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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ \8 t9 |2 t# H
GONADOTROPIN' F7 V+ I4 O6 B0 e0 @8 i) D& t
RICHARD C. KLUGO* AND JOSEPH C. CERNY
5 }6 p4 j# o, v6 g* Y& ?* R. Q: ~From the Division of Urology, Henry Ford Hospital, Detroit, Michigan$ z& M6 W2 c& \. F5 G
ABSTRACT
& J  N* F  {% w4 g1 m1 |8 ?Five patients were treated with gonadotropin and topical testosterone for micropenis associated
# d$ ~! D- P0 ?with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- R" Y" S- W; ^( j6 x- ]7 m
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone9 c. ]4 L( q5 r- o" i9 u
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: S" r9 J- D( c7 C0 u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
  b$ Q" }) G' ^2 ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average% `9 Q$ [6 H- e! f+ ~/ C
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
2 ~( x& c' |# [1 e% ?! Koccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
& p7 A; _9 D) y; {& |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- T5 G! |% M) \3 Z: ]* ]. d& x. Cgrowth. The response appears to be greater in younger children, which is consistent with previ-8 b5 B7 U) C& h  Z% z( o
ously published studies of age-related 5 reductase activity.* }. @7 M2 i" n* U" L; C
Children with microphallus regardless of its etiology will
; U5 K) t% r- x6 Krequire augmentation or consideration for alteration of exter-
! o* [4 O* V3 Q9 o, ^nal genitalia. In many instances urethroplasty for hypo-
- r" b) c/ T6 i' n7 b! aspadias is easier with previous stimulation of phallic growth.
5 r4 s! ?- m5 @% k  a& J$ u& qThe use of testosterone administered parenterally or topically& g8 B5 r0 O$ D; q# f4 @0 X7 O5 C
has produced effective phallic growth. 1- 3 The mechanism of
7 Z( \+ b; b/ \6 ^8 C( S$ Qresponse has been considered as local or systemic. With this" k$ w, T1 `2 j/ M% j
in mind we studied 5 children with microphallus for response# t" e5 n: Y" p* O
to gonadotropin and to topical testosterone independently./ Y+ `4 m0 j! w1 ?5 X
MATERIALS AND METHODS
' ~1 `) R; K4 N+ e. u1 BFive 46 XY male subjects between 3 and 17 years old were
( ]* a% W" v/ nevaluated for serum testosterone levels and hypothalamic
3 y" N$ }& O2 t5 {function. Of these 5 boys 2 were considered to have Kallmann's3 X' k4 t7 A: S: p2 A/ P2 W3 v- ~
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-* R7 K3 `$ N3 p
lamic deficiency. After evaluation of response to luteinizing
3 C3 b, y/ _5 v2 p* j; Y" Vhormone-releasing hormone these patients were treated with
! V* X9 C: r, q. V: C2 P3 l1,000 units of gonadotropin weekly for 3 weeks. Six weeks" F& }) |6 u' b- o. n+ _
after completion of gonadotropin therapy 10 per cent topical; ]6 y: g. P1 z5 p( P
testosterone was applied to the phallus twice daily for 3 weeks.
' }; Y9 N9 d% s) O8 g$ @6 A9 ySerum testosterone, luteinizing hormone and follicle-stimulat-
5 r* t, M" K- e4 j) K  o6 b. n1 Ring hormone were monitored before, during and after comple-
& k, f1 t: _: ~tion of each phase of therapy. Penile stretch length was
' Q0 Y! x" T5 X$ g* Lobtained by measuring from the symphysis pubis to the tip of% ]0 B* }( [1 ?1 U* x
the glans. Penile circumferential (girth) measurements were
5 ^+ l( L3 a! p! B- k4 ]# k* q9 bobtained using an orthopedic digital measuring device (see3 Z. W& b) f+ @6 A9 N  [( W! x
figure).$ f. b5 {( g; l" G; q5 ]& J) ]
RESULTS
9 P7 N9 O, `4 M  [1 L" sSerum testosterone increased moderately to levels between" B3 }  [& i" F/ E( z& y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-  H- g3 P# G( {1 Y* G4 _' a( Z
terone levels with topical testosterone remained near pre-
, x; n! }  e8 t: streatment levels (35 ng./dl.) or were elevated to similar levels) `1 Q, E! W) S. x' i2 U
developed after gonadotropin therapy (96 ng./dl.). Higher
, p9 z0 b1 Y7 O3 R* F* G! O! Nserum levels were noted in older patients (12 and 17 years old),- D% i5 g& o, J$ ^1 x7 U7 H2 D" Q
while lower levels persisted in younger patients (4, 8, and 106 `8 I' F+ f7 d+ k9 w' S9 i
years old) (see table). Despite absence of profound alterations
4 q: P4 M6 P, A6 [6 b/ Z! |of serum testosterone the topical therapy provided a greater
8 x9 D. w# I: h6 ?$ C+ u; LAccepted for publication July 1, 1977. ·# ?5 u9 j  D; ?+ K3 S
Read at annual meeting of American Urological Association,
% k- J2 c, E; b; WChicago, Illinois, April 24-28, 1977.
