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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 k, N3 e$ V" }8 sGONADOTROPIN! C3 d/ R3 X  ^* r! i7 d- R
RICHARD C. KLUGO* AND JOSEPH C. CERNY* w  S) O2 Y! m& q
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan! [: S6 ?, H8 p2 V: ?
ABSTRACT
* h3 b$ E( M$ x, V( @Five patients were treated with gonadotropin and topical testosterone for micropenis associated  v/ O$ F. W. N! K: a. i
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 y+ ], c/ T# B. A# n' C; ?( z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 m6 `' m9 @& c/ i' S6 O! ucream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' B) c" i( F, _5 A! U  q+ w! bfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 k, g& m/ x+ l! w7 nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; s6 z) r0 _  ?) R6 I. hincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 `! v* Y- L3 ~% t% ^
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ k8 D9 X  e6 q1 t* N( M+ o) j% x
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, A( C# K  _- f1 M$ X) y$ M
growth. The response appears to be greater in younger children, which is consistent with previ-! N/ f9 J+ T+ q% S. z1 Q: c
ously published studies of age-related 5 reductase activity.
# n) \$ Q4 p& p- \# AChildren with microphallus regardless of its etiology will4 G( z/ d1 I2 f
require augmentation or consideration for alteration of exter-
" @6 P) s$ M  K' _+ ?nal genitalia. In many instances urethroplasty for hypo-
% {8 U' K- V# fspadias is easier with previous stimulation of phallic growth.
2 Y! b3 B- s3 x8 GThe use of testosterone administered parenterally or topically
* v( w- `) _/ x) Y* v9 O% Khas produced effective phallic growth. 1- 3 The mechanism of
( W) F4 V5 [3 n4 Hresponse has been considered as local or systemic. With this3 g8 D& c0 `3 Y' ]0 |7 D
in mind we studied 5 children with microphallus for response$ V6 L; o4 ?! a$ |4 r7 D! u
to gonadotropin and to topical testosterone independently.  X3 l! B! v% y$ S- `: y
MATERIALS AND METHODS4 Y) }5 s' G6 y; i9 q: _9 H( n, {
Five 46 XY male subjects between 3 and 17 years old were5 Q$ V  A6 b4 O0 |  b) m* N% n
evaluated for serum testosterone levels and hypothalamic& y( |( _# R! f  H/ b/ p$ L
function. Of these 5 boys 2 were considered to have Kallmann's
& c( V- a* S* b3 `# Jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-: v* |$ k4 h# D& W( }* Y
lamic deficiency. After evaluation of response to luteinizing2 l, f& y* w, F7 J  P# x- k, _
hormone-releasing hormone these patients were treated with( V/ Z6 A; H6 V3 c& N
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
1 i: C5 z3 d1 \' v* c7 L7 x" r' U; Rafter completion of gonadotropin therapy 10 per cent topical
# r) ~8 Y- i; ntestosterone was applied to the phallus twice daily for 3 weeks.4 o$ l+ ?5 [7 Q
Serum testosterone, luteinizing hormone and follicle-stimulat-" U8 \. `2 |8 [7 n
ing hormone were monitored before, during and after comple-' n# h6 d8 s3 e* _0 w; O. w
tion of each phase of therapy. Penile stretch length was
. ~$ a( e1 L7 j+ s4 v; Hobtained by measuring from the symphysis pubis to the tip of0 g& m* C3 K* t# @! d2 `" @5 J0 P4 Q
the glans. Penile circumferential (girth) measurements were
* u* s* ]- `" ]; Q6 Y; R3 vobtained using an orthopedic digital measuring device (see7 ]/ T  d. x4 ?! ]8 z
figure)./ a: g2 T0 k" w% D
RESULTS& h1 X7 ?$ P! _) ]; u
Serum testosterone increased moderately to levels between
% f  n7 B9 s9 ^4 ^50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  k$ j' M2 C2 ^terone levels with topical testosterone remained near pre-# y4 p# P, {' L4 r3 h: U# i
treatment levels (35 ng./dl.) or were elevated to similar levels% b% t, P! _! m' i' z( d
developed after gonadotropin therapy (96 ng./dl.). Higher/ W' J- `; [- C0 q4 j, g& O% G1 Z# U
serum levels were noted in older patients (12 and 17 years old),: q+ F1 p$ d0 i1 l0 A2 i# r
while lower levels persisted in younger patients (4, 8, and 10# j" t! Q8 b! m6 e. D
years old) (see table). Despite absence of profound alterations
* |! b& `' Q8 wof serum testosterone the topical therapy provided a greater
; R* P' M: c* _$ l! yAccepted for publication July 1, 1977. ·0 t5 v  i! \' H
Read at annual meeting of American Urological Association,
  f3 P2 o4 w) l5 {  ?3 ~8 IChicago, Illinois, April 24-28, 1977./ F' u* P+ s) o9 n" k8 |" i
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 H) W) |. D4 \. T2799 W. Grand Blvd., Detroit, Michigan 48202.! \$ J; t5 f' h/ E0 h/ p; ^1 l
improvement in phallic growth compared to gonadotropin.
