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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 s: u% `* t! N' mGONADOTROPIN
9 G  @2 V4 C; L% b; SRICHARD C. KLUGO* AND JOSEPH C. CERNY) m! ~6 s5 D7 ~
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan  F( N, I! }* @# Y/ J/ H* P8 X7 ^
ABSTRACT
2 y8 z1 ~" s& Y7 I6 T8 E! |4 xFive patients were treated with gonadotropin and topical testosterone for micropenis associated: a3 r# g4 @" J8 u/ J
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' F# {4 A8 {1 P. \8 v; c" ytropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( b1 K' _3 t9 H0 \: Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( c1 l- S2 ?2 Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! q0 B1 D3 x8 g  |0 t) m
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 S8 A7 o4 r- o+ l  l3 y
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
! L" I  l6 i% Ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This. [9 Y! u- A) E. ^, I
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) l4 A6 G2 Y( L  _( q, cgrowth. The response appears to be greater in younger children, which is consistent with previ-0 C; v0 d; Q5 T8 d
ously published studies of age-related 5 reductase activity.' q& }% y. G" V1 a$ z- ]: V% M. i
Children with microphallus regardless of its etiology will
9 A% ~$ Z$ w4 }/ Qrequire augmentation or consideration for alteration of exter-
9 a5 U) F  E; r9 X; B) S' |' Knal genitalia. In many instances urethroplasty for hypo-
% l; b: c/ _7 @1 c0 Ospadias is easier with previous stimulation of phallic growth.
  S! E* T' z8 T' k  o9 x. wThe use of testosterone administered parenterally or topically8 I1 N  `$ H/ H; o- X5 m" W5 z0 U
has produced effective phallic growth. 1- 3 The mechanism of) t! x9 q4 w- u5 I% }- L7 P0 E; _3 _
response has been considered as local or systemic. With this
: K: ~" d/ t4 {# Q7 N' Lin mind we studied 5 children with microphallus for response, y* c) h6 x5 _# a
to gonadotropin and to topical testosterone independently.
4 J/ {* U/ i; u, p( gMATERIALS AND METHODS/ i/ c+ Q5 S0 q: ^
Five 46 XY male subjects between 3 and 17 years old were4 c7 C8 \* d' M0 G& I
evaluated for serum testosterone levels and hypothalamic
. b7 E, n8 L4 afunction. Of these 5 boys 2 were considered to have Kallmann's
1 j+ z0 T" \/ y/ l: lsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 Q* W( c* s; o6 {5 X4 j2 Mlamic deficiency. After evaluation of response to luteinizing4 }% v% M/ C- D
hormone-releasing hormone these patients were treated with
. L" h8 w1 z% U. Y! V0 z6 j1,000 units of gonadotropin weekly for 3 weeks. Six weeks
9 C$ f1 j+ s% H4 _: Lafter completion of gonadotropin therapy 10 per cent topical9 S# W7 [. f1 Z8 W
testosterone was applied to the phallus twice daily for 3 weeks.
$ z8 T& F9 B* D4 J2 m6 O6 B8 SSerum testosterone, luteinizing hormone and follicle-stimulat-
- ?8 w" y' L: A% king hormone were monitored before, during and after comple-* J9 U' I8 H& ~; v4 M
tion of each phase of therapy. Penile stretch length was
4 X& T" j, P+ c- {obtained by measuring from the symphysis pubis to the tip of
' V; N- b6 Z5 [  y/ Cthe glans. Penile circumferential (girth) measurements were6 a4 b- L0 S0 k5 @2 L
obtained using an orthopedic digital measuring device (see
" m7 W9 t3 D; `% J+ J6 M+ y7 bfigure).4 C" e& B# F" X% X* q' _" q; o  k
RESULTS
% K" l- g8 m9 WSerum testosterone increased moderately to levels between
5 t5 B' r* s( u$ X# Y- X; I50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
- x; \! x: W# |terone levels with topical testosterone remained near pre-0 W8 C& W) L0 x  r& y, C  T
treatment levels (35 ng./dl.) or were elevated to similar levels" T- y- R( F  R; r- j/ i
developed after gonadotropin therapy (96 ng./dl.). Higher) Z0 C* v6 `4 ~; A2 T
serum levels were noted in older patients (12 and 17 years old),1 |; o6 }4 W+ j; |8 A! i/ ~; a# G
while lower levels persisted in younger patients (4, 8, and 10
: x# V, K) Z- c% ~years old) (see table). Despite absence of profound alterations
9 J' N" ]! |' m/ n% E: v$ Mof serum testosterone the topical therapy provided a greater4 ?: f- `/ h* O4 Z( [4 b
Accepted for publication July 1, 1977. ·0 _8 Z; p4 Q" m
Read at annual meeting of American Urological Association,
. k6 I9 ?' j4 e0 OChicago, Illinois, April 24-28, 1977.  ^# c) v1 y* I- K$ a# j: Z
* Requests for reprints: Division of Urology, Henry Ford Hospital,
% E" G# S( n, ^0 Q$ ]3 D8 F2 U2799 W. Grand Blvd., Detroit, Michigan 48202.- P5 U) u- w  ^9 e$ P
improvement in phallic growth compared to gonadotropin.
