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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 x# Q& O" f: \GONADOTROPIN! B& B8 l" d* l. S7 T6 M& A
RICHARD C. KLUGO* AND JOSEPH C. CERNY
* w* W" m8 X: B2 MFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ g, Y9 ^! o: x% T6 h) _, `+ ?2 k9 }ABSTRACT; i; Y4 d9 B5 r9 _& _* }8 `
Five patients were treated with gonadotropin and topical testosterone for micropenis associated& L+ E$ `9 P2 {; n2 ?% _
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-7 a. |" a: K, f+ c5 N! O. i
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone- H6 o# s8 C; i  c- }8 }8 ~
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent" J8 z9 U3 d& f+ G+ i
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
& F4 F* \" g+ L5 y! [7 [  Aincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
& t, e* m2 J# |: N( L8 Sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# @3 W8 Z& h8 Y  boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This" u" h' n# K; O( M
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 f: O+ ~; [4 ^/ x! p. agrowth. The response appears to be greater in younger children, which is consistent with previ-
& y4 e) {4 W; _3 `6 Q3 |' a/ Oously published studies of age-related 5 reductase activity.
# N4 y  I! ~! A8 m# n8 g5 fChildren with microphallus regardless of its etiology will: G  n1 V( ]% N! X  q
require augmentation or consideration for alteration of exter-
8 G; U& Y; h3 V3 F& ^nal genitalia. In many instances urethroplasty for hypo-
! Y# K2 l3 r# t; A& Tspadias is easier with previous stimulation of phallic growth.
$ D# E/ s1 ~5 s" S( rThe use of testosterone administered parenterally or topically4 k* \. ~5 f. \
has produced effective phallic growth. 1- 3 The mechanism of# z* P9 B. s! |" z
response has been considered as local or systemic. With this
( f4 w# d& N% |in mind we studied 5 children with microphallus for response
0 I. Q+ D# P* r9 |to gonadotropin and to topical testosterone independently.$ V0 S& F% x* b+ R( M) }  H
MATERIALS AND METHODS
- |5 q1 b! r) d, UFive 46 XY male subjects between 3 and 17 years old were
, K* p. S" @/ oevaluated for serum testosterone levels and hypothalamic
/ g- z4 k2 ?1 g* Tfunction. Of these 5 boys 2 were considered to have Kallmann's1 E7 h' G  F. H. v
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 q7 ?! r3 t+ j' W  o( |lamic deficiency. After evaluation of response to luteinizing
) T. e- L1 |0 X" l8 ~4 N; Z5 vhormone-releasing hormone these patients were treated with
1 |2 G/ X( f" ?6 Y$ F8 ]9 h1,000 units of gonadotropin weekly for 3 weeks. Six weeks
7 J' @# z( W: B3 R3 E' ]after completion of gonadotropin therapy 10 per cent topical, v) T. t* C0 h6 C: @4 P- o; c
testosterone was applied to the phallus twice daily for 3 weeks.
+ b  N% o' B; X: e5 X& E0 p1 ISerum testosterone, luteinizing hormone and follicle-stimulat-
' e1 K, N9 K8 v/ Uing hormone were monitored before, during and after comple-1 M/ R) _; z- ^" \" U5 t6 r+ \" E
tion of each phase of therapy. Penile stretch length was
5 j# r  o6 A2 H; J) l6 Y. i/ {obtained by measuring from the symphysis pubis to the tip of
' N* m5 i; f+ g" Rthe glans. Penile circumferential (girth) measurements were
+ s; i" F8 L1 Mobtained using an orthopedic digital measuring device (see' ?! d) U9 H1 `
figure).
. M% H0 s0 u' I! Z6 ~RESULTS
  V3 s4 @, ^0 bSerum testosterone increased moderately to levels between( U' M8 k7 _" s3 B* M
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: P( ~( A# N3 y* h4 |2 d# C3 x
terone levels with topical testosterone remained near pre-
5 e- r/ d0 j- C% j* t" k1 C( qtreatment levels (35 ng./dl.) or were elevated to similar levels1 b  }( g8 s2 c' ^; `# {
developed after gonadotropin therapy (96 ng./dl.). Higher
( V/ F8 p. O! H' r( f/ v: Oserum levels were noted in older patients (12 and 17 years old),% ]3 k6 b4 z5 ~) T) c3 o& @
while lower levels persisted in younger patients (4, 8, and 10
  }/ \* c3 i: j! T, r% cyears old) (see table). Despite absence of profound alterations
2 z; N' b7 T) Iof serum testosterone the topical therapy provided a greater0 \3 N0 ]( A! N( y# m
Accepted for publication July 1, 1977. ·
: w1 v" h) ~2 R5 w( }Read at annual meeting of American Urological Association,- J) J) r. m) s+ q3 f2 X! C8 G6 A% Y- a
Chicago, Illinois, April 24-28, 1977.
