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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 j5 T0 |) j0 y3 e1 n, y  O$ e% x: K0 YGONADOTROPIN( \8 Z- f8 t2 [7 d2 f8 O5 n
RICHARD C. KLUGO* AND JOSEPH C. CERNY  q3 R5 r! ?, G3 E2 N. U
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan4 O5 _. P' [- R
ABSTRACT
6 a" ^* r/ a' XFive patients were treated with gonadotropin and topical testosterone for micropenis associated3 W$ |- B: s8 n% J! `. I; X
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-' g) R: x( H+ j, I
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: T1 d2 J$ q' Z, Y" p+ W7 `cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent) L7 W. j* g1 v! F
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
4 ~9 \' X; `8 ^5 T* F: q9 C; Pincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average" K+ \( {* J) J0 _" N" V
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ Z$ W: K& D. \, t6 c- yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 W; V* G7 \0 G; `2 @study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
9 m. M9 X" c* E4 B6 [) vgrowth. The response appears to be greater in younger children, which is consistent with previ-
8 j* t1 s7 u5 q! d* g8 i+ o/ aously published studies of age-related 5 reductase activity.! r- L) m% {" m( A$ Y. l  C
Children with microphallus regardless of its etiology will1 C% u. T! [- b& v: w* v* [
require augmentation or consideration for alteration of exter-0 X. L5 y, x3 @% A/ V
nal genitalia. In many instances urethroplasty for hypo-
2 ^0 p! p% E( @$ n5 e' w1 @# k& Hspadias is easier with previous stimulation of phallic growth.: h1 S2 B3 M) }: n
The use of testosterone administered parenterally or topically% ~' v0 l# w, ^0 u" n! I4 l- ^
has produced effective phallic growth. 1- 3 The mechanism of! }5 l' N! B7 G/ _* J0 L* [/ }% Q
response has been considered as local or systemic. With this; x  C5 c+ k9 `, [' _$ r. B
in mind we studied 5 children with microphallus for response
" m) v0 L; M; Y$ hto gonadotropin and to topical testosterone independently.- p% _; F! W4 M0 P( E5 Q) Y# S3 \- C( Q
MATERIALS AND METHODS, p, N# w7 ]+ L- p) [
Five 46 XY male subjects between 3 and 17 years old were1 G8 M6 Z) G' F6 T; A
evaluated for serum testosterone levels and hypothalamic
5 N  X8 |' S4 d3 n! R. vfunction. Of these 5 boys 2 were considered to have Kallmann's9 v% f9 J/ K8 n+ b% f; @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-  @$ }1 v* @. n* O3 b
lamic deficiency. After evaluation of response to luteinizing3 i' m& _/ Z5 e, t! a
hormone-releasing hormone these patients were treated with
9 M- Q4 ?  {: p1,000 units of gonadotropin weekly for 3 weeks. Six weeks
" i4 n* H" G! V! `after completion of gonadotropin therapy 10 per cent topical% J( e  U4 ~6 J
testosterone was applied to the phallus twice daily for 3 weeks.
& V* b- l' k5 M& O+ tSerum testosterone, luteinizing hormone and follicle-stimulat-
; ~; f1 l+ w( b- B7 v# Ring hormone were monitored before, during and after comple-9 @7 Q6 z) v3 ~8 j% A2 f0 K, x
tion of each phase of therapy. Penile stretch length was" N7 i) S: S. s. h. q
obtained by measuring from the symphysis pubis to the tip of
$ b2 j( |6 t- @" o# fthe glans. Penile circumferential (girth) measurements were9 b8 H; a0 a8 c/ _& ?/ E9 N
obtained using an orthopedic digital measuring device (see
; P5 v! r' t2 f& j& @: o: hfigure).
6 y/ j7 ?. k3 ?7 |7 m$ B' {RESULTS
3 ~9 t) o: `' y& e2 {6 Q; `Serum testosterone increased moderately to levels between
' [9 X8 \1 v7 M* J. S50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ g: a$ _) H. H5 ]) pterone levels with topical testosterone remained near pre-
9 k* h- }% b$ I. F/ q+ ztreatment levels (35 ng./dl.) or were elevated to similar levels
% X3 p5 ]' @, y* g# I# c) Ydeveloped after gonadotropin therapy (96 ng./dl.). Higher) x/ z, ~2 X. y1 }5 O) L. C3 L
serum levels were noted in older patients (12 and 17 years old),5 B5 W6 g- l: a& G5 U2 O
while lower levels persisted in younger patients (4, 8, and 10  N& }4 z) q* @# u* o8 P
years old) (see table). Despite absence of profound alterations+ n, X2 R  k# n- e5 b( ?( Q7 F
of serum testosterone the topical therapy provided a greater2 X8 n* N4 ~1 T/ I+ y* W
Accepted for publication July 1, 1977. ·
$ P% V$ T) a3 ]4 W+ G+ o- d6 P4 MRead at annual meeting of American Urological Association,; \) P" a4 W; \: v7 r
Chicago, Illinois, April 24-28, 1977.
