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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND5 x/ {1 O' A! X% F) n5 [$ b
GONADOTROPIN1 g3 b" v* Q! g) y* ?+ I7 b  {
RICHARD C. KLUGO* AND JOSEPH C. CERNY
% @% m5 h! R! C1 v% nFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan9 Q; G6 f' p2 M5 m
ABSTRACT
. j2 r! j( X7 M( bFive patients were treated with gonadotropin and topical testosterone for micropenis associated
; @* T; p# Y4 e' B" |with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
- q  S: L7 O; O( E8 rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone  u  `# Z. u3 R$ U* Z% b
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 B8 ], `% L1 A5 y, u6 [+ f
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" }) `' L  Q+ l; L" N" t
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 q3 f# |4 e+ D. iincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; C2 L6 g  W7 B; J
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
: Q2 ~) d0 p/ y( q5 t+ ~study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% K1 _$ K, D9 k, b
growth. The response appears to be greater in younger children, which is consistent with previ-
* d  X* a* H4 Y, D% iously published studies of age-related 5 reductase activity.! C" c' j* O9 G, e3 f8 i
Children with microphallus regardless of its etiology will& D' ]1 L3 L% l1 @% e- r
require augmentation or consideration for alteration of exter-2 G, z6 a3 O5 ]1 r; A
nal genitalia. In many instances urethroplasty for hypo-
  L% x9 W0 A. l5 o" o% [, Uspadias is easier with previous stimulation of phallic growth.
$ Q- C/ m0 W$ f9 TThe use of testosterone administered parenterally or topically
3 }1 ?# x/ R" Z! v- Q. L( }9 Qhas produced effective phallic growth. 1- 3 The mechanism of
9 `: C% W5 l4 T/ C* Gresponse has been considered as local or systemic. With this/ N- Y6 X/ O/ `4 N
in mind we studied 5 children with microphallus for response' P7 {* J. X9 T3 O0 t, O, c
to gonadotropin and to topical testosterone independently.
! k$ \2 v( k/ OMATERIALS AND METHODS) S  v3 k& N4 F6 V5 ?0 Y
Five 46 XY male subjects between 3 and 17 years old were" d  |. b2 M1 i) q
evaluated for serum testosterone levels and hypothalamic/ O9 l9 d4 z! W$ x7 i( Z; w  |. v# n, `
function. Of these 5 boys 2 were considered to have Kallmann's  S; e& `6 X% m1 I+ b
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
  m5 y6 W: h* l, a8 z7 Alamic deficiency. After evaluation of response to luteinizing. U; G: w8 ^4 q# m, W
hormone-releasing hormone these patients were treated with4 m8 h- ]* p! }: Y$ e
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 z7 ]7 I" I6 L& m6 X% c& Rafter completion of gonadotropin therapy 10 per cent topical
2 I/ f4 T) c3 ~' a/ Mtestosterone was applied to the phallus twice daily for 3 weeks.
6 f7 m6 c' n* u  \% zSerum testosterone, luteinizing hormone and follicle-stimulat-- V$ g9 A7 d5 Q- N
ing hormone were monitored before, during and after comple-
$ g% e3 Z( k, s" k( @tion of each phase of therapy. Penile stretch length was
7 i4 V% s4 n( G- _# ]obtained by measuring from the symphysis pubis to the tip of- U, ^: O: s( G+ g% y9 f2 R$ f  A
the glans. Penile circumferential (girth) measurements were
6 b: S& U$ {! g, d! Yobtained using an orthopedic digital measuring device (see$ V1 M! a$ P- o( }8 ^5 k& I+ ?9 U2 t# e
figure).9 r0 Q8 j4 J! o
RESULTS
' G4 {$ w8 }* }; w$ V* ]  _Serum testosterone increased moderately to levels between1 b5 U$ ^% p1 ]" S. `" i% l. _
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! g% v; z- z, J5 e
terone levels with topical testosterone remained near pre-
# H* E8 T" H6 C' b5 E% w* Wtreatment levels (35 ng./dl.) or were elevated to similar levels
) ^5 i+ @  x% S6 \developed after gonadotropin therapy (96 ng./dl.). Higher' }7 V2 A1 n' w4 W
serum levels were noted in older patients (12 and 17 years old),' f9 b1 ~6 ?# s4 H) L+ m
while lower levels persisted in younger patients (4, 8, and 10
' {0 |7 _8 |4 x( c1 D( nyears old) (see table). Despite absence of profound alterations
+ I) \) y1 Z' J1 X) Hof serum testosterone the topical therapy provided a greater
1 g- L! o* S2 f, ?4 M( KAccepted for publication July 1, 1977. ·
) h4 p5 q1 s/ Y! b* XRead at annual meeting of American Urological Association,
+ W8 r" j& M4 [4 \Chicago, Illinois, April 24-28, 1977.
