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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
0 K& b2 Y0 n. c) L, sGONADOTROPIN; w+ d6 T z& u4 B
RICHARD C. KLUGO* AND JOSEPH C. CERNY7 n: h, e3 R( M6 H
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 v/ d% G. p' Z, T3 \& ]ABSTRACT0 r! K3 _* V3 j9 `( A
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
a+ I7 ?2 d/ @" B9 E0 h" iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-7 \7 f" w2 K* J/ c% Z( V
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) w' D0 r. Z, E4 o4 O
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
0 P: H+ A6 @: t. efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent, X% a1 {& c5 h! z- G
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
' d' _9 e3 d7 \) w0 [4 {/ y- H% Zincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 P# q( w! m( }; B. ]
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
" b+ c8 P, a4 f2 u9 w8 o* ~study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
4 {2 _; ~* g1 f% {growth. The response appears to be greater in younger children, which is consistent with previ-
Z! |( z( p6 s' W! P4 C# U2 }" Nously published studies of age-related 5 reductase activity.- g0 F2 ?# n& q }8 A
Children with microphallus regardless of its etiology will5 W2 k' K% Y! P2 w' q
require augmentation or consideration for alteration of exter-
/ N$ @% W6 L# v* u0 N, Mnal genitalia. In many instances urethroplasty for hypo-, C4 x) N; r6 ^. h5 _1 \
spadias is easier with previous stimulation of phallic growth.7 H% X3 C& J1 ^2 a1 L8 X! v
The use of testosterone administered parenterally or topically0 f0 X8 J: D: `1 D! v' A6 p
has produced effective phallic growth. 1- 3 The mechanism of% i; ]4 B+ \) a2 s+ [ n- H D
response has been considered as local or systemic. With this' u& K. G' K/ @7 O7 Q
in mind we studied 5 children with microphallus for response" ^: ^8 a: x9 L" v. J( l
to gonadotropin and to topical testosterone independently.
6 [. u+ r. b/ s+ h! s" o1 _) AMATERIALS AND METHODS
; X8 L( Z- y0 I8 N# a* y* `Five 46 XY male subjects between 3 and 17 years old were
5 k! V3 W, j* Qevaluated for serum testosterone levels and hypothalamic
9 K) Q* h% }+ k/ dfunction. Of these 5 boys 2 were considered to have Kallmann's
1 C/ |6 [) b% H% V$ Ssyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 B( k# E4 M# flamic deficiency. After evaluation of response to luteinizing
6 V' x; g% I- V+ [! k) ^hormone-releasing hormone these patients were treated with
! G5 L% @$ u& A# ~1,000 units of gonadotropin weekly for 3 weeks. Six weeks! S; i, T( ^' O; ?* s
after completion of gonadotropin therapy 10 per cent topical
! X; W" F, }( l' Htestosterone was applied to the phallus twice daily for 3 weeks.& _. U) O: r# r/ k: E3 x% f
Serum testosterone, luteinizing hormone and follicle-stimulat-! v+ M! J2 Z. T3 O4 ] b+ F1 t
ing hormone were monitored before, during and after comple- F8 N& o5 C6 X1 b3 y |: f. p3 H
tion of each phase of therapy. Penile stretch length was! h5 ?" u: g7 R( T9 m
obtained by measuring from the symphysis pubis to the tip of4 v# x0 z9 a& C- k+ B4 @
the glans. Penile circumferential (girth) measurements were. }% D9 i+ V; \$ k
obtained using an orthopedic digital measuring device (see
9 U' G) }# S4 ]) I3 B( ^8 C# R( Kfigure).
! O* f. l8 c# k0 J- LRESULTS
0 h. z9 ~/ @5 |& QSerum testosterone increased moderately to levels between/ t* s/ [$ t" I3 u$ h) J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
5 Y4 d- E$ R, K1 dterone levels with topical testosterone remained near pre-
5 G8 [1 i9 U4 c% atreatment levels (35 ng./dl.) or were elevated to similar levels
& |" |3 |/ U3 K4 Y* K, k& e( Adeveloped after gonadotropin therapy (96 ng./dl.). Higher: O. D$ `# H9 g; k5 ~1 O* z% x! w
serum levels were noted in older patients (12 and 17 years old),
9 d6 l$ ^; V$ h7 L$ \) t. `4 Dwhile lower levels persisted in younger patients (4, 8, and 10
# y1 S% t! P- Ayears old) (see table). Despite absence of profound alterations O! `7 o ?/ _ J/ Y( b
of serum testosterone the topical therapy provided a greater
% s V2 _% f! R2 l/ UAccepted for publication July 1, 1977. ·
$ `0 {. @0 v! {( z4 ]+ iRead at annual meeting of American Urological Association," z4 V) p f7 k, ^- g
Chicago, Illinois, April 24-28, 1977.; ~; r- ~, |+ l
* Requests for reprints: Division of Urology, Henry Ford Hospital,
, W+ ^; g( P0 ^ m2799 W. Grand Blvd., Detroit, Michigan 48202.0 ]' b4 l1 u# ^5 ^& M2 y
improvement in phallic growth compared to gonadotropin.
