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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND8 c: [5 x0 w# ?+ e
GONADOTROPIN& x! Z  X+ k6 s  q' m9 l7 V) |
RICHARD C. KLUGO* AND JOSEPH C. CERNY# Z8 F. g9 Q6 P, }
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& r& O) {4 V' F& ~% [. SABSTRACT, B. O/ b% m/ \, o3 G2 J
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
6 U; @* `1 D; Cwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 q: H- r) Z! H: d" z& Gtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone9 Y: [6 g0 N2 m& f3 n* N
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
. r+ G! Z2 e4 Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" ~: m8 Z  H9 }3 B( n9 R1 L* W2 d" [. C
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average" @0 F& ?* |. x2 Z' [) A
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response% a  _; R) Y  o6 E" j- e* a' x
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This7 a5 ^0 ?5 t1 Q
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile4 k) S% P9 }, m8 u1 I7 d( E3 ]+ W
growth. The response appears to be greater in younger children, which is consistent with previ-5 B6 x3 @% b$ `4 B8 |( r* }
ously published studies of age-related 5 reductase activity.% ]+ s; m$ i% ?) C
Children with microphallus regardless of its etiology will2 e( N5 Q5 K! g) q& Q+ ~
require augmentation or consideration for alteration of exter-# W+ {3 e% S0 t& \) X, |3 j
nal genitalia. In many instances urethroplasty for hypo-  f+ h( o; p3 M0 b
spadias is easier with previous stimulation of phallic growth.
& w/ V" S2 F; w/ d! X$ ]4 ZThe use of testosterone administered parenterally or topically
+ u1 c1 L9 e" C2 B5 G  z, ohas produced effective phallic growth. 1- 3 The mechanism of
+ |8 H" N& n6 K; Oresponse has been considered as local or systemic. With this. l1 ?2 y* v3 ]( u0 m
in mind we studied 5 children with microphallus for response
9 Y) z: n$ A) _! W& kto gonadotropin and to topical testosterone independently.7 q! ~/ W; O3 {
MATERIALS AND METHODS
" C, W) E3 @/ L2 ^; t9 GFive 46 XY male subjects between 3 and 17 years old were1 i/ C- ?5 a' R) u* i  p8 }+ ^2 o
evaluated for serum testosterone levels and hypothalamic& l# L( N( z7 Z1 _8 w
function. Of these 5 boys 2 were considered to have Kallmann's
0 |/ P/ U6 g0 h! V1 osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 ~' X8 j4 j) V3 ~2 Z& {$ o+ ?
lamic deficiency. After evaluation of response to luteinizing
. c2 y+ i4 e3 g: e1 [8 ]hormone-releasing hormone these patients were treated with2 o- n' y2 R6 d0 ?* n2 t, A4 \) b( p
1,000 units of gonadotropin weekly for 3 weeks. Six weeks* ~9 p0 b. Z, ?& t
after completion of gonadotropin therapy 10 per cent topical
" m/ j9 }6 J4 R" _. R1 ktestosterone was applied to the phallus twice daily for 3 weeks.: O  ^! K' K; k& a- M' C0 W
Serum testosterone, luteinizing hormone and follicle-stimulat-
7 ]: _3 Z4 Q3 `& Zing hormone were monitored before, during and after comple-1 T# c9 L  O. C9 J' b; r) B
tion of each phase of therapy. Penile stretch length was
( a  z, C2 N( _5 cobtained by measuring from the symphysis pubis to the tip of
4 p! {! V( D- U2 E5 Y% Ethe glans. Penile circumferential (girth) measurements were
& H% f7 ^; Z+ e5 H2 f# c: p5 X% L# }obtained using an orthopedic digital measuring device (see" b: P' |4 G8 |  F* A  M: N
figure).. S3 `  Z$ L/ C, K- P; a
RESULTS
- h* @2 }7 H4 W- eSerum testosterone increased moderately to levels between
$ X9 P& P- ^- j50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
: \% N/ I( b* o: l" M5 Q( V3 {) W7 eterone levels with topical testosterone remained near pre-2 p" i9 q5 s  Y/ G
treatment levels (35 ng./dl.) or were elevated to similar levels# ?( y+ T% {7 K# _9 m$ H% O. z) \
developed after gonadotropin therapy (96 ng./dl.). Higher
; k6 S2 C  x- d- pserum levels were noted in older patients (12 and 17 years old),
; a+ o4 @/ ?# i% Nwhile lower levels persisted in younger patients (4, 8, and 106 @8 B0 `3 d: `& W
years old) (see table). Despite absence of profound alterations  z; A2 B2 h- ~' k! v% D3 m
of serum testosterone the topical therapy provided a greater
( ?  v$ f# u8 gAccepted for publication July 1, 1977. ·
5 L* t* M% e; i. V7 O) u/ q0 rRead at annual meeting of American Urological Association,8 o+ o  E9 x+ N% `
Chicago, Illinois, April 24-28, 1977.
