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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND+ F% ?  X3 F3 b, B$ Q3 C% _
GONADOTROPIN: H) u4 t) C. f( o: }, K
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 Z% z+ I  [3 j, [% i- o6 H4 i  aFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan: _& S0 T* [! x  M. o8 J( ^
ABSTRACT3 ~8 j# x4 ?1 {( G; e+ m- J- Q! A
Five patients were treated with gonadotropin and topical testosterone for micropenis associated; x0 ?0 H8 |: b
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-$ n2 d6 H& h/ [; z2 L/ ^& `# d# N
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone" W# v$ h2 l' P# o
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 w1 L/ W' P+ K! \/ G8 v& ~
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
) E4 b- ~! w" \( y- l/ k! Yincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average# H2 g8 \( k- H& z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 f3 \& M* O- B/ x/ e2 Ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( G- W0 b! p5 r# G$ V0 A( M% ~study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile/ N# u) i: [! T1 y6 N
growth. The response appears to be greater in younger children, which is consistent with previ-
! S4 I' Z2 X& ~8 Sously published studies of age-related 5 reductase activity.! h* S. S' s' t* C0 \
Children with microphallus regardless of its etiology will2 i% a' Z7 F7 b( U' o! k/ h
require augmentation or consideration for alteration of exter-
  y5 R" [3 K2 }nal genitalia. In many instances urethroplasty for hypo-& I) f, |# O7 p; B7 F
spadias is easier with previous stimulation of phallic growth.
' o8 B$ ?3 v5 U6 l2 `: Z# z; H3 _The use of testosterone administered parenterally or topically. m$ q) V  D, d5 E: H
has produced effective phallic growth. 1- 3 The mechanism of
: G  u, ~. H; R, Nresponse has been considered as local or systemic. With this
# u- m2 M. ?% Y0 J/ G" iin mind we studied 5 children with microphallus for response  z7 J1 R2 _. k. D1 A9 C6 u0 i3 A
to gonadotropin and to topical testosterone independently.6 @# ?  J& M9 ]2 G) U
MATERIALS AND METHODS$ |# r# p0 a9 @4 Y: z: E8 T
Five 46 XY male subjects between 3 and 17 years old were' F5 W) `* B( |2 C3 w/ A
evaluated for serum testosterone levels and hypothalamic2 T9 U0 r  ]9 y6 C$ e' i9 {, E/ \4 B
function. Of these 5 boys 2 were considered to have Kallmann's
5 ]3 e/ u. V! A+ n2 Q7 _8 x! M) [syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 i% z+ Z/ ]! ^8 x7 e& J
lamic deficiency. After evaluation of response to luteinizing3 u! e2 u8 G  L! T6 `
hormone-releasing hormone these patients were treated with: q/ h( I0 _2 ?. D: e" j1 u  O
1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ T# q8 m+ B0 `+ S
after completion of gonadotropin therapy 10 per cent topical8 K4 F( m& l$ I2 @; C( q; P
testosterone was applied to the phallus twice daily for 3 weeks.* \+ Q4 b! e5 X2 E, g9 x1 b3 V6 G
Serum testosterone, luteinizing hormone and follicle-stimulat-6 c4 [  ?6 T% Y& C# P6 i. U
ing hormone were monitored before, during and after comple-
" b& v/ n% V4 ^7 D. x" [tion of each phase of therapy. Penile stretch length was' ?7 W% d, }, y( ?* h4 x5 D2 y
obtained by measuring from the symphysis pubis to the tip of% ]& I9 i$ V# ?, w% k
the glans. Penile circumferential (girth) measurements were
( d" Q7 }: C. L+ xobtained using an orthopedic digital measuring device (see1 a+ h9 F( s+ q+ }- s
figure).
" g$ X1 Y3 o$ S' o* I, z. y* ?RESULTS
# `/ Q2 g* z. D, D4 F. O$ JSerum testosterone increased moderately to levels between. `. {9 x* C5 @$ {
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-. L1 J7 k7 o% q  j) q; }; x
terone levels with topical testosterone remained near pre-8 o: B8 r% _6 E- o: Z9 K  ?$ ]! _* X
treatment levels (35 ng./dl.) or were elevated to similar levels, T. f8 Y1 g- I( K9 q* [
developed after gonadotropin therapy (96 ng./dl.). Higher
2 g& t7 l3 x. t- S- @  V" X0 C0 zserum levels were noted in older patients (12 and 17 years old),/ N. u) N* ^# b
while lower levels persisted in younger patients (4, 8, and 100 q% k% f3 d5 e! U" h2 X
years old) (see table). Despite absence of profound alterations8 D# B' u, L4 Y
of serum testosterone the topical therapy provided a greater
* G& w) @1 H1 K$ H* ]Accepted for publication July 1, 1977. ·; V1 L) F- T! F
Read at annual meeting of American Urological Association,
/ B9 j6 B( x# nChicago, Illinois, April 24-28, 1977.