: Y( e, S6 H( d) n' ~( T1 D; m# @* Requests for reprints: Division of Urology, Henry Ford Hospital,; p0 n. D; K) A! L& V
2799 W. Grand Blvd., Detroit, Michigan 48202.
. L! M1 Y3 W" q. N9 n8 Eimprovement in phallic growth compared to gonadotropin.
5 Q4 u6 T0 {1 n/ [Average phallic growth with gonadotropin was 14.3 per cent& |& h4 n% S4 N( {+ \% z# ^% w9 `6 p
increase in length and 5.0 per cent increase of girth. Topical
8 g  M* t# D2 u* _1 Jtestosterone produced a 60.0 per cent increase of phallic length0 u% `2 o5 @* i9 P, h
and 52.9 per cent increase of girth (circumference). The
- l. T! X, P" p; Iresponse to topical testosterone was greatest in children be-. |  c& b+ D( v7 b6 x" D" ]
tween 4 and 8 years old, with a gradual decrease to age 176 |' m: E1 ^0 M# M
years (see table).( Z$ r) k) _3 R, T
DISCUSSION
* A) x& r4 F& n- j% u# z2 b/ TTopical testosterone has been used effectively by other* X0 @. K8 T: Y: b; _: c. I
clinicians but its mode of action remains controversial. Im-0 [! C6 p* ^+ O# E5 J0 N# e
mergut and associates reported an excellent growth response
6 f7 b7 b# q. i: Ato topical testosterone with low levels of serum testosterone,2 H- N; d; M% Q* r  @, Y, J
suggesting a local effect.1 Others have obtained growth re-
2 K1 `2 n8 ^" r, c) h! `' g- Osponse with high. levels of serum testosterone after topical
% q7 X# j5 H* U# T) Vadministration, suggesting a systemic response. 3 The use of
/ o9 O: A* x$ C+ o6 N4 U# Pgonadotropin to obtain levels of serum testosterone compara-6 B; C" D$ j/ X+ ^; f* X, S4 y
ble to levels obtained with topical testosterone would seem to
8 x5 }$ V/ `9 v4 rprovide a means to compare the relative effectiveness of
* n- y) r% V6 C4 p5 V' Vtopical testosterone to systemic testosterone effect. It cer-- Q$ l, |/ ~4 Y! ~& o
tainly has been established that gonadotropin as well as par-5 u. `/ \5 g5 \. v1 @
enteral testosterone administration will produce genital
8 C3 A1 q: j1 F$ N4 D) Jgrowth. Our report shows that the growth of the phallus was% l6 q9 }$ Y+ W+ F- D. @
significantly greater with topical applications than with go-( J, a" o+ R( d& ^, I* j
nadotropin, particularly in children less than 10 years old.
6 W7 V# v: C! R# MThe levels of serum testosterone remained similar or lower% H  o2 ~9 ~& f/ o; s
than with gonadotropin during therapy, suggesting that topi-
  a' d- p! i# ^* v- Ecal application produces genital growth by its local effect as; n' z% F+ m* J  F2 g
well as its systemic effect.
" ~2 y7 w) c" \$ `, q5 Y4 R$ y% bReview of our patients and their growth response related to1 g0 c8 _4 R" }1 C, I& d3 @
age shows a greater growth response at an earlier age. This is
6 l6 H9 k8 K. Zconsistent with the findings of Wilson and Walker, who
2 o7 ~, _, D6 p# D9 u: ~. b: J' greported an increased conversion of testosterone to dihydrotes-
4 R: Z7 d! E. v- \9 x* w, Qtosterone in the foreskin of neonates and infants.4 This activ-
/ T. n8 s/ o9 M$ hity gradually decreases with age until puberty when it ap-
- s1 p0 n6 t% |5 b+ yproaches the same level of activity as peripheral skin. It may
7 M& s9 i) K; Z6 S4 G4 nwell be that absorption of testosterone is less when applied at2 L" a7 k* ~; F5 N* z9 z3 O# [
an earlier age as suggested by lower serum levels in children& L  |" U; ?! B. ?; a1 u) P" l, W
less than 10 years old. This fact may be explained by the
( a( x; z, p; R3 g4 F; u/ ogreater ability of phallic skin to convert testosterone to dihy-
/ k) k  D, ?. j% [" Odrotestosterone at this age. Conversely, serum levels in older
; ]3 \& ^& Z0 ]5 K  }& C5 vpatients were higher, possibly because of decreased local
  r! P+ K7 O6 X- K6672 o9 _% c$ c5 s. F  e) ~
668 KLUGO AND CERNY
/ h  x; Z+ R: K3 l" iPt. Age
; R) H" v5 l- Z2 o: E(yrs.)
