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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
( [9 @3 q  A' r+ p0 r  NGONADOTROPIN+ O- `8 P' C( _4 V$ C. A
RICHARD C. KLUGO* AND JOSEPH C. CERNY8 O3 h$ y6 y# {7 R. G3 i: F
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# M2 b3 L2 J" r9 L0 _. t6 K' kABSTRACT, ^" z) w8 {# i5 l& A
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 i! D) _8 q' x+ N7 Owith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ k! T2 s, n0 |, U2 Ctropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone- s# w' X; V! P; d! Q! \9 w, d
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, Z3 W5 O! x7 w+ U
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent/ s; `9 l# ]4 x
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% _0 ]/ K$ N5 p. I( Y) vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response% s' _0 q" R3 `& C( i9 |" |  `( Y9 w
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ [& f* S/ A/ m7 G
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
3 e# F" D" |! @) ygrowth. The response appears to be greater in younger children, which is consistent with previ-
$ ~% S1 M2 g5 t* t2 ]3 z' E' Dously published studies of age-related 5 reductase activity.
  _; y. r& g  b+ N  iChildren with microphallus regardless of its etiology will
5 e; r& g0 e( `, `  l3 l" M0 I/ L  R# Crequire augmentation or consideration for alteration of exter-$ B& }3 x: h3 P1 s
nal genitalia. In many instances urethroplasty for hypo-
8 a7 d- {0 y% H/ ^. Yspadias is easier with previous stimulation of phallic growth.3 g  i* R% r9 Z
The use of testosterone administered parenterally or topically( y& b/ d, ^0 i1 t
has produced effective phallic growth. 1- 3 The mechanism of
& H2 c: m8 Y, X; i% |" ?response has been considered as local or systemic. With this6 }% K7 O' Z+ t) J
in mind we studied 5 children with microphallus for response
0 D* F5 r  l9 T/ q: ?% \to gonadotropin and to topical testosterone independently.
+ f# ]% J& m; [- }/ v. i+ SMATERIALS AND METHODS* w0 K9 z1 F) B& q
Five 46 XY male subjects between 3 and 17 years old were
- w3 Y0 B- S% Bevaluated for serum testosterone levels and hypothalamic9 K* Q% |: E: V" h
function. Of these 5 boys 2 were considered to have Kallmann's8 W$ M* ~6 B; u2 @0 X6 y
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-% p7 W/ l2 q1 n" S& ^2 T) P+ J
lamic deficiency. After evaluation of response to luteinizing/ A1 j1 z; u  R/ t6 R
hormone-releasing hormone these patients were treated with
: ~. N' ?  _* }) k+ {" x4 O1,000 units of gonadotropin weekly for 3 weeks. Six weeks
5 o7 t5 N- t" `  @2 Z2 K! ]after completion of gonadotropin therapy 10 per cent topical0 ^! n$ W0 O# M3 M  R6 k6 L
testosterone was applied to the phallus twice daily for 3 weeks.
( x# ^. Z9 h& R7 G4 D" XSerum testosterone, luteinizing hormone and follicle-stimulat-: F1 A0 k5 z, T7 C; E4 W* D! b
ing hormone were monitored before, during and after comple-2 K, [% B% v8 B5 u' w8 f* G) C
tion of each phase of therapy. Penile stretch length was
! l3 w& D3 M: S& }1 @$ X; Nobtained by measuring from the symphysis pubis to the tip of
* I) l; w: a4 S- B- x& j5 E' cthe glans. Penile circumferential (girth) measurements were4 K9 |' a3 W  C. n5 c
obtained using an orthopedic digital measuring device (see
+ m( K  q, O: l* Z- h% I6 zfigure).1 {# W* n3 }  P! G- y; X
RESULTS
4 K  I/ {# V. U; L4 K# \Serum testosterone increased moderately to levels between
; \* D0 W+ z' j) Y$ V50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
) }( T% F3 @7 Q1 I4 I1 \5 Aterone levels with topical testosterone remained near pre-0 ~7 c- L$ m$ b: i& ?, X
treatment levels (35 ng./dl.) or were elevated to similar levels: q; h6 J- t' g7 G6 R8 }
developed after gonadotropin therapy (96 ng./dl.). Higher6 U5 a1 G  C0 }! h9 E
serum levels were noted in older patients (12 and 17 years old),+ @" n4 C- F' E* j+ ~
while lower levels persisted in younger patients (4, 8, and 10' i$ x2 H2 \9 }. y& Q' I6 a  N: K
years old) (see table). Despite absence of profound alterations( V  Z5 u9 x" k. P% R. t# {
of serum testosterone the topical therapy provided a greater: O7 S: w3 {* B6 e
Accepted for publication July 1, 1977. ·
- X! q2 t# {6 R9 f5 y# Q3 QRead at annual meeting of American Urological Association,! e$ S( c0 _& L& F
Chicago, Illinois, April 24-28, 1977.
