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long7857

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fengliu521

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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
GONADOTROPIN
2 X; W4 o" |5 ?8 ^1 HRICHARD C. KLUGO* AND JOSEPH C. CERNY
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 v$ N) N4 N. oABSTRACT
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
0 S" N2 i: `5 q6 v+ Uwith 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
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
occurred 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.
- t; v; ?; _2 B% T9 Y5 o! K! [. @2 }& DChildren with microphallus regardless of its etiology will
; m! x+ @/ ?$ l) Erequire 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
: D$ T* O6 E  Shas produced effective phallic growth. 1- 3 The mechanism of
! u& d: _- o) ~, A; G( ^  {response has been considered as local or systemic. With this
in mind we studied 5 children with microphallus for response
to gonadotropin and to topical testosterone independently.
MATERIALS AND METHODS
. g. s) Y* T6 O* N- E: m# zFive 46 XY male subjects between 3 and 17 years old were
" F$ M# [. T2 oevaluated 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
3 i9 t% `5 u# g! N" R* Rhormone-releasing hormone these patients were treated with
  D3 h/ i1 r1 R! q( F6 a% [$ g1,000 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.
Serum testosterone, luteinizing hormone and follicle-stimulat-
! J0 W; ]4 {* Ging hormone were monitored before, during and after comple-
tion of each phase of therapy. Penile stretch length was
4 K8 y3 I$ D0 E- g4 `obtained by measuring from the symphysis pubis to the tip of
$ L. U5 A5 n6 t0 V/ C9 ithe glans. Penile circumferential (girth) measurements were
5 w3 M! G$ D6 I3 @+ n- pobtained using an orthopedic digital measuring device (see
- V/ I3 l. ]8 L4 L9 m, ifigure).
' j3 D$ x5 m; T7 R1 @) B0 WRESULTS
Serum testosterone increased moderately to levels between
3 B. _; K/ b- M% N4 ]50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  d$ V1 F7 o6 v) Hterone levels with topical testosterone remained near pre-
* Z: V2 k: \1 b0 Ytreatment levels (35 ng./dl.) or were elevated to similar levels
developed after gonadotropin therapy (96 ng./dl.). Higher
serum levels were noted in older patients (12 and 17 years old),
while lower levels persisted in younger patients (4, 8, and 10
0 }' ]& Z% |6 h+ Iyears old) (see table). Despite absence of profound alterations
& c* l* G7 ]1 N4 `/ |of serum testosterone the topical therapy provided a greater
Accepted for publication July 1, 1977. ·
Read at annual meeting of American Urological Association,
" B6 X9 s& \! p, q$ Q4 aChicago, Illinois, April 24-28, 1977.
- }4 r4 b& l; z0 f+ r# P% t. ]* Requests for reprints: Division of Urology, Henry Ford Hospital,
2799 W. Grand Blvd., Detroit, Michigan 48202.
improvement in phallic growth compared to gonadotropin.
5 h7 B. `+ b' C/ Q7 j7 d6 j1 T& o$ VAverage phallic growth with gonadotropin was 14.3 per cent
2 j9 ^! T  g  |" A0 t, y( Z) tincrease in length and 5.0 per cent increase of girth. Topical
  t3 A1 T  f( l1 \7 Y& Dtestosterone 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-
! |/ B6 X% ^4 W7 _9 J; d: ftween 4 and 8 years old, with a gradual decrease to age 17
