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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# R( D/ v, H4 x+ K: e* k1 f" h
GONADOTROPIN% z  S3 x$ X8 a
RICHARD C. KLUGO* AND JOSEPH C. CERNY. b4 ^# Y) u& c+ c
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 V+ J: C7 y# e
ABSTRACT' u/ r. w8 L4 n
Five patients were treated with gonadotropin and topical testosterone for micropenis associated) L) ?: ^# X9 o' y2 I: C7 u- S
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
2 O' n! X" k# D* t+ P. Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 {0 U7 x+ k3 F
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: }0 n; }, @3 j4 w+ |1 `for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
' J; a; b8 e/ Y/ F2 m/ ^* B7 a  ?increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
' e: D8 U0 X3 x* xincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response* o- t2 D2 r# q7 {# P
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
/ c+ s2 [, Z& [- Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile& v! O5 k8 E0 |
growth. The response appears to be greater in younger children, which is consistent with previ-6 Y' z! L( q. J$ g8 Z
ously published studies of age-related 5 reductase activity.
, U$ Y  X7 i5 k- A5 NChildren with microphallus regardless of its etiology will: Z2 S1 `- `! B$ n% \. B
require augmentation or consideration for alteration of exter-
! H6 E; w; E. _7 b* R/ f2 ynal genitalia. In many instances urethroplasty for hypo-
: s) G: h3 m4 Uspadias is easier with previous stimulation of phallic growth.
# N! A' A. K7 `- UThe use of testosterone administered parenterally or topically
3 ]4 @5 G+ M1 G1 M* Ihas produced effective phallic growth. 1- 3 The mechanism of* D  A1 x, a/ S' ^* X) W9 N& n
response has been considered as local or systemic. With this
, w% m$ k) D, Z, H! K7 ^; Win mind we studied 5 children with microphallus for response' n; Y# l! ~1 T# b6 b
to gonadotropin and to topical testosterone independently.
0 [# ]2 @' w! `3 n* JMATERIALS AND METHODS
* G7 n9 v" c! r5 _Five 46 XY male subjects between 3 and 17 years old were, ]8 f. ]: G7 z: i# c2 \$ P
evaluated for serum testosterone levels and hypothalamic
$ }/ j% ]" t- u2 g' Vfunction. Of these 5 boys 2 were considered to have Kallmann's
7 y! R; s7 b+ Ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 z7 o0 i0 H" h, `! _$ }) n8 J% zlamic deficiency. After evaluation of response to luteinizing! Z# E& Z# n- g2 W* u1 V9 K
hormone-releasing hormone these patients were treated with
$ ~7 a" w' m4 F3 d1 e) [9 g1,000 units of gonadotropin weekly for 3 weeks. Six weeks: T% b3 U' c8 B* @) I4 ~  K0 i; d
after completion of gonadotropin therapy 10 per cent topical
) p/ u* G# w8 j; ^% O, \# Ztestosterone was applied to the phallus twice daily for 3 weeks.  i: G! O1 C8 W. L% Y% ~' U
Serum testosterone, luteinizing hormone and follicle-stimulat-
* W& z2 T- j* d5 s/ `& ?ing hormone were monitored before, during and after comple-
/ H8 _- h  O6 N. k4 ?tion of each phase of therapy. Penile stretch length was% _8 I( j  a- m7 D2 l
obtained by measuring from the symphysis pubis to the tip of, b. p  q( l8 r, c2 z, i! M
the glans. Penile circumferential (girth) measurements were
1 T5 u* V; q' O! Z# _obtained using an orthopedic digital measuring device (see& u" R' e6 a9 N/ j; Z# O, A1 @
figure).
% V; A# b. Q! Q; Z' NRESULTS
# m+ u3 m% R6 J5 _& ~Serum testosterone increased moderately to levels between# z& j; E, ^9 c. r' Z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
" C' Q& i7 n4 ]0 O3 }1 e  rterone levels with topical testosterone remained near pre-
: l3 U& E! a2 F) K  F# Ctreatment levels (35 ng./dl.) or were elevated to similar levels' H- ~( q2 W9 l2 ^. h
developed after gonadotropin therapy (96 ng./dl.). Higher
3 [, Q0 h' E9 D9 E9 {2 J7 Zserum levels were noted in older patients (12 and 17 years old),# w& B9 T8 w. E+ y7 \  ^
while lower levels persisted in younger patients (4, 8, and 10% M' j2 D& l2 }( {% N/ B" Q# r; c7 X& ]
years old) (see table). Despite absence of profound alterations
: v) E9 h" I1 w: rof serum testosterone the topical therapy provided a greater/ L$ K( {; |) B" x+ z3 U+ x* Z
Accepted for publication July 1, 1977. ·  ^0 [  J; ?5 w1 l8 t; |
Read at annual meeting of American Urological Association,
. t" a$ j- W' \1 y) C0 `5 }; N1 MChicago, Illinois, April 24-28, 1977.
