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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 }4 j7 F( F' \  h/ j$ X  _GONADOTROPIN
2 t' n( |3 {' C! E4 f' nRICHARD C. KLUGO* AND JOSEPH C. CERNY
* f5 T4 l, ?/ D7 O- O: CFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
8 e7 y0 E5 ^9 b6 O) }3 }ABSTRACT& Z, @. K( l. |3 j+ H
Five patients were treated with gonadotropin and topical testosterone for micropenis associated, t4 _$ x2 d+ u3 \; @
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" W4 ?0 Q$ o- K% N% t. J! B# O" `
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# {& Z" o% P+ Z- |4 U
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 ~  ~+ c# |" F$ M3 H2 Ffor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 }4 h7 k8 a7 e( n3 A
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average, U  i% f3 J/ q: e5 e. A
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 i: a+ h' ^" s" j4 a
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
7 P0 `- I  R/ L' E# ~4 R( Estudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile. P" G8 @8 E- b) i
growth. The response appears to be greater in younger children, which is consistent with previ-
$ d# U, K# o9 A1 p4 u& d- T7 i, L) vously published studies of age-related 5 reductase activity.
* V. V5 F; }2 ?" W, MChildren with microphallus regardless of its etiology will
$ o9 z7 g- P6 n, M$ ?& W- Nrequire augmentation or consideration for alteration of exter-
" h* L8 A' ?* K4 |nal genitalia. In many instances urethroplasty for hypo-
. t" W, s6 c: h5 V0 Qspadias is easier with previous stimulation of phallic growth.+ Y9 E2 V2 |! ?: F
The use of testosterone administered parenterally or topically, s8 ]9 b4 o  }$ g( r
has produced effective phallic growth. 1- 3 The mechanism of6 F  K$ T3 e0 p4 |/ [" Y# j
response has been considered as local or systemic. With this9 I$ N; T' n& D$ y& [
in mind we studied 5 children with microphallus for response
; y! {" ?0 G' j/ {* Wto gonadotropin and to topical testosterone independently.! ]$ k$ ~6 v1 k& e
MATERIALS AND METHODS
0 ?1 {. V) ?' ?Five 46 XY male subjects between 3 and 17 years old were" p, J  d2 o" \
evaluated for serum testosterone levels and hypothalamic9 y: Q* P* B7 u
function. Of these 5 boys 2 were considered to have Kallmann's
6 V0 V( v- g9 Qsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-( k' U  L: |% T3 H. S# j0 y
lamic deficiency. After evaluation of response to luteinizing
# \9 V  c' h7 s- N8 |( w' shormone-releasing hormone these patients were treated with# j' b+ d/ u5 W. a0 h' H
1,000 units of gonadotropin weekly for 3 weeks. Six weeks  Q' e1 t$ k( U& X+ D8 M/ p: ]" `
after completion of gonadotropin therapy 10 per cent topical: j' M( \1 |; [, S4 V  v/ r
testosterone was applied to the phallus twice daily for 3 weeks.
0 b+ r) m' S# z* B% rSerum testosterone, luteinizing hormone and follicle-stimulat-
& o; y" T3 C* f4 n/ n  w( n2 uing hormone were monitored before, during and after comple-
$ U- ^3 J& p. ~$ jtion of each phase of therapy. Penile stretch length was& G6 J. P9 r! @- s. y
obtained by measuring from the symphysis pubis to the tip of/ q2 E$ f+ b- ]3 j% o% p4 N; D% Z
the glans. Penile circumferential (girth) measurements were
. [1 H  C/ w# i, f  Q7 G5 n  I9 Gobtained using an orthopedic digital measuring device (see. {/ i- t! h4 w7 `+ M' c( ?
figure).
9 f( w6 t0 w+ ERESULTS0 L2 ?' f6 c% {) ?, L# ?5 [
Serum testosterone increased moderately to levels between
/ a2 ?) a, }# ?! B3 |( @% s% P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
, J; s& {) ]* a5 N: y: dterone levels with topical testosterone remained near pre-) L0 S3 X6 {2 Q$ d) r$ I
treatment levels (35 ng./dl.) or were elevated to similar levels; U) `( D1 ^: X# D5 |8 R2 Y8 l, w9 V
developed after gonadotropin therapy (96 ng./dl.). Higher* B+ X8 s4 @9 _
serum levels were noted in older patients (12 and 17 years old),7 n# C* N5 v/ c5 ^
while lower levels persisted in younger patients (4, 8, and 10
' v8 S5 o# n* cyears old) (see table). Despite absence of profound alterations
: m/ ~( P2 i0 M* }8 P: ?of serum testosterone the topical therapy provided a greater
1 v2 V' _, `  AAccepted for publication July 1, 1977. ·+ B$ X' [1 [7 Y$ L4 C
Read at annual meeting of American Urological Association,
, v* d7 a1 K" ^# sChicago, Illinois, April 24-28, 1977.
