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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 E' C5 O, S; B# _  nGONADOTROPIN
. M- y! t- u9 w6 v, ~! ERICHARD C. KLUGO* AND JOSEPH C. CERNY
6 G4 h  J- W- X' A5 j$ C$ TFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan  b& I/ o& f- g" W7 x$ W1 O3 g0 Z
ABSTRACT
$ {: G% i- m4 y; {1 gFive patients were treated with gonadotropin and topical testosterone for micropenis associated
8 [3 R6 y: |! D& Z. dwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 L- Y4 g% O' atropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
1 e, G  B9 G; a3 R* jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* ~' f8 N! m, q8 J" U+ Nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent& G" v, D: p* d3 a' C/ n
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: R" @+ U5 a, D  [
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response( n# O* {: l& D/ u
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 u. x6 M8 {$ h; _
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 W# S  a& P! [0 n! S
growth. The response appears to be greater in younger children, which is consistent with previ-
- L8 X9 m/ d2 \5 U. x* }ously published studies of age-related 5 reductase activity.
) C0 W6 t1 Y  K1 [2 B$ K0 _, ?Children with microphallus regardless of its etiology will. i% q1 J" _3 h6 b) T, F& }' P9 e
require augmentation or consideration for alteration of exter-
, B% s  Z. K+ p! I- `3 A5 Nnal genitalia. In many instances urethroplasty for hypo-
' E9 x* Q/ X. c! M+ `2 lspadias is easier with previous stimulation of phallic growth.8 p3 Z1 k1 M" z/ w. V
The use of testosterone administered parenterally or topically, o2 Y- J2 b5 s9 \6 ]! V: S  }
has produced effective phallic growth. 1- 3 The mechanism of/ k: e6 @0 W9 U5 w" x
response has been considered as local or systemic. With this( A& l4 J' L, }$ N
in mind we studied 5 children with microphallus for response6 u" f4 [( i# k. d& m
to gonadotropin and to topical testosterone independently.
6 {2 [/ C! D. n% T0 M. hMATERIALS AND METHODS
+ f8 R( X8 o- |9 oFive 46 XY male subjects between 3 and 17 years old were( ?3 n# E0 J- w9 p& p
evaluated for serum testosterone levels and hypothalamic
1 f. h& K- e5 X7 h- ^function. Of these 5 boys 2 were considered to have Kallmann's' Q1 T7 V7 p. O% I
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-3 w6 z; A& b- D0 ?/ R0 W# R
lamic deficiency. After evaluation of response to luteinizing
2 `% `6 K4 F( M) s3 Z5 b3 Phormone-releasing hormone these patients were treated with3 X. }+ H5 v9 A8 f1 K4 Q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks+ |& _" r  p; U
after completion of gonadotropin therapy 10 per cent topical( e2 Z! T& q" ]
testosterone was applied to the phallus twice daily for 3 weeks.
. G3 Z5 t1 ?; g5 }Serum testosterone, luteinizing hormone and follicle-stimulat-& j1 [. X# s3 o5 A* R' f- q
ing hormone were monitored before, during and after comple-! y# Q" K, Z8 k' g
tion of each phase of therapy. Penile stretch length was3 }) y7 b, c3 n! R
obtained by measuring from the symphysis pubis to the tip of
6 b' g; _1 q& x: H0 ]# r& Gthe glans. Penile circumferential (girth) measurements were
. d" S% q+ |  iobtained using an orthopedic digital measuring device (see6 Y: T/ _) O1 p2 k- P7 I5 M+ O
figure).
, `4 M& y, K' L& d( z, oRESULTS* U; b  ?3 G& J  c; n# o# @
Serum testosterone increased moderately to levels between
  _4 k1 x- u( y5 ~5 J50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
" R! k* r; N( \+ ]terone levels with topical testosterone remained near pre-. c/ l* f8 e( R
treatment levels (35 ng./dl.) or were elevated to similar levels
3 k4 D5 H$ C/ B( @) j( Gdeveloped after gonadotropin therapy (96 ng./dl.). Higher
6 ~7 ]  m" U9 H  F/ Q9 Cserum levels were noted in older patients (12 and 17 years old),1 G6 n) g% T5 r; n4 M& F- `
while lower levels persisted in younger patients (4, 8, and 10
4 p8 U( Q0 ?, a, Jyears old) (see table). Despite absence of profound alterations5 _% S( S, ~8 U1 Q0 B9 O
of serum testosterone the topical therapy provided a greater, m7 F8 i0 G6 ]- D8 [9 J
Accepted for publication July 1, 1977. ·
+ T) n: ]; e" K$ a! @5 jRead at annual meeting of American Urological Association,3 v8 _3 c2 ]9 H  v3 F: g
Chicago, Illinois, April 24-28, 1977.6 G8 {! h7 S  D& z0 j' R
* Requests for reprints: Division of Urology, Henry Ford Hospital,) R6 m: L* K! _5 I5 J
