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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
. `/ h" k7 E5 S5 X% ?GONADOTROPIN& m% m/ \0 j  j" {  i8 u: h0 B) i& @9 z
RICHARD C. KLUGO* AND JOSEPH C. CERNY
+ ^9 j! ~. N) L9 e% d" n6 P5 {8 }From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 M4 ^# `* ~  ]' O+ Z$ U% C. TABSTRACT6 }3 a/ J! Y" w8 }0 ]8 j
Five patients were treated with gonadotropin and topical testosterone for micropenis associated3 ?; w3 K# g$ ^% N/ Y/ X- x
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 y6 z" b6 N1 O" Z) z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 h( X1 b2 @! g- \1 c4 Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. D# Z+ D1 Q/ _* P1 s4 ^/ y
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 i7 i, H, v0 D% l+ [increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average" Q" f) a; R3 X$ ]% S* I
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ q% T$ y! {. x( O/ Poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 B, u- G8 O  Q8 O8 j% vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
9 m5 z3 e! ]8 V/ i& egrowth. The response appears to be greater in younger children, which is consistent with previ-
5 I( ?5 [) b: N/ Y2 rously published studies of age-related 5 reductase activity.
$ w% T- q, `# E( h' |. \Children with microphallus regardless of its etiology will
. ?8 }3 ~  W* x% |4 x0 X. r- Qrequire augmentation or consideration for alteration of exter-
& ^8 W/ x, t" m* {0 }nal genitalia. In many instances urethroplasty for hypo-
7 p! ?+ h+ ^* I' S( Vspadias is easier with previous stimulation of phallic growth.4 y1 m1 Y* N* E) @/ ^% x
The use of testosterone administered parenterally or topically  M" Z! f" B+ |+ q
has produced effective phallic growth. 1- 3 The mechanism of  r! l8 u4 o) y0 G7 ?
response has been considered as local or systemic. With this
- X: o* N9 [. Yin mind we studied 5 children with microphallus for response
: f& u/ M+ p5 I9 Y$ N2 nto gonadotropin and to topical testosterone independently.
3 ?  a5 x3 k5 K) a6 dMATERIALS AND METHODS
/ r: e$ ~/ k; t% a3 u/ ?  D& DFive 46 XY male subjects between 3 and 17 years old were
. x/ O# i  r6 ^( E4 O: Xevaluated for serum testosterone levels and hypothalamic) Q/ g3 a- _& M, M
function. Of these 5 boys 2 were considered to have Kallmann's
; x5 N( {: @7 r& @; U2 f; zsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-) B6 ?7 n  e. i, ]
lamic deficiency. After evaluation of response to luteinizing! m& G7 g# d1 @: m& {# v, F. w
hormone-releasing hormone these patients were treated with& \+ e1 |3 ?$ Y/ d/ U* b
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 x5 L' c& w) Z4 }after completion of gonadotropin therapy 10 per cent topical. K' W8 `8 I0 C  o9 L
testosterone was applied to the phallus twice daily for 3 weeks.! Q, k5 A2 a) G, T* ~
Serum testosterone, luteinizing hormone and follicle-stimulat-1 ^! ~- G' I5 r! V' [4 G* {' a
ing hormone were monitored before, during and after comple-6 l( D5 y  L2 {! C
tion of each phase of therapy. Penile stretch length was
* I# J/ t2 y" p% \8 Qobtained by measuring from the symphysis pubis to the tip of! {: x0 I0 l/ P/ Z/ p- ^* V
the glans. Penile circumferential (girth) measurements were  B2 C6 t4 @6 ]
obtained using an orthopedic digital measuring device (see$ C8 l- y8 m( P6 ]- s; G; l' H
figure).' U' [2 o' {5 q8 |" T2 ~/ ~. F
RESULTS
3 P+ f# l+ y# J/ t! K0 g% m# ^, s' BSerum testosterone increased moderately to levels between0 `3 O, q' b7 J8 x  W
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 B  ^& I0 ]: Aterone levels with topical testosterone remained near pre-$ c9 B7 j; C  J" _/ Y- l+ Z
treatment levels (35 ng./dl.) or were elevated to similar levels  @; D3 E! ~) M+ d# @0 a
developed after gonadotropin therapy (96 ng./dl.). Higher! S4 I3 \" e. N5 j" o
serum levels were noted in older patients (12 and 17 years old),
* v" f+ Z" L& Y1 \6 H( `while lower levels persisted in younger patients (4, 8, and 10
7 ]) e: y7 {; h6 P$ Gyears old) (see table). Despite absence of profound alterations* q/ X5 K! N) P' Z
of serum testosterone the topical therapy provided a greater1 H5 \1 Q6 `9 ?. @0 ~, Y0 r; h
Accepted for publication July 1, 1977. ·+ C- ^+ J# d$ ?: p9 n0 F; V3 }
Read at annual meeting of American Urological Association,( f2 l: E2 v1 h: B- S; V( d- @
Chicago, Illinois, April 24-28, 1977.2 I& g, M: @7 C2 B$ U2 T
* Requests for reprints: Division of Urology, Henry Ford Hospital,
' N7 p! n) J3 X. Y* U2799 W. Grand Blvd., Detroit, Michigan 48202.
- }4 E7 n, s! qimprovement in phallic growth compared to gonadotropin.
3 y2 @) j. r8 O" C5 M" c, f. WAverage phallic growth with gonadotropin was 14.3 per cent5 Q' o6 [) H' _& e+ S6 I
increase in length and 5.0 per cent increase of girth. Topical
5 Z3 |4 V- ~) Gtestosterone produced a 60.0 per cent increase of phallic length+ H& T  b* O7 k# c- H4 e4 C" W
and 52.9 per cent increase of girth (circumference). The
- c  u) ?4 m8 C" z9 K' Wresponse to topical testosterone was greatest in children be-8 l+ e( g5 o) `& w+ w" j: R/ `& a5 u
tween 4 and 8 years old, with a gradual decrease to age 17
5 s2 v+ T5 N* ?& Q/ w1 P; syears (see table).1 G( C# d9 B2 K- J
DISCUSSION0 \- d* B. `1 L" Z! ~: B! K, D4 G3 w
Topical testosterone has been used effectively by other' W* ^6 W& E3 e( w
clinicians but its mode of action remains controversial. Im-
0 E7 F- F: e- L2 o2 Imergut and associates reported an excellent growth response
1 y; M( F& v, N+ r9 Hto topical testosterone with low levels of serum testosterone,: A; F& }6 j( B, |/ [; r
suggesting a local effect.1 Others have obtained growth re-
  ?, h/ l! G1 |. i7 Hsponse with high. levels of serum testosterone after topical
( L1 r, e$ I  ^. K6 eadministration, suggesting a systemic response. 3 The use of
+ X! \2 x8 Y: ]3 r+ [6 ~$ h3 Dgonadotropin to obtain levels of serum testosterone compara-
6 C% o! ~( g$ X8 }ble to levels obtained with topical testosterone would seem to' h) i  Q# h+ ^8 G5 K
provide a means to compare the relative effectiveness of) M/ ~3 q0 B9 B$ I+ A
topical testosterone to systemic testosterone effect. It cer-2 J" X6 q* a* x: u, N
tainly has been established that gonadotropin as well as par-
1 F7 I  H5 A& K) e1 f; m4 |  }enteral testosterone administration will produce genital. s1 s. Q1 x( \9 h2 ~# y3 A$ Z
growth. Our report shows that the growth of the phallus was
/ Y4 ^% [' o/ m, m8 qsignificantly greater with topical applications than with go-
6 X  _. l% ^2 c& d: enadotropin, particularly in children less than 10 years old.! J0 o3 W( [1 W. j. N* @
The levels of serum testosterone remained similar or lower
1 J6 g. U% y" q8 tthan with gonadotropin during therapy, suggesting that topi-. f# Q' {" g2 p/ u3 D8 ?/ o2 y! V
cal application produces genital growth by its local effect as6 C; s5 H% V- c
well as its systemic effect.
) h# a( Q+ V6 z4 k- n9 j  ~Review of our patients and their growth response related to" \/ f# ], H3 l% b; ?
age shows a greater growth response at an earlier age. This is8 ^! \& u4 v3 v; a1 l5 Y8 j0 e# [% a
consistent with the findings of Wilson and Walker, who1 }$ b$ [/ K7 f2 q1 H
reported an increased conversion of testosterone to dihydrotes-
* f- z" m% M8 ~3 T7 @tosterone in the foreskin of neonates and infants.4 This activ-% a1 W3 p/ `- w1 v
ity gradually decreases with age until puberty when it ap-
3 t; w* Y: n" `1 a7 ~7 Iproaches the same level of activity as peripheral skin. It may- E- p4 }0 Z- q9 p% q
well be that absorption of testosterone is less when applied at
! i# U6 h% u- b5 e# aan earlier age as suggested by lower serum levels in children: i2 ]! V3 i$ B9 j! C4 ]/ r/ `
less than 10 years old. This fact may be explained by the
& i) C+ ^! }0 N# Z6 _6 b" C3 }greater ability of phallic skin to convert testosterone to dihy-
, K4 E( p* h( Wdrotestosterone at this age. Conversely, serum levels in older7 E; _. p1 D7 a3 c8 t( y
patients were higher, possibly because of decreased local
0 K4 u( g* v8 g: F; u' ?667
) t* d) d) ?9 n668 KLUGO AND CERNY$ M- \) J% Q# f4 U# G* T9 P
Pt. Age% i$ W2 g; z& f4 }$ M1 b) q* \. E2 l
(yrs.)
