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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# _5 `1 I! z5 b z& ?) r5 ^
GONADOTROPIN$ G5 d! ^ Y( u- h7 T
RICHARD C. KLUGO* AND JOSEPH C. CERNY( z3 F$ e& _- h$ d4 A
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
3 Z+ H5 m; a" O! Q! `ABSTRACT
4 G; u; ~' S* n0 Q! [7 z" ?Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( E6 y( U* b! F; owith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
6 ]% O6 z n. Y0 H: Ltropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
" r$ D, P$ R7 @* `9 A8 w: V& ~cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; @* Q( t9 {/ s, zfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 b/ g( c4 C) o( f& y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
7 e! S2 d% T: H- x+ iincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ v* P! E2 }: R( I& g: J5 a
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
9 s/ \$ S3 f# ]6 {& S( h& Astudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile9 l1 T( P% l1 F5 x7 r. n$ |- V/ `. }
growth. The response appears to be greater in younger children, which is consistent with previ-+ ~& L% j9 k' ?. S: }9 ?
ously published studies of age-related 5 reductase activity." F' l Q1 q Y8 l: R2 P J3 J
Children with microphallus regardless of its etiology will4 D/ x, z# |0 u& ~$ [9 k! |
require augmentation or consideration for alteration of exter-
4 {# q( M# I; I+ hnal genitalia. In many instances urethroplasty for hypo-
9 u8 C9 T) [6 U, i/ w9 ospadias is easier with previous stimulation of phallic growth.
; ?: m7 o" B$ z- E YThe use of testosterone administered parenterally or topically
/ b0 U0 P* X! }* lhas produced effective phallic growth. 1- 3 The mechanism of
3 G4 j3 k% \- |, Oresponse has been considered as local or systemic. With this
/ a2 _0 @$ u3 M7 \in mind we studied 5 children with microphallus for response( l6 ~% j9 v; A+ H
to gonadotropin and to topical testosterone independently. Y; R) `! e Z3 d
MATERIALS AND METHODS8 t4 i$ n: W. v9 w- W" T- s
Five 46 XY male subjects between 3 and 17 years old were
/ D2 g7 Z* W' g3 p$ C3 C+ }1 x. Yevaluated for serum testosterone levels and hypothalamic2 ]/ B$ ?0 B& U+ m( T! ~2 ?2 B
function. Of these 5 boys 2 were considered to have Kallmann's; f/ h# E% a4 N8 z9 ]1 x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ A0 H. g8 Z8 J3 d2 E: j, G
lamic deficiency. After evaluation of response to luteinizing1 [% F2 O, U9 a n) J4 w3 h8 T' E
hormone-releasing hormone these patients were treated with. P! {0 c2 W( q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
( @6 e7 w7 i7 z9 ~$ \( nafter completion of gonadotropin therapy 10 per cent topical
3 l! D4 ?4 h. g* ? U9 ~testosterone was applied to the phallus twice daily for 3 weeks.1 r3 {: Z0 G9 J* W4 r2 T- f
Serum testosterone, luteinizing hormone and follicle-stimulat-& q; e0 k2 X# E
ing hormone were monitored before, during and after comple-) J+ O+ I1 A2 A( q) k7 t# n1 I
tion of each phase of therapy. Penile stretch length was* S/ r7 x+ w/ @' \' G
obtained by measuring from the symphysis pubis to the tip of' M* }8 R% ^& y4 l6 }$ n0 G' d
the glans. Penile circumferential (girth) measurements were- u- K! b( V+ Z
obtained using an orthopedic digital measuring device (see
* a' k* c- p) `figure).
+ c$ a. {* N+ y3 z p4 `- HRESULTS7 a# {9 R" o# k/ z- V, y: n
Serum testosterone increased moderately to levels between k, J0 F& a: b8 P+ J4 b" E
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
! w; E; U# l3 j l& ^1 }terone levels with topical testosterone remained near pre-/ A- a& T# P/ K+ v8 \; A( w- X6 Z( W
treatment levels (35 ng./dl.) or were elevated to similar levels! K' e4 k% Z& Q, l
developed after gonadotropin therapy (96 ng./dl.). Higher) L. c: [- h' l4 `8 Y. t0 j, s% z
serum levels were noted in older patients (12 and 17 years old),* ~0 h( _2 u* j; h
while lower levels persisted in younger patients (4, 8, and 10
) ^. [* T. q) T, T, f8 l G5 m8 @years old) (see table). Despite absence of profound alterations6 h) R0 X8 a" o, A) q' b; U7 }
of serum testosterone the topical therapy provided a greater
8 N0 L- [8 Z. |& z; G/ |Accepted for publication July 1, 1977. ·
g: w* S7 ]% @Read at annual meeting of American Urological Association,) p% U: t3 C- u! A j2 j' L5 T5 }
Chicago, Illinois, April 24-28, 1977.6 O7 Z8 l$ s* R5 C
* Requests for reprints: Division of Urology, Henry Ford Hospital,
Y% y' E6 N U0 W/ r2799 W. Grand Blvd., Detroit, Michigan 48202.3 I" H3 z0 G4 x# g1 B/ A# R1 s
improvement in phallic growth compared to gonadotropin.
