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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND! L* D* n9 o' ^7 s
GONADOTROPIN2 Z5 u" q3 E. t0 R3 ?' |0 J8 `
RICHARD C. KLUGO* AND JOSEPH C. CERNY6 ?0 }6 [- q- F9 o
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 ^3 n) m4 w" j3 \! DABSTRACT
5 t: L$ q4 ?! C% ]5 _Five patients were treated with gonadotropin and topical testosterone for micropenis associated
4 E8 N( l+ y; x' _" x, J7 uwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 @& b( }+ T/ [9 ~3 M. S
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone  N: z$ e. _; Y! A
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
. g$ o2 ~. g6 x+ Gfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 i/ L' j9 D2 @+ j- q' K. R$ U
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average$ @' `+ U8 d1 {- n! e* b0 y
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 W' R/ `6 D8 ^# y, y, ?
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
7 V3 g3 d/ Z. l( qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 m0 B0 w1 r8 @! p" x( k$ ^( ?growth. The response appears to be greater in younger children, which is consistent with previ-4 p' k5 O7 j8 A- y0 v& q
ously published studies of age-related 5 reductase activity.
# A( J& G: a1 U( [; |Children with microphallus regardless of its etiology will
. ~( M5 L" w% {* W2 p0 zrequire augmentation or consideration for alteration of exter-
: g3 Z# j" m1 {+ ^6 Hnal genitalia. In many instances urethroplasty for hypo-
) L* A+ z& q$ }& Nspadias is easier with previous stimulation of phallic growth.
+ U- N9 G. h8 x1 D7 b1 |6 ~* cThe use of testosterone administered parenterally or topically. @' Y1 I7 Y1 R
has produced effective phallic growth. 1- 3 The mechanism of" j0 T* y* |2 r. `5 y$ w) `
response has been considered as local or systemic. With this: t6 J/ d0 b7 X) @7 z% j9 ^* X
in mind we studied 5 children with microphallus for response1 n* I2 J3 [5 A; E4 [
to gonadotropin and to topical testosterone independently.8 O' P, z% C' y$ o$ O
MATERIALS AND METHODS
% L( K! ?' h# N. @/ vFive 46 XY male subjects between 3 and 17 years old were
/ y6 L5 j1 n  @7 n) B; p  g' b! p. |evaluated for serum testosterone levels and hypothalamic. {: m) [# ?" A3 u) k
function. Of these 5 boys 2 were considered to have Kallmann's$ a" {8 }8 o$ n
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
. L8 `' t5 @0 ], r& C3 Plamic deficiency. After evaluation of response to luteinizing
( y* r0 @* U; |8 O7 Zhormone-releasing hormone these patients were treated with9 v* Q; ?$ H# w5 }' T& B% b- R8 y# x4 ~
1,000 units of gonadotropin weekly for 3 weeks. Six weeks  b* ^  g4 y9 B, I! c. F
after completion of gonadotropin therapy 10 per cent topical
- K7 u8 K8 g, rtestosterone was applied to the phallus twice daily for 3 weeks.
8 a4 O% x' m5 _  g* zSerum testosterone, luteinizing hormone and follicle-stimulat-
# c4 t& B- D! king hormone were monitored before, during and after comple-% T# k/ m- P( q& ?2 a9 F& q
tion of each phase of therapy. Penile stretch length was
  K1 f" T' M1 ]# O# G: dobtained by measuring from the symphysis pubis to the tip of) c7 f* ~/ p% t: \* @1 a
the glans. Penile circumferential (girth) measurements were' r" k) O8 b' T, `+ R$ T  \
obtained using an orthopedic digital measuring device (see
. M5 X5 @7 y8 Kfigure).
; G: h' T6 F1 _" zRESULTS
$ u4 D. m, ]6 `Serum testosterone increased moderately to levels between
! r9 k% @: I- `0 F  y: r  [50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  e: s# f) h; q7 k# V& aterone levels with topical testosterone remained near pre-# f2 {+ a6 g% L) J# j; ]
treatment levels (35 ng./dl.) or were elevated to similar levels3 r: h3 Y' u5 Q4 q
developed after gonadotropin therapy (96 ng./dl.). Higher
; L2 Y8 i( _; @; L7 c, \serum levels were noted in older patients (12 and 17 years old),
7 E5 W" Q$ u# V8 A6 |: Swhile lower levels persisted in younger patients (4, 8, and 10, P3 N) N; V, m+ c+ l
years old) (see table). Despite absence of profound alterations
" M3 M5 E& W3 W2 Eof serum testosterone the topical therapy provided a greater$ Q3 q4 p6 i. h* A% g) I/ }
Accepted for publication July 1, 1977. ·1 I9 g2 b1 F: _. r) h" J1 }  r& o0 U2 t
Read at annual meeting of American Urological Association,
; ~; C* ^" @# @) oChicago, Illinois, April 24-28, 1977.
