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註冊時間2023-5-6精華在線時間 小時米币 最後登錄1970-1-1 
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| RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND . L& J  i7 q0 ]) f4 PGONADOTROPIN
 % j7 D2 q/ ?9 Q9 Z0 BRICHARD C. KLUGO* AND JOSEPH C. CERNY
 4 ]8 G, G4 v7 }7 W% nFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
 ' |' }# j8 z9 K( zABSTRACT3 U/ o2 _7 ], F. i5 u+ j
 Five patients were treated with gonadotropin and topical testosterone for micropenis associated
 e" O: K& o+ }with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-; Z$ }- |% r+ u, l
 tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ g; s) |& X1 ^$ o" N
 cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, e  I4 y  m9 L) [
 for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 \9 K8 i/ I$ w! q% J! j8 @# ?2 A; `
 increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average* I# V6 R" m# s( \) F' `4 ?6 r7 G/ c
 increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
 3 @1 V9 x$ t" B( g1 D2 w! Goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
 9 |4 b" P: w7 _; kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile5 h' w% P. @5 ^4 ]4 {. ~" x
 growth. The response appears to be greater in younger children, which is consistent with previ-: M, ]& e3 S, ]
 ously published studies of age-related 5 reductase activity.% G8 @( A$ J0 t- ^2 s& d9 ^! Y
 Children with microphallus regardless of its etiology will
 7 N4 F0 U2 ~  Frequire augmentation or consideration for alteration of exter-9 D* O9 Y- x" w: ^# `9 q: ?
 nal genitalia. In many instances urethroplasty for hypo-
 , `: l, z8 L+ S/ P5 Mspadias is easier with previous stimulation of phallic growth.
 : s$ \/ C. w+ A3 J: E8 _The use of testosterone administered parenterally or topically
 9 s0 l; {9 ^, ]7 ~has produced effective phallic growth. 1- 3 The mechanism of! ], p3 A, o- G
 response has been considered as local or systemic. With this
 4 M- e9 K# Z! W; T+ E8 ?in mind we studied 5 children with microphallus for response" v; |; K5 p% h8 S3 j3 ]0 `' W
 to gonadotropin and to topical testosterone independently." u+ g' n  }& [* M+ v% \% z, c
 MATERIALS AND METHODS, `& G. @$ T9 r5 M4 p, I
 Five 46 XY male subjects between 3 and 17 years old were# i* u) x- y0 [8 o, @  w/ ?* ]6 _
 evaluated for serum testosterone levels and hypothalamic
 * c0 b& ^7 I: c" c$ X# ~. lfunction. Of these 5 boys 2 were considered to have Kallmann's
 8 J6 E- n0 |  m" R! asyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
 " [! Q: v9 p7 a1 i3 s( i4 y. Ulamic deficiency. After evaluation of response to luteinizing$ p2 e4 S8 s5 Q1 Z: U6 {. P
 hormone-releasing hormone these patients were treated with# g! {4 }4 m& K+ [& \7 T
 1,000 units of gonadotropin weekly for 3 weeks. Six weeks  d# ~: C& \* r/ L6 f$ f
 after completion of gonadotropin therapy 10 per cent topical0 U) ]/ d. M( G2 F
 testosterone was applied to the phallus twice daily for 3 weeks.2 s: c+ D$ X4 @# X
 Serum testosterone, luteinizing hormone and follicle-stimulat-8 w5 x/ C7 t! g8 ]( `
 ing hormone were monitored before, during and after comple-
 5 F1 p' _# Q9 `2 }, btion of each phase of therapy. Penile stretch length was- \& M- }# h: I3 B/ W4 x
 obtained by measuring from the symphysis pubis to the tip of
 / Y7 u6 P* `# b5 ythe glans. Penile circumferential (girth) measurements were# F, }5 p  V  |5 n; y+ I: r
 obtained using an orthopedic digital measuring device (see! y6 P2 D# B) p& L4 Q- \0 R
 figure).! ?( y+ x8 j- z, b- Q; d" }; F
 RESULTS/ l. D" Y; N' U5 E" a0 P3 F
 Serum testosterone increased moderately to levels between0 S- T# y# D% i9 V4 P* s
 50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-/ D* N. I6 \/ S+ [  V# l
 terone levels with topical testosterone remained near pre-
 ! ^# L3 q4 \6 ^2 j+ D! @' Vtreatment levels (35 ng./dl.) or were elevated to similar levels
 $ t( t! D; r4 K% Rdeveloped after gonadotropin therapy (96 ng./dl.). Higher
 % k0 y7 h* \4 q% L- ^" k3 Aserum levels were noted in older patients (12 and 17 years old),% J# u! `$ z  w) l- j
 while lower levels persisted in younger patients (4, 8, and 106 O& H) _1 A& Q9 n
 years old) (see table). Despite absence of profound alterations, Y" o: c2 |  w8 L- J" l
 of serum testosterone the topical therapy provided a greater/ D  a2 Y( G5 w* N6 v
 Accepted for publication July 1, 1977. ·
 * x  y9 x1 N6 N( \. nRead at annual meeting of American Urological Association,- r2 _: w$ O" b6 \0 D
 Chicago, Illinois, April 24-28, 1977.
