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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% I7 b' D% {7 M. T2 s" r
GONADOTROPIN2 L7 C- g% Q, {/ h3 ^( @
RICHARD C. KLUGO* AND JOSEPH C. CERNY( t' [0 L0 c6 [4 e0 ]/ d
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan% x; Z' ?$ C+ ]8 ]: z
ABSTRACT$ W* n; E4 G( ?) _$ A- F  R3 V
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
+ @6 W& f, q+ \5 w8 y1 C8 U2 g* Pwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
6 H1 M% J5 i) F, j0 stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# v2 {+ w$ Y1 Y) {" y9 V4 Tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
2 G2 C( u4 @7 \3 J& dfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: B- D7 w& D  E1 G$ U: g& G
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average& {' k8 L$ U7 j
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
' U8 J4 k' U1 Voccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This, B& Y) h  G. b! z2 {/ D7 K
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile4 ]+ ^+ q1 j9 t8 N
growth. The response appears to be greater in younger children, which is consistent with previ-" c6 c( O) T# _4 c
ously published studies of age-related 5 reductase activity.* R% L9 |( X' N5 q1 S
Children with microphallus regardless of its etiology will
- h7 ^) L5 Z# F% Orequire augmentation or consideration for alteration of exter-$ G% [( T: L+ b* k$ _( B6 R
nal genitalia. In many instances urethroplasty for hypo-
, p7 W* ?; d% s8 @+ Dspadias is easier with previous stimulation of phallic growth.
, ^4 [3 n! G7 i" f7 ~3 a1 V1 ?The use of testosterone administered parenterally or topically
% X0 `9 H% F0 `5 N' Lhas produced effective phallic growth. 1- 3 The mechanism of: F" _" C* Q" p4 L6 o8 X
response has been considered as local or systemic. With this$ Z5 j3 G2 P$ R# ^9 h6 t
in mind we studied 5 children with microphallus for response# _1 L  c1 r  g6 q1 i" N. _( c, E/ Y
to gonadotropin and to topical testosterone independently.
# d% V- h3 m! l" ~6 c  ZMATERIALS AND METHODS
0 i; l% d+ B+ j# t4 x4 qFive 46 XY male subjects between 3 and 17 years old were) F& b8 J) P+ J0 j, b2 u* L# D! C
evaluated for serum testosterone levels and hypothalamic$ u( T# ?& e# H
function. Of these 5 boys 2 were considered to have Kallmann's) z) L8 N9 m2 f( ~
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' H* X6 D3 N4 v( {. @$ Z) ^" s
lamic deficiency. After evaluation of response to luteinizing3 y* e" i& E3 C5 I& [0 w$ F
hormone-releasing hormone these patients were treated with9 l$ G- k6 P9 f/ t5 i: r# }
1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 x7 f9 I  I4 [3 L( Z
after completion of gonadotropin therapy 10 per cent topical2 q9 _) {) A6 f* _; O
testosterone was applied to the phallus twice daily for 3 weeks.
- u. H. B, n0 x, U: O; @; d7 SSerum testosterone, luteinizing hormone and follicle-stimulat-; I* ]& [$ Y% C/ `# p0 U
ing hormone were monitored before, during and after comple-% i4 a' [/ c  P* r$ F( M
tion of each phase of therapy. Penile stretch length was; }  J$ M- g7 N0 `& V
obtained by measuring from the symphysis pubis to the tip of
; \! c2 @0 K9 Z. P+ @( fthe glans. Penile circumferential (girth) measurements were4 e* D# }, Y; l$ z8 Y7 T4 [
obtained using an orthopedic digital measuring device (see
+ E% d# V7 Y8 k3 r3 ~+ Afigure).8 y; w: J& O$ u
RESULTS( A1 Q: C7 y9 b+ K1 ^; m: A
Serum testosterone increased moderately to levels between$ q# H/ }5 L1 n) Q8 |0 b) K; G" w
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-. s- i! v* o5 G
terone levels with topical testosterone remained near pre-* W, g) Q9 [, s7 K  [
treatment levels (35 ng./dl.) or were elevated to similar levels
) A1 o& y  T1 I6 pdeveloped after gonadotropin therapy (96 ng./dl.). Higher
! n( o0 V1 r4 c6 a& Gserum levels were noted in older patients (12 and 17 years old),$ f5 q. V+ J9 N- Q% U
while lower levels persisted in younger patients (4, 8, and 10
4 R! ~) r) ~: B4 b1 M8 Qyears old) (see table). Despite absence of profound alterations5 X% n5 v8 S9 q; u8 e. e
of serum testosterone the topical therapy provided a greater' n; o# b- y3 j. m
Accepted for publication July 1, 1977. ·: s& v% s$ {, M" T
Read at annual meeting of American Urological Association,- |) ]/ B$ g9 G# [, G2 ~
Chicago, Illinois, April 24-28, 1977.
