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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: e( Z( p+ @8 `' V2 C
GONADOTROPIN
% m" F" F, B# Q2 K* u3 fRICHARD C. KLUGO* AND JOSEPH C. CERNY) K5 I0 B4 a) K# v" O  e6 D
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
- a; o; Y0 [( ZABSTRACT- |- W. H' r& E! r8 i* H( X
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( ]2 y5 d4 j7 j* Hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-4 U" i" C$ i+ E+ \6 }
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 n( D) n9 ]7 `' K- b1 s6 R( P
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. c9 Z( |! a9 w5 N4 {( |* i
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent8 @$ L3 h# X. t
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
  R) v  D2 [  Q$ ]/ V9 G9 \. e, Nincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# V4 \( |' Z; u3 }* Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 f) c$ f) p; @
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
" q( b0 T9 J3 z* R. v+ v$ ogrowth. The response appears to be greater in younger children, which is consistent with previ-4 }4 W0 v6 ^3 s/ `6 }
ously published studies of age-related 5 reductase activity.
$ }* t* {- G+ P! |5 m. X8 YChildren with microphallus regardless of its etiology will4 d0 M- ~) ~: a( q1 S9 ~* O
require augmentation or consideration for alteration of exter-( w$ C% o, l  R! m
nal genitalia. In many instances urethroplasty for hypo-
* E6 ~# i" z' U0 W- a* E" A/ l" zspadias is easier with previous stimulation of phallic growth.+ j* j* x% p* v7 a
The use of testosterone administered parenterally or topically
/ C. P5 @' V5 i" `+ K% ]) chas produced effective phallic growth. 1- 3 The mechanism of# E% U: `( s7 E8 y
response has been considered as local or systemic. With this, K3 F  |1 v* o; O
in mind we studied 5 children with microphallus for response
! S! w1 ]0 S# t, ?7 V) x8 I+ Q; dto gonadotropin and to topical testosterone independently.
, B, ^# v) z3 ^MATERIALS AND METHODS
6 n& Y7 w+ ~" ]) Z) e# y, a( oFive 46 XY male subjects between 3 and 17 years old were+ r* X( t& q) g  I2 v' E
evaluated for serum testosterone levels and hypothalamic: I6 q$ z+ |! H
function. Of these 5 boys 2 were considered to have Kallmann's
. b; l' y( Y6 I0 C+ y1 e9 ~- @3 Ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-# M0 r5 `& C3 H2 y/ J
lamic deficiency. After evaluation of response to luteinizing; j$ h+ O8 J0 _, p( O
hormone-releasing hormone these patients were treated with
3 \6 O9 S& Y6 M7 \1,000 units of gonadotropin weekly for 3 weeks. Six weeks. C; N5 q; k! ^$ ~  Z* |3 G' n
after completion of gonadotropin therapy 10 per cent topical6 p" W; M% A- c! S: V2 |$ |
testosterone was applied to the phallus twice daily for 3 weeks.
7 s: a% S3 `0 N' Q+ QSerum testosterone, luteinizing hormone and follicle-stimulat-
: H% _* C" k. ?  x# ^. Xing hormone were monitored before, during and after comple-
! P* d0 p2 |9 t& s* Ftion of each phase of therapy. Penile stretch length was
1 l7 X1 ?* X" r! I$ A2 f$ Mobtained by measuring from the symphysis pubis to the tip of
, @3 X) J( ^4 @the glans. Penile circumferential (girth) measurements were
8 y, A* J( H+ Q" J8 j: _$ Dobtained using an orthopedic digital measuring device (see
/ k' u$ T! X+ ^  e4 X2 N: N& Hfigure).# O4 w% R1 `9 P. k/ W
RESULTS8 H; s% P7 ], n# l9 Y2 ]; J/ m3 Q* h( i
Serum testosterone increased moderately to levels between
# H) C9 V" ]! P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-+ E" T: @& f9 e3 P1 c
terone levels with topical testosterone remained near pre-
2 \7 e1 G1 W. h( ?" utreatment levels (35 ng./dl.) or were elevated to similar levels/ r7 ^. v  T( U" H
developed after gonadotropin therapy (96 ng./dl.). Higher
# V, s) d1 ^5 y) e# @9 bserum levels were noted in older patients (12 and 17 years old),
7 u5 [, H# G# H4 b( Qwhile lower levels persisted in younger patients (4, 8, and 10  f1 X0 @$ F0 w) P' P
years old) (see table). Despite absence of profound alterations2 _+ B$ a8 M' T/ A2 @
of serum testosterone the topical therapy provided a greater. D9 f  V' a6 k8 H2 R; r% W: Q) U
Accepted for publication July 1, 1977. ·) k; q: ?5 M( E8 w+ S6 E
Read at annual meeting of American Urological Association,: ~' ?$ G$ m: q! n% a  ^
Chicago, Illinois, April 24-28, 1977.
& k: p- y" ?+ s& X: G) C* Requests for reprints: Division of Urology, Henry Ford Hospital,
- j( l% u% ]" u; E% B: y- a2 U8 j% F2799 W. Grand Blvd., Detroit, Michigan 48202.7 b9 Q( b8 t' Z5 w: R( [# }& M2 f
improvement in phallic growth compared to gonadotropin.
# t% M9 o# S. vAverage phallic growth with gonadotropin was 14.3 per cent
1 f1 m. d3 g8 e( U( tincrease in length and 5.0 per cent increase of girth. Topical) U# z2 T* q; s. W! J: _
testosterone produced a 60.0 per cent increase of phallic length& a- M; Y$ R+ G% w$ T: j
and 52.9 per cent increase of girth (circumference). The: l. y$ s5 \  q5 x$ j
response to topical testosterone was greatest in children be-5 D, x! |" e% W% {
tween 4 and 8 years old, with a gradual decrease to age 17
, J0 y) {9 j% Y$ {% U6 p! m! \" Ryears (see table).! d8 E) N; Z% e! Q
DISCUSSION/ d( T! f3 L9 z6 [
Topical testosterone has been used effectively by other: u. n+ c' W% [2 ?
clinicians but its mode of action remains controversial. Im-6 a9 Y, p* V8 O7 G& c
mergut and associates reported an excellent growth response
: T. E  O/ Z6 T4 f9 u+ }7 ^2 rto topical testosterone with low levels of serum testosterone,3 X) S+ b" D8 e8 p" w9 |
suggesting a local effect.1 Others have obtained growth re-
# w; ^; ~8 J, k' F; B2 N7 S- Q6 Dsponse with high. levels of serum testosterone after topical9 E* q0 o' F, T& s- h9 n' ?; S
administration, suggesting a systemic response. 3 The use of# ?0 u0 l2 R# Y9 P
gonadotropin to obtain levels of serum testosterone compara-: s+ x6 i( `  {) c
ble to levels obtained with topical testosterone would seem to
1 A" S" Q% e# z  C8 Cprovide a means to compare the relative effectiveness of- l8 n9 H& K& j( [0 p0 u! U
topical testosterone to systemic testosterone effect. It cer-: f- z* T- \. Z% J7 Q
tainly has been established that gonadotropin as well as par-6 g) d" b/ f# q) W- T2 S+ p
enteral testosterone administration will produce genital
1 c! Z6 ?) B& n1 ~5 O, W( P) `9 Bgrowth. Our report shows that the growth of the phallus was, \" ?$ `/ v5 F* b, a* \' K
significantly greater with topical applications than with go-" k  ?$ H' t0 X
nadotropin, particularly in children less than 10 years old.
! M7 o( l( h) X1 }: i* @4 _7 Q0 fThe levels of serum testosterone remained similar or lower
" V' Z* Q; C7 f# i6 |" p: L! _8 lthan with gonadotropin during therapy, suggesting that topi-
6 {( q3 z# s. A8 s) c& G# acal application produces genital growth by its local effect as/ C2 a3 V& U; E1 |  T
well as its systemic effect.9 M- K" M& z# u' @+ e# g; B
Review of our patients and their growth response related to5 M0 a" _: s5 J: \4 u2 f
age shows a greater growth response at an earlier age. This is$ R$ S0 ^1 F  J; S" u
consistent with the findings of Wilson and Walker, who
" Z' |+ M" i; ~5 Vreported an increased conversion of testosterone to dihydrotes-' w1 |, ^4 h' i0 S% ^* U
tosterone in the foreskin of neonates and infants.4 This activ-
; K+ ?( s6 J$ P3 nity gradually decreases with age until puberty when it ap-  M4 i6 J! U/ }1 K% P/ n1 _
proaches the same level of activity as peripheral skin. It may
$ O( [5 |) n$ s# @well be that absorption of testosterone is less when applied at
0 b- B% x" t; g3 Pan earlier age as suggested by lower serum levels in children
2 C' V; l& {& Pless than 10 years old. This fact may be explained by the
/ |8 ^5 P8 t, D5 Mgreater ability of phallic skin to convert testosterone to dihy-4 k( c4 F8 W0 S8 A% p8 |, @
drotestosterone at this age. Conversely, serum levels in older5 ~! E  B* y8 E3 P% R2 X8 ~1 q
patients were higher, possibly because of decreased local% ?$ a% E* a8 q( Q% S& y! b) p  N
667" @0 m* B. s: X% {5 P0 O6 _
668 KLUGO AND CERNY$ j7 L- X$ R1 H8 N% w: s4 W! f
Pt. Age5 K! x2 M5 h( N* Z# w( {
(yrs.)
