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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND! V7 P! R$ C* K5 `' _$ i9 m$ \! y8 Y
GONADOTROPIN  L2 [8 y; E9 z* S6 {2 R  I
RICHARD C. KLUGO* AND JOSEPH C. CERNY9 N5 e+ [( ^; Z8 C# ~8 o  ?
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan, i+ F3 Q4 D, T" k. \7 y# o' X3 X
ABSTRACT
( r0 q; E0 r* q6 ^& mFive patients were treated with gonadotropin and topical testosterone for micropenis associated
  \0 F! u0 z# I9 gwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
% q6 y0 T7 t* i, G% `" Ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
6 U: o. z& i/ c+ `8 qcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 d3 z! t& H3 w6 R1 gfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% z- n1 y2 ?( X: F/ X- Rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: y5 o8 ]+ a8 E( x& m- ?1 x6 i: Lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
( V  s; T/ ?' p7 y3 G- @occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% |5 f  s# @) H, z6 rstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 x3 c3 k" b* P7 pgrowth. The response appears to be greater in younger children, which is consistent with previ-
! X7 s+ j! E+ j/ c2 Yously published studies of age-related 5 reductase activity.
9 O/ Y( o: @- Q* s) f! SChildren with microphallus regardless of its etiology will
2 {8 p# c5 @9 R( C6 Grequire augmentation or consideration for alteration of exter-
9 l+ O# M" ?. Z$ q/ ^nal genitalia. In many instances urethroplasty for hypo-
6 s9 A3 _! ^. _" C6 w! n' xspadias is easier with previous stimulation of phallic growth.
7 N7 M) m. Z5 ~+ n6 p0 |The use of testosterone administered parenterally or topically
7 V# n" {2 N/ p  F+ Mhas produced effective phallic growth. 1- 3 The mechanism of
4 o) w" B" v9 R3 y/ G3 ]3 Iresponse has been considered as local or systemic. With this- }3 k2 U0 M0 f
in mind we studied 5 children with microphallus for response
1 z# X7 t9 M9 F3 B/ pto gonadotropin and to topical testosterone independently.
/ l0 w& [1 N7 _/ ^MATERIALS AND METHODS# y: m  D+ Y$ ?% a% @
Five 46 XY male subjects between 3 and 17 years old were# Y) j8 O" d  L9 }& b0 L9 v
evaluated for serum testosterone levels and hypothalamic' G% n; O( l3 P6 I( T# ~% _
function. Of these 5 boys 2 were considered to have Kallmann's
' k7 z$ a9 [  o! e; J( C: s  |syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' o# y  _" t% ?; o( B3 d# H2 Wlamic deficiency. After evaluation of response to luteinizing* \4 @4 @' U: L4 N
hormone-releasing hormone these patients were treated with
( O) L) `% \  t5 C; P1,000 units of gonadotropin weekly for 3 weeks. Six weeks- q8 B5 w/ k0 T; m$ [+ f# q& i! G
after completion of gonadotropin therapy 10 per cent topical
9 q7 _3 j0 x1 E; F9 k. s1 jtestosterone was applied to the phallus twice daily for 3 weeks.
6 R* U& u: ?3 b) w- T( ASerum testosterone, luteinizing hormone and follicle-stimulat-6 E& D2 F+ Z3 z* D
ing hormone were monitored before, during and after comple-
/ M6 ]1 ~% l  L' y2 ?7 Z; i% ution of each phase of therapy. Penile stretch length was
. w3 P2 \; l- y6 d3 X1 _5 `obtained by measuring from the symphysis pubis to the tip of  Y& d1 \# {; a0 l
the glans. Penile circumferential (girth) measurements were9 b: e  {3 [. `: T. z2 {
obtained using an orthopedic digital measuring device (see
5 \! x, Y& b! _& i4 Mfigure).
  j2 p2 n) D" o9 KRESULTS' V! G8 C* ^7 Y# z% ]5 n
Serum testosterone increased moderately to levels between8 C. w4 o7 {- M
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 i% C) Y$ D: x8 z
terone levels with topical testosterone remained near pre-
7 Y+ |7 y; M1 ]3 b0 htreatment levels (35 ng./dl.) or were elevated to similar levels1 D& `7 [1 c, @0 K: d* h; g% x
developed after gonadotropin therapy (96 ng./dl.). Higher( M% T2 d& b# c5 W# W7 g. M
serum levels were noted in older patients (12 and 17 years old),
5 R  v8 q7 y1 d# k! _( ^while lower levels persisted in younger patients (4, 8, and 10' C/ h; d9 P1 n) G4 W8 i2 w
years old) (see table). Despite absence of profound alterations
4 c! o. ^4 u$ K+ |of serum testosterone the topical therapy provided a greater) h& w( e' ]  v7 `, u+ l2 |
Accepted for publication July 1, 1977. ·
5 s( E9 M0 L8 i3 a( y; qRead at annual meeting of American Urological Association,
; F' w7 v1 D2 y- G1 [3 ]Chicago, Illinois, April 24-28, 1977.& L' j$ r( i( ]+ `
* Requests for reprints: Division of Urology, Henry Ford Hospital,# J% u5 D4 s) X7 H+ A