8 Y6 {/ F- _/ L  N* Requests for reprints: Division of Urology, Henry Ford Hospital,+ L1 V( `. T5 e: G* O; b
2799 W. Grand Blvd., Detroit, Michigan 48202.
# N4 R! t, V. Fimprovement in phallic growth compared to gonadotropin.
" e, F$ T- d) l4 ~Average phallic growth with gonadotropin was 14.3 per cent* e$ `5 g& ~# Q$ s. I
increase in length and 5.0 per cent increase of girth. Topical* o# u. A  z$ [  _; W- N' P
testosterone produced a 60.0 per cent increase of phallic length
' {# J; I! W; R+ X! b. Oand 52.9 per cent increase of girth (circumference). The
) e0 g4 U3 c! D, x' lresponse to topical testosterone was greatest in children be-1 r: `& ]+ Z+ F( [. D& z) L
tween 4 and 8 years old, with a gradual decrease to age 17; \; c4 O- Q( Q& c
years (see table).
  D0 k) d6 U+ p$ t* u' N( S) PDISCUSSION
: G9 n0 [. W' U% E; `Topical testosterone has been used effectively by other6 m- r' i, X) O
clinicians but its mode of action remains controversial. Im-
, t/ Z' k2 V; S; o8 w! nmergut and associates reported an excellent growth response
$ t+ i6 {% _6 i  Q/ ~0 Fto topical testosterone with low levels of serum testosterone,9 \- Y5 o9 c6 M0 L/ x# U
suggesting a local effect.1 Others have obtained growth re-3 Y+ O9 C1 p1 ?2 G' F, x
sponse with high. levels of serum testosterone after topical
3 V3 U, h: M1 ]/ Padministration, suggesting a systemic response. 3 The use of: |2 Y% H; Q% o0 i8 }
gonadotropin to obtain levels of serum testosterone compara-
& C7 K# ~% p1 B* r5 h; Able to levels obtained with topical testosterone would seem to% A3 a9 n: h" j4 l# q
provide a means to compare the relative effectiveness of
' Q0 n3 Z) E1 etopical testosterone to systemic testosterone effect. It cer-9 n$ @# q; r$ N9 P# ]7 j
tainly has been established that gonadotropin as well as par-0 a8 F: N& k, T# o# |. D$ }; \
enteral testosterone administration will produce genital7 C( ~, P, z1 K# Y% K
growth. Our report shows that the growth of the phallus was: p6 q: H8 r( T# p
significantly greater with topical applications than with go-5 a# f9 i1 x' \' k$ l1 n$ j- o
nadotropin, particularly in children less than 10 years old.& e- q# M9 G5 ], x9 l
The levels of serum testosterone remained similar or lower
: }0 R; K6 D7 V% Y, z- j. F( \than with gonadotropin during therapy, suggesting that topi-
4 @3 Z# Z( @# z1 A' dcal application produces genital growth by its local effect as. F, E8 X' ~2 t/ @% l9 c
well as its systemic effect.. R) u/ m; a! L6 P5 ]" u& T1 B
Review of our patients and their growth response related to
( [. K% I3 g" ?: qage shows a greater growth response at an earlier age. This is7 l+ E& F1 x& a2 R' D
consistent with the findings of Wilson and Walker, who
) F9 L. w4 a) Rreported an increased conversion of testosterone to dihydrotes-: j" t. y+ C8 ~* l' e" f
tosterone in the foreskin of neonates and infants.4 This activ-4 l2 K8 l, F' r3 L. w; N
ity gradually decreases with age until puberty when it ap-
' v1 H$ n5 F0 `! y! V; v/ `proaches the same level of activity as peripheral skin. It may- W# v, F  Z- Z
well be that absorption of testosterone is less when applied at0 E+ {$ }9 }5 C! n) L2 p
an earlier age as suggested by lower serum levels in children" K! @8 b, L$ V8 i! v
less than 10 years old. This fact may be explained by the
8 x$ u% E5 Q' e+ f% G5 i% bgreater ability of phallic skin to convert testosterone to dihy-% u. G* Q( K3 f3 ^. {
drotestosterone at this age. Conversely, serum levels in older
$ u( O! l* @& e2 h, V5 mpatients were higher, possibly because of decreased local, C! U) k7 C- P# H$ {. V# D
667* r7 p  U& b2 }
668 KLUGO AND CERNY
! @% A8 s: S, {1 \! RPt. Age  m4 T1 S! V4 u$ H6 {
(yrs.)
