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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; Q, N0 _2 m3 XGONADOTROPIN
: S" C" Z2 R" K1 ^* l' Z$ MRICHARD C. KLUGO* AND JOSEPH C. CERNY7 V' x. L) k" P* B  N
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan* {8 c5 Z; ?, M4 `
ABSTRACT7 r. C8 W. P6 O
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
! T0 d) M+ B& z; B& }: L# lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: S* w( I$ ~9 M. B+ H4 |3 ^  U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. u4 J" m0 y4 G5 [6 N, R6 ?
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 ?- _3 X* A' Q" X
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ j* L5 p  M& P* lincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average2 t9 z+ S) E: t- S9 K# ~2 M6 X; `6 f
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 _3 E* v# I* |' H7 u2 X" yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
. ?+ y- f! O$ E' ?study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% [! i. D5 O" J
growth. The response appears to be greater in younger children, which is consistent with previ-
6 g$ n% M$ S7 a. x& W# Q$ `6 Rously published studies of age-related 5 reductase activity.' ?& d5 m4 G  F5 `
Children with microphallus regardless of its etiology will! r6 o# }) c( b9 }6 q: F5 e. o
require augmentation or consideration for alteration of exter-$ U8 D1 D2 c* e" r
nal genitalia. In many instances urethroplasty for hypo-# D5 k6 |/ t, U) t. n* U* i
spadias is easier with previous stimulation of phallic growth.* y8 O( W0 s% G/ X* Y) g) }) P
The use of testosterone administered parenterally or topically
* K9 w) n+ h7 X0 v( L8 A* fhas produced effective phallic growth. 1- 3 The mechanism of
" c: g. M0 J, F% r% W7 Presponse has been considered as local or systemic. With this: w1 \9 ?% P2 g: e! |, a9 K
in mind we studied 5 children with microphallus for response
/ P. O) G  e  A* d& ]to gonadotropin and to topical testosterone independently.* v1 P' H$ \5 J" i/ w* Q$ o6 y' J
MATERIALS AND METHODS
2 ^, V: V7 f- f1 C1 x9 ?1 w7 JFive 46 XY male subjects between 3 and 17 years old were
! @& b+ R) y, @" X4 S4 Y7 l# xevaluated for serum testosterone levels and hypothalamic
; |" b# v0 R% s  k! Gfunction. Of these 5 boys 2 were considered to have Kallmann's
) I" t# f9 L0 {1 m! n6 Ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
/ d, N0 g+ \; w# G. J/ M( Wlamic deficiency. After evaluation of response to luteinizing/ @  z5 F- y: b( d, U* M
hormone-releasing hormone these patients were treated with
& [9 `) ]  @  N1 ^1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 R2 n& s- n. Z1 Q
after completion of gonadotropin therapy 10 per cent topical
) p( x* v2 ]2 i- Xtestosterone was applied to the phallus twice daily for 3 weeks.6 f* t% G4 q8 `! |9 w! t8 i
Serum testosterone, luteinizing hormone and follicle-stimulat-
2 k/ ~, b/ ^6 p4 E4 T. U3 p# t; qing hormone were monitored before, during and after comple-1 j' ~8 K; D6 {5 Y
tion of each phase of therapy. Penile stretch length was
" @2 b3 q% s  |* o" C" wobtained by measuring from the symphysis pubis to the tip of
* \5 ^# \0 N, W/ r: Q+ }( Ythe glans. Penile circumferential (girth) measurements were1 I7 U' ^0 V: f7 D: B
obtained using an orthopedic digital measuring device (see( d$ M/ Y  N# ]* O
figure).5 q! `+ n9 Y' i
RESULTS
3 w; A9 p* a  `2 Q0 b5 Q; @6 _: pSerum testosterone increased moderately to levels between
' b* x2 U% h' S5 c% f3 o: W50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
; z. y! P; ^/ C2 r8 Zterone levels with topical testosterone remained near pre-
  J- ]- L% e9 H' a. ptreatment levels (35 ng./dl.) or were elevated to similar levels2 f( y' D" ~% r
developed after gonadotropin therapy (96 ng./dl.). Higher; U" X8 r2 j* F. `
serum levels were noted in older patients (12 and 17 years old),8 Q, [$ F# U4 ^; C. s8 S, a% z
while lower levels persisted in younger patients (4, 8, and 10
! T2 D8 T& @/ Z$ l# \7 Ayears old) (see table). Despite absence of profound alterations
+ g" N8 N! r& A1 g5 K! l0 R$ h8 Iof serum testosterone the topical therapy provided a greater4 i% ~# F( R. P  ]7 L6 I, B! K. h
Accepted for publication July 1, 1977. ·1 ^7 c& D5 M5 K3 L* j6 y
Read at annual meeting of American Urological Association,
. j4 K! |- I+ g6 t! `# TChicago, Illinois, April 24-28, 1977.