2799 W. Grand Blvd., Detroit, Michigan 48202.
. ^) @+ N$ [8 }1 G) J: y- d! E/ C5 ?improvement in phallic growth compared to gonadotropin., v( S  b- {2 B, }$ z! B% B/ m
Average phallic growth with gonadotropin was 14.3 per cent1 S* T/ \, e! R4 x7 A
increase in length and 5.0 per cent increase of girth. Topical
+ c, K  I* C: k$ Etestosterone produced a 60.0 per cent increase of phallic length
, Y$ s9 o3 X8 M/ S6 cand 52.9 per cent increase of girth (circumference). The
7 P" I+ L; E, w/ {; Q  Lresponse to topical testosterone was greatest in children be-
( u0 C  v3 E/ ^  t) ltween 4 and 8 years old, with a gradual decrease to age 17$ d& m* G# |. @! K" G& _3 t2 g) E3 h
years (see table).
3 }9 m1 x# W( _( C) fDISCUSSION
/ @/ A$ T2 _7 ~4 @6 ~8 Y' J$ h7 d9 STopical testosterone has been used effectively by other
: \) z7 b. H# @$ B5 R$ r6 Qclinicians but its mode of action remains controversial. Im-& X, P6 c3 U" n. \8 q. f* Q0 Z9 X
mergut and associates reported an excellent growth response! ^) t9 Z- _; h# F6 ~: `. }! `7 s  b
to topical testosterone with low levels of serum testosterone,, f0 N# X7 Z, g- N3 Q, B
suggesting a local effect.1 Others have obtained growth re-5 C0 y& n. R6 ~* x* g
sponse with high. levels of serum testosterone after topical) }% l5 `3 n' E; m/ _" _
administration, suggesting a systemic response. 3 The use of
# J. E; A6 B/ C* J! @# c) ]- L. \1 ~gonadotropin to obtain levels of serum testosterone compara-; v& f) B# \+ D2 F/ a  [' I
ble to levels obtained with topical testosterone would seem to) U, \) w& e. n$ b& d# s& A' j* V
provide a means to compare the relative effectiveness of
% z" H$ Y" P6 k0 gtopical testosterone to systemic testosterone effect. It cer-& j' j0 s7 q2 d2 J' r3 r* _
tainly has been established that gonadotropin as well as par-: N" m3 @; t* J% o) r( B
enteral testosterone administration will produce genital
6 l# Q' u, e+ R5 x, \7 ]2 s8 z' ^growth. Our report shows that the growth of the phallus was
( a# f0 s' _% csignificantly greater with topical applications than with go-
% [* f/ P' H' y( mnadotropin, particularly in children less than 10 years old.
5 U- k) P" S; x1 q! \+ l  R% oThe levels of serum testosterone remained similar or lower
" w( g' M* q$ X( X' fthan with gonadotropin during therapy, suggesting that topi-
7 Z5 R* `; Q# n& l2 Z' o; qcal application produces genital growth by its local effect as2 m6 I0 a9 q! x! ]. {  r
well as its systemic effect.
