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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: S! I  ?2 C4 J  j
GONADOTROPIN
$ V& v' S# F# YRICHARD C. KLUGO* AND JOSEPH C. CERNY( ^0 H9 a9 Q/ F% y8 e: A; \
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan5 L- T  s9 _" ?4 R  u& T7 r* A7 ?
ABSTRACT
: y0 U- a; R: l: IFive patients were treated with gonadotropin and topical testosterone for micropenis associated' n2 z, Q: d2 A
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
" |' Z& ^# r! J% B+ `7 ^' |tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 X0 c6 |$ |0 C8 ^8 V' xcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' v0 Y' a7 Q1 Y$ I! i% d. p
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
) ?' V" Z! X& H) B: v$ v- p+ Uincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average- S, I0 _% C, Z; I9 d: L
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
, z. q2 u  Z* x/ k$ X0 H! H8 poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 U4 R* D, O3 u: ^study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- L  |. S( Z7 t) z( _growth. The response appears to be greater in younger children, which is consistent with previ-
- n# B& F2 P: d+ H( Tously published studies of age-related 5 reductase activity.' A+ G+ U, a: Q" A. ~9 i' _
Children with microphallus regardless of its etiology will4 \- P$ r" ^0 ~/ P
require augmentation or consideration for alteration of exter-
$ p* Z! v" H: V# j- \7 M! gnal genitalia. In many instances urethroplasty for hypo-
& P! Q6 ~1 G0 n6 g( Ispadias is easier with previous stimulation of phallic growth.
; q; T4 k/ p* @" V6 N7 e( {) T% VThe use of testosterone administered parenterally or topically  J0 X/ p+ D' l$ l& }* |) g  K
has produced effective phallic growth. 1- 3 The mechanism of
8 n; g! E0 ]# C! gresponse has been considered as local or systemic. With this9 L5 f' p- J* k# N; {: n  z+ R
in mind we studied 5 children with microphallus for response9 R6 L+ t- M2 g6 w9 m% l
to gonadotropin and to topical testosterone independently.; m5 t( e. [* w- o  }- M- w
MATERIALS AND METHODS& H% `5 Q3 Z( {7 k
Five 46 XY male subjects between 3 and 17 years old were
, F& A" L2 h6 X$ \( tevaluated for serum testosterone levels and hypothalamic+ o/ \6 H# M! m# }5 t% u# h
function. Of these 5 boys 2 were considered to have Kallmann's& E6 t" F- G# H/ _- J5 K5 T" Q
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-- b& v9 P1 E) m" u: i
lamic deficiency. After evaluation of response to luteinizing
3 R8 g. X& g9 C0 J% qhormone-releasing hormone these patients were treated with% h' ^" `5 y+ e$ B9 q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks# d" y' k- R# [6 g, e
after completion of gonadotropin therapy 10 per cent topical
6 l; `, Q. _' E6 O# Jtestosterone was applied to the phallus twice daily for 3 weeks.5 v' m, k  G, d8 a+ M
Serum testosterone, luteinizing hormone and follicle-stimulat-; U1 _7 q! P0 I! `' _7 X- j
ing hormone were monitored before, during and after comple-6 w/ s* x0 {( g; N1 M
tion of each phase of therapy. Penile stretch length was! x& V* t% f( x$ A' h; ^" r
obtained by measuring from the symphysis pubis to the tip of) G0 S* w' a+ J* v) O' _9 I
the glans. Penile circumferential (girth) measurements were
  O: |! u; w1 Q- X' k0 Z0 v. `obtained using an orthopedic digital measuring device (see) G4 a# S+ t4 }+ U! S) q$ G
figure).( C/ E3 b! I5 a2 i$ |* }  O& X
RESULTS
* {4 E* e/ J" R  d3 Z0 x5 TSerum testosterone increased moderately to levels between
4 F- J% U* z6 y; w6 b: ]) K: W50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
& N4 o5 A4 `0 ?. G0 s# H8 G7 rterone levels with topical testosterone remained near pre-9 Y" P2 r& M! e/ ~
treatment levels (35 ng./dl.) or were elevated to similar levels4 Z$ q" P$ e: p& I; S
developed after gonadotropin therapy (96 ng./dl.). Higher. {& M  U; T7 `0 Z+ E
serum levels were noted in older patients (12 and 17 years old),
, O0 W- z4 F# Hwhile lower levels persisted in younger patients (4, 8, and 10
7 z7 t/ b2 V3 x" Z# ]9 `8 x; [years old) (see table). Despite absence of profound alterations2 @' M9 ~; B7 L' z5 z
of serum testosterone the topical therapy provided a greater
! z2 J$ i( V0 ^0 `Accepted for publication July 1, 1977. ·
' [- K1 s" |% G8 f6 _* V0 h3 MRead at annual meeting of American Urological Association,. Q  p/ N7 G% B
Chicago, Illinois, April 24-28, 1977.
