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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" p" w7 n, q: {7 @" L% W9 _  q- m0 kGONADOTROPIN
9 P9 `- M6 {0 n/ L: GRICHARD C. KLUGO* AND JOSEPH C. CERNY# N% w$ {  t5 Y$ m
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& ^7 A$ [& x/ P7 X7 X% u, C
ABSTRACT8 W' E7 t! R9 W- T  F* f
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( k. i  G/ Y7 m! P$ {with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-; f- h4 E: G8 @4 |( N7 `7 i
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone, a1 Q, n9 N+ a) {: l7 u. [) g: u
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent% e7 W" Z- z$ B0 z1 C3 @
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 l; l$ r. e/ s8 G% O: O' ~5 o3 D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average* i' J6 ^; z& e0 {
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 U, C) [: V$ n$ s
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( u9 ], V# f* k& q
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
& ]4 H4 \. x: k  K& tgrowth. The response appears to be greater in younger children, which is consistent with previ-
9 R, i: S) \/ u- H( Bously published studies of age-related 5 reductase activity.
* g" h  Z/ D" \$ J* dChildren with microphallus regardless of its etiology will5 }3 o$ ?$ b6 c$ o
require augmentation or consideration for alteration of exter-; q7 n* `9 p) c6 t
nal genitalia. In many instances urethroplasty for hypo-( ^5 y+ [/ h0 B7 d$ [
spadias is easier with previous stimulation of phallic growth.
, ^' l! ^. X* [8 Q( Y8 PThe use of testosterone administered parenterally or topically
( h! t: S# b1 p5 N" M( y6 bhas produced effective phallic growth. 1- 3 The mechanism of1 }4 s: `2 R( W" A1 V! `0 }
response has been considered as local or systemic. With this+ ?3 R* j7 Q' Y% Z4 G9 E
in mind we studied 5 children with microphallus for response$ }# {- T& R& b  W
to gonadotropin and to topical testosterone independently.6 o5 ?+ e4 E3 }' r
MATERIALS AND METHODS
* r: X  v* y. UFive 46 XY male subjects between 3 and 17 years old were: p5 P. r6 h- ~+ D  ~
evaluated for serum testosterone levels and hypothalamic  L" Q6 ^, [% o# L
function. Of these 5 boys 2 were considered to have Kallmann's
. R, g% _( Z) [4 n9 Z  {* w  s* ^+ msyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! _' I3 ?% f6 e1 ^8 \, o* P% l, Klamic deficiency. After evaluation of response to luteinizing
, R8 X% g, o" k* thormone-releasing hormone these patients were treated with
0 b: ]/ m0 S- P' l1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* h4 e/ w# j- O6 r6 Zafter completion of gonadotropin therapy 10 per cent topical, k/ I& |/ y. s( S5 n9 h
testosterone was applied to the phallus twice daily for 3 weeks.* h) ]0 _: D/ A
Serum testosterone, luteinizing hormone and follicle-stimulat-) V( P0 r" S# R7 T( q2 n2 {5 D
ing hormone were monitored before, during and after comple-! }9 s1 n9 {2 e' o, V/ [2 B
tion of each phase of therapy. Penile stretch length was7 X2 Z# P4 J! ~  k! ]
obtained by measuring from the symphysis pubis to the tip of  ^' {+ u; ~1 _( T& k/ J
the glans. Penile circumferential (girth) measurements were
( i& q; V) W0 M$ G( ?) y! Z! Hobtained using an orthopedic digital measuring device (see3 w0 ?7 X8 T$ U" v7 |
figure).  Q2 y8 J& J+ H" w- [
RESULTS
) J$ e) r8 F7 a4 ISerum testosterone increased moderately to levels between1 c3 J" R% s2 O  P1 x! y$ O
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
9 m9 O  D- [9 @+ M$ i( D; eterone levels with topical testosterone remained near pre-
) g# d8 N  Y4 W: d) c& ztreatment levels (35 ng./dl.) or were elevated to similar levels, y% w' i9 F6 A4 o8 i4 j
developed after gonadotropin therapy (96 ng./dl.). Higher
9 c* x/ _$ H. _serum levels were noted in older patients (12 and 17 years old),9 J% A1 Y  ~. C
while lower levels persisted in younger patients (4, 8, and 10
7 M7 C+ _/ c8 l9 r" Ryears old) (see table). Despite absence of profound alterations
" [0 J& f' T, G& e4 C: a; qof serum testosterone the topical therapy provided a greater
3 Z  D1 x$ V5 ZAccepted for publication July 1, 1977. ·* V( G9 d4 u+ x0 P" g5 ^8 C
Read at annual meeting of American Urological Association,
* L8 ?5 p; o9 r* Z& fChicago, Illinois, April 24-28, 1977.
