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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 . ?; a4 R& Z1 i8 W( p# lGONADOTROPIN
 $ X2 h0 H; m3 A8 @- _7 d: dRICHARD C. KLUGO* AND JOSEPH C. CERNY
 0 y( z2 M7 Y2 v0 ?From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& X4 W8 C. G+ K. e
 ABSTRACT
 8 s9 G2 t6 a) s- d5 @. a6 ^Five patients were treated with gonadotropin and topical testosterone for micropenis associated
 ; h0 H5 \- m& R# o5 hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
 & g+ _& l& B1 L4 c# w0 m! K0 wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
 7 U- l- y: N* ^' Qcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 Q( M! o7 G1 l) w7 q5 {; a
 for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
 ; Q; P: y, V* F7 W( |increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average( p# Z0 y% I: L" v5 r. d1 D8 h
 increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
 / I: M$ P) c7 k& Z, ^6 w3 Doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 a: r7 P! d" B  `3 \
 study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
 6 o6 f- Z, m- a! i, j. A$ `$ b+ ^- _+ O7 wgrowth. The response appears to be greater in younger children, which is consistent with previ-, U1 U2 t2 c8 q$ c$ p( {, F
 ously published studies of age-related 5 reductase activity.
 * B+ B9 z; I# Q8 E5 c7 u  L* KChildren with microphallus regardless of its etiology will
 ; `, \7 Z2 K$ {% f) h6 J4 a. lrequire augmentation or consideration for alteration of exter-9 _' w7 v; X2 G
 nal genitalia. In many instances urethroplasty for hypo-6 l: ^. O  O& B9 R9 k
 spadias is easier with previous stimulation of phallic growth.: W, N# T' m2 L% R+ g
 The use of testosterone administered parenterally or topically# z% [1 t5 U: W& \7 k
 has produced effective phallic growth. 1- 3 The mechanism of' P1 ?* A4 }5 \: V1 ?
 response has been considered as local or systemic. With this
 $ e4 F* ?1 ~$ ?  h" g8 R8 O# F9 V- Uin mind we studied 5 children with microphallus for response
 5 h& a! W( x. g9 s3 ~7 m( Xto gonadotropin and to topical testosterone independently.
 ' r- p; n  ^, h7 CMATERIALS AND METHODS
 * x7 \' R. J+ t; [: I: K# l6 d3 pFive 46 XY male subjects between 3 and 17 years old were
 & U& }9 [/ O7 j6 @' qevaluated for serum testosterone levels and hypothalamic
 ' @" k6 P) |6 \% O/ Zfunction. Of these 5 boys 2 were considered to have Kallmann's
 ! y0 M& M( I- b$ s+ `syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
 * r, }3 q2 C% P3 l0 G) o4 Plamic deficiency. After evaluation of response to luteinizing7 q) j3 p' o( a4 ]) [
 hormone-releasing hormone these patients were treated with
 ; K' r/ r) }9 c  _1,000 units of gonadotropin weekly for 3 weeks. Six weeks
 ( l( h0 C# i5 m' U6 e2 X$ Jafter completion of gonadotropin therapy 10 per cent topical
 . ~; j' E8 }: |9 W  Otestosterone was applied to the phallus twice daily for 3 weeks.
 ) I: f" s1 A- c! L8 ^7 Y5 BSerum testosterone, luteinizing hormone and follicle-stimulat-
 , a8 x( w& f- B  b0 z0 `- Ying hormone were monitored before, during and after comple-
 $ P. X' [+ ?, e9 Y' Rtion of each phase of therapy. Penile stretch length was
 / ]) j& l' ~1 p0 robtained by measuring from the symphysis pubis to the tip of
 ; f" |- t% h. }2 ?) ]the glans. Penile circumferential (girth) measurements were/ t3 ~7 `1 O/ A2 f) ^( b- s9 Z0 K
 obtained using an orthopedic digital measuring device (see
 / f, F2 l  L( t6 s6 E- jfigure).+ ], a) M% b( t6 i- F' t
 RESULTS9 I9 e. h6 u1 u) u
 Serum testosterone increased moderately to levels between/ `2 n, O1 D4 x5 v& Z
 50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 i, R$ m+ n% w
 terone levels with topical testosterone remained near pre-5 g6 b+ Q$ T+ p9 ^9 e
 treatment levels (35 ng./dl.) or were elevated to similar levels( \: k6 b8 O: H
 developed after gonadotropin therapy (96 ng./dl.). Higher9 F+ Y* a1 y% ?6 S+ G* N
 serum levels were noted in older patients (12 and 17 years old),
 " _# y* i8 \4 h# Y3 Y/ J. Jwhile lower levels persisted in younger patients (4, 8, and 10
 6 X5 z, b- l9 A' e. E' ]years old) (see table). Despite absence of profound alterations
 ( C: D$ ?; d! jof serum testosterone the topical therapy provided a greater
 5 t& n3 }' G1 v7 I' d1 M: jAccepted for publication July 1, 1977. ·
 " Z* Q8 p% ?; |$ i# I# H0 TRead at annual meeting of American Urological Association,
 - c# V! w) u; A3 t( P& zChicago, Illinois, April 24-28, 1977.
