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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 z" p# e9 A/ k0 @$ I' F# |GONADOTROPIN1 e$ ^. d! z$ c+ n9 G5 i, a  a
RICHARD C. KLUGO* AND JOSEPH C. CERNY
& i! ]# D; ], N7 iFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' g2 p( a) l5 s) c
ABSTRACT
9 A  k+ Q$ ?, }$ @: ^1 |$ D5 O8 OFive patients were treated with gonadotropin and topical testosterone for micropenis associated
$ q. p* J/ r7 iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) \! N' Y7 D# ^: _/ Utropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
6 n* r" _; p' y" r* o1 u/ zcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
# i8 I' u7 W' P8 ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent8 E% P7 K9 p0 k3 C/ T# S! u
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average, E" G7 F- n( Z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response1 w' E1 D9 o+ g4 B) h) q. f
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 u" g# \  y; q- |  N6 h2 t
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 i- S. C. Q$ O8 M! H
growth. The response appears to be greater in younger children, which is consistent with previ-
4 n+ ~* R/ A5 \8 w+ E6 q, b$ dously published studies of age-related 5 reductase activity.) w' H3 L- k/ U, K
Children with microphallus regardless of its etiology will
$ C2 i! y% ?0 E8 ?  B+ p* erequire augmentation or consideration for alteration of exter-
; ]% X; A- q! b; V  J9 u5 {nal genitalia. In many instances urethroplasty for hypo-
% K$ q5 J7 h. a; sspadias is easier with previous stimulation of phallic growth./ l8 b9 {$ g# k1 {2 C1 A' W. k" F
The use of testosterone administered parenterally or topically. M, J+ o- y! P8 i1 K4 j
has produced effective phallic growth. 1- 3 The mechanism of
. e6 @* x( Y& d  ~response has been considered as local or systemic. With this
5 u" M& Z. N8 U" W. Q8 cin mind we studied 5 children with microphallus for response
; ~% C  X. `+ B  O1 Wto gonadotropin and to topical testosterone independently./ w4 p, u' ~: @8 i6 }) m
MATERIALS AND METHODS4 ?0 s6 |. a  N' n7 l. p8 L
Five 46 XY male subjects between 3 and 17 years old were
9 x7 N: R% ~9 t7 S7 zevaluated for serum testosterone levels and hypothalamic
0 m  S6 X; Z2 I- U8 ufunction. Of these 5 boys 2 were considered to have Kallmann's( @: `* ~5 d) p* h0 y# O! F) m% j
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-3 y' G0 d* s2 X! `" W  k7 l
lamic deficiency. After evaluation of response to luteinizing
# I- C2 B) |3 k9 }hormone-releasing hormone these patients were treated with# V" O5 U" H# K+ r
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 j9 q% e% }3 f1 E2 ^. V% D; qafter completion of gonadotropin therapy 10 per cent topical3 i4 ?& P. ]" Q
testosterone was applied to the phallus twice daily for 3 weeks.
1 W: B4 ~3 |0 Q5 GSerum testosterone, luteinizing hormone and follicle-stimulat-( n* \) e6 j# U. t! C7 j/ N1 ?) q
ing hormone were monitored before, during and after comple-
9 m/ G" n) E9 |3 s1 Q; Ntion of each phase of therapy. Penile stretch length was5 L5 P8 M1 ~  [8 g: }
obtained by measuring from the symphysis pubis to the tip of
$ i( B- b/ q* y# _the glans. Penile circumferential (girth) measurements were
$ Y5 N; m9 B+ l0 v5 }# Robtained using an orthopedic digital measuring device (see) L6 L, {/ e4 v- Q7 ^
figure).1 s" x# K# S0 y3 Q0 R) g
RESULTS# Q' F: t0 U, q* |3 G( ^
Serum testosterone increased moderately to levels between
7 [; Y0 f8 U% ~9 |50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-9 ?! h, a" v; ~" U+ S! ~
terone levels with topical testosterone remained near pre-* N  f# S" h6 `
treatment levels (35 ng./dl.) or were elevated to similar levels
" t4 n; Y; Z4 w! ideveloped after gonadotropin therapy (96 ng./dl.). Higher6 T" M, d% Q( z% G# A: I
serum levels were noted in older patients (12 and 17 years old),- L1 ^: L$ v9 ~: f# w
while lower levels persisted in younger patients (4, 8, and 10! o% G5 e/ T# |4 _4 {* T- o1 W2 o
years old) (see table). Despite absence of profound alterations8 B+ ^) }9 }2 u! F
of serum testosterone the topical therapy provided a greater& {9 H' D6 R8 }4 T6 U/ c2 u6 X
Accepted for publication July 1, 1977. ·
" `! W# D6 M0 k# C( y" GRead at annual meeting of American Urological Association,
3 f6 g$ _; {5 G4 M/ lChicago, Illinois, April 24-28, 1977.  @; L7 [$ o3 ?8 r6 ~
* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 K/ j3 {" w( W) a: u9 Q# o. x# z2799 W. Grand Blvd., Detroit, Michigan 48202.& r( n: q9 I5 J
improvement in phallic growth compared to gonadotropin.
