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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND( t$ l; ?4 Q9 ?* C, z& t
GONADOTROPIN
. U% P( q' \" x5 V( dRICHARD C. KLUGO* AND JOSEPH C. CERNY
# m( ~# O7 H1 t. F: d2 P" {% jFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan+ @+ c' f1 X6 M1 r9 X5 n
ABSTRACT
' [5 X, f) u  W" A8 V, AFive patients were treated with gonadotropin and topical testosterone for micropenis associated; Q/ y" v; ?0 r" \% [8 d
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
1 W) T4 G3 ?5 U( ?tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ t& c6 f. k) H" N  q: Z
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, P5 U6 @2 M# m+ E  Z# q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 g+ m; m" D2 v$ @! o- e/ Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average* s* Z* _# Y: v$ s) ?2 E
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ U' Z( X$ D- n7 C6 ^. q$ Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 Q& C$ q/ L5 A* _3 `: ostudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 ~+ ^9 O3 N4 X& J5 {2 \growth. The response appears to be greater in younger children, which is consistent with previ-0 c# ^6 F* E& K& X) I
ously published studies of age-related 5 reductase activity.
- q. K$ r, {) uChildren with microphallus regardless of its etiology will
) `' i: e/ g% P: s' Xrequire augmentation or consideration for alteration of exter-
" S. U, @, u+ V/ ?- y7 g1 Mnal genitalia. In many instances urethroplasty for hypo-
. W" V5 K0 R) ~3 `- L1 Wspadias is easier with previous stimulation of phallic growth.
6 _( |$ Y. R1 rThe use of testosterone administered parenterally or topically3 t, f* P; o/ E6 r
has produced effective phallic growth. 1- 3 The mechanism of( i' w# z0 f9 s6 r. x
response has been considered as local or systemic. With this0 W+ T; J% o- m, x+ y6 n9 ^' R
in mind we studied 5 children with microphallus for response) `0 K' c8 V/ m8 |2 L! `5 v
to gonadotropin and to topical testosterone independently.. K& c8 e. C, `, n
MATERIALS AND METHODS
' g. j( ?( G& O5 [9 f$ qFive 46 XY male subjects between 3 and 17 years old were0 r2 q( E5 ?' {8 R& u8 d4 A; s: v# @% z
evaluated for serum testosterone levels and hypothalamic) h" {; N. d' u1 L
function. Of these 5 boys 2 were considered to have Kallmann's2 t( K6 V/ x. ?; _
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
% c" n+ P- J9 I  D5 r0 slamic deficiency. After evaluation of response to luteinizing
' H1 `9 D$ p0 m. q+ Thormone-releasing hormone these patients were treated with! `4 n8 x0 h/ Q' j. m) t! U( s) L
1,000 units of gonadotropin weekly for 3 weeks. Six weeks2 A: Y: t$ h. x
after completion of gonadotropin therapy 10 per cent topical
! F! n# o& c8 E* F/ btestosterone was applied to the phallus twice daily for 3 weeks.
8 c+ Q/ ^$ f# \& gSerum testosterone, luteinizing hormone and follicle-stimulat-
9 n: ]- U) k! s6 M+ sing hormone were monitored before, during and after comple-
  K) W0 s: e" M2 _1 h( k2 htion of each phase of therapy. Penile stretch length was
/ a5 }5 E2 P) H& v- Sobtained by measuring from the symphysis pubis to the tip of7 s$ q4 m) p7 U% p8 L& f
the glans. Penile circumferential (girth) measurements were
! Q2 v+ m8 p5 v+ ^% `obtained using an orthopedic digital measuring device (see. t3 l9 b, o* Z, V8 _) f
figure).
8 Y: x. A/ ]( ^7 _RESULTS# _3 p3 L- {0 L- N1 z0 W
Serum testosterone increased moderately to levels between* a9 d9 k+ T) J& R
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ R6 B4 h/ y/ E$ H* [# X
terone levels with topical testosterone remained near pre-! i+ Y& }" S4 y8 d2 R, M
treatment levels (35 ng./dl.) or were elevated to similar levels
$ N/ O' W. a1 u8 A( n! @developed after gonadotropin therapy (96 ng./dl.). Higher
" p7 C0 `8 h; o3 h8 P4 ?serum levels were noted in older patients (12 and 17 years old),
/ p3 X# h- H! x' S' `" H( g+ _% O: zwhile lower levels persisted in younger patients (4, 8, and 10
9 S' d5 A: M2 d( lyears old) (see table). Despite absence of profound alterations
8 p. i8 w' R% s$ S# |of serum testosterone the topical therapy provided a greater
8 s: b. a5 |6 C& Y/ DAccepted for publication July 1, 1977. ·+ {0 P8 }* C( l/ I) D0 q
Read at annual meeting of American Urological Association,- _5 W' ]. y- S, J2 Q
Chicago, Illinois, April 24-28, 1977.) r5 b+ G) @) h
* Requests for reprints: Division of Urology, Henry Ford Hospital,
, i* H+ S5 G( g7 w! `2799 W. Grand Blvd., Detroit, Michigan 48202.
