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fengliu521

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kaifka

RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
GONADOTROPIN
5 G9 j( E" o% F* ^: r8 gRICHARD C. KLUGO* AND JOSEPH C. CERNY
) x$ d, o* ^1 QFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# ]  S. N9 C  PABSTRACT
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
! {' F, N8 w. X- X( h/ s) `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
6 F# ^9 [6 y1 ^! V) Rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
6 y7 P5 H. u# l- Roccurred 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.
( b6 W7 A3 O8 W4 _+ G( ~Children with microphallus regardless of its etiology will
require augmentation or consideration for alteration of exter-
nal genitalia. In many instances urethroplasty for hypo-
spadias is easier with previous stimulation of phallic growth.
The use of testosterone administered parenterally or topically
+ I  i" ~$ t5 c" Thas produced effective phallic growth. 1- 3 The mechanism of
response has been considered as local or systemic. With this
- {, J6 J# a; p  ]6 Jin mind we studied 5 children with microphallus for response
to gonadotropin and to topical testosterone independently.
! m3 ~  X( R  Z( `% HMATERIALS AND METHODS
Five 46 XY male subjects between 3 and 17 years old were
evaluated 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
' V1 I8 c0 I! c' P1,000 units of gonadotropin weekly for 3 weeks. Six weeks
after completion of gonadotropin therapy 10 per cent topical
" A) o& k. T2 W$ |( d; F8 X) S0 _testosterone was applied to the phallus twice daily for 3 weeks.
Serum testosterone, luteinizing hormone and follicle-stimulat-
6 t* y' n) W$ Ding hormone were monitored before, during and after comple-
tion of each phase of therapy. Penile stretch length was
% J9 T7 Y# O( kobtained by measuring from the symphysis pubis to the tip of
. D' w  |. q/ g& ~. ^) Mthe glans. Penile circumferential (girth) measurements were
obtained using an orthopedic digital measuring device (see
1 B2 ]  E* D6 Q: F4 O/ l$ U. p! [figure).
RESULTS
0 `4 g  m8 B6 J: ]% HSerum testosterone increased moderately to levels between
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
terone levels with topical testosterone remained near pre-
treatment levels (35 ng./dl.) or were elevated to similar levels
developed after gonadotropin therapy (96 ng./dl.). Higher
" m) J3 f* `( K( h0 Lserum levels were noted in older patients (12 and 17 years old),
3 @/ ?( Q) g: b. k6 j( [& @while lower levels persisted in younger patients (4, 8, and 10
% ~9 {* F- I" }( p$ U/ Nyears old) (see table). Despite absence of profound alterations
5 B! {2 U) T  h( B/ sof serum testosterone the topical therapy provided a greater
; a4 V' X* H' q( N* t* \: s9 [Accepted for publication July 1, 1977. ·
5 N  t  Y: d# ]! o9 C" y" f( {Read at annual meeting of American Urological Association,
Chicago, Illinois, April 24-28, 1977.
2 d0 S: l0 f5 p( u: V+ q& X, [* Requests for reprints: Division of Urology, Henry Ford Hospital,
2799 W. Grand Blvd., Detroit, Michigan 48202.
/ {( n) J, U9 wimprovement in phallic growth compared to gonadotropin.
Average phallic growth with gonadotropin was 14.3 per cent
8 I3 ~7 W4 g5 s3 w0 e! ]4 rincrease in length and 5.0 per cent increase of girth. Topical
( b$ L$ j! h* v4 gtestosterone produced a 60.0 per cent increase of phallic length
and 52.9 per cent increase of girth (circumference). The
response to topical testosterone was greatest in children be-
tween 4 and 8 years old, with a gradual decrease to age 17
years (see table).
7 t9 F' v* t$ F7 u4 zDISCUSSION
% H( Q( c0 w! ]% sTopical testosterone has been used effectively by other
clinicians but its mode of action remains controversial. Im-
# ~% i5 @( t- f% h) C7 ^% m, umergut and associates reported an excellent growth response
to topical testosterone with low levels of serum testosterone,
. H/ I3 ]) d, @, W+ W% Esuggesting a local effect.1 Others have obtained growth re-
sponse with high. levels of serum testosterone after topical
administration, suggesting a systemic response. 3 The use of
' c& r) a- h% k6 Rgonadotropin to obtain levels of serum testosterone compara-
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-
* M4 X. }- \2 P4 t% X3 i' J6 ]tainly has been established that gonadotropin as well as par-
enteral testosterone administration will produce genital
* x. z' a8 }- y) l, b7 {% |growth. Our report shows that the growth of the phallus was
significantly greater with topical applications than with go-
: E4 B0 |& q" {0 c, ^$ Rnadotropin, 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
" T& E+ a4 j$ E  a5 bwell as its systemic effect.
# z) I! K2 E( c  {4 oReview of our patients and their growth response related to
5 |) G7 e& I+ I; ^age 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-
) H. d) \& T8 ^) _" t7 Ytosterone in the foreskin of neonates and infants.4 This activ-
# n& k; `* l4 City gradually decreases with age until puberty when it ap-
: K! K4 g* M, }$ hproaches the same level of activity as peripheral skin. It may
well be that absorption of testosterone is less when applied at
$ e- }( @7 I+ R  z" ^( Dan earlier age as suggested by lower serum levels in children
less 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
patients were higher, possibly because of decreased local
667
668 KLUGO AND CERNY
Pt. Age
/ h. {: r/ C& p" p/ H% ~+ a(yrs.)
