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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% R4 Y' l* p, L; B; ]
GONADOTROPIN/ ?# f3 C8 d' }9 o! o
RICHARD C. KLUGO* AND JOSEPH C. CERNY
1 A( S7 J! z. W$ Z+ v. n) FFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
; e' F' J9 A3 h4 bABSTRACT
5 l& s% Q8 o( C* i4 ZFive patients were treated with gonadotropin and topical testosterone for micropenis associated
2 J4 y0 c& b' D9 w( i5 b* ]with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-* O7 }( R: v. n2 Q" U4 _
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) J' D- ?& J0 C4 _! q
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 Q( L7 W1 J5 B6 m, B& Q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: d6 c4 f! Z6 ^2 G
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average/ a; P% s* z& ?- i9 ^# ]8 _
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response/ d' M1 G7 w$ x" i/ n
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% O" T# S2 W" E+ i! O) L lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 e! |3 I1 g4 K( c" M5 \
growth. The response appears to be greater in younger children, which is consistent with previ-
, }5 x; ?1 y. V( cously published studies of age-related 5 reductase activity.* p- z: x4 M5 T* u# s v
Children with microphallus regardless of its etiology will
; x, H1 [. T. @0 krequire augmentation or consideration for alteration of exter-7 A( k. {/ d3 N
nal genitalia. In many instances urethroplasty for hypo-
# y, k2 i' m6 v2 o; L' sspadias is easier with previous stimulation of phallic growth.
9 V. y2 w% e* q# _7 zThe use of testosterone administered parenterally or topically
- B+ ?3 \* K, H% D' \has produced effective phallic growth. 1- 3 The mechanism of
! @$ N, J" N# z- k* S% \& Hresponse has been considered as local or systemic. With this' R5 P% _8 u6 O8 Y& C2 ?
in mind we studied 5 children with microphallus for response2 B% I7 F3 Q/ W# V/ h2 \: I5 `9 [
to gonadotropin and to topical testosterone independently.
" J8 l$ J: ^* c6 n: O( |0 h% VMATERIALS AND METHODS/ N6 r' g" J% R* L$ C% q6 F. K
Five 46 XY male subjects between 3 and 17 years old were8 ?. z4 C- q$ i k
evaluated for serum testosterone levels and hypothalamic' s9 \+ |3 ^- D+ r. Q7 b% X
function. Of these 5 boys 2 were considered to have Kallmann's; ^4 O$ G3 ]7 A, p( x+ ]
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-( N' Q" Z& ?7 I8 R
lamic deficiency. After evaluation of response to luteinizing
. g6 ?' ?0 Y$ O: Q% Lhormone-releasing hormone these patients were treated with
1 X7 a1 X" s( m J0 @6 R7 |" x1,000 units of gonadotropin weekly for 3 weeks. Six weeks1 T: h; m# p; f( S7 W' E8 O' R
after completion of gonadotropin therapy 10 per cent topical
' B1 B' G! K2 f# x7 g4 Ptestosterone was applied to the phallus twice daily for 3 weeks.
& I5 X) Z3 J9 M+ N5 ZSerum testosterone, luteinizing hormone and follicle-stimulat-$ b7 B3 t8 E. k! W
ing hormone were monitored before, during and after comple-
! y+ ~/ k2 t& a# b" ztion of each phase of therapy. Penile stretch length was: n# } T$ Q) k- Z6 i6 W
obtained by measuring from the symphysis pubis to the tip of
$ i H# B t! w4 Othe glans. Penile circumferential (girth) measurements were! U* C; j8 T5 ?, N. V% W
obtained using an orthopedic digital measuring device (see
3 }3 U( K8 K" R$ T; a& n6 x; afigure).7 R5 W4 z. c" Z4 @% v' g( @
RESULTS! \- @" {9 N" b* N. L) c6 B7 C' s
Serum testosterone increased moderately to levels between/ K- @. i0 S0 q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% l8 U4 ^8 N$ b, \terone levels with topical testosterone remained near pre-
4 p7 l8 n) `8 d9 g1 gtreatment levels (35 ng./dl.) or were elevated to similar levels
8 S5 f" O2 o5 O) A4 e# k9 Cdeveloped after gonadotropin therapy (96 ng./dl.). Higher
: G* J6 o7 R0 E. D Zserum levels were noted in older patients (12 and 17 years old),
* }6 \% U" @6 T3 b* C9 Y6 {while lower levels persisted in younger patients (4, 8, and 107 H4 L; s, e4 @+ }) y
years old) (see table). Despite absence of profound alterations
$ e4 T; L7 r( G, ^$ w- E. M _of serum testosterone the topical therapy provided a greater
" ` Z4 U- m& d9 [- v# D7 O# r# c B4 oAccepted for publication July 1, 1977. ·
; |8 G# y; u! H0 }Read at annual meeting of American Urological Association,
: n2 t: H" ]* W% @( G% `; q6 k/ X5 KChicago, Illinois, April 24-28, 1977.