% Y9 i1 p' p$ s4 C- W, Z4 P7 ^" y* Requests for reprints: Division of Urology, Henry Ford Hospital,4 P/ i/ e) g) ]; a  a
2799 W. Grand Blvd., Detroit, Michigan 48202.
& ?$ d% [4 H$ H4 @" p* ?! M7 eimprovement in phallic growth compared to gonadotropin.# I. c& \9 N! A8 v6 c, q. x$ M
Average phallic growth with gonadotropin was 14.3 per cent
% n# \1 ?, G: y8 Oincrease in length and 5.0 per cent increase of girth. Topical
" W3 n& F( J& A; y9 J% d+ c2 p7 i# g) Ltestosterone produced a 60.0 per cent increase of phallic length& y( O) t: a  k5 P% @
and 52.9 per cent increase of girth (circumference). The2 D3 m  G3 _* y/ |$ T3 o% M4 f6 ^1 D4 Z
response to topical testosterone was greatest in children be-
% v( i! |% `( v6 j2 Qtween 4 and 8 years old, with a gradual decrease to age 17
* L; |, U4 @' byears (see table).8 N8 o( ]! H2 P' Q2 w  X% \: ]
DISCUSSION
3 o  h/ Z+ [0 |9 x4 K/ W" I1 K( ITopical testosterone has been used effectively by other: z8 e( b2 _& g9 S
clinicians but its mode of action remains controversial. Im-4 z& \) l8 Q8 l9 I
mergut and associates reported an excellent growth response1 m$ o' J1 E! T5 l$ S+ h- ^" m# p
to topical testosterone with low levels of serum testosterone,2 A6 n9 b0 C, l8 G8 P6 N
suggesting a local effect.1 Others have obtained growth re-: x8 s! `2 k2 E2 J
sponse with high. levels of serum testosterone after topical
+ e3 a2 B- P7 |) p4 Y5 `administration, suggesting a systemic response. 3 The use of0 o  m' Z0 T' C8 Y! [
gonadotropin to obtain levels of serum testosterone compara-
: T- N( Q$ E4 v+ E1 f2 E' r5 kble to levels obtained with topical testosterone would seem to
% M* t  }+ d" c1 tprovide a means to compare the relative effectiveness of4 h1 i, P# m$ `; ^
topical testosterone to systemic testosterone effect. It cer-* _% ^' c( d. V8 F3 h
tainly has been established that gonadotropin as well as par-
8 U; \' i; o0 \' o! R2 q, Aenteral testosterone administration will produce genital
7 d* {8 A4 U* ]2 n' q/ L2 [6 \/ Bgrowth. Our report shows that the growth of the phallus was: c* z- F& r- t( P
significantly greater with topical applications than with go-
* C' I- x4 e% Q1 vnadotropin, particularly in children less than 10 years old.
& c' ~. o1 D- }: L8 v9 JThe levels of serum testosterone remained similar or lower2 o$ S. |! _1 l3 ^
than with gonadotropin during therapy, suggesting that topi-
0 Y3 s. ?/ y+ Y! S1 K: e: gcal application produces genital growth by its local effect as
: N- Q( s) G5 |, G9 Twell as its systemic effect.
) e, K2 U6 f* _9 H1 ]+ T- m8 VReview of our patients and their growth response related to
- l( E, n! X, R: s, F" N# Dage shows a greater growth response at an earlier age. This is" V8 F1 P+ z/ M. s
consistent with the findings of Wilson and Walker, who. n+ }- z0 s+ q, q/ K1 t8 ?