  @4 h  C2 S! I2 a1 B+ y! m0 ESerum Testosterone Phallus (cm.) Change Length
(ng./dl.) Girth x Length (%)
% q" K! V4 O/ w( v4
8
10
12
8 e1 ]8 {; D' _17
Gonadotropin
/ y& ^/ m- e+ U2 l/ t71.6 2.0 X 3 16.6
50.4 4.0 X 5.0 20.0
22.0 4.5 X 4.0 25.0
84.6 4.0 X 4.5 11.1
8 x4 U# L0 _" S9 r85.9 4.5 X 5.5 9.0
Av. 14.3
1 s7 s/ w6 r& A* g0 `4
8
10
4 e- q5 |2 W  L$ {12
' w$ X3 Q5 V6 b% w5 f17
Topical testosterone
34.6 4.5 X 6.5 85
38.8 6.0 X 8.5 70
40.0 6.0 X 6.5 62.5
93.6 6.0 X 7.0 55.5
( }) b2 D4 u$ q6 e8 @6 ^95.0 6.5 X 7.0 27.2
Av. 60.0
available testosterone. Again, emphasis should be placed on
0 @4 w, G# b) K) p9 V1 I3 ]early therapy when lower levels of testosterone appear to
provide the best responses. The earlier therapy is instituted
0 s6 K( V# X7 ?% W! s2 cthe more likely there will be an excellent response with low
serum levels. Response occurs throughout adolescence as
noted in nomograms of phallic growth. 7 The actual response
to a given serum level of testosterone is much greater at birth
& o% j) ?& U) Z4 W/ C' o  yand gradually decreases as boys reach puberty. This is most
3 D! E; h- z8 U5 P8 x- W. v3 o  clikely related to the conversion of testosterone to dihydrotes-
! n& }* j6 e3 s& H8 w8 ]tosterone and correlates well with the studies of testosterone
conversion in foreskin at various ages.
# @1 b6 w* T, O' A! j" k" f+ ?The question arises regarding early treatment as to whether
one might sacrifice ultimate potential growth as with acceler-
ated bone growth. The situation appears quite the reverse
" P1 c6 T8 N/ B  k* S1 f( Z; q" Nwith phallic response. If the early growth period is not used
: R- C) J) f, @( P1 K' K( M8 E( Uwhen 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
/ ?; B: O) `/ ]8 u2 Abe that some patients will show little or no response to any
0 v6 X2 q* @3 G1 Hform of therapy. This would suggest a defect in the ability to
convert testosterone to dihydrotestosterone and indicate that
" u. K$ a' X/ k4 U% Jphallic and peripheral skin, and subcutaneous tissue should
. O* N6 H* f5 O' mbe compared for 5a reductase activity.
A, loop enlarges to measure penile girth in millimeters. B,
: a! B$ ~9 F# j" zexample of penile girth computed easily and accurately.
conversion of testosterone to dihydrotestosterone. It is in this
older group that others have noted high levels of serum
testosterone with topical application. It would also appear
0 ]0 n4 k# u! O2 s; Hthat phallic response during puberty is related directly to the
serum testosterone level. There also is other evidence of local
response to testosterone with hair growth and with spermato-
) Q- ^  P- t7 @6 H! Hgenesis. 5• 6
+ \/ x9 G2 W% @/ k. M  x2 c$ BAdministration of larger doses of gonadotropin or systemic
* L/ S3 q: c$ w4 H  I( Ztestosterone, as well as topical applications that produce
- U  e3 A, m# Hhigher levels of serum testosterone (150 to 900 ng./dl.), will
: ?' A* r, n' y6 yalso produce phallic growth but risks accelerated skeletal
3 U. I- O2 N1 P' z6 mmaturation even after stopping treatment. It would appear
# G: s4 C9 o$ e( _) h  lthat this may be avoided by topical applications of testosterone
  z. w: W! v$ X. Yand monitoring of serum testosterone. Even with this control
6 u5 U  t! ]3 P0 uthe duration of our therapy did not exceed 3 weeks at any
time. It is apparent that the prepuberal male subject may
suffer accelerated bone growth with testosterone levels near
9 K5 p1 G$ \% ^8 Q, \200 ng./dl. When skeletal maturation is complete the level of
serum testosterone can be maintained in the 700 to 1,300 ng./
* N5 V4 K$ ~0 b. Mdl. range to stimulate phallic growth and secondary sexual
changes. Therefore, after skeletal maturation parenteral tes-
tosterone 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
7 J$ X8 r" m' \  hdepends upon intrinsic testicular activity and may require
prolonged administration for any response.
Alternately, topical testosterone does not depend upon tes-
ticular function and may provide a more constant level of
) C9 ^: L7 j: F' f+ n& D  LREFERENCES
5 Y* ]4 y  Z' W0 s5 G- H: F1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
. Q* l4 a/ z3 Z' |, GR.: The local application of testosterone cream to the prepub-
ertal phallus. J. Urol., 105: 905, 1971.
% c( Y1 u# f! |8 A# U, \2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
+ I( c+ Y# x/ O/ b7 X$ ltreatment for micropenis during early childhood. J. Pediat.,
$ o" Q# y3 O8 h( ?6 {9 V1 ?6 t83: 247, 1973.
, l3 W8 e: e( I# J4 w3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
one therapy for penile growth. Urology, 6: 708, 1975.
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
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.
) g) C. q  e# g; B5 g% [6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
1 F2 w8 _8 @0 ~6 gandrogenic effect of interstitial cell tumor of the testis. J.
Urol., 104: 774, 1970.
( N2 ~' t- ~1 G7 ^# M' t" p$ N7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
tion in the male genitalia from birth to maturity. J. Urol., 48: