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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 i6 W" @; j% J9 n! f7 mGONADOTROPIN
' V- [5 h0 ~9 }. fRICHARD C. KLUGO* AND JOSEPH C. CERNY
6 R2 T5 y7 @3 F6 E; I9 y+ R% h, [From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% t; ?, ?3 M  s/ m( EABSTRACT
/ m$ n$ G, n6 N0 A& L3 bFive patients were treated with gonadotropin and topical testosterone for micropenis associated& u* u* Q4 Y: A4 w
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ A7 l8 c. e! `! F# W3 g3 \  D! D/ I
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone: A: C$ T7 Z. ?) R% l% k. C7 e
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 M9 [& F7 Y7 }2 C7 I  b9 E0 a# B. Z, Mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent- a( F4 _2 R! k0 f
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
# j; o# v! ]& @2 t: l2 r: yincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
! U9 l% F" S4 l7 y0 _& |" `occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
1 u1 H! h5 S4 w+ a1 x+ m) ~( Tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 y' c* z0 a; i) r" G6 ~
growth. The response appears to be greater in younger children, which is consistent with previ-
, }7 v6 g/ M. t9 `# F) |6 S" q6 Q% l, qously published studies of age-related 5 reductase activity.
  G* X( X/ b0 s8 |! ]: K! T) UChildren with microphallus regardless of its etiology will) r5 ^" s/ s4 ?5 S) ~
require augmentation or consideration for alteration of exter-) E2 d' R& H" c5 z- ^+ y3 m
nal genitalia. In many instances urethroplasty for hypo-
  ^) x  }$ y4 |spadias is easier with previous stimulation of phallic growth.% ?) }" i; {! N+ P
The use of testosterone administered parenterally or topically/ l+ Q, S( h; n& x5 D* I
has produced effective phallic growth. 1- 3 The mechanism of
% v% \$ M: N/ }response has been considered as local or systemic. With this- j' e# j7 o4 l% s# p1 f/ i! B
in mind we studied 5 children with microphallus for response
. Q3 u: g/ Y* L7 V# Ato gonadotropin and to topical testosterone independently.
0 Y' T, E# L3 j& RMATERIALS AND METHODS( @/ E* M3 u; y  H
Five 46 XY male subjects between 3 and 17 years old were
, ?% w; X5 d' f* fevaluated for serum testosterone levels and hypothalamic
% G' X& D2 |2 s# e* p1 b& B6 @$ Ufunction. Of these 5 boys 2 were considered to have Kallmann's( N" {6 G5 L9 O% J: b
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
5 e; [$ I! I% o1 U5 S0 U; r& rlamic deficiency. After evaluation of response to luteinizing( t5 F8 c% r% u+ W1 Y  x
hormone-releasing hormone these patients were treated with
! `! U! S9 H! [( G  i* }' z1,000 units of gonadotropin weekly for 3 weeks. Six weeks" T8 j+ H; g3 p( f
after completion of gonadotropin therapy 10 per cent topical
: p) ?" C$ ^) wtestosterone was applied to the phallus twice daily for 3 weeks.
# W% I8 G. t5 k2 f# ISerum testosterone, luteinizing hormone and follicle-stimulat-7 K# S% \  M$ X2 s: _9 a) ^
ing hormone were monitored before, during and after comple-' E: v4 }( \" R) S7 ?% }2 _; N
tion of each phase of therapy. Penile stretch length was
# g( O$ S) x: ~obtained by measuring from the symphysis pubis to the tip of
7 |/ R3 Y) [1 a0 J6 L4 Q; \the glans. Penile circumferential (girth) measurements were
) [/ E- T3 I' V7 g* I' f  |/ Vobtained using an orthopedic digital measuring device (see
  Y# C! N- \# d/ X- wfigure).
1 V1 r* v' m( I0 ARESULTS
: `  U3 C9 k& c- y) d# g8 ^! ~Serum testosterone increased moderately to levels between/ D& p$ R1 r! A
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
2 \: R4 \0 `) e$ }terone levels with topical testosterone remained near pre-
. Y% l( a8 x* ~3 B( k- Ctreatment levels (35 ng./dl.) or were elevated to similar levels' u$ ~5 i' r2 H8 X( a
developed after gonadotropin therapy (96 ng./dl.). Higher% d7 @9 S. ~! C. e2 C/ E( n6 u$ Q  b7 q
serum levels were noted in older patients (12 and 17 years old),$ L6 W7 ?- P3 o: t
while lower levels persisted in younger patients (4, 8, and 10/ X' L1 |; A9 h) \* _2 i
years old) (see table). Despite absence of profound alterations
1 N( a; D2 _0 K) ]of serum testosterone the topical therapy provided a greater  p- H$ {# |% a9 x
Accepted for publication July 1, 1977. ·/ _2 z) T- k9 m9 i. A
Read at annual meeting of American Urological Association,4 f/ o& P! z: g% D
Chicago, Illinois, April 24-28, 1977.6 F7 d* M9 U& s4 ]% b+ N0 G- h
* Requests for reprints: Division of Urology, Henry Ford Hospital,* f) u* F7 w) p/ M" M& F1 z
