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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ O: O. x0 Z4 H( r  b+ F# d
GONADOTROPIN
' l+ L' U9 H& g8 `7 ~RICHARD C. KLUGO* AND JOSEPH C. CERNY
* [5 }% f" I- [" Q  D7 lFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: Y; K/ Y0 @8 K  bABSTRACT
4 c( I1 R' b: h+ N0 lFive patients were treated with gonadotropin and topical testosterone for micropenis associated
: u, U4 t  U, n+ Mwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-( G4 s5 p5 N; n; Y" M3 E" Z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
8 \! j0 e) E3 u. Ycream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: G' @7 \. B/ [2 n8 B& Afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
) j( y6 {7 I/ U! M6 y  vincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average7 M& Y% q# [% k5 x, g; a" a8 P6 ^) J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
( J# P7 h. @9 Y3 doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This  h' C+ f8 [2 h% W
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* r/ K. g3 h0 W; h4 Y" p+ jgrowth. The response appears to be greater in younger children, which is consistent with previ-
, q; c+ t* ^$ N. U' u- W4 K) [ously published studies of age-related 5 reductase activity.) N6 H. ?) r2 C* i
Children with microphallus regardless of its etiology will
0 o- K" g  ]  Y- Yrequire augmentation or consideration for alteration of exter-
4 |" {6 }# v/ f# d9 K8 Cnal genitalia. In many instances urethroplasty for hypo-
6 h( T  ~' Z" I* Hspadias is easier with previous stimulation of phallic growth.
1 v1 |7 I: q) t- K" [3 G0 DThe use of testosterone administered parenterally or topically
: H  {+ y6 O* ?: L, d3 G! mhas produced effective phallic growth. 1- 3 The mechanism of; ~+ v1 S$ {6 P3 e# ?5 p
response has been considered as local or systemic. With this
( C$ t$ o* s) U3 b) Rin mind we studied 5 children with microphallus for response+ X0 r! i) c: t7 o7 L5 A
to gonadotropin and to topical testosterone independently.9 `; Q9 z4 j- d) I2 P" [/ F4 ^) J# c
MATERIALS AND METHODS& W9 F0 X7 O' Z) _8 e$ @4 ~
Five 46 XY male subjects between 3 and 17 years old were
8 l7 B! C8 j+ z! R5 }! mevaluated for serum testosterone levels and hypothalamic& n" W. _, u3 M+ J7 `: q7 ]9 B
function. Of these 5 boys 2 were considered to have Kallmann's
0 w0 [/ J# a# L& Vsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
1 _& {. Y0 H7 J2 @  Jlamic deficiency. After evaluation of response to luteinizing
& V+ p+ W! o! P5 \9 C9 S, Ihormone-releasing hormone these patients were treated with% a. b* i+ {8 a# @
1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 F2 z/ E' l4 U! s' H8 j
after completion of gonadotropin therapy 10 per cent topical1 x& P3 q2 z- n5 [2 w' q* t
testosterone was applied to the phallus twice daily for 3 weeks., e( f1 i1 }8 S- e3 d% ?" M
Serum testosterone, luteinizing hormone and follicle-stimulat-
- y9 I+ _, |( Z8 b1 Xing hormone were monitored before, during and after comple-
- \8 I, c$ }, m! e$ Ktion of each phase of therapy. Penile stretch length was
; S- N! Q: I. Dobtained by measuring from the symphysis pubis to the tip of# Z; \/ f- M9 Z) V5 @" C
the glans. Penile circumferential (girth) measurements were
3 J7 W7 l3 d# X- b% i* x. A4 Uobtained using an orthopedic digital measuring device (see, f2 ]3 r3 S! U2 W( Q0 l) T
figure).' b2 V$ B' t. x8 R
RESULTS: L  Z( ^- h  `* y# O