% b+ s+ j ?" J. m1 M, F7 k( ZAverage phallic growth with gonadotropin was 14.3 per cent
; D5 H, ^0 {9 X0 K5 O+ ^- Xincrease in length and 5.0 per cent increase of girth. Topical2 g' E- u3 I$ s D4 W, h; E; h/ M
testosterone produced a 60.0 per cent increase of phallic length
H2 z" |& d% B% M0 fand 52.9 per cent increase of girth (circumference). The( F- d) |- R& D! ]
response to topical testosterone was greatest in children be-9 ]5 ^0 g# r% Z1 o/ d
tween 4 and 8 years old, with a gradual decrease to age 17
$ Y$ X, K' @: g5 M& eyears (see table).+ C7 J+ }9 s+ M8 x
DISCUSSION( g5 J9 h0 C# `, [$ x h \& X
Topical testosterone has been used effectively by other) N z/ [/ T9 i! \7 m) [3 A
clinicians but its mode of action remains controversial. Im-
) }, g, \0 |: a; }$ R( [mergut and associates reported an excellent growth response
9 y0 F: Q0 H! y$ J$ L, y, Tto topical testosterone with low levels of serum testosterone,
" o/ `3 \ t: hsuggesting a local effect.1 Others have obtained growth re-
& c2 S) _/ [& Z/ S$ ]* |6 _6 F4 g3 }sponse with high. levels of serum testosterone after topical
% [0 f: k3 O; Z- t; q" U6 u0 Cadministration, suggesting a systemic response. 3 The use of( R5 q" Z7 G% A0 t# |1 t
gonadotropin to obtain levels of serum testosterone compara-
+ X t7 q) s w' y5 p! b3 H' V2 qble to levels obtained with topical testosterone would seem to
9 Z1 h1 @2 H" F6 Eprovide a means to compare the relative effectiveness of6 [. {; g: N ]% I0 J O
topical testosterone to systemic testosterone effect. It cer-
/ P( x$ k8 P# X3 K6 m8 X8 y5 [tainly has been established that gonadotropin as well as par- @3 g/ d7 [0 Z
enteral testosterone administration will produce genital
1 K. b6 C& T: J+ u1 ugrowth. Our report shows that the growth of the phallus was
; g- Y: p R" M, W( J! G0 O6 l( Tsignificantly greater with topical applications than with go-
2 `) t, m& v6 {0 H1 S1 Y' I" M9 Lnadotropin, particularly in children less than 10 years old.
8 a, \# u9 h: ]! ?- ?4 N* mThe levels of serum testosterone remained similar or lower; F7 ]' U1 y, F Q# z: m
than with gonadotropin during therapy, suggesting that topi- N$ _; b: i) @6 J7 w$ [
cal application produces genital growth by its local effect as: o( H; E5 e6 {8 W% {! n% S" e
well as its systemic effect.