reported an increased conversion of testosterone to dihydrotes-
* t, g' B0 r. xtosterone in the foreskin of neonates and infants.4 This activ-/ p* O: l: E$ Y7 [/ Z" g
ity gradually decreases with age until puberty when it ap-" u" i$ G5 E, u% O- J
proaches the same level of activity as peripheral skin. It may0 H0 O1 x$ [% M  _4 y
well be that absorption of testosterone is less when applied at
0 }, _4 ~4 O- N; \! Jan earlier age as suggested by lower serum levels in children7 [8 p# n: s  K& E) p
less than 10 years old. This fact may be explained by the
0 J7 c3 {* T3 p& a0 ~# P9 s% B, Ogreater ability of phallic skin to convert testosterone to dihy-
# `8 E, Q2 X) K4 Y. h/ R2 Ydrotestosterone at this age. Conversely, serum levels in older
- I$ P" Y4 [& i7 P) d2 Cpatients were higher, possibly because of decreased local4 n8 e/ i, L+ u+ I! }: _' Y7 X
667
; D8 O6 o8 `  v, s668 KLUGO AND CERNY
5 e  H# R) V! K$ I+ K$ sPt. Age/ L7 B1 p4 S, a
(yrs.)' w! Z7 q7 r# s. b7 z0 r
Serum Testosterone Phallus (cm.) Change Length4 ~* A( e" Q8 U) }
(ng./dl.) Girth x Length (%)9 P5 _8 s3 a1 `' @7 |" d, e
49 N) r, p- x, U* f% W3 c( ]! s
8) u* ~: D* x+ N+ c6 g
10
( f8 ?. ]2 `; M( _12
+ j+ E9 h; b# D3 i& F6 Q175 O) j) P6 B/ {. }6 G+ @; v$ B6 m) W
Gonadotropin: r5 t1 R# I% X" K8 A7 D: |
71.6 2.0 X 3 16.6
7 b! `! m" [& o. C% M, x" u6 z& W50.4 4.0 X 5.0 20.0  H7 X* }5 I* p
22.0 4.5 X 4.0 25.0
; S+ d1 w3 Q) S* P; f84.6 4.0 X 4.5 11.1
' I3 n9 h% N' m/ P" ]85.9 4.5 X 5.5 9.0
) r1 h7 R6 Q" z# X! F+ WAv. 14.3
0 E9 ~( P, i2 f4 A1 ]44 w# D' Q' u# C8 |
8
! }7 F7 I' m5 Z10
/ c' N! b! v1 s, E12
' T) u  S8 ^! a8 x! d17
( o' v: x9 F5 H  @' \9 o6 A  HTopical testosterone
  `4 n/ ~) I; \. A34.6 4.5 X 6.5 85
2 d- H) S1 Z+ k' W/ {38.8 6.0 X 8.5 706 l" w. W4 T0 p$ S
40.0 6.0 X 6.5 62.5
- h% n3 l3 F. I# L5 a93.6 6.0 X 7.0 55.5+ O7 M! `5 m% C$ C- W1 I2 L
95.0 6.5 X 7.0 27.2
0 J0 W+ A9 x0 y8 E: IAv. 60.0
$ U9 V) B1 b3 L0 Navailable testosterone. Again, emphasis should be placed on
/ |6 o# f5 X7 L0 c& X% dearly therapy when lower levels of testosterone appear to
* t( d9 N$ A! u3 b" oprovide the best responses. The earlier therapy is instituted1 S, f3 }0 W, j: V
the more likely there will be an excellent response with low
% S0 O. _- Q- |+ }$ {" U+ Zserum levels. Response occurs throughout adolescence as
# Y6 X' Q+ g# k0 d! [7 qnoted in nomograms of phallic growth. 7 The actual response
% C& F  d5 |; ~: }4 U9 Eto a given serum level of testosterone is much greater at birth! }9 `& v. B3 J1 ]5 q' ^; B. X4 o; [# H
and gradually decreases as boys reach puberty. This is most
$ }* s6 G+ l" l7 f- mlikely related to the conversion of testosterone to dihydrotes-
* g' w( b1 B6 Z1 y( s$ L7 ~( Stosterone and correlates well with the studies of testosterone
& i% h! p+ L' n9 ~conversion in foreskin at various ages.) o- f% k  d5 C9 U( Y! {5 Q0 ]
The question arises regarding early treatment as to whether0 c% `$ ~& c' _) Z( k/ }/ E# {, v
one might sacrifice ultimate potential growth as with acceler-
2 c% t1 H1 \3 C# B* H4 q, sated bone growth. The situation appears quite the reverse
2 x% {/ T( |& v5 O% }with phallic response. If the early growth period is not used9 I8 P+ T2 I- Z0 d+ a3 Y: _
when 5a reductase activity is greatest then potential growth  E5 c; o) }. {2 Z" E4 C7 v
may be lost. We have not observed any regression of growth
9 h9 s/ I# w: m; ]attained with topical or gonadotropin therapy. It may well- C3 U1 j+ n3 a+ g* s1 k8 E* s
be that some patients will show little or no response to any
1 a, k" g$ _. N9 O8 p6 Uform of therapy. This would suggest a defect in the ability to
) U+ T. W$ p- L$ c8 U9 Qconvert testosterone to dihydrotestosterone and indicate that9 @' d4 e, n5 A" L" `
phallic and peripheral skin, and subcutaneous tissue should
! Q$ o& j+ P  y) k* A7 U: _" cbe compared for 5a reductase activity.  G; z% D5 C* f, }7 l
A, loop enlarges to measure penile girth in millimeters. B,
. c1 L5 w. F( |example of penile girth computed easily and accurately.