- x; M- p( G, i- W1 B* Requests for reprints: Division of Urology, Henry Ford Hospital,( K- o; \3 e4 u; \2 T- o' c6 c* d* u
2799 W. Grand Blvd., Detroit, Michigan 48202.& X3 ~3 Z8 V' u* |6 h" `
improvement in phallic growth compared to gonadotropin.
; ?; a: M- p  S) j% G6 fAverage phallic growth with gonadotropin was 14.3 per cent' E8 O2 ?/ N" l
increase in length and 5.0 per cent increase of girth. Topical
# Q& P* Z. O: k) `" Ftestosterone produced a 60.0 per cent increase of phallic length0 X6 _6 k4 x1 N/ s
and 52.9 per cent increase of girth (circumference). The; ^* t  p* t" h' F5 `
response to topical testosterone was greatest in children be-- y  ^8 y3 x+ Y7 w. t+ T; F
tween 4 and 8 years old, with a gradual decrease to age 17
1 w0 y0 V% a. e# E) [/ Byears (see table).
% }9 J( r' k4 }  R2 HDISCUSSION! S5 L. Z, L8 ]) G5 B2 E7 a6 J+ Y. j
Topical testosterone has been used effectively by other
. z' N4 U: ]8 h! z. n+ U( }clinicians but its mode of action remains controversial. Im-
% s. S- D9 w7 k3 s- r! Bmergut and associates reported an excellent growth response+ c, @7 g5 Z# ?, Q) |4 }$ g
to topical testosterone with low levels of serum testosterone,; ~& ?  h* Y( |0 e8 \
suggesting a local effect.1 Others have obtained growth re-1 F6 R! j* b# G3 |: Q
sponse with high. levels of serum testosterone after topical
% ~' K/ Z% `! P4 nadministration, suggesting a systemic response. 3 The use of
. a- j9 O: }% ^  n) n3 ggonadotropin to obtain levels of serum testosterone compara-
) h: @& A6 ]' Q3 E4 O- }4 ^. ^: Gble to levels obtained with topical testosterone would seem to* t- r, z! f0 X* d4 p
provide a means to compare the relative effectiveness of
+ S8 N8 b( R- L' W2 V1 A, ~) Htopical testosterone to systemic testosterone effect. It cer-
+ P- w2 ?, k( v4 mtainly has been established that gonadotropin as well as par-8 {6 \. o% ~8 ~1 m# b2 o
enteral testosterone administration will produce genital  [- d1 S+ S1 q. l
growth. Our report shows that the growth of the phallus was
$ t$ n; Q2 z; u8 rsignificantly greater with topical applications than with go-" K; r7 {% n, ?0 J
nadotropin, particularly in children less than 10 years old.8 c0 [# _) D  I1 ?
The levels of serum testosterone remained similar or lower8 z# H( m% `+ j* h8 I# k
than with gonadotropin during therapy, suggesting that topi-% H* x! H8 b& M
cal application produces genital growth by its local effect as1 c1 @( c, L) d7 I: `. i1 M# j
well as its systemic effect.0 V9 V0 C2 }& [+ ~& E8 o) w! x
Review of our patients and their growth response related to
7 c8 \4 i0 t9 X) z) Z5 Tage shows a greater growth response at an earlier age. This is
: G( K0 ?2 [$ I  Econsistent with the findings of Wilson and Walker, who
  w. y1 Z6 e1 z$ nreported an increased conversion of testosterone to dihydrotes-
4 l" A5 d+ X% Q" O! l; btosterone in the foreskin of neonates and infants.4 This activ-. z- @  k1 }' K& }5 H1 C* n. n
ity gradually decreases with age until puberty when it ap-
: L# z! a- u& s4 X6 n7 \+ Iproaches the same level of activity as peripheral skin. It may
: w. E& j$ |1 k. I& k3 Iwell be that absorption of testosterone is less when applied at  D' Q5 \' m# ^  \
an earlier age as suggested by lower serum levels in children2 Q( ~* S: N8 q& S% c3 S
