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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; b3 ^5 e5 N5 x  C9 FGONADOTROPIN
3 j% `# ?# V" Y2 o1 c. ~RICHARD C. KLUGO* AND JOSEPH C. CERNY
8 z& B$ L! k: J3 rFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan* {) {5 X+ u+ C7 c/ y7 u  [6 H, g7 g
ABSTRACT6 ?) V0 v4 E4 k2 q) K# d
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
$ M: t) z- G8 M$ L/ Bwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 r+ @: s, T8 Q: k6 S# u
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) o6 u' P3 N( u1 a1 l( k- wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' b; ^# Z0 C) x: ~# L, ifor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent+ Y$ T( F9 U; _& I' [6 z0 O7 f# d
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) S% r# U  y9 B. z+ Z8 ?increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 V4 w# d4 f$ G  b/ Y+ K  aoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' o$ b% _& }: i! G& D7 [study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile' X+ e  s6 e* {7 C  ^" g( m
growth. The response appears to be greater in younger children, which is consistent with previ-, E( ~8 h  `8 R3 ?
ously published studies of age-related 5 reductase activity.  b- L5 k9 [1 D: U* P; q! ]: r
Children with microphallus regardless of its etiology will
7 j1 F3 m; T: urequire augmentation or consideration for alteration of exter-
4 D* B0 h' s/ s! Tnal genitalia. In many instances urethroplasty for hypo-
4 k* t0 S: {. G2 O1 @- D5 x+ gspadias is easier with previous stimulation of phallic growth.: q9 d- z: }; G9 u% o& K. K# A0 a
The use of testosterone administered parenterally or topically
8 t! J% K" [5 J5 {5 I1 T3 c' Hhas produced effective phallic growth. 1- 3 The mechanism of
7 h3 g9 t9 H- U* _( U* O, P) |response has been considered as local or systemic. With this* i2 L5 |9 w7 b# E: u
in mind we studied 5 children with microphallus for response2 [5 }$ d/ ~! l) G+ _
to gonadotropin and to topical testosterone independently.* o/ {# e9 j9 U% O! B
MATERIALS AND METHODS
5 ^$ I$ A$ [9 p! g: }1 |. F, AFive 46 XY male subjects between 3 and 17 years old were5 g7 ~7 k- r( w+ z$ Q
evaluated for serum testosterone levels and hypothalamic
# r0 h. j7 D& b) J' A4 Efunction. Of these 5 boys 2 were considered to have Kallmann's2 X0 h& k( W' X1 m! I1 d5 M8 M
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-% _, l( l6 g1 E0 |  l
lamic deficiency. After evaluation of response to luteinizing/ l- _( Z+ `, q( @5 q6 X$ y% j/ i3 `. F
hormone-releasing hormone these patients were treated with& x' X7 C, U! L! E4 v' N
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: A' F3 S3 _2 R: n: {2 Rafter completion of gonadotropin therapy 10 per cent topical: M3 b: c+ F* Y2 \8 I( k. X$ I; d
testosterone was applied to the phallus twice daily for 3 weeks.6 M0 q" \  Y. I, a3 ]$ x, g
Serum testosterone, luteinizing hormone and follicle-stimulat-) ]9 ?5 R6 S9 R" t% M+ y
ing hormone were monitored before, during and after comple-
+ \6 A; e0 ~8 n  ftion of each phase of therapy. Penile stretch length was
; i: C% r# t% D% Q, bobtained by measuring from the symphysis pubis to the tip of+ K0 C0 Q, ?6 e. D, F
the glans. Penile circumferential (girth) measurements were
/ y+ f' \3 Q6 N4 K4 @obtained using an orthopedic digital measuring device (see
) k$ }0 O& b: q/ I! Dfigure).; X: |  w: K3 _; b
RESULTS
) _: z3 N& y/ O% R- w9 WSerum testosterone increased moderately to levels between5 x, }" }$ W: r/ @2 \( l6 }8 Y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 T: N7 S4 |8 x7 G8 B- Qterone levels with topical testosterone remained near pre-6 n: m4 r+ D( [0 P3 I% |3 b( }9 v
treatment levels (35 ng./dl.) or were elevated to similar levels1 \9 t# m; T5 d' |8 n+ R" K
developed after gonadotropin therapy (96 ng./dl.). Higher
# C; W/ Z" N# v$ zserum levels were noted in older patients (12 and 17 years old),
" k! L7 R5 P% b% H8 F2 a: s8 g: Rwhile lower levels persisted in younger patients (4, 8, and 10
. i1 S4 F( s+ X0 G6 Zyears old) (see table). Despite absence of profound alterations0 W2 K3 J+ B, J
of serum testosterone the topical therapy provided a greater( {' U3 F! |! a! }  v5 C* z
Accepted for publication July 1, 1977. ·
! r) s5 c  Z( J" [Read at annual meeting of American Urological Association,' A8 H! l+ C8 [0 y
Chicago, Illinois, April 24-28, 1977.
