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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 n% ?, k7 \1 L: h. {8 E* y0 eGONADOTROPIN" t: B- d( ~) s! F% \7 s5 m
RICHARD C. KLUGO* AND JOSEPH C. CERNY
5 R* f/ b# b7 B7 S% J# B3 sFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# v  B# p: Z8 ?+ \$ f7 e; a. GABSTRACT
$ J9 l# y! N5 L3 b$ R+ zFive patients were treated with gonadotropin and topical testosterone for micropenis associated
% L  J7 F4 Q! Y( {% C4 a6 [$ awith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
2 a% t  i- D$ wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone6 m& C! W, ]1 o: d; A
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 V( m+ P. Y4 Z" b- [. xfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ ?- i5 k+ [  A5 Wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
8 J' {" d3 R5 F8 M3 `increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# j+ ?1 |% |+ F9 N+ h- F1 ~8 Doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This) t, a0 U) v* Z+ A( _  `5 F, \: M
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile& i, ~/ p3 d! `& {* y: a7 u$ L, h
growth. The response appears to be greater in younger children, which is consistent with previ-9 B5 {/ o% {4 `' ~3 E! w' S* z0 ]
ously published studies of age-related 5 reductase activity.& F4 @. }( L5 ]% ]2 j/ P9 j
Children with microphallus regardless of its etiology will
- f( [! E2 m- W! Grequire augmentation or consideration for alteration of exter-% o+ ?" V( S6 Z, c+ h: M; ]1 }
nal genitalia. In many instances urethroplasty for hypo-
+ I0 `5 O$ U- T2 `" R! uspadias is easier with previous stimulation of phallic growth.
% @1 P' |5 v6 k. p# z. zThe use of testosterone administered parenterally or topically+ p% m) K, z4 e0 X% S4 r  L
has produced effective phallic growth. 1- 3 The mechanism of
8 u4 D' N0 D9 u* i% a" f8 |4 S* vresponse has been considered as local or systemic. With this& Q) s$ Y& y) U% X- ^9 s
in mind we studied 5 children with microphallus for response$ q- `/ v" c2 X2 g4 a( f7 k  w
to gonadotropin and to topical testosterone independently.
% R& J7 e" e1 u3 b) B+ AMATERIALS AND METHODS
# {5 U/ ]6 `- k) jFive 46 XY male subjects between 3 and 17 years old were$ Z* h) @, D% L- ^: N6 |
evaluated for serum testosterone levels and hypothalamic
: U5 ~4 [8 e7 hfunction. Of these 5 boys 2 were considered to have Kallmann's/ x- I5 @, P3 a; t% |3 ]
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
% [4 F0 p1 _; s% elamic deficiency. After evaluation of response to luteinizing
% s) V0 W. l0 u4 x' V" Ahormone-releasing hormone these patients were treated with$ X1 m# m3 p. q8 `7 K- z, b: h
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
3 c; D& Y! O5 h6 Y# j' _after completion of gonadotropin therapy 10 per cent topical5 S/ x* R5 r9 r3 O
testosterone was applied to the phallus twice daily for 3 weeks.+ a# W/ t3 O3 r, m& ^! b/ r
Serum testosterone, luteinizing hormone and follicle-stimulat-# p' Z2 K8 f/ P( C# Q/ j0 d/ ]8 r
ing hormone were monitored before, during and after comple-& ?5 o- i  i' O* Q
tion of each phase of therapy. Penile stretch length was
. K% z, v) r- R! ~obtained by measuring from the symphysis pubis to the tip of
3 j- ]" K- a6 {3 {0 Uthe glans. Penile circumferential (girth) measurements were
) H' H" U, @+ A) jobtained using an orthopedic digital measuring device (see* I  K( u/ u" k" s& w- }1 \
figure).
/ d. O- }4 m0 C. y9 q; B$ Q7 PRESULTS
5 m- ~+ V$ V& |! l1 BSerum testosterone increased moderately to levels between
6 l* [- p3 A0 b" j- P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 ?8 @; w8 d1 E" m; Uterone levels with topical testosterone remained near pre-; G5 x% z% e" g7 O+ Z4 n* C
treatment levels (35 ng./dl.) or were elevated to similar levels! H3 q( u3 u+ c4 y3 f) R. g3 |
developed after gonadotropin therapy (96 ng./dl.). Higher
# f9 p8 i' ]+ a% lserum levels were noted in older patients (12 and 17 years old),: V5 l  u- s- o/ V9 D
while lower levels persisted in younger patients (4, 8, and 10
& @2 q2 g5 Z& W9 x. e# Z* ayears old) (see table). Despite absence of profound alterations
( Q) y2 D2 \; @) f- Pof serum testosterone the topical therapy provided a greater$ ^7 C* p! f# w) d% m
Accepted for publication July 1, 1977. ·
, ^/ H6 H1 b( {7 k% y9 mRead at annual meeting of American Urological Association,) K) U/ q9 b- Q7 Y3 t
Chicago, Illinois, April 24-28, 1977.
