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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND1 }( A3 a6 c9 E; T+ ^
GONADOTROPIN1 \$ u8 @% F  b+ _1 \* y
RICHARD C. KLUGO* AND JOSEPH C. CERNY
  q- O( z2 I4 x; u7 P$ ~! q% _! _, _$ {From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 f9 H6 h: {. PABSTRACT( T& ]" v! P* E; M" z0 e) T0 F: O. \
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
1 u) M8 i8 E$ }6 iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 @, U3 a+ F0 A' p
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone( \6 t; W$ g0 P2 {: X# S! [2 C
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 Z& ]) C9 B) a2 }2 Mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 ]# W# W) ?5 h+ H
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: Z: I% q/ \+ g: s; y2 `! F
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 X5 o% I. `9 B# t/ G3 @occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% {2 T! G: q. F7 X- w' z& dstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* |1 X/ B& [% o( H4 e9 k% Ggrowth. The response appears to be greater in younger children, which is consistent with previ-
* }, f9 K0 ^3 Fously published studies of age-related 5 reductase activity./ d" Z& ^2 z! B# d: \/ a
Children with microphallus regardless of its etiology will. y  ]3 w; E, D& D
require augmentation or consideration for alteration of exter-
$ C# k! G5 V; @9 t; L  e: z! Hnal genitalia. In many instances urethroplasty for hypo-
5 ~+ ^/ e, L3 A9 Qspadias is easier with previous stimulation of phallic growth.6 b5 p- F6 C  Q! {& X8 k
The use of testosterone administered parenterally or topically
8 ?$ @7 x) k4 _9 f- n3 Yhas produced effective phallic growth. 1- 3 The mechanism of9 ]& z& K" R3 p$ [0 x7 t
response has been considered as local or systemic. With this9 r+ d- d8 c% {" O; `3 [
in mind we studied 5 children with microphallus for response
4 g0 l' t9 G/ W' p4 kto gonadotropin and to topical testosterone independently./ e/ j7 I4 q4 m
MATERIALS AND METHODS
# ^9 k. E! p& f# C; S+ r) s; nFive 46 XY male subjects between 3 and 17 years old were
# m0 Z' }) _! W/ }8 F% e+ s, i$ nevaluated for serum testosterone levels and hypothalamic
8 n' K7 f, z5 Z4 m/ nfunction. Of these 5 boys 2 were considered to have Kallmann's
) }3 W. P- O, O* L8 z* a0 hsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
. ?! y* A$ \' Mlamic deficiency. After evaluation of response to luteinizing
% E% \2 x/ Z. i2 k! H1 n8 n. nhormone-releasing hormone these patients were treated with- B9 I& |6 C9 \9 X0 V
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
9 y* x7 k& {: Y- Q7 X( m; \after completion of gonadotropin therapy 10 per cent topical
0 Q7 Q9 K6 x: T2 b6 ~testosterone was applied to the phallus twice daily for 3 weeks.: U8 _  s1 W5 k7 f' a1 |
Serum testosterone, luteinizing hormone and follicle-stimulat-
& q# ^! U& L9 w2 Ving hormone were monitored before, during and after comple-1 o3 E% d5 t% {$ i0 n8 v, j
tion of each phase of therapy. Penile stretch length was% r; ?& u: |3 z3 o" l! n4 \( f2 X
obtained by measuring from the symphysis pubis to the tip of5 j  {) N$ ~2 v: p  p$ D. C" A
the glans. Penile circumferential (girth) measurements were
" ^0 Z& o* c1 q/ _/ pobtained using an orthopedic digital measuring device (see" J8 \' \6 M* M6 U! t
figure).
5 j2 \. l) i. e" g' bRESULTS- L5 O8 z: n" U- H/ q  m! d9 u
Serum testosterone increased moderately to levels between
+ {' h% j% V; G. o3 P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
! A8 W' i  u, a' g0 Y# Uterone levels with topical testosterone remained near pre-
5 J" m5 r& X+ G4 L5 f6 s. j/ ntreatment levels (35 ng./dl.) or were elevated to similar levels7 o# \/ x. A, }2 G! i, p9 B
developed after gonadotropin therapy (96 ng./dl.). Higher
, h) L5 Q8 P( n, B' A3 [serum levels were noted in older patients (12 and 17 years old),
" Q% i3 B9 G. W0 d, cwhile lower levels persisted in younger patients (4, 8, and 104 x) s. `  I6 D1 ]3 U; h% N. j
years old) (see table). Despite absence of profound alterations+ b; w7 V9 W; I6 z" Z
of serum testosterone the topical therapy provided a greater
( e: Q: p( s# z+ }  q1 T6 ZAccepted for publication July 1, 1977. ·! g* |% h" e1 Q6 U; j
Read at annual meeting of American Urological Association,) y$ }% H- t# L
Chicago, Illinois, April 24-28, 1977.5 f2 j% ~5 ?8 x; d! F( S: h5 D
* Requests for reprints: Division of Urology, Henry Ford Hospital,8 g0 M+ w% g8 q