- p  D9 |( B0 ~1 iAverage phallic growth with gonadotropin was 14.3 per cent
; E: s. S: Q' b, C, T2 \increase in length and 5.0 per cent increase of girth. Topical+ \+ D  q3 X# E6 r/ p/ x7 L! y
testosterone produced a 60.0 per cent increase of phallic length! x# E1 J; y( m) n& I0 {* K
and 52.9 per cent increase of girth (circumference). The
' W6 \# F9 a& @! \response to topical testosterone was greatest in children be-
( |* O( h  I2 t; Q: a* dtween 4 and 8 years old, with a gradual decrease to age 17
4 S% ]3 d; T  |" B% L! A7 Eyears (see table).7 y5 m& o* K% O0 a0 ^+ J8 q: M7 n& U7 q
DISCUSSION
+ _$ @8 r, ^9 N9 U0 M6 T- qTopical testosterone has been used effectively by other, }6 U4 w/ y% J0 g/ E5 J& f6 U- V- ~
clinicians but its mode of action remains controversial. Im-, d) s% v+ O2 Q. |
mergut and associates reported an excellent growth response
9 k+ M: g  H5 u5 B$ bto topical testosterone with low levels of serum testosterone,
$ ^9 L1 Z5 b2 R. ^. {2 ]+ O* f, ysuggesting a local effect.1 Others have obtained growth re-
, C4 x/ A4 v, U7 I; y# B7 P: [- Q; osponse with high. levels of serum testosterone after topical& A( s- x, V! p. N' J, W
administration, suggesting a systemic response. 3 The use of
( v; i, X, Z" U) ogonadotropin to obtain levels of serum testosterone compara-8 D: ?/ P- B* @+ k) ?
ble to levels obtained with topical testosterone would seem to
& a; c, E4 L& L+ Z4 H# H, @3 [# Zprovide a means to compare the relative effectiveness of
$ c$ l% y+ |  q) K1 atopical testosterone to systemic testosterone effect. It cer-
. s0 F5 F/ ?8 r! Mtainly has been established that gonadotropin as well as par-) |" ]' R) p9 L* c" q- l: P
enteral testosterone administration will produce genital
! }9 a! B8 j' _  A7 }$ tgrowth. Our report shows that the growth of the phallus was; f# R  W% K0 R8 r' F7 y
significantly greater with topical applications than with go-: h0 m/ |6 F8 Q
nadotropin, particularly in children less than 10 years old.1 f  V( G' v* z; I7 ~. v
The levels of serum testosterone remained similar or lower
- l7 N' o0 R$ N) h5 zthan with gonadotropin during therapy, suggesting that topi-
: s0 j  Q1 r0 b) @cal application produces genital growth by its local effect as. W7 ~; t( P4 p' t. o
well as its systemic effect.
3 K0 `; E1 L( d" }Review of our patients and their growth response related to
5 p2 A2 K/ l  j5 l* [age shows a greater growth response at an earlier age. This is3 Y) K8 r7 i! P8 r' |
consistent with the findings of Wilson and Walker, who5 P6 X1 U; X! s' _
reported an increased conversion of testosterone to dihydrotes-2 C3 g" V- P/ b4 \5 O, `
tosterone in the foreskin of neonates and infants.4 This activ-8 o/ ~! h- a. E3 U4 H
ity gradually decreases with age until puberty when it ap-' K. n6 v$ s  w
proaches the same level of activity as peripheral skin. It may" x% j' k' h5 a/ l  B' L
well be that absorption of testosterone is less when applied at! M: `. u1 g& [8 C
an earlier age as suggested by lower serum levels in children# f+ [+ s# }8 g5 J& T7 j5 u* b% I; m7 O" {
less than 10 years old. This fact may be explained by the: _- k4 @6 l7 Q8 Z0 r% Z6 n
greater ability of phallic skin to convert testosterone to dihy-1 D( N7 X/ a8 k* m- l+ T5 ^: q
drotestosterone at this age. Conversely, serum levels in older
' n0 U$ }$ Q  {8 S' W: c% E. zpatients were higher, possibly because of decreased local( j/ L5 Y, P* M- A$ a- }; V, \- m& v3 y
667
: v# T# r" P1 k3 n( J1 G0 o; C668 KLUGO AND CERNY
  u2 K  Z6 u% @% ^" s* XPt. Age
5 o& W( A+ u0 y( K(yrs.)