! b7 e# ]9 S/ P- _/ NAverage phallic growth with gonadotropin was 14.3 per cent' p! z6 u& D; s/ E, E
increase in length and 5.0 per cent increase of girth. Topical
4 L. T  q4 j  }$ \# R3 B0 stestosterone produced a 60.0 per cent increase of phallic length
+ ^( O: j$ x7 M7 D: [" c* yand 52.9 per cent increase of girth (circumference). The
) F5 G) x& D9 X* m$ a8 K/ y  Hresponse to topical testosterone was greatest in children be-
2 h0 m: Q. O( p( E+ T1 |; |tween 4 and 8 years old, with a gradual decrease to age 17) i$ {' i' b, ^9 }' [& S  i
years (see table).- r" |  a) y& ^( p# }
DISCUSSION
. K: X9 F7 p( [Topical testosterone has been used effectively by other
& s- X" U0 g$ }' H- q/ Z7 B9 ^8 Y5 Aclinicians but its mode of action remains controversial. Im-: M8 N; {7 U: H" B- c
mergut and associates reported an excellent growth response
3 q# _6 J" r% `3 {  z0 Tto topical testosterone with low levels of serum testosterone,, F6 I# t; W. _  ]0 }, q3 x: I4 z
suggesting a local effect.1 Others have obtained growth re-
) S  e* V6 b7 Fsponse with high. levels of serum testosterone after topical- z1 Z( h$ }8 ~/ R* ]+ |9 o4 w6 F: i
administration, suggesting a systemic response. 3 The use of
% S! r- ]) k% |1 y  ]" {- fgonadotropin to obtain levels of serum testosterone compara-, ]+ [% P2 |" {2 @0 q2 |; p
ble to levels obtained with topical testosterone would seem to
; i9 K" d7 h9 k% zprovide a means to compare the relative effectiveness of
0 O6 a* ]  Q; Z& V* Y6 otopical testosterone to systemic testosterone effect. It cer-
- P& t1 {8 w; @& Ktainly has been established that gonadotropin as well as par-
! ?; z; w% y. K- Senteral testosterone administration will produce genital
7 q8 \+ `7 g+ m" kgrowth. Our report shows that the growth of the phallus was
7 N9 m* d) O: B  Msignificantly greater with topical applications than with go-! h# o7 V8 R- D
nadotropin, particularly in children less than 10 years old.
1 ?5 O$ o+ K1 E6 m# \7 E1 w& g1 W- TThe levels of serum testosterone remained similar or lower! _+ {2 v! F$ {  M5 W" [
than with gonadotropin during therapy, suggesting that topi-
, Y- ^4 Q; |2 K5 m* F* W0 Mcal application produces genital growth by its local effect as
5 e( I+ k4 k! c6 ]6 M2 y: rwell as its systemic effect.
) O" `1 R  s( I6 Q4 O$ r. a$ M4 dReview of our patients and their growth response related to
, ?) G  g  P0 d  v8 h. {  y) k/ rage shows a greater growth response at an earlier age. This is6 V5 Y7 K6 a% |& V
consistent with the findings of Wilson and Walker, who
5 i$ h! |. }) E% w: k0 W( Y- `reported an increased conversion of testosterone to dihydrotes-
9 p% A* y4 M& B3 [" {" Mtosterone in the foreskin of neonates and infants.4 This activ-: D" U3 E4 C7 @, D8 N
ity gradually decreases with age until puberty when it ap-- Q6 `7 \+ _8 h( L; N! t. c7 W/ j9 U
proaches the same level of activity as peripheral skin. It may
% M1 }; p  n% K' G' wwell be that absorption of testosterone is less when applied at
5 e9 R7 Z  u- S2 Man earlier age as suggested by lower serum levels in children
9 Y5 M5 l. J* i, R1 ~3 hless than 10 years old. This fact may be explained by the
7 }% o) |! z3 X' _4 n9 I1 tgreater ability of phallic skin to convert testosterone to dihy-( T& r2 f2 R4 \: g( r+ O, ?
drotestosterone at this age. Conversely, serum levels in older% W% O: i; C& \# i, T
patients were higher, possibly because of decreased local
' w) z: Z8 V- q" [667  h) ?' S% Z) l5 D& S+ Z
668 KLUGO AND CERNY
4 @: ^. B  S2 ?& h" }. JPt. Age0 m! O/ `, K: H1 _: s& {/ \3 G
(yrs.)