 2 Y5 \. R1 S3 O! F* Requests for reprints: Division of Urology, Henry Ford Hospital,6 V( F0 r. x% g$ m" j  n) p  B: i
 2799 W. Grand Blvd., Detroit, Michigan 48202.
 ( t0 e2 v2 f: R/ f- ^improvement in phallic growth compared to gonadotropin.
 0 h) i2 Z- P% V8 bAverage phallic growth with gonadotropin was 14.3 per cent
 8 l+ ~# P$ E- q: nincrease in length and 5.0 per cent increase of girth. Topical* K2 |6 J- o  _" w0 E
 testosterone produced a 60.0 per cent increase of phallic length9 S1 M% u- C, u6 N, }( Y7 y9 e
 and 52.9 per cent increase of girth (circumference). The/ c1 B' ]  w* E- v% j( e
 response to topical testosterone was greatest in children be-
 3 H* s5 {2 k6 I  s0 S3 X; z# K% ]4 ktween 4 and 8 years old, with a gradual decrease to age 17
 3 G1 j$ O  K+ s5 H% xyears (see table).
 ( x( F3 U6 G% w: e/ D& C' d5 V0 IDISCUSSION
 * M. r% [* ]7 |4 ?Topical testosterone has been used effectively by other! a, |0 |- @; D6 y9 ^
 clinicians but its mode of action remains controversial. Im-
 % e* J5 R! z7 W2 O. ~' Tmergut and associates reported an excellent growth response/ l8 {9 o# S3 n) r! r) c
 to topical testosterone with low levels of serum testosterone,, ]0 V  z( V. j
 suggesting a local effect.1 Others have obtained growth re-1 z2 a/ @/ p! o5 x0 j: O7 H, N- b
 sponse with high. levels of serum testosterone after topical5 m9 m1 Q7 m, y- ~7 K5 z
 administration, suggesting a systemic response. 3 The use of
 5 Y8 _( d; \  Z4 ?gonadotropin to obtain levels of serum testosterone compara-# p8 P$ {. n6 j* B" H  ^
 ble to levels obtained with topical testosterone would seem to
 9 f3 E# j& P( n# J+ ?* o1 R/ B+ Yprovide a means to compare the relative effectiveness of
 % C' k, }9 F( j, v& v; wtopical testosterone to systemic testosterone effect. It cer-$ U  M4 A0 N4 E! [
 tainly has been established that gonadotropin as well as par-
 - ?; ?2 D& [7 I' B; B3 denteral testosterone administration will produce genital
 8 ?  x; m8 I$ g1 ]1 f; pgrowth. Our report shows that the growth of the phallus was
 3 N% G/ E' o# R8 V" R- Wsignificantly greater with topical applications than with go-' y# u3 o3 r: m
 nadotropin, particularly in children less than 10 years old.
 9 k* g6 D" F$ D) J  A' M9 v3 ZThe levels of serum testosterone remained similar or lower
 $ O1 w9 L) }7 b( x& R# othan with gonadotropin during therapy, suggesting that topi-5 Z3 E/ m6 b9 H* e* H
 cal application produces genital growth by its local effect as3 e+ c2 @: v2 r$ c# n6 O
 well as its systemic effect.4 C  j8 F% g, s. j
 Review of our patients and their growth response related to
 : O; V4 k$ @, P; D. w( s! tage shows a greater growth response at an earlier age. This is
 8 Y2 \6 y6 {" Q$ ^consistent with the findings of Wilson and Walker, who
 1 F( o6 U% u) I3 q) K* \reported an increased conversion of testosterone to dihydrotes-
 ' w: w- J2 C- r6 Y# I* Qtosterone in the foreskin of neonates and infants.4 This activ-" ?6 N3 u- M/ v! k) C
 ity gradually decreases with age until puberty when it ap-
 & ^' j% i" C+ Z& hproaches the same level of activity as peripheral skin. It may
 1 z4 c- |, f6 d1 Ywell be that absorption of testosterone is less when applied at
 1 }/ t9 M, G1 B- lan earlier age as suggested by lower serum levels in children. D" w- C" l7 r3 }  k
 less than 10 years old. This fact may be explained by the