  z) @& R' X) Y9 c% {5 F* Requests for reprints: Division of Urology, Henry Ford Hospital,
- P  K7 s- q* r9 p. x  O2799 W. Grand Blvd., Detroit, Michigan 48202.- W* G* g8 B9 y1 I
improvement in phallic growth compared to gonadotropin.
4 W/ l( D# D# T" ~. Y2 I/ ~Average phallic growth with gonadotropin was 14.3 per cent
+ W& T3 F; e1 R. R! d2 vincrease in length and 5.0 per cent increase of girth. Topical5 I6 G- o: E6 R$ `0 t( l
testosterone produced a 60.0 per cent increase of phallic length
8 P) o5 r) H2 {) j& N9 Jand 52.9 per cent increase of girth (circumference). The! Y& K+ t9 Y. J
response to topical testosterone was greatest in children be-
# g* N8 y* l+ Ctween 4 and 8 years old, with a gradual decrease to age 17
5 t% a- l0 Z" C' Xyears (see table).- N2 u, ]2 O' ^  r
DISCUSSION' f  n/ j9 u" l+ n& Q8 z6 G
Topical testosterone has been used effectively by other
4 q$ d- H, }  N. K# Yclinicians but its mode of action remains controversial. Im-  I$ ?/ a) u: Q2 v0 O; h, H/ ^
mergut and associates reported an excellent growth response2 f1 N4 l/ J* O* l1 C2 L- O
to topical testosterone with low levels of serum testosterone,  t% A- U7 N0 y
suggesting a local effect.1 Others have obtained growth re-
& r2 C$ O% F  D6 _$ C; i  Lsponse with high. levels of serum testosterone after topical5 r% F1 N  h* c3 h- I( H. C# ?6 x
administration, suggesting a systemic response. 3 The use of# F8 X8 t$ P$ D) P8 n
gonadotropin to obtain levels of serum testosterone compara-
( A" i2 m6 i) k6 }* j" H- F+ ?ble to levels obtained with topical testosterone would seem to- u$ n' }' j4 G& O  y! w1 ^2 q% Z. T7 _
provide a means to compare the relative effectiveness of
. I  |# W8 v4 R; }topical testosterone to systemic testosterone effect. It cer-0 @- q% F3 n/ Q/ R
tainly has been established that gonadotropin as well as par-' c- t: m8 ^. t4 c7 C4 b1 B
enteral testosterone administration will produce genital
& a6 h& V5 m$ ^( E* Pgrowth. Our report shows that the growth of the phallus was
1 z5 ~6 L, p4 Z4 A1 {3 b* E$ ^significantly greater with topical applications than with go-
* x7 f1 T, S" W" F& O: Y% `nadotropin, particularly in children less than 10 years old., y, i; f8 v* K
The levels of serum testosterone remained similar or lower
1 j: I8 a& V' l; j* C0 ]( r' Wthan with gonadotropin during therapy, suggesting that topi-2 L/ K7 n8 ~7 `% R4 ^8 C0 t9 O* m8 c% I
cal application produces genital growth by its local effect as
* R- c# ~' a1 owell as its systemic effect.  G! w9 Q4 B# ?4 }! |7 d
Review of our patients and their growth response related to9 `6 D( A& C$ j8 m
age shows a greater growth response at an earlier age. This is# F9 ^8 M6 V7 j: l' V8 N
consistent with the findings of Wilson and Walker, who
) c0 |: f; Z( a5 O5 [; z2 X( W( wreported an increased conversion of testosterone to dihydrotes-
  v, s7 K+ }& e: @$ t' Utosterone in the foreskin of neonates and infants.4 This activ-' k, `- u' L3 Q# S$ v) H9 {# z
ity gradually decreases with age until puberty when it ap-
- z; J  @) k; i( @; t7 T- Fproaches the same level of activity as peripheral skin. It may
7 E5 w( b, r/ q! l: k! A# |  lwell be that absorption of testosterone is less when applied at
+ K& {$ ~4 d+ z3 can earlier age as suggested by lower serum levels in children" m4 p# e; t+ y* }1 ^$ C
