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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" d; f( W" N, r% t+ ^9 h! n
GONADOTROPIN
" f3 Z/ T9 T/ O; M6 H6 n$ TRICHARD C. KLUGO* AND JOSEPH C. CERNY. ^. d: x# [, \! |5 n3 p
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, ?" Z6 F7 P7 F5 g  V1 X- D+ X, e  a$ `$ lABSTRACT2 {  n/ Y  w4 m& f4 c! R
Five patients were treated with gonadotropin and topical testosterone for micropenis associated) L# v3 r1 j# l9 Q5 S
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
4 _/ D9 W2 _- n6 E3 z7 O1 E. m( ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! r- Y5 q4 Y" jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 F' z/ _4 v$ c. c  efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. {) U4 b3 t7 U
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
- F+ |4 ~% x  T1 f. h2 y: F! Oincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response2 y, M* [/ f- h' h5 ~
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
  h! J- u7 t* w2 r+ e  P& qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 v5 w8 z& c5 N/ N' h. x1 u/ F
growth. The response appears to be greater in younger children, which is consistent with previ-
& F% P* P- i" D0 `ously published studies of age-related 5 reductase activity.' Q+ {3 Q3 D. }
Children with microphallus regardless of its etiology will! R% |6 k) j- f$ @! ?, }! g
require augmentation or consideration for alteration of exter-, z7 [; {8 y: Z' P/ s+ s( g* q
nal genitalia. In many instances urethroplasty for hypo-
7 l( C: n9 N0 L0 Z6 ^& D# Aspadias is easier with previous stimulation of phallic growth.
  k+ \% v/ \5 r& w8 a) _' L! Z* m$ PThe use of testosterone administered parenterally or topically
. ^/ \) w5 y  Q" H! D. F9 \( Ghas produced effective phallic growth. 1- 3 The mechanism of
% X: i/ H" T3 f: uresponse has been considered as local or systemic. With this, Q6 d" o4 P' e$ G/ y' Y
in mind we studied 5 children with microphallus for response
; N0 D: X, F0 n9 b" X9 Vto gonadotropin and to topical testosterone independently.
/ k1 K$ c3 R, X+ t# f2 GMATERIALS AND METHODS$ O0 Y' @' [6 k% J' o
Five 46 XY male subjects between 3 and 17 years old were' [+ {/ O, Y9 g% z6 ^
evaluated for serum testosterone levels and hypothalamic
1 G+ C" W0 b5 l8 U: Rfunction. Of these 5 boys 2 were considered to have Kallmann's  K4 K- \3 j0 M1 X
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
; p: p: H6 Y7 i0 \lamic deficiency. After evaluation of response to luteinizing
) y* K6 y! u* Fhormone-releasing hormone these patients were treated with
: U0 K/ \4 R2 N6 c1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 w$ V( C& |3 z8 n9 D, x0 _after completion of gonadotropin therapy 10 per cent topical
- z( w/ n  v& \testosterone was applied to the phallus twice daily for 3 weeks.
- K* H( H; P& BSerum testosterone, luteinizing hormone and follicle-stimulat-7 X; d/ \: j2 E& E& U. \  l
ing hormone were monitored before, during and after comple-5 q  a( H6 Y/ a4 Q. {# T- T
tion of each phase of therapy. Penile stretch length was
+ g5 }: G- ?/ h6 Iobtained by measuring from the symphysis pubis to the tip of
! h# j, A' s* B( S% p5 c9 Wthe glans. Penile circumferential (girth) measurements were+ M+ j0 K7 r& N
obtained using an orthopedic digital measuring device (see% M! Q, h& W) }3 c( N2 v
figure).! |3 ~' v3 A5 a' C* ^
RESULTS
3 o# B8 R4 {0 e5 @  CSerum testosterone increased moderately to levels between
; p; |0 ^/ c. q- g& W50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
. r" n, C% E- W3 ?7 ^terone levels with topical testosterone remained near pre-
; e) @) @* m. V, ^& g2 c3 H7 }treatment levels (35 ng./dl.) or were elevated to similar levels, O2 b1 T- H7 a8 [% n
developed after gonadotropin therapy (96 ng./dl.). Higher2 o$ U* N1 m5 O6 Y0 J6 v
serum levels were noted in older patients (12 and 17 years old),
1 A" [/ ]5 Q. W& @& O5 ^while lower levels persisted in younger patients (4, 8, and 10
* K" h0 K& z" H& s* eyears old) (see table). Despite absence of profound alterations3 Q0 o9 I% G8 `7 @' G: K
of serum testosterone the topical therapy provided a greater$ w1 e" z& i1 M% L5 G' G
Accepted for publication July 1, 1977. ·& t2 _. i2 {. j5 S4 ?) k5 y5 s
Read at annual meeting of American Urological Association,
# `( {, c6 k! l8 D3 b# @Chicago, Illinois, April 24-28, 1977.$ I8 k7 u) p" h* i/ y3 ^
* Requests for reprints: Division of Urology, Henry Ford Hospital,
6 h: \+ q( C1 q& H" Y5 t4 x2799 W. Grand Blvd., Detroit, Michigan 48202.6 f( w9 q$ L+ z: D4 i
improvement in phallic growth compared to gonadotropin.