 * E+ b' F, m; g+ x. a6 g+ v* Requests for reprints: Division of Urology, Henry Ford Hospital,
 5 o# L7 }# D; q. R) Z/ i  e8 i# J2799 W. Grand Blvd., Detroit, Michigan 48202.
 ! u6 U  a2 g8 [improvement in phallic growth compared to gonadotropin., v( p. X/ V3 T: x
 Average phallic growth with gonadotropin was 14.3 per cent5 L) x6 D- Q! d# ?3 K
 increase in length and 5.0 per cent increase of girth. Topical* Q, p7 B2 Q9 q1 X  r: i. {' k
 testosterone produced a 60.0 per cent increase of phallic length: }6 L* C! S. _6 H
 and 52.9 per cent increase of girth (circumference). The
 ! a0 U# f9 z! Xresponse to topical testosterone was greatest in children be-0 X7 m; e; c1 V# u7 r
 tween 4 and 8 years old, with a gradual decrease to age 17
 % g  P; f$ x" Eyears (see table).9 `& b( a- m8 w2 H; z" Y5 ]
 DISCUSSION
 , F  E  V% S/ U. F# w. kTopical testosterone has been used effectively by other
 3 X% }2 p- S" a- Iclinicians but its mode of action remains controversial. Im-
 0 ?& V% P, g% w# V  g7 smergut and associates reported an excellent growth response8 g3 L# B* X; j+ N6 w5 H, m
 to topical testosterone with low levels of serum testosterone,
 2 Z! k5 C+ `6 }9 ]suggesting a local effect.1 Others have obtained growth re-
 8 _1 Z4 O: M+ \& i0 P% Y  Usponse with high. levels of serum testosterone after topical, w3 b& Z5 S. g0 E
 administration, suggesting a systemic response. 3 The use of
 ( U) g) H2 ?% M7 M2 }! Pgonadotropin to obtain levels of serum testosterone compara-0 C/ U- }# A' ^; u& N
 ble to levels obtained with topical testosterone would seem to$ n4 |# B, A' P5 x
 provide a means to compare the relative effectiveness of
 8 R8 v/ e4 r3 j" ^- K' a4 utopical testosterone to systemic testosterone effect. It cer-
 " p' S3 v8 t6 Z* rtainly has been established that gonadotropin as well as par-( g4 _% a; E6 T3 @6 G
 enteral testosterone administration will produce genital4 D$ j$ j* v4 \3 ], u$ _7 z
 growth. Our report shows that the growth of the phallus was8 E+ A3 {/ U/ F2 n8 t: K2 }7 D
 significantly greater with topical applications than with go-/ }3 j5 I; |6 v( A' ^) W
 nadotropin, particularly in children less than 10 years old.* @2 s* J& f- k2 S9 a; z) I: {
 The levels of serum testosterone remained similar or lower
 1 F; @6 M/ @9 o0 _/ }* h# \; u4 sthan with gonadotropin during therapy, suggesting that topi-- n; K% D& |  N/ a* t1 h; M& N6 Y
 cal application produces genital growth by its local effect as3 V# ^5 i: a" ?8 k
 well as its systemic effect.
 7 T! s3 Q% G/ ^4 L" V) w# oReview of our patients and their growth response related to
 ; N6 h6 p- ?0 h; L& P0 vage shows a greater growth response at an earlier age. This is
 ' b6 v4 P  V0 q. Nconsistent with the findings of Wilson and Walker, who
 & A4 K4 O/ [; ^. L% ureported an increased conversion of testosterone to dihydrotes-! ]  N6 S3 C$ j( `! W8 B9 N5 ^9 s
 tosterone in the foreskin of neonates and infants.4 This activ-' Q, D* e* l' F+ G9 O7 Q
 ity gradually decreases with age until puberty when it ap-0 t/ Y7 j/ I# h3 ~$ A6 z. @
 proaches the same level of activity as peripheral skin. It may9 L4 o9 U* s1 Q  [$ M  f- ?, N: @
 well be that absorption of testosterone is less when applied at$ C& T+ }) @) |7 v2 O8 \" J' R
 an earlier age as suggested by lower serum levels in children* v* b- ^3 {" F, T' B
 less than 10 years old. This fact may be explained by the
 $ s6 M8 j8 ]5 G6 }7 ?4 u5 R; _* egreater ability of phallic skin to convert testosterone to dihy-
 2 t: x$ F! c9 N' W7 idrotestosterone at this age. Conversely, serum levels in older+ h' n: u% M! S/ H( x2 a4 H1 P
 patients were higher, possibly because of decreased local. `' r0 r8 z0 F  x
 667( ^' r8 H+ x9 Y' c' A0 {
 668 KLUGO AND CERNY
 3 A  X+ }6 i- I- \Pt. Age' @& e6 G3 e3 j0 L
 (yrs.)
