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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND2 R) F9 v3 |% Z8 T0 f
GONADOTROPIN
/ r6 N: `) W" Y% cRICHARD C. KLUGO* AND JOSEPH C. CERNY
! O- d& Q( ^' m. HFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
7 [2 u# b; C* g' B( }, `ABSTRACT. X. @: ?! U+ k
Five patients were treated with gonadotropin and topical testosterone for micropenis associated. t/ `' B# e1 g  V/ M$ Y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( i, v* {, i0 d% A  v" Ktropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ o9 D- J4 I/ |$ O% M3 C
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 o( f- ?" y4 I! m! T2 Q  N
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
, S* s7 J7 z& t3 G1 Q) fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
0 ^  e. l3 a( K- [3 Yincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ D( G- A4 p3 C/ m" A
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
6 k2 V$ q! Y$ ~/ E; E9 f4 C2 |2 `study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 P" ]- x+ A" l' T9 U+ k' k. y9 w
growth. The response appears to be greater in younger children, which is consistent with previ-
1 w9 T7 V1 Y+ c/ l' sously published studies of age-related 5 reductase activity.
# N+ h$ o* C! SChildren with microphallus regardless of its etiology will
' l, V- }; R) ~' \4 [; Y" X; s2 `require augmentation or consideration for alteration of exter-
: u0 i: h) N, H& d8 @  [% ]! F/ \nal genitalia. In many instances urethroplasty for hypo-2 `% ]: z2 U. }: n
spadias is easier with previous stimulation of phallic growth.6 B9 \" v& C" G6 r+ B3 V
The use of testosterone administered parenterally or topically
0 w6 v* f: J/ Y% g6 W, Rhas produced effective phallic growth. 1- 3 The mechanism of# Q2 R1 {  N3 D5 U
response has been considered as local or systemic. With this  ]( t; H  D4 t1 n4 V6 K* V5 \
in mind we studied 5 children with microphallus for response
' Q% D0 d' s6 h' B2 pto gonadotropin and to topical testosterone independently.' E; a5 \2 \' k! ]  A4 @8 [
MATERIALS AND METHODS9 _; W, {6 Z8 Z! |
Five 46 XY male subjects between 3 and 17 years old were  x* R6 [7 F/ j
evaluated for serum testosterone levels and hypothalamic: ?5 O3 j, g: Q; P
function. Of these 5 boys 2 were considered to have Kallmann's
1 z- S1 y2 r  f- `7 s. Y& jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
) g* R5 g: t% B( ?1 k6 Z$ e- Elamic deficiency. After evaluation of response to luteinizing
) d- n- A0 L& ~: R5 Q' Shormone-releasing hormone these patients were treated with
9 @0 u$ J+ h4 s1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: p. T5 u0 e& o/ t2 V. p$ Z; jafter completion of gonadotropin therapy 10 per cent topical
# R2 L- b' Y. m3 l. p4 `' m- Ptestosterone was applied to the phallus twice daily for 3 weeks.4 g& v5 x1 S. J4 s0 I6 y, x! e' h+ J
Serum testosterone, luteinizing hormone and follicle-stimulat-
1 z6 V) Y) B; L! z' {: ^# [+ Wing hormone were monitored before, during and after comple-
1 a' {/ }# Q3 Otion of each phase of therapy. Penile stretch length was
* C" b2 _' C7 g7 _obtained by measuring from the symphysis pubis to the tip of. o8 w6 B/ Y$ {3 g" x- r8 X+ I# }
the glans. Penile circumferential (girth) measurements were; C" l( j6 m+ p( L+ a" ?. ]0 Q
obtained using an orthopedic digital measuring device (see6 h9 }" M& x. V: O3 i7 i
figure).
# V1 E$ q/ S# N) T( h3 VRESULTS
; q5 o) x) j$ a* wSerum testosterone increased moderately to levels between! q0 q+ N* n$ B9 S( r% {
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
2 d& \  ~0 |% [6 z+ a+ T- aterone levels with topical testosterone remained near pre-
- @3 r% l0 b& c, r! R0 Wtreatment levels (35 ng./dl.) or were elevated to similar levels; d- e% t2 e0 c9 w$ q: N' g
developed after gonadotropin therapy (96 ng./dl.). Higher; R5 `) T, ]! B' ]% k
serum levels were noted in older patients (12 and 17 years old),
8 C0 u# x# n" u5 I" l8 Q4 b7 {6 |while lower levels persisted in younger patients (4, 8, and 10
0 W  e4 J# `1 X$ p2 C% Yyears old) (see table). Despite absence of profound alterations: Q' \$ m' M& k0 P
of serum testosterone the topical therapy provided a greater; \, C! `* c  P3 t
Accepted for publication July 1, 1977. ·
8 N, V1 {0 \* t) d, [: SRead at annual meeting of American Urological Association,
3 v# \. T3 f( }) |Chicago, Illinois, April 24-28, 1977.. k1 z7 F( x: ~- m; S& U9 F7 b8 l
* Requests for reprints: Division of Urology, Henry Ford Hospital,+ F1 W! a! v: \
