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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" [. @: m6 z' sGONADOTROPIN
' V' y8 j6 `/ e) m; S- G8 ^) nRICHARD C. KLUGO* AND JOSEPH C. CERNY
8 e+ f/ A( D! J3 mFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 z. P. w, K6 X' u, x0 n" p
ABSTRACT
2 F* F* p) A7 k! TFive patients were treated with gonadotropin and topical testosterone for micropenis associated6 d9 A" n/ B% `. T' b
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ K% H5 i7 Y+ N6 P# [) `tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone" _) r: V" c$ L+ U6 j t
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 Q4 d" i2 b7 P: d n+ i3 N
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 [6 x. @$ m4 j/ ^( a+ l) Z
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
d1 X( p. w0 ~) [increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response t/ L+ V% Z1 S7 t4 P; p" i, Z
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( c+ M0 N( N2 a. Cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% t4 t+ J5 J. ^7 q l+ t, @& Cgrowth. The response appears to be greater in younger children, which is consistent with previ-
- \) S" U7 `8 N$ j" u9 m- m/ y9 hously published studies of age-related 5 reductase activity.
. m) I/ j. b6 a; Y7 YChildren with microphallus regardless of its etiology will
8 u! d0 d. A' O0 V) g Arequire augmentation or consideration for alteration of exter- h9 u; r8 C+ D
nal genitalia. In many instances urethroplasty for hypo-' {! ?; k6 U0 W: j4 k& w
spadias is easier with previous stimulation of phallic growth.
( b! {) T* x$ b( B; Z rThe use of testosterone administered parenterally or topically- d: X% N Z. h' N1 q
has produced effective phallic growth. 1- 3 The mechanism of
- X$ `* o# P z2 Presponse has been considered as local or systemic. With this
2 ~5 F& _) L8 s2 [7 sin mind we studied 5 children with microphallus for response
# K# ^2 o, e6 zto gonadotropin and to topical testosterone independently.
4 ~) L: v3 N, T5 iMATERIALS AND METHODS
/ Q: X/ e- g( S q! r! P$ qFive 46 XY male subjects between 3 and 17 years old were3 ~" y8 f8 ]- Q" H5 Y
evaluated for serum testosterone levels and hypothalamic
8 ]" M# m4 L ]function. Of these 5 boys 2 were considered to have Kallmann's
8 M* Y& u* P- i( ]syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-& Q" R6 U4 `1 ]* j+ f! E
lamic deficiency. After evaluation of response to luteinizing
0 g9 U. E6 L' p5 d) Thormone-releasing hormone these patients were treated with
+ O- O& H- s* {" G1,000 units of gonadotropin weekly for 3 weeks. Six weeks1 y8 Q) M* g& W
after completion of gonadotropin therapy 10 per cent topical
; o$ K" d! `5 S8 X1 d: I# ]testosterone was applied to the phallus twice daily for 3 weeks.9 B7 ]0 s+ {% p+ ~% Y; t
Serum testosterone, luteinizing hormone and follicle-stimulat-% X- P2 b+ |" w! p; [, n
ing hormone were monitored before, during and after comple-. [; K2 W9 \- e$ X
tion of each phase of therapy. Penile stretch length was) \' C6 ? g) v& {+ C
obtained by measuring from the symphysis pubis to the tip of; g) \( H. X2 X9 W
the glans. Penile circumferential (girth) measurements were
) ^5 I. z+ V0 }5 s; r! o- i5 Fobtained using an orthopedic digital measuring device (see
6 c7 a; ^7 K+ P1 u, `figure).. a4 s! q4 Y0 b% q8 @, g
RESULTS& }9 X: b- b3 P/ h9 y& c; d: |. O
Serum testosterone increased moderately to levels between3 z# S m+ i2 W5 ^3 \. Q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ `8 N/ }8 O0 T! lterone levels with topical testosterone remained near pre-6 {0 M2 T1 [- b. I% K) U
treatment levels (35 ng./dl.) or were elevated to similar levels9 W9 z% X4 l& o5 K
developed after gonadotropin therapy (96 ng./dl.). Higher( P! g: B4 N9 b2 K; X! t9 ~6 r
serum levels were noted in older patients (12 and 17 years old),
) h3 J2 Z( _5 y. _while lower levels persisted in younger patients (4, 8, and 10) `/ H( o6 j3 T* O# Q
years old) (see table). Despite absence of profound alterations9 U, W' c1 g; m, B0 X7 Z
of serum testosterone the topical therapy provided a greater
7 l1 {1 H I0 R: A2 a" K- UAccepted for publication July 1, 1977. ·
1 v8 H: A& k+ z) s$ v1 s5 zRead at annual meeting of American Urological Association,8 x ~* Z5 m! A: i% S
Chicago, Illinois, April 24-28, 1977.: r" Q3 ?: e. [2 d" w/ w: |0 H
* Requests for reprints: Division of Urology, Henry Ford Hospital,
- v' k; v% K+ A* J* |" E" u0 b2799 W. Grand Blvd., Detroit, Michigan 48202.
