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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% N  ^! W% m, P5 ?1 {! _$ x
GONADOTROPIN! U9 V- @- C1 A1 N8 p
RICHARD C. KLUGO* AND JOSEPH C. CERNY$ p+ G, a# D0 C1 o
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan0 `( f: D" S' m9 b- E$ v
ABSTRACT: J8 y, B& [1 p- n1 K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' S$ ^! s' S" m0 e8 L6 ^) n( m
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
  U: ]; B; }$ r( }! Rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: D2 G$ Y! d1 s6 X$ t( F% Fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent- p! s  o! a: J/ ~+ S9 P
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
1 U% g$ ?: G$ R0 b1 j/ `9 c4 }increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 V; u* ?. X0 vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
) b: S; B' \& r4 a1 Woccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 P6 T  F' ~0 Y+ u* B' ]' n
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- c$ ]2 D+ _3 u3 ^growth. The response appears to be greater in younger children, which is consistent with previ-4 M- _1 c4 ~# o/ v9 A/ M
ously published studies of age-related 5 reductase activity.
" w; t, C5 ?# B3 B; MChildren with microphallus regardless of its etiology will
; O5 C  L& h! ~7 ~require augmentation or consideration for alteration of exter-
0 ]; z* o; [" M" W1 ?nal genitalia. In many instances urethroplasty for hypo-* Z; c" R% R0 t! \' n8 |( \0 d
spadias is easier with previous stimulation of phallic growth.
- D* z" d0 R; ^The use of testosterone administered parenterally or topically$ H4 M+ i0 R+ g
has produced effective phallic growth. 1- 3 The mechanism of
) l8 r0 B, t' A0 n% ~* ]$ `5 oresponse has been considered as local or systemic. With this7 ]  p& }' x" @9 R
in mind we studied 5 children with microphallus for response
" H! D2 {& ^5 |0 ~5 W8 n! lto gonadotropin and to topical testosterone independently.
, \' R' F; t& u6 W3 u, pMATERIALS AND METHODS- D! n9 x" I. `7 o; A. S+ [4 H
Five 46 XY male subjects between 3 and 17 years old were! e) C. J0 {4 g' B- ~; e2 k! T
evaluated for serum testosterone levels and hypothalamic: j1 u- @3 @- b2 F! {0 ?+ K
function. Of these 5 boys 2 were considered to have Kallmann's* i! L% X- ~( ?$ y/ F& o
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' G8 _+ q  y1 N  i1 Glamic deficiency. After evaluation of response to luteinizing
, V3 h  X* c, J- R4 v8 E, Zhormone-releasing hormone these patients were treated with
5 p1 l) I1 g" K1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& Q+ z% p, e# F$ P" V$ f* Safter completion of gonadotropin therapy 10 per cent topical" r! c+ R, t; i+ r* w
testosterone was applied to the phallus twice daily for 3 weeks.
6 C' N& t$ C. N0 }6 @6 H* iSerum testosterone, luteinizing hormone and follicle-stimulat-6 E8 E- ~  Y- l  ]
ing hormone were monitored before, during and after comple-, j: v6 |2 B9 I" S
tion of each phase of therapy. Penile stretch length was
& m$ L$ `' q  Y$ E) d6 m, O$ o5 Zobtained by measuring from the symphysis pubis to the tip of: g) A1 b* T; `! W4 Z; D& \
the glans. Penile circumferential (girth) measurements were
$ J: M, [0 H6 Z& m( c4 d$ Lobtained using an orthopedic digital measuring device (see2 f2 J& Y4 G# S, E
figure).
8 C+ R( e; r7 R- n" TRESULTS
  |( Z1 V. i" pSerum testosterone increased moderately to levels between8 ?* }* H  |' x7 \* G' u5 k6 r* E
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  D. A! J* A  e9 @; p" }terone levels with topical testosterone remained near pre-
2 O% ]) S* K4 c, ^9 {treatment levels (35 ng./dl.) or were elevated to similar levels1 F6 S4 _/ G: c5 g
developed after gonadotropin therapy (96 ng./dl.). Higher: l. a1 h) \* n* _
serum levels were noted in older patients (12 and 17 years old),
. l( }& a" Q/ l# N! g) W' awhile lower levels persisted in younger patients (4, 8, and 10
* v2 U4 X; V' `2 K1 F% A" Ryears old) (see table). Despite absence of profound alterations5 X( b$ `+ ~. G% M& c# c3 Q  e# c# o
of serum testosterone the topical therapy provided a greater* [! ~1 F' W9 t# h$ \* A( S
Accepted for publication July 1, 1977. ·  v$ Z& e! `: I4 l+ q7 g+ j' ~9 @# N
Read at annual meeting of American Urological Association,% G; p2 I* J& N# C& w) [+ d
Chicago, Illinois, April 24-28, 1977.  [( f3 `) w3 _
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 ~. {$ c+ N+ }! _- U' s
2799 W. Grand Blvd., Detroit, Michigan 48202.: K: D' Z& R8 w! `9 M" `' h
improvement in phallic growth compared to gonadotropin., j9 b0 k1 q6 [1 v' q: O
Average phallic growth with gonadotropin was 14.3 per cent- F+ p, y, C; v) g. ]0 ~- j
increase in length and 5.0 per cent increase of girth. Topical
, h# }( `5 m( E8 g! D. Y+ Gtestosterone produced a 60.0 per cent increase of phallic length
9 H2 Q" X( W% ]: w% n+ Gand 52.9 per cent increase of girth (circumference). The: ^& Z, O$ X8 ?; y! \
response to topical testosterone was greatest in children be-
; g) i" k: x1 |/ A: G0 Htween 4 and 8 years old, with a gradual decrease to age 17
1 y, C2 p; E3 u8 K8 i. t' E9 xyears (see table).0 i2 g: z; u% _6 S& M; U! N# V
DISCUSSION) N5 e0 Z/ x- }/ g! e6 [1 c
Topical testosterone has been used effectively by other7 s9 e( s% K7 g" }1 U* ^. O  v. K
clinicians but its mode of action remains controversial. Im-1 [0 H7 o5 y+ O4 d% m& y
mergut and associates reported an excellent growth response
, J8 N. m9 m) R; h$ vto topical testosterone with low levels of serum testosterone,
) I' H4 Q: P1 _  ^: qsuggesting a local effect.1 Others have obtained growth re-1 F8 U0 v' N5 M
sponse with high. levels of serum testosterone after topical0 k6 `" n3 P2 @1 e
administration, suggesting a systemic response. 3 The use of
0 j, }$ Y! @+ _3 \3 d, U# Fgonadotropin to obtain levels of serum testosterone compara-
9 |4 o4 P5 _! C# _" h5 m2 ]% z3 Cble to levels obtained with topical testosterone would seem to
, I6 Q0 s& {5 mprovide a means to compare the relative effectiveness of. s& d7 U* W2 s* {
topical testosterone to systemic testosterone effect. It cer-
: s0 ?. q; I! ~1 itainly has been established that gonadotropin as well as par-
; d# [/ ]' @5 d; _: `enteral testosterone administration will produce genital/ v1 q1 I% n) L7 s$ N; @
growth. Our report shows that the growth of the phallus was$ d4 ^" j6 \; K) q" |3 u- G. h& Y
significantly greater with topical applications than with go-8 S. @' J/ j( j! j# ^
nadotropin, particularly in children less than 10 years old.
! u7 i7 J3 b1 }$ _. b7 H9 _The levels of serum testosterone remained similar or lower7 n1 I7 H* i$ g$ _! U) Y) M
than with gonadotropin during therapy, suggesting that topi-
3 V& `% H) n( ]$ c; Ncal application produces genital growth by its local effect as
  W/ O. p. ^+ Lwell as its systemic effect.
+ T  S4 Y& h9 R) B% G$ mReview of our patients and their growth response related to
# e, m; G; d% Vage shows a greater growth response at an earlier age. This is; l% }- H& F6 @8 k8 T  Z/ i: ]3 Y
consistent with the findings of Wilson and Walker, who. a: a6 ~8 c5 D
reported an increased conversion of testosterone to dihydrotes-/ o4 B" c" v/ ]5 Y7 ?
tosterone in the foreskin of neonates and infants.4 This activ-
, \8 [4 T" ^$ ^6 d1 m; a& W# p! ?- p- bity gradually decreases with age until puberty when it ap-% P; Q$ n7 n5 N4 C2 H) v# \
proaches the same level of activity as peripheral skin. It may( d7 P! `& {0 n1 t" O
well be that absorption of testosterone is less when applied at
- \( n( s. d5 N6 d0 S* Uan earlier age as suggested by lower serum levels in children! P8 Y. |5 f( e3 w1 M( D
less than 10 years old. This fact may be explained by the
7 v! g1 i! ^/ R+ Q5 fgreater ability of phallic skin to convert testosterone to dihy-
& V, p; T+ U& Ddrotestosterone at this age. Conversely, serum levels in older% \; U! Z1 J0 H# k
patients were higher, possibly because of decreased local  N2 H: U; m5 f8 k; Q( \- g' k8 \
667
; P* k- ~+ B0 s+ v/ E668 KLUGO AND CERNY# ?6 \2 n6 s# W/ D3 P: ~# Y, J
Pt. Age
  _2 g; k+ P- ~6 i(yrs.)