, c7 v: o2 i- |- p' R. I9 x* Requests for reprints: Division of Urology, Henry Ford Hospital,- P+ x* m! m$ G1 X+ e9 A
2799 W. Grand Blvd., Detroit, Michigan 48202.
& ^) m+ B+ I% k4 b+ Gimprovement in phallic growth compared to gonadotropin.
: c/ D8 K" ]0 K% z" l  FAverage phallic growth with gonadotropin was 14.3 per cent
- m+ w+ i) z& D  ]0 hincrease in length and 5.0 per cent increase of girth. Topical
8 G! B9 d# E8 C& d6 n/ rtestosterone produced a 60.0 per cent increase of phallic length# Y+ n; b2 h8 ]& K5 E
and 52.9 per cent increase of girth (circumference). The( M7 E( o7 {" m5 J$ w' o4 ~1 p. h
response to topical testosterone was greatest in children be-- |- H5 o4 H7 w& F% n3 A
tween 4 and 8 years old, with a gradual decrease to age 17; k# u; J5 U) o
years (see table).5 B& c# A8 j* j" W0 U; q
DISCUSSION
. s; j  u3 ]9 z4 ETopical testosterone has been used effectively by other9 r1 b) g0 z& r2 w( G( _; n
clinicians but its mode of action remains controversial. Im-
! ?; V( H) i" X8 P- Jmergut and associates reported an excellent growth response
% a* V; I# g+ Q2 hto topical testosterone with low levels of serum testosterone," t( Q& x7 c5 N0 \* y. r+ S1 k
suggesting a local effect.1 Others have obtained growth re-; s/ T: W, o% @8 r# U! W
sponse with high. levels of serum testosterone after topical
, P( U# v# M3 cadministration, suggesting a systemic response. 3 The use of
. a8 R7 N$ p7 q2 c. V1 e0 `gonadotropin to obtain levels of serum testosterone compara-8 Q1 [; x7 q& _, r) x
ble to levels obtained with topical testosterone would seem to
/ {' U. u8 ~( v% H6 q+ y, Tprovide a means to compare the relative effectiveness of
: @" S& B% q& x9 d" I+ atopical testosterone to systemic testosterone effect. It cer-2 a5 M3 ?2 }/ C+ P
tainly has been established that gonadotropin as well as par-8 ^/ [5 _5 n) J' _3 O0 o
enteral testosterone administration will produce genital
1 `2 g0 q( J4 y7 G) ^0 wgrowth. Our report shows that the growth of the phallus was
% Q  C% G, o  M& D  m7 Z& g) ^. i" {significantly greater with topical applications than with go-0 E0 Y+ T/ o2 d/ k# |; @2 p# |
nadotropin, particularly in children less than 10 years old.
: Y- x9 G* K  Q# ^- K) R4 T8 R5 yThe levels of serum testosterone remained similar or lower
  C4 }2 X8 ?. E$ B& ^than with gonadotropin during therapy, suggesting that topi-
( h; K0 n7 M% |6 Q/ R  ^9 Xcal application produces genital growth by its local effect as4 v  l1 O- a$ M2 w' o0 c
well as its systemic effect.: k) R* `% J) p/ M6 P# j, b% `3 h
Review of our patients and their growth response related to1 @$ e* n8 M) |+ l7 n
age shows a greater growth response at an earlier age. This is
! B+ l7 R3 G# s2 k0 c2 t; X0 [/ S& `consistent with the findings of Wilson and Walker, who: D$ J: u) S, q. d+ g
reported an increased conversion of testosterone to dihydrotes-3 T& e2 ~' g7 I1 `
tosterone in the foreskin of neonates and infants.4 This activ-- W4 {$ |& Y+ G; q3 Z2 P
ity gradually decreases with age until puberty when it ap-8 P; }1 m; s( v1 X! h
proaches the same level of activity as peripheral skin. It may* S8 n% T* n5 |8 I( ~+ v
well be that absorption of testosterone is less when applied at
1 V% o* Z, R$ W( ~an earlier age as suggested by lower serum levels in children
% [" p$ o) r9 e: Zless than 10 years old. This fact may be explained by the* p. h0 W9 F' X# ^$ Q7 Z
greater ability of phallic skin to convert testosterone to dihy-
, a2 ?) u4 L; g' m5 }drotestosterone at this age. Conversely, serum levels in older; T3 N+ l- H! c4 I, K7 u
patients were higher, possibly because of decreased local( q7 L& w( w, g( L$ Q, M7 M
667
3 |% K: ^( p! }668 KLUGO AND CERNY
: W1 J* s% Q# \6 kPt. Age
+ x( E6 o& v$ F% l(yrs.)
