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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 i3 L0 W. g. B% h/ }$ k8 c/ w/ v
GONADOTROPIN
- n  B' K- B% A/ S( f1 Q; w% B4 iRICHARD C. KLUGO* AND JOSEPH C. CERNY
' F: m$ x, o3 _2 XFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' j' w5 b- Y% W3 q. j( ~+ `ABSTRACT1 U! U4 G* o3 [$ s! V# m; y" H
Five patients were treated with gonadotropin and topical testosterone for micropenis associated6 w$ t+ i  Q  Y% G$ Y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ _' @( u& n5 L* W# S3 t
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) f5 t; o# s" P& f* k' b
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' y) A! E: N% Y+ \' L& c; Efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
- Y8 o4 G$ ]) A# q/ |3 |/ x6 ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 O. V4 H8 L4 m1 _# f8 S6 |
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response" a4 R% y* x6 v
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# {/ X1 x- f- S8 _& r" q$ ]study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 j6 M& w) J' b/ L9 Y
growth. The response appears to be greater in younger children, which is consistent with previ-
- z7 \8 h2 Z" b7 }! yously published studies of age-related 5 reductase activity.4 ^' R; e( I) N, w" l& s
Children with microphallus regardless of its etiology will
' q$ \+ ^5 j7 g% M. j1 ]require augmentation or consideration for alteration of exter-
. r3 A4 v! M  S7 h( Q+ B" a! l7 znal genitalia. In many instances urethroplasty for hypo-; H! s- `6 M0 C) m
spadias is easier with previous stimulation of phallic growth.
( o6 I& O' R1 C# J' eThe use of testosterone administered parenterally or topically
: S2 h+ v. R" n, t1 N, L: G. \has produced effective phallic growth. 1- 3 The mechanism of
1 K  A2 Y2 A5 U7 Q3 q5 Xresponse has been considered as local or systemic. With this8 B8 D: g  @; k" \$ P
in mind we studied 5 children with microphallus for response. E  i0 t, Y* \$ A/ O
to gonadotropin and to topical testosterone independently.0 H4 p% s; c5 g$ s/ z$ M$ F: `1 T6 L% R
MATERIALS AND METHODS
8 U1 Q# I4 T  \Five 46 XY male subjects between 3 and 17 years old were7 M- J9 n# v- C0 d9 p+ z
evaluated for serum testosterone levels and hypothalamic
) N$ H' v1 O% f0 ~( n8 D) N& yfunction. Of these 5 boys 2 were considered to have Kallmann's
& h0 H9 S  n$ [+ jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 q7 @9 T4 ^) w+ A
lamic deficiency. After evaluation of response to luteinizing
+ `. x; _- r6 whormone-releasing hormone these patients were treated with
6 x. v. r, |' g, i6 p* d9 @1,000 units of gonadotropin weekly for 3 weeks. Six weeks) N9 i2 W) f0 \4 M0 Y" m- c( u
after completion of gonadotropin therapy 10 per cent topical
2 w0 X' d) V- Rtestosterone was applied to the phallus twice daily for 3 weeks.
6 b4 @4 u3 L( A. X& R1 ]" u$ ESerum testosterone, luteinizing hormone and follicle-stimulat-
6 @) ^' \4 n' m/ _% y' O8 Y+ p7 Xing hormone were monitored before, during and after comple-4 k2 S2 a, u* l( }) u4 W
tion of each phase of therapy. Penile stretch length was
4 n/ \: A7 ~- t2 H# Cobtained by measuring from the symphysis pubis to the tip of! T' q: ]2 t" h) d, X4 H' t
the glans. Penile circumferential (girth) measurements were! H& l0 v! G' S7 `* k: l# Z, @& d
obtained using an orthopedic digital measuring device (see0 G8 S/ r: a2 }  A; Z
figure).6 U: j" q6 ?$ }6 ]' T
RESULTS, ]3 m- P# W; H7 e
Serum testosterone increased moderately to levels between1 }2 a' J) B8 A* Y# R
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  S' r3 {8 [* q2 T, l( Z; rterone levels with topical testosterone remained near pre-, w2 l4 r( i% K6 J, R
treatment levels (35 ng./dl.) or were elevated to similar levels
  c6 E+ m( p/ jdeveloped after gonadotropin therapy (96 ng./dl.). Higher
  c% \; p) p+ ~9 U% a& S, Rserum levels were noted in older patients (12 and 17 years old),1 v9 z) O6 M8 T7 R2 v
while lower levels persisted in younger patients (4, 8, and 10
/ W, ], _- b: X, ^' I1 zyears old) (see table). Despite absence of profound alterations
9 G4 R: K2 n/ o) {9 jof serum testosterone the topical therapy provided a greater
! v. |  Z# `- Q8 I2 jAccepted for publication July 1, 1977. ·
$ V# p, E$ R" O9 R% j( LRead at annual meeting of American Urological Association,' k- i: Z6 c' Y0 J2 X, ~
Chicago, Illinois, April 24-28, 1977., K3 X/ Y( D. }/ q' O7 ~
* Requests for reprints: Division of Urology, Henry Ford Hospital,+ h+ N. H8 u! b) s
2799 W. Grand Blvd., Detroit, Michigan 48202.* z! x2 S# r4 [, P& o% g
improvement in phallic growth compared to gonadotropin.