/ t1 w1 O1 V$ }- LSerum Testosterone Phallus (cm.) Change Length
% V% l4 i5 H$ e! [- W9 e# `% e" \(ng./dl.) Girth x Length (%)8 s$ t$ O+ C1 \: a. e
4
& H4 w5 W, E/ Y$ W1 R: \( i8! _7 u+ O) ]$ g. I( N7 \8 f6 B
109 @2 \. u% w7 p2 [. `. p# y  U
12
& ]  l( s7 o* Y17- j' ~  j3 [" `3 L( L+ S" x
Gonadotropin
# D; o! A( L0 O0 e7 w: \8 Y, @. u9 B71.6 2.0 X 3 16.6% K1 [$ ^% t) q2 `' r1 H
50.4 4.0 X 5.0 20.0  {1 J, \. g' d) j5 Y" I
22.0 4.5 X 4.0 25.0$ c( B- r8 m% f6 V1 p. V/ o& z
84.6 4.0 X 4.5 11.1& L( ]2 }. \  k& O
85.9 4.5 X 5.5 9.0$ x( R" [! F0 z1 w' w! u
Av. 14.3: W8 x& t6 Q/ J8 M6 _
41 o' G" O# P( B4 e
8$ b" O5 N( S6 t% H5 p" J
10
8 H- H' P' h$ h12
1 W% n& j& p: h; {% r; J' n17
1 {! r' l4 v- {8 j+ y' i* q1 S4 WTopical testosterone- K; M0 ]$ i4 {6 \7 e7 q
34.6 4.5 X 6.5 85
* C3 p+ P, C* T' f2 Z/ \' N38.8 6.0 X 8.5 70, {" X8 h% @* x1 V# [) r
40.0 6.0 X 6.5 62.5
/ u. o. B8 i$ d& n% C- U93.6 6.0 X 7.0 55.5/ H  W( q2 Y1 X0 n5 A! A& ^
95.0 6.5 X 7.0 27.2
* `: m: N+ a+ j7 T4 f. y! g1 _! VAv. 60.02 Z8 m, L/ N; }' v4 d3 r
available testosterone. Again, emphasis should be placed on
: F4 q, y9 k  r4 e# bearly therapy when lower levels of testosterone appear to
3 o. A( q* e' ~) V/ T& P5 }% A1 Uprovide the best responses. The earlier therapy is instituted
0 T5 J' b5 m* M9 t; Z% ^the more likely there will be an excellent response with low
/ f% e. S: v7 V8 Fserum levels. Response occurs throughout adolescence as. m( A0 ~0 k+ c+ J
noted in nomograms of phallic growth. 7 The actual response& R4 G& A1 S$ J; |6 v. R7 d* E
to a given serum level of testosterone is much greater at birth( Q5 [1 n  @1 W) U, [
and gradually decreases as boys reach puberty. This is most* u0 A/ U, `' V5 C# N$ l9 y- W7 C
likely related to the conversion of testosterone to dihydrotes-: b0 U! q& g: g& s" Z
tosterone and correlates well with the studies of testosterone; b0 N$ H, y9 o' q
conversion in foreskin at various ages.+ G1 e7 ^3 J" [
The question arises regarding early treatment as to whether. d+ e) F- N' U% [+ ?
