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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ L! j; K& F" {
GONADOTROPIN
L; d0 w$ L/ h; ~: R I; aRICHARD C. KLUGO* AND JOSEPH C. CERNY
* z- L% q: I4 ~4 }From the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 z! R% Q& F; X+ ?9 m' i4 _
ABSTRACT
* N0 h" b/ m8 D! I- i0 y! [, ^Five patients were treated with gonadotropin and topical testosterone for micropenis associated3 R" [2 }" @) Q: @( W- `; h
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-# Y, ?6 J6 Q6 L( P
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
6 d8 t8 @2 [1 H, t& T+ mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ `& Q: z( x$ S4 I2 w
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ s! n- D0 F3 W; k/ @0 h* C
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: H$ h* K9 w8 h3 |3 c; Q! e8 ^
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: E' t5 s) B' ?3 r, i4 v/ @
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
. a6 `3 \: y9 {, f1 _study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile3 q! c B; @% S' ]
growth. The response appears to be greater in younger children, which is consistent with previ-. _6 c1 B+ g5 N
ously published studies of age-related 5 reductase activity.
' t% r& o% k# t: a3 nChildren with microphallus regardless of its etiology will
- p/ p4 f5 I4 M# `% \require augmentation or consideration for alteration of exter-
/ [5 _1 |: o- N, B7 M/ [nal genitalia. In many instances urethroplasty for hypo-, x( [ D/ r/ P' X; t1 b2 G4 j; {( D
spadias is easier with previous stimulation of phallic growth.
% O) N' K* ~9 @% B6 pThe use of testosterone administered parenterally or topically/ x0 J+ e0 \( Z- S% ^' [ f
has produced effective phallic growth. 1- 3 The mechanism of ?& d( X V- i8 A
response has been considered as local or systemic. With this! v: U$ I* G' W9 J' i U7 m9 E: Z
in mind we studied 5 children with microphallus for response
$ K. f) u+ F( g/ sto gonadotropin and to topical testosterone independently.- K7 R$ T% n+ c% U, e8 ?: x1 K
MATERIALS AND METHODS3 k8 N8 q4 m5 b+ H* P# f1 \
Five 46 XY male subjects between 3 and 17 years old were: s9 L" `" [4 o2 x0 X+ _
evaluated for serum testosterone levels and hypothalamic& i- v1 n6 Y( [+ d
function. Of these 5 boys 2 were considered to have Kallmann's
" K, k6 X- n) ~4 B& c8 u# vsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 H# [: Y3 ~" j" N: T' N2 @* g% n
lamic deficiency. After evaluation of response to luteinizing
& P" M, `* r: b2 \+ Mhormone-releasing hormone these patients were treated with1 G4 I7 G0 [/ C0 \0 a* I, q! w9 i
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
+ D0 T, z) f& |5 V7 @5 K( S8 V8 L% hafter completion of gonadotropin therapy 10 per cent topical
% z6 E" }6 I% w8 E |0 A, S5 L$ O& A$ jtestosterone was applied to the phallus twice daily for 3 weeks.. L4 c) ~) Q0 V$ F
Serum testosterone, luteinizing hormone and follicle-stimulat-
6 Q$ p3 E- I+ @8 a/ \ing hormone were monitored before, during and after comple-4 M- K! |/ T6 R- D- I+ B
tion of each phase of therapy. Penile stretch length was
' z5 P* n2 h. y- z# }' B2 kobtained by measuring from the symphysis pubis to the tip of
( p. o9 e1 R' t6 J% j- g4 |, `the glans. Penile circumferential (girth) measurements were
5 p; `% m9 |; |8 U) O' b$ ^obtained using an orthopedic digital measuring device (see
- U; S t& Q# a3 r( ~figure).: w7 c, _7 W3 y# y5 k, E
RESULTS
0 @4 `( N1 H6 }3 N9 `9 Q* x0 _& lSerum testosterone increased moderately to levels between. v& X, ~7 Z+ n
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-" r3 L' c) l/ o$ _5 i5 C
terone levels with topical testosterone remained near pre-
/ R) K: N% t2 Z) J" m' n+ y% s, }treatment levels (35 ng./dl.) or were elevated to similar levels! D+ @* [+ w; Y7 o
developed after gonadotropin therapy (96 ng./dl.). Higher
n& P! @# h7 \& @serum levels were noted in older patients (12 and 17 years old),2 D4 R# f$ Y! V
while lower levels persisted in younger patients (4, 8, and 10" `) ^& G) i6 n* s- P/ l# V
years old) (see table). Despite absence of profound alterations
% U" ]; f- x- ~of serum testosterone the topical therapy provided a greater
/ T2 Y, K# p+ S) JAccepted for publication July 1, 1977. ·
# E# M6 ?: Q0 x) \% C9 _% j! BRead at annual meeting of American Urological Association," v4 y2 G$ G" b& I
Chicago, Illinois, April 24-28, 1977.$ z& o* F) l& A- F
* Requests for reprints: Division of Urology, Henry Ford Hospital,
% K U5 T9 {- e( ]% [0 P7 p2799 W. Grand Blvd., Detroit, Michigan 48202.