2799 W. Grand Blvd., Detroit, Michigan 48202.
, `) z: {; V9 A* Q8 O) k8 Fimprovement in phallic growth compared to gonadotropin.  e4 N  u" m5 b, O
Average phallic growth with gonadotropin was 14.3 per cent
5 N5 ^( H4 O9 W  ?3 m1 _increase in length and 5.0 per cent increase of girth. Topical
0 J: \9 S- H3 y# e$ E: y8 b3 [testosterone produced a 60.0 per cent increase of phallic length
0 F& Y3 k6 q; i: o% i& uand 52.9 per cent increase of girth (circumference). The
$ u4 a  I( f" j) aresponse to topical testosterone was greatest in children be-
1 E+ o5 u8 S) `' c+ W& Qtween 4 and 8 years old, with a gradual decrease to age 17
$ G! j+ o' G# k/ P) x! Iyears (see table).
0 g2 ~! G7 h* |& @6 I$ G7 ZDISCUSSION
7 }( c6 Y- k1 Z' X9 qTopical testosterone has been used effectively by other
$ W" {6 f& C% {9 E0 I8 M5 l* B+ \) rclinicians but its mode of action remains controversial. Im-
! t+ Z* Q1 {7 {2 omergut and associates reported an excellent growth response
2 f' U  O1 a8 mto topical testosterone with low levels of serum testosterone,
7 a' Z( j, N9 r2 }5 ysuggesting a local effect.1 Others have obtained growth re-: E$ D6 n1 ]5 Z+ [( B( c
sponse with high. levels of serum testosterone after topical; Y" b0 V, z1 \4 H
administration, suggesting a systemic response. 3 The use of
; |+ ^+ n% ~8 \gonadotropin to obtain levels of serum testosterone compara-3 H: `0 y& a7 Z
ble to levels obtained with topical testosterone would seem to
. B% P: I) c4 t3 ^provide a means to compare the relative effectiveness of$ M: y( }/ C9 l$ H8 ]% B% E
topical testosterone to systemic testosterone effect. It cer-- |1 g; G8 o3 Y2 s3 q
tainly has been established that gonadotropin as well as par-
8 L1 Y8 C9 ]: c9 K6 tenteral testosterone administration will produce genital$ g# S+ t- ]6 X3 R/ v1 l
growth. Our report shows that the growth of the phallus was1 P/ N. ^3 F: _- Y# C5 Q# s, I
significantly greater with topical applications than with go-9 H1 \* G4 f; m
nadotropin, particularly in children less than 10 years old.
2 w% g7 Y/ S8 t. r) bThe levels of serum testosterone remained similar or lower
4 q+ l+ G7 J7 E+ d, M. Zthan with gonadotropin during therapy, suggesting that topi-3 U/ j0 B) g% r2 E. G
cal application produces genital growth by its local effect as
7 h  f7 W' Z% y) ^" ]well as its systemic effect.$ }( j2 N' d0 X0 h1 f1 |
Review of our patients and their growth response related to+ q/ l2 a' ?: t+ U- f" _
age shows a greater growth response at an earlier age. This is& G9 P" i! s  Y7 b4 D6 X7 v
consistent with the findings of Wilson and Walker, who
0 A3 q, X7 {$ C# ^reported an increased conversion of testosterone to dihydrotes-
6 z. a$ m; c1 rtosterone in the foreskin of neonates and infants.4 This activ-
5 k& s6 c% a6 [7 _ity gradually decreases with age until puberty when it ap-
3 ^+ f: P8 [; E: qproaches the same level of activity as peripheral skin. It may
) S7 A0 g0 Z$ nwell be that absorption of testosterone is less when applied at
5 Z- a8 f, i6 U: Ran earlier age as suggested by lower serum levels in children
' f0 a$ E' j7 |/ Jless than 10 years old. This fact may be explained by the7 |) `1 s$ C. M! C4 U3 ?1 u
greater ability of phallic skin to convert testosterone to dihy-& E: d1 S) d* L- S# Q7 {- F