$ x" m8 ^# h! D1 N" Iimprovement in phallic growth compared to gonadotropin.# K' i( Y! f, c: D* X3 R
Average phallic growth with gonadotropin was 14.3 per cent8 s& X) a8 u. C( Q! ]
increase in length and 5.0 per cent increase of girth. Topical
6 [7 o" v  ~% M" H) Z7 w7 Btestosterone produced a 60.0 per cent increase of phallic length) D  i6 R; y! C+ A' G6 \9 A
and 52.9 per cent increase of girth (circumference). The, j+ Q. n/ q  H. B8 b
response to topical testosterone was greatest in children be-
# P% U& A- G) `) c  S) K( p. btween 4 and 8 years old, with a gradual decrease to age 17
6 \# ~% v, Q4 M7 }years (see table).
  n' v* d3 o, KDISCUSSION  a7 r/ C0 b6 b9 {7 ?, y: x
Topical testosterone has been used effectively by other
; k+ k2 u; U5 p4 {, p- q/ kclinicians but its mode of action remains controversial. Im-/ @- m4 r  M( ?1 b: I; X( O
mergut and associates reported an excellent growth response' b% K3 m+ S7 z# ]+ d" l0 o
to topical testosterone with low levels of serum testosterone,
7 \2 Y) t$ A9 ^% W- wsuggesting a local effect.1 Others have obtained growth re-& W; l  L: k, ~9 @6 P
sponse with high. levels of serum testosterone after topical
& P7 z% E& E! r" {% `administration, suggesting a systemic response. 3 The use of  _5 S+ f+ e" x9 _, x$ P
gonadotropin to obtain levels of serum testosterone compara-
1 [# m$ A6 J5 B. M. d( [ble to levels obtained with topical testosterone would seem to2 s& w2 w, v$ _
provide a means to compare the relative effectiveness of
$ O" ~4 l0 n( j2 {5 S7 Z% [' utopical testosterone to systemic testosterone effect. It cer-
" l" Z6 I9 ^( y+ e6 U' [tainly has been established that gonadotropin as well as par-
: j; f" H- e# e/ |! I: O5 _enteral testosterone administration will produce genital
+ ]7 P" x* {- L6 u& Bgrowth. Our report shows that the growth of the phallus was
1 T1 ^. ]. G" e+ v- J+ F( C9 asignificantly greater with topical applications than with go-9 k4 k+ n; O/ \" ?4 k
nadotropin, particularly in children less than 10 years old.( d. f  K2 z1 v# C8 M
The levels of serum testosterone remained similar or lower; ?. X/ t' |2 ~
than with gonadotropin during therapy, suggesting that topi-7 l! I6 K$ k6 v8 W2 y. B
cal application produces genital growth by its local effect as) ^- l6 l* S9 a7 l) v# V/ C- h
well as its systemic effect.5 w9 r/ y# W9 Y4 R4 w
Review of our patients and their growth response related to
4 Y' c* c& s- Z2 hage shows a greater growth response at an earlier age. This is
+ c! j. H8 p+ _- p4 j- Pconsistent with the findings of Wilson and Walker, who, G4 y) E! u3 H0 Y
reported an increased conversion of testosterone to dihydrotes-6 k& O9 D7 `) V: D: M4 C- y
tosterone in the foreskin of neonates and infants.4 This activ-, f" v/ a% V* X) F
ity gradually decreases with age until puberty when it ap-
$ G) C8 ^4 {( Y& ^proaches the same level of activity as peripheral skin. It may
( x+ G( H: B4 Jwell be that absorption of testosterone is less when applied at
: T6 t0 j  @7 [/ J9 ran earlier age as suggested by lower serum levels in children# j6 r/ K9 t( J8 V/ W% l
less than 10 years old. This fact may be explained by the
- k, g0 ~) E! ~5 j1 a+ k9 Bgreater ability of phallic skin to convert testosterone to dihy-
; t7 u2 v( D4 }: Wdrotestosterone at this age. Conversely, serum levels in older3 B# A0 e3 \; [, j; x
patients were higher, possibly because of decreased local/ r/ Z6 G1 c9 m0 Z  ^
667
) g: T1 J' a3 y% \668 KLUGO AND CERNY9 B) [3 j/ K5 c0 B, ^# l: D
Pt. Age
" b+ x! V7 t- `/ H2 n2 t(yrs.)
