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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
% P6 L1 p$ q' g, |GONADOTROPIN. Z# b0 S, W: ?) F$ Q$ k
RICHARD C. KLUGO* AND JOSEPH C. CERNY
6 W5 _6 H5 G1 oFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan% h* X" l/ v2 `# b: [
ABSTRACT
* f+ H- g9 r1 Y7 F% z( |  G5 c$ |Five patients were treated with gonadotropin and topical testosterone for micropenis associated5 v! ~4 d7 C9 F9 I5 \5 s$ F
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-, U: Q; `% L; y' F$ c! M: B- m- P
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
/ l  C; O& M- E; F  j! p5 n# P+ s( [cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
. X8 ]6 \7 m- i$ r9 ]+ `4 tfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 W; N, B2 m& V' Q% t4 c
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average/ F0 L& [- x! u/ z8 ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 |" y0 T6 N, d5 |
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This* P6 [% H3 L9 I" v5 y+ L9 b$ \2 v
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
! T3 H5 p- J  C& }5 Ggrowth. The response appears to be greater in younger children, which is consistent with previ-
) H/ d. q. @. uously published studies of age-related 5 reductase activity.
  ~. v" o- d9 P% A1 q! c  S: I+ uChildren with microphallus regardless of its etiology will7 b5 q9 w* {- b' B
require augmentation or consideration for alteration of exter-  V, n) g8 e/ _/ i9 `8 c* z
nal genitalia. In many instances urethroplasty for hypo-# \1 x  K( T) g
spadias is easier with previous stimulation of phallic growth.
! n  o2 M0 _! E# Z8 U+ CThe use of testosterone administered parenterally or topically
% e/ q  T4 B$ ]7 G1 v! phas produced effective phallic growth. 1- 3 The mechanism of& _, b' H# Z9 R! r
response has been considered as local or systemic. With this& ~# ]* D# M8 C1 T6 H! G5 A
in mind we studied 5 children with microphallus for response
; O8 c; y6 d4 uto gonadotropin and to topical testosterone independently.
# i: C: n& O  a) \. P! sMATERIALS AND METHODS3 x$ j6 D8 `& }% W
Five 46 XY male subjects between 3 and 17 years old were' I/ X! e9 G9 b( r( T
evaluated for serum testosterone levels and hypothalamic( `6 a1 ^& X2 b9 i) S/ c( j
function. Of these 5 boys 2 were considered to have Kallmann's
9 p5 ~% U4 y; ?9 ^3 g6 \- m8 Vsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-# L' M: p# L: o
lamic deficiency. After evaluation of response to luteinizing! h6 N$ m( r# X3 L
hormone-releasing hormone these patients were treated with
7 S- L# q: k5 h/ y3 M  _1,000 units of gonadotropin weekly for 3 weeks. Six weeks
' Q" \& y3 w2 b0 L' k( e* o8 Fafter completion of gonadotropin therapy 10 per cent topical( Z/ ~) H5 j  v; t2 |7 W+ G
testosterone was applied to the phallus twice daily for 3 weeks.6 B- e6 x. s* c2 j5 Y
Serum testosterone, luteinizing hormone and follicle-stimulat-
& T  d. ]' @3 r: Y5 W1 aing hormone were monitored before, during and after comple-& A' _9 }! ^8 C2 O
tion of each phase of therapy. Penile stretch length was5 p: o2 _6 S4 y1 F4 w
obtained by measuring from the symphysis pubis to the tip of
4 W' x+ c' ^. r4 }the glans. Penile circumferential (girth) measurements were
% V. o0 i; m/ v0 V' T& l4 A7 T3 Aobtained using an orthopedic digital measuring device (see; `7 c. [) d/ Y- e
figure).! ^9 K, t. D! h2 P
RESULTS
1 D3 X0 ^4 U; @5 O3 w% {Serum testosterone increased moderately to levels between
/ p. u% e, h" s$ d50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ M, X' ?7 S/ N5 b8 ]7 R9 r
terone levels with topical testosterone remained near pre-; ^1 _+ C. `  H$ q7 }
treatment levels (35 ng./dl.) or were elevated to similar levels
2 |9 ~  M: T' e- H( O' S+ W* ^developed after gonadotropin therapy (96 ng./dl.). Higher
7 O. D# [/ w/ K1 R8 ~, qserum levels were noted in older patients (12 and 17 years old),3 @6 g3 r: g7 A8 g( y# P& \
while lower levels persisted in younger patients (4, 8, and 10
9 _7 Q6 ^0 G0 J% Kyears old) (see table). Despite absence of profound alterations
5 L# T! o8 V% ?* \, l2 R$ O4 Mof serum testosterone the topical therapy provided a greater5 @- Y: j9 g% O/ A$ `' m
Accepted for publication July 1, 1977. ·
( A8 a5 N$ l$ Z$ D& N! \Read at annual meeting of American Urological Association,
: {) f1 K7 g4 u, e+ T4 Y- {$ g. r$ tChicago, Illinois, April 24-28, 1977.
