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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
4 R' s3 o6 U  s; @& R' EGONADOTROPIN
" `' `- {1 @; jRICHARD C. KLUGO* AND JOSEPH C. CERNY' B$ y- G* G3 d4 i- s3 V: [
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 X# k! Q; S2 v, H
ABSTRACT
% B+ D1 ]& Q( p* l% Q( ~Five patients were treated with gonadotropin and topical testosterone for micropenis associated$ I; v5 V. c2 C  _* K2 r$ d
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; E8 X- v, _% _$ e' K" Ntropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# n, B3 q4 N0 t
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
/ W& v# k+ d' z' ~9 H& T# R5 cfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 N) M6 t" R9 z# v2 B7 _0 f
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 N$ K& y( n' E3 K! n  {1 M) X2 y5 |
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
- i- B6 M& O+ [9 qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' ]/ b; O; b" S; Ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) j7 q. B6 U; _+ r- xgrowth. The response appears to be greater in younger children, which is consistent with previ-5 c" }7 E9 K/ q2 Z2 H5 b; q
ously published studies of age-related 5 reductase activity.' X7 o! F* N6 N4 z& N; N+ j3 \$ p
Children with microphallus regardless of its etiology will
# T/ {. D# z! i2 O" l6 hrequire augmentation or consideration for alteration of exter-( o. ^! f' i6 e! v* q+ S4 d1 I
nal genitalia. In many instances urethroplasty for hypo-& H1 E2 h+ d; z" Q- X4 A& J
spadias is easier with previous stimulation of phallic growth.
5 s* @0 V0 g9 V9 fThe use of testosterone administered parenterally or topically
5 y+ @( e* s: k# b( Y( ihas produced effective phallic growth. 1- 3 The mechanism of- k6 z! J) k$ }2 c
response has been considered as local or systemic. With this& w9 S3 }, _4 l5 ]$ r
in mind we studied 5 children with microphallus for response
6 h7 E6 f2 J% v7 _3 Mto gonadotropin and to topical testosterone independently.
. C, U5 }: l* `+ N6 S- `1 p) V. ?MATERIALS AND METHODS* E+ w$ O& D2 `0 Q, C( F8 d
Five 46 XY male subjects between 3 and 17 years old were
3 P9 y$ g, e5 j/ I9 t4 C  C4 eevaluated for serum testosterone levels and hypothalamic
# s9 s; \+ |* ]6 ]: r0 yfunction. Of these 5 boys 2 were considered to have Kallmann's
) s3 \) v; t7 f, L0 Asyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! P' W4 {6 X( plamic deficiency. After evaluation of response to luteinizing
4 J5 @6 i9 {( F0 L$ a& g( }8 Ahormone-releasing hormone these patients were treated with
* M* x3 r1 `, g1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. S1 p  @7 E4 v! H# z. Jafter completion of gonadotropin therapy 10 per cent topical
; h8 n5 H" `, p. u, L$ C5 |testosterone was applied to the phallus twice daily for 3 weeks.
* a( ~6 F' a$ H7 u& YSerum testosterone, luteinizing hormone and follicle-stimulat-
% j( T, ]; {% v. s: o5 {" iing hormone were monitored before, during and after comple-
4 O/ p! B+ Y* p$ x) ]5 h- l* Btion of each phase of therapy. Penile stretch length was
2 [% x, \) G3 G9 p, H" H$ C/ m% Qobtained by measuring from the symphysis pubis to the tip of
" w0 t" W6 J# c- C" }* Tthe glans. Penile circumferential (girth) measurements were
: G, r2 u! ^$ M* {, fobtained using an orthopedic digital measuring device (see2 h0 {& Q; R% S9 y2 x; f4 J# _
figure).% p. l, W" c8 M) X
RESULTS1 r5 ^# ?3 m& U7 L# c' C' q* P
Serum testosterone increased moderately to levels between- D( n6 w, o. D/ K3 P1 J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ M2 t: O1 u( F- b: `' lterone levels with topical testosterone remained near pre-: Z# n$ H* p* X0 W# @9 m5 i
treatment levels (35 ng./dl.) or were elevated to similar levels
% b8 }0 F* t3 M3 n7 g& wdeveloped after gonadotropin therapy (96 ng./dl.). Higher5 X8 k% X* b  |. `6 K" J
serum levels were noted in older patients (12 and 17 years old),
4 p8 j- w1 Y; H. Wwhile lower levels persisted in younger patients (4, 8, and 102 X9 q# Q' K. D/ i! v
years old) (see table). Despite absence of profound alterations
! C7 G, g3 @" E6 }* o( [of serum testosterone the topical therapy provided a greater
& G3 X5 z/ `. E/ c9 B- t% ZAccepted for publication July 1, 1977. ·
- \+ o0 Q. f& X: ^1 t* ~Read at annual meeting of American Urological Association,$ O% L- g5 a0 J
Chicago, Illinois, April 24-28, 1977.