Serum testosterone increased moderately to levels between3 D- E. ~% ^7 o% q# p
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-, z9 j2 o: g+ r$ Q
terone levels with topical testosterone remained near pre-& z% S* o, e, Z" j& \! C
treatment levels (35 ng./dl.) or were elevated to similar levels
# c2 G" r+ S9 cdeveloped after gonadotropin therapy (96 ng./dl.). Higher4 E0 e' F  a7 Z5 Q6 G
serum levels were noted in older patients (12 and 17 years old),
- g* n% q; Z0 R; p4 {  p) t: mwhile lower levels persisted in younger patients (4, 8, and 10
/ _, C) G7 Z. G- m. |years old) (see table). Despite absence of profound alterations/ Y4 @+ x7 w) I" s; Y4 I
of serum testosterone the topical therapy provided a greater7 t9 r) f5 k$ ^- ~* \& Q! y
Accepted for publication July 1, 1977. ·% s$ p  }8 _& f- e
Read at annual meeting of American Urological Association,
9 @! Y5 d1 h$ vChicago, Illinois, April 24-28, 1977.7 ?$ ]% ]9 T1 o) y3 P8 N+ W
* Requests for reprints: Division of Urology, Henry Ford Hospital,; Q5 O/ E; ?& C3 r
2799 W. Grand Blvd., Detroit, Michigan 48202.# A  x2 }2 C/ F; y0 m! F/ h7 N! C  B
improvement in phallic growth compared to gonadotropin.1 C& p3 z; |/ q# g3 I" u
Average phallic growth with gonadotropin was 14.3 per cent
/ P" Y( B7 e- h: E/ W* wincrease in length and 5.0 per cent increase of girth. Topical( o" W& ?1 D/ T! M- ^) X
testosterone produced a 60.0 per cent increase of phallic length
  \: V! D" G. H$ Y7 eand 52.9 per cent increase of girth (circumference). The
0 R0 \% Q4 W( aresponse to topical testosterone was greatest in children be-4 }7 Z7 v5 x! c4 H% B' z* p% p3 @
tween 4 and 8 years old, with a gradual decrease to age 17
% N) G8 w. U! g3 Gyears (see table).( A+ l9 x0 v$ g) B* h
DISCUSSION
$ L- m3 q0 n% l/ L; d* M3 m" Z/ oTopical testosterone has been used effectively by other
: p' S# ^: c9 `! aclinicians but its mode of action remains controversial. Im-  Z7 x- v2 H& Y0 @
mergut and associates reported an excellent growth response
! s: O, q1 R6 \* h9 b+ j1 h& Sto topical testosterone with low levels of serum testosterone,
5 \( |% }$ m, J, a+ Qsuggesting a local effect.1 Others have obtained growth re-
) a# i# F. c' y5 x+ x* Ssponse with high. levels of serum testosterone after topical" [9 ?1 n* P( E/ X7 D3 i! {; o
administration, suggesting a systemic response. 3 The use of, F0 g6 }* ~9 v
gonadotropin to obtain levels of serum testosterone compara-2 j- z7 U/ f3 K9 ]* {8 x
ble to levels obtained with topical testosterone would seem to
1 n1 ^6 D0 U7 \; z. }. G# yprovide a means to compare the relative effectiveness of
3 x' Z- H" ^6 P9 y. B! mtopical testosterone to systemic testosterone effect. It cer-
( L4 Y6 `5 ^9 p! Ftainly has been established that gonadotropin as well as par-  I! ~1 ]  e( t* t/ |( L
enteral testosterone administration will produce genital
" c; u0 c- B  d& U' M5 Jgrowth. Our report shows that the growth of the phallus was
& z; X/ F6 \/ esignificantly greater with topical applications than with go-
2 |* C6 l6 u, N# m9 D& `nadotropin, particularly in children less than 10 years old.
6 H, C! a. L5 }' E. N, U) XThe levels of serum testosterone remained similar or lower' I3 z$ t+ L$ C
than with gonadotropin during therapy, suggesting that topi-
. i$ i7 i( j& m/ Y$ x/ ecal application produces genital growth by its local effect as( R5 f, r! g6 p- ~' c6 n& H0 J6 E* H
well as its systemic effect.
