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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND7 O" C/ F8 v1 N. X' F9 K% N2 p
GONADOTROPIN* @: y# f8 k! U2 }
RICHARD C. KLUGO* AND JOSEPH C. CERNY7 U6 D6 N% m" `/ N! U0 F" c4 k
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& `& R6 W, e3 V6 \6 N& W3 S8 c
ABSTRACT4 t$ K% L. L5 p5 K( K/ d* n4 [
Five patients were treated with gonadotropin and topical testosterone for micropenis associated9 g1 a; i/ A  r8 }  d+ |
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-* U% c9 E& Z, p, o% l; x
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 K6 ?. ~2 C" d& T2 s: s
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* \, P- O& \! ^+ G, B! j7 ?
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 ?7 v" y) {3 a7 y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
* m3 W3 G/ S6 h+ t0 m& b, }increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response! L5 u, N6 u, X) q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( C9 C$ g+ G, ~) ?9 {. P" l
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! R8 ^* O" t0 f
growth. The response appears to be greater in younger children, which is consistent with previ-
# a! e- f: E4 t& Sously published studies of age-related 5 reductase activity.) `4 B! J1 z8 Z5 [
Children with microphallus regardless of its etiology will
( r, b7 ^' r+ vrequire augmentation or consideration for alteration of exter-% y" L( \' l% D- s1 l; R4 r. {
nal genitalia. In many instances urethroplasty for hypo-
; R% p" ?. B1 |! i5 y3 ?spadias is easier with previous stimulation of phallic growth.: C$ _: Z4 T1 r& }' p% @9 |
The use of testosterone administered parenterally or topically
7 g8 f2 S$ O5 Y, P6 S7 w* _4 p# ghas produced effective phallic growth. 1- 3 The mechanism of
0 g( k% P5 t7 t; Wresponse has been considered as local or systemic. With this
' P  B- S  l7 W, b" v$ Zin mind we studied 5 children with microphallus for response1 G: o4 p& u* W
to gonadotropin and to topical testosterone independently.
- e* T. V. |( G) c. \. z$ XMATERIALS AND METHODS
) ~8 g+ e7 d6 Q1 @8 @5 }Five 46 XY male subjects between 3 and 17 years old were2 [4 G7 D2 F( w( b
evaluated for serum testosterone levels and hypothalamic( h$ @9 x4 O9 Q3 z
function. Of these 5 boys 2 were considered to have Kallmann's3 I1 H$ L9 g0 m
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 q& @1 A2 S' e7 F$ C" Zlamic deficiency. After evaluation of response to luteinizing
. p$ D& w9 k& v# U% b- y+ Rhormone-releasing hormone these patients were treated with5 O- G7 d. x+ t: F
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% V* p; t9 Q- H4 Xafter completion of gonadotropin therapy 10 per cent topical
3 w' h" T, R0 u2 ztestosterone was applied to the phallus twice daily for 3 weeks." R- t; W- z: P4 n; O
Serum testosterone, luteinizing hormone and follicle-stimulat-
. Q" J6 A! ]2 d% P. @ing hormone were monitored before, during and after comple-  P! N8 F8 ]; |3 a# V% w! M
tion of each phase of therapy. Penile stretch length was
& [+ d9 H* @6 fobtained by measuring from the symphysis pubis to the tip of8 _$ I9 @8 \- i9 F0 O
the glans. Penile circumferential (girth) measurements were. Q6 W6 \2 K, c: e0 X$ n2 i( e
obtained using an orthopedic digital measuring device (see
5 h! s! j) s6 J- h1 V0 f3 Y- G2 afigure).. a( l5 d7 e; u, w; X
RESULTS, d# |+ m7 f6 E4 }- v
Serum testosterone increased moderately to levels between2 q4 U- I$ J3 ?/ F) J. _8 p
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ }- \- [3 ~% q% q! Gterone levels with topical testosterone remained near pre-
- m" d6 f. c  u. y% V$ Q- X6 itreatment levels (35 ng./dl.) or were elevated to similar levels
5 _, a) a- [: Hdeveloped after gonadotropin therapy (96 ng./dl.). Higher2 r5 Q& T5 o7 {5 X- G& C
serum levels were noted in older patients (12 and 17 years old),& t: W& G6 f9 J
while lower levels persisted in younger patients (4, 8, and 10
- N) r% k+ \7 m' y3 K: r7 O. Jyears old) (see table). Despite absence of profound alterations$ M8 |4 m% O& x- {. l& p
of serum testosterone the topical therapy provided a greater7 M0 j3 Z0 M5 Z
Accepted for publication July 1, 1977. ·" W7 T& k. u3 ]
Read at annual meeting of American Urological Association,
: f/ i( c- x3 P1 A$ f" }Chicago, Illinois, April 24-28, 1977.2 Z4 @! S- L  b2 Z* L
* Requests for reprints: Division of Urology, Henry Ford Hospital,$ n0 L, v- a, ^# n3 {; _
2799 W. Grand Blvd., Detroit, Michigan 48202.# `6 y6 a9 y4 O9 |# @' q0 z
improvement in phallic growth compared to gonadotropin.