8 S, [# K. \, m5 M( R/ Z* Requests for reprints: Division of Urology, Henry Ford Hospital,
5 }, Q3 z0 |. @% ]: c2799 W. Grand Blvd., Detroit, Michigan 48202.
4 m& u% M: B: H* B  W, Uimprovement in phallic growth compared to gonadotropin.' d2 N4 `7 U- ?. C1 B. o- W
Average phallic growth with gonadotropin was 14.3 per cent
3 M% U5 p+ f7 O5 [/ L5 @increase in length and 5.0 per cent increase of girth. Topical5 A7 j" A: `0 r9 n/ ~4 O
testosterone produced a 60.0 per cent increase of phallic length1 p0 V7 e3 I: ~3 l
and 52.9 per cent increase of girth (circumference). The
0 ~! x; C2 \, {# q& {! ^response to topical testosterone was greatest in children be-! h" Z" m5 `9 w5 L- b
tween 4 and 8 years old, with a gradual decrease to age 17) {$ m3 t! N; e1 h$ D
years (see table).
% T3 ~& Q$ @+ `. C! [* vDISCUSSION+ ]% O( {8 `1 f; C1 L( x
Topical testosterone has been used effectively by other
, u! p  m( y, ]3 q9 vclinicians but its mode of action remains controversial. Im-
2 Z" N+ _8 z0 n# `mergut and associates reported an excellent growth response
( d, ^! b7 m" \% eto topical testosterone with low levels of serum testosterone,
3 f! e7 T. b1 V, _0 L% J1 E; W8 }suggesting a local effect.1 Others have obtained growth re-, U% l, v) }7 `( a
sponse with high. levels of serum testosterone after topical& |. o' \% v4 Z4 z# c" T) L
administration, suggesting a systemic response. 3 The use of  n1 l$ i0 |- f. L. m% i! Y5 P) `
gonadotropin to obtain levels of serum testosterone compara-0 x5 o/ v9 }1 I0 _' v- |+ T
ble to levels obtained with topical testosterone would seem to( D! y' _' E2 B' \# }2 V" V1 a3 `
provide a means to compare the relative effectiveness of4 f6 S0 j8 B& y+ S, I
topical testosterone to systemic testosterone effect. It cer-2 f; x3 n' {  N: t
tainly has been established that gonadotropin as well as par-( C) r: Q& y9 |+ b+ C. e# N
enteral testosterone administration will produce genital& E8 ?0 U1 x* o
growth. Our report shows that the growth of the phallus was" m* A+ ?+ K+ q: I3 ?8 h
significantly greater with topical applications than with go-
% J( z- b1 X2 Z# nnadotropin, particularly in children less than 10 years old.; \# J4 v% y' p
The levels of serum testosterone remained similar or lower
' I, X$ H4 ^, q( p9 F" bthan with gonadotropin during therapy, suggesting that topi-% H+ C# N$ I+ V6 w& Q  c; D
cal application produces genital growth by its local effect as' e5 |* G& ]$ ~5 i3 |! B
well as its systemic effect.
* Q$ _+ ^( ~; u- R8 y% D4 uReview of our patients and their growth response related to! b" L: Q3 C5 h. C0 S
age shows a greater growth response at an earlier age. This is4 Z9 N/ K  F! y& i
consistent with the findings of Wilson and Walker, who
: u/ u+ `* u2 E' ~reported an increased conversion of testosterone to dihydrotes-% {1 y( D1 W# P$ L- L" o
tosterone in the foreskin of neonates and infants.4 This activ-
7 w* N6 e. s: O  Kity gradually decreases with age until puberty when it ap-
4 @; b) J( v4 [( [* gproaches the same level of activity as peripheral skin. It may
; P' t# E+ w1 C1 }) |5 H& L+ ewell be that absorption of testosterone is less when applied at
: o# @! p6 c3 D" f% T' J( San earlier age as suggested by lower serum levels in children
* U% V; T8 ~- X7 I& X. o- \less than 10 years old. This fact may be explained by the
$ I" T! [$ N: }3 V5 {" T5 [6 C: I7 ?! p2 Fgreater ability of phallic skin to convert testosterone to dihy-* L5 S( ^& q3 C
drotestosterone at this age. Conversely, serum levels in older
8 ?& M* |2 R. Q. r* C) @; \patients were higher, possibly because of decreased local
; @0 P* n3 \: J6 v! b* m/ H% Y0 P6675 w( K5 f3 P# b# u* ^+ Z3 K0 u
668 KLUGO AND CERNY
: k* [, |8 V: [4 H& }% g- E) {Pt. Age7 A3 v" p: C& ?