" p2 _7 z# u& [( ]' Q0 C; ~; QReview of our patients and their growth response related to
% ~- J" ?* ?; k4 Aage shows a greater growth response at an earlier age. This is8 b: l3 t4 ?! C  V7 T. j6 k4 g
consistent with the findings of Wilson and Walker, who6 z3 |" E7 @8 y, E1 F! I1 g0 Q
reported an increased conversion of testosterone to dihydrotes-) z- B; D. P, v+ s' a2 `3 }
tosterone in the foreskin of neonates and infants.4 This activ-
% S" I2 Y" x! W& P1 K, wity gradually decreases with age until puberty when it ap-
4 d; X7 M" J6 i% y' C- p5 xproaches the same level of activity as peripheral skin. It may9 H  n" k1 v% c* X& P
well be that absorption of testosterone is less when applied at
* H1 A. K& e, q. ran earlier age as suggested by lower serum levels in children
/ I' [' d" p4 b/ j. `' @4 D, Z. ]less than 10 years old. This fact may be explained by the
9 }- I; [; L2 z& ~8 J9 y, T, Qgreater ability of phallic skin to convert testosterone to dihy-
5 J4 R5 C, y& ~5 wdrotestosterone at this age. Conversely, serum levels in older
7 H7 }" m; I# x9 C% r5 qpatients were higher, possibly because of decreased local+ T) ^% G" l3 l" n. V. U, j, t$ S
6675 N' Q2 y; q5 r( O/ S, A- t
668 KLUGO AND CERNY
' I# e( y5 U4 |Pt. Age
' U# }2 d1 u: b# T2 f) Y( H" v(yrs.)& k2 ]4 G$ ^# }8 f4 ^7 Z3 ^9 b' Y, H
Serum Testosterone Phallus (cm.) Change Length: j$ D' S: J. _- ?4 q" j
(ng./dl.) Girth x Length (%)
8 W: M. {* A5 ]) U# B) Y: H48 b- D- \6 M* H! E) H& u+ P+ c0 o
8; [7 k* h; J' b6 Z
10. t. G) E9 x% n; s2 t8 Q
12
9 n4 b! h- |: `+ O7 t8 o5 B5 k17- i/ ~+ r0 }2 ^2 m9 P/ |6 A, [, s3 T
Gonadotropin
, {, D0 S$ @9 y' x/ V) i1 I$ T* X9 I71.6 2.0 X 3 16.63 F# o3 _3 E! m4 s9 x
50.4 4.0 X 5.0 20.0
  h$ x% |5 L2 N22.0 4.5 X 4.0 25.0& |% Z! o5 h- O4 S/ M# c
84.6 4.0 X 4.5 11.1* m% g. g9 S8 v9 u( w% M; Q4 {& K$ Q
85.9 4.5 X 5.5 9.0, r& }' l( ~1 N: }  y; Y
Av. 14.3; I# O. y2 F  D- g6 P0 k8 F2 q) p
4
. q4 K. R& F5 f1 X0 {( h( V$ }( R8/ ^9 z' ]+ X1 _
10
; z2 C7 i% _7 d4 H1 O5 |12/ n4 o) F: |/ h0 q0 I5 u) w- J
179 K7 i, L5 O5 Q7 m+ Q$ A9 P5 a, ^
Topical testosterone
: F9 G( n0 V- [9 A+ X- R8 U34.6 4.5 X 6.5 85; `6 {4 g; G; n, q2 u2 L
38.8 6.0 X 8.5 702 [  e, p% x# k2 }$ l9 l9 s
40.0 6.0 X 6.5 62.5
% f1 [$ ?# @' R( r93.6 6.0 X 7.0 55.5
2 v: s3 b) f5 E( g95.0 6.5 X 7.0 27.2
% O4 c  O, b) |& x. ^! LAv. 60.0; V; L& Y' ~0 {1 _/ W$ B8 v9 n* a/ P
available testosterone. Again, emphasis should be placed on
' {, C: g1 D! ?early therapy when lower levels of testosterone appear to; v8 ~' p# R; l- g$ }% u
provide the best responses. The earlier therapy is instituted
. d) U  @+ o2 ?. ^9 i( z1 ]% sthe more likely there will be an excellent response with low: D6 R' d" Y: x* U
serum levels. Response occurs throughout adolescence as/ e; `$ D2 J1 W7 D' s! R& K
noted in nomograms of phallic growth. 7 The actual response& Z$ Q0 J' ]) N+ r
to a given serum level of testosterone is much greater at birth
) o  Q4 }) I8 ~; a6 hand gradually decreases as boys reach puberty. This is most, s, a) G) m: e, X: N0 K
likely related to the conversion of testosterone to dihydrotes-# b$ _( [6 q: o) P, H  l
tosterone and correlates well with the studies of testosterone% F! h+ ?$ y/ L/ K/ d# u
conversion in foreskin at various ages.' `& D& H4 L, h, ^, X5 y2 z) C4 v
The question arises regarding early treatment as to whether; g7 N! L% S+ d. O/ e
one might sacrifice ultimate potential growth as with acceler-8 S7 I* }* ?; _! O) R2 v5 s
ated bone growth. The situation appears quite the reverse
% n6 o! g0 z2 |9 P' Gwith phallic response. If the early growth period is not used; l2 f8 H% ^9 E' L$ J
when 5a reductase activity is greatest then potential growth, M* _3 j3 G: H( N' M( E
may be lost. We have not observed any regression of growth
1 {" d& v0 I  _( dattained with topical or gonadotropin therapy. It may well
: Z6 D* j" h" h( R& v# kbe that some patients will show little or no response to any
8 t8 a: b. V% Y$ d- ^: S, Wform of therapy. This would suggest a defect in the ability to: p. W# Z1 ]9 L, U& Y
convert testosterone to dihydrotestosterone and indicate that
+ v( r0 b& u: s5 X9 ]phallic and peripheral skin, and subcutaneous tissue should
, d2 i5 R6 b, c1 fbe compared for 5a reductase activity.