2799 W. Grand Blvd., Detroit, Michigan 48202.
3 I* M  g$ q( v7 K0 ximprovement in phallic growth compared to gonadotropin.9 ^" _# ~% o& s, A% i
Average phallic growth with gonadotropin was 14.3 per cent
. A2 X& {8 W: z4 L' Nincrease in length and 5.0 per cent increase of girth. Topical$ C3 G; _" J( q1 I$ A- V0 A. x
testosterone produced a 60.0 per cent increase of phallic length% @0 C9 ~" i* ^' C
and 52.9 per cent increase of girth (circumference). The5 R9 N: T7 m% j1 k3 Q% w/ m
response to topical testosterone was greatest in children be-) v* i7 }! e! R7 w0 x
tween 4 and 8 years old, with a gradual decrease to age 17
. J$ H* {9 x- B1 |* @1 I( Oyears (see table).6 ?' Y. L, b( ], S
DISCUSSION% a) B1 h/ ]# R1 _$ n8 U
Topical testosterone has been used effectively by other3 D& {6 S" F# G4 b) J
clinicians but its mode of action remains controversial. Im-
' ?! n! N2 y' \7 D) H3 Cmergut and associates reported an excellent growth response: j& X- Z; A% c( b+ B9 M! ^
to topical testosterone with low levels of serum testosterone," v5 x9 n2 X, P  F" @
suggesting a local effect.1 Others have obtained growth re-
7 ]8 Y) D& B$ d6 }sponse with high. levels of serum testosterone after topical
. X+ u3 `1 Q* m8 U7 ^administration, suggesting a systemic response. 3 The use of. S6 b9 K! y3 [5 `3 P
gonadotropin to obtain levels of serum testosterone compara-" Z! @. r. i5 {' o/ I; M+ o
ble to levels obtained with topical testosterone would seem to
3 T7 W( X. v2 f: _$ iprovide a means to compare the relative effectiveness of  |& I3 n' S6 m
topical testosterone to systemic testosterone effect. It cer-' _: u0 l9 v2 P& a3 v& N# Q
tainly has been established that gonadotropin as well as par-# r" l# T" |  i+ ]3 ?
enteral testosterone administration will produce genital8 H% B6 h( ]) F) L) N/ M. s* w8 o
growth. Our report shows that the growth of the phallus was. }& M3 `% K  N; R+ E) r
significantly greater with topical applications than with go-' Q+ r& j) A( V; m+ n* F: k
nadotropin, particularly in children less than 10 years old.  {, _' s$ U& E3 R4 R
The levels of serum testosterone remained similar or lower& [) T8 U" Y. j# Q7 @2 E
than with gonadotropin during therapy, suggesting that topi-0 l" H0 a% L0 l. @6 w7 I" W! n2 M
cal application produces genital growth by its local effect as) n0 L- z" A' `. I# C
well as its systemic effect.0 Y5 o4 B9 C% J( P
Review of our patients and their growth response related to
5 G  H: v5 c% m: W- S4 E9 a( T# Page shows a greater growth response at an earlier age. This is+ c! V) p3 y( Z7 X; q9 Y# K
consistent with the findings of Wilson and Walker, who
1 k& j1 E+ E& q( Jreported an increased conversion of testosterone to dihydrotes-
* a# |+ ~& B4 A' R( z, ?tosterone in the foreskin of neonates and infants.4 This activ-" ]7 h  I, b+ ^5 L  `
ity gradually decreases with age until puberty when it ap-7 U: I  @, y2 L( H" p) j
proaches the same level of activity as peripheral skin. It may# |$ J3 h# `* q
well be that absorption of testosterone is less when applied at
& `3 b' S  g$ Q# O  @an earlier age as suggested by lower serum levels in children) {/ y5 ^# Y2 {* J, L" E
less than 10 years old. This fact may be explained by the% g; D' E! ]: {+ a: N8 I
greater ability of phallic skin to convert testosterone to dihy-
  i$ L) ~; J9 ~' ~' E. ^drotestosterone at this age. Conversely, serum levels in older
' X) ]) y; e) B4 u5 ]  T+ r, Vpatients were higher, possibly because of decreased local
9 P3 ^/ ~2 n; U3 `; b667
7 \) Z- \+ b# M1 j* W6 b, T6 A668 KLUGO AND CERNY
% k% g% S2 r8 Q" @; N; OPt. Age
  T8 C2 ^* V- {' c: e0 E(yrs.)
