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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND2 ^3 c# [, a5 [1 y, J/ \: p) w
GONADOTROPIN% ]2 _/ y. }: z. P3 w8 d! S
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 q" d% ~+ R7 h3 \, vFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
/ `2 H, ^( D1 X- o0 pABSTRACT
* z) w( V1 _0 t0 y1 Q( kFive patients were treated with gonadotropin and topical testosterone for micropenis associated @9 e$ G2 n6 ?7 y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-7 m0 Z* U8 t5 G; n4 P
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone( Z( G' H. H$ S; j& M( L! I
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 i# d+ \' ~: s- n6 dfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. S) ]2 i* G: Y- K
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
' t. r* L/ J: }9 Pincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ l/ S; L% R1 ?2 B/ Soccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 L7 t; y0 H3 x$ l7 Q$ E
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile/ w2 e( k0 w2 D- Y! n- O
growth. The response appears to be greater in younger children, which is consistent with previ-
L) G/ E U! a5 E+ o+ Cously published studies of age-related 5 reductase activity.
8 e9 O7 q3 ^) nChildren with microphallus regardless of its etiology will" t/ P. _) R! t
require augmentation or consideration for alteration of exter-2 l, {$ w, v# W
nal genitalia. In many instances urethroplasty for hypo-
% r& I7 E3 [9 \- |* D. fspadias is easier with previous stimulation of phallic growth.0 ]' B% J u( w I5 y1 _' v& x2 u
The use of testosterone administered parenterally or topically
" l9 m( X9 @1 fhas produced effective phallic growth. 1- 3 The mechanism of, ?! D& K, E/ p
response has been considered as local or systemic. With this4 ^' @: ~( Z- y$ R* A: y
in mind we studied 5 children with microphallus for response7 x% r+ ?1 A) d5 C N+ I
to gonadotropin and to topical testosterone independently.
( A/ y# g# K! o; n& b) UMATERIALS AND METHODS: V1 x" e; O$ Y
Five 46 XY male subjects between 3 and 17 years old were% U6 L4 U2 o. I9 V ?: ]8 O
evaluated for serum testosterone levels and hypothalamic
2 Q. B$ h0 A1 x- ]* I |3 gfunction. Of these 5 boys 2 were considered to have Kallmann's
* J( Y$ i" C6 S7 ?7 Ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 G! i" k! m: L) I0 v( ]
lamic deficiency. After evaluation of response to luteinizing+ y( v! K2 F. D( m- Q
hormone-releasing hormone these patients were treated with
' \& w# j3 k3 s6 \( \! G1,000 units of gonadotropin weekly for 3 weeks. Six weeks) e% {& `- f( G3 S6 q
after completion of gonadotropin therapy 10 per cent topical/ i& B; K# K5 u! H
testosterone was applied to the phallus twice daily for 3 weeks.' Q8 d- x% E# E7 Y) S# \& [7 ?3 U
Serum testosterone, luteinizing hormone and follicle-stimulat-- k1 S& I! Q6 d$ k) s
ing hormone were monitored before, during and after comple-7 t2 H1 U1 x* [; r) I
tion of each phase of therapy. Penile stretch length was6 X: ~: }1 }, Y6 ?% e
obtained by measuring from the symphysis pubis to the tip of+ Z5 Z4 Q8 S. ~5 z- s5 y9 i
the glans. Penile circumferential (girth) measurements were1 U+ ?3 t# U$ @5 @' X, x$ w
obtained using an orthopedic digital measuring device (see- o6 n8 D- d$ E; Z$ `
figure)." V3 C5 I& h# o; F
RESULTS
; V! L0 c- [- I* N# t6 QSerum testosterone increased moderately to levels between0 [1 T8 k% h- Z D0 p) Z' r
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 | f2 I8 x6 h# t5 c0 ^
terone levels with topical testosterone remained near pre-+ u N+ w+ V3 R, w, I6 L
treatment levels (35 ng./dl.) or were elevated to similar levels! C! {' e4 G% ^: z
developed after gonadotropin therapy (96 ng./dl.). Higher
2 j) W" f+ w+ K: l5 b# x! ]4 {! dserum levels were noted in older patients (12 and 17 years old),7 f, |. J; b9 }
while lower levels persisted in younger patients (4, 8, and 10" I. U, c( ] u$ P8 U6 o, R
years old) (see table). Despite absence of profound alterations
* o% g$ J& V; @. Dof serum testosterone the topical therapy provided a greater
* z7 x* M: a$ e' V# q0 FAccepted for publication July 1, 1977. ·. k" U; K" ]* e
Read at annual meeting of American Urological Association,
7 G* i3 W8 y' c4 ~* A% v6 EChicago, Illinois, April 24-28, 1977.' p7 }' d2 p& B1 G% @0 W
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 t/ E9 T# H2 E# c) w% D. L9 J
2799 W. Grand Blvd., Detroit, Michigan 48202.7 p+ H% p# ^ t5 C" p
improvement in phallic growth compared to gonadotropin., B0 x6 t# x1 u; g0 f1 c
Average phallic growth with gonadotropin was 14.3 per cent
# z+ h$ |" g/ tincrease in length and 5.0 per cent increase of girth. Topical
2 Y% `1 X9 g/ _! _6 b# ^1 etestosterone produced a 60.0 per cent increase of phallic length
" l+ Y$ q) ~5 `0 v7 c/ vand 52.9 per cent increase of girth (circumference). The# w; P$ X |5 e. Z; C& J
response to topical testosterone was greatest in children be-
8 `0 X8 _, k7 L7 btween 4 and 8 years old, with a gradual decrease to age 17
/ k7 n% ~7 d1 E4 jyears (see table).
, P5 M/ F: a! h: u2 n4 [DISCUSSION
5 o' r4 Z% s: Z- V! ^- s- jTopical testosterone has been used effectively by other
! \) c3 D9 B' E9 O. Jclinicians but its mode of action remains controversial. Im-1 Y/ b; o1 ]& J1 G/ a0 k3 f
mergut and associates reported an excellent growth response2 M: O8 h& H# J; Q9 j) G# p% U
to topical testosterone with low levels of serum testosterone,
# G. n8 I' z- Z/ xsuggesting a local effect.1 Others have obtained growth re-9 [9 U( j, b r: W2 f6 F& A( J
sponse with high. levels of serum testosterone after topical1 z$ G. K! p M' c/ c7 L# x
administration, suggesting a systemic response. 3 The use of' ~) d' o' K; @6 q+ V0 S
gonadotropin to obtain levels of serum testosterone compara-3 O$ Z& x7 Q+ p% C, J/ d$ J% b$ C% D
ble to levels obtained with topical testosterone would seem to
5 |$ X% x; L2 {8 W; ~8 q! Bprovide a means to compare the relative effectiveness of
: M+ }# x/ C% h+ ~2 Ntopical testosterone to systemic testosterone effect. It cer-; d3 v8 z* \; k; {
tainly has been established that gonadotropin as well as par-. B' h3 ~2 i3 K4 V! h+ U$ ~
enteral testosterone administration will produce genital
+ n- }9 H; w( ^3 {8 M" i& ]growth. Our report shows that the growth of the phallus was/ `8 Q: q k( r# Q; |, x
significantly greater with topical applications than with go-
# D9 j/ L* D/ F2 b5 anadotropin, particularly in children less than 10 years old. [" `3 f6 s3 A& T7 X( m
The levels of serum testosterone remained similar or lower/ z5 [4 ^. g( M) C: ]
than with gonadotropin during therapy, suggesting that topi-0 w) V" }0 M5 @
cal application produces genital growth by its local effect as9 | G: C: l& X A: \8 t7 Z) K' F
well as its systemic effect.
) I& L2 g) \* \Review of our patients and their growth response related to& [) m R" Z- e8 q
age shows a greater growth response at an earlier age. This is
5 d& p. i& I( j" W1 oconsistent with the findings of Wilson and Walker, who
+ i, |" Q6 H7 k& c1 l+ Lreported an increased conversion of testosterone to dihydrotes-2 t% A: W6 O @0 y! A
tosterone in the foreskin of neonates and infants.4 This activ-
+ n) j) e: i! tity gradually decreases with age until puberty when it ap-
. i. Y% F1 Z' Q1 l% a/ [/ Fproaches the same level of activity as peripheral skin. It may! `! N& v$ `! h
well be that absorption of testosterone is less when applied at
8 ~1 e2 Z: y# E ian earlier age as suggested by lower serum levels in children
& v% f9 Z# ^7 G0 s* `less than 10 years old. This fact may be explained by the* M) I, l1 r: M+ k. V$ @: ~( q
greater ability of phallic skin to convert testosterone to dihy-, F2 k2 e2 ?7 ?- a1 _" w' M
drotestosterone at this age. Conversely, serum levels in older& a7 o& z. E9 x7 S C4 d+ P
patients were higher, possibly because of decreased local
# G# X h7 }! Y667
8 d! a6 o/ l5 k# a668 KLUGO AND CERNY
. x; y' A1 J2 P5 ]+ `Pt. Age3 z# N0 e1 M5 C" k
(yrs.)
