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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND; g1 n6 v9 y2 R4 u4 L+ k/ Y
GONADOTROPIN: j3 ]" ] S* v1 G% f0 Y
RICHARD C. KLUGO* AND JOSEPH C. CERNY
) i ^% Y5 A" O: c9 tFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan: B8 a. c/ W. v$ F9 C2 R' f
ABSTRACT; q: r- |, ]% O
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
/ I* S& M1 P! ?3 x' r4 Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ D0 L% k# R( L( Z5 ^1 Utropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone+ x: ]- x0 s) G' n
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 l+ x6 _/ S: A6 G2 rfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
# B# b5 U8 \8 y1 C& o+ y6 F0 }increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average- h" V1 g# m1 @% k1 h, X" g
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# i) O% n! R! b- ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, b, U7 x' p( K% a& K- f; H, M) Ystudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# g0 J2 t" Y, s5 _growth. The response appears to be greater in younger children, which is consistent with previ-
% q' L) _' [0 A8 o3 gously published studies of age-related 5 reductase activity.
6 I, w' r' \& {6 n- z I( eChildren with microphallus regardless of its etiology will, `. \4 y4 b( ?0 u* Q \9 B
require augmentation or consideration for alteration of exter-
: c$ w# H# |5 v4 F: R+ }7 }) Unal genitalia. In many instances urethroplasty for hypo-5 j6 x$ M. x7 p9 {/ o* A+ A
spadias is easier with previous stimulation of phallic growth.; C( M, w# j/ {- y! [
The use of testosterone administered parenterally or topically2 }* b6 z# x2 V9 _) t( P
has produced effective phallic growth. 1- 3 The mechanism of: G. w& G9 O5 h7 r. T' x! E9 G. T" a
response has been considered as local or systemic. With this
0 ~: M) w8 o5 ~/ Z/ z2 a2 ~in mind we studied 5 children with microphallus for response, u3 Z# [6 p$ [% h6 c9 B
to gonadotropin and to topical testosterone independently.
) b# E W' n: X% i _2 ^) UMATERIALS AND METHODS
4 m$ R6 B5 x/ t! y8 VFive 46 XY male subjects between 3 and 17 years old were) L) @3 S: r5 @7 H ]& |: \. |1 j
evaluated for serum testosterone levels and hypothalamic
3 I3 C. _2 I. E: ]7 |1 J4 Sfunction. Of these 5 boys 2 were considered to have Kallmann's
1 H3 h2 G. [; X( p" K" @syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-6 X% H( D8 C; k& }! Q/ ^+ G
lamic deficiency. After evaluation of response to luteinizing+ {5 l3 F! |( k, H- B! g
hormone-releasing hormone these patients were treated with
' O$ x* p% Q) S _" r; g+ Y( ?+ @0 m& f# ~1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! b# b# m6 D1 g- n4 V; v7 jafter completion of gonadotropin therapy 10 per cent topical
6 A. K: h A8 S9 _4 {testosterone was applied to the phallus twice daily for 3 weeks.0 M$ N# S2 J" M6 w
Serum testosterone, luteinizing hormone and follicle-stimulat-
( \% [$ @5 d, k! c5 i5 D2 Ving hormone were monitored before, during and after comple-6 H$ G% y$ g; a Z# d3 u
tion of each phase of therapy. Penile stretch length was+ @9 z7 i: ]9 F4 B/ a
obtained by measuring from the symphysis pubis to the tip of6 a3 J5 n1 z9 ^" ^9 ?' q" k7 B7 n1 R
the glans. Penile circumferential (girth) measurements were
! I$ [9 [3 v$ } c+ uobtained using an orthopedic digital measuring device (see/ e% m* f) Z- x& {0 U6 S9 r/ @7 g6 Q
figure).
