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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 L8 {0 a. t& `* n5 v. ~' x. AGONADOTROPIN7 n/ f* h2 x0 V1 h! Q4 n' J% j
RICHARD C. KLUGO* AND JOSEPH C. CERNY
1 {3 o! k" }; C* R3 A% s1 C; l  _7 S- kFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan! o4 g( @) N& D) W6 e3 s
ABSTRACT
$ z1 K) G5 D1 r" {6 S; b. FFive patients were treated with gonadotropin and topical testosterone for micropenis associated# x7 o4 z; J8 ^! V
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ f: m; @- R6 E% b" k: U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
" f. f/ r# ~/ {7 R/ _+ M* c0 fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. d% j0 }4 e+ I- Z5 K5 d
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 B  U2 d3 ~/ W7 W6 Q" h8 Jincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) U. m$ ~  t4 c) Uincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 W8 N8 K% k) D$ m- ?1 q6 u, [8 P" ~+ Q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
! ^( l0 g: K$ B$ s1 ostudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 K7 }' L5 `0 ], U
growth. The response appears to be greater in younger children, which is consistent with previ-
% k& s/ |; y# b3 T" `  dously published studies of age-related 5 reductase activity.: d. P( ]9 j( a' {9 }/ F
Children with microphallus regardless of its etiology will
0 R( y2 \" m( g! frequire augmentation or consideration for alteration of exter-
/ `9 o# ^0 |  D5 U% T) [1 |nal genitalia. In many instances urethroplasty for hypo-4 ]1 x5 A9 x9 }
spadias is easier with previous stimulation of phallic growth.
7 q# ^0 f+ s& }% g) h+ |! VThe use of testosterone administered parenterally or topically! ^* @/ E( n+ i! [6 H
has produced effective phallic growth. 1- 3 The mechanism of6 x+ v% A9 J& l2 X: ^1 d/ T
response has been considered as local or systemic. With this' x# |9 O- q$ h5 u& ?) X# [
in mind we studied 5 children with microphallus for response
# w+ R: ~, C6 y' P+ A1 x1 Uto gonadotropin and to topical testosterone independently.% z, e6 I! q9 e( K+ _
MATERIALS AND METHODS& k2 x7 h! ^* b* W1 T! r' u
Five 46 XY male subjects between 3 and 17 years old were* W8 l* A3 Q* y0 |4 m# {1 s
evaluated for serum testosterone levels and hypothalamic1 h6 D% o; Z9 b# N& l+ A
function. Of these 5 boys 2 were considered to have Kallmann's
& O9 I7 s. z" F- }( \syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 ~. B" a" X& ^3 X) `, |8 l$ D9 m0 U
lamic deficiency. After evaluation of response to luteinizing2 a+ u* ^6 P* `2 L, _- {* F! r
hormone-releasing hormone these patients were treated with' e( X* R6 G+ I6 N
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
, B8 c& u" ]3 Z  Nafter completion of gonadotropin therapy 10 per cent topical' ^/ W+ o8 e( \8 m
testosterone was applied to the phallus twice daily for 3 weeks.
* x' o2 J" {1 y( s2 v' Q8 l$ TSerum testosterone, luteinizing hormone and follicle-stimulat-) p$ P: }  q& _8 t% Y& O
ing hormone were monitored before, during and after comple-
7 N0 p" t) f4 c5 H: R. Ction of each phase of therapy. Penile stretch length was' `/ Q  w/ G$ V1 H1 ~6 ?5 A5 T
obtained by measuring from the symphysis pubis to the tip of
- M- x  F/ X, H# dthe glans. Penile circumferential (girth) measurements were
# ^. L7 ?4 u4 d9 l7 I, R1 B, hobtained using an orthopedic digital measuring device (see
) b* w3 M" m/ J# I6 F( H& P# nfigure).
$ P& u4 W/ A6 u8 g1 x; gRESULTS, I9 c+ j/ T/ `( C
Serum testosterone increased moderately to levels between9 Q  }' F+ v; t3 J0 Z4 w
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
6 y. d6 z# ?% V2 Vterone levels with topical testosterone remained near pre-
$ U( |+ R7 W( B7 b7 W7 m; ^treatment levels (35 ng./dl.) or were elevated to similar levels
! K- z" y: M0 Qdeveloped after gonadotropin therapy (96 ng./dl.). Higher0 K! K+ |7 I1 x# t# s( }) X
serum levels were noted in older patients (12 and 17 years old),0 u& i, X  c$ R% ^# ?7 s
while lower levels persisted in younger patients (4, 8, and 10
1 {) f0 Z5 i4 J5 Jyears old) (see table). Despite absence of profound alterations
$ h' \2 M! F" z9 q; i5 E  Qof serum testosterone the topical therapy provided a greater0 B: R& i) b, r4 r
Accepted for publication July 1, 1977. ·
$ i6 n; [( w+ H) q! e' eRead at annual meeting of American Urological Association,