9 ?' X/ _, ?# [* M* Requests for reprints: Division of Urology, Henry Ford Hospital,8 w6 @  \+ ]' C. p. t9 f5 a: l
2799 W. Grand Blvd., Detroit, Michigan 48202.
; Q, F  {3 Z5 G* wimprovement in phallic growth compared to gonadotropin.% r6 ]6 k( P9 y3 q6 }) D2 ~1 p
Average phallic growth with gonadotropin was 14.3 per cent4 i8 g+ c9 v4 W+ J; ^" y) @
increase in length and 5.0 per cent increase of girth. Topical6 M7 t# C0 T$ ^6 Y- [
testosterone produced a 60.0 per cent increase of phallic length
+ ^5 n, e& _' Q( n4 \and 52.9 per cent increase of girth (circumference). The& A/ P0 V. \$ K) t8 [; t
response to topical testosterone was greatest in children be-& I) y: _& ^' Z6 q
tween 4 and 8 years old, with a gradual decrease to age 17* c  e0 e. s5 q+ n
years (see table).
% V# l0 J0 M5 E: S8 n: UDISCUSSION
2 C, ^  {. l: Z+ ^/ PTopical testosterone has been used effectively by other( e' J, w! |$ d( S
clinicians but its mode of action remains controversial. Im-4 b! e/ ~) [& h( k1 }1 o# w7 e
mergut and associates reported an excellent growth response! |3 h% n9 V! k, _% J7 P
to topical testosterone with low levels of serum testosterone,
* p* E, P) {! H6 P  d  Ysuggesting a local effect.1 Others have obtained growth re-9 ?5 g0 f& g6 ], m; h( d( ^. h0 b& n
sponse with high. levels of serum testosterone after topical  f! d* b3 C& g. c5 }% M& A8 u
administration, suggesting a systemic response. 3 The use of( ^  ~3 Y+ v# E1 I) {9 {$ ?1 s
gonadotropin to obtain levels of serum testosterone compara-# [0 L$ f, U8 n3 N
ble to levels obtained with topical testosterone would seem to
, S# ~( |; P* cprovide a means to compare the relative effectiveness of
4 c5 S& Y9 I5 }0 ]topical testosterone to systemic testosterone effect. It cer-7 V" \- ?. F7 Z% K# B4 r
tainly has been established that gonadotropin as well as par-
+ S; S1 V2 R( \$ b. q+ }enteral testosterone administration will produce genital
0 N) P/ j/ \9 p  d0 T5 x  V; G& ngrowth. Our report shows that the growth of the phallus was$ Z; l  k- }/ m5 [; \: V
significantly greater with topical applications than with go-$ k# o! |! ~+ g" T
nadotropin, particularly in children less than 10 years old.
" j6 i" j1 t! P8 }4 ?5 FThe levels of serum testosterone remained similar or lower' R( o! O* u( L! u, ]: C
than with gonadotropin during therapy, suggesting that topi-
, l& x1 c, |0 ^cal application produces genital growth by its local effect as
5 |  n, R! g3 Y& a* ^+ l5 Swell as its systemic effect.
2 V8 U6 z9 M9 O6 V2 k+ w4 W1 z7 t/ ]" oReview of our patients and their growth response related to, Y, C  M- M; a+ s! y8 K7 O
age shows a greater growth response at an earlier age. This is/ H0 B* k0 I# f1 c( f5 A
consistent with the findings of Wilson and Walker, who
2 Y+ r( k- a/ |reported an increased conversion of testosterone to dihydrotes-9 h& S, L3 Z- Y) n/ R5 D1 W
tosterone in the foreskin of neonates and infants.4 This activ-
( v; s" w) r3 fity gradually decreases with age until puberty when it ap-( h+ ?- B9 [, Z2 n  A
proaches the same level of activity as peripheral skin. It may$ m2 p6 q7 Z, Z! x$ k) H
well be that absorption of testosterone is less when applied at
1 N' }9 M  W4 q! m1 Yan earlier age as suggested by lower serum levels in children  g5 f7 P# W' M) A) x# s/ s
less than 10 years old. This fact may be explained by the  G/ z8 l( W3 j. J. H: m. M! ^, {
greater ability of phallic skin to convert testosterone to dihy-
% j5 [: i3 A( O) Ddrotestosterone at this age. Conversely, serum levels in older
& S8 x2 A2 G4 _4 T( upatients were higher, possibly because of decreased local
, N" Q) y0 S; z/ Q  T+ z+ Q6 j6676 S' m! a' E) c7 w3 _# ^
668 KLUGO AND CERNY
' B; A0 z  o6 @Pt. Age- }- S! d2 ?. O* M. @9 X8 a! o% W
(yrs.)
/ C( p8 l5 F( p- CSerum Testosterone Phallus (cm.) Change Length9 y2 j6 l$ r. K+ ^4 H
(ng./dl.) Girth x Length (%)
" H5 G0 F( x: F  V/ X8 E# s# W  \( H4
9 p9 A1 T; o' ~( j) J  P% F' L' n8
$ L, X1 x8 m. Q* c! D. I4 ~10
* h7 V( Q% Z1 i! Z12
& f8 j# v+ T4 }) x8 S: r: K3 N17# G' ?* Y" d8 J' m; k1 H
Gonadotropin
- T9 Y3 X( Y9 G) l' y71.6 2.0 X 3 16.6
- L# N* c, l+ L  I4 @50.4 4.0 X 5.0 20.0
" T& x% r3 |" [. e5 {/ f( g! W22.0 4.5 X 4.0 25.00 v* \- C3 D7 S) w  a' a
84.6 4.0 X 4.5 11.1) l" y) Z+ q9 q7 R8 R2 i
85.9 4.5 X 5.5 9.0# M% D0 u! _' [* I
Av. 14.33 {" A. [! C7 w
4
0 k" w* {/ |2 L* V8: x0 _2 X  r- A; t0 j
10
! n, I8 h8 _' H" W% F4 A0 p12) ]1 l3 V; {4 E! l
17/ G2 _  @) n& k& \; m: k
Topical testosterone9 D" b$ P5 {$ K: I
34.6 4.5 X 6.5 85
( R& L+ |9 Y" L! _1 Y: {38.8 6.0 X 8.5 70
# e2 G. D3 R3 P. b3 i+ X. ^40.0 6.0 X 6.5 62.5
4 k, |4 ~( i/ x2 q* L# g93.6 6.0 X 7.0 55.5; `5 h( l  F, N$ O% d& \6 E! S) G
95.0 6.5 X 7.0 27.24 f; |( O( M# Y, ]2 m" ^( }7 t1 R
Av. 60.0" B* w5 O4 s% G% U
available testosterone. Again, emphasis should be placed on1 n1 p7 g) Y3 g0 [; r; S/ E+ m# V1 r
early therapy when lower levels of testosterone appear to
4 K0 e/ E$ k7 Q* pprovide the best responses. The earlier therapy is instituted; w, ~+ @& g5 S8 |. D" P
the more likely there will be an excellent response with low- w) g' M) `* f
serum levels. Response occurs throughout adolescence as9 T) h3 I6 m5 X% v/ e
noted in nomograms of phallic growth. 7 The actual response
9 }7 s0 t3 A6 w) \+ I" r+ v& Mto a given serum level of testosterone is much greater at birth$ X. f- }3 p0 s% `2 u0 o
and gradually decreases as boys reach puberty. This is most
5 a8 N) n; b/ t2 \- n" blikely related to the conversion of testosterone to dihydrotes-: `, N  g3 V: G, U) a
tosterone and correlates well with the studies of testosterone
( C  v, _# D" u" Wconversion in foreskin at various ages.
' [# u" \: ?$ A2 F& s6 aThe question arises regarding early treatment as to whether
  b) M5 y" P- n7 Q3 G- xone might sacrifice ultimate potential growth as with acceler-
1 L9 F$ f) n+ }$ `+ e5 a* Xated bone growth. The situation appears quite the reverse. ~# ]/ @2 H$ U$ Y& F8 r
with phallic response. If the early growth period is not used, m* _9 x7 C. [  l% k; K- H  N% J  `
when 5a reductase activity is greatest then potential growth
% r$ u) ?2 n1 }2 Z1 G' Qmay be lost. We have not observed any regression of growth
- A- o7 I% d! t. ]& i  lattained with topical or gonadotropin therapy. It may well
+ B  z9 J6 L( [' E5 H/ j3 K, U3 Z, kbe that some patients will show little or no response to any. W. o! _" `9 a/ K* }% h
form of therapy. This would suggest a defect in the ability to
0 d& d& r: s9 [; |/ J0 [4 C: Fconvert testosterone to dihydrotestosterone and indicate that
( P) N* o! x0 v- K( V$ K( Vphallic and peripheral skin, and subcutaneous tissue should* p2 f' d/ {5 l* D" f7 C" e
be compared for 5a reductase activity.