drotestosterone at this age. Conversely, serum levels in older
) x6 H' o3 o9 t3 lpatients were higher, possibly because of decreased local+ }- o  {1 r6 Z# U
667
- p$ j; J$ g# w" o$ n; x3 N668 KLUGO AND CERNY
. P# {8 J! q3 r2 b# vPt. Age
! s3 b/ ?# z" C8 K0 X5 n* I- v% J(yrs.)& o* ]% E( v$ _, d! \) X. I
Serum Testosterone Phallus (cm.) Change Length
: q/ U+ L; _2 ?& v2 @: Z(ng./dl.) Girth x Length (%)% \; c9 w, ~7 f8 ^- o
44 ]6 O$ W* Y6 j% @9 L5 C% [, R
8  k4 A7 l3 J7 v- d* Z
10! }3 {) }& r3 r) m2 J
12
: }. d8 w7 C" b% I17
7 ]* d0 x( C4 x- [. `! T" `+ z) yGonadotropin9 m( z* L4 T7 Q* l
71.6 2.0 X 3 16.66 D4 t9 D7 N3 r/ R( s! \) Z
50.4 4.0 X 5.0 20.0
( h2 x9 Y" ^6 D  N. S9 l" ~; ]' a22.0 4.5 X 4.0 25.0
" |  H0 f$ B  r, L84.6 4.0 X 4.5 11.1
' V0 \1 q6 |& Q3 r- _- M# I85.9 4.5 X 5.5 9.0
, N; d& q4 f0 @1 Q, s5 }Av. 14.3
) ?- c6 d+ V- x' V# B3 R2 O" @4
! o- L0 K9 L+ q, m- a8# `: U9 C3 Y: ~0 d
101 c4 ~' l6 k" w# G& D
121 I" c% y# w% b" E7 d- U
179 r/ f- J. x% V/ o
Topical testosterone. i8 b6 _9 y8 w/ K# _. O# X
34.6 4.5 X 6.5 85
9 `5 k0 I1 a) Y8 q7 \38.8 6.0 X 8.5 70" |. A  b* E# O* }4 a/ G
40.0 6.0 X 6.5 62.5
6 }6 H4 y6 `" y2 y4 f, ^/ |93.6 6.0 X 7.0 55.5
- z3 i" I9 ?0 `! J/ T5 S# a3 e95.0 6.5 X 7.0 27.2
9 K4 V0 `6 U: D5 F7 I8 b" X% ]6 VAv. 60.0
2 t" U, T3 L6 i- w8 r7 ?( T9 ^$ g+ O7 Eavailable testosterone. Again, emphasis should be placed on
( a8 N! n8 j/ O2 a3 ~early therapy when lower levels of testosterone appear to
: ?  L& C3 j, q: ^' mprovide the best responses. The earlier therapy is instituted8 C7 N! l- i: e
the more likely there will be an excellent response with low
/ o7 C; {3 @: d2 @: }7 Bserum levels. Response occurs throughout adolescence as
3 A( V! b$ N- s; e. Dnoted in nomograms of phallic growth. 7 The actual response
) i  i. A8 o  h" d" \  q: m- Kto a given serum level of testosterone is much greater at birth
& m3 ^4 }) A& F4 h0 }and gradually decreases as boys reach puberty. This is most, b( I* k2 A7 M: c) I- X
likely related to the conversion of testosterone to dihydrotes-; {1 B/ `" Q6 F9 z7 p! T: l, [8 o9 q
tosterone and correlates well with the studies of testosterone1 M' B) T3 T7 _: f* L
conversion in foreskin at various ages." P% t3 I: u9 `+ w! {
The question arises regarding early treatment as to whether3 t2 t8 G+ a4 K' [3 Y) k  m
one might sacrifice ultimate potential growth as with acceler-* Y+ M- c, d1 e, u
ated bone growth. The situation appears quite the reverse8 }) r8 _+ R  n
with phallic response. If the early growth period is not used
/ M4 T4 B/ d6 z, L2 \when 5a reductase activity is greatest then potential growth' g/ B' X7 C0 _+ b5 i% f
may be lost. We have not observed any regression of growth
& ?. @+ @0 i2 t: a2 xattained with topical or gonadotropin therapy. It may well
: c9 r% p- K  i1 z, h6 g  J4 Ebe that some patients will show little or no response to any5 ~" _/ R* `& x  d2 o4 o
form of therapy. This would suggest a defect in the ability to( {3 ], m* u' J- @
convert testosterone to dihydrotestosterone and indicate that
6 s3 i0 n, ?7 G3 L' g5 A) z2 `2 Iphallic and peripheral skin, and subcutaneous tissue should% z; D( v3 i1 k* d+ j2 m! r6 v$ J
be compared for 5a reductase activity.