# U5 w% u" K2 a* @% E4 i1 F. f- mChicago, Illinois, April 24-28, 1977.
8 y7 w1 c7 A6 y- v3 \- L* Requests for reprints: Division of Urology, Henry Ford Hospital," F- I( U+ K' d5 |
2799 W. Grand Blvd., Detroit, Michigan 48202.
1 [" D: ?6 x! ^. a1 L3 _improvement in phallic growth compared to gonadotropin.  B$ ^& e% l/ h$ P  |1 K/ m5 p
Average phallic growth with gonadotropin was 14.3 per cent( g8 E& U4 H" n3 ^1 A" Q4 C& \9 E
increase in length and 5.0 per cent increase of girth. Topical6 ]8 O( j: N0 K% j
testosterone produced a 60.0 per cent increase of phallic length& m. n! @0 u/ H7 R6 I
and 52.9 per cent increase of girth (circumference). The
! q: `+ y3 D5 i$ L! bresponse to topical testosterone was greatest in children be-6 y8 E% V9 Q. f# B* a8 z
tween 4 and 8 years old, with a gradual decrease to age 17
% C5 W& v: R2 Pyears (see table).
9 T3 z4 _$ u( jDISCUSSION& t5 E4 i& f4 T
Topical testosterone has been used effectively by other# J: a  _0 O2 ~9 R2 O
clinicians but its mode of action remains controversial. Im-
, V. C- |( x0 m: f1 v: }2 b# Smergut and associates reported an excellent growth response
. j0 W1 @- a7 r) y+ kto topical testosterone with low levels of serum testosterone,
4 N+ H& f8 w1 S: R& e4 [- p# Esuggesting a local effect.1 Others have obtained growth re-% M  _% J" v2 g9 y$ g2 y1 o9 v! z
sponse with high. levels of serum testosterone after topical
! P: G# X0 L4 ~5 @) L* ~& Gadministration, suggesting a systemic response. 3 The use of" x: e+ h" }# W& T1 S1 O2 ]+ o+ S/ g
gonadotropin to obtain levels of serum testosterone compara-
5 `; ?' c2 `, R* G  `ble to levels obtained with topical testosterone would seem to7 j( L, Z2 S( `: i$ r6 A
provide a means to compare the relative effectiveness of& \1 o! o  Z; ~" D3 N- y& I
topical testosterone to systemic testosterone effect. It cer-
! V$ W1 t& X; l' g/ e  wtainly has been established that gonadotropin as well as par-
. ~2 H! J' y  ^8 s, |enteral testosterone administration will produce genital8 x8 z$ J1 Y9 C2 W! l
growth. Our report shows that the growth of the phallus was) G! _3 |6 F1 H; u5 Z8 ?1 e
significantly greater with topical applications than with go-2 }1 L9 [5 q9 X5 U
nadotropin, particularly in children less than 10 years old.; x( K7 K) L. u8 e7 ?! ^; `* O
The levels of serum testosterone remained similar or lower( H2 E& W4 c7 V3 s- \* q6 H5 H( T
than with gonadotropin during therapy, suggesting that topi-6 C: E/ q+ `; t7 R( e
cal application produces genital growth by its local effect as+ E5 @; Q: T6 X% H  y6 I
well as its systemic effect.
4 X( [' ^1 ^& d& kReview of our patients and their growth response related to5 B! M/ ]" @3 q+ r! t
age shows a greater growth response at an earlier age. This is
2 F/ U+ ?$ h7 ~  L# `consistent with the findings of Wilson and Walker, who
% o( k# m, A6 r# T/ vreported an increased conversion of testosterone to dihydrotes-& q; M6 l" D8 a! r( M# u( t
tosterone in the foreskin of neonates and infants.4 This activ-
+ Y- w. H" o4 o: Q. h/ Dity gradually decreases with age until puberty when it ap-8 U2 X! g- j/ P7 U, y
proaches the same level of activity as peripheral skin. It may
4 `! S* V4 j* q( _' C$ g: Jwell be that absorption of testosterone is less when applied at5 Q9 J: x" z3 Q: I1 u
an earlier age as suggested by lower serum levels in children
' b+ H1 x8 w5 h; Dless than 10 years old. This fact may be explained by the7 Q8 y9 N( d- o0 [  B& \. [: m
greater ability of phallic skin to convert testosterone to dihy-/ O0 U9 m  ~: G7 E; o) z
drotestosterone at this age. Conversely, serum levels in older$ P8 W4 \) J/ |( h& O$ v) G2 l
