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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 b/ {% O! U9 o# c0 _( O* V, v( [7 |GONADOTROPIN
* T+ w/ ~5 L  E) _( gRICHARD C. KLUGO* AND JOSEPH C. CERNY
; ~! W: H3 E9 n" r% C# l9 vFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan: Y6 h! J) W; @4 I! N' p
ABSTRACT
3 X# |7 j/ ?3 S: j4 }# DFive patients were treated with gonadotropin and topical testosterone for micropenis associated
. R1 P$ I4 r2 nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. s+ u3 C9 C9 O0 S& ^6 j: Ftropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ H/ K! ~5 r0 i7 H0 o* L
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
) C" R$ @: R' @+ q' m  L$ vfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent7 q( T2 e1 j3 e: N1 t! B- A: [
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
  D1 G& o! x1 p3 I+ b2 aincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response' Y' X- j. A+ o8 t! o/ r* D
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This2 n! x  v* F( l9 D- I  E
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ @: T' y# A7 U5 o8 Vgrowth. The response appears to be greater in younger children, which is consistent with previ-% B- r. o+ m' w* h8 N4 `  ^; O
ously published studies of age-related 5 reductase activity.0 Y9 y- A+ F+ _# F$ g! P# X
Children with microphallus regardless of its etiology will
! i4 E# [* U1 W5 ]/ m  C( brequire augmentation or consideration for alteration of exter-5 r7 s. b7 f- }* c* |6 u
nal genitalia. In many instances urethroplasty for hypo-, L. o& L% ~9 @. ^, [3 u3 Z4 F" X' T
spadias is easier with previous stimulation of phallic growth.
/ W- \. s+ h+ Z) n, f4 p: q- TThe use of testosterone administered parenterally or topically
  {% L1 z" m9 H% Shas produced effective phallic growth. 1- 3 The mechanism of
3 A' L1 {1 ]7 j+ Gresponse has been considered as local or systemic. With this
5 I. I+ ?+ V- U9 x: |, }in mind we studied 5 children with microphallus for response. A' A( U0 _7 ^- ], W/ E* a
to gonadotropin and to topical testosterone independently.
3 S) N3 |0 `2 _9 g1 C( HMATERIALS AND METHODS
! M3 c: K" ]' z9 TFive 46 XY male subjects between 3 and 17 years old were
' ?0 B9 l* D) i2 Cevaluated for serum testosterone levels and hypothalamic7 o) |# |) r( U
function. Of these 5 boys 2 were considered to have Kallmann's
# @6 e/ V6 N; Ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" S- E  X4 V' q" V
lamic deficiency. After evaluation of response to luteinizing! R8 [3 E: e1 k$ U+ x
hormone-releasing hormone these patients were treated with
' q* O1 Q2 H) K- b' j6 b1 _1,000 units of gonadotropin weekly for 3 weeks. Six weeks
, }& p/ ]) q! d" w) |8 ^* y' }; Dafter completion of gonadotropin therapy 10 per cent topical
% L+ n* {$ c$ K0 Y/ ?& N/ Stestosterone was applied to the phallus twice daily for 3 weeks.( H% M1 c! K$ z- B% ], a" a
Serum testosterone, luteinizing hormone and follicle-stimulat-' G8 W: Y" y. T# A
ing hormone were monitored before, during and after comple-
: Q* M( ^* C7 m! J: p4 W' r: Xtion of each phase of therapy. Penile stretch length was2 l* ^# J, |/ I! q) h1 c' H3 A
obtained by measuring from the symphysis pubis to the tip of
1 g; o- T5 f2 l. w/ ]the glans. Penile circumferential (girth) measurements were
* t0 D2 x. e9 Kobtained using an orthopedic digital measuring device (see
% j; G' M; R( \" C+ Ffigure).
' a# p" I  u; l! d4 ?1 S# PRESULTS
6 b6 w7 ~% v! P( sSerum testosterone increased moderately to levels between
4 j- W1 E4 w) @. G. q50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* Q- f3 p( m- y  t! a
terone levels with topical testosterone remained near pre-3 ~1 n" L& [. k, |0 Z
treatment levels (35 ng./dl.) or were elevated to similar levels
- J6 V4 m8 v" }1 f1 }! a( t: v# bdeveloped after gonadotropin therapy (96 ng./dl.). Higher
& `$ U, u; k$ U$ |5 Kserum levels were noted in older patients (12 and 17 years old),
9 w. E2 o, p- K# l8 d+ @while lower levels persisted in younger patients (4, 8, and 10
: u' S5 }8 u7 Oyears old) (see table). Despite absence of profound alterations1 n$ `* b9 v) h4 H& y( f* S
of serum testosterone the topical therapy provided a greater
, G, D6 v1 c+ rAccepted for publication July 1, 1977. ·
9 U" m: {3 k7 X4 B$ o5 wRead at annual meeting of American Urological Association,5 N$ e6 d3 A( c: m4 y' m
Chicago, Illinois, April 24-28, 1977.7 }  X& [) D6 h& T: ^" o
* Requests for reprints: Division of Urology, Henry Ford Hospital,0 k4 y/ D: J. r# W6 N