) `+ @" K/ ^# r  b9 R( J* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 b* ]+ r  @5 L0 U  J: }/ `2799 W. Grand Blvd., Detroit, Michigan 48202.1 x+ m2 A: i. U- [# s
improvement in phallic growth compared to gonadotropin.
, R+ k) r: \9 ~' L+ f, a- JAverage phallic growth with gonadotropin was 14.3 per cent* e$ _6 b  d$ u5 j
increase in length and 5.0 per cent increase of girth. Topical8 B) f/ k# f/ |- D2 d% A. A- O
testosterone produced a 60.0 per cent increase of phallic length8 Z" x) f% T# E9 u) O6 P
and 52.9 per cent increase of girth (circumference). The, C1 w7 x, y' l$ _8 N& B
response to topical testosterone was greatest in children be-
- l" A# v9 O6 D8 v2 j9 Gtween 4 and 8 years old, with a gradual decrease to age 17( d- k2 g  q1 j
years (see table).
4 w2 w. U/ \3 Z) }5 _1 h- p! BDISCUSSION
. n' i3 }" G; vTopical testosterone has been used effectively by other( Y: g4 @# d) Z* u- ]& |
clinicians but its mode of action remains controversial. Im-
* S# o, b* l7 B" L3 rmergut and associates reported an excellent growth response4 S' M3 I. w( |2 O. v
to topical testosterone with low levels of serum testosterone,
/ p# }8 z; a6 v' O. s3 vsuggesting a local effect.1 Others have obtained growth re-
1 k9 i7 V" ?0 F, ^2 |! _! k1 Isponse with high. levels of serum testosterone after topical( [7 d- n5 Z0 P/ p, m- b. j
administration, suggesting a systemic response. 3 The use of  }( |+ Q* d9 L
gonadotropin to obtain levels of serum testosterone compara-6 l; C. d- E; m9 b, L
ble to levels obtained with topical testosterone would seem to
- K5 [9 ]2 p3 Lprovide a means to compare the relative effectiveness of# C- x& p; \2 ~& G0 h) M
topical testosterone to systemic testosterone effect. It cer-" U( G7 y7 U4 ]  x
tainly has been established that gonadotropin as well as par-
1 N4 Z- P7 p/ Tenteral testosterone administration will produce genital1 ~( r1 s" u* z8 d8 ]
growth. Our report shows that the growth of the phallus was
( O0 ?2 N$ j9 ?2 _1 wsignificantly greater with topical applications than with go-. ^- s+ m; N/ h* F' V6 {, N
nadotropin, particularly in children less than 10 years old.
" }: G  H( }9 l2 c3 H! KThe levels of serum testosterone remained similar or lower
9 U! ~; o& D4 B+ Othan with gonadotropin during therapy, suggesting that topi-1 Q8 Q/ o: z/ u# r/ x
cal application produces genital growth by its local effect as
% _2 \/ t: q8 h6 B2 Hwell as its systemic effect.
( `% ?) I% d" w3 TReview of our patients and their growth response related to
% I# Y4 j; V( s6 t: I: aage shows a greater growth response at an earlier age. This is$ J) r: l. Z1 v0 B; N; F( B: z9 X; H
consistent with the findings of Wilson and Walker, who1 ]( `8 f' H. _$ r6 G) I
reported an increased conversion of testosterone to dihydrotes-
9 D! I- y: n/ k; ?4 c: jtosterone in the foreskin of neonates and infants.4 This activ-& @* R+ ^' o, ]( Y+ @; n
ity gradually decreases with age until puberty when it ap-9 D8 N, U8 O0 U, L* D. N7 a  W: h
proaches the same level of activity as peripheral skin. It may6 {4 ?- a# a0 _+ A8 [& m
well be that absorption of testosterone is less when applied at
8 A# L# \# V! C$ F- i) S0 @( ^0 Pan earlier age as suggested by lower serum levels in children
! H+ g$ o2 ]' @$ `% p$ {* Hless than 10 years old. This fact may be explained by the. w5 T1 s, ?% A% W& @
greater ability of phallic skin to convert testosterone to dihy-0 q! |7 v8 \8 u, K, q5 ^5 a  G
drotestosterone at this age. Conversely, serum levels in older
' I3 Y. I# P& z3 _- mpatients were higher, possibly because of decreased local2 }- m! p+ l; c! X/ K
667
$ W. n8 b0 ~3 ]# y9 U668 KLUGO AND CERNY
4 j- c4 O! \) R7 _; y8 ?1 f2 |Pt. Age
2 _$ z5 U* S* _5 ~$ R( p(yrs.)
