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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 |2 e) v% H) U1 z# X% ^, BGONADOTROPIN( s$ q  l6 V2 r3 e' u
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 D' s* q  r/ x  Y  J0 |From the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 l8 s7 @6 Q" G# n
ABSTRACT/ e& u( Q6 j+ s. G" ?2 |  e
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' D3 {1 ]) B1 E! K+ Y/ d- h
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-7 b6 r# G4 s! W3 b
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 N0 ]8 |4 Y4 p* r2 C3 g4 `
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 `' n& c9 K. V) o
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% B) T! p6 w7 @3 `' G: Kincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average4 ]8 V, z) [! ^% P
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response! ?3 _& V9 p; B$ `7 d
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
& V' a$ A- I+ ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; \& K- Q5 ~. o7 |2 H+ e( U# p5 agrowth. The response appears to be greater in younger children, which is consistent with previ-
4 g: d) \$ K' C$ V0 }0 Fously published studies of age-related 5 reductase activity.
+ e% Z9 o2 ]( F! mChildren with microphallus regardless of its etiology will
. v; L0 J9 f/ u  Zrequire augmentation or consideration for alteration of exter-
+ E' c5 q) n$ W2 H0 Cnal genitalia. In many instances urethroplasty for hypo-
" O# {; _# ^1 n9 _. S  U/ D# y( vspadias is easier with previous stimulation of phallic growth.
) w8 v9 a* e0 J0 OThe use of testosterone administered parenterally or topically( l) m' }* F( A9 e- y
has produced effective phallic growth. 1- 3 The mechanism of
( A2 \$ |/ J) H2 m: V; `7 Dresponse has been considered as local or systemic. With this9 K9 d6 k# b) T8 Y6 l1 M
in mind we studied 5 children with microphallus for response1 X* y* V; z3 o: w$ N5 a
to gonadotropin and to topical testosterone independently.
6 U9 m9 y# r; uMATERIALS AND METHODS) g" Q, D% n: T) ]# u2 B2 c% m' L
Five 46 XY male subjects between 3 and 17 years old were1 i5 [& n5 M0 `% B
evaluated for serum testosterone levels and hypothalamic) [6 M8 k2 @. T& L8 Z- k
function. Of these 5 boys 2 were considered to have Kallmann's0 H2 u9 O/ a& s- `# D5 a
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" U( H2 c' j/ X' B' r7 r
lamic deficiency. After evaluation of response to luteinizing
3 R$ @" d- {- U2 m) C& }$ F3 [1 [hormone-releasing hormone these patients were treated with4 z- h5 _- N7 p: t6 t3 I8 N
1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ i0 e* d) P, H2 C- ?% p
after completion of gonadotropin therapy 10 per cent topical9 `4 {. a" k' p$ X9 B
testosterone was applied to the phallus twice daily for 3 weeks.
- q* r: W" E) v; Y. bSerum testosterone, luteinizing hormone and follicle-stimulat-
# ]& q, Q0 ~  k2 z% ving hormone were monitored before, during and after comple-7 e7 t0 o) d  m6 B1 t
tion of each phase of therapy. Penile stretch length was/ l, ?7 v/ R3 D' m9 c
obtained by measuring from the symphysis pubis to the tip of; r) X; g0 C( g% m/ K- S
the glans. Penile circumferential (girth) measurements were
$ C* \% G5 i6 Z4 b' l0 ?obtained using an orthopedic digital measuring device (see& m& t3 T$ c+ z3 W$ x' d) Z
figure).% A' M+ H/ v! C& e# p9 u
RESULTS
$ x; D+ e8 H) z8 Q3 {2 dSerum testosterone increased moderately to levels between1 M/ D  q7 Q# C; \& m, G% m
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 [6 ]5 x' F4 v: q4 v* s$ x
terone levels with topical testosterone remained near pre-
" o0 m* G9 N) o; Qtreatment levels (35 ng./dl.) or were elevated to similar levels* d3 H* _* E$ k
developed after gonadotropin therapy (96 ng./dl.). Higher2 y5 e- n- k4 E1 j( G6 a0 ]
serum levels were noted in older patients (12 and 17 years old),3 j+ ?: R- K& q* [! a) X
while lower levels persisted in younger patients (4, 8, and 10
6 T) j' ?. |1 `  P8 n" a3 s" eyears old) (see table). Despite absence of profound alterations- q( U* ~+ D6 ?/ @
of serum testosterone the topical therapy provided a greater  z- s, u4 F, L: B
Accepted for publication July 1, 1977. ·; X/ F1 {. ^5 q% O3 a
Read at annual meeting of American Urological Association,
; k, q; w5 d7 W6 p/ U( z0 f3 TChicago, Illinois, April 24-28, 1977.