! P6 z/ n, k# z' X7 {4 ~* Requests for reprints: Division of Urology, Henry Ford Hospital,  _" M! D* L. M4 l0 r1 b
2799 W. Grand Blvd., Detroit, Michigan 48202.9 [( D+ O9 L+ Z' ^9 N, l
improvement in phallic growth compared to gonadotropin.
0 u4 F1 u: g: {+ k& U  k7 Q. JAverage phallic growth with gonadotropin was 14.3 per cent; m% Q/ I5 W1 O$ S6 _4 @
increase in length and 5.0 per cent increase of girth. Topical
* H6 g% h' N7 K& w; f+ ~# xtestosterone produced a 60.0 per cent increase of phallic length4 i0 W( m3 i. w
and 52.9 per cent increase of girth (circumference). The
1 [2 w# ?/ Y5 g0 z3 zresponse to topical testosterone was greatest in children be-3 H( E2 R& h2 {) x
tween 4 and 8 years old, with a gradual decrease to age 17. @5 E5 Y, O' m; g3 K0 m! @
years (see table).
6 E6 y, P1 a9 C4 p- O( i0 SDISCUSSION" t: V4 D  n7 I2 J" ]
Topical testosterone has been used effectively by other7 o- ~6 Z7 Z2 m# }4 M: P0 d. V. d
clinicians but its mode of action remains controversial. Im-* o! Q, Q4 f1 E$ j
mergut and associates reported an excellent growth response
; @4 e' f2 L; A" B' }6 B' @( Fto topical testosterone with low levels of serum testosterone,
; n% k2 `0 Y; O" u& W8 p/ ~suggesting a local effect.1 Others have obtained growth re-
5 Y& N2 c% T& d# A3 asponse with high. levels of serum testosterone after topical5 B2 n& B* |  n/ C0 L6 h8 [! O
administration, suggesting a systemic response. 3 The use of0 Q4 c$ \9 f. d
gonadotropin to obtain levels of serum testosterone compara-( r+ Y. G0 U8 q6 M5 b1 d/ ^& T
ble to levels obtained with topical testosterone would seem to
$ y- f/ }& {5 R+ |5 W' l3 t& z- yprovide a means to compare the relative effectiveness of& }) [/ g- n( `1 `3 i4 s
topical testosterone to systemic testosterone effect. It cer-
, S  U3 q4 G6 b: w( ]" xtainly has been established that gonadotropin as well as par-2 g, @6 q3 `) h6 |% W
enteral testosterone administration will produce genital
. Z% R5 V. z9 [. s  q0 pgrowth. Our report shows that the growth of the phallus was
5 I: T. {4 d8 P8 usignificantly greater with topical applications than with go-; O3 X; K9 T* l
nadotropin, particularly in children less than 10 years old.
- c9 a. J- _' Z9 vThe levels of serum testosterone remained similar or lower
/ Y9 b( v8 M6 j2 D3 Othan with gonadotropin during therapy, suggesting that topi-5 |( W* s$ Y2 g; {6 `0 }/ R
cal application produces genital growth by its local effect as
) t% d' j# |7 K! Q& m: e- U: Y3 mwell as its systemic effect.