+ M, ~5 A; {# `% r* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 p! g# `- O& U5 k) b. y2799 W. Grand Blvd., Detroit, Michigan 48202.! C, o4 N9 e" U( p/ `. D
improvement in phallic growth compared to gonadotropin.9 s# e- D5 c0 |, ~. r! k! H6 }
Average phallic growth with gonadotropin was 14.3 per cent
& C8 v' b. Z, f  R7 P! x* Vincrease in length and 5.0 per cent increase of girth. Topical
  w' _6 I: r9 d  b) w' C9 U. \testosterone produced a 60.0 per cent increase of phallic length
- n4 l7 E) k, }  ^5 S" Q$ Cand 52.9 per cent increase of girth (circumference). The- @! `6 Z; g# k$ C( f4 A
response to topical testosterone was greatest in children be-- X; }% d$ X1 w5 `; Z1 Q% V! E
tween 4 and 8 years old, with a gradual decrease to age 17  A( K2 k( \1 x( D9 u! W, F
years (see table)., |4 {! V2 r7 a7 V( a4 Y  i" \1 a
DISCUSSION0 B! W* Y1 h  g. K
Topical testosterone has been used effectively by other- I" [# O1 W. E7 k3 D
clinicians but its mode of action remains controversial. Im-* S. R" W: l5 u4 `6 J. \+ w
mergut and associates reported an excellent growth response
- i  ]/ o5 x- k5 K' f7 [1 D( wto topical testosterone with low levels of serum testosterone,- R7 e7 p* L. g. i7 R5 |8 d2 }
suggesting a local effect.1 Others have obtained growth re-
" P- S' c7 U  F  N, Tsponse with high. levels of serum testosterone after topical
& V5 z, E( Y. @; aadministration, suggesting a systemic response. 3 The use of
2 ^% C+ w+ c! {; c1 B  O# f. dgonadotropin to obtain levels of serum testosterone compara-" P. T/ T& v: n, c
ble to levels obtained with topical testosterone would seem to0 k0 b2 d5 ^& L, R( `2 B
provide a means to compare the relative effectiveness of& s8 J$ v' d, q, ^9 E) y
topical testosterone to systemic testosterone effect. It cer-
0 @! k/ Q, e9 j5 Otainly has been established that gonadotropin as well as par-8 x8 n% w0 o6 i7 ]' X6 ?
enteral testosterone administration will produce genital
7 G5 s  S, t( b1 Q; Tgrowth. Our report shows that the growth of the phallus was
& P  Q# G. X7 rsignificantly greater with topical applications than with go-* K, c5 m: k( w9 d6 T: f
nadotropin, particularly in children less than 10 years old.5 I1 `5 ^, k7 U% j4 M
The levels of serum testosterone remained similar or lower- z% L# y. E3 f6 D2 E& s2 j7 W
than with gonadotropin during therapy, suggesting that topi-% q' l4 Y2 @6 q5 V0 P
cal application produces genital growth by its local effect as
+ I9 ]( n; }8 E2 Y& Y& t1 X% ewell as its systemic effect.
5 ^4 J* g1 I' n' p5 C+ bReview of our patients and their growth response related to, b: `+ I" u& M
age shows a greater growth response at an earlier age. This is6 X: D; K8 s: U" g" I7 C
consistent with the findings of Wilson and Walker, who
0 c4 `# ]( ^: U4 u% preported an increased conversion of testosterone to dihydrotes-( a: P" J5 e' D7 A: _
tosterone in the foreskin of neonates and infants.4 This activ-# C0 C2 w. N3 u! N+ ]- j, Q0 s" `
ity gradually decreases with age until puberty when it ap-
, s/ ~1 R5 t# u( g9 Q6 ~9 \+ ~& mproaches the same level of activity as peripheral skin. It may  n! n# s: `& J
well be that absorption of testosterone is less when applied at" g$ }  \& P1 c
an earlier age as suggested by lower serum levels in children
% L, Z+ U" F. {! iless than 10 years old. This fact may be explained by the
% G9 K+ i) d, v# Dgreater ability of phallic skin to convert testosterone to dihy-5 J$ }, C: T8 W. l2 h" N5 Y/ h
drotestosterone at this age. Conversely, serum levels in older
! _+ ^! Y* Y4 t- x+ g' T+ rpatients were higher, possibly because of decreased local
. I* }- J. y7 h; }667
' k% G- c9 P& A+ n668 KLUGO AND CERNY$ X# o* [$ p2 _0 O
Pt. Age( C) u; ], r1 ^) I* f
(yrs.)- n8 u( L, b1 V- c' K( p
Serum Testosterone Phallus (cm.) Change Length2 z0 a* j" c3 B: P$ S
(ng./dl.) Girth x Length (%)# K# B0 u1 P9 s% v; t* Z
4
. g8 }3 q7 l- M6 q8
; n, F* G+ Q# j' M10/ Y# r% t: C/ }
12- a& n' _( g7 v5 w
17
& w4 w* C( ^2 S* P! R# aGonadotropin/ F; J9 C9 \  l8 ~% ?
