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fengliu521

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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
+ m9 I0 b/ _6 q; h1 w( S: k! oGONADOTROPIN
# u/ m, u0 I1 r, W- v4 h$ bRICHARD C. KLUGO* AND JOSEPH C. CERNY
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
0 ?8 Y3 a) K! iABSTRACT
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 g/ N" O! G9 z, w- Hincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% ?- N3 H8 @( H" m2 Z, v6 f/ goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
growth. The response appears to be greater in younger children, which is consistent with previ-
ously published studies of age-related 5 reductase activity.
9 I2 `: v0 f: ?' _Children with microphallus regardless of its etiology will
& ~4 `# r8 a9 }$ A* m: erequire augmentation or consideration for alteration of exter-
nal genitalia. In many instances urethroplasty for hypo-
. V' m9 H( Q1 n5 P1 S( uspadias is easier with previous stimulation of phallic growth.
The use of testosterone administered parenterally or topically
has produced effective phallic growth. 1- 3 The mechanism of
1 [) A! t1 {7 \. X- Iresponse has been considered as local or systemic. With this
0 c1 l2 a/ e/ v1 _( _in mind we studied 5 children with microphallus for response
! ^6 o1 K2 k, j- o& _to gonadotropin and to topical testosterone independently.
MATERIALS AND METHODS
/ t" S- N; J) {, ~5 |Five 46 XY male subjects between 3 and 17 years old were
' s3 ~' y* z3 l& ^$ tevaluated for serum testosterone levels and hypothalamic
function. Of these 5 boys 2 were considered to have Kallmann's
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
lamic deficiency. After evaluation of response to luteinizing
hormone-releasing hormone these patients were treated with
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
after completion of gonadotropin therapy 10 per cent topical
testosterone was applied to the phallus twice daily for 3 weeks.
  S5 S+ ^$ U  m" \Serum testosterone, luteinizing hormone and follicle-stimulat-
ing hormone were monitored before, during and after comple-
+ x  D  K7 j  X) u$ M3 @tion of each phase of therapy. Penile stretch length was
obtained by measuring from the symphysis pubis to the tip of
the glans. Penile circumferential (girth) measurements were
obtained using an orthopedic digital measuring device (see
, e' g/ \1 F" G. }; K( Bfigure).
RESULTS
, @/ H: i8 ~; ^! x! @Serum testosterone increased moderately to levels between
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
terone levels with topical testosterone remained near pre-
- N; U% x! Q1 q2 `8 mtreatment levels (35 ng./dl.) or were elevated to similar levels
4 N. ~6 ~- P- {9 |* pdeveloped after gonadotropin therapy (96 ng./dl.). Higher
5 _/ d) N8 F" S% c9 pserum levels were noted in older patients (12 and 17 years old),
$ g. _1 L& N4 t- q& [9 o/ V( hwhile lower levels persisted in younger patients (4, 8, and 10
, b  O& |' Z( w$ i" Kyears old) (see table). Despite absence of profound alterations
2 R4 b. f. u+ U3 K* T0 v3 p, |+ `of serum testosterone the topical therapy provided a greater
Accepted for publication July 1, 1977. ·
Read at annual meeting of American Urological Association,
5 N" L# e2 Q  P( ?: p9 P# QChicago, Illinois, April 24-28, 1977.
* Requests for reprints: Division of Urology, Henry Ford Hospital,
2799 W. Grand Blvd., Detroit, Michigan 48202.
9 G* |' t  E) ?% T4 a0 @improvement in phallic growth compared to gonadotropin.
Average phallic growth with gonadotropin was 14.3 per cent
0 b# m$ P5 N  U0 u3 _) z% Aincrease in length and 5.0 per cent increase of girth. Topical
testosterone produced a 60.0 per cent increase of phallic length
, N% m' y4 A" _and 52.9 per cent increase of girth (circumference). The
3 G7 q) x& I; c! X5 B# @, [7 T' |7 cresponse to topical testosterone was greatest in children be-
tween 4 and 8 years old, with a gradual decrease to age 17
years (see table).