( P$ z4 ^6 c5 B3 W# i* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 {. |. w+ Z' R2799 W. Grand Blvd., Detroit, Michigan 48202.2 S: A+ j3 x) {
improvement in phallic growth compared to gonadotropin.
/ V; j0 W& h) b5 [9 i4 u" eAverage phallic growth with gonadotropin was 14.3 per cent
6 Q; M' D& u; k" lincrease in length and 5.0 per cent increase of girth. Topical) w6 q) X- d0 S5 q% \: n
testosterone produced a 60.0 per cent increase of phallic length
& f7 A6 D6 }, o! Vand 52.9 per cent increase of girth (circumference). The
) f2 K9 x2 ~& g) fresponse to topical testosterone was greatest in children be-* P. C) @! F3 D7 f% V; }! X
tween 4 and 8 years old, with a gradual decrease to age 17
7 n/ M5 n8 g5 yyears (see table).
/ J1 L0 A( R, q9 s1 d2 c) @& ]DISCUSSION! @4 ~. Q5 A' q
Topical testosterone has been used effectively by other
0 c0 w( o( B5 d# Eclinicians but its mode of action remains controversial. Im-" J& n% Y- c5 R! |0 [1 l2 D0 r6 {
mergut and associates reported an excellent growth response
$ F- m5 c# ]5 y" G9 U& kto topical testosterone with low levels of serum testosterone,
( o# T; }$ E: g- Q9 e6 J7 ]4 h, ysuggesting a local effect.1 Others have obtained growth re-
/ v3 S4 k; |5 k, V* Ysponse with high. levels of serum testosterone after topical
' e! Q( i X; I7 D3 I5 d1 W8 Dadministration, suggesting a systemic response. 3 The use of" S1 G* r z5 I. I5 m
gonadotropin to obtain levels of serum testosterone compara-
" r1 _& u4 w$ kble to levels obtained with topical testosterone would seem to
2 w8 k8 r* u" R, vprovide a means to compare the relative effectiveness of+ e+ g q- y0 D
topical testosterone to systemic testosterone effect. It cer-
, b1 K4 x% s% K! i2 ctainly has been established that gonadotropin as well as par- W; f" g: E; O+ g. V
enteral testosterone administration will produce genital
" g0 b' d$ y( U# u' W$ ~growth. Our report shows that the growth of the phallus was
& x1 q/ Z$ _5 K# O9 l( K* zsignificantly greater with topical applications than with go-
/ y0 T& N& l1 K) ?( T9 Rnadotropin, particularly in children less than 10 years old.: }+ p `% b3 e
The levels of serum testosterone remained similar or lower
% v% {1 D/ B' L I/ [! ]than with gonadotropin during therapy, suggesting that topi-- M1 J! x8 _5 q% g! f0 d0 c
cal application produces genital growth by its local effect as+ o$ a! V, i+ r8 z3 i3 I
well as its systemic effect.1 h1 X5 I% r) B+ c: E6 T
Review of our patients and their growth response related to6 D- E1 W4 O4 w; H. B& I' q. ]2 X
age shows a greater growth response at an earlier age. This is
2 m9 ~% ]. F, U6 B8 I* {2 q/ ~! Pconsistent with the findings of Wilson and Walker, who% f3 G2 m% n# @+ L E
reported an increased conversion of testosterone to dihydrotes-- {- N0 ]# n5 z# T' T2 ]# m1 C
tosterone in the foreskin of neonates and infants.4 This activ-
# L: ?% G' L# l1 z9 t! y5 hity gradually decreases with age until puberty when it ap-
0 d& D' x- S( T. r& \: Eproaches the same level of activity as peripheral skin. It may
+ q! O8 w4 `1 ?well be that absorption of testosterone is less when applied at7 c0 S' B) F- X' d/ b& T( w
an earlier age as suggested by lower serum levels in children
, Q& G7 s$ b5 A7 S" Aless than 10 years old. This fact may be explained by the9 ~0 i& y: _( S. Z
