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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: L& i# Z: G) U/ g2 B2 ?  _, @+ ^
GONADOTROPIN/ U& h. l# F2 i& w$ m" T
RICHARD C. KLUGO* AND JOSEPH C. CERNY2 i. C& Y# q; a8 ^4 F% h
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! A6 p* |  E1 m# H' sABSTRACT2 X7 q% P4 i4 d0 v
Five patients were treated with gonadotropin and topical testosterone for micropenis associated2 T# M: J2 X9 Z/ l8 W
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 \  P, ^& J4 E3 C+ r
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
5 |0 n" y7 d0 N/ D6 vcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent4 Z0 n0 b$ b6 |  G
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent8 V# f6 e& f1 t* A( [
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 |- {" F0 P+ g% C" B1 oincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% C" w+ Q+ ]) n5 ~! Boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( e' V$ [6 H2 w( u/ Xstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 s+ A3 m) T& T' m' u" H: y4 O, ~
growth. The response appears to be greater in younger children, which is consistent with previ-
# Q* u  a$ n7 f' o& Oously published studies of age-related 5 reductase activity.
+ v& l: t$ e+ i  I3 FChildren with microphallus regardless of its etiology will. w$ v+ r0 e7 T* P0 E( R5 e
require augmentation or consideration for alteration of exter-
  g6 R; o& V; s' H2 j4 d9 onal genitalia. In many instances urethroplasty for hypo-
2 y8 R. W; z) T+ ^" X, Zspadias is easier with previous stimulation of phallic growth.
- `  a8 ?+ Q# q& z$ Z+ _! zThe use of testosterone administered parenterally or topically" V. ~- p3 S0 _" l0 D; X+ V
has produced effective phallic growth. 1- 3 The mechanism of! I- @1 E* N3 L( s* E2 B
response has been considered as local or systemic. With this8 D( d, b. d1 F% s6 \  [9 q
in mind we studied 5 children with microphallus for response
- y7 y( w. u5 \. rto gonadotropin and to topical testosterone independently.
) d: X, w2 C' Y8 XMATERIALS AND METHODS( W- @, U3 s7 [3 p+ G$ V
Five 46 XY male subjects between 3 and 17 years old were
8 Q, k$ i' P6 L) zevaluated for serum testosterone levels and hypothalamic  W' c. h- H6 a1 A' Q6 v
function. Of these 5 boys 2 were considered to have Kallmann's
9 C( k7 I" W3 R$ a, }; Qsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
  r. N# E% X) w, T+ Xlamic deficiency. After evaluation of response to luteinizing. f+ c/ C4 ?2 d6 R- W
hormone-releasing hormone these patients were treated with% y3 T) B, N) f) g- t- F
1,000 units of gonadotropin weekly for 3 weeks. Six weeks' N; D" Q0 |! ~6 E# m2 q
after completion of gonadotropin therapy 10 per cent topical
/ _; _% T& q  f+ o. Utestosterone was applied to the phallus twice daily for 3 weeks.
& L5 \  Y7 d" W0 @Serum testosterone, luteinizing hormone and follicle-stimulat-
. B8 b0 m- N6 P: ^  eing hormone were monitored before, during and after comple-- _1 U1 M# Z: W5 `) z9 A( A6 H# d
tion of each phase of therapy. Penile stretch length was/ ?6 \2 @* B! X5 `. b
obtained by measuring from the symphysis pubis to the tip of% u6 O5 d* s1 h3 L
the glans. Penile circumferential (girth) measurements were
" r  H# ?( A. x; {/ U2 `$ J; Oobtained using an orthopedic digital measuring device (see8 O  m! E/ d" Q; V  j+ R! o
figure).4 S4 r1 n2 p+ h+ ?. j# p
RESULTS
0 j$ ~: S3 H, j8 q* q" L( D  L3 NSerum testosterone increased moderately to levels between: c0 K$ ~1 `( ]. E- z1 f
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-% h) v! B. `/ l' W4 C: _, r9 N
terone levels with topical testosterone remained near pre-
& R3 J: i7 K2 E; S9 f9 l3 ?& Z& Ztreatment levels (35 ng./dl.) or were elevated to similar levels
3 p! x7 ?( ]) P. O! A- e# X3 _developed after gonadotropin therapy (96 ng./dl.). Higher1 o  I% n9 D) Z, ]3 s+ i
serum levels were noted in older patients (12 and 17 years old),
9 l8 w) `  D1 Y' ~: ^while lower levels persisted in younger patients (4, 8, and 105 ?9 k& ^1 c& q! C7 B
years old) (see table). Despite absence of profound alterations) G% E3 p( m9 E5 t. w
of serum testosterone the topical therapy provided a greater! [6 i0 x* G3 [0 h2 f- t: z: l
Accepted for publication July 1, 1977. ·
. n; Y% K4 U( V, R2 k5 GRead at annual meeting of American Urological Association,
; N2 Q8 X$ m+ [3 fChicago, Illinois, April 24-28, 1977.