# L* D9 L+ r' k. Q( WDISCUSSION
. Z1 R1 n6 `7 z1 ZTopical testosterone has been used effectively by other
8 T8 m# F& Z4 l& p& }% B/ R& Tclinicians but its mode of action remains controversial. Im-
8 J5 A' @; c# ?( Mmergut and associates reported an excellent growth response
! H+ `$ J$ z" x: ^to topical testosterone with low levels of serum testosterone,
suggesting a local effect.1 Others have obtained growth re-
sponse with high. levels of serum testosterone after topical
6 x* W  m; F9 }/ V% P( W( m7 A; Padministration, suggesting a systemic response. 3 The use of
7 T! o5 ]& y+ X  T  b" b- \0 igonadotropin to obtain levels of serum testosterone compara-
7 P' B  x  K, s: |ble to levels obtained with topical testosterone would seem to
provide a means to compare the relative effectiveness of
topical testosterone to systemic testosterone effect. It cer-
' L1 \6 H3 D4 D3 ~/ b9 Ktainly has been established that gonadotropin as well as par-
- Y/ A& ^1 m) u; Jenteral testosterone administration will produce genital
growth. Our report shows that the growth of the phallus was
significantly greater with topical applications than with go-
nadotropin, particularly in children less than 10 years old.
The levels of serum testosterone remained similar or lower
than with gonadotropin during therapy, suggesting that topi-
cal application produces genital growth by its local effect as
/ J2 A' B6 g- q* m" e, [& Owell as its systemic effect.
1 {) _; s4 f* c( q( eReview of our patients and their growth response related to
# t- z! o. H9 U7 L. f, ~9 Lage shows a greater growth response at an earlier age. This is
consistent with the findings of Wilson and Walker, who
reported an increased conversion of testosterone to dihydrotes-
6 ]: c$ d  \, `' S# W3 ltosterone in the foreskin of neonates and infants.4 This activ-
ity gradually decreases with age until puberty when it ap-
proaches the same level of activity as peripheral skin. It may
well be that absorption of testosterone is less when applied at
7 a) S6 ?0 ?6 \) u% j: W$ V/ F( |an earlier age as suggested by lower serum levels in children
7 r4 b4 X8 ^" |4 c2 ~; d! D6 Jless than 10 years old. This fact may be explained by the
greater ability of phallic skin to convert testosterone to dihy-
drotestosterone at this age. Conversely, serum levels in older
. Y" c. j% q2 E' V+ q3 Apatients were higher, possibly because of decreased local
6 c& k6 g+ F7 v9 X667
668 KLUGO AND CERNY
Pt. Age
; D, U1 G3 r1 U4 N5 g4 g(yrs.)
! G, p2 ?4 w  ]$ \. P5 J* w7 wSerum Testosterone Phallus (cm.) Change Length
" T! }! Y  T) g( ]! F( R* k(ng./dl.) Girth x Length (%)
4
8
, C, D" P, Y. L2 t$ j10
12
17
% k1 p: e' o3 wGonadotropin
71.6 2.0 X 3 16.6
: B% @, m  S. a! u& e# d6 `/ Z0 C50.4 4.0 X 5.0 20.0
- S1 S9 d, ~* T22.0 4.5 X 4.0 25.0
( U7 _; a* F  J2 R% M! J84.6 4.0 X 4.5 11.1
85.9 4.5 X 5.5 9.0
Av. 14.3
4
; @. p2 L$ x5 _& V6 y- }8
. C0 X0 l- H8 j: B10
12
17
3 @0 k1 D1 p0 \2 Z2 z$ f! `Topical testosterone
  ~' q% b; r# ?8 }4 g8 _34.6 4.5 X 6.5 85
8 S% N: ~8 _% u. i38.8 6.0 X 8.5 70
, @9 O2 P& c) i* q$ T: s40.0 6.0 X 6.5 62.5
93.6 6.0 X 7.0 55.5
95.0 6.5 X 7.0 27.2
Av. 60.0
8 T. T; E; [/ ^; K+ Eavailable testosterone. Again, emphasis should be placed on
3 w# K, |7 T8 m& K* i3 fearly therapy when lower levels of testosterone appear to
- K) x, W) X9 I) c8 Jprovide the best responses. The earlier therapy is instituted
3 N1 f% x, K! [% nthe more likely there will be an excellent response with low
" ?: Z2 {- _" e& y9 y* Y0 H2 sserum levels. Response occurs throughout adolescence as
noted in nomograms of phallic growth. 7 The actual response
5 N; K& T: \! p+ n& jto a given serum level of testosterone is much greater at birth
and gradually decreases as boys reach puberty. This is most
& _! f- A7 C( N3 V& P! b( T$ Slikely related to the conversion of testosterone to dihydrotes-
" ?6 f+ l9 N, d! i0 {' ztosterone and correlates well with the studies of testosterone
conversion in foreskin at various ages.