3 t$ [- x# v$ ~- F: q5 s* Requests for reprints: Division of Urology, Henry Ford Hospital,
# Y7 O2 L$ R4 \2799 W. Grand Blvd., Detroit, Michigan 48202.
- E" Q" {0 _! b3 Y3 ~# g, m9 fimprovement in phallic growth compared to gonadotropin.& ^; X$ Y! t! |' k0 U/ s
Average phallic growth with gonadotropin was 14.3 per cent% p, p+ X3 j1 y4 l
increase in length and 5.0 per cent increase of girth. Topical: m; v) u0 q, W1 u8 o1 C7 F# D
testosterone produced a 60.0 per cent increase of phallic length
# p4 x' R3 K( F; f( m! k1 `and 52.9 per cent increase of girth (circumference). The1 z$ @7 G0 ?8 z& ]0 `$ t) ?2 w
response to topical testosterone was greatest in children be-: @! p! i' n5 R+ o  @+ k& P
tween 4 and 8 years old, with a gradual decrease to age 17
; C' i2 s/ c; t( o: Byears (see table).- K' O' a" ^+ h, G8 c6 [/ m( Y
DISCUSSION6 Z' p' Y! i% I
Topical testosterone has been used effectively by other9 Z6 ]* l. I! W+ R; U) M6 A
clinicians but its mode of action remains controversial. Im-& i- h1 k6 |  P. `2 y. @  d/ O2 q
mergut and associates reported an excellent growth response3 Z6 H9 f. C5 A# c1 r
to topical testosterone with low levels of serum testosterone,
# M5 u2 y7 \! M0 A- u% j) Xsuggesting a local effect.1 Others have obtained growth re-; ~- N9 k) S4 |  P9 V  `1 x5 F6 j
sponse with high. levels of serum testosterone after topical8 \- H2 W" T  z& `: I* Q
administration, suggesting a systemic response. 3 The use of
+ R* {: E8 X' X4 D1 L+ Igonadotropin to obtain levels of serum testosterone compara-
6 C+ X+ M2 d: X: _ble to levels obtained with topical testosterone would seem to
3 f: i! U2 z# Gprovide a means to compare the relative effectiveness of
* Y! U% w' ^; S9 ~+ ltopical testosterone to systemic testosterone effect. It cer-
! Y4 j& Z3 L6 L+ H/ x, H( btainly has been established that gonadotropin as well as par-( d/ d% A9 J5 N# d. D$ S
enteral testosterone administration will produce genital8 U  o" ~* c5 V5 L: n. a9 y$ T
growth. Our report shows that the growth of the phallus was8 p1 V- T/ o+ L( ^
significantly greater with topical applications than with go-, F: f+ S4 k# c+ ?, _. _4 Q, ?# }+ C+ a
nadotropin, particularly in children less than 10 years old.  P( f, t% m. L+ s
The levels of serum testosterone remained similar or lower
# }4 I' I' R1 l8 {/ I2 x5 o) X* H' Tthan with gonadotropin during therapy, suggesting that topi-
0 z4 ^3 [# `! r; ]. }( ^( r/ Kcal application produces genital growth by its local effect as0 U& L: y. a4 ?$ U4 F* N
well as its systemic effect.