greater ability of phallic skin to convert testosterone to dihy-
) R' T) ]0 ?5 X, i6 m- r2 mdrotestosterone at this age. Conversely, serum levels in older' w3 n) {% Q( s1 o9 d1 h% G' E% o
patients were higher, possibly because of decreased local/ g2 s* ?; ~- B: |6 b, z' I
667
& b* U; h$ X' V) V2 j% S# @668 KLUGO AND CERNY8 B* j7 c+ o; \9 o X% {) S- S- j
Pt. Age
+ r! i# P o7 O( a Z(yrs.)% R& d: H; d) c# }6 d8 ]$ p. _
Serum Testosterone Phallus (cm.) Change Length
; U4 s2 W0 `% S* D1 t" M(ng./dl.) Girth x Length (%)
: I: }4 A& t# Q! B, d8 N4
- q. X: i" `7 w3 j7 b5 X1 L; L$ d: @. Z8
1 {$ z! Z: I: P3 W8 `# G' _8 i108 y4 w R6 {6 `
128 [9 A3 ^4 q0 A3 ? v
17
! c' o$ t% q, v* P0 c; D) l6 vGonadotropin C. @+ X4 h" r1 C f$ _
71.6 2.0 X 3 16.6
; \" Y* j) {/ L! J* j, M50.4 4.0 X 5.0 20.0
0 _& m# X. x9 E5 b" b1 w22.0 4.5 X 4.0 25.05 s) L4 T3 \* w8 R2 J% p
84.6 4.0 X 4.5 11.1
R! o3 ~" x: n, s8 U- \! V85.9 4.5 X 5.5 9.07 W ?8 J) B4 x
Av. 14.3
* M3 F/ B8 p9 P% _; @, `4
! G+ _5 Y* u4 X8. E0 P( l1 l& h- x4 L( U
10
* [7 x6 @5 m E' S) t12! N( Z5 \) f/ t
17
, X; t- t& S8 O0 \2 {+ A7 r( D6 \Topical testosterone
9 [& c7 v* u+ L0 J34.6 4.5 X 6.5 852 N( h- M4 l' \* O% K
38.8 6.0 X 8.5 70* j7 P i2 ~1 P7 u( t2 [) d
40.0 6.0 X 6.5 62.50 j) V$ V1 w& w1 s/ o! Z3 I
93.6 6.0 X 7.0 55.57 X5 J( w0 Q R, o! b
95.0 6.5 X 7.0 27.2
# J# a& z2 `4 G- |+ V" ^* N1 kAv. 60.09 q4 D. r2 d# j# J* M# D
available testosterone. Again, emphasis should be placed on
1 ^+ P* I2 M4 z, g5 pearly therapy when lower levels of testosterone appear to
3 K* K, y+ h+ O4 cprovide the best responses. The earlier therapy is instituted- y2 g7 l1 y I3 n4 c
the more likely there will be an excellent response with low+ E+ T, f3 l# t" a1 q
serum levels. Response occurs throughout adolescence as
1 U4 p3 r: p: B7 r4 wnoted in nomograms of phallic growth. 7 The actual response3 I% D7 \$ k2 r9 t" T+ a
to a given serum level of testosterone is much greater at birth
* R6 S0 N! N( ~9 s8 h- y! ^- Band gradually decreases as boys reach puberty. This is most
) T; }* ~ W3 T" e" J4 flikely related to the conversion of testosterone to dihydrotes-
; t3 M! N7 h' n* `% c. }9 Gtosterone and correlates well with the studies of testosterone
! |; N' D4 y$ u; g: g- v: k5 Jconversion in foreskin at various ages.
& S, F. \' Q9 F4 nThe question arises regarding early treatment as to whether, l( T0 h1 ]2 F- r8 H% m+ W
one might sacrifice ultimate potential growth as with acceler-
' \- j f. k0 n0 n2 K: ?9 Mated bone growth. The situation appears quite the reverse) L2 [8 [5 x5 U" l0 h3 s1 d
with phallic response. If the early growth period is not used
0 v2 G# [( d5 [ |! wwhen 5a reductase activity is greatest then potential growth
- F* x, \6 g" ?/ L0 e" t1 d. bmay be lost. We have not observed any regression of growth
7 C) V/ F' K3 ]# H0 a( Gattained with topical or gonadotropin therapy. It may well$ U( j% v1 L5 a1 U" ^6 ]
be that some patients will show little or no response to any
+ a4 U7 }/ Z# E# o# N: Nform of therapy. This would suggest a defect in the ability to
) u: v' a% z4 W+ S9 Wconvert testosterone to dihydrotestosterone and indicate that4 C7 S3 t9 ]2 s+ I/ D& h7 S6 P4 K0 X
phallic and peripheral skin, and subcutaneous tissue should
! U! J2 \5 w0 P2 Qbe compared for 5a reductase activity.
