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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND- }" Y7 k% n+ b
GONADOTROPIN( g, |; `9 [) @2 c' w9 {
RICHARD C. KLUGO* AND JOSEPH C. CERNY" c0 s3 v* g( p! q' h# k
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# e$ e( n2 z1 n$ S7 GABSTRACT
7 k7 c! U5 y' j, K% [Five patients were treated with gonadotropin and topical testosterone for micropenis associated0 y3 z( B/ v  I
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 P* m1 B! b; u2 K
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ C' `. h# c6 [; R5 n
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
, v) m0 Q* a  i* }" N2 @0 d2 R1 i- hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. y# U5 a' s3 w7 F/ B: K/ L% _8 n
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: x5 u( u" m' j3 J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
2 F% H4 E# Q  W6 j: Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This7 f3 ^/ K  E% p
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
8 L. R! E, I4 f$ c2 Qgrowth. The response appears to be greater in younger children, which is consistent with previ-0 P+ p4 T, ?: J+ T, Y/ y
ously published studies of age-related 5 reductase activity.$ q1 D. q4 {% s8 u, s9 F- f8 P
Children with microphallus regardless of its etiology will  B6 @8 v" Q  c; E! J- Q+ Z) |  ^
require augmentation or consideration for alteration of exter-
& S, ^2 i" ?6 Q! F, j7 K5 nnal genitalia. In many instances urethroplasty for hypo-
. x, n! l2 v% @$ [5 T6 E( e+ j6 j5 B( \spadias is easier with previous stimulation of phallic growth.
3 K7 R4 K8 _& rThe use of testosterone administered parenterally or topically; I1 ^* y2 `% _" n5 b$ m/ h: m
has produced effective phallic growth. 1- 3 The mechanism of/ o" o3 i" R& k9 a4 P7 r
response has been considered as local or systemic. With this
1 \3 K2 k" z: H: x/ |0 I3 v" Cin mind we studied 5 children with microphallus for response
4 l6 Y" j) U9 wto gonadotropin and to topical testosterone independently.
5 i2 Q* x5 U( l( k! C$ o. _MATERIALS AND METHODS
) v$ L  }. f- s/ fFive 46 XY male subjects between 3 and 17 years old were
# `8 W% U& F1 a( `( nevaluated for serum testosterone levels and hypothalamic
7 q( C4 D- {3 G0 Pfunction. Of these 5 boys 2 were considered to have Kallmann's1 q8 ?) k% M8 F4 \
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 @: f6 P  c4 W+ d& glamic deficiency. After evaluation of response to luteinizing
5 @1 k2 t- E7 Zhormone-releasing hormone these patients were treated with2 ?7 l5 s- q- u8 y, t
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. y- U/ G% c/ X& s. p% k% e  ?! cafter completion of gonadotropin therapy 10 per cent topical' R4 N1 ?% r: F5 T  m. P5 k
testosterone was applied to the phallus twice daily for 3 weeks.
3 g2 X# H8 z7 h9 n) v: ?Serum testosterone, luteinizing hormone and follicle-stimulat-6 g6 U, \. C5 ]" M# m1 ~" h
ing hormone were monitored before, during and after comple-- h3 T$ q  b0 r
tion of each phase of therapy. Penile stretch length was# A1 U( `9 Q( J0 u; T
obtained by measuring from the symphysis pubis to the tip of
0 w+ ~/ S+ {. f8 Ythe glans. Penile circumferential (girth) measurements were/ d, E8 g; @4 h4 t
obtained using an orthopedic digital measuring device (see2 U/ s1 o# U  S$ R8 Y' b
figure).
! K- @4 p: c4 t# G5 YRESULTS
- Y# t* t: @- LSerum testosterone increased moderately to levels between
) f! ^: N" w% d* O+ ^; W50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ m" ~8 R- }, U3 M: j
terone levels with topical testosterone remained near pre-( |) f+ z- o; s; {/ S" I: }
treatment levels (35 ng./dl.) or were elevated to similar levels
& N0 o1 T0 J# Hdeveloped after gonadotropin therapy (96 ng./dl.). Higher
" n/ a$ j8 Q3 s9 i# p- w- b1 {; ^serum levels were noted in older patients (12 and 17 years old),
0 f( e4 [1 K( i6 a/ swhile lower levels persisted in younger patients (4, 8, and 10% M9 w6 U7 p% h/ f# o; g
years old) (see table). Despite absence of profound alterations
. S3 L6 Q5 ~2 `8 h; I% d* r2 Aof serum testosterone the topical therapy provided a greater
2 z+ V. c( _, V# `9 yAccepted for publication July 1, 1977. ·
9 s; @, I- a4 c4 PRead at annual meeting of American Urological Association,0 ?: h2 M) ]; |1 p: G" \
Chicago, Illinois, April 24-28, 1977.' J% u! i. R7 e
* Requests for reprints: Division of Urology, Henry Ford Hospital,4 @) P7 s- _/ {$ ?
