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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
* }' o$ d' r: l, I. rGONADOTROPIN
% Y+ R  k2 V8 n9 ?/ m5 aRICHARD C. KLUGO* AND JOSEPH C. CERNY
8 B4 l* M& C8 D) r1 h7 v$ y; C2 YFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan& O' s, d; k2 P7 p
ABSTRACT
& ^" H6 i' M% H& j. p2 x' W. R7 w* \Five patients were treated with gonadotropin and topical testosterone for micropenis associated
0 B8 [, i3 E: A3 D. ?7 Jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
& ^. P% S  y( g, P% ntropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone& ?) w" V* g0 L
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 m7 }- s, E6 F6 Dfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 i5 R! ?0 m* c9 {' ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
5 r( ^/ j( m/ D  M; Pincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; u! ?# R$ E+ C* W, t1 w  g8 M8 e
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This0 A1 z6 ?1 R, l7 |
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile9 `- a) o# p2 l1 o
growth. The response appears to be greater in younger children, which is consistent with previ-
6 i: }4 @/ c  Z, rously published studies of age-related 5 reductase activity.
0 y% t0 n. U  Q# p& XChildren with microphallus regardless of its etiology will5 Y. K" E9 H/ Y6 Q. B  f
require augmentation or consideration for alteration of exter-
4 l, @" ^2 }4 ~! u- E6 Nnal genitalia. In many instances urethroplasty for hypo-* P3 F0 s0 o: G/ P+ u6 k
spadias is easier with previous stimulation of phallic growth.
1 r  }8 K: ?% IThe use of testosterone administered parenterally or topically
* x! J. {: n6 d( x$ Mhas produced effective phallic growth. 1- 3 The mechanism of0 `" K2 e# C, I
response has been considered as local or systemic. With this
% K* q+ ?( V, R' e( b1 C" D( min mind we studied 5 children with microphallus for response: O9 l* [( U' N& y
to gonadotropin and to topical testosterone independently.
( r) |5 t. V4 _4 f9 ~5 G5 I8 ]MATERIALS AND METHODS
% b3 F+ N! M* f" v4 t% D5 a/ |Five 46 XY male subjects between 3 and 17 years old were3 w5 _& w( t$ I% e4 b
evaluated for serum testosterone levels and hypothalamic
+ R$ P8 T2 C7 a* ~function. Of these 5 boys 2 were considered to have Kallmann's3 K! a0 j  e9 p9 c4 w6 m2 y1 w* x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
9 [$ D0 F' a* x6 _$ p; e7 r8 mlamic deficiency. After evaluation of response to luteinizing+ [$ n3 k* L+ H2 r: S& w1 b
hormone-releasing hormone these patients were treated with% F- o/ O; G' }- a3 H  u( v
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 [8 z1 f( t! W- i4 ^% v; ?after completion of gonadotropin therapy 10 per cent topical' R: f! p( D7 I/ W3 o
testosterone was applied to the phallus twice daily for 3 weeks.
! {& T8 W0 Z  jSerum testosterone, luteinizing hormone and follicle-stimulat-9 I7 y+ Z( U) [# }! p
ing hormone were monitored before, during and after comple-
3 `) y4 Q* N6 Vtion of each phase of therapy. Penile stretch length was6 E) t: h5 Z* q" _5 ^( ?% o
obtained by measuring from the symphysis pubis to the tip of( K  N: n$ o) H$ z
the glans. Penile circumferential (girth) measurements were; M3 f2 X) `1 e. {: W, u& j3 l
obtained using an orthopedic digital measuring device (see  G# a0 l& g7 G! S, N
figure).! p1 d- m6 e7 H
RESULTS
& U! m4 S: L: A" g! XSerum testosterone increased moderately to levels between
' u% A- L9 x% U. P: `1 _) M50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 G; |( y) X* V4 M& }. pterone levels with topical testosterone remained near pre-
" e, Y! Y: |  P, _- gtreatment levels (35 ng./dl.) or were elevated to similar levels( s% o4 y, l4 T6 `: P  n" v% S! I7 ]
developed after gonadotropin therapy (96 ng./dl.). Higher# p8 \( O( `. `
serum levels were noted in older patients (12 and 17 years old),
0 E  {1 {. U% Zwhile lower levels persisted in younger patients (4, 8, and 10
: ?0 G# O0 Y$ u- u" Fyears old) (see table). Despite absence of profound alterations; G! M5 s) ]) S1 G
of serum testosterone the topical therapy provided a greater
9 d  a5 J2 W& n1 Z/ s7 z3 iAccepted for publication July 1, 1977. ·
, y% w8 [1 b7 @  Z6 `' ~Read at annual meeting of American Urological Association,
, a0 {( v& N6 v, x# m, a7 k9 ^Chicago, Illinois, April 24-28, 1977.