2799 W. Grand Blvd., Detroit, Michigan 48202.
( R" N4 U8 W! f" ~! yimprovement in phallic growth compared to gonadotropin.5 B) Q1 \7 n% o) l2 B9 G
Average phallic growth with gonadotropin was 14.3 per cent
' u, E7 R( J% i5 x/ L, Bincrease in length and 5.0 per cent increase of girth. Topical
$ a) r, o  {6 L* M$ b' htestosterone produced a 60.0 per cent increase of phallic length, |1 b8 h9 f$ c& y
and 52.9 per cent increase of girth (circumference). The7 i* p$ z' e  p) {* b
response to topical testosterone was greatest in children be-4 P8 p; B9 Y, I! Y) l6 q/ H5 _
tween 4 and 8 years old, with a gradual decrease to age 171 j, n$ f0 c8 W" U4 x. D
years (see table).
3 v0 f8 @+ n! Y/ X! t4 IDISCUSSION
! H  P- k6 t! i7 PTopical testosterone has been used effectively by other8 ]% ]* M* g- l( q
clinicians but its mode of action remains controversial. Im-2 p" i! n4 O* M( v, f! z
mergut and associates reported an excellent growth response  Q$ h3 A) l3 A  r& I# m$ t/ B6 |1 F* z
to topical testosterone with low levels of serum testosterone,
; K1 O7 b0 i1 G! lsuggesting a local effect.1 Others have obtained growth re-! d; P3 \8 l8 S! W5 y
sponse with high. levels of serum testosterone after topical
/ ~7 R2 {% I% K% `administration, suggesting a systemic response. 3 The use of
# t& Y/ p" r! Z: x1 c. Rgonadotropin to obtain levels of serum testosterone compara-
9 f6 m# H* e) E8 S# ible to levels obtained with topical testosterone would seem to
+ u) z* y7 D  D& G, E- mprovide a means to compare the relative effectiveness of
. C) O8 Q& @4 Q' y8 F/ X( Btopical testosterone to systemic testosterone effect. It cer-
' D  M7 N7 G6 n2 U+ O7 @tainly has been established that gonadotropin as well as par-/ P/ \( f+ c" _, @9 m$ J
enteral testosterone administration will produce genital
9 h, V( Q. ^' z4 s. \, l5 vgrowth. Our report shows that the growth of the phallus was; C* @0 i0 z2 m% ^+ h2 E0 v! m9 c
significantly greater with topical applications than with go-
4 y5 F' `/ Q8 Lnadotropin, particularly in children less than 10 years old.5 e9 e& F- v9 L1 y; x
The levels of serum testosterone remained similar or lower
. ~9 |' z2 ^) k5 E( }' a; k; Y, `than with gonadotropin during therapy, suggesting that topi-
7 O5 V; B& g6 U  x3 y; z; [6 d. tcal application produces genital growth by its local effect as! V) k1 F% r9 C& ]1 j1 c' i
well as its systemic effect./ Q0 R% ~" w1 ]: M/ O
Review of our patients and their growth response related to' `1 P" h8 S) ]. `7 K) x
age shows a greater growth response at an earlier age. This is
3 w# Z0 N% T  h% r/ g3 y; [consistent with the findings of Wilson and Walker, who. q6 s# ?/ c% S, Z6 h* {) _% }0 i
reported an increased conversion of testosterone to dihydrotes-$ d, Y- @# H' W
tosterone in the foreskin of neonates and infants.4 This activ-
8 N4 L6 R/ O3 tity gradually decreases with age until puberty when it ap-6 N# ]" ^  @' ]+ Z
proaches the same level of activity as peripheral skin. It may' b, A% e  g5 I! u- S3 C' Z
well be that absorption of testosterone is less when applied at2 f$ l- m0 A8 I
an earlier age as suggested by lower serum levels in children
, e5 G' t" c" E* m2 H& S8 D9 o5 @less than 10 years old. This fact may be explained by the