; o; }* b5 o, ~4 nAverage phallic growth with gonadotropin was 14.3 per cent
' H  C% Q( \2 Dincrease in length and 5.0 per cent increase of girth. Topical! e& i4 _; V8 d8 B4 K( @
testosterone produced a 60.0 per cent increase of phallic length
" `7 N  e- N. P5 C) P9 Yand 52.9 per cent increase of girth (circumference). The
% e' n6 i) A* X0 i. t1 qresponse to topical testosterone was greatest in children be-
2 e' l5 \5 E, u: A1 F) }7 Gtween 4 and 8 years old, with a gradual decrease to age 17
2 J; \. t+ ~5 e4 K2 J! iyears (see table).  u# r3 Z' q; {
DISCUSSION
6 {) C# f- P+ T: aTopical testosterone has been used effectively by other
7 b( ]  j# l3 G/ @5 h" C5 O& Oclinicians but its mode of action remains controversial. Im-) ~  \+ s* ~# {# e' s
mergut and associates reported an excellent growth response
1 v0 M& n7 e  w$ I) z& }to topical testosterone with low levels of serum testosterone,$ M% `: C. m" p3 y, x6 ~' j3 R, ?; |* ?
suggesting a local effect.1 Others have obtained growth re-$ z. e' Y- g; b! K$ w" i; s
sponse with high. levels of serum testosterone after topical( d4 d3 A7 j9 H! q7 A$ R
administration, suggesting a systemic response. 3 The use of
9 c* n4 ?0 o5 A: N' bgonadotropin to obtain levels of serum testosterone compara-! x- ~4 \. m- l7 M, I
ble to levels obtained with topical testosterone would seem to* j) S# j/ u+ Z3 I5 M
provide a means to compare the relative effectiveness of5 [) o) X2 Q* g1 U& J# |8 P, r
topical testosterone to systemic testosterone effect. It cer-
3 L) y/ \4 ?6 utainly has been established that gonadotropin as well as par-- ^4 x: f6 b% G* ]) R& N
enteral testosterone administration will produce genital
6 {+ c5 Q8 }. d' S9 g0 J7 Ygrowth. Our report shows that the growth of the phallus was
6 }7 T0 v  r4 u% K& Z# x6 u0 }significantly greater with topical applications than with go-% G. m3 K0 R+ V9 t/ R  V
nadotropin, particularly in children less than 10 years old.
. o4 c8 c+ C0 E- jThe levels of serum testosterone remained similar or lower" G) _/ K. o; G: V1 G% X6 B5 R
than with gonadotropin during therapy, suggesting that topi-
/ t' I- f5 B$ k* ocal application produces genital growth by its local effect as2 E$ K; ~" D6 l  i. Q
well as its systemic effect.' D( z2 x, D! q; ^' C* i* X* l
Review of our patients and their growth response related to( |6 c; D6 H2 I  ]2 S: N. n
age shows a greater growth response at an earlier age. This is
* s, l. D  x% n# Jconsistent with the findings of Wilson and Walker, who! u6 J+ s$ H( j2 }
reported an increased conversion of testosterone to dihydrotes-, V, m# }: @9 l% _+ P2 S
tosterone in the foreskin of neonates and infants.4 This activ-
' U/ @9 E" h/ s' jity gradually decreases with age until puberty when it ap-2 R$ w0 j% B  m: h8 W
proaches the same level of activity as peripheral skin. It may& J" P3 A' B' V8 J' Q3 O
well be that absorption of testosterone is less when applied at
$ Q* T$ l7 F2 \# k- W) `: |* Dan earlier age as suggested by lower serum levels in children  W6 X; Y2 s1 e' m# e5 H
less than 10 years old. This fact may be explained by the
. _! d- B/ R4 E( ]' xgreater ability of phallic skin to convert testosterone to dihy-2 s9 u* I: W; H4 ]
drotestosterone at this age. Conversely, serum levels in older
- H2 E! V9 }, ppatients were higher, possibly because of decreased local
9 D) v& z+ q$ ]2 i% e0 m1 K) Z667
- z2 G# d  p8 ~3 ?668 KLUGO AND CERNY
( P$ r. j" X5 }# ePt. Age
& s0 Z- [( i) i) H4 x% m# b(yrs.)