2799 W. Grand Blvd., Detroit, Michigan 48202.4 N- c6 l( S; B# I6 q
improvement in phallic growth compared to gonadotropin.  t6 S8 Q$ R% i. m' H# n( q+ w8 X
Average phallic growth with gonadotropin was 14.3 per cent
6 C( o" U  i6 O! ^& L; {7 u8 Xincrease in length and 5.0 per cent increase of girth. Topical1 |5 t- w+ o9 [# y( r
testosterone produced a 60.0 per cent increase of phallic length% D, q# C9 ?' g7 S7 @, T
and 52.9 per cent increase of girth (circumference). The
% ^. E% a+ E& l8 _  h5 p0 ~- Sresponse to topical testosterone was greatest in children be-; ~; q* {* C7 t: B  p
tween 4 and 8 years old, with a gradual decrease to age 17; u9 d% W5 w, X' q6 h
years (see table).
: U/ B) @/ q2 K9 ?/ t' d! zDISCUSSION( u# u  ~( E: F! Q, Y: `
Topical testosterone has been used effectively by other
- ~; R% D6 I/ `* R3 F8 t& ?4 _clinicians but its mode of action remains controversial. Im-  w) l  j1 f/ |" K3 k, Q) `
mergut and associates reported an excellent growth response
* d- B8 z' d3 @; eto topical testosterone with low levels of serum testosterone,) \& [' V* t( v$ U; t8 y. t
suggesting a local effect.1 Others have obtained growth re-
7 N4 e( a5 X. ^0 v, t7 x( d% Asponse with high. levels of serum testosterone after topical/ i+ \4 P; t9 x: A; e
administration, suggesting a systemic response. 3 The use of5 B3 q, ]2 ~# D# W: F! f/ n
gonadotropin to obtain levels of serum testosterone compara-
1 ]9 s; m# w# s4 f# Bble to levels obtained with topical testosterone would seem to
5 o: T: _7 c( q7 `provide a means to compare the relative effectiveness of# S$ F$ S9 |7 \8 L
topical testosterone to systemic testosterone effect. It cer-
3 D0 M* N3 d$ v1 D2 M5 W5 R6 Mtainly has been established that gonadotropin as well as par-- M! \; L* a. L+ l, K) W
enteral testosterone administration will produce genital2 A+ Z4 L/ g& s% m" {0 M. l  b$ B
growth. Our report shows that the growth of the phallus was1 |5 r# l2 R% }9 ~1 ~! ]
significantly greater with topical applications than with go-4 q4 T5 _, G1 e5 `" t
nadotropin, particularly in children less than 10 years old.
7 k- V  y0 E0 v9 e2 r: d3 L; }The levels of serum testosterone remained similar or lower% r$ `# r9 O: L' U7 d2 ~) P. R) q
than with gonadotropin during therapy, suggesting that topi-1 D/ F3 [2 G' N! `
cal application produces genital growth by its local effect as3 o) G6 {1 B; O& w, B' v
well as its systemic effect.
2 a$ a% f, Q4 c, Z4 CReview of our patients and their growth response related to; k5 |7 T! x  C, V6 A. G# \+ q
age shows a greater growth response at an earlier age. This is
$ l! g, a# V7 Y1 Oconsistent with the findings of Wilson and Walker, who; D7 W) i9 x3 }" _1 p5 ]4 _# K
reported an increased conversion of testosterone to dihydrotes-
- C7 \& N! z' R& q7 ~2 \& ktosterone in the foreskin of neonates and infants.4 This activ-
7 P/ [- c  k( G( [ity gradually decreases with age until puberty when it ap-0 P9 q5 \& Y4 f4 Z# u
proaches the same level of activity as peripheral skin. It may
( f  x+ R8 m, _: s2 J0 p/ twell be that absorption of testosterone is less when applied at0 ~2 H, q0 B, Q) w/ \1 G
an earlier age as suggested by lower serum levels in children
2 V. F0 x" e4 }less than 10 years old. This fact may be explained by the
% U2 P) F2 O" |greater ability of phallic skin to convert testosterone to dihy-: {2 Q" O5 |& m( Z( R' y3 P; W) s
drotestosterone at this age. Conversely, serum levels in older* B3 E3 r5 m- Z1 ?  G( L
patients were higher, possibly because of decreased local% J2 @6 u# g( [
667
* ?0 N. }) o! O668 KLUGO AND CERNY3 e1 S7 K2 A+ X* T! Q
Pt. Age
7 `' U$ ~% ^' I6 X( A(yrs.)