5 i' A$ x0 S2 A2 `2 ?3 uRESULTS
3 s; r3 n: `! L; ]& N- f1 bSerum testosterone increased moderately to levels between! @3 L2 ?7 f# }6 X* m* `- G
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
. }& A. v& _0 ~terone levels with topical testosterone remained near pre-( m1 U# P I- o$ G
treatment levels (35 ng./dl.) or were elevated to similar levels
' G- z) i2 X! q0 e. u* wdeveloped after gonadotropin therapy (96 ng./dl.). Higher
: c$ Z' y4 Y: s% S6 L* bserum levels were noted in older patients (12 and 17 years old),- o" ^8 `) e( r- S5 r2 l
while lower levels persisted in younger patients (4, 8, and 10
% c# m6 r' Q) ]& L% U* |years old) (see table). Despite absence of profound alterations
$ Y+ R8 }5 k; d% F$ t+ p% ]of serum testosterone the topical therapy provided a greater
( b, q" H- l, I4 o" }( |Accepted for publication July 1, 1977. ·; s. q6 P& H" b% f7 A/ Q( z6 z" `
Read at annual meeting of American Urological Association," w4 j; p; d! F- G/ |
Chicago, Illinois, April 24-28, 1977.! x; k% G" r0 g% i
* Requests for reprints: Division of Urology, Henry Ford Hospital,
% l3 w5 P: S5 U8 K4 _2 e+ r2799 W. Grand Blvd., Detroit, Michigan 48202.6 o9 g& h6 c8 G
improvement in phallic growth compared to gonadotropin.( N# x% q, B7 `
Average phallic growth with gonadotropin was 14.3 per cent
; R' B& C2 H8 l6 ~/ n0 {increase in length and 5.0 per cent increase of girth. Topical
% R& x, \" h! ~; J0 Ktestosterone produced a 60.0 per cent increase of phallic length/ H, d' {9 [9 J I+ p0 A
and 52.9 per cent increase of girth (circumference). The! T I, L' W4 O, W" W3 s, }
response to topical testosterone was greatest in children be-4 u, l; Z2 f% H' Z
tween 4 and 8 years old, with a gradual decrease to age 17) A7 s8 P) a, m% `- i1 M
years (see table).
8 x: T: o* \ i3 v0 G! {7 h! m; Z8 rDISCUSSION4 I% O- U; `4 V$ z6 E
Topical testosterone has been used effectively by other9 e. p" T3 s* k' K
clinicians but its mode of action remains controversial. Im-
2 K0 I7 ?' I/ W/ m# dmergut and associates reported an excellent growth response
( s! y* d3 _. q! e: K2 ]3 H! v2 X4 Cto topical testosterone with low levels of serum testosterone,
* _* t3 A; S; G" rsuggesting a local effect.1 Others have obtained growth re-
, Q6 K" g5 q! Wsponse with high. levels of serum testosterone after topical# n# e+ y& o7 Y& l0 `+ [; k! }
administration, suggesting a systemic response. 3 The use of5 l! f* g, ?: K8 F' ~& A! }0 |
gonadotropin to obtain levels of serum testosterone compara-
7 x+ n- t9 X3 M$ O" K+ Able to levels obtained with topical testosterone would seem to
3 z& i* @ G+ |0 W4 j5 B4 `" jprovide a means to compare the relative effectiveness of
, `' h3 w8 w% m6 A( ktopical testosterone to systemic testosterone effect. It cer-2 t. C K# h `$ T" y( T
tainly has been established that gonadotropin as well as par-5 c8 k$ J% t0 w2 G7 A
enteral testosterone administration will produce genital' t* s6 I& q+ V( s9 p
growth. Our report shows that the growth of the phallus was$ c3 X; B$ b1 M' f! x- I
significantly greater with topical applications than with go-; U! y9 m" q3 K
nadotropin, particularly in children less than 10 years old.; h) l- W: v! Z6 B
The levels of serum testosterone remained similar or lower
" G9 r2 ?( n6 V4 n$ ]than with gonadotropin during therapy, suggesting that topi-2 f1 c9 u+ T$ H" E
cal application produces genital growth by its local effect as
1 f( L- d9 _1 A" O- w. rwell as its systemic effect.6 [, Y7 E% ~. }; L1 ?
Review of our patients and their growth response related to
: {# U. G) n- }5 {3 K5 Kage shows a greater growth response at an earlier age. This is, v: t$ p( i0 L0 B* i
consistent with the findings of Wilson and Walker, who# Z6 }2 u0 [. V: h
reported an increased conversion of testosterone to dihydrotes-
: |- G! t+ g! }( O. mtosterone in the foreskin of neonates and infants.4 This activ-2 }. \$ S! u# ^% t& p
ity gradually decreases with age until puberty when it ap-
4 { V' j& d& R$ y3 a4 ^proaches the same level of activity as peripheral skin. It may
' m' D2 @' P9 F5 y1 ?3 M7 [0 k; Mwell be that absorption of testosterone is less when applied at
- C# n8 w# z: ~; ]- ` e" z: E) _an earlier age as suggested by lower serum levels in children
# X9 V% [ e4 O: U" x( x: Eless than 10 years old. This fact may be explained by the
; _! f9 k" p" O# I1 ]greater ability of phallic skin to convert testosterone to dihy-
. [6 \- V& a, A3 y0 V: T7 Kdrotestosterone at this age. Conversely, serum levels in older. r) X0 Z8 J- b% S$ d% [
patients were higher, possibly because of decreased local7 ]8 G/ K5 B' W- j+ q2 @* `
667
% x) b) ]4 e2 A. V668 KLUGO AND CERNY5 ]' V/ ~" q# S' g# m
Pt. Age! i& U& p) [8 s5 ]
(yrs.)
