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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
$ n) V ~$ B S: O C9 \3 QGONADOTROPIN
( j7 f9 M& i) {# n: v5 m: q/ {RICHARD C. KLUGO* AND JOSEPH C. CERNY
! J/ @# b7 Z8 w& ?From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% [4 V% `1 l& j* T: |ABSTRACT- A E( _3 L5 W% w- A9 h. }
Five patients were treated with gonadotropin and topical testosterone for micropenis associated" C* [* i5 H5 n+ G0 g( M0 g$ T
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
2 f* e6 X6 t. V* L4 E4 _tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
7 H* {' a/ {" A5 {$ ^# ], {0 S( Ccream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 s5 Q" m8 B/ A: r3 R% o) y; Zfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
& z; I; Z$ s2 o" {* Eincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average; X/ v! j1 d3 C# V o
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response# `; D5 A* c$ X" I: M$ k
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This3 L" @7 n2 t2 C7 s/ R2 ?2 z
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 Z7 I. F+ X0 x( A8 T9 i
growth. The response appears to be greater in younger children, which is consistent with previ-
6 j- a3 e- m o$ `7 ~ously published studies of age-related 5 reductase activity.
0 z5 }% i. x* Q0 l7 jChildren with microphallus regardless of its etiology will
" d4 L. e: V. G( zrequire augmentation or consideration for alteration of exter-
3 g6 m0 y2 i' Z3 }8 enal genitalia. In many instances urethroplasty for hypo-
1 T4 U/ }- `. y4 q# M: w, J/ Lspadias is easier with previous stimulation of phallic growth.5 w {+ z; |4 a$ W0 j6 L
The use of testosterone administered parenterally or topically
9 D# m' A) r) c" h, P/ p# Y! ]; |has produced effective phallic growth. 1- 3 The mechanism of; j" K- m, F) T: [/ Y! w
response has been considered as local or systemic. With this$ {6 E7 N( Z) C- B" G9 S: X
in mind we studied 5 children with microphallus for response0 D. e5 ?. z: O/ R
to gonadotropin and to topical testosterone independently.5 z9 n/ O: o2 l0 r% g% [9 |/ ?; M S
MATERIALS AND METHODS" ~ T# T7 ?# Z
Five 46 XY male subjects between 3 and 17 years old were$ v6 q) r* N; ~
evaluated for serum testosterone levels and hypothalamic
. U' W2 J4 [; v- Z, t* V9 N* ifunction. Of these 5 boys 2 were considered to have Kallmann's$ j) d. V& W# Z: @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
: w, c# B) S+ Q3 y) Ylamic deficiency. After evaluation of response to luteinizing
7 u1 T a! q9 g7 S/ G/ Z0 vhormone-releasing hormone these patients were treated with
* v/ U: L0 z/ S. b; K$ }* M1,000 units of gonadotropin weekly for 3 weeks. Six weeks! M6 G M5 ?! C( k
after completion of gonadotropin therapy 10 per cent topical
% [' i" N3 c: G. \8 ^3 ^testosterone was applied to the phallus twice daily for 3 weeks.
/ X2 T5 q/ \( Z" X. a" ESerum testosterone, luteinizing hormone and follicle-stimulat-
& I$ n, W% [. x( D5 H+ i8 U4 ^+ Y$ Oing hormone were monitored before, during and after comple-
: _5 y4 Z% e8 M7 Mtion of each phase of therapy. Penile stretch length was
4 \! E5 o6 H! H1 Tobtained by measuring from the symphysis pubis to the tip of
; K5 C! u1 c X9 x1 R) q" j4 C, M' V- ythe glans. Penile circumferential (girth) measurements were2 \; p4 }1 k- ^- U' b
obtained using an orthopedic digital measuring device (see
5 E* P% L' R* z2 L5 ^figure).# E8 c4 u& V F1 Y
RESULTS
% N4 \+ j9 y7 ]# R' JSerum testosterone increased moderately to levels between/ Y- S7 J" R4 x7 |& e9 q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos- Z% [2 z9 Z; h2 M5 X: E; z. i
terone levels with topical testosterone remained near pre-
. s* \) ?( @" G1 ^treatment levels (35 ng./dl.) or were elevated to similar levels9 b( E/ t. Y( c; v% H9 u1 u* X# b
developed after gonadotropin therapy (96 ng./dl.). Higher
' l6 f: _/ ^( L9 s! Xserum levels were noted in older patients (12 and 17 years old),
0 a2 d4 Z5 f2 a8 I( _while lower levels persisted in younger patients (4, 8, and 10
% \/ Z9 |: t4 a2 {years old) (see table). Despite absence of profound alterations7 s2 d# k" x/ R6 W" i
of serum testosterone the topical therapy provided a greater L- q) @( {( Z7 [1 V0 Z( R
Accepted for publication July 1, 1977. ·
* u0 A; W" ~( t& Y0 r, YRead at annual meeting of American Urological Association,& ]2 M( I6 J( K& m4 {& k7 i1 e1 a
Chicago, Illinois, April 24-28, 1977.) G H* F2 f- M( m2 Z) a- W
* Requests for reprints: Division of Urology, Henry Ford Hospital,2 a3 F+ g+ e% {2 A& T# b' A" m6 I
2799 W. Grand Blvd., Detroit, Michigan 48202.
8 I% K2 v7 x; v; V4 mimprovement in phallic growth compared to gonadotropin.
# G, ?( X: c) t8 h5 oAverage phallic growth with gonadotropin was 14.3 per cent
& a, m: c6 `/ P2 O- ?2 S' m b# Zincrease in length and 5.0 per cent increase of girth. Topical
$ H, ^5 |' d, l) X& O9 _' @testosterone produced a 60.0 per cent increase of phallic length5 v# t6 [) j5 v7 S5 S5 S7 m) }
and 52.9 per cent increase of girth (circumference). The! ^3 z& V2 E- N8 k/ ?
response to topical testosterone was greatest in children be-( @$ P1 ~' m4 H5 K8 p3 r6 X
tween 4 and 8 years old, with a gradual decrease to age 17
* {: U( c& v x) {8 v3 q+ |& Iyears (see table).
g; U; Y2 T0 l" _: _" }DISCUSSION
) s R# x9 V( u+ W' gTopical testosterone has been used effectively by other) d2 C S+ {3 ]! L( j8 q
clinicians but its mode of action remains controversial. Im-
2 E, y" D) T. g' y( Cmergut and associates reported an excellent growth response
+ }8 V* \1 U, C9 K5 ^( W0 k5 xto topical testosterone with low levels of serum testosterone,6 `$ r, }6 U; k7 |* T
suggesting a local effect.1 Others have obtained growth re-2 p k4 V! I# k
sponse with high. levels of serum testosterone after topical
2 E1 V; m; H8 B Vadministration, suggesting a systemic response. 3 The use of
- ? z. \/ o" M( c7 `4 hgonadotropin to obtain levels of serum testosterone compara-( q2 K4 }5 H/ y; X. @7 X8 j' u
ble to levels obtained with topical testosterone would seem to
s- @9 C$ E8 U6 Q1 cprovide a means to compare the relative effectiveness of2 e/ r- Q/ F0 g8 P5 F4 Q" k* l5 }3 [
topical testosterone to systemic testosterone effect. It cer-
- Y5 L, Q( Q/ s7 S5 a$ btainly has been established that gonadotropin as well as par-
6 a" g; B/ d }. I: ~enteral testosterone administration will produce genital
e$ }( J' T$ Q& T+ U/ jgrowth. Our report shows that the growth of the phallus was
* r1 e# j" Z u3 t9 I* e* rsignificantly greater with topical applications than with go-/ ?" u; K, }2 G8 }& G
nadotropin, particularly in children less than 10 years old.
' w8 a0 N+ _# Z+ X! e8 S1 y9 xThe levels of serum testosterone remained similar or lower
5 v% m5 j( y' x7 `- `- lthan with gonadotropin during therapy, suggesting that topi-9 Y/ Y, J, {+ M
cal application produces genital growth by its local effect as
9 h* Y L7 r. Q1 |: p. u4 cwell as its systemic effect.
. L* ]+ t3 R) t" }6 q( @9 oReview of our patients and their growth response related to+ L$ P. p; \" Z
age shows a greater growth response at an earlier age. This is7 q# Y+ X2 N/ P% U/ Z2 h
consistent with the findings of Wilson and Walker, who( _" \6 y& E5 A4 L+ V8 z) b
reported an increased conversion of testosterone to dihydrotes-3 L# L. r* L8 t1 D% M
tosterone in the foreskin of neonates and infants.4 This activ-( }6 g2 \/ F8 n5 S8 L
ity gradually decreases with age until puberty when it ap-& f) o. J& h, O- c A" F0 X
proaches the same level of activity as peripheral skin. It may3 x- S# H# H( X! |
well be that absorption of testosterone is less when applied at
2 O! L' \$ i6 e/ han earlier age as suggested by lower serum levels in children a/ r1 i. n' v8 G# E
less than 10 years old. This fact may be explained by the* v# V5 t$ U' m* t: I! Q
greater ability of phallic skin to convert testosterone to dihy-- p' O& r! Q5 T: U, H0 t
drotestosterone at this age. Conversely, serum levels in older- Y" Y: z) G% l
patients were higher, possibly because of decreased local
, n. `7 L1 j; s667! l; I! O( g/ O! `
668 KLUGO AND CERNY
3 B. ?% m3 A2 E& KPt. Age5 Q% N8 B7 L) ^# _- Q$ I- k
(yrs.)
5 @ h. Y- X' d; ?! HSerum Testosterone Phallus (cm.) Change Length. N, J1 R5 D5 h6 j; j
(ng./dl.) Girth x Length (%)
8 _5 Y& Y! C! g- @# f" P- [40 U' K1 E" I! n6 ?
8! H, l* H1 I, u& ^, m
10
3 Q- o5 `, X) e12: Q- z: Z' e8 o: I& e
17; I, n* C1 ]$ w; z- X5 g1 l
Gonadotropin
6 u5 g P, U: M: i% O3 y% J6 ]0 e71.6 2.0 X 3 16.6
+ Z$ C8 Y. L0 _0 j3 R3 k! K* _; u50.4 4.0 X 5.0 20.0' { U( F! |" I. d& c X; x
22.0 4.5 X 4.0 25.05 O9 g7 s% o' o) U& m5 Q) z% u
84.6 4.0 X 4.5 11.1* {$ v" v8 r/ U$ L, T5 G' x
85.9 4.5 X 5.5 9.0
% S! p0 o0 @7 F9 y' x6 sAv. 14.35 f4 ^8 `9 ^ F- b) _. M, k
4
* C1 x$ \% [2 o- i4 E& h: ^4 S* z3 ~8# Q- c1 O! p5 m% _2 d, p
10& X2 ]' Z" D/ Y6 a9 T6 E R
12; U2 z, E, L7 f! C" r0 X4 S7 H! h
17
) A! z t o# p6 A" i0 {Topical testosterone
/ ]; Z( @, U5 G34.6 4.5 X 6.5 85
k9 \5 Y) F. \ c5 n38.8 6.0 X 8.5 70
; o+ v9 I! ~ z8 X3 b& }7 q40.0 6.0 X 6.5 62.5
" ]1 `% i* d0 J0 V* v% N! A93.6 6.0 X 7.0 55.5( e% |* I( g/ j* F0 J% Z2 j/ h
95.0 6.5 X 7.0 27.2
6 I/ V& i" j# k) P ?, [Av. 60.0
) k" d8 z5 L& Q$ q5 ~! l2 c( W; t5 _available testosterone. Again, emphasis should be placed on
# \; G5 M) @# m; p( }early therapy when lower levels of testosterone appear to: y/ X5 U: l9 J, c2 p `5 x, L5 ~
provide the best responses. The earlier therapy is instituted
. n2 [: |; a3 ^8 O) ?% sthe more likely there will be an excellent response with low
# n* z- K7 C3 P' ]8 k" lserum levels. Response occurs throughout adolescence as
. B7 M7 k7 m f; u: R: |: rnoted in nomograms of phallic growth. 7 The actual response* H1 o7 ^9 c+ Z2 v: U
to a given serum level of testosterone is much greater at birth# _6 h7 k: F/ D( K- b0 _
and gradually decreases as boys reach puberty. This is most
, ^, ?; n' ?3 e# olikely related to the conversion of testosterone to dihydrotes-7 ?/ E- h! j" s1 }5 v5 s
tosterone and correlates well with the studies of testosterone2 e# E- s9 W" w/ L+ p9 E9 Z, H
conversion in foreskin at various ages.
" F' _6 p+ `! z+ A% c6 ?: QThe question arises regarding early treatment as to whether
0 W7 [( n4 y! p; t5 ~1 z' Eone might sacrifice ultimate potential growth as with acceler-* E/ Y& Q* f3 _' [9 h
ated bone growth. The situation appears quite the reverse
' W3 h/ a. q, a1 Q, N& twith phallic response. If the early growth period is not used# u* ?( e1 J( ]7 A8 h: ]
when 5a reductase activity is greatest then potential growth$ B( I; A+ P; \# W! F' x+ x
may be lost. We have not observed any regression of growth' \4 u3 e* Z/ E6 P. ~5 P8 ^1 N
attained with topical or gonadotropin therapy. It may well0 R0 ^3 ]) i" S6 }
be that some patients will show little or no response to any+ e' K1 |; n# m- p; M4 `
form of therapy. This would suggest a defect in the ability to! `8 ]7 h( h2 K1 K
convert testosterone to dihydrotestosterone and indicate that
- l' C) ^/ m6 R( C: o( ]% Q, P3 Bphallic and peripheral skin, and subcutaneous tissue should$ | U V' @ i) P% b \9 z
be compared for 5a reductase activity.8 Z: Y0 y+ ~( L' N) t& I; g8 l. c
A, loop enlarges to measure penile girth in millimeters. B,7 k( F& E3 G9 x% ~+ q4 Q
example of penile girth computed easily and accurately.