$ p8 y9 x) V9 r# `Serum Testosterone Phallus (cm.) Change Length
6 a# u  V7 d% p1 ]0 l6 X: x" o(ng./dl.) Girth x Length (%)
& D" Q2 x# D8 n; z* z4: d% U* x7 l4 x3 f1 P6 @
8" P% ]8 Y- W6 }2 R
10- T/ E& U0 g3 ~
12& Y8 J! s+ l4 E
17/ o5 Q9 |1 q" p& [. L' T0 S- c
Gonadotropin
; s% t3 J% E- N6 D% _71.6 2.0 X 3 16.69 g7 V: H, e' s, S
50.4 4.0 X 5.0 20.0
9 N" r& K9 H: N6 E/ e# z22.0 4.5 X 4.0 25.0
) d3 V1 w$ l# i! q. z6 R; C( v84.6 4.0 X 4.5 11.1
" y7 w, O" [7 y5 q8 K( r. n85.9 4.5 X 5.5 9.0
9 G& m' Q1 ^' U) |: NAv. 14.38 S9 r* \0 u+ u+ g4 u- A
4
% M% j% q. ?* A8 P8
  E/ [9 z8 c; z) ^106 h" \' R5 J! f2 Z; x7 t7 R
121 C4 C$ W/ W1 g
17
' r" J' K; M! V4 o& T2 FTopical testosterone2 Q/ u$ h3 v! K1 i$ y2 D! B+ s
34.6 4.5 X 6.5 857 x' h- n" Z3 i) D( L0 i
38.8 6.0 X 8.5 709 C& C% t/ |6 ^5 s4 u# _2 L  G
40.0 6.0 X 6.5 62.54 o+ L2 K9 f9 p( w
93.6 6.0 X 7.0 55.5
" p2 m' [! p/ k: K( k  n& j" l95.0 6.5 X 7.0 27.2
  Z( V6 U2 [* wAv. 60.0
+ h2 u) M% L# d; J& r& J; T% Wavailable testosterone. Again, emphasis should be placed on# [3 N" p; `) ]* J3 V
early therapy when lower levels of testosterone appear to* }( s! b4 V: J" p# d
provide the best responses. The earlier therapy is instituted6 z; l; c9 i4 b9 k9 [5 F6 o7 ?! ?
the more likely there will be an excellent response with low
; J+ w; e  M: _$ g3 yserum levels. Response occurs throughout adolescence as
; |3 L5 m' B7 v$ \$ b: S1 P, Rnoted in nomograms of phallic growth. 7 The actual response; e8 `6 I' J1 i& |( R
to a given serum level of testosterone is much greater at birth! A. @$ C: `4 I5 A  ?
and gradually decreases as boys reach puberty. This is most
6 C, m% q& ^9 Flikely related to the conversion of testosterone to dihydrotes-
6 }; P# s6 Y+ r  ztosterone and correlates well with the studies of testosterone2 K# y6 a; |: F; b+ F; `0 z; S
conversion in foreskin at various ages.9 {: g+ I6 P' o( ?9 W
The question arises regarding early treatment as to whether
1 M% \% f9 `% M- Vone might sacrifice ultimate potential growth as with acceler-6 O) E  n  A$ e3 s5 \
ated bone growth. The situation appears quite the reverse
+ K1 h- z! b2 c8 ~; j$ owith phallic response. If the early growth period is not used
& {3 v* `7 t& X8 L+ m7 Bwhen 5a reductase activity is greatest then potential growth
3 f6 N9 o5 A. B" U" v/ d' b, _! ymay be lost. We have not observed any regression of growth+ V; m% t5 a8 N0 t+ e& u& m$ s8 w4 u
attained with topical or gonadotropin therapy. It may well" y4 }5 y7 N8 n8 V8 k7 N2 f
be that some patients will show little or no response to any
/ r1 d7 Y& d- |6 R3 G. V! _form of therapy. This would suggest a defect in the ability to. v- o$ M- S/ [2 y/ k; S, m
convert testosterone to dihydrotestosterone and indicate that" P' w( V' M' K$ G  u9 G
phallic and peripheral skin, and subcutaneous tissue should
' l  F* D1 Y+ C. W& \be compared for 5a reductase activity.) t( Y; I4 {3 i/ Z' c/ C4 p
A, loop enlarges to measure penile girth in millimeters. B,7 g, |7 C* D9 }& k+ o5 v' `
example of penile girth computed easily and accurately." Q; W$ n7 v4 C& j" r9 w
conversion of testosterone to dihydrotestosterone. It is in this1 T* g6 @# W/ N
older group that others have noted high levels of serum
7 r6 S+ v% f: {9 S4 ktestosterone with topical application. It would also appear  A$ D# d( T3 b; ~9 \# }
that phallic response during puberty is related directly to the7 d( P) h& T8 k" `8 }: {
serum testosterone level. There also is other evidence of local