( Y7 G7 @/ Y) v2 T7 p" M( m* Requests for reprints: Division of Urology, Henry Ford Hospital,! z8 Z, y7 h- J$ f! [0 V/ j
2799 W. Grand Blvd., Detroit, Michigan 48202.
: L. G6 B$ \# W. }" N" |- himprovement in phallic growth compared to gonadotropin.
" \2 `# Y% b3 x, U, |8 OAverage phallic growth with gonadotropin was 14.3 per cent' S  ]6 h5 {4 F+ A% X
increase in length and 5.0 per cent increase of girth. Topical
( V: [! L) C6 r2 L- ktestosterone produced a 60.0 per cent increase of phallic length
+ |2 J/ j$ g9 Y* K" l# G+ ~- Mand 52.9 per cent increase of girth (circumference). The
# i" O* [8 l# Y$ a7 |( xresponse to topical testosterone was greatest in children be-8 v  a. v1 U  }, A- E
tween 4 and 8 years old, with a gradual decrease to age 179 ~4 r* m  K  [3 L  \/ I8 V% ]) y
years (see table).7 G  M- _. Z7 R' E. j' s
DISCUSSION
& [7 B+ N) O, h4 K1 [* c9 c6 xTopical testosterone has been used effectively by other
& ?$ C9 |7 ^7 a- _# L( gclinicians but its mode of action remains controversial. Im-
' W1 `! ]4 B$ f- Bmergut and associates reported an excellent growth response6 e3 ~! w1 T8 j
to topical testosterone with low levels of serum testosterone,& F; S/ o- x( |/ Q! D* V
suggesting a local effect.1 Others have obtained growth re-, A, b- q) H6 K! m! h& a9 [* ~
sponse with high. levels of serum testosterone after topical
7 p& J. g/ B( O6 padministration, suggesting a systemic response. 3 The use of! c" p( ~( V) t, m) L6 v
gonadotropin to obtain levels of serum testosterone compara-
& @' d2 \0 m1 d2 Ible to levels obtained with topical testosterone would seem to/ g8 Y0 D4 n7 \' ~8 Q, L
provide a means to compare the relative effectiveness of
% C. i2 _' @. D4 D4 Ptopical testosterone to systemic testosterone effect. It cer-
7 ?" ~! m) o) R$ E$ Ttainly has been established that gonadotropin as well as par-
6 `! b* \- @/ N! F8 Zenteral testosterone administration will produce genital3 L, ?* n8 {- X1 y' w+ i* D
growth. Our report shows that the growth of the phallus was, z2 u3 Z2 p+ M
significantly greater with topical applications than with go-! g7 z8 b  r7 j9 ]. F9 b# o
nadotropin, particularly in children less than 10 years old.4 ]7 E) S+ i* c( t1 c, |) D
The levels of serum testosterone remained similar or lower# c( j* _3 n: {/ z7 U
than with gonadotropin during therapy, suggesting that topi-) ?# e9 m8 f0 x4 m/ |
cal application produces genital growth by its local effect as
) n% K$ L0 Q- t* h' xwell as its systemic effect.
  }/ Y6 I7 K/ d/ Y3 ]& X( t" l0 GReview of our patients and their growth response related to
$ A* m# q) R5 G5 Gage shows a greater growth response at an earlier age. This is
. Q9 R0 w" i5 q7 e1 w6 M! y) p: Jconsistent with the findings of Wilson and Walker, who: ^+ s; Z+ D( G% u  q7 K
reported an increased conversion of testosterone to dihydrotes-
: d+ y! b/ r4 A' d, a% Ztosterone in the foreskin of neonates and infants.4 This activ-3 i. S) z" J/ v) f& J& @! J
ity gradually decreases with age until puberty when it ap-
* B5 _8 o. e' R1 h; F2 jproaches the same level of activity as peripheral skin. It may; l3 C' s: ^) O+ G3 i
well be that absorption of testosterone is less when applied at
, l6 Y& q% L8 U6 r8 a" q8 c5 v. D9 Yan earlier age as suggested by lower serum levels in children$ R) s! ]# ^6 a! ?
less than 10 years old. This fact may be explained by the
8 b# [! @3 l! k3 F7 ?+ mgreater ability of phallic skin to convert testosterone to dihy-7 E# Z0 c: b/ n' k& W+ M! ~
drotestosterone at this age. Conversely, serum levels in older0 h8 ]0 U, E: W* l$ z
patients were higher, possibly because of decreased local
8 m, ?* r, A: v# D: J* W667
1 X% j  H- n- m0 x/ Q" D+ N0 m668 KLUGO AND CERNY$ F+ N, _! O1 m1 b! i
Pt. Age. x3 h$ ]8 e  ]% L2 U4 |
(yrs.)
