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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND- c! K3 x+ G! \: m
GONADOTROPIN
7 d6 G: @. m- e% [) DRICHARD C. KLUGO* AND JOSEPH C. CERNY
/ n! M/ p! g$ rFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan0 [5 ]# C# R/ `: |! g% e
ABSTRACT2 x$ V+ X( W9 Y. T+ X
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
5 J( [- D: e$ H& k7 N* Cwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
- \# M  i" w. a+ ?9 j) Ktropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 ]1 [. `; x. |/ l* x( Lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 V; J8 e! N9 yfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 j0 O9 l3 I+ h+ j+ M9 J! Xincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average7 J" P: D8 m/ p) y2 C0 M9 j5 H; N
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response. Z  N* X0 A# ?
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
! V. R9 l" o- h* d% a" {: {7 gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
! I. z) |+ P6 U- k' D' Ogrowth. The response appears to be greater in younger children, which is consistent with previ-, M8 z3 D  z& Y3 D. _/ c. u9 Y
ously published studies of age-related 5 reductase activity.. q( d" V3 U: ^* `
Children with microphallus regardless of its etiology will; q4 Y# y) f% F2 t
require augmentation or consideration for alteration of exter-' L3 G; d4 e! J6 d
nal genitalia. In many instances urethroplasty for hypo-
' N/ A9 n. d1 G5 D4 Z7 g' _spadias is easier with previous stimulation of phallic growth.
6 s5 L; Q4 q- v2 f6 FThe use of testosterone administered parenterally or topically* ?3 p8 F1 l$ K7 Y2 v$ f' d+ r* x" E8 p
has produced effective phallic growth. 1- 3 The mechanism of
4 @6 l% l* j1 _+ b. L/ I# tresponse has been considered as local or systemic. With this0 n" O( w0 |! p/ k# G5 E
in mind we studied 5 children with microphallus for response
3 C' K" t' F, H. I: yto gonadotropin and to topical testosterone independently.$ C9 Q7 K# l/ B. D7 S, L
MATERIALS AND METHODS
$ ^; i1 K  j6 {- N+ aFive 46 XY male subjects between 3 and 17 years old were
8 Q8 E  C6 E7 h6 U+ @* Jevaluated for serum testosterone levels and hypothalamic
* f' @& w; n# B) f$ `* y- rfunction. Of these 5 boys 2 were considered to have Kallmann's
0 Y, t: Z+ u$ s2 {syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' [* s7 \5 b/ z0 }% U
lamic deficiency. After evaluation of response to luteinizing6 m3 c: i* z! [- E- ^! r
hormone-releasing hormone these patients were treated with- U4 B3 v: _5 B1 K! t7 h1 i
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 R+ a' |$ P0 Q: k& bafter completion of gonadotropin therapy 10 per cent topical
. u+ T% ?2 c, Utestosterone was applied to the phallus twice daily for 3 weeks." v) C% r6 y" e" }3 v
Serum testosterone, luteinizing hormone and follicle-stimulat-
2 P2 p; u) R' E5 C, [ing hormone were monitored before, during and after comple-$ S) i! D: m: n7 Q
tion of each phase of therapy. Penile stretch length was
/ M8 e. C9 z- e4 `obtained by measuring from the symphysis pubis to the tip of
  _; `( y1 Y- [) Y; m4 C  v" }the glans. Penile circumferential (girth) measurements were! z3 s& {' `6 e+ C
obtained using an orthopedic digital measuring device (see
1 i* M6 J5 b0 [  M/ R0 n% }figure).. t& I6 Z  u% W6 Y
RESULTS, Z  p( }+ r6 G. c: W
Serum testosterone increased moderately to levels between
$ S0 y- D2 u& D3 h4 p50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-& d/ u4 d- F7 S, J; c, D# ~
terone levels with topical testosterone remained near pre-
" J( _7 S4 U6 `* D! v0 Btreatment levels (35 ng./dl.) or were elevated to similar levels
6 `' |1 l* z3 U0 _, Ideveloped after gonadotropin therapy (96 ng./dl.). Higher
& `2 U# L. m+ o/ a2 ]: i  A! J3 D% Pserum levels were noted in older patients (12 and 17 years old),% Q  ^4 P; ^* R
while lower levels persisted in younger patients (4, 8, and 10) m. k3 r; w, @) N. P: z  u
years old) (see table). Despite absence of profound alterations
/ H9 b/ R% A$ }( C3 E, Iof serum testosterone the topical therapy provided a greater' |+ D6 Q1 |/ S) v$ ]8 i
Accepted for publication July 1, 1977. ·  |2 C, h: L% J/ q: [& ?
