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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ b1 f9 R" I8 T, F& i
GONADOTROPIN% H7 z; I' u$ v  D
RICHARD C. KLUGO* AND JOSEPH C. CERNY* U, O1 g0 D! z
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 ?, k- l" P2 ~/ }$ I: a+ y& c) ?
ABSTRACT
- ^9 w0 r4 t6 |0 N. gFive patients were treated with gonadotropin and topical testosterone for micropenis associated, z* U  {) L% M# d( c% U% X2 ?
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; V# T: i8 b# q) S$ ]5 c' E" Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone; v9 H5 Z& ^9 @2 O7 D$ U: P
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 ]$ t. d  v. N+ b3 sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent; o+ J4 B' u/ A" u; K4 M7 B' \9 p
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average( D0 W+ z) Z- \: A
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response- ]" W, p/ c# I+ s, _! e
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This0 z# C( [, d; V) l
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ g$ p; ^7 e8 v$ r" N7 a! X& |
growth. The response appears to be greater in younger children, which is consistent with previ-
4 e  P" f: A; ?9 t, w# Fously published studies of age-related 5 reductase activity.
* ?$ `: G1 I/ P% y( l0 q0 M9 ?+ IChildren with microphallus regardless of its etiology will6 x! P) Y9 Z2 d8 B- a
require augmentation or consideration for alteration of exter-( _! o" _/ H; w2 g2 d& g
nal genitalia. In many instances urethroplasty for hypo-% N# j! p7 x) _+ ^5 G- o
spadias is easier with previous stimulation of phallic growth.
5 @# \% {6 B2 d/ nThe use of testosterone administered parenterally or topically' |. o5 X  d: ^+ ^7 D
has produced effective phallic growth. 1- 3 The mechanism of( b% ^& z6 _: M; [  @8 Y, V3 g
response has been considered as local or systemic. With this! Y/ v/ a) p/ x9 J9 @3 W1 t
in mind we studied 5 children with microphallus for response0 @/ K# @% P6 q* F5 o
to gonadotropin and to topical testosterone independently.& Q; o$ O* C8 g8 h9 H7 E
MATERIALS AND METHODS
% j( T: [( r" d" t7 i( v2 g. sFive 46 XY male subjects between 3 and 17 years old were" T2 l8 z2 E8 L& w0 [- }
evaluated for serum testosterone levels and hypothalamic+ C9 e8 ]# `1 W- M( I: u0 J8 v
function. Of these 5 boys 2 were considered to have Kallmann's
' o8 }* Y9 c! Fsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 Y. {6 I* M5 D1 nlamic deficiency. After evaluation of response to luteinizing6 d. A: V* G7 G2 z9 o
hormone-releasing hormone these patients were treated with3 B% L% ~% j& {8 c
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
- a# s# `+ J: ~( B8 G# j- \after completion of gonadotropin therapy 10 per cent topical
! o% k  [3 B8 j# ltestosterone was applied to the phallus twice daily for 3 weeks.6 z7 w5 ]2 \5 K5 }
Serum testosterone, luteinizing hormone and follicle-stimulat-
2 ~, _$ L; J! {0 ~! ling hormone were monitored before, during and after comple-& v( l2 S1 k! W8 _8 q8 E
tion of each phase of therapy. Penile stretch length was- W  L3 @0 i7 m; x+ v
obtained by measuring from the symphysis pubis to the tip of1 J3 }( p1 {6 R2 N
the glans. Penile circumferential (girth) measurements were( v( |8 S8 Q. R; L% R
obtained using an orthopedic digital measuring device (see
, q; C/ r: X( B$ D/ W. Kfigure).