0 s: h' }/ H5 D4 ^Serum Testosterone Phallus (cm.) Change Length! q2 z! T  k8 f+ N9 U
(ng./dl.) Girth x Length (%)
1 R( N, {1 y: a% `- J4
9 k2 Q- K- T) H* |2 F9 v' ?4 S" ?) r8
' o9 M- Q9 V  @# N6 a10
4 r3 b$ |" R$ X# ^; a9 L" t125 c' q' l4 q1 `* ]; f2 d
17* K7 |4 J$ c, K+ v4 Y2 c
Gonadotropin
: X; K. O: _( r3 y5 r# L71.6 2.0 X 3 16.6
. `& Y% [; ]; a* ^2 }( z. _50.4 4.0 X 5.0 20.0( D* @9 t1 i+ j/ ~
22.0 4.5 X 4.0 25.0
0 C4 w8 j% k5 C8 s# m7 L+ Y2 N84.6 4.0 X 4.5 11.1
! F1 u* f/ n  \85.9 4.5 X 5.5 9.0. |! ~! @. A4 `& V" h
Av. 14.30 A" |: c' g8 Z0 S# R
4
/ v6 E' L1 {( o  V+ j83 W7 ]3 c8 n/ w+ V
10
5 J: X8 T! w% }% n12# c- w7 `/ g" A  E3 k
17
9 _, T3 _4 d4 [6 e8 l2 pTopical testosterone' `' N. q0 }5 Y" g$ d" |
34.6 4.5 X 6.5 85" \9 b, |& [1 d" Y$ E) m
38.8 6.0 X 8.5 70$ G/ f! F, g5 R" Y3 o
40.0 6.0 X 6.5 62.5
# J3 y" R) Z  ?! b" }2 O% q) z8 P93.6 6.0 X 7.0 55.57 a- Y) |" A# J3 r3 `8 Q
95.0 6.5 X 7.0 27.2
$ Q- ^) D. x0 z: L1 E# s; ?Av. 60.0+ I5 x" f5 t4 ^& P* b4 f& c
available testosterone. Again, emphasis should be placed on$ c9 e: B, A, Z0 `
early therapy when lower levels of testosterone appear to
# U: X0 y$ I5 f: E9 o8 n% Gprovide the best responses. The earlier therapy is instituted
: `  M9 _2 m$ H, jthe more likely there will be an excellent response with low  p! B" h4 g' Y1 ~0 _- d
serum levels. Response occurs throughout adolescence as
8 v/ Z/ ]4 c9 t& k& Xnoted in nomograms of phallic growth. 7 The actual response
# n5 o, p; j) B7 Yto a given serum level of testosterone is much greater at birth* E1 N- W# `* C
and gradually decreases as boys reach puberty. This is most
; P$ `# {+ Z: r, h* H6 G* O1 zlikely related to the conversion of testosterone to dihydrotes-
# [% @5 p% W( qtosterone and correlates well with the studies of testosterone: V8 g* A* [: k
conversion in foreskin at various ages.
. w! q0 C- |7 j/ p9 [. qThe question arises regarding early treatment as to whether
2 n0 t, G& q3 a. u8 t9 i3 Xone might sacrifice ultimate potential growth as with acceler-1 t- |% E0 d) o' {2 R# M) h
ated bone growth. The situation appears quite the reverse: j2 r3 u. @( {4 W
with phallic response. If the early growth period is not used% ?0 N( l& N' D, [6 l
when 5a reductase activity is greatest then potential growth9 s) Y8 U: W) J" B* i4 r$ b& Z3 `
may be lost. We have not observed any regression of growth
+ _0 q, D; c9 [% S7 Qattained with topical or gonadotropin therapy. It may well
+ l  |1 F7 j4 d  L, R5 J' T! Zbe that some patients will show little or no response to any* d+ q9 k/ q! N; `  f) X
form of therapy. This would suggest a defect in the ability to
. \  x) ^8 b7 Yconvert testosterone to dihydrotestosterone and indicate that$ @4 \! C3 z5 T% H, \& w2 K
phallic and peripheral skin, and subcutaneous tissue should# G2 X; `+ u4 j$ T
be compared for 5a reductase activity.