/ ?, A' x* U- \" Z1 h3 gReview of our patients and their growth response related to; @4 ]" T  z7 V7 C
age shows a greater growth response at an earlier age. This is: y) S  }# V$ Z* G- x& q1 r
consistent with the findings of Wilson and Walker, who
4 b, u- ~7 f' N8 R% Creported an increased conversion of testosterone to dihydrotes-& }# y5 Z5 c/ k. }2 G' W3 m& n, V) x
tosterone in the foreskin of neonates and infants.4 This activ-$ g* T1 h4 D# U! W% X( u9 b
ity gradually decreases with age until puberty when it ap-0 ~  v+ W+ N0 Q  f& E0 u4 \" t' a* D
proaches the same level of activity as peripheral skin. It may
" s! M1 N# Y5 Y; j1 E5 `" Awell be that absorption of testosterone is less when applied at' x# R9 s0 R  C9 N: A3 L7 @
an earlier age as suggested by lower serum levels in children+ u: t  a* b7 M7 G6 w: M5 V0 G
less than 10 years old. This fact may be explained by the( O+ r* v, ?4 m6 `/ [1 i
greater ability of phallic skin to convert testosterone to dihy-. o5 E4 h, Q* A
drotestosterone at this age. Conversely, serum levels in older  s: u( M1 [3 a
patients were higher, possibly because of decreased local
! R; O2 M; ^+ U  k7 e9 Q. R* R: e: R667
4 B/ [( a/ |. n1 e5 o668 KLUGO AND CERNY
  X) y; M+ p+ s% y. o' v8 l8 ?: FPt. Age
! n* `) t+ m8 Y# d9 e(yrs.)$ K: B& A  Z, L; {* k9 E; i$ u
Serum Testosterone Phallus (cm.) Change Length
) g; p8 e  C0 j$ e) w4 F/ _(ng./dl.) Girth x Length (%)
1 f8 s# u" q( e# b: B! B" ?. ~! y4
4 c, Q, E" D2 \, h) V8
; ]1 [- ~: k. V( C/ [  ^10
0 U4 s0 U& I1 K/ B  d12
  Z1 k% p. t3 L: w17
7 b6 J% u8 D  AGonadotropin
+ K# M" @6 o6 ?/ o3 d  _71.6 2.0 X 3 16.6/ A. c% P5 A* Z: L' H( ~
50.4 4.0 X 5.0 20.0' h$ }/ |" P8 e: K4 R
22.0 4.5 X 4.0 25.0, g: T  ~1 L0 {! Z# E6 l
84.6 4.0 X 4.5 11.1& a) L4 I8 J) Z% L% g1 s
85.9 4.5 X 5.5 9.0- z  ~/ e. ]( I% a* }% b
Av. 14.37 j( ^  D0 V5 N$ ]
4, U- X" S7 ^# X' }. x; E) t
8
$ H! P9 j9 K4 r: v8 f10. w& X. D+ A; X% d- {7 Q. N- d5 Z& r
12
3 a  g" K, T3 x$ W, l& x# W1 Y$ l17! ?3 s4 O' U3 J8 o  G3 Q/ C4 h4 z
Topical testosterone
& p' K8 ~& B3 y3 }3 C' o7 P- ~34.6 4.5 X 6.5 85
, F. [3 t; Z: @" k  V38.8 6.0 X 8.5 708 e, j7 {' R; w  f2 ~8 ~6 l
40.0 6.0 X 6.5 62.5
* Q: w. J0 R  w2 o" Z93.6 6.0 X 7.0 55.5
- y( W% j1 @! D$ _2 v6 b# M* M/ T6 G95.0 6.5 X 7.0 27.2: o3 v2 M. y+ k$ b5 K! Y& g
Av. 60.0
) O8 V" p- V7 y; ~5 n% uavailable testosterone. Again, emphasis should be placed on9 ^5 u5 `$ X: M% V
early therapy when lower levels of testosterone appear to
0 [3 |9 P$ f3 }8 Q4 v& Aprovide the best responses. The earlier therapy is instituted
* k) n4 V. i2 Q: L; @, c/ Kthe more likely there will be an excellent response with low
" g# _8 U+ G2 X0 N: e8 n, u* [serum levels. Response occurs throughout adolescence as
. v2 o5 B% U7 tnoted in nomograms of phallic growth. 7 The actual response
, w$ O7 E  i# w  w/ Vto a given serum level of testosterone is much greater at birth
3 j8 J% t/ o0 Fand gradually decreases as boys reach puberty. This is most
+ q% ^0 e6 h, }2 g" Rlikely related to the conversion of testosterone to dihydrotes-" F9 P8 q6 O- O- I; y
tosterone and correlates well with the studies of testosterone
8 [5 w: h. y: e6 @# @9 A- Q  L! Aconversion in foreskin at various ages.
7 d9 X9 V, J( m7 JThe question arises regarding early treatment as to whether6 `6 S9 @% n0 r' P# h
one might sacrifice ultimate potential growth as with acceler-
5 D& o, l$ k: q9 h/ a" Uated bone growth. The situation appears quite the reverse; G. h1 v" g8 E+ n' q
with phallic response. If the early growth period is not used
  o7 I* F+ E6 k3 N5 |: H) y9 R$ m/ |  Owhen 5a reductase activity is greatest then potential growth9 v, J8 B8 f: t
may be lost. We have not observed any regression of growth
  F- S- V  {3 T" Xattained with topical or gonadotropin therapy. It may well
6 Y( h& _+ c" pbe that some patients will show little or no response to any% Z6 `7 i. Q7 E
form of therapy. This would suggest a defect in the ability to
- V4 i$ U: x6 w: `! tconvert testosterone to dihydrotestosterone and indicate that
' M7 q6 h: t5 u( ?phallic and peripheral skin, and subcutaneous tissue should
5 }% n' b% l' B7 O* @be compared for 5a reductase activity.% |% s% C. ]  A" f, d7 B
A, loop enlarges to measure penile girth in millimeters. B,/ U" A" M8 z6 P4 i9 R$ X8 Z
example of penile girth computed easily and accurately.
