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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND  s; b# w* n0 ]3 Q& g
GONADOTROPIN
& l% A9 K, F' v8 z& B. t$ ERICHARD C. KLUGO* AND JOSEPH C. CERNY
; s4 f* J2 b# w6 p5 L. ^0 GFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ C: Z3 x8 c2 {( q7 G) ~) }& q" oABSTRACT
6 @7 ]. T8 y) |Five patients were treated with gonadotropin and topical testosterone for micropenis associated5 [3 T9 {! S0 h1 ]
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
0 C" j9 k4 b! t# F' h% K5 Gtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone( H- j$ C# h' f5 j2 O+ ^
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
# Y7 ^. R* M# F+ r. v) ffor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! F6 K, w  _7 w
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
* w% P5 t+ r0 \5 _& a& |increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
  g9 b$ j: \! r: `* q! b' N% moccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 @$ I( i5 L  \$ x" t" A
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
  T1 \6 k. I% a! agrowth. The response appears to be greater in younger children, which is consistent with previ-
8 E, j6 A9 p6 k! cously published studies of age-related 5 reductase activity.9 N' r4 k2 ]& T& J3 @6 S7 y" U% j
Children with microphallus regardless of its etiology will" k+ |" n' A) F0 v1 L8 s: E4 T
require augmentation or consideration for alteration of exter-, F9 d) _5 \3 X0 o( T* y9 N% G' u
nal genitalia. In many instances urethroplasty for hypo-' N) Q  S# Q5 J$ ]8 x6 _
spadias is easier with previous stimulation of phallic growth.
  B( N, C: z. O0 _; oThe use of testosterone administered parenterally or topically
+ L6 o& E- c% \has produced effective phallic growth. 1- 3 The mechanism of8 [9 G# _0 [7 y( M0 k
response has been considered as local or systemic. With this4 |9 O! S; t8 m% i3 G
in mind we studied 5 children with microphallus for response7 F. a0 A0 K" X5 ?9 d8 ~2 H
to gonadotropin and to topical testosterone independently.) f; c2 i% K1 |
MATERIALS AND METHODS
& y! k( o- \- G5 ZFive 46 XY male subjects between 3 and 17 years old were( w' l. y# k& y- n% h" N* U
evaluated for serum testosterone levels and hypothalamic
1 [. |: q. d3 b4 q% T( Y% c. ~! {function. Of these 5 boys 2 were considered to have Kallmann's
2 T+ r3 ~' q) G3 Q( Z0 Nsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-. R& U6 O$ c7 v# w/ O9 E
lamic deficiency. After evaluation of response to luteinizing
2 u' O0 ~7 B5 d& dhormone-releasing hormone these patients were treated with
3 y& m! Y* i9 X7 E) k1 N1,000 units of gonadotropin weekly for 3 weeks. Six weeks
$ g6 ?/ h7 w; J; u/ |; hafter completion of gonadotropin therapy 10 per cent topical
# }- n+ `% q5 h  }2 w3 H7 T# {$ gtestosterone was applied to the phallus twice daily for 3 weeks.$ Z' ?9 A, ~! N1 h& @
Serum testosterone, luteinizing hormone and follicle-stimulat-4 O1 m8 R' L. U  z: \, T4 b; O
ing hormone were monitored before, during and after comple-
7 m+ O1 l8 c; g7 r+ ]tion of each phase of therapy. Penile stretch length was
; r% A: ^0 c) Yobtained by measuring from the symphysis pubis to the tip of
, q8 j7 H: ^: kthe glans. Penile circumferential (girth) measurements were6 r' @# k; C- T. k" O' @8 O
obtained using an orthopedic digital measuring device (see
! }! w- x" ?; |) S8 x$ M  Yfigure).
. D# l- o! R7 Y3 DRESULTS' n) C  e# z) a, q9 i# r
Serum testosterone increased moderately to levels between
; B& H" l$ w1 l" v! |50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ J4 Y0 u& {8 q( R+ w3 z
terone levels with topical testosterone remained near pre-" V# t+ K: w9 E* t! u# ^0 Y: h
treatment levels (35 ng./dl.) or were elevated to similar levels' U( {+ `* O) f. i
developed after gonadotropin therapy (96 ng./dl.). Higher
  e5 E9 h7 k5 |7 wserum levels were noted in older patients (12 and 17 years old),6 ?# g, D7 q- @' J" \: h9 i
while lower levels persisted in younger patients (4, 8, and 10
- O: @! Q, [' E4 N7 x  x+ Y; X4 Iyears old) (see table). Despite absence of profound alterations7 h# z6 S* O2 \4 O' K9 N2 ^
of serum testosterone the topical therapy provided a greater
6 R% G/ x( n$ S- C+ @8 O' KAccepted for publication July 1, 1977. ·
5 V! R& x; e6 B  d' ~; oRead at annual meeting of American Urological Association,
; g) `6 N& R4 T2 t; b" b& QChicago, Illinois, April 24-28, 1977.