  L' `  i$ z. o; I: L* Requests for reprints: Division of Urology, Henry Ford Hospital,
* o, `; i1 C* k  q6 s2799 W. Grand Blvd., Detroit, Michigan 48202.
; |, c0 E- |5 Q5 yimprovement in phallic growth compared to gonadotropin.
/ h% C) J' K5 h1 ]4 n) @: zAverage phallic growth with gonadotropin was 14.3 per cent
) @/ y+ \+ y* k9 \$ L) A0 `) D+ Vincrease in length and 5.0 per cent increase of girth. Topical
6 f' q; S# p7 J& S- Z9 J) ]; Gtestosterone produced a 60.0 per cent increase of phallic length
: x6 g  C4 f: I- P/ o' L2 Zand 52.9 per cent increase of girth (circumference). The
: N0 E7 Q4 q8 ~4 ?- rresponse to topical testosterone was greatest in children be-: ~  M# A8 C. _5 m3 V
tween 4 and 8 years old, with a gradual decrease to age 178 T. c3 Q# p. k5 a9 p
years (see table).: t5 D8 m- ?2 ]1 @# g) q8 ]
DISCUSSION* H% I, E9 ]# h+ S. t) f3 T( [3 k
Topical testosterone has been used effectively by other; g+ y  c) X( i- d2 k
clinicians but its mode of action remains controversial. Im-
$ i3 D; `7 h# `' |2 Dmergut and associates reported an excellent growth response5 E! W! }0 `. A' T/ ~7 d
to topical testosterone with low levels of serum testosterone,
4 Y$ ~# }) M) R6 W  ]suggesting a local effect.1 Others have obtained growth re-
/ l2 v3 E: s0 y) \: i7 ~sponse with high. levels of serum testosterone after topical0 N8 [: o' Q4 P! i1 \, t3 E
administration, suggesting a systemic response. 3 The use of$ U/ j) e4 u; F4 I: q2 g
gonadotropin to obtain levels of serum testosterone compara-
* V) f, V6 F8 e! dble to levels obtained with topical testosterone would seem to
0 y" {1 `) W$ X- Vprovide a means to compare the relative effectiveness of( I/ g/ e! G5 V4 A7 _- a
topical testosterone to systemic testosterone effect. It cer-9 v, A9 G0 d  ~% I) k: \: j, C
tainly has been established that gonadotropin as well as par-# h/ O4 x5 M: b& _, F' \
enteral testosterone administration will produce genital
& [3 V, m' ~% w  mgrowth. Our report shows that the growth of the phallus was
7 s. Q) Q' {5 Q1 e$ g8 E: P  @1 u3 ~significantly greater with topical applications than with go-4 F1 {+ \% k8 k/ ^. y7 ?( y1 L
nadotropin, particularly in children less than 10 years old.
' z- }) g. j* j: V; w* S: l) s6 cThe levels of serum testosterone remained similar or lower, {& x# P! K$ F# P8 ?
than with gonadotropin during therapy, suggesting that topi-
4 g* t3 a1 P8 h$ [cal application produces genital growth by its local effect as+ N  p8 Y5 d6 A) W/ o& u! l8 X" `' H
well as its systemic effect.' Z1 v' q. T: A# i( _& t
Review of our patients and their growth response related to) G5 e% u* J5 H3 D
age shows a greater growth response at an earlier age. This is
, U5 _/ h9 P* |. n6 U: j% lconsistent with the findings of Wilson and Walker, who
* m3 l1 M8 k/ treported an increased conversion of testosterone to dihydrotes-
; t! M; v' |1 z. A5 t1 s5 [" ptosterone in the foreskin of neonates and infants.4 This activ-* d$ M8 P  U) O6 i/ F0 Y) Q9 D% C
ity gradually decreases with age until puberty when it ap-
& k% Y- l3 B. P; z  dproaches the same level of activity as peripheral skin. It may
3 `5 k3 g0 Z  E6 s4 ]0 Rwell be that absorption of testosterone is less when applied at
3 e5 [+ o. s: `9 T3 Y$ aan earlier age as suggested by lower serum levels in children
( I  C% ~% Z. V' F3 Uless than 10 years old. This fact may be explained by the9 a- Y- ~0 V0 E' ~! A