$ |4 |1 D% W& `; u8 [2 H- v* Requests for reprints: Division of Urology, Henry Ford Hospital,
" N0 c+ w- |# I4 N' s/ D0 L2799 W. Grand Blvd., Detroit, Michigan 48202.
1 S, a) `" G' a  ^improvement in phallic growth compared to gonadotropin.8 }9 U, v: a" p7 C
Average phallic growth with gonadotropin was 14.3 per cent
! M3 X1 x: e: d- o  N7 D9 u/ Eincrease in length and 5.0 per cent increase of girth. Topical
) f4 M7 g% G) _9 C& o& S! stestosterone produced a 60.0 per cent increase of phallic length2 p7 e- v6 O, I. a$ [2 T* s  s
and 52.9 per cent increase of girth (circumference). The2 O# m2 X8 b! K+ s
response to topical testosterone was greatest in children be-( W3 p, M4 V  r3 R& }
tween 4 and 8 years old, with a gradual decrease to age 17
$ _" E. j0 D: W, g2 W3 l1 q3 Y! L% }years (see table).& o/ N& u0 ^5 q  _8 L* V
DISCUSSION$ M& |( y4 t+ W- [+ j! q' q  j, X
Topical testosterone has been used effectively by other
1 w! S2 q% O4 d+ Kclinicians but its mode of action remains controversial. Im-8 f* b: y& w6 z5 ]
mergut and associates reported an excellent growth response/ B5 v; o# B2 \& ]& C) G
to topical testosterone with low levels of serum testosterone,
  r8 M- I! c" ~" H7 j0 e# V0 }+ ksuggesting a local effect.1 Others have obtained growth re-) Z7 J0 m; `, q) ~8 [* n4 s
sponse with high. levels of serum testosterone after topical
& d2 n3 k% ^6 Hadministration, suggesting a systemic response. 3 The use of7 ^# D; L$ ^4 w7 i
gonadotropin to obtain levels of serum testosterone compara-% b! {+ T% c0 q9 b
ble to levels obtained with topical testosterone would seem to
' w0 U9 z/ s; j. x% c& Kprovide a means to compare the relative effectiveness of9 Z8 D& x  H9 I/ u
topical testosterone to systemic testosterone effect. It cer-
& R  |, j2 Y% b1 ?- E7 Ctainly has been established that gonadotropin as well as par-) _4 ~+ j) U+ }  t$ s
enteral testosterone administration will produce genital
# J9 z9 l6 c" \6 |" ggrowth. Our report shows that the growth of the phallus was& R9 }) J6 Z2 ~. w  Q' c) w
significantly greater with topical applications than with go-: ~" R- L; J/ q! U0 \1 g2 |
nadotropin, particularly in children less than 10 years old.
  M8 ]4 y& U% a/ @- w" ~' J  sThe levels of serum testosterone remained similar or lower" \% C- R% }; F$ S; i4 w+ y
than with gonadotropin during therapy, suggesting that topi-- K0 ], J8 [3 H4 F: j% ]2 N
cal application produces genital growth by its local effect as* \9 n6 M* {* d+ u  y
well as its systemic effect.
; L. }9 H6 }. \3 Y; zReview of our patients and their growth response related to  N4 V0 t, Y0 k# Q. x' P' Y6 W
age shows a greater growth response at an earlier age. This is
8 d9 O: }- C9 w1 X, Iconsistent with the findings of Wilson and Walker, who2 h+ o9 E6 |( k$ O& w
reported an increased conversion of testosterone to dihydrotes-
/ s) g/ s# x! {7 t2 x. V6 F, Otosterone in the foreskin of neonates and infants.4 This activ-, i$ R+ E$ [9 J* l0 v7 Y" E
ity gradually decreases with age until puberty when it ap-3 U; Y5 s. h$ k0 S
proaches the same level of activity as peripheral skin. It may6 E8 u9 S) M; ]" U; m' O/ n% s
well be that absorption of testosterone is less when applied at" L$ w: P- K( y
an earlier age as suggested by lower serum levels in children& D; K' G6 p0 ]( a
less than 10 years old. This fact may be explained by the
3 b, R6 q. a* v: G$ V1 }- k4 Wgreater ability of phallic skin to convert testosterone to dihy-
4 T7 s7 {' a9 Fdrotestosterone at this age. Conversely, serum levels in older
- x! P( g* N- u+ {/ h  ^0 U$ Fpatients were higher, possibly because of decreased local! M7 ~  }6 T3 s/ D
667- [. @+ h9 f! y1 R6 @0 y: ?