+ C9 ^0 z: P( aSerum Testosterone Phallus (cm.) Change Length
9 u6 n' L. p2 z4 J, M(ng./dl.) Girth x Length (%)
% y# u: \1 |& y0 v& l  }1 y4 h& s44 k" j1 R* |) ^1 ^9 `3 Z- @
8( s3 X) ?7 y, c8 k0 U" Z* }3 Y
10
/ E, D7 c, h$ H2 Y% i. b5 I124 j2 M* p* H1 N4 \) {; `0 P  O
17
7 C9 S$ H+ u5 @Gonadotropin) k5 E' u+ S4 v0 r- A1 H, Z  Y
71.6 2.0 X 3 16.6) g. [+ n. ~/ O, h9 S. k+ l
50.4 4.0 X 5.0 20.0
8 b. y1 t! H4 y0 q1 Y. W: Z1 S22.0 4.5 X 4.0 25.0
* ~" s/ C' X1 z- B: `84.6 4.0 X 4.5 11.14 E0 J, ^& }0 T& g$ e
85.9 4.5 X 5.5 9.0
- I0 Z+ f  }: j6 h7 \3 ]/ c- MAv. 14.36 Q* G9 K0 c1 o2 v% S5 Z3 y; `, v
4
; }4 r8 G+ L# J6 Q8% A$ x1 w+ T! i( ]3 x4 _
10" A2 a9 x6 _0 r4 w4 G
12
0 [6 O+ T2 I6 j! `& v17$ x" \, Z6 i1 `
Topical testosterone
' F. c3 H5 N8 A7 i- j1 V, k34.6 4.5 X 6.5 850 Z( e! B4 `+ U/ |* I# @- a
38.8 6.0 X 8.5 706 A2 I) l5 F, n% R
40.0 6.0 X 6.5 62.5; J, [& T3 U9 _9 ]+ ]' U. m
93.6 6.0 X 7.0 55.5
' t, O/ x+ V' e% _. Y# j0 j95.0 6.5 X 7.0 27.2* J0 D; [$ Z! B# X8 N! p
Av. 60.0* ]8 N( n* K) G( r7 _: S& u
available testosterone. Again, emphasis should be placed on
, p+ T; F$ T; ]2 jearly therapy when lower levels of testosterone appear to
0 a" v, E* P3 X$ b+ D% Q9 Eprovide the best responses. The earlier therapy is instituted- c4 p$ T% g) M# o. S2 C. C2 x9 j
the more likely there will be an excellent response with low. l  n& o" D& a" j
serum levels. Response occurs throughout adolescence as! x) W. x" g: S0 |( _, Q- g
noted in nomograms of phallic growth. 7 The actual response- O; _( [% k1 y) j5 E9 x+ N* S
to a given serum level of testosterone is much greater at birth7 n) g9 I# T8 y  Y2 M1 Q& G- H
and gradually decreases as boys reach puberty. This is most
: A7 [# m& y+ a5 Slikely related to the conversion of testosterone to dihydrotes-
3 p. u  l- e/ L0 Dtosterone and correlates well with the studies of testosterone
1 b8 J* M& t9 \9 `1 m% Zconversion in foreskin at various ages.
* L. Y- S0 \. _* oThe question arises regarding early treatment as to whether' l* X. N, B- e0 \4 w
one might sacrifice ultimate potential growth as with acceler-: [8 k3 N  J' k: }& q
ated bone growth. The situation appears quite the reverse) B4 q, F% x& b9 s3 O
with phallic response. If the early growth period is not used/ u& P4 P% e) {8 {8 ~
when 5a reductase activity is greatest then potential growth6 G6 v% b: e) [
may be lost. We have not observed any regression of growth$ _0 n+ u) Q  w- b
attained with topical or gonadotropin therapy. It may well
1 ?" U' A0 V0 Sbe that some patients will show little or no response to any% r1 M6 ?5 S2 u0 Q
form of therapy. This would suggest a defect in the ability to
: k6 U$ \% ?: R/ x8 u3 [convert testosterone to dihydrotestosterone and indicate that
. |6 _2 Y0 W. [9 Z5 Pphallic and peripheral skin, and subcutaneous tissue should- ^- w  V+ L7 n  \& x
be compared for 5a reductase activity.
) X1 a, H4 b9 j$ j% r$ lA, loop enlarges to measure penile girth in millimeters. B,/ X2 Q3 T4 b# D  ?$ O9 W9 w% @
example of penile girth computed easily and accurately.