71.6 2.0 X 3 16.6% H0 E- e9 K8 J. _5 {3 M9 S6 |/ W
50.4 4.0 X 5.0 20.0
0 X9 U; m# m6 [6 j22.0 4.5 X 4.0 25.06 e; q- T1 t; u/ F4 M
84.6 4.0 X 4.5 11.1
# f; {6 p1 L7 g( {% {1 X2 M1 N# @85.9 4.5 X 5.5 9.0: ]3 d+ W' Z/ J5 w
Av. 14.3
, t. B- w, |5 q7 q4
3 q8 @$ c# }' w8
# }8 U% a6 w  ^  I10
# M0 c* ^% U2 q5 Y. c$ G; e12
9 a4 t, i5 h+ m) d178 D; q2 @9 Y& ~  Y, Y% z
Topical testosterone: L9 `2 {0 k) x4 o& ?/ G- M: y
34.6 4.5 X 6.5 85/ T8 V# c! n) T  b! S- l3 ]  W+ i
38.8 6.0 X 8.5 70
) y; O2 ?$ ?. Q) p; o) ?40.0 6.0 X 6.5 62.5
* p" L+ j& Z+ _& ]! H' g. w93.6 6.0 X 7.0 55.5
/ _& J  s% O0 Z7 a95.0 6.5 X 7.0 27.2
) a) r5 W) J; ]% K2 b& K5 q9 {Av. 60.0/ u1 ?, T4 o4 V) B8 q3 J5 d  A
available testosterone. Again, emphasis should be placed on
6 ?% P7 U# ^8 j+ o$ t# x, O' Hearly therapy when lower levels of testosterone appear to2 s& A1 D5 t: A" L2 \+ E; e3 C
provide the best responses. The earlier therapy is instituted
- N" c" u7 i) v- athe more likely there will be an excellent response with low
/ g  c6 x" Y* e8 D: _1 o, Dserum levels. Response occurs throughout adolescence as
: a# L. j( W" Fnoted in nomograms of phallic growth. 7 The actual response
" S" x: x: W2 E8 P2 o8 d8 F) F1 nto a given serum level of testosterone is much greater at birth
7 Z, I! O8 A9 j" wand gradually decreases as boys reach puberty. This is most
: J( {% O) n# }# c$ Y- ?* elikely related to the conversion of testosterone to dihydrotes-# m1 C; P. T7 e* j2 z2 c; G. \
tosterone and correlates well with the studies of testosterone' Y" K/ {% R4 ?4 y* ?( q
conversion in foreskin at various ages.
) X- a: s9 b0 h) b& Z7 F2 j. rThe question arises regarding early treatment as to whether
$ ]5 }  Q6 P% ?/ Eone might sacrifice ultimate potential growth as with acceler-
1 c0 U. l5 q" F5 w0 a6 Lated bone growth. The situation appears quite the reverse
1 D, E' Q  ?( E- h' D: @with phallic response. If the early growth period is not used
/ D, v- ]0 V6 }when 5a reductase activity is greatest then potential growth: {; S# s- t2 g1 d+ q7 U7 ~" `
may be lost. We have not observed any regression of growth
+ u" A' K) A0 E* p* u9 Pattained with topical or gonadotropin therapy. It may well/ I: P' q/ W' R+ s$ _) z& Y7 z
be that some patients will show little or no response to any
% l: Z/ y, s$ h2 W$ O$ f0 Xform of therapy. This would suggest a defect in the ability to2 |3 l9 X. E9 \) I% C
convert testosterone to dihydrotestosterone and indicate that
% e! l, y  U. Ophallic and peripheral skin, and subcutaneous tissue should
& x0 n! b' K- g, dbe compared for 5a reductase activity.
