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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* Y( b! x; H  N: f1 ]# {6 v' @
GONADOTROPIN
$ K1 S, b# v4 w0 rRICHARD C. KLUGO* AND JOSEPH C. CERNY; K! N1 c* q4 |
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& w4 O1 |6 w$ J6 B9 g. j  p
ABSTRACT
# I# a+ l/ H$ X) GFive patients were treated with gonadotropin and topical testosterone for micropenis associated' U+ R$ l& Z- v6 c9 u
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-# o2 t' v' s, ~5 j
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: Q# o2 h% N5 v9 L. M; icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
- M4 y. M8 Q3 \4 m# b7 ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 @% a" m2 E' u# ~, Jincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average- p- Z; k$ I+ c# V; L
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ [9 g0 M3 y0 C2 Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ w. z2 w3 u5 u8 S1 _" lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# J, x0 \/ Q4 W* B6 n, _: E" qgrowth. The response appears to be greater in younger children, which is consistent with previ-
8 e; ~% _' }% b1 ]ously published studies of age-related 5 reductase activity./ j  t2 w  d" Z& F5 r* d
Children with microphallus regardless of its etiology will
1 h5 x9 Y8 N6 @0 n+ I# S' ?! Jrequire augmentation or consideration for alteration of exter-
: [1 ^( B: i4 k: S9 c+ N9 B- j; U( Xnal genitalia. In many instances urethroplasty for hypo-
( u2 d7 C' u; E- N2 t1 y; ~- p% U. espadias is easier with previous stimulation of phallic growth.
. J5 |/ _& L/ d+ Z* ?5 D) zThe use of testosterone administered parenterally or topically
! Z" M) ~' A8 `7 f1 S1 K! chas produced effective phallic growth. 1- 3 The mechanism of5 [, O* E. A: f5 Z6 @- c
response has been considered as local or systemic. With this! L: P4 n! r% u$ v7 x
in mind we studied 5 children with microphallus for response' w2 i5 F6 C) c* v3 r% n9 B# k  Y8 d
to gonadotropin and to topical testosterone independently.
" c8 ?6 h5 X9 ]MATERIALS AND METHODS
+ f6 M- u% J8 n! u, h* g) CFive 46 XY male subjects between 3 and 17 years old were
0 u9 r8 B8 n) D1 e$ S, K7 `evaluated for serum testosterone levels and hypothalamic
3 G9 x9 Q0 b0 x5 X; Y/ }; v7 r) }0 ifunction. Of these 5 boys 2 were considered to have Kallmann's
7 f* h  N9 j% Z1 L" |syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( x6 p' h( u7 @2 L+ w4 {lamic deficiency. After evaluation of response to luteinizing/ j9 T8 s. @1 P1 D
hormone-releasing hormone these patients were treated with6 j: y4 L7 f6 e7 a6 s, l+ P
1,000 units of gonadotropin weekly for 3 weeks. Six weeks! b- i) Q5 D. y5 M5 {. I
after completion of gonadotropin therapy 10 per cent topical  F( ~: @! \: K' R% A
testosterone was applied to the phallus twice daily for 3 weeks.1 a: c0 n2 A  C5 D% y4 \; h' L* Z
Serum testosterone, luteinizing hormone and follicle-stimulat-0 y6 o4 o8 y+ k. V
ing hormone were monitored before, during and after comple-9 P, _) e, N& [
tion of each phase of therapy. Penile stretch length was
3 d# e) n' i4 l1 Oobtained by measuring from the symphysis pubis to the tip of$ L: i9 h. ]( |1 D: p
the glans. Penile circumferential (girth) measurements were
$ F5 a# H2 ^4 j! c/ T. aobtained using an orthopedic digital measuring device (see  I3 M* `0 b- [/ j6 }! t. F" M) u$ {1 W
figure).
% I# u9 o3 T# J1 d4 C& g9 dRESULTS
; ?! ]0 T7 G; ~! D/ N' MSerum testosterone increased moderately to levels between7 c- V- b6 R* M4 W- K
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 P* L* l+ ~& D% {% b- tterone levels with topical testosterone remained near pre-' o0 m, l- F9 `8 W
treatment levels (35 ng./dl.) or were elevated to similar levels% r5 s  k: ~9 z, k4 L0 e, P
developed after gonadotropin therapy (96 ng./dl.). Higher
  `% M# K# s  Q: u8 u2 x9 W( Mserum levels were noted in older patients (12 and 17 years old),
$ Q5 M& p$ ]* E6 C% e+ k2 dwhile lower levels persisted in younger patients (4, 8, and 10% [5 `! J. T# t
years old) (see table). Despite absence of profound alterations
- x/ L, k0 }' B, r* pof serum testosterone the topical therapy provided a greater2 S0 g% q1 H% Q# X( o
Accepted for publication July 1, 1977. ·; ], l" I* r' Z- ]% u" j! ]1 z
Read at annual meeting of American Urological Association,
  R7 j* j9 p. V$ Y1 M& j( PChicago, Illinois, April 24-28, 1977.