* b) j) [# I% x, OReview of our patients and their growth response related to
0 J  E+ A- N& R' U  ]8 M, `age shows a greater growth response at an earlier age. This is
: H3 V8 r( |+ i0 m0 T+ ~! `consistent with the findings of Wilson and Walker, who' q4 n! r; U" U% y- A5 F
reported an increased conversion of testosterone to dihydrotes-
' @, K% t7 k. H. }( Q# Ntosterone in the foreskin of neonates and infants.4 This activ-/ K* A% T9 E+ ~
ity gradually decreases with age until puberty when it ap-
+ m9 e. O: [) n: {proaches the same level of activity as peripheral skin. It may
3 @6 a/ j, R$ @' `- N1 x2 x5 H( Iwell be that absorption of testosterone is less when applied at  H3 _; U2 ~" I& n# B
an earlier age as suggested by lower serum levels in children
3 f4 V, ~5 x  w, m' B/ ]* Lless than 10 years old. This fact may be explained by the% }  P+ g) _; D* v; c
greater ability of phallic skin to convert testosterone to dihy-
# D1 A/ J* w  _- cdrotestosterone at this age. Conversely, serum levels in older
/ f5 c4 L! U2 A. u5 }patients were higher, possibly because of decreased local6 ~3 Y: K2 c. g: F3 `' A# w
667
( l# o. [2 t; I- n' z3 l+ O668 KLUGO AND CERNY# v0 i) n- P; V5 Y# R1 g& T
Pt. Age: q7 F, y) K5 y) ^2 E: T4 A
(yrs.); D4 a+ e' a: U  `# y
Serum Testosterone Phallus (cm.) Change Length2 p) o2 M0 u- R: Y) R; i8 |/ o
(ng./dl.) Girth x Length (%): w) R7 V1 D7 ]3 F: S8 Z
4- [6 a$ F( \$ @, n) M8 Y: \% e  i& V
8
8 D! w0 b: W+ T9 `3 B5 [$ h10
$ M( Q* v2 M9 u: U0 q12
" f0 t) f" H: n& ~" z* {. k5 L175 Y7 d& [0 U) ]4 R3 ]4 y
Gonadotropin- M* _# F9 p# x' A' a6 J
71.6 2.0 X 3 16.65 {; o1 B9 e% q# d% Q
50.4 4.0 X 5.0 20.0
1 F1 \) P/ B0 j. G3 H7 I# q& X22.0 4.5 X 4.0 25.0+ Q( M) x& Z# d! \/ G
84.6 4.0 X 4.5 11.1
) T" L$ M" q! j8 S( e. Z/ o8 Q85.9 4.5 X 5.5 9.0
8 x2 a/ F  \  BAv. 14.3
1 a6 o, v7 v: y- I* V4, ?  T2 y% k, M5 f
8
6 v1 I" @: b" ~1 ]- y1 r10
/ S5 e0 e# M6 z3 o' e3 ?- w& r12& ]/ f0 k/ [! i" ~, u$ D
17
2 b# X4 i. H, r5 K1 c9 H( [, rTopical testosterone4 e. `3 d* ]  P
34.6 4.5 X 6.5 85
+ E+ C) u4 l0 O" r38.8 6.0 X 8.5 700 K6 y2 V, w2 d4 D) U/ N+ u# c
40.0 6.0 X 6.5 62.5
4 [7 K8 O% \+ x93.6 6.0 X 7.0 55.5
, S9 u5 J( N- i' P95.0 6.5 X 7.0 27.2
6 D  {1 e. K4 jAv. 60.07 L  M! `. Y8 g; `1 y) P- B3 p7 K1 w
available testosterone. Again, emphasis should be placed on& V. k+ e7 m' }
early therapy when lower levels of testosterone appear to# w# W9 }4 B- [
provide the best responses. The earlier therapy is instituted
/ @* p% |# _) Z% L" O) qthe more likely there will be an excellent response with low, {) _+ E; L+ H; C7 y4 T
serum levels. Response occurs throughout adolescence as: `3 F6 m. y  V  }* @2 }: N
noted in nomograms of phallic growth. 7 The actual response+ s& H/ Y9 k/ n0 V0 t0 C- {
to a given serum level of testosterone is much greater at birth; v/ b7 u; m2 w! E  r/ g
and gradually decreases as boys reach puberty. This is most$ b0 o0 U! B2 o* X2 e* c, g
likely related to the conversion of testosterone to dihydrotes-
  ]9 U+ G6 \* ltosterone and correlates well with the studies of testosterone; _; U+ H6 s, G3 ]; a2 S
conversion in foreskin at various ages.0 i) B, b& v7 R( k/ \
The question arises regarding early treatment as to whether7 h$ R9 ~* G# ^# D8 a; s4 g
one might sacrifice ultimate potential growth as with acceler-2 c! C5 R. u5 R$ d* ^/ U5 W1 \7 `
ated bone growth. The situation appears quite the reverse! @+ ?5 n- D1 d8 {
with phallic response. If the early growth period is not used
$ A& ]7 U* d" m5 Y" I; mwhen 5a reductase activity is greatest then potential growth
3 P6 V' X, Y7 ]7 a, a0 w' ?may be lost. We have not observed any regression of growth
, \& Z  Y: G# R0 Z: r+ z( {# cattained with topical or gonadotropin therapy. It may well
7 d, M4 \& a0 v* w. ?/ N$ M$ Fbe that some patients will show little or no response to any
0 b$ p( O0 D2 L: r& b* P/ m# Jform of therapy. This would suggest a defect in the ability to- I" _& b4 H7 ^4 z" [
convert testosterone to dihydrotestosterone and indicate that
/ g) t0 Z0 \1 S$ `# ^# Tphallic and peripheral skin, and subcutaneous tissue should
- z$ \9 a, P  _% wbe compared for 5a reductase activity.& B: g, {  C) P
A, loop enlarges to measure penile girth in millimeters. B,7 Y5 d5 @* y* I6 C4 P
example of penile girth computed easily and accurately.
