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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, i, M8 f. t2 l2 ]  k; IGONADOTROPIN* @4 v5 U3 R$ R. @" i# \
RICHARD C. KLUGO* AND JOSEPH C. CERNY( r. X: p! @7 Y
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
8 {2 {. F6 o3 H; tABSTRACT
4 E8 L' i# d" e0 y" s1 ]8 iFive patients were treated with gonadotropin and topical testosterone for micropenis associated
) \$ v3 C0 a/ ~" K( Xwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- w- y! E4 w4 o% e8 w7 E  E
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% G! [) Z7 d' j& }0 |cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 B# d( N) C# w9 Z/ v  Nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent3 P8 v. i: z! ~5 H' [- M
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average# Z, Z- L1 Z3 {
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response! q. @, R) f. V# Y0 d/ E
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( X" s/ n, o9 B& ]% G1 x
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ q/ F( T# \: A( |9 F0 G# v) agrowth. The response appears to be greater in younger children, which is consistent with previ-
' h/ E2 ~& Q( I: }* |& }ously published studies of age-related 5 reductase activity.- u/ R: B; X4 G" G% `
Children with microphallus regardless of its etiology will8 i0 Y: l3 a* O1 w5 ]" z% b4 B
require augmentation or consideration for alteration of exter-' i2 I8 W( ]/ k. d) p0 _9 x1 l
nal genitalia. In many instances urethroplasty for hypo-
% L2 H! M! g1 k5 N0 [spadias is easier with previous stimulation of phallic growth.3 E! `4 j7 @) D' \
The use of testosterone administered parenterally or topically
2 N; K% L9 b( a" _8 E& Ghas produced effective phallic growth. 1- 3 The mechanism of, \' ?. W. X6 I5 H) I
response has been considered as local or systemic. With this
1 a  g0 s' q( y8 b) i0 X2 win mind we studied 5 children with microphallus for response6 u4 q3 U& a) z( x  L- Z  q
to gonadotropin and to topical testosterone independently.9 l( Y6 o# b' N5 n1 d: w  w. g
MATERIALS AND METHODS6 x. t7 k& Q8 i$ J
Five 46 XY male subjects between 3 and 17 years old were; `: U& q7 t: B3 _
evaluated for serum testosterone levels and hypothalamic. s5 k+ K$ t7 J" F& ?; _9 z
function. Of these 5 boys 2 were considered to have Kallmann's
, d" l+ ?  I8 r, L" r' R/ e/ E! csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( {# w: ?' N' q$ h" n. Plamic deficiency. After evaluation of response to luteinizing
& Y$ b9 U* |5 i: F4 zhormone-releasing hormone these patients were treated with! Z% o  y8 I& I3 F
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
' g1 I# W3 I  B) Yafter completion of gonadotropin therapy 10 per cent topical
1 M9 f& v/ n3 r5 s1 Otestosterone was applied to the phallus twice daily for 3 weeks.# P$ K' F- M1 E/ m1 M
Serum testosterone, luteinizing hormone and follicle-stimulat-' V) n4 q0 I( O; |( e3 `3 A
ing hormone were monitored before, during and after comple-$ ]; @+ H9 l4 z. p& \8 r( G' s7 ~
tion of each phase of therapy. Penile stretch length was
6 [! I4 i+ [/ y3 c3 n# x5 _obtained by measuring from the symphysis pubis to the tip of
5 M1 S3 a" \$ E3 ~5 fthe glans. Penile circumferential (girth) measurements were
" [$ z" f+ N5 Wobtained using an orthopedic digital measuring device (see
2 U% q+ i0 b* H1 W7 Ufigure).
6 M; e  f. K  G0 vRESULTS
2 L4 g) p  T) {8 Q1 M& ~Serum testosterone increased moderately to levels between
7 V: _8 \5 ~" ^50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-# r+ G7 k8 {. T
terone levels with topical testosterone remained near pre-
3 S6 l" P" E6 M# a$ ]% Ztreatment levels (35 ng./dl.) or were elevated to similar levels
: |" V8 ?  o8 H( y2 \! d. fdeveloped after gonadotropin therapy (96 ng./dl.). Higher8 l  U" K  N  o  ?4 C7 M3 m+ i* S
serum levels were noted in older patients (12 and 17 years old),5 r- ^2 G8 T; J$ o. \
while lower levels persisted in younger patients (4, 8, and 10& [8 o; F! R9 x2 u" G* ^
years old) (see table). Despite absence of profound alterations, ~3 y; E9 j0 n! A5 b/ s4 `
of serum testosterone the topical therapy provided a greater
4 C6 D3 x" @3 _' w  uAccepted for publication July 1, 1977. ·* {5 H/ y( @) L3 g
Read at annual meeting of American Urological Association,# d' {. s* e. [+ \7 \
Chicago, Illinois, April 24-28, 1977.
