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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 a' u& H2 O" x3 N% WGONADOTROPIN4 Q" s: i4 D' Y4 U5 Q( g
RICHARD C. KLUGO* AND JOSEPH C. CERNY/ G1 W8 ?7 H ~7 I( i' y( T( t
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% ]1 g4 z9 T$ S4 _3 eABSTRACT
, d5 V5 p1 e( nFive patients were treated with gonadotropin and topical testosterone for micropenis associated5 R2 g- z& {1 g$ ^
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-' p. Y$ j; Y/ H" |, ~ v# R
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ S2 E+ l! _% n5 k1 M
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: {: n" ~" m1 q# S# h) U0 Q" b" O
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 h# M3 G# }" _
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 R9 ^7 w- _3 u9 N; g
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 v# N3 D. `" L) Q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' T8 z! @, f' s( vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 E1 I! p$ k7 Z. B: L3 W0 O
growth. The response appears to be greater in younger children, which is consistent with previ-
+ t8 C9 b& T7 g5 \$ d: R) y! \; Vously published studies of age-related 5 reductase activity.3 A+ F5 q- g }% j6 H) C8 C0 V
Children with microphallus regardless of its etiology will0 T; H. X* C4 l+ a* r% u6 G$ Q
require augmentation or consideration for alteration of exter- l! n9 {8 F- X# T) ~$ k, ~
nal genitalia. In many instances urethroplasty for hypo-+ n* \( v7 a: r) }" r
spadias is easier with previous stimulation of phallic growth.2 N% k7 B% x, f3 ^6 g- \
The use of testosterone administered parenterally or topically3 d7 `. ~+ }2 l$ ^
has produced effective phallic growth. 1- 3 The mechanism of+ h0 x$ s9 E: w: b- c
response has been considered as local or systemic. With this) W- x6 e* z; a; A- ?) i7 x% n' ~2 U
in mind we studied 5 children with microphallus for response( ^8 E0 F6 C3 i
to gonadotropin and to topical testosterone independently.
& `( X( c" a8 v! f4 L; BMATERIALS AND METHODS
$ Q: v7 y" ~0 J+ z" }Five 46 XY male subjects between 3 and 17 years old were" A9 c+ @* g" ]1 x' b
evaluated for serum testosterone levels and hypothalamic
) [( G6 t3 Y* a/ z `8 Xfunction. Of these 5 boys 2 were considered to have Kallmann's
6 H( T) W2 G' [/ k$ o6 asyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
; T+ D- J" u' b0 s1 ?! @lamic deficiency. After evaluation of response to luteinizing
) H. A/ R0 M* Q5 o' X% i4 Y" U2 Ahormone-releasing hormone these patients were treated with
% j8 G7 q7 S1 e1,000 units of gonadotropin weekly for 3 weeks. Six weeks' I$ @( O9 k" K
after completion of gonadotropin therapy 10 per cent topical9 k2 P: e3 y, c* K2 _3 Y `3 \ M
testosterone was applied to the phallus twice daily for 3 weeks.
: Y8 X' X ?) N' OSerum testosterone, luteinizing hormone and follicle-stimulat-
: M) o0 W% F$ b1 |6 M4 n0 ning hormone were monitored before, during and after comple-
' E/ N2 d; L; Z! d" Q* m; ]& ^" ^" ntion of each phase of therapy. Penile stretch length was
5 x- o: B6 c3 w# \. q! y. v. Tobtained by measuring from the symphysis pubis to the tip of
- y) s, i& R& W5 xthe glans. Penile circumferential (girth) measurements were
7 L, G- t: f" b" \# X. n; Fobtained using an orthopedic digital measuring device (see+ ^$ B3 J) ~+ R; N% t
figure).
@) U8 r5 a# h j2 f( hRESULTS
2 q2 p1 K+ O+ [8 VSerum testosterone increased moderately to levels between
3 H8 h- R/ r9 I. Z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-+ n+ z) P" @! n+ a
terone levels with topical testosterone remained near pre- K, q4 Y0 O# k
treatment levels (35 ng./dl.) or were elevated to similar levels' J( k" r( t `# W7 f
developed after gonadotropin therapy (96 ng./dl.). Higher9 z2 w1 l* V- o4 h1 t" y
serum levels were noted in older patients (12 and 17 years old),
3 z2 R5 }6 \( U1 U8 Q4 |while lower levels persisted in younger patients (4, 8, and 10
. G3 v3 P) |) s; p4 E% o; Qyears old) (see table). Despite absence of profound alterations; T% P& X) b- U5 r8 I6 s
of serum testosterone the topical therapy provided a greater
2 _+ j3 _- G8 {; e+ B5 NAccepted for publication July 1, 1977. ·
% H7 i2 w8 `4 X) U& VRead at annual meeting of American Urological Association,+ T7 e: B! m2 Q' f( K6 W- F3 e3 y
Chicago, Illinois, April 24-28, 1977.9 s9 k: X; n. D' i9 c" Y( K
* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 A8 `. i* [$ I" U4 K+ h$ @2799 W. Grand Blvd., Detroit, Michigan 48202.
