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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
! T" o3 H( K5 \" M+ VGONADOTROPIN
' |* w1 i3 o, C( X$ O/ [% s9 qRICHARD C. KLUGO* AND JOSEPH C. CERNY
' Z- g4 ]& Z: \1 T2 i! B, G4 sFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 @4 G4 A1 J& q7 WABSTRACT
- J( I& k+ s, j/ G; k3 y6 HFive patients were treated with gonadotropin and topical testosterone for micropenis associated- n- J# i/ }" E0 U, T6 V* {
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) u2 p1 E9 b/ O" A& ]  Vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone: L1 M/ H/ i6 N& z, L* r
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 }( x0 P* |/ m: T" ?for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
' a0 G; I5 H# Q4 Tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
& E# g6 o+ a3 |; P- U: y+ jincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 F8 j5 l- o) e
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 E" d7 d- X1 O) vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
" B  F, N( m8 S, R5 _* z/ l- jgrowth. The response appears to be greater in younger children, which is consistent with previ-
. t+ F/ t: P# p# ?/ a' e% N4 Rously published studies of age-related 5 reductase activity.* n+ ~: _+ D1 X, h# ~( }
Children with microphallus regardless of its etiology will
/ O3 W! t5 z. Prequire augmentation or consideration for alteration of exter-! i3 u+ e) `) X/ Z+ T
nal genitalia. In many instances urethroplasty for hypo-5 b% C* U- M, M1 I" k, C
spadias is easier with previous stimulation of phallic growth.
( s. l6 g" r- FThe use of testosterone administered parenterally or topically) p0 k  \3 I) p7 _, q2 n! V# ]8 N
has produced effective phallic growth. 1- 3 The mechanism of$ e4 D# K& `- M
response has been considered as local or systemic. With this
: V. t4 F; c% H: o$ h& X& Min mind we studied 5 children with microphallus for response
5 a1 r$ A; \3 q9 I& h- }to gonadotropin and to topical testosterone independently.0 J3 x$ k- Q2 D/ I# @
MATERIALS AND METHODS
9 W1 P* u/ o7 s( I* eFive 46 XY male subjects between 3 and 17 years old were$ z/ X+ p) h& f2 O% G
evaluated for serum testosterone levels and hypothalamic
+ M; W# {; o1 Wfunction. Of these 5 boys 2 were considered to have Kallmann's* Q$ |# S0 ^4 c0 e- f
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
# H% p% A  x4 b! k* {) Slamic deficiency. After evaluation of response to luteinizing, W# j5 v& w# l  `3 t5 d
hormone-releasing hormone these patients were treated with: z% f) u, r- p  f* G
1,000 units of gonadotropin weekly for 3 weeks. Six weeks) @9 o, X, r. G5 u3 j* B
after completion of gonadotropin therapy 10 per cent topical
' x9 y; R" h: P9 w+ u: x0 [testosterone was applied to the phallus twice daily for 3 weeks.# E" v) `+ p) ?; n: ^
Serum testosterone, luteinizing hormone and follicle-stimulat-
$ u- n+ d( u! Uing hormone were monitored before, during and after comple-
% A6 ^& n# c! U4 ^, M/ L7 l3 E* `tion of each phase of therapy. Penile stretch length was/ w$ c5 G- C4 e/ o( Z$ b7 K
obtained by measuring from the symphysis pubis to the tip of! z3 M- Q! g. P: C
the glans. Penile circumferential (girth) measurements were
9 T. Z" _  k: Qobtained using an orthopedic digital measuring device (see
. w; k+ |( r( rfigure).0 j. o; \9 p4 ]# |+ v
RESULTS- p2 C( y% e9 k7 T8 B+ |; s2 X# U
Serum testosterone increased moderately to levels between
5 X9 N6 V' r9 r) g3 b50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-3 q1 A+ \! A$ Q! W, F
terone levels with topical testosterone remained near pre-0 m2 M" c, R. e. w0 a2 d3 Z, b! N
treatment levels (35 ng./dl.) or were elevated to similar levels
# n" i% F; u3 A. d# J5 ]1 {4 _developed after gonadotropin therapy (96 ng./dl.). Higher; d& x* `! l! E1 `) A2 A& B! A
serum levels were noted in older patients (12 and 17 years old),2 \' Z% R/ h( M/ o3 `
while lower levels persisted in younger patients (4, 8, and 10
( {9 X: ?5 h; t6 @' ~. O0 k1 Byears old) (see table). Despite absence of profound alterations- l. _$ [- y8 p
of serum testosterone the topical therapy provided a greater
9 S5 @( B- A9 u  d- B$ k# QAccepted for publication July 1, 1977. ·
* c: A0 B$ N+ [, r& o1 E, YRead at annual meeting of American Urological Association,! [" d# T6 f7 ^8 l9 m8 s+ o+ q' L5 `
Chicago, Illinois, April 24-28, 1977.