# t2 n9 Z$ g7 L- U& J4 @* Requests for reprints: Division of Urology, Henry Ford Hospital,5 o; z3 d  c! o) _/ a, a: b
2799 W. Grand Blvd., Detroit, Michigan 48202.
( m6 T! o) t( O# l2 a/ Ximprovement in phallic growth compared to gonadotropin.1 h! q5 y( m( p  L3 g4 S1 P
Average phallic growth with gonadotropin was 14.3 per cent5 p/ X( Y1 v* Z3 G, |
increase in length and 5.0 per cent increase of girth. Topical. ]' f3 q2 s* K1 A0 B. M
testosterone produced a 60.0 per cent increase of phallic length) m6 ?; R! ~" A- W4 s3 A
and 52.9 per cent increase of girth (circumference). The5 q1 [5 y0 z" i, W! f
response to topical testosterone was greatest in children be-
$ A. f2 z+ D9 q: i6 S, g# F1 _6 J, dtween 4 and 8 years old, with a gradual decrease to age 17
0 \$ |5 N$ Y% r% {years (see table).
1 g5 w% A& K) S  h0 s- RDISCUSSION0 e4 i" q: Q: n0 \* y' T" o
Topical testosterone has been used effectively by other- x1 f* G+ S% S" F
clinicians but its mode of action remains controversial. Im-
; E7 f$ q- I" o9 z' w6 R# Zmergut and associates reported an excellent growth response7 z6 `0 R% z# k( ~* {" c: ?  ~. y. G
to topical testosterone with low levels of serum testosterone,- `( A, m+ ^# ~) C
suggesting a local effect.1 Others have obtained growth re-2 o' g0 @5 t% C8 o6 D8 r
sponse with high. levels of serum testosterone after topical
" f9 @- `' s  }7 n" n; i+ gadministration, suggesting a systemic response. 3 The use of
: D0 g+ u9 Q6 Lgonadotropin to obtain levels of serum testosterone compara-
" x$ U& i, I. s2 m3 Q4 Cble to levels obtained with topical testosterone would seem to( V: ^4 {( `4 i9 f% x- k
provide a means to compare the relative effectiveness of
( ~' Q" m+ T- F" T  L6 i5 xtopical testosterone to systemic testosterone effect. It cer-
6 H+ C: u1 X8 b1 A5 R1 a' ]& Jtainly has been established that gonadotropin as well as par-
  b  t6 \) ~5 `0 Q4 uenteral testosterone administration will produce genital; q6 h- g7 u* Q, ?# i3 c
growth. Our report shows that the growth of the phallus was8 G. |" `0 t0 v' l  y$ m
significantly greater with topical applications than with go-
% j% K# S! k. L3 D6 Qnadotropin, particularly in children less than 10 years old.5 E+ d0 k7 F0 R0 U( ~( r* q/ U
The levels of serum testosterone remained similar or lower
8 O. T) ?1 [! D% N& lthan with gonadotropin during therapy, suggesting that topi-* T2 K9 `2 b4 Z" L3 s
cal application produces genital growth by its local effect as
! x* q! U; v" U- E4 ?7 Awell as its systemic effect.
! ~/ Q0 b) G2 u5 i! yReview of our patients and their growth response related to# [5 P1 Q3 K7 {, k3 R3 O
age shows a greater growth response at an earlier age. This is
8 c' Q$ f# r' C6 A5 K5 Q4 ^- Fconsistent with the findings of Wilson and Walker, who4 l. G3 g+ N0 T& R) v2 W& ~$ u' m+ D
reported an increased conversion of testosterone to dihydrotes-3 {& M- k- s- S, m# P
tosterone in the foreskin of neonates and infants.4 This activ-
4 r( g( f% r5 o( T, ]- wity gradually decreases with age until puberty when it ap-  y0 [2 m# ]1 K* u& |6 `' V6 p
proaches the same level of activity as peripheral skin. It may
0 x) w/ v' Y% e- B' t9 k% Uwell be that absorption of testosterone is less when applied at
3 N5 g( S- d5 B4 a/ f+ @& P6 san earlier age as suggested by lower serum levels in children7 X  N: L+ F1 a: G/ X# ?9 G
less than 10 years old. This fact may be explained by the
7 @& G6 Z" J2 E$ j7 {greater ability of phallic skin to convert testosterone to dihy-5 z/ Q" n1 {0 j  K  d3 P" |
drotestosterone at this age. Conversely, serum levels in older, u2 F/ u1 Z- [1 h3 t) O( {
patients were higher, possibly because of decreased local
) |* p% k  Y& _; X0 K1 }667) F& C. D: |# ^) n0 V
668 KLUGO AND CERNY6 m* u; V. s; A5 E( {+ t6 @
Pt. Age: Z" b7 J$ f6 ?3 I6 c
(yrs.)