$ \# e* B1 z* ~Serum Testosterone Phallus (cm.) Change Length
8 I0 o, W5 R( k3 \$ |(ng./dl.) Girth x Length (%)! S9 H! Y4 ]( Q4 _) [0 j
45 c6 B3 K. {4 C
8- |* C: [1 d! H8 p, A3 z# c  ^
10
( z& T, y0 S; }9 d' U. X- V12
% i. Z, o; n5 I3 G17
, ^9 R# v# Y+ E; A7 \Gonadotropin
# B# d3 F' D1 Y  u71.6 2.0 X 3 16.6
- H$ K. Y' _3 f% a* k* m50.4 4.0 X 5.0 20.0
* d5 d7 }% L. u22.0 4.5 X 4.0 25.0
5 ]2 ^; M$ {& b0 ^84.6 4.0 X 4.5 11.1
8 b: R! D. j5 C# l0 V6 b( W85.9 4.5 X 5.5 9.08 c& K8 o2 {& [1 k
Av. 14.3
2 g3 n& v% G1 S4+ k2 b0 l; I6 U2 T; }
8" m  K4 z: ]( O* b8 l3 [0 Z% S" X, K
10
% I4 P" ]. o' c  @12
* u# ~! O! [; v  ?0 @9 j" `# g17
$ C' E$ [* a4 Y& Q6 WTopical testosterone
/ t' O- y2 n% P  I6 g34.6 4.5 X 6.5 85
. a- T6 r+ `2 b  D7 R& L38.8 6.0 X 8.5 70: q# N( T) P9 {4 y
40.0 6.0 X 6.5 62.5
6 v6 w; h, ?$ [. [8 E93.6 6.0 X 7.0 55.5
" c  \6 f* v* X7 ^. }( e3 f95.0 6.5 X 7.0 27.2
% x' ?3 B$ U" L* iAv. 60.0
1 Z9 ~9 I+ ?; F9 {, pavailable testosterone. Again, emphasis should be placed on7 A$ Q% {2 V& {% G) G1 P
early therapy when lower levels of testosterone appear to
: G* R) Y/ f1 D5 L1 \9 _5 [  h% e5 ~provide the best responses. The earlier therapy is instituted
# @" R" M: H, h; gthe more likely there will be an excellent response with low7 c4 f5 I$ C7 _' i5 b
serum levels. Response occurs throughout adolescence as8 ~1 t' [; l0 m- `- g% W1 j7 w
noted in nomograms of phallic growth. 7 The actual response. D) c2 w) N8 A, |; t
to a given serum level of testosterone is much greater at birth3 A8 {, U. e% Y1 ~- k' l
and gradually decreases as boys reach puberty. This is most
; N8 m3 _' d$ i! }7 j9 {likely related to the conversion of testosterone to dihydrotes-* Y" a. O/ S7 M! J
tosterone and correlates well with the studies of testosterone8 I  Z: o( O3 U2 N0 r0 L
conversion in foreskin at various ages.
& ^0 S# _( ^1 @1 y# h* CThe question arises regarding early treatment as to whether
& P  @6 C5 ?8 M7 E6 G% gone might sacrifice ultimate potential growth as with acceler-/ F' ~4 V! m* j& z2 V1 J- i# {
ated bone growth. The situation appears quite the reverse  |! m* [" H2 G) p4 x
with phallic response. If the early growth period is not used5 Z: }; ^0 ?) ]& P! d& Y
when 5a reductase activity is greatest then potential growth! v; k, `; _% v
may be lost. We have not observed any regression of growth
) ]8 T: x: E& X0 u. b4 lattained with topical or gonadotropin therapy. It may well& q& _. W. t* H! C+ B
be that some patients will show little or no response to any( ~- [, K  V7 W: C, p, u& j  o
form of therapy. This would suggest a defect in the ability to
0 y9 E% K3 y$ Q: o7 o: N( e# q5 x% Gconvert testosterone to dihydrotestosterone and indicate that: T, y# m7 Q+ v
phallic and peripheral skin, and subcutaneous tissue should, x$ q5 V( p3 Q
be compared for 5a reductase activity.
