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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND1 g0 `: ]- \; O' n* J, p
GONADOTROPIN
2 U0 m5 c# Y, j' u0 ^: e8 mRICHARD C. KLUGO* AND JOSEPH C. CERNY
# h. _' p4 t+ c, J, M2 \2 ZFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
3 ~8 `  k4 x# C/ q, zABSTRACT
8 M& q/ t  Z2 l$ M/ Y8 z0 S/ ^Five patients were treated with gonadotropin and topical testosterone for micropenis associated* Y3 B0 t! p$ ]
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-) Q) E: j- Z2 f9 G$ |
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! M3 b; ?# @# Q. Vcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( P  E3 t2 D! g7 {5 D% A4 bfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 a5 z* U1 ~  B" b* x
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average) f: O3 l0 p+ P$ B" H, G: s  k( ^
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" k2 w) u; ?6 x/ X( Koccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# n- y# W- l. _4 x
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) E$ M: X( b+ {% [8 fgrowth. The response appears to be greater in younger children, which is consistent with previ-$ R- r" u% g: D' h. Z
ously published studies of age-related 5 reductase activity." n. D( F& N5 J8 m
Children with microphallus regardless of its etiology will
2 q+ }! E6 K8 l# ?. xrequire augmentation or consideration for alteration of exter-! t/ M: |0 B/ m7 x, F! ]  s
nal genitalia. In many instances urethroplasty for hypo-
3 y1 b8 H$ C. xspadias is easier with previous stimulation of phallic growth.# D5 X9 }$ R- w, O# a2 `
The use of testosterone administered parenterally or topically
% k! p7 w9 z4 d9 [2 l6 Jhas produced effective phallic growth. 1- 3 The mechanism of* l, o2 r9 P* T- b; C
response has been considered as local or systemic. With this* W6 f) `! M. I5 t) S6 p! E
in mind we studied 5 children with microphallus for response
* C+ K" w* V$ s0 i, uto gonadotropin and to topical testosterone independently.
" f% E) G; P+ z5 R  mMATERIALS AND METHODS
9 E" p% v9 F0 {# L- `% {: S7 F+ uFive 46 XY male subjects between 3 and 17 years old were% m/ g. m* L" ]; Q1 h' @
evaluated for serum testosterone levels and hypothalamic/ {1 K. K2 B4 T
function. Of these 5 boys 2 were considered to have Kallmann's
9 G; T6 c3 _5 H5 a7 y. M( P$ psyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 }' ?; P* ^2 w/ L5 O: U
lamic deficiency. After evaluation of response to luteinizing
8 w4 O  r2 m% [) x, H5 ]- u9 A3 O4 Lhormone-releasing hormone these patients were treated with' W! \7 ^' I3 T- H' V7 o
1,000 units of gonadotropin weekly for 3 weeks. Six weeks+ W6 |2 C$ L& e3 Z+ v& O
after completion of gonadotropin therapy 10 per cent topical
" o+ s) T7 h. a' otestosterone was applied to the phallus twice daily for 3 weeks.1 K# c8 Z) a1 t. a
Serum testosterone, luteinizing hormone and follicle-stimulat-. H- ~. [$ ]/ e
ing hormone were monitored before, during and after comple-/ Z. a) E4 v3 g; Q1 S
tion of each phase of therapy. Penile stretch length was
3 c7 S* O0 M. ?5 b0 hobtained by measuring from the symphysis pubis to the tip of, I# k- ?* E7 N$ N
the glans. Penile circumferential (girth) measurements were/ h. W) v6 T0 {- F, @: r$ k6 M
obtained using an orthopedic digital measuring device (see' P% B, x" Y$ A/ ~
figure).
+ C1 N; r2 h4 U* l' a# xRESULTS
# F4 K4 v; g& j9 o8 R, o% ^" Y& tSerum testosterone increased moderately to levels between6 h" C+ |$ F' M4 j  ]
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 t6 p2 r8 h' s  l; x- ?, e! s8 Rterone levels with topical testosterone remained near pre-
0 z, H  j: @0 @& r4 ttreatment levels (35 ng./dl.) or were elevated to similar levels5 d! R+ O1 m  b& U
developed after gonadotropin therapy (96 ng./dl.). Higher, I8 L# n" c5 V  }6 l5 s' S
serum levels were noted in older patients (12 and 17 years old),, Q1 o4 |- r" f7 l
while lower levels persisted in younger patients (4, 8, and 10. z: t$ C, Y8 m, X/ ^) l. E" A
years old) (see table). Despite absence of profound alterations
% n7 h1 Y/ F% W6 p! n/ x; nof serum testosterone the topical therapy provided a greater
& g) \- p1 Q+ M+ z4 l2 D  PAccepted for publication July 1, 1977. ·) h' K4 @* B4 i1 Z
Read at annual meeting of American Urological Association,
% s: u' F2 x9 q3 wChicago, Illinois, April 24-28, 1977.