( X8 ~, |) ]+ L$ K$ q9 e2 r! d6 VAverage phallic growth with gonadotropin was 14.3 per cent
% y3 f% ^2 |1 P4 J. M$ B" kincrease in length and 5.0 per cent increase of girth. Topical
- `# s' F/ J5 h! ~" ?% E/ Y7 otestosterone produced a 60.0 per cent increase of phallic length
7 z8 V8 h: x, |, u- @+ c6 K6 @and 52.9 per cent increase of girth (circumference). The. q& B% x" r$ s7 A" ^8 S
response to topical testosterone was greatest in children be-: `* ?# X+ s8 h! l& B+ G
tween 4 and 8 years old, with a gradual decrease to age 17' Z- K. |2 z1 y* P# |! P0 x9 y
years (see table)./ q: ^8 v5 \4 q
DISCUSSION5 T8 o0 a: m/ o
Topical testosterone has been used effectively by other0 d6 N9 K" Q7 ?: m5 ]9 C" ]+ c4 d
clinicians but its mode of action remains controversial. Im-
( X+ U1 S; D9 s, ?* D8 Jmergut and associates reported an excellent growth response
9 e! Z G" o6 \! @' }to topical testosterone with low levels of serum testosterone,1 q6 Q. ^/ U3 c" `/ P. ^0 M/ p" t) B
suggesting a local effect.1 Others have obtained growth re-
1 ^/ d' U. Z. s- h, Usponse with high. levels of serum testosterone after topical
$ i3 d+ U2 w+ \3 qadministration, suggesting a systemic response. 3 The use of
$ F& ^2 J% S ]gonadotropin to obtain levels of serum testosterone compara-
& i1 ]0 {& J" |& t% d: pble to levels obtained with topical testosterone would seem to2 f# \% n/ E$ q) v( N* {
provide a means to compare the relative effectiveness of" f4 v9 ?( q: K2 G% z
topical testosterone to systemic testosterone effect. It cer-
& J! Q4 T3 i9 w% F4 Stainly has been established that gonadotropin as well as par-
' n# o/ K0 ?8 |; n. |& o: a1 \enteral testosterone administration will produce genital B3 u& l2 X' E+ s+ w8 i% ?, x% R3 |
growth. Our report shows that the growth of the phallus was' ~7 P/ _3 x1 L) v2 g
significantly greater with topical applications than with go- l: f! x0 `& h) o
nadotropin, particularly in children less than 10 years old." i, e" E! M" [7 W. b9 Y
The levels of serum testosterone remained similar or lower
9 n' `" \2 l+ ?than with gonadotropin during therapy, suggesting that topi-0 @' E, l. w: ?) d e; C
cal application produces genital growth by its local effect as
6 k, Z) C& C; S: h: x% g& w" Fwell as its systemic effect.