( f3 A" _- [1 @# a" Y3 B4 X# _* Requests for reprints: Division of Urology, Henry Ford Hospital,$ ~- e, i3 u# x# d
2799 W. Grand Blvd., Detroit, Michigan 48202.
4 _0 D3 Y6 L) n0 aimprovement in phallic growth compared to gonadotropin.
, C% `0 \3 N: u9 C: k" \9 o5 HAverage phallic growth with gonadotropin was 14.3 per cent2 d4 _/ j6 J# B! J- m% D& V
increase in length and 5.0 per cent increase of girth. Topical
/ {& v0 k- F* utestosterone produced a 60.0 per cent increase of phallic length, a# w; `$ g: E3 c/ w0 q0 N$ A
and 52.9 per cent increase of girth (circumference). The8 w5 ?% g0 {1 A/ c: R
response to topical testosterone was greatest in children be-$ p2 d' ]4 m. O; H) G# ~
tween 4 and 8 years old, with a gradual decrease to age 17( z, k: ~2 `+ _- C% l. A8 `3 i
years (see table).
' E7 D, u% O5 z( ~5 E; D' DDISCUSSION7 G" H1 K. a+ c8 U% O/ ~2 `. O1 ?
Topical testosterone has been used effectively by other
% E) u: }8 B' `7 L. Aclinicians but its mode of action remains controversial. Im-/ Q" C( T9 V8 y& F+ ^
mergut and associates reported an excellent growth response7 r7 h4 n$ d/ E+ s$ Z6 D$ U+ a
to topical testosterone with low levels of serum testosterone,
) z* z5 v! S$ K0 D) G. bsuggesting a local effect.1 Others have obtained growth re-: K* l, ?& x6 C0 S0 m* N. n# D
sponse with high. levels of serum testosterone after topical1 t& `1 u' P" K+ E1 j
administration, suggesting a systemic response. 3 The use of
6 o$ v& P- b& F) \4 s8 f. X6 Lgonadotropin to obtain levels of serum testosterone compara-
$ c" K5 [1 p. [( t6 Sble to levels obtained with topical testosterone would seem to$ Q5 E9 g% `9 B" E
provide a means to compare the relative effectiveness of) r+ ^% ?; S( K8 L$ S# J! X7 r5 i
topical testosterone to systemic testosterone effect. It cer-
4 H; o0 U3 `& ?& h7 Y  I/ ]tainly has been established that gonadotropin as well as par-$ p9 r9 u; V/ l1 z7 j
enteral testosterone administration will produce genital9 h* L9 p, N3 ~
growth. Our report shows that the growth of the phallus was
9 O4 |2 M, C0 R+ }significantly greater with topical applications than with go-5 h3 r  M& L3 j5 P( F3 P" U8 v! N
nadotropin, particularly in children less than 10 years old.: {% T; _5 f2 e. O* ~' p, U8 m/ h
The levels of serum testosterone remained similar or lower
: O/ [$ }# y1 {3 Sthan with gonadotropin during therapy, suggesting that topi-; [' i/ M; n' @3 {9 F5 N
cal application produces genital growth by its local effect as
3 E1 R" r6 U0 D4 n$ K) M6 X' O: twell as its systemic effect.% Z- D( |# W8 Q+ J2 [+ @1 j
Review of our patients and their growth response related to
- B( \" M/ @2 X' Q! w7 Wage shows a greater growth response at an earlier age. This is
! C! t& ^) p) E* D0 iconsistent with the findings of Wilson and Walker, who
! l2 W9 m& r) _1 k2 f/ [( \% }+ `  d. ~reported an increased conversion of testosterone to dihydrotes-
2 ~& H  r% E. Q& Y9 @; ttosterone in the foreskin of neonates and infants.4 This activ-
# @9 o1 V1 y6 a9 s# city gradually decreases with age until puberty when it ap-3 H8 E! L/ e! ^# @; D  a7 }8 h9 w5 t
proaches the same level of activity as peripheral skin. It may* u, X# f( J: Y: d) y8 A
well be that absorption of testosterone is less when applied at
2 ~$ T1 T  [% Y1 ?4 U8 |; D' Xan earlier age as suggested by lower serum levels in children
