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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND7 X2 Z3 H# X6 r+ E: v3 w9 g6 {) Q3 j
GONADOTROPIN
8 e [7 Q6 [, W5 G/ `. u3 `8 X! q7 FRICHARD C. KLUGO* AND JOSEPH C. CERNY
6 j0 }* ~9 L- i/ Q9 o7 i& N& p2 R; EFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' W& `+ p! f! c/ I tABSTRACT& ~4 p& K. x* P" G3 u* i
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
! i2 b1 G# Z4 B( `with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 U8 T( G y1 u' V6 u" c; rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 Q) T; i: E8 t- Z
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( n* ?; ~: g6 }0 `# [& afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 c. N. V3 D* `3 O
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 m* f2 d1 v' I! z( Y H! D. h2 R
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
* q; B0 S4 b4 L0 Noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 l& @$ U. M8 B U! R0 ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* s4 d" | O# ^ igrowth. The response appears to be greater in younger children, which is consistent with previ-" A) ~* p/ ~5 }9 ~
ously published studies of age-related 5 reductase activity.1 J8 n0 T3 s, Q# M
Children with microphallus regardless of its etiology will1 n$ R8 o$ ~8 a) ]7 U0 v3 m/ J
require augmentation or consideration for alteration of exter-
2 p1 A6 f$ P8 |' f' e, o+ ]" }nal genitalia. In many instances urethroplasty for hypo-
8 g, F! d9 S% Q( Hspadias is easier with previous stimulation of phallic growth.3 F. q3 ^; t" q
The use of testosterone administered parenterally or topically1 Q6 P/ o7 |; y% e0 S( _
has produced effective phallic growth. 1- 3 The mechanism of
' ?& u3 |* Q& v! O0 C |1 Tresponse has been considered as local or systemic. With this
1 c2 D }, T1 Q" J# D g# ein mind we studied 5 children with microphallus for response1 ~6 p4 E' q: F
to gonadotropin and to topical testosterone independently.) L5 C" g: i. ^! y/ V$ k# u
MATERIALS AND METHODS0 ~5 X& Z* z r; }9 G
Five 46 XY male subjects between 3 and 17 years old were( T* u/ p5 y7 u- @
evaluated for serum testosterone levels and hypothalamic: p* h5 v1 W4 U+ A6 q
function. Of these 5 boys 2 were considered to have Kallmann's
! x9 d3 C4 |( `3 v. K1 usyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 d: ~! ]( s/ I* X% Y
lamic deficiency. After evaluation of response to luteinizing
* v: ?) |8 G4 j7 z/ b" [hormone-releasing hormone these patients were treated with2 j/ {: q% N/ }& T
1,000 units of gonadotropin weekly for 3 weeks. Six weeks# Q. G2 r8 n9 a* m/ r+ ]
after completion of gonadotropin therapy 10 per cent topical
- |7 C, z1 R* Dtestosterone was applied to the phallus twice daily for 3 weeks.
% U6 `0 x# r- S, m; }7 {; f9 YSerum testosterone, luteinizing hormone and follicle-stimulat-) M# q$ T1 f$ x# o" w% b, ]* {
ing hormone were monitored before, during and after comple-0 k7 Q4 P1 m& K$ B( f- {
tion of each phase of therapy. Penile stretch length was
7 w! T) K r S- g0 V# ]obtained by measuring from the symphysis pubis to the tip of3 F6 [0 P, ?; y) m& i+ ?4 D7 t
the glans. Penile circumferential (girth) measurements were( {" _: @8 @2 Y6 O# q) O
obtained using an orthopedic digital measuring device (see
. C" V/ S4 ~8 E9 t% P' ffigure).2 f% S( ? Z3 g: h
RESULTS
6 } u0 }8 U' C$ K: ]) iSerum testosterone increased moderately to levels between/ r) C" ~+ Z( S8 E: U
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-2 b, o# Z/ {9 R h) L
terone levels with topical testosterone remained near pre-3 t7 \% _- \; ~5 D5 c) p7 K) J* N
treatment levels (35 ng./dl.) or were elevated to similar levels' L- S# j0 \+ D0 q5 k. ]
developed after gonadotropin therapy (96 ng./dl.). Higher
1 m- q. E8 j1 q# Zserum levels were noted in older patients (12 and 17 years old),
7 q2 g" u8 y# q- c2 ywhile lower levels persisted in younger patients (4, 8, and 10, R9 b* H, e4 D8 K* Y
years old) (see table). Despite absence of profound alterations7 L8 P% P; D$ F- S& W5 I* |
of serum testosterone the topical therapy provided a greater
# d" r* c) Y0 ZAccepted for publication July 1, 1977. ·
! a% W5 |7 \3 P$ d- G+ y% \Read at annual meeting of American Urological Association,
! T ~- x* }4 fChicago, Illinois, April 24-28, 1977.