1 s6 F- D" A! D+ ^3 ^$ ~1 O, dimprovement in phallic growth compared to gonadotropin." y+ h, t5 z% z! i6 J
Average phallic growth with gonadotropin was 14.3 per cent
# z3 V* `9 S; z8 A8 }increase in length and 5.0 per cent increase of girth. Topical
) [7 d7 w' g9 W0 G; _testosterone produced a 60.0 per cent increase of phallic length
% w4 r9 M8 D( L1 m6 }6 \and 52.9 per cent increase of girth (circumference). The- Q/ o8 M* C6 {: R; Y8 P0 B
response to topical testosterone was greatest in children be-
2 h, |# p6 @1 n/ Btween 4 and 8 years old, with a gradual decrease to age 17 E, v' j# Z5 C5 d
years (see table).
( J; b6 p0 E5 O$ b. ^DISCUSSION- l- ~/ w* j. N a) L7 W
Topical testosterone has been used effectively by other
; f8 J1 t4 h3 y+ ?! P- sclinicians but its mode of action remains controversial. Im-; N' t/ K, w! h T# M4 |% M
mergut and associates reported an excellent growth response& l0 |+ o; M8 ?
to topical testosterone with low levels of serum testosterone,/ x7 \) p% [ Z, j" {( O) w+ b
suggesting a local effect.1 Others have obtained growth re- z6 V% q9 \3 Q5 t; Q
sponse with high. levels of serum testosterone after topical
# e- i- f5 b4 uadministration, suggesting a systemic response. 3 The use of
1 n9 P% R' p B# j/ Q! [5 [gonadotropin to obtain levels of serum testosterone compara-
; ?0 O9 @9 Y m3 }ble to levels obtained with topical testosterone would seem to- K" `: @, s6 W0 {) m
provide a means to compare the relative effectiveness of
: f3 l. r* |; P! y' M* w3 } ktopical testosterone to systemic testosterone effect. It cer-
}9 P4 z9 J/ m7 Y# j. W/ Ttainly has been established that gonadotropin as well as par-- v% i9 U# B8 W) v6 @
enteral testosterone administration will produce genital5 H( p. W* T7 M% y& I+ T/ h7 o
growth. Our report shows that the growth of the phallus was
6 k1 e) G6 c1 {5 ?significantly greater with topical applications than with go-. R6 |: k9 A7 y5 _& m2 @, V
nadotropin, particularly in children less than 10 years old.
: G# j" u& K- I' o" W& ?9 b; oThe levels of serum testosterone remained similar or lower) r/ j m9 e7 U. K: |, Q3 W/ R7 b! y& C
than with gonadotropin during therapy, suggesting that topi-
, {5 B# g( t5 z, p5 F9 K6 f: {; D& ?cal application produces genital growth by its local effect as
% T: G( ^2 b. @' f: E; Uwell as its systemic effect.