patients were higher, possibly because of decreased local
# m" T% H8 u. e8 T: K667
0 l6 ?' V0 x9 W0 ~7 n) v: S" A668 KLUGO AND CERNY
4 d4 c# \* S/ c. H6 ~( u) tPt. Age
0 M5 c3 m+ u' k& C) r(yrs.)
. U" w" S9 \0 v7 T- I" [Serum Testosterone Phallus (cm.) Change Length: `$ V% ~; V2 m! d4 ^  ?+ ]* v
(ng./dl.) Girth x Length (%)6 }0 G+ B4 Q6 A, s1 t4 ~
4
; h4 f' U  ~5 [8
; M, v7 ]8 V- O/ M2 ^- \100 i5 P5 z. R5 v( s
12
* ~6 h- m& D7 X' i5 g5 m8 B17
. P9 `5 \7 d. S0 @9 Q% E: sGonadotropin
3 k1 `. O) N. _7 V2 T71.6 2.0 X 3 16.6
* {  X# L; L. U  Z' i3 o5 S50.4 4.0 X 5.0 20.0
8 x6 ^6 e. V9 _& n' A22.0 4.5 X 4.0 25.0  w$ o: p3 W" G0 n6 }
84.6 4.0 X 4.5 11.1
9 n( S3 c& n3 N; a85.9 4.5 X 5.5 9.0
3 S0 F% c3 k: g3 fAv. 14.3
" `& k  x' f/ m  P4. y- |' l8 t/ C7 ~" }- [" {9 ^" q
8. O" |8 D0 f' Z' t! O
109 u' G& g0 Z4 `. b3 G+ j8 r% K
12( ?* E  f! i: W4 h
17' m; t" k0 [4 J0 w9 z/ k3 P" ~
Topical testosterone
8 G  O, _- \6 |' U3 A  y34.6 4.5 X 6.5 850 I7 U( t2 h0 W4 H9 O+ Q
38.8 6.0 X 8.5 70% w% B  A( P" f; R' k
40.0 6.0 X 6.5 62.54 R9 w1 K. d* ^+ y( m3 [$ L
93.6 6.0 X 7.0 55.5: C% L' w6 c- W# v
95.0 6.5 X 7.0 27.29 B! V9 q  m, A: o
Av. 60.0% ]1 }5 E+ _, H5 K; g( Q( L4 g
available testosterone. Again, emphasis should be placed on
( e8 b) B! _: d$ tearly therapy when lower levels of testosterone appear to
. w, h- L8 h: Y8 W  dprovide the best responses. The earlier therapy is instituted% M5 D) x! b8 v0 p9 R8 J& Z: j
the more likely there will be an excellent response with low
: Z, w) B* X3 L! Y, ]5 Pserum levels. Response occurs throughout adolescence as
: R/ W  I6 L% q! R% h" B5 |1 hnoted in nomograms of phallic growth. 7 The actual response+ l- }( u; y: e# S, d
to a given serum level of testosterone is much greater at birth+ @  e- x" O- v; ?+ M# {  `
and gradually decreases as boys reach puberty. This is most! B7 s2 C5 y) }4 S
likely related to the conversion of testosterone to dihydrotes-. }0 f+ R9 x  T2 E# u7 x
tosterone and correlates well with the studies of testosterone
6 r5 e& H9 {0 a2 i5 j: z& F0 F' hconversion in foreskin at various ages.9 q) d# \. X, }) B
The question arises regarding early treatment as to whether; u6 h; m& x/ y; a7 v! c1 b7 V
one might sacrifice ultimate potential growth as with acceler-% ?+ j" c4 q: W* p
ated bone growth. The situation appears quite the reverse
7 h. C1 V, r2 v- C7 |! Twith phallic response. If the early growth period is not used  H) c% O3 C6 f4 X0 k2 T% W5 T% X
when 5a reductase activity is greatest then potential growth# z" E. y. G% `* E: s
may be lost. We have not observed any regression of growth# A! I9 f9 s) @5 W
attained with topical or gonadotropin therapy. It may well
, V" B; j( S/ m2 r- ?2 zbe that some patients will show little or no response to any  _4 _* P  H' g2 z% P
form of therapy. This would suggest a defect in the ability to. t! Y+ L& w; ?  F) O
convert testosterone to dihydrotestosterone and indicate that
' m# E& s2 C( gphallic and peripheral skin, and subcutaneous tissue should  p: I* \7 ?& I- s$ v
be compared for 5a reductase activity.1 j. j, H4 w- m5 a) B
A, loop enlarges to measure penile girth in millimeters. B,
( B' e: D7 ^' p7 jexample of penile girth computed easily and accurately.) S# {6 n/ z; G7 v
conversion of testosterone to dihydrotestosterone. It is in this, P( H$ J, t9 o/ c& f+ V
older group that others have noted high levels of serum; y5 ~1 Z+ b* W. W) [, _: C
testosterone with topical application. It would also appear