; N& t9 a1 g5 i0 v( J- `Serum Testosterone Phallus (cm.) Change Length
* m% W7 L! o6 O: I(ng./dl.) Girth x Length (%)2 @6 P9 l+ W% F7 h, ?
49 [% A- e- q! ]& I
89 Q! e9 `# V% a% ?3 n/ H0 J
10
1 `8 p' I! z4 N' F3 v8 j12
( [$ S$ _% u6 C3 N3 d: s' {17
# v( n7 w+ ~8 P/ a1 ~  U' ?Gonadotropin
0 o3 G8 e; D4 H& d5 o: _71.6 2.0 X 3 16.6
8 v* X5 ]4 X8 w9 c2 H. l' ~$ J50.4 4.0 X 5.0 20.0$ w" X8 v/ f7 ^2 e) @$ S
22.0 4.5 X 4.0 25.0, l! }, ^  Q6 l7 Q
84.6 4.0 X 4.5 11.1
1 t  l( ^* Q5 M, c1 O' E. _% N85.9 4.5 X 5.5 9.0
1 L# M, x3 O" _4 L+ P6 W4 \1 b- O2 qAv. 14.3
0 ~# z. k! c% @8 Q" F4  R9 h( e8 G. w; }3 W. p
8
- ?9 W8 @* F# [, Z9 w! O7 C, f103 b5 r- u$ ]( R/ |: l) j0 w
12
! b8 t2 c. d( ~; U8 c0 L17
9 ?3 i  S; E5 K9 H) o' kTopical testosterone2 @& ]6 H7 O4 p! {$ s; [, m: @
34.6 4.5 X 6.5 85! I3 a& W: }: m: B
38.8 6.0 X 8.5 70
8 ~* m' b6 u+ d40.0 6.0 X 6.5 62.5+ K- C1 r8 h- V* h# U) Z9 R) e
93.6 6.0 X 7.0 55.5' i+ _+ A0 L) W4 v3 w- o1 L# S( V2 g
95.0 6.5 X 7.0 27.2
# ]$ k. x/ ?: nAv. 60.0+ a6 G% f3 r& I8 E7 D. y
available testosterone. Again, emphasis should be placed on
5 _  ?3 R' F' F6 w4 U# bearly therapy when lower levels of testosterone appear to
) G" W) Q% o$ cprovide the best responses. The earlier therapy is instituted& y; b/ @5 B( K* ?! E+ ~) s1 u( ^
the more likely there will be an excellent response with low% k' l, g7 f: G: S8 n+ k" A
serum levels. Response occurs throughout adolescence as4 _- b: Y: Y$ V" U
noted in nomograms of phallic growth. 7 The actual response  O6 ?3 ?( m( ]* H0 s
to a given serum level of testosterone is much greater at birth% V. q! @: E( c0 i1 ^' B9 m
and gradually decreases as boys reach puberty. This is most
, }. W$ g1 {. ?likely related to the conversion of testosterone to dihydrotes-% g/ |9 @6 R) v: F
tosterone and correlates well with the studies of testosterone
. o  k) c5 ?  n# }. R  sconversion in foreskin at various ages.
, O3 u' d: x6 {5 v/ F9 YThe question arises regarding early treatment as to whether) U. }3 S  ^* W% o; [4 o
one might sacrifice ultimate potential growth as with acceler-
0 `1 G& {( n0 S' jated bone growth. The situation appears quite the reverse
& v: _( q. R* {8 `: K3 Y3 _7 Fwith phallic response. If the early growth period is not used
' J6 _0 c# _' K9 rwhen 5a reductase activity is greatest then potential growth
. Y" Z' S( o! Q' R0 ~may be lost. We have not observed any regression of growth( P! I% `# [1 t
attained with topical or gonadotropin therapy. It may well
+ P% u! V3 ~5 _* C( v* Q* A* z7 obe that some patients will show little or no response to any; k  j: |% P* e
form of therapy. This would suggest a defect in the ability to
; |3 H1 v8 `% _: F0 uconvert testosterone to dihydrotestosterone and indicate that) Z* v) Q1 H+ U' G! V) V
phallic and peripheral skin, and subcutaneous tissue should
( e' [* R5 j1 ~4 T, }7 Qbe compared for 5a reductase activity.