; |7 R- ]  ^% n' j' T* Requests for reprints: Division of Urology, Henry Ford Hospital,( Q) a7 R& K$ @
2799 W. Grand Blvd., Detroit, Michigan 48202.
* N: h; C0 [" Vimprovement in phallic growth compared to gonadotropin.2 s' o- C) U& Q) l
Average phallic growth with gonadotropin was 14.3 per cent
' G0 X1 p" F9 m, C% Sincrease in length and 5.0 per cent increase of girth. Topical4 J" U! j" `1 k  x: m
testosterone produced a 60.0 per cent increase of phallic length
) E- n+ n2 ]' Aand 52.9 per cent increase of girth (circumference). The* q3 N1 W; J- h- ~! ?
response to topical testosterone was greatest in children be-
' ~% v8 g4 Z( O- p* jtween 4 and 8 years old, with a gradual decrease to age 17: w1 X4 n5 E9 F( m2 X, ?* F: y
years (see table).
+ T# W7 ]/ z! X7 k1 X+ ?$ [DISCUSSION2 z: n; z: i8 p- S/ M7 k
Topical testosterone has been used effectively by other& r$ M7 o( l+ a: ?, e0 B
clinicians but its mode of action remains controversial. Im-- n& ^7 u$ }- d- e5 b+ s
mergut and associates reported an excellent growth response
7 ]/ r* H  x& c9 m* |& {to topical testosterone with low levels of serum testosterone,& X9 M  ~- S, }( v1 y! V
suggesting a local effect.1 Others have obtained growth re-( M3 m3 F5 y. ?! ]( \
sponse with high. levels of serum testosterone after topical
5 j: ^0 Z1 G& [8 _administration, suggesting a systemic response. 3 The use of1 Z- P2 V+ C" W9 M
gonadotropin to obtain levels of serum testosterone compara-( T* p. C' J9 I4 y# g
ble to levels obtained with topical testosterone would seem to
5 e( S$ u, f" F8 {( N1 r. c  u4 Wprovide a means to compare the relative effectiveness of
3 p& @" A' b. c- etopical testosterone to systemic testosterone effect. It cer-
$ \0 A9 F& Y. T9 {8 {tainly has been established that gonadotropin as well as par-: J. U2 ~, x2 m: V
enteral testosterone administration will produce genital" x8 h+ _, ]& y* \
growth. Our report shows that the growth of the phallus was
2 s: Y* Q3 l6 c+ ?5 Msignificantly greater with topical applications than with go-4 Z" Y4 Z. v4 }
nadotropin, particularly in children less than 10 years old.! Z0 q( o( I$ X% R  R
The levels of serum testosterone remained similar or lower
; E0 F* K' v2 _: H- [6 Ithan with gonadotropin during therapy, suggesting that topi-
7 Z6 h% J1 i) J4 [+ B( ]# ?5 m( ucal application produces genital growth by its local effect as
1 S1 _& L* }0 W1 l3 [2 L+ hwell as its systemic effect.) p8 R# J9 T+ @8 W# x  i4 [
Review of our patients and their growth response related to3 \( F& c0 W# h/ h5 D
age shows a greater growth response at an earlier age. This is1 E/ ]/ y+ y$ h) H9 Y. p
consistent with the findings of Wilson and Walker, who) D) |+ t/ n5 g
reported an increased conversion of testosterone to dihydrotes-
: y$ h# K7 ?5 d8 Jtosterone in the foreskin of neonates and infants.4 This activ-
$ u* d, u! r2 p% m$ ]* X1 r* kity gradually decreases with age until puberty when it ap-
  \3 j0 e" I$ }( ]% Tproaches the same level of activity as peripheral skin. It may8 e7 k: A9 p5 l; ^+ `6 `( m6 i4 h: Z
well be that absorption of testosterone is less when applied at
4 b+ A/ x4 b# g, `, O8 `: ^. pan earlier age as suggested by lower serum levels in children' Y( g1 G+ U( J4 y- G' O6 Q' U
less than 10 years old. This fact may be explained by the6 U6 A) C/ k$ a
greater ability of phallic skin to convert testosterone to dihy-7 t1 u  g: S/ s0 N* J% G' n
drotestosterone at this age. Conversely, serum levels in older
# q9 _! ^0 C, @patients were higher, possibly because of decreased local- q9 U0 E+ t: X( }
667/ ~0 D+ x6 M. V0 F" A: Q1 x/ S
668 KLUGO AND CERNY# Y! |0 c  r0 s2 M+ g
Pt. Age
( B" b6 ~( p, s' A0 D(yrs.)