 9 H9 J! Z8 I- ^0 V1 s) m: w- lSerum Testosterone Phallus (cm.) Change Length
 + R  ?5 o! L9 \% z(ng./dl.) Girth x Length (%)
 3 [4 Z6 p" ]" |, B3 |4 g! o. j8 c4
 2 I: C& ?- H$ V# I6 g, [8
 g2 k2 K6 a; X! `+ n; i10
 + s+ {; t' s0 e12
 & Z6 E5 `8 g" {' r; W# d17. i8 l% X/ l+ m+ @/ R; ^7 `
 Gonadotropin, j: A2 f$ m5 L5 w* _
 71.6 2.0 X 3 16.6
 2 D; y! e1 Z. v  O$ u50.4 4.0 X 5.0 20.0
 ) m7 {' l9 i" S1 x22.0 4.5 X 4.0 25.03 M. N( y1 ~7 i% v, M; G
 84.6 4.0 X 4.5 11.1. w+ i: T4 M8 D# P3 N: o
 85.9 4.5 X 5.5 9.0
 " A& {% `$ u1 TAv. 14.3
 7 A1 X/ {- q# U3 D% k4
 # C; ?1 U: P  v9 O+ |86 Z! m0 D2 r1 ~1 B) h7 v% w  s
 10% ^- L# U2 i/ B& L
 12
 , Q- t  v& g& G176 g4 q$ s( J# \4 w
 Topical testosterone
 9 @; i% P/ I: ]1 {" h- B$ m- j34.6 4.5 X 6.5 85
 0 q* _' B. e! k# T38.8 6.0 X 8.5 70" y( c: C, N4 i, @- Y, N
 40.0 6.0 X 6.5 62.5
 ; |; {( p+ Q7 u6 k7 K. y93.6 6.0 X 7.0 55.5
 & w7 v3 M4 A3 |# P6 p- O; N95.0 6.5 X 7.0 27.2( {) s/ s9 J5 p& o8 m; w# }) o6 T
 Av. 60.0
 / \# r; Y% k2 Uavailable testosterone. Again, emphasis should be placed on
 8 M1 Q3 b" e& F, l* o: vearly therapy when lower levels of testosterone appear to1 N9 G) N& G4 a. H
 provide the best responses. The earlier therapy is instituted3 m" u( U& @& c# G
 the more likely there will be an excellent response with low
 S2 G4 {) D( `. Rserum levels. Response occurs throughout adolescence as
 + ?7 B7 X9 y. \/ ?% `* H! }- |noted in nomograms of phallic growth. 7 The actual response' j& C3 l6 G5 p- ]
 to a given serum level of testosterone is much greater at birth
 : K/ r& c' o% j' _# j5 x6 `  Pand gradually decreases as boys reach puberty. This is most" X2 y2 T" x' r& i. f5 x9 e; Y; X9 r
 likely related to the conversion of testosterone to dihydrotes-- d; ~; }6 w3 W6 D+ M! |7 f
 tosterone and correlates well with the studies of testosterone
 0 }, `# d& z' {" hconversion in foreskin at various ages.