8 G8 J! `+ n& e3 n0 [$ CA, loop enlarges to measure penile girth in millimeters. B,
4 G% g- {6 D; c, Eexample of penile girth computed easily and accurately.
; n5 J* Z  ]0 nconversion of testosterone to dihydrotestosterone. It is in this
& G  y9 x: y- E* a7 k3 z  \% _9 |* r) Dolder group that others have noted high levels of serum
8 ^) B8 c2 r+ `* Jtestosterone with topical application. It would also appear
9 B1 l4 ^* c) y' gthat phallic response during puberty is related directly to the
5 i9 z6 p8 I0 [* l# hserum testosterone level. There also is other evidence of local
- G* Q# o4 r( V- F8 yresponse to testosterone with hair growth and with spermato-# X3 f0 A2 V! [" k% ~1 d& h
genesis. 5• 6: A+ M6 }5 T. Q, E! f- I
Administration of larger doses of gonadotropin or systemic  ]; T7 V+ X* K, {- U- n1 ?/ |; K
testosterone, as well as topical applications that produce
2 R5 ?, H/ E+ _, R( Z2 Lhigher levels of serum testosterone (150 to 900 ng./dl.), will  a  ]) C# u# ]* Z
also produce phallic growth but risks accelerated skeletal/ A! ^& V- C$ B5 H
maturation even after stopping treatment. It would appear" ?- ?" Y$ z; w' X/ \* M& V
that this may be avoided by topical applications of testosterone
0 A$ w/ @6 p9 S' H8 A% R+ |1 Gand monitoring of serum testosterone. Even with this control
, \4 q) u2 U5 W7 d+ v6 |( Z2 Gthe duration of our therapy did not exceed 3 weeks at any
; u2 O( x- A/ G0 Q( U% j& R7 Qtime. It is apparent that the prepuberal male subject may
1 ^3 _. i" r& n( Y# o- q$ Ssuffer accelerated bone growth with testosterone levels near
$ b9 K4 P4 j. P9 l5 S- E200 ng./dl. When skeletal maturation is complete the level of3 }. o, ~  s$ I' _0 A- i$ K
serum testosterone can be maintained in the 700 to 1,300 ng./
- w; O* h7 `; e( }4 X& Odl. range to stimulate phallic growth and secondary sexual! e: l# ^' x' w" a6 X2 c
changes. Therefore, after skeletal maturation parenteral tes-
& C! o% ?  G! ?8 H; `/ ^tosterone may be used to advantage. Before skeletal matura-9 A) t' W! `8 |2 e& ]. t
tion care must be taken to avoid maintaining levels of serum9 C7 z, l% ?# ~& G5 b
testosterone more than 100 ng./dl. Low-dose gonadotropin8 j  W! ~% ~2 O% K  B7 I$ ]
depends upon intrinsic testicular activity and may require
! m* r! T) H( Iprolonged administration for any response." [0 c3 N( R6 l8 o1 }
Alternately, topical testosterone does not depend upon tes-
4 [7 o4 X1 S( N! W4 L7 P' Z3 ]  ~9 _) qticular function and may provide a more constant level of
/ [6 S: @# N. y; @; VREFERENCES
, U1 Y7 m7 n" t3 r. _$ m1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 _/ ^! P  ?* r* B; n  yR.: The local application of testosterone cream to the prepub-
3 a% _8 J1 G& Q9 uertal phallus. J. Urol., 105: 905, 1971.
# O: e5 d) X+ m  m8 P& z) w& ^2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 O- m. E! [  O$ m; Ktreatment for micropenis during early childhood. J. Pediat.,
& P& G# t: H- V) |0 H83: 247, 1973.
5 e7 I9 R/ _7 }3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-8 {, b1 a) I* ~' T- F1 y
one therapy for penile growth. Urology, 6: 708, 1975.
& A3 ]) N7 |$ F1 S% z( h- `0 D) g4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
4 E% {' P  `- b) E  Ato 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 |+ J5 ~& N; C1 tskin slices of man. J. Clin. Invest., 48: 371, 1969.6 o; U5 Y* e7 u1 q$ p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% J  d8 L& e' L: ~9 n$ q
by topical application of androgens. J.A.M.A., 191: 521, 1965.
( m7 T0 v! b$ X0 `. d6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, O4 f5 ^+ j" P6 K: M
androgenic effect of interstitial cell tumor of the testis. J.
( s4 Q3 a. X' m6 [3 cUrol., 104: 774, 1970.6 Q" ^# a+ @- u2 \8 m, L/ f
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-% V7 V5 F1 n9 L, O8 }5 f9 d8 L
tion in the male genitalia from birth to maturity. J. Urol., 48:
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