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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND& n5 H0 Z% m3 X, ] I( P
GONADOTROPIN
3 L) w5 m; W( R) XRICHARD C. KLUGO* AND JOSEPH C. CERNY* K2 f. `1 @: {- P
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! e3 Q! J0 ^. T/ dABSTRACT
! f4 s& y" K7 |% e' aFive patients were treated with gonadotropin and topical testosterone for micropenis associated
3 Z. O* v% c3 I( Y/ `: ]8 pwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-; I" \, N! o9 ~8 O, G* K3 O
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone0 t$ K: B& o" Q t0 @6 q8 ~. J
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 g9 h4 {0 Q9 x& T. @& C2 _4 N6 ]for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
! \" Y/ M+ a3 G3 c0 W# ~. i. Mincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
0 x3 C; t( g! H* }* f3 Tincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: N; C; |* k' W
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 b! m4 y0 O7 f2 cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 O) ~+ u; Z5 h& E
growth. The response appears to be greater in younger children, which is consistent with previ-8 d' ^/ X, y# [0 V9 E2 u
ously published studies of age-related 5 reductase activity.# E) Y8 b& K' u
Children with microphallus regardless of its etiology will3 k0 E) } @) a
require augmentation or consideration for alteration of exter-
: a# X) K$ n! jnal genitalia. In many instances urethroplasty for hypo-
6 n2 |) p3 u* @, Vspadias is easier with previous stimulation of phallic growth.3 f* }* L {, m l4 S: s; q5 z
The use of testosterone administered parenterally or topically- t" e. t( J- P7 f. x
has produced effective phallic growth. 1- 3 The mechanism of" Q2 h0 _! h1 T; b' _- F) J; e7 h: k
response has been considered as local or systemic. With this5 v4 J5 J# `# u: @# a; ~1 z" `% g5 f
in mind we studied 5 children with microphallus for response; L/ G3 `2 a T! a: ^% Y
to gonadotropin and to topical testosterone independently.; B( V6 [' m/ l8 z' _% e+ ]5 _* R
MATERIALS AND METHODS
D+ j( L; ]) Y6 }# M$ OFive 46 XY male subjects between 3 and 17 years old were d1 w+ K1 Y7 }' `9 U
evaluated for serum testosterone levels and hypothalamic% _( C& y) W H0 c! J! i+ [
function. Of these 5 boys 2 were considered to have Kallmann's
9 \. u" I3 L) j; R d2 ]4 E* esyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-6 Z! ]9 r7 t* h% n# [9 @4 f$ \
lamic deficiency. After evaluation of response to luteinizing6 E1 m6 `3 w* i+ ]$ x! L( ?
hormone-releasing hormone these patients were treated with% e& v, v% g. i6 _, ?
1,000 units of gonadotropin weekly for 3 weeks. Six weeks" T3 K1 k# I# q$ |! k' q4 D
after completion of gonadotropin therapy 10 per cent topical
6 ^1 r2 f/ M2 b6 T8 L) b, R- Ttestosterone was applied to the phallus twice daily for 3 weeks.
0 O/ d F( I. a2 T) E6 {1 ^Serum testosterone, luteinizing hormone and follicle-stimulat-! K. j( V! I; q" x9 l& p9 q: U
ing hormone were monitored before, during and after comple-
# _' H/ d7 {' z* t; q, Q# _) k0 e1 \' Jtion of each phase of therapy. Penile stretch length was( W% V6 J9 k8 J. }
obtained by measuring from the symphysis pubis to the tip of! |) H K& E: C1 m4 q3 Q
the glans. Penile circumferential (girth) measurements were& m$ L# p9 L# O t, m% Q' p" H
obtained using an orthopedic digital measuring device (see9 \ C4 f- ]" H% e; u
figure).
2 r% v$ ^8 M# T3 }6 kRESULTS
% t5 d [! \( a0 u+ M9 n1 eSerum testosterone increased moderately to levels between& i9 r7 M1 n2 p: U, J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# S; o1 g9 B U+ F* c: mterone levels with topical testosterone remained near pre-
: c. y# L% ^9 \5 a( R& Htreatment levels (35 ng./dl.) or were elevated to similar levels
9 o' J7 V9 ^1 Odeveloped after gonadotropin therapy (96 ng./dl.). Higher
7 N0 i7 Q1 Z8 [2 Nserum levels were noted in older patients (12 and 17 years old), D: _) V' E4 o5 B! k
while lower levels persisted in younger patients (4, 8, and 10, n, }* z9 ~+ C% A9 f. a$ i
years old) (see table). Despite absence of profound alterations
( C/ A% N0 n5 |9 Y+ ?1 vof serum testosterone the topical therapy provided a greater% p! Y H) \ x H r8 X# {
Accepted for publication July 1, 1977. ·
6 [. {* i6 W6 ~- D& HRead at annual meeting of American Urological Association,
. W& v" ~( H: Y1 I; b) x$ h4 b9 xChicago, Illinois, April 24-28, 1977.
