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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, M! q7 A0 W( jGONADOTROPIN$ x7 n, M3 i* G- ]
RICHARD C. KLUGO* AND JOSEPH C. CERNY
( F: j/ g: n: B8 tFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan- F6 }; W+ s0 m# r# n3 P, @6 p6 x* Y
ABSTRACT8 S2 _8 P2 r/ j5 P- l/ q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
2 o0 A3 M0 |% ?9 e* Y' h+ gwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ {2 q' N% c: A# T- z* n1 \tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( `. f, c) `! q2 H; {cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
9 y( `: L, q4 ~0 a9 I( B! ], `9 Efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 P4 c9 ]! M) R
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 x3 T+ P+ ~1 @, u' Sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% c$ ?  Y$ @, _0 `- _- W2 o4 }occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
& ~  ~9 A2 l" M1 T3 k! [study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; P) f" M/ i' c/ r# ], tgrowth. The response appears to be greater in younger children, which is consistent with previ-
3 P. ~3 w  P3 b  @0 |ously published studies of age-related 5 reductase activity.
" G8 N8 d/ r9 L9 F1 Q4 LChildren with microphallus regardless of its etiology will
  ^+ G! i- z5 g6 Q3 krequire augmentation or consideration for alteration of exter-: F" B( b3 h7 s/ ^
nal genitalia. In many instances urethroplasty for hypo-) J9 a* m, m8 u4 f8 ^0 a
spadias is easier with previous stimulation of phallic growth.8 J3 T( O7 L3 ~8 z
The use of testosterone administered parenterally or topically
0 d2 o5 }$ c  P$ z# n6 s" Chas produced effective phallic growth. 1- 3 The mechanism of
, I  @! l6 d1 j' X3 ~% r+ N  _response has been considered as local or systemic. With this
9 U9 y: K5 f4 w! W  e, ?in mind we studied 5 children with microphallus for response3 {. j  Z6 R6 Z* U6 O0 i
to gonadotropin and to topical testosterone independently.
( i) G* t8 e' MMATERIALS AND METHODS# v% w: }2 J1 T/ l' d
Five 46 XY male subjects between 3 and 17 years old were
1 c- x* I. v2 H  Z6 F' E9 Cevaluated for serum testosterone levels and hypothalamic
! h6 P4 h+ i' z1 ^function. Of these 5 boys 2 were considered to have Kallmann's! ]- h/ G" m6 H) w
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
/ P( x2 X8 p' s8 j$ R% hlamic deficiency. After evaluation of response to luteinizing
$ o3 |# M  d- G: o' D' b; ehormone-releasing hormone these patients were treated with- L& C, y* X4 h! d
1,000 units of gonadotropin weekly for 3 weeks. Six weeks) J6 [, l' ^4 k% a1 w# T" T
after completion of gonadotropin therapy 10 per cent topical
; e2 C1 P, L% w  otestosterone was applied to the phallus twice daily for 3 weeks.
: A6 ?- L- V+ l4 ~. nSerum testosterone, luteinizing hormone and follicle-stimulat-; N; Z5 J" Y4 B6 U: o/ Z
ing hormone were monitored before, during and after comple-
0 X: V8 d3 i: gtion of each phase of therapy. Penile stretch length was
+ Z; W% l& F8 e9 wobtained by measuring from the symphysis pubis to the tip of
- L& |$ }; U4 J$ f5 C+ V3 Q' sthe glans. Penile circumferential (girth) measurements were4 W: h0 D* F9 [! m0 R
obtained using an orthopedic digital measuring device (see% D( r1 k7 f6 U! S6 R
figure).
! g5 g5 V) q# ?0 F0 z* B# q; HRESULTS# I, H  }+ `" ~- T4 J& v
Serum testosterone increased moderately to levels between
  M/ d+ p) M$ k! U50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 t; _7 O+ X" g8 y* _
terone levels with topical testosterone remained near pre-4 L5 O9 Y' y5 e+ C, t' C; ]  z
treatment levels (35 ng./dl.) or were elevated to similar levels$ R) C, I/ M; `7 i
developed after gonadotropin therapy (96 ng./dl.). Higher
& m6 c2 r7 J; D: V2 M! Userum levels were noted in older patients (12 and 17 years old),
* z8 l: s: J1 F! U# [while lower levels persisted in younger patients (4, 8, and 10
8 v( P9 ~1 R. f' _2 uyears old) (see table). Despite absence of profound alterations8 T: Z/ _2 k- g* |  H7 H
of serum testosterone the topical therapy provided a greater2 H% t8 m0 A# r
Accepted for publication July 1, 1977. ·
# {2 G0 L: R. r' \" KRead at annual meeting of American Urological Association,' Z8 C5 F$ A) s! ~! o4 e
Chicago, Illinois, April 24-28, 1977.