: x) |+ O/ F1 X+ b# }Serum Testosterone Phallus (cm.) Change Length) c. I( {" C& q. _' |( u
(ng./dl.) Girth x Length (%)& ~# j* s$ t1 P0 f- p" R
4" i% h# r$ M1 U7 p7 i+ }
8
( Y; _# p. W/ e; Z. [10, B4 ^$ j6 a: ?5 q, U+ X4 y+ @
12; N7 J9 }5 E, s5 i4 i; L
17& G0 e! H$ A: D+ ]9 Q
Gonadotropin9 ]( |8 M* M4 I2 u+ m- |
71.6 2.0 X 3 16.6
9 d9 z& U1 p7 P) ^. F" u50.4 4.0 X 5.0 20.0; M7 l: h% E4 b8 t3 r
22.0 4.5 X 4.0 25.0
. ]. U+ F( G: J* h, k( T+ [" I84.6 4.0 X 4.5 11.1
0 Z( [! p0 P& a. `) K+ i85.9 4.5 X 5.5 9.0) ^! T3 ?& \& I7 [
Av. 14.3& B+ p# N. t5 @' y+ D1 @
4  {$ b! `1 p7 {6 p: ^3 w1 |
89 \' o5 L! C! e5 E7 h" m
10/ h5 j' ~+ F4 \2 x
125 ~8 B" [, x! \- A- _2 v6 h2 D
17% d( g" u0 T$ M7 n  a. x
Topical testosterone
1 W8 l0 ^* U2 }! H5 u* n4 f34.6 4.5 X 6.5 85# [4 l6 B: A+ N) V* S. U# }6 z+ T" S
38.8 6.0 X 8.5 70
7 J; L3 E2 J+ @+ a1 }9 f3 ]40.0 6.0 X 6.5 62.5& h( m; {+ ~* {) S; Q* a2 }
93.6 6.0 X 7.0 55.5
: P" M7 \6 ]& k3 X- G; Q) u( r95.0 6.5 X 7.0 27.2
9 D' d$ f; w( [7 ]& a" S8 jAv. 60.01 k1 K/ a7 k2 r3 C2 J, c0 d  Q; ~
available testosterone. Again, emphasis should be placed on
- X2 X1 f7 k8 }+ S3 ~  J) m* Rearly therapy when lower levels of testosterone appear to, q5 L/ z+ q# M" Y7 w1 R
provide the best responses. The earlier therapy is instituted. M( D: u- p0 ?; C% b. u  Y- F1 t) {
the more likely there will be an excellent response with low9 C& W" ^' f8 n1 P
serum levels. Response occurs throughout adolescence as
" Z" \# H2 S8 Unoted in nomograms of phallic growth. 7 The actual response9 j2 L; A% w# u  c$ W: b: V" c
to a given serum level of testosterone is much greater at birth
* u* |" k& T# _. hand gradually decreases as boys reach puberty. This is most
5 H% ^& J4 q: T& |! Z2 Qlikely related to the conversion of testosterone to dihydrotes-
, ^2 h# W  G5 ^3 @1 H8 jtosterone and correlates well with the studies of testosterone
5 N9 o- u! K- V' V' E( Zconversion in foreskin at various ages.2 N! r' r% i& v
The question arises regarding early treatment as to whether! V0 i4 n" h( o% `$ B+ J1 [3 u6 J
one might sacrifice ultimate potential growth as with acceler-7 K1 _8 S6 L- I) e
ated bone growth. The situation appears quite the reverse
! Q9 W0 E: p$ Kwith phallic response. If the early growth period is not used
4 V/ I: \4 U% A) y6 P% Wwhen 5a reductase activity is greatest then potential growth4 w# U# j5 y/ _6 ]) p
may be lost. We have not observed any regression of growth
# R8 o1 _" D4 M6 Qattained with topical or gonadotropin therapy. It may well; J1 V$ I9 `3 ^  k0 d8 H0 W
be that some patients will show little or no response to any: A% P4 K, u* s* J: ]& E) C7 L
form of therapy. This would suggest a defect in the ability to
' D: r; n0 z! C% ]8 N  cconvert testosterone to dihydrotestosterone and indicate that
/ d' t% u7 w2 p( r2 }phallic and peripheral skin, and subcutaneous tissue should
3 N5 |+ n: C3 Z% W* U& Xbe compared for 5a reductase activity.3 r# g. e9 B; \; D: x( e* z
A, loop enlarges to measure penile girth in millimeters. B,* k) B; o% O9 Y! v) U: t0 ^9 H
example of penile girth computed easily and accurately.: K5 q4 u  ^7 K7 `! Y
conversion of testosterone to dihydrotestosterone. It is in this- @$ X. }# V& l; I" b' E; M. D7 A
older group that others have noted high levels of serum9 U5 D: N  Q0 m( F8 V8 F5 n
testosterone with topical application. It would also appear
$ x% c+ T0 A9 w' V- U0 hthat phallic response during puberty is related directly to the