; q* C" c2 [7 |% M9 ?* v" hA, loop enlarges to measure penile girth in millimeters. B,
, D4 I/ h1 h3 `1 i7 J# B1 c$ T# kexample of penile girth computed easily and accurately.; ~3 e9 g! Z, U1 N4 p& `2 @# _
conversion of testosterone to dihydrotestosterone. It is in this: R8 w- i  `* ?8 O6 ^; b/ v& p+ ^1 s
older group that others have noted high levels of serum
# B0 x, T$ z8 J/ |0 [testosterone with topical application. It would also appear
' z# `0 e+ ~% u8 {+ ]: wthat phallic response during puberty is related directly to the1 }3 y5 U/ \$ F% r1 q2 q* s9 D
serum testosterone level. There also is other evidence of local
% \7 ^& C$ z$ Mresponse to testosterone with hair growth and with spermato-0 Z( s1 }; U' P
genesis. 5• 66 i0 D  K  u3 t
Administration of larger doses of gonadotropin or systemic8 E5 Z0 I- _% K3 \0 Z( H
testosterone, as well as topical applications that produce$ A* [7 f& {. Z+ s, z- t
higher levels of serum testosterone (150 to 900 ng./dl.), will' k: P! T8 [# `5 U
also produce phallic growth but risks accelerated skeletal/ m7 }5 Y! z! M2 Z+ N$ X4 ?
maturation even after stopping treatment. It would appear, n1 l2 `! \: F, p! M8 p
that this may be avoided by topical applications of testosterone
/ m+ J6 O: l# J$ Gand monitoring of serum testosterone. Even with this control
/ T2 y/ n3 z7 N9 y" @- uthe duration of our therapy did not exceed 3 weeks at any9 i! c4 \1 i8 Z8 M( u" T! r5 V5 ?
time. It is apparent that the prepuberal male subject may: t" U' s9 S* @$ T0 [5 \
suffer accelerated bone growth with testosterone levels near& ?, [9 @9 f* N1 u" n2 B
200 ng./dl. When skeletal maturation is complete the level of2 a2 A% G% [" t* y* G! W
serum testosterone can be maintained in the 700 to 1,300 ng./* N' f" T2 j. k
dl. range to stimulate phallic growth and secondary sexual
! h: _8 X- Y- ?( schanges. Therefore, after skeletal maturation parenteral tes-
, r; G: y4 F8 F9 otosterone may be used to advantage. Before skeletal matura-
3 a, n( \( R+ k+ Mtion care must be taken to avoid maintaining levels of serum& n" L# e7 _+ l3 f+ j1 @
testosterone more than 100 ng./dl. Low-dose gonadotropin/ X, s/ o0 @! Q0 s' Y" Z) f; D& p
depends upon intrinsic testicular activity and may require" Z! @) \: m/ |$ W: ?1 V
prolonged administration for any response.0 y0 @) U- [; E  n4 R
Alternately, topical testosterone does not depend upon tes-7 m2 J. E3 c" l5 }, t# W3 W
ticular function and may provide a more constant level of
- l3 Z2 \( i1 P. I) ^8 zREFERENCES
2 C9 I5 ^+ O6 R8 i) p1 I9 z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
% q3 o& U7 |5 C8 j8 NR.: The local application of testosterone cream to the prepub-( W& Z2 y. S9 u8 k: V2 ?% w7 g
ertal phallus. J. Urol., 105: 905, 1971.; Z; j$ H( f0 m/ B4 J1 J
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' _1 O# t9 o; U% `2 d0 f  w' d% Y+ ytreatment for micropenis during early childhood. J. Pediat.,' |4 s. r) r3 D. w8 F! {8 y/ m
83: 247, 1973.
7 L/ s0 _  x" W% F3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, j7 S3 I- W$ w! X$ t: D2 |/ m
one therapy for penile growth. Urology, 6: 708, 1975.9 C8 @! {2 Z$ O$ \6 b% R
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 `% I) W5 G- w1 `# ], n( zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
+ b6 y6 M  Z, W( kskin slices of man. J. Clin. Invest., 48: 371, 1969.
$ w* \1 y* O2 z1 i0 F5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
; l' p2 I( D! p5 d) d% Tby topical application of androgens. J.A.M.A., 191: 521, 1965.- J; Y! N" B3 `. e- k) H' i
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, T! W9 R% z3 y  C- aandrogenic effect of interstitial cell tumor of the testis. J.! E1 J, f' h$ W9 [+ f) {  y
Urol., 104: 774, 1970.* E, X& t8 ~4 {6 q# Z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 l+ H' g6 r8 c/ r
tion in the male genitalia from birth to maturity. J. Urol., 48:
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