Read at annual meeting of American Urological Association,; m2 L1 W2 y) F* l9 z: O) ?7 a
Chicago, Illinois, April 24-28, 1977.+ z, ~! L% W6 {# k/ k6 \
* Requests for reprints: Division of Urology, Henry Ford Hospital,
3 R, L# [% ]/ n6 ~( E4 H6 I2799 W. Grand Blvd., Detroit, Michigan 48202.
& I% g( \( |3 C5 w1 simprovement in phallic growth compared to gonadotropin.. L% [3 N4 c3 B  d$ Z
Average phallic growth with gonadotropin was 14.3 per cent
" r  B- O, L, \: ~increase in length and 5.0 per cent increase of girth. Topical
0 {- K( H3 }& ]. E9 dtestosterone produced a 60.0 per cent increase of phallic length
4 F/ p+ A% [3 w. \8 Dand 52.9 per cent increase of girth (circumference). The
1 U+ W, f2 i: v! V5 Q- bresponse to topical testosterone was greatest in children be-
" O7 [* b: v9 Rtween 4 and 8 years old, with a gradual decrease to age 17& W5 c' o- B0 p  H
years (see table).* i8 N( u. ~  V$ ?) s0 h
DISCUSSION
7 r# L1 ~4 A: d7 K1 |1 A% z4 R7 }Topical testosterone has been used effectively by other
1 J4 r# i; I$ t% j3 F9 @2 ^  Jclinicians but its mode of action remains controversial. Im-1 B; ]3 C( e0 O1 u3 y, l
mergut and associates reported an excellent growth response
' {2 ^" w9 r+ V% E) qto topical testosterone with low levels of serum testosterone,
7 n' x1 N) R( Xsuggesting a local effect.1 Others have obtained growth re-
$ g' L( U  v6 m5 Nsponse with high. levels of serum testosterone after topical1 `0 U0 J+ x" E7 O, ?1 u4 _+ }
administration, suggesting a systemic response. 3 The use of' O( m% S6 H4 ?2 a& z
gonadotropin to obtain levels of serum testosterone compara-+ H7 O, F& N7 J% g) `, r) [
ble to levels obtained with topical testosterone would seem to
: m5 E! O! [: W+ _provide a means to compare the relative effectiveness of! h- n# s9 z" r- X4 U
topical testosterone to systemic testosterone effect. It cer-
4 z! Q# }7 j8 @2 Atainly has been established that gonadotropin as well as par-
+ v5 M9 |% g" q* T* X" r9 Qenteral testosterone administration will produce genital/ @+ c/ F$ x( ?* \& s  V
growth. Our report shows that the growth of the phallus was$ n7 G0 L& m/ Y6 d% I$ `; P! J
significantly greater with topical applications than with go-, p( h' b, H* x2 y% h( d2 e
nadotropin, particularly in children less than 10 years old.
% Q% o/ D/ R; S* Y$ V6 gThe levels of serum testosterone remained similar or lower
8 e' e0 c% e+ |than with gonadotropin during therapy, suggesting that topi-
! K+ i3 A- _# D* g! T" bcal application produces genital growth by its local effect as
! p5 Q+ w. W8 f$ v' @5 Twell as its systemic effect.
8 g) K; C5 J9 ^( \4 U& Y5 b6 ^Review of our patients and their growth response related to( h9 c& g  j3 p5 C& A' F
age shows a greater growth response at an earlier age. This is
  t: g# G0 s7 s; l- m7 |$ ^consistent with the findings of Wilson and Walker, who
: Z+ q9 N- Z# b9 w% greported an increased conversion of testosterone to dihydrotes-
5 e( E2 f4 ~2 o" [+ Htosterone in the foreskin of neonates and infants.4 This activ-
5 p0 J" h9 n) w4 m: bity gradually decreases with age until puberty when it ap-$ G) i, j4 }; l4 h
proaches the same level of activity as peripheral skin. It may
- s/ E/ k/ s" kwell be that absorption of testosterone is less when applied at: Z5 C) U) n1 c% L/ [* ^: U( @) ]
an earlier age as suggested by lower serum levels in children; v6 R+ V- i" [' Y9 ]4 s
less than 10 years old. This fact may be explained by the: h0 l  j. M' d; [: `
greater ability of phallic skin to convert testosterone to dihy-& w: ~, y" V) N  X6 ^' R" [7 s( T; ?
drotestosterone at this age. Conversely, serum levels in older' q- E$ H8 n' Q
patients were higher, possibly because of decreased local
; N: P5 V; _# p. J667% U7 G/ h$ P8 J! ^6 ~) m
668 KLUGO AND CERNY0 V4 b7 u8 x! Q5 `% N
Pt. Age+ d) R9 m9 r! C7 H/ X8 q' i; g
(yrs.)