# y$ I0 v0 h& L7 ^8 ~* Requests for reprints: Division of Urology, Henry Ford Hospital,
& a+ |# w" B8 O0 d4 A2 c- q2799 W. Grand Blvd., Detroit, Michigan 48202.. t5 Z) l& \- @$ [
improvement in phallic growth compared to gonadotropin.
6 Z2 _, c' Z* k  Q. t- L2 Y1 nAverage phallic growth with gonadotropin was 14.3 per cent
. u; x" U! S  n6 e0 R, j" n% C: gincrease in length and 5.0 per cent increase of girth. Topical
9 |2 w3 X6 v" btestosterone produced a 60.0 per cent increase of phallic length+ |# U% h. U; e* r, n
and 52.9 per cent increase of girth (circumference). The' U4 a2 p- z* O; n3 {1 g. ~  A, o% b
response to topical testosterone was greatest in children be-: Y3 l# C! _1 V, T( p: w& D
tween 4 and 8 years old, with a gradual decrease to age 17/ N2 e! A( Y% f. |5 c) y4 n
years (see table).
4 t8 f! a, E; _# v7 }DISCUSSION  J$ {! T+ C9 m  F& M1 D6 G
Topical testosterone has been used effectively by other
8 U: c6 g# ^6 R1 V) Q  l* Fclinicians but its mode of action remains controversial. Im-& J" R& ~( T5 u5 s) c5 q
mergut and associates reported an excellent growth response
% t( B3 W: j# cto topical testosterone with low levels of serum testosterone,0 \& t) e. {2 ?% u2 ~
suggesting a local effect.1 Others have obtained growth re-
: ^7 U! A9 w# \7 p7 r2 H( qsponse with high. levels of serum testosterone after topical; J7 }6 e3 O3 u. F2 w0 ~. H
administration, suggesting a systemic response. 3 The use of
7 S% @$ L1 W; }6 c* w) N/ F; y( Z4 Tgonadotropin to obtain levels of serum testosterone compara-
) K! U: Q7 ~! \' y$ M# kble to levels obtained with topical testosterone would seem to
4 z$ n- F5 J* e* gprovide a means to compare the relative effectiveness of
- P" u# @+ P9 g! Q  S: Ltopical testosterone to systemic testosterone effect. It cer-. j8 ^5 q, _: {7 Y0 `- {
tainly has been established that gonadotropin as well as par-1 y5 ]$ w' X/ A* l. U5 W9 T
enteral testosterone administration will produce genital0 H2 b* y, ?" o
growth. Our report shows that the growth of the phallus was9 K( p9 ^( l' I1 S6 t' p
significantly greater with topical applications than with go-
; u! q& y% h. L" |: X* snadotropin, particularly in children less than 10 years old.
2 U4 V( V9 e9 z7 x  yThe levels of serum testosterone remained similar or lower
& n5 N8 V) ?' r3 Sthan with gonadotropin during therapy, suggesting that topi-! x4 M0 b8 d# x
cal application produces genital growth by its local effect as
! L" E/ C/ j8 X- B) n$ V- l0 P' \well as its systemic effect.
/ U" ~, ]! o% E( ?! B5 aReview of our patients and their growth response related to
; `. `; W* V$ G" }% p6 i) Kage shows a greater growth response at an earlier age. This is7 C2 s, L+ q9 e
consistent with the findings of Wilson and Walker, who1 i1 K! l& N2 u& A# M9 X" r; A) F
reported an increased conversion of testosterone to dihydrotes-
7 U# L  z& R( t$ t- Ltosterone in the foreskin of neonates and infants.4 This activ-& i. C% T; ]# E% v8 q7 l# e0 L
ity gradually decreases with age until puberty when it ap-
7 Y: a! t0 u+ fproaches the same level of activity as peripheral skin. It may
$ B" z  a# r1 J2 twell be that absorption of testosterone is less when applied at
- G# F2 C) G' zan earlier age as suggested by lower serum levels in children
4 x5 w) ]3 k1 m% H8 H7 r$ oless than 10 years old. This fact may be explained by the
- d; N+ [1 j5 F, j2 E1 ^1 N: ^- Ygreater ability of phallic skin to convert testosterone to dihy-; |6 i( \( y" j) {) V! l
drotestosterone at this age. Conversely, serum levels in older
( c* ]0 [+ ~" L. l' }( r& apatients were higher, possibly because of decreased local
# D5 C6 j1 a- a# e! g" e4 W667& r. |0 o; }( ^- Y( A
668 KLUGO AND CERNY) I6 M* c/ r; `' q/ _6 O
Pt. Age3 C; K* z. _' p& S, a( F
(yrs.)