* u& Y6 X8 g. |- x4 J4 |, U* Requests for reprints: Division of Urology, Henry Ford Hospital,( y- m% V6 h0 w* B9 f5 o& V7 b9 U
2799 W. Grand Blvd., Detroit, Michigan 48202.
+ J! ?/ h( _. v7 D  ]improvement in phallic growth compared to gonadotropin.
! b. g5 R) K6 H( c1 LAverage phallic growth with gonadotropin was 14.3 per cent
, e. m8 Z0 L' v( a0 {" iincrease in length and 5.0 per cent increase of girth. Topical
- Y9 A) f5 q7 e' H  p7 L, Utestosterone produced a 60.0 per cent increase of phallic length
7 ?+ |. N8 X% ^6 N6 }, jand 52.9 per cent increase of girth (circumference). The
0 S8 `( H3 a* w! S+ v# a8 m8 Eresponse to topical testosterone was greatest in children be-8 B. ?  q! J- c6 ~4 E2 }
tween 4 and 8 years old, with a gradual decrease to age 17
3 n3 |2 {5 u" Wyears (see table).
4 X% V) O2 `' k0 m) W) qDISCUSSION
# M) q, r9 a& Z, hTopical testosterone has been used effectively by other5 _7 @/ E- u3 r" N& p
clinicians but its mode of action remains controversial. Im-9 T8 ]/ x6 H# x; i
mergut and associates reported an excellent growth response0 f) U) @, |# n$ ^4 o- l. z
to topical testosterone with low levels of serum testosterone,, w1 @4 y5 t: h1 N9 Z1 l
suggesting a local effect.1 Others have obtained growth re-
& x) b( N7 G1 m& t$ Gsponse with high. levels of serum testosterone after topical3 g0 h% W7 i, c! G, a
administration, suggesting a systemic response. 3 The use of
& U$ S# G; Y2 j9 Qgonadotropin to obtain levels of serum testosterone compara-
6 O. O* ]- C: w2 o9 N6 ^# D  zble to levels obtained with topical testosterone would seem to3 F  T/ R7 a) y4 K
provide a means to compare the relative effectiveness of' `& O$ x# j" _4 z. B' L) W5 ~
topical testosterone to systemic testosterone effect. It cer-" s# X9 _; |/ I
tainly has been established that gonadotropin as well as par-
  L3 E: d4 ^( Q5 Oenteral testosterone administration will produce genital. Q7 e0 W- z3 l& d
growth. Our report shows that the growth of the phallus was
+ ~3 X0 M/ W  Vsignificantly greater with topical applications than with go-6 l% Z' b" l9 C
nadotropin, particularly in children less than 10 years old.
" V5 H) D- F, HThe levels of serum testosterone remained similar or lower
0 a# U. q+ h( F' L2 H( w1 j% gthan with gonadotropin during therapy, suggesting that topi-
8 b# L5 q# t0 g+ }. o6 ycal application produces genital growth by its local effect as2 r1 u) Q* ^5 E' Z, h( {# ~
well as its systemic effect.
5 V+ |$ K* H8 M* ^Review of our patients and their growth response related to* g6 g8 E9 q) g) c( z* H+ }
age shows a greater growth response at an earlier age. This is
' M' E4 z- d1 a2 L  Nconsistent with the findings of Wilson and Walker, who# i+ G) d. x( `' N2 d6 |3 k8 l
reported an increased conversion of testosterone to dihydrotes-
1 Z' P! O% m+ A" P2 Y% f/ Rtosterone in the foreskin of neonates and infants.4 This activ-
2 X" ^" E. X$ l& hity gradually decreases with age until puberty when it ap-
7 A) }. a3 y/ Rproaches the same level of activity as peripheral skin. It may
' K: J7 x: Y" x: ~& L/ w& J7 g$ K3 Ewell be that absorption of testosterone is less when applied at
* a( l" s8 l. e7 m% Uan earlier age as suggested by lower serum levels in children& F! E6 f2 e. l6 Z
less than 10 years old. This fact may be explained by the
! t/ d4 M' V- m" A6 @9 J2 Igreater ability of phallic skin to convert testosterone to dihy-. D  Q0 {+ B' B; v, W0 H. V1 U+ C% w
drotestosterone at this age. Conversely, serum levels in older
2 V, V- X' r! Z9 I4 O( ~1 Bpatients were higher, possibly because of decreased local% _  O' c# p8 `# e
667, P: O* L  O9 v: c4 q# O
668 KLUGO AND CERNY
3 x2 L0 \% a7 T3 K- y$ L; R& {Pt. Age) M( d" F; I; t: }. `; U
(yrs.)