9 ^5 j' ]  ]3 B! D; kRESULTS; j  {! S4 n  O$ P
Serum testosterone increased moderately to levels between( q. ?  F+ I1 `8 S, t( v
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
! e( D) c# A& ~; R4 [3 Q3 t! G! M5 D: Rterone levels with topical testosterone remained near pre-, _# e/ t8 \. t' N# Q2 C3 x; m
treatment levels (35 ng./dl.) or were elevated to similar levels" x5 `  F& H$ @. [1 g6 g
developed after gonadotropin therapy (96 ng./dl.). Higher
8 \4 y) m7 r( }3 c! iserum levels were noted in older patients (12 and 17 years old)," \/ ]* H$ a3 y9 ]
while lower levels persisted in younger patients (4, 8, and 10
( H) u; p6 y$ _3 [years old) (see table). Despite absence of profound alterations7 W! a6 L7 N3 H  [
of serum testosterone the topical therapy provided a greater
5 m7 J6 G# j2 rAccepted for publication July 1, 1977. ·1 |1 c7 H, c2 s* s4 d
Read at annual meeting of American Urological Association,
$ [) c. D9 c3 c; v$ j, _, t: YChicago, Illinois, April 24-28, 1977.5 m1 c/ C; O, t! k& E, I, i
* Requests for reprints: Division of Urology, Henry Ford Hospital,# Z8 @2 U6 D4 s
2799 W. Grand Blvd., Detroit, Michigan 48202./ b4 T( F1 A) O) s0 F# ~8 G; H) o
improvement in phallic growth compared to gonadotropin.# `1 r- |6 A; L8 m$ V
Average phallic growth with gonadotropin was 14.3 per cent
# [: f, T' z' l' U8 y2 Z; U. ~increase in length and 5.0 per cent increase of girth. Topical% x7 f0 J2 R) I( F9 j- a# O6 s
testosterone produced a 60.0 per cent increase of phallic length
  N" a3 r0 F$ [. P- `and 52.9 per cent increase of girth (circumference). The
4 r5 n( n& k$ ?response to topical testosterone was greatest in children be-, V! o; Z' |! y' [
tween 4 and 8 years old, with a gradual decrease to age 17$ P# g8 G9 B& |2 p  ?. R4 L8 `4 o
years (see table).
3 z5 U  T4 x- Q, v0 u. FDISCUSSION% C. p. f$ N; u& @- o- m
Topical testosterone has been used effectively by other2 d& P5 g) L, t; x/ U  i+ Z% s
clinicians but its mode of action remains controversial. Im-# p3 x! V" c- ~( N
mergut and associates reported an excellent growth response/ _/ g7 v; E5 W1 p. U
to topical testosterone with low levels of serum testosterone,( l) m6 V7 M' f
suggesting a local effect.1 Others have obtained growth re-
& P2 t! ~$ N' p2 p3 C' gsponse with high. levels of serum testosterone after topical' t% H) h/ f2 K! @! {9 I2 T
administration, suggesting a systemic response. 3 The use of* E- S3 D& b6 \4 k9 {8 t& a
gonadotropin to obtain levels of serum testosterone compara-
; T2 S- X: R  @4 R9 L# able to levels obtained with topical testosterone would seem to0 i( M7 D, n, p- E0 J
provide a means to compare the relative effectiveness of
1 F! e! o1 W5 L: d  ^topical testosterone to systemic testosterone effect. It cer-1 t& h  {' d) n
tainly has been established that gonadotropin as well as par-" F# a$ Y3 E6 L4 u
enteral testosterone administration will produce genital: t9 n, |" T+ c. I% a% u$ }- i8 K
growth. Our report shows that the growth of the phallus was! _5 q# r' Z6 [- h7 v
significantly greater with topical applications than with go-; ], D0 Y* y% S1 h5 g9 V( }8 h
nadotropin, particularly in children less than 10 years old.' c% L4 G/ p# _
The levels of serum testosterone remained similar or lower3 A3 f( O7 K( |# g4 y) G
than with gonadotropin during therapy, suggesting that topi-) @; I+ V/ i- L; @
cal application produces genital growth by its local effect as
5 q5 I2 y8 s, r# E/ [$ Vwell as its systemic effect.
2 l8 [0 S, p" r5 OReview of our patients and their growth response related to
% [( R: X4 z7 [9 ?3 h* S; M5 {" oage shows a greater growth response at an earlier age. This is1 N8 p* k2 s! o& h+ D: g/ m/ j' L
consistent with the findings of Wilson and Walker, who2 }+ h; Z) z) z7 J" q9 A4 V7 X6 E
reported an increased conversion of testosterone to dihydrotes-
  X) a+ B6 V! q; R  otosterone in the foreskin of neonates and infants.4 This activ-
. v& `' Y& n1 fity gradually decreases with age until puberty when it ap-
8 I1 {* w. R. ^; M$ |proaches the same level of activity as peripheral skin. It may, d( K! ^2 G" I# d: s% q: C3 S
well be that absorption of testosterone is less when applied at' W/ l7 d* a* J! d  c8 R
an earlier age as suggested by lower serum levels in children/ X* x# L$ U+ P( A; z2 u. c6 d5 r
less than 10 years old. This fact may be explained by the! E3 Y/ S, }. S; ]! s& {
greater ability of phallic skin to convert testosterone to dihy-  m0 W6 j" @1 x& ]4 q
drotestosterone at this age. Conversely, serum levels in older
  W" x/ C7 A/ D- F& cpatients were higher, possibly because of decreased local7 l/ y: A0 D+ F+ w
667
1 J9 V! G; Z7 j# s1 }( K668 KLUGO AND CERNY0 A. T4 P( Y3 e6 R/ o/ W1 o! [
Pt. Age) v0 @' P, g; j- ?# O7 y) y
(yrs.), d1 [6 o5 P  E" U* u& [$ A
Serum Testosterone Phallus (cm.) Change Length- f# W2 h: \. ]& \' a5 S6 j, N
(ng./dl.) Girth x Length (%)
- f! M4 ?. B+ [3 \  l6 U6 e41 w7 x0 F' S2 ~# g) t( E0 Z
8
8 x. k9 l9 n; C- X5 w% R7 h. }10$ W9 b/ ~( o% e8 F, `2 C, Z0 p
122 G  j7 F4 X: }# h
17& W. D$ q3 w0 N# K3 I% u
Gonadotropin' Y+ k1 R  }4 X' D1 ?