less than 10 years old. This fact may be explained by the
+ a! Q/ r/ I+ a3 I# J( Vgreater ability of phallic skin to convert testosterone to dihy-0 K& [$ i4 C3 l* i1 B8 ]
drotestosterone at this age. Conversely, serum levels in older
. {3 U7 {: t5 w) _patients were higher, possibly because of decreased local) T3 j$ R! x4 v/ R9 w. t: A! L
667' j2 p( ~& E; e; n4 h! C
668 KLUGO AND CERNY' T! ?% l7 w) \2 K" u2 `/ {; c, ]
Pt. Age0 A2 K% X& b0 \" ?% b
(yrs.)* v& L# b& g$ s# i
Serum Testosterone Phallus (cm.) Change Length( Z; R$ l5 S4 e" d9 J/ y, g
(ng./dl.) Girth x Length (%)
( ?) {& _3 Y1 @8 X2 |49 m( Z" _  [2 D6 L0 @
8
, v: `: f+ A2 a) L10
% u: E* x& E/ g& u+ }' d. M12: B- q# g6 W) o# O
17
8 B6 j0 l* J; G5 W, w. R0 J9 L4 j$ m0 VGonadotropin; ~/ x  S- _6 v, }" X) h9 s* m
71.6 2.0 X 3 16.6
8 w+ O# H6 _$ |/ u, k50.4 4.0 X 5.0 20.0& }" f+ q  l* |! z7 L. H) x
22.0 4.5 X 4.0 25.0' V* n/ V" C$ i+ w0 r& y! o
84.6 4.0 X 4.5 11.1
0 E! H4 U) Y* h85.9 4.5 X 5.5 9.0: d6 z0 L5 p. z+ E7 _( O6 m* g3 t( F
Av. 14.3
7 Q) A0 x4 z. L' ~4
! U$ }7 F; ^, M% V' ~# V87 c; X0 z7 G1 r5 A' B% v
10
8 g. Y5 I' t! l7 p124 P' f$ E' n1 W0 I9 O* V9 P1 \
17- s* e. X8 k( V- y
Topical testosterone2 ^0 f. J) ~" X5 o4 ~* I
34.6 4.5 X 6.5 85; L+ {6 s" B. i6 B
38.8 6.0 X 8.5 70
5 g' P3 k" J  o/ ?+ g' B, d$ |0 R9 ?40.0 6.0 X 6.5 62.5
  t% {' A, w0 a9 o6 Y93.6 6.0 X 7.0 55.51 `3 ~8 p8 |8 V# l5 O# K
95.0 6.5 X 7.0 27.2
# M. i0 i/ S' W1 o0 _( `Av. 60.0( J% A& R0 k" ]0 v- i+ K
available testosterone. Again, emphasis should be placed on: u3 Y; Y- D6 G* W* Y. D
early therapy when lower levels of testosterone appear to
5 D, [3 G; t, Y- ?- H& Yprovide the best responses. The earlier therapy is instituted9 G- r4 l% x. {+ h/ \' C! s
the more likely there will be an excellent response with low
, L* t8 n% S# p% q, i* M# q: tserum levels. Response occurs throughout adolescence as) o9 n" v8 x/ }$ R& B8 W' K6 K
noted in nomograms of phallic growth. 7 The actual response
: T# p3 u3 W9 N, Dto a given serum level of testosterone is much greater at birth
8 q" N7 O$ a3 J% D- j6 z, @; Oand gradually decreases as boys reach puberty. This is most
! |% U! v6 [" ~likely related to the conversion of testosterone to dihydrotes-$ t# y# W$ r1 x) G
tosterone and correlates well with the studies of testosterone
  \' N" p) B9 h$ I, oconversion in foreskin at various ages.
; o- h- z5 a6 S. j' s& FThe question arises regarding early treatment as to whether( ?6 ]& E5 \8 q3 }$ I
one might sacrifice ultimate potential growth as with acceler-
9 ~9 d4 \: Q" R" Tated bone growth. The situation appears quite the reverse" n* f& e* f( a' j
with phallic response. If the early growth period is not used1 }, N) T, _, Z: w* G
when 5a reductase activity is greatest then potential growth
3 M* O) Y) i0 M4 a& M, Ymay be lost. We have not observed any regression of growth2 |% R5 A0 i9 r. N( O" U  Z
attained with topical or gonadotropin therapy. It may well# ^9 K& q, z& t
be that some patients will show little or no response to any2 m8 D7 b: R! }4 Y" B0 m$ A7 n
form of therapy. This would suggest a defect in the ability to
! q/ s# J" I' V# n7 J& q1 B, xconvert testosterone to dihydrotestosterone and indicate that2 D' x0 e4 W. u7 }( H6 }
phallic and peripheral skin, and subcutaneous tissue should. u% g  T/ W8 x, J
be compared for 5a reductase activity.
