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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
' t3 z$ G2 p( w/ k) ZGONADOTROPIN
; M; h# {0 |. iRICHARD C. KLUGO* AND JOSEPH C. CERNY, |% P# \% c% \4 g, [
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan# n6 g! y7 o: A5 b
ABSTRACT* C) r, P6 H3 y: \% Q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
0 O0 m) X% P: g5 N- W: D1 D% a% Z( ewith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 @( ^9 [, H4 z( Gtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' U1 S# l/ m) L0 V2 A: e; s4 x
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
# V$ P: R7 O; E8 ^for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) p4 Z9 p1 ] K; q) v9 j% P$ y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
p, S1 X* i" W1 H* S& F3 K) cincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response* |4 F; K- s2 T0 ^8 c- G; c1 U# N
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 w' r' j$ x/ o# ~& N& S* B9 ^
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 O% }2 {& f7 J: S0 n6 R
growth. The response appears to be greater in younger children, which is consistent with previ-
$ c/ K! F# v$ e% Jously published studies of age-related 5 reductase activity.
6 ~: L O- U( l# j9 }& E) ^; zChildren with microphallus regardless of its etiology will' |3 C) P2 ? u1 S* {
require augmentation or consideration for alteration of exter-
& A* g5 X/ o( ~nal genitalia. In many instances urethroplasty for hypo-
1 l/ e& _, b6 t7 N2 x9 [spadias is easier with previous stimulation of phallic growth.2 X# U/ V6 |* R
The use of testosterone administered parenterally or topically9 \: g7 b8 x: U3 a, c% V; r5 Q
has produced effective phallic growth. 1- 3 The mechanism of& F- ^; p( K- ]: l5 d
response has been considered as local or systemic. With this* i. o+ M {8 k/ F3 ~) j
in mind we studied 5 children with microphallus for response
c2 K4 [. x1 j0 m7 h8 r5 S- mto gonadotropin and to topical testosterone independently.
. G+ c- W5 I/ m9 H" j0 YMATERIALS AND METHODS& n! c3 `8 P6 ]! E6 e
Five 46 XY male subjects between 3 and 17 years old were
x1 Z0 x# @1 Aevaluated for serum testosterone levels and hypothalamic6 G8 h- Z$ J0 f I) o8 F
function. Of these 5 boys 2 were considered to have Kallmann's
; Z) M/ R7 C7 \0 fsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-$ ^% |; j# y$ ]3 p
lamic deficiency. After evaluation of response to luteinizing
3 g% e6 ]/ _- }" Y+ M; khormone-releasing hormone these patients were treated with
7 e- X9 M/ `* H# g1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. n2 U5 D% j" _! U* ~8 iafter completion of gonadotropin therapy 10 per cent topical+ }5 X5 h, v: N/ k' I& y$ T- s: p- Y
testosterone was applied to the phallus twice daily for 3 weeks.' X* }$ ?3 w4 h8 u8 Y" x& I: Q
Serum testosterone, luteinizing hormone and follicle-stimulat-
5 L+ S1 i0 U8 Ping hormone were monitored before, during and after comple-% P4 u) T) m. v5 E7 O) ^5 l3 r( s* O
tion of each phase of therapy. Penile stretch length was7 o: }2 r7 y3 y8 b& M
obtained by measuring from the symphysis pubis to the tip of
# r y3 ^6 P$ }: B$ othe glans. Penile circumferential (girth) measurements were8 N* d4 i7 o5 G, Y
obtained using an orthopedic digital measuring device (see+ r2 G: ^1 a$ O* s) O
figure).
- b* X8 N/ F( A: j sRESULTS
. H3 e! [7 h+ ~9 t$ y& ^+ WSerum testosterone increased moderately to levels between
8 A2 k% \0 o' x3 P& a50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ _5 B3 ]) P* D9 S/ S6 z2 ^
terone levels with topical testosterone remained near pre-
6 z4 J) Y# O3 X+ D3 @treatment levels (35 ng./dl.) or were elevated to similar levels
4 f8 C3 ]5 O7 ^' T- x( edeveloped after gonadotropin therapy (96 ng./dl.). Higher
" u7 @+ W3 z9 [: d# }& p% `4 q9 Aserum levels were noted in older patients (12 and 17 years old),9 P2 V8 \* j2 p+ B
while lower levels persisted in younger patients (4, 8, and 10. V0 u, {% Y0 o q7 T
years old) (see table). Despite absence of profound alterations
7 b/ s$ M' c2 @9 U. e. Rof serum testosterone the topical therapy provided a greater
% }7 Y4 d6 i# \Accepted for publication July 1, 1977. ·3 I# y: v5 @. I; Q% h, R' _! P
Read at annual meeting of American Urological Association,& p) T+ @ r( {/ P$ q
Chicago, Illinois, April 24-28, 1977., `2 ]: Q/ J4 F" C8 N; j
* Requests for reprints: Division of Urology, Henry Ford Hospital,
- a3 M6 j8 q# \! H2799 W. Grand Blvd., Detroit, Michigan 48202.