/ }3 c; q# C( P' z. m% S; U7 v+ T* Requests for reprints: Division of Urology, Henry Ford Hospital,5 q( o( |( K9 `: z3 H* l
2799 W. Grand Blvd., Detroit, Michigan 48202.
* C# ]! C. L; `1 R- cimprovement in phallic growth compared to gonadotropin.
% y; Z8 M2 O; |2 o+ H1 dAverage phallic growth with gonadotropin was 14.3 per cent
; a! o* y" X, S! q, {! aincrease in length and 5.0 per cent increase of girth. Topical
" H  m7 U: {( Ctestosterone produced a 60.0 per cent increase of phallic length
+ ^. H/ ?) c. W* j# z7 {* ~: f9 U- Yand 52.9 per cent increase of girth (circumference). The
$ P; ]$ \6 V! T  p9 A! @response to topical testosterone was greatest in children be-# E( j. l: G. \- ^
tween 4 and 8 years old, with a gradual decrease to age 17: N( |) H: b# f* z1 t. o" m
years (see table).7 X$ V7 ^4 ?1 i9 `- v' ?
DISCUSSION. |5 n1 `  u2 [" N5 ?
Topical testosterone has been used effectively by other3 \* R( {. J$ R. f3 o5 ]( L% A) L" N
clinicians but its mode of action remains controversial. Im-
/ Q* X/ l3 e3 n+ m& Wmergut and associates reported an excellent growth response
+ v2 G9 j' @( i% n( xto topical testosterone with low levels of serum testosterone,) x  B3 ?( \6 _" ~- q% c1 d- H
suggesting a local effect.1 Others have obtained growth re-& H+ X/ O' L6 g6 f2 ?& T0 ~" Q
sponse with high. levels of serum testosterone after topical
$ U/ U. L3 h1 g: {. Yadministration, suggesting a systemic response. 3 The use of
. ~: g1 p5 S4 }, M9 u6 ~- Mgonadotropin to obtain levels of serum testosterone compara-
& E  U* j, F9 A9 l9 G9 uble to levels obtained with topical testosterone would seem to
6 ]5 q& ]) N8 P  u- Uprovide a means to compare the relative effectiveness of
- N3 ^5 Z9 P1 N) E, Ntopical testosterone to systemic testosterone effect. It cer-
( X- ?4 e  [* I5 L+ k' {# Etainly has been established that gonadotropin as well as par-5 R0 j: a- a7 Q" J  R2 g4 J
enteral testosterone administration will produce genital, Y% O8 R, L) O* C
growth. Our report shows that the growth of the phallus was
: l% V6 c) j6 M" fsignificantly greater with topical applications than with go-! v" F3 H& C2 [, }
nadotropin, particularly in children less than 10 years old.
/ v7 w, _+ ^0 ?, ]0 fThe levels of serum testosterone remained similar or lower
  e* V2 ^* a1 Y, P; y% Sthan with gonadotropin during therapy, suggesting that topi-
1 p: i- z4 r$ b2 I% @+ kcal application produces genital growth by its local effect as
# ?7 }- J# |, C7 V; Gwell as its systemic effect.: p0 \3 H  {7 M; A
Review of our patients and their growth response related to1 W& I) z6 M9 M1 x$ H5 p
age shows a greater growth response at an earlier age. This is+ ?  w- x# b+ y, A5 }  ^
consistent with the findings of Wilson and Walker, who3 E5 e( U! q* Q# |9 I7 J
reported an increased conversion of testosterone to dihydrotes-
2 V) U1 B3 p, p4 K/ @% K8 j+ Xtosterone in the foreskin of neonates and infants.4 This activ-* p6 X: [" o5 K4 U  k3 F# O
ity gradually decreases with age until puberty when it ap-' V8 u8 X1 e' t% }2 n$ t
proaches the same level of activity as peripheral skin. It may. O/ w, h5 p$ N8 H& W
well be that absorption of testosterone is less when applied at2 O: y, M. g; Y3 R! e: k
an earlier age as suggested by lower serum levels in children2 \2 E! X5 I2 E% I7 r& d' E7 {
less than 10 years old. This fact may be explained by the
& z/ x" s) t( j6 s/ Dgreater ability of phallic skin to convert testosterone to dihy-/ ]& Q2 L! q: ~
drotestosterone at this age. Conversely, serum levels in older
9 u3 z# X- A5 M, I2 Vpatients were higher, possibly because of decreased local
6 B' b* g) T# ~: i6 _: D6675 P5 K/ Q' @1 x5 D. n
668 KLUGO AND CERNY
' o7 |) Z9 z- R! G! a4 B' lPt. Age$ q0 ~" a4 }( }. h* X
(yrs.)