( K5 C! n8 ~1 vReview of our patients and their growth response related to, ^. M* e" `6 x8 V3 {
age shows a greater growth response at an earlier age. This is" {: l4 S+ t$ ^) A' b" Z7 k
consistent with the findings of Wilson and Walker, who9 u& Z( v$ Y1 r
reported an increased conversion of testosterone to dihydrotes-
3 F5 E) \& [6 Z, ?: V; rtosterone in the foreskin of neonates and infants.4 This activ-
$ ~4 P3 T q; c [& mity gradually decreases with age until puberty when it ap-$ d% ~' A0 a0 |9 k4 _7 H/ o) C2 b
proaches the same level of activity as peripheral skin. It may
) _( I, m5 Q; C) A, [! P0 dwell be that absorption of testosterone is less when applied at$ p1 h/ e: K4 i% U8 t+ }+ Q! z
an earlier age as suggested by lower serum levels in children
. r, k) Y6 i7 xless than 10 years old. This fact may be explained by the' k& |- u L0 Q2 ^9 r
greater ability of phallic skin to convert testosterone to dihy-- w- Y# N3 C2 f- _9 V
drotestosterone at this age. Conversely, serum levels in older
/ f/ p# F( N. S* t/ D9 r) L- Qpatients were higher, possibly because of decreased local
( r: C8 k, q3 M667! U ^( _" }+ |
668 KLUGO AND CERNY) z4 ]* m7 |0 p$ ?* |, U
Pt. Age
0 h2 _8 W9 s- L* T7 g. x, r O(yrs.)" S2 H' H. E9 A v
Serum Testosterone Phallus (cm.) Change Length9 b" ~8 v& D% i. U) u- g. d
(ng./dl.) Girth x Length (%)
/ u' p/ Z! ~$ O1 P6 C7 S45 _" h4 ?* r+ G
8
! f7 D) N" ]8 j3 f P108 v1 y5 E3 E6 v% ]2 S( K: T
12 u, H, u+ b; \ F& d5 ^7 o9 s! g# O
17
9 W. b0 K3 Q0 NGonadotropin# b9 f4 [2 B2 P# z
71.6 2.0 X 3 16.6
+ J$ V; ]7 A, F# p50.4 4.0 X 5.0 20.08 r4 ~6 X# O% r8 \1 m
22.0 4.5 X 4.0 25.0
$ g4 Y& B! K E, D f0 R. s, L84.6 4.0 X 4.5 11.14 n# m+ K2 H; d/ R" q. h7 p3 i
85.9 4.5 X 5.5 9.0
4 `" I' s# A+ y* rAv. 14.3& y: {+ E4 [7 K: E6 m
4
A% O8 ~+ U& X) I) }8+ R- W& c% Q9 ]) T/ f9 G
10
9 n1 `. s B+ g$ W12
% W, o2 Y2 D# ]' p9 \17
* [) Q) P, n" J @7 a' d: T( w6 pTopical testosterone
0 A( o+ x- |+ }# r( b+ b# x34.6 4.5 X 6.5 85
; F+ L- A; G2 F- U& g3 S: z9 b38.8 6.0 X 8.5 70 i( ~/ {: ]- e( b7 _" f* Z! q
40.0 6.0 X 6.5 62.59 ~, H0 t5 p* F
93.6 6.0 X 7.0 55.5
! Z+ f. j2 O+ c) n) B8 Y/ P95.0 6.5 X 7.0 27.2
& X1 _; S( |/ @$ k& j. G, HAv. 60.0
" ~7 ?0 h3 B. F3 [& xavailable testosterone. Again, emphasis should be placed on
) I8 I3 s1 Q- n$ oearly therapy when lower levels of testosterone appear to! P6 k; S$ N* \; G4 _6 {4 i; T8 @
provide the best responses. The earlier therapy is instituted/ s8 }+ _: H. A6 Y2 C# k
the more likely there will be an excellent response with low( s: U+ n* E# b
serum levels. Response occurs throughout adolescence as6 B4 P* B" n" K% `3 P
noted in nomograms of phallic growth. 7 The actual response
g2 S" Z3 V7 Z- M6 m" nto a given serum level of testosterone is much greater at birth
: f% C3 g7 v( ?9 X/ Uand gradually decreases as boys reach puberty. This is most
" o7 g( V, G' T: L- flikely related to the conversion of testosterone to dihydrotes-) o! ?; k! W: j/ `2 b/ z2 O+ C: x
tosterone and correlates well with the studies of testosterone
; b2 K# [# l% O ]" {9 lconversion in foreskin at various ages.! D# [2 t0 k5 ]% M) A% \& v% ^
The question arises regarding early treatment as to whether
v; J7 x! ?& h7 K6 f, K; mone might sacrifice ultimate potential growth as with acceler-# A5 P. _ v7 k0 i! B- j
ated bone growth. The situation appears quite the reverse0 R; i" Z1 i! [2 }4 \/ c& {
with phallic response. If the early growth period is not used8 w8 |8 W+ R) L$ ]! x3 T
when 5a reductase activity is greatest then potential growth' \* d5 R% J, j! ]
may be lost. We have not observed any regression of growth; M: B* a" o5 ]: B1 v) V) Y4 o
attained with topical or gonadotropin therapy. It may well. |/ Q) W+ @9 v; w" w+ k# O5 h# x
be that some patients will show little or no response to any
# C; k- _; u$ ~3 z3 I9 ]7 uform of therapy. This would suggest a defect in the ability to$ d8 w2 l% M" P# V. ~
convert testosterone to dihydrotestosterone and indicate that
. ~8 q! X, I( k) q0 q! p0 V4 Bphallic and peripheral skin, and subcutaneous tissue should