/ I, N) y5 k. f6 V1 jSerum Testosterone Phallus (cm.) Change Length8 N& Q6 ~  g/ T  z6 y3 N
(ng./dl.) Girth x Length (%)/ N7 X8 H$ M3 u* m& X
41 t" g4 A: C" Z1 ?# \( f  B% i
88 `4 t% N: h+ |3 |7 p
10
9 r, \# I+ J5 H& h0 }' [) R12
" N% r- z7 v7 k# G/ R+ O17
! a7 k0 ?  r9 w8 L) p  bGonadotropin
8 e" `9 B  M/ C8 v) y7 B" h2 u3 x71.6 2.0 X 3 16.6' A( {5 ]0 F6 }2 _  [. B# p; |3 M
50.4 4.0 X 5.0 20.0
1 L# V4 C  K( @9 \9 J22.0 4.5 X 4.0 25.02 y" r4 O' {& g+ K/ t8 Q
84.6 4.0 X 4.5 11.1( }9 d! [* s5 f
85.9 4.5 X 5.5 9.0; Z( y2 B* b; p
Av. 14.3% e4 I# _' f3 o( Q6 o3 \8 j) J% P
4
1 G- r) F9 |2 H1 e! v8
2 p1 I  o+ Z# M* ?+ N2 E( z7 [106 V; {' M1 {4 h
12) |. ]4 d6 S8 ?( s$ V9 j9 {$ J) c2 M
17
. t( W+ e0 s; l& }2 TTopical testosterone
/ N6 J/ H' n% k2 C# K* o3 B6 N34.6 4.5 X 6.5 85
( j- {: X0 J  T7 J4 {* M5 z38.8 6.0 X 8.5 70  @: q+ k% Z/ ?0 Y- c4 _
40.0 6.0 X 6.5 62.5
3 ]* f& V9 r" ]93.6 6.0 X 7.0 55.5
% d- {% `) E- v' [+ r* _8 }/ Z95.0 6.5 X 7.0 27.2
+ x3 b3 b( P4 UAv. 60.0
4 ~( l: h0 K1 s2 W, k1 J# z2 lavailable testosterone. Again, emphasis should be placed on
: K+ P' }- s& e# \6 Rearly therapy when lower levels of testosterone appear to# a* m; ]3 o+ `3 [" A- K  b( Z9 B
provide the best responses. The earlier therapy is instituted$ J: {8 t6 ~0 R6 \) I
the more likely there will be an excellent response with low
1 ?; o. I  @) N; xserum levels. Response occurs throughout adolescence as6 P, }2 V3 ]" j4 l' c# r4 x
noted in nomograms of phallic growth. 7 The actual response' O0 d5 T  s' y1 h, b
to a given serum level of testosterone is much greater at birth! ^% v2 R# _/ q% Z/ P$ N: ~  p1 X( g, ]
and gradually decreases as boys reach puberty. This is most! _" b$ \, m% w& E0 N
likely related to the conversion of testosterone to dihydrotes-
; V# [) \4 S7 Y% b; |tosterone and correlates well with the studies of testosterone7 j" x% j. O5 h
conversion in foreskin at various ages.9 T1 d) ?, {0 w) {4 q% k
The question arises regarding early treatment as to whether5 u, D2 t' A7 s; @4 a, ?& S
one might sacrifice ultimate potential growth as with acceler-$ i; j/ e1 r3 f9 B. c
ated bone growth. The situation appears quite the reverse9 K# s1 K0 l: n* |1 `
with phallic response. If the early growth period is not used+ S2 R# H8 T" i: K! D, S
when 5a reductase activity is greatest then potential growth0 z- Z+ B; d4 x) i
may be lost. We have not observed any regression of growth2 B) b7 O7 u0 l, C" N  z1 X
attained with topical or gonadotropin therapy. It may well3 I) s  a- ]6 P9 t& s$ _
be that some patients will show little or no response to any
' y- f! X  W/ Vform of therapy. This would suggest a defect in the ability to, @' y7 p4 u' j% x1 j
convert testosterone to dihydrotestosterone and indicate that
& f4 d7 u6 c& j# e$ M2 uphallic and peripheral skin, and subcutaneous tissue should# j, [  l8 @; ^
be compared for 5a reductase activity.( x& C8 ~) o" N0 w+ M( b3 |% y
A, loop enlarges to measure penile girth in millimeters. B,
/ Q, w& e* u9 p% i+ x9 v) _% }example of penile girth computed easily and accurately.