) `2 Q) k" |; S  r$ d0 M0 z% h$ vSerum Testosterone Phallus (cm.) Change Length
/ S; D* l6 t! m4 N: E* H(ng./dl.) Girth x Length (%)) j9 a+ j* s: h* H7 }( o0 H- [
4
- t9 Y% j- O( w/ L2 e" S4 G8) C3 V5 {* C) K  [" P9 O4 m2 |. }
10( U: k2 Q3 ^, p# j
12" o" x+ u7 Q7 G6 q  P$ w# u
17
1 Z+ l' ~. G/ K- O, gGonadotropin
5 g1 a3 ~: v  C% V  z5 \+ H- e  E71.6 2.0 X 3 16.6
* p; q. m8 o4 ^: U  T  t4 _50.4 4.0 X 5.0 20.0
  l- w% J  O2 _7 ~$ u7 m# P22.0 4.5 X 4.0 25.0
9 j# g) D# ~. v8 Y! [4 z8 g' `84.6 4.0 X 4.5 11.1, z5 W; C9 N# e! M# [" K
85.9 4.5 X 5.5 9.03 p% R" S1 D/ ~
Av. 14.37 x6 Q" s* `- y- l# x5 M( F) x1 q
4
6 G! ~* K+ a% ~4 f5 [8: W( X, i6 @  p/ |# }
10
3 P, ?: \! Q4 W( |* o9 p12
3 ], G; W: g3 H+ G' \  g2 `; b# ]171 t/ q' i: u8 ?$ n" K$ Y4 L- z. c
Topical testosterone, R4 i6 f0 \$ x' z
34.6 4.5 X 6.5 85
% k" H* d5 d1 N  @38.8 6.0 X 8.5 70
, M/ u; q3 d0 k+ E# c40.0 6.0 X 6.5 62.5
' E' a7 i5 @7 Y* o; `" W1 w* ^) }6 H7 I93.6 6.0 X 7.0 55.5
- x. o- |/ A! D3 c% r7 p95.0 6.5 X 7.0 27.2- p: O  ~* e% i& M$ a9 e
Av. 60.0
+ W0 l- R& N% V" H- T1 W, tavailable testosterone. Again, emphasis should be placed on
; U' h8 U; n' H% M" c: J0 qearly therapy when lower levels of testosterone appear to
% h5 q$ g( R% Nprovide the best responses. The earlier therapy is instituted2 b* x8 y3 O4 `# ~/ }0 j; k" t
the more likely there will be an excellent response with low2 l. |. G: E1 m: s9 U* G! a
serum levels. Response occurs throughout adolescence as5 B3 F0 J4 t. M6 ?
noted in nomograms of phallic growth. 7 The actual response% |4 P. r- r8 G" l, ]
to a given serum level of testosterone is much greater at birth, [: g% Z2 z' n$ t
and gradually decreases as boys reach puberty. This is most
) U% T/ \& N3 J) }8 l2 G9 Ulikely related to the conversion of testosterone to dihydrotes-2 I" t( ]- v& M/ a  l; Z; y
tosterone and correlates well with the studies of testosterone
; L: M" A  {/ D9 R- Q4 s/ zconversion in foreskin at various ages.8 D* ?' n  A# E' \: f) h6 P& `
The question arises regarding early treatment as to whether0 t) g3 H* J/ @
one might sacrifice ultimate potential growth as with acceler-
3 s2 `5 [0 G# M5 X& d) A: ]ated bone growth. The situation appears quite the reverse& }+ L' \' P, F% R; r$ t
with phallic response. If the early growth period is not used, ?4 \/ n3 ~4 f4 g
when 5a reductase activity is greatest then potential growth
# ]" J1 x# `  y( I0 {may be lost. We have not observed any regression of growth- G2 T. M- E. X$ ~% u- T
attained with topical or gonadotropin therapy. It may well( [( J8 f! y) v5 j3 Y& O8 W2 u
be that some patients will show little or no response to any
) n* _! g- K6 S- Bform of therapy. This would suggest a defect in the ability to1 j2 t6 h. c% r9 T
convert testosterone to dihydrotestosterone and indicate that( `& m  H# o! x2 T9 D& B
phallic and peripheral skin, and subcutaneous tissue should: O% f$ @3 `! k, r5 _7 [5 E0 J
be compared for 5a reductase activity.