* E5 c2 z- Y X( e) lconversion of testosterone to dihydrotestosterone. It is in this
4 I. i, b' B! Molder group that others have noted high levels of serum
+ T2 Y3 y7 |: L! Z8 q: s1 jtestosterone with topical application. It would also appear3 F q- k# I. x1 j5 r, S
that phallic response during puberty is related directly to the! O7 _1 q2 Y$ B) ~. \6 G
serum testosterone level. There also is other evidence of local
5 O* D2 S6 ^; E6 l" Zresponse to testosterone with hair growth and with spermato-: X' @' y$ E: v! D
genesis. 5• 6
* R' c0 h8 [/ Z- T4 r) |5 XAdministration of larger doses of gonadotropin or systemic
) r. U& i% I# W e4 m1 V+ z- ztestosterone, as well as topical applications that produce
7 x0 h) a5 m( a+ r1 K5 ghigher levels of serum testosterone (150 to 900 ng./dl.), will% h8 y8 W; }/ R! m4 O$ i
also produce phallic growth but risks accelerated skeletal
! ?8 K0 C- @ o R( r% ?/ ^, L- G% Imaturation even after stopping treatment. It would appear
6 }# }! ~3 c1 A( U/ Y7 E3 ethat this may be avoided by topical applications of testosterone" u0 G! ^6 L4 W5 P8 x) M5 V* k
and monitoring of serum testosterone. Even with this control9 Y t, A" @, S9 r( c+ n
the duration of our therapy did not exceed 3 weeks at any
% Y/ |( ^& S! A9 a+ Q5 ptime. It is apparent that the prepuberal male subject may
) w! P$ ^! q$ h1 x4 `. m+ Nsuffer accelerated bone growth with testosterone levels near' S9 {6 `: ]9 O( c4 ^
200 ng./dl. When skeletal maturation is complete the level of% H# v, E, D8 N6 u n
serum testosterone can be maintained in the 700 to 1,300 ng./
3 S' X+ k8 z6 Q' _) Bdl. range to stimulate phallic growth and secondary sexual3 d; B8 m T/ A1 ~+ N
changes. Therefore, after skeletal maturation parenteral tes-7 m1 p" Z2 r9 z* D4 K
tosterone may be used to advantage. Before skeletal matura-+ O' S1 @" ]( b5 E
tion care must be taken to avoid maintaining levels of serum
8 Z* Z0 }$ ] V" ]' p: Vtestosterone more than 100 ng./dl. Low-dose gonadotropin
7 h# o. l) c: w% Zdepends upon intrinsic testicular activity and may require, g) s" |- w3 Z
prolonged administration for any response., d5 g% m1 e/ f' u- T
Alternately, topical testosterone does not depend upon tes-
# m/ c/ g9 v2 P" c3 \ticular function and may provide a more constant level of
# D5 T0 v8 W. L1 O& y9 a" Y/ AREFERENCES
; t+ O8 ~# U, n3 C' p- w1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# F6 }: l5 F9 Q/ F3 P% t8 C3 q8 @: u
R.: The local application of testosterone cream to the prepub-: s) }9 Z. |8 d; [+ d
ertal phallus. J. Urol., 105: 905, 1971./ Y, X1 J$ `* R. b+ H
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
/ |( u; t; o& b9 L: O b% |treatment for micropenis during early childhood. J. Pediat.,8 n8 p! @3 N7 D1 S$ i: h
83: 247, 1973.7 |5 \' R8 P5 x0 d
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 l) N) h: a) W
one therapy for penile growth. Urology, 6: 708, 1975.. \6 Q: D4 T& p
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
2 G9 [% u6 a% Lto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
% H; J4 |, M, C) p$ C2 G: j7 Z/ g$ Uskin slices of man. J. Clin. Invest., 48: 371, 1969.
2 r1 u. e, D. Q- N, `" T5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, \: b& ?3 g/ T/ j. J" J
by topical application of androgens. J.A.M.A., 191: 521, 1965.; v8 u: _# }- {
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
* ?4 w: M5 V N/ P( iandrogenic effect of interstitial cell tumor of the testis. J.# ~3 s4 _) b9 j/ @6 B
Urol., 104: 774, 1970.
1 v0 t% s( Z, g3 H& A g2 o7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
" X6 K) x9 L6 K) mtion in the male genitalia from birth to maturity. J. Urol., 48: |
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