2799 W. Grand Blvd., Detroit, Michigan 48202.
5 W/ V7 d, c" u  v' Dimprovement in phallic growth compared to gonadotropin.
' A# H7 S' R) B9 J9 x+ `' |Average phallic growth with gonadotropin was 14.3 per cent
2 b1 \6 G% N0 i7 B$ `increase in length and 5.0 per cent increase of girth. Topical" z$ y" v: Y+ g5 o6 @
testosterone produced a 60.0 per cent increase of phallic length
& h) j0 z4 H9 e# X' C4 [and 52.9 per cent increase of girth (circumference). The8 D% b( I- T, L5 u3 N& @( d
response to topical testosterone was greatest in children be-
& A2 x4 V  G! u# Y. P2 w3 ^" otween 4 and 8 years old, with a gradual decrease to age 17% A4 S% F. L3 E, e( w/ {
years (see table).
3 I/ C7 n7 o" ~7 p5 jDISCUSSION- b; a0 [! {7 u8 x3 u  U
Topical testosterone has been used effectively by other) F3 H. p0 r' ~; O
clinicians but its mode of action remains controversial. Im-; |! Q8 Y  O1 R% |
mergut and associates reported an excellent growth response+ l( E. Y* F, {5 K
to topical testosterone with low levels of serum testosterone,( Q' ~* N; H  e# A* H. O
suggesting a local effect.1 Others have obtained growth re-
* \: V9 Y2 O  |2 `  Nsponse with high. levels of serum testosterone after topical$ L- w  t2 e; C$ e% E* q
administration, suggesting a systemic response. 3 The use of: V; H& {$ |5 v1 x
gonadotropin to obtain levels of serum testosterone compara-/ {, e+ c% [' X3 Z1 G
ble to levels obtained with topical testosterone would seem to
& H) m. p7 S0 g  S: gprovide a means to compare the relative effectiveness of" X$ l6 J* X$ k
topical testosterone to systemic testosterone effect. It cer-
. Y+ v. Q9 W- C% Z7 m. stainly has been established that gonadotropin as well as par-1 T& ?4 x$ }. `# x
enteral testosterone administration will produce genital. w7 i' y& J1 q- |) n: M1 h) S& X
growth. Our report shows that the growth of the phallus was
, S4 l; V3 \  v! r, Ksignificantly greater with topical applications than with go-8 v, A) a, l- R# c! ~6 Z  m
nadotropin, particularly in children less than 10 years old.8 G" V+ V% }& m1 ^/ ^- E
The levels of serum testosterone remained similar or lower* ^' {# a  j* `* \9 ?7 u3 ^
than with gonadotropin during therapy, suggesting that topi-
* n" B# v  n9 v. {cal application produces genital growth by its local effect as& s3 f5 B  {; o* I" D
well as its systemic effect.0 j# `" `( [' `; O, F
Review of our patients and their growth response related to' u$ ^% Q. s! u
age shows a greater growth response at an earlier age. This is9 Q, f9 I) i# l/ o7 I
consistent with the findings of Wilson and Walker, who
4 h7 Q! Y# d2 d9 ]+ Creported an increased conversion of testosterone to dihydrotes-. ~7 v+ _4 ^, Z, V" D5 e3 A5 C
tosterone in the foreskin of neonates and infants.4 This activ-  l- [3 V- m4 A: h3 J) L. n  ^( [
ity gradually decreases with age until puberty when it ap-! g7 B# k" z$ [* F& b) w
proaches the same level of activity as peripheral skin. It may
2 p. {& ]7 y: t4 p* r9 |well be that absorption of testosterone is less when applied at/ `! L5 G0 R- A0 D- j) E
an earlier age as suggested by lower serum levels in children
' T, U$ Z. \) Tless than 10 years old. This fact may be explained by the
$ C* `+ ]& c6 X; [  `greater ability of phallic skin to convert testosterone to dihy-
; g  |' \# D! t  u, f: ndrotestosterone at this age. Conversely, serum levels in older9 }7 F7 d$ C0 t# w' D
patients were higher, possibly because of decreased local7 ?8 V! J. j: n1 C3 o2 ]% i2 s5 q
667# m: n3 A( F9 `4 `! r8 t" j1 T6 C
668 KLUGO AND CERNY9 }, f) d6 |- s7 y$ s8 {
Pt. Age' t7 G9 \4 r8 B7 n7 X% D  }
(yrs.)
2 D, y0 p8 `& O# N% S; o  OSerum Testosterone Phallus (cm.) Change Length3 f, t8 {4 P  w" A
(ng./dl.) Girth x Length (%)
6 q" E) b5 s9 @8 p% G9 C* W47 z2 o  q/ A3 c
8$ ^, l. b. h* B4 s8 S
105 P1 M  |4 @% r6 L- v9 c
12
; i7 w# k9 _2 o6 ?17
  Z7 c$ \% O; DGonadotropin
) T9 f" h8 `1 x3 U. }7 S8 k71.6 2.0 X 3 16.6! j: `$ ^" i; D8 t8 N
50.4 4.0 X 5.0 20.08 n/ c( G4 |. u3 a4 U, ^
22.0 4.5 X 4.0 25.0
8 U* ~0 A5 U, Q9 g% g84.6 4.0 X 4.5 11.1
7 r7 t5 ^, f5 B# g. @8 _85.9 4.5 X 5.5 9.0
5 {8 x) e( V% s3 fAv. 14.3* ^" j& {. D; q+ T! _* V4 G* E
4' j% {" g; S  A' @  P
8, l! _  C/ L. _" a9 P: H
10
) ~8 t9 N; _: U; b8 J, o7 k12
) p+ h2 R: l3 F( E: \( A# [17
6 ]0 P- X, W$ f6 HTopical testosterone2 ^2 @* H" O* r
34.6 4.5 X 6.5 85: p! u* e; [5 U4 ~
38.8 6.0 X 8.5 70$ E5 i$ n0 {- {. p% f
40.0 6.0 X 6.5 62.5% G( L  n6 L. {
93.6 6.0 X 7.0 55.5" y+ _  D% v* ~* E" d' r  R" M
95.0 6.5 X 7.0 27.2% e6 B7 a" }. f  q8 y0 c  ^
Av. 60.0
: Z* T6 T! H0 javailable testosterone. Again, emphasis should be placed on
' u  y+ H1 S8 yearly therapy when lower levels of testosterone appear to
& ]+ M/ I; m- E9 l( r/ b! {+ ]8 tprovide the best responses. The earlier therapy is instituted0 X# r; o3 s" y8 V: N9 i$ b
the more likely there will be an excellent response with low
# I" `$ }# b8 p1 z, Rserum levels. Response occurs throughout adolescence as
6 m4 D4 H9 @: Qnoted in nomograms of phallic growth. 7 The actual response+ x8 O2 s& C  [3 }8 `# o+ ^
to a given serum level of testosterone is much greater at birth/ A# ?' F. j+ S
and gradually decreases as boys reach puberty. This is most; ~& O% N9 ~1 G& q4 ]4 @1 z
likely related to the conversion of testosterone to dihydrotes-
0 U4 _% p% B: p' ~4 B, btosterone and correlates well with the studies of testosterone6 z. F! R5 V3 r- o3 D
conversion in foreskin at various ages.
2 `- B1 v' p* h2 u/ w. sThe question arises regarding early treatment as to whether
" c! Q* S. m8 Y$ T! uone might sacrifice ultimate potential growth as with acceler-
- ^" M+ e+ w  N- v& L1 dated bone growth. The situation appears quite the reverse
) i* |. E3 B+ ~4 Uwith phallic response. If the early growth period is not used
) L, h4 _( p" B9 N. Swhen 5a reductase activity is greatest then potential growth6 D, G% Z* A# F7 Y
may be lost. We have not observed any regression of growth, ]3 r7 \2 ]5 Z  ]0 \% t8 r
attained with topical or gonadotropin therapy. It may well! y- F9 @' V0 g3 l4 G, q
be that some patients will show little or no response to any* d6 V7 b6 W( F' ~1 Q
form of therapy. This would suggest a defect in the ability to
  {, [" y( K; Z. z# Y* v# cconvert testosterone to dihydrotestosterone and indicate that7 j& L7 A0 `+ @- v" s- `& q
phallic and peripheral skin, and subcutaneous tissue should
4 C( `3 r4 z9 p8 h; d) x: nbe compared for 5a reductase activity.
9 C) x1 t' b- J0 x9 ^2 P- WA, loop enlarges to measure penile girth in millimeters. B,6 B5 F. ^6 f, J+ w/ Z9 N% Y! u
example of penile girth computed easily and accurately.
