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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
* r! m" x( D3 ]+ a6 Y& GGONADOTROPIN4 g3 V3 E' C7 ~0 s  t8 K
RICHARD C. KLUGO* AND JOSEPH C. CERNY
% D, c. X/ ]* m( kFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan5 E- S2 Z! B; k; ~# b+ T  o
ABSTRACT
, o- K* q4 a7 o3 Z0 f& f; B! L& c; FFive patients were treated with gonadotropin and topical testosterone for micropenis associated9 v8 T8 H4 [) {8 s1 J+ O" L
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! X, Q6 s' k% v1 G' d  M$ x3 C" S( A; L5 ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 E0 ~0 X' ^8 y2 Y
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
  f% [+ E1 A2 a: ]$ Kfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent- [- f" P4 d! h" q
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
7 O) }$ m9 Q( d. X$ ]% L6 d8 L0 d" Qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: A) b- `( P- O5 b
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
5 E  j' S* p/ N0 nstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile4 J: [. [& s% C1 m& B
growth. The response appears to be greater in younger children, which is consistent with previ-
8 `6 F3 G# v7 Zously published studies of age-related 5 reductase activity.  N2 `7 ~9 B6 |! M3 i( \
Children with microphallus regardless of its etiology will! u* I, d+ T/ t; C) `1 Z( ]5 W
require augmentation or consideration for alteration of exter-3 ], w6 @; V1 C2 h* K
nal genitalia. In many instances urethroplasty for hypo-
  y2 m1 n6 e# {; u- I# z( xspadias is easier with previous stimulation of phallic growth.  h, ]6 l4 I# ], H6 X+ H' _2 s7 X: y
The use of testosterone administered parenterally or topically  d( W: ^7 A( P% P
has produced effective phallic growth. 1- 3 The mechanism of5 z0 N, e3 U! {2 B0 X0 L8 g
response has been considered as local or systemic. With this/ X. h' p# X9 S: [: U
in mind we studied 5 children with microphallus for response
* I9 ]2 O* l: W7 E& ^# Rto gonadotropin and to topical testosterone independently.* [  i1 w# l& M5 P  ]. U5 `0 }# E5 L
MATERIALS AND METHODS( \9 I. ^( q, H: c
Five 46 XY male subjects between 3 and 17 years old were4 U2 V9 K% v5 d" ?& Z. Y
evaluated for serum testosterone levels and hypothalamic4 ^) X9 `1 ~4 y1 d! G# u' v* m
function. Of these 5 boys 2 were considered to have Kallmann's) f8 o/ a1 ~4 y$ a/ j
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 V4 j8 V. N* p* R. G; z0 l! z. a
lamic deficiency. After evaluation of response to luteinizing1 W. Q% B+ x0 F
hormone-releasing hormone these patients were treated with* j! |! {" U$ l6 [- L1 n, [
1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 I2 q/ h! p5 o
after completion of gonadotropin therapy 10 per cent topical5 d1 @& R+ d/ c) x- Q1 y' g- S
testosterone was applied to the phallus twice daily for 3 weeks.
, ]+ k7 N9 E1 h8 lSerum testosterone, luteinizing hormone and follicle-stimulat-
6 k1 Z- ?" k  k3 ^ing hormone were monitored before, during and after comple-5 l( `6 g( d! T$ y- f
tion of each phase of therapy. Penile stretch length was
# O7 C6 P9 v& w( F4 ^, L& gobtained by measuring from the symphysis pubis to the tip of$ h0 M0 Z9 j: _0 ^) D
the glans. Penile circumferential (girth) measurements were' i8 X  i2 F9 _0 V$ {4 p/ N
obtained using an orthopedic digital measuring device (see
# Q3 m$ @8 y' X  |5 Z, A2 `$ }( O3 C) tfigure).# q& \. u  n% |9 o8 [4 w
RESULTS
, c% g4 F: i0 V' \$ A- uSerum testosterone increased moderately to levels between
! R' i+ D% @, z2 H9 _, g50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
( i! K2 S$ c) G. }" P' _terone levels with topical testosterone remained near pre-" P* [: m8 ]5 V' m- C& ^
treatment levels (35 ng./dl.) or were elevated to similar levels
% `" @* w, M& ndeveloped after gonadotropin therapy (96 ng./dl.). Higher) T  ?( S( X3 \$ D9 x# x
serum levels were noted in older patients (12 and 17 years old),( R& c; q( O3 u7 f1 q6 l
while lower levels persisted in younger patients (4, 8, and 10. `0 m. @  O, _* A, L
years old) (see table). Despite absence of profound alterations
8 `0 p% V  r0 I1 S! J* uof serum testosterone the topical therapy provided a greater
, l  u9 b4 k1 M' I  Y5 _Accepted for publication July 1, 1977. ·
4 d$ X2 ^& S/ N8 ^0 @; GRead at annual meeting of American Urological Association,
& C$ i, `  V# ]5 ]: ]+ |Chicago, Illinois, April 24-28, 1977.6 d9 n( |8 N: \1 k8 w
* Requests for reprints: Division of Urology, Henry Ford Hospital,
& U  ]4 b* e& b6 p  N6 _6 ~( t2799 W. Grand Blvd., Detroit, Michigan 48202.