9 V+ p' T! G6 n* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 ?* c3 O3 ?7 L' r+ |2799 W. Grand Blvd., Detroit, Michigan 48202.0 d, k& P& j7 q9 n' y
improvement in phallic growth compared to gonadotropin.
" `+ m3 y4 P6 MAverage phallic growth with gonadotropin was 14.3 per cent
- a# k0 V! z$ N7 P' _" z0 Fincrease in length and 5.0 per cent increase of girth. Topical3 U( i8 z, f" x% M; Y
testosterone produced a 60.0 per cent increase of phallic length: L6 m8 p; U" t- X* b" k
and 52.9 per cent increase of girth (circumference). The
2 c' t5 T% v) B8 E" Z9 x) g/ Y& |response to topical testosterone was greatest in children be-
2 i, k" G5 [  E' Etween 4 and 8 years old, with a gradual decrease to age 175 j( ~2 ?  {0 ^' K) U) X
years (see table).
& q- {+ q4 ]' _- GDISCUSSION
8 t+ n2 l- b, s4 I$ N( d! mTopical testosterone has been used effectively by other
# ^/ B; {% j5 `# ]clinicians but its mode of action remains controversial. Im-8 d, l4 V" f5 `3 J
mergut and associates reported an excellent growth response
1 U# e. V& H+ ?/ h' f7 a' N) xto topical testosterone with low levels of serum testosterone,
$ p8 ]* K- m  v* \6 R4 j; L0 O7 Psuggesting a local effect.1 Others have obtained growth re-; M7 ?4 L2 @5 H: W, F
sponse with high. levels of serum testosterone after topical  F6 `  |8 K" `3 C6 k. f$ i( O
administration, suggesting a systemic response. 3 The use of
7 J! f/ k9 i, s+ u7 agonadotropin to obtain levels of serum testosterone compara-
3 u' y% {9 |8 Able to levels obtained with topical testosterone would seem to! ]3 Y5 E1 c5 I
provide a means to compare the relative effectiveness of
* R$ ^/ w* h+ M: k+ rtopical testosterone to systemic testosterone effect. It cer-$ u- R" L1 T2 q# d( H
tainly has been established that gonadotropin as well as par-, E- H8 m& @& m& E: }5 L
enteral testosterone administration will produce genital
) I2 ^) e$ }8 D  Kgrowth. Our report shows that the growth of the phallus was
( i3 ~9 r$ l1 ]3 M  N% e- L: z. ^significantly greater with topical applications than with go-- }0 [3 t4 S2 Y  Y9 I
nadotropin, particularly in children less than 10 years old.8 W  K5 Y( @) X; M5 v6 V& s7 N; W
The levels of serum testosterone remained similar or lower
5 V' E$ a, Q2 w9 [& j/ }- c' h, _3 jthan with gonadotropin during therapy, suggesting that topi-& a4 C+ v# x" I4 _& _
cal application produces genital growth by its local effect as
% _2 E/ j8 |! t' a, Vwell as its systemic effect.
$ S5 G1 q3 V/ W3 Q& xReview of our patients and their growth response related to
0 h! {6 c8 e  wage shows a greater growth response at an earlier age. This is8 r+ z2 H0 V  N( v5 U
consistent with the findings of Wilson and Walker, who
0 B- s: V  v' X4 o& X1 L2 Nreported an increased conversion of testosterone to dihydrotes-& z. [3 b9 T( F/ X
tosterone in the foreskin of neonates and infants.4 This activ-
" l$ c" r: t8 K, y; s' g: S! gity gradually decreases with age until puberty when it ap-
+ h' H" c" W) t* kproaches the same level of activity as peripheral skin. It may
$ v! p, E* F0 Zwell be that absorption of testosterone is less when applied at# l# ]1 x. _! a; g+ M" T
an earlier age as suggested by lower serum levels in children. s+ B# w( f6 a1 T5 F. X, m) V
less than 10 years old. This fact may be explained by the1 X0 {, _& [- P8 R; S1 B
greater ability of phallic skin to convert testosterone to dihy-, @0 c, n' s  U
drotestosterone at this age. Conversely, serum levels in older  ~5 A9 I3 N3 V7 ~1 o! n, t
patients were higher, possibly because of decreased local
) C5 F# }8 z5 K6 H667
  J5 K: F  P! A4 Y) n668 KLUGO AND CERNY, x% l5 J2 C; n+ Z% E
Pt. Age
3 l( S' o+ N7 T& d(yrs.)