  ?" o$ R) p9 D' {9 vSerum Testosterone Phallus (cm.) Change Length
- W$ ~) F* ?; N6 D7 q5 S4 w(ng./dl.) Girth x Length (%)
; x6 ?6 h' ^$ i3 L- V4% ?" c  R+ ?9 p( q4 r
8
" i6 n) j6 ]- A) [4 H10
  m! m' j; u+ b. E: @. Q! o12
# q8 X4 u& z8 f6 ?& S- d+ F) O5 R17
; z! ?$ j  @( mGonadotropin, f* w6 H* {( W$ Y& t% b
71.6 2.0 X 3 16.6
! r+ W% g7 q' z' h50.4 4.0 X 5.0 20.0
& K8 d' v! n/ n$ d% b22.0 4.5 X 4.0 25.0
) `( s  m' H. N) G. }, [7 A6 t84.6 4.0 X 4.5 11.1
" i  ~. ^3 z) m. I' Z85.9 4.5 X 5.5 9.0
3 G; ]+ W+ ~* O0 [Av. 14.35 G/ b; V* _8 w" n" V. p# [- ?
4# d; `# o$ O# d& H& N1 i
8
8 @- S4 [3 H/ B8 d2 V6 Q) u3 b3 Z8 z10
- R# A) S8 p3 d2 o' ^0 \12
( @# @$ M! _: g/ @, l17
0 V+ [/ o, v) I+ HTopical testosterone
2 l& r9 [4 Q8 v" ]) b7 T1 k" }7 M34.6 4.5 X 6.5 852 U0 {! u- ?8 X  y# V5 E
38.8 6.0 X 8.5 706 n4 ~2 W% i; o* G$ F
40.0 6.0 X 6.5 62.5$ ^3 S* b. p& M0 b; V+ Y
93.6 6.0 X 7.0 55.5
- m& e; u! A% O/ B# g95.0 6.5 X 7.0 27.2
3 a' o# d) p/ T3 `: mAv. 60.0
: a% f8 `( W+ D2 A! U9 bavailable testosterone. Again, emphasis should be placed on  U& R0 T% r5 z+ O0 I/ @
early therapy when lower levels of testosterone appear to; z9 o- E& ^" M) {; J( f
provide the best responses. The earlier therapy is instituted/ W# l6 h1 g; }: U3 @! c
the more likely there will be an excellent response with low
- j7 M+ P4 O' W# {) k) r1 i2 Rserum levels. Response occurs throughout adolescence as
0 S7 I6 B$ P' W2 d' inoted in nomograms of phallic growth. 7 The actual response
3 z8 @' \: D2 w* Q# {! J7 zto a given serum level of testosterone is much greater at birth
6 e3 ]! f1 H1 Y; j* B' M% cand gradually decreases as boys reach puberty. This is most9 M* h2 y- ?+ k+ M
likely related to the conversion of testosterone to dihydrotes-& ^) f+ J8 I# y; I) l
tosterone and correlates well with the studies of testosterone  Q4 q, Q# i1 @
conversion in foreskin at various ages.
& }. O3 m, n3 W4 q2 y( `8 uThe question arises regarding early treatment as to whether
  X% U! G, D' ]% ~& j; z2 Yone might sacrifice ultimate potential growth as with acceler-3 Z- U! M8 M( G, f* n+ \; m
ated bone growth. The situation appears quite the reverse
; t; F# N+ z+ t, W. r. A  w( _with phallic response. If the early growth period is not used! t8 D1 k. w1 U
when 5a reductase activity is greatest then potential growth- C! s' R) U+ m" Z; m0 W
may be lost. We have not observed any regression of growth3 J/ x& O( _- j2 k. @0 S" E
attained with topical or gonadotropin therapy. It may well& {' W, ?6 U4 }6 l* j* J2 _' C
be that some patients will show little or no response to any1 ?0 s9 D9 U. s3 W( ?) e
form of therapy. This would suggest a defect in the ability to, W1 W' o3 u9 h. X2 J2 S9 E
convert testosterone to dihydrotestosterone and indicate that9 Z2 {+ \' I, j+ C4 t
phallic and peripheral skin, and subcutaneous tissue should
' D1 N" W8 a. q+ h" d. a8 X8 Hbe compared for 5a reductase activity.( i# K9 c% s% `+ J( C
A, loop enlarges to measure penile girth in millimeters. B,
$ k3 P8 d$ ~2 e) P+ U9 }example of penile girth computed easily and accurately.
