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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
0 F& J9 O# u: s" F0 H' xGONADOTROPIN" J% e, m8 d7 ~; f8 K
RICHARD C. KLUGO* AND JOSEPH C. CERNY# [+ X$ f+ ]3 l) _6 q2 W3 N: ]
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan8 d! F9 z. d4 e0 `  v
ABSTRACT8 t# r3 ]) s; [! V) B$ n
Five patients were treated with gonadotropin and topical testosterone for micropenis associated1 j: ?4 r7 A- b  r+ R
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( `! U5 q6 W& ntropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
- }9 F8 B' C1 z( d3 z8 ~cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( A7 u8 Z$ w2 C! s9 Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent6 Q- h' E! v. G" T6 Y* S
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average- d% Z) m  H- t2 f( F
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ }- x: e) w) X2 w5 d- G7 ?2 O3 ]occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# V- b! \% U- {( n6 }
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- x. O. K$ o$ igrowth. The response appears to be greater in younger children, which is consistent with previ-' l5 f( s( D0 \, x8 [. ?3 F
ously published studies of age-related 5 reductase activity.
4 D8 e6 e- _1 j5 ^% P. X  W4 }Children with microphallus regardless of its etiology will7 y# K/ L4 ]9 b! `5 t
require augmentation or consideration for alteration of exter-, f5 }8 {3 z* i1 h8 s
nal genitalia. In many instances urethroplasty for hypo-; e8 _9 A+ t% L
spadias is easier with previous stimulation of phallic growth.
  s& x3 E* m; O. F6 O5 x  XThe use of testosterone administered parenterally or topically
4 A5 p# Y! D9 t7 n3 c9 f2 b8 J; }has produced effective phallic growth. 1- 3 The mechanism of
2 U( ^0 A! ^, r* d8 `response has been considered as local or systemic. With this0 F2 ]8 j/ o3 e: U: j
in mind we studied 5 children with microphallus for response- s" I% \0 c, G! e
to gonadotropin and to topical testosterone independently.8 T: F7 Y! l* p7 b8 e: P
MATERIALS AND METHODS' w2 `' A* l% G/ q0 v
Five 46 XY male subjects between 3 and 17 years old were& ^( P! u$ _2 J4 o+ ]% Z
evaluated for serum testosterone levels and hypothalamic
1 |% M- N2 G& bfunction. Of these 5 boys 2 were considered to have Kallmann's% v3 \0 ]) n3 `! J1 b3 ~
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 M% D; [) U3 w/ O9 Wlamic deficiency. After evaluation of response to luteinizing/ S+ j' Z) w) k) T6 `
hormone-releasing hormone these patients were treated with
) X/ c! P6 F7 F1,000 units of gonadotropin weekly for 3 weeks. Six weeks. e+ F/ ?1 C: v0 p( c! ]
after completion of gonadotropin therapy 10 per cent topical1 V4 j, Y* a6 t' N% O
testosterone was applied to the phallus twice daily for 3 weeks.7 U6 e  ~) _$ z" ?- V. e8 \
Serum testosterone, luteinizing hormone and follicle-stimulat-0 e/ e& {2 r6 Y8 }* ~. \% o
ing hormone were monitored before, during and after comple-$ u7 f) U" S6 s8 q9 u, A
tion of each phase of therapy. Penile stretch length was, u( o2 \2 O8 Q7 }& ^2 ?! m
obtained by measuring from the symphysis pubis to the tip of
* e; e& }7 s; `( K# |4 F6 vthe glans. Penile circumferential (girth) measurements were$ K9 Y& h5 A  d
obtained using an orthopedic digital measuring device (see3 C- `% [0 m' h0 P4 U
figure).
7 B7 x9 Z& N2 u! ]RESULTS
+ S/ ]( f. m, h, R) l# MSerum testosterone increased moderately to levels between
5 k1 v) G# |3 A+ f50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 ?  d  p/ x/ L5 Cterone levels with topical testosterone remained near pre-
+ |' C6 l/ c; ]" g3 _1 b. Ztreatment levels (35 ng./dl.) or were elevated to similar levels
0 W  i: c7 k; I& U9 Qdeveloped after gonadotropin therapy (96 ng./dl.). Higher
6 ^* V2 y/ e+ X( p+ dserum levels were noted in older patients (12 and 17 years old),  Z1 Y$ \9 @: B. p+ P: A
while lower levels persisted in younger patients (4, 8, and 10
2 }7 W2 y9 v9 P' f# l- B* Yyears old) (see table). Despite absence of profound alterations. o- j/ d9 t2 w2 A! f  m
of serum testosterone the topical therapy provided a greater6 |1 L  E# ~  \# B
Accepted for publication July 1, 1977. ·
* Y0 g  b5 i" x7 M% s. F# QRead at annual meeting of American Urological Association,
+ A) v! L9 y9 k6 P9 y2 kChicago, Illinois, April 24-28, 1977.; h+ _; Q8 G- `5 a$ R* N- m3 i
* Requests for reprints: Division of Urology, Henry Ford Hospital,/ p* R$ h/ }' _" I* f
2799 W. Grand Blvd., Detroit, Michigan 48202.
) w+ h: w" s$ h. Vimprovement in phallic growth compared to gonadotropin.