$ Y& C, m5 Z) MReview of our patients and their growth response related to! P2 {9 R8 q& v: N2 h( V$ m
age shows a greater growth response at an earlier age. This is9 F5 f( D/ f2 [5 U( c4 D1 @
consistent with the findings of Wilson and Walker, who
: p& A# U0 q4 H% W5 `( |1 treported an increased conversion of testosterone to dihydrotes-% ^; }( m' n: N
tosterone in the foreskin of neonates and infants.4 This activ-
! }& t* Q" X6 a3 _ity gradually decreases with age until puberty when it ap-* m' F& k/ }% O6 _  z
proaches the same level of activity as peripheral skin. It may
' N; e2 t! o& g( M! _; @" r$ twell be that absorption of testosterone is less when applied at
; q7 C$ W8 A, B- T6 U2 N* Tan earlier age as suggested by lower serum levels in children
, p  r) d! Q2 g% Q6 Zless than 10 years old. This fact may be explained by the- [2 T  X' j9 i- g% F, {
greater ability of phallic skin to convert testosterone to dihy-
# W3 g+ X6 C8 Ldrotestosterone at this age. Conversely, serum levels in older
* c; c% |6 Z8 v  o, B# Bpatients were higher, possibly because of decreased local5 n- h6 D- c) E, J
667! e$ Q4 U- D9 e- F7 N
668 KLUGO AND CERNY
/ F( |  P9 T9 W# V4 TPt. Age( K' G: I: u) P: ?% h
(yrs.)' l. c) H  P) x* Y  P
Serum Testosterone Phallus (cm.) Change Length2 f" C% K3 ^% N0 M4 b
(ng./dl.) Girth x Length (%)
: A+ D; C4 ]+ @7 O6 ]7 _$ a& N5 r4
: l" Z8 j: h, u3 U9 @! m! n8
7 P0 O9 J2 Q4 n& r10
7 i$ }$ A; U9 Q129 w9 ^5 y3 i. h4 I6 c
178 X+ p# L) g  o" a! K
Gonadotropin
: L% b& g2 z+ K4 o3 F* w71.6 2.0 X 3 16.6( U( ^) j2 r  b4 X4 d6 A
50.4 4.0 X 5.0 20.06 |4 X/ W$ d& \+ T4 L+ S8 w/ n
22.0 4.5 X 4.0 25.0
7 M# u0 ?% Y7 |+ ?- {84.6 4.0 X 4.5 11.1: c) O% W! k0 W0 A3 d( T
85.9 4.5 X 5.5 9.0
3 {. M+ q+ P( v. I5 O7 E7 E$ r  aAv. 14.3
* F* ]0 M% A4 f3 J4' {( p0 T; \" {8 z9 l
85 F% a6 \; [0 e% n
10
) C% w9 Y- c8 r1 r/ K123 o$ S9 I7 o! }: e2 k- D. e0 y
174 m; h4 w: a2 y$ a& t
Topical testosterone
7 M7 ]: z+ s3 X% V( l) |. E! t34.6 4.5 X 6.5 85. o, w; C* t# [4 [+ l/ N) l
38.8 6.0 X 8.5 70
- n0 A0 J. a0 i9 h5 m1 u40.0 6.0 X 6.5 62.5
5 z5 \0 ]3 n* S' [' W( \93.6 6.0 X 7.0 55.5
$ ~2 J1 f5 y# S& F: n) Z95.0 6.5 X 7.0 27.2
; J) w+ A+ v1 W- }Av. 60.0
4 }$ T  K: i' E$ m1 S3 L) U" \/ Aavailable testosterone. Again, emphasis should be placed on; }0 @# Q3 L; x9 a1 p
early therapy when lower levels of testosterone appear to
9 L9 \% ^% ^4 A2 O4 k( K  p7 r6 B3 ~provide the best responses. The earlier therapy is instituted$ N6 X. A) i& k, L' _
the more likely there will be an excellent response with low' j% k( @* e, N
serum levels. Response occurs throughout adolescence as& x" g: e6 B3 e! h8 C8 _; T$ H
noted in nomograms of phallic growth. 7 The actual response
0 U# B+ P1 X$ b; f& {- C5 Hto a given serum level of testosterone is much greater at birth
1 s$ N/ P, y7 Y0 X) r8 k! zand gradually decreases as boys reach puberty. This is most
$ c& S9 W+ G2 V* A: k8 B- _1 clikely related to the conversion of testosterone to dihydrotes-
( \3 i* M# Q$ A( ttosterone and correlates well with the studies of testosterone. k2 x9 \/ f# C) V# |/ O8 r
conversion in foreskin at various ages.
0 f) u- T( }( OThe question arises regarding early treatment as to whether
8 h# k, D; C. C# D8 _  Qone might sacrifice ultimate potential growth as with acceler-
" z8 ?6 ?1 W! `3 e% j1 F3 t# ~ated bone growth. The situation appears quite the reverse
0 L% A) Q) O% Q: C8 ]with phallic response. If the early growth period is not used8 u) E3 p/ ]9 \- U( d% J# X
when 5a reductase activity is greatest then potential growth
1 ^) E/ w6 n( o7 \1 g( Z2 W9 Qmay be lost. We have not observed any regression of growth
  `3 V) L/ W0 |+ f3 w: Lattained with topical or gonadotropin therapy. It may well; z( ]. t3 U1 u( u& p0 B1 G
be that some patients will show little or no response to any2 R6 z& {1 J7 Q: E
form of therapy. This would suggest a defect in the ability to
/ f8 q  y' K8 P* n8 gconvert testosterone to dihydrotestosterone and indicate that
. m' F2 b) O6 `5 Lphallic and peripheral skin, and subcutaneous tissue should
9 r  Y. x( k& H# p' m: Mbe compared for 5a reductase activity.