: S6 P& x6 b) ^/ |  S, ISerum Testosterone Phallus (cm.) Change Length# {& W$ W7 F- h# l8 o! v
(ng./dl.) Girth x Length (%)
% H( g  u" G3 l8 Z- ?4  y0 r  z3 N+ N3 b; N7 _8 E
8
4 n* t! Q! Z  p  h1 V: M! j' U10
+ V- y; E' {9 ~% I4 a2 r12
/ t. b, d, S2 ^3 H17
3 B: f! J* D$ d4 [; F) t  |" dGonadotropin
/ i9 L& p( z+ }/ Q71.6 2.0 X 3 16.68 D) l3 r2 R9 O. s
50.4 4.0 X 5.0 20.0
# H1 B' {8 W' ]( S, m7 H) {22.0 4.5 X 4.0 25.0
; n7 \9 |3 z8 P! G% Y% B% a84.6 4.0 X 4.5 11.1( J3 `& H/ s8 W9 S/ [7 O9 C
85.9 4.5 X 5.5 9.0
3 |4 Y7 R3 d; ~( nAv. 14.3! S. z4 M. g: D. @7 i* o
4
5 k6 x9 e8 N3 L; C/ K" ]8
7 L$ U( z! Q- k( d# u0 W+ n10
; W# U! ]. G$ O& j12% _- o5 L# k6 H) |
17
  l6 a3 U: t6 K( F6 ]Topical testosterone1 F" H" A' p3 T- \% @% o
34.6 4.5 X 6.5 856 h8 b& F! S1 K/ G  A; {
38.8 6.0 X 8.5 708 h' `, ]3 S% j1 E. k( m; c( W. }. Y- p
40.0 6.0 X 6.5 62.5
4 V+ f) Q/ Q* A93.6 6.0 X 7.0 55.58 ?: X9 E7 u6 k  a3 K: Q/ G% {( x; h! M
95.0 6.5 X 7.0 27.2- j  t0 h6 g% Q# |
Av. 60.0# z! E. N) y( k( c4 a1 }
available testosterone. Again, emphasis should be placed on' }/ B0 a: D6 p8 T! A
early therapy when lower levels of testosterone appear to
0 {* g' Z, {/ t1 v& ]4 m; Jprovide the best responses. The earlier therapy is instituted6 Q- v" q% A- W5 a
the more likely there will be an excellent response with low
/ T, n& n7 y- j, B2 ]3 Cserum levels. Response occurs throughout adolescence as) v; n& t9 m: Y( U( h
noted in nomograms of phallic growth. 7 The actual response2 N  Y1 B! \- J8 s: p( _; D2 [' g
to a given serum level of testosterone is much greater at birth
& ]4 C8 a2 S" s& cand gradually decreases as boys reach puberty. This is most% N, q/ d+ [! O: u1 m9 w
likely related to the conversion of testosterone to dihydrotes-$ I! m* l% O9 e0 X7 y
tosterone and correlates well with the studies of testosterone$ N+ o4 ^8 ~6 X! f" u5 ^
conversion in foreskin at various ages.
1 R, G' c/ C* r" YThe question arises regarding early treatment as to whether
, g: ]3 J8 @8 }: b9 v) C* a- A; pone might sacrifice ultimate potential growth as with acceler-
) E2 ~$ O: b+ }( P9 zated bone growth. The situation appears quite the reverse
; l: \$ B9 M) c, R: c( J4 H( T& Ywith phallic response. If the early growth period is not used# d  f6 V% ^9 w7 S1 \$ G& d
when 5a reductase activity is greatest then potential growth8 b+ B+ I6 M4 x, ]# U
may be lost. We have not observed any regression of growth9 d* M/ C. V5 ]- g9 Y* T
attained with topical or gonadotropin therapy. It may well2 K8 S( Y1 z; j0 T
be that some patients will show little or no response to any. B# o: q: D) S) T5 l: p$ {, ?# b
form of therapy. This would suggest a defect in the ability to
! f8 j' ^; V) @$ U, Y/ V4 Jconvert testosterone to dihydrotestosterone and indicate that0 ?  E% Q; h3 T2 b
phallic and peripheral skin, and subcutaneous tissue should
& x1 C( D  X# g* Zbe compared for 5a reductase activity.! u  j" G8 M& j2 N
A, loop enlarges to measure penile girth in millimeters. B,& L% z$ w/ l% V' S" a" h
example of penile girth computed easily and accurately.