, W- U  a0 }3 H9 nSerum Testosterone Phallus (cm.) Change Length
- _1 [* b5 ]0 g, `2 c# I(ng./dl.) Girth x Length (%)$ R/ k+ K* e# y5 T- J
4
5 Y  h' w$ P" ], c/ t83 Z. A  d" c) Y  V8 f% t
10
& B% ]. q: o. N4 q- ]) C8 J12+ y  W1 D0 c6 \* j
17
' b7 w% j* F/ A$ y, b( l% [Gonadotropin- X/ M! X; v9 Y# x% j
71.6 2.0 X 3 16.6. v  q8 P5 a  J$ w+ _
50.4 4.0 X 5.0 20.0# h9 E8 M$ X+ b* O& P9 ?! O+ c$ A
22.0 4.5 X 4.0 25.0% q* A, s! f3 Q
84.6 4.0 X 4.5 11.1
# X0 U) {/ d7 A1 G6 E85.9 4.5 X 5.5 9.08 O- w; M6 A) X4 c9 q# q
Av. 14.3
* ?' A7 N# q8 D! `, F. t, h43 K' V$ C) C0 F  y7 T- o$ ?, K0 ^
8( j) K4 g0 R2 _4 v' O  B# c
10
5 `  Z7 k0 v2 R! g12
# p* m- m2 [; |; a) F) u# d$ D17, j, G1 r2 r, ^- r0 S* a
Topical testosterone2 E0 C6 `' ^+ g* X
34.6 4.5 X 6.5 85
0 T! S7 {/ T) S, a/ K38.8 6.0 X 8.5 703 e. i; I# w& \  `" ^
40.0 6.0 X 6.5 62.5
, w5 [1 K' K/ c1 @- S. g* a93.6 6.0 X 7.0 55.5( m4 k* T* j5 f- W; Y
95.0 6.5 X 7.0 27.2. U( i# g3 ~3 h% l/ C0 w4 p
Av. 60.0
4 O5 t3 S$ \' _* t1 Ravailable testosterone. Again, emphasis should be placed on! w: I: V8 D+ Q% d
early therapy when lower levels of testosterone appear to
/ Q1 ~* N8 x! O8 p1 |provide the best responses. The earlier therapy is instituted
4 X+ O+ `5 K( [) M9 W% a3 bthe more likely there will be an excellent response with low$ D7 x* Y3 L+ x- M7 F9 a+ Z8 \
serum levels. Response occurs throughout adolescence as
. F. }/ n  m1 _noted in nomograms of phallic growth. 7 The actual response
! @  a( d3 {) h2 [+ ito a given serum level of testosterone is much greater at birth- r9 \% [. Q8 u
and gradually decreases as boys reach puberty. This is most/ T% l. v2 l, z1 n7 m* B( n
likely related to the conversion of testosterone to dihydrotes-
) J+ c7 b; p  N% Ztosterone and correlates well with the studies of testosterone+ {$ z( g4 I; t; `
conversion in foreskin at various ages.8 D1 n" H4 s6 U5 n" H' h$ G
The question arises regarding early treatment as to whether1 C2 K* r) V* [) B* S' t
one might sacrifice ultimate potential growth as with acceler-4 C; o$ n0 f# Q
ated bone growth. The situation appears quite the reverse
- e9 G4 [. w  }3 P$ Y* Ewith phallic response. If the early growth period is not used
, P" m$ s) }' Xwhen 5a reductase activity is greatest then potential growth
- A  g4 d! X  z- i4 V8 omay be lost. We have not observed any regression of growth8 ~# e( h7 ~1 N5 q
attained with topical or gonadotropin therapy. It may well
! |4 U; F' f# g/ m+ i8 A2 M( q3 gbe that some patients will show little or no response to any' X% s. j3 ?* |3 C% g+ E0 J& E1 i
form of therapy. This would suggest a defect in the ability to" M; D8 z0 ?1 g2 \& R. r
convert testosterone to dihydrotestosterone and indicate that* q) m7 P$ F& C
phallic and peripheral skin, and subcutaneous tissue should
3 ]" Z+ K4 a! }0 w2 V! d2 ^be compared for 5a reductase activity.0 _2 e: e2 J" E( P0 O" r. \
A, loop enlarges to measure penile girth in millimeters. B,
: A6 v' l5 B' }- \0 Y; J% wexample of penile girth computed easily and accurately.