2 g$ L2 n+ f% \" T5 Q/ V3 ^Serum Testosterone Phallus (cm.) Change Length
7 P" J5 y. J: V8 K* }/ _& D8 X(ng./dl.) Girth x Length (%)( Q$ ^7 T* W. Q
4
, o, _2 U3 u$ F! q. \0 b8 }9 v8$ {& v. S0 m) T2 N7 _/ L' S, `! C
10
' H" o% P6 @0 w- u- j! `* a! t12
, P' @! y/ h+ o$ n' `17
+ [# B8 K4 G0 BGonadotropin1 G: u4 E" s2 i  M, m4 {+ h, T
71.6 2.0 X 3 16.6
7 l* i$ A- U3 T4 Q: w50.4 4.0 X 5.0 20.0( c) Q" r2 v3 v! y
22.0 4.5 X 4.0 25.00 g0 i5 z. T8 H# D  R+ u( Q8 b
84.6 4.0 X 4.5 11.16 |; X7 m# P9 t$ J2 N: O
85.9 4.5 X 5.5 9.0, U8 a3 _. c) F: i  B/ [- m
Av. 14.3& H/ I9 b4 @* I8 b6 t; Y
47 O9 J. Y( d; s- I1 Q
8
: x8 `! e6 O: J. H' `/ K$ t* a10) Q$ s. Z* F" O+ h
12
1 _9 W$ _9 J. m  X+ d, S* _17% @% X% p( K# _3 ~# ^+ b
Topical testosterone9 Q  C* M7 H8 E! R" W
34.6 4.5 X 6.5 85% ]$ H% S( x+ A2 d, {! l
38.8 6.0 X 8.5 70
- Z7 s' Q) j; N( I0 R40.0 6.0 X 6.5 62.5: E' q1 \" ^2 B; w
93.6 6.0 X 7.0 55.5
- Q0 G6 N$ R* F. e95.0 6.5 X 7.0 27.2
& H6 \7 W8 l* OAv. 60.0
% L# N/ G6 B) K- @$ h. }1 E& N* wavailable testosterone. Again, emphasis should be placed on% I0 u0 B! |6 z; b
early therapy when lower levels of testosterone appear to3 r" y, F0 J. F+ F3 R* [! h
provide the best responses. The earlier therapy is instituted
8 p) |$ i; P- {6 ]+ Qthe more likely there will be an excellent response with low* q# P  B  Q! O, N- c  U2 M
serum levels. Response occurs throughout adolescence as
2 J/ N4 S, g; S% E$ c" F+ Znoted in nomograms of phallic growth. 7 The actual response9 C$ C& X* }" T7 n
to a given serum level of testosterone is much greater at birth& C4 u# e9 W& Q
and gradually decreases as boys reach puberty. This is most
2 i; v- E/ P/ P0 \6 xlikely related to the conversion of testosterone to dihydrotes-* c' g2 E! {5 ^; s! r2 ?
tosterone and correlates well with the studies of testosterone3 {4 g0 @" }4 D- C& v6 p
conversion in foreskin at various ages.
  G% G. q% y- M& cThe question arises regarding early treatment as to whether
& e: Y$ b  W- t( G0 p! k5 None might sacrifice ultimate potential growth as with acceler-
: L1 @( [$ F7 `0 J0 u( xated bone growth. The situation appears quite the reverse
8 w4 N, k4 M+ ?6 M/ I) v% ~with phallic response. If the early growth period is not used
2 }& Z; e# u& B6 z* ]9 k7 Owhen 5a reductase activity is greatest then potential growth
0 ]% T9 O( ^+ ]- V* I7 Fmay be lost. We have not observed any regression of growth
4 N' H; o$ [2 V+ e5 k! f! Dattained with topical or gonadotropin therapy. It may well
' H) v1 k2 J0 V$ Jbe that some patients will show little or no response to any
! w8 {  W, K+ ]3 Y7 Q/ I- J1 _form of therapy. This would suggest a defect in the ability to) Q( y; a$ u4 B8 `# |8 R3 o: Z
convert testosterone to dihydrotestosterone and indicate that
% r# P% e  X; N+ g( |# }, Ophallic and peripheral skin, and subcutaneous tissue should  c. e9 {' P6 o6 t7 {: K
be compared for 5a reductase activity.