- [8 A# c- t, l1 ZReview of our patients and their growth response related to" z, L( a+ w% N' G
age shows a greater growth response at an earlier age. This is
) }1 J% m6 @1 D# N( L$ uconsistent with the findings of Wilson and Walker, who0 t2 Y5 L/ A5 i V6 y
reported an increased conversion of testosterone to dihydrotes-$ @9 a7 B* s( Y1 n5 F, t
tosterone in the foreskin of neonates and infants.4 This activ-8 h6 x3 P# ?) S" w8 ~1 C$ ], s# g* z
ity gradually decreases with age until puberty when it ap-; s; N8 H9 T% K" h7 c
proaches the same level of activity as peripheral skin. It may {3 Z: y4 r3 f; y" N
well be that absorption of testosterone is less when applied at8 `8 v0 h% j: e# `8 n
an earlier age as suggested by lower serum levels in children
8 Y% M" o' I2 Nless than 10 years old. This fact may be explained by the
& C) |) r2 e" e5 I5 jgreater ability of phallic skin to convert testosterone to dihy-/ z; k. i: ^' k/ Y% {# j l
drotestosterone at this age. Conversely, serum levels in older
; o% w- P3 d/ F6 M0 A& |9 G0 Spatients were higher, possibly because of decreased local& f" @0 f1 B% l. q
667
6 `$ \. u5 G+ H* F668 KLUGO AND CERNY
# G0 p+ F. t* y0 GPt. Age+ L8 D: ]7 u+ h( U- h" Y
(yrs.)/ Q. o9 n. a! h) t- h3 v) g
Serum Testosterone Phallus (cm.) Change Length& b ]6 z, ~! D2 q: x
(ng./dl.) Girth x Length (%)
2 E4 ^) ~8 w/ m$ C* q) q) e46 x/ \; o% G" @7 {
8
1 L4 ] O2 H2 L* O10
1 W1 h) O: y3 Y( B9 ]12
: r& n1 K6 W4 y6 V# J4 F17
5 n' m+ A8 X" ^Gonadotropin. |6 x# }/ Y0 B
71.6 2.0 X 3 16.6
1 X/ o6 E: v* o% c8 k50.4 4.0 X 5.0 20.0
! x0 e! ] c( C, `+ C" F22.0 4.5 X 4.0 25.0* N1 R! e" K5 e! N8 Y, p
84.6 4.0 X 4.5 11.1
, o9 B9 o, Y! n$ T4 g85.9 4.5 X 5.5 9.03 h8 [ g! C+ ?
Av. 14.3
! X/ D9 I+ @% B# h; Z# f# @" u4
+ N f$ ]5 `6 b2 w8
8 }1 Z4 v Y) Z0 \1 a6 y @10
: C5 z3 V8 I# F- k; `12 q o/ u8 Z W' c3 B
17
, |: M& X! P- m" t8 \" n2 m: o% Y' XTopical testosterone
) u% j, @* l- s- t; f$ r/ D34.6 4.5 X 6.5 85
6 a( s3 y* C Y! h# l" k38.8 6.0 X 8.5 709 T0 F7 j+ z, M% A; `, S
40.0 6.0 X 6.5 62.56 S! ]2 X: G$ d; G8 |
93.6 6.0 X 7.0 55.5
5 Z9 O6 Y: Z6 b. x% f& x3 K- ^95.0 6.5 X 7.0 27.2
) y1 k8 ]4 p+ g( N! p% MAv. 60.0* a$ b: V2 ~+ K! s
available testosterone. Again, emphasis should be placed on
6 K' g7 l2 f; r: u* I+ A0 M# Q% nearly therapy when lower levels of testosterone appear to. N& ~3 m. e U
provide the best responses. The earlier therapy is instituted( l: T( W. i! E
the more likely there will be an excellent response with low$ ^5 S# t9 x+ r
serum levels. Response occurs throughout adolescence as
7 F7 b5 Z5 h+ c+ |$ a. |# ^/ u, Enoted in nomograms of phallic growth. 7 The actual response
4 ~1 A' P- X- ~/ O xto a given serum level of testosterone is much greater at birth1 w: {# r- y( V1 i8 `
and gradually decreases as boys reach puberty. This is most
# b& ^: `2 C; |/ {( V, nlikely related to the conversion of testosterone to dihydrotes-
$ b w9 F: F. x; O# J4 L+ ktosterone and correlates well with the studies of testosterone
2 q# e, m' q8 _5 Iconversion in foreskin at various ages.
' e+ d3 l$ r0 I2 U( d2 [/ yThe question arises regarding early treatment as to whether& K: D. J! o$ h( ?2 @
one might sacrifice ultimate potential growth as with acceler-
, F) Z/ F2 x6 Y8 i6 d6 mated bone growth. The situation appears quite the reverse0 l% f* Y( D/ g9 b
with phallic response. If the early growth period is not used
4 h7 a. X) Z4 `0 _when 5a reductase activity is greatest then potential growth
, m- y3 K! Z$ ~% tmay be lost. We have not observed any regression of growth* ]0 B) P- x9 H' N8 _$ C2 D" e
attained with topical or gonadotropin therapy. It may well9 ?7 g/ R3 M6 r/ B2 G
be that some patients will show little or no response to any
( G9 n+ W4 k' |3 q- c0 Aform of therapy. This would suggest a defect in the ability to ?; B" o A, w) Q8 j* f$ I% ~# F5 V
convert testosterone to dihydrotestosterone and indicate that: s4 w# }6 B5 e$ j* ]# S1 o
phallic and peripheral skin, and subcutaneous tissue should
$ e" n! l/ n6 l, ~7 ~be compared for 5a reductase activity.5 M: ?6 p8 e6 T$ y0 ~# I6 b _
A, loop enlarges to measure penile girth in millimeters. B,: x! L3 \8 z1 I/ g. w5 y
example of penile girth computed easily and accurately.