( l# V# X3 a: U7 w5 n* L' m( W6 T' YA, loop enlarges to measure penile girth in millimeters. B,
8 `3 c, I8 o- Z& [example of penile girth computed easily and accurately.% ]7 I! ?. b6 d$ q. _
conversion of testosterone to dihydrotestosterone. It is in this
( O4 \. U. x7 colder group that others have noted high levels of serum4 s, w1 k/ M. H
testosterone with topical application. It would also appear
5 T/ F0 |5 f3 a8 i  f& ethat phallic response during puberty is related directly to the
% i+ i# T, s' s( _serum testosterone level. There also is other evidence of local' ?. A: ^, m; N& @9 |/ q0 l
response to testosterone with hair growth and with spermato-
$ v/ w1 [* ^; ygenesis. 5• 6
5 j# Y' @1 |! J5 Z5 L$ BAdministration of larger doses of gonadotropin or systemic- N+ h9 H5 b- N0 S; W! }0 G' X9 \
testosterone, as well as topical applications that produce" d; B2 y1 b1 O1 S1 Y* m% ?
higher levels of serum testosterone (150 to 900 ng./dl.), will1 |. ?. Z5 R$ ?/ V- k+ j. R
also produce phallic growth but risks accelerated skeletal- {! G0 U& @& R& D; Z" S
maturation even after stopping treatment. It would appear
: N9 G: u9 S- y7 L  w0 zthat this may be avoided by topical applications of testosterone; M# e( t3 S' Q/ ^! J
and monitoring of serum testosterone. Even with this control& p8 s4 N/ |, j6 p7 U
the duration of our therapy did not exceed 3 weeks at any
/ C  N( n, K8 P- J& U4 X+ ytime. It is apparent that the prepuberal male subject may6 w$ {, C1 t) `0 w$ c( c( W, w
suffer accelerated bone growth with testosterone levels near
9 d2 |2 A+ S8 ~200 ng./dl. When skeletal maturation is complete the level of7 F, S: m% _: c+ @; N
serum testosterone can be maintained in the 700 to 1,300 ng./
8 t  `* E6 ~# D. }& t7 Ldl. range to stimulate phallic growth and secondary sexual
" r" D8 M; B' c- R8 r! I0 \changes. Therefore, after skeletal maturation parenteral tes-! G0 I, K5 g3 `" \- \
tosterone may be used to advantage. Before skeletal matura-  o+ r  f. C# @4 d% r6 E
tion care must be taken to avoid maintaining levels of serum
9 Z+ A5 ^6 K3 T1 e" Dtestosterone more than 100 ng./dl. Low-dose gonadotropin/ T  m3 ]$ c' b) P% ?% s( g
depends upon intrinsic testicular activity and may require) W! L+ L0 p$ m2 _# r& C1 J# G' y
prolonged administration for any response./ Z9 A9 H% ^) F4 @" h# Z
Alternately, topical testosterone does not depend upon tes-
) j! q9 d) b$ N8 x& xticular function and may provide a more constant level of
( ?. ^5 H( f. D; v2 n* D* sREFERENCES
! r( s  q& v" b0 V) _6 G; t1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 P3 i1 k$ N& ?3 N+ R0 z
R.: The local application of testosterone cream to the prepub-. H& y! y/ y; ?9 w% P" {* `  H( h
ertal phallus. J. Urol., 105: 905, 1971.
0 o8 Q  ?) G4 I2 K# K, W( R4 N) w2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone0 y4 M6 V; P8 y( C0 T
treatment for micropenis during early childhood. J. Pediat.,# A% M5 D- D0 q. @# ]. R
83: 247, 1973.: F: C) H; v! ^: t' l! p" ~
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
  L3 W' k' v$ g, i# V  Hone therapy for penile growth. Urology, 6: 708, 1975.
1 @% A0 [* N7 [6 J8 l4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
5 c2 q" I2 R4 ^7 L1 `1 Fto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, \% H7 c0 U3 kskin slices of man. J. Clin. Invest., 48: 371, 1969.6 r! k! _  g7 ~# a
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth; R1 V( V) R4 s9 q' Q2 k
by topical application of androgens. J.A.M.A., 191: 521, 1965.) t; ^# U  q5 R8 P
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 P' @8 ?2 {0 d# @; r' oandrogenic effect of interstitial cell tumor of the testis. J.% Y$ }6 n1 @8 a
Urol., 104: 774, 1970.6 f& y: W% Z+ U! T+ B, h
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
  y2 E9 x3 \/ b( K% }) |tion in the male genitalia from birth to maturity. J. Urol., 48:
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