! w. n, f# n. v$ w! `# S) Q9 n0 hless than 10 years old. This fact may be explained by the
% \3 j' C9 S1 }& Z; Z  Tgreater ability of phallic skin to convert testosterone to dihy-% u0 v8 q0 w" R, p/ N+ ]1 z
drotestosterone at this age. Conversely, serum levels in older9 \0 m' |0 }/ x" o
patients were higher, possibly because of decreased local
# s5 A/ u% |, {7 t' X667
% V3 L2 I5 V/ s" S668 KLUGO AND CERNY
  p0 M6 t7 [  w# z8 G. i' X4 p7 M2 J6 HPt. Age
8 U0 \% a2 v4 ^2 w) ?(yrs.), s( a; R9 |8 d; f+ }
Serum Testosterone Phallus (cm.) Change Length
- A& ~% i! g+ F& K(ng./dl.) Girth x Length (%)
( S' z/ {; O: ?1 C4
+ X+ B* h6 ~' `/ ]; r9 a5 `88 \. l3 o! O+ B5 \/ C3 J4 j; ~
10
& j, f% T  W) i9 `8 w129 L% u% x1 x) V* P8 B8 h1 }4 N
17# ]7 O2 D+ n3 V9 E8 w- k, q9 d$ _
Gonadotropin
7 O/ H: m6 b4 V; z4 g71.6 2.0 X 3 16.6% y: I/ @) |; o
50.4 4.0 X 5.0 20.0
$ ^% ~' j. b2 Z* P8 O22.0 4.5 X 4.0 25.0
2 C. |+ _, @$ Z. f84.6 4.0 X 4.5 11.11 P. }8 S' {  ?- J! m6 i: o
85.9 4.5 X 5.5 9.0* ]5 H) H( ^9 C+ x' O; ?
Av. 14.3! T0 d6 I6 n+ e6 h; E$ V
4, G. Q, B! ~8 L9 i
8) s5 Y4 E1 {7 ^1 x& Z  R+ \
10
9 u& y: ~- e+ }& G* s12
* H" J4 w; m0 S4 B17# P% M* J% G0 K& n2 j
Topical testosterone
) }3 a+ M9 p1 l" F34.6 4.5 X 6.5 859 H0 i7 l! e( k: h
38.8 6.0 X 8.5 70% J3 I( I+ W4 S# l. U- C
40.0 6.0 X 6.5 62.5
# P  R  a' R0 o: ?93.6 6.0 X 7.0 55.5  s0 U# F6 N! Q, R& V/ d  ]
95.0 6.5 X 7.0 27.2
7 }, _; u. ^) r1 VAv. 60.02 C' e* G" o' [* t. [- R- l
available testosterone. Again, emphasis should be placed on. P; d; j* D+ D4 `
early therapy when lower levels of testosterone appear to' M! r: h9 j. C* f. h
provide the best responses. The earlier therapy is instituted8 [  |5 |* X6 U$ ~$ R9 e
the more likely there will be an excellent response with low
  @- w% ~. \. H$ Pserum levels. Response occurs throughout adolescence as* c# x5 A4 W- J: G' d# z2 ?3 A8 P
noted in nomograms of phallic growth. 7 The actual response& I- N1 `2 n. L
to a given serum level of testosterone is much greater at birth; ~0 m& E9 b  S, u) ^
and gradually decreases as boys reach puberty. This is most
  K5 D8 `. a4 C% r  ?! ]* y6 Z0 hlikely related to the conversion of testosterone to dihydrotes-) Y$ _! p  P: \5 p' }( ~
tosterone and correlates well with the studies of testosterone( @& U5 M  B% [! U
conversion in foreskin at various ages.% ^; e8 q3 Y; c1 d1 G4 P! `
The question arises regarding early treatment as to whether& k# a  q3 x2 ]" x4 O
one might sacrifice ultimate potential growth as with acceler-2 [) {; S; w* y6 |' y2 e" A
ated bone growth. The situation appears quite the reverse2 z8 r, k  C2 N% A0 p, d
with phallic response. If the early growth period is not used
8 s4 L( w8 y+ ?6 Y- e- I$ kwhen 5a reductase activity is greatest then potential growth
- b9 [; ^7 Y5 cmay be lost. We have not observed any regression of growth
; m/ f7 |$ r5 w9 E% {attained with topical or gonadotropin therapy. It may well; K1 v, v" H0 J. _' s
be that some patients will show little or no response to any7 L4 H- f4 ~: n3 y
form of therapy. This would suggest a defect in the ability to! y2 w2 F9 n6 f+ O) d  H
convert testosterone to dihydrotestosterone and indicate that
% a7 M( C7 P" \7 I. Dphallic and peripheral skin, and subcutaneous tissue should- a$ J  A% l  m) n& F0 |3 U% d
be compared for 5a reductase activity.