* `* i9 T6 r* s( _( _; y. _$ NA, loop enlarges to measure penile girth in millimeters. B," e, K# _, W7 o/ L4 V9 @: u4 J
example of penile girth computed easily and accurately.
& F9 ]) {! y, Cconversion of testosterone to dihydrotestosterone. It is in this6 l' e+ j! h7 b5 S
older group that others have noted high levels of serum* r9 l. ^: i4 c
testosterone with topical application. It would also appear" `8 t7 R0 A, |- Z' R
that phallic response during puberty is related directly to the
0 \1 H+ g& i- F: W) c0 ^serum testosterone level. There also is other evidence of local9 P5 Q6 P; P3 G, C2 H
response to testosterone with hair growth and with spermato-* _1 z( {& l/ Q+ e
genesis. 5• 6
( u) U  K' r% o  L2 i+ ZAdministration of larger doses of gonadotropin or systemic
9 w. I* B! _% `( k+ ^testosterone, as well as topical applications that produce7 P. |' p" p2 ~, H
higher levels of serum testosterone (150 to 900 ng./dl.), will& H2 X' _  }4 m, G3 F% `
also produce phallic growth but risks accelerated skeletal
) _# \; R! I% t2 h1 Tmaturation even after stopping treatment. It would appear
% R# r1 w* g+ I0 x  m: Xthat this may be avoided by topical applications of testosterone2 t4 c$ T0 w( j6 {& D
and monitoring of serum testosterone. Even with this control
, {& S; E3 |. Uthe duration of our therapy did not exceed 3 weeks at any. I5 j1 x- n  x5 x1 M1 ?9 f
time. It is apparent that the prepuberal male subject may
6 C  Q; H: ^1 c6 n; w% H/ msuffer accelerated bone growth with testosterone levels near6 K& R$ q/ H% M) J. H) M3 }) m% I
200 ng./dl. When skeletal maturation is complete the level of1 X$ e. `/ s& z, ?& @1 q
serum testosterone can be maintained in the 700 to 1,300 ng.// N/ H5 t9 M+ l* {* X; g# T
dl. range to stimulate phallic growth and secondary sexual: h% J: S7 n1 U, U; S0 d
changes. Therefore, after skeletal maturation parenteral tes-
' ]9 E5 K( h9 n) `tosterone may be used to advantage. Before skeletal matura-
6 o9 S% ^4 d, n  |tion care must be taken to avoid maintaining levels of serum& U7 m# n) b6 e, M  [, P. M3 h
testosterone more than 100 ng./dl. Low-dose gonadotropin2 |7 O+ q( B7 f, F; B6 M0 T0 k
depends upon intrinsic testicular activity and may require
$ i- V: _$ E  tprolonged administration for any response.8 n3 @* \9 _- N* g" i
Alternately, topical testosterone does not depend upon tes-
0 s: x5 E& {5 n4 cticular function and may provide a more constant level of( g6 T& Y' @: O: s5 E; w+ D& m/ f
REFERENCES* F4 A) I7 C, e( |0 {
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
5 g7 f  p* w/ e" dR.: The local application of testosterone cream to the prepub-
$ g( X* g4 J9 }6 G  Sertal phallus. J. Urol., 105: 905, 1971.# ?- V4 {4 L, L2 L8 j3 Z
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone& B5 e9 B. m3 I7 d( V  \$ ^
treatment for micropenis during early childhood. J. Pediat.,
- b6 m5 H$ ~7 x! d83: 247, 1973.
  w( H) W( X5 `* K/ O3 ]" X' O3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
- X5 f3 n: p4 `1 d. Z5 m1 h8 Z% Wone therapy for penile growth. Urology, 6: 708, 1975.
. V) Z3 s; v5 K, X2 {4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) C7 ]+ F8 T" q. G- f2 }to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% t; [; x! e! ?( j, ]
skin slices of man. J. Clin. Invest., 48: 371, 1969.
" j! V6 W, v1 g; u0 q2 p5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) ^1 y* b$ c+ v) P- V8 X
by topical application of androgens. J.A.M.A., 191: 521, 1965.
" j# h" \8 B7 o1 K1 A4 B7 C1 W6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 n0 V7 H8 M4 G) u
androgenic effect of interstitial cell tumor of the testis. J.' n+ }) [: P; V& T
Urol., 104: 774, 1970.0 f) A  i/ o! n8 H% ~  ^
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
9 _8 c, a& Z. |% ction in the male genitalia from birth to maturity. J. Urol., 48:
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