4 ^6 |/ q+ C$ s; F* Requests for reprints: Division of Urology, Henry Ford Hospital,: M0 y9 V) G5 T% V! A+ J! d# |! H
2799 W. Grand Blvd., Detroit, Michigan 48202.8 i$ _+ C0 ?, q9 ]/ m/ q- T
improvement in phallic growth compared to gonadotropin.( R+ s' [7 l$ ?
Average phallic growth with gonadotropin was 14.3 per cent1 [9 o. Q& }7 l
increase in length and 5.0 per cent increase of girth. Topical2 _+ J$ U8 }- i6 M& a! D& p
testosterone produced a 60.0 per cent increase of phallic length
/ s( F3 C; S* ^4 s# Y, Pand 52.9 per cent increase of girth (circumference). The/ d: L4 m5 O# _4 o* v# z
response to topical testosterone was greatest in children be-
# c, M/ ^' _; [3 gtween 4 and 8 years old, with a gradual decrease to age 17
- d3 Z" I4 f! g" j" V5 R8 T% yyears (see table).* Z4 E  u6 R4 c
DISCUSSION. P( Y7 [: x' `( ^6 Z$ A3 O/ K
Topical testosterone has been used effectively by other4 @1 \9 q2 I0 j  ^& S- l  D
clinicians but its mode of action remains controversial. Im-
5 e% C5 t/ @1 o5 K% p% D9 dmergut and associates reported an excellent growth response4 O5 y; W, u( d0 Q! T. i: r6 V) \; Y
to topical testosterone with low levels of serum testosterone,6 [$ T7 |3 m; G
suggesting a local effect.1 Others have obtained growth re-+ h+ U& R! ^7 H& m. ~
sponse with high. levels of serum testosterone after topical
6 P/ D1 h$ o8 N, b) j: t) h0 Dadministration, suggesting a systemic response. 3 The use of# v$ _8 ]7 F( j, @9 ]
gonadotropin to obtain levels of serum testosterone compara-9 ]0 L9 r/ Y! w0 a7 L/ z
ble to levels obtained with topical testosterone would seem to
) u* m( O( F& \7 oprovide a means to compare the relative effectiveness of
+ v( E# O# U, @6 z9 j5 K# Atopical testosterone to systemic testosterone effect. It cer-6 z- M' {$ `. G: d3 T5 s
tainly has been established that gonadotropin as well as par-8 L5 s8 @6 H+ P  ^/ J2 K
enteral testosterone administration will produce genital* Z0 L* Q" n  c. [' J
growth. Our report shows that the growth of the phallus was9 r, y1 y7 j; x& _/ w7 @+ R
significantly greater with topical applications than with go-
8 W- X1 K- d7 U9 v, onadotropin, particularly in children less than 10 years old.
' X, [/ I* s5 X  K: Y. b( V: W. GThe levels of serum testosterone remained similar or lower
. c% G6 M: |" u9 V  M7 ]' \9 Bthan with gonadotropin during therapy, suggesting that topi-. K9 V' S  E- s# m4 h# ]( b5 g3 [
cal application produces genital growth by its local effect as
6 I8 N. q3 r9 V2 j0 y+ owell as its systemic effect.
! J0 Y0 ^" T9 i- W& U( k- g/ JReview of our patients and their growth response related to# A% s; D# t; t/ f3 J9 i$ p
age shows a greater growth response at an earlier age. This is4 s# Z) u& a; v, a% k
consistent with the findings of Wilson and Walker, who
& l* p# Y1 w5 [8 _* i5 q: y8 B" sreported an increased conversion of testosterone to dihydrotes-
% j* f3 {3 x2 r" h2 dtosterone in the foreskin of neonates and infants.4 This activ-
3 j" }3 k4 Q; N( @ity gradually decreases with age until puberty when it ap-4 s& J/ Q, f! m8 b  }  d
proaches the same level of activity as peripheral skin. It may
6 v+ D! U4 @9 `3 ywell be that absorption of testosterone is less when applied at
( ^! @" w5 _8 ^an earlier age as suggested by lower serum levels in children
- B& e) V2 b$ Q8 i, Sless than 10 years old. This fact may be explained by the
- E5 f2 [' ^3 N$ N! }: dgreater ability of phallic skin to convert testosterone to dihy-
+ U/ \0 n3 g' J9 ]( a# C3 `drotestosterone at this age. Conversely, serum levels in older
4 C3 E# O/ V4 j. q9 Dpatients were higher, possibly because of decreased local
5 U  H# ?' {& Z  A9 K6677 x% @( X/ N) l9 j! @
668 KLUGO AND CERNY
: Y9 s3 G3 c# b% U; fPt. Age
! P$ K' t- ]2 u* c8 V8 Y2 z, k$ O(yrs.)