( i' D' G5 R6 L  G" rgreater ability of phallic skin to convert testosterone to dihy-
. O% j( ^+ Q5 qdrotestosterone at this age. Conversely, serum levels in older' K( Q- Y. }/ m" ^7 A
patients were higher, possibly because of decreased local( h- [( N- M( V0 n+ y) S
667
. }& k. v/ ]( h& |! n) j- c% i668 KLUGO AND CERNY% q$ X3 }) }7 U8 @" w
Pt. Age
9 h. K" ], v, [" d  D/ p(yrs.)- L$ A' w  A' w, g* Q$ R
Serum Testosterone Phallus (cm.) Change Length, E$ ]! Y& K3 |' \
(ng./dl.) Girth x Length (%)
" {' Z9 I& u) g$ J4
( }2 R) |$ B6 {4 Q" P84 ~* M6 Q' N1 o
10
, m$ V8 e+ _9 ?' K; K; O' {124 }: r# [, t, m& W# E7 v4 A
17
5 u2 j- s& s# X0 }4 BGonadotropin5 h6 X* W7 e8 o* a( @. e
71.6 2.0 X 3 16.6
# C$ {  l3 K- }/ t' e5 j50.4 4.0 X 5.0 20.0
8 b* Q. U% k* z4 n" k5 a% G/ e7 w22.0 4.5 X 4.0 25.0
7 A. j% U# d" y' ^84.6 4.0 X 4.5 11.1! F; `+ F4 f  u: J  K1 h
85.9 4.5 X 5.5 9.0; H7 Q0 F' G' H7 s
Av. 14.3- E9 ~1 J0 K! r5 h" W
4$ Z, ^- z! d$ u
8
0 f# F! v, F! f1 b  S4 e+ z, b109 `0 ~2 |6 e' U3 `# }# \/ x! M
126 h4 I) Z9 p4 J9 G* X% y
17
; _4 f4 G& u& F3 f/ _1 DTopical testosterone: A+ w5 i" c7 q  Y" E, m: P
34.6 4.5 X 6.5 85
7 d7 n) S5 R2 W: r: }38.8 6.0 X 8.5 70
: |! H. \2 [& _% T) p9 {+ s40.0 6.0 X 6.5 62.5
$ Z9 D$ ~* d, [93.6 6.0 X 7.0 55.56 J' G# W& l5 r. v0 L! v
95.0 6.5 X 7.0 27.2& _; A# d) q0 y1 Y4 n+ w
Av. 60.0
! b  }- e) m& b# |. ?; B& havailable testosterone. Again, emphasis should be placed on
0 ~, q; g# Q+ p2 O/ {+ Kearly therapy when lower levels of testosterone appear to) N' I: g+ l7 C1 V" I) N, k
provide the best responses. The earlier therapy is instituted* {% J! A4 h# ?3 `, R, i4 i2 F: x
the more likely there will be an excellent response with low
6 c9 H' i. a5 i- ]6 Pserum levels. Response occurs throughout adolescence as
) U8 U1 `, }: I' s" B& o* d' Rnoted in nomograms of phallic growth. 7 The actual response6 p6 W% T' ?; P" F2 Z4 Q0 k- u
to a given serum level of testosterone is much greater at birth! {' `6 u+ O! j- b3 S0 K! `
and gradually decreases as boys reach puberty. This is most
+ i) J- F/ A$ i/ t& s9 dlikely related to the conversion of testosterone to dihydrotes-
7 s- g- }5 A# c) E" ?tosterone and correlates well with the studies of testosterone. C1 c0 P0 c, D6 X0 `1 O; {; v+ j
conversion in foreskin at various ages.
& f9 f3 m0 g$ r1 b( U5 hThe question arises regarding early treatment as to whether% M, \* A  n$ Q
one might sacrifice ultimate potential growth as with acceler-
: `/ G$ a( Z8 t' g5 oated bone growth. The situation appears quite the reverse
2 K/ s; T% I$ r' p! N+ u- Lwith phallic response. If the early growth period is not used
; w3 X% B$ B. M3 [9 C' c0 Ewhen 5a reductase activity is greatest then potential growth
& W! M" _! [7 e  L2 Gmay be lost. We have not observed any regression of growth0 w1 O( |; |* B  ]
attained with topical or gonadotropin therapy. It may well" \8 f/ j5 s3 M- f
be that some patients will show little or no response to any
7 C* V5 @! U! v1 m- W7 `* l  v% w8 _( oform of therapy. This would suggest a defect in the ability to0 R# e) k  @+ Y' d6 c
convert testosterone to dihydrotestosterone and indicate that
4 ~4 L# b1 A5 w7 d( c  iphallic and peripheral skin, and subcutaneous tissue should& \7 K3 r  F. Q, U) Y
be compared for 5a reductase activity.