' p$ n7 C! C# l) w% uimprovement in phallic growth compared to gonadotropin.
2 ~" R% o" J! X) O ~) XAverage phallic growth with gonadotropin was 14.3 per cent' ~5 J5 o3 x# n% d
increase in length and 5.0 per cent increase of girth. Topical
6 f/ v- j, b& e9 atestosterone produced a 60.0 per cent increase of phallic length
$ W# R+ `: v) x0 ?3 [and 52.9 per cent increase of girth (circumference). The
4 M8 G/ _: E" \/ @response to topical testosterone was greatest in children be-5 r3 ^# t+ r% L1 |4 t( C
tween 4 and 8 years old, with a gradual decrease to age 17- v: R8 m% j6 h; E
years (see table).2 j4 j7 X2 m, A2 L
DISCUSSION
' |. s; ^ {2 S% x! RTopical testosterone has been used effectively by other
9 k( A) B/ l( y* X9 Zclinicians but its mode of action remains controversial. Im-
V" `3 M- i$ k4 f: Y6 Xmergut and associates reported an excellent growth response: ]0 J$ F! S4 [! W
to topical testosterone with low levels of serum testosterone,+ a+ v1 R+ o" G; r: n, P
suggesting a local effect.1 Others have obtained growth re-
, d8 P6 {4 v$ C& usponse with high. levels of serum testosterone after topical- u, g' D0 k* `5 l" {
administration, suggesting a systemic response. 3 The use of
) ^5 X, L' F T# ?% Qgonadotropin to obtain levels of serum testosterone compara-; P8 D1 ~1 c3 o- e9 U7 b
ble to levels obtained with topical testosterone would seem to
( {" ~" c9 p2 [. t5 m1 ~, K, B3 E4 w5 E- hprovide a means to compare the relative effectiveness of
% S. ~' ~8 y2 I* V' {topical testosterone to systemic testosterone effect. It cer-: B( M7 A! ?- t6 @% }
tainly has been established that gonadotropin as well as par-( r3 G& @5 M% O5 Z2 ^
enteral testosterone administration will produce genital2 I; e5 m2 R8 ]7 I8 R8 q% F
growth. Our report shows that the growth of the phallus was3 h0 g6 o* Z. T( H' A% B2 w z) ~
significantly greater with topical applications than with go-
4 p9 m* `2 v' @2 k6 p! Z$ e* Fnadotropin, particularly in children less than 10 years old." U" p0 Q5 }% l
The levels of serum testosterone remained similar or lower2 A% S% d6 ]3 O, N& l2 d! @
than with gonadotropin during therapy, suggesting that topi-
' `& n0 a# E; _0 b ncal application produces genital growth by its local effect as
6 t$ q7 C2 h, k: A8 Bwell as its systemic effect.