: I' e- n' G- T* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 G- }3 H! L8 K  x5 o9 c/ J2799 W. Grand Blvd., Detroit, Michigan 48202.
- q0 `2 P" F2 S1 ?improvement in phallic growth compared to gonadotropin.! \- p6 }8 ?- A# n: A
Average phallic growth with gonadotropin was 14.3 per cent
7 D6 Q; n! Y& t- d+ Z$ ~increase in length and 5.0 per cent increase of girth. Topical
; M" a1 A" U% stestosterone produced a 60.0 per cent increase of phallic length
: z6 S' m. l5 ]) S/ G& Hand 52.9 per cent increase of girth (circumference). The
# _3 C$ L  B0 |6 m+ K$ Jresponse to topical testosterone was greatest in children be-
5 P9 F$ T% }0 j. l! M' S( Mtween 4 and 8 years old, with a gradual decrease to age 17+ G$ t# b# s9 B6 u+ {8 W4 l$ A
years (see table).
2 F1 u7 N7 F: }4 s. K7 ]+ _DISCUSSION
7 Y# t1 P; B5 GTopical testosterone has been used effectively by other+ `9 {# K2 t$ S9 L4 C" k
clinicians but its mode of action remains controversial. Im-; S+ Y6 S1 Y8 v+ f; E
mergut and associates reported an excellent growth response
  f+ k, D: C6 P' zto topical testosterone with low levels of serum testosterone,
0 E- i# ?, ?0 w8 T) ]suggesting a local effect.1 Others have obtained growth re-
5 ~/ ]$ I+ u- E5 P2 d2 ?3 F( Rsponse with high. levels of serum testosterone after topical2 }8 a1 |. o( M2 L5 _! F* o
administration, suggesting a systemic response. 3 The use of
6 m+ _6 S& {5 K  {' Z. D( `2 ?gonadotropin to obtain levels of serum testosterone compara-9 J. N( o+ U! E
ble to levels obtained with topical testosterone would seem to
7 g$ g0 @0 u; Hprovide a means to compare the relative effectiveness of
  K9 A, o4 u" }topical testosterone to systemic testosterone effect. It cer-  }9 g) D% w4 G1 x( g+ K
tainly has been established that gonadotropin as well as par-
5 H4 ~( O- R: ?0 [+ G# [- Genteral testosterone administration will produce genital4 i5 U: M7 n3 V$ w; d2 j# d( @
growth. Our report shows that the growth of the phallus was, e6 p$ Q. o& j/ P6 N( Y# e
significantly greater with topical applications than with go-: [6 G( v; ^3 T. z& i% S- [
nadotropin, particularly in children less than 10 years old.3 t& d! X2 N7 c( S! a  m& e
The levels of serum testosterone remained similar or lower
. U4 b" R$ O$ Gthan with gonadotropin during therapy, suggesting that topi-* o7 x, ~8 Q6 `9 A- X( l6 F
cal application produces genital growth by its local effect as: ]% x# {; S1 o" ^
well as its systemic effect.