- N" o( U% S( u- j( n3 {& |7 GSerum Testosterone Phallus (cm.) Change Length
; K4 [$ C6 o9 O  c  A2 _% C: o(ng./dl.) Girth x Length (%)
8 p- }8 h6 n: Q2 ]8 ?9 m4) Y2 C4 m+ H8 V$ ~
8
! Y& d, T+ U& j' @$ N108 e: Q' D: c5 h9 F8 a' U
12' I: R" ~  E& R) J1 X. f+ j% U. ?# Y
17% a/ C. ]8 r  p
Gonadotropin
$ u. Z( v3 X. T" Y* J) Y- s+ ]71.6 2.0 X 3 16.6
& O5 R  T& m$ J+ {% X50.4 4.0 X 5.0 20.0
' }) S8 y% Q7 S22.0 4.5 X 4.0 25.08 w0 \, g, p7 ?! w) W
84.6 4.0 X 4.5 11.1
" X2 w/ n* [3 h, z85.9 4.5 X 5.5 9.0
- q$ f) z. i6 t* i; d4 d! rAv. 14.3# a* w! A6 v0 d! W
42 z" ^  o. F7 C; `. ^' w
8
3 V4 k+ M0 V! ~10) X1 `; \+ k* F4 q( F
125 n4 j& N% r/ t$ j2 g3 n
17' e5 @( I9 E: V  |  Y! l/ z8 B
Topical testosterone
& C" ?3 h3 C4 C2 v! c: c; l8 t34.6 4.5 X 6.5 85
  z. N& O$ ?* i- |! P* U+ w38.8 6.0 X 8.5 70# W2 E* ^8 R# h: L2 }+ _
40.0 6.0 X 6.5 62.5
- \- u0 p+ ~5 t3 f3 Q2 e, n93.6 6.0 X 7.0 55.5( H# Z/ R9 u' f! h4 }
95.0 6.5 X 7.0 27.2
( p' i1 x: Z+ l8 `. pAv. 60.0% K. Z% b+ Q# s" m
available testosterone. Again, emphasis should be placed on
' Q% s' y5 I1 d: qearly therapy when lower levels of testosterone appear to
1 t! H9 X5 j/ ?. t  S! s6 s6 Vprovide the best responses. The earlier therapy is instituted
) ^2 V5 T, s' m3 M/ B: }the more likely there will be an excellent response with low; C7 f- `! V- _! l% U
serum levels. Response occurs throughout adolescence as" ?3 D1 W) |, m8 g
noted in nomograms of phallic growth. 7 The actual response" ?6 x) {* H: l& C, n; z/ e. r
to a given serum level of testosterone is much greater at birth5 x, q. d" U- H8 L& h$ f2 v3 O
and gradually decreases as boys reach puberty. This is most4 e* Y! O' v% w! k% Z, T
likely related to the conversion of testosterone to dihydrotes-% q% X# D5 N6 f# g, b" A  T
tosterone and correlates well with the studies of testosterone
3 u  Q& U6 Y7 Cconversion in foreskin at various ages.
