C. J) J0 R( {+ v, Y
tosterone in the foreskin of neonates and infants.4 This activ-% d ]+ ]$ Q6 I
ity gradually decreases with age until puberty when it ap-
, l& T+ E9 s' e4 M+ iproaches the same level of activity as peripheral skin. It may
( N3 h5 j$ E0 Z- m8 [well be that absorption of testosterone is less when applied at
6 L/ Z& s% `% c( j* _+ Man earlier age as suggested by lower serum levels in children$ s3 ?$ m. q8 K) O! M
less than 10 years old. This fact may be explained by the
9 M$ u- F- q& P2 e" b6 [greater ability of phallic skin to convert testosterone to dihy-! U& b2 W3 ?, R4 o) v7 c
drotestosterone at this age. Conversely, serum levels in older
/ D$ Y; u3 ]3 S7 D4 tpatients were higher, possibly because of decreased local! ]3 C; h0 T4 ?' Y2 ]9 A' `+ m
667& x8 I) a% [# |8 x8 a# c
668 KLUGO AND CERNY' O/ \- L! V: k8 O$ U* m+ Z
Pt. Age! j# _1 C: }( s8 C5 m* M) ?( d
(yrs.)1 c& }6 P5 G. K0 H8 j$ ~5 c8 I4 S
Serum Testosterone Phallus (cm.) Change Length: y- t8 M, R+ r
(ng./dl.) Girth x Length (%)) s! d, H4 _, {% A6 i
4
7 Y [2 o5 M; j) E8/ P& |% |% w9 O5 i- C7 c! ^. j
102 x( a: S! Q1 f2 c+ Q
122 x P* C: Y* v) e2 j
17* O7 s* a3 l* A1 [3 V+ v9 g
Gonadotropin, B0 o% ?, i/ X3 w H8 i
71.6 2.0 X 3 16.64 d5 ]: s8 v- k4 J2 `! M
50.4 4.0 X 5.0 20.04 D( B7 V& O& g+ O0 T6 \ T+ R
22.0 4.5 X 4.0 25.0. _9 n% M+ \- ~+ f! E; o1 n0 n
84.6 4.0 X 4.5 11.18 b, g5 J% l# U' H
85.9 4.5 X 5.5 9.0: p4 D. Z, w& A/ V3 F: x7 ]) N
Av. 14.3
* I: p3 S; [+ E# }7 [( X L4
: u' m h! {0 X* | v4 N4 K8 X8
; Y: m& F, b' v: e& t: F }! D4 w10
& D( \2 S; y0 R) M* U/ f12
% m" U' ]; ` m# V5 F5 e6 T17( M) ]& ]* s4 y
Topical testosterone1 h& c" [+ i' I* t, H
34.6 4.5 X 6.5 85 ~6 e7 j& t+ a( d
38.8 6.0 X 8.5 707 j! V# h4 ?/ D2 ~
40.0 6.0 X 6.5 62.5" f8 U3 t7 m: l
93.6 6.0 X 7.0 55.59 y" d: U" ]+ [$ u; e5 S
95.0 6.5 X 7.0 27.2# U: L) N* u* N/ ?" b# }2 M+ B- J
Av. 60.0
) O& w( B* A* b1 H+ \available testosterone. Again, emphasis should be placed on, U5 v- l1 j/ l! e
early therapy when lower levels of testosterone appear to8 R2 G. @, L3 B' m: X2 D! ~8 \
provide the best responses. The earlier therapy is instituted
/ Z' T8 H1 x3 rthe more likely there will be an excellent response with low
; P! d- I: p9 e9 u4 O6 tserum levels. Response occurs throughout adolescence as
1 e# s& y1 Z6 {# g. K" Z Jnoted in nomograms of phallic growth. 7 The actual response
: m/ Z3 M/ V: u6 M4 wto a given serum level of testosterone is much greater at birth
) m: X# d) J* d" wand gradually decreases as boys reach puberty. This is most
. e) [/ E: p' dlikely related to the conversion of testosterone to dihydrotes-3 Z$ I% ^) q E F; B- i3 g: I
tosterone and correlates well with the studies of testosterone
/ Q" ]4 _5 G1 w- _conversion in foreskin at various ages.