, C9 i* ~. F8 z: t  w1 S- e, ?Review of our patients and their growth response related to9 m4 O: @( N' |5 c, H
age shows a greater growth response at an earlier age. This is' t! r  h  b7 M9 I! |
consistent with the findings of Wilson and Walker, who) h0 m  {# T* \
reported an increased conversion of testosterone to dihydrotes-
0 o; H" p1 ^2 b) \  Jtosterone in the foreskin of neonates and infants.4 This activ-- y6 J: _4 m" Q$ z5 N0 e9 h0 T5 ~
ity gradually decreases with age until puberty when it ap-2 I+ j, s# Z1 f' ~) D" E9 U! z0 Z! v
proaches the same level of activity as peripheral skin. It may+ i0 d5 {* X7 s) j
well be that absorption of testosterone is less when applied at& Z0 p; L/ X! ^+ x
an earlier age as suggested by lower serum levels in children
9 i# c+ t: m! I* a7 x! b; K; @: {less than 10 years old. This fact may be explained by the+ _! r+ \2 Z( r( S" I& s! {+ b: n4 B% X
greater ability of phallic skin to convert testosterone to dihy-
, e6 g/ i: U0 u4 e& z# s& c: Rdrotestosterone at this age. Conversely, serum levels in older
9 p# W( E; |9 Y* M) u0 Z/ Qpatients were higher, possibly because of decreased local
# `: a: k. Q- p7 j667
/ R9 V( k, V/ F668 KLUGO AND CERNY
& |/ l" ^1 s2 f3 A* ePt. Age% ^4 |! I. Z- d5 H3 m$ F
(yrs.)! p: x" q1 G: @: G$ u; z9 t
Serum Testosterone Phallus (cm.) Change Length
: ?! a1 l5 v. _& j(ng./dl.) Girth x Length (%)
! v5 G6 X  R( U/ Q4
2 A0 z6 x5 n( i8 r& I8# \7 t+ [+ P# o% N5 |: k9 M% R
10, G) v& z5 r) |8 ?7 L
12
1 }3 w4 v9 @8 p' V175 a- B* E3 ^1 C. i( M2 c9 l
Gonadotropin% L6 N4 O7 K7 t0 h. u
71.6 2.0 X 3 16.6
: n) O& @) _+ S9 `1 s50.4 4.0 X 5.0 20.0' R; R! l0 A3 M  R
22.0 4.5 X 4.0 25.0
) [; `, I3 X& z  e  o- N& U84.6 4.0 X 4.5 11.1) v1 ?& K! O+ G$ |
85.9 4.5 X 5.5 9.0
2 T) y3 g+ n1 U( c' a/ g( ]" nAv. 14.37 D5 Q+ _  K. c: y& }
44 k9 ?' ?7 w2 m" M% q  C
8) ~' y2 J4 a3 v* c
10
, V4 u# ~' r1 G" u! C& N12
' m! Y  A4 Q+ Z8 M17: l! c* T* q4 g7 ^) Z
Topical testosterone5 f) P, E/ x" G' l: B' i
34.6 4.5 X 6.5 85+ K# O, c8 z4 h% u! v
38.8 6.0 X 8.5 70
+ ~( ^' y; M. r2 ]40.0 6.0 X 6.5 62.5- W* M: ]9 T! h; x; X
93.6 6.0 X 7.0 55.5
9 G" l6 R0 X  {% [4 b0 b% ~4 q95.0 6.5 X 7.0 27.2
8 v. x* @2 w9 f! [4 IAv. 60.0! P$ j7 H) g$ A$ |4 z( Q
available testosterone. Again, emphasis should be placed on! Y: N3 f8 L8 y& g5 Z1 _( ~
early therapy when lower levels of testosterone appear to: T9 V, T% S  R9 S' ~5 a) A
provide the best responses. The earlier therapy is instituted; o, g8 u8 a7 ~! G5 f
the more likely there will be an excellent response with low
3 H# z4 s/ w) a0 Y+ q$ Y1 e3 T3 oserum levels. Response occurs throughout adolescence as
4 l" v7 W) e8 D3 D! o* inoted in nomograms of phallic growth. 7 The actual response
5 }, J  Y6 K7 }- z/ Fto a given serum level of testosterone is much greater at birth
. w' x7 r  T  gand gradually decreases as boys reach puberty. This is most
! ^7 {/ k1 {+ X  z9 p7 R0 K, }likely related to the conversion of testosterone to dihydrotes-) ]! z! g: k0 D9 o5 e% g( m
tosterone and correlates well with the studies of testosterone
" b  H. Q' Z! a1 ^4 x% S" Zconversion in foreskin at various ages.; s2 P% E( V+ {; L9 s' B
The question arises regarding early treatment as to whether" G3 P4 [8 e3 E
one might sacrifice ultimate potential growth as with acceler-$ R( d$ `$ h' D! a  M% h- q) b
ated bone growth. The situation appears quite the reverse
2 g- ?8 q' U0 g4 Awith phallic response. If the early growth period is not used
- k# |' J$ v5 l; z0 jwhen 5a reductase activity is greatest then potential growth
5 y" M2 W, c/ s4 Fmay be lost. We have not observed any regression of growth
4 j9 ~1 W5 e/ a( r6 Pattained with topical or gonadotropin therapy. It may well9 V' P. e. J8 }2 O, C$ g
be that some patients will show little or no response to any
' t. k5 M+ T# uform of therapy. This would suggest a defect in the ability to0 N5 @2 d5 I0 p0 E, m; [
convert testosterone to dihydrotestosterone and indicate that( w  r# |8 [. l  z) H
phallic and peripheral skin, and subcutaneous tissue should
( P' V2 r3 X3 N) _3 K- M7 O! Ibe compared for 5a reductase activity.
