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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND7 j, B% `, }! s0 G$ @
GONADOTROPIN
' ?, I' t4 w) J" r2 X1 q* |RICHARD C. KLUGO* AND JOSEPH C. CERNY% f4 G: u; Y7 w+ C* b# e( H' Q; Q/ u
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 X8 D( ~' o: [9 a
ABSTRACT% ^! G+ }! _" m8 c% ^/ ]# o! _
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
* A, D6 J! Y( t2 T3 lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
9 N2 H9 w! W, M, u4 ytropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( R1 H. U* S; `1 ycream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" C' i! }, s% B1 ~. hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 B7 U7 s1 z& k; Gincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: j8 _0 V+ W: dincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response9 q! ^5 d9 q! v+ D6 m
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; H0 g6 P8 u, k8 k# Z
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, E$ v* S: ~$ `; t  g3 E
growth. The response appears to be greater in younger children, which is consistent with previ-& D+ `+ _; T, i
ously published studies of age-related 5 reductase activity.
% w! |+ `* S2 c/ n9 L/ y) EChildren with microphallus regardless of its etiology will
1 @9 {1 m6 w7 I# zrequire augmentation or consideration for alteration of exter-" e8 A8 F# ~  b7 {0 f
nal genitalia. In many instances urethroplasty for hypo-. b$ f/ d3 ^$ n- l% E9 ?% A) a: \
spadias is easier with previous stimulation of phallic growth.
" S9 `- b+ |% t" ~4 t$ FThe use of testosterone administered parenterally or topically
: }$ c4 v  ~2 z1 Phas produced effective phallic growth. 1- 3 The mechanism of
8 z& B& O' |# `3 g% _& tresponse has been considered as local or systemic. With this
8 F! P! }4 K) Q0 Gin mind we studied 5 children with microphallus for response
+ x- T% m7 |: S4 J1 ]' Bto gonadotropin and to topical testosterone independently.
" M4 t6 D: q+ G( m3 |MATERIALS AND METHODS1 G" ^' s, x, Y0 y- @; c
Five 46 XY male subjects between 3 and 17 years old were
1 R8 U( e1 Z9 K8 \evaluated for serum testosterone levels and hypothalamic
% |! i5 |7 S' Kfunction. Of these 5 boys 2 were considered to have Kallmann's
. s0 O6 \* }8 ]" g4 l* @syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 h3 I. y- Q+ l! u$ T3 V( S7 D0 Q9 h
lamic deficiency. After evaluation of response to luteinizing& L5 U; J) D8 H2 v4 l8 U( f
hormone-releasing hormone these patients were treated with
2 Z  u  j. k0 n; \7 Z) [9 n1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 X# s$ `$ l( m& Q" Jafter completion of gonadotropin therapy 10 per cent topical6 |9 Y$ l' e/ U0 K, K
testosterone was applied to the phallus twice daily for 3 weeks.
' I0 c* J( R+ ^" w" d4 s: M+ rSerum testosterone, luteinizing hormone and follicle-stimulat-
+ c9 G' V% O. @$ h# j2 H- Aing hormone were monitored before, during and after comple-
6 ?- t- @: m; x6 etion of each phase of therapy. Penile stretch length was( O9 r% V" p0 S4 M3 |
obtained by measuring from the symphysis pubis to the tip of" y" h: P2 P: b6 l( W' r. b5 W# q
the glans. Penile circumferential (girth) measurements were
  o; p4 g7 q  lobtained using an orthopedic digital measuring device (see
, K% H0 P: G* m9 ^1 r4 Yfigure).
, n) v5 Q  ^, j) h5 j0 `RESULTS
# l$ i* ]. b! S+ d# P! J" Q4 hSerum testosterone increased moderately to levels between
3 S# `, K8 Z7 k! P0 D# K$ o50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  w7 W8 r9 R* e8 j2 }terone levels with topical testosterone remained near pre-
( z5 C9 Q6 H* ?3 Gtreatment levels (35 ng./dl.) or were elevated to similar levels
. T2 e  O( p/ b2 {) y' J4 vdeveloped after gonadotropin therapy (96 ng./dl.). Higher  b, P1 [6 D" F* d$ q3 u
serum levels were noted in older patients (12 and 17 years old),! ^3 L: C$ W8 _$ {9 J
while lower levels persisted in younger patients (4, 8, and 10/ T" m6 d. |2 k) \
years old) (see table). Despite absence of profound alterations7 S; ?" l5 s& E0 H
of serum testosterone the topical therapy provided a greater
- T3 d: K8 O' j7 aAccepted for publication July 1, 1977. ·
2 \+ b! |: J: w2 t( u$ HRead at annual meeting of American Urological Association,5 S- g, O- q2 s
Chicago, Illinois, April 24-28, 1977.