 / r) n9 E8 r: [7 cThe question arises regarding early treatment as to whether
 : y7 w$ g' s2 `' a7 mone might sacrifice ultimate potential growth as with acceler-4 K6 N0 v9 W' J1 i0 I' E
 ated bone growth. The situation appears quite the reverse
 4 z+ ~; a+ g& x, `# swith phallic response. If the early growth period is not used6 O' g8 f% v7 W8 w" _# p$ \- N4 b  X
 when 5a reductase activity is greatest then potential growth+ ?2 X+ @5 s. f& {( D( I: ?$ D1 E
 may be lost. We have not observed any regression of growth4 {) N  J9 Z6 s6 V2 [: u% \5 e
 attained with topical or gonadotropin therapy. It may well
 ) `& T8 q2 x$ H4 @$ D* U" gbe that some patients will show little or no response to any& K" D! R/ }( m* X# o* \
 form of therapy. This would suggest a defect in the ability to
 ! k& q# C' ~# Gconvert testosterone to dihydrotestosterone and indicate that) V; b) P+ w8 T+ k' I
 phallic and peripheral skin, and subcutaneous tissue should
 & ~' `; t/ o8 ~0 |% d7 _* Qbe compared for 5a reductase activity./ |3 U% z, W4 \; y( `# T; R
 A, loop enlarges to measure penile girth in millimeters. B,
 $ f6 {9 K& a# D7 m9 z8 E9 @) Texample of penile girth computed easily and accurately.! S' t  y2 Z+ q/ F3 B% u7 e
 conversion of testosterone to dihydrotestosterone. It is in this' X5 C1 D3 p0 D6 e7 ?+ B  c0 h
 older group that others have noted high levels of serum& }. P, W# R2 {. ?: F( j  i3 F" e
 testosterone with topical application. It would also appear, m& ~( J% x4 D: }
 that phallic response during puberty is related directly to the
 % H) b  y0 y$ Tserum testosterone level. There also is other evidence of local4 @: O4 `% m/ q' @. Y, M( S
 response to testosterone with hair growth and with spermato-
 3 ~* c. Y; E" S5 o  [- c. Igenesis. 5• 65 z  P% e- ~) C, e0 O
 Administration of larger doses of gonadotropin or systemic* Y* O2 ^& Q9 Z$ l# [1 c
 testosterone, as well as topical applications that produce# p6 A6 N2 K7 V) a. r" Z
 higher levels of serum testosterone (150 to 900 ng./dl.), will- W* W! D$ ~- O  q0 S% ~0 u
 also produce phallic growth but risks accelerated skeletal3 B$ l5 ~2 a5 U& X9 Z
 maturation even after stopping treatment. It would appear
 ! p9 k; x+ B5 z5 h( k% h8 X* C9 Pthat this may be avoided by topical applications of testosterone' ~! U" W$ y2 M
 and monitoring of serum testosterone. Even with this control
 4 l; Z2 t8 V  W2 A. H) M( }the duration of our therapy did not exceed 3 weeks at any
 C# y9 M. |0 F/ K" B' Htime. It is apparent that the prepuberal male subject may
 ( I3 W1 {# @/ w2 X$ [2 Usuffer accelerated bone growth with testosterone levels near
 & t8 k2 D* I1 a& d3 c' R* R" x200 ng./dl. When skeletal maturation is complete the level of+ T2 p9 }4 c" l6 a: [3 x
 serum testosterone can be maintained in the 700 to 1,300 ng./  S# c9 ~) x/ A/ j2 A& i6 i& e
 dl. range to stimulate phallic growth and secondary sexual
 - Y" Y9 n; ~6 j+ x: B( o( |& R$ Achanges. Therefore, after skeletal maturation parenteral tes-
 ) H% V/ K, b9 t# b, Ttosterone may be used to advantage. Before skeletal matura-( k& t, a. p) n
 tion care must be taken to avoid maintaining levels of serum
 0 O/ z7 s' b$ N9 Q  ?testosterone more than 100 ng./dl. Low-dose gonadotropin
 8 z0 u/ L3 A* C9 O+ q+ P1 G# gdepends upon intrinsic testicular activity and may require' z+ d- K2 \1 T; u
 prolonged administration for any response.
 p, z3 a; ]& a+ Z5 O# uAlternately, topical testosterone does not depend upon tes-
 : @5 D- A  }5 S8 V, rticular function and may provide a more constant level of# Q( g+ W7 V6 w! M1 ?  @
 REFERENCES
 + T; U. L  o# x+ e4 z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ E) Q' o: O; T! ]" L8 h
 R.: The local application of testosterone cream to the prepub-9 |, y% o8 g, {2 @( `* y
 ertal phallus. J. Urol., 105: 905, 1971.
 , M& F2 H" [6 M3 U7 ?% R2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone+ F0 p2 n8 H; C: x
 treatment for micropenis during early childhood. J. Pediat.,
 1 D: C5 C$ ^  |" C83: 247, 1973., w) H; y8 z+ r7 [4 Z6 Y/ `
 3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-4 k3 B+ i% N+ H0 O; X5 t
 one therapy for penile growth. Urology, 6: 708, 1975.
 ; y8 w# h4 g3 @& D7 A4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) b. b  [% M# Q+ |
 to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by# x' Z. {# W( P0 B2 R9 S( ?9 O
 skin slices of man. J. Clin. Invest., 48: 371, 1969.7 |( t  y  }/ m& [. A8 T
 5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
 . G- @$ f$ [$ G# Vby topical application of androgens. J.A.M.A., 191: 521, 1965.
 . D7 P! U1 X- L; y- K' m6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
 - I  i. P1 b; U4 q+ a$ G. randrogenic effect of interstitial cell tumor of the testis. J.
 6 M' t$ j; o5 e# }Urol., 104: 774, 1970.' B/ L- P2 z7 K$ L& a
 7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-  W' l* S9 ^4 A& z; R7 C4 L+ k/ l
 tion in the male genitalia from birth to maturity. J. Urol., 48:
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