4 y# D& h. U8 b7 Q% M: P* Requests for reprints: Division of Urology, Henry Ford Hospital,3 e6 c/ r+ }  _5 O1 |! S6 ~
2799 W. Grand Blvd., Detroit, Michigan 48202.5 O5 H4 a9 L9 g: }$ \
improvement in phallic growth compared to gonadotropin.
9 T" u  K6 K" iAverage phallic growth with gonadotropin was 14.3 per cent
  m3 Z- k4 a: v5 Zincrease in length and 5.0 per cent increase of girth. Topical
6 \3 p" z! K! I8 atestosterone produced a 60.0 per cent increase of phallic length
/ S9 I1 D& U' j5 _) t5 vand 52.9 per cent increase of girth (circumference). The+ X: G- c2 x  L% V: g
response to topical testosterone was greatest in children be-
' L5 {5 ?  O6 x. P8 F* x* Jtween 4 and 8 years old, with a gradual decrease to age 17
, W  r6 M, W' p$ I1 L! C, i+ Qyears (see table).
" T6 n2 R  n0 e' G$ L2 E# ~1 lDISCUSSION
7 r+ o: `" D7 eTopical testosterone has been used effectively by other; F! g; ?1 b% B- V
clinicians but its mode of action remains controversial. Im-
; ~4 d3 Q' c1 a, }mergut and associates reported an excellent growth response
9 Z$ F8 s# s" T2 r2 r0 T' Mto topical testosterone with low levels of serum testosterone,
5 R+ {2 ~% x$ {7 T" Usuggesting a local effect.1 Others have obtained growth re-
4 u8 F1 v: v1 d8 Q6 Rsponse with high. levels of serum testosterone after topical
/ V- |! [+ C9 `. E4 D; I$ Vadministration, suggesting a systemic response. 3 The use of  X' x7 ^# l( v# w8 B
gonadotropin to obtain levels of serum testosterone compara-( |7 L( S' P( j( C! l* F
ble to levels obtained with topical testosterone would seem to; D8 d) F% A  X
provide a means to compare the relative effectiveness of
3 N/ K% U; P3 Btopical testosterone to systemic testosterone effect. It cer-
" d: l* e( f! k) [tainly has been established that gonadotropin as well as par-" `8 r; H) J: f4 R! D
enteral testosterone administration will produce genital# J  |2 A% m' T7 ^9 B. A
growth. Our report shows that the growth of the phallus was
* w6 B4 X  I8 Qsignificantly greater with topical applications than with go-
* i) Z' X" z2 N" [8 m" inadotropin, particularly in children less than 10 years old.
0 k3 l4 {5 x1 o2 mThe levels of serum testosterone remained similar or lower
+ X/ ^0 R( V, rthan with gonadotropin during therapy, suggesting that topi-
5 x* L8 v- Z6 V9 Y% l# P; Scal application produces genital growth by its local effect as' X# ~& o3 Z) t2 C
well as its systemic effect.
1 a" W/ W" m6 ^, X4 O# N, |Review of our patients and their growth response related to
9 `8 f* y% N8 O3 Q' s. ]- Vage shows a greater growth response at an earlier age. This is
" ]1 o! d" ]9 g! ?" n) V& V; x9 V5 Vconsistent with the findings of Wilson and Walker, who
9 q) j8 N2 W3 dreported an increased conversion of testosterone to dihydrotes-
- I! d2 n; ^7 ]- mtosterone in the foreskin of neonates and infants.4 This activ-
3 k- N* `3 j* Tity gradually decreases with age until puberty when it ap-
% y: m8 f1 g/ V$ b- I" v7 |0 J# Wproaches the same level of activity as peripheral skin. It may" n. G1 o2 C1 D+ f4 d+ w8 Y
well be that absorption of testosterone is less when applied at
3 a$ ?" ?, p) r6 \$ r; M. j4 Lan earlier age as suggested by lower serum levels in children
5 e% B' h1 X) F9 S, Dless than 10 years old. This fact may be explained by the
! I( I5 T1 a* u' q' ^/ Ygreater ability of phallic skin to convert testosterone to dihy-
' f+ N( q$ z3 n; idrotestosterone at this age. Conversely, serum levels in older# @) N, _  s0 r5 W( P
patients were higher, possibly because of decreased local; k* r& K- g0 `
667
% ?2 [3 F/ e3 B2 Q0 y' `668 KLUGO AND CERNY
( S" i; c& ~% _3 i4 `Pt. Age
2 d* K% {! C$ y% P(yrs.)