, N5 i. i" o2 u# z/ t$ s$ t% ximprovement in phallic growth compared to gonadotropin.
1 W3 g$ |4 [8 U: |7 ]Average phallic growth with gonadotropin was 14.3 per cent
! p: p: j. l2 r4 jincrease in length and 5.0 per cent increase of girth. Topical
`; H' S+ n p5 f+ R6 s* A9 Vtestosterone produced a 60.0 per cent increase of phallic length- U; @9 p. @' m- {
and 52.9 per cent increase of girth (circumference). The
$ u4 {2 U( T, `0 V" j! E7 @response to topical testosterone was greatest in children be-- t N: T& e7 X/ |6 x- R
tween 4 and 8 years old, with a gradual decrease to age 17: o9 z& r3 ^4 R; W4 O2 o
years (see table).
& ~7 g7 M2 I& B# m i$ HDISCUSSION# J2 K% m( B, b* u" P
Topical testosterone has been used effectively by other
2 v- d( v5 G* o% r- t" oclinicians but its mode of action remains controversial. Im-
! {1 S7 o! `0 V6 Z' xmergut and associates reported an excellent growth response1 P: | _4 r, g
to topical testosterone with low levels of serum testosterone,! U, {* U8 l5 x( \0 S' i
suggesting a local effect.1 Others have obtained growth re-7 i2 m0 Q: `) k) g
sponse with high. levels of serum testosterone after topical/ ]6 p L7 ?! }# t
administration, suggesting a systemic response. 3 The use of8 z6 ?# P% M& O4 V: a
gonadotropin to obtain levels of serum testosterone compara-/ I* r' w" l: \; ]$ @
ble to levels obtained with topical testosterone would seem to8 W# B1 H3 s6 M
provide a means to compare the relative effectiveness of9 }, I% S; P# M+ @( i
topical testosterone to systemic testosterone effect. It cer-
4 h' [, x. b# Xtainly has been established that gonadotropin as well as par-
- W- M: t. V% O$ _$ _ Y- Tenteral testosterone administration will produce genital2 P5 }1 A7 {+ [0 _
growth. Our report shows that the growth of the phallus was
2 I) |! [- H- M1 w4 }significantly greater with topical applications than with go-0 C& d2 H# B- p- ^0 Y! z5 p
nadotropin, particularly in children less than 10 years old.
& k) A0 `1 m" O" y5 m5 b! j' bThe levels of serum testosterone remained similar or lower$ h m0 f. b m4 I
than with gonadotropin during therapy, suggesting that topi-4 k( \& s, n G
cal application produces genital growth by its local effect as
( p; a2 @! v( C* ~7 z: z0 v" j6 qwell as its systemic effect.
+ y# ^: p8 r: b3 XReview of our patients and their growth response related to2 F7 R P0 ^& I! r9 v g
age shows a greater growth response at an earlier age. This is& d$ g" `3 z2 {: z B* [6 K
consistent with the findings of Wilson and Walker, who" y! f: A# t$ ]: [3 k1 l
reported an increased conversion of testosterone to dihydrotes-
* O7 _4 L( r8 }tosterone in the foreskin of neonates and infants.4 This activ-3 H9 z! N' B& d3 r( h* V* E' L
ity gradually decreases with age until puberty when it ap-
; P; |0 n$ b. Z. d4 l, o, Mproaches the same level of activity as peripheral skin. It may
3 H% [$ K: }& A1 Q2 Uwell be that absorption of testosterone is less when applied at, ~8 L t" [' `
an earlier age as suggested by lower serum levels in children7 I3 @$ h' [4 K. X
less than 10 years old. This fact may be explained by the4 S* Y4 ^, j& F5 D- z
greater ability of phallic skin to convert testosterone to dihy-
1 ~, i6 U- W" G" M) ldrotestosterone at this age. Conversely, serum levels in older+ U8 N7 m( i H+ D
patients were higher, possibly because of decreased local
' E4 Y+ h7 q& C* s8 ]667
' x1 F- s2 _# x$ ]* r3 E668 KLUGO AND CERNY8 z) ~1 f V" _# c2 r8 K3 D/ v
Pt. Age2 a% _2 T5 V' j0 z ~
(yrs.)