2799 W. Grand Blvd., Detroit, Michigan 48202.
* y/ ]0 e$ v& W& Z! j2 uimprovement in phallic growth compared to gonadotropin.7 t& _/ s5 o" {  q% o" T$ Q
Average phallic growth with gonadotropin was 14.3 per cent
& `2 h5 n' y8 k' s) [$ zincrease in length and 5.0 per cent increase of girth. Topical
: g( V! J2 l# @: B0 ktestosterone produced a 60.0 per cent increase of phallic length- U/ S' _0 H0 V6 h) y/ B
and 52.9 per cent increase of girth (circumference). The- Y* U" ~6 v$ v0 g9 u, o$ y9 V
response to topical testosterone was greatest in children be-
! M  d. F  l. C& o/ Qtween 4 and 8 years old, with a gradual decrease to age 17
  Y3 u4 ^" i, Z9 C! Byears (see table)./ k; e: I/ T3 O* Q7 P( Q; D9 U
DISCUSSION
4 o! ?# O3 x" t9 x' LTopical testosterone has been used effectively by other
( J0 `, a/ f9 [! I$ K& Hclinicians but its mode of action remains controversial. Im-
+ E; A* t3 @" A( bmergut and associates reported an excellent growth response& X2 W9 [2 _) T" z; O& z
to topical testosterone with low levels of serum testosterone,
9 U% Z+ W$ O$ d5 e3 v# asuggesting a local effect.1 Others have obtained growth re-
" w. m& A; Q9 v& isponse with high. levels of serum testosterone after topical
* W3 L2 ~% I# `  Y  F0 Oadministration, suggesting a systemic response. 3 The use of
1 O  T* d. d) rgonadotropin to obtain levels of serum testosterone compara-
( s7 C; o  C8 p6 q- cble to levels obtained with topical testosterone would seem to
/ E" k; I7 W( B; wprovide a means to compare the relative effectiveness of7 Z5 q) R' B4 t
topical testosterone to systemic testosterone effect. It cer-
7 S9 n/ c: f& a& ttainly has been established that gonadotropin as well as par-6 ~4 q7 y! f4 _$ X" n. |
enteral testosterone administration will produce genital
8 s5 D) F& ]: D/ ]5 Bgrowth. Our report shows that the growth of the phallus was
( Q/ @- Q+ d5 N# d3 K4 Z4 zsignificantly greater with topical applications than with go-
9 S/ ~6 D2 p+ `% W, W* b. Lnadotropin, particularly in children less than 10 years old.& g3 F/ H, k" ]. \7 L
The levels of serum testosterone remained similar or lower6 v* y7 N& c+ ^
than with gonadotropin during therapy, suggesting that topi-% B; N% v) V) Z2 T
cal application produces genital growth by its local effect as
/ G* T. _& f  L/ x6 a1 d  \well as its systemic effect.