1 L: X! m8 M% c1 `: A4 Sconversion of testosterone to dihydrotestosterone. It is in this" A9 e) g+ I* l! _; H
older group that others have noted high levels of serum
5 |: v  T/ M( ctestosterone with topical application. It would also appear! @/ |3 E; {. r4 t7 b2 z/ I% X% R  v
that phallic response during puberty is related directly to the
7 ]% W; e  R4 gserum testosterone level. There also is other evidence of local. {, M/ }0 a% r+ H
response to testosterone with hair growth and with spermato-2 S* S! @" }. t8 q0 Y7 k9 }8 s
genesis. 5• 6! g2 m& ]& R; {' u, i: ~- B
Administration of larger doses of gonadotropin or systemic9 d6 f' o9 i* A% w8 \3 L
testosterone, as well as topical applications that produce1 e7 e) _, j9 z
higher levels of serum testosterone (150 to 900 ng./dl.), will9 `9 C1 s, f# G- C! W) @: `$ ~
also produce phallic growth but risks accelerated skeletal
- W' \; a- \! }1 vmaturation even after stopping treatment. It would appear
' L$ D) p; L: Vthat this may be avoided by topical applications of testosterone
3 v5 y3 c: P6 g' I  Yand monitoring of serum testosterone. Even with this control1 Q& i' v  L3 g& X
the duration of our therapy did not exceed 3 weeks at any
+ j4 `9 G$ ]/ P! rtime. It is apparent that the prepuberal male subject may
( R9 j( Q$ R% F4 O7 {suffer accelerated bone growth with testosterone levels near3 i$ q; O. I) W( G$ q/ G
200 ng./dl. When skeletal maturation is complete the level of
7 H, @7 y" D0 wserum testosterone can be maintained in the 700 to 1,300 ng./' T2 e- u3 I2 U3 Q5 Q! \+ r* Z" F
dl. range to stimulate phallic growth and secondary sexual
" ]* S4 H' a9 C+ g7 cchanges. Therefore, after skeletal maturation parenteral tes-& W  f. g" w/ D- e/ Z( \
tosterone may be used to advantage. Before skeletal matura-) Y7 C5 d0 v  O$ K! R) q( |
tion care must be taken to avoid maintaining levels of serum
; Q. L7 p9 }! C5 _% Vtestosterone more than 100 ng./dl. Low-dose gonadotropin
/ Y. c4 }8 r* u: y7 G6 Z. Edepends upon intrinsic testicular activity and may require7 F/ G9 n; X3 M9 }
prolonged administration for any response.
5 N; j. m! A0 zAlternately, topical testosterone does not depend upon tes-# w, n: C% h; @& X" T0 g5 e
ticular function and may provide a more constant level of
% p  ^$ Z5 w" f* u9 ~0 `* b% O+ P$ SREFERENCES: a/ @& q, A* x1 E0 A
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ }4 J" `. V& E5 s
R.: The local application of testosterone cream to the prepub-
/ P' z1 ~8 s8 Y. q! eertal phallus. J. Urol., 105: 905, 1971.
3 u9 M6 l! T' N9 j6 V2 R2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. n4 r' E2 {$ f6 V' g/ g( q3 I2 f& `
treatment for micropenis during early childhood. J. Pediat.,
2 }" V, ?/ `; a1 N83: 247, 1973.' }' }6 P* {# e! G1 [3 v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# g6 G3 N( h& {/ m
one therapy for penile growth. Urology, 6: 708, 1975.4 d4 b' Q/ }& g: U8 g4 [
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
  B: x2 a9 N: e) v1 N2 X; L' Hto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 ?' u: b4 C  [$ G
skin slices of man. J. Clin. Invest., 48: 371, 1969.& y1 f2 D( U1 j, k6 K* m. A
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 Y: v5 F8 o5 _+ T0 Y1 E
by topical application of androgens. J.A.M.A., 191: 521, 1965.2 c7 h3 G- L% U# o
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
% V0 f, _) j" a1 m' k4 q+ d" Nandrogenic effect of interstitial cell tumor of the testis. J.
2 U( i. E1 V, _" [: [. SUrol., 104: 774, 1970.9 J8 [+ u2 `) f- e
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 X2 T' B2 A& z9 I% C- y5 ption in the male genitalia from birth to maturity. J. Urol., 48:
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