# S0 k- r* F0 t1 j& z1 t& n( k) NSerum Testosterone Phallus (cm.) Change Length  g6 Y3 M: X/ M/ m' `2 i& R% t, _/ [7 K
(ng./dl.) Girth x Length (%)7 n7 @2 P$ \& x# L0 q& x3 H
4' Q$ ~. c% F3 o* c4 a0 Q
8& {3 o) L) r1 }/ U1 [1 k% P
10' Q8 y# x4 Y/ m* z' A% ?
12
+ H) R: W: X& `) ^4 E17" ]& B9 M5 `& _) a
Gonadotropin
+ U7 f8 d% v! C5 c* Q71.6 2.0 X 3 16.6/ {2 n% m% ^! p" z7 O+ K
50.4 4.0 X 5.0 20.0
4 H2 h  F$ h- h" q22.0 4.5 X 4.0 25.0% w, i7 c; m$ ]6 y, I
84.6 4.0 X 4.5 11.1% r2 O+ {( y$ @/ m' ?& e$ M: Y" v' ?
85.9 4.5 X 5.5 9.0
4 f4 ^& u! Z/ n: {! j9 hAv. 14.33 \8 O" _( h; ^
4
: c% R, F: x2 i! Y$ \8
  Q6 a* I  [% I* S% z7 P; S; Z10% r7 r4 B8 R. ^' u$ n! K
12
8 c$ a* p% `9 t# D8 V9 H* e17
7 ]- v2 ]; T. ]+ n( MTopical testosterone
+ _' G* Q8 O& T1 p  L4 p5 s7 M34.6 4.5 X 6.5 85% U- [: c& o. \9 t) E7 {5 N
38.8 6.0 X 8.5 70
% r0 L$ ?& _' H; r* Q7 A# q40.0 6.0 X 6.5 62.52 ^( R: z3 z* w. z/ |
93.6 6.0 X 7.0 55.53 e" U2 b$ |  T# ^
95.0 6.5 X 7.0 27.21 ]6 B* {, n8 G3 f7 s
Av. 60.0
" ]5 b- b) d1 s+ ]available testosterone. Again, emphasis should be placed on4 e* w/ C% e& V: }! R
early therapy when lower levels of testosterone appear to
8 d, E# b7 j6 D# L0 Jprovide the best responses. The earlier therapy is instituted' x  O* b& I1 h, K% F0 ^4 `0 M$ j. K
the more likely there will be an excellent response with low
7 @) r$ m5 x; ]& @) P* `. Jserum levels. Response occurs throughout adolescence as. v; W+ G; B) M' A1 d' B) |9 \
noted in nomograms of phallic growth. 7 The actual response
' r  d0 Q9 k+ jto a given serum level of testosterone is much greater at birth
6 n; q9 b' {" y" z/ M( b3 k# Tand gradually decreases as boys reach puberty. This is most
; M  {5 |5 I8 D( _+ {likely related to the conversion of testosterone to dihydrotes-
4 x8 f! t! E* s% i; O" @tosterone and correlates well with the studies of testosterone
5 I) ], ^% }4 w# L: z1 Rconversion in foreskin at various ages.
. t9 v+ O9 r1 |+ rThe question arises regarding early treatment as to whether
4 n" o7 w( n, C/ a. F9 rone might sacrifice ultimate potential growth as with acceler-, H( ?8 b8 @0 {+ w. O" n
ated bone growth. The situation appears quite the reverse. ?" I( M3 m0 s: ?! g
with phallic response. If the early growth period is not used
( {) ]; K+ h: J& n: Jwhen 5a reductase activity is greatest then potential growth
2 q* n! d  I, \0 {: Dmay be lost. We have not observed any regression of growth
2 Y  J( h0 v7 V7 X% iattained with topical or gonadotropin therapy. It may well
) v. t9 I9 Q3 W' U+ i3 vbe that some patients will show little or no response to any" R9 x0 X: i- H/ n$ ~9 ~8 A
form of therapy. This would suggest a defect in the ability to4 {* b. X, a) C6 u+ B7 K( E6 ~' r% V
convert testosterone to dihydrotestosterone and indicate that  I1 ~2 T0 x8 W9 e. x8 u
phallic and peripheral skin, and subcutaneous tissue should5 i. ~, q6 k2 q
be compared for 5a reductase activity.+ e* S  @' }6 Q9 @0 j
A, loop enlarges to measure penile girth in millimeters. B,; V3 b6 P. j& E2 ^2 I
example of penile girth computed easily and accurately.