- }+ l8 L; u( f5 M; ]: h* Requests for reprints: Division of Urology, Henry Ford Hospital,
J2 R) k, E- O4 }2799 W. Grand Blvd., Detroit, Michigan 48202./ H9 d% a1 O. p: ~
improvement in phallic growth compared to gonadotropin.
! k+ e2 n/ r! R) l) PAverage phallic growth with gonadotropin was 14.3 per cent9 l, {/ a( N7 J) u
increase in length and 5.0 per cent increase of girth. Topical
6 `. x: y$ N/ Z C2 stestosterone produced a 60.0 per cent increase of phallic length: b+ W$ f" y5 x- ~5 _2 x" `
and 52.9 per cent increase of girth (circumference). The, b' j0 I" F. J
response to topical testosterone was greatest in children be-
% X$ Q% E. v D& itween 4 and 8 years old, with a gradual decrease to age 17
4 j& {. M( `5 { o6 H& W) O3 yyears (see table).* A* J5 N$ Y. U3 C( K: f- A1 v; K
DISCUSSION) o' j0 }' I7 e. V' H4 `1 K
Topical testosterone has been used effectively by other: a ^& S0 x" t& e! Q% ^0 P
clinicians but its mode of action remains controversial. Im-* @1 A0 T4 Y8 Y R, {, D
mergut and associates reported an excellent growth response% q. b$ h6 [# X# \7 \5 K
to topical testosterone with low levels of serum testosterone,
) g! @( Q7 B2 p) L. Isuggesting a local effect.1 Others have obtained growth re-
7 a# _( @ J3 {+ t( o! \sponse with high. levels of serum testosterone after topical. T% Y5 s$ A# f
administration, suggesting a systemic response. 3 The use of8 r) \ l$ ^8 c" h7 ^
gonadotropin to obtain levels of serum testosterone compara-
/ g0 A) w/ q5 D+ p' ]# @ble to levels obtained with topical testosterone would seem to
, ]: E* t! v R: Bprovide a means to compare the relative effectiveness of
2 H. d. {9 d$ R& G) gtopical testosterone to systemic testosterone effect. It cer-
4 z. F0 g- b W9 }tainly has been established that gonadotropin as well as par-3 k# s8 y9 p! G* R
enteral testosterone administration will produce genital
3 _2 J) A9 x- m3 I3 ^# \, `growth. Our report shows that the growth of the phallus was+ q! V* y6 U0 n0 x1 t6 {9 M
significantly greater with topical applications than with go- y& l% i3 R# ]9 I/ f! ?
nadotropin, particularly in children less than 10 years old.
( U- ~( k0 r( L) KThe levels of serum testosterone remained similar or lower
" l3 a- O' T" n2 n" @& |. zthan with gonadotropin during therapy, suggesting that topi-
9 i8 s" U* ] P1 N3 Y& wcal application produces genital growth by its local effect as
6 C5 E% m- O9 m) iwell as its systemic effect.
+ g. u# {2 h, H4 w& K5 z/ O9 CReview of our patients and their growth response related to% k' s0 |, |/ R; L b& [: v$ [
age shows a greater growth response at an earlier age. This is
4 r& l9 F; b/ sconsistent with the findings of Wilson and Walker, who% Z% I) ~) c E7 q# l
reported an increased conversion of testosterone to dihydrotes-5 I$ O! I& H8 [* d6 b1 R5 @
tosterone in the foreskin of neonates and infants.4 This activ-( R- N5 x5 e8 L0 b. n6 I* G, q
ity gradually decreases with age until puberty when it ap-
2 v; k- F; p7 y& s: \proaches the same level of activity as peripheral skin. It may
4 I7 B( E. B2 A( J9 D1 D$ Q& vwell be that absorption of testosterone is less when applied at7 ]5 e' P6 O7 v! o a7 }7 Q
an earlier age as suggested by lower serum levels in children. ]" j1 s( v2 e. m
less than 10 years old. This fact may be explained by the
% q* q0 l9 m+ i) M, _; pgreater ability of phallic skin to convert testosterone to dihy-
" _- v" I3 v% Odrotestosterone at this age. Conversely, serum levels in older2 [! Y1 o; C: H( [" D$ ~
patients were higher, possibly because of decreased local0 N# e+ P3 m* Z9 {
667% F6 x" Z) `2 b Z
668 KLUGO AND CERNY4 t1 d& T5 L8 C/ D. \6 v
Pt. Age) q. X& s; K" @* x$ L5 `, B, b
(yrs.)# b1 ]% G8 b% b# H2 c3 K2 ^
Serum Testosterone Phallus (cm.) Change Length
$ ?7 Y. X. g0 p: u6 Z+ A& w(ng./dl.) Girth x Length (%): A3 a5 o/ v( K9 J9 ~+ G
4' w0 [! \# j) Z; D. i. F
8
1 I) `6 p/ n/ m! ^$ H( _( ^0 d10
, A8 M/ Q* C% t, c" @- h; E12" U6 C- |3 d/ j# b0 v, B
173 M' g0 ?0 C# m4 z' _
Gonadotropin6 R P: M6 H. v/ |. Q' }8 n5 w
71.6 2.0 X 3 16.6, E ~) R' \- n7 g" `9 f( F* Q
50.4 4.0 X 5.0 20.08 V; A! s/ T5 t( n& @$ E" K" h
22.0 4.5 X 4.0 25.0# w8 ~$ ~# n; {, i; z- W6 R
84.6 4.0 X 4.5 11.14 M/ g1 U0 y b0 |9 O/ K& `( y* I
85.9 4.5 X 5.5 9.0. N, ?: v' F5 e
Av. 14.3
: e, l# ]! ^/ x: J! {49 j3 {; \6 F F+ U2 c8 J
80 e; [9 O. v2 d* q& [
10
5 N! C M6 C3 `' `7 y( N12% p1 ]. l( }; D9 L- Z4 R5 w
17+ R r2 r1 R. _' E- W% l
Topical testosterone
4 @- b: V$ n# a; j, ]34.6 4.5 X 6.5 85
) p1 m# E- [, y38.8 6.0 X 8.5 70/ `8 r$ T% `5 r* d! ?; f2 y, D
40.0 6.0 X 6.5 62.5) J1 d. I+ C I a: m+ P4 r
93.6 6.0 X 7.0 55.5
; [. k5 n6 J( s# Z95.0 6.5 X 7.0 27.2
( k% y `1 T2 YAv. 60.0& o+ `! ?3 s+ s$ ^
available testosterone. Again, emphasis should be placed on. c2 w& l( y0 @& ]
early therapy when lower levels of testosterone appear to+ _7 _7 [6 \! G) K D+ a, [+ n
provide the best responses. The earlier therapy is instituted
/ e* k4 B5 A. ~$ u' C4 G: I. E9 Jthe more likely there will be an excellent response with low
$ J! J& B; r- D6 ^4 Z l- L1 Tserum levels. Response occurs throughout adolescence as0 v5 F( l8 @0 w/ y% n. ^
noted in nomograms of phallic growth. 7 The actual response" p- B D2 U: T2 l
to a given serum level of testosterone is much greater at birth9 U5 w7 q3 L( `! q: b; J: W: D
and gradually decreases as boys reach puberty. This is most
: e- i/ X) V/ a( k9 W( c1 d* ^: x+ Rlikely related to the conversion of testosterone to dihydrotes-
7 `9 l$ W. Y( L* f+ [/ d ktosterone and correlates well with the studies of testosterone
! s9 M1 A# p: `) T; Rconversion in foreskin at various ages.
* z# L+ _3 {. TThe question arises regarding early treatment as to whether
?. j+ K6 e( t* r, [one might sacrifice ultimate potential growth as with acceler-% Z5 U: B. G& N5 z$ b! f6 p3 \
ated bone growth. The situation appears quite the reverse
9 N5 T) w1 ^3 a& p+ Hwith phallic response. If the early growth period is not used, o% P, q7 w S
when 5a reductase activity is greatest then potential growth) s! Z1 c: K) l9 c) x5 ~ P
may be lost. We have not observed any regression of growth
! P* `6 I3 m/ u9 jattained with topical or gonadotropin therapy. It may well
$ k! Q$ V+ O7 f- g: L1 Pbe that some patients will show little or no response to any
8 r4 h* i% _, H" _' h3 Q. F$ k+ Xform of therapy. This would suggest a defect in the ability to
6 f* e9 u$ c" X+ d+ jconvert testosterone to dihydrotestosterone and indicate that
2 m3 D4 c1 K+ W: e" aphallic and peripheral skin, and subcutaneous tissue should
5 s. L# m& `7 Bbe compared for 5a reductase activity.: p9 n1 Q% o5 g6 l) Y0 U
A, loop enlarges to measure penile girth in millimeters. B,! u) [. T7 g; z% q+ V
example of penile girth computed easily and accurately.