less than 10 years old. This fact may be explained by the# ]0 ~* B8 t8 L' T$ f+ l7 X
greater ability of phallic skin to convert testosterone to dihy-9 j/ a% u# r1 S& O9 n
drotestosterone at this age. Conversely, serum levels in older
0 q) v3 I( k. T' p. [patients were higher, possibly because of decreased local
) L9 D2 P( P' m& a8 Y667
: E" f- }  N  Q  K668 KLUGO AND CERNY
4 h" _: H  }2 U2 J3 S1 Z2 [Pt. Age
/ g3 S6 h- |  c3 ^& r2 s4 u(yrs.)  M& _8 g8 M' ~" _8 E; p
Serum Testosterone Phallus (cm.) Change Length
5 ?2 g0 G) k5 w; C+ ]& p(ng./dl.) Girth x Length (%)6 @9 Y$ l/ r. f% {5 T7 V0 K
4( G( Q) y9 \1 z# C2 N+ @( g0 I
8
* a* ~$ G. p9 S  a+ q3 B3 l2 o10. x' [0 F$ l, s7 S7 M$ h
12
  |; E9 M8 B+ {: \8 R* L17
+ X: j; M' ~# XGonadotropin$ j6 g4 V% Q: w) P
71.6 2.0 X 3 16.6
7 [/ r% z9 r  i' R4 q' U50.4 4.0 X 5.0 20.09 @0 x3 \6 L5 v( R+ M, g
22.0 4.5 X 4.0 25.0+ ?" E: I/ `( j2 b
84.6 4.0 X 4.5 11.18 j9 `: v  X# W- X8 b+ R$ N
85.9 4.5 X 5.5 9.0$ m& @0 S# D7 P8 f4 X' X7 M' A
Av. 14.3) R0 _1 T' [2 f* }' g* h4 A
44 }0 R  X9 y  z; d
8
  f1 V0 o( W. b& |% f10
) f' [4 f2 l; G# T8 }* e) K0 Z1 e' w124 s4 A2 x" }2 u# d$ t: }4 E; o+ Q8 u" m! t
17+ V7 y. `3 ~8 ~( U3 ~6 H  P
Topical testosterone( U0 Y5 V9 J" Y/ o! \" R
34.6 4.5 X 6.5 85. U  \5 t+ z" G. \
38.8 6.0 X 8.5 70
0 G: M. D, M5 Y40.0 6.0 X 6.5 62.5
0 X" o+ ^: A- a% i( K93.6 6.0 X 7.0 55.5
& T4 J2 o0 g7 s9 M- v95.0 6.5 X 7.0 27.2" E* A/ j2 B% s% g+ u; j
Av. 60.0- @4 {% D2 C2 d/ R( U
available testosterone. Again, emphasis should be placed on. M" P: i. W3 O% B
early therapy when lower levels of testosterone appear to& _0 `5 K9 v4 C/ T( B5 A
provide the best responses. The earlier therapy is instituted
8 R9 y3 ^6 T. d9 R0 \7 gthe more likely there will be an excellent response with low5 x3 Z+ K7 n" e' q) i6 s" x
serum levels. Response occurs throughout adolescence as
' ^0 x6 h* c4 {noted in nomograms of phallic growth. 7 The actual response
% i) Y" J) ?, x, o0 t+ y- Mto a given serum level of testosterone is much greater at birth4 A( s# i- I7 x/ o
and gradually decreases as boys reach puberty. This is most, K; ?0 G; r6 A0 I1 h/ n8 I  J
likely related to the conversion of testosterone to dihydrotes-
: M* {3 [- d8 E/ k& i  Itosterone and correlates well with the studies of testosterone# L/ H4 z' D! f) s! a, M" F7 ?7 J
conversion in foreskin at various ages.& P9 M. F  R. s8 l; v
The question arises regarding early treatment as to whether
3 q; C! d. a' `one might sacrifice ultimate potential growth as with acceler-7 m$ |& t+ R: S
ated bone growth. The situation appears quite the reverse3 q: r! p7 g3 u6 R+ Z7 n( k
with phallic response. If the early growth period is not used( }3 K1 {. A% |) Y5 T! F: C
when 5a reductase activity is greatest then potential growth
  @; i8 X0 g0 L$ u% Y) N; V6 W" `( \  }may be lost. We have not observed any regression of growth. C5 B2 B0 {6 n
attained with topical or gonadotropin therapy. It may well4 t! M/ F( D9 l$ u
be that some patients will show little or no response to any
- }: U6 g* M6 e% Zform of therapy. This would suggest a defect in the ability to
, N2 o: g& H* F6 _9 s3 oconvert testosterone to dihydrotestosterone and indicate that
9 F7 i9 A7 Y+ v4 S2 U* Z" ^phallic and peripheral skin, and subcutaneous tissue should$ c. H8 {& Y1 Y4 C
be compared for 5a reductase activity.