1 C& E) p0 \. x- e. ethat phallic response during puberty is related directly to the8 x1 U, T7 u3 ^8 c, \/ K
serum testosterone level. There also is other evidence of local
; q, R; K2 t" \4 Fresponse to testosterone with hair growth and with spermato-3 h* D1 ^4 f+ }' D
genesis. 5• 6/ Z: G) u0 w1 `( D  m
Administration of larger doses of gonadotropin or systemic
* [) {" r, ~5 K$ }* {% utestosterone, as well as topical applications that produce4 i0 g' a) i2 p, e4 f# M
higher levels of serum testosterone (150 to 900 ng./dl.), will
0 t. Y! o. x0 g; Nalso produce phallic growth but risks accelerated skeletal$ N6 ~- N, u. g- j* q
maturation even after stopping treatment. It would appear! V, M4 e( I, E% g, |6 ^
that this may be avoided by topical applications of testosterone
' E% P- Y/ w" ]4 Fand monitoring of serum testosterone. Even with this control
+ C( [& @8 ?% g' ]! A  @5 Mthe duration of our therapy did not exceed 3 weeks at any* D# J, Q% F" J: D  W
time. It is apparent that the prepuberal male subject may
) s9 X! z+ a& o- m2 V' w1 ysuffer accelerated bone growth with testosterone levels near
* U. {% ]; o" s0 W$ _+ T200 ng./dl. When skeletal maturation is complete the level of2 g5 `% @6 H. T
serum testosterone can be maintained in the 700 to 1,300 ng./2 Y1 t- i5 f. o( I7 H
dl. range to stimulate phallic growth and secondary sexual* v7 p8 M( U2 W; E/ q
changes. Therefore, after skeletal maturation parenteral tes-
, p0 {" @3 s$ y( Ptosterone may be used to advantage. Before skeletal matura-
9 ]2 W- Q- i0 q* ~/ ption care must be taken to avoid maintaining levels of serum- D& V" e' ]! U. R
testosterone more than 100 ng./dl. Low-dose gonadotropin
4 S+ m; ~: k" M8 Y8 ^8 X; Wdepends upon intrinsic testicular activity and may require
0 ~8 B% j4 {  [; M2 J8 x% i$ Iprolonged administration for any response.  `6 |" J: \: y( B
Alternately, topical testosterone does not depend upon tes-, Q0 R  G+ E$ D
ticular function and may provide a more constant level of) s, B9 C  W5 f" K
REFERENCES( ~+ B! t8 @7 I* V) d7 Y. R
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
. P$ F  u* f1 D  `2 L4 uR.: The local application of testosterone cream to the prepub-
: K; M: M3 }5 Lertal phallus. J. Urol., 105: 905, 1971.
3 X% z  {8 b) e3 @: `6 T# y% h2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
; Q9 `/ r" E4 d) Streatment for micropenis during early childhood. J. Pediat.,4 Z, V' y) H* R* ~% v
83: 247, 1973.
1 I, I; z% u! L/ O) x3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-8 J' R) u" {" S; D
one therapy for penile growth. Urology, 6: 708, 1975.9 C5 b1 D( a* S: L% U7 i
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) n1 g2 U9 c; o# H- G3 Qto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( [/ U/ J. I6 k$ o8 g
skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 w7 w% r: e) s( t5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
: a; w- e1 [) ~; L3 Uby topical application of androgens. J.A.M.A., 191: 521, 1965.2 @3 s) @; [# ], V6 C) R' n
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ T1 g, Z( }0 s; zandrogenic effect of interstitial cell tumor of the testis. J.4 X3 ?( u* n( j/ |
Urol., 104: 774, 1970.( W$ ^0 f) ]- d
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* S9 l, c( f" g8 N# g
tion in the male genitalia from birth to maturity. J. Urol., 48:
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