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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
) ]- o; x. X: SGONADOTROPIN
9 ]5 A. o6 @6 } s& M' qRICHARD C. KLUGO* AND JOSEPH C. CERNY
' f# m' v% J' k( x5 HFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
; t1 m2 X9 T: |0 E; Y. W2 YABSTRACT% l1 M" o, M7 `1 m* c1 w# h
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' Y! g: X7 {' U* p" K
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ L0 S; w5 p- O. g
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# I# t, e4 j: z' P
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
/ P% F1 i. J, _for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 s8 b2 y0 y9 y' ?; r$ Z% @increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average# Z" q3 O, |& `# ~
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 _4 r* s [9 |: Z) Boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This0 @$ g0 x: L- G ]
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 b+ j/ d% z, z% |- rgrowth. The response appears to be greater in younger children, which is consistent with previ-% z) k' W4 R: O/ s& w. ]% s
ously published studies of age-related 5 reductase activity.0 p2 C7 R% {& t2 o
Children with microphallus regardless of its etiology will3 s% Z8 U) T+ N" q @
require augmentation or consideration for alteration of exter-
& r& f" h! Q+ T" Y; I y1 znal genitalia. In many instances urethroplasty for hypo-
/ w" g% b% ^% @! Dspadias is easier with previous stimulation of phallic growth.
6 W. M8 V, @# z6 wThe use of testosterone administered parenterally or topically) I$ S0 V/ E. d# p4 F* f8 e" @7 b
has produced effective phallic growth. 1- 3 The mechanism of7 P: C8 K' Y! G
response has been considered as local or systemic. With this
. @: l# @& Q- o- M( S; Din mind we studied 5 children with microphallus for response
- h6 V6 Q! F' i, R, s- t+ dto gonadotropin and to topical testosterone independently.$ i- S) }0 ^( o$ x+ R
MATERIALS AND METHODS9 i. n2 L$ f5 I
Five 46 XY male subjects between 3 and 17 years old were
6 b+ \, q4 n( \: Q! @: n& \evaluated for serum testosterone levels and hypothalamic
, R# z' @9 y9 I. ]- }: yfunction. Of these 5 boys 2 were considered to have Kallmann's4 r: z U; i* y$ A. m
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" H$ g: r# N, h- t
lamic deficiency. After evaluation of response to luteinizing
+ b7 [% D5 w, T$ shormone-releasing hormone these patients were treated with
, |0 c3 U2 _) X1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 N9 ^' `4 M2 K# Y+ K; j3 X
after completion of gonadotropin therapy 10 per cent topical
9 c' }6 g7 ]. f' G) qtestosterone was applied to the phallus twice daily for 3 weeks.
* }4 \$ Q1 `* V0 A5 C$ i& H: nSerum testosterone, luteinizing hormone and follicle-stimulat-
, V4 ?6 q: }: n" y, E4 ~ing hormone were monitored before, during and after comple-8 D$ [2 F+ ]" P2 u
tion of each phase of therapy. Penile stretch length was, b! l6 Z" \, j: x
obtained by measuring from the symphysis pubis to the tip of
7 |0 `4 P3 r7 r8 T) P# c* Mthe glans. Penile circumferential (girth) measurements were# B$ F+ ]" v0 F, Q" K
obtained using an orthopedic digital measuring device (see
2 V& ?2 C3 c: P" t0 Q2 y; Nfigure).
1 K9 b9 V6 H( M! f. h7 XRESULTS
- T u+ `. q7 ?. `+ n/ |Serum testosterone increased moderately to levels between
! {$ {& K0 @3 v/ ?6 [5 H+ n0 S2 @50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' K; Y5 W% l6 o3 _4 f6 @% m
terone levels with topical testosterone remained near pre-
1 c5 R4 [% a/ X" v n$ N7 Mtreatment levels (35 ng./dl.) or were elevated to similar levels
% C) s2 L; e, o7 C$ x# u6 T5 n( k& Tdeveloped after gonadotropin therapy (96 ng./dl.). Higher
. H, l) K$ @* B& e6 Qserum levels were noted in older patients (12 and 17 years old),* N4 S! V$ P2 M) `/ r
while lower levels persisted in younger patients (4, 8, and 10
1 Z( q' ]# x8 P4 t: P4 Jyears old) (see table). Despite absence of profound alterations! {6 D' f" h& g1 z4 ^! W/ s( n
of serum testosterone the topical therapy provided a greater; d5 e9 O' e: k# X
Accepted for publication July 1, 1977. ·5 K2 }5 e( |7 A2 ^& {
Read at annual meeting of American Urological Association,
. t+ O2 y C" H8 M$ }* aChicago, Illinois, April 24-28, 1977.0 N7 b+ x0 a3 h% e
* Requests for reprints: Division of Urology, Henry Ford Hospital,
, [" A: Z/ V% D7 Z# ]" J2 B2799 W. Grand Blvd., Detroit, Michigan 48202.