greater ability of phallic skin to convert testosterone to dihy-, R+ h) k% S3 r5 K
drotestosterone at this age. Conversely, serum levels in older
& D4 a* ?  G% m1 Zpatients were higher, possibly because of decreased local
/ {& x; \* V& k: z667+ T7 ^5 t/ V4 A. X) y
668 KLUGO AND CERNY
: T1 F/ T6 A$ h5 D& v9 RPt. Age/ \' P4 Y( Q* i; b  |$ q
(yrs.)9 K& j1 F! Z1 f1 |% Z2 F5 l
Serum Testosterone Phallus (cm.) Change Length
! w3 _9 T( L; D( j(ng./dl.) Girth x Length (%)# O# \4 l6 }3 `: _6 U! w' A
4
# G( C- l& j& h89 B$ j2 f6 R4 {( d- ^  n0 K6 ]
10
& O5 w7 W$ K7 w! Q% |) O7 Q4 F12
6 R" t' Y2 O$ |  j3 U# r  x" ^17/ Z2 |! `7 h2 I
Gonadotropin
4 Q' k7 j* V0 S8 `, Y, ^71.6 2.0 X 3 16.6
+ u. w; R5 D. E, G3 `, p50.4 4.0 X 5.0 20.0
$ T! p0 Y3 |2 _7 _22.0 4.5 X 4.0 25.0
2 C7 n6 S" G1 o5 H84.6 4.0 X 4.5 11.1
! W% j5 n% I' I6 u5 g  I- q85.9 4.5 X 5.5 9.0
. R+ Y; q6 b, {" g2 E- d4 qAv. 14.3& X' T/ B5 H, `  f# y5 {9 ?
4
$ k- q0 ^2 _, m8
1 V% Q+ t# J8 Z" X" u' G10
6 |# k. @; L3 c4 u1 f12
2 |$ F4 d) ?& r17" v5 T& j' h: K1 y% u
Topical testosterone
. k8 f* Z' p3 ?7 y/ M0 Z34.6 4.5 X 6.5 85% K; s) X. `: e
38.8 6.0 X 8.5 70
1 R3 e2 n: ]" B9 T0 l40.0 6.0 X 6.5 62.5
* O! e' l6 e" K3 l/ v' T93.6 6.0 X 7.0 55.5
0 q( ^, D( z, ~  K5 X95.0 6.5 X 7.0 27.2
# W6 c7 |, {' E/ bAv. 60.0
6 ^0 E! B' Y* s3 ?, n3 Navailable testosterone. Again, emphasis should be placed on
$ v0 j& O' V# searly therapy when lower levels of testosterone appear to
0 v4 M2 G. a. n% X( r! h& W% l0 X: a! ~0 Bprovide the best responses. The earlier therapy is instituted% }! J" y+ _! I. n
the more likely there will be an excellent response with low
% \4 k! @" u; `8 zserum levels. Response occurs throughout adolescence as
& E# }9 B/ h" K+ \' k- Inoted in nomograms of phallic growth. 7 The actual response
" p+ ^; G- B" L' G# k, o0 wto a given serum level of testosterone is much greater at birth4 h0 [" ]# |) z- P$ I- c* V1 Z
and gradually decreases as boys reach puberty. This is most4 Z& O  `5 j. W' g( A
likely related to the conversion of testosterone to dihydrotes-
0 j5 v+ j# P8 I9 O+ Z1 Ttosterone and correlates well with the studies of testosterone
1 A- F1 w' P& |5 M7 ?: tconversion in foreskin at various ages.
# N; ^+ c4 C; MThe question arises regarding early treatment as to whether
! ^) O- z( Z5 B/ ]' J# tone might sacrifice ultimate potential growth as with acceler-# R' {+ ?9 L( W- N! e4 x1 b. h+ d
ated bone growth. The situation appears quite the reverse
" o8 f1 y* m9 a& B7 s2 swith phallic response. If the early growth period is not used) W0 f- I9 e4 K6 Z" G- x
when 5a reductase activity is greatest then potential growth0 O( k4 S: ^1 b/ Z, M' m
may be lost. We have not observed any regression of growth% ^; @* S" X3 I0 h
attained with topical or gonadotropin therapy. It may well
. k3 a  ^' s1 u7 l$ ~2 Ube that some patients will show little or no response to any8 B" R8 r, P9 k; b$ |9 \
form of therapy. This would suggest a defect in the ability to
- E. U: ]* ]' Z* c0 a8 c3 B6 u  G- Z; iconvert testosterone to dihydrotestosterone and indicate that
/ ?- a' j  e% s6 I+ k3 Ephallic and peripheral skin, and subcutaneous tissue should
" I* a. u$ f+ M4 S( tbe compared for 5a reductase activity.3 \/ z  {3 {( F2 d, r
A, loop enlarges to measure penile girth in millimeters. B,
/ Q- g4 m: T9 k( t8 q- X% Pexample of penile girth computed easily and accurately.