- T  ~! p7 f3 N& wA, loop enlarges to measure penile girth in millimeters. B,3 w; i3 q; A* X$ C
example of penile girth computed easily and accurately.
% O$ V) q1 z' L) rconversion of testosterone to dihydrotestosterone. It is in this- J' y2 h0 t+ o4 a. K# U1 @5 M
older group that others have noted high levels of serum6 a4 N5 w$ p. {2 y% r7 \" h
testosterone with topical application. It would also appear
8 w0 k) Z3 ^1 i& _& ]6 e. tthat phallic response during puberty is related directly to the
* m3 Y% U& P2 H$ i4 J; l' L- s, Vserum testosterone level. There also is other evidence of local8 @1 a3 t  l: C0 H8 [
response to testosterone with hair growth and with spermato-0 |3 O- x7 I! G' ]
genesis. 5• 6/ D6 t* v0 W# \6 c$ j; W
Administration of larger doses of gonadotropin or systemic- b4 Q& H8 m, B1 k
testosterone, as well as topical applications that produce
. ]- r7 w! s1 _: _- rhigher levels of serum testosterone (150 to 900 ng./dl.), will; T( [, @4 d7 ^2 t; h9 I- k
also produce phallic growth but risks accelerated skeletal7 ^1 ?( a* D2 {/ o: `
maturation even after stopping treatment. It would appear
* j( E+ O8 `0 a* q2 K; gthat this may be avoided by topical applications of testosterone( _! h, x: t/ w9 W( ?: J. l
and monitoring of serum testosterone. Even with this control7 \- n1 S% U/ @  s' E( g
the duration of our therapy did not exceed 3 weeks at any
# [) ^) A) J" Q: N0 dtime. It is apparent that the prepuberal male subject may4 i6 A8 }1 {4 I1 _# S
suffer accelerated bone growth with testosterone levels near# e! w1 }! R) x" G2 K, d+ v' A
200 ng./dl. When skeletal maturation is complete the level of' U+ V5 h6 {" [* J. f' r; z
serum testosterone can be maintained in the 700 to 1,300 ng./
8 S; u0 I! A7 X; K3 s  mdl. range to stimulate phallic growth and secondary sexual
0 @) L; b& s+ ^3 r, y; f+ uchanges. Therefore, after skeletal maturation parenteral tes-
) ]+ g: m: i; |) n; ktosterone may be used to advantage. Before skeletal matura-
% z. G. j7 x1 b# l) Ktion care must be taken to avoid maintaining levels of serum& i2 w" F% g6 g: s
testosterone more than 100 ng./dl. Low-dose gonadotropin
4 _9 \9 j( X) d) c  M# Odepends upon intrinsic testicular activity and may require8 P$ b3 v+ e1 v4 c5 c* E' |# o
prolonged administration for any response./ ~& Z5 B2 c% c8 K& D( C) k
Alternately, topical testosterone does not depend upon tes-
# L/ k- V2 c8 E5 f  u6 D, w7 hticular function and may provide a more constant level of6 j8 S; p, ^$ c# s1 Y: b  Q8 A
REFERENCES. S7 p) U& W2 `% P3 p3 Q
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,5 |7 ~- i- J- j; C
R.: The local application of testosterone cream to the prepub-: W5 }% `. Z1 x( N
ertal phallus. J. Urol., 105: 905, 1971.
2 L, z7 P7 b3 f4 l/ C' q- @2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ S- t5 A: W2 Q
treatment for micropenis during early childhood. J. Pediat.,; h9 t3 d5 E: O# Z2 ]$ v
83: 247, 1973.  P$ K1 k# j  @+ I1 R2 v' Y
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 K5 w0 Z5 i( s5 P, eone therapy for penile growth. Urology, 6: 708, 1975.
; _  P4 A4 J9 B0 @4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; {. v8 i2 j1 R: z7 p0 T: |to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& R5 m3 r6 L- r; k6 A# m* O. J: @skin slices of man. J. Clin. Invest., 48: 371, 1969.
" `: N& o! U4 P. m; B3 m6 g5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ ^5 u4 S$ Y+ m/ E
by topical application of androgens. J.A.M.A., 191: 521, 1965.% k- v% t- B: a6 g4 b4 z
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local2 O% M* }9 h/ |- A3 V2 L6 U
androgenic effect of interstitial cell tumor of the testis. J.
$ ]$ {' O6 O( j6 J. WUrol., 104: 774, 1970.
( K5 i/ `/ P: M( G; ~. h8 N8 s7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-& E1 N" [0 M* g% Q! I5 b3 D
tion in the male genitalia from birth to maturity. J. Urol., 48:
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