$ B" ^' t, T; Bconversion of testosterone to dihydrotestosterone. It is in this0 V. J1 B) d# m/ c# W% z" F
older group that others have noted high levels of serum4 K- ]3 J) B- Z
testosterone with topical application. It would also appear& L- U1 C: J9 e9 D) a7 Q5 J& y, j" R
that phallic response during puberty is related directly to the$ `0 G1 J) p3 O
serum testosterone level. There also is other evidence of local
' I% P5 R  ]3 F; v5 sresponse to testosterone with hair growth and with spermato-& R. n4 @  n) o- l3 r% b( _' {
genesis. 5• 65 i! t! {4 _, T$ u/ ~7 S
Administration of larger doses of gonadotropin or systemic) j1 r% S9 q0 t: M
testosterone, as well as topical applications that produce
/ S: S/ i3 |! O& ~( jhigher levels of serum testosterone (150 to 900 ng./dl.), will
) ~6 \6 p& W! o/ ^3 y  lalso produce phallic growth but risks accelerated skeletal
' W3 x  ~# g7 {' v" wmaturation even after stopping treatment. It would appear/ ]# ]; O$ w/ b4 n% }9 S8 w
that this may be avoided by topical applications of testosterone0 r. C* C) F& D5 t$ T0 q/ t' @# [8 L
and monitoring of serum testosterone. Even with this control
, F7 h5 y& Z6 l2 L- O: S2 K: w4 Zthe duration of our therapy did not exceed 3 weeks at any
$ _9 o4 h5 g( Q# r! x1 etime. It is apparent that the prepuberal male subject may
. i0 z2 w) n- j; ~* X, m0 r, xsuffer accelerated bone growth with testosterone levels near' p1 ?1 I% p$ U; b! Z0 J. z+ x
200 ng./dl. When skeletal maturation is complete the level of
5 i: _1 U& s4 Y  y6 ~0 wserum testosterone can be maintained in the 700 to 1,300 ng./6 _7 t! V) q: g  q
dl. range to stimulate phallic growth and secondary sexual
/ A( n( u% Z' u2 |6 O& [changes. Therefore, after skeletal maturation parenteral tes-/ _; z& J) [3 }& @  y* P& ~
tosterone may be used to advantage. Before skeletal matura-' d* v0 _2 c" a( R5 {( Y
tion care must be taken to avoid maintaining levels of serum
. x( q3 U+ H% K2 i* q" etestosterone more than 100 ng./dl. Low-dose gonadotropin
1 d9 v2 K- X) B1 ]( I+ c  D1 |4 X/ odepends upon intrinsic testicular activity and may require$ |" K$ ?3 x6 s: z$ D
prolonged administration for any response.+ {+ M5 _, e) m  T& a0 ^
Alternately, topical testosterone does not depend upon tes-
: T7 {) B1 c( W, D$ u1 T/ Sticular function and may provide a more constant level of
& C; c/ J" p6 M# ~. G% i$ S' `REFERENCES
( b5 ^- ^5 ^* s8 G$ x5 `$ E( K7 D5 d& C1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ _6 r7 x; Z/ H2 ?. u& x
R.: The local application of testosterone cream to the prepub-" i( @6 S( ~4 L" e3 H
ertal phallus. J. Urol., 105: 905, 1971.
5 W3 F4 p# o4 G3 w8 F' `2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
" A6 J+ T; C, f" rtreatment for micropenis during early childhood. J. Pediat.,
. Y! f6 e& T" P' S3 W83: 247, 1973.
0 W4 x, A# @; n0 [2 T+ ?. A0 Q3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' {2 _: j% H1 L7 O5 \4 f+ s/ P3 r- Pone therapy for penile growth. Urology, 6: 708, 1975.
* O+ A4 v4 Y/ g3 u. C4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone: D  F8 c) m& \0 j
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 P8 E6 L# z" _0 Xskin slices of man. J. Clin. Invest., 48: 371, 1969.
8 y2 L9 ]6 z2 k6 z3 r1 ?1 s5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ X* K9 S) o9 N; H1 ]1 S% G" ?by topical application of androgens. J.A.M.A., 191: 521, 1965.5 _1 F6 m6 x  P0 q: e2 M- S3 b* c
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
7 s) {  u2 p% u$ u" \7 Aandrogenic effect of interstitial cell tumor of the testis. J.
4 e# _4 C8 u$ P0 a  \7 o& Z1 HUrol., 104: 774, 1970.
) @: b, |. ^! `5 a7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
% S9 W+ L9 ^( E4 Vtion in the male genitalia from birth to maturity. J. Urol., 48:
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