1 ?8 ^7 v3 p+ F7 r& S0 G8 @( oSerum Testosterone Phallus (cm.) Change Length
" e: D; b6 d8 p3 m(ng./dl.) Girth x Length (%)
/ ~" U! R- h# }- V8 p7 R# I4
$ S; ]1 U; R- h. I8
1 A6 R' P4 V$ A5 i' T2 h' ~10
( }( U* s# x( v4 e' Z12
1 `- T9 Q! _% L$ u178 v$ k0 A4 j' O
Gonadotropin8 b- g. f$ _' D- e6 `3 A- H
71.6 2.0 X 3 16.6
1 Z% `& o' \9 S* p+ m50.4 4.0 X 5.0 20.0
3 s4 t7 R9 C* d/ A; K* _22.0 4.5 X 4.0 25.0  D; d, g: _8 O" P9 v" y* S
84.6 4.0 X 4.5 11.17 g& F4 o. f# y7 [
85.9 4.5 X 5.5 9.09 U) b) O( h- h5 i! o- Z
Av. 14.3
) w3 b1 _1 G" Q3 ], \( Z+ s4
" z7 T6 f" F9 Q7 h8
7 q8 |: m! h/ l9 \  `, j& V* \+ F10
5 e" B* I6 l3 ^- R' ~12" G# J; x) f4 b& n% J6 B" E7 V
17
, G6 p; T5 r* uTopical testosterone5 @, K$ J: P/ j: m- ]
34.6 4.5 X 6.5 85% i) J" p7 M! g5 E. R! V3 Z% [
38.8 6.0 X 8.5 70- Z$ z) w) m* |
40.0 6.0 X 6.5 62.5, E4 U$ e1 G3 T' x
93.6 6.0 X 7.0 55.5
& y2 L9 U. T4 s9 A95.0 6.5 X 7.0 27.2
' h& G/ `- H: P. R* bAv. 60.0/ ]! |- z1 N. E, p6 g. ^
available testosterone. Again, emphasis should be placed on3 t# k6 _- U9 V1 y5 k# x
early therapy when lower levels of testosterone appear to
6 a- x- l! X) @( g% A3 V' ~. ?provide the best responses. The earlier therapy is instituted* V* ?) X, c" K$ Q6 H
the more likely there will be an excellent response with low
' h8 ~' D+ i/ H) j# ]$ Aserum levels. Response occurs throughout adolescence as5 K1 W) D, x, _- F. t4 K0 D& m8 l5 F
noted in nomograms of phallic growth. 7 The actual response4 Q8 y2 X! X7 x8 r, [
to a given serum level of testosterone is much greater at birth
+ O+ S" \% Y) W, Gand gradually decreases as boys reach puberty. This is most
8 m- L5 V4 d5 P5 W' X) m5 Jlikely related to the conversion of testosterone to dihydrotes-
2 Q3 z1 }) W9 i& o7 Htosterone and correlates well with the studies of testosterone  |7 g  l: L% D6 q2 c% w/ ~
conversion in foreskin at various ages.
- D: o( U0 n' c9 z% |: LThe question arises regarding early treatment as to whether
* J4 ~+ N8 e' b, d; c% Hone might sacrifice ultimate potential growth as with acceler-# l: W) T3 t6 B) _5 |  C% V* G
ated bone growth. The situation appears quite the reverse2 m2 O$ N5 Q* p5 o. c) d
with phallic response. If the early growth period is not used& }" J' v! u% F# m) Q* }
when 5a reductase activity is greatest then potential growth
  a+ K) o/ [  |) {* A! }may be lost. We have not observed any regression of growth
" D! H, h! I1 f: rattained with topical or gonadotropin therapy. It may well
/ S& J8 e; j( P' t" y1 n3 D$ tbe that some patients will show little or no response to any, \9 R  F" Z5 s. ^
form of therapy. This would suggest a defect in the ability to! B  y+ C& r+ Z* g
convert testosterone to dihydrotestosterone and indicate that2 F3 n! ]( g- A; p' _. [9 U, \9 w