5 B5 b/ x! V, a* n% e; j9 Cimprovement in phallic growth compared to gonadotropin.
$ O; \4 a1 c P! r' R- V" UAverage phallic growth with gonadotropin was 14.3 per cent" j) `/ r- f# _" a9 h$ g M
increase in length and 5.0 per cent increase of girth. Topical
3 v) a& u2 K4 }& |/ F; c; F; Htestosterone produced a 60.0 per cent increase of phallic length
- Q a# h: E0 |/ G. X/ t) u$ P" Rand 52.9 per cent increase of girth (circumference). The
% ^7 ^% `" {" ]5 [% lresponse to topical testosterone was greatest in children be-$ P4 P' |2 q$ @" q4 F/ T
tween 4 and 8 years old, with a gradual decrease to age 17/ `/ m D2 }0 k6 C2 k- t: `9 @9 V
years (see table)./ \8 a6 c! v- R; a
DISCUSSION) v. J' @' P i2 y: ?( L- A1 f4 D' |" f
Topical testosterone has been used effectively by other
, }- e' O, Q2 Q1 e& Fclinicians but its mode of action remains controversial. Im-
) z0 }( F6 X. A$ g% O+ a/ }mergut and associates reported an excellent growth response
5 L$ P% ], B8 Q% w' _+ f) J7 ]to topical testosterone with low levels of serum testosterone,% S6 t- z# F. u, Z; N w& [
suggesting a local effect.1 Others have obtained growth re-- N4 \2 C: b6 l8 q
sponse with high. levels of serum testosterone after topical4 H9 i8 Z# ^! f3 B* r( j3 c, h
administration, suggesting a systemic response. 3 The use of& }& P& }+ A7 Z: t* \
gonadotropin to obtain levels of serum testosterone compara-/ C2 x T" N* S( A+ h
ble to levels obtained with topical testosterone would seem to
9 `$ z0 e- x! d) Zprovide a means to compare the relative effectiveness of
, `# x. z7 q6 ^. \8 rtopical testosterone to systemic testosterone effect. It cer-$ L: \% U& c( r8 I2 k) d0 o, |- J
tainly has been established that gonadotropin as well as par-; k9 k% ~: X4 d
enteral testosterone administration will produce genital
) m6 t3 p7 Q1 v' S4 kgrowth. Our report shows that the growth of the phallus was
5 t& J) V2 ]* dsignificantly greater with topical applications than with go-
+ v1 r; q. P% }& J7 xnadotropin, particularly in children less than 10 years old.% R% U7 O8 W0 X1 O" c
The levels of serum testosterone remained similar or lower
; V; p3 A: G+ I& Z; ~6 Dthan with gonadotropin during therapy, suggesting that topi-7 ` P2 K1 c7 w$ I$ G
cal application produces genital growth by its local effect as
8 O4 W# o2 M C# e% J1 q% Ywell as its systemic effect.# s( Y& \" I4 a. i. a: d
Review of our patients and their growth response related to8 c# b; u* J$ y
age shows a greater growth response at an earlier age. This is
5 V! N& _6 r8 k3 C- ~5 \; fconsistent with the findings of Wilson and Walker, who4 a8 H9 R* L! X' x% p2 \! c
reported an increased conversion of testosterone to dihydrotes-
! [- W, E2 _; g1 Wtosterone in the foreskin of neonates and infants.4 This activ- Z3 p% ~9 C7 _$ h- |
ity gradually decreases with age until puberty when it ap-
: o2 d3 ?* q) p: e* X) D( Pproaches the same level of activity as peripheral skin. It may# V( f+ b0 B" }4 Z k1 a$ g
well be that absorption of testosterone is less when applied at
) T, e& k$ @+ H5 ^5 P5 B" I6 G: ean earlier age as suggested by lower serum levels in children
2 {: ^# _( B2 Bless than 10 years old. This fact may be explained by the
5 n6 `8 \0 o& @; u, S% k% ngreater ability of phallic skin to convert testosterone to dihy-: y9 ?' M9 ] ?4 P$ c