668 KLUGO AND CERNY9 P) @' j7 p- ], k, f- ^0 `" F
Pt. Age: t7 W# ^1 ~; T: t: Q
(yrs.); ?; V" ]) b* Q: f- \, k
Serum Testosterone Phallus (cm.) Change Length
' R5 [% l+ O" Z1 n8 Z% Q(ng./dl.) Girth x Length (%)& {6 G! n  j  @  t
4
0 Q3 m2 Y# U1 D9 A. e* u8
* a# ^; |9 Y& b/ c8 a102 X  \/ o! U0 z/ g. t! h
12
1 W( ]$ E) y2 P( k' J17
% R8 v( G* d( T7 T, H, A, D! ^! qGonadotropin
3 O2 _9 h$ z& T4 }% R; k1 w71.6 2.0 X 3 16.6
3 R9 T) D0 m) U, U50.4 4.0 X 5.0 20.0: }" W# c0 \1 U; Z0 v* K: d/ X# ^
22.0 4.5 X 4.0 25.0
& |  m( Q$ Z% h. k0 s2 u' b$ _' w84.6 4.0 X 4.5 11.1
- m: W8 z- z/ T; d85.9 4.5 X 5.5 9.08 Q  N. K( }  [
Av. 14.3/ u1 d5 E0 A9 }# z6 f
4- |. s1 L% S$ `$ }
8
6 m' v! k3 W  M/ W0 I101 i  F3 L8 C/ g+ G# {$ F  c% v
123 j! |9 k7 t: {6 }/ v/ \& N
17
( z1 _& l& A* {Topical testosterone
- u- o" K& s2 U/ b* W* y34.6 4.5 X 6.5 85; x5 T6 w* ~7 J: K  m, n
38.8 6.0 X 8.5 70
8 U( ^1 ]2 ~* O/ O% A40.0 6.0 X 6.5 62.5
% `% n. N/ a0 p" R$ A& ~( B0 K8 r5 e93.6 6.0 X 7.0 55.5
7 E0 L6 S% [, d" I9 c" Y95.0 6.5 X 7.0 27.21 }- d. x; A1 ]0 L
Av. 60.0
' K! I# V6 K, f" ~7 e7 ?# favailable testosterone. Again, emphasis should be placed on# @; W% h9 g5 n4 K. J
early therapy when lower levels of testosterone appear to! g; f5 S; ?+ A6 M7 D2 k% {
provide the best responses. The earlier therapy is instituted! L$ U3 M; W) v9 Z% H! K( f
the more likely there will be an excellent response with low
$ s4 C) ?9 Z9 Z. ^serum levels. Response occurs throughout adolescence as
$ Q5 h! ~5 S& \$ ^& {4 rnoted in nomograms of phallic growth. 7 The actual response' h+ T. q& Z0 Y  w, }" ^- i
to a given serum level of testosterone is much greater at birth
- Q( k) r: r1 W- Xand gradually decreases as boys reach puberty. This is most9 N, O% j6 Z: A! u: K
likely related to the conversion of testosterone to dihydrotes-
0 ^# `/ h( D7 k2 U3 F9 Ctosterone and correlates well with the studies of testosterone
! k# f/ j7 n) n8 }% [& o/ r3 ^# M. xconversion in foreskin at various ages.
; Q  V% A6 f9 ?The question arises regarding early treatment as to whether
# O+ E$ L4 l: n3 e8 Z, cone might sacrifice ultimate potential growth as with acceler-
. K# F4 f$ P' Y$ E* qated bone growth. The situation appears quite the reverse' c% F. f; N( b& b- C' Q% P4 V  c
with phallic response. If the early growth period is not used
1 n' h+ m9 _! R1 ^' V" N7 Z6 rwhen 5a reductase activity is greatest then potential growth6 t  P2 W% v, Y- F
may be lost. We have not observed any regression of growth8 n; C6 j8 o+ \
attained with topical or gonadotropin therapy. It may well
7 z/ s' A8 j0 C& j9 Hbe that some patients will show little or no response to any
. o% @% p/ {  jform of therapy. This would suggest a defect in the ability to
' X2 G' q) }# {convert testosterone to dihydrotestosterone and indicate that
' {1 @* E( ]% U3 p2 aphallic and peripheral skin, and subcutaneous tissue should  ?9 u0 M) i) h2 e
be compared for 5a reductase activity.