1 j" g; s' a: X& DA, loop enlarges to measure penile girth in millimeters. B,
- t$ U1 Z/ c6 n4 q2 U  I, Lexample of penile girth computed easily and accurately.
& E3 W6 N2 N$ [$ s2 ~: fconversion of testosterone to dihydrotestosterone. It is in this
$ a+ C) @0 F) Y# j" T+ _older group that others have noted high levels of serum+ t7 k6 i& p5 A
testosterone with topical application. It would also appear4 _1 D" o8 P  j0 |
that phallic response during puberty is related directly to the
8 O$ B( E7 E3 U$ G# Z* F- mserum testosterone level. There also is other evidence of local
8 Y( w9 Q& e6 f+ [7 a; y7 Aresponse to testosterone with hair growth and with spermato-# g; Y4 Z  x; j9 @
genesis. 5• 6% i: k+ e4 _1 M6 C. D
Administration of larger doses of gonadotropin or systemic
: `2 m& U; W/ J3 s6 |: E6 itestosterone, as well as topical applications that produce
# \4 L& J0 F: C& hhigher levels of serum testosterone (150 to 900 ng./dl.), will
: R% f# |4 _" ^1 m5 g' S! w% Nalso produce phallic growth but risks accelerated skeletal! P0 x9 k9 F$ L- o( P% Y
maturation even after stopping treatment. It would appear) T% e6 w0 C) G
that this may be avoided by topical applications of testosterone; P# M# u6 h$ z; F  j% M( K: w
and monitoring of serum testosterone. Even with this control
& G9 }# w- E  m" \5 X$ bthe duration of our therapy did not exceed 3 weeks at any
. J% a) V' p/ s2 Jtime. It is apparent that the prepuberal male subject may
. Z5 `- z6 I, _9 Lsuffer accelerated bone growth with testosterone levels near
5 G. R9 [, ~* ?" V* I200 ng./dl. When skeletal maturation is complete the level of
# L8 s! _: U8 P& }/ W: jserum testosterone can be maintained in the 700 to 1,300 ng./
6 n: S( S( ?. n0 I) Adl. range to stimulate phallic growth and secondary sexual5 ^. \+ n. G" v: @5 v
changes. Therefore, after skeletal maturation parenteral tes-
( L# a- R' e* D& Atosterone may be used to advantage. Before skeletal matura-9 |8 c, R2 Y( G, d8 x9 t( Q0 e
tion care must be taken to avoid maintaining levels of serum
; U& k, B: [, ?* Otestosterone more than 100 ng./dl. Low-dose gonadotropin
) W! `8 ?2 D; k$ Jdepends upon intrinsic testicular activity and may require, r2 f. G' i4 g9 i9 f
prolonged administration for any response.
0 l- y/ W+ ?2 \& ?* W) \Alternately, topical testosterone does not depend upon tes-% P. x' V! r2 s2 p7 D4 G* y
ticular function and may provide a more constant level of/ v0 t* X8 L* ^# u7 D5 ]. Y# p, l
REFERENCES
- t& {) B; k; r$ w" ^& G1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
! K" T' Q4 Y% `% W$ g- g+ ]R.: The local application of testosterone cream to the prepub-5 e9 f2 W/ r3 Z( y
ertal phallus. J. Urol., 105: 905, 1971.
; `. v7 A: @3 U7 m5 D2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 V. e" B5 D$ Q% d4 Z! otreatment for micropenis during early childhood. J. Pediat.,1 ?  Z* d8 y! \. Y1 w- b7 ]
83: 247, 1973.; D2 Y; h% u2 |0 P3 {: _) Q* U) `3 w
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' r/ L3 w3 r. O# {- e* D
one therapy for penile growth. Urology, 6: 708, 1975.
6 s) @/ @! Z; e- D. h4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone2 ~  K1 U& r& @5 }* u9 F8 x
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 b0 x2 [+ C1 S3 \
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 d$ @0 p& C6 ]) A& f# u; d' x( _
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth9 B+ R2 r. P/ ~; w
by topical application of androgens. J.A.M.A., 191: 521, 1965./ u0 W/ n: S  c/ Z; Q. e
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local; `. ~% Q% y8 {8 ]$ a
androgenic effect of interstitial cell tumor of the testis. J.: _1 k  o3 M1 N" y* q+ f
Urol., 104: 774, 1970.7 F& y' U) j1 `1 ]. F( E. z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ ^* i, O( h% z% otion in the male genitalia from birth to maturity. J. Urol., 48:
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