2 V/ l* Z2 R- A3 D+ i/ C' v) }conversion of testosterone to dihydrotestosterone. It is in this
" a8 B# }0 t* m3 K9 W7 w% \9 _' Uolder group that others have noted high levels of serum( a; L! y3 f' `. ]# u
testosterone with topical application. It would also appear
) s0 Y# D# z) I- ~' U; ythat phallic response during puberty is related directly to the
- ~) Y& ^4 Z- V& N/ K& a' o" S5 mserum testosterone level. There also is other evidence of local/ Y! {* f: l: R# J( b
response to testosterone with hair growth and with spermato-7 Z% Y' p3 I  ?. t% d# ]+ X* S
genesis. 5• 6
" @1 c/ l& V& j* ^1 q! X; \Administration of larger doses of gonadotropin or systemic$ s- M: d, B8 M$ ]0 a4 t
testosterone, as well as topical applications that produce
" Z# _0 X0 h& b# N8 Ohigher levels of serum testosterone (150 to 900 ng./dl.), will* G2 v$ e) J7 C$ X& q7 T0 b
also produce phallic growth but risks accelerated skeletal
" \! A) A0 u: Qmaturation even after stopping treatment. It would appear. t& R1 b- ^3 d9 l5 w* n
that this may be avoided by topical applications of testosterone! c' [2 \& a+ t. S4 I
and monitoring of serum testosterone. Even with this control  t1 M7 e" Y& |2 O1 i6 ~
the duration of our therapy did not exceed 3 weeks at any
, n# H8 r) ]7 G' u7 g8 w' d  gtime. It is apparent that the prepuberal male subject may
! y& V& g5 A- V' M; @, A. Qsuffer accelerated bone growth with testosterone levels near) G6 e/ k, e. F5 N
200 ng./dl. When skeletal maturation is complete the level of3 g5 V  i$ s6 J9 M
serum testosterone can be maintained in the 700 to 1,300 ng./
7 U5 T' S' e! h; y) y/ L& \dl. range to stimulate phallic growth and secondary sexual! W; s, j+ C8 c% C# z! a0 z
changes. Therefore, after skeletal maturation parenteral tes-
- L/ i  J  B* f6 [7 |tosterone may be used to advantage. Before skeletal matura-
/ t5 g, t& b) Z" y2 m- qtion care must be taken to avoid maintaining levels of serum
0 I; \! q' Y% c% Jtestosterone more than 100 ng./dl. Low-dose gonadotropin
5 a# A5 m  q& Edepends upon intrinsic testicular activity and may require5 @3 q3 p' o2 [) Z. C1 T3 p
prolonged administration for any response.2 |! _. a; ?8 f$ r0 n
Alternately, topical testosterone does not depend upon tes-6 ?) T" q7 f6 s* |( Z4 h4 S
ticular function and may provide a more constant level of
( b  q8 U  d' a2 O* dREFERENCES
+ W( A9 o( L2 n# w# g. f6 u1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,0 P2 @. I) e- y% O* D/ [( u
R.: The local application of testosterone cream to the prepub-3 n" o% |, i4 `( T6 @
ertal phallus. J. Urol., 105: 905, 1971.
, _( O6 v" c3 T8 ^2 f2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, w1 E* ]9 \1 f! V# a
treatment for micropenis during early childhood. J. Pediat.,  a/ C, X" W. K9 J- F' a
83: 247, 1973.
( M) H! T: q3 r; }3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* O/ H7 }. \# Y1 K' l$ Aone therapy for penile growth. Urology, 6: 708, 1975.
. ?: r) u& F7 F* r' l2 A( |+ \4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone% S' v$ L$ R* ^1 @% \
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 P5 J  \8 A' F$ ?6 N0 q4 [% w
skin slices of man. J. Clin. Invest., 48: 371, 1969.8 [0 k/ O  U7 {6 b# e" c
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
! u9 D% }4 M7 G0 u+ q) Y& E; Wby topical application of androgens. J.A.M.A., 191: 521, 1965.! e7 f! |: Y% ]# o
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
* w; e# j, d' f% s  Y! }1 jandrogenic effect of interstitial cell tumor of the testis. J.
' o0 r- Y( ~6 o1 n0 kUrol., 104: 774, 1970./ C9 C( m# P( ~7 I7 ^* U
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-: P' H. H, u1 T; m: R1 f2 v, R2 t7 d
tion in the male genitalia from birth to maturity. J. Urol., 48:
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