* s; f- R5 E5 m4 d( cAverage phallic growth with gonadotropin was 14.3 per cent0 N$ U8 B2 y: w9 H
increase in length and 5.0 per cent increase of girth. Topical6 D% N6 _/ u1 ]
testosterone produced a 60.0 per cent increase of phallic length9 [0 Y- {! [% T0 s0 |% c
and 52.9 per cent increase of girth (circumference). The' t6 G" c9 J5 y1 _3 `! p
response to topical testosterone was greatest in children be-* a8 C$ T; H! ~& p9 Z2 \
tween 4 and 8 years old, with a gradual decrease to age 17
6 f$ b" y' I4 u6 }0 ]9 @' B) _" Tyears (see table).! f7 y; G7 H  M' H* _2 w1 t. s
DISCUSSION7 i7 A8 F7 b6 v, L) y7 h
Topical testosterone has been used effectively by other2 ?7 \1 J8 J3 g5 Z7 j* z9 f
clinicians but its mode of action remains controversial. Im-
, A- n! Q) A# l6 Tmergut and associates reported an excellent growth response
0 [+ v7 A7 I4 k3 B' \to topical testosterone with low levels of serum testosterone,
" E! W. S% ~6 a2 r4 M$ hsuggesting a local effect.1 Others have obtained growth re-
6 y' s" }' ?" B% v5 Osponse with high. levels of serum testosterone after topical" M7 Z1 y1 a0 f' ]' X; F1 J
administration, suggesting a systemic response. 3 The use of7 y( S. M8 ^, E9 l2 ]
gonadotropin to obtain levels of serum testosterone compara-  Y) ^  P6 v) k' A+ p
ble to levels obtained with topical testosterone would seem to( ~; f9 [/ Q& L7 O
provide a means to compare the relative effectiveness of
9 D5 l% ?! f% X. R0 }topical testosterone to systemic testosterone effect. It cer-
+ R" H0 I  H# w8 Y, L9 `* Utainly has been established that gonadotropin as well as par-9 ?! Y8 V7 o+ e, `/ y3 C
enteral testosterone administration will produce genital
& u4 g, j  i+ y, {/ t( a3 }6 Lgrowth. Our report shows that the growth of the phallus was7 U2 k+ U' ]+ t( B* i3 N- b
significantly greater with topical applications than with go-3 Y( w  |6 P; J
nadotropin, particularly in children less than 10 years old./ N8 h! i& f- j( `1 P, P
The levels of serum testosterone remained similar or lower
% X: A8 z" {8 t3 p0 _; y( Othan with gonadotropin during therapy, suggesting that topi-( m: N0 n& l# C
cal application produces genital growth by its local effect as/ |0 r8 f9 J' p1 O" |
well as its systemic effect.