: Q5 o6 b4 L' K; IThe question arises regarding early treatment as to whether
/ T2 a4 I8 t K! q' n6 ?one might sacrifice ultimate potential growth as with acceler-
4 O# R6 k4 R9 D, ^ n" K( `) jated bone growth. The situation appears quite the reverse* S! ~2 B9 b2 n$ u4 F E& z$ ~
with phallic response. If the early growth period is not used
0 M, l. r3 o: S' Dwhen 5a reductase activity is greatest then potential growth1 X" [: h# h$ K- [1 q
may be lost. We have not observed any regression of growth
: R7 x/ ~! ~: }5 i) oattained with topical or gonadotropin therapy. It may well
; E# S9 c7 x# g0 p6 R( I7 Lbe that some patients will show little or no response to any
3 G9 z0 c( r' Q5 Y( g( K0 Eform of therapy. This would suggest a defect in the ability to" q j) t* \% Q! h/ e/ R# u
convert testosterone to dihydrotestosterone and indicate that" @5 B8 n: L# h
phallic and peripheral skin, and subcutaneous tissue should+ P/ r9 O' f+ K: w7 b; L
be compared for 5a reductase activity.9 `6 N) s' \8 \9 L- ~
A, loop enlarges to measure penile girth in millimeters. B,: P5 D* M f( K1 w( Y* T# _
example of penile girth computed easily and accurately.
/ X" ~+ Q, K# ?- J' M2 Z5 ^& X% Z, wconversion of testosterone to dihydrotestosterone. It is in this
! y, _# r- U" jolder group that others have noted high levels of serum
5 ^# f6 `' v7 a e& Z$ J; Xtestosterone with topical application. It would also appear
5 S' Z( W& ?& p, k- Ythat phallic response during puberty is related directly to the
9 H2 ^& u5 ]2 gserum testosterone level. There also is other evidence of local8 S: U& x d3 q3 `# I
response to testosterone with hair growth and with spermato-+ l" m7 L4 l, |
genesis. 5• 6
/ {9 q. K1 h% O2 BAdministration of larger doses of gonadotropin or systemic
- [ x7 @! u6 G* q* |0 v9 jtestosterone, as well as topical applications that produce
0 M# B- r) ?) h0 I7 xhigher levels of serum testosterone (150 to 900 ng./dl.), will* y7 t1 P) ] R; B e
also produce phallic growth but risks accelerated skeletal6 g! a4 f4 C6 Y, w C' N! b
maturation even after stopping treatment. It would appear3 ^; N) {0 M, _! L& V3 O2 \5 O
that this may be avoided by topical applications of testosterone( X9 Q- Z: \& L
and monitoring of serum testosterone. Even with this control
, \( C$ ^ c# Lthe duration of our therapy did not exceed 3 weeks at any
; B2 u A9 q' q3 C$ M9 Htime. It is apparent that the prepuberal male subject may) M1 d$ E) e0 O7 {1 T% e
suffer accelerated bone growth with testosterone levels near
* H4 R! I. k/ M# {4 X6 v200 ng./dl. When skeletal maturation is complete the level of
0 ]6 D1 U8 y6 a+ l1 Tserum testosterone can be maintained in the 700 to 1,300 ng./) @, S( k: R/ w
dl. range to stimulate phallic growth and secondary sexual; q) b% @, ~. R; ^; v0 p1 w
changes. Therefore, after skeletal maturation parenteral tes-
/ w, X( ]& \! L' W5 [tosterone may be used to advantage. Before skeletal matura-
) J3 ?- C. ^6 v: S" ]3 `tion care must be taken to avoid maintaining levels of serum8 i5 F- I3 ~0 C5 Y9 s
testosterone more than 100 ng./dl. Low-dose gonadotropin
& Y2 ]) s6 Q. [) ^( z cdepends upon intrinsic testicular activity and may require+ n$ j; W: W) s' P1 ^
prolonged administration for any response., K: Z( q1 T6 p8 d
Alternately, topical testosterone does not depend upon tes-, w/ k4 F5 @( d% z
ticular function and may provide a more constant level of* t4 j) j, p$ n
REFERENCES
1 i1 G: Q6 Y/ M" ]2 f$ f1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 T8 L/ C5 Y8 RR.: The local application of testosterone cream to the prepub-
0 U, }+ w. t: }) x; }ertal phallus. J. Urol., 105: 905, 1971.
; Q, A$ Q! i1 d' w2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 c/ k, |, u" e; ? I
treatment for micropenis during early childhood. J. Pediat.,
0 _% K0 l) X' {% h, K7 E1 k83: 247, 1973.& C7 U+ C4 Y" A. I# }5 x
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" |/ r a" C5 ?% ]& W3 _one therapy for penile growth. Urology, 6: 708, 1975.. O6 Q. H9 w; Z- g( J- |6 d. [
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; O* {' E4 h3 \) bto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by w: Y K5 |+ z9 J
skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 m& x' |, c% ?# d! g5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth! c0 B) d/ m; A1 R0 ~& |3 s
by topical application of androgens. J.A.M.A., 191: 521, 1965.
: M( K: S! d8 h7 ~! W/ M6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ {$ m8 W: o# c) Q( D. D3 y
androgenic effect of interstitial cell tumor of the testis. J.
& p6 `# b, i/ x7 d& Z8 f6 o+ KUrol., 104: 774, 1970.
" C9 g4 e" o n) G! S2 k; k0 V" w7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 I! t4 F4 E' i$ ption in the male genitalia from birth to maturity. J. Urol., 48: |
|