5 c0 W8 t2 M/ B/ hSerum Testosterone Phallus (cm.) Change Length
( D9 \, f* U: m0 e(ng./dl.) Girth x Length (%)
, @) K$ N2 S% ?& p; \4) j) g, H* Q& L# ^ r2 q7 S
8, R% S9 c+ Y N# w8 @
10* w1 r7 n' ?9 v \8 W/ M
12$ Z- {- Z) o3 z3 b
17# b1 H9 u, ]' \; ?
Gonadotropin
$ m. D6 } C+ S/ O, b4 r: U71.6 2.0 X 3 16.6
; k- a" m/ Y0 R w+ [0 Z% H50.4 4.0 X 5.0 20.0
' c# g" i( ~( ?9 C; u22.0 4.5 X 4.0 25.05 L: {' D* V* O3 K1 S- v# O
84.6 4.0 X 4.5 11.1
/ H3 u/ X+ t0 D0 z) b85.9 4.5 X 5.5 9.01 z7 n0 t8 |8 i, F* C! R
Av. 14.3& g7 s8 p9 K% j# ^8 [
4
8 {! q! K0 m2 w/ f! \8
" |. R. r# M2 L1 q# G. T. j10
3 V. m' j; Z3 {! R" o/ ^0 j9 d12
+ M! t9 K+ h/ I' Z17
: P' [$ I2 }) R. N: aTopical testosterone
8 @5 Q9 w+ t7 e+ t9 x34.6 4.5 X 6.5 85
; f3 o: y$ A! J- }7 o4 j38.8 6.0 X 8.5 70, |3 @( n( W- ]4 C& f h
40.0 6.0 X 6.5 62.5+ L; b5 e, y# l& j
93.6 6.0 X 7.0 55.5; y+ W1 d# M# u P: q
95.0 6.5 X 7.0 27.2* |* y, x; S/ \3 i3 j( E( r% s
Av. 60.0
, W0 V; s3 a$ s" H; Mavailable testosterone. Again, emphasis should be placed on
; K1 r" K3 S% r5 C6 @ _early therapy when lower levels of testosterone appear to( T7 T1 g0 n7 ]. R3 ~" k
provide the best responses. The earlier therapy is instituted
4 {( B1 f5 U& hthe more likely there will be an excellent response with low3 z2 {, y$ _# X' D
serum levels. Response occurs throughout adolescence as* }$ |5 w( I$ S
noted in nomograms of phallic growth. 7 The actual response2 V9 U: C0 ~: V" q/ ^ Q S
to a given serum level of testosterone is much greater at birth
: w" j% }3 }) n% b) a+ Zand gradually decreases as boys reach puberty. This is most x* F% ]& F& i4 H) _6 a; F: @
likely related to the conversion of testosterone to dihydrotes-
# {6 ~, w! Q0 W, G4 R- }tosterone and correlates well with the studies of testosterone
8 a( z0 G; T M( G q! kconversion in foreskin at various ages.
0 P0 v( q# ^, @The question arises regarding early treatment as to whether
. x6 u2 ?- ^: h( V. Qone might sacrifice ultimate potential growth as with acceler-
0 ~/ W7 g1 F( O g+ x; M, }+ Y9 nated bone growth. The situation appears quite the reverse, p! A4 R3 U( c+ N8 @
with phallic response. If the early growth period is not used
7 G1 E3 O8 q# {% `) ?when 5a reductase activity is greatest then potential growth" G8 x. b/ z& V5 d# |2 G. I8 z, P
may be lost. We have not observed any regression of growth* \! O/ }' S6 `+ C1 y' D( }; G
attained with topical or gonadotropin therapy. It may well, H# D. Z d* y" `8 F+ h
be that some patients will show little or no response to any9 T) m+ z1 h6 C/ O
form of therapy. This would suggest a defect in the ability to
& o4 X. [& A ?- l1 S& @0 bconvert testosterone to dihydrotestosterone and indicate that
( p0 i$ l6 A Q+ Uphallic and peripheral skin, and subcutaneous tissue should" D% G, H6 Q: C) I4 ~
be compared for 5a reductase activity.