3 y% Q4 `# E# t2 |) j* ^Serum Testosterone Phallus (cm.) Change Length% Q( F8 F7 {* }7 G
(ng./dl.) Girth x Length (%)2 ~0 E$ I. V; _. Y+ m/ _5 j
4
4 [2 r& D/ Y" ]4 B: C1 [8
2 ^% t/ P+ w, T# K- j8 @0 g10
7 Y. w, V- b# N9 e4 Z12! G3 Z, ]1 `, l/ W
17! g3 T6 D, O* g3 R
Gonadotropin
! a0 W4 D" a! S7 B; x71.6 2.0 X 3 16.66 x% F% E0 R1 ~' D, \
50.4 4.0 X 5.0 20.0
$ G4 o6 \$ @4 F9 [- I7 E22.0 4.5 X 4.0 25.0
! T' P( K2 S) n9 e0 E84.6 4.0 X 4.5 11.1
  t& k- K, R. S* n5 E85.9 4.5 X 5.5 9.0
2 }3 Q7 ^0 u8 y- lAv. 14.31 U5 D0 t6 X% z' T" v& [5 h+ l
4
' D) B! W0 r' t5 h( ~8
9 S1 Y( `" x4 ]! ?0 O% H- q' I. D104 |! h( t# o* [9 G. C
12' |+ o' f& C$ W& u
17
1 H) [$ _, i( |+ x& T$ n" H" fTopical testosterone
1 M- v* p2 N* l, Z1 t% J& @34.6 4.5 X 6.5 85
+ V0 z8 Y$ L  l- D8 y6 P38.8 6.0 X 8.5 70% R+ x5 {! _0 ]" n% x
40.0 6.0 X 6.5 62.5& c% B  V7 t" y
93.6 6.0 X 7.0 55.5! z1 Q! N& `( U  h! p
95.0 6.5 X 7.0 27.25 b' z8 f, u7 G, @
Av. 60.0% u' j; ]( h/ u4 ~
available testosterone. Again, emphasis should be placed on9 A- x; u; [0 u: e0 B5 n) l4 ]
early therapy when lower levels of testosterone appear to3 Z. y% [1 f  [* ]" b: O
provide the best responses. The earlier therapy is instituted
" K" c% D% r/ h3 k  V5 Wthe more likely there will be an excellent response with low
, L$ r' a* h# k, O1 }  j! oserum levels. Response occurs throughout adolescence as9 J9 |2 C7 l" G9 ^' U
noted in nomograms of phallic growth. 7 The actual response
3 _1 a0 x8 r( K7 o' }/ h: ?to a given serum level of testosterone is much greater at birth3 K& j/ Y- g5 N9 W3 m
and gradually decreases as boys reach puberty. This is most5 ^2 b; {' w$ p0 a5 m- v  {
likely related to the conversion of testosterone to dihydrotes-
  P$ X  v3 d7 T+ r; K3 U% Ftosterone and correlates well with the studies of testosterone
5 g+ e3 _* e% r* E1 \conversion in foreskin at various ages.
+ s3 l+ G$ i+ H1 e) g  n2 n) yThe question arises regarding early treatment as to whether% ?8 @* \8 {1 O; }1 m0 i' |9 X1 `
one might sacrifice ultimate potential growth as with acceler-/ L) c8 ~/ r" u  d% X* A" ?
ated bone growth. The situation appears quite the reverse
# k' ]7 Q$ y4 x; {; A( a$ {with phallic response. If the early growth period is not used
0 z/ m4 R: O9 Dwhen 5a reductase activity is greatest then potential growth7 v- i+ |' B2 }# f8 u4 _) I
may be lost. We have not observed any regression of growth" G/ A- U4 C( c* F* L- M
attained with topical or gonadotropin therapy. It may well
+ A5 X+ K& K8 y' E) ~% }+ \- }9 mbe that some patients will show little or no response to any
' j8 \4 [" O) k8 ?. `form of therapy. This would suggest a defect in the ability to5 q2 `" Q6 K4 P* L
convert testosterone to dihydrotestosterone and indicate that- a! B* F/ p7 z# H! V0 r
phallic and peripheral skin, and subcutaneous tissue should; S, t7 z5 X; H6 I3 R7 z  Q" |
