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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 G" ?1 L F% E) X# [8 b: E7 z- e# X% QGONADOTROPIN
: W6 K0 p b' ~0 _4 Y' u8 hRICHARD C. KLUGO* AND JOSEPH C. CERNY
( P6 g2 t% `6 k6 |: w) ^From the Division of Urology, Henry Ford Hospital, Detroit, Michigan7 x. C9 C+ t' n4 U K2 x& k" C% C
ABSTRACT- v; ]9 v; o! w. x
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
" a- i+ C$ R# I; a! F( y6 Lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- b6 ?4 l$ @6 e: e" B
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone6 ?+ W6 \7 c3 P6 w" w
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 z6 o- n! h3 D4 E& Bfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ {4 K( v O+ y. pincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average8 T7 h, h$ [( w& h& g( X
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
, i. k- u% w( s; c& I/ D* J+ r9 eoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This" P, U6 v: G% {6 P( N9 K
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile3 T2 |6 f' B2 E, w V, u9 l
growth. The response appears to be greater in younger children, which is consistent with previ-. v( c3 `& ~$ `1 r! Q
ously published studies of age-related 5 reductase activity.
* n% u$ F& @! `3 R. @" r, ` _2 ?) @! |Children with microphallus regardless of its etiology will
4 B/ i& W; G( I+ v3 H; W* B8 q( c6 urequire augmentation or consideration for alteration of exter-
\5 h# E7 l/ y; I% N8 Cnal genitalia. In many instances urethroplasty for hypo-
* k: n5 S# e+ p* _4 V9 Aspadias is easier with previous stimulation of phallic growth.
8 }8 n/ }+ H% R3 uThe use of testosterone administered parenterally or topically8 M. R5 D9 v/ |: g: g; W& g
has produced effective phallic growth. 1- 3 The mechanism of2 ?% ^" t7 O8 H( v
response has been considered as local or systemic. With this) R! y9 t, H1 U" Z$ s( n
in mind we studied 5 children with microphallus for response
9 C% q, n6 p0 f/ \; F5 I8 G! i xto gonadotropin and to topical testosterone independently.1 e' l/ x4 _5 J( T% B
MATERIALS AND METHODS
% S% ~4 q7 W. ?1 j% b1 A( mFive 46 XY male subjects between 3 and 17 years old were6 Q% @* ]: E9 D. _- K/ w X! `
evaluated for serum testosterone levels and hypothalamic* [9 C! u; Q- g' L# \, P! |
function. Of these 5 boys 2 were considered to have Kallmann's
5 k& w7 b' y9 z1 Z1 isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, x: R: w4 S9 F( J0 m6 r$ d
lamic deficiency. After evaluation of response to luteinizing
4 `% c( H7 }; [& Dhormone-releasing hormone these patients were treated with/ U. G9 u+ E" E! s7 V6 @
1,000 units of gonadotropin weekly for 3 weeks. Six weeks+ d" q( q' h" T) q' K- ~+ A g' l: Q: W
after completion of gonadotropin therapy 10 per cent topical
3 ~5 h. @1 T; q6 ytestosterone was applied to the phallus twice daily for 3 weeks.
7 r* F) X( K7 r8 _4 {Serum testosterone, luteinizing hormone and follicle-stimulat-
4 ~+ j8 _9 t! E8 k' t3 c" Aing hormone were monitored before, during and after comple-, y( J3 m8 |6 Y, |9 f
tion of each phase of therapy. Penile stretch length was7 T5 }2 |4 y& o7 y$ w) h
obtained by measuring from the symphysis pubis to the tip of# q/ W' |( O* A' i2 ~$ K
the glans. Penile circumferential (girth) measurements were
& x7 ]8 b6 f+ d/ ^obtained using an orthopedic digital measuring device (see
9 l e4 x2 y' f1 Z# ffigure). v9 y) v: e3 E. w! ]& b
RESULTS4 Z [. |1 N6 h% x5 r+ x
Serum testosterone increased moderately to levels between0 C1 n! i7 v* ]$ ]2 d: y8 @" j
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* l. n1 \, Z# d7 \
terone levels with topical testosterone remained near pre-0 p# h# K5 m% X: e/ ^: a
treatment levels (35 ng./dl.) or were elevated to similar levels4 v Z4 M! u& f) u3 ?4 j
developed after gonadotropin therapy (96 ng./dl.). Higher
4 B6 t/ P1 O8 Q- k; r% r- B' z$ Cserum levels were noted in older patients (12 and 17 years old),
3 ~2 r, u# Z2 L3 Uwhile lower levels persisted in younger patients (4, 8, and 10
# ] F- f1 m% {5 z( \years old) (see table). Despite absence of profound alterations! X. Q4 M0 C9 f$ u" T/ R
of serum testosterone the topical therapy provided a greater
2 r+ _8 z6 L7 O! N3 ]8 H( iAccepted for publication July 1, 1977. ·
( n) `8 z+ G! s/ _! URead at annual meeting of American Urological Association,
0 {0 @( p* B+ z: k# @Chicago, Illinois, April 24-28, 1977.