  y$ z3 Y, h. M* L4 i, aAverage phallic growth with gonadotropin was 14.3 per cent5 Z2 r0 O1 T8 j
increase in length and 5.0 per cent increase of girth. Topical
2 @& ?, |/ t6 N. L( g% e8 btestosterone produced a 60.0 per cent increase of phallic length+ L" x1 a) _, T- o  ~
and 52.9 per cent increase of girth (circumference). The! ~+ s) t- z2 \
response to topical testosterone was greatest in children be-
& Y. j7 y3 h, _8 ^6 s' |tween 4 and 8 years old, with a gradual decrease to age 17
& M' h" s" E8 R$ O' E* Byears (see table).; e$ f" [4 e( ]: [0 U. D7 Q4 |
DISCUSSION
, i# ?9 O2 b6 Y6 j% ]8 |# ZTopical testosterone has been used effectively by other
  E  D' E2 [9 T( v; @, c2 a% cclinicians but its mode of action remains controversial. Im-
" K* G0 K6 Y. O7 Zmergut and associates reported an excellent growth response, q" {& W- _! v- }$ z
to topical testosterone with low levels of serum testosterone,
3 n  |& ]) K$ J7 K. Jsuggesting a local effect.1 Others have obtained growth re-
# w6 \* i! O% ?8 ?9 D% ssponse with high. levels of serum testosterone after topical1 A! \3 a; F- R$ b+ g% }
administration, suggesting a systemic response. 3 The use of' ^8 n: I( i) E9 t8 K' I
gonadotropin to obtain levels of serum testosterone compara-
! x- Y6 E( H( s  K9 a/ Eble to levels obtained with topical testosterone would seem to4 b! g  j* @1 M, U. H, a( A
provide a means to compare the relative effectiveness of
" p3 `$ b4 ~. J! t% T6 _: F+ w; Mtopical testosterone to systemic testosterone effect. It cer-5 r7 b0 q5 S: `8 X1 k+ T2 E! Z1 h
tainly has been established that gonadotropin as well as par-9 t% m/ _$ W! A  S$ I% q! Q$ u( h
enteral testosterone administration will produce genital
3 L: @$ L) A  o( w9 q0 Fgrowth. Our report shows that the growth of the phallus was; a/ v! f8 |8 p* `8 ]# F( m
significantly greater with topical applications than with go-
' P/ i0 s4 F- V9 g% w. e# z, a/ @nadotropin, particularly in children less than 10 years old.6 o% l# P$ u, t2 |$ ~8 x$ N1 Q. ~' v
The levels of serum testosterone remained similar or lower
. d4 r8 V& ~% ]- K9 c5 bthan with gonadotropin during therapy, suggesting that topi-7 E( G& h! o) D
cal application produces genital growth by its local effect as
1 h% T3 @" n% Y% v* _+ i  I5 Hwell as its systemic effect.
3 P1 j: |9 Y% p( Y2 gReview of our patients and their growth response related to; T5 S4 V! Q& s" ?* Y' A
age shows a greater growth response at an earlier age. This is9 a: x9 @- q4 i" ^" Z) g9 u2 i
consistent with the findings of Wilson and Walker, who( D, @! O5 o! F. |( ^- h
reported an increased conversion of testosterone to dihydrotes-2 K* L) _6 _: t# T; [! S
tosterone in the foreskin of neonates and infants.4 This activ-
! @0 Y* x0 B( s3 mity gradually decreases with age until puberty when it ap-
4 h' Z& f% g! d; X; F4 eproaches the same level of activity as peripheral skin. It may* e. C, B$ p" t/ W2 g& \$ |% h
well be that absorption of testosterone is less when applied at3 T* z3 O" X# {& I  y0 ~
an earlier age as suggested by lower serum levels in children) n2 e$ X9 T+ _. r$ w
less than 10 years old. This fact may be explained by the
& T) D) G3 u! i5 ngreater ability of phallic skin to convert testosterone to dihy-" G3 m) ~9 O. ?5 r6 e
drotestosterone at this age. Conversely, serum levels in older
8 o: y$ Y; B/ u& l+ P. n% R# h# Ipatients were higher, possibly because of decreased local
* A2 U# u+ i' Q; X% k/ m4 B667
! v' w% E) |1 T' q9 j668 KLUGO AND CERNY0 P* [% [' n9 g* l9 b
Pt. Age
* q1 Y7 [: l# W- y3 ], s7 |1 Z6 T(yrs.)