2 B0 O4 S+ I6 l: f! {; }years (see table).
9 B5 ^- k1 h9 l+ W- m  N1 X( MDISCUSSION
Topical testosterone has been used effectively by other
  I( |4 a: N2 C' gclinicians but its mode of action remains controversial. Im-
2 ^. U& |; b! C4 w) Z$ b% H: f, rmergut and associates reported an excellent growth response
1 t0 x+ P. W7 T0 M  v" oto topical testosterone with low levels of serum testosterone,
% ~- B* U1 _* m  ~suggesting a local effect.1 Others have obtained growth re-
# k' n6 l$ z! a, A3 \' {) ~sponse with high. levels of serum testosterone after topical
administration, suggesting a systemic response. 3 The use of
gonadotropin to obtain levels of serum testosterone compara-
ble to levels obtained with topical testosterone would seem to
* N: X- @) ]8 |4 b9 B. S/ ?provide a means to compare the relative effectiveness of
% P4 Z& m7 j/ E* D8 @topical testosterone to systemic testosterone effect. It cer-
tainly has been established that gonadotropin as well as par-
$ w* F! k# \1 \enteral testosterone administration will produce genital
growth. Our report shows that the growth of the phallus was
significantly greater with topical applications than with go-
8 }+ T6 Q$ G" w' L3 n9 |nadotropin, particularly in children less than 10 years old.
: d  _4 P0 e% u/ u$ h3 BThe levels of serum testosterone remained similar or lower
) S5 \3 S% A- [than with gonadotropin during therapy, suggesting that topi-
cal application produces genital growth by its local effect as
well as its systemic effect.
/ L9 o$ y" k/ x. b% f+ `Review of our patients and their growth response related to
! D' |- f5 A8 S% B0 `1 tage shows a greater growth response at an earlier age. This is
consistent with the findings of Wilson and Walker, who
1 t. S$ X. y, f3 B% sreported an increased conversion of testosterone to dihydrotes-
tosterone in the foreskin of neonates and infants.4 This activ-
3 w+ C) k" K9 D& f5 dity gradually decreases with age until puberty when it ap-
proaches the same level of activity as peripheral skin. It may
0 O$ A9 ^2 |/ @' I- lwell be that absorption of testosterone is less when applied at
- F  }! g, q+ K# i- Can earlier age as suggested by lower serum levels in children
less than 10 years old. This fact may be explained by the
& ]5 V6 C: [8 W8 ^greater ability of phallic skin to convert testosterone to dihy-
drotestosterone at this age. Conversely, serum levels in older
) e. f, `9 d  S: ypatients were higher, possibly because of decreased local
" i3 m* z) R- W. A' q0 Z667
668 KLUGO AND CERNY
) y9 D& Z8 T! W3 Y' \  y; XPt. Age
(yrs.)
! ^* S/ |( j% |* t, \Serum Testosterone Phallus (cm.) Change Length
' }3 H+ @7 y7 y. N" E5 Y5 c3 J(ng./dl.) Girth x Length (%)
& y" O& Q9 }7 T7 n# J4
8
; H; v& \, b) Y5 x# J% ^  U5 B" H10
/ F" Z5 [: e: V5 L$ |) n7 c12
; n( v5 r, Z5 V7 D* H# C17
! h, Q: O3 A( [' lGonadotropin
4 Q/ _: h% M1 N& g6 {7 v71.6 2.0 X 3 16.6
9 T* e* `4 b( V" h50.4 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
, n/ _/ M* ]7 j) t0 u$ u* E85.9 4.5 X 5.5 9.0
Av. 14.3
1 _( y9 t6 f9 `1 K! o  w  e/ b4
8
10
, ~% D1 i6 q  S12
+ F. M+ B+ N. \9 ]$ }: L17
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
+ m: V6 j, D8 l95.0 6.5 X 7.0 27.2
7 G) p2 l0 U$ C4 jAv. 60.0
: L8 I) s9 g2 F3 k+ i3 _3 h3 |' Y: Kavailable testosterone. Again, emphasis should be placed on
. E; n1 S3 S. h2 S/ C( y& learly therapy when lower levels of testosterone appear to
provide the best responses. The earlier therapy is instituted
) D0 g5 {0 h$ I+ Xthe more likely there will be an excellent response with low
7 R, Y) B- ^- U* I" j6 Y/ x2 {! n& aserum levels. Response occurs throughout adolescence as
noted in nomograms of phallic growth. 7 The actual response
8 `) G- ?7 g$ O* ]to a given serum level of testosterone is much greater at birth
and gradually decreases as boys reach puberty. This is most
likely related to the conversion of testosterone to dihydrotes-
7 `- C& M! \7 D/ ^1 e* s( r- ?tosterone and correlates well with the studies of testosterone
conversion in foreskin at various ages.