/ n8 ?- m& Q& x# ~! D9 ?& h. U. [9 gconversion of testosterone to dihydrotestosterone. It is in this* v  p4 o( T6 q4 B& O6 [$ L9 a3 I; n9 {
older group that others have noted high levels of serum
+ Q* `: m/ w+ X9 C5 l8 itestosterone with topical application. It would also appear+ m: n5 N1 E5 z; K. L! F2 j
that phallic response during puberty is related directly to the
2 ^5 N+ _+ z6 E) Eserum testosterone level. There also is other evidence of local% g2 K. Q/ Z+ r/ Y6 @0 r
response to testosterone with hair growth and with spermato-
0 N5 n! J( ~7 t# c4 Ygenesis. 5• 6
0 z! M6 N  n, ~( a' pAdministration of larger doses of gonadotropin or systemic1 W" ~% G" n' Q/ F0 ^
testosterone, as well as topical applications that produce
1 V; W+ _* e) J5 phigher levels of serum testosterone (150 to 900 ng./dl.), will
- S: E$ Q/ Z. h7 L9 yalso produce phallic growth but risks accelerated skeletal
: O4 |' ]  V+ M7 z* ]maturation even after stopping treatment. It would appear5 S0 s' w5 a0 \
that this may be avoided by topical applications of testosterone7 `% `7 k: M" H& A; K2 v
and monitoring of serum testosterone. Even with this control
3 X2 L+ S; V3 d$ rthe duration of our therapy did not exceed 3 weeks at any
% B6 h0 O. @' w/ d, n- p3 Btime. It is apparent that the prepuberal male subject may2 p5 Q; S8 a: j/ n* C+ U
suffer accelerated bone growth with testosterone levels near
( p1 M- x7 \! Y- k/ Z/ X200 ng./dl. When skeletal maturation is complete the level of
" Y, m+ }. U- |* n. X: U3 Wserum testosterone can be maintained in the 700 to 1,300 ng./% H8 w* H7 r% W8 ^
dl. range to stimulate phallic growth and secondary sexual9 j$ m# e; ?9 ~! b  \: @5 G
changes. Therefore, after skeletal maturation parenteral tes-
( K' O9 n" l6 H2 G# W# L& [" c- \tosterone may be used to advantage. Before skeletal matura-
. X* l) @) x8 X* L- ]$ ]tion care must be taken to avoid maintaining levels of serum7 t8 J$ Z, h" |1 D4 l5 `% R( d: m+ k
testosterone more than 100 ng./dl. Low-dose gonadotropin
. e6 y& X% b. S& d/ _depends upon intrinsic testicular activity and may require2 y3 S4 W4 Z* s  I3 F
prolonged administration for any response.
' E3 T5 e. Q- E+ U4 [- pAlternately, topical testosterone does not depend upon tes-
  @4 u. n7 B/ Q- @2 C3 Qticular function and may provide a more constant level of
, Y8 g- n6 u) i& J, nREFERENCES
+ T5 r: T6 c$ j5 n, J1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,: p' u. r( j2 P$ f. i" J( t
R.: The local application of testosterone cream to the prepub-
( {: r9 `$ E. m4 Y1 b% {4 {ertal phallus. J. Urol., 105: 905, 1971.
; p: y4 |  v+ g; E: [2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ a7 i5 x3 g; d. m( ]- h% ?! H
treatment for micropenis during early childhood. J. Pediat.,
. Z* {/ B- D8 N; @83: 247, 1973.2 j' p& A. R. G  L" A' x
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' n& h; m" D4 \) x
one therapy for penile growth. Urology, 6: 708, 1975.
( p) H3 r, s" }2 g, @' C5 h) e3 J4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) ]0 X+ J9 G: T/ M: Eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. g. q4 }. R4 s; r
skin slices of man. J. Clin. Invest., 48: 371, 1969.. n3 [# z6 t+ Q+ k5 [+ ~) S6 I
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth  F  x' ^( g. k
by topical application of androgens. J.A.M.A., 191: 521, 1965.
, b! V3 x: l3 w" `' f6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local7 l& {5 N! m2 i" x6 [
androgenic effect of interstitial cell tumor of the testis. J.* i9 J: F9 g+ A6 ^( ^' [
Urol., 104: 774, 1970.. o" D2 L/ E! b+ o
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
5 P$ N  P( h+ q' g4 h" H; Ltion in the male genitalia from birth to maturity. J. Urol., 48:
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