be compared for 5a reductase activity.' Q4 K; l# {8 a! t# t  s2 _, V
A, loop enlarges to measure penile girth in millimeters. B,
7 O' S0 V1 v6 }$ a. N( dexample of penile girth computed easily and accurately.
  V% P3 H& P2 v( l, g7 _4 J( \- tconversion of testosterone to dihydrotestosterone. It is in this
" q& r5 m, E. u- Zolder group that others have noted high levels of serum
6 n2 p' `  y" r3 B8 H6 e9 ?testosterone with topical application. It would also appear5 C& s9 K' G( G+ L, p  W
that phallic response during puberty is related directly to the! U: t# O! N6 s8 s- e) h
serum testosterone level. There also is other evidence of local
- L% L) T1 U3 P) P  ]& j5 b1 A% `response to testosterone with hair growth and with spermato-6 z- d; t& [4 _! T, G. H  u
genesis. 5• 6% D8 B8 E: @! @5 |' ~
Administration of larger doses of gonadotropin or systemic+ }1 Z6 l' @- h8 f9 h
testosterone, as well as topical applications that produce9 S3 R0 L" u5 S
higher levels of serum testosterone (150 to 900 ng./dl.), will
# P6 v! S6 @5 |5 z$ galso produce phallic growth but risks accelerated skeletal% l% e# x: b" n% F7 D: q! P' a
maturation even after stopping treatment. It would appear7 P3 u* Z9 z6 `) D' S( O
that this may be avoided by topical applications of testosterone- U' B. L7 ?+ x# Y" P1 G( |7 m$ w
and monitoring of serum testosterone. Even with this control
8 H0 \# P' Z" I' P& }the duration of our therapy did not exceed 3 weeks at any) t: e2 L& X" A- G  {1 a
time. It is apparent that the prepuberal male subject may* [  f/ V1 z! @; P9 [$ t  S  a3 A
suffer accelerated bone growth with testosterone levels near3 N0 y1 d' ?) s9 K: k  }# ?
200 ng./dl. When skeletal maturation is complete the level of' L3 a9 }7 I5 y3 y! x8 j$ m
serum testosterone can be maintained in the 700 to 1,300 ng./
, w5 E: j( u# }dl. range to stimulate phallic growth and secondary sexual
! g9 ?2 T. h6 G# rchanges. Therefore, after skeletal maturation parenteral tes-) Z- E# z7 C. p. [4 Q1 {' D
tosterone may be used to advantage. Before skeletal matura-: @$ v' w6 {1 d  N& }, r, u
tion care must be taken to avoid maintaining levels of serum  d: N  ?  f6 E6 m+ Q& B
testosterone more than 100 ng./dl. Low-dose gonadotropin
  v3 H8 [' F0 F$ zdepends upon intrinsic testicular activity and may require
7 @( {7 c3 y0 z0 M9 z) r( e* bprolonged administration for any response.
  R: t! E! R6 v. s5 N" i) PAlternately, topical testosterone does not depend upon tes-. _3 X2 A' g/ X- B# y- N
ticular function and may provide a more constant level of; c/ z& Q" c$ K8 P1 e! R  T
REFERENCES
% D( V3 g: H% p! m/ l5 {9 }1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 |' l% r& }+ Y% V1 WR.: The local application of testosterone cream to the prepub-! d- g1 ~( h- ^2 ~5 G0 v8 C
ertal phallus. J. Urol., 105: 905, 1971.# v7 ~# U" }; j3 U
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, Z( y- V% U7 S" k( h4 ]
treatment for micropenis during early childhood. J. Pediat.,$ D6 u3 ^# b9 E) O& F3 E/ T' U
83: 247, 1973.) u; M" b+ c" Q+ z
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
: W& ^6 U0 k! O6 @' Mone therapy for penile growth. Urology, 6: 708, 1975.3 v% o9 ^$ J- c5 @  ~' F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 G+ q7 A7 F- x5 uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. w" E" |( k$ x7 ^8 e
skin slices of man. J. Clin. Invest., 48: 371, 1969.
* I$ u- _( p+ H* i- }5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. R/ D/ s9 H8 x' T
by topical application of androgens. J.A.M.A., 191: 521, 1965.0 O& D, f$ v! M. W4 q
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 }: I( b7 Y9 J9 `9 j0 n
androgenic effect of interstitial cell tumor of the testis. J.4 ^' a5 f1 o  u3 J7 ^8 C
Urol., 104: 774, 1970.2 C" U$ h# h. h  h% g! y
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
6 m8 |3 n3 h# q* etion in the male genitalia from birth to maturity. J. Urol., 48:
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