drotestosterone at this age. Conversely, serum levels in older0 v2 j# Q) g& s" {4 z# t
patients were higher, possibly because of decreased local
# ?$ H- ]- Y+ r3 n5 Z1 a/ g) R% J667
( v# j- o2 r @& O7 m668 KLUGO AND CERNY
0 x# v! v% I% s9 R. l0 ^Pt. Age
u0 d* b- J& v9 y2 T(yrs.)5 g" z, u$ q! t2 k" \' y0 Z2 y
Serum Testosterone Phallus (cm.) Change Length1 P6 L, m. y' j/ W9 b" K
(ng./dl.) Girth x Length (%)
, n ^6 O& F0 f6 i$ m% c( N40 C6 D) }3 y1 L' \; B# i
8
5 _0 G8 V& w5 l109 `& C9 @* F3 j$ }& m7 m% s
120 c/ ^1 y; M. Z, _& T
17! i7 ~5 c j }/ J1 z. U% O
Gonadotropin w8 }. M8 l' j' p4 [8 g- E1 F
71.6 2.0 X 3 16.6
/ z s8 H8 f; q6 R4 I- b50.4 4.0 X 5.0 20.0
6 O, b7 G5 M3 {) I, H22.0 4.5 X 4.0 25.0" P8 {) b7 A9 |6 _+ F2 @
84.6 4.0 X 4.5 11.1. x( w( z; L/ _! E9 D) Y7 r
85.9 4.5 X 5.5 9.04 {- Q% v: _% Z
Av. 14.3
5 Q2 B7 }3 d6 B* e7 }( |4
4 v3 Q( Z8 |& ?* c87 x+ `; I7 [/ Y/ J) p; e3 P/ s
10( V- ]2 I7 E# o
12, K0 @. [8 S7 B5 b
17. S8 W" f9 G! _* {) ?
Topical testosterone
: e+ {. b- w6 G34.6 4.5 X 6.5 85
4 E/ @' n/ H1 w38.8 6.0 X 8.5 70
6 l1 Z2 B/ M+ t8 z* X9 e40.0 6.0 X 6.5 62.5' ]/ |8 Y# ~( R1 m9 I9 ~& V2 L
93.6 6.0 X 7.0 55.5
2 ^- C9 D; p M* Q1 K95.0 6.5 X 7.0 27.2: R" |+ B& K7 V9 n4 H
Av. 60.0
% d- w, y) `% [5 j' ]0 `3 _available testosterone. Again, emphasis should be placed on! j( Q1 y* J, j- s5 r p. x
early therapy when lower levels of testosterone appear to, x0 R4 ^, e! e( w8 A$ Y
provide the best responses. The earlier therapy is instituted
6 g, |0 f* H* n% j) |) S7 Gthe more likely there will be an excellent response with low
' y" ?' i) x3 _& M& k9 f& ^serum levels. Response occurs throughout adolescence as5 o% a2 ~ Y# M; P# d8 u
noted in nomograms of phallic growth. 7 The actual response( a( L9 l j* P2 R( U
to a given serum level of testosterone is much greater at birth5 [3 S7 w' ^" q0 w- S+ {. K: z
and gradually decreases as boys reach puberty. This is most
% N# ~ S+ V( R: J: n& {9 D3 t: wlikely related to the conversion of testosterone to dihydrotes-5 ^4 g0 h* X, Y( F( @
tosterone and correlates well with the studies of testosterone O# ]/ x% W9 Y! A0 b* } @
conversion in foreskin at various ages.% ~1 j: Y& Y9 h9 P% Y
The question arises regarding early treatment as to whether* {! a$ Z, {+ ~4 r/ r: w- ]
one might sacrifice ultimate potential growth as with acceler-/ k4 Z' @* m: G7 F) o) k
ated bone growth. The situation appears quite the reverse
) \- O4 J; ~" vwith phallic response. If the early growth period is not used
3 l9 D& J7 o O" p; J, |! h' awhen 5a reductase activity is greatest then potential growth/ f" n$ x: j) Y, c8 c; s
may be lost. We have not observed any regression of growth
' }7 c( t! g. n8 g. F/ Qattained with topical or gonadotropin therapy. It may well
( V+ b. @+ l6 N. J2 Z) lbe that some patients will show little or no response to any
! U# M& N/ w/ I2 h. aform of therapy. This would suggest a defect in the ability to
9 ~, Y. P9 T; p5 W: k% C1 lconvert testosterone to dihydrotestosterone and indicate that" Q6 t7 i3 ~1 O6 f# j J
phallic and peripheral skin, and subcutaneous tissue should
* o* X+ @" o" ]be compared for 5a reductase activity.9 f9 \1 P, y" }& o
A, loop enlarges to measure penile girth in millimeters. B," Z; T+ z3 I* t( H5 R! n
example of penile girth computed easily and accurately.