* H+ |6 K$ r5 J3 w7 I  G) T  sconversion of testosterone to dihydrotestosterone. It is in this
$ `. O5 i& J* D$ \8 \- o  S7 {older group that others have noted high levels of serum
+ b; t$ R4 M  f# Z- Ktestosterone with topical application. It would also appear
/ s  j+ D. k1 k$ E0 s" b; R; |7 p/ qthat phallic response during puberty is related directly to the: B7 y9 n3 I7 X3 \9 o+ m! r
serum testosterone level. There also is other evidence of local! g) L  g$ D5 Q6 f- I& j
response to testosterone with hair growth and with spermato-9 e+ Q1 c1 X9 I+ m8 k+ M- {
genesis. 5• 6$ ^! z. `2 Q: n; S4 V, v
Administration of larger doses of gonadotropin or systemic5 @% {4 x9 J8 o# @7 C: v
testosterone, as well as topical applications that produce0 ]: N, ?: @% ^% k* L* J
higher levels of serum testosterone (150 to 900 ng./dl.), will6 c9 w" L2 b2 `" i; l- ~# d) K
also produce phallic growth but risks accelerated skeletal
& T$ X0 b' ^7 G$ ]maturation even after stopping treatment. It would appear  M9 Z$ ^5 x3 f/ Y( o) Y# L
that this may be avoided by topical applications of testosterone$ ?. x( b3 G4 a6 z) U9 T: q
and monitoring of serum testosterone. Even with this control. U; v5 S9 ^' R
the duration of our therapy did not exceed 3 weeks at any
  e2 c4 L. u) l* X. j; n6 qtime. It is apparent that the prepuberal male subject may" O; ]+ R" w( }# }
suffer accelerated bone growth with testosterone levels near
0 \# Z0 g2 ^$ p4 I200 ng./dl. When skeletal maturation is complete the level of
0 k9 A- u! z5 I1 F* Rserum testosterone can be maintained in the 700 to 1,300 ng./
) G3 F/ I5 A, x: a* C+ R7 G/ ^dl. range to stimulate phallic growth and secondary sexual( q3 w. m% y; _& p, D% o( v* t$ A: Z
changes. Therefore, after skeletal maturation parenteral tes-9 H: i1 T! D( [; S
tosterone may be used to advantage. Before skeletal matura-% ^6 d! p$ T; v& r/ G
tion care must be taken to avoid maintaining levels of serum
( t. Y' h! c* h. [! ntestosterone more than 100 ng./dl. Low-dose gonadotropin0 _- v0 f# P* Y! \4 `) b
depends upon intrinsic testicular activity and may require
( u. j  E8 W- h  J% lprolonged administration for any response.+ w7 N4 F- O: a& R) C+ X
Alternately, topical testosterone does not depend upon tes-6 o0 ]3 X8 Y( b9 H9 [9 g
ticular function and may provide a more constant level of
# ]1 e8 g+ U1 E. A, i- T; XREFERENCES$ ]. Q/ h+ R5 I$ j) C! e
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 M% s/ M: n0 g$ X; J2 u) w
R.: The local application of testosterone cream to the prepub-$ s. {& y# G$ b$ Y  Q
ertal phallus. J. Urol., 105: 905, 1971.
* {" {0 j  |% u  u2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone6 y6 o' s1 D. s( u' C3 t4 \$ P
treatment for micropenis during early childhood. J. Pediat.,
6 \9 M2 N( z; s" {5 v7 l( f- ^83: 247, 1973.; t/ h! d$ n4 i
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( Y2 d2 {4 r4 H
one therapy for penile growth. Urology, 6: 708, 1975.
2 [3 q4 K. o( e6 H* |, _% d" \4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 Q! w) j% }$ i- [# P" T$ R; {5 ]; t- U
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% A' O: C' k9 w+ i: I# v# R7 ^
skin slices of man. J. Clin. Invest., 48: 371, 1969.
2 ?9 B" b) S# `/ y. M8 k5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) h7 S# }" c8 n* P0 W. w
by topical application of androgens. J.A.M.A., 191: 521, 1965.$ D2 Y. K5 ~8 Z" ~+ @% A
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 S8 X6 H* f! y1 X4 V( `) z% K0 eandrogenic effect of interstitial cell tumor of the testis. J.5 ^% l5 W7 B! U5 m& K, ~6 ~
Urol., 104: 774, 1970." R5 a" F- ^. a2 s9 ~$ r" z7 Z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 P4 T3 ]( U/ ?
tion in the male genitalia from birth to maturity. J. Urol., 48:
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