( v' e2 Z T0 X0 i% u/ [6 s1 p* Requests for reprints: Division of Urology, Henry Ford Hospital,* n. H' u/ u3 a7 [
2799 W. Grand Blvd., Detroit, Michigan 48202.% B/ |/ K. G3 ~
improvement in phallic growth compared to gonadotropin.) Y3 q' t, F! I$ V
Average phallic growth with gonadotropin was 14.3 per cent
/ N" @9 @: m+ mincrease in length and 5.0 per cent increase of girth. Topical( _4 {3 }) X" n2 P" i4 O8 m! {' v
testosterone produced a 60.0 per cent increase of phallic length
: R ]2 ?7 R0 }% w3 M5 b/ A1 Cand 52.9 per cent increase of girth (circumference). The# ], V9 Q- m' o9 _( g
response to topical testosterone was greatest in children be-/ {9 e) L( m; a" P* r. {4 ^8 N
tween 4 and 8 years old, with a gradual decrease to age 17
( F0 t3 R: _' H" e% Q8 eyears (see table)." s/ }( Z0 Q$ \8 a" r) c0 Q
DISCUSSION
! J" B' w0 O7 W8 Y) p' z1 m$ |Topical testosterone has been used effectively by other( ~: ~0 }. @4 a
clinicians but its mode of action remains controversial. Im-
2 K, w/ a8 [1 {. g9 emergut and associates reported an excellent growth response
' ` G2 A, C: X! m& M! \9 m$ Z( Lto topical testosterone with low levels of serum testosterone,
& D- B' h, j' ?0 n1 }suggesting a local effect.1 Others have obtained growth re-3 S# v$ a( c5 r) l- |' d8 E
sponse with high. levels of serum testosterone after topical
/ F5 |5 k" O- Fadministration, suggesting a systemic response. 3 The use of
) k' v! _' I0 e# K, T" mgonadotropin to obtain levels of serum testosterone compara-
! j9 y* v/ v3 ^! E7 c' \ble to levels obtained with topical testosterone would seem to5 b2 o r( z( E: P, m$ u* ~+ v- @
provide a means to compare the relative effectiveness of
0 [ x6 U9 J9 J) s; U- m$ }0 Itopical testosterone to systemic testosterone effect. It cer-$ E8 S' W( N; \/ ]% r
tainly has been established that gonadotropin as well as par-+ c k3 z& e Y
enteral testosterone administration will produce genital
0 x2 l4 t% e/ G. L3 lgrowth. Our report shows that the growth of the phallus was
4 J* V" m& S1 n$ W# J$ F! {significantly greater with topical applications than with go-
+ c+ D N/ o o. W" u$ d- bnadotropin, particularly in children less than 10 years old.5 {& ]: g/ F5 J' b% k0 r. I
The levels of serum testosterone remained similar or lower
! J2 R D! n- ?% Q- I2 \4 x! g3 F fthan with gonadotropin during therapy, suggesting that topi-! v; N! n& `2 J% ?2 U c; x% p
cal application produces genital growth by its local effect as% U; k" c; `, M8 V" y4 N
well as its systemic effect.
/ H! Q( k. z, {% D& b' W# i) `Review of our patients and their growth response related to i6 l* y- z, @6 j- d
age shows a greater growth response at an earlier age. This is _- D- H6 p( }7 M5 D
consistent with the findings of Wilson and Walker, who) R2 J: V0 h$ M
reported an increased conversion of testosterone to dihydrotes-1 v$ K2 |) ?2 i7 ~6 {
tosterone in the foreskin of neonates and infants.4 This activ-2 I/ E6 H7 t( Q2 o! t d
ity gradually decreases with age until puberty when it ap-
]$ v7 S, }6 J0 k, sproaches the same level of activity as peripheral skin. It may+ ?& r6 R8 n3 n( D+ ]: e+ X
well be that absorption of testosterone is less when applied at
! U) r8 q! G, n/ g; ?) W; ean earlier age as suggested by lower serum levels in children2 Q" D& d# t7 f Z* k
less than 10 years old. This fact may be explained by the
9 O' \& s- n: r" d! `greater ability of phallic skin to convert testosterone to dihy-9 |, C: d {& E" Z- y2 {
drotestosterone at this age. Conversely, serum levels in older% t( J% z- }5 l
patients were higher, possibly because of decreased local
+ u! n% R: |& t667+ `+ [/ x C6 P, U4 K9 ~, a3 p
668 KLUGO AND CERNY7 C9 R5 b' }: H. Z- q. Y A3 U1 \9 A
Pt. Age
, ?( {- V% z8 H(yrs.)