% i+ Q1 N& M( M/ XA, loop enlarges to measure penile girth in millimeters. B,
1 m# a, j! T% h) g9 f. W7 u7 {example of penile girth computed easily and accurately.
9 p+ R: w3 P# x, [conversion of testosterone to dihydrotestosterone. It is in this- q; K% c) X0 A
older group that others have noted high levels of serum
* h% N! \0 w. E- otestosterone with topical application. It would also appear
7 d* F: w) F0 ^) {, E/ K! Othat phallic response during puberty is related directly to the# T! z' S& m4 @2 Q/ o+ v$ j4 Z
serum testosterone level. There also is other evidence of local- n- W, @2 M) y" l/ G+ o
response to testosterone with hair growth and with spermato-5 U7 P. x7 E1 Z, Z$ |0 }1 }; _
genesis. 5• 6' x# B) |- B2 I
Administration of larger doses of gonadotropin or systemic* j/ d/ W5 _# H/ u. e0 r( f( F
testosterone, as well as topical applications that produce) G2 R) ?, U! |" c( b( P
higher levels of serum testosterone (150 to 900 ng./dl.), will
+ O% M" f1 p2 `also produce phallic growth but risks accelerated skeletal
+ \* }) L1 N! I+ H: v' `$ R  b- ematuration even after stopping treatment. It would appear
4 }! H, X2 e9 C2 `that this may be avoided by topical applications of testosterone
0 w9 Y" W6 _0 _6 band monitoring of serum testosterone. Even with this control7 C9 `" `6 M2 q  {
the duration of our therapy did not exceed 3 weeks at any- T8 t* t' m& r/ N
time. It is apparent that the prepuberal male subject may2 l, v4 h! e) T: ?
suffer accelerated bone growth with testosterone levels near8 \# h8 l  A8 j- J* m6 a  X
200 ng./dl. When skeletal maturation is complete the level of
* w# G  p( b' s/ ~  f$ tserum testosterone can be maintained in the 700 to 1,300 ng./9 Y! U# @1 S3 r& |
dl. range to stimulate phallic growth and secondary sexual
2 n( ^+ R0 E+ Y" rchanges. Therefore, after skeletal maturation parenteral tes-8 Y( E" O/ g7 K. g6 V* ^% k! ?1 E) ~$ L7 c
tosterone may be used to advantage. Before skeletal matura-& O3 J; i$ L8 A3 }! {
tion care must be taken to avoid maintaining levels of serum
, U' t, r) }# ~9 Q0 y8 Xtestosterone more than 100 ng./dl. Low-dose gonadotropin
+ L# z& j+ c0 P8 Q- ^1 `' |depends upon intrinsic testicular activity and may require# `' |& G$ I( g% R% L
prolonged administration for any response.# l2 b0 O, W  g
Alternately, topical testosterone does not depend upon tes-: z8 d; k' d) k3 ^' s* c) i8 G+ o; v+ a
ticular function and may provide a more constant level of
0 z! }* ?% A" t. ]; H4 F, eREFERENCES
) m' h6 O7 Q. j1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,, @. ], Y; ?  z( B# r  u$ u
R.: The local application of testosterone cream to the prepub-
2 d5 U. k7 I  P/ t, i/ xertal phallus. J. Urol., 105: 905, 1971.
$ H% Y4 {, n9 k4 D2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ Z1 V" I3 P  H! ~, J
treatment for micropenis during early childhood. J. Pediat.,' h* a7 T6 F8 }) j# H  J# T1 J
83: 247, 1973.8 S, n& G+ [0 _/ R  t: f" T( E
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
: W9 |& P2 v- K. o  P: yone therapy for penile growth. Urology, 6: 708, 1975.
8 H/ x7 |. u0 y% y1 ?4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
% i/ s0 F3 M) Q6 p4 X2 Vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 Q0 L& c6 R2 r; Gskin slices of man. J. Clin. Invest., 48: 371, 1969.
+ {7 ]5 p0 g  _, t' ~5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 ~  \8 @  b/ ?% c% g, Q/ o; U
by topical application of androgens. J.A.M.A., 191: 521, 1965.
, E+ J) \( ^# S6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 u( u9 r1 w+ s) ]6 wandrogenic effect of interstitial cell tumor of the testis. J.
* y/ G4 [- P; k) iUrol., 104: 774, 1970.
- n) t' k% A  ^! R! e0 \  Y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
5 U: E- @' i) d9 Z9 Qtion in the male genitalia from birth to maturity. J. Urol., 48:
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