& n) c% w3 B5 w2 V' A; gA, loop enlarges to measure penile girth in millimeters. B,& ?5 f) o; ~# a# y6 i' d, u3 @- i) l
example of penile girth computed easily and accurately.; V& F- N. Z+ ?$ L: Q- M/ Y5 G" r
conversion of testosterone to dihydrotestosterone. It is in this% ^- g$ D4 [. l! g3 \3 e0 C- s
older group that others have noted high levels of serum  L3 s: g# d" Y$ G0 L7 k
testosterone with topical application. It would also appear2 r. f# D2 B) u# e8 h% [7 R$ Q' P
that phallic response during puberty is related directly to the
8 q0 M5 n0 i$ k& U! }5 sserum testosterone level. There also is other evidence of local* z/ E) g9 X8 `2 A6 a8 N
response to testosterone with hair growth and with spermato-7 T* q! K& `, D: \
genesis. 5• 6
, W4 S% Z  r, B! o7 qAdministration of larger doses of gonadotropin or systemic/ G5 Y+ _" R) J( a4 P
testosterone, as well as topical applications that produce8 T- u/ ?( c. ~. ?( a. X
higher levels of serum testosterone (150 to 900 ng./dl.), will
' i. [% s* i; p# a) f9 @4 Malso produce phallic growth but risks accelerated skeletal3 [5 j9 e  E5 n# d) ?
maturation even after stopping treatment. It would appear  F* n; J7 E& q) w" H
that this may be avoided by topical applications of testosterone
% q8 ^# q" i8 L2 G8 G1 ~and monitoring of serum testosterone. Even with this control: M; y+ f8 M* P* y0 p# F: e
the duration of our therapy did not exceed 3 weeks at any7 E* ^5 B3 Q2 g- o
time. It is apparent that the prepuberal male subject may& B& `# x2 W! [1 y. o# i; z
suffer accelerated bone growth with testosterone levels near
7 V  N: C$ F& ]1 |3 Y( v2 r200 ng./dl. When skeletal maturation is complete the level of
, V0 h( A& ?8 p7 `serum testosterone can be maintained in the 700 to 1,300 ng./) Q- ]$ p* A7 j# x7 [+ ]
dl. range to stimulate phallic growth and secondary sexual
( J, A! t0 r; H4 C% C& ~/ {changes. Therefore, after skeletal maturation parenteral tes-
! S/ S0 J; \* Z; |( e; L. T4 Rtosterone may be used to advantage. Before skeletal matura-% k. s0 a3 j1 K+ X3 ^7 D
tion care must be taken to avoid maintaining levels of serum
* I( C2 P$ [' x0 h% a1 Jtestosterone more than 100 ng./dl. Low-dose gonadotropin
5 v# Y& }- J; a; J6 W% i% qdepends upon intrinsic testicular activity and may require
6 c* d4 R  j( E# oprolonged administration for any response.
. T. \& a1 m$ F9 ]# j/ C" cAlternately, topical testosterone does not depend upon tes-' j( Q* t, Z2 j. b* T' {! A& D
ticular function and may provide a more constant level of/ f" j" l& t5 h( a+ P
REFERENCES
& u5 W0 c$ w" I+ B. V1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 F/ W, S, P+ u: N5 W+ z- ?# U$ UR.: The local application of testosterone cream to the prepub-& d7 ~$ r8 Y: V- B& T* B- h
ertal phallus. J. Urol., 105: 905, 1971." S, P- t6 H0 n+ d0 |+ e
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
* i2 |3 r4 K; H( v6 n; m/ Mtreatment for micropenis during early childhood. J. Pediat.,
" K0 E9 @. k. ^) B6 r83: 247, 1973.
" y+ I" G+ D  [3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-  k2 p$ U! E) V8 ]$ ]0 d
one therapy for penile growth. Urology, 6: 708, 1975.
' h3 i2 T5 K# X" Q4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 I6 O$ X" {: V; S2 k4 L' V9 \to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by! M* s/ l4 K9 n2 a5 D
skin slices of man. J. Clin. Invest., 48: 371, 1969.( X' o( f# X% p& Q# U( z  @7 \
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth; ~3 W% l" M! |1 V4 _. m
by topical application of androgens. J.A.M.A., 191: 521, 1965.4 y% k4 e4 W- |
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 I' O$ n# u. Q! S2 d. U
androgenic effect of interstitial cell tumor of the testis. J.( g5 t+ }" _7 F1 _1 C$ ?
Urol., 104: 774, 1970.: j) w8 c  g# Y5 v7 f8 v
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; D. `/ @% x. e/ V4 c6 M+ ~# R3 ktion in the male genitalia from birth to maturity. J. Urol., 48:
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