/ m! P$ B7 p5 H# k$ P1 ?Average phallic growth with gonadotropin was 14.3 per cent
2 x# S( \- N# S; h' _! t7 iincrease in length and 5.0 per cent increase of girth. Topical
0 C" l. u! f  w* {1 gtestosterone produced a 60.0 per cent increase of phallic length7 `1 U! W% g+ D
and 52.9 per cent increase of girth (circumference). The
' z+ n' S' ?' W2 D+ K% d' ^* }response to topical testosterone was greatest in children be-4 F7 g6 M6 I; v
tween 4 and 8 years old, with a gradual decrease to age 173 o* b$ x( }& a
years (see table).5 y2 b' O% Q& O2 E0 x$ Q  I) P; j8 t
DISCUSSION/ n) n3 O  N& `) q9 ^
Topical testosterone has been used effectively by other
  _, T5 G( I" j, `, R  q0 bclinicians but its mode of action remains controversial. Im-
* x8 f, P# F: g. s) A1 fmergut and associates reported an excellent growth response% L: x% z2 R% q3 G* i
to topical testosterone with low levels of serum testosterone,. [# K& j& M+ j9 W
suggesting a local effect.1 Others have obtained growth re-- C+ p% i- A. z1 N7 o5 M, ?
sponse with high. levels of serum testosterone after topical, B, K1 K3 o% x2 h* D
administration, suggesting a systemic response. 3 The use of
6 |  w1 y1 ~9 q5 a" R) Jgonadotropin to obtain levels of serum testosterone compara-9 F' O6 ~( g- n4 u
ble to levels obtained with topical testosterone would seem to/ e! P  q8 C$ f* O% [' V
provide a means to compare the relative effectiveness of
  p; a' @0 G1 |* m, g2 @( I' ~topical testosterone to systemic testosterone effect. It cer-
) _& N7 p& P. I) T' h$ r& `" m2 Etainly has been established that gonadotropin as well as par-& t) P3 R/ C" _2 [$ S2 A( |
enteral testosterone administration will produce genital2 Y* f) I; ?4 h& t! a
growth. Our report shows that the growth of the phallus was1 ?  [! F" }2 [
significantly greater with topical applications than with go-  Q1 G3 r5 g, D$ D
nadotropin, particularly in children less than 10 years old.
: _% S+ H0 a0 u, J6 o! Q, CThe levels of serum testosterone remained similar or lower7 ]% R: v; q1 J9 D4 t5 E. q
than with gonadotropin during therapy, suggesting that topi-. M. f7 g( c( o( V. x8 V' P+ j
cal application produces genital growth by its local effect as: L2 n  }- \7 \9 x
well as its systemic effect.
: C1 h; o1 G. I( BReview of our patients and their growth response related to
( O& P$ {( H& C$ n2 V0 Mage shows a greater growth response at an earlier age. This is% U, P- `. w! ^8 b/ R0 n3 J8 o* A
consistent with the findings of Wilson and Walker, who9 D9 |3 ]% n! J; b
reported an increased conversion of testosterone to dihydrotes-
: j1 ?+ c. U1 A' ~- c8 Utosterone in the foreskin of neonates and infants.4 This activ-3 W# u2 G) ~5 G0 L" @, R
ity gradually decreases with age until puberty when it ap-  t) r* n# A) ?- [. y1 o/ f
proaches the same level of activity as peripheral skin. It may+ R! j8 c1 R) k  ]4 |7 v' U" c
well be that absorption of testosterone is less when applied at& t5 n2 ]- t+ c. m; g5 U- d
an earlier age as suggested by lower serum levels in children
6 i2 s" d4 o" n  a2 nless than 10 years old. This fact may be explained by the
2 X4 t" |' l2 |( A4 Z+ jgreater ability of phallic skin to convert testosterone to dihy-
  x. ]  g/ |8 E& \! @drotestosterone at this age. Conversely, serum levels in older
/ d: s6 M% r  P& n* F. T# f: Tpatients were higher, possibly because of decreased local& S: T  d* [6 D; u7 m3 u% q8 s
667
# L% z9 B, \  D668 KLUGO AND CERNY
/ N" T  K. G) r: G6 {; ^/ a3 h* {Pt. Age
: t% E/ i  ]/ M1 b9 I(yrs.)