: j. [2 o" S- e0 @; u( a% L" Aimprovement in phallic growth compared to gonadotropin.
4 m8 e$ u+ G6 w2 Q( xAverage phallic growth with gonadotropin was 14.3 per cent G8 g& q4 q7 A; n/ E5 i% ]8 G( s2 O4 ^
increase in length and 5.0 per cent increase of girth. Topical0 g7 d+ A/ \/ H/ X
testosterone produced a 60.0 per cent increase of phallic length8 r+ T7 ~+ _( f8 \
and 52.9 per cent increase of girth (circumference). The d8 @+ q1 I4 R E8 d2 g j
response to topical testosterone was greatest in children be-
% l5 b: d- R7 e3 @. W _/ {( Ttween 4 and 8 years old, with a gradual decrease to age 174 n' T; Z2 a' u4 _) `% K
years (see table).
4 q( l: K4 s" r1 lDISCUSSION
/ Q" w9 m7 e9 g$ F% K( T7 k0 z: DTopical testosterone has been used effectively by other: [* V, }$ L9 i9 Y/ D7 a0 E
clinicians but its mode of action remains controversial. Im-
, p! D2 {& {$ |% f0 Jmergut and associates reported an excellent growth response
" q* r4 p6 }# ]to topical testosterone with low levels of serum testosterone,# s, {2 g' c8 f0 g9 K i7 B
suggesting a local effect.1 Others have obtained growth re-
2 q4 ~( Y6 _/ K- {5 _sponse with high. levels of serum testosterone after topical
, E- H% c6 p4 g% `. O* m5 Fadministration, suggesting a systemic response. 3 The use of
" }; E x8 N; w1 Mgonadotropin to obtain levels of serum testosterone compara-+ F% k" A" i- S, Z" q
ble to levels obtained with topical testosterone would seem to
8 x L7 [% c" F9 hprovide a means to compare the relative effectiveness of
& W7 B9 m' y2 C- u; v& X9 K, A0 Gtopical testosterone to systemic testosterone effect. It cer-
/ v7 r7 t7 L0 K" y5 x; W: ctainly has been established that gonadotropin as well as par-, ~2 }+ k) q1 `2 f7 }: J5 z, V
enteral testosterone administration will produce genital$ ~+ K" K. ~& K0 e
growth. Our report shows that the growth of the phallus was
. ^& E' }/ D, `" v. \0 S/ asignificantly greater with topical applications than with go-
+ T# L7 ~" _. Snadotropin, particularly in children less than 10 years old.
1 P3 ?4 y* ?2 y' F' iThe levels of serum testosterone remained similar or lower! u+ T$ `$ ?( m5 G0 T O
than with gonadotropin during therapy, suggesting that topi-
, C* }* l: H. v; t7 P* Ccal application produces genital growth by its local effect as
- |3 Q3 [! L8 uwell as its systemic effect.9 I7 `# ^+ f5 g+ N a& V/ P
Review of our patients and their growth response related to' G7 `' T# m+ D
age shows a greater growth response at an earlier age. This is
- S z9 z8 j2 k, ~# l, C& rconsistent with the findings of Wilson and Walker, who& h% r+ M" u" o6 s2 N
reported an increased conversion of testosterone to dihydrotes-
& _$ i8 k( C3 |+ Ptosterone in the foreskin of neonates and infants.4 This activ-
1 J7 g% J! K4 b3 l; |ity gradually decreases with age until puberty when it ap-
( d# y8 }+ K' Hproaches the same level of activity as peripheral skin. It may
$ w. a, H; l e9 G* _well be that absorption of testosterone is less when applied at' R; @4 N0 e) [; t7 |5 @+ a
an earlier age as suggested by lower serum levels in children
: p6 ~: p2 m* e6 _less than 10 years old. This fact may be explained by the
3 p* x4 n2 \5 ^, t- ^- O, V% Dgreater ability of phallic skin to convert testosterone to dihy-, G0 f. i$ C) i) n6 P% x+ a
drotestosterone at this age. Conversely, serum levels in older
& K0 W4 y/ E' V [3 q6 J' W; F4 Ypatients were higher, possibly because of decreased local
( [. V$ `5 b k5 F5 g" v2 E- s667" V- g. h$ [' L2 O s% J$ C
668 KLUGO AND CERNY6 M1 Z* o7 D! x; E- m
Pt. Age
$ w3 l' p; P+ R) G& J/ ]6 \+ u(yrs.)