) ?! W$ W/ @- \' q* j4 \# z6 D, J+ p* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 @- L9 h3 B4 B: v# R2799 W. Grand Blvd., Detroit, Michigan 48202.+ o5 f# w8 U6 H! c/ F
improvement in phallic growth compared to gonadotropin.1 [9 B. ~! m2 \: }
Average phallic growth with gonadotropin was 14.3 per cent
/ [' q) K: p7 `" |% c% Lincrease in length and 5.0 per cent increase of girth. Topical
) d/ L% W& {' A7 _) atestosterone produced a 60.0 per cent increase of phallic length8 g% D( I% Q" P9 ?  k
and 52.9 per cent increase of girth (circumference). The4 z7 J: ?* z6 G5 r4 E9 c, \# X
response to topical testosterone was greatest in children be-
0 b! Y' a' \) ~3 V0 f0 Ntween 4 and 8 years old, with a gradual decrease to age 17
7 ^! h1 J1 q) K, W9 A' H; ]1 byears (see table).) R9 T8 G% U, Y7 s. G2 Z. j
DISCUSSION
5 ~: D: V4 S9 k5 D6 jTopical testosterone has been used effectively by other
2 n, F4 G# ]8 }0 g6 A; xclinicians but its mode of action remains controversial. Im-: O! J; C1 B5 O9 b
mergut and associates reported an excellent growth response- o' r. m4 B+ h
to topical testosterone with low levels of serum testosterone,; i+ {9 \9 f$ \" p" f
suggesting a local effect.1 Others have obtained growth re-
+ C8 @/ g6 D, p* rsponse with high. levels of serum testosterone after topical
3 r7 I  ^! M6 jadministration, suggesting a systemic response. 3 The use of
% v' w/ T# \8 }0 C! cgonadotropin to obtain levels of serum testosterone compara-
7 [% ^; S1 u3 }9 j8 kble to levels obtained with topical testosterone would seem to
$ t# R; c8 E  M. T  C) c' Bprovide a means to compare the relative effectiveness of
6 ^. w4 o, s0 I' ]$ Atopical testosterone to systemic testosterone effect. It cer-. ~4 D3 M* v% H( x& t
tainly has been established that gonadotropin as well as par-
! W- S6 t0 {" X: benteral testosterone administration will produce genital5 S5 @# w' u( I+ M2 S
growth. Our report shows that the growth of the phallus was
% f0 @8 s( }9 gsignificantly greater with topical applications than with go-) s: C) g4 |1 {) L6 U
nadotropin, particularly in children less than 10 years old.; }# k, w3 p  r
The levels of serum testosterone remained similar or lower0 W. O" j1 x$ `3 \" F' `7 G
than with gonadotropin during therapy, suggesting that topi-8 g3 s$ s3 y8 J5 Q1 D
cal application produces genital growth by its local effect as
1 O% ]+ h0 G0 v% y7 v: Cwell as its systemic effect.# z. J! t9 ^! z8 |' A
Review of our patients and their growth response related to
; y+ ~+ C6 V  u% I5 n2 y6 Y) Yage shows a greater growth response at an earlier age. This is6 u6 Z  H. t7 ~1 j7 G4 x- q
consistent with the findings of Wilson and Walker, who
) ^( {. G# @' m2 treported an increased conversion of testosterone to dihydrotes-
, f- ^# ]% A% u. r7 Mtosterone in the foreskin of neonates and infants.4 This activ-, V" x0 J$ T  {5 R/ j0 a6 N: X9 V
ity gradually decreases with age until puberty when it ap-
+ W5 P  v( {- X3 c' T' D8 uproaches the same level of activity as peripheral skin. It may
( a7 k) P, `% Q3 a: O$ m& V( o! vwell be that absorption of testosterone is less when applied at
0 N# O( _" x3 L  p6 y7 b, van earlier age as suggested by lower serum levels in children
* Q0 Q$ R5 @4 Y) F: c$ ?" W# pless than 10 years old. This fact may be explained by the4 }5 x, A( P) t. U
greater ability of phallic skin to convert testosterone to dihy-
5 c4 v, m" e. P* ?drotestosterone at this age. Conversely, serum levels in older! r2 }; v& o) w& M
patients were higher, possibly because of decreased local& C0 A! [( @2 w5 o
667
6 `" P/ I, p: I8 P( o) b) j7 m668 KLUGO AND CERNY8 g( |1 T. P) `; \; l. d5 u& F
Pt. Age
& J- B, S! |% i& O5 Z- i(yrs.)