) a3 l0 g2 v! L+ Rconversion of testosterone to dihydrotestosterone. It is in this7 `3 r9 o$ O- ?# N; p) C( z5 F
older group that others have noted high levels of serum
4 X* v- H5 a% u4 otestosterone with topical application. It would also appear0 L; ?8 w5 w& S) d
that phallic response during puberty is related directly to the
( }2 V3 e4 e* c  N2 }0 Nserum testosterone level. There also is other evidence of local2 D7 w" V+ x% ?: B) W" g+ a
response to testosterone with hair growth and with spermato-
8 }% g/ O$ Q$ U. a2 sgenesis. 5• 6
+ n4 N. H/ e  Z* }! [Administration of larger doses of gonadotropin or systemic
: K4 `9 H, v( [/ Vtestosterone, as well as topical applications that produce4 [8 R# s& E, ~+ L3 @5 j$ v7 F
higher levels of serum testosterone (150 to 900 ng./dl.), will
) e  K$ D2 u% T& S' i" B# J" Ralso produce phallic growth but risks accelerated skeletal6 G* o6 b5 u! [
maturation even after stopping treatment. It would appear
) Z& u" p3 ?6 hthat this may be avoided by topical applications of testosterone
' v" H# R" T+ k" Nand monitoring of serum testosterone. Even with this control
; c$ @4 P8 [; I& \: Jthe duration of our therapy did not exceed 3 weeks at any+ Q6 y' o5 U( R2 W/ a, U& N2 X( B- I
time. It is apparent that the prepuberal male subject may
  e+ u5 }7 h- J" D# I6 t$ U) rsuffer accelerated bone growth with testosterone levels near8 L: i6 i* X0 v: z5 y& G
200 ng./dl. When skeletal maturation is complete the level of
# `1 q% P; g6 X/ x+ K' K: Oserum testosterone can be maintained in the 700 to 1,300 ng./
2 ^4 |! [* |2 {% D! m+ `. V: ~dl. range to stimulate phallic growth and secondary sexual% E+ Y/ w# J) C4 ?
changes. Therefore, after skeletal maturation parenteral tes-( L( i8 z$ X- N% C* {6 v" ?
tosterone may be used to advantage. Before skeletal matura-4 a: t! [% l$ D; ?- J3 b
tion care must be taken to avoid maintaining levels of serum2 r7 r$ O9 i3 \7 {
testosterone more than 100 ng./dl. Low-dose gonadotropin8 Y! W+ v. X4 J2 t$ @
depends upon intrinsic testicular activity and may require7 C6 S. y# w) n
prolonged administration for any response.
3 E5 b* V0 D2 J' i& gAlternately, topical testosterone does not depend upon tes-; |% P$ p" a3 o2 P# ^2 |0 _+ Q
ticular function and may provide a more constant level of
8 s: E% Q) H0 T  `* x, w% L5 xREFERENCES
6 w' C6 s6 }# I1 o2 |2 L; f1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,, }2 J8 p0 O; `( u
R.: The local application of testosterone cream to the prepub-
! ?/ @. s9 y% u6 n  u. Nertal phallus. J. Urol., 105: 905, 1971.- b- y# f1 a2 g- }$ [% f8 {
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% [; D( i- V5 b! v0 d: ]/ s) B
treatment for micropenis during early childhood. J. Pediat.,
3 E& L  F1 |, n- l83: 247, 1973.6 D. x+ P7 p7 X, h1 ^
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' H' e5 \2 ]  L
one therapy for penile growth. Urology, 6: 708, 1975.
+ d) X! V- Y; h8 `: U4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
$ t7 Z1 T: y9 W$ z$ U0 V7 Oto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
1 @0 M0 q7 ]8 B4 k' Vskin slices of man. J. Clin. Invest., 48: 371, 1969.
* D8 C& `' ]( K9 N: h& ?# D5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth  m! }: Y& G  M9 x5 n( J; s% H
by topical application of androgens. J.A.M.A., 191: 521, 1965.
4 v6 }- R' T9 e- \6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
% |) \3 \2 z& L" s( G) H' x2 ]3 qandrogenic effect of interstitial cell tumor of the testis. J.
9 D6 D6 |$ Q+ X/ M3 w1 SUrol., 104: 774, 1970.
" E9 V# ?" z- R# G) D' R$ }* e7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( l$ l6 S! L' L4 ]2 Z9 ation in the male genitalia from birth to maturity. J. Urol., 48:
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