& S. n' N+ U0 uSerum Testosterone Phallus (cm.) Change Length
) l4 Q M3 b; ~; P) t(ng./dl.) Girth x Length (%)
' f% p5 }0 Y4 d) \3 v0 P* M I4
: J4 r# |6 i8 K8 \81 x( z- l4 i+ ^6 g- _
10- h' z, o' X: t5 E
12
: w% p9 j: a* f! T17
$ ~ b; \5 U+ ?9 W: O: h" zGonadotropin
1 B2 q3 E$ Q H) A1 ^71.6 2.0 X 3 16.6) n, G9 c/ X' T/ C Y7 g
50.4 4.0 X 5.0 20.0+ {0 V5 Z7 l( {0 p8 d( U" ]) `2 ^
22.0 4.5 X 4.0 25.0
! e! X2 s9 H! T! F0 Z84.6 4.0 X 4.5 11.12 i, w! P- j# H8 u1 v3 e& ^ F
85.9 4.5 X 5.5 9.0/ S+ F0 x0 a) X5 Q
Av. 14.3% X: S9 j# U# r+ Z
4" y* z" f5 e" l+ c# J d, }
8. E% ~! p$ J/ G
10
! R, D y5 }# O! ]: y7 V/ s12+ I+ `2 x J" x. t- d1 @
177 Q7 P# }+ z& e r
Topical testosterone
5 W1 j: X6 }2 c% R% q34.6 4.5 X 6.5 85
( x; r7 T! ]: P$ h; V38.8 6.0 X 8.5 70/ j8 K, ~: Q0 ]* u2 L
40.0 6.0 X 6.5 62.5
) f9 I5 a1 B1 [, e0 y- n# @ g& o93.6 6.0 X 7.0 55.5. A: Z2 V' W2 [8 G; `' Z
95.0 6.5 X 7.0 27.2$ G1 ^4 ]! j t% X/ v8 Q
Av. 60.0
# m7 Q2 y8 ?% Z6 Favailable testosterone. Again, emphasis should be placed on; H9 v" [: }" }
early therapy when lower levels of testosterone appear to' @( n# _/ h. ]7 h
provide the best responses. The earlier therapy is instituted# }. ^* ~; O% ^, ~. w: ?9 h8 a
the more likely there will be an excellent response with low
0 p( c D! v3 Y2 R, e c# Aserum levels. Response occurs throughout adolescence as
0 T N( H( `% ?* e/ F3 I3 {noted in nomograms of phallic growth. 7 The actual response
, M& a' p! E; T3 z' rto a given serum level of testosterone is much greater at birth
9 T0 r$ `% k9 a$ Band gradually decreases as boys reach puberty. This is most
& S- Z9 @$ ?- {. l! j% glikely related to the conversion of testosterone to dihydrotes-: W5 b3 i6 @$ L+ _2 f0 q
tosterone and correlates well with the studies of testosterone. I% D; ?8 R% {" g
conversion in foreskin at various ages.
" R7 V% O+ L! p6 hThe question arises regarding early treatment as to whether, l+ ?0 R% B: [: y# k# t5 |# l
one might sacrifice ultimate potential growth as with acceler-1 u* R# S' O( ?" M
ated bone growth. The situation appears quite the reverse
" }7 \, j; T) V8 }; V; M* Cwith phallic response. If the early growth period is not used
q1 m, f/ r+ Q$ ^! U- @& [when 5a reductase activity is greatest then potential growth7 X& x7 N) s& d, @- _7 X2 a
may be lost. We have not observed any regression of growth- {! F: _6 N. ^, }) X
attained with topical or gonadotropin therapy. It may well; f& L6 ~# {) n9 r
be that some patients will show little or no response to any
9 ~' {/ c0 _2 }3 S) S' tform of therapy. This would suggest a defect in the ability to
) l: [) q0 V! s% J0 \3 z$ Wconvert testosterone to dihydrotestosterone and indicate that
; W# o* d" W1 s' M, Zphallic and peripheral skin, and subcutaneous tissue should* i+ F) G9 g3 M: y
be compared for 5a reductase activity.