8 v; m7 Z6 M% O) N8 X. j; j6 T5 y8 YA, loop enlarges to measure penile girth in millimeters. B,2 Z. Z% ?, j6 F( c
example of penile girth computed easily and accurately.
6 i; O" {6 d7 N' x, X- ^conversion of testosterone to dihydrotestosterone. It is in this
9 h" T, G- J- ?+ Rolder group that others have noted high levels of serum
, \2 k/ h+ s9 i& j4 d, A( rtestosterone with topical application. It would also appear
. P! W6 O( Z9 J% ~6 M, N6 Gthat phallic response during puberty is related directly to the( @2 b: Z: M+ X! O/ x: C* l
serum testosterone level. There also is other evidence of local
4 A/ q& Y2 k; m- e, I1 kresponse to testosterone with hair growth and with spermato-5 g+ L' V1 }: x: V" h
genesis. 5• 6
9 `. e, p# K0 \% T/ G5 X, B( KAdministration of larger doses of gonadotropin or systemic( N9 Y% t% O) e
testosterone, as well as topical applications that produce
) P, Q: p! {8 f# @higher levels of serum testosterone (150 to 900 ng./dl.), will! ^/ U6 U) {" t& p3 d
also produce phallic growth but risks accelerated skeletal/ K" `* g9 ?2 |5 R
maturation even after stopping treatment. It would appear l5 D. n, G8 n" B9 s# s+ c
that this may be avoided by topical applications of testosterone; s% p- U8 q' _ Z- ]2 ?- V
and monitoring of serum testosterone. Even with this control5 E! \( U+ |4 i! O r3 R8 ^6 Z
the duration of our therapy did not exceed 3 weeks at any# l3 a: @6 ]& ~
time. It is apparent that the prepuberal male subject may
$ d) Y" I5 S9 `( E( X! N- ?suffer accelerated bone growth with testosterone levels near
1 m- E+ V; h6 }8 |200 ng./dl. When skeletal maturation is complete the level of8 U) q. J6 i) t/ s0 l) a+ L
serum testosterone can be maintained in the 700 to 1,300 ng./5 H3 {/ A" W5 }4 Y6 g' a/ {
dl. range to stimulate phallic growth and secondary sexual
) K3 X2 _+ H3 ?7 D7 z! Achanges. Therefore, after skeletal maturation parenteral tes-/ f) ^" V& @1 M( I8 y
tosterone may be used to advantage. Before skeletal matura-
! Q9 W0 t& ]' R) V: ^tion care must be taken to avoid maintaining levels of serum# E" l, p% I. i
testosterone more than 100 ng./dl. Low-dose gonadotropin* L0 J2 v5 w* j: X
depends upon intrinsic testicular activity and may require
: G: B4 ~* @! l# m8 cprolonged administration for any response.5 G, U$ S" Y5 ?; X
Alternately, topical testosterone does not depend upon tes-
; W7 E: f1 `6 m9 t0 ^9 vticular function and may provide a more constant level of$ L6 |6 ^: O- M8 }, G
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/ N5 _) f9 i( P6 l% zR.: The local application of testosterone cream to the prepub-* H$ _( H: [0 T, V) O& u3 k
ertal phallus. J. Urol., 105: 905, 1971.
3 F' ]( O+ A3 S9 j" j: y0 Y. a2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 q. w) Z7 t9 I$ l+ D* \3 }( m8 e
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83: 247, 1973.
# f& `8 B# q3 B9 c, v! ?0 W0 B% j3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 }/ Q( J3 h/ w5 Bone therapy for penile growth. Urology, 6: 708, 1975.
6 c |$ {& K3 B9 ~4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 _$ v4 o/ |# D# q* n3 tto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by O5 J' Z, a7 K; Z7 h2 t
skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 O Z0 @" b/ T/ i0 Z9 O5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth/ I- w8 J5 o7 ]- i z! R
by topical application of androgens. J.A.M.A., 191: 521, 1965.
- Z, }( g: O6 D6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 q& \3 d, {5 Q6 C4 e
androgenic effect of interstitial cell tumor of the testis. J.
/ ^6 i& F" X% vUrol., 104: 774, 1970.
+ [9 [* `! F; J6 y( A: g. L7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-) f! {% U) G' Q* L) j8 @4 O6 E
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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