3 s2 Z! f" k! W- C' R3 Sbe compared for 5a reductase activity.% v. `. R% X! H9 k
A, loop enlarges to measure penile girth in millimeters. B,
" m, [ L- K' U; N* _example of penile girth computed easily and accurately.6 q2 T, N1 I+ y# k: |3 M
conversion of testosterone to dihydrotestosterone. It is in this! f& `) \/ W& M
older group that others have noted high levels of serum. A4 D! h9 K) s, [, Q
testosterone with topical application. It would also appear* H6 Q) E: M7 I% a8 r7 Q/ w2 b8 t
that phallic response during puberty is related directly to the
+ s, {5 L7 w* g- k3 X5 b% eserum testosterone level. There also is other evidence of local7 W$ Q; `/ O, F" x! d6 N
response to testosterone with hair growth and with spermato-
6 v' @( c# k, O5 i; R+ agenesis. 5• 6$ i$ ?6 {- j; b. O- o! Z+ T
Administration of larger doses of gonadotropin or systemic. Q$ G. c/ _+ d1 ]! v
testosterone, as well as topical applications that produce i# u' {) J0 T% H3 m( a1 r2 ^+ G0 R: c
higher levels of serum testosterone (150 to 900 ng./dl.), will, I% A" X8 Z2 ~9 q! l
also produce phallic growth but risks accelerated skeletal
6 m* f- ^# v% f3 g0 ^maturation even after stopping treatment. It would appear
7 x7 t/ h/ N9 e ithat this may be avoided by topical applications of testosterone
* _0 a$ W! ~; V1 l! T6 |4 a3 o" a& }3 sand monitoring of serum testosterone. Even with this control
9 m2 i4 @: S- u* v7 T6 gthe duration of our therapy did not exceed 3 weeks at any) G V) B; j1 j, b! H0 Y8 h
time. It is apparent that the prepuberal male subject may
$ A3 h5 y$ d$ ^9 W* x" N5 Lsuffer accelerated bone growth with testosterone levels near
- n2 v0 M J3 r! s( Y9 ~- O* N" I8 a200 ng./dl. When skeletal maturation is complete the level of7 g9 d4 @8 G: i G+ Q8 j% `
serum testosterone can be maintained in the 700 to 1,300 ng./, O! d4 x( C* Z
dl. range to stimulate phallic growth and secondary sexual
+ J6 l B/ y3 G) g! wchanges. Therefore, after skeletal maturation parenteral tes-1 l x0 {' O1 f0 C% a, L
tosterone may be used to advantage. Before skeletal matura-) M% P9 A! C6 F) r7 r3 w
tion care must be taken to avoid maintaining levels of serum+ T( c" ^9 W( | b X) z7 p. G4 g
testosterone more than 100 ng./dl. Low-dose gonadotropin
& ~- b: F: e0 Y0 wdepends upon intrinsic testicular activity and may require
# f8 S9 e4 @3 ?, sprolonged administration for any response.9 b O1 ?9 b+ K0 ]
Alternately, topical testosterone does not depend upon tes-4 M: z! P6 P& k1 {9 |$ B( e: ]' [
ticular function and may provide a more constant level of
) a. u& b z2 o4 A/ uREFERENCES
4 k1 { s4 |/ b: X1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,: z9 v+ y0 h; k# G+ i* d$ F
R.: The local application of testosterone cream to the prepub-
7 N5 g* w0 {/ o) Qertal phallus. J. Urol., 105: 905, 1971.
& e5 }7 ~6 X- ^8 D- m0 |+ M2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
+ s* }/ i5 W" t: n g6 m7 q: Mtreatment for micropenis during early childhood. J. Pediat.,
+ b5 M r' E% `. B- y% j83: 247, 1973.
9 W/ ]: R# b9 S: k' k r% I* }) `3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 I4 R3 m6 f, R9 v4 d; kone therapy for penile growth. Urology, 6: 708, 1975.
, C- W3 @* b' b3 P' r3 I3 B4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone o" w& g) V" A2 a# x
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by p; f$ x4 [+ [8 |5 R- k) g. o
skin slices of man. J. Clin. Invest., 48: 371, 1969.
: j+ ~6 Y: u4 {( q5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
1 o# j6 q- b+ ^7 `0 z" pby topical application of androgens. J.A.M.A., 191: 521, 1965.
7 u) }: o+ }( j" x" U; @& z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ R3 B! w, b' h% t7 ~
androgenic effect of interstitial cell tumor of the testis. J.
: n* |$ n8 m6 WUrol., 104: 774, 1970.
, j1 ]5 R1 }8 {, @' o7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
j* |4 G5 l4 F/ l. Y$ V. Stion in the male genitalia from birth to maturity. J. Urol., 48: |
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