4 j7 {: G6 }  r* G& g$ _' RSerum Testosterone Phallus (cm.) Change Length
4 H7 m$ ~# G/ o* @/ ~(ng./dl.) Girth x Length (%)
' `/ i0 O6 c: {9 Q, {43 {7 @2 Y+ j1 F* L. U- \! |8 S6 t
80 `2 m; ~8 ?3 [% e
10) Y* Q1 V0 q/ K' q" L& c7 v, P
12
7 Z8 d5 H  k0 G1 @8 N1 S# u; j17, @0 [( B$ g1 _* r
Gonadotropin. |: ^( @4 ]  I/ W( I# J
71.6 2.0 X 3 16.6
5 K  s. w- T& l) W% E50.4 4.0 X 5.0 20.0
% T0 U- o& X5 `: S, i: F22.0 4.5 X 4.0 25.07 s+ q$ i3 G% u
84.6 4.0 X 4.5 11.1# x: Q) P- }0 ]% n
85.9 4.5 X 5.5 9.0
, e2 Y' f) E: U& f+ |0 y* q; S5 eAv. 14.3; y3 {, r$ {) Q& B- p! c- ~2 v; ]
4# Q6 j7 @# M& w# L0 ?1 }
8  O9 Q: _$ g: D" @3 [+ ^: K) U
10
  t# Z) F: ~: [- w/ a! I5 a12
1 x9 P2 u- ^( L( m. f' a( O0 e17
1 |" w; I0 Z9 m4 a* KTopical testosterone% B# S% @% _  w9 p
34.6 4.5 X 6.5 851 R0 l* v4 }2 U6 X* s# s
38.8 6.0 X 8.5 70& {0 n6 R2 c  }- U' S- f
40.0 6.0 X 6.5 62.5
- x0 u$ T1 R; d6 b8 l6 B93.6 6.0 X 7.0 55.5
5 k# g7 g) T/ l) G95.0 6.5 X 7.0 27.2; M: E* Y: `# ?
Av. 60.0
1 v* H3 n4 S+ S# [! B9 @available testosterone. Again, emphasis should be placed on
$ K1 e, g% Y, \0 \% Xearly therapy when lower levels of testosterone appear to
8 S' f2 M: e0 g: c6 ~provide the best responses. The earlier therapy is instituted
: @& z; M& k2 ?# R' {5 S" \% }9 Lthe more likely there will be an excellent response with low
. N: D. g9 {: P5 yserum levels. Response occurs throughout adolescence as9 p( f) M% j5 N, `; y3 e
noted in nomograms of phallic growth. 7 The actual response3 _- D: R7 ~0 T/ V' ^% i2 _
to a given serum level of testosterone is much greater at birth% q( C# [8 r& N) T3 R8 `
and gradually decreases as boys reach puberty. This is most
3 F) N6 B( {; @9 xlikely related to the conversion of testosterone to dihydrotes-
4 T- ~1 _2 `& y! F2 J3 Q7 S/ E4 `tosterone and correlates well with the studies of testosterone$ M- g7 b3 o( I: x( \
conversion in foreskin at various ages.
8 R7 Y# f% \5 `8 B; K( t/ nThe question arises regarding early treatment as to whether
" t' y) [' c4 u, }% A, X) None might sacrifice ultimate potential growth as with acceler-; y) D7 ?8 i8 w% N
ated bone growth. The situation appears quite the reverse; W  s. v9 T+ ?( j, Z
with phallic response. If the early growth period is not used
. k; [* d8 |1 K/ N' ]/ kwhen 5a reductase activity is greatest then potential growth* h, |' B. a/ {' x* v
may be lost. We have not observed any regression of growth
9 R! o2 _6 d3 T3 i1 u( rattained with topical or gonadotropin therapy. It may well
6 \. F+ ^+ ?8 Z9 M- y4 ]be that some patients will show little or no response to any
. Q7 Z, {- {& x! l6 i, g8 vform of therapy. This would suggest a defect in the ability to
& Z/ X/ k7 L2 xconvert testosterone to dihydrotestosterone and indicate that
- P; u/ w! Q% u! N% gphallic and peripheral skin, and subcutaneous tissue should1 f: z7 U( ~2 r3 G9 D0 \% J
be compared for 5a reductase activity.