one might sacrifice ultimate potential growth as with acceler-
' ~9 A1 `  ~! B. g: e3 k7 Vated bone growth. The situation appears quite the reverse
) E: p6 h" d5 c3 x) m6 n& iwith phallic response. If the early growth period is not used1 v  [2 G2 `2 G
when 5a reductase activity is greatest then potential growth$ t( {( @" c! v
may be lost. We have not observed any regression of growth
' S' W+ P( B  m2 h0 Uattained with topical or gonadotropin therapy. It may well
! ~, L& c  c. F: Y* Z- Nbe that some patients will show little or no response to any  S' @+ Z- V) D; x0 \0 }, s0 r" N1 [
form of therapy. This would suggest a defect in the ability to# i8 B3 M  B( d/ ]- ]) _. ]# J
convert testosterone to dihydrotestosterone and indicate that
7 z) J$ F1 b2 _9 w* V, g; xphallic and peripheral skin, and subcutaneous tissue should7 X  B  y' |: D4 V
be compared for 5a reductase activity.0 P4 ?' t+ j# r1 Y2 ], ~" ^- w# q
A, loop enlarges to measure penile girth in millimeters. B,% b# j& A( h9 p; {  g
example of penile girth computed easily and accurately.+ ~$ C. c9 t* E# z
conversion of testosterone to dihydrotestosterone. It is in this- C4 k: }# p, M% ]' ~3 W
older group that others have noted high levels of serum( s4 q# Y4 J! E9 M: Q, f* }
testosterone with topical application. It would also appear5 X' E9 l: ?$ p
that phallic response during puberty is related directly to the
, T+ V) v8 R! K% l; l7 ~serum testosterone level. There also is other evidence of local
' y) U6 t" v( ]5 K, H" oresponse to testosterone with hair growth and with spermato-5 l# r" ?7 e" E* T7 R3 X
genesis. 5• 6! {: |( q" @, n8 @  F9 C2 ~7 J# b
Administration of larger doses of gonadotropin or systemic
6 a& W8 L# J; @, j$ T& mtestosterone, as well as topical applications that produce
1 L/ J4 b" @' g1 I/ ^/ r, rhigher levels of serum testosterone (150 to 900 ng./dl.), will
9 q3 F6 j5 r' O7 R( K; Palso produce phallic growth but risks accelerated skeletal
- E# J% L" a' w* Nmaturation even after stopping treatment. It would appear
% M, x1 ~7 H2 c  |6 ~* X$ uthat this may be avoided by topical applications of testosterone
! j. Q$ p1 H/ v* i* m3 a" ~and monitoring of serum testosterone. Even with this control
. m, B! m1 x1 J/ gthe duration of our therapy did not exceed 3 weeks at any
, m2 S/ l, ~2 h" C4 ~$ P' Btime. It is apparent that the prepuberal male subject may8 |4 u3 d  c5 y( T- C; q
suffer accelerated bone growth with testosterone levels near" I9 o+ g' {" E7 U
200 ng./dl. When skeletal maturation is complete the level of
. |9 A- j$ S0 \$ Jserum testosterone can be maintained in the 700 to 1,300 ng./- m+ i$ p( M, G
dl. range to stimulate phallic growth and secondary sexual( E8 M. p! y7 S4 {7 z) x
changes. Therefore, after skeletal maturation parenteral tes-
- `& n7 I/ [1 _* Q9 p& jtosterone may be used to advantage. Before skeletal matura-, ~2 F" ]+ Z( C1 x5 O# s  u
tion care must be taken to avoid maintaining levels of serum: z! |! T8 u1 d6 C% ?
testosterone more than 100 ng./dl. Low-dose gonadotropin! v" M1 ?: ^- E# [& ]+ h
depends upon intrinsic testicular activity and may require
3 e7 ?2 c. _! ?/ Z3 P3 U  Dprolonged administration for any response./ S$ R/ J- e3 v
Alternately, topical testosterone does not depend upon tes-, e$ `6 ~: W+ S9 C
ticular function and may provide a more constant level of
. `) {7 z! P: ~4 rREFERENCES& F8 c$ I6 q$ w( u$ c. D. W5 ^, M. z
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,0 u1 c, E1 `9 Y
R.: The local application of testosterone cream to the prepub-
6 D4 T1 h" Y* K) qertal phallus. J. Urol., 105: 905, 1971.  o& B- C. r. V7 d6 F. _
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 Q7 D$ J0 [1 j/ t0 w3 rtreatment for micropenis during early childhood. J. Pediat.,
% W7 r) A$ I4 G# Y1 G+ u" Z: v83: 247, 1973.
6 N. Y% a6 K. N  |3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-" A, K* u1 o* ~( w  O
one therapy for penile growth. Urology, 6: 708, 1975.0 X: ]4 _. b1 {# P( K& W5 D  Y, v
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone  ?! |! `$ K, _( k
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by9 s# c& r! q) Z/ Y9 o7 {! [
skin slices of man. J. Clin. Invest., 48: 371, 1969.
. L  t  R* ?4 ~6 l9 d# e5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 h4 M2 n% x: J0 Cby topical application of androgens. J.A.M.A., 191: 521, 1965.
0 J+ }9 a  s9 t+ Y; l6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. N" w/ A3 L$ W; r7 K% A) Q% |androgenic effect of interstitial cell tumor of the testis. J.
% |( E9 ~2 g: k5 CUrol., 104: 774, 1970.
# \! O$ x4 i- m  @4 c0 J7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-3 D5 W# |+ [& {# C& O" u4 J) y6 q
tion in the male genitalia from birth to maturity. J. Urol., 48:
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