1 j2 Z% N) L. A. C% l/ p. e* FSerum Testosterone Phallus (cm.) Change Length( J6 _- ^- c3 v. O
(ng./dl.) Girth x Length (%)1 r) H/ ^4 L, e" K5 F% j( w: T
47 F/ M, J4 `" |, B" u2 R  h
8' m, K/ P. s3 [8 m9 i/ o) a: T& O
10
8 r0 H% w+ c7 V' H' z& g12, }$ L' N/ C. @7 A( E. }
17* G  Q6 r  k3 i7 ~7 O  l% U
Gonadotropin
% A& B5 T4 ?7 \$ |. \. U71.6 2.0 X 3 16.6
0 x& c0 O- R4 V0 M4 v1 V50.4 4.0 X 5.0 20.0
2 i/ m8 h1 J. Y- P22.0 4.5 X 4.0 25.0: w3 d% G4 r& O' L4 b( q/ J. [
84.6 4.0 X 4.5 11.1
( ]# \/ q5 H: t  ?3 M, b85.9 4.5 X 5.5 9.0
, o. L0 t. H2 x) DAv. 14.3
0 V8 ]: D$ f8 C7 e2 o! W. N4# \/ b4 H/ M/ x' f( L, g7 j$ q
8
% o/ B* e  E4 n% t* ]$ K8 p10- M0 r2 Q/ E! O+ j# A1 A
12
. x5 a; E8 g# V1 q$ P! ^/ {17
& c5 n8 L/ W+ [4 X( x8 U: pTopical testosterone
1 d' I) [2 s3 Z. t1 Z34.6 4.5 X 6.5 85" r/ X0 H0 ?  z- _* k. v
38.8 6.0 X 8.5 70
. K" A( Y" r2 C, Q. u40.0 6.0 X 6.5 62.5
4 _  O; a" W. N1 F: B7 ]9 D93.6 6.0 X 7.0 55.55 M: r- ^: z! u+ K; j
95.0 6.5 X 7.0 27.29 h: H2 |/ C$ [, \3 T" n9 F' {/ H
Av. 60.0
" z5 Q) }( p! E! f6 w! H; M# M+ S/ Ravailable testosterone. Again, emphasis should be placed on& _5 w+ i/ P/ c6 x2 G: I4 M9 c
early therapy when lower levels of testosterone appear to8 X7 @5 Q3 s* ?8 O/ E$ w
provide the best responses. The earlier therapy is instituted" T( ?$ P& v! I+ v5 A
the more likely there will be an excellent response with low
1 T; h1 w3 c6 H$ B5 j- `7 ]serum levels. Response occurs throughout adolescence as. K* [* y" m5 V. n
noted in nomograms of phallic growth. 7 The actual response
1 X/ `/ s; H  |to a given serum level of testosterone is much greater at birth( f7 L9 E2 ~. |8 F9 w$ J
and gradually decreases as boys reach puberty. This is most3 B/ C2 a- O" a
likely related to the conversion of testosterone to dihydrotes-4 O4 M1 s1 k+ r7 m1 e0 c  |: Z  e
tosterone and correlates well with the studies of testosterone
( J& z. t. U/ U/ A' o" m* ?conversion in foreskin at various ages.% R0 ?2 M- n, {) Z( S1 Z8 j: J1 x; n
The question arises regarding early treatment as to whether
& V- }* m5 F/ D4 Y9 @, ^6 W6 t5 l+ hone might sacrifice ultimate potential growth as with acceler-; O: g# X: s; t
ated bone growth. The situation appears quite the reverse) L% v6 |; ~6 G  D
with phallic response. If the early growth period is not used
. c$ |' B$ p: t8 C) c$ hwhen 5a reductase activity is greatest then potential growth  L1 n: |5 `( |2 p# k
may be lost. We have not observed any regression of growth% M8 p, `" }/ w  E4 m7 R9 g. B1 o$ P
attained with topical or gonadotropin therapy. It may well: V# d1 a! W) d( r8 u
be that some patients will show little or no response to any* Y3 b' W: N9 T( _% _' m& p) ?9 {
form of therapy. This would suggest a defect in the ability to
* Q! g( H1 M, zconvert testosterone to dihydrotestosterone and indicate that
7 v9 h% |& m4 _- u5 Dphallic and peripheral skin, and subcutaneous tissue should  R0 A& q0 R/ V: p, ^( t) t
be compared for 5a reductase activity.