) X* ?  \. {$ n+ {) J0 OSerum Testosterone Phallus (cm.) Change Length: c- m4 |) C' m- G' u. I
(ng./dl.) Girth x Length (%)
* J: K8 V. r0 M4
6 o# t# t6 s) ~) c9 L# ]8: R5 H/ p8 ^6 N1 @$ i9 i
10
) r6 \0 F  c" A" l7 t12
- R+ X- V2 B  V% m$ l. R. \) q179 {5 _0 ?. z' ], V+ s. D! R
Gonadotropin4 x4 A: X( X& \, `% S1 u  d$ W. l
71.6 2.0 X 3 16.6
) O3 t; h& K/ V+ ?" R# E4 |50.4 4.0 X 5.0 20.00 c: G9 P& {# d
22.0 4.5 X 4.0 25.08 u. u  [& G, B
84.6 4.0 X 4.5 11.1% j  }1 p* x8 e' \% w( N( N1 b1 s0 l
85.9 4.5 X 5.5 9.0
; t1 @$ [8 h+ B! bAv. 14.3
+ W* q0 G8 U; ~4 T) y  t4
7 C4 @" J; _& \  i2 L$ e8
7 B1 L! \; @9 U10* i2 {" ^: `$ V0 u3 }. x$ @- n5 N
12
/ q4 ~" O. V) [/ y0 D17. ~" R; t5 ^. u, V6 n8 u
Topical testosterone
; E! J. O' Q: ]' w) H34.6 4.5 X 6.5 851 b8 U. m, r5 R- N0 C8 p& O
38.8 6.0 X 8.5 704 s, G* C% F- r3 w5 Y( l
40.0 6.0 X 6.5 62.52 I. \1 D5 g( u( L& ]- g
93.6 6.0 X 7.0 55.54 l& q7 v' j9 G
95.0 6.5 X 7.0 27.2
6 [3 l2 W& D7 t/ |& T8 _& d, tAv. 60.0; p& S& M5 {  L9 p7 A
available testosterone. Again, emphasis should be placed on
1 z* E* u. m9 q6 u$ V# t% Eearly therapy when lower levels of testosterone appear to
; f5 t3 U( E; a/ E8 zprovide the best responses. The earlier therapy is instituted* M/ j/ _& W3 r) a/ B
the more likely there will be an excellent response with low( u  d' L3 f; X5 [
serum levels. Response occurs throughout adolescence as
/ }1 O+ }7 M) l8 Gnoted in nomograms of phallic growth. 7 The actual response
/ q0 b9 Y" d" vto a given serum level of testosterone is much greater at birth" `, N2 l: X6 E& q
and gradually decreases as boys reach puberty. This is most! y% b: B7 K5 `6 ^4 K! L! ?
likely related to the conversion of testosterone to dihydrotes-
9 l. e8 v: H) _" S7 ytosterone and correlates well with the studies of testosterone
  f8 U7 B' G( E2 F9 Q+ Mconversion in foreskin at various ages." i. y6 l+ z. A: p3 l1 n8 v9 p' C
The question arises regarding early treatment as to whether
) v7 j- t. y/ bone might sacrifice ultimate potential growth as with acceler-3 g! k% p! v4 |
ated bone growth. The situation appears quite the reverse
5 ]0 O' @3 j* e2 A/ e' kwith phallic response. If the early growth period is not used6 y; ]8 S$ M- t) \
when 5a reductase activity is greatest then potential growth
3 j, [. S4 X' B5 w) w8 _may be lost. We have not observed any regression of growth9 Y8 |, ]- b% E* c- ~
attained with topical or gonadotropin therapy. It may well
8 z% X$ H! o, S& F# t5 Vbe that some patients will show little or no response to any
+ O, c, h+ V5 Iform of therapy. This would suggest a defect in the ability to5 x- S! |+ @/ I. p; c* u% p
convert testosterone to dihydrotestosterone and indicate that2 V3 j& M; M1 G! q# d) Y
phallic and peripheral skin, and subcutaneous tissue should
/ N9 n, p$ c- E9 g% Sbe compared for 5a reductase activity.8 k4 D$ R6 ^* ~
A, loop enlarges to measure penile girth in millimeters. B,
. S: k, C  ~% l! Mexample of penile girth computed easily and accurately.# E! g# h, [/ J$ E
conversion of testosterone to dihydrotestosterone. It is in this& f! Y# t4 Z% I4 N  m) }# t# w
older group that others have noted high levels of serum
, _/ h( U+ P  p% k( B/ V+ z- V! {testosterone with topical application. It would also appear. g; a7 N: }. a/ l5 ^1 M
that phallic response during puberty is related directly to the
* N! S! H" b; F) N; h% V0 N/ ^serum testosterone level. There also is other evidence of local1 W. {, W" D% H6 @
response to testosterone with hair growth and with spermato-/ A/ z, ]& x$ q3 r3 b. x; q
genesis. 5• 60 {0 P+ s# M- D; [3 `
Administration of larger doses of gonadotropin or systemic" n& L/ r& s0 a; M  B- d5 u- L+ v
testosterone, as well as topical applications that produce
$ J* z# ?( R( L* X: P0 g$ mhigher levels of serum testosterone (150 to 900 ng./dl.), will
' Y6 |. x) P; T' @. ]0 palso produce phallic growth but risks accelerated skeletal* J1 |0 z' j- G+ {" m
maturation even after stopping treatment. It would appear1 x2 A# d' B8 u! s- `
that this may be avoided by topical applications of testosterone
/ c! o: K! X; B; L4 U9 \( Mand monitoring of serum testosterone. Even with this control  Z5 b3 w8 `7 Q) K; e
the duration of our therapy did not exceed 3 weeks at any4 E  i1 b. A) s" H! U& T- L9 ^- ^/ K
time. It is apparent that the prepuberal male subject may6 O1 w5 ^. _4 B( ?4 `4 }4 i3 F) R6 E
suffer accelerated bone growth with testosterone levels near
4 k3 j% @$ b" _1 W# N200 ng./dl. When skeletal maturation is complete the level of: I! Y" f1 U. X$ ^
serum testosterone can be maintained in the 700 to 1,300 ng./- C! N0 y# w7 S: W- `5 i
dl. range to stimulate phallic growth and secondary sexual
+ B) C) q+ c0 ]changes. Therefore, after skeletal maturation parenteral tes-( U- ^. l1 h8 n+ _
tosterone may be used to advantage. Before skeletal matura-# X+ d2 I" I5 J9 g; J- _
tion care must be taken to avoid maintaining levels of serum# g7 @: h; u. U2 U1 K. p
testosterone more than 100 ng./dl. Low-dose gonadotropin9 I) A8 k; i5 F! v
depends upon intrinsic testicular activity and may require8 I, {. q6 p9 d# i
prolonged administration for any response., U( W# W8 }3 [5 V
Alternately, topical testosterone does not depend upon tes-
6 B2 P) [/ D0 ?0 t7 T( J. zticular function and may provide a more constant level of
3 h3 H0 @0 v, F9 KREFERENCES2 `, k1 i- p4 r9 J$ \+ ^, T
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,, [7 Y! B. }( ]5 o" J3 D
R.: The local application of testosterone cream to the prepub-4 T/ p: W/ B) ]% I
ertal phallus. J. Urol., 105: 905, 1971.
! j$ j2 ?/ t6 F7 X' r7 r2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 a" y9 U7 L$ t$ ktreatment for micropenis during early childhood. J. Pediat.,: F% S5 s- s9 v+ d: X, `- U. t; f
83: 247, 1973.; t' e* [% R) g6 F- y- E' u
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' }+ y5 R. }( n
one therapy for penile growth. Urology, 6: 708, 1975.7 {( o) e% e* I% k8 z; Z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 D+ J  f" ]2 K) ^6 S: f% A! \3 wto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, ~. y+ P3 q; W; b# x# eskin slices of man. J. Clin. Invest., 48: 371, 1969.
$ A- p" q# |9 B! c: ^) A* f$ L5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ F8 |7 T+ L# f- J& O
by topical application of androgens. J.A.M.A., 191: 521, 1965.' G* X( P# k0 K0 s5 `5 |7 c
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) r, h0 }# m$ U% R4 R# L8 u
androgenic effect of interstitial cell tumor of the testis. J.+ B) p' `- t" o5 T2 u
Urol., 104: 774, 1970.  L" Y+ m7 h" }) t( G
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( D+ f& l& f+ T/ {8 }
tion in the male genitalia from birth to maturity. J. Urol., 48:
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