% I8 m5 u) _3 ?$ N2 uSerum Testosterone Phallus (cm.) Change Length
& [9 x3 Q. j2 x' I4 P7 p& \(ng./dl.) Girth x Length (%)) C* h! |7 q( a9 J  h
43 C- T2 L2 h6 I) Z. ^; s
83 ~- h4 Q  r6 Y; ~$ K2 {- h
10. T4 J, @; ]) p( ^% j% F
122 R1 N: M1 q% H( J- ?
17% l+ P. M" S8 v% i9 L! Y
Gonadotropin; Q7 W* `: Z  g
71.6 2.0 X 3 16.60 h/ k+ C1 K* Z$ f0 j9 ?
50.4 4.0 X 5.0 20.0
6 R8 n0 D! v! w5 D" Q, o22.0 4.5 X 4.0 25.0* ]9 I0 ?' h: p) B4 K; j
84.6 4.0 X 4.5 11.1
1 [: O1 l+ j) t# v+ Z' ]1 ?/ m; I85.9 4.5 X 5.5 9.0
4 a5 g: b0 Z, j. q5 l# G: G' g3 r' tAv. 14.34 q9 P; S. L" M) R6 v4 s$ G
4# ?/ i7 k" ^2 J
8
) _6 m; d3 E  i10/ [' a& U0 J7 v5 h$ M, p# R5 J( O) W
121 r( T/ I2 Y5 L) A, l& z& z
17
  Q: m' ]4 _: P5 a; c7 O1 M8 FTopical testosterone% u) D- Q* _% s1 m/ [, s
34.6 4.5 X 6.5 85
( _+ Y8 L& f- c- O2 c38.8 6.0 X 8.5 70, ?7 p" h. h6 c" p3 Q% ?
40.0 6.0 X 6.5 62.5
, u% k- _6 u1 ^' W$ j$ D93.6 6.0 X 7.0 55.5; B  @9 P  U+ M+ f4 v5 E
95.0 6.5 X 7.0 27.2$ @4 b2 o! `5 Z. g" D6 I6 I' f: \
Av. 60.0- s# b* T: g  y5 A6 t% F) i$ v
available testosterone. Again, emphasis should be placed on
- s5 ]+ j: G* f( u2 _early therapy when lower levels of testosterone appear to! T. l6 U7 s5 D8 i9 \" v
provide the best responses. The earlier therapy is instituted5 H/ A& ]) W* b0 y
the more likely there will be an excellent response with low
. |0 x. ^7 w1 t2 k, yserum levels. Response occurs throughout adolescence as
8 x) Z, b/ }6 D* E8 ]noted in nomograms of phallic growth. 7 The actual response
. h1 U7 [9 S# g: Y4 |to a given serum level of testosterone is much greater at birth
. l- Y+ I; V/ ]2 }; nand gradually decreases as boys reach puberty. This is most
- ]( @+ \0 M$ D. z  elikely related to the conversion of testosterone to dihydrotes-
$ i, i  m7 p' ^" e6 x; Dtosterone and correlates well with the studies of testosterone4 u: x0 o8 X8 \
conversion in foreskin at various ages.* W7 }. r- U7 R; n
The question arises regarding early treatment as to whether
2 q& m- T/ Y$ |; o" Q8 z9 F2 V) Uone might sacrifice ultimate potential growth as with acceler-9 }. O9 ?7 J# C4 E- o# ?