& Y  v4 A7 V5 Q, U8 c( cSerum Testosterone Phallus (cm.) Change Length
& t+ U8 G+ N/ }  b9 x! p(ng./dl.) Girth x Length (%)8 z+ y2 Y. N1 Z) i
4
* U% K) I5 Y" u+ M8
2 t( z& P' {8 Y" ^! A10
0 s6 u) i) s" {9 y) y$ h6 S3 h12: |. T5 a7 }6 Y- p
176 X6 a5 H- F( j( f. [, z
Gonadotropin
) R* a% y4 Y) w! Q6 S! l: H1 j& W71.6 2.0 X 3 16.63 E& b6 |5 l1 X) Z3 \
50.4 4.0 X 5.0 20.04 `& V# I5 j( a& t) Z/ X& q
22.0 4.5 X 4.0 25.00 |0 l+ h4 I% s/ j
84.6 4.0 X 4.5 11.1* t. }/ h: r5 [7 ]" [
85.9 4.5 X 5.5 9.0
! _# P9 `0 C- {, [6 E: q8 ZAv. 14.3
- c5 S* z! S0 j6 n! B" z41 l" Z: T! E+ K
8! X: u& v. u' Z  `; w
10$ v/ O# }$ M0 K/ p8 F2 `. F0 L
12
1 f1 E& I# R1 G% x17' O+ [, ~5 r: M7 x& V2 T4 c, j
Topical testosterone
, J  G: u% E5 N8 A34.6 4.5 X 6.5 85
  l( y; F3 ?8 c+ G6 l: ^4 |38.8 6.0 X 8.5 70
+ W$ y, h3 |0 ]( c9 ?9 u: H40.0 6.0 X 6.5 62.5
9 A) j# k# H8 L93.6 6.0 X 7.0 55.5/ V1 e% ?( A7 f1 z5 L( ?
95.0 6.5 X 7.0 27.2$ ?# r8 f/ T' B8 i! k8 C0 a" S
Av. 60.0& Z) t, m1 S; k' ?
available testosterone. Again, emphasis should be placed on; [! F) U! F  {& H9 H8 |5 S9 t+ i
early therapy when lower levels of testosterone appear to
7 f9 |5 H. o) mprovide the best responses. The earlier therapy is instituted
/ I% u' `6 e' \+ ^" h7 Q) zthe more likely there will be an excellent response with low- R, y! a" X9 \: {; M! v4 s0 Y$ B
serum levels. Response occurs throughout adolescence as
9 X/ z3 o7 |+ E4 p3 N. mnoted in nomograms of phallic growth. 7 The actual response$ |4 d& A4 Y' Q2 X, I
to a given serum level of testosterone is much greater at birth: l8 F) t- A3 _0 c  `. Y
and gradually decreases as boys reach puberty. This is most
+ G9 D( i2 N. g5 jlikely related to the conversion of testosterone to dihydrotes-
6 @0 i7 O' o: @% A- jtosterone and correlates well with the studies of testosterone
* L! U/ Y+ M% o! |conversion in foreskin at various ages.! I2 I$ r9 H; w* N
The question arises regarding early treatment as to whether" F. d, B$ i6 \7 k4 h  e* ~) U1 }% o
one might sacrifice ultimate potential growth as with acceler-
$ a5 i7 h6 ~: E6 U. ~ated bone growth. The situation appears quite the reverse
# E  A4 q! E5 m& K1 F& Twith phallic response. If the early growth period is not used
. J$ k2 \+ D1 P3 u3 G" T! O, ywhen 5a reductase activity is greatest then potential growth( G; Y* a; u2 p( C1 j! M: t3 \, [
may be lost. We have not observed any regression of growth$ A& G: V6 I' b- N+ Y( N