6 A; F1 j( w2 N0 u, j; v& J4 Q* Requests for reprints: Division of Urology, Henry Ford Hospital,2 V- R( O0 Q: c3 g3 F" u! P: B
2799 W. Grand Blvd., Detroit, Michigan 48202.
) l, }3 E4 p) W% Himprovement in phallic growth compared to gonadotropin.! `& x2 c4 s' o- b1 h0 W) c
Average phallic growth with gonadotropin was 14.3 per cent; I0 z% B `# J% b+ `9 o. F
increase in length and 5.0 per cent increase of girth. Topical; Y7 h8 ~* t% l# {' S1 E& T; Y
testosterone produced a 60.0 per cent increase of phallic length! `4 F: a1 a" j. t
and 52.9 per cent increase of girth (circumference). The& j9 n) m% x A# g5 O
response to topical testosterone was greatest in children be-
- p$ \ a3 F6 Y1 }tween 4 and 8 years old, with a gradual decrease to age 179 n. q1 i: a" z
years (see table).1 h! j1 O& c5 i
DISCUSSION
, a) W( _6 G1 n+ |4 lTopical testosterone has been used effectively by other$ `. v; v$ I5 E+ j4 a5 e
clinicians but its mode of action remains controversial. Im-
- j( u# D$ Q( j1 v+ Smergut and associates reported an excellent growth response0 c8 U1 r) N I; w1 W; h3 x7 {: N. U/ A
to topical testosterone with low levels of serum testosterone,
& a: v; ?$ G; p- ?, ?% ]suggesting a local effect.1 Others have obtained growth re-
% g1 k, Q7 Z; e; O! l0 q3 Y- P' ^sponse with high. levels of serum testosterone after topical" D0 f2 v2 T! M) `
administration, suggesting a systemic response. 3 The use of
/ Z% X7 _/ C1 ~1 N0 V( Jgonadotropin to obtain levels of serum testosterone compara-0 b9 R. V8 g" `
ble to levels obtained with topical testosterone would seem to% k' r+ P" d7 g
provide a means to compare the relative effectiveness of
+ b( y6 ]5 {4 P) z8 B# Q" `' `topical testosterone to systemic testosterone effect. It cer-
+ b' X5 O# l; J: d- ?! utainly has been established that gonadotropin as well as par-
6 v" ^' |# a# ^ {% P7 tenteral testosterone administration will produce genital0 R6 `( H U% ?/ P3 Y9 w; F
growth. Our report shows that the growth of the phallus was
0 T6 e' ] ` k4 {significantly greater with topical applications than with go-
, O z* f% t5 E" Gnadotropin, particularly in children less than 10 years old.
7 I0 J+ a7 [7 q: Z$ tThe levels of serum testosterone remained similar or lower) [7 |4 j7 w- o7 `4 N6 \" L
than with gonadotropin during therapy, suggesting that topi-
% y& s( z3 w( ]! D5 L5 G" acal application produces genital growth by its local effect as7 L0 o P: `: t/ T" N& {
well as its systemic effect., g. L' i0 T/ ]2 m8 i: w' o" P3 L
Review of our patients and their growth response related to5 u4 h2 W& [ H/ p
age shows a greater growth response at an earlier age. This is
& I! \+ u. e- q' G; G4 dconsistent with the findings of Wilson and Walker, who
; ~2 y, ?6 d+ [8 K1 U0 x8 ~- X2 Xreported an increased conversion of testosterone to dihydrotes- I7 q6 I/ P2 y& h8 v
tosterone in the foreskin of neonates and infants.4 This activ-
- x5 L0 H& Z0 _ity gradually decreases with age until puberty when it ap-
& q$ h1 l M$ `7 V# b& V! Wproaches the same level of activity as peripheral skin. It may
7 x; R: n4 O0 f; _& w0 g% Xwell be that absorption of testosterone is less when applied at
& f8 a2 B4 R" ^3 K; i- e' v% _+ Aan earlier age as suggested by lower serum levels in children
" ^/ V8 B: y) P6 a2 W- ?less than 10 years old. This fact may be explained by the8 D- U( F7 h7 F
greater ability of phallic skin to convert testosterone to dihy-- i) M* B3 ~) d7 v3 e
drotestosterone at this age. Conversely, serum levels in older j, {# P: N* ~7 |1 l9 r
patients were higher, possibly because of decreased local
, V9 {" E j7 O667; X5 W5 V5 Y- `
668 KLUGO AND CERNY
- ?: f+ h1 ~6 K2 v( v; zPt. Age9 i/ y) X: q2 p/ o- S
(yrs.)