; B# _& }7 g9 s2 i0 `. p5 H" O+ E" jimprovement in phallic growth compared to gonadotropin.6 [: I0 A  s/ D; K, z& u1 p
Average phallic growth with gonadotropin was 14.3 per cent9 f8 g7 }* T0 E9 e2 X8 |) q
increase in length and 5.0 per cent increase of girth. Topical  ^5 W0 f& o6 Z% p, v0 g
testosterone produced a 60.0 per cent increase of phallic length
7 P7 o$ Z" q5 f" |7 z5 g2 i. Kand 52.9 per cent increase of girth (circumference). The7 B) I1 y3 V: b- p3 {' T9 [8 E; j
response to topical testosterone was greatest in children be-, r% V2 D9 S  a
tween 4 and 8 years old, with a gradual decrease to age 17
6 r$ E" T. m& A) Vyears (see table).2 k6 Y3 Q, l. ^* y# v/ t. [
DISCUSSION- c/ d! ~7 i* x" u0 [; u
Topical testosterone has been used effectively by other
+ P5 o5 R/ a" ?! F; ]( w) S$ _' Pclinicians but its mode of action remains controversial. Im-
! q* Q' Z7 O5 G& h+ }- lmergut and associates reported an excellent growth response
# I9 E5 M  ]  rto topical testosterone with low levels of serum testosterone,  F, F1 }' w0 C$ N
suggesting a local effect.1 Others have obtained growth re-( b1 N  c. w, S7 i, e5 X' e3 U
sponse with high. levels of serum testosterone after topical3 C; N( P1 _  p) M& i
administration, suggesting a systemic response. 3 The use of3 u4 O! C! g* O% P, b8 L" g
gonadotropin to obtain levels of serum testosterone compara-
3 ]. S& B* }& C5 Pble to levels obtained with topical testosterone would seem to) q5 k( p# b0 h/ H7 @, ~- {6 Q
provide a means to compare the relative effectiveness of
0 u8 o$ c2 o' Dtopical testosterone to systemic testosterone effect. It cer-- l' V- ?" E+ H+ r! U2 i
tainly has been established that gonadotropin as well as par-
: H) |4 s8 c0 ~0 m/ H9 Benteral testosterone administration will produce genital3 P. s. A4 [4 O! P1 o0 y
growth. Our report shows that the growth of the phallus was" c  E* E' \! ]& {$ g" `
significantly greater with topical applications than with go-7 Q0 P, W% V7 O$ n0 |# r% }
nadotropin, particularly in children less than 10 years old.
" N$ l: _* ~% h9 d7 U; tThe levels of serum testosterone remained similar or lower5 W( W9 q/ a% y0 p; q8 P" w* Z
than with gonadotropin during therapy, suggesting that topi-( @  G3 i  I6 V& V" J; ^8 H. s
cal application produces genital growth by its local effect as
/ \& `( r$ w+ u* o( Dwell as its systemic effect.# ^" A- e# k9 Q: d( c
Review of our patients and their growth response related to' x% o$ g0 R: X% z6 H( |' o
age shows a greater growth response at an earlier age. This is
$ G4 V+ z1 g6 u3 zconsistent with the findings of Wilson and Walker, who) \1 P$ h" c2 L% V( b, P
reported an increased conversion of testosterone to dihydrotes-
! Z& k# B+ N. a) F7 gtosterone in the foreskin of neonates and infants.4 This activ-
' w6 F7 x, t+ `6 h" R# ]! Jity gradually decreases with age until puberty when it ap-5 H% G5 R3 b& _& w  \' F% R
proaches the same level of activity as peripheral skin. It may
4 m  ~+ i/ }2 S0 cwell be that absorption of testosterone is less when applied at
& v( m2 y) [) o. r( r3 Zan earlier age as suggested by lower serum levels in children
% G  U3 o7 A9 v! {less than 10 years old. This fact may be explained by the; b) C% e4 @  V) x4 i% Q: K
greater ability of phallic skin to convert testosterone to dihy-
1 `' s. M- t+ Wdrotestosterone at this age. Conversely, serum levels in older
8 M; F' N# V4 C! u6 epatients were higher, possibly because of decreased local
( y1 h- P( |$ H0 W7 a667( u4 u  `% ?% U  ^% _
668 KLUGO AND CERNY8 T9 M( x+ r9 ~8 o5 t
Pt. Age% _9 j! Q% D. Q* a
(yrs.)