. l, P. d2 Z4 V* U/ M! `0 tSerum Testosterone Phallus (cm.) Change Length5 F4 O7 v* x# l$ B
(ng./dl.) Girth x Length (%)+ e' h& a' z$ e- a
4
2 r" U. e- y: \' v8 J$ e L6 L0 h0 O8
8 d+ e- T$ L. e4 O10
" S" w" C) h& P5 k6 S. K) ?5 }127 l0 v* u! j8 o! @3 W
17
5 z7 L6 O. `7 P# kGonadotropin
# z0 P! _" z+ ]7 @71.6 2.0 X 3 16.64 J* s( g- q0 o2 U0 e/ X
50.4 4.0 X 5.0 20.09 A4 @% W3 G o* w; b! d
22.0 4.5 X 4.0 25.0
! T4 g# p) L& e( p- ]4 Q8 j G84.6 4.0 X 4.5 11.1/ p, R; p% ?! P! C: j e& B
85.9 4.5 X 5.5 9.0. y( a r0 _0 h2 N3 J3 o% c! _7 y
Av. 14.3) R# v$ q% c* V
4, @' R# `% }0 ~# R
8
5 N! E! a: d* A/ n5 r0 x4 z0 ?5 X10
: h1 t' N& E: ^$ N12! B* o$ z. D7 h1 P& ]2 e
17; ^5 M9 w5 A3 ?, F! g! g, a; R
Topical testosterone
6 }& N1 I7 q% H) W7 q6 p* ?. ~, O34.6 4.5 X 6.5 85/ z% s2 e- m( B# V' m0 n1 n8 } N% y
38.8 6.0 X 8.5 70
0 X1 ]4 |% j& i* w z# @% w7 u40.0 6.0 X 6.5 62.56 d& |5 d6 K) O3 I
93.6 6.0 X 7.0 55.5
& b0 N0 X* n, N* z8 s95.0 6.5 X 7.0 27.23 ?/ d" ~7 F, u/ ^) E4 N) `7 i
Av. 60.0
7 W7 ]( ^0 D# N* X2 ravailable testosterone. Again, emphasis should be placed on: k# m5 q" \& W( x8 @/ ^5 T
early therapy when lower levels of testosterone appear to
) j. V! X! m) E( h4 Q; Jprovide the best responses. The earlier therapy is instituted5 ]8 I3 A# z5 ` h
the more likely there will be an excellent response with low
6 \5 l0 U; K' b- E- pserum levels. Response occurs throughout adolescence as% _ L! j: @9 l. A m
noted in nomograms of phallic growth. 7 The actual response1 _ C* {9 }8 j3 |' [0 \! @8 F
to a given serum level of testosterone is much greater at birth Z4 P7 S% A/ q% S
and gradually decreases as boys reach puberty. This is most2 D0 O! b4 v* z
likely related to the conversion of testosterone to dihydrotes-
9 O3 i, o( R5 A+ @tosterone and correlates well with the studies of testosterone
- n) Z9 q Y( ~8 c0 b- kconversion in foreskin at various ages.