( ]- {! J5 R, j* G* pSerum Testosterone Phallus (cm.) Change Length
# D5 D3 t' ]9 j(ng./dl.) Girth x Length (%)
. i3 U/ k2 z |% M6 l: d. i8 U4; t! ?; U: V& F2 I: c4 r R
8
) D/ _/ ^6 C5 p8 j+ O% z10
% M C+ T" l! j$ v12
9 O0 v' l$ Y& Y$ u17( g1 q- W+ _" U
Gonadotropin
& w! r& w% [& U' Z$ a4 X7 g; X71.6 2.0 X 3 16.6
: Q* ]! f, b }; G! X3 b/ ]50.4 4.0 X 5.0 20.0( P- A; N6 R) g9 T$ d, [
22.0 4.5 X 4.0 25.0% n, w; n. c) d7 E: ?' _) j$ m: B+ `) d" P
84.6 4.0 X 4.5 11.1+ [- z; _2 Q8 |' F7 G
85.9 4.5 X 5.5 9.03 o# }" H1 F6 s& G6 P1 F- I
Av. 14.3
& z. z9 F1 Y+ T8 l4
# N% a: s+ v" K6 [& c8) z" S X, J( a, u R/ j
10
/ v& C1 V. m1 h# V12
9 k& `1 b h3 ?0 n3 J170 l, \2 t+ R" b4 b/ ^
Topical testosterone* d8 @; G+ |( E
34.6 4.5 X 6.5 85
( [; ?6 b- I5 x4 y9 ~4 V38.8 6.0 X 8.5 70$ N- ^! m6 ^2 k4 r9 ~
40.0 6.0 X 6.5 62.5# v2 J3 [' w2 U7 B( {* D8 q
93.6 6.0 X 7.0 55.5$ ]7 G' @& M7 B& H
95.0 6.5 X 7.0 27.2
0 [, U$ `. \4 \9 OAv. 60.0 t6 g( y+ @- k! ~7 X3 z; S3 Q
available testosterone. Again, emphasis should be placed on
4 a+ L2 H. M& w |1 w" learly therapy when lower levels of testosterone appear to
6 |2 W: u* K* Y0 rprovide the best responses. The earlier therapy is instituted
9 a7 r6 b* _( s" n) Z! c) B) Zthe more likely there will be an excellent response with low
5 X& Q5 `. Y. k. j. f% R- E" sserum levels. Response occurs throughout adolescence as
+ |4 X& E; q) J) {0 ynoted in nomograms of phallic growth. 7 The actual response s: C6 ^# w1 P: p7 D- R
to a given serum level of testosterone is much greater at birth: a \# d- Q! t( i P' ^# t% Z4 U
and gradually decreases as boys reach puberty. This is most
! P8 s! C8 W: v Z1 n! r% Xlikely related to the conversion of testosterone to dihydrotes-
( L$ I; e& G7 i. J0 Ttosterone and correlates well with the studies of testosterone8 D: f H, D* K5 d6 r7 V8 r
conversion in foreskin at various ages.
% F8 E( C3 E. r, G3 z/ O0 |The question arises regarding early treatment as to whether
. [3 t* e j: M5 ^: zone might sacrifice ultimate potential growth as with acceler-
) m1 j. c+ Z* F( J" g9 f4 zated bone growth. The situation appears quite the reverse5 ]: `* |: J3 h+ c4 [
with phallic response. If the early growth period is not used& A* G# y- r+ k, f' {8 c
when 5a reductase activity is greatest then potential growth+ ~( W. @3 r' p( j9 u
may be lost. We have not observed any regression of growth
6 P2 h0 L( Q0 `0 w) ~attained with topical or gonadotropin therapy. It may well" l- ~0 P+ `# M4 z
be that some patients will show little or no response to any! \; `4 O' J5 i( g
form of therapy. This would suggest a defect in the ability to
& j9 Y1 s E# f# j0 n* ^& P$ Lconvert testosterone to dihydrotestosterone and indicate that! |% w7 a+ C8 o+ S# Z/ e
phallic and peripheral skin, and subcutaneous tissue should* `9 d9 Z, D4 b1 ^
be compared for 5a reductase activity.2 c5 M7 [. C$ F- i N1 [
A, loop enlarges to measure penile girth in millimeters. B,# `5 M* G& d; X* B2 G
example of penile girth computed easily and accurately.3 C' L' K! p$ M+ \
conversion of testosterone to dihydrotestosterone. It is in this# N' d& V$ s( M1 ? n% u& ?$ ?