 : N7 W. D( f! w+ |: {# m/ z) cgreater ability of phallic skin to convert testosterone to dihy-
 % `  X# R& [0 Y) ~& [. Z* n: @' }$ ^2 fdrotestosterone at this age. Conversely, serum levels in older# \9 W9 X# \' h  x1 U
 patients were higher, possibly because of decreased local' C, S. M+ J% ^! y+ a: J
 667
 6 T& ~/ p* ?: B8 a. G1 c' {668 KLUGO AND CERNY
 $ [0 i. [1 ?, z$ hPt. Age% g+ [) E5 Z$ H+ |
 (yrs.), z1 g0 W' l) Z9 h  I
 Serum Testosterone Phallus (cm.) Change Length( g0 h1 W( z4 j- I4 P3 ]
 (ng./dl.) Girth x Length (%)
 8 h9 z$ s7 T  J) ?' k) _; [4! ~* ]: O9 F8 n6 _, F* k5 \
 8
 4 a# g. R8 F6 n9 I7 t10, x+ r0 [' m( e0 M
 12
 ! D3 `# g! s5 m; Q) V, q% S17  O5 z1 w& X4 w
 Gonadotropin
 " o" M" C: L' i+ C: {' _% O1 u71.6 2.0 X 3 16.6
 1 R/ r+ x- }4 o- H" E50.4 4.0 X 5.0 20.0( x' |) z9 k2 {1 h( [9 x
 22.0 4.5 X 4.0 25.0+ W0 m+ S5 V5 R
 84.6 4.0 X 4.5 11.1
 6 M3 `7 M; s  }. t85.9 4.5 X 5.5 9.00 p/ S$ ^/ n/ D- @# H7 J
 Av. 14.3
 / }7 A9 c: Y# H# J4
 0 P1 g2 i* n7 r# R4 `, B8( b8 y# k" {8 d) d; A
 10
 + t; _* q3 m& m# ^: ?12: k7 }* _7 }% P& a% W  G0 n) a
 17
 0 C' S  d6 ~6 p: g1 k/ a, b& DTopical testosterone! x" [# v; L' a: U" e
 34.6 4.5 X 6.5 859 e. N' F/ P% T# y- C) A, E
 38.8 6.0 X 8.5 707 u+ f" [* j& y' w" [3 b
 40.0 6.0 X 6.5 62.5) ^8 A( P% v9 l$ a) ?2 b
 93.6 6.0 X 7.0 55.5. ^- s7 w8 T- t+ {% F5 P
 95.0 6.5 X 7.0 27.28 c* ~, U+ I$ I) U
 Av. 60.0
 , _0 z$ e! {4 c6 c& b1 K  k3 U, t- Z* wavailable testosterone. Again, emphasis should be placed on1 `' X9 X7 {; n+ u5 i( y
 early therapy when lower levels of testosterone appear to4 a( O$ x% A, m" P7 ?
 provide the best responses. The earlier therapy is instituted' s( j- p6 D7 u. }6 H6 _+ K  [
 the more likely there will be an excellent response with low
 5 K" h2 e( w$ ~7 n$ `9 Q4 pserum levels. Response occurs throughout adolescence as2 Y' {  |8 ]6 s% w' l" u
 noted in nomograms of phallic growth. 7 The actual response
 6 a! L8 v; L, ~, H& m8 Fto a given serum level of testosterone is much greater at birth
 ! n0 O* S6 A: Y& k" E" o2 rand gradually decreases as boys reach puberty. This is most  E" R2 T% Q! P* K
 likely related to the conversion of testosterone to dihydrotes-6 U) }! I" q- x
 tosterone and correlates well with the studies of testosterone. Q2 A2 `4 U& p# w  S
 conversion in foreskin at various ages.8 Q# j& h+ H! B) h. H5 @0 _; N& x
 The question arises regarding early treatment as to whether( t6 w- ?: s, g. a* j' W  {4 k
 one might sacrifice ultimate potential growth as with acceler-+ i2 _" }) O9 Q6 f8 F5 c2 P
 ated bone growth. The situation appears quite the reverse
 " j! V5 c' b$ f6 A* Wwith phallic response. If the early growth period is not used& q7 I' w  }$ ]8 a
 when 5a reductase activity is greatest then potential growth
 % Z! H+ a- y% n" Ymay be lost. We have not observed any regression of growth
 - v1 \# A' G' w1 @. \) ?attained with topical or gonadotropin therapy. It may well. n5 n5 X. @' Y: s# E# B$ A
 be that some patients will show little or no response to any  Z: L/ Q; R) a; \3 m8 Y5 s7 c
 form of therapy. This would suggest a defect in the ability to
 T3 \" ?  q. \7 p# Fconvert testosterone to dihydrotestosterone and indicate that* W- H+ o( f! [/ f( g* V
 phallic and peripheral skin, and subcutaneous tissue should
 ! I& Z$ J, B* G: k3 P' Ube compared for 5a reductase activity.