7 ^6 o3 L8 b7 w: o( [; nconversion of testosterone to dihydrotestosterone. It is in this$ Y! B% k& Y3 I6 N7 M" {
older group that others have noted high levels of serum4 k. v  p# v' z0 v8 l& W
testosterone with topical application. It would also appear
% y' T. q* ~7 g! A+ Ithat phallic response during puberty is related directly to the
1 p0 i" B0 _5 ]( J2 G3 Mserum testosterone level. There also is other evidence of local
' q& v/ N3 A' Z, Cresponse to testosterone with hair growth and with spermato-
) o1 L- x6 d% G: m2 ]; Egenesis. 5• 6
/ D* ?1 h" N: R1 T3 S3 v& yAdministration of larger doses of gonadotropin or systemic
( {; U: \8 w& F3 |; m7 `* |6 L/ qtestosterone, as well as topical applications that produce
$ C7 I! Z  w/ ?+ c8 Z& chigher levels of serum testosterone (150 to 900 ng./dl.), will
7 T$ G$ q4 ~  F2 H" @3 w  salso produce phallic growth but risks accelerated skeletal2 B* c' z' O) E& G8 G* p
maturation even after stopping treatment. It would appear
4 w" Q0 Q; Z5 k$ Z* d, ]9 Wthat this may be avoided by topical applications of testosterone, n! s. G5 a6 I6 }  T
and monitoring of serum testosterone. Even with this control
! R0 C+ c: }4 O( rthe duration of our therapy did not exceed 3 weeks at any
6 |3 f% d$ H6 b/ u5 Xtime. It is apparent that the prepuberal male subject may( l+ J: Z0 D# n$ D' a- t2 ?
suffer accelerated bone growth with testosterone levels near
& B% Z/ |5 ?6 `0 j200 ng./dl. When skeletal maturation is complete the level of
2 _9 z- L. O$ x- \& d: a. t6 sserum testosterone can be maintained in the 700 to 1,300 ng./
5 E8 Q6 }* K  g0 r, [* idl. range to stimulate phallic growth and secondary sexual/ K& T8 M* E. s0 `: f# i) n
changes. Therefore, after skeletal maturation parenteral tes-
8 g" Q; b  k2 O8 N; mtosterone may be used to advantage. Before skeletal matura-
/ ?0 o7 }8 i9 \% Q& Y6 X; stion care must be taken to avoid maintaining levels of serum
0 T* c. r7 a6 V. N# D& Vtestosterone more than 100 ng./dl. Low-dose gonadotropin: E  \& e4 }7 m: J+ Q
depends upon intrinsic testicular activity and may require) L1 L" \: I$ e; U& j+ G, U
prolonged administration for any response.
; P6 ^" @1 F- E- q7 }5 w! }Alternately, topical testosterone does not depend upon tes-( J( G+ T; _6 D$ R0 y
ticular function and may provide a more constant level of7 ~- o9 o9 l9 s8 F
REFERENCES
& U  ^0 w  |" M3 T5 d0 w5 T2 P7 l1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# I) j3 W, u+ y& Z" I* v! k$ ~
R.: The local application of testosterone cream to the prepub-  y# Q  D/ Z6 r
ertal phallus. J. Urol., 105: 905, 1971.
+ O4 Y' f  W* o) Z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
# }6 G# {) i+ c8 v0 Xtreatment for micropenis during early childhood. J. Pediat.,/ H' @+ Z3 B2 V2 B
83: 247, 1973., y! M& ~/ Y/ y# e
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' l8 y- b" {' s# }; g# wone therapy for penile growth. Urology, 6: 708, 1975.% s& J- R! N$ P8 c) T
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
+ s$ m9 ^6 X! O$ wto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& R6 B6 f) h. W: R5 t  E9 sskin slices of man. J. Clin. Invest., 48: 371, 1969.
/ @/ D# l) Q8 Y5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth- j! T+ _$ r3 p. K" s& D
by topical application of androgens. J.A.M.A., 191: 521, 1965.
% s% i, ?3 ?) ^6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) j0 r2 [2 z: @1 l1 r' i
androgenic effect of interstitial cell tumor of the testis. J.
0 N( U. o& q/ P' m+ |Urol., 104: 774, 1970.0 |/ W- U! w( a2 a1 {* ?
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-3 F; `1 c+ l" P. f7 b& E
tion in the male genitalia from birth to maturity. J. Urol., 48:
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