' G2 D# K' i/ [: r$ O8 \* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 J1 q3 i8 _% e- ^! Z2799 W. Grand Blvd., Detroit, Michigan 48202.
* R- J9 G1 a2 P' Mimprovement in phallic growth compared to gonadotropin.6 p: X' v) X- ~+ f  D
Average phallic growth with gonadotropin was 14.3 per cent0 A5 \+ V, h5 z; q
increase in length and 5.0 per cent increase of girth. Topical
7 P! T' i7 \7 V& t% _, Btestosterone produced a 60.0 per cent increase of phallic length
, p+ g5 J2 ^% Q2 k! R* W$ Pand 52.9 per cent increase of girth (circumference). The
9 b. Q. g, V) r, @' B# bresponse to topical testosterone was greatest in children be-
. R) ^& N. J4 u/ `; Itween 4 and 8 years old, with a gradual decrease to age 17" @% s7 k! ~5 R8 O5 W
years (see table).
, B4 d- Z+ x! RDISCUSSION$ x/ Z0 p8 _; L
Topical testosterone has been used effectively by other
, c* ^2 V# o: [& {/ |' bclinicians but its mode of action remains controversial. Im-3 u( w" b) ~( O6 h" f6 r
mergut and associates reported an excellent growth response! t: d$ e0 ~( i4 ]/ ~
to topical testosterone with low levels of serum testosterone," o; p5 ^" ?/ Q0 G
suggesting a local effect.1 Others have obtained growth re-8 d, z# r* @1 E( n  \( M* ~
sponse with high. levels of serum testosterone after topical
* F0 c' \! p8 t& N2 ]administration, suggesting a systemic response. 3 The use of
) a2 I& ~5 X: V& z$ cgonadotropin to obtain levels of serum testosterone compara-
: E& v5 c+ q2 [# V5 @# Mble to levels obtained with topical testosterone would seem to8 ~4 J0 v5 i! w0 N
provide a means to compare the relative effectiveness of
, Z/ p7 Q3 I4 X9 etopical testosterone to systemic testosterone effect. It cer-
' _. l! h: E( p8 mtainly has been established that gonadotropin as well as par-& z0 g% m* }6 z/ A' r
enteral testosterone administration will produce genital
: Z/ I# e% m/ C' Bgrowth. Our report shows that the growth of the phallus was, [# a2 |# _9 z* \  n
significantly greater with topical applications than with go-. {' I) o% f0 D" c  Q
nadotropin, particularly in children less than 10 years old.4 o3 n4 H$ R' n* @- V5 q7 m
The levels of serum testosterone remained similar or lower
3 I' ]3 f* U( o0 j, m/ t" athan with gonadotropin during therapy, suggesting that topi-4 H7 L: p% |8 i2 D- @
cal application produces genital growth by its local effect as
" v6 p& p* K. v; b& b% @: vwell as its systemic effect.
. K/ N# b: Z8 R* yReview of our patients and their growth response related to
$ a/ ~/ U4 X2 r& kage shows a greater growth response at an earlier age. This is
3 v9 m% h7 M0 U' [8 z2 qconsistent with the findings of Wilson and Walker, who
; a2 N" x3 C( L4 h4 ~# Dreported an increased conversion of testosterone to dihydrotes-5 G9 @  K$ j9 c, U- f
tosterone in the foreskin of neonates and infants.4 This activ-  W6 @" ^% @- R2 j+ v' M
ity gradually decreases with age until puberty when it ap-) q/ R. _3 S. f# l; W. p  S
proaches the same level of activity as peripheral skin. It may1 Y2 Q- s8 d# t, d" u3 I6 M
well be that absorption of testosterone is less when applied at/ z% \) J( _6 b- w" f
an earlier age as suggested by lower serum levels in children
0 O, d4 m6 q$ a; J! S9 H; j9 iless than 10 years old. This fact may be explained by the
6 g" p! b* y0 ]' g9 N0 I7 u; N6 X: [2 Ugreater ability of phallic skin to convert testosterone to dihy-# y( h) ]0 d2 t! S
drotestosterone at this age. Conversely, serum levels in older
; I9 O$ ?& e) ^; {. e1 Cpatients were higher, possibly because of decreased local
( w: q) q$ K/ Z* \: u667( R7 t+ z# S) j1 Y
668 KLUGO AND CERNY8 l1 ~1 |3 i! G' B
Pt. Age% X  h# x( O+ ^9 U
(yrs.)