8 [8 m2 g& S7 _6 O& {$ ASerum Testosterone Phallus (cm.) Change Length
6 d$ l& i8 ^6 \' L& z( i(ng./dl.) Girth x Length (%)8 ?5 c: A) d; m- z
4$ e9 t* @& s, z/ X
8
5 F6 U: Y# Z* }5 |' D2 n8 _$ u10
; G* G# r* G9 i" j# ^' f12
) c2 n' u( P+ U$ t+ ~7 ]6 u175 H, L3 o5 |& z# g/ \; C" W2 _5 ^
Gonadotropin
5 ]# S+ r, K4 w8 D71.6 2.0 X 3 16.6$ g+ k& M0 k4 M( g" Z' O8 e
50.4 4.0 X 5.0 20.0' T4 o' R$ O1 C3 p* u) |7 P
22.0 4.5 X 4.0 25.0, R. t# P5 d) F$ o4 Q
84.6 4.0 X 4.5 11.16 u7 `% y; x1 K+ F# e; `! e
85.9 4.5 X 5.5 9.0) q' l* A: [& ]" ?  v% f$ h* T" J7 K% P
Av. 14.3
: j' k7 x$ H4 I( j2 g4
# s, s9 x6 w3 j. i2 Z/ Z3 r! C* ^8
5 B. }( M' W+ J, L% X8 F9 g7 ]( @10
  V4 [5 Z+ t6 L5 y9 h) q6 ]12$ U5 L# ~3 }% n; h% Q
17/ ~% q6 s- w1 T8 d# ]$ I
Topical testosterone
- q* ?2 a$ }; N. u4 w( z34.6 4.5 X 6.5 85
' u5 o  h) A2 [7 v( P8 y38.8 6.0 X 8.5 70' s- v: b/ Q" Z: \! s; H6 c( ]+ L
40.0 6.0 X 6.5 62.5" R; ?" K$ A/ G' q  K0 g
93.6 6.0 X 7.0 55.5
1 H' X& i, T  n0 o4 _95.0 6.5 X 7.0 27.2
1 h2 ?( ?, f1 E* S! l5 \Av. 60.0
$ Y! O0 J' I' q/ y; navailable testosterone. Again, emphasis should be placed on
: j5 [$ C9 h$ n, d) Aearly therapy when lower levels of testosterone appear to
+ Q; J* T. ~$ y, r5 U$ Dprovide the best responses. The earlier therapy is instituted# @/ M2 e, h4 I: @, D
the more likely there will be an excellent response with low7 Q& A: f6 f( O8 @6 u4 T# t- N
serum levels. Response occurs throughout adolescence as& E- k& ?2 W" [* I8 s
noted in nomograms of phallic growth. 7 The actual response
1 K* Z) m. \; |) F8 D- S) [to a given serum level of testosterone is much greater at birth9 {- i( v6 U; H% G  |3 M- h
and gradually decreases as boys reach puberty. This is most
2 G& U1 ^0 d3 V, mlikely related to the conversion of testosterone to dihydrotes-/ N8 g# Y; n& R- n
tosterone and correlates well with the studies of testosterone" N" E- Z$ o2 z2 N6 A% J$ X' o- _
conversion in foreskin at various ages.$ P  W2 Y! g$ K+ V: d/ f. o3 G
The question arises regarding early treatment as to whether9 ?# x4 a8 f5 j1 L) p  i
one might sacrifice ultimate potential growth as with acceler-
, K$ n/ Z: v8 e# v- e$ Tated bone growth. The situation appears quite the reverse2 A" {$ C" t/ U6 u4 B
with phallic response. If the early growth period is not used
  C, M8 y* P  ?6 o4 Vwhen 5a reductase activity is greatest then potential growth
' T/ A) E, s' ?* D/ Z( X0 t8 dmay be lost. We have not observed any regression of growth
6 z  f0 I% J" M1 L2 u2 ?attained with topical or gonadotropin therapy. It may well" R( F* n  ^& c
be that some patients will show little or no response to any
) }$ |' {2 o4 |4 ~form of therapy. This would suggest a defect in the ability to+ |2 e6 U: r% d  E; k
convert testosterone to dihydrotestosterone and indicate that
& w5 d! U9 m+ z" ]4 xphallic and peripheral skin, and subcutaneous tissue should
  h. C2 Q9 H4 p8 u( ]6 ?  `be compared for 5a reductase activity.