The question arises regarding early treatment as to whether
one might sacrifice ultimate potential growth as with acceler-
9 y8 ?" A) M+ [2 `( a1 L1 @' ^ated bone growth. The situation appears quite the reverse
with phallic response. If the early growth period is not used
when 5a reductase activity is greatest then potential growth
may be lost. We have not observed any regression of growth
attained with topical or gonadotropin therapy. It may well
be that some patients will show little or no response to any
form of therapy. This would suggest a defect in the ability to
: c9 ]6 c! Q+ i2 _/ gconvert testosterone to dihydrotestosterone and indicate that
  s* v; o9 D* [) i& W# Vphallic and peripheral skin, and subcutaneous tissue should
$ a# ^& f2 p% o* U  ]8 q$ I' Qbe compared for 5a reductase activity.
& O, i! ?4 J2 t3 g: t9 d9 e' X: a1 fA, loop enlarges to measure penile girth in millimeters. B,
example of penile girth computed easily and accurately.
2 s6 S% ?- k7 c6 w: econversion of testosterone to dihydrotestosterone. It is in this
* c- _( f7 I3 o; _older group that others have noted high levels of serum
7 a+ V- U5 N( l! R5 h- D0 ntestosterone with topical application. It would also appear
, A- b2 J7 x5 `- Kthat phallic response during puberty is related directly to the
serum testosterone level. There also is other evidence of local
  Q5 Z6 Q' `! W# h1 zresponse to testosterone with hair growth and with spermato-
genesis. 5• 6
Administration of larger doses of gonadotropin or systemic
testosterone, as well as topical applications that produce
5 K  ^3 c! O& ?1 A: Ahigher levels of serum testosterone (150 to 900 ng./dl.), will
- s5 F# ?% m2 a7 Salso produce phallic growth but risks accelerated skeletal
, r, y5 l; K  L. Smaturation even after stopping treatment. It would appear
1 K) [- W4 ]; d1 tthat this may be avoided by topical applications of testosterone
  ^) I& u1 W; j1 G, Zand monitoring of serum testosterone. Even with this control
7 }1 o2 G! z" h( cthe duration of our therapy did not exceed 3 weeks at any
2 F0 I! ^; T8 h* y7 P7 Gtime. It is apparent that the prepuberal male subject may
suffer accelerated bone growth with testosterone levels near
# X2 l9 j4 Q% K" A( Q200 ng./dl. When skeletal maturation is complete the level of
serum testosterone can be maintained in the 700 to 1,300 ng./
6 E3 F6 G4 K, U! pdl. range to stimulate phallic growth and secondary sexual
' o: c  [+ T! A4 c3 Y( {5 Ychanges. Therefore, after skeletal maturation parenteral tes-
: n% j% s4 ^% n4 g7 ]8 Ftosterone may be used to advantage. Before skeletal matura-
tion care must be taken to avoid maintaining levels of serum
testosterone more than 100 ng./dl. Low-dose gonadotropin
) G5 P9 o1 t; j: x9 V5 }depends upon intrinsic testicular activity and may require
7 s8 |  ~3 P! Wprolonged administration for any response.
Alternately, topical testosterone does not depend upon tes-
2 ~1 U- b1 p: l. l: ]ticular function and may provide a more constant level of
: q" N2 i: k; k2 I% u4 fREFERENCES
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
R.: The local application of testosterone cream to the prepub-
) _% @  a+ r( n0 F' y0 F, Kertal phallus. J. Urol., 105: 905, 1971.
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
treatment for micropenis during early childhood. J. Pediat.,
83: 247, 1973.
+ p2 W$ G2 E* K8 [5 x- t& R9 K3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
3 S3 o# x* ?7 B( y8 Vone therapy for penile growth. Urology, 6: 708, 1975.
6 D; L( h' y, X" P6 W4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
5 o) s7 S& \9 N. G  a2 y0 {3 I. Xto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
; m, f* _6 [' P- i* N' ?skin slices of man. J. Clin. Invest., 48: 371, 1969.
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
by topical application of androgens. J.A.M.A., 191: 521, 1965.
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
androgenic effect of interstitial cell tumor of the testis. J.
Urol., 104: 774, 1970.
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ [% m' t1 a8 Z4 `- y, D7 vtion in the male genitalia from birth to maturity. J. Urol., 48: