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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND( ]( i; o' {6 }( i/ @3 @& k, K' t
GONADOTROPIN* P" G5 ?+ j/ [2 I) v7 n3 y$ ~1 c
RICHARD C. KLUGO* AND JOSEPH C. CERNY+ K, `- ^9 g( h0 Q; o0 ?9 A; p5 D. P
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan( y: y9 w7 b" [% |: k
ABSTRACT
7 ^# A! t5 |* V$ e, ]+ [* iFive patients were treated with gonadotropin and topical testosterone for micropenis associated
* N6 R6 d& j( E& Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. F$ e) L- X& U2 itropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone% u5 R1 H  @9 i# k
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent; M" ?5 x7 K; l  I9 ]
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 i0 `. L/ P% {- o
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 J3 z$ Z; |% k5 w5 E. y9 {, Mincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response  i$ }) ]3 F7 k) y
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- z3 b) l. Z$ l' Cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile: L9 Q! d# E, i" z4 b
growth. The response appears to be greater in younger children, which is consistent with previ-* ]4 n! @' w6 \7 c
ously published studies of age-related 5 reductase activity.
3 s" X0 e( m/ R& `3 c# b, EChildren with microphallus regardless of its etiology will5 [- P4 ^' u- C7 G6 u0 _
require augmentation or consideration for alteration of exter-2 j4 g1 Q" S5 c8 t& H# a' K
nal genitalia. In many instances urethroplasty for hypo-8 d; @  K* b$ I! a; E
spadias is easier with previous stimulation of phallic growth.: }% y4 U1 n+ R& l6 {! d7 v
The use of testosterone administered parenterally or topically/ {6 I6 m# c1 M) T" \  }
has produced effective phallic growth. 1- 3 The mechanism of
4 z) K; m9 z, h* O- Tresponse has been considered as local or systemic. With this
0 y# R, z2 d3 g, `- Min mind we studied 5 children with microphallus for response
, L0 a6 U- H7 j, ^$ e4 F- m9 sto gonadotropin and to topical testosterone independently.
) S1 x1 j# R: l* xMATERIALS AND METHODS
1 i% @/ T3 i6 ~6 H& ^Five 46 XY male subjects between 3 and 17 years old were
% c* A3 W$ }( ~( c/ Y8 zevaluated for serum testosterone levels and hypothalamic3 f4 U* \+ k& R3 X" N: d3 P
function. Of these 5 boys 2 were considered to have Kallmann's- s( R6 H" w) V% ?( X) W
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; T0 B+ Z  _" @$ s7 ]
lamic deficiency. After evaluation of response to luteinizing
1 {/ [% \1 X& r% L" ]! f$ Mhormone-releasing hormone these patients were treated with' o; H- K  w( f- n* G( W2 u
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* n& o( j) j' n) \after completion of gonadotropin therapy 10 per cent topical% F* o! z" b3 h
testosterone was applied to the phallus twice daily for 3 weeks.+ ]" u) S# E. F+ q3 R, j
Serum testosterone, luteinizing hormone and follicle-stimulat-
% ~6 f7 x3 F, I  Y% Zing hormone were monitored before, during and after comple-0 z) p& z, e5 b" x- a7 ^3 V, w' l
tion of each phase of therapy. Penile stretch length was
7 d8 w* H2 J0 ]/ y' t4 Vobtained by measuring from the symphysis pubis to the tip of4 ]2 g% S5 X2 K3 t& E# `- O
the glans. Penile circumferential (girth) measurements were% v& L) _( D/ S- I$ y4 p( q. t# {! \
obtained using an orthopedic digital measuring device (see
: P; u2 Z8 Z7 u/ Nfigure).
4 y, I1 V3 G' I6 ]2 ?2 b& oRESULTS8 E4 p, V' n& D* [9 ?: }1 w4 k
Serum testosterone increased moderately to levels between$ ~  A. z3 ]& v
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ q* W% [. x( Q" Qterone levels with topical testosterone remained near pre-
. X$ q& F; `, R/ k! a: o4 atreatment levels (35 ng./dl.) or were elevated to similar levels' ?$ S5 l/ _2 f9 y/ d
developed after gonadotropin therapy (96 ng./dl.). Higher: d  N1 R; D5 e
serum levels were noted in older patients (12 and 17 years old),
( j/ l9 q( c- s8 ?/ O% Q3 [while lower levels persisted in younger patients (4, 8, and 10
7 @1 e0 k' E3 \0 }0 k3 {5 B6 nyears old) (see table). Despite absence of profound alterations+ C8 {) n( _+ e, a/ D  R
of serum testosterone the topical therapy provided a greater
% h" b: k6 X' W, E  C- s/ zAccepted for publication July 1, 1977. ·
& c/ a5 s. Z+ X* s  `9 @7 G, aRead at annual meeting of American Urological Association,
. h+ [# o1 O8 l2 x; dChicago, Illinois, April 24-28, 1977.8 J6 f' [) A& [3 J
* Requests for reprints: Division of Urology, Henry Ford Hospital,
! Y0 d* _* ?) d4 E6 w2799 W. Grand Blvd., Detroit, Michigan 48202.9 N, o5 C; a) m2 l/ p7 |
improvement in phallic growth compared to gonadotropin.7 H* O; W% @. q1 i9 }# B# n! a. G
Average phallic growth with gonadotropin was 14.3 per cent
# P/ m1 d8 ]9 Oincrease in length and 5.0 per cent increase of girth. Topical
8 q, E* V- K8 F) i0 P( q3 Qtestosterone produced a 60.0 per cent increase of phallic length
) l; d! w% ]2 u4 Z! mand 52.9 per cent increase of girth (circumference). The
0 q9 V6 ]- y, ^. e: R9 e; iresponse to topical testosterone was greatest in children be-) c8 i# `- L; A( g
tween 4 and 8 years old, with a gradual decrease to age 173 w3 M9 y  J" ?* ]+ N  a7 O% _
years (see table).
8 u# d* J# G/ rDISCUSSION
* @; @) [7 v' U( q( Q- Y6 q; ^Topical testosterone has been used effectively by other/ \+ ?5 T* E' ~+ j1 T. s% C2 s! c
clinicians but its mode of action remains controversial. Im-
: T8 ?) [  u6 w% fmergut and associates reported an excellent growth response0 I( p3 e4 _" y) m- l8 n
to topical testosterone with low levels of serum testosterone,
" u' z- o" k6 G5 l: [! `+ Nsuggesting a local effect.1 Others have obtained growth re-
* a) J- C8 w- J/ _. Fsponse with high. levels of serum testosterone after topical3 N5 V2 B" X3 N  g. o& ^
administration, suggesting a systemic response. 3 The use of3 b& L! Z& y# \  b
gonadotropin to obtain levels of serum testosterone compara-9 r+ G' J+ B: a3 d+ c* k
ble to levels obtained with topical testosterone would seem to! U, |5 f! O$ y' E  k7 @
provide a means to compare the relative effectiveness of) C, J' u1 _! K1 {2 _6 j
topical testosterone to systemic testosterone effect. It cer-
5 X$ S0 N4 D% I5 [% b- x0 ftainly has been established that gonadotropin as well as par-
  Y2 y' c% f* [enteral testosterone administration will produce genital
& `' n; z- S" L+ Q, _2 \& H7 K# P  Egrowth. Our report shows that the growth of the phallus was
3 h: M) b( K9 _# [significantly greater with topical applications than with go-" N9 [& U6 K% ~) E' s# t
nadotropin, particularly in children less than 10 years old.
! E! ^2 b1 m8 h& _6 [4 \+ J! VThe levels of serum testosterone remained similar or lower
& [/ V& l/ E6 {4 V+ Jthan with gonadotropin during therapy, suggesting that topi-1 A$ K# ?+ z* |3 c
cal application produces genital growth by its local effect as( l6 z9 [; R. g  x% h
well as its systemic effect.* v9 \5 Q  o, Y' R
Review of our patients and their growth response related to. F3 B& X+ L, D2 v
age shows a greater growth response at an earlier age. This is
8 w, p  e5 ?, f) D5 p; W7 Y" bconsistent with the findings of Wilson and Walker, who
! p+ I2 ~) I$ \9 |reported an increased conversion of testosterone to dihydrotes-4 V( p+ L! M! \' C6 c
tosterone in the foreskin of neonates and infants.4 This activ-
6 Z; n% ?% m7 Dity gradually decreases with age until puberty when it ap-
, n1 `% i5 @- E, V4 Gproaches the same level of activity as peripheral skin. It may# {0 ]$ F2 w4 b" N* V; D
well be that absorption of testosterone is less when applied at3 _# Q% F& t3 n3 F& g1 P
an earlier age as suggested by lower serum levels in children& {4 N# n, J" T7 t; r: d
less than 10 years old. This fact may be explained by the, ?* r( @" u  s! j& R
greater ability of phallic skin to convert testosterone to dihy-, g' {8 C( M4 m7 f5 K& l  }' H. G
drotestosterone at this age. Conversely, serum levels in older" [0 I; ~/ w3 X. i
patients were higher, possibly because of decreased local
6 j% X2 }  M8 t667
, d% _$ t5 H$ c8 t& ~668 KLUGO AND CERNY
5 `/ s# Q  }6 ~3 b- I. qPt. Age; _* }/ w0 c9 {
(yrs.)
/ ?3 f# w: G8 f7 A8 dSerum Testosterone Phallus (cm.) Change Length
0 O% d% A" s2 L: w0 E(ng./dl.) Girth x Length (%)
* Q7 j( |3 u3 }9 E8 r4
& d- P1 ^8 r; z1 ~) m! j8
/ W! s. p8 j+ S. e6 q10
3 J! n3 x- K' ?& \$ Z, E. J2 e7 r2 B12
; T$ o+ u# H# y! ~  \4 m175 `9 F1 E4 |% c/ c- j* j, C
Gonadotropin$ }( A; G) q+ q: \+ b) o
71.6 2.0 X 3 16.69 d' S% F# [% A; }8 B& Z
50.4 4.0 X 5.0 20.0
# Z4 t- o) C1 @: b22.0 4.5 X 4.0 25.0
/ s& o, H/ a: ?84.6 4.0 X 4.5 11.1; N3 y, G2 x3 r1 c  P/ B
85.9 4.5 X 5.5 9.0( O& ^& ]2 p9 o9 L2 Z$ J/ p
Av. 14.32 {: K) w0 [- ?1 Q+ s5 w1 C
4- W$ X8 ]& w9 c# x
8# V5 R, I& b: T5 G- F$ E; Z* @. g
10+ _( q) o+ c+ `( m( r
12. L! [" j  B+ _
17! F, R; k# G6 L' K$ j5 h1 M. C) m% _
Topical testosterone3 T) \) s7 y$ e% L. V) K8 Z# ]: v
34.6 4.5 X 6.5 85
* _4 K6 l6 V/ u7 ]' N$ T& ?38.8 6.0 X 8.5 70
9 T( S7 y( U/ ?40.0 6.0 X 6.5 62.5
/ d: y% Z4 C9 u1 l! K5 q  z$ _+ {/ B93.6 6.0 X 7.0 55.5
! x% t" C2 y, W6 k  ]95.0 6.5 X 7.0 27.2
/ `" _/ H" A1 l' w+ F. aAv. 60.0* }9 g; }% x8 P  k) A* N6 |
available testosterone. Again, emphasis should be placed on
; T+ P1 B! d/ ?2 d; f) Kearly therapy when lower levels of testosterone appear to
1 q$ j! Z1 v& h# g) g. A& pprovide the best responses. The earlier therapy is instituted
6 c+ v% k( f& h* J* Hthe more likely there will be an excellent response with low
7 x/ v9 @4 S  y( }9 N3 N# mserum levels. Response occurs throughout adolescence as9 Y, V2 Z8 m" f
noted in nomograms of phallic growth. 7 The actual response
6 K/ N6 t$ q& z/ l; Yto a given serum level of testosterone is much greater at birth' ?2 E7 w' }7 b: r
and gradually decreases as boys reach puberty. This is most8 O, j0 k+ Z4 A  C! E" ?( Q- k. h
likely related to the conversion of testosterone to dihydrotes-
  O8 G% n! S, e( j: f( Dtosterone and correlates well with the studies of testosterone
0 H: i6 e" T7 \% v" {8 f+ Uconversion in foreskin at various ages.
% H2 {% z  ^* O/ H, k/ D9 RThe question arises regarding early treatment as to whether- T" o- Z; s6 L/ }) V2 ~4 f
one might sacrifice ultimate potential growth as with acceler-
$ v$ i' M' G1 P! o9 U& b3 eated bone growth. The situation appears quite the reverse
6 V( x* Z2 `0 w9 G$ Dwith phallic response. If the early growth period is not used
8 a( T2 I( G  ~% o: H. Q0 S5 |when 5a reductase activity is greatest then potential growth- }5 [8 D& t  C* q
may be lost. We have not observed any regression of growth8 R# _1 X7 d, e
attained with topical or gonadotropin therapy. It may well
# v. O# f8 G, `" s; obe that some patients will show little or no response to any' H9 O) ^9 {4 m. p( d
form of therapy. This would suggest a defect in the ability to
' o% g# [5 i7 V$ M, {convert testosterone to dihydrotestosterone and indicate that
& o$ {6 t; @' ?3 y; j. dphallic and peripheral skin, and subcutaneous tissue should/ F% \- Y. V$ A3 c+ t! k
be compared for 5a reductase activity.  O1 m) J: g3 q. f1 c" d0 D
A, loop enlarges to measure penile girth in millimeters. B,
- ?" G. B; b$ ?example of penile girth computed easily and accurately.( a! l1 X! v1 ?' F  L
conversion of testosterone to dihydrotestosterone. It is in this
1 @& [, F2 z: q( j8 ]older group that others have noted high levels of serum0 j* N- |1 n) s' a$ ^3 T4 j8 f
testosterone with topical application. It would also appear4 I3 o" e, k: _- E
that phallic response during puberty is related directly to the
5 y$ N. A; L7 ]. kserum testosterone level. There also is other evidence of local
- K) l$ V+ T- \& d" `response to testosterone with hair growth and with spermato-
- Z- t( |; }$ K3 _8 N. u* fgenesis. 5• 6
. r( _- W) u4 E3 ^Administration of larger doses of gonadotropin or systemic
/ U9 r' l* Q( B$ D& ctestosterone, as well as topical applications that produce9 Q$ q+ A, I) Z0 k) j" C/ N
higher levels of serum testosterone (150 to 900 ng./dl.), will- |4 o/ A: F  |) Q% s/ p, z/ ^
also produce phallic growth but risks accelerated skeletal
1 P, i7 {  U$ f3 l* j7 A. @maturation even after stopping treatment. It would appear
" d1 v: d+ q8 K6 z/ M. {3 _that this may be avoided by topical applications of testosterone2 V" d9 c5 @& p) C/ e4 S' o
and monitoring of serum testosterone. Even with this control% @# p  H' B1 G# n, J5 A% Z* B
the duration of our therapy did not exceed 3 weeks at any
& `1 H4 j. @5 n/ v1 a* M5 d5 K7 o' itime. It is apparent that the prepuberal male subject may
7 Y7 J% Y. Y' U+ r4 wsuffer accelerated bone growth with testosterone levels near: l; a: K0 _* w5 ^+ _# p
200 ng./dl. When skeletal maturation is complete the level of
3 J- S6 Z- x! x4 M# C+ vserum testosterone can be maintained in the 700 to 1,300 ng./& V4 Q2 U1 [9 [; X( y
dl. range to stimulate phallic growth and secondary sexual+ _4 C$ y$ s$ X% g7 R( z9 D
changes. Therefore, after skeletal maturation parenteral tes-0 }' x" w& j/ V
tosterone may be used to advantage. Before skeletal matura-
% X5 a7 k, n. A, \! ition care must be taken to avoid maintaining levels of serum
# X) v* Y- V/ |' ~testosterone more than 100 ng./dl. Low-dose gonadotropin
) e1 ?3 ?$ V  |) G4 m$ V4 Udepends upon intrinsic testicular activity and may require' W. @1 |0 q* ?, K
prolonged administration for any response.
/ Z6 b$ P& a4 F* t7 a3 }Alternately, topical testosterone does not depend upon tes-
8 T! R+ W+ ]* U8 S; C: ~ticular function and may provide a more constant level of  p( X9 G+ q" R3 Q' H+ ]' {( G8 s5 T
REFERENCES; H$ b1 W% V% J
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
/ m  n6 u9 Q1 X0 F4 X4 }& ^8 p/ ]3 iR.: The local application of testosterone cream to the prepub-
4 R% P' t: ]9 t$ Y5 gertal phallus. J. Urol., 105: 905, 1971.
; |/ f  W$ \+ Z" m4 C/ w3 R2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 z& J$ k7 I5 ]  {treatment for micropenis during early childhood. J. Pediat.,
) j& `7 b6 a  k, G: u83: 247, 1973.
( A# V: u( f* E, s- f3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
% h( {0 A" W) c5 v+ T# n) Rone therapy for penile growth. Urology, 6: 708, 1975.' T1 ]4 h0 f1 X
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone% @( o* \2 N. y' |2 @; x9 z8 q
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ {: y: y5 z/ k/ P$ q
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ t7 n) g0 H% n3 r# t1 _" i8 ~0 N
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- F, K, I# G6 U( C5 rby topical application of androgens. J.A.M.A., 191: 521, 1965.
0 X4 o: `  t  t8 \- n6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ h# q, c7 X! o8 F  A
androgenic effect of interstitial cell tumor of the testis. J.
, i  o7 p1 m2 `  v  T0 w% JUrol., 104: 774, 1970.. }$ X% n- z( N% T7 c$ z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 R& n9 q3 C% v3 X( n
tion in the male genitalia from birth to maturity. J. Urol., 48:
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