! [# p6 t7 b; v: g9 ?* wSerum Testosterone Phallus (cm.) Change Length
/ G0 h9 @9 Q3 P! {(ng./dl.) Girth x Length (%)* D1 E8 M% C4 [: Q" n
4
5 P2 n+ k; v$ W: j& p& D2 E8
' r/ k2 H: ?; Y, x* n/ a  B2 Q10
: `$ f) S3 M# L5 Q! Q0 ?2 C12
) v' }- o& {3 _1 q9 o17) _6 I1 |3 d: U) a1 F) W/ }/ m
Gonadotropin0 D% ^" V+ r& Q# \/ f( r! j; t2 y
71.6 2.0 X 3 16.6: h- v5 Q2 X3 u1 e' v
50.4 4.0 X 5.0 20.0" {) t5 b5 v5 Z1 b3 R5 u
22.0 4.5 X 4.0 25.04 ]+ Y) m0 _) \$ _
84.6 4.0 X 4.5 11.1
5 n3 Q; {6 |9 l# M. P85.9 4.5 X 5.5 9.0
/ Z2 V3 c' v  i+ b8 BAv. 14.3: J, F9 [  ]2 \7 c7 J) L) Y
4+ S5 [2 y! a1 R; N! u
8
2 X. ?. I7 O# l8 ~$ A10& `& h" m* F/ h: {" @; ]
12
  R8 E, r3 u, R! N- ]- V176 P7 N2 F1 _7 J$ B8 r* q
Topical testosterone; \6 f) U3 s1 q( X6 T6 X
34.6 4.5 X 6.5 85
! H" a; B6 X: U! T* b4 g& ]38.8 6.0 X 8.5 70
2 B! m/ {) r- h. c0 v( V40.0 6.0 X 6.5 62.5
- Y: S. b0 x! {2 K93.6 6.0 X 7.0 55.5
2 x4 Y5 z0 I/ U. B95.0 6.5 X 7.0 27.2
+ Y2 F7 v1 A+ b* rAv. 60.04 L1 i1 x* N4 f9 Y! X
available testosterone. Again, emphasis should be placed on
$ w% Q; P3 W- D0 Q" wearly therapy when lower levels of testosterone appear to8 B2 f, {" `; c
provide the best responses. The earlier therapy is instituted: T7 g- o$ m7 m6 P) ?7 I, A; @- X
the more likely there will be an excellent response with low6 X  B. D2 B- F4 N  K" R$ V
serum levels. Response occurs throughout adolescence as4 B2 i! B( S6 ]* i; G% _
noted in nomograms of phallic growth. 7 The actual response
- U& C6 k0 [" w" Xto a given serum level of testosterone is much greater at birth8 M; x2 R  S5 x; H
and gradually decreases as boys reach puberty. This is most: V3 e& n* |' v+ D  _9 `' P
likely related to the conversion of testosterone to dihydrotes-0 X# n3 |6 u  u
tosterone and correlates well with the studies of testosterone* X3 A) b4 v. ^0 K! v
conversion in foreskin at various ages.
9 b4 o; Z; z: C- t& \% o" {The question arises regarding early treatment as to whether
) l& Z, d- ^9 `4 n  ?one might sacrifice ultimate potential growth as with acceler-
# g" b, L' _* U/ Q) V: G/ o4 e( Gated bone growth. The situation appears quite the reverse
9 I8 r5 G* o7 d* B) U) ewith phallic response. If the early growth period is not used3 A1 z4 V7 \, N# c* k
when 5a reductase activity is greatest then potential growth. Z9 A# c6 d7 P" q7 H
may be lost. We have not observed any regression of growth+ }$ O) ]# r; G* p
attained with topical or gonadotropin therapy. It may well
, O! k) w, b$ G0 Q) Kbe that some patients will show little or no response to any3 T) k. @# f& J( X& H
form of therapy. This would suggest a defect in the ability to. S6 l: F- k. q- G: n
convert testosterone to dihydrotestosterone and indicate that
' X- w8 t! u3 [2 e. G( Gphallic and peripheral skin, and subcutaneous tissue should% z- T2 s7 J: A# g: e
be compared for 5a reductase activity.