. x5 X# A3 x% s1 A4 b1 b. jconversion of testosterone to dihydrotestosterone. It is in this" [4 ?  ^$ t, D$ i$ G
older group that others have noted high levels of serum0 q; f2 O( G* R
testosterone with topical application. It would also appear
. p$ N: f$ N6 t& j* c3 p" E/ Wthat phallic response during puberty is related directly to the
0 B  e' E# E8 l# R0 Dserum testosterone level. There also is other evidence of local: l  t3 r- l4 o. e( e( f
response to testosterone with hair growth and with spermato-
9 }( a& t: h) V" G% A( J* l" N" R: tgenesis. 5• 6
- N3 O, B9 o; E* O2 |Administration of larger doses of gonadotropin or systemic
# a/ l+ o- ?( y% U! e5 z( O  Ftestosterone, as well as topical applications that produce/ k8 F: H6 Q5 x  p1 d
higher levels of serum testosterone (150 to 900 ng./dl.), will6 Y4 z' X' y4 N! I" v# G
also produce phallic growth but risks accelerated skeletal' y8 e, m! A8 g- R. M
maturation even after stopping treatment. It would appear( a0 i" b# y6 ]: O* y
that this may be avoided by topical applications of testosterone6 t( b1 z+ G* A9 }; U% F
and monitoring of serum testosterone. Even with this control
3 I" j, |0 L7 z" Pthe duration of our therapy did not exceed 3 weeks at any
" b% b( `$ ?# w+ L$ g( H. x/ R0 ?time. It is apparent that the prepuberal male subject may
3 X0 s+ g4 K. y2 b. Lsuffer accelerated bone growth with testosterone levels near. \+ I/ \) S2 [- y
200 ng./dl. When skeletal maturation is complete the level of/ P8 R: z" P4 e% B3 z
serum testosterone can be maintained in the 700 to 1,300 ng./6 k9 G& ]' t6 R& {" O7 b& u$ \! W
dl. range to stimulate phallic growth and secondary sexual
  E* E8 P. {" H& {4 b  ochanges. Therefore, after skeletal maturation parenteral tes-
: Y; M# v) W! J7 n! n2 utosterone may be used to advantage. Before skeletal matura-
8 q  W: ]* |# n! @: X5 _( wtion care must be taken to avoid maintaining levels of serum
& t1 X# J  m5 r% Y$ K0 ]; {1 etestosterone more than 100 ng./dl. Low-dose gonadotropin
7 H6 S" v* E) S, D* {$ w! L. zdepends upon intrinsic testicular activity and may require
- [3 u) f3 D: n/ x+ y  _prolonged administration for any response.: p2 H& h- k0 w" U+ }. \
Alternately, topical testosterone does not depend upon tes-
. e( O% M# ^- }' [- R- oticular function and may provide a more constant level of
9 d9 \7 V& N( r0 ^- kREFERENCES# u& z  w. G8 r# J3 B+ E
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks," R9 T- V7 y2 Y1 X
R.: The local application of testosterone cream to the prepub-( V; y5 }0 f% o0 t8 v
ertal phallus. J. Urol., 105: 905, 1971.! n1 a3 }5 u) I* a8 j
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# q& K: Q; ]. p% I3 r. K
treatment for micropenis during early childhood. J. Pediat.,! s# T! w, J% _
83: 247, 1973.' P% A  T; H, X. {, v4 N# J& ^
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 J) Z# x6 w+ E, G! S: S7 K- W
one therapy for penile growth. Urology, 6: 708, 1975.9 S; ^+ K, I* ~1 \5 R1 t$ g- N
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 e7 i0 U" ~, I+ `# I4 ?8 ]
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 M' `; H: U  s+ Uskin slices of man. J. Clin. Invest., 48: 371, 1969.
; X- K% P2 O. V  U( w. G) n5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ H7 @, f2 l  W9 P- h, ]2 ]
by topical application of androgens. J.A.M.A., 191: 521, 1965.% O" \  e! c& o5 b9 R
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local! Q. A, c" k$ m' l, e
androgenic effect of interstitial cell tumor of the testis. J.2 f! u: [+ s/ G
Urol., 104: 774, 1970.6 V6 [) M; X7 J* ]
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-! `, V0 `% w9 C* K- f4 N. @5 Y8 M9 ~
tion in the male genitalia from birth to maturity. J. Urol., 48:
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