$ U7 y" Q2 A& W& g- x0 V/ e* jconversion of testosterone to dihydrotestosterone. It is in this
* [3 I8 ?/ K& g  I9 Golder group that others have noted high levels of serum
% }; r2 S/ P7 [5 q5 Htestosterone with topical application. It would also appear9 C3 Q$ B: K( J. n; q4 ~; V
that phallic response during puberty is related directly to the
- |6 ~& y# s1 w6 B' r+ a% N: Y, Sserum testosterone level. There also is other evidence of local
9 V& s6 e6 {) B/ A6 |. k2 gresponse to testosterone with hair growth and with spermato-
: u8 V5 n3 l# H! Z3 hgenesis. 5• 6
) y9 S3 y" M3 ?5 c' U  k  _& dAdministration of larger doses of gonadotropin or systemic
- }; d1 O# _6 t" l' Itestosterone, as well as topical applications that produce
) e+ G, n# w' w' V$ {3 U" w7 ]higher levels of serum testosterone (150 to 900 ng./dl.), will
3 v) H% ]- j/ \5 a/ Salso produce phallic growth but risks accelerated skeletal9 N' z1 J& L0 `; b
maturation even after stopping treatment. It would appear
9 ~- d" R" H# E; t2 F# g. T" |4 dthat this may be avoided by topical applications of testosterone* K5 N: {; c. d+ `- M4 b
and monitoring of serum testosterone. Even with this control
5 b* @" M# F/ V. d. Y( f. kthe duration of our therapy did not exceed 3 weeks at any6 o; J/ m, r& [2 \. x$ [
time. It is apparent that the prepuberal male subject may% x$ i8 b* a' o
suffer accelerated bone growth with testosterone levels near3 @7 ]7 N9 o, Y- n- b8 L/ Q
200 ng./dl. When skeletal maturation is complete the level of5 R8 x) R2 j) C. e2 L
serum testosterone can be maintained in the 700 to 1,300 ng./
8 \! D; p) m( W! f8 adl. range to stimulate phallic growth and secondary sexual
% c$ n9 G* {0 [& Ichanges. Therefore, after skeletal maturation parenteral tes-
+ c; `; q* u9 g& Stosterone may be used to advantage. Before skeletal matura-
8 g; E% `# e; Mtion care must be taken to avoid maintaining levels of serum
0 U; b1 w+ i+ f, k8 Qtestosterone more than 100 ng./dl. Low-dose gonadotropin; b6 A* W5 Z* H& j! L: F+ e
depends upon intrinsic testicular activity and may require
2 E& V% A# M. @& m% H; `2 Iprolonged administration for any response.
, o9 q( z8 ^$ x9 OAlternately, topical testosterone does not depend upon tes-
1 O* `4 `* w/ m' g! Pticular function and may provide a more constant level of1 c5 A% r. O) s3 Y: c& d; ?
REFERENCES
  p' @" Q* e5 p+ Q! J% P1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 [% j9 k" U4 R8 e
R.: The local application of testosterone cream to the prepub-& Q  H9 e- c/ q# Q# U5 K% R7 q
ertal phallus. J. Urol., 105: 905, 1971.
3 j! ?+ h4 Z% {2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 S: b9 ~' v0 B. @3 Otreatment for micropenis during early childhood. J. Pediat.,+ }, \8 B( p$ H6 a- t. X
83: 247, 1973.
% V0 c1 t0 I! `0 {2 z- T3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' ^& @; C' E2 R" aone therapy for penile growth. Urology, 6: 708, 1975.
4 y0 h% s: n9 p4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
. n3 |/ |+ R' n$ K0 Kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by0 x- W! [: i# {, y5 U
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ W6 }: ?2 Z, E  r
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 y# v; o$ L' F, R, v/ |by topical application of androgens. J.A.M.A., 191: 521, 1965.- q9 E( ]+ k" N# ^# f2 d/ z
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local' f) y  T8 E( q) Y: a- h- h7 f
androgenic effect of interstitial cell tumor of the testis. J.0 t; }3 Z, H. y+ D: G
Urol., 104: 774, 1970.8 z5 p# R0 c8 _# L% K( L0 D& j
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ v: m7 m$ l& }  V. N3 N' K
tion in the male genitalia from birth to maturity. J. Urol., 48:
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