- L1 B5 n- j C/ s5 d# RThe question arises regarding early treatment as to whether& i# D5 o$ i- ^/ E) T
one might sacrifice ultimate potential growth as with acceler-
3 Y% z0 G- j6 hated bone growth. The situation appears quite the reverse
( i( E5 ]9 H* A gwith phallic response. If the early growth period is not used
5 {2 J6 q" z& v$ }when 5a reductase activity is greatest then potential growth
/ ?! q* I4 n4 s, E3 N" Z: }may be lost. We have not observed any regression of growth1 u4 a2 Z$ P9 P+ x/ k
attained with topical or gonadotropin therapy. It may well
; n! a; G) k1 rbe that some patients will show little or no response to any
4 B1 w8 m( s6 }* W6 R' {form of therapy. This would suggest a defect in the ability to0 y: ~! p7 Z0 A
convert testosterone to dihydrotestosterone and indicate that. s2 ?7 U2 `" u# z
phallic and peripheral skin, and subcutaneous tissue should
4 z9 |4 S( t, k2 b/ Z3 Xbe compared for 5a reductase activity.! ?, T. F; p) o3 M& b: D$ P: [/ r9 x
A, loop enlarges to measure penile girth in millimeters. B,3 f6 g9 J8 f# V1 R" w4 V1 z
example of penile girth computed easily and accurately." y' x1 {3 U! p2 I" [
conversion of testosterone to dihydrotestosterone. It is in this
3 o9 U4 o3 w" p z+ S8 Nolder group that others have noted high levels of serum
. M/ m( y* c$ Q/ d1 U# etestosterone with topical application. It would also appear
4 S3 ?' ], P, O. f6 Ethat phallic response during puberty is related directly to the' c1 w1 u, u; v" v: R5 k3 U9 t
serum testosterone level. There also is other evidence of local i, ?1 q$ C% n4 q- k8 c
response to testosterone with hair growth and with spermato-; F$ Q4 r3 C" Y" Z q
genesis. 5• 6
8 W" m3 Q5 u* y: PAdministration of larger doses of gonadotropin or systemic, F+ V' \! X/ M! f* g( E. }9 _& ~; j
testosterone, as well as topical applications that produce% Y% i& p7 e. s
higher levels of serum testosterone (150 to 900 ng./dl.), will/ `* D" V E* ]3 `+ ^8 Z
also produce phallic growth but risks accelerated skeletal: y v" v8 K+ z! |. [# P
maturation even after stopping treatment. It would appear; ^. ?$ I& s( Z4 K% s: N
that this may be avoided by topical applications of testosterone
1 z) v* ?0 Z- ^7 Z# j( ^and monitoring of serum testosterone. Even with this control% ?" Z+ X8 f7 Y4 l" U
the duration of our therapy did not exceed 3 weeks at any# d. w% J1 H/ I; A; v4 a8 k; Z
time. It is apparent that the prepuberal male subject may. v7 E: h7 a& u" W3 ?% m8 }4 P" V
suffer accelerated bone growth with testosterone levels near/ }: @+ E, f0 p8 o' B Z
200 ng./dl. When skeletal maturation is complete the level of
0 j. o+ \0 t4 _; Qserum testosterone can be maintained in the 700 to 1,300 ng./" ~# I2 \# `; [7 l4 S5 d A0 Z z
dl. range to stimulate phallic growth and secondary sexual
% v4 C2 g/ y# @' D, _+ t% J# Schanges. Therefore, after skeletal maturation parenteral tes- e) l- G% Z- M+ o1 `0 \) Z0 a
tosterone may be used to advantage. Before skeletal matura-
- x) C- h/ t/ S# qtion care must be taken to avoid maintaining levels of serum2 H" w0 K4 t3 r% `& ^/ o" `
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ c# ?$ K# [5 N3 ]: z1 i, Gdepends upon intrinsic testicular activity and may require* k( O- N7 H( s' {
prolonged administration for any response.
7 c+ m$ Q2 U0 HAlternately, topical testosterone does not depend upon tes-
: u6 }' c1 N( _( C- Cticular function and may provide a more constant level of
5 M& [" k3 [" s. yREFERENCES& ]: U2 R0 [- O2 y7 s
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 J) O( ]# T3 L6 X, W# ]R.: The local application of testosterone cream to the prepub-+ h5 d' R' i! l. J, d4 l3 L4 l/ \" E
ertal phallus. J. Urol., 105: 905, 1971.+ e2 N8 R: J4 ?
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( K# s) U) M0 Y2 m5 I* @treatment for micropenis during early childhood. J. Pediat.,& E2 o- I6 C8 n J- i* T2 [* V6 A9 ^2 l
83: 247, 1973.) a, `- z' ]: K3 v f( H8 X8 ?
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
1 S. x; P- Q7 M+ j4 _" Bone therapy for penile growth. Urology, 6: 708, 1975. O0 w# ~3 O2 C! B+ V/ C
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 E; B' D4 j. x/ Vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- X/ ~* Y: D/ L9 w6 Kskin slices of man. J. Clin. Invest., 48: 371, 1969.
9 K" C7 {9 f, w. b" R- h5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) N7 x/ e* z( e. F( Y! L" j
by topical application of androgens. J.A.M.A., 191: 521, 1965.5 L+ M" L8 z: L7 \) e2 X m; U
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
) x1 W9 ]( C2 X( R6 w/ `: e7 ~androgenic effect of interstitial cell tumor of the testis. J.
5 @3 I1 P$ \( J! @2 V& Y. _3 X4 HUrol., 104: 774, 1970.
: d$ U5 q1 Z) h3 \! `& M7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
, f; k# H, i u6 `9 Stion in the male genitalia from birth to maturity. J. Urol., 48: |
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