! X8 W) a" r5 s' M8 [) B0 I3 d; @A, loop enlarges to measure penile girth in millimeters. B,& j7 @7 `2 F& f0 @7 d
example of penile girth computed easily and accurately.5 i( A; p# I4 r9 B/ ^" y6 U
conversion of testosterone to dihydrotestosterone. It is in this+ M2 U$ a: C. m6 W
older group that others have noted high levels of serum7 Y8 _$ w& S% x3 p& N2 H
testosterone with topical application. It would also appear: D, X$ s) X5 r8 @" g- f# d
that phallic response during puberty is related directly to the) e2 w  }- i8 v$ A7 l
serum testosterone level. There also is other evidence of local* ?3 M, p: ^0 m- A* n5 q
response to testosterone with hair growth and with spermato-7 r% c3 C- k3 [# V/ p  [/ u
genesis. 5• 6  F/ F4 |: V" T8 }$ E8 I4 O
Administration of larger doses of gonadotropin or systemic' {9 r4 E3 D2 {. }
testosterone, as well as topical applications that produce
9 }- j3 w, s! |- [2 w  O9 Rhigher levels of serum testosterone (150 to 900 ng./dl.), will
, X4 ^, ~. A9 t, _3 |also produce phallic growth but risks accelerated skeletal
$ X  F# |# O! C) M: Dmaturation even after stopping treatment. It would appear
$ h( [, z% a1 P. `that this may be avoided by topical applications of testosterone
. G+ J' N( k, @& h1 f/ _9 `and monitoring of serum testosterone. Even with this control; I( v8 L4 x+ I! E3 S) q
the duration of our therapy did not exceed 3 weeks at any
4 q8 t7 f# ~" Q( h: H8 E( Stime. It is apparent that the prepuberal male subject may
7 H9 G: s$ _; W* ~6 q% L5 nsuffer accelerated bone growth with testosterone levels near
# n, l$ ?: [5 n4 N* l200 ng./dl. When skeletal maturation is complete the level of
3 B: \6 t+ X# |9 p$ eserum testosterone can be maintained in the 700 to 1,300 ng./8 m5 r: G! j7 a: Y
dl. range to stimulate phallic growth and secondary sexual; X1 ]" F0 l, |# z/ H; A+ v
changes. Therefore, after skeletal maturation parenteral tes-* A: i4 T; L4 `
tosterone may be used to advantage. Before skeletal matura-- E2 C4 f! U: ?0 F2 E+ q+ `5 \* D* \
tion care must be taken to avoid maintaining levels of serum) m) J) n' p0 }2 m7 i/ F3 w! S
testosterone more than 100 ng./dl. Low-dose gonadotropin# \' M2 w5 R0 a3 ]5 ]7 M
depends upon intrinsic testicular activity and may require9 R4 \5 N6 f3 R7 p4 y5 X
prolonged administration for any response.4 C2 t$ b& p2 F. K9 b2 k
Alternately, topical testosterone does not depend upon tes-
: j5 r; w7 m6 G5 c! m; Vticular function and may provide a more constant level of; L) w/ k9 W/ V
REFERENCES. U# u% ^: m- k) k$ L, N
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ g% G2 M! f" r# x
R.: The local application of testosterone cream to the prepub-( n/ D( S7 r  ?8 l
ertal phallus. J. Urol., 105: 905, 1971.5 P: G- C- _8 Y% y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# L! k5 H7 ?" O( L& \" `8 h
treatment for micropenis during early childhood. J. Pediat.,
/ `' ?1 ?, Y4 ^) ?8 P83: 247, 1973.# \& M. z* v! P, N% M$ G
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
3 F6 _4 J6 E' {# X9 qone therapy for penile growth. Urology, 6: 708, 1975.5 i1 ]8 h! L4 e% [
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ |, \$ h$ k( F' g1 [
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
0 h& ~3 }3 _1 K8 |  J6 K# ?: C+ \! _skin slices of man. J. Clin. Invest., 48: 371, 1969.
& S! U- S: n9 I% N3 {+ H* B( U5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth4 ]) I4 m* i8 X0 K
by topical application of androgens. J.A.M.A., 191: 521, 1965.. S* q* f3 p1 M8 U0 W3 f( s
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 j& V# A, L; ~6 ~$ S
androgenic effect of interstitial cell tumor of the testis. J.5 ]9 b) T0 k" p+ o0 ?" @% [4 F  t/ A% l, N
Urol., 104: 774, 1970.
5 a  ]- c9 {8 e0 b1 ?6 B7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( h3 v" I- v1 u: o  h
tion in the male genitalia from birth to maturity. J. Urol., 48:
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