1 m3 ]4 q  X! s/ M: P! xresponse to testosterone with hair growth and with spermato-
  ?) M- k9 L: i  T3 e# p0 _, B! egenesis. 5• 63 V' k1 }4 r% U7 i1 [7 j
Administration of larger doses of gonadotropin or systemic. O2 X8 ~& X8 ^: g
testosterone, as well as topical applications that produce
4 ~1 j7 D: G5 B4 B1 a& u! \1 M. Thigher levels of serum testosterone (150 to 900 ng./dl.), will
! ?( z3 y8 D8 e) Q( ~. E9 B( P# Palso produce phallic growth but risks accelerated skeletal7 p5 V# i- L. v9 }8 C, t$ d
maturation even after stopping treatment. It would appear8 `( C" [2 _6 |8 K
that this may be avoided by topical applications of testosterone
$ [# Z) U* k- A$ Gand monitoring of serum testosterone. Even with this control' {1 E" U3 ]" L
the duration of our therapy did not exceed 3 weeks at any
( o  g/ q* P# b' Z* ^5 Vtime. It is apparent that the prepuberal male subject may
- H. e& q& N" \  k, e( H# Ysuffer accelerated bone growth with testosterone levels near
: H: a" n, O6 C- |, v200 ng./dl. When skeletal maturation is complete the level of
$ s! |+ n2 u1 R* }4 _serum testosterone can be maintained in the 700 to 1,300 ng./, n$ i/ e! m1 u6 J% t
dl. range to stimulate phallic growth and secondary sexual  ?! q( Z0 N9 m
changes. Therefore, after skeletal maturation parenteral tes-- e' h* a) ^& l+ [' N8 ]
tosterone may be used to advantage. Before skeletal matura-
& k. Q/ s( p+ x2 _8 ]7 y" B. a9 Ftion care must be taken to avoid maintaining levels of serum
) c" U5 A2 C- I$ @% u' c' w4 X1 Y" h3 \testosterone more than 100 ng./dl. Low-dose gonadotropin
6 x& X2 a' L& w9 R: O, @* tdepends upon intrinsic testicular activity and may require
1 s5 ^" @, I! Z& [2 u. l, eprolonged administration for any response.3 r2 z2 ?/ h/ w# Y1 W/ U. [
Alternately, topical testosterone does not depend upon tes-$ t0 n0 F$ R$ _  E1 I0 ]
ticular function and may provide a more constant level of0 C% ~" p& U1 `7 s) U( K
REFERENCES1 C: v; Q, ~% B0 m/ J9 h$ k  T- N
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
& \: Y, B) V# [R.: The local application of testosterone cream to the prepub-
# \& @# q- m& y5 I$ B( H; {" K% @ertal phallus. J. Urol., 105: 905, 1971.& F# S& A/ e' L* O; y) f
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 P( _0 G1 d8 |4 r$ }, k/ @
treatment for micropenis during early childhood. J. Pediat.,
& P" o, E' D8 {7 |7 |/ M0 d83: 247, 1973.* `! k5 [6 {% a/ \, Q2 A+ m& i
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. Y& K1 d9 L4 c) p" C7 R" l
one therapy for penile growth. Urology, 6: 708, 1975.9 }2 \! M( q3 S, Y9 V- z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
4 [: e, j5 h2 _$ m- r, jto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( `  d* p2 S8 t' \- H' @. x
skin slices of man. J. Clin. Invest., 48: 371, 1969.) ]( ]3 N& N( X' c: x3 z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' T. S0 R. V+ C7 w4 U
by topical application of androgens. J.A.M.A., 191: 521, 1965.
0 j& ]) B; A2 P) \. J, _6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ ^6 P' p+ u/ Y  X4 |# x& Sandrogenic effect of interstitial cell tumor of the testis. J.
. Y; t/ c$ x4 b# `% K- ?4 cUrol., 104: 774, 1970.
; ~+ {( O' @) z2 U; q% L5 U7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-3 e: @) I3 S" _, \# W$ p8 k$ f7 D
tion in the male genitalia from birth to maturity. J. Urol., 48:
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