ated bone growth. The situation appears quite the reverse& J! C: B) I. d6 D, Z
with phallic response. If the early growth period is not used4 |& K: Z: @. B$ |
when 5a reductase activity is greatest then potential growth
) w. Y% J% H$ Tmay be lost. We have not observed any regression of growth2 O# Q2 o% {- L7 W
attained with topical or gonadotropin therapy. It may well; l5 c4 s7 B3 e6 k- Q' ], ~# c
be that some patients will show little or no response to any" z6 q  z" q. \- L9 H
form of therapy. This would suggest a defect in the ability to& B: K, H7 s1 m! k. i
convert testosterone to dihydrotestosterone and indicate that
% [. h7 \! z1 R% Pphallic and peripheral skin, and subcutaneous tissue should
" z: s% d, `2 S: y- N4 T2 ?- s, Gbe compared for 5a reductase activity.6 m) R8 r. D. U9 Q( j. |3 J7 q
A, loop enlarges to measure penile girth in millimeters. B,
! y1 u* d9 F# G; r: `6 d$ M* B$ qexample of penile girth computed easily and accurately.5 t) e  P5 k+ V0 `
conversion of testosterone to dihydrotestosterone. It is in this
- t" c; `8 y8 Q' L* Q  W. Y& J. colder group that others have noted high levels of serum
5 p6 D9 _$ O7 wtestosterone with topical application. It would also appear5 T9 g4 e2 h# Z+ k6 i% z: N  a7 N
that phallic response during puberty is related directly to the
2 k6 {4 N" U% s$ o8 oserum testosterone level. There also is other evidence of local. m5 {% i  x$ ~; J2 s
response to testosterone with hair growth and with spermato-
& T$ h5 O& X+ ]6 R! ?, hgenesis. 5• 6
& R1 x. o* Z5 A& Z" _% R$ AAdministration of larger doses of gonadotropin or systemic
2 n7 g* P3 I; J: l% q, e. G" Ytestosterone, as well as topical applications that produce. ~% J" y# a/ \6 i
higher levels of serum testosterone (150 to 900 ng./dl.), will" O1 O( t+ ]7 J' ]# Z9 x+ W0 V
also produce phallic growth but risks accelerated skeletal
3 P* J  Q2 t8 V+ ^( Rmaturation even after stopping treatment. It would appear$ @* ^1 _( p  a& x  J
that this may be avoided by topical applications of testosterone: H! R9 g& m0 a' f3 `/ N
and monitoring of serum testosterone. Even with this control3 Z3 J) h: B  |+ h1 L3 U% w
the duration of our therapy did not exceed 3 weeks at any
* T& W0 s+ q& I7 f7 ztime. It is apparent that the prepuberal male subject may0 s; D$ q( ~: }! D$ B
suffer accelerated bone growth with testosterone levels near
" U, C2 X& |6 O) e/ n200 ng./dl. When skeletal maturation is complete the level of
! Y6 G# D7 @" H' _: f- Vserum testosterone can be maintained in the 700 to 1,300 ng./
9 p# t$ o  X8 U6 j  M4 J. a3 d. a+ Ldl. range to stimulate phallic growth and secondary sexual$ c" c$ y4 z# M3 W
changes. Therefore, after skeletal maturation parenteral tes-
8 }5 |2 O1 S; P' `# ntosterone may be used to advantage. Before skeletal matura-% m- T2 P& q& I% X; W) q
tion care must be taken to avoid maintaining levels of serum! z; ^! k5 B! u2 C; R- a
testosterone more than 100 ng./dl. Low-dose gonadotropin. c9 X; W& Z2 M" t( e
depends upon intrinsic testicular activity and may require
! `0 i7 A0 h0 q+ z. Zprolonged administration for any response.; w& I+ _0 K. t7 k# {
Alternately, topical testosterone does not depend upon tes-0 S9 }$ X  m9 ^) t* D
ticular function and may provide a more constant level of
6 a- |* B4 [6 x" s' l, E; `REFERENCES
4 B! A% [2 j. Q9 o0 C+ J5 \# N' {1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,  e) w8 b7 b7 M5 }" ?) W  H
R.: The local application of testosterone cream to the prepub-7 M* [  F3 U2 s0 j( i
ertal phallus. J. Urol., 105: 905, 1971.
3 z( d: q( @: ]0 x& {2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
; `$ \% d; O2 }  a0 D; q8 Wtreatment for micropenis during early childhood. J. Pediat.,9 C7 V9 t0 @# _) n/ ^9 @
83: 247, 1973.
& V1 Q' N/ @+ [2 N) t4 x$ u# O! b3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
1 U! _! B: I3 h/ Mone therapy for penile growth. Urology, 6: 708, 1975.# G# \* M# U1 r( y( d8 X4 r
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
" V* k, ^- r7 sto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 G8 |% Z: ]9 \, u+ Z
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ H  G; T, }/ d1 ]* z2 O" w
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ Q' J- k  O7 D7 Bby topical application of androgens. J.A.M.A., 191: 521, 1965.
5 N. Q& \! [. y6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
& k1 N8 X4 V; j7 Zandrogenic effect of interstitial cell tumor of the testis. J.5 M$ Q" N1 p$ N+ ^3 }  b5 l5 i
Urol., 104: 774, 1970.
$ j9 g4 ~; C4 }7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' x7 a3 U3 A) w0 [( a, otion in the male genitalia from birth to maturity. J. Urol., 48:
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