& h- P  Q% }0 N$ Z+ X- c. JReview of our patients and their growth response related to  `, z" |3 e+ ]; W% T5 J5 N
age shows a greater growth response at an earlier age. This is
! H2 V* F. S5 s1 O0 c  Zconsistent with the findings of Wilson and Walker, who
8 o! V5 G) i. m& O& r6 ~# s2 y# r7 Vreported an increased conversion of testosterone to dihydrotes-
6 }; b: c4 Q' O( R% d4 ^+ }3 c& ztosterone in the foreskin of neonates and infants.4 This activ-
4 I8 d, ^8 W  K: ?8 D* city gradually decreases with age until puberty when it ap-
& y  `2 j/ |! p5 e  E1 Q5 W2 dproaches the same level of activity as peripheral skin. It may
3 p: x$ Y# u0 ]- rwell be that absorption of testosterone is less when applied at
+ A. Y' m8 H+ W( Tan earlier age as suggested by lower serum levels in children* \3 D) N' E& |: T* m
less than 10 years old. This fact may be explained by the
3 ]9 G! Z2 Y8 v: j" x4 r2 dgreater ability of phallic skin to convert testosterone to dihy-& l' ~5 S- d: A
drotestosterone at this age. Conversely, serum levels in older$ M7 S$ z2 `2 `- B% f, @. ^
patients were higher, possibly because of decreased local/ X5 H" Z6 s4 g* W9 G
667* X9 T9 S: Z* i4 f3 \1 s$ B! ~& y4 B0 |+ T
668 KLUGO AND CERNY
2 s+ s3 I5 j" r' a: }' NPt. Age8 d0 R3 }7 B9 {
(yrs.)4 [6 H0 h4 Z; O  [6 i
Serum Testosterone Phallus (cm.) Change Length
, j4 Y2 p; G$ C; Y( s(ng./dl.) Girth x Length (%)
% w' p3 N6 R7 w* o$ l2 j45 L* q. ^0 B/ C
8
# }  i0 s8 L6 N  F! D# j103 Y& L' U8 h* g$ f8 _
12
) h# G, Y; r) e. V9 G  c$ z% E17) R) A$ v# _: M8 C! D+ |) u9 n
Gonadotropin9 b7 W3 f# N7 i& l% D# |. _
71.6 2.0 X 3 16.6: U0 ]9 T, M3 m. n
50.4 4.0 X 5.0 20.0+ Z6 ]6 `/ Q0 D5 m! E" w
22.0 4.5 X 4.0 25.0
9 O! ^& N0 q) I7 \2 ?84.6 4.0 X 4.5 11.1
3 D5 K" D* l9 d& q5 A: p85.9 4.5 X 5.5 9.0
$ c" @% t$ A7 W+ nAv. 14.3
. n5 m) m: O  G8 _4
9 v( e4 ~7 x' @% t1 _8 f8
% l9 E' L- s' Y3 [% F9 p10* K, T( ]- E2 ~% o
12/ E; u* }; I3 l. t
17
3 {- n+ z7 Q) K3 \( h! h- }Topical testosterone: p; T" m- y# I, P5 o* y8 C
34.6 4.5 X 6.5 85
( D: |% \4 N; g4 L5 P6 @+ _" t38.8 6.0 X 8.5 70: M- c# @& q, U6 B* r1 C- c1 `" D
40.0 6.0 X 6.5 62.5+ O( [. I) s0 I4 ^( d( K
93.6 6.0 X 7.0 55.5
( O1 E+ C% t0 H; D) o/ x5 O95.0 6.5 X 7.0 27.2
6 S* n: n# F" w( R1 AAv. 60.0
" D- @2 C; v; |# y& ~6 c! k6 Javailable testosterone. Again, emphasis should be placed on5 {9 I8 ^! V1 j6 C# E
early therapy when lower levels of testosterone appear to
% ?5 L4 t) Q% p( t2 w/ \provide the best responses. The earlier therapy is instituted
# d! W1 H: _: d4 M* }the more likely there will be an excellent response with low
& S& A/ Q, V! e" k# C$ {serum levels. Response occurs throughout adolescence as
9 t8 E/ Z3 X& Q5 J+ Gnoted in nomograms of phallic growth. 7 The actual response
2 X" n" Y, M: k. G. Jto a given serum level of testosterone is much greater at birth  E+ K5 d! G3 J
and gradually decreases as boys reach puberty. This is most
0 x1 p5 @3 H( v  Alikely related to the conversion of testosterone to dihydrotes-0 r+ V/ L- ?3 ^+ c
tosterone and correlates well with the studies of testosterone
5 B0 \$ a. m; B1 nconversion in foreskin at various ages.
' {9 k; S; E5 C) S" n9 I. L1 s6 B) T; hThe question arises regarding early treatment as to whether* O! g5 {, q9 O5 ]
one might sacrifice ultimate potential growth as with acceler-5 A. S, \" _+ V, I0 t$ X4 \0 Y
ated bone growth. The situation appears quite the reverse
* H4 j! \8 m; }6 W& t. o. }with phallic response. If the early growth period is not used
- H$ `/ v7 z# \1 Bwhen 5a reductase activity is greatest then potential growth3 i& q2 @9 u7 k# `
may be lost. We have not observed any regression of growth- A3 g8 P6 u/ ^# P
attained with topical or gonadotropin therapy. It may well
- V( M' B# E  L4 D/ E6 p7 r$ mbe that some patients will show little or no response to any
7 ]4 G: }/ p( h% Dform of therapy. This would suggest a defect in the ability to
- S# a( k8 I+ S- C1 ^* E- hconvert testosterone to dihydrotestosterone and indicate that
. K8 g1 b9 C/ w( L$ Z( E) {$ l* |. K% pphallic and peripheral skin, and subcutaneous tissue should7 }$ X  ]2 n( J; v: y$ Y
be compared for 5a reductase activity.. u0 h& M: }% T' D- G7 x0 v
A, loop enlarges to measure penile girth in millimeters. B,1 }+ _3 X8 \! U2 f( v5 u  y$ U
example of penile girth computed easily and accurately.