attained with topical or gonadotropin therapy. It may well
# e/ I8 U+ N; _4 Ebe that some patients will show little or no response to any
# ?1 }' A3 c6 Eform of therapy. This would suggest a defect in the ability to8 t+ `/ @1 u% F
convert testosterone to dihydrotestosterone and indicate that# P' Z1 J  c! j
phallic and peripheral skin, and subcutaneous tissue should
8 R4 p4 n$ e+ E3 I6 P% Abe compared for 5a reductase activity.6 C' J* D* E; i. B2 o# C: l
A, loop enlarges to measure penile girth in millimeters. B,
9 E+ E4 ]! G  d/ W( [( Vexample of penile girth computed easily and accurately.
3 Z/ ?+ |- `# U' a2 q2 r3 Uconversion of testosterone to dihydrotestosterone. It is in this
# A( M; B+ n+ k, ]older group that others have noted high levels of serum
; j; i5 R- p/ j' btestosterone with topical application. It would also appear
( t: O2 J* {# h0 L" y4 }: }% F* Qthat phallic response during puberty is related directly to the5 L, P9 {+ c1 |$ L' E
serum testosterone level. There also is other evidence of local0 L9 @& H5 V9 F5 H
response to testosterone with hair growth and with spermato-$ c2 a* B% J) }% s; D
genesis. 5• 6
9 e  E/ k- w& f9 L4 Y4 h% ^  z) z2 IAdministration of larger doses of gonadotropin or systemic- O- f) [0 w: Q# ^7 V3 }
testosterone, as well as topical applications that produce
( K. `% G) d3 R7 z' q% ]higher levels of serum testosterone (150 to 900 ng./dl.), will3 ?% U. W' w' b! v- m
also produce phallic growth but risks accelerated skeletal
6 i* L( P  T3 K; a9 Q' Omaturation even after stopping treatment. It would appear# O: T; I+ H& {. u* V
that this may be avoided by topical applications of testosterone  @! ?& Z% V  t( T! }/ v4 e8 r
and monitoring of serum testosterone. Even with this control
4 k' y- R* L( f0 q+ m& Mthe duration of our therapy did not exceed 3 weeks at any' Q7 j  _6 z. t
time. It is apparent that the prepuberal male subject may
7 i1 F( t' A4 d) z, [/ q/ E/ Osuffer accelerated bone growth with testosterone levels near
; f( J& X$ F! ?+ x2 G1 o/ u200 ng./dl. When skeletal maturation is complete the level of, P. |& n- |1 R0 O+ l9 A7 F* }, v9 y
serum testosterone can be maintained in the 700 to 1,300 ng./+ K+ _! q# ^& ]8 t. l# ]- s; }  Q( g- o
dl. range to stimulate phallic growth and secondary sexual3 ^% k5 L7 g, |5 }! u2 s1 Q
changes. Therefore, after skeletal maturation parenteral tes-& h. ~, ?5 b' m% |) @2 d" L! v: b" a" `
tosterone may be used to advantage. Before skeletal matura-
" Z: J) W- R, {, stion care must be taken to avoid maintaining levels of serum& n+ y- l) k# |1 O
testosterone more than 100 ng./dl. Low-dose gonadotropin4 ~" J  Y9 H0 E% _" \9 ~; g6 s$ s
depends upon intrinsic testicular activity and may require: \( T9 y. g/ s0 h, q$ A6 ?
prolonged administration for any response.* g) l9 @6 Z2 I. I7 M
Alternately, topical testosterone does not depend upon tes-
# ?" p6 n) _- v( @$ L( kticular function and may provide a more constant level of
9 I6 J  v, z- [" ?7 r; j1 X# YREFERENCES
8 G& p  X. D( n3 @$ a$ H7 B- r& ^1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 C2 x+ q/ B; a6 ~R.: The local application of testosterone cream to the prepub-
. r! W" Q9 S4 \9 b; y0 p3 {  zertal phallus. J. Urol., 105: 905, 1971.
: B1 j; `) H  j. {' R4 f1 X! M2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 h5 [# Q9 Y4 V8 {/ Z3 |
treatment for micropenis during early childhood. J. Pediat.,( D# C) f/ u" p
83: 247, 1973.) a0 F: v8 h* Z' I. c5 I$ a. C
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
7 D2 y. |: |, l/ U; X9 lone therapy for penile growth. Urology, 6: 708, 1975.2 @$ F* q8 s" l; U6 }2 a
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! L) p) \! ?1 [to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 i, E5 S+ l# D! l
skin slices of man. J. Clin. Invest., 48: 371, 1969.
% {/ C- R9 w3 _6 E# j+ a5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
$ X$ v3 {7 ^2 ^  F% A# Pby topical application of androgens. J.A.M.A., 191: 521, 1965.4 r6 V, l! m, d
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
: a! a5 @$ o( T2 t+ }6 A. {androgenic effect of interstitial cell tumor of the testis. J./ Z# D# _! K: \) b; H! `
Urol., 104: 774, 1970.
. F. A9 z! U: |5 Y3 Z7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. g" W1 V( I  K' Ytion in the male genitalia from birth to maturity. J. Urol., 48:
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