: o2 E5 k7 H& r) {8 }. I* Requests for reprints: Division of Urology, Henry Ford Hospital,8 f: m7 P3 J1 E1 p
2799 W. Grand Blvd., Detroit, Michigan 48202./ r  P" o5 D' Z) N$ [. F2 Y
improvement in phallic growth compared to gonadotropin.
! T% q# x7 Q1 I4 \+ T% Z* _Average phallic growth with gonadotropin was 14.3 per cent- d+ j1 a9 f* W  t- f5 ~
increase in length and 5.0 per cent increase of girth. Topical! F7 ~+ J) ]( j! H  T; }
testosterone produced a 60.0 per cent increase of phallic length4 t4 A5 O& K, D+ c3 W$ O
and 52.9 per cent increase of girth (circumference). The
5 R0 K- F  x& k# ?1 ?response to topical testosterone was greatest in children be-6 l, M3 Q9 z) u3 T* y* D7 M- g
tween 4 and 8 years old, with a gradual decrease to age 17
0 [: N; d' x$ k  H" D# Myears (see table).
) |( {- j- p0 g4 s/ \5 `1 B" a+ i8 [; iDISCUSSION
5 T, [- J$ D% _4 s! WTopical testosterone has been used effectively by other  ~, {% \: ^) m
clinicians but its mode of action remains controversial. Im-
* X( Q# u/ X, lmergut and associates reported an excellent growth response
( a  j; f2 ~) t3 Xto topical testosterone with low levels of serum testosterone,
& e! u3 u$ z2 ?% ]- Y. T  Xsuggesting a local effect.1 Others have obtained growth re-9 [9 e0 ]+ \# D5 g! I! V
sponse with high. levels of serum testosterone after topical4 F2 k7 A' i* ~# ?. ]- E8 B
administration, suggesting a systemic response. 3 The use of
; Z6 q% F, J& ?, P  [gonadotropin to obtain levels of serum testosterone compara-- O2 g; U5 @4 D+ G
ble to levels obtained with topical testosterone would seem to  L9 U/ @, [# J6 Z6 M
provide a means to compare the relative effectiveness of' p& b% a+ o0 u! l5 n
topical testosterone to systemic testosterone effect. It cer-
- z" R# a' q$ o; {: B/ M7 H; Htainly has been established that gonadotropin as well as par-
4 e( B8 w  c) ^' E; E  menteral testosterone administration will produce genital1 d$ ~2 r" }) v. i  @
growth. Our report shows that the growth of the phallus was
# a7 p# g$ ]7 S8 L% R5 g5 Csignificantly greater with topical applications than with go-! h& y5 j. f5 g1 E% M
nadotropin, particularly in children less than 10 years old.5 _4 U- W, r5 d! i# O! F
The levels of serum testosterone remained similar or lower
% p4 T3 i) F" F6 D7 P" E" tthan with gonadotropin during therapy, suggesting that topi-
& d2 C/ Q/ X9 u8 K" gcal application produces genital growth by its local effect as
/ U0 N% F) p' \; F: Uwell as its systemic effect.
- O6 s' s9 T$ y0 h; }3 lReview of our patients and their growth response related to
7 a# L5 L! Z& `  O: D- bage shows a greater growth response at an earlier age. This is
" {8 ?+ T( q& ~3 P8 _consistent with the findings of Wilson and Walker, who) s5 W! V& {5 M# s7 [; i
reported an increased conversion of testosterone to dihydrotes-! b2 \4 J" N8 [- f0 N6 J: u5 |. r) m
tosterone in the foreskin of neonates and infants.4 This activ-7 i* ^8 O- ~( _7 e
ity gradually decreases with age until puberty when it ap-1 R4 q+ X  W6 N4 o! d2 t
proaches the same level of activity as peripheral skin. It may1 c& n" [( [$ h4 Q9 _5 n7 i
well be that absorption of testosterone is less when applied at
/ L/ H6 r, e" o* C, L! r- m! A; Y- han earlier age as suggested by lower serum levels in children" Q. v6 k2 }/ e; X& M
less than 10 years old. This fact may be explained by the2 ]7 `5 k+ I5 |3 d5 S% Y6 D
greater ability of phallic skin to convert testosterone to dihy-
+ S9 Y9 d7 [# U( q  v: udrotestosterone at this age. Conversely, serum levels in older- `2 I3 U$ V5 x( h+ Q
patients were higher, possibly because of decreased local
" W$ h! W& x2 A$ I667
: ~$ Y1 R; ~. o5 f9 N' r668 KLUGO AND CERNY
4 @* k; ?& N: n9 n9 e# j9 Q- `Pt. Age1 d( N3 Q& A# \. L  V8 N4 n) t
(yrs.)
  c2 j* X8 Q5 ?2 X: j4 }6 NSerum Testosterone Phallus (cm.) Change Length5 B3 i1 I& H- W( a4 C4 u) B
(ng./dl.) Girth x Length (%)- I: a9 x2 m% Y2 F( z" Q, n
4+ L! G4 G' _9 V# R# _6 i; U! j. i5 {8 B
8" c4 U6 ?, j: x+ s5 M) z
10' v& d! r' h/ y3 l' a" _7 e
12# n0 |! J4 R+ _$ ~% w/ U" K
17
% M# n  a2 w. O  ^' uGonadotropin
, G- a; Y, k  Y& q) h# w" L$ I71.6 2.0 X 3 16.6# q& E0 h) {  Y; a+ L+ x
50.4 4.0 X 5.0 20.0
+ l, e$ i; f/ r& l( @3 ]8 E22.0 4.5 X 4.0 25.0
4 @" ^  `/ b- s4 p8 Y9 i9 [84.6 4.0 X 4.5 11.1
$ e6 K  s1 t1 o85.9 4.5 X 5.5 9.03 Z, E* H% c  i) `; C2 I' Q$ _
Av. 14.3
4 K. [7 b3 k# j+ O& f8 D, u! H3 |47 z, o! R: U8 L' P- Q- U# r2 s) R
8
) w+ G" v5 v. ?4 J10% J: Z+ e/ R* r, Z* B2 a, X3 g
12
5 I1 k  h1 N: E( i! G' }17
" Z$ U+ a' O6 c* h9 a9 dTopical testosterone8 y, _; x( K8 Y
34.6 4.5 X 6.5 85( K* j- }( {, X* _' n
38.8 6.0 X 8.5 70
, m7 E2 N, N  H; l40.0 6.0 X 6.5 62.5& ?1 {( b7 |9 C1 ~5 S% K
93.6 6.0 X 7.0 55.5: L3 w% D7 O) S% Q5 o5 X' b
95.0 6.5 X 7.0 27.2
$ M6 s: N! ?9 M: F% R' v2 @Av. 60.0- B5 T, Y6 g8 p
available testosterone. Again, emphasis should be placed on
1 k; ~( R5 U3 R+ xearly therapy when lower levels of testosterone appear to
0 X( }3 S& f; y9 v% Wprovide the best responses. The earlier therapy is instituted
; H) P% O" R; r" `( h+ z: hthe more likely there will be an excellent response with low
  T/ q7 x" \2 M3 [7 u) Zserum levels. Response occurs throughout adolescence as( s' N# I# R( O2 D) U, s  i3 z& \
noted in nomograms of phallic growth. 7 The actual response
9 `# _: n2 J( lto a given serum level of testosterone is much greater at birth. c5 A4 V, I9 k1 X, o& J. u: G/ C9 L
and gradually decreases as boys reach puberty. This is most9 `, s+ d, {3 ~( ]
likely related to the conversion of testosterone to dihydrotes-, r" s+ z" e0 O0 E' ?3 u& q
tosterone and correlates well with the studies of testosterone( X+ u" V0 W" a2 z3 u% w. p# W
conversion in foreskin at various ages.
' o# o3 _- A2 f: P3 fThe question arises regarding early treatment as to whether0 L$ e7 }/ I, Y: ^4 S; @
one might sacrifice ultimate potential growth as with acceler-% U1 G6 q$ N6 i7 g; W
ated bone growth. The situation appears quite the reverse) m* G8 S, G0 j8 {6 M
with phallic response. If the early growth period is not used
8 |4 W, J- ]; J) iwhen 5a reductase activity is greatest then potential growth: _% O! ]" s6 [- |5 p  A
may be lost. We have not observed any regression of growth4 B/ f& Y% n3 ?( N( o( P
attained with topical or gonadotropin therapy. It may well% D+ m  p6 J0 Y
be that some patients will show little or no response to any# m, v- d; f+ k& _# O
form of therapy. This would suggest a defect in the ability to
: O2 s& y! \' o5 C2 Vconvert testosterone to dihydrotestosterone and indicate that
, [& K% ]: f. R* F1 B' bphallic and peripheral skin, and subcutaneous tissue should5 I, ~. N- i, S. R
be compared for 5a reductase activity.
( n6 X' q( m- y  kA, loop enlarges to measure penile girth in millimeters. B,% z, T* s7 }0 Y9 u8 Q& v
example of penile girth computed easily and accurately.
8 K9 B. v1 a! T# `8 z1 h$ Q8 d3 u/ J6 cconversion of testosterone to dihydrotestosterone. It is in this
  P# I8 Z  j  f% X) Polder group that others have noted high levels of serum
* y( m5 G2 X, H9 J1 Stestosterone with topical application. It would also appear' g2 _; A: o3 T4 [4 r9 x; l
that phallic response during puberty is related directly to the: M1 X1 d# X6 \
serum testosterone level. There also is other evidence of local5 m- @1 v' C9 A1 S) {4 g4 B
response to testosterone with hair growth and with spermato-# b, m8 K8 t2 f' Q
genesis. 5• 6
; M  A7 C9 I8 s5 c+ QAdministration of larger doses of gonadotropin or systemic! E5 f& i) c& }  k6 }$ R! R' n
testosterone, as well as topical applications that produce
! v1 t- K: u: V  V, `higher levels of serum testosterone (150 to 900 ng./dl.), will! G  S1 V: [" Y8 |; o5 T
also produce phallic growth but risks accelerated skeletal- M. S9 X% `/ f/ _: o
maturation even after stopping treatment. It would appear
; A/ U) D& Y, Q0 Q  Jthat this may be avoided by topical applications of testosterone& R7 `  ]% C6 V* {. o
and monitoring of serum testosterone. Even with this control  T  b2 g. Z9 @3 D1 M: Z
the duration of our therapy did not exceed 3 weeks at any
8 a  |* S+ M, i2 itime. It is apparent that the prepuberal male subject may* Q# ]8 D! f4 q+ r0 j2 F
suffer accelerated bone growth with testosterone levels near
& Q, o) f2 }% [7 j2 Z9 S- L# O. H200 ng./dl. When skeletal maturation is complete the level of
) D7 j$ ^, t& C: `- oserum testosterone can be maintained in the 700 to 1,300 ng./+ L/ E! }$ }: I  A) n
dl. range to stimulate phallic growth and secondary sexual! D5 \2 M) [% B" M1 c( v% B, C
changes. Therefore, after skeletal maturation parenteral tes-
* n3 }+ m9 G) J) O( _) [tosterone may be used to advantage. Before skeletal matura-
/ \. q7 h. y! Btion care must be taken to avoid maintaining levels of serum
- j. Y# O5 U; C) B( K3 Ktestosterone more than 100 ng./dl. Low-dose gonadotropin) Q4 y8 e* ~1 \% P  @" m# K
depends upon intrinsic testicular activity and may require5 {3 K4 U3 l" v
prolonged administration for any response.( \' {5 j* L1 R. l
Alternately, topical testosterone does not depend upon tes-
8 s$ J" t# y' u; T6 {7 p! _9 Bticular function and may provide a more constant level of/ [  Q' T- n* t0 |% ^  `# N
REFERENCES
- ^$ A* V' X$ Y) K  r1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,0 G: O2 {! Q% I) f6 W# [
R.: The local application of testosterone cream to the prepub-; I+ ?; V2 ~% S: s9 h. E2 a3 g
ertal phallus. J. Urol., 105: 905, 1971.
% t+ s* u+ v: u5 o2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- ]) \$ q, X6 v- S2 I6 M
treatment for micropenis during early childhood. J. Pediat.,
! n: G! G) T+ P1 B7 l83: 247, 1973.
1 t, A/ u9 ]# ]7 O7 c% @- N3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' ^& o7 r, Z9 f  P5 e* _' E, Z5 J
one therapy for penile growth. Urology, 6: 708, 1975.* O& U1 T) d( a: U. L% ]
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) v) D5 V* Z3 Kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# m5 x1 q1 i% pskin slices of man. J. Clin. Invest., 48: 371, 1969.; ?8 T% m3 b* d2 X  |. r
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: C8 D' _, l+ F' g0 i$ n: F. W' A
by topical application of androgens. J.A.M.A., 191: 521, 1965.
8 H& T- B" L3 ]' G" z. S6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
6 w9 f- }/ H  w9 E0 @) ~! y' zandrogenic effect of interstitial cell tumor of the testis. J.
/ u1 G+ a( t; V  H& X. F, @2 ~Urol., 104: 774, 1970.
& [3 x% p, K& _( w4 H7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 ?3 }2 |# ]8 \# k
tion in the male genitalia from birth to maturity. J. Urol., 48:
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