* Y7 q# L/ M8 ?# A! JA, loop enlarges to measure penile girth in millimeters. B,
+ U7 f6 K& m8 V5 [& [4 r4 Yexample of penile girth computed easily and accurately.+ Z) M+ ?* ?+ z& ?- m$ G7 c
conversion of testosterone to dihydrotestosterone. It is in this% [8 I4 {  X3 z9 L, j6 v
older group that others have noted high levels of serum
2 ]: m% a# d. I4 q' H5 K0 ~testosterone with topical application. It would also appear
7 t9 g; }, R0 }. Z% u  wthat phallic response during puberty is related directly to the, L0 E, i! g  H$ Z& |4 e  `* d
serum testosterone level. There also is other evidence of local
- J' s5 |. ~, Sresponse to testosterone with hair growth and with spermato-
0 L% I! `2 {$ U( }4 h7 e" pgenesis. 5• 6% g3 E9 X6 G% _; G
Administration of larger doses of gonadotropin or systemic4 {, S/ [# B5 y% S& s7 @4 p& L
testosterone, as well as topical applications that produce% M; d+ n5 `+ M
higher levels of serum testosterone (150 to 900 ng./dl.), will
  `4 w* `+ J) k: z% K( ~" [also produce phallic growth but risks accelerated skeletal& C: g$ v: s. P6 H) a
maturation even after stopping treatment. It would appear- n( t3 k$ g( J5 f4 i  ^$ {
that this may be avoided by topical applications of testosterone
" Z4 _# m, L0 C; b( Z7 z( C7 \. Kand monitoring of serum testosterone. Even with this control
2 t1 z+ g# q2 tthe duration of our therapy did not exceed 3 weeks at any1 W9 B" a$ O1 N" G, c  U
time. It is apparent that the prepuberal male subject may3 r; M! Q& L/ I+ Q* o, W* i. h
suffer accelerated bone growth with testosterone levels near
- d5 G" E1 }8 E' p8 c5 D/ X4 }200 ng./dl. When skeletal maturation is complete the level of
6 T, D" ]/ @$ o$ G, {( `# mserum testosterone can be maintained in the 700 to 1,300 ng./
* V6 Y0 b6 [4 ^" m. }" mdl. range to stimulate phallic growth and secondary sexual6 G4 ~/ p) b2 ?2 H. x9 R
changes. Therefore, after skeletal maturation parenteral tes-
4 J+ q( _, a9 U8 l! Btosterone may be used to advantage. Before skeletal matura-1 X) w9 z4 a  C/ I
tion care must be taken to avoid maintaining levels of serum
% W! ?7 W/ @+ d0 ?6 xtestosterone more than 100 ng./dl. Low-dose gonadotropin0 W& U, c3 a7 D$ s. c: J: [
depends upon intrinsic testicular activity and may require
& Q' O8 c$ t; \- r3 Aprolonged administration for any response.
, _! ^3 U( t1 @' O! ?7 P( TAlternately, topical testosterone does not depend upon tes-
% N, a' }/ K/ S* n% G0 qticular function and may provide a more constant level of
9 T. p! r8 W0 H" H. \" ?. BREFERENCES
2 R4 n& m; k' o$ j9 f1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,) s0 c- F# D  x5 a/ E' i9 E
R.: The local application of testosterone cream to the prepub-
3 N: \2 A; y/ Z; q6 b* P1 Y% B2 qertal phallus. J. Urol., 105: 905, 1971.
" U+ k  ]/ T# `$ Z" ]7 @2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone  T2 Z; S+ N# z3 j, ^5 O/ H3 j/ f
treatment for micropenis during early childhood. J. Pediat.,
* I: L0 Y! f+ Q4 j3 G* k" J83: 247, 1973.
5 s/ T( v) C( [% l% M( V7 B3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* r$ o2 u3 O8 D* b/ D8 Mone therapy for penile growth. Urology, 6: 708, 1975.
1 K0 I' n  @6 Z# \3 P4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' h: L0 k1 A6 g1 G+ V" E
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by; F9 J1 _5 R8 w3 y, p4 S7 B: o
skin slices of man. J. Clin. Invest., 48: 371, 1969.& O7 I; F8 u0 I1 S
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
9 D0 }0 j) H  x* a4 P4 Xby topical application of androgens. J.A.M.A., 191: 521, 1965.( O7 k$ N$ U2 M6 P" X
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ E$ q0 P9 ]5 Z/ ^4 I4 A7 b# N
androgenic effect of interstitial cell tumor of the testis. J.
0 i: G  s8 P1 e0 |Urol., 104: 774, 1970.
! H  e5 M2 T2 |7 _# j7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
4 u8 ]- ]( `9 ~1 Q- Z+ _tion in the male genitalia from birth to maturity. J. Urol., 48:
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