7 V# M, L5 e& I9 dSerum Testosterone Phallus (cm.) Change Length
* U! I3 i' ]& q(ng./dl.) Girth x Length (%)
& Y" |+ f( L$ N% B7 N4
6 k* J) |8 O/ a7 B4 H86 ~" H( N& [9 K* G3 ^  n
10
5 f- Q0 L  \' h2 k123 ~) b/ U( s9 q
177 m$ K5 @! P! {5 p" U3 p
Gonadotropin
' G5 [0 x6 l4 s% h* r& L71.6 2.0 X 3 16.6* W) e) t$ _# B" _
50.4 4.0 X 5.0 20.0! f: Q5 C# \* P/ I5 i) C
22.0 4.5 X 4.0 25.0
+ E7 U) w( L& d6 P9 H1 w84.6 4.0 X 4.5 11.1
8 H% g( R& L% D0 }8 d) S85.9 4.5 X 5.5 9.02 ]* X; J, ~8 v
Av. 14.3
- n3 S, b, _1 X' s) A4 T40 p' a* |8 J. B
85 k: n2 a' h# u. _
10
; Y. {0 r; n- @( W4 ~5 d12
* e: o1 P, g6 I5 g* t' S17
* J$ K2 ]0 q$ w2 {8 M0 D/ YTopical testosterone2 k5 v4 _, _& B4 w
34.6 4.5 X 6.5 854 p. \3 S( `% _$ J  l+ F  A: ^
38.8 6.0 X 8.5 705 b! l7 E5 I- M3 `. m8 Y
40.0 6.0 X 6.5 62.5$ ^/ j) K: I" Y1 g7 Y3 J" e* E5 j
93.6 6.0 X 7.0 55.5. h& |# G( f7 r) W+ N
95.0 6.5 X 7.0 27.2
8 p0 ?. h6 l- @  w$ r* e! U% o3 I: TAv. 60.0# N2 {. W8 G, l" _* ~  A
available testosterone. Again, emphasis should be placed on2 c6 a  E$ L: Q+ X8 O* X/ T- {/ ?
early therapy when lower levels of testosterone appear to; ?& z1 T# W. m* P
provide the best responses. The earlier therapy is instituted
8 J0 n2 ^, R: b6 S% Cthe more likely there will be an excellent response with low
$ @8 p7 u8 s  M% Userum levels. Response occurs throughout adolescence as( ^1 n& X5 h7 S5 t7 S& z
noted in nomograms of phallic growth. 7 The actual response
6 }/ y/ t! s5 E0 \( c4 ]  oto a given serum level of testosterone is much greater at birth
3 @1 s  ]: H/ k0 J: m( y" Y- aand gradually decreases as boys reach puberty. This is most
$ S4 c- `3 m$ W) }' I4 Slikely related to the conversion of testosterone to dihydrotes-
# s5 Z4 A7 E! h1 h5 l% h2 `tosterone and correlates well with the studies of testosterone
7 E" G) v( N& M9 P1 g; @. [conversion in foreskin at various ages.8 a$ J3 z7 E8 M4 U
The question arises regarding early treatment as to whether' Z: Y  C9 s# g$ W
one might sacrifice ultimate potential growth as with acceler-3 {6 ~# ]" d6 r5 I; \. K3 e& y2 L
ated bone growth. The situation appears quite the reverse; a1 L3 v6 Z2 g# u( N
with phallic response. If the early growth period is not used
! s8 {  f8 s7 ?0 ?! g# e2 ]when 5a reductase activity is greatest then potential growth
( G3 V5 @; c& B& D4 m. fmay be lost. We have not observed any regression of growth1 k( r1 B3 l$ @; p
attained with topical or gonadotropin therapy. It may well# d0 \/ _. q- L3 _3 E
be that some patients will show little or no response to any
# b& e# P1 y, O+ {0 r* y  z4 t& Yform of therapy. This would suggest a defect in the ability to6 ]& X% ^  N/ ]$ I# X  U
convert testosterone to dihydrotestosterone and indicate that4 y1 t( Z* g- f5 H& ~
phallic and peripheral skin, and subcutaneous tissue should
& N. ?' O; O  o: ebe compared for 5a reductase activity.3 ]. p& B5 l3 l% _; A
A, loop enlarges to measure penile girth in millimeters. B,. o9 J$ B+ G) u
example of penile girth computed easily and accurately.