& ~: K) I1 M% t) n3 GReview of our patients and their growth response related to
$ [3 ?& t$ `2 Y1 Nage shows a greater growth response at an earlier age. This is& Y9 V4 W) G9 J
consistent with the findings of Wilson and Walker, who
  S1 v- @. i; w0 ~$ ^6 oreported an increased conversion of testosterone to dihydrotes-
' ~. i. P$ E9 q. Htosterone in the foreskin of neonates and infants.4 This activ-
4 F9 ~5 g8 Y, h' v% w9 z* d1 C$ ?, eity gradually decreases with age until puberty when it ap-% P- I$ O1 S2 i5 u5 L7 b' Z
proaches the same level of activity as peripheral skin. It may
9 F+ ]5 p# F4 d' ~2 d  Pwell be that absorption of testosterone is less when applied at% A" ^6 d1 z3 R/ V2 `; f! h" j
an earlier age as suggested by lower serum levels in children) u1 t5 b0 ~+ G- {% X7 G" E
less than 10 years old. This fact may be explained by the
: u7 U# u0 }4 `greater ability of phallic skin to convert testosterone to dihy-7 \8 D, p, F* F" D7 J! @* q
drotestosterone at this age. Conversely, serum levels in older8 [8 r: c0 f) f1 d# Q4 z' ^5 J
patients were higher, possibly because of decreased local
! g; O- p, J" H  |3 t6679 \$ e: ^2 W7 X& ]3 s; T
668 KLUGO AND CERNY+ l% a8 F3 [& h# p" V
Pt. Age) M( M. t+ A3 A+ H1 R1 l/ M- _
(yrs.). N/ y9 O2 S' m; U
Serum Testosterone Phallus (cm.) Change Length
) j" E+ H4 c' f; y- ?' c& s$ A(ng./dl.) Girth x Length (%)
  {6 a6 ~8 ^7 w# r1 J4
9 T* F, |* \) ~; E& B8
# V$ b  f( \0 o- {8 \10
: T% {) A; h7 Q  A120 u4 W- r! P* j5 `7 i  e6 ?5 z
178 Y9 ~7 [4 V0 G6 f% r. O
Gonadotropin
1 V! B* \/ j. E4 m, C71.6 2.0 X 3 16.6# K, }0 a3 i  A- s7 [
50.4 4.0 X 5.0 20.0
# {: |7 ]0 M- B5 s! p22.0 4.5 X 4.0 25.0
& t& x5 S/ z3 k. {6 g2 V84.6 4.0 X 4.5 11.18 l% z: g# k$ Y4 p5 h9 R% ?  y* L: G
85.9 4.5 X 5.5 9.0  d1 ?- p/ f+ }* V3 D' u6 o
Av. 14.3; q0 C, N7 |/ h
4! l+ w# A/ c: ?! h
8+ A: k' B, B' ]
10
; X% N$ h8 L. N' x12# p5 k! v1 s0 _# _. n: b0 S
17
/ ~: G. X, j( A" d- ?" lTopical testosterone
+ B2 ~- u8 c, h1 a8 F; M2 v1 ~' I34.6 4.5 X 6.5 854 R. Y. `/ l9 g8 N% S
38.8 6.0 X 8.5 701 S( A0 Z2 z/ N
40.0 6.0 X 6.5 62.54 G! i8 ~% V) b2 }  n* \6 ?
93.6 6.0 X 7.0 55.5
) n# V# }* X  p. B0 m8 q3 u95.0 6.5 X 7.0 27.27 c8 w# m7 p6 D! r( X( U, ?
Av. 60.0$ m$ H; w: Q( J7 g# }' `- j
available testosterone. Again, emphasis should be placed on" H0 L: e5 y  S9 S( i8 Y
early therapy when lower levels of testosterone appear to4 ^' t% M5 B% T& v/ K1 q
provide the best responses. The earlier therapy is instituted) {9 q' `2 l6 B
the more likely there will be an excellent response with low6 s" ]8 i4 x$ H: O" k
serum levels. Response occurs throughout adolescence as* l' g. N9 v, D; F
noted in nomograms of phallic growth. 7 The actual response5 x8 a) v- f  b" e( Q
to a given serum level of testosterone is much greater at birth$ L0 z, p& [  g9 H
and gradually decreases as boys reach puberty. This is most0 @3 S* H( o/ a9 k; Z
likely related to the conversion of testosterone to dihydrotes-
+ S8 u/ K% D9 p6 _. ctosterone and correlates well with the studies of testosterone
% H- ~. C* M& o7 k; {0 iconversion in foreskin at various ages.
7 H4 `/ R3 N+ m( H" qThe question arises regarding early treatment as to whether5 u6 Z) o$ {; w+ m. t
one might sacrifice ultimate potential growth as with acceler-
3 g  ^# Y6 d9 f8 S$ Vated bone growth. The situation appears quite the reverse  Y) h& {0 q# K9 v9 m8 d8 a
with phallic response. If the early growth period is not used
' I5 M& v! i0 ~7 g! kwhen 5a reductase activity is greatest then potential growth+ E* x$ O, w& q2 _
may be lost. We have not observed any regression of growth; }( x- G1 `  e
attained with topical or gonadotropin therapy. It may well
) p- W; D/ [, ~, Pbe that some patients will show little or no response to any# W) P3 t' g8 [& P
form of therapy. This would suggest a defect in the ability to2 ~8 d  L# k! M" A  s
convert testosterone to dihydrotestosterone and indicate that7 r- x, M7 u/ G; @/ b8 w4 j
phallic and peripheral skin, and subcutaneous tissue should/ n9 T; p4 ]0 F% o  o
be compared for 5a reductase activity.