: M/ }  M4 y. o, D5 nA, loop enlarges to measure penile girth in millimeters. B,
2 e6 t" Q. a  aexample of penile girth computed easily and accurately.5 ~; a/ ]6 c! d6 z8 P
conversion of testosterone to dihydrotestosterone. It is in this! q% R& s/ ~0 f# G* `8 w: f
older group that others have noted high levels of serum* k3 D3 p0 E& \$ j) W) S
testosterone with topical application. It would also appear
/ s. z2 Q% P# e7 v0 pthat phallic response during puberty is related directly to the/ c* [% \: m' [5 Z5 G7 L
serum testosterone level. There also is other evidence of local
' L1 o3 B  c1 _7 ]; L4 }* {response to testosterone with hair growth and with spermato-
4 m9 o8 p2 k' t# `' o& vgenesis. 5• 6
: M' ~# N: \0 t% ^) `& `Administration of larger doses of gonadotropin or systemic
7 R7 s4 u* A$ s+ vtestosterone, as well as topical applications that produce
: Z3 |9 U: b# K, D7 A+ ?- w8 g6 thigher levels of serum testosterone (150 to 900 ng./dl.), will
( t" w7 {  H' k7 @# d$ Balso produce phallic growth but risks accelerated skeletal
- A; [" G, y, _- @2 b4 u5 t1 `maturation even after stopping treatment. It would appear8 ?3 ^) e6 p$ `0 I+ n; h
that this may be avoided by topical applications of testosterone6 y. D$ C2 e* y
and monitoring of serum testosterone. Even with this control1 G' U  Q; o* O
the duration of our therapy did not exceed 3 weeks at any
* v5 {$ j8 H  `* M0 T0 Wtime. It is apparent that the prepuberal male subject may
/ L7 V' h) R3 d; o% J  n1 gsuffer accelerated bone growth with testosterone levels near
' G5 u8 x' K" A" o9 V! _3 s200 ng./dl. When skeletal maturation is complete the level of- n2 n( [6 q  n7 q3 u9 A
serum testosterone can be maintained in the 700 to 1,300 ng./
/ O& v7 Q0 ]7 T" xdl. range to stimulate phallic growth and secondary sexual: I' w* f4 l% r  `, D; u
changes. Therefore, after skeletal maturation parenteral tes-# p* |* S5 X8 q  k
tosterone may be used to advantage. Before skeletal matura-- `9 i5 H& Y# O. l2 z. n% U4 l0 L
tion care must be taken to avoid maintaining levels of serum! k2 @: W, e  W9 _. W
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ l* ~: h1 l: y" j+ Gdepends upon intrinsic testicular activity and may require- d( E$ n- c0 B5 |% `. f
prolonged administration for any response.- K: W3 h) b( a' l! e( v8 q
Alternately, topical testosterone does not depend upon tes-
1 p/ y7 E. T2 J2 ]ticular function and may provide a more constant level of
5 ?& A' b5 D5 |' \& o" wREFERENCES6 V- b' e( z; o# h1 w
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
2 A: F4 n! c, U# gR.: The local application of testosterone cream to the prepub-
0 \  P0 c' |/ _7 Q# ]) X7 `ertal phallus. J. Urol., 105: 905, 1971.
% I  L( f& O, G3 x2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone; W- s8 o# h9 H
treatment for micropenis during early childhood. J. Pediat.,
9 N/ X  h  |8 f* W9 q83: 247, 1973.
7 |, p: ~4 I4 e1 V- y3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-9 y" E- ?) W5 E9 n
one therapy for penile growth. Urology, 6: 708, 1975.
: M7 a7 O, A- `/ z, R4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* x# v2 G  n' V9 L& _8 D( bto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
0 e& G0 _7 ~8 Z+ Q- m; lskin slices of man. J. Clin. Invest., 48: 371, 1969.8 M% {2 S; e+ [- q: c
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 w7 Q: r, |* I- h- V9 d
by topical application of androgens. J.A.M.A., 191: 521, 1965.
7 {3 I+ F5 E2 D8 T" d; P& \6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ a& C" _% g; g; h$ K( N
androgenic effect of interstitial cell tumor of the testis. J.1 n9 o; a$ ]1 L; Q6 C
Urol., 104: 774, 1970.
/ |: ^0 ^& F) {$ x- v5 {. V& O7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
2 ^% o* J; `. C: g1 Y* Ntion in the male genitalia from birth to maturity. J. Urol., 48:
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