: H* {6 w$ j6 ]6 X( ~+ pconversion of testosterone to dihydrotestosterone. It is in this
8 ^8 x% ?! y/ Lolder group that others have noted high levels of serum- Y6 @, p3 Z4 n
testosterone with topical application. It would also appear
4 c; _! E: F7 V' Mthat phallic response during puberty is related directly to the  E  N! O3 l5 J1 d+ F
serum testosterone level. There also is other evidence of local) L4 N$ r7 R% a/ [( A& @
response to testosterone with hair growth and with spermato-) B+ I9 B6 b5 E# d" x
genesis. 5• 6
8 h8 Y# v% u  H8 A1 T. c+ \Administration of larger doses of gonadotropin or systemic
2 @; k: G' g7 A  r% Z3 y( btestosterone, as well as topical applications that produce
2 D& {  V$ w$ s6 J. B+ y; d8 whigher levels of serum testosterone (150 to 900 ng./dl.), will0 P; ~6 L1 J# b9 p0 c
also produce phallic growth but risks accelerated skeletal' [( |2 H% T' X9 e
maturation even after stopping treatment. It would appear7 n( D4 d. g) `$ n6 {1 ?, r+ ^
that this may be avoided by topical applications of testosterone2 A" W$ R) Q  `2 s( l5 I
and monitoring of serum testosterone. Even with this control
+ b7 M; `. @: Xthe duration of our therapy did not exceed 3 weeks at any
8 z: o* S# _9 v" ?, Stime. It is apparent that the prepuberal male subject may# R8 A6 Z/ A0 u  y8 ?% V
suffer accelerated bone growth with testosterone levels near- t4 f8 V5 z0 \/ d; i4 o2 u+ N
200 ng./dl. When skeletal maturation is complete the level of
) ]% [( Y7 w0 t( ?, ^: r6 C) pserum testosterone can be maintained in the 700 to 1,300 ng./5 z5 G, J. v- O7 I+ L+ `
dl. range to stimulate phallic growth and secondary sexual* D$ J2 c7 Y5 T: @! U3 g
changes. Therefore, after skeletal maturation parenteral tes-! K0 y1 r. N7 o5 s4 x
tosterone may be used to advantage. Before skeletal matura-# E% H' ~1 U: R3 Q7 \+ Q
tion care must be taken to avoid maintaining levels of serum- e* T( g' v, y8 l! {2 i
testosterone more than 100 ng./dl. Low-dose gonadotropin6 h* \9 g1 m9 y* z7 p
depends upon intrinsic testicular activity and may require
* C4 K; F: p9 e+ `* Cprolonged administration for any response.! a6 C$ E+ F- `$ p
Alternately, topical testosterone does not depend upon tes-
$ u' A, d1 P2 S) Q7 c8 p+ h3 sticular function and may provide a more constant level of
/ a, F( P) q' o1 S$ W9 h, ]REFERENCES
' K7 i  K) G, }  q& ]$ Y1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ f, X6 l1 A# I' V1 H
R.: The local application of testosterone cream to the prepub-
* X6 o- U# j8 fertal phallus. J. Urol., 105: 905, 1971.
% \/ c$ J! A8 Y9 \8 d2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
# D# S+ _; e7 v3 }treatment for micropenis during early childhood. J. Pediat.,
* l* K/ r5 f0 m83: 247, 1973.7 O& N, a$ p+ Q* K2 f8 i* m
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; U$ {5 {% ?8 `% f& [
one therapy for penile growth. Urology, 6: 708, 1975.. Z$ @3 r2 r8 L  d1 c0 L
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* m8 O) M  z* w  _, ?" Z' k; zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by0 s0 t1 R8 F; d# @# A, l; k6 l' X
skin slices of man. J. Clin. Invest., 48: 371, 1969.& N/ c+ T, @; H# b9 l' H" m* ]
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
0 {: K0 [' }9 b7 p0 W% H* qby topical application of androgens. J.A.M.A., 191: 521, 1965.
( ^, v, k% B* ]# v0 e6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 O* L" D( x' z
androgenic effect of interstitial cell tumor of the testis. J.) K3 X4 A, E, e
Urol., 104: 774, 1970.
9 k" y% @, j: G2 h/ N$ P7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
5 q" o" u" r# ^) d! K* wtion in the male genitalia from birth to maturity. J. Urol., 48:
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