1 r9 M; B: k8 q, {Serum Testosterone Phallus (cm.) Change Length
2 {# E" k' \7 l& k1 d! d(ng./dl.) Girth x Length (%)
( V, I3 N4 i( Y2 B9 l4 i& Q* r+ e45 P+ o$ }3 X; t8 I5 _# S# T# x
80 p- F' Y( X, n, D# o- B
10  l! y/ @/ g+ |7 `
124 q  L6 o7 w! f; V) @+ `
17, J9 e9 W/ R( x; ~! ~
Gonadotropin! y6 h- O2 v. r$ N
71.6 2.0 X 3 16.64 `6 B- B, O. s7 S; D+ J
50.4 4.0 X 5.0 20.08 K/ C3 z, G" @. J4 g3 e& E1 K2 k. ?
22.0 4.5 X 4.0 25.0. [4 E! V+ Q$ k8 h5 S
84.6 4.0 X 4.5 11.1$ Y9 l  C! F' E0 [/ ]% _$ U$ o
85.9 4.5 X 5.5 9.0
& V2 `+ ]( p2 pAv. 14.35 K) n4 g7 q6 R4 M  g
4
7 z' H5 E. k$ Y, p) i8
. X  c0 k6 h6 w: {. q10
! T8 Y+ w! j- `% o: t12
, W) G0 ]2 X2 Z5 |% L  p" l4 ]179 V  l6 t1 z+ o
Topical testosterone
9 |1 t7 Q) z5 p% c( u* N34.6 4.5 X 6.5 85
, `! f$ z& ~4 ]: Y( m: e38.8 6.0 X 8.5 70' V7 U3 x: f1 O$ ~
40.0 6.0 X 6.5 62.5  F/ e3 G( r. ]7 S9 G
93.6 6.0 X 7.0 55.5
9 U5 C/ p! w2 T95.0 6.5 X 7.0 27.2
: |  ]# ~3 z% aAv. 60.0
5 A- {0 w+ y- D8 ]9 ^available testosterone. Again, emphasis should be placed on
$ a) P! V4 Z/ s* d5 wearly therapy when lower levels of testosterone appear to) y; M) ?  B: `* g7 `% d
provide the best responses. The earlier therapy is instituted5 U# ?3 M2 ^8 L/ P
the more likely there will be an excellent response with low
' @- }3 ?4 K$ l9 x! c# [- Cserum levels. Response occurs throughout adolescence as8 E8 l7 z* o: U; h; @2 X" D
noted in nomograms of phallic growth. 7 The actual response
2 e$ N& l, y- G" o# bto a given serum level of testosterone is much greater at birth
, ~0 z4 C/ l; m* aand gradually decreases as boys reach puberty. This is most8 ?' e- R5 M% [
likely related to the conversion of testosterone to dihydrotes-
+ M% h0 ]8 y. p0 s# Gtosterone and correlates well with the studies of testosterone2 a3 l- y" X% f3 Q  f7 ]  e! y
conversion in foreskin at various ages.9 P& h* f, S1 G9 I3 Y) P* R6 Q
The question arises regarding early treatment as to whether, Y6 {3 o% B+ q' n  T$ o3 L
one might sacrifice ultimate potential growth as with acceler-
# P7 H" S5 P; m+ x4 e% T" }ated bone growth. The situation appears quite the reverse& I$ B8 q( i7 ~
with phallic response. If the early growth period is not used, U& x9 U" K8 I6 |/ ^# Z5 f$ \' x
when 5a reductase activity is greatest then potential growth
7 \+ P( _$ A% E" |may be lost. We have not observed any regression of growth
! r" N) O3 H; i( T1 aattained with topical or gonadotropin therapy. It may well
4 E9 s6 v' V! |( g4 m9 v" K, \be that some patients will show little or no response to any8 D5 @- F3 ]. e, P' F& c
form of therapy. This would suggest a defect in the ability to2 C+ D7 ~; m: \$ k" G
convert testosterone to dihydrotestosterone and indicate that
! }. b1 L- d- Y7 x# {' o, P2 Cphallic and peripheral skin, and subcutaneous tissue should
- h' H8 F6 V: C) H9 h# Xbe compared for 5a reductase activity.# s! S- i% m! E+ |3 ~! _8 s
A, loop enlarges to measure penile girth in millimeters. B,/ N+ Q! |8 o. d/ P9 }  l
example of penile girth computed easily and accurately.