* l6 l! J! M& R" B) `+ X9 s% WAverage phallic growth with gonadotropin was 14.3 per cent
7 d% i# m  ], X, U4 H" P: bincrease in length and 5.0 per cent increase of girth. Topical1 F4 W5 T( J3 q% ]' J6 H9 p; O
testosterone produced a 60.0 per cent increase of phallic length+ e5 y! H- u  Z
and 52.9 per cent increase of girth (circumference). The
. P3 a6 }7 V+ Y; d! P6 eresponse to topical testosterone was greatest in children be-
" a" w8 F  `5 f* f4 btween 4 and 8 years old, with a gradual decrease to age 17: N) `' w8 Q, ~4 m/ r, s
years (see table)." W/ i' j: C8 E6 A
DISCUSSION
- h" C( ]( G6 `! R- l- ]Topical testosterone has been used effectively by other
7 \9 F- v7 N  R, u5 C( T' J1 e( Iclinicians but its mode of action remains controversial. Im-
: V( `6 C& E- o2 P/ S# g3 Z0 ~/ Q& C& hmergut and associates reported an excellent growth response
* K  i% [6 O! R, G# Uto topical testosterone with low levels of serum testosterone,
- z" X' A$ v0 zsuggesting a local effect.1 Others have obtained growth re-* j& d1 N' G+ t9 l. F, [
sponse with high. levels of serum testosterone after topical- V' R7 l* L: ~! Q
administration, suggesting a systemic response. 3 The use of+ Y/ \$ d9 b8 X; T' E2 a; q0 \
gonadotropin to obtain levels of serum testosterone compara-) ^1 m  z( h8 u2 C& p" _
ble to levels obtained with topical testosterone would seem to( ]) T! A& f2 ?' @
provide a means to compare the relative effectiveness of# B1 W3 |  {+ y# h9 d
topical testosterone to systemic testosterone effect. It cer-2 N% C" \) I  _* m! [, k, [
tainly has been established that gonadotropin as well as par-
, Y/ P- ^' ]9 X5 ?( H* T3 o/ `enteral testosterone administration will produce genital$ y# J9 W8 j. w3 B& O5 Y
growth. Our report shows that the growth of the phallus was4 ~$ s* h, f* \! {) [
significantly greater with topical applications than with go-* r; C! R8 q1 I! s7 g8 ]
nadotropin, particularly in children less than 10 years old.
3 T6 a9 j5 U( B2 j. aThe levels of serum testosterone remained similar or lower2 P3 w/ }$ }+ j0 i% e0 J4 Y
than with gonadotropin during therapy, suggesting that topi-
) v5 V2 i6 E* Y" j6 w0 ]cal application produces genital growth by its local effect as
5 L3 \& F0 ^2 p7 S9 dwell as its systemic effect.: A( P4 F4 J* p& Y% E. V
Review of our patients and their growth response related to
/ _% k3 ^8 ~+ H. m7 d" ~age shows a greater growth response at an earlier age. This is
5 d8 v1 [) T- Yconsistent with the findings of Wilson and Walker, who
: p' `: \% U- o( U, S: ?4 Sreported an increased conversion of testosterone to dihydrotes-
+ T# `/ M( r, Wtosterone in the foreskin of neonates and infants.4 This activ-4 e1 s6 N7 o. C
ity gradually decreases with age until puberty when it ap-4 l4 d1 c, `) i% r: |
proaches the same level of activity as peripheral skin. It may% w; a2 j5 j, L5 _
well be that absorption of testosterone is less when applied at) {  A5 V3 S1 E( c) H1 e& s
an earlier age as suggested by lower serum levels in children) r& {3 r( }. J; K  h! |3 m
less than 10 years old. This fact may be explained by the
% N4 R. d4 C8 J  [2 Agreater ability of phallic skin to convert testosterone to dihy-
2 U( s/ G4 J9 b" `- n7 H* Bdrotestosterone at this age. Conversely, serum levels in older) L$ c5 C4 n+ u5 r* O( a" W
patients were higher, possibly because of decreased local
: J% T" _$ v, w0 [667
- q+ ]) j6 Z+ g; g) V; O- W; y668 KLUGO AND CERNY6 J: e* u# B. g% d1 m
Pt. Age; \+ y/ y" M  K+ O$ T
(yrs.)  H7 x) ~/ z: y
Serum Testosterone Phallus (cm.) Change Length& r" G. ?; a& n6 L# a8 Z
(ng./dl.) Girth x Length (%)  \3 I5 u; A8 O1 [/ Y( ]& Q
4
( t$ q; a+ L- Y  h) K: Z1 l87 p- [$ `8 f' l- N$ a9 l# a, G
102 |6 x$ R9 P# s
12
6 f8 t8 X( _9 v8 e+ e2 X  }17
0 t  c( G2 V. H8 X) e7 [& U9 VGonadotropin. D% [( u. p$ _) r( w  P; c
71.6 2.0 X 3 16.6
" S9 y( l1 E! Y2 D0 w. E50.4 4.0 X 5.0 20.0
  w, l9 J5 n6 n1 u6 Q22.0 4.5 X 4.0 25.0
8 ~# e. l  n. O9 |84.6 4.0 X 4.5 11.1
- c2 c, k9 ?5 J9 ^1 r4 i& s85.9 4.5 X 5.5 9.0- w( F' v* p0 K& [/ y6 z* @
Av. 14.3# a' g0 r  Y4 z4 t: n
4
( a3 y( @3 l4 x# Q8
& e' O4 y9 f% C0 v, U" m* N2 c$ H10, b+ H. V# |7 K2 Z
12
+ ?3 z; J) f5 u, A; T- S$ z17$ y2 j  q; D+ K+ V5 `9 O. T
Topical testosterone3 \3 X! q9 f, c! Y
34.6 4.5 X 6.5 85" `7 u$ Z( w8 j% c6 D& k) d, N
38.8 6.0 X 8.5 70
' q6 {" v8 C* u40.0 6.0 X 6.5 62.5
4 ?+ l' ?$ Z! Y+ H' Y2 ]93.6 6.0 X 7.0 55.55 n! D( \, Z5 H
95.0 6.5 X 7.0 27.2- ^1 i, ]1 X. S. I* h3 c) c& q
Av. 60.0
, e+ Y  j, d& Y$ V5 p3 g3 I. qavailable testosterone. Again, emphasis should be placed on" q2 J/ h  F7 o2 @
early therapy when lower levels of testosterone appear to
' n0 ]( a4 g5 [9 nprovide the best responses. The earlier therapy is instituted
' L" ?4 Y4 X7 s! F% r& {the more likely there will be an excellent response with low8 d* V. \4 ~- Z* b* e3 j' Q) C
serum levels. Response occurs throughout adolescence as( ~* D  y/ c1 o  l
noted in nomograms of phallic growth. 7 The actual response4 P  d3 v! U; C- r0 F
to a given serum level of testosterone is much greater at birth
. X* N1 F# f( y0 q" q- B8 v7 `- ?" Dand gradually decreases as boys reach puberty. This is most
/ {; R  `9 I! c1 K1 w, Y7 xlikely related to the conversion of testosterone to dihydrotes-
: `, ]9 i% |$ x8 y2 ftosterone and correlates well with the studies of testosterone
  |& a6 D1 F: ^; u9 |$ mconversion in foreskin at various ages.
+ F; p4 s- _: c* r) L9 l: yThe question arises regarding early treatment as to whether
; G6 z% ?/ k0 R. U( fone might sacrifice ultimate potential growth as with acceler-
: V; A1 j# v0 e0 Q. Zated bone growth. The situation appears quite the reverse( A1 T" Y* l& s- R
with phallic response. If the early growth period is not used
1 E  U1 Q* E1 [% E0 h; V7 ^when 5a reductase activity is greatest then potential growth( T3 f3 K6 O* ?7 z& p  f7 G
may be lost. We have not observed any regression of growth
; g/ K* _7 T. @+ X" j2 t  @% battained with topical or gonadotropin therapy. It may well
  C% F4 X. ?' I# I( l& ?be that some patients will show little or no response to any
- `1 d, P4 O0 l& pform of therapy. This would suggest a defect in the ability to
2 V% R- C, `  {7 l% I7 [' w! aconvert testosterone to dihydrotestosterone and indicate that
3 k- M9 V; ^6 hphallic and peripheral skin, and subcutaneous tissue should
% H# G* E# g  Y& r( U, h1 Z1 jbe compared for 5a reductase activity.