71.6 2.0 X 3 16.6, |5 i: |" U7 N4 ?* z' q4 G# e1 d
50.4 4.0 X 5.0 20.0
) Z' M' h( _& ^6 v! Q4 @% N22.0 4.5 X 4.0 25.09 `2 o9 h" F" ]
84.6 4.0 X 4.5 11.14 c5 s% b+ |1 u% ~4 E$ l. f
85.9 4.5 X 5.5 9.0, j& P3 M7 g  W2 G
Av. 14.3
" k5 [# a" h2 |+ I% l  a4
6 ~8 I! d  O3 V% o8" m: N" T, ~4 O+ h4 g* m1 \6 \& @
10
0 @' @2 g* j; s9 f9 \12
- ^/ g& U( Q. N- b! [  t  A172 R. C# g2 X" G9 ~! C0 |* N$ S
Topical testosterone7 `, _  z0 G/ u# P+ _- L
34.6 4.5 X 6.5 85
: F. t+ ~) |* A! \. l38.8 6.0 X 8.5 703 V5 _' ]% Y' a; h( w0 L, Q* v
40.0 6.0 X 6.5 62.5
$ s: a( e- V6 c+ V/ ]) m( [93.6 6.0 X 7.0 55.5
, y% d6 T) b3 l+ ]3 [" n95.0 6.5 X 7.0 27.29 b/ x+ P, ]& E; m$ ?# b6 L; |
Av. 60.0
+ U+ e7 a/ e1 {! T- L. Q2 {+ vavailable testosterone. Again, emphasis should be placed on
" }- f9 S/ e8 f9 e* B" }early therapy when lower levels of testosterone appear to$ [: ?/ t( z' l7 }3 Y, c
provide the best responses. The earlier therapy is instituted
3 @) R8 t" Q' `8 m, o" D9 Nthe more likely there will be an excellent response with low
0 G) Q4 Y6 E! ^5 ]; H7 @serum levels. Response occurs throughout adolescence as
& Z0 r( Z3 h$ fnoted in nomograms of phallic growth. 7 The actual response
+ W: n8 b5 F( _4 v" I$ A3 F% ito a given serum level of testosterone is much greater at birth4 {7 C9 D% p( m
and gradually decreases as boys reach puberty. This is most: j+ x* B; Q- c8 u: ]; _% S
likely related to the conversion of testosterone to dihydrotes-
, W& B" Z" _+ xtosterone and correlates well with the studies of testosterone
" K6 }# X: T: ]' m& G" Bconversion in foreskin at various ages.
* {/ g; W% _! w2 z$ kThe question arises regarding early treatment as to whether
7 x( @- u) e( f8 d( [$ c* G- Fone might sacrifice ultimate potential growth as with acceler-1 {& o# i& t2 \2 F: P: P
ated bone growth. The situation appears quite the reverse
2 P7 X0 l; ]4 V/ D0 V9 h& m7 gwith phallic response. If the early growth period is not used2 M- J9 i1 ~' ]- c. R$ j
when 5a reductase activity is greatest then potential growth$ R! g# Q% E  T6 R; Z
may be lost. We have not observed any regression of growth
5 Q6 F! R0 d- ~6 E) h- r8 Hattained with topical or gonadotropin therapy. It may well
/ e+ f4 g. W6 ?) t: ube that some patients will show little or no response to any
1 |" l; L; C+ D* xform of therapy. This would suggest a defect in the ability to
$ e/ h) v* Y8 Uconvert testosterone to dihydrotestosterone and indicate that& o8 d3 Z, b& b+ T1 y, a4 b9 \
phallic and peripheral skin, and subcutaneous tissue should7 N! a+ s4 Q6 Y: g9 L' `  z- v
be compared for 5a reductase activity.