1 {: p" Z! S7 B1 c$ T3 e4 nconversion of testosterone to dihydrotestosterone. It is in this4 a5 a% V3 t: x2 l
older group that others have noted high levels of serum* Y2 }( B% K4 P# y5 z
testosterone with topical application. It would also appear! A8 F" z* Z& `; S' R# D
that phallic response during puberty is related directly to the( V! ^& d. T) |! P: y' d
serum testosterone level. There also is other evidence of local. r/ J0 m" @9 j( {, a
response to testosterone with hair growth and with spermato-6 A! `- p$ m  e2 s" {; }
genesis. 5• 6% R  w" J( ^7 [9 t* U2 q% S, Q; H  E
Administration of larger doses of gonadotropin or systemic6 n8 z; K2 n8 w% k/ O' \
testosterone, as well as topical applications that produce
8 j$ \8 P3 n) J8 u* mhigher levels of serum testosterone (150 to 900 ng./dl.), will& n, U; U- O# ]+ V5 k, |: e6 i
also produce phallic growth but risks accelerated skeletal
+ W  q, A4 ?" G6 K0 xmaturation even after stopping treatment. It would appear
; E8 Q1 |) \) G% {, Y3 n5 L, k  mthat this may be avoided by topical applications of testosterone: ~; |" a& B4 \6 V) `  |
and monitoring of serum testosterone. Even with this control, Q+ I; @+ ~. D. T
the duration of our therapy did not exceed 3 weeks at any
8 L1 A, n  N8 s5 G: s# wtime. It is apparent that the prepuberal male subject may
$ b* P8 i2 X4 _! Vsuffer accelerated bone growth with testosterone levels near% O" v2 t$ X) H8 C. [0 f
200 ng./dl. When skeletal maturation is complete the level of5 Y9 [' v7 Y7 n* A  p0 }
serum testosterone can be maintained in the 700 to 1,300 ng./
  u- p0 |2 M: F$ C/ P1 i6 x* p& c1 ~/ pdl. range to stimulate phallic growth and secondary sexual
" e2 f$ w2 f8 a' R1 [9 o$ gchanges. Therefore, after skeletal maturation parenteral tes-
; t% F" y! a+ p  t3 Utosterone may be used to advantage. Before skeletal matura-/ v  S, V9 u' i. S6 C
tion care must be taken to avoid maintaining levels of serum4 v" W* F0 K8 t
testosterone more than 100 ng./dl. Low-dose gonadotropin
6 G& _$ K4 E& R# udepends upon intrinsic testicular activity and may require
; C3 k0 _( `& k6 Iprolonged administration for any response.+ f; b& U/ K) S7 b) N
Alternately, topical testosterone does not depend upon tes-
1 A" ^% Y  }" @( \* U9 ?/ ?ticular function and may provide a more constant level of
6 x9 S% H' A! s  \6 N$ mREFERENCES
2 ~% Z' r" N8 t) G1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
! R, D$ n: P% J9 z; d3 V1 {3 vR.: The local application of testosterone cream to the prepub-; k/ ~% u7 h8 k8 y4 R, ^
ertal phallus. J. Urol., 105: 905, 1971.
8 v( M8 f1 v" q) M9 X) W2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% J! k- L4 N9 e5 D. l' `1 _treatment for micropenis during early childhood. J. Pediat.,
2 |$ Y7 ^5 H  f. t! X# Y83: 247, 1973.$ |  @. @1 y" z: ?/ D
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 |0 O' A" w1 `2 b/ d# E  w0 none therapy for penile growth. Urology, 6: 708, 1975.2 T  H" D" J. K( Q5 b1 V
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ f- W/ O- U: A4 d4 W1 M% r. o
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by! i6 e1 V6 F9 j; x& O$ W
skin slices of man. J. Clin. Invest., 48: 371, 1969., }* ~; F# K# P, g
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
  h, g5 |, s8 M# T) N5 t- R, Zby topical application of androgens. J.A.M.A., 191: 521, 1965.( P3 k! q4 N9 l
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local3 |( i! F1 b+ Z5 d4 A" u# R
androgenic effect of interstitial cell tumor of the testis. J.
8 g3 l9 ?9 ]" k1 o" m; f$ t4 lUrol., 104: 774, 1970.
# L; I8 C$ T2 `/ Q, l7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-. B, g0 P% Q" D! F
tion in the male genitalia from birth to maturity. J. Urol., 48:
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