! l' Y/ p& G6 C6 Y/ TThe question arises regarding early treatment as to whether
) K7 M& `" o/ ?( E0 \  Y3 N0 [one might sacrifice ultimate potential growth as with acceler-
6 f; P5 _0 q* T: J' wated bone growth. The situation appears quite the reverse1 y) D, f9 o; j) u
with phallic response. If the early growth period is not used
2 {" Y. X8 x4 [when 5a reductase activity is greatest then potential growth/ G/ d8 T& m7 \. t+ K! _- @
may be lost. We have not observed any regression of growth
/ c$ m3 k' |5 P: L% C; l' L% Jattained with topical or gonadotropin therapy. It may well" R2 M3 Y# f6 ?+ J- o
be that some patients will show little or no response to any. L, R; y" Q/ z# s# @& @( V
form of therapy. This would suggest a defect in the ability to' k( `; J0 ?2 U# N* e
convert testosterone to dihydrotestosterone and indicate that
+ d4 l7 l! _& E1 ?+ Zphallic and peripheral skin, and subcutaneous tissue should: i; P1 m/ Y, c! v
be compared for 5a reductase activity.) B3 i+ I  k8 W. s/ t  P% F
A, loop enlarges to measure penile girth in millimeters. B,+ E( R7 D' n1 y
example of penile girth computed easily and accurately.. ~" f% @2 l+ ^5 n4 J/ {. K; b
conversion of testosterone to dihydrotestosterone. It is in this
" F. M9 H9 P  e" j! n7 V' Folder group that others have noted high levels of serum
: U$ x" }- o7 ]) R5 z& ttestosterone with topical application. It would also appear" i" ~; H, i8 M& S; C. D
that phallic response during puberty is related directly to the- c0 |# p* L9 T0 n/ F# G$ d
serum testosterone level. There also is other evidence of local6 e& d- N1 h; g* z$ U
response to testosterone with hair growth and with spermato-
: c2 x, y3 A5 A$ u5 I: E  I6 i7 Vgenesis. 5• 6& q  l3 \  s' ?, f/ F8 J# S
Administration of larger doses of gonadotropin or systemic
8 C! X8 r) j) z2 N. E& a/ @testosterone, as well as topical applications that produce
# D0 B' f! z* C6 F) ahigher levels of serum testosterone (150 to 900 ng./dl.), will1 I/ V3 k0 Q" K. P0 t% [9 M
also produce phallic growth but risks accelerated skeletal2 Q9 O, ^3 b' j$ H
maturation even after stopping treatment. It would appear( e2 R& p- |  r6 x. a
that this may be avoided by topical applications of testosterone% f3 I, r4 A4 j9 h9 v, Q* ?! o
and monitoring of serum testosterone. Even with this control
# L8 k0 E. C6 I; Hthe duration of our therapy did not exceed 3 weeks at any
- H/ j) B* V( Q& Z- ?5 I, L& y5 @; I6 ltime. It is apparent that the prepuberal male subject may
  f- X& W- i3 m9 f, U, esuffer accelerated bone growth with testosterone levels near
* j0 E2 D; v, w) {5 |1 k( g200 ng./dl. When skeletal maturation is complete the level of
" v: b( Z3 ^; V2 M; }serum testosterone can be maintained in the 700 to 1,300 ng./
/ o' V8 x% X+ Fdl. range to stimulate phallic growth and secondary sexual5 ]' i2 f8 ?4 {& j$ {+ X
changes. Therefore, after skeletal maturation parenteral tes-! w5 d8 H: [9 k+ Y0 _
tosterone may be used to advantage. Before skeletal matura-
. U7 r2 j( \! W# n) Z; V8 ~tion care must be taken to avoid maintaining levels of serum
2 \% F" W3 \2 Ktestosterone more than 100 ng./dl. Low-dose gonadotropin
% `; u  o( R7 p- \depends upon intrinsic testicular activity and may require/ @* Z' `" _" L" U& B% x( ]$ h
prolonged administration for any response.
6 n& ~* \$ k% y; F3 ?5 q$ F& FAlternately, topical testosterone does not depend upon tes-/ }, E' Q! k+ ^: z) `! d; R! {
ticular function and may provide a more constant level of: T1 i% s6 X# {+ J& B2 B5 K
REFERENCES& |2 J0 b/ O+ V: I$ }
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
! I% E& V: J4 `R.: The local application of testosterone cream to the prepub-
9 e& ?3 m# e3 R4 y. R- hertal phallus. J. Urol., 105: 905, 1971.
- M: F. w* N5 P3 I# ?& V2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- h: H" s+ ]# T8 H9 O8 `4 @1 P/ N
treatment for micropenis during early childhood. J. Pediat.,0 R, A6 X' v$ i5 i+ V+ G
83: 247, 1973.
; @4 k$ c  w8 X5 d! v" L) b3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( N  A' d) Z  }" J. M" r
one therapy for penile growth. Urology, 6: 708, 1975.
3 g% }7 U5 V' d3 e4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 c9 k2 X- d: E* N( Y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by4 S% L+ J' c. s* u1 d
skin slices of man. J. Clin. Invest., 48: 371, 1969.  @9 d5 G& G6 a- f7 s
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 [$ G* W3 l8 `% Y5 G: W% x% h
by topical application of androgens. J.A.M.A., 191: 521, 1965./ h' E" r& ]2 v6 B7 ^9 P
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, I% g5 ]) `( ]) H
androgenic effect of interstitial cell tumor of the testis. J.2 b; A1 X) o) ~+ N
Urol., 104: 774, 1970.' q$ m+ ~6 Z4 ]* O9 x9 p% L
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& r% B; `6 u" R/ N) f4 }tion in the male genitalia from birth to maturity. J. Urol., 48:
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