~. V: [3 |/ |: _' YSerum Testosterone Phallus (cm.) Change Length
( V: a1 V0 b2 p4 U3 e& _2 a(ng./dl.) Girth x Length (%)) D7 P+ u) k3 d( S& K1 k
4
6 q5 g3 t5 S8 T7 U8 g8) C& X/ U$ ~- I5 k/ o ]3 v
10 y% z1 F2 ]6 i& W U; M1 F
12
1 ~" f2 t$ z# i$ O+ h17
8 [0 H9 ]0 D. {7 oGonadotropin. q1 v% H0 m {( I0 E2 H
71.6 2.0 X 3 16.6
3 z% \; j- t, d6 M# E0 p' R g50.4 4.0 X 5.0 20.0
1 [! `2 ^2 q2 \7 Z% k% E4 y22.0 4.5 X 4.0 25.0
9 [- j9 Z* T: y$ m( g4 `. g) `84.6 4.0 X 4.5 11.1$ o8 c0 y; H+ C: J! w. `2 }
85.9 4.5 X 5.5 9.0
7 J' q' ^; ]( ~, }* U" H: }( yAv. 14.33 C! m( ?- C, L
4( I5 O1 G V1 t, ^5 i+ }
8
. i/ X" h- X& U; e10; E* Y7 g; t" s
12
$ V2 ^: G- B6 e5 C* Q5 B5 c17
9 u5 @# W2 y$ I8 vTopical testosterone
) m5 M2 R9 ^5 F" Z7 ~& t- n34.6 4.5 X 6.5 85, a$ j: S, D% V
38.8 6.0 X 8.5 70; K2 z0 N9 g# a9 B! X
40.0 6.0 X 6.5 62.54 y8 J+ E5 h8 f+ F
93.6 6.0 X 7.0 55.5' m* R1 t8 `& b% {
95.0 6.5 X 7.0 27.2
, o2 C7 w# [" |Av. 60.04 j8 f2 H, D# f+ H. c* w
available testosterone. Again, emphasis should be placed on8 e! R% p1 [( C2 p8 w5 j
early therapy when lower levels of testosterone appear to
8 T, B" R% D$ A! T& \provide the best responses. The earlier therapy is instituted
/ p+ i9 S! G0 h6 _, U$ Z$ Qthe more likely there will be an excellent response with low8 F; P& @9 V- K, e" K- X4 F, D* |0 G
serum levels. Response occurs throughout adolescence as
+ } D/ b6 m! c$ C: z q) J. Unoted in nomograms of phallic growth. 7 The actual response1 o- p( R6 W$ Z# m
to a given serum level of testosterone is much greater at birth
+ e; v M9 @# F4 A3 ~8 \- Band gradually decreases as boys reach puberty. This is most
0 g* h. k8 q, |* M* f. l6 Klikely related to the conversion of testosterone to dihydrotes-- R l: r+ Z* Z: ^9 |$ }5 C. H9 a" E
tosterone and correlates well with the studies of testosterone2 V8 a$ @1 m& u' \: N1 r/ s3 g
conversion in foreskin at various ages.