2 w+ Z* E& ^7 n. p5 d$ hSerum Testosterone Phallus (cm.) Change Length
7 b& C. Y7 H( C# K, D" V3 I(ng./dl.) Girth x Length (%)
# v* s2 ^ S% P# U4
% h7 j! ]( R- R& J/ H+ ~+ N8) A: D" o; g v, H+ Y' U
10, I% N6 M" t( _* @
12& E2 _5 f" `1 P. A, A h/ v0 c8 ?
17
( D, q) N) N: q3 X) R3 ?Gonadotropin
8 E: w! E9 C, F71.6 2.0 X 3 16.6/ E3 R, g& [4 X( J/ A
50.4 4.0 X 5.0 20.0
: A/ f1 v& h* H, W! C! T2 v22.0 4.5 X 4.0 25.0/ i$ ?; T) T, v
84.6 4.0 X 4.5 11.1
+ c0 {, [. G1 r" [5 g+ ~85.9 4.5 X 5.5 9.0
) u: x' A$ s9 C& d4 b! o; G) a$ ]Av. 14.37 N8 }" v" K4 n2 T! j! A# l
4# I% o$ ?+ B% R
8
9 j$ P& h& ~3 Y0 n' O7 H. {% e105 l* f% x5 W& n7 B
120 E. y: c L O& c8 I
17( d0 a, I- ~9 T) P" r, J
Topical testosterone
% D. \" X4 M+ f5 n34.6 4.5 X 6.5 85
5 o, C, s& U% s0 o38.8 6.0 X 8.5 70% b6 q" k o. j' ~0 H4 g9 C: S/ f2 _
40.0 6.0 X 6.5 62.5+ |6 f; U0 O# u7 u) a4 _1 ]
93.6 6.0 X 7.0 55.5
7 }7 H+ {" P, S8 Q9 W95.0 6.5 X 7.0 27.28 A7 v- X" s4 m$ C) N
Av. 60.0
/ M' C4 N0 {3 Y* s" i0 D( aavailable testosterone. Again, emphasis should be placed on S6 h5 p* ]0 K2 V$ J! F! [8 _! Q
early therapy when lower levels of testosterone appear to3 O+ C" `3 o" V: P% |+ A2 K
provide the best responses. The earlier therapy is instituted# J: D, E) [( U
the more likely there will be an excellent response with low) _: a& R" ]/ Z z: X. @6 _" e
serum levels. Response occurs throughout adolescence as& r$ q4 j0 _% Q: ^! V, a: e
noted in nomograms of phallic growth. 7 The actual response2 U# H9 z" o! B t; @1 i! B4 f
to a given serum level of testosterone is much greater at birth
; E% `5 _4 c0 v& r, @and gradually decreases as boys reach puberty. This is most
! n' G2 X2 Y; f6 jlikely related to the conversion of testosterone to dihydrotes-
( q- m1 U+ t$ B7 stosterone and correlates well with the studies of testosterone
- J) R; w1 C- q+ s: I7 f" E" jconversion in foreskin at various ages.7 i, t2 o n. Z! c/ J" ?4 `$ u
The question arises regarding early treatment as to whether( w' r! c. ]3 X2 L% s
one might sacrifice ultimate potential growth as with acceler-
0 y2 m. x8 Z. [7 Fated bone growth. The situation appears quite the reverse
& ]7 S' x5 Y6 {+ Y' e& f! [3 Kwith phallic response. If the early growth period is not used
9 R' n- T" c) E/ i5 g& X3 @when 5a reductase activity is greatest then potential growth
- F& R2 _/ X' \5 X- H( Kmay be lost. We have not observed any regression of growth
7 J, j! W3 |7 l( ^2 @! z: }/ J9 [* v6 Qattained with topical or gonadotropin therapy. It may well1 \4 V8 J; N2 a
be that some patients will show little or no response to any1 B# p" l* E- p: L3 s3 v: u
form of therapy. This would suggest a defect in the ability to
1 H7 b9 v# n0 \& t/ G+ ?convert testosterone to dihydrotestosterone and indicate that# ]" k: n: @& b: f6 Y
phallic and peripheral skin, and subcutaneous tissue should# D7 T: V: ~7 n- o# E
be compared for 5a reductase activity.- a A5 U; u7 k o
A, loop enlarges to measure penile girth in millimeters. B,9 I9 {( T+ {; {- |
example of penile girth computed easily and accurately." Q$ {( O. g' e8 E, {( R) w
conversion of testosterone to dihydrotestosterone. It is in this) V9 c% G; ?2 M( M/ _
older group that others have noted high levels of serum) O* G8 j6 I8 {: c- J
testosterone with topical application. It would also appear
- p X) E* g9 P4 n0 W: K! `that phallic response during puberty is related directly to the