5 W% n+ k3 |2 f- J* S1 [/ m2 eA, loop enlarges to measure penile girth in millimeters. B,
/ N5 @" Y3 b, K" eexample of penile girth computed easily and accurately.+ W  {* X1 G0 ]" n( [4 s
conversion of testosterone to dihydrotestosterone. It is in this7 D" n0 Z( l, s* y- }6 v+ y
older group that others have noted high levels of serum
+ ]' l; ~: Q8 Ktestosterone with topical application. It would also appear2 s$ G* z, q, X, M5 \
that phallic response during puberty is related directly to the
& [6 j" R5 ^3 d5 u( ]serum testosterone level. There also is other evidence of local
) i3 e# u! D( oresponse to testosterone with hair growth and with spermato-# i; N, o% ]) K: ^+ }3 X4 U  ?
genesis. 5• 6) n# X/ N: q3 H: W2 y
Administration of larger doses of gonadotropin or systemic6 G6 C) Z: c+ s; k% T  e$ @7 Q
testosterone, as well as topical applications that produce
8 b) b, ~7 G) q% c' Uhigher levels of serum testosterone (150 to 900 ng./dl.), will
( T6 x7 H; w1 x9 z+ V/ Falso produce phallic growth but risks accelerated skeletal
' A2 G7 F- U: ~2 O5 Zmaturation even after stopping treatment. It would appear* x% r2 q1 e) ?5 Q) R4 ~- E
that this may be avoided by topical applications of testosterone
* h6 x# J5 Z- x3 ^7 mand monitoring of serum testosterone. Even with this control
( ~( [' H% f9 k( dthe duration of our therapy did not exceed 3 weeks at any
# [. I' A% |1 W9 stime. It is apparent that the prepuberal male subject may
% W. I+ K1 x$ [, h& Q6 N( isuffer accelerated bone growth with testosterone levels near8 q$ u* _- S' I! D" _' _! {% J
200 ng./dl. When skeletal maturation is complete the level of6 L' v, v( K9 j4 O
serum testosterone can be maintained in the 700 to 1,300 ng./+ v% ~: V# ^# h+ c* A" N6 f* [
dl. range to stimulate phallic growth and secondary sexual8 z4 r. e/ F, D$ R& c! C' u) f
changes. Therefore, after skeletal maturation parenteral tes-
$ z2 j2 m" y, w) Etosterone may be used to advantage. Before skeletal matura-
% o) K. k+ H% ^1 H4 mtion care must be taken to avoid maintaining levels of serum
+ _. \/ y* W4 atestosterone more than 100 ng./dl. Low-dose gonadotropin
8 F" c- ?0 q5 u+ l* D3 P0 Gdepends upon intrinsic testicular activity and may require  s2 d7 N8 `) f+ T* W
prolonged administration for any response.
; q9 f( e" J0 e- O0 w) wAlternately, topical testosterone does not depend upon tes-
4 T" u/ V- h7 c* [- S9 t& \ticular function and may provide a more constant level of. l( P0 H8 S2 t! q! W5 |. v+ P
REFERENCES8 W5 t1 @- M6 P7 p8 f9 I
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 A! w4 w# l/ [% D- W0 ?  W( cR.: The local application of testosterone cream to the prepub-& v  S, C" U3 j2 ^
ertal phallus. J. Urol., 105: 905, 1971.
+ R# X4 n* t4 z$ D* `2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
  J/ s- v0 _- c' V) U2 `; c) _) btreatment for micropenis during early childhood. J. Pediat.,
  _5 f: K/ M2 O1 N83: 247, 1973.2 z% p8 `" F2 ?! ~$ c8 O. |# U3 U0 r( U
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. I2 ]/ M  s, O+ W! u( G, r; R4 J5 u
one therapy for penile growth. Urology, 6: 708, 1975.& \0 F+ S- O' S
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
$ Y9 N. W, \) w9 ?2 Q, Gto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
( O: t, |1 ?9 \skin slices of man. J. Clin. Invest., 48: 371, 1969.
4 `: d5 r: H" U& @5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, o: c0 c3 N, u4 V- |
by topical application of androgens. J.A.M.A., 191: 521, 1965.
1 T( Z2 d! L/ E( r/ u6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. [$ o1 o* E. o2 z. X; z* d
androgenic effect of interstitial cell tumor of the testis. J.
! T9 \6 o' n( F7 V/ @' w; V% WUrol., 104: 774, 1970.
% z; d$ P! a- P6 g; `5 l7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-# k, t, k7 i7 d( R# I
tion in the male genitalia from birth to maturity. J. Urol., 48:
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