0 @& b$ D% A' D7 IReview of our patients and their growth response related to
1 i$ I ]* D% O2 } lage shows a greater growth response at an earlier age. This is
6 n. Y9 {( f2 n( }! e8 B! P2 _consistent with the findings of Wilson and Walker, who
3 A% `& d1 o" W7 g% ]- X3 R+ dreported an increased conversion of testosterone to dihydrotes-
8 c1 m9 Z' x3 o& ^tosterone in the foreskin of neonates and infants.4 This activ-5 l& _) m0 n! p. z
ity gradually decreases with age until puberty when it ap-
1 w* [% k% l* x# fproaches the same level of activity as peripheral skin. It may
4 I [1 p9 x1 Z1 D5 I7 Twell be that absorption of testosterone is less when applied at( s# h( T2 s' } n
an earlier age as suggested by lower serum levels in children
. K# x$ n; D5 q2 u6 Mless than 10 years old. This fact may be explained by the
0 m% t) d6 d! \1 ]; Ngreater ability of phallic skin to convert testosterone to dihy-
* k4 Q; }6 y! c: F' rdrotestosterone at this age. Conversely, serum levels in older1 W$ _: Y# w3 M6 `
patients were higher, possibly because of decreased local
9 C% z4 x, B( Q/ p( H* W8 S, h667. g3 n% O6 G: O& E1 Q$ p
668 KLUGO AND CERNY B1 a, B! n( Q+ k: R/ _4 V
Pt. Age1 J1 N/ d7 V- U" C1 F
(yrs.). j9 g0 |( o) b
Serum Testosterone Phallus (cm.) Change Length- i: m6 r2 R. N0 u2 Y( I) P5 Y
(ng./dl.) Girth x Length (%)
& M1 q: n3 y/ k1 \# g6 k+ ~4! n! G. Q. h' E1 Y# t: T& M
8$ a5 O2 [: U2 f) z/ z" h
10+ }3 b& w5 z. b6 d2 _7 {: N) R7 o
12
7 b4 f6 L1 n; E8 y* @# Q: T17
3 J0 J( Q1 F+ e" L3 }, fGonadotropin
2 S2 ?$ w6 P0 A( _) C71.6 2.0 X 3 16.6
: g. B2 J/ C( a: Y o* A7 [50.4 4.0 X 5.0 20.0
F- U* ^2 \! ~$ o; @ q; ?9 s22.0 4.5 X 4.0 25.0
) ?. y" D3 u2 g/ y; P* `7 h/ K: z84.6 4.0 X 4.5 11.18 Q3 g6 h8 Q5 T. ~$ D+ z* d
85.9 4.5 X 5.5 9.0
5 X6 _0 c4 c. [Av. 14.3
! H4 A/ t" g6 H* C8 F! ^% U' t2 Y4
/ R/ {! Z0 S! ^% G: p/ |8
6 a) S. a p; e0 E1 U1 ^7 T/ n102 R% y! \; U; U' ?
12
. f0 p& r% w* E. A17
: z' a. t' v) W# r6 n5 i2 q4 q7 YTopical testosterone
3 y& L0 t+ ^ ~0 B34.6 4.5 X 6.5 851 K0 t, \+ g1 s9 |- i4 f+ S
38.8 6.0 X 8.5 70
( ?, h& `6 ?% ?! Z40.0 6.0 X 6.5 62.59 O$ t1 N, x0 } s# m- r3 {# Z
93.6 6.0 X 7.0 55.5
! k: _* c+ X- o, Y$ w; _$ P95.0 6.5 X 7.0 27.2+ b: ~6 X) [+ W4 J
Av. 60.0
2 X$ S5 q! r7 u; Mavailable testosterone. Again, emphasis should be placed on
3 [8 S" H. \' K" cearly therapy when lower levels of testosterone appear to5 o" X5 U! m5 D
provide the best responses. The earlier therapy is instituted
5 R+ p5 n! J- @6 Z+ ~the more likely there will be an excellent response with low
7 Z2 f: t6 L6 D* Y" z/ c. hserum levels. Response occurs throughout adolescence as6 u1 C7 t2 O: U$ h' f4 R
noted in nomograms of phallic growth. 7 The actual response
6 J- ?7 E4 w; L8 }0 M( M9 ]to a given serum level of testosterone is much greater at birth$ v+ Z" j" `$ n! X6 i! O% w6 F i
and gradually decreases as boys reach puberty. This is most& u2 u, R- j0 |9 @5 p; ^0 y
likely related to the conversion of testosterone to dihydrotes-
6 _1 B% a$ f8 n6 M" ^- ftosterone and correlates well with the studies of testosterone
2 x3 }+ M! x0 h& j8 g* Vconversion in foreskin at various ages.
. u2 i& U9 N& `# `* {The question arises regarding early treatment as to whether
. {! o7 `2 l4 F' ~1 N5 Bone might sacrifice ultimate potential growth as with acceler-8 X8 O, K* I3 c x" F$ a* I b: Z
ated bone growth. The situation appears quite the reverse) f8 k \, z9 y7 ^7 j: U
with phallic response. If the early growth period is not used
% l: f4 M3 i8 wwhen 5a reductase activity is greatest then potential growth0 x: J1 l9 Z! G% y0 e% f1 w
may be lost. We have not observed any regression of growth2 N% A8 t" m- C6 \. k; ~
attained with topical or gonadotropin therapy. It may well% T4 X) X# `" e# B
be that some patients will show little or no response to any& `/ w+ l& l/ i1 d& h3 O