* c( c* C2 }( M4 F; zserum testosterone level. There also is other evidence of local
0 U/ @1 \& T! t- r& I7 Presponse to testosterone with hair growth and with spermato-3 R* r) K. Z8 i
genesis. 5• 62 w7 F0 n7 W( G0 Q5 m- k# Z5 ?" N
Administration of larger doses of gonadotropin or systemic
% Q. v( g" G! Y3 a( ]3 U* Stestosterone, as well as topical applications that produce
' K3 O: L) q4 ^2 V- Ehigher levels of serum testosterone (150 to 900 ng./dl.), will! p2 i6 y8 R" q
also produce phallic growth but risks accelerated skeletal" t) N# B4 c& O% X* S7 M% l
maturation even after stopping treatment. It would appear
) ^3 d' N% P0 @( \( C& A/ z2 |that this may be avoided by topical applications of testosterone
+ p2 E: H q5 land monitoring of serum testosterone. Even with this control
; ~9 M) e. u' J* k. zthe duration of our therapy did not exceed 3 weeks at any
9 g6 }. K& [: y8 c8 D& q6 Btime. It is apparent that the prepuberal male subject may' q( s7 q: b6 z3 e0 s. \7 }5 P
suffer accelerated bone growth with testosterone levels near
6 _4 x" L+ Z. @1 a3 H3 _( e200 ng./dl. When skeletal maturation is complete the level of
1 ^$ F1 r- T& A, S8 h6 Q! a) @9 N8 ^serum testosterone can be maintained in the 700 to 1,300 ng./, M( P% Y5 ^* n7 z7 W$ e6 n
dl. range to stimulate phallic growth and secondary sexual
3 M5 _5 Z) H% `changes. Therefore, after skeletal maturation parenteral tes-
: ]4 E* ]& k) G3 a* {tosterone may be used to advantage. Before skeletal matura-
# N. W" G' Q, ]! V/ Stion care must be taken to avoid maintaining levels of serum
9 I$ w2 i5 x0 {: m7 Btestosterone more than 100 ng./dl. Low-dose gonadotropin
+ j* V( ?( ^6 C5 l. e3 r8 c0 Hdepends upon intrinsic testicular activity and may require& B1 J. e8 W# P+ W9 Z# j( L
prolonged administration for any response.: F! [* s9 y8 K
Alternately, topical testosterone does not depend upon tes-9 g A( F2 ]7 f- _: N/ X
ticular function and may provide a more constant level of5 q2 f+ @0 s0 T9 j$ R/ Y
REFERENCES
$ y( o9 J' {# p' c# {$ W1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,5 L/ s$ m1 ?/ ?5 n M
R.: The local application of testosterone cream to the prepub-
) E# i* s, T6 y* \ertal phallus. J. Urol., 105: 905, 1971.
& t6 r* y! f! {4 t2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
- \; g0 u$ x& N8 U5 n& dtreatment for micropenis during early childhood. J. Pediat.,
, g7 g% M9 O! _: E) H8 D2 y( |4 F83: 247, 1973.
& _. ~7 _- \+ d0 l$ o3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 [* |- s( n) _" |2 L8 C! j) E z
one therapy for penile growth. Urology, 6: 708, 1975.
8 J* t7 J& _% w) e4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& a4 j2 C$ R* h( H- z& {
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by) ^, }* w1 N3 \( i$ Z. n) z n
skin slices of man. J. Clin. Invest., 48: 371, 1969.
' X/ ~! w) i4 M; P& A5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 L) d2 r* b) y' e0 oby topical application of androgens. J.A.M.A., 191: 521, 1965.) }' z, d+ o k
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 h6 b' [5 ^% d# e% @. mandrogenic effect of interstitial cell tumor of the testis. J. s6 X8 S$ ~+ C
Urol., 104: 774, 1970.
8 `$ O5 f$ d5 y' `* \9 N7 f' m7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; I, P4 f9 r/ I$ ]) B. R& o/ ~tion in the male genitalia from birth to maturity. J. Urol., 48: |
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