# K; n6 O6 N' K! UA, loop enlarges to measure penile girth in millimeters. B,
8 a2 W! c0 D; Y2 Z2 W: V; vexample of penile girth computed easily and accurately./ U& i5 u4 ^# I/ Z. Z2 _8 w0 y
conversion of testosterone to dihydrotestosterone. It is in this' {$ f: l- h/ ^2 D  I- l3 `
older group that others have noted high levels of serum
- J, G7 S4 N. g! h0 ]2 Stestosterone with topical application. It would also appear9 J! @4 X  h# d+ Q  ^. e& C
that phallic response during puberty is related directly to the+ s2 H8 {. }0 ?" P
serum testosterone level. There also is other evidence of local0 c+ q2 b/ b# k, U! S) @
response to testosterone with hair growth and with spermato-
: C! r- N" m: U: Pgenesis. 5• 6
9 T1 [3 ~, G6 a4 [% ?+ |6 OAdministration of larger doses of gonadotropin or systemic
4 Z. l% |. _! n: F& ^$ X4 etestosterone, as well as topical applications that produce: R/ A+ r, Y8 i- F
higher levels of serum testosterone (150 to 900 ng./dl.), will
8 w, V/ y! M6 N4 Q+ X' Qalso produce phallic growth but risks accelerated skeletal7 _: S( f: @, v: E% q" C! _
maturation even after stopping treatment. It would appear" s) m1 V* H* J3 }# W$ e
that this may be avoided by topical applications of testosterone
& P6 u; A: T( m, i9 ^and monitoring of serum testosterone. Even with this control' v* B1 K( I3 c! b6 {
the duration of our therapy did not exceed 3 weeks at any% y3 l0 R. b, w
time. It is apparent that the prepuberal male subject may0 y% c% B% R6 L# n+ E
suffer accelerated bone growth with testosterone levels near
8 o4 W6 j4 o  z- w1 g200 ng./dl. When skeletal maturation is complete the level of8 M8 N7 C( t$ b# T! P: p: U5 K
serum testosterone can be maintained in the 700 to 1,300 ng./4 J& i! ?* O% z6 a0 l( w" @( ]
dl. range to stimulate phallic growth and secondary sexual  W/ ?: L* _5 Q  o; c
changes. Therefore, after skeletal maturation parenteral tes-
5 \- P7 C2 R, K7 O  O0 Atosterone may be used to advantage. Before skeletal matura-8 H5 O; V7 a8 }6 p( ?$ i
tion care must be taken to avoid maintaining levels of serum
7 U8 J; W7 p5 L9 l: X- s9 [testosterone more than 100 ng./dl. Low-dose gonadotropin9 j# Y6 n: w5 A
depends upon intrinsic testicular activity and may require
: D* c3 c' d' B6 V! J: ^% hprolonged administration for any response.
- |+ A2 ~/ k) o# H: |0 iAlternately, topical testosterone does not depend upon tes-9 }' W- z+ W) ?- {8 M1 e; W
ticular function and may provide a more constant level of/ v; p! l% B% t  g5 f/ \
REFERENCES
4 i5 }7 @( _( L( f3 c1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 U2 j$ D% ~& C* ^4 bR.: The local application of testosterone cream to the prepub-
9 B2 Z3 n3 z8 b1 ]0 _ertal phallus. J. Urol., 105: 905, 1971.
7 G  N/ Z: Q0 Q3 q3 P: H2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( H! A5 n2 O) W9 Y7 h
treatment for micropenis during early childhood. J. Pediat.,
& |: f: o5 W7 ^' H83: 247, 1973.0 J: g' {% D7 i9 b; l
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ R0 X  ]$ L) G- G" F9 Bone therapy for penile growth. Urology, 6: 708, 1975.
2 e: O7 m. ]1 v# N' m) [4 N4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 L$ R. k& T# @: g$ c# @8 T+ Cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by0 P, }3 O& E; @% @
skin slices of man. J. Clin. Invest., 48: 371, 1969.8 e1 F1 q6 p( V" H6 `( }
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
$ \- P+ \% t, h! E* J1 ~! j) tby topical application of androgens. J.A.M.A., 191: 521, 1965.
9 o. p' Z7 m6 H# [  G) t) m3 r- m6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
" y, C1 b: l2 Z0 W' Qandrogenic effect of interstitial cell tumor of the testis. J.1 d" ?: O2 r; {( p/ d
Urol., 104: 774, 1970.
$ t* g: @+ H' k, M* A9 j& q7 k/ I8 `7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-) {" x, o) i0 }/ o+ Q' V) c
tion in the male genitalia from birth to maturity. J. Urol., 48:
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