(yrs.)
5 Q  W/ \# ?2 D! @1 Y4 cSerum Testosterone Phallus (cm.) Change Length
, S0 i8 S! A1 f+ o0 H(ng./dl.) Girth x Length (%); m- K  p: p; b* }2 t9 E" f8 \
4
5 x, ^/ H# u6 A2 C5 s8
! q( D5 j* M% j( z) |! l10
( ]  S3 e+ X/ `. h) ~6 \12
" R" L* x1 L* x5 v( a17# ~/ Q" T% p7 |1 Y
Gonadotropin9 S. h$ f) r6 h% D9 [0 ]: n
71.6 2.0 X 3 16.6. L4 l9 J- c1 ^3 D4 d" |! O. L
50.4 4.0 X 5.0 20.0
+ D6 ]9 |0 Q" y  e" i: L/ w22.0 4.5 X 4.0 25.0  Q8 J0 h4 L4 T  A
84.6 4.0 X 4.5 11.1
4 d$ K6 `8 w9 U: ]85.9 4.5 X 5.5 9.0
- }0 f* [7 B# BAv. 14.3
8 O' z( H% P1 [0 T" g7 S3 x4) x4 u- A6 z7 H5 V' Q; t
8
4 L9 @9 c3 e# @9 |3 D) w10
( u/ G! ^) B" P! Q2 {12
# m$ p+ h( |9 a$ E& o0 {17
/ I  x0 b3 T6 C% sTopical testosterone
+ N- k/ R. Z0 D- k34.6 4.5 X 6.5 85! V* J, o- E. j5 X; A
38.8 6.0 X 8.5 70  |$ ~; x7 {. T" c; O* X; Q3 F( n
40.0 6.0 X 6.5 62.5
- V- z; ^  L: J: M5 X- q* [93.6 6.0 X 7.0 55.5
: J: ]# z& a2 P/ l- M( r0 p  i95.0 6.5 X 7.0 27.2
3 b1 g: A- l6 j; R; pAv. 60.0
! a# b9 ]) n  ^2 r# D. Zavailable testosterone. Again, emphasis should be placed on1 S7 U, F$ ^6 V0 |
early therapy when lower levels of testosterone appear to
7 O6 m7 }  P( hprovide the best responses. The earlier therapy is instituted
& a' y7 S# R; xthe more likely there will be an excellent response with low3 D5 Y; s- t9 Y8 B! ~
serum levels. Response occurs throughout adolescence as
+ }$ Y, d; u# d7 t1 Dnoted in nomograms of phallic growth. 7 The actual response6 I% \( \! ]% j1 ?" w) A& [! {) [
to a given serum level of testosterone is much greater at birth
6 }( C; J1 @. i" O, Y; B% Jand gradually decreases as boys reach puberty. This is most
$ L* [4 @' t5 v+ ^: Clikely related to the conversion of testosterone to dihydrotes-
; q8 m6 n* I: X" G& I* n! x2 Jtosterone and correlates well with the studies of testosterone
' E8 k, d% U6 j: X" bconversion in foreskin at various ages.
% ~- S' ^+ I7 d+ x3 j# K! C1 @The question arises regarding early treatment as to whether
6 i+ c3 `0 q6 P  v/ Lone might sacrifice ultimate potential growth as with acceler-
! C+ J/ b5 o; N0 q) v3 i; N) |ated bone growth. The situation appears quite the reverse9 W2 O3 l7 R6 {3 l( k+ Y4 n
with phallic response. If the early growth period is not used- h2 D: f. V6 [, v# w+ e
when 5a reductase activity is greatest then potential growth
0 [7 F% O) J3 W8 [  jmay be lost. We have not observed any regression of growth4 R! Q' X2 i& w& \; E  m! z
attained with topical or gonadotropin therapy. It may well
0 Z, ^: R0 x9 _, d, k7 H! _" Ybe that some patients will show little or no response to any
/ \' q9 z0 I; t: v; Eform of therapy. This would suggest a defect in the ability to
9 D; I# J; j" D0 W! K/ g3 Sconvert testosterone to dihydrotestosterone and indicate that
+ N2 t; @: z# Yphallic and peripheral skin, and subcutaneous tissue should5 c5 `0 f6 p* [3 A6 {' e' T( O' h
be compared for 5a reductase activity.