* h  R& z' @1 JA, loop enlarges to measure penile girth in millimeters. B,3 y4 b5 F9 `6 ?, T; u
example of penile girth computed easily and accurately.
* P; ?7 {/ G( F' xconversion of testosterone to dihydrotestosterone. It is in this; H5 @0 g1 ^8 T5 _) R
older group that others have noted high levels of serum
1 [) N" E1 z( x: w$ p8 z: S& jtestosterone with topical application. It would also appear
: v6 g+ I) O, m3 ?8 I. M) Q9 d6 ithat phallic response during puberty is related directly to the
9 S# |2 W$ X" v8 jserum testosterone level. There also is other evidence of local
+ r0 d: U1 [  `7 L" F3 zresponse to testosterone with hair growth and with spermato-( \, S. k5 Y' K3 o# S* C8 e: F% \
genesis. 5• 6: W" Y1 h2 Z9 r+ x) U6 e4 N' e
Administration of larger doses of gonadotropin or systemic
) h  ]/ f# V. e/ g& D6 d$ Z  P; X( @testosterone, as well as topical applications that produce
0 @: u" B- P2 u; f% @higher levels of serum testosterone (150 to 900 ng./dl.), will
* c+ ?1 y3 z2 H4 }# d1 Z3 Walso produce phallic growth but risks accelerated skeletal
# z  y8 |" r6 O4 {8 L' \$ l9 Amaturation even after stopping treatment. It would appear
2 E2 U+ }/ s& {( x# ?; Uthat this may be avoided by topical applications of testosterone
# K: r. x* o3 I: V# B9 j8 uand monitoring of serum testosterone. Even with this control0 n% Y( ]; P9 h- V
the duration of our therapy did not exceed 3 weeks at any* g- y) z4 Z# Q0 ?/ H; y7 {; m
time. It is apparent that the prepuberal male subject may
6 i) {, I( F4 y2 P+ `  ]suffer accelerated bone growth with testosterone levels near
) @# p" }( I- F( b! f, @200 ng./dl. When skeletal maturation is complete the level of
! `7 v5 q1 _& N# y: n  R! w2 Cserum testosterone can be maintained in the 700 to 1,300 ng./3 n" |8 p3 Q) q+ h# Z1 c
dl. range to stimulate phallic growth and secondary sexual
' v; G; g+ s( {0 Q8 b/ Rchanges. Therefore, after skeletal maturation parenteral tes-7 A; B- l$ L# N# Q+ \7 g' R
tosterone may be used to advantage. Before skeletal matura-& W4 O. [4 o9 w6 w& ~( q
tion care must be taken to avoid maintaining levels of serum
0 y3 A6 N" V, I8 ttestosterone more than 100 ng./dl. Low-dose gonadotropin; A5 Q4 [' l& q  M: y2 a
depends upon intrinsic testicular activity and may require
2 I) t8 n  D' H" D, |prolonged administration for any response." v- O6 B6 v- q; Z5 J/ `
Alternately, topical testosterone does not depend upon tes-) L6 H6 s+ N$ ^' q  a" k' `
ticular function and may provide a more constant level of
2 c! v4 V7 @0 ^4 r0 R: TREFERENCES+ B  G& F: Q* u
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 l$ z$ T/ ?, h1 W, J
R.: The local application of testosterone cream to the prepub-
5 M5 B2 W' I9 D& jertal phallus. J. Urol., 105: 905, 1971.
' Y9 o/ c3 u& Z- N4 f1 p$ v2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone' C, Y( P" e) v4 V: P9 A
treatment for micropenis during early childhood. J. Pediat.,2 a3 p  a* H( o3 y9 D
83: 247, 1973.
/ v. E* ~. |2 I9 D2 K3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-  {1 g2 t, Q8 Q% A1 K  H6 Y
one therapy for penile growth. Urology, 6: 708, 1975.. P$ u  x+ m; S" }& y, O9 F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone7 N$ @# W, b# J4 [: o! y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, }6 H2 A3 I5 }skin slices of man. J. Clin. Invest., 48: 371, 1969.
" K0 n' l( Q+ l! }# ^/ `5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% w! m% w- U) s: f
by topical application of androgens. J.A.M.A., 191: 521, 1965.: Z: ~: Q; H& Z& a
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 I0 W& a& M: h+ U  J9 R$ B& Dandrogenic effect of interstitial cell tumor of the testis. J.
2 i5 X3 {$ I; y2 L/ gUrol., 104: 774, 1970.
$ _6 o$ R( Z0 Y' M6 d' s. y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
- J, y9 D+ _8 t. e: t6 E* wtion in the male genitalia from birth to maturity. J. Urol., 48:
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