) o6 E& b8 L! `- ^7 {serum testosterone level. There also is other evidence of local
. q. ]( F1 ^- Jresponse to testosterone with hair growth and with spermato-* E1 [. a, k3 q& R
genesis. 5• 6' T7 d8 e! L! I- Q7 q
Administration of larger doses of gonadotropin or systemic
) }, N$ P# E- a, g. `$ \testosterone, as well as topical applications that produce
" ~% W) s" ]- {; U6 K5 X8 Jhigher levels of serum testosterone (150 to 900 ng./dl.), will
; i1 d/ J) O8 F; d; Yalso produce phallic growth but risks accelerated skeletal
6 D; E6 _+ J, q- d0 Jmaturation even after stopping treatment. It would appear! Y8 E5 b  E4 q0 k7 }; m
that this may be avoided by topical applications of testosterone, t( b$ @7 O  }) ]+ H7 }
and monitoring of serum testosterone. Even with this control1 p( T4 E- j! q% x# J
the duration of our therapy did not exceed 3 weeks at any
- F7 y/ D2 _# |6 ?  \3 r% d9 gtime. It is apparent that the prepuberal male subject may
0 ~- @0 r; s/ T* X% ~/ V- D$ Ksuffer accelerated bone growth with testosterone levels near' E5 \0 ]0 Z! X1 W( ]
200 ng./dl. When skeletal maturation is complete the level of' U" I4 c$ M9 v: K
serum testosterone can be maintained in the 700 to 1,300 ng./! `) G! W/ r- |, f' d7 [7 ]) I; B) R
dl. range to stimulate phallic growth and secondary sexual- u; A( v1 B! H% O- U9 V
changes. Therefore, after skeletal maturation parenteral tes-
3 O' A" ?9 o! T7 wtosterone may be used to advantage. Before skeletal matura-
1 R/ W/ e/ h& N$ W  M* Y( @4 ktion care must be taken to avoid maintaining levels of serum
, N6 f; l- N& otestosterone more than 100 ng./dl. Low-dose gonadotropin0 |; b  S/ d1 O- q9 ^  C% f1 V) q
depends upon intrinsic testicular activity and may require
8 F2 W. ]" ?) bprolonged administration for any response.2 t# w: l+ x4 }, r2 _
Alternately, topical testosterone does not depend upon tes-- j  g$ v7 f* }0 J! F4 Z
ticular function and may provide a more constant level of0 @! B: @7 ?! c5 D- d
REFERENCES: B0 Z$ s+ N) A2 l+ S
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% w$ o# f' w4 A/ X- e- g
R.: The local application of testosterone cream to the prepub-
1 ~- A: }# |+ }ertal phallus. J. Urol., 105: 905, 1971.
) l1 {: i) E6 O1 H9 }2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 D+ G+ c! i/ T
treatment for micropenis during early childhood. J. Pediat.,
0 j2 i6 b' A4 e3 X1 C83: 247, 1973.- U- c6 E- C' j: Q
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 z6 l" p2 l/ K9 ]: |. w5 Z
one therapy for penile growth. Urology, 6: 708, 1975.
4 C5 i. x2 `0 H% A1 W4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: Z" S. _3 l8 s; R1 y; O, h, ~8 zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by7 w3 p/ m% s- H0 S( K6 T# @2 z: j
skin slices of man. J. Clin. Invest., 48: 371, 1969.& @* q/ i+ x5 Y, G
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
' x; b1 j( F$ }" Q( @  }by topical application of androgens. J.A.M.A., 191: 521, 1965.
, E6 z' @9 P5 G6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# T. Y! `. q: D4 Wandrogenic effect of interstitial cell tumor of the testis. J.% d% v2 A% N( N# h4 |
Urol., 104: 774, 1970.+ Z6 d: b9 |6 u2 G, y
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* a3 t9 m, @* g" ^8 v6 z
tion in the male genitalia from birth to maturity. J. Urol., 48:
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