' r- O8 ~; \1 R( VSerum Testosterone Phallus (cm.) Change Length
$ f- ^# _5 \2 l5 b) O, x; A(ng./dl.) Girth x Length (%)
" S4 ?( I/ ^" Z. x0 B! U4" W8 |  N: ]* M# Y5 W, L
8% Q) n: r1 X( G' Q0 _
10% `+ f3 n& t( @) k- m! b0 u
12
' P8 e0 J, e  t17
0 I' n0 {% X* c1 b% o" W5 EGonadotropin
8 q8 }, y) ~. |# D71.6 2.0 X 3 16.63 R9 b; x+ F0 a5 ?1 I
50.4 4.0 X 5.0 20.01 E- x  ^: R1 g3 b6 L/ Q4 c9 c
22.0 4.5 X 4.0 25.0
7 ~4 R8 w, t# }: x) T84.6 4.0 X 4.5 11.1  j0 c* x& x9 X9 ^
85.9 4.5 X 5.5 9.0; L5 E4 m. k1 i; w! Z. T) H$ ^
Av. 14.3, M8 a( x  U3 r$ V7 F2 ^
4
3 Z: Y' \1 N+ b9 ]: B% A8
9 I" g- C. _( q3 C# o10  Q! m# d. o) i2 T9 R' a
12
$ h6 |% y# z! D0 v176 K0 W$ ], L- j! i
Topical testosterone5 K8 K6 B* i$ L* y
34.6 4.5 X 6.5 85& b# W. {9 K% A9 Q9 m! k* |$ o
38.8 6.0 X 8.5 70
# |0 w. x* g! }# }: [8 }40.0 6.0 X 6.5 62.5  N! q% f9 Q2 {# `- r+ ]6 D
93.6 6.0 X 7.0 55.5/ t, ~+ h9 ]9 y2 d) e
95.0 6.5 X 7.0 27.2
. }" g3 ~' Q" ^" {5 FAv. 60.04 s$ H' {0 N6 N
available testosterone. Again, emphasis should be placed on
/ k' e/ Y& Z* j3 \' `early therapy when lower levels of testosterone appear to
5 Z, K1 s2 Z) [! }6 iprovide the best responses. The earlier therapy is instituted& D' U9 ]. @; ]
the more likely there will be an excellent response with low: P/ d2 M1 e, Z/ ~/ }
serum levels. Response occurs throughout adolescence as
  L3 l9 Y4 I8 W  b( u/ unoted in nomograms of phallic growth. 7 The actual response" @1 u" B, j& V" @/ a
to a given serum level of testosterone is much greater at birth0 @/ f# f5 n5 b2 `6 X
and gradually decreases as boys reach puberty. This is most& V+ }6 K9 q: [) _: F* @
likely related to the conversion of testosterone to dihydrotes-  v6 Q/ l- H2 b
tosterone and correlates well with the studies of testosterone4 o4 }' y! ^- F+ Y! P5 R' Y9 f
conversion in foreskin at various ages.
! T3 c, S# u7 ^" N0 sThe question arises regarding early treatment as to whether  k: e- e7 z% |0 W
one might sacrifice ultimate potential growth as with acceler-
9 e1 _6 d/ H$ K( @& b2 fated bone growth. The situation appears quite the reverse8 Z( t+ R4 I3 v9 Y
with phallic response. If the early growth period is not used
, S6 x2 V4 V3 a0 Vwhen 5a reductase activity is greatest then potential growth6 p, ?8 O$ a; C
may be lost. We have not observed any regression of growth
$ ?% M* n3 t/ l! k: Vattained with topical or gonadotropin therapy. It may well
1 i8 R! @8 t7 P) Z% L; n  {- b# ube that some patients will show little or no response to any
2 [- {% A% L! F, \% a5 A# Bform of therapy. This would suggest a defect in the ability to; E: N, [$ F: S. b) H9 q. m
convert testosterone to dihydrotestosterone and indicate that$ w+ f( `- |3 c% b
phallic and peripheral skin, and subcutaneous tissue should: j9 |+ T* ^% H9 v, V5 A; p
be compared for 5a reductase activity.
4 j+ M0 C7 ^" S9 j. {A, loop enlarges to measure penile girth in millimeters. B,$ J7 F2 U: N* V6 a
example of penile girth computed easily and accurately.