[# R" x# c5 U& N. h/ Rconversion of testosterone to dihydrotestosterone. It is in this
, F' `! E8 D; V! m$ L( G3 S5 kolder group that others have noted high levels of serum
1 a3 |* M6 o% ^testosterone with topical application. It would also appear
+ o7 w$ p- p% T: t* ?. Dthat phallic response during puberty is related directly to the/ z2 b3 g' J/ R# w
serum testosterone level. There also is other evidence of local
2 a( P8 G7 Y1 f( o. x9 i# vresponse to testosterone with hair growth and with spermato-
$ d& t# W8 B( |) v% N( T& A* y: `genesis. 5• 67 \! L q& B x$ s. E$ m* z' M+ g1 r m
Administration of larger doses of gonadotropin or systemic7 m4 Q* t! l5 ]1 j6 x/ x
testosterone, as well as topical applications that produce% a9 p. r8 `8 ^ ?
higher levels of serum testosterone (150 to 900 ng./dl.), will7 \* W/ J' l6 g" `! e& ]+ w! o! A
also produce phallic growth but risks accelerated skeletal4 l8 g) ?8 U1 O+ g, T0 }
maturation even after stopping treatment. It would appear4 ^2 D& Q1 J6 I/ C4 C x( M
that this may be avoided by topical applications of testosterone
4 q( l4 X( R) e: K+ B0 band monitoring of serum testosterone. Even with this control
" S. S# \1 {; S" @, i8 Rthe duration of our therapy did not exceed 3 weeks at any
1 ~& j% @- X4 ?. ?$ \5 Mtime. It is apparent that the prepuberal male subject may9 I+ R l" i' i' p- Y! X
suffer accelerated bone growth with testosterone levels near4 k% j0 s d! F) `! S0 P
200 ng./dl. When skeletal maturation is complete the level of
+ s N& ^) M$ j- rserum testosterone can be maintained in the 700 to 1,300 ng./
+ m: P8 @1 O# @8 `. r; h( Wdl. range to stimulate phallic growth and secondary sexual7 a, W% C5 x# H9 [7 P0 |9 L
changes. Therefore, after skeletal maturation parenteral tes-% |+ U* i8 R+ ^1 c6 k* }9 p- @" N
tosterone may be used to advantage. Before skeletal matura-
( R' r1 W* l: Q2 a1 v7 |tion care must be taken to avoid maintaining levels of serum
U! X4 d( Z2 Y: ptestosterone more than 100 ng./dl. Low-dose gonadotropin
# R# Q3 F3 A" i. x% ^( i* v# rdepends upon intrinsic testicular activity and may require
3 q9 v5 y" X; H( \prolonged administration for any response.
* N0 N0 T% D! y9 v: z* PAlternately, topical testosterone does not depend upon tes-
5 K* i: I! k0 g3 f2 Iticular function and may provide a more constant level of
# O/ Y4 W2 N+ p7 |, y, oREFERENCES. m& l! N. Q8 a
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& d( a+ `8 Q5 |% O, @2 r
R.: The local application of testosterone cream to the prepub-
: `$ Z4 x1 B! Y! h0 r# H, iertal phallus. J. Urol., 105: 905, 1971.. d% T4 t: m' W5 }
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 d; i0 N2 D3 n- s+ ?6 ftreatment for micropenis during early childhood. J. Pediat.,
5 [( {& e) E% Y5 m3 u83: 247, 1973., D; m9 t6 y0 _) V
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 I) J3 {7 q& \* X! G0 yone therapy for penile growth. Urology, 6: 708, 1975.5 y" l1 u& z) w# M+ J9 z6 G
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' X, h/ H* y6 ]2 B: A
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# F" o7 |0 C& R; B( S- Yskin slices of man. J. Clin. Invest., 48: 371, 1969.
4 X5 b1 b9 Z( X" e8 i2 R: w f4 L5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth6 o# h, [& ?, R8 d+ Z B
by topical application of androgens. J.A.M.A., 191: 521, 1965.* f# H/ w# m4 L& X
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 Y, t9 k0 ^$ t! S9 m
androgenic effect of interstitial cell tumor of the testis. J.
3 V9 O3 V' A( zUrol., 104: 774, 1970.
, M9 Z0 s5 h4 \7 s0 X5 L- R7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
4 X- y% r6 D; M$ k% Ztion in the male genitalia from birth to maturity. J. Urol., 48: |
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