" I! H. v4 W* ]# G6 |8 c3 @, kSerum Testosterone Phallus (cm.) Change Length& d' ~; `0 b: q8 r6 }
(ng./dl.) Girth x Length (%)
- [; i# g9 f. M5 u% {! |4
5 m, \5 \/ F; {2 }9 L+ O8; i9 `# g* e; ~/ Z
10
" `: u* j9 B( C/ Y* a4 }6 @12, g& Y8 W4 l- b1 ~! O5 d' r8 g
17
7 m$ R3 f, x/ P- H1 t: x+ cGonadotropin
" s2 |! B( ?% j. |6 j71.6 2.0 X 3 16.66 T1 ?* |* |: x6 w$ e' w
50.4 4.0 X 5.0 20.0
& O; e7 _8 b% ?, F5 j/ t22.0 4.5 X 4.0 25.0
. ?" \7 F  L" {& {# }2 `84.6 4.0 X 4.5 11.1
! H* r6 x6 s0 }/ A4 V% v5 _85.9 4.5 X 5.5 9.0
" K; J6 b6 ?! X( d* y4 N0 Y; eAv. 14.3* M. y# c0 o3 P) s
4
/ Y& s& V  o, ~6 X1 |" L8 }8; f- k' O: z6 K# Z3 b
10
9 \- a8 M  I8 d; k! U$ f! j- A12$ K' y2 V" c$ a0 w  B
17
( p# ]1 y: l0 M! W. _! |5 [9 q. |' ^' gTopical testosterone+ M8 ]/ N( O% u& O4 Q+ L/ I5 [3 Z+ c
34.6 4.5 X 6.5 85
& C) Q0 Y8 ]* _: `, x0 P38.8 6.0 X 8.5 70) [" j* g4 G8 S1 B* I
40.0 6.0 X 6.5 62.5
# u& `5 G5 W  J93.6 6.0 X 7.0 55.5
6 ?. k0 [# f# \* [4 n( m6 w95.0 6.5 X 7.0 27.2
4 h/ e4 c  W* \Av. 60.0
: t6 c( q' A" M# qavailable testosterone. Again, emphasis should be placed on% T. l* N; ~* |7 P7 ^* N
early therapy when lower levels of testosterone appear to
, ]0 I7 G+ U* \6 m2 Nprovide the best responses. The earlier therapy is instituted
/ r* b* j0 e" D  Z* Jthe more likely there will be an excellent response with low/ x, t+ r2 K2 {5 `" ?
serum levels. Response occurs throughout adolescence as4 W: Z6 c. o8 N5 c$ Y
noted in nomograms of phallic growth. 7 The actual response- S( I' {' Y7 I* d( W  S9 L' p2 ^
to a given serum level of testosterone is much greater at birth
9 n3 J1 B4 c; }and gradually decreases as boys reach puberty. This is most9 U" M/ ?+ a  ^
likely related to the conversion of testosterone to dihydrotes-) X" V$ s" B$ X9 `  j
tosterone and correlates well with the studies of testosterone
+ j3 ^8 m+ b; ]( Cconversion in foreskin at various ages.
$ u( ?0 J; Y/ ~, _  I/ V, FThe question arises regarding early treatment as to whether3 n4 t; W$ i0 _, _
one might sacrifice ultimate potential growth as with acceler-+ q% t/ t, ]; y5 I& _
ated bone growth. The situation appears quite the reverse2 I6 m$ y# |! l1 T8 z
with phallic response. If the early growth period is not used) W9 i7 F  g) Q  F5 S( f$ s
when 5a reductase activity is greatest then potential growth
) v! q6 a1 }0 }. E* l2 Rmay be lost. We have not observed any regression of growth( E% D1 f9 [6 {6 o5 X
attained with topical or gonadotropin therapy. It may well
( r3 c9 l. J' a7 u2 @4 qbe that some patients will show little or no response to any
1 Y- N8 }# V) m: W$ dform of therapy. This would suggest a defect in the ability to
3 [; p4 Y6 ~/ C1 mconvert testosterone to dihydrotestosterone and indicate that$ Z* m* M0 X$ F: Y
phallic and peripheral skin, and subcutaneous tissue should% @1 \% N# T% ^
be compared for 5a reductase activity.9 y: E4 u. \* J! z
A, loop enlarges to measure penile girth in millimeters. B,$ c/ L# F' |9 s4 e; `
example of penile girth computed easily and accurately.