# [( H' H7 X2 O) r0 e" o8 QA, loop enlarges to measure penile girth in millimeters. B,
9 I4 n5 W6 i6 x  Y+ ?3 }5 g& z' hexample of penile girth computed easily and accurately.
  [+ W/ F+ p. J5 |  X3 ~. wconversion of testosterone to dihydrotestosterone. It is in this7 U- [+ c) A& j+ R  N+ s! `/ m
older group that others have noted high levels of serum
( ]7 ]' P& T: q! d0 Atestosterone with topical application. It would also appear
0 Z3 n& V. q* H# Q. dthat phallic response during puberty is related directly to the$ Z! a- K! s* X( T- f  @
serum testosterone level. There also is other evidence of local5 W: w) d1 M+ E8 Z7 \+ q
response to testosterone with hair growth and with spermato-
1 N+ ]8 j, h5 s" S& D: Agenesis. 5• 6
0 z, q2 i  u+ ^Administration of larger doses of gonadotropin or systemic
7 a4 p# V4 Z2 ?/ M) x) _5 K$ dtestosterone, as well as topical applications that produce
* F, M% l" C( z) {" E4 p" Z7 b& Jhigher levels of serum testosterone (150 to 900 ng./dl.), will
2 E! g+ ^# @+ j% ^; h0 Dalso produce phallic growth but risks accelerated skeletal' H7 r8 ^% k6 h- h
maturation even after stopping treatment. It would appear
% k7 k! G  |) Z* Q5 [that this may be avoided by topical applications of testosterone
+ [; ~: @/ r* m* t' z( Tand monitoring of serum testosterone. Even with this control+ v# H2 ~: @7 q: l8 ^+ D2 M' a, t; U% q
the duration of our therapy did not exceed 3 weeks at any
0 d+ R- {% k9 F& Btime. It is apparent that the prepuberal male subject may8 Z! ]8 h( o5 f
suffer accelerated bone growth with testosterone levels near1 y& m4 s! v$ U  L$ s+ H  F/ G
200 ng./dl. When skeletal maturation is complete the level of
* {! K) O8 i- Jserum testosterone can be maintained in the 700 to 1,300 ng./
) h/ P" K' _; i6 m) Kdl. range to stimulate phallic growth and secondary sexual
# n+ Y: S1 e* {changes. Therefore, after skeletal maturation parenteral tes-6 s# |; Q+ B2 ]* D/ B
tosterone may be used to advantage. Before skeletal matura-* B4 \0 ?7 b# u3 a* I
tion care must be taken to avoid maintaining levels of serum
/ u9 I$ d; Y; J" r7 T+ f% d# Ntestosterone more than 100 ng./dl. Low-dose gonadotropin
( Q6 v' r1 r2 W7 _4 w: j6 Idepends upon intrinsic testicular activity and may require- Y' C9 ~* j5 Z, @6 v
prolonged administration for any response.
) y, R5 k7 o( GAlternately, topical testosterone does not depend upon tes-+ `/ {: i4 E+ q* a. u
ticular function and may provide a more constant level of
0 Y. |6 V! Z; e- j+ J, g, sREFERENCES
2 C: n. d' x2 w# k2 ^" t1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,0 Q" T: S! h. L6 Z( o0 T
R.: The local application of testosterone cream to the prepub-
& \; K. B1 d+ D+ _! f2 {5 Nertal phallus. J. Urol., 105: 905, 1971.3 L3 F9 s6 K. h/ H" J8 Q! ^# A
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
" W7 v& R, n* ^+ }5 ]; Ktreatment for micropenis during early childhood. J. Pediat.,
- S3 P/ s9 b, U5 y" y& V83: 247, 1973.
5 h0 ?, _, E7 h& x1 j1 _# U5 @( y3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
2 Z8 g( ?  D" \/ g( X% V& ~one therapy for penile growth. Urology, 6: 708, 1975.& B( q( ]  ]( h$ Y
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& l: L4 w' h- |7 g2 t6 Z2 wto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
0 q$ L' A1 B) W# bskin slices of man. J. Clin. Invest., 48: 371, 1969.8 C  P4 Z. F5 k' X& B3 X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ F: y2 \/ v9 @- l8 g2 {" @# e
by topical application of androgens. J.A.M.A., 191: 521, 1965.) B/ J1 G! N. o& c8 i9 x
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
5 {9 }6 [* n/ E8 I& n: bandrogenic effect of interstitial cell tumor of the testis. J.
) Q$ T7 D1 A( b. n  jUrol., 104: 774, 1970.
$ ^; I9 X% c2 [, c+ W8 }9 T7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
* J/ }* v2 D# K0 z" @: O! {tion in the male genitalia from birth to maturity. J. Urol., 48:
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