+ h C: o0 t; G7 B2 p# M: tA, loop enlarges to measure penile girth in millimeters. B,2 J% o2 B( g; ^
example of penile girth computed easily and accurately.( X2 v) B# q3 |/ s5 Y: s$ A
conversion of testosterone to dihydrotestosterone. It is in this
1 Y0 i' }% P6 b" `8 Y% Y( tolder group that others have noted high levels of serum
* C; p; g* D* z5 k; rtestosterone with topical application. It would also appear
3 o: |. j& I1 W- e! ~$ w6 p+ @1 w4 ]that phallic response during puberty is related directly to the8 n: k* c. F: m7 V9 r
serum testosterone level. There also is other evidence of local6 x# q# q7 |4 e7 L6 s' q% ?
response to testosterone with hair growth and with spermato-8 n- N* o ~" R# r
genesis. 5• 6
8 X- T' p$ q E' K7 l+ f7 gAdministration of larger doses of gonadotropin or systemic* V1 }. V; p8 f( |) M/ ?3 O5 E8 j, {
testosterone, as well as topical applications that produce, G" y O. S7 W! `0 D" q
higher levels of serum testosterone (150 to 900 ng./dl.), will- _3 h% F6 b# Y3 p* D# c, x( a' n+ k+ I7 @
also produce phallic growth but risks accelerated skeletal4 C5 @/ e3 a& E9 o3 h: @
maturation even after stopping treatment. It would appear( \, @- d; @+ b2 B. I# O3 `
that this may be avoided by topical applications of testosterone$ |1 E# n4 ]6 v6 U: C9 g5 W7 c, ^
and monitoring of serum testosterone. Even with this control7 s7 j: ~ K/ ?% c$ a
the duration of our therapy did not exceed 3 weeks at any
; `. Y6 Q0 r1 K( ?" qtime. It is apparent that the prepuberal male subject may7 U2 J) b. x7 B% z' k
suffer accelerated bone growth with testosterone levels near6 h& d; m& T1 F. u& ^( t3 a
200 ng./dl. When skeletal maturation is complete the level of
9 Q& W" a) g* R6 r0 Y3 W6 G% V P `serum testosterone can be maintained in the 700 to 1,300 ng./
3 m9 R N; e# n \6 P3 Y! I4 \+ idl. range to stimulate phallic growth and secondary sexual4 T, j# }5 i6 u c4 z2 G' z
changes. Therefore, after skeletal maturation parenteral tes-/ `$ g- h! C; H- F& S- X l$ V. K
tosterone may be used to advantage. Before skeletal matura-' E3 ]6 r+ f5 @6 l+ [
tion care must be taken to avoid maintaining levels of serum, m# i5 j' I, E7 G& r2 W
testosterone more than 100 ng./dl. Low-dose gonadotropin7 I& N2 T) d1 G7 k
depends upon intrinsic testicular activity and may require
( I( _+ ]* t1 v) yprolonged administration for any response.
: J: H- t- ], d0 @. c2 H* jAlternately, topical testosterone does not depend upon tes-
6 R' G1 X& h$ E1 G g1 C4 a Vticular function and may provide a more constant level of
$ K% ^' y4 D& I9 |REFERENCES9 t6 t% y4 D- q6 X, z$ T6 c9 m; M
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: o4 |+ z; w. `; n% g4 DR.: The local application of testosterone cream to the prepub-) k0 a9 F6 [) v5 g0 n
ertal phallus. J. Urol., 105: 905, 1971.+ o* w: f3 g& O: U7 t e
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 m) P( g: Z1 i* R; ~$ a. J
treatment for micropenis during early childhood. J. Pediat.,! D5 r% J! w7 R& J0 m" V
83: 247, 1973.$ W$ n$ O9 s; ^* k
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( k; z# [; t- N4 H6 P6 Mone therapy for penile growth. Urology, 6: 708, 1975.8 D+ b% K% [: O& z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ y( U8 f' k; q" }
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
+ u0 U" W" t, J: X- z( @skin slices of man. J. Clin. Invest., 48: 371, 1969.
|$ H' c& d' P3 V& a) v; _5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ O6 y2 L8 L9 o* G" N0 O9 D/ ^2 r
by topical application of androgens. J.A.M.A., 191: 521, 1965.5 Q4 O7 D9 h& A! ^" U/ b
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ A v+ ] `, g2 X' M( A
androgenic effect of interstitial cell tumor of the testis. J.% c- L: ?0 V( y+ T, m
Urol., 104: 774, 1970.
+ K) m4 L- s5 p9 h; P7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& q7 a* T. ]" q6 L$ `tion in the male genitalia from birth to maturity. J. Urol., 48: |
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