: k; d* ~; n* u2 z: I' iA, loop enlarges to measure penile girth in millimeters. B,
4 O) r7 \" g. I, c3 X- Vexample of penile girth computed easily and accurately.7 I' G5 }9 [% v# k" J& s  {
conversion of testosterone to dihydrotestosterone. It is in this
: |+ \; J& `  ^7 K% k1 g$ }older group that others have noted high levels of serum3 W& c9 z) F5 `3 B' q9 I! o0 c- n
testosterone with topical application. It would also appear
  M) D+ t  w$ a6 U. h1 O9 _6 Kthat phallic response during puberty is related directly to the
( I9 Q2 [& p7 W. u+ l# }serum testosterone level. There also is other evidence of local
0 I% C' o+ L1 k- V9 F4 w5 V" Eresponse to testosterone with hair growth and with spermato-
; o6 e) ?. T: D* v5 v* G/ k$ Rgenesis. 5• 6
9 e/ D- r# S& v1 AAdministration of larger doses of gonadotropin or systemic
  `/ X3 p% Z+ @1 ttestosterone, as well as topical applications that produce3 {7 L( E  F  f
higher levels of serum testosterone (150 to 900 ng./dl.), will1 d. k6 {/ a- K6 P1 U3 X
also produce phallic growth but risks accelerated skeletal
% u  q- K+ p2 C. H! Cmaturation even after stopping treatment. It would appear
( z- E, h: W5 P5 \  R0 Rthat this may be avoided by topical applications of testosterone5 K1 m" ?5 O, }- O
and monitoring of serum testosterone. Even with this control# ~0 }3 ]; R  E; [2 V
the duration of our therapy did not exceed 3 weeks at any$ l7 N7 x6 I7 w7 {, @" Z5 e# W5 _
time. It is apparent that the prepuberal male subject may
  v, @" W  @" O/ D3 p6 V2 csuffer accelerated bone growth with testosterone levels near
0 z3 P- W& g% f4 E200 ng./dl. When skeletal maturation is complete the level of
8 s# O/ f  V6 c9 f) @serum testosterone can be maintained in the 700 to 1,300 ng./( M- ]1 m' k+ j* S! a' B+ M
dl. range to stimulate phallic growth and secondary sexual
9 \( L' m" F) Ochanges. Therefore, after skeletal maturation parenteral tes-
" b7 p( |! P" d$ F6 ptosterone may be used to advantage. Before skeletal matura-/ c- j9 z" ^. v, Q# R
tion care must be taken to avoid maintaining levels of serum
1 @0 R, t' G9 L% ]+ {testosterone more than 100 ng./dl. Low-dose gonadotropin4 ]+ J# v1 l# I* |: g: D, r
depends upon intrinsic testicular activity and may require
; C/ g' x' b5 L- t( l- }prolonged administration for any response.0 K4 n1 ]/ n% i6 F! m- X. Y( \
Alternately, topical testosterone does not depend upon tes-
" A2 u* O* ~# j% R( O. I4 W) Iticular function and may provide a more constant level of+ A8 j2 c0 z8 |8 T8 H* B
REFERENCES3 K9 d- z* h6 s& x
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' M8 x1 g- d: o" r2 ?
R.: The local application of testosterone cream to the prepub-
0 D0 H# k+ B- E; Rertal phallus. J. Urol., 105: 905, 1971.
# \0 g- v  G, @" q# j  H2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
+ c. ~6 q* R1 b# S9 _$ [3 X: otreatment for micropenis during early childhood. J. Pediat.,
5 d) h* k  y' h83: 247, 1973.. Y2 T! ^' A' ?( V
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 K  T/ |8 t* f' S) Y- Gone therapy for penile growth. Urology, 6: 708, 1975.
* q5 \4 W: r4 d+ k6 M1 x4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone# p8 G9 R, Z$ P2 [; o- b
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 @: x* G$ i0 a2 B- n! O2 H) R9 qskin slices of man. J. Clin. Invest., 48: 371, 1969.9 x+ X" a3 R: M+ T% N: L
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, [" t! K% A2 H7 c4 wby topical application of androgens. J.A.M.A., 191: 521, 1965.
* W' o8 h; V4 l; A' |0 E6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 C: q* r$ {, L/ S+ h# E0 E( ]androgenic effect of interstitial cell tumor of the testis. J.& o( a- O9 g8 D! b2 J
Urol., 104: 774, 1970.3 f) R) |! \" b5 g3 B2 F! e4 P) D
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; a& \, e" M; Z" a- E  {tion in the male genitalia from birth to maturity. J. Urol., 48:
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