" q4 K5 t9 z8 {( ^6 OThe question arises regarding early treatment as to whether
& o" c* d- P( }one might sacrifice ultimate potential growth as with acceler-
/ T+ s0 H5 T& z" L' F7 Dated 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
8 e* c. A" Q1 O  s% F3 N5 lform of therapy. This would suggest a defect in the ability to
$ [9 ]; v' i( tconvert testosterone to dihydrotestosterone and indicate that
phallic and peripheral skin, and subcutaneous tissue should
# M1 ~: H  y  @1 u1 J1 Bbe compared for 5a reductase activity.
A, loop enlarges to measure penile girth in millimeters. B,
  k2 p! E' F2 w# A5 Qexample of penile girth computed easily and accurately.
conversion of testosterone to dihydrotestosterone. It is in this
2 M. O$ v  i: [older group that others have noted high levels of serum
% i1 r' r+ R- P3 A( ztestosterone with topical application. It would also appear
that 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-
genesis. 5• 6
Administration of larger doses of gonadotropin or systemic
testosterone, as well as topical applications that produce
higher levels of serum testosterone (150 to 900 ng./dl.), will
- ]3 O+ f& Z0 x: g% L! ]1 ~also produce phallic growth but risks accelerated skeletal
& m! ]& p# ]3 R- U" f, u8 f+ Dmaturation even after stopping treatment. It would appear
( [/ t3 V& ]2 Y0 cthat this may be avoided by topical applications of testosterone
1 `7 r) M. T: f& xand monitoring of serum testosterone. Even with this control
the duration of our therapy did not exceed 3 weeks at any
' }- ^/ d/ Q) Y9 Y: y% n/ x5 Jtime. It is apparent that the prepuberal male subject may
suffer accelerated bone growth with testosterone levels near
+ _6 o' {% f0 b0 F$ R9 B! o+ }& @200 ng./dl. When skeletal maturation is complete the level of
serum testosterone can be maintained in the 700 to 1,300 ng./
dl. range to stimulate phallic growth and secondary sexual
changes. Therefore, after skeletal maturation parenteral tes-
2 i0 v/ u3 ], Htosterone may be used to advantage. Before skeletal matura-
0 ]8 f5 p$ n6 a/ I8 mtion care must be taken to avoid maintaining levels of serum
" h0 |0 v: y$ _) l* Q2 htestosterone more than 100 ng./dl. Low-dose gonadotropin
depends upon intrinsic testicular activity and may require
& K3 @- B* l) ?( u+ _prolonged administration for any response.
9 F* V8 w6 d2 n) JAlternately, topical testosterone does not depend upon tes-
ticular function and may provide a more constant level of
REFERENCES
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 A; f: ], H$ q! d$ ]R.: The local application of testosterone cream to the prepub-
) m+ c! j! i9 K* t  p& hertal 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.
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 U. n! u" g  N, n7 \one therapy for penile growth. Urology, 6: 708, 1975.
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- d, e9 \2 Z- m9 l9 Z' h; bto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 S! q- ?- `0 m2 Q: K0 xskin 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.
5 J( S/ s  q( A' q, F6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ N- t& k% A* z* ~8 S9 j  Aandrogenic effect of interstitial cell tumor of the testis. J.
* G  ^( r4 n, |' G/ a1 d9 O' D/ ?Urol., 104: 774, 1970.
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
! }* T. `5 p- C  t8 D$ ~0 a6 Ation in the male genitalia from birth to maturity. J. Urol., 48: