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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND& H4 y8 Y9 V& t2 K2 r1 j8 b1 @
GONADOTROPIN: f" t# T& n5 Z- Q( \6 q7 _
RICHARD C. KLUGO* AND JOSEPH C. CERNY
: e; }5 J7 V2 s* H5 NFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan: v b: }! {* i8 E( D7 P
ABSTRACT6 ? D5 N, Q+ k, q D# f0 }* a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated2 l% \ \( W. J5 i
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-1 }& D& K1 Z4 `
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
w% a' A1 O( S* t* J) P3 c% ~cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! ?7 u8 _* Q) ?( A. D& Sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ x7 q5 [: q9 c4 ~increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average W/ c, [: m% q1 p- _; l6 a: x I
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response& z4 ^4 u+ e o8 m. u8 y% O, }
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; y( ^- T3 A/ p
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
+ f2 j1 x; W0 b/ O4 ~& xgrowth. The response appears to be greater in younger children, which is consistent with previ-0 \: Y9 v/ v1 o) y1 J# ~0 q
ously published studies of age-related 5 reductase activity.7 c; F% ^3 h5 S- D* d% c
Children with microphallus regardless of its etiology will! _( ?7 |5 {% C$ v
require augmentation or consideration for alteration of exter-: c; P8 c L2 H/ _+ h* e
nal genitalia. In many instances urethroplasty for hypo-3 G8 y7 Y0 x4 z) A z' K
spadias is easier with previous stimulation of phallic growth.
. D: b+ c% o; i% eThe use of testosterone administered parenterally or topically- Q% @, n7 r, w3 p0 I
has produced effective phallic growth. 1- 3 The mechanism of
: p" H+ ?( Q7 E; eresponse has been considered as local or systemic. With this ~. i% m, E6 @$ w- Y4 p
in mind we studied 5 children with microphallus for response4 k3 [. z5 ?+ q M4 d" N
to gonadotropin and to topical testosterone independently.
" H- N& A! g: q. TMATERIALS AND METHODS
# Q* i+ f2 W5 D* B7 M$ u T: R. ^Five 46 XY male subjects between 3 and 17 years old were
1 b! V" \# ~9 Q" n. B' C3 oevaluated for serum testosterone levels and hypothalamic
3 f* p: M7 d* w2 l+ r) T" Q8 ~function. Of these 5 boys 2 were considered to have Kallmann's! z# R7 S, Q# N F/ Y
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-% m, |$ F& H+ \3 p+ V, [+ K% }
lamic deficiency. After evaluation of response to luteinizing
- N, i l V7 a$ p. s6 ?8 ^6 w+ Shormone-releasing hormone these patients were treated with
1 j+ `; G; K1 l" X- g h1,000 units of gonadotropin weekly for 3 weeks. Six weeks
5 G4 s; U$ d7 J6 Y0 R' ~after completion of gonadotropin therapy 10 per cent topical, K* _" J* }% A( t* p. |
testosterone was applied to the phallus twice daily for 3 weeks.4 u! t8 b3 a, U# h0 A5 v
Serum testosterone, luteinizing hormone and follicle-stimulat-( S) ^' i7 ] `, H4 u8 N) P
ing hormone were monitored before, during and after comple-+ s7 r/ o5 I- G2 F) z+ q
tion of each phase of therapy. Penile stretch length was
" }& ? z6 n8 ?7 g" @obtained by measuring from the symphysis pubis to the tip of2 M) Y6 S8 H; H1 {! Q
the glans. Penile circumferential (girth) measurements were
- v6 ~ [* e z) O3 t1 _obtained using an orthopedic digital measuring device (see* H* L8 V# N" ?% m" P w8 y
figure).
0 Y% [* b! L8 s6 M7 v: MRESULTS
, c4 ?# _/ T3 O5 n4 S* ~Serum testosterone increased moderately to levels between, ~# n' c$ {" C2 J2 V- ?
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
" q; X2 V+ ^ h2 ^terone levels with topical testosterone remained near pre-+ V0 L$ T7 n1 {6 l' o5 C
treatment levels (35 ng./dl.) or were elevated to similar levels
: q/ U" {$ x' g: wdeveloped after gonadotropin therapy (96 ng./dl.). Higher# Z( g* N" [* R) H u0 W
serum levels were noted in older patients (12 and 17 years old),( c) w( W8 F' W% p# b
while lower levels persisted in younger patients (4, 8, and 10/ w! E) i2 g- v+ z9 b
years old) (see table). Despite absence of profound alterations
2 c" u1 B; O+ j5 ?7 ?9 hof serum testosterone the topical therapy provided a greater# A* ^3 P" F1 a+ A
Accepted for publication July 1, 1977. ·
0 h6 Y" M" E' }' O/ ^( B2 C7 bRead at annual meeting of American Urological Association,
* i8 V- E( d6 n) ?) Y# \" vChicago, Illinois, April 24-28, 1977.7 q& ~0 j( D! w9 B6 k; k
* Requests for reprints: Division of Urology, Henry Ford Hospital,' D, m2 W5 i3 y5 ]% ^
2799 W. Grand Blvd., Detroit, Michigan 48202.
: O w7 ?7 S2 z& y4 ]. n3 p" ]9 cimprovement in phallic growth compared to gonadotropin.
7 G' R8 l8 h7 F8 b1 m5 A% mAverage phallic growth with gonadotropin was 14.3 per cent8 r E" c1 c* C. t
increase in length and 5.0 per cent increase of girth. Topical, g/ t, Z4 Z8 e: }
testosterone produced a 60.0 per cent increase of phallic length
; i# M9 |* [; R, Z6 @and 52.9 per cent increase of girth (circumference). The3 H3 J: p6 q, ^3 y4 q* ?$ v
response to topical testosterone was greatest in children be-& W( n& Z S1 s( n
tween 4 and 8 years old, with a gradual decrease to age 17
5 P) y; j* X9 U; S4 F* f% ~" R6 Xyears (see table).
0 W$ Y9 i" Y3 Q5 ]. O' T0 HDISCUSSION
8 s3 x+ F: m2 g3 b3 `% g4 }Topical testosterone has been used effectively by other
; ]8 U) x: t9 t# P% I. S1 P, ~) ?clinicians but its mode of action remains controversial. Im-
; A2 V( ?; ~3 E) l. v# Z1 ^5 }mergut and associates reported an excellent growth response; l& j- T( `, M2 z2 Q2 [
to topical testosterone with low levels of serum testosterone,
- l) m# s9 h- h+ L9 s9 C7 esuggesting a local effect.1 Others have obtained growth re-
8 H; A" j. j7 h4 P+ ?: ]$ n' [- ]% Dsponse with high. levels of serum testosterone after topical
8 O/ K5 f4 _7 `3 H( q2 h$ r1 V6 madministration, suggesting a systemic response. 3 The use of
/ J5 l# V4 t6 E v' w) agonadotropin to obtain levels of serum testosterone compara-4 |" Q& W6 X. o. e. k: B5 l
ble to levels obtained with topical testosterone would seem to1 p# ^6 }; W) B/ O
provide a means to compare the relative effectiveness of n7 [- i/ C8 A. P" E0 o, Q
topical testosterone to systemic testosterone effect. It cer-2 @$ \, }* L! T2 ]0 a1 a8 t0 ]
tainly has been established that gonadotropin as well as par-
7 [" }2 @8 e& g) _) @' Genteral testosterone administration will produce genital
7 Q5 N# @' y9 X1 G+ B% Q L( Bgrowth. Our report shows that the growth of the phallus was$ m' b- ~/ A# f f. ^
significantly greater with topical applications than with go-# D- _9 [1 D! e i
nadotropin, particularly in children less than 10 years old.
" U# U: D4 B1 P/ XThe levels of serum testosterone remained similar or lower/ e4 W* ]4 \* V
than with gonadotropin during therapy, suggesting that topi-
) f( p% t3 |- b2 h4 B0 }cal application produces genital growth by its local effect as
2 c+ I2 t! y: y* _3 M d/ Y# R/ g4 rwell as its systemic effect.7 f9 U' j0 j( h2 J& ] |: h( P
Review of our patients and their growth response related to3 q: y- _, x% M! M! O5 _* E
age shows a greater growth response at an earlier age. This is
. i6 r1 h) I& R' vconsistent with the findings of Wilson and Walker, who; J1 P3 [9 {% R
reported an increased conversion of testosterone to dihydrotes-! z9 I; F1 Z* ~8 O
tosterone in the foreskin of neonates and infants.4 This activ-
# \' w2 z, I/ X. u# Jity gradually decreases with age until puberty when it ap-
|, { k' B3 z; \) N% eproaches the same level of activity as peripheral skin. It may
: R3 |3 r# [$ zwell be that absorption of testosterone is less when applied at
6 {: q5 h4 ?6 E8 t$ X3 Pan earlier age as suggested by lower serum levels in children5 F# H4 t6 b, h+ q% ?0 z
less than 10 years old. This fact may be explained by the" v% h* b) ^7 G
greater ability of phallic skin to convert testosterone to dihy-, v4 L0 k7 `8 L! Y& o8 D
drotestosterone at this age. Conversely, serum levels in older5 y. [& z% @1 n/ k. W
patients were higher, possibly because of decreased local
3 J( H9 i, c7 K; o667
' W+ V& @* ^2 a/ s668 KLUGO AND CERNY
% s/ `$ g B mPt. Age j T) K6 Y' d1 z0 y6 `& N: H
(yrs.)) {: ?2 d2 J8 }% A- {
Serum Testosterone Phallus (cm.) Change Length3 x) N( F% J2 e( w1 E
(ng./dl.) Girth x Length (%)
% [% ?) f6 k# u8 P2 x# L3 j% Y49 H! Z: V' M: `" x- M4 T
8! {% N) S( `. ^
10
/ W& o( J1 i' f3 ^" K8 U/ \6 Q7 L" G12
' }* e( O* [1 q17
1 \+ }# i7 o, F2 ^4 z: b& @( _: xGonadotropin* {$ ~1 @6 q! T$ g' H
71.6 2.0 X 3 16.6" ]) }$ d: H8 s7 \$ T% X. p9 c( @
50.4 4.0 X 5.0 20.0
% p1 u" d3 J; E" y" Q' |! ^& r0 `22.0 4.5 X 4.0 25.0
; U9 {# a4 w% Z2 T3 X1 ~9 S2 ^84.6 4.0 X 4.5 11.1, _, R1 G/ b1 t* e2 L- X
85.9 4.5 X 5.5 9.09 a! w) z& t0 m& @" h4 |
Av. 14.3+ t. V4 E6 @ n/ c9 e
45 g# g+ I' x$ v' u+ x T
8
$ E! P8 n/ s2 X0 v) p10
" m& ]$ k' T3 u! f" I12
. J! f3 ]+ |( C/ p5 B17% W: a9 y0 P4 ?* t
Topical testosterone
2 |: ]# `. g; b# v y: L34.6 4.5 X 6.5 85
" t$ t/ @" d8 D& {* R38.8 6.0 X 8.5 709 j4 {' r5 q7 E: C7 R' f
40.0 6.0 X 6.5 62.5
R* z r. J% J93.6 6.0 X 7.0 55.5: G/ v- r. R6 A2 I! ]
95.0 6.5 X 7.0 27.2
l/ F# T; U" U6 Q& o4 [% hAv. 60.0- I3 N! k( B- w2 v
available testosterone. Again, emphasis should be placed on
. c" Z6 X, I' Tearly therapy when lower levels of testosterone appear to: X _! V0 u% n8 r% @
provide the best responses. The earlier therapy is instituted3 X! c' @/ f7 P; b+ G
the more likely there will be an excellent response with low5 O1 D6 F5 C7 b9 Q3 O8 T U
serum levels. Response occurs throughout adolescence as; D$ T; y0 D9 i
noted in nomograms of phallic growth. 7 The actual response+ {$ K3 }* n$ _( }3 z
to a given serum level of testosterone is much greater at birth
: D& }; z3 n; {and gradually decreases as boys reach puberty. This is most
2 i S9 \( O; j0 [likely related to the conversion of testosterone to dihydrotes-7 c' q. i4 H0 F# Y
tosterone and correlates well with the studies of testosterone& D! J q6 Q% h2 K' `: q' G
conversion in foreskin at various ages.
% C0 Q( [* w+ ~4 sThe question arises regarding early treatment as to whether$ }+ H8 s& a# L4 D( X
one might sacrifice ultimate potential growth as with acceler-
' b" N& f8 w# uated bone growth. The situation appears quite the reverse' Y" i, W/ z4 Y3 Q5 Q
with phallic response. If the early growth period is not used5 y" E1 k4 M2 X3 } w% `) |& o* o
when 5a reductase activity is greatest then potential growth3 b2 I+ ?4 @5 P4 ]$ c
may be lost. We have not observed any regression of growth
' H) J+ Q2 r- j K% zattained with topical or gonadotropin therapy. It may well! n+ J$ t4 a+ ]3 @/ Q
be that some patients will show little or no response to any
9 B6 J I9 }0 l f, s5 w$ cform of therapy. This would suggest a defect in the ability to X3 A) ~% q2 ?4 _
convert testosterone to dihydrotestosterone and indicate that
& [+ u1 g0 s* D: {: ~! \# Nphallic and peripheral skin, and subcutaneous tissue should
- c' F6 C) T/ r5 ^% }* E! @* ]. mbe compared for 5a reductase activity.0 O: D5 f g" X. ~& {$ |4 W1 U
A, loop enlarges to measure penile girth in millimeters. B,. H) w% i7 S; J' D! v8 U' Q O
example of penile girth computed easily and accurately.
- r- P+ `2 x1 F# B0 @/ ]- z7 Pconversion of testosterone to dihydrotestosterone. It is in this! @0 N6 o3 V0 W" ^& z+ @" W( T
older group that others have noted high levels of serum
$ S7 K. T2 O' Y7 ytestosterone with topical application. It would also appear- X2 v+ S/ Q4 G- o
that phallic response during puberty is related directly to the
4 S' v- _* Z1 \3 ^+ x t/ x, w; iserum testosterone level. There also is other evidence of local F. c1 G% d$ b+ } M
response to testosterone with hair growth and with spermato-& U: K. E, E/ q( I$ k H" G
genesis. 5• 6
0 F/ w0 n- c+ N0 y5 t8 M! eAdministration of larger doses of gonadotropin or systemic# V5 D7 t V$ Y! T5 s, ]% U
testosterone, as well as topical applications that produce
9 }2 G! }: B( B6 v- V( r# Nhigher levels of serum testosterone (150 to 900 ng./dl.), will( I( w8 ^: v3 J
also produce phallic growth but risks accelerated skeletal7 S' M% P1 _% \% P
maturation even after stopping treatment. It would appear3 f2 \6 E3 f$ m& U, ?8 }1 v
that this may be avoided by topical applications of testosterone5 R4 d$ {; M* L( @9 j. x. q% f2 K
and monitoring of serum testosterone. Even with this control) P( M1 b* |& M$ c" I
the duration of our therapy did not exceed 3 weeks at any( K* Y$ f/ h' e
time. It is apparent that the prepuberal male subject may- {* p" d6 W' x( M9 @
suffer accelerated bone growth with testosterone levels near
& ]! Y# `4 m9 M4 O6 |# j4 a200 ng./dl. When skeletal maturation is complete the level of! E! C+ A, m. \! s {: [' g/ z
serum testosterone can be maintained in the 700 to 1,300 ng./
3 |& ]4 m$ i9 H: o- D1 G& Jdl. range to stimulate phallic growth and secondary sexual% n( I% T- O' J" {/ X6 N
changes. Therefore, after skeletal maturation parenteral tes- [! c5 [8 a3 ?: a# f
tosterone may be used to advantage. Before skeletal matura-: }" |6 H1 ~) x7 \3 _9 U) g8 _
tion care must be taken to avoid maintaining levels of serum
3 l# s( \6 b S9 p1 L& P0 Atestosterone more than 100 ng./dl. Low-dose gonadotropin% K5 y1 O5 l: K( o; M3 }7 e: Y
depends upon intrinsic testicular activity and may require
- H2 f2 x) J! |) W8 Iprolonged administration for any response.+ f% a2 W2 g: t5 ?. t, V, z# D/ d1 Z
Alternately, topical testosterone does not depend upon tes-
/ t! J6 s% X2 O- X$ Cticular function and may provide a more constant level of
0 e! u/ j: J2 s; ZREFERENCES
. T! T- f e$ b8 p1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 K! e) Z0 g' l' y$ U! `) I0 @R.: The local application of testosterone cream to the prepub-
/ N5 K. T5 u4 s" y6 W. }/ @5 l) Pertal phallus. J. Urol., 105: 905, 1971.. ]1 ^, U+ d9 E( B! L$ a; j4 n
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. r9 F8 C5 d$ w4 R5 y
treatment for micropenis during early childhood. J. Pediat.,6 _% a; S' w0 b& \( n( F
83: 247, 1973.
8 a+ o+ j; ?2 g( _0 {3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
- c4 R8 W6 ?$ _, P [, ?one therapy for penile growth. Urology, 6: 708, 1975.
. {! W: O0 S. {( B% n$ U4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) Q& i l4 k! W% O& W, i( {
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 }% O8 _( h3 S! I( Lskin slices of man. J. Clin. Invest., 48: 371, 1969.8 L- N0 q4 b- l; r! T2 q
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
% O: I+ y0 x v4 \6 P" Oby topical application of androgens. J.A.M.A., 191: 521, 1965.
" j$ W. o' C3 `" Y6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local; B" @; u/ Y5 o: k
androgenic effect of interstitial cell tumor of the testis. J.
0 t8 s2 R: e* [* qUrol., 104: 774, 1970.3 D; x. D8 f4 f
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
9 N1 H0 ]% _! i! {2 f+ ~tion in the male genitalia from birth to maturity. J. Urol., 48: |
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