% V2 h5 R: ?( m# @A, loop enlarges to measure penile girth in millimeters. B,6 |4 t( t0 }2 p2 H" W8 j, T
example of penile girth computed easily and accurately.
! d3 e, a& s7 M3 k- M* `8 P2 _conversion of testosterone to dihydrotestosterone. It is in this4 P+ F2 v  J+ F/ L
older group that others have noted high levels of serum
, r5 f( s/ ?( E; n; Z# Ntestosterone with topical application. It would also appear
: x' M: U$ ?/ T- N$ Cthat phallic response during puberty is related directly to the
2 N# v7 w" V5 b& X, Mserum testosterone level. There also is other evidence of local
7 g6 L5 b: J( fresponse to testosterone with hair growth and with spermato-
6 w. y2 ^8 J, B) t# T0 Kgenesis. 5• 6
, z8 f! {* Q: {4 @) JAdministration of larger doses of gonadotropin or systemic' z- @# D4 }) k) F0 p/ o  C1 {
testosterone, as well as topical applications that produce
! G" c1 W7 N5 f+ qhigher levels of serum testosterone (150 to 900 ng./dl.), will
. x& W- P8 W% Q3 ?9 b8 galso produce phallic growth but risks accelerated skeletal
) i3 o% d3 X7 e' f. f! B; L1 Cmaturation even after stopping treatment. It would appear
4 k8 I  [$ p! I  M7 _& l5 Athat this may be avoided by topical applications of testosterone. {6 h* t( d( Y
and monitoring of serum testosterone. Even with this control
5 ~& B& y/ F: N7 m4 X; Lthe duration of our therapy did not exceed 3 weeks at any1 H1 Y( R5 x, Q6 J
time. It is apparent that the prepuberal male subject may
' f3 v! e; C" S$ i( v! @: C. z3 Hsuffer accelerated bone growth with testosterone levels near1 i3 s3 h& e2 h1 F  b4 p
200 ng./dl. When skeletal maturation is complete the level of5 P7 l, ~- f. a8 v
serum testosterone can be maintained in the 700 to 1,300 ng./
9 h0 _! [6 g$ N8 m* e/ g# odl. range to stimulate phallic growth and secondary sexual
- z3 C0 i( G6 \% achanges. Therefore, after skeletal maturation parenteral tes-  k- V* u' z9 R8 J5 f; p+ h
tosterone may be used to advantage. Before skeletal matura-- k+ W5 L  q* m3 d5 D
tion care must be taken to avoid maintaining levels of serum
1 D9 I+ K, ^3 Ctestosterone more than 100 ng./dl. Low-dose gonadotropin
2 Q! Y4 K6 ^1 j7 T' pdepends upon intrinsic testicular activity and may require) \  k0 M  R8 m
prolonged administration for any response.
; h6 m! ^9 n: p; L: aAlternately, topical testosterone does not depend upon tes-$ e4 D+ X# C7 T9 }$ n9 @, I1 x
ticular function and may provide a more constant level of
4 n$ ?1 I& m  G+ `" ?+ n7 H" QREFERENCES: d! M6 K" e2 x2 N7 c: G) X
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ W" \0 q' P) _: s/ Y" j( }+ A
R.: The local application of testosterone cream to the prepub-$ x+ d3 ?3 _" Q+ s/ Z; m+ b- U
ertal phallus. J. Urol., 105: 905, 1971.
: f/ ^! n& C% L3 ]* Z8 c2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- b* T) D6 I, j/ q0 i' D
treatment for micropenis during early childhood. J. Pediat.,' K& }* \4 x5 \" ]1 X! j
83: 247, 1973., i, h$ B- Y6 Y' V( `3 i
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
! T# m# M* ~7 q0 _8 g$ p- |one therapy for penile growth. Urology, 6: 708, 1975.
+ D0 Q) }, C* ?, E( _( S5 Z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone2 ?. Q; i5 t3 }1 W% D
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by9 Q1 v' \: O! V, ~& m
skin slices of man. J. Clin. Invest., 48: 371, 1969.
* Z+ y0 d6 P9 S  R& y3 |5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth; |0 t  I6 o4 d/ w* _4 x% V
by topical application of androgens. J.A.M.A., 191: 521, 1965.
- w- a% K, _. g$ Y+ T7 G7 p7 w6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 a' c4 e) C3 }! U
androgenic effect of interstitial cell tumor of the testis. J.
: v* T: L  r" J* ^Urol., 104: 774, 1970." _5 O4 s  I. F/ z& D
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' d! {& z6 h. \# [0 `tion in the male genitalia from birth to maturity. J. Urol., 48:
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