2 J, W/ ]) t1 K' @. M" h. \The question arises regarding early treatment as to whether
) u3 M# @! D* K1 v: V6 n5 i" Mone might sacrifice ultimate potential growth as with acceler-; A0 e6 y$ { @" X) {) p7 S
ated bone growth. The situation appears quite the reverse: Y6 f' E8 v( D% T ?& N, D" E0 s9 y
with phallic response. If the early growth period is not used
9 f* s5 S9 g6 Y! N' Lwhen 5a reductase activity is greatest then potential growth
. D3 \4 {/ X, U7 ], g9 X' e, Cmay be lost. We have not observed any regression of growth
4 E1 V/ R; Z9 F3 W( P$ ^& Y" xattained with topical or gonadotropin therapy. It may well6 A8 I: n$ _' w' X' p
be that some patients will show little or no response to any
% N. x t! k8 V( D; Eform of therapy. This would suggest a defect in the ability to
0 }- e" [2 ?9 F4 z" T! l% X7 Iconvert testosterone to dihydrotestosterone and indicate that
( n% U& b) W& M) e3 J- e: O/ d+ vphallic and peripheral skin, and subcutaneous tissue should
: o) V* Y- r* |* o$ r5 G& F! D" ^be compared for 5a reductase activity.+ ~$ c% d% I U& S
A, loop enlarges to measure penile girth in millimeters. B,
* |% t7 n1 d0 J! H6 iexample of penile girth computed easily and accurately.' S" m& J2 i. T* x- [
conversion of testosterone to dihydrotestosterone. It is in this' L- L: G: s# u+ U
older group that others have noted high levels of serum0 I; E' k% @+ h# |" o
testosterone with topical application. It would also appear4 [& H1 f3 k. s" T, }/ a
that phallic response during puberty is related directly to the! ^( L* R( n: T, Y4 o
serum testosterone level. There also is other evidence of local% K' i& D$ r0 i) a3 n
response to testosterone with hair growth and with spermato-
4 o( [) n6 O( ]$ _* Bgenesis. 5• 6
' w1 A6 R: ]+ `Administration of larger doses of gonadotropin or systemic% M2 V0 n5 B. w
testosterone, as well as topical applications that produce( t7 h; t. s- O
higher levels of serum testosterone (150 to 900 ng./dl.), will
' d2 U& H+ U balso produce phallic growth but risks accelerated skeletal. [) K7 D% T; x3 q
maturation even after stopping treatment. It would appear* A, u, C$ p& H" y$ L( g3 p/ ~
that this may be avoided by topical applications of testosterone, O5 |, Z+ S4 Q5 G" b
and monitoring of serum testosterone. Even with this control o$ g2 q& n6 t4 | b3 ?
the duration of our therapy did not exceed 3 weeks at any& R, z( K! w) ?( `& d
time. It is apparent that the prepuberal male subject may R2 ?( W% e- ^) C( A
suffer accelerated bone growth with testosterone levels near* J3 N* `4 ~9 L/ a( B* y2 A
200 ng./dl. When skeletal maturation is complete the level of
, J1 T, K9 N: m2 r! {serum testosterone can be maintained in the 700 to 1,300 ng./
" ?- e9 t0 @2 \5 Mdl. range to stimulate phallic growth and secondary sexual6 A5 E+ T) X5 P# J9 f& ?# {
changes. Therefore, after skeletal maturation parenteral tes-
9 S0 }0 Q8 l" u# C5 B5 [tosterone may be used to advantage. Before skeletal matura-( ?: U6 r' _2 a) }% J
tion care must be taken to avoid maintaining levels of serum
- ?! K% Y( G$ r# _/ }* R8 Z$ J Itestosterone more than 100 ng./dl. Low-dose gonadotropin- ^9 r9 c& o1 @, b
depends upon intrinsic testicular activity and may require
+ i( i% {8 t+ R" O5 F" jprolonged administration for any response.
2 I4 w# L! i' rAlternately, topical testosterone does not depend upon tes-
) R6 Z1 c( d; I' q& hticular function and may provide a more constant level of
% J9 B# H( { {8 D! } VREFERENCES
j& B6 `1 N3 V1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 O; E/ B$ D1 A8 O
R.: The local application of testosterone cream to the prepub-7 }+ x; I5 _) v
ertal phallus. J. Urol., 105: 905, 1971.+ d* y' [9 p0 g2 U S9 i
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" X( k; {( w4 L: I
treatment for micropenis during early childhood. J. Pediat.,
* [9 B4 q0 ^& _, a$ @83: 247, 1973.$ \( ~7 h1 g. o
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 V1 w# b$ y+ L( @: H* w
one therapy for penile growth. Urology, 6: 708, 1975.0 r; {) I8 q! G8 b' U
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: U3 Z0 }/ b& C8 z* qto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by! e5 t/ k7 t) \5 ~
skin slices of man. J. Clin. Invest., 48: 371, 1969.
3 @4 U Y! d/ @* g" R i. V5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ o7 W/ C' o" j* Cby topical application of androgens. J.A.M.A., 191: 521, 1965.2 V4 F; \9 W2 O9 ?! G
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local' J3 q/ I \5 i, t$ F, M
androgenic effect of interstitial cell tumor of the testis. J.
- H9 g2 m7 [8 U$ V: pUrol., 104: 774, 1970.7 t$ J- m$ T2 i, F$ q, ~, r" ^
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ A& _+ G5 |6 H& i: K5 x: Ption in the male genitalia from birth to maturity. J. Urol., 48: |
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