form of therapy. This would suggest a defect in the ability to
# M, |; j' r2 Oconvert testosterone to dihydrotestosterone and indicate that
6 {' y! {* q; ^phallic and peripheral skin, and subcutaneous tissue should
- V# x3 J8 {8 o; n2 kbe compared for 5a reductase activity.* O, X/ B7 A% R+ H0 F
A, loop enlarges to measure penile girth in millimeters. B,
9 Y4 Z3 i, G, o$ Kexample of penile girth computed easily and accurately.
2 S& p/ Y* y1 k6 L8 lconversion of testosterone to dihydrotestosterone. It is in this7 c( h7 y8 C y) Y$ d2 t
older group that others have noted high levels of serum
9 T2 S% b; `, n( {) rtestosterone with topical application. It would also appear4 d. \7 t3 ^2 l9 I
that phallic response during puberty is related directly to the
H t$ ]0 _5 Q/ r9 Y. h1 ]" i' Tserum testosterone level. There also is other evidence of local# Z! [/ f; { o0 } Q
response to testosterone with hair growth and with spermato-
5 l; D- |$ C1 n' t6 x2 T1 zgenesis. 5• 6
$ |4 i3 K! q$ b1 {* [Administration of larger doses of gonadotropin or systemic% y7 m; f: L! S4 A9 P" u. ^& T. h" x
testosterone, as well as topical applications that produce
2 z; t# |% t9 Lhigher levels of serum testosterone (150 to 900 ng./dl.), will
/ P; ~! @" Q& X8 A4 W$ W: Halso produce phallic growth but risks accelerated skeletal
! w" V6 \! s, x8 `' u* b+ S. Imaturation even after stopping treatment. It would appear' t# L `! S- J. \0 [' k
that this may be avoided by topical applications of testosterone
5 y2 W& y9 F% `+ Jand monitoring of serum testosterone. Even with this control" L5 y* \% e3 b2 q8 T9 k4 A; ]
the duration of our therapy did not exceed 3 weeks at any
% h, d* h- `5 q) }. @( htime. It is apparent that the prepuberal male subject may1 O, x& \: o% T
suffer accelerated bone growth with testosterone levels near
+ D0 p) U, M% E& c7 e' V200 ng./dl. When skeletal maturation is complete the level of
3 f, `: q; |) f9 t% @9 q- Cserum testosterone can be maintained in the 700 to 1,300 ng./
8 f6 X5 s* j# M, X" R, Tdl. range to stimulate phallic growth and secondary sexual |7 W' p& J& ~2 A/ ]6 }0 s
changes. Therefore, after skeletal maturation parenteral tes-& N" W: Y% v% W6 S' d
tosterone may be used to advantage. Before skeletal matura-4 D0 S, R5 U% E8 y0 E& z* n) M) P
tion care must be taken to avoid maintaining levels of serum6 E, D& P7 r* [1 H- z
testosterone more than 100 ng./dl. Low-dose gonadotropin
9 [4 V: ?% I% z9 }$ v* jdepends upon intrinsic testicular activity and may require0 [! ^, `8 q2 [+ e) [0 c
prolonged administration for any response.
% x% L$ g. C9 |& x( n3 @) z8 IAlternately, topical testosterone does not depend upon tes-
8 h. e7 O* t- F2 H }ticular function and may provide a more constant level of
$ Z5 |1 N( Q6 u9 @$ T0 O8 C' K$ k/ tREFERENCES: \+ d( v9 M" e% a
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 N* f0 F( [$ bR.: The local application of testosterone cream to the prepub- | i) f a3 W# t, J, ` [
ertal phallus. J. Urol., 105: 905, 1971.
# G( f7 r1 x% S4 i2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
+ @9 E4 j" J7 Z7 |5 u$ t+ dtreatment for micropenis during early childhood. J. Pediat.,
/ A1 R0 {5 l4 e, ]! L. a! k83: 247, 1973.: }# ]2 Y0 D, Z, y) G! \" s
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 ~" j% a; U# O7 g$ n
one therapy for penile growth. Urology, 6: 708, 1975.
/ g8 c( J2 V' V6 B3 X9 b" [4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
# y* J7 z+ C& t7 ?- r# Rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ f# E8 ?9 L' H) t/ K
skin slices of man. J. Clin. Invest., 48: 371, 1969.: Y& D' n# u: y& A: T" D
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) r. m6 A' F' W! y5 J- ~" F4 hby topical application of androgens. J.A.M.A., 191: 521, 1965.. \ |: H, q- C. l+ _
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! h$ t7 O/ v& \/ \) Z1 t' j5 }androgenic effect of interstitial cell tumor of the testis. J.
0 s$ J- H" @2 mUrol., 104: 774, 1970." H0 o [; W* M+ q) z1 |
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 {: Y$ @; N5 ution in the male genitalia from birth to maturity. J. Urol., 48: |
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