 - K+ A6 @6 J0 J  }3 v0 j5 h/ }A, loop enlarges to measure penile girth in millimeters. B,
 , Q9 V. }- j' s& Mexample of penile girth computed easily and accurately.# x' m0 i# |  T: h
 conversion of testosterone to dihydrotestosterone. It is in this2 o' R& H& q0 w- M
 older group that others have noted high levels of serum
 * h' l% w+ a& h! d9 ^5 itestosterone with topical application. It would also appear
 3 [6 c7 [7 K7 t, M1 Hthat phallic response during puberty is related directly to the
 , J- h& u+ t3 L0 [3 l  e- Dserum testosterone level. There also is other evidence of local3 Z" H$ y! n+ K; J
 response to testosterone with hair growth and with spermato-
 C; g9 Z/ C7 Y, t( ?genesis. 5• 6
 . q3 H) J8 ?; m/ i! ?- z, SAdministration of larger doses of gonadotropin or systemic% L1 X8 ]3 x$ x7 C% c
 testosterone, as well as topical applications that produce
 3 V5 @1 @+ p: }+ mhigher levels of serum testosterone (150 to 900 ng./dl.), will. t/ f$ k9 f: k- v# V. w; }7 s
 also produce phallic growth but risks accelerated skeletal1 e0 b; x) j2 y- X6 w, b
 maturation even after stopping treatment. It would appear7 r2 B) p6 [' n2 I+ O8 W1 x
 that this may be avoided by topical applications of testosterone
 2 D9 p( o: J, T" i4 ~and monitoring of serum testosterone. Even with this control/ l! c# v* _0 s  Q: V
 the duration of our therapy did not exceed 3 weeks at any6 Y3 ~2 ~$ \/ i. T3 O4 g' O$ h
 time. It is apparent that the prepuberal male subject may8 G% Y8 y6 }& j/ u) r
 suffer accelerated bone growth with testosterone levels near% y$ Q9 Q9 {+ m) U5 r
 200 ng./dl. When skeletal maturation is complete the level of
 % l! y& y6 Y2 X3 qserum testosterone can be maintained in the 700 to 1,300 ng./
 F" U1 G3 z% ]8 M; z( v; ydl. range to stimulate phallic growth and secondary sexual
 : ^* [' N8 L: w7 h# ychanges. Therefore, after skeletal maturation parenteral tes-& `+ Y3 G" m5 }& h3 v( ]2 H6 Z
 tosterone may be used to advantage. Before skeletal matura-: N3 V% _$ j& C' l9 x3 t
 tion care must be taken to avoid maintaining levels of serum
 4 P$ }  v! v2 Z; ktestosterone more than 100 ng./dl. Low-dose gonadotropin
 % o' v) H" M( r& w1 F& |depends upon intrinsic testicular activity and may require
 & n8 R9 R% @! xprolonged administration for any response.9 W. O9 h* n% G% j0 u( h! ~
 Alternately, topical testosterone does not depend upon tes-
 ! `- x) N) j' j: T1 g$ ?ticular function and may provide a more constant level of
 - F' F, D) c& S) U  W6 `3 YREFERENCES3 q6 p) v, x4 N. G8 p' y) Y: }2 P
 1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
 - j9 \# V0 y+ w, A. k  _R.: The local application of testosterone cream to the prepub-
 ) `3 T9 b- ]9 i6 {ertal phallus. J. Urol., 105: 905, 1971.4 B/ `( H9 X  }5 O( f3 H- |
 2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
 7 V: X' Z# r1 ?3 Rtreatment for micropenis during early childhood. J. Pediat.,2 p4 e! R1 C' ~4 b3 v
 83: 247, 1973.
 ! W. y2 D/ q" u7 K' |3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 z+ d$ v2 [& `- }" g" u+ U+ ~* u
 one therapy for penile growth. Urology, 6: 708, 1975.
 / w7 z- a, M6 [: O. g( y( P4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone  H, \% o3 u& K6 o9 h+ F4 l2 c7 O2 C
 to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by" f; i" o5 o' J2 p' c' c, G% K, j
 skin slices of man. J. Clin. Invest., 48: 371, 1969.0 L6 I7 T# E. i; {0 P
 5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
 1 F4 B$ t* O/ W$ fby topical application of androgens. J.A.M.A., 191: 521, 1965.2 B9 C( ?, p2 L0 d, _4 N4 u4 F/ \
 6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
 7 U, C1 }! O) t" y; k  C0 m; f0 Vandrogenic effect of interstitial cell tumor of the testis. J.
 + f* w6 C3 e* N- hUrol., 104: 774, 1970.
 Z; g- [/ l% i1 W! O4 q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 s0 j! p2 X2 t: a
 tion in the male genitalia from birth to maturity. J. Urol., 48:
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