/ i4 k$ c: w6 u; ~A, loop enlarges to measure penile girth in millimeters. B,
+ ~3 _1 A7 {0 ?% Sexample of penile girth computed easily and accurately.
1 w. t. f+ E& ?) _; s0 z1 r4 D6 xconversion of testosterone to dihydrotestosterone. It is in this. l3 |6 H* M& W* Y' S1 q
older group that others have noted high levels of serum
% w/ Z& m4 w/ atestosterone with topical application. It would also appear
) w  I1 F0 ]# f* m5 U' `that phallic response during puberty is related directly to the7 u4 _1 w1 H0 F4 F: x
serum testosterone level. There also is other evidence of local( c: A( U; h9 q
response to testosterone with hair growth and with spermato-5 f( t7 f, J9 n( O9 M
genesis. 5• 6
& Z: h8 w5 q& i# E3 R, V7 IAdministration of larger doses of gonadotropin or systemic
0 s4 [; c: h/ S2 J& k/ qtestosterone, as well as topical applications that produce! J* `& [/ P3 l0 {
higher levels of serum testosterone (150 to 900 ng./dl.), will
. M+ Y8 w( v4 q, n3 dalso produce phallic growth but risks accelerated skeletal
& R( y6 `! b; P6 Lmaturation even after stopping treatment. It would appear
+ p/ v0 s" Q+ I+ tthat this may be avoided by topical applications of testosterone
( i/ i+ Q" r. j8 j9 Q" h! C" hand monitoring of serum testosterone. Even with this control8 y; ]' s# u. [4 d$ V
the duration of our therapy did not exceed 3 weeks at any
0 \# @: Y1 r. Y! c2 ~% Atime. It is apparent that the prepuberal male subject may: P. T5 R; H, v/ F7 N
suffer accelerated bone growth with testosterone levels near) G0 R0 d. `7 K4 L2 v# L
200 ng./dl. When skeletal maturation is complete the level of0 h/ ]8 D, n" v. }. z2 N7 [
serum testosterone can be maintained in the 700 to 1,300 ng./" y% k) i; K6 P) l4 l! n7 F
dl. range to stimulate phallic growth and secondary sexual
& {* Q! b5 a2 A9 gchanges. Therefore, after skeletal maturation parenteral tes-
" D: I' B- D9 L# Y$ K" o, ztosterone may be used to advantage. Before skeletal matura-
/ W2 F$ q2 O3 J' A/ a- b. t* o( Xtion care must be taken to avoid maintaining levels of serum
5 ~4 o1 a: a6 Ktestosterone more than 100 ng./dl. Low-dose gonadotropin
$ Y& F) t+ t6 W) Zdepends upon intrinsic testicular activity and may require& M; X; ]- E) |4 j0 d
prolonged administration for any response.( a0 S# V5 ?3 H; t" y
Alternately, topical testosterone does not depend upon tes-
; G6 ^- \8 n; V- Qticular function and may provide a more constant level of' \8 W  @! R1 |5 D
REFERENCES2 B' S3 |' z8 ^( F: M
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 f5 a3 A  J( f$ c9 N/ xR.: The local application of testosterone cream to the prepub-7 P" l9 ^5 r0 G9 M- a- F$ H' t( O
ertal phallus. J. Urol., 105: 905, 1971.
4 A' G# u6 W& U% f  S2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 s6 |& k+ q9 @* b4 G& J  dtreatment for micropenis during early childhood. J. Pediat.,1 c% O; i/ x6 ?0 u4 y  b3 Y3 J9 t
83: 247, 1973.
' x. K1 w- ~+ k+ e! H& ~0 |3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-9 A8 l/ p7 F) P! |
one therapy for penile growth. Urology, 6: 708, 1975.0 I1 ^  m8 o) C! i$ v, c2 V9 Z2 J
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone( z& K, T, x; I) O+ f+ Z3 u
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* X, I. f- P- N, ~skin slices of man. J. Clin. Invest., 48: 371, 1969.
" x4 u) v9 r# z5 A5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth  J9 j/ G) [4 `) ]
by topical application of androgens. J.A.M.A., 191: 521, 1965.: G  S6 n$ e+ |/ [% t* E
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 @, J( j! ~3 ^% ?8 iandrogenic effect of interstitial cell tumor of the testis. J.7 N, ?9 y5 F  ^( C: d
Urol., 104: 774, 1970.! S9 r& K2 g7 K; Y+ O* Y
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; F- b1 _- x5 V4 i. Z1 G. h+ \, K" `
tion in the male genitalia from birth to maturity. J. Urol., 48:
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