" f$ E* _$ C% Xconversion of testosterone to dihydrotestosterone. It is in this
% s; j7 X6 b% G5 i6 y8 x3 a7 S7 Eolder group that others have noted high levels of serum; H& f' g( o) B$ ]8 n$ z
testosterone with topical application. It would also appear& ~2 P# n" p/ P
that phallic response during puberty is related directly to the5 v- z) K% x0 O# N9 u/ p2 K
serum testosterone level. There also is other evidence of local# s0 {" _8 R3 C" M9 E: \4 V  b  ?! n: {
response to testosterone with hair growth and with spermato-! A; I, n" V. i' ]9 W7 u8 G# i
genesis. 5• 6
, r: b+ o! z( M  i0 TAdministration of larger doses of gonadotropin or systemic$ E2 v8 x+ @9 ^) g1 V' d! _+ Q
testosterone, as well as topical applications that produce1 g& |$ W8 d, n; v) X" i
higher levels of serum testosterone (150 to 900 ng./dl.), will! r6 k# q% ?' {5 P) W) J
also produce phallic growth but risks accelerated skeletal* H% w& C) y( J$ o  ?
maturation even after stopping treatment. It would appear
( C8 t6 ]. h2 X' _, r2 ~& ythat this may be avoided by topical applications of testosterone
( b' Q, l1 j7 J- a4 B* D+ R& d, tand monitoring of serum testosterone. Even with this control* x4 Y* H4 @: V& u6 V
the duration of our therapy did not exceed 3 weeks at any
, ?( u( g  ]7 P0 W+ s; Ytime. It is apparent that the prepuberal male subject may* H9 R7 H6 E3 n6 B* I5 T2 a
suffer accelerated bone growth with testosterone levels near, a- Z, e0 ]6 q
200 ng./dl. When skeletal maturation is complete the level of
+ q2 [  S6 N9 y  y0 N0 S5 a- M) zserum testosterone can be maintained in the 700 to 1,300 ng./
" i6 O8 C! M( @) vdl. range to stimulate phallic growth and secondary sexual
* _5 U" k/ Q* [- c& zchanges. Therefore, after skeletal maturation parenteral tes-1 t  g4 n6 |( \7 T! d
tosterone may be used to advantage. Before skeletal matura-
" H' L7 p, S# _, e' Ytion care must be taken to avoid maintaining levels of serum( ]3 e4 O& T; c2 Y: Y* }  q
testosterone more than 100 ng./dl. Low-dose gonadotropin" T7 y  P9 ]3 [
depends upon intrinsic testicular activity and may require; `, F: c1 p9 I5 |
prolonged administration for any response.
% w( D( R9 z- qAlternately, topical testosterone does not depend upon tes-! {( \1 Z* T  O. R
ticular function and may provide a more constant level of
# @) y4 z1 A( [8 AREFERENCES
" r9 @$ T% z' q1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% m9 f; l# s, d8 ^. V# _
R.: The local application of testosterone cream to the prepub-7 Z$ i; ~* T+ |9 j! Z! t' S% f% R
ertal phallus. J. Urol., 105: 905, 1971.
6 U5 t! A/ E+ t( I- c& x: o2 @9 o2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! v' M# c' W0 j2 i( A' m4 ?' ~- C4 @treatment for micropenis during early childhood. J. Pediat.,4 P& O, b* S3 v$ {+ S$ b& K
83: 247, 1973.
% \  A0 q. t; y; }. H- T5 W3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
- S! w7 Y, k& U% Done therapy for penile growth. Urology, 6: 708, 1975.3 t  l6 _8 k" v1 J
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( ?1 }3 s; }4 \+ x7 d4 a5 \3 X2 Nto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. y# E$ u$ `% N: n* z- N9 G
skin slices of man. J. Clin. Invest., 48: 371, 1969." L/ y7 z1 S: a3 Y( O
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 t! D$ U% T" j4 C0 B3 Y. K
by topical application of androgens. J.A.M.A., 191: 521, 1965.
. f" H2 w' u$ J( f/ `. ~; w& t$ x( m6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) {5 y6 Y8 G& E% ?0 Q( `) v
androgenic effect of interstitial cell tumor of the testis. J." p; `+ d3 I, e1 Q' Q# x3 s
Urol., 104: 774, 1970.
* c' ~# Z7 q. s7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-! ~0 l* S) ~4 T7 _7 O# n
tion in the male genitalia from birth to maturity. J. Urol., 48:
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