phallic and peripheral skin, and subcutaneous tissue should
7 F# W) V1 Z8 t+ ^, Q0 ?- Xbe compared for 5a reductase activity.
: j4 b! `  f2 d( d* X* gA, loop enlarges to measure penile girth in millimeters. B,
( Q2 @3 V2 u) l4 D0 _example of penile girth computed easily and accurately.  R; B+ G+ |  I7 W& a
conversion of testosterone to dihydrotestosterone. It is in this: a; V. I: @2 h8 Z; _
older group that others have noted high levels of serum
" t3 I6 R( ]- d" l7 B0 b8 ^testosterone with topical application. It would also appear
0 T( P0 {1 Y/ x1 \that phallic response during puberty is related directly to the
3 C+ y9 e3 E, b- f* mserum testosterone level. There also is other evidence of local
/ c1 @4 y1 m! o  cresponse to testosterone with hair growth and with spermato-
2 L& ]" ]( V0 c2 y4 j* xgenesis. 5• 61 E6 u' k; n3 i
Administration of larger doses of gonadotropin or systemic" c$ ^/ b9 c0 b' x% z  z
testosterone, as well as topical applications that produce
  J: k) Z" z' V, m6 D# X# yhigher levels of serum testosterone (150 to 900 ng./dl.), will
0 E% P: F. _1 ~$ f$ N) n* [also produce phallic growth but risks accelerated skeletal* U8 S7 Y% I- O3 i! n
maturation even after stopping treatment. It would appear. c/ L* k. {# x3 C) Y* a# ]) U/ W
that this may be avoided by topical applications of testosterone# {" d: a' M2 A* {+ d
and monitoring of serum testosterone. Even with this control
* V, f( Z3 b! Y# sthe duration of our therapy did not exceed 3 weeks at any
5 L) Y: n8 `, `3 a  P) m/ E' Z% xtime. It is apparent that the prepuberal male subject may9 e1 @( e9 K  u5 [  c
suffer accelerated bone growth with testosterone levels near
- v! }; ?  k: X$ |0 Y! U! Y7 O% p8 @( e200 ng./dl. When skeletal maturation is complete the level of  Y7 ]2 I" |5 j- I4 K2 H* s1 j
serum testosterone can be maintained in the 700 to 1,300 ng.// o" s1 K& n4 t/ w" R; p
dl. range to stimulate phallic growth and secondary sexual
' {: t0 x/ l  H7 G  Tchanges. Therefore, after skeletal maturation parenteral tes-
  D3 @) V% r, d6 C4 W, o( etosterone may be used to advantage. Before skeletal matura-
. `: x2 t! @) E1 wtion care must be taken to avoid maintaining levels of serum
% A" `9 Y+ X9 ?& Y$ I" [testosterone more than 100 ng./dl. Low-dose gonadotropin  g5 Z7 Q# |, C$ k* ^3 {
depends upon intrinsic testicular activity and may require
% c* Z; S+ E  k7 C* n# S! L# [) nprolonged administration for any response.
( \  @) a9 @$ ]( {! @8 nAlternately, topical testosterone does not depend upon tes-
1 S6 W. Y  M, N. L* pticular function and may provide a more constant level of
! x6 v, w/ ?& |: J, u! K$ {REFERENCES- e8 `4 L6 Y" d" R
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
7 Y: N" R! W! n3 h$ Q3 ~6 P  @R.: The local application of testosterone cream to the prepub-  @# V) f# s2 l& a
ertal phallus. J. Urol., 105: 905, 1971.
5 x) k2 `# y" a$ I8 n. @) G, ^2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone) T: ?7 B1 @$ A
treatment for micropenis during early childhood. J. Pediat.,
5 R8 W  P7 c  n83: 247, 1973.
' v; b9 J' J6 _% t# u3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 x1 M5 v8 Q/ [+ ^7 X. B* Eone therapy for penile growth. Urology, 6: 708, 1975.7 x2 F0 i1 e: |, O; j1 s1 h
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 C! O* W. |! Z$ c" `
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* q, Q) y  l9 x
skin slices of man. J. Clin. Invest., 48: 371, 1969.  F1 k+ [/ R) E8 A  `+ ?
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
6 M" a! R- b5 p; e6 W5 `% Uby topical application of androgens. J.A.M.A., 191: 521, 1965.
6 v/ }6 C3 E9 Y1 E0 c6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- _' [3 E" a& u
androgenic effect of interstitial cell tumor of the testis. J., r3 A+ z  F6 @6 o
Urol., 104: 774, 1970.
7 I2 G3 F$ n$ z# h4 m7 t5 Q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 _: S* L" J0 r. k. G
tion in the male genitalia from birth to maturity. J. Urol., 48:
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