* E7 \& u0 i+ w8 Q* \A, loop enlarges to measure penile girth in millimeters. B," _/ E5 I  ^8 Y/ I- S
example of penile girth computed easily and accurately.
! O$ [3 r9 B7 k+ k$ Z4 _conversion of testosterone to dihydrotestosterone. It is in this
" T  V- p0 ^! `. b5 |1 Iolder group that others have noted high levels of serum5 s$ \9 x8 F4 c7 X( _4 V2 W- J
testosterone with topical application. It would also appear/ E' y( Z  }% X: d! }8 E+ x
that phallic response during puberty is related directly to the
: F4 c1 n) c' Wserum testosterone level. There also is other evidence of local4 @) y, ]: L' @" p
response to testosterone with hair growth and with spermato-: D2 f, i6 Z; J  u0 L$ d
genesis. 5• 6- P, d/ R2 C8 d1 }- f
Administration of larger doses of gonadotropin or systemic: l: n! `6 i) n9 p7 H  j/ A
testosterone, as well as topical applications that produce/ p- c" V/ g5 j' [6 ^4 v
higher levels of serum testosterone (150 to 900 ng./dl.), will, r& s& Q7 t) t
also produce phallic growth but risks accelerated skeletal2 A5 F5 s* H9 b, d1 o3 s  _
maturation even after stopping treatment. It would appear
% L8 W) d7 I+ K& h4 P9 |6 ithat this may be avoided by topical applications of testosterone
2 ^3 G/ y+ Q3 ~7 H) Y: Z9 L" gand monitoring of serum testosterone. Even with this control
- |( S0 L6 f- bthe duration of our therapy did not exceed 3 weeks at any6 X- w( Y; [; ~; i7 I) Z4 Q
time. It is apparent that the prepuberal male subject may, M4 _5 m, s: A  v: v/ P) d
suffer accelerated bone growth with testosterone levels near
+ E. @, E3 E) z; i- b8 v200 ng./dl. When skeletal maturation is complete the level of9 p4 l1 G$ {7 t1 N- w/ ^' O
serum testosterone can be maintained in the 700 to 1,300 ng./
$ i1 ]& P) w0 _& kdl. range to stimulate phallic growth and secondary sexual
$ k/ c/ P0 Y: W3 r4 Zchanges. Therefore, after skeletal maturation parenteral tes-& k6 s  V( q1 ]8 u* B5 J6 L2 b: k
tosterone may be used to advantage. Before skeletal matura-' z7 h" G- C) m4 e! u( a
tion care must be taken to avoid maintaining levels of serum
# K3 n6 v7 _4 e3 m) ?; ~testosterone more than 100 ng./dl. Low-dose gonadotropin& L; O: ~' v  }, S+ V" \
depends upon intrinsic testicular activity and may require, I* l! c* G) w9 H7 G
prolonged administration for any response.
8 V& V0 T* G4 K* iAlternately, topical testosterone does not depend upon tes-
3 E" m; I0 [% s$ k% f# Xticular function and may provide a more constant level of! O/ r( q5 L/ r" D: z3 V! Y5 o
REFERENCES6 q3 ?# X: |  \% b
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 c: {- h9 z% G+ z- E! g  q, b1 n+ S
R.: The local application of testosterone cream to the prepub-: h4 s; g; @: M6 ?. }" G9 X
ertal phallus. J. Urol., 105: 905, 1971., W# ^; a6 L" g0 ?: |# g' s
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 f& s- i) o1 |2 Ntreatment for micropenis during early childhood. J. Pediat.,4 A1 [( W4 K* d5 p/ ]
83: 247, 1973.
) ]0 \6 `1 U9 `) D9 p; J9 K$ ^  |8 ^! z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 v' f8 g$ m1 q! o5 @6 }' Mone therapy for penile growth. Urology, 6: 708, 1975.
7 S. f; a* r- P, i- t, f4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( U* G: }9 h/ x' ~7 Zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
$ `$ |0 X. L$ M; k2 Q9 Vskin slices of man. J. Clin. Invest., 48: 371, 1969.
  S' |% I% {, }( |2 R: O7 L% f5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ X& F) ^7 Y" T2 `4 A! o5 E. h
by topical application of androgens. J.A.M.A., 191: 521, 1965.
; d9 t$ M" O1 G: [' k6 |6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
7 q9 H* F/ H% H! Handrogenic effect of interstitial cell tumor of the testis. J.3 Y$ F$ v. L2 E5 P
Urol., 104: 774, 1970.9 K9 g, A) ]! Z& v4 f. L$ |" C
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* }# t' L3 o7 U2 A4 n
tion in the male genitalia from birth to maturity. J. Urol., 48:
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