# ]+ ]0 ^5 A" J, V+ I! ]A, loop enlarges to measure penile girth in millimeters. B,
4 g0 p0 c4 z+ S7 f( Xexample of penile girth computed easily and accurately.+ \5 a+ h# |* u9 n: ~' f
conversion of testosterone to dihydrotestosterone. It is in this
( T1 ~! \! @( }. [: \* \older group that others have noted high levels of serum( h' g4 s0 }  f' S( @
testosterone with topical application. It would also appear* h# c' {# _1 l( _
that phallic response during puberty is related directly to the" |) R  [( e8 ]) ]
serum testosterone level. There also is other evidence of local
: @* z4 X& m; G7 m: C' u( Kresponse to testosterone with hair growth and with spermato-8 R% U) m9 S3 Z0 y, r1 }/ ?
genesis. 5• 6
5 x4 K$ G3 x# g' E( OAdministration of larger doses of gonadotropin or systemic
1 S/ ?+ A- y* P7 ~6 ~testosterone, as well as topical applications that produce& ?6 p7 D/ @$ I3 C7 e4 T
higher levels of serum testosterone (150 to 900 ng./dl.), will7 n- t+ u, O" z# k, h
also produce phallic growth but risks accelerated skeletal- A2 J- y8 h! k2 ?+ r- V5 N
maturation even after stopping treatment. It would appear
. ?  s3 b- X2 O2 q/ Sthat this may be avoided by topical applications of testosterone! R8 X6 \8 N: K! M( J0 `0 T/ m, O. f
and monitoring of serum testosterone. Even with this control) T8 H" r0 D: ^( B
the duration of our therapy did not exceed 3 weeks at any% o4 T- q  i. r; ]% Z% @
time. It is apparent that the prepuberal male subject may
) G8 O: f5 d2 ], g& E3 z& c  |) fsuffer accelerated bone growth with testosterone levels near% d2 g4 p5 p# ^- U" }) I
200 ng./dl. When skeletal maturation is complete the level of8 |5 B7 |3 i, S" m( V
serum testosterone can be maintained in the 700 to 1,300 ng./
) w% ~8 m2 ^7 H  B* S( e1 V  G6 ^* Fdl. range to stimulate phallic growth and secondary sexual
) x. R: X3 E+ [/ u& u0 Nchanges. Therefore, after skeletal maturation parenteral tes-: |: E$ i2 D" }3 n
tosterone may be used to advantage. Before skeletal matura-
3 C4 g: m& y) \6 q' A. A$ S& ^tion care must be taken to avoid maintaining levels of serum
9 j/ O2 p7 K* N8 C6 ztestosterone more than 100 ng./dl. Low-dose gonadotropin3 H; ~& D: Z6 w
depends upon intrinsic testicular activity and may require
6 U1 A3 E( j  f3 u+ `& ]) vprolonged administration for any response./ G% p& ]8 R5 h. J
Alternately, topical testosterone does not depend upon tes-
+ i8 A7 F0 J; Z' iticular function and may provide a more constant level of1 F, y* u3 P$ d. J
REFERENCES1 m  ^7 v& m) F: A8 ^
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,+ Y4 \( s1 y2 _" R! B" ?
R.: The local application of testosterone cream to the prepub-$ B. ]+ x9 L, Q6 C; u
ertal phallus. J. Urol., 105: 905, 1971." B) ?1 O1 `$ V0 N1 a, q- T
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! F3 {+ N2 X! M& ptreatment for micropenis during early childhood. J. Pediat.,: `, }- w8 h( U. c) p( |* a
83: 247, 1973.! k( C5 K# B4 s" K! ~/ P% q6 z: y
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( ~( {% ^( V/ Y; g
one therapy for penile growth. Urology, 6: 708, 1975.
* B1 p9 L6 y) x8 W4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ M5 U- k. I* R8 U( F1 X, M6 ^
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
8 P1 S) p& O/ jskin slices of man. J. Clin. Invest., 48: 371, 1969." T+ v' c# C2 D# \
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
7 Y+ j* |  e) b; gby topical application of androgens. J.A.M.A., 191: 521, 1965.$ }) A" w( g5 r" {& l. o1 K! J: C
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 K1 u* ~5 R8 K4 F! ~8 S
androgenic effect of interstitial cell tumor of the testis. J.
9 Y# }9 G" W2 {7 E; e3 pUrol., 104: 774, 1970.% [6 A( V3 D& d: h( m
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; @* x* N5 R) V/ m+ Q* |$ w5 `' dtion in the male genitalia from birth to maturity. J. Urol., 48:
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