older group that others have noted high levels of serum/ I/ o( q1 l$ f& I, m- C0 ^
testosterone with topical application. It would also appear
; _1 }$ s6 Q+ Q, H! Othat phallic response during puberty is related directly to the
: |/ b: _- c. S I1 Vserum testosterone level. There also is other evidence of local
: |/ S: X6 N# L; A+ ~response to testosterone with hair growth and with spermato-! i$ X: [! z o0 \8 L* f
genesis. 5• 6! P- g4 Z) z, c! G
Administration of larger doses of gonadotropin or systemic& C5 q, _* u3 i, C" N! H
testosterone, as well as topical applications that produce
6 P2 W+ T! `8 }# a+ qhigher levels of serum testosterone (150 to 900 ng./dl.), will R9 W4 Z( j/ W; A9 R1 m
also produce phallic growth but risks accelerated skeletal4 d! ]+ A# ]: b/ H* z
maturation even after stopping treatment. It would appear! f( O3 |4 {, n, `
that this may be avoided by topical applications of testosterone% k* Q& Y/ h o$ \
and monitoring of serum testosterone. Even with this control
4 m" ~+ k U+ B+ V9 h% t! W6 ~the duration of our therapy did not exceed 3 weeks at any4 {7 m5 q5 @& W, a/ n* R* S
time. It is apparent that the prepuberal male subject may
. H/ c- [$ |4 ~1 ?+ Xsuffer accelerated bone growth with testosterone levels near
/ \; n% I9 ~) d) |% \* \( K" M200 ng./dl. When skeletal maturation is complete the level of
) u' {: I+ Z% h$ E1 Z! Tserum testosterone can be maintained in the 700 to 1,300 ng./
$ |% t! Y, h/ M& o" w1 x" J# F% Fdl. range to stimulate phallic growth and secondary sexual! _8 i q/ Q& ~" a0 r0 d- k1 c% _9 b% q
changes. Therefore, after skeletal maturation parenteral tes-2 ?6 S5 R+ f: R: S" T6 w. s( T
tosterone may be used to advantage. Before skeletal matura-1 z1 J; G* V1 i# e
tion care must be taken to avoid maintaining levels of serum
0 ~, o8 t. _! R! Ttestosterone more than 100 ng./dl. Low-dose gonadotropin& j$ {2 x3 n9 w9 A. I
depends upon intrinsic testicular activity and may require$ H0 d$ X( Z5 b# ^( s
prolonged administration for any response.: w1 k) x6 T& V+ P- O- f
Alternately, topical testosterone does not depend upon tes-4 y# q/ y+ D: M Q# e: v! Q3 ~
ticular function and may provide a more constant level of
* I0 w; S" a3 N+ O1 KREFERENCES
0 j. D$ h! ?, H! F3 z w" {1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; ?4 x! K' M2 q( f ?" ~R.: The local application of testosterone cream to the prepub-
. z& d9 G" N3 s4 S$ Gertal phallus. J. Urol., 105: 905, 1971./ G) \* A8 `$ s
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone v8 F) U$ w# T8 Z
treatment for micropenis during early childhood. J. Pediat.,
7 q6 _& w9 ^( P! O! W% U83: 247, 1973.. [& m- L2 {8 b+ u
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-2 B. i- c+ [+ t. x5 f
one therapy for penile growth. Urology, 6: 708, 1975.
( s+ G2 \' X- [; v* S4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
0 ~& \- h$ s3 Dto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 h- \" k0 g# n; j- ?5 C' n. }0 L
skin slices of man. J. Clin. Invest., 48: 371, 1969.; W% o# b" ~: U* x/ R6 y
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 u4 `8 e- k4 W3 V I$ J; }
by topical application of androgens. J.A.M.A., 191: 521, 1965.# H9 X6 J }# h7 y A- K' w0 W$ P1 t
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. J0 p( E( w. Y1 x! h! C# y2 Xandrogenic effect of interstitial cell tumor of the testis. J.# t- [+ u% W i ?5 l, c5 i
Urol., 104: 774, 1970.
* N2 U6 y1 m( O- p) L7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-% v/ r( I" D6 l
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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