6 @% @# T- ?9 hReview of our patients and their growth response related to
$ k0 o% a$ I& r3 `. Zage shows a greater growth response at an earlier age. This is
2 D( t4 |2 i# U& x; K+ Uconsistent with the findings of Wilson and Walker, who. A# L. z X8 C! P. f% Q) t
reported an increased conversion of testosterone to dihydrotes-+ L9 p! @8 c# \/ \& d
tosterone in the foreskin of neonates and infants.4 This activ-
4 Z5 |; C+ K m2 x6 Lity gradually decreases with age until puberty when it ap-
3 g3 y6 ?5 q+ p9 B* x; P$ F; Cproaches the same level of activity as peripheral skin. It may
- U; x; |- a9 M4 z' N3 O2 \2 s) F/ `! Zwell be that absorption of testosterone is less when applied at
x5 W/ X7 ^; G8 b3 `( W6 Uan earlier age as suggested by lower serum levels in children' I- U5 |% U. O' V
less than 10 years old. This fact may be explained by the; M8 D1 P6 C9 |, c
greater ability of phallic skin to convert testosterone to dihy-
7 W) z& Y* ^% f" n n" Vdrotestosterone at this age. Conversely, serum levels in older
# e o: r/ g. q7 f& O3 u3 X4 }patients were higher, possibly because of decreased local' E6 V+ L C9 S+ j
667% p5 y* }' k8 G% M6 H
668 KLUGO AND CERNY
2 N* M4 w9 [8 CPt. Age$ S3 }6 Y, I" U x# m- j" P
(yrs.)$ B) R4 B" T( C. y' y2 _& b3 B
Serum Testosterone Phallus (cm.) Change Length
( P( L; B1 k& X: E( p. P+ }1 @(ng./dl.) Girth x Length (%)/ r( A+ K2 S9 \* V+ Y
4
# g; u) M0 s3 [- K" R84 b$ ^% R* R7 }5 Z% U7 c
10
7 f4 @0 ?; p9 |' H12
+ s5 d2 Z. o. D17
t0 X5 G* O9 W4 C. dGonadotropin0 t! i1 K- h+ o2 j/ c0 `8 r
71.6 2.0 X 3 16.65 K" A/ _/ Y3 }" ~" {# |
50.4 4.0 X 5.0 20.0
5 M+ I. ]/ k3 q( A22.0 4.5 X 4.0 25.0& |8 T! J5 y+ |5 P P7 o7 l) t
84.6 4.0 X 4.5 11.1
; K, c+ s' h" K4 J1 k( [85.9 4.5 X 5.5 9.0" Z+ [2 Z5 _8 n9 i$ K% U+ y
Av. 14.3
3 z: w$ S7 W/ T! k9 ^( w; m49 [. p. v* D+ b! K, s1 B
8
% v4 o$ a0 S1 `& R0 K' ^10
: ~* R; B! n: L; l) S12
6 e' i8 `( ]: E( v3 u2 S- K17. h, Y' T$ o% N& W' l
Topical testosterone
7 Q \+ \7 J7 U9 D$ |34.6 4.5 X 6.5 85/ K& J$ H* o- v
38.8 6.0 X 8.5 70# G9 G9 M j) P: f, C: g. J; [
40.0 6.0 X 6.5 62.5- T( o3 ^& ^0 X) w O
93.6 6.0 X 7.0 55.5* k! b3 S, C" T, [
95.0 6.5 X 7.0 27.2
7 W# h8 W6 H& F) _Av. 60.0" z5 z1 }2 C( i4 w5 e& A
available testosterone. Again, emphasis should be placed on
7 X) g: M; r: x1 e. rearly therapy when lower levels of testosterone appear to
~5 ~' T' F2 F8 _! i9 Vprovide the best responses. The earlier therapy is instituted
4 m2 ^% K- M$ x$ W& a1 @the more likely there will be an excellent response with low
' Y7 e* y1 i- dserum levels. Response occurs throughout adolescence as2 y: U2 ?3 @$ e4 t7 F$ z: A
noted in nomograms of phallic growth. 7 The actual response
5 n1 c g& Z+ ^) sto a given serum level of testosterone is much greater at birth
& m" [4 k( R& _. Eand gradually decreases as boys reach puberty. This is most: @ ]: A% m4 G. T6 S
likely related to the conversion of testosterone to dihydrotes-/ \; p0 Y: l9 b" M$ p* W
tosterone and correlates well with the studies of testosterone
, K* u* D, E1 @. z uconversion in foreskin at various ages.# a1 X" K. X* \& K `
The question arises regarding early treatment as to whether- d/ ~$ y3 a1 i+ Y+ j
one might sacrifice ultimate potential growth as with acceler-* o8 `% [2 H: f! M
ated bone growth. The situation appears quite the reverse
6 |4 g' N7 z8 N7 u/ Bwith phallic response. If the early growth period is not used
1 N% W2 y8 n- a+ m8 c- S# y9 `) jwhen 5a reductase activity is greatest then potential growth4 w% w$ h$ U* |# |% _ Y
may be lost. We have not observed any regression of growth9 t, i8 h# G0 E1 T
attained with topical or gonadotropin therapy. It may well
) @" ?. U2 T9 x: Obe that some patients will show little or no response to any x1 }$ l0 T% Q0 [; a" B( w6 @
form of therapy. This would suggest a defect in the ability to& M; f) S5 o y% n5 T
convert testosterone to dihydrotestosterone and indicate that' s( n! y7 b( `5 v
phallic and peripheral skin, and subcutaneous tissue should x* h; Y# H$ R5 E1 S
be compared for 5a reductase activity.