6 K2 y" s% c& H8 c$ @; jconversion of testosterone to dihydrotestosterone. It is in this3 n/ X  O% E8 Q  ?! p
older group that others have noted high levels of serum- q5 k2 I6 u4 \! r( h
testosterone with topical application. It would also appear& f' G# e5 n: v
that phallic response during puberty is related directly to the
8 M! _  V& h( O4 Q( \serum testosterone level. There also is other evidence of local" x; ?; a5 I+ u3 E  _# j
response to testosterone with hair growth and with spermato-
% w: s7 }  M, o& U2 k( Cgenesis. 5• 6, D- M/ v- Y. k
Administration of larger doses of gonadotropin or systemic* |8 U+ y2 m+ s" Q
testosterone, as well as topical applications that produce
& S* p2 a9 q4 _& J1 S: g9 Xhigher levels of serum testosterone (150 to 900 ng./dl.), will
  t/ e- ^7 A4 z: ialso produce phallic growth but risks accelerated skeletal
% [4 [* q6 ^7 D. }& Fmaturation even after stopping treatment. It would appear
# D: A' R( E  U' ]9 R& gthat this may be avoided by topical applications of testosterone0 ~/ s& x1 ~4 g
and monitoring of serum testosterone. Even with this control* g  J. B9 ]' V- [( }/ x
the duration of our therapy did not exceed 3 weeks at any2 S! S0 i/ H# l- |1 Q0 J6 P
time. It is apparent that the prepuberal male subject may! O8 S7 i8 C) F3 [
suffer accelerated bone growth with testosterone levels near
3 x3 z; R& ~* O7 [7 T200 ng./dl. When skeletal maturation is complete the level of$ z0 s; N$ r6 F2 b$ H
serum testosterone can be maintained in the 700 to 1,300 ng./
  |) y" F1 ~3 g  cdl. range to stimulate phallic growth and secondary sexual
8 X( Q/ x9 _& z! Hchanges. Therefore, after skeletal maturation parenteral tes-
# @, _' e% Z+ l7 d7 Utosterone may be used to advantage. Before skeletal matura-
8 A0 f9 a, u0 M$ qtion care must be taken to avoid maintaining levels of serum8 l2 y7 b. u2 e' v4 V" [
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ |; R* Z6 U) M5 n  c  M: @- fdepends upon intrinsic testicular activity and may require
3 A2 }3 d/ _- Hprolonged administration for any response.
, D! @9 D& g# \8 u2 c5 GAlternately, topical testosterone does not depend upon tes-
* K+ f) z2 U* Uticular function and may provide a more constant level of
* q! c% O" E5 {( XREFERENCES; H7 |; t% f: v+ n; @: w
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# I. R2 L1 P( `
R.: The local application of testosterone cream to the prepub-
. [+ b1 z6 u; R( Eertal phallus. J. Urol., 105: 905, 1971.2 C( W3 b( t* p0 w
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone  f" q0 Q0 p( X4 `$ y
treatment for micropenis during early childhood. J. Pediat.,
  P& j1 Q+ |- E, t. B) c8 w0 W83: 247, 1973., j  K! a) b( o  g( @7 v; s( s/ o  L' Y
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* q0 O6 t8 d8 h, O# C; ]& ~one therapy for penile growth. Urology, 6: 708, 1975.
8 C0 m/ v" [8 E  }( H2 C- }4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' j' F7 f0 Y. a$ n6 a) m! Z$ U' ]to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% J6 ]! }3 f' C4 x; Y: \
skin slices of man. J. Clin. Invest., 48: 371, 1969.& Z( D. J: A+ D4 n. L
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth7 `% h. {! ^7 e
by topical application of androgens. J.A.M.A., 191: 521, 1965.7 v# g7 Q. f( F. R$ y
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) \8 P: z" U! L" I, D
androgenic effect of interstitial cell tumor of the testis. J.
! Q% C/ X. |( I+ s6 o/ W( [Urol., 104: 774, 1970.
; _+ a) K5 s8 A' @8 Y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 T/ y* O+ v7 B# i
tion in the male genitalia from birth to maturity. J. Urol., 48:
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