, \# N. _3 P5 v5 B6 @conversion of testosterone to dihydrotestosterone. It is in this
* T% Y/ Z: k9 G' h8 ]% e; F1 ~older group that others have noted high levels of serum
4 Y/ F* L* @! Z4 s& g( N( X) Jtestosterone with topical application. It would also appear) N) M2 H1 Y* Y5 w, @
that phallic response during puberty is related directly to the
+ ^8 r) ]9 N7 I. ^7 a" tserum testosterone level. There also is other evidence of local& B; u7 o" h" W$ w, ~; X
response to testosterone with hair growth and with spermato-
7 i2 J* c% ~) ]7 J# z% S/ Jgenesis. 5• 6) H" T9 g3 Q7 }8 h, p
Administration of larger doses of gonadotropin or systemic2 A* o0 N' O8 I1 H
testosterone, as well as topical applications that produce( z2 ~& }$ Q0 h- M. Z# K5 M
higher levels of serum testosterone (150 to 900 ng./dl.), will7 E% ?5 B2 G! Z8 K0 J- n
also produce phallic growth but risks accelerated skeletal
+ |6 w9 Z0 D5 C, @2 k9 Rmaturation even after stopping treatment. It would appear
1 b# D2 A+ x$ M2 [  Othat this may be avoided by topical applications of testosterone
* f/ d* N, S& M* Pand monitoring of serum testosterone. Even with this control
) [5 ]  g9 T, k6 a; V+ Kthe duration of our therapy did not exceed 3 weeks at any3 |- n1 Z( O4 C( F1 S
time. It is apparent that the prepuberal male subject may2 J% p" ^7 q3 |4 C
suffer accelerated bone growth with testosterone levels near& H& x+ w# C! f3 f. S: y, v
200 ng./dl. When skeletal maturation is complete the level of
5 J+ y& C: E1 Z, zserum testosterone can be maintained in the 700 to 1,300 ng./- n$ q% D1 D5 z3 {' t9 E' F
dl. range to stimulate phallic growth and secondary sexual; _$ n" d( ?. K
changes. Therefore, after skeletal maturation parenteral tes-' r9 I7 j- C. v. @3 g1 Z+ V
tosterone may be used to advantage. Before skeletal matura-; D, k, V4 ?& ?0 V7 Q# u3 F- ^2 B1 O
tion care must be taken to avoid maintaining levels of serum  g" H$ S, I( o) X
testosterone more than 100 ng./dl. Low-dose gonadotropin5 ^  `6 V2 }" f+ b7 Y
depends upon intrinsic testicular activity and may require
- ~* x+ r# v* U6 D( {2 t- `9 Xprolonged administration for any response.
4 o: o/ r! b2 vAlternately, topical testosterone does not depend upon tes-4 @8 ~7 x% ?) k! i/ c+ x
ticular function and may provide a more constant level of7 Q1 A- N, J- R3 n$ H% \/ t
REFERENCES# o# _5 h3 ~8 q% L4 k
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
" `  t7 K7 F0 k6 ^' Z% SR.: The local application of testosterone cream to the prepub-
! P  k+ r3 d1 ?) g$ K* pertal phallus. J. Urol., 105: 905, 1971.2 i8 W; J8 m* O: v% z3 A
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 M% ]; }8 d7 }+ N/ ?* k/ o) \treatment for micropenis during early childhood. J. Pediat.,
  X5 Z: x- ^' l3 L83: 247, 1973.5 {4 o; V$ \' I" Y8 @
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 ^9 @/ w9 B0 g! f. l, @one therapy for penile growth. Urology, 6: 708, 1975.
# E% M- }$ O! _, H3 Z- u: m! L$ q! x4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 N8 W; O8 }; _/ w1 K$ v
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. ]5 r) M1 ~) }) m/ w
skin slices of man. J. Clin. Invest., 48: 371, 1969.
  B/ D, Z2 `3 W5 ?5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ k* H/ y; o# `. `/ h9 Q
by topical application of androgens. J.A.M.A., 191: 521, 1965.
  R2 |4 F4 p/ C/ b1 P6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
" M% }' c' U1 f  S# x+ tandrogenic effect of interstitial cell tumor of the testis. J.
8 P5 H2 G1 m  w1 w1 m" b* xUrol., 104: 774, 1970.
$ J9 b6 p4 j( M/ C9 f7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-9 ]) l' C' c/ N' z8 g4 z* u# R
tion in the male genitalia from birth to maturity. J. Urol., 48:
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