" S3 @( q) R4 j& l5 qconversion of testosterone to dihydrotestosterone. It is in this  i& p" W2 a! c/ p3 @3 `
older group that others have noted high levels of serum1 h0 A  q- ~! ]; H6 b3 z5 r) P' U
testosterone with topical application. It would also appear
' |; X! [, I. f2 _5 ?that phallic response during puberty is related directly to the
) V! t- G/ m3 t, L9 F) A4 g8 f. _8 Pserum testosterone level. There also is other evidence of local
' q/ v9 F9 Y9 b# u  x$ Gresponse to testosterone with hair growth and with spermato-
  w2 d( `0 C. W- [2 @+ Ggenesis. 5• 6
7 _. F. m* e, ?, ]- W" h+ iAdministration of larger doses of gonadotropin or systemic
- p$ a% q7 N) |4 g2 P5 Y8 itestosterone, as well as topical applications that produce1 }5 m( U2 m. Z9 S3 k5 X
higher levels of serum testosterone (150 to 900 ng./dl.), will- G# _9 S9 T3 y# R
also produce phallic growth but risks accelerated skeletal
8 s# B$ Q* j+ Z" R+ dmaturation even after stopping treatment. It would appear! b* F5 R8 M. W. w( p) f" g( h
that this may be avoided by topical applications of testosterone/ d; L  ~9 A4 P1 V% u) V
and monitoring of serum testosterone. Even with this control4 f; ^; H7 O/ j6 v2 ~$ w# @% W
the duration of our therapy did not exceed 3 weeks at any" P3 b# B* _  @5 X0 q
time. It is apparent that the prepuberal male subject may4 M+ E6 [- X! d% q1 v3 i2 o" |
suffer accelerated bone growth with testosterone levels near! \( A. s' J, ]: C- m: C$ s6 m
200 ng./dl. When skeletal maturation is complete the level of
1 M$ @) x. g+ H) x. }* f, v6 u. zserum testosterone can be maintained in the 700 to 1,300 ng./
. c  @8 d9 b: r# N" j9 Q! Z. odl. range to stimulate phallic growth and secondary sexual( _# g9 h2 F' i6 d) }9 L8 p. `
changes. Therefore, after skeletal maturation parenteral tes-2 W  @9 b9 K/ W  d$ g% ~+ v$ G: H# s
tosterone may be used to advantage. Before skeletal matura-* s: B3 v2 D) d) F
tion care must be taken to avoid maintaining levels of serum; k# O3 T- ^* N0 p, `% B6 H% Z! q1 x, }9 o
testosterone more than 100 ng./dl. Low-dose gonadotropin. s! |7 g- E- N6 r6 n
depends upon intrinsic testicular activity and may require
0 n, b: S% V. `/ F3 E8 R2 xprolonged administration for any response.
( v. \& }0 x* NAlternately, topical testosterone does not depend upon tes-8 s& ^1 |7 e- w6 d; W; U+ W+ S' ?- c
ticular function and may provide a more constant level of3 _* {  A* J- b" X. b0 n" b& |
REFERENCES) f) A' d. G9 `' [
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
  x' o& k$ F* ?R.: The local application of testosterone cream to the prepub-
, U! W. x' e5 B0 b4 aertal phallus. J. Urol., 105: 905, 1971.
( z# Y  A: }2 S1 a' H2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 S0 `1 V2 R% ?- N6 Q2 jtreatment for micropenis during early childhood. J. Pediat.,
& n7 |, x$ V5 E& [83: 247, 1973.* G- j/ v: u) z* N9 G) S
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-4 T' A7 T# W9 U9 o9 ?7 M; m+ C1 j
one therapy for penile growth. Urology, 6: 708, 1975.
8 h/ C2 s$ Z- L7 g9 s9 R7 ^4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone: Z( e1 F( n7 m/ ]& M4 O
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& I2 r5 S* p0 ?% C. |' _skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 A/ ^3 H$ C$ `5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% E1 C& Y# U( q$ r% e7 w9 C
by topical application of androgens. J.A.M.A., 191: 521, 1965.
0 p: h' a: R- s, k/ ^6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; {, X6 }6 f7 R' a9 Sandrogenic effect of interstitial cell tumor of the testis. J." W$ K8 ^( Y* s( [' M! e& b
Urol., 104: 774, 1970.
: ^& S9 `+ {! C7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ @7 V5 d' J/ Z; e3 s3 `/ E7 R$ ^tion in the male genitalia from birth to maturity. J. Urol., 48:
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