/ _* F* ~4 e1 _( |; nA, loop enlarges to measure penile girth in millimeters. B,
! @& x$ s; ~, ]- L9 O$ b: H3 xexample of penile girth computed easily and accurately.: U6 t2 ?, j: ]- X
conversion of testosterone to dihydrotestosterone. It is in this" q' b e& |2 ?# l' Y: O' X: E) b
older group that others have noted high levels of serum
5 w6 P( }& j) p9 R; B. _testosterone with topical application. It would also appear1 v% Z' K* w' ^. }7 z
that phallic response during puberty is related directly to the
$ }( P5 R) B2 s @6 M4 ^: B! Qserum testosterone level. There also is other evidence of local
# ]2 `$ l/ p/ z% S+ |: Fresponse to testosterone with hair growth and with spermato-
5 ?( \; @# p4 m/ H' f, c+ ]' k( sgenesis. 5• 6/ |- q9 c/ }! e/ k7 E( H& R: h
Administration of larger doses of gonadotropin or systemic
, o) ]$ X2 d6 V$ v; t* Qtestosterone, as well as topical applications that produce
' X+ o2 a3 N" L" ~1 A% `higher levels of serum testosterone (150 to 900 ng./dl.), will
7 D! ]* u2 \% P0 Q9 _also produce phallic growth but risks accelerated skeletal0 A3 J3 v; s; P: a" A: A
maturation even after stopping treatment. It would appear
( u# E) Q1 J7 fthat this may be avoided by topical applications of testosterone! ^% G4 r! r% A, J
and monitoring of serum testosterone. Even with this control
/ J; ~) K; d) _ e% {8 p2 Mthe duration of our therapy did not exceed 3 weeks at any
, t1 D* a) M$ utime. It is apparent that the prepuberal male subject may' }9 i+ |' C) b
suffer accelerated bone growth with testosterone levels near
+ m0 P. n- n1 }200 ng./dl. When skeletal maturation is complete the level of$ _8 A( M# F, O, U* I% v( Y: C r
serum testosterone can be maintained in the 700 to 1,300 ng./
! R$ w u! K* K, cdl. range to stimulate phallic growth and secondary sexual" l" `% Y) X Q8 H0 g4 D2 Z
changes. Therefore, after skeletal maturation parenteral tes-$ T" w; Z6 b: Z6 R
tosterone may be used to advantage. Before skeletal matura-
3 m% Q6 f0 Q6 }5 f/ }% c0 _9 Ction care must be taken to avoid maintaining levels of serum% \$ q( _3 ]) ]4 K7 R% t' j% D
testosterone more than 100 ng./dl. Low-dose gonadotropin9 K1 \2 p! y# G9 q+ y" I
depends upon intrinsic testicular activity and may require
: [! e) j; ~) d0 U) T; hprolonged administration for any response.
! O7 P" m8 s9 MAlternately, topical testosterone does not depend upon tes-& Z" E3 w- u' [" O
ticular function and may provide a more constant level of, E9 x) Y `- D) u6 L. Z3 C! D" d) B
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: {/ G! y; _+ E( T( G1 f! H1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; o3 b3 P ^9 N0 C6 K5 U" G4 [1 H, H
R.: The local application of testosterone cream to the prepub-" n9 O, Q; @9 V2 Q+ V) I
ertal phallus. J. Urol., 105: 905, 1971.( V0 @* X& R7 A3 S
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 W2 Y/ f: G5 @- P# t% Z. F) _
treatment for micropenis during early childhood. J. Pediat.,: f' S- X* T+ E$ ~
83: 247, 1973.# ^) Z( X) u% j, Q$ Q7 R+ |
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-: F) [, {8 ]7 M; k
one therapy for penile growth. Urology, 6: 708, 1975.% Z" a8 d# ~ s( }3 J# |, I4 v% h
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
4 Y3 n6 O/ h" d% o, [2 o7 |% Sto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* d4 Q* @( k$ B7 L- askin slices of man. J. Clin. Invest., 48: 371, 1969.
: K: N8 A" y: }: l1 \5 [* d5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- ~1 \9 W( @) E; A* J3 j( w7 Bby topical application of androgens. J.A.M.A., 191: 521, 1965.3 W+ c7 |+ B$ ^3 x$ O& D/ w" i
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. s, r7 Y9 v/ @( w; Q" m% U: V( ~7 iandrogenic effect of interstitial cell tumor of the testis. J.7 A, ?# V& X: |/ A/ t2 Q
Urol., 104: 774, 1970.
$ g+ g6 y2 F# u, [7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( l' ?. a/ X$ l s$ L8 G* C
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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