7 D3 _' y/ _( w' R) o$ k  ^, PA, loop enlarges to measure penile girth in millimeters. B,' b5 F( A7 N) P0 L
example of penile girth computed easily and accurately.( u# {8 Z: V. r* ^$ U$ O
conversion of testosterone to dihydrotestosterone. It is in this. o% N3 K0 v9 Z. X( x1 @
older group that others have noted high levels of serum+ J5 A$ w9 M0 t
testosterone with topical application. It would also appear
9 h7 w3 ]; l2 n; q: T8 |( I+ B8 cthat phallic response during puberty is related directly to the; T0 Q8 A$ D  c, v4 l+ C/ k5 @
serum testosterone level. There also is other evidence of local
8 H# R3 a6 [" l; g' [9 rresponse to testosterone with hair growth and with spermato-3 ?6 o/ J# R  k3 _
genesis. 5• 6
4 B( A$ X" `# Z9 Z/ x! oAdministration of larger doses of gonadotropin or systemic6 U% d; \9 h  F3 W( Q/ [6 |& I
testosterone, as well as topical applications that produce! ?! ^5 |! \+ F" [
higher levels of serum testosterone (150 to 900 ng./dl.), will5 A3 ^% k4 i' J  u
also produce phallic growth but risks accelerated skeletal4 Q# O" E6 v$ r% t' e. _
maturation even after stopping treatment. It would appear
  {9 r1 r- ?3 d/ ]. c8 bthat this may be avoided by topical applications of testosterone+ h9 {2 Q7 e# Q, W6 w2 a, l3 Q2 ^
and monitoring of serum testosterone. Even with this control3 K8 K$ x/ V1 D8 b  ^+ A9 k
the duration of our therapy did not exceed 3 weeks at any: M* a1 A# H; |/ Q& B( k/ Y. F
time. It is apparent that the prepuberal male subject may
! a. v& x/ z1 t0 l0 y3 K9 D# bsuffer accelerated bone growth with testosterone levels near( i$ u* M$ s& Y. \% i0 t
200 ng./dl. When skeletal maturation is complete the level of
. h- ?( k' I& w0 zserum testosterone can be maintained in the 700 to 1,300 ng./+ Y5 c1 t  U  M2 z  }8 `, C
dl. range to stimulate phallic growth and secondary sexual
0 C* ^3 a" I7 f- Y5 Ychanges. Therefore, after skeletal maturation parenteral tes-4 I5 a+ \5 {& Y8 b* a7 S$ b
tosterone may be used to advantage. Before skeletal matura-: y4 `6 E3 n+ J+ c2 a1 |
tion care must be taken to avoid maintaining levels of serum$ Z; m7 b* u/ [% I6 s/ N8 d  T) d
testosterone more than 100 ng./dl. Low-dose gonadotropin$ D: |8 O/ |" M* D" {' Q' ]$ [
depends upon intrinsic testicular activity and may require
& r2 E' ]! @5 g5 m$ U1 ]prolonged administration for any response.+ I7 l* q5 E; |6 c) D5 q/ E
Alternately, topical testosterone does not depend upon tes-
  N1 j& Y2 N7 q8 r# K1 t9 l" _  zticular function and may provide a more constant level of
$ y2 C% T: V" d1 UREFERENCES0 R0 \3 G& c8 J1 j$ l  X6 M
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- _5 \% J( K  h% T4 s7 }
R.: The local application of testosterone cream to the prepub-
( j* ^+ D9 ~6 n! c) o0 kertal phallus. J. Urol., 105: 905, 1971.
$ U2 }7 c' j( X8 ^2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
- R; f# }- n  ~; ~treatment for micropenis during early childhood. J. Pediat.,7 y" R6 O$ \, f) o! F
83: 247, 1973.+ ]4 F5 ^) A3 t- c* Z% t7 D
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, K! U6 \* {. z: Q' L& ]
one therapy for penile growth. Urology, 6: 708, 1975.6 {) N# H4 t% Z. B. J( K
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone, J  s% k; T4 O' d8 Y* T
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 ^5 l5 l9 S/ }  D7 D
skin slices of man. J. Clin. Invest., 48: 371, 1969.
0 v/ R7 A) y" [% Q3 i+ w1 I5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 q' c4 X2 |) b9 y
by topical application of androgens. J.A.M.A., 191: 521, 1965.9 w# ^; s# r" C
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local* r, R" S$ m. E7 \
androgenic effect of interstitial cell tumor of the testis. J.
0 A: R/ k0 G3 nUrol., 104: 774, 1970./ `, ?1 D5 g/ K2 h( O, W& J! n
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-6 T0 }( d# ?8 D) Z8 S  t
tion in the male genitalia from birth to maturity. J. Urol., 48:
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