' ?6 {$ `$ K5 w# Y, o8 oconversion of testosterone to dihydrotestosterone. It is in this
5 k8 {0 u4 T3 C/ r8 Zolder group that others have noted high levels of serum
3 ^$ M) U9 |7 h7 `, n1 |& p3 Qtestosterone with topical application. It would also appear/ B% T# e3 ^6 D2 ?. H/ |
that phallic response during puberty is related directly to the- O! l( q o2 M. }; l3 C* ?
serum testosterone level. There also is other evidence of local
# \& w+ Y1 C6 ?& P/ p! o7 v0 Kresponse to testosterone with hair growth and with spermato-
, ]6 o; }+ k [$ l9 K7 ?6 rgenesis. 5• 6" N4 c7 ]4 T; A) H7 q2 r5 Q
Administration of larger doses of gonadotropin or systemic
7 c1 U ~$ }% W( m: q2 |testosterone, as well as topical applications that produce
6 o6 W+ C$ o! x5 Lhigher levels of serum testosterone (150 to 900 ng./dl.), will7 ]& \" I, q! |; @
also produce phallic growth but risks accelerated skeletal
; B( |% n9 l+ r& \( p1 _9 smaturation even after stopping treatment. It would appear
: z6 X) R5 H8 \6 _+ y8 V7 E/ lthat this may be avoided by topical applications of testosterone4 P; R$ }* F8 v3 ~2 V
and monitoring of serum testosterone. Even with this control
* J- \" A+ }8 |3 Y7 C# D/ v+ Y7 ~the duration of our therapy did not exceed 3 weeks at any
2 G: E% R8 @: A/ Ttime. It is apparent that the prepuberal male subject may# e/ u) p% d2 _$ S( G; g
suffer accelerated bone growth with testosterone levels near& X0 S; S. Y5 v& a4 [ N2 q" U
200 ng./dl. When skeletal maturation is complete the level of
3 B _ a' G; j% I, [serum testosterone can be maintained in the 700 to 1,300 ng./
+ R+ K# c' E! r1 A! j8 Mdl. range to stimulate phallic growth and secondary sexual
+ u3 A5 [- p8 R; \; T0 E8 y: u* }changes. Therefore, after skeletal maturation parenteral tes-
( T- @$ i* ]0 t: K; Ltosterone may be used to advantage. Before skeletal matura-
4 E- K# c+ a) Ktion care must be taken to avoid maintaining levels of serum6 n/ L: P$ p" X) |# y. P
testosterone more than 100 ng./dl. Low-dose gonadotropin
) L& U/ }. d9 S1 ldepends upon intrinsic testicular activity and may require
$ i( @2 |. F6 Y4 F* n/ d) k. v9 K: sprolonged administration for any response.
: t/ b% |0 I2 F, \; A, hAlternately, topical testosterone does not depend upon tes-
5 b! [3 p+ _1 d7 I3 e) I. ^ticular function and may provide a more constant level of
, B7 ^! J4 r/ P' HREFERENCES
6 d4 o! f2 B; O. e6 f1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( h) f1 N1 A2 m2 R) M( r
R.: The local application of testosterone cream to the prepub-9 |8 r4 B7 R. ^! P: z
ertal phallus. J. Urol., 105: 905, 1971.
! I' f$ `6 y* K5 J3 V2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% {0 V! t, ~7 |4 C5 r* }; w
treatment for micropenis during early childhood. J. Pediat.,
) y+ F+ w) O" Y, [# z83: 247, 1973.- r0 L) D! d# _- I5 c; K
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 G" N0 n" u* O! @. N: Z6 a* Aone therapy for penile growth. Urology, 6: 708, 1975.
* Z5 h! Z- Q# N) x# s1 Z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
0 v% N+ N( z' v; ?' T' `to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. F2 z3 V/ Y9 e7 e, `' S" Nskin slices of man. J. Clin. Invest., 48: 371, 1969.
% B: B# Q4 {: M5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ f0 d- o" ?% u! r4 \- Fby topical application of androgens. J.A.M.A., 191: 521, 1965.
. z, h$ o3 S, B3 J/ _( M6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ t0 p% ~3 E: L C! m
androgenic effect of interstitial cell tumor of the testis. J.1 G, t9 J% E J3 H' \8 k
Urol., 104: 774, 1970.. J& |9 O0 B$ _3 M1 X
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ [7 R: w+ I o) Ztion in the male genitalia from birth to maturity. J. Urol., 48: |
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