4 ?, J; c) I" @A, loop enlarges to measure penile girth in millimeters. B,8 D1 g3 N6 V# S* `
example of penile girth computed easily and accurately.5 ~5 }6 q  {$ }# b% @* z
conversion of testosterone to dihydrotestosterone. It is in this
( T' K) a. y; G, V1 {older group that others have noted high levels of serum( a. b3 C" }: }; ~! D! x9 e: f5 v; U
testosterone with topical application. It would also appear
* C* J! Q; r# w& d# A! F9 Dthat phallic response during puberty is related directly to the+ A8 Q2 \3 M% U$ o' }
serum testosterone level. There also is other evidence of local
1 P( e) U+ a+ M0 h, |$ a# Uresponse to testosterone with hair growth and with spermato-1 j- u+ t  e2 h. {. n
genesis. 5• 64 H8 j9 ~3 _1 H
Administration of larger doses of gonadotropin or systemic
: A. q6 H& ]4 }  }5 Xtestosterone, as well as topical applications that produce
: n  ]$ E+ D. `higher levels of serum testosterone (150 to 900 ng./dl.), will
6 S  m7 H  w2 R3 ]/ a; Balso produce phallic growth but risks accelerated skeletal
; s9 O2 F9 R/ s1 I$ xmaturation even after stopping treatment. It would appear
' V- \8 q7 Y( M* G9 `8 ?2 _that this may be avoided by topical applications of testosterone
( v( \/ o' g# W: C1 ]- uand monitoring of serum testosterone. Even with this control
; t2 f4 J9 J( g0 f; K# @5 C  cthe duration of our therapy did not exceed 3 weeks at any9 d8 t% K2 q. K9 |
time. It is apparent that the prepuberal male subject may
3 ]- K1 m$ a* {. H, _# Gsuffer accelerated bone growth with testosterone levels near+ K+ w: q6 s2 t; v6 \$ N, h
200 ng./dl. When skeletal maturation is complete the level of
. N" k% R- o3 wserum testosterone can be maintained in the 700 to 1,300 ng./
8 A# J4 A) n: Sdl. range to stimulate phallic growth and secondary sexual" @  A# s. {& j' t
changes. Therefore, after skeletal maturation parenteral tes-! d; q2 I$ G1 |- j8 Z% z
tosterone may be used to advantage. Before skeletal matura-- @3 @5 R% G; ?# J4 i6 C/ r; [
tion care must be taken to avoid maintaining levels of serum
; k: l9 y. W7 }1 _, e. ^0 Htestosterone more than 100 ng./dl. Low-dose gonadotropin
& I2 s: U+ e: R' T9 |: edepends upon intrinsic testicular activity and may require7 e$ b: m  m+ {8 ^8 O- N
prolonged administration for any response./ {4 X$ W8 N( s  P0 v" U
Alternately, topical testosterone does not depend upon tes-9 Q2 Z  ^  y* z9 g# B( i4 g
ticular function and may provide a more constant level of1 b% K, @7 _$ y3 ?; t1 k
REFERENCES
* c, X, \, h4 l* f1 f  ^1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
# m3 J' D8 Y( @2 O+ SR.: The local application of testosterone cream to the prepub-
# I4 j- X' q0 T0 `$ gertal phallus. J. Urol., 105: 905, 1971.8 u: y2 @: g3 t% L6 Q% u
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 k7 y* T" V* h4 B8 e+ f; F% otreatment for micropenis during early childhood. J. Pediat.,; L: e, V# c/ g# O) y
83: 247, 1973./ Y* j- E9 N2 ~
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
) w: H" @, z& u9 Y' O' _& wone therapy for penile growth. Urology, 6: 708, 1975.* K. U6 k' B' o7 P# {
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
0 s: V4 x$ _! _5 c+ g" M* Bto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: X& V  t6 r. l) N; j- Dskin slices of man. J. Clin. Invest., 48: 371, 1969.$ a9 X. a: p- e4 k/ u  U9 R
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth- B" \7 ~* B' R, |9 b
by topical application of androgens. J.A.M.A., 191: 521, 1965.; [" N& w" u/ @; L6 |
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local7 e0 h+ r8 j8 l8 L8 i
androgenic effect of interstitial cell tumor of the testis. J.
6 N6 v) A' Z2 f6 r7 {Urol., 104: 774, 1970.9 K/ i$ ~6 I0 D  g
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 d7 [- ?, }' [/ J3 a" B
tion in the male genitalia from birth to maturity. J. Urol., 48:
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