' r5 O( N" @% k) ~  rconversion of testosterone to dihydrotestosterone. It is in this! M& Q: ~7 \6 Y* X- U
older group that others have noted high levels of serum( k) Q. J/ j9 g2 P; o( O) r3 B
testosterone with topical application. It would also appear
4 l2 @& K" ^2 E+ W6 @( s( ethat phallic response during puberty is related directly to the- b' C! N7 C! n2 v. H
serum testosterone level. There also is other evidence of local1 B! }. ^- X4 x; ]$ D) J
response to testosterone with hair growth and with spermato-
8 H, V$ o$ O7 Xgenesis. 5• 6
% E& P* t7 M" M  DAdministration of larger doses of gonadotropin or systemic% f, i* ~7 `# P) G+ s
testosterone, as well as topical applications that produce. z; a' C2 _! {, c5 W4 w
higher levels of serum testosterone (150 to 900 ng./dl.), will
3 ^2 V# Q' d$ [  u$ I: U/ S: Ralso produce phallic growth but risks accelerated skeletal
8 X6 Y4 {% G0 X% E1 T# X6 ^7 ]6 pmaturation even after stopping treatment. It would appear. K: o% C3 k6 f" r0 }
that this may be avoided by topical applications of testosterone
; h. _7 x+ j8 f+ ^" s2 }  e  @and monitoring of serum testosterone. Even with this control4 o; \2 h, i- n* i
the duration of our therapy did not exceed 3 weeks at any
3 I9 V  C7 h3 dtime. It is apparent that the prepuberal male subject may  V& E- h9 \1 v! H3 Z
suffer accelerated bone growth with testosterone levels near9 h/ T! H3 ?0 x3 R1 W
200 ng./dl. When skeletal maturation is complete the level of
7 {0 t. `3 w1 a* n9 U, Vserum testosterone can be maintained in the 700 to 1,300 ng./
/ ?2 ~  {9 l: ]' K$ l5 rdl. range to stimulate phallic growth and secondary sexual
# U/ S( I! ]9 g" N0 gchanges. Therefore, after skeletal maturation parenteral tes-$ ]: `' {: n8 K$ l: X- b" a
tosterone may be used to advantage. Before skeletal matura-
% Y2 {  ~4 h! r  P% \7 Rtion care must be taken to avoid maintaining levels of serum
* q3 |; M) V% t0 ^testosterone more than 100 ng./dl. Low-dose gonadotropin
$ @/ B$ u; l% H/ U3 I2 A9 r7 Y$ p  Pdepends upon intrinsic testicular activity and may require  p9 i: a; K3 z9 d
prolonged administration for any response.
) ^1 @2 O6 m! e8 D% S+ rAlternately, topical testosterone does not depend upon tes-
  y5 B& j& G6 E! }" hticular function and may provide a more constant level of1 k3 y# B0 B8 m7 G+ A. i
REFERENCES
) h/ e* O" O) ]" J" ]' @1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' [8 [1 w5 e& \  F+ ?7 b
R.: The local application of testosterone cream to the prepub-
5 B4 O" |- L7 r6 G" Q' T6 B9 aertal phallus. J. Urol., 105: 905, 1971.
6 A" y3 a" c( s/ L2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) d# \. c1 E/ c8 s7 J+ Ctreatment for micropenis during early childhood. J. Pediat.,
+ O9 P/ y% ~) b% t2 @83: 247, 1973.# r" V/ }" B% x$ y5 V7 F# t( [
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' N1 P, I( G$ E% Q8 Z' kone therapy for penile growth. Urology, 6: 708, 1975.
5 r% p2 e4 Z% y3 @. e! {4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 c, s' p* X6 ]to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# A6 u* j6 ^2 h6 m; H0 _skin slices of man. J. Clin. Invest., 48: 371, 1969.
& n% \9 l& }+ ^' E: |2 v5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
  n( N+ U9 \3 w# [- Hby topical application of androgens. J.A.M.A., 191: 521, 1965./ ]( q3 K3 c! `
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ g$ F9 \% B1 f4 w; M  d2 E: W+ ~/ p
androgenic effect of interstitial cell tumor of the testis. J.* T+ r$ t* \6 l. a  _" Y
Urol., 104: 774, 1970.
1 j& g( O& P1 R; N8 R' i/ d7 {# @7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
3 S8 |, _4 ?& d' D8 Dtion in the male genitalia from birth to maturity. J. Urol., 48:
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