3 o5 v. e) K3 b6 d' CA, loop enlarges to measure penile girth in millimeters. B,, V% k. ~$ }0 b  |: a- V" R2 e  Y2 ]
example of penile girth computed easily and accurately.
6 U4 p) T1 \/ e, _conversion of testosterone to dihydrotestosterone. It is in this
3 J* n& D: ?8 kolder group that others have noted high levels of serum( x5 ?! Z0 {2 N- `) }3 }. r
testosterone with topical application. It would also appear3 ]& T9 x" `2 b: g) k, ~8 G
that phallic response during puberty is related directly to the5 ?9 c) @+ v5 P- C0 B+ }
serum testosterone level. There also is other evidence of local
; ]6 J1 j: _6 f" r, r- fresponse to testosterone with hair growth and with spermato-' H. _; L7 g1 C
genesis. 5• 6
. [% ]& D' s" _6 H( y+ X4 hAdministration of larger doses of gonadotropin or systemic
" [  T# F1 T+ z2 B$ j2 O$ h5 Wtestosterone, as well as topical applications that produce: p: h0 d# V/ W6 m  M' ^" q! ^
higher levels of serum testosterone (150 to 900 ng./dl.), will" B+ E4 _$ ^' x8 V7 g7 a
also produce phallic growth but risks accelerated skeletal
- t0 K2 w( [2 S. g  v# |maturation even after stopping treatment. It would appear
. I# m! ^# [+ Q! P  ithat this may be avoided by topical applications of testosterone% e0 U) o; I2 a2 Q3 o, w
and monitoring of serum testosterone. Even with this control2 w, G3 U5 U1 |; S
the duration of our therapy did not exceed 3 weeks at any
# v9 C* ~+ E9 W" M" k2 Ktime. It is apparent that the prepuberal male subject may! H. j. X9 H" q* ^. C; N) s
suffer accelerated bone growth with testosterone levels near! p& Z9 Y: r! s! J4 g+ E
200 ng./dl. When skeletal maturation is complete the level of
( @& n3 F# B, J" f5 E1 ~serum testosterone can be maintained in the 700 to 1,300 ng./6 N# K+ P  u- f
dl. range to stimulate phallic growth and secondary sexual% ?" ^/ b+ ?  }2 B
changes. Therefore, after skeletal maturation parenteral tes-( I7 o  l7 j; e* Q  ]4 A/ D3 d
tosterone may be used to advantage. Before skeletal matura-
( y- }* Q4 i+ _! ^, Ytion care must be taken to avoid maintaining levels of serum
# A' v3 b. O2 I) _testosterone more than 100 ng./dl. Low-dose gonadotropin7 {  l3 M, {) ?* s! O8 L# O
depends upon intrinsic testicular activity and may require
$ z( u' U" {2 H: x2 _: Uprolonged administration for any response.
1 M8 k# ~! E( S# @* ~. {Alternately, topical testosterone does not depend upon tes-$ J1 {0 r7 Y, m* ^% G
ticular function and may provide a more constant level of
/ t8 C9 R: x4 A; A4 [' AREFERENCES2 n' m& W  _, t5 |: x
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 p, k+ X% Z8 M3 M( ^' ]( |R.: The local application of testosterone cream to the prepub-
$ ^" r7 _3 B% F8 aertal phallus. J. Urol., 105: 905, 1971.4 G$ a' |" [. n. M( g4 J, ^
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
0 A. h- ?% R$ _. p  L2 ]treatment for micropenis during early childhood. J. Pediat.,
/ b: l3 D2 a# u; `7 {83: 247, 1973.3 z, \3 H: O1 E" f$ P
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 p" l: [3 T1 I% Tone therapy for penile growth. Urology, 6: 708, 1975.! x& T4 n8 A& b( d! b0 x
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
0 F( n0 n6 {* q  _9 S6 cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ j9 u& f% U9 L$ A
skin slices of man. J. Clin. Invest., 48: 371, 1969.
* I$ m# p/ \" _1 }0 W, S5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth- v7 }$ U; {  i: @
by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ i" M; `/ i" u8 F6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ o) ?' {% {2 M6 O/ H: x; Tandrogenic effect of interstitial cell tumor of the testis. J.
/ z1 h! ]4 i& ?3 a0 yUrol., 104: 774, 1970.9 `" j8 l0 c1 p5 W) o4 h
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
, I* E  Y5 S! c- a( N$ x% l4 Qtion in the male genitalia from birth to maturity. J. Urol., 48:
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