2 w! r+ u1 n _- t% y) [conversion of testosterone to dihydrotestosterone. It is in this
9 v! Q6 S5 H0 u/ G; k& }# Yolder group that others have noted high levels of serum
6 F! e* Q6 ?, b( K. N1 A8 A4 @testosterone with topical application. It would also appear
+ R% p) @ E8 H+ ]" tthat phallic response during puberty is related directly to the
1 I: F; C: D( R% z$ e8 K) G9 s, mserum testosterone level. There also is other evidence of local
: d4 q$ ~: F1 g8 qresponse to testosterone with hair growth and with spermato-
7 X( c f0 J! `. ?genesis. 5• 6
. L- y+ Q. P2 R0 }Administration of larger doses of gonadotropin or systemic: A+ H5 Z5 r8 u- a$ J, P# G
testosterone, as well as topical applications that produce
1 f" F* V6 t3 d5 F, u! `higher levels of serum testosterone (150 to 900 ng./dl.), will9 `$ O* D. X1 U) f3 _
also produce phallic growth but risks accelerated skeletal
7 H7 \) X/ s) \7 R/ X$ Ematuration even after stopping treatment. It would appear
5 C8 Z$ r2 U! Rthat this may be avoided by topical applications of testosterone) m- i1 P! S+ \
and monitoring of serum testosterone. Even with this control
6 k* ]- Q1 k, u4 othe duration of our therapy did not exceed 3 weeks at any
- Y) N0 G! W0 o# N" j$ Dtime. It is apparent that the prepuberal male subject may" F; x9 ^1 L: N, p3 m7 J# ] U
suffer accelerated bone growth with testosterone levels near
2 Z6 [ i" I( w- J; _: B200 ng./dl. When skeletal maturation is complete the level of
2 J* }- y, K7 F1 kserum testosterone can be maintained in the 700 to 1,300 ng./
+ r5 I. _' u# }( mdl. range to stimulate phallic growth and secondary sexual
+ R1 k# h& o2 d* Ochanges. Therefore, after skeletal maturation parenteral tes-, \6 M& `% B& L( x) I
tosterone may be used to advantage. Before skeletal matura-
! \) j3 F3 v7 r* P _$ htion care must be taken to avoid maintaining levels of serum
& p* K; X6 v9 Xtestosterone more than 100 ng./dl. Low-dose gonadotropin
+ I* {: J3 \9 e$ zdepends upon intrinsic testicular activity and may require
3 V, C5 o" t% n1 E( J- iprolonged administration for any response.
: P! v5 r7 Z$ ?0 r% I, \Alternately, topical testosterone does not depend upon tes-
0 \ K5 j$ r( ^/ r Cticular function and may provide a more constant level of
& R* G: E) D' X7 HREFERENCES
9 L; p# }4 W2 v1 j; R" U* a1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 B, ^* [2 S0 w3 D1 P% \# Z
R.: The local application of testosterone cream to the prepub-) E! P' e" S" ~7 G1 ?1 z
ertal phallus. J. Urol., 105: 905, 1971.3 {0 @. {' x/ o9 Z9 U4 J" r/ B
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 \3 Z2 I' s& X
treatment for micropenis during early childhood. J. Pediat.,
' N f) n7 P: x, I0 ~6 T83: 247, 1973.. ]4 U# ]# F: }" ^0 F
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-: `0 }) A; l0 _3 W; z, T- w
one therapy for penile growth. Urology, 6: 708, 1975.
/ {6 Z+ t" F- T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 P- @- l( w1 [2 f* F1 L3 X
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
) ?* J4 b0 J& O* Y fskin slices of man. J. Clin. Invest., 48: 371, 1969.
" F% N- k$ Q- d( q* A0 n, X5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ ^' `4 a+ c, ]- v' o5 p
by topical application of androgens. J.A.M.A., 191: 521, 1965.
N: g% o+ |& W& D3 }6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 M t: T1 B0 Q! b9 ?
androgenic effect of interstitial cell tumor of the testis. J., ]2 e, T4 {' W8 V0 L" N
Urol., 104: 774, 1970.
1 c. I! Y! |4 f' ?% c7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 R1 k D$ |4 b; A
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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