: ~) i; B) D' r1 S& s: J4 iA, loop enlarges to measure penile girth in millimeters. B,' _! {: ]# a$ K6 {
example of penile girth computed easily and accurately.
" ]( W; b1 X+ i: ~2 u3 ]) ?  }! x6 Zconversion of testosterone to dihydrotestosterone. It is in this& Z: R( F3 ~6 x, p# z+ v% j
older group that others have noted high levels of serum
( i7 w; l3 H; _. X4 U- E6 t, \/ I$ ztestosterone with topical application. It would also appear& S9 D2 {; f4 [7 y3 V0 i
that phallic response during puberty is related directly to the; y8 ^- X9 ?' i% j1 l
serum testosterone level. There also is other evidence of local
) e7 f: K. Z( ]1 N- @' Zresponse to testosterone with hair growth and with spermato-
$ ?! C/ [1 o3 ~5 H" q( q& }genesis. 5• 6# e1 n5 b$ a$ L3 [/ @/ c
Administration of larger doses of gonadotropin or systemic
" p' Y7 Q1 O' ltestosterone, as well as topical applications that produce% B8 ^1 O( F% C+ J* I
higher levels of serum testosterone (150 to 900 ng./dl.), will/ @  Y/ X3 D+ ?
also produce phallic growth but risks accelerated skeletal
  c: P+ j6 K6 |( D7 i5 U$ L8 hmaturation even after stopping treatment. It would appear& R/ ?+ y1 H3 W( Y) m3 o
that this may be avoided by topical applications of testosterone8 s% l# N4 ?2 {; k3 w7 {' L( h
and monitoring of serum testosterone. Even with this control6 p/ R# W7 z/ z4 L' S" Y0 B# c
the duration of our therapy did not exceed 3 weeks at any" x( p& b% G2 n
time. It is apparent that the prepuberal male subject may% J0 O0 `. i* n  W% I! I; l  q! z
suffer accelerated bone growth with testosterone levels near& W9 M# M" M6 J! k* h
200 ng./dl. When skeletal maturation is complete the level of( Z" q( ?! I! ]  ]; r
serum testosterone can be maintained in the 700 to 1,300 ng./' }& j* h2 {! u
dl. range to stimulate phallic growth and secondary sexual
0 |+ K$ i! y2 T( N5 e+ hchanges. Therefore, after skeletal maturation parenteral tes-
( f; n/ w- }( O9 y- b' itosterone may be used to advantage. Before skeletal matura-8 c) ?1 k- s) V) c  e4 Q5 J
tion care must be taken to avoid maintaining levels of serum9 X" h5 o  ^, M+ F) [; [  n
testosterone more than 100 ng./dl. Low-dose gonadotropin1 O0 y2 _; z. r* \* |5 i% i
depends upon intrinsic testicular activity and may require, W: Z; ?5 |$ X# M
prolonged administration for any response.7 C8 y: P, W7 b: y0 ^2 b
Alternately, topical testosterone does not depend upon tes-
" a  M2 z9 m0 J5 bticular function and may provide a more constant level of
0 h" ^  ~2 M+ @' R+ C; w9 Q$ m$ aREFERENCES. V6 L7 ]( |0 t
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: z7 Q: S" s7 p) g9 eR.: The local application of testosterone cream to the prepub-% l! c, p9 Q4 x3 b4 x/ @3 o
ertal phallus. J. Urol., 105: 905, 1971.2 f8 b/ w+ }4 E6 g! s
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
$ X$ t+ j- [0 rtreatment for micropenis during early childhood. J. Pediat.,
! G0 c+ s- U2 S9 L! p/ _83: 247, 1973.2 ~, Y$ U+ K3 Q; ~; y: s# ^& k$ ~
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# |; B3 _' G& F, c* W# R  s1 F/ fone therapy for penile growth. Urology, 6: 708, 1975.% d, ?" j, w; C# h4 L
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone+ c+ Z! Y3 `2 z5 A; i; v# ~
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 ]1 S$ r$ D9 f* {/ W' \. A. nskin slices of man. J. Clin. Invest., 48: 371, 1969.
; r3 h: o! R  H9 M5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
1 `0 a( e  O. m- Yby topical application of androgens. J.A.M.A., 191: 521, 1965.
- E. W) _! d, V) K  V6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local5 |4 i* s2 {' u7 {) h3 W7 U& H2 L
androgenic effect of interstitial cell tumor of the testis. J.  x* c8 ^5 ]8 M( @5 l  T
Urol., 104: 774, 1970., P7 s( L* Y( g
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-/ |+ e: r: y& c. _
tion in the male genitalia from birth to maturity. J. Urol., 48:
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