+ \ ?9 p# m* y* WA, loop enlarges to measure penile girth in millimeters. B,
- C2 n1 [' Q0 H+ y9 u+ T# | {example of penile girth computed easily and accurately.0 {2 v% X; ^8 S K9 z2 R
conversion of testosterone to dihydrotestosterone. It is in this# S6 @" t% @8 b) C
older group that others have noted high levels of serum% Q/ D5 H6 n! r$ z$ q2 o
testosterone with topical application. It would also appear
% V M6 o+ V4 J* w8 O5 R: Qthat phallic response during puberty is related directly to the
/ \+ c$ G; e" |# I4 f# ?! Mserum testosterone level. There also is other evidence of local9 O/ ?9 c# A0 ~" P
response to testosterone with hair growth and with spermato-
1 Y q+ P* Q0 h. ygenesis. 5• 6
; ?# N7 q o; k7 i/ j0 U' r$ i; x6 LAdministration of larger doses of gonadotropin or systemic
. }3 d+ D% ]( J/ T5 Gtestosterone, as well as topical applications that produce! a3 Y% q8 H1 v0 A8 \+ y
higher levels of serum testosterone (150 to 900 ng./dl.), will
9 m b) Z3 w$ b, ualso produce phallic growth but risks accelerated skeletal/ O% p! b/ P; _) s1 T4 z2 s7 A8 j6 {
maturation even after stopping treatment. It would appear
, v( y5 N: m7 Kthat this may be avoided by topical applications of testosterone
9 t7 H8 A( ~" u" X# S) b& Uand monitoring of serum testosterone. Even with this control
8 c8 ?* [' u% L& Rthe duration of our therapy did not exceed 3 weeks at any( G' V6 x' H$ Q$ u" A1 q
time. It is apparent that the prepuberal male subject may
7 x1 Y7 b7 g- ^9 tsuffer accelerated bone growth with testosterone levels near
, c- R0 K- |* n) [200 ng./dl. When skeletal maturation is complete the level of/ S" ~6 i" p6 c H2 D
serum testosterone can be maintained in the 700 to 1,300 ng./
) l: A8 V" d' j. X3 e# P1 w6 u+ \7 `dl. range to stimulate phallic growth and secondary sexual3 E3 {7 ^+ U) U3 ^3 Z
changes. Therefore, after skeletal maturation parenteral tes-
. e R, g1 R7 W7 rtosterone may be used to advantage. Before skeletal matura-
, z* N* p" \! ]% `8 ~# x+ Otion care must be taken to avoid maintaining levels of serum# l% R; E8 z$ v: e; u! s+ ~
testosterone more than 100 ng./dl. Low-dose gonadotropin% c* r7 d. F4 C+ E- j
depends upon intrinsic testicular activity and may require4 l& {8 V- r: y0 P' J5 ~3 y0 y
prolonged administration for any response.: Y; V+ ^8 j8 i" b, x
Alternately, topical testosterone does not depend upon tes-
, m, D: {- I+ l) ^. g& C( Fticular function and may provide a more constant level of
8 G) k1 Q; {: y3 ?REFERENCES
8 y9 p" K+ T! f+ X; |1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 b: Z, Z$ G& G4 U$ F
R.: The local application of testosterone cream to the prepub-- M# {2 F% }% s8 J
ertal phallus. J. Urol., 105: 905, 1971.( D% Q5 E; _/ n7 D" Q- a
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 I: _% p6 W( j; P6 A. O Vtreatment for micropenis during early childhood. J. Pediat.,
5 C- g# G, s. l/ p$ f83: 247, 1973.6 J' i, q! M5 G" o
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-9 u! x/ j2 J8 _! |* X5 {
one therapy for penile growth. Urology, 6: 708, 1975. _9 t1 j3 D9 ^2 r: L, ]
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) h( h0 G- z# C
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- a3 L, Z) b+ _skin slices of man. J. Clin. Invest., 48: 371, 1969.
0 {3 R% ?/ H3 J3 Q5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, e% G. B. z) b7 ?/ v: I
by topical application of androgens. J.A.M.A., 191: 521, 1965.
1 i7 h. u5 L' _$ j* M! O" t6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
7 o4 Q/ Z' _* b/ L9 c f7 f$ [androgenic effect of interstitial cell tumor of the testis. J.+ t4 R6 F$ B4 c' F
Urol., 104: 774, 1970.5 J5 F2 P7 [: w. f2 ]
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 l: ?% ~! A) O# v
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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