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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
# m, W1 u6 V5 {1 C6 Q1 CGONADOTROPIN6 i/ ^+ g- ^: D, B" f1 i
RICHARD C. KLUGO* AND JOSEPH C. CERNY
& U- R6 U' J; t$ W' W [From the Division of Urology, Henry Ford Hospital, Detroit, Michigan% K- B3 s+ C f6 W6 { D9 [" D
ABSTRACT
5 {4 s0 B* M4 M! h9 ~0 p# xFive patients were treated with gonadotropin and topical testosterone for micropenis associated- `2 r5 K3 e" J* E" o/ `. U) ~
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-; n; D/ R: J2 x" K# M
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% K, A( J _/ v* u0 [2 Mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
9 X; c% x3 R% W) Q" F. |2 Qfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
6 J! d% T7 d" Y" u- E+ ^5 l% F4 }; E9 Oincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average# K5 a$ R ~1 v
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ ^$ ?+ b- Q! g& Q' l! Noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
: Z) p; B4 K B: ^) y2 ?. w$ E8 ?study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile g, p. X! K9 @' @
growth. The response appears to be greater in younger children, which is consistent with previ-1 M5 r8 o$ }7 b. y; o, `) z8 T
ously published studies of age-related 5 reductase activity.6 l3 p4 N: M5 j1 ?* ]0 H
Children with microphallus regardless of its etiology will
' Y/ w: h" W& L8 K- V" ?require augmentation or consideration for alteration of exter-
. ?6 W( U% ^; f* d/ Znal genitalia. In many instances urethroplasty for hypo-, P, H8 _$ v4 z* S' O- C
spadias is easier with previous stimulation of phallic growth.& b6 O j0 K9 R0 J0 y+ j, u6 L4 z
The use of testosterone administered parenterally or topically
4 r; K% ~8 i7 O$ O, ^, ^has produced effective phallic growth. 1- 3 The mechanism of& B* _. t% Q3 L) \
response has been considered as local or systemic. With this' I- {, b. t; B2 j
in mind we studied 5 children with microphallus for response h8 |3 b. l# ]+ m# p) b6 `. O
to gonadotropin and to topical testosterone independently.1 W( ?6 H7 ]; ^' D
MATERIALS AND METHODS
) E( O4 @% p7 K6 w" wFive 46 XY male subjects between 3 and 17 years old were- |) \) G, o' m3 Z/ j
evaluated for serum testosterone levels and hypothalamic
$ f( N4 n. R" C5 M3 U1 cfunction. Of these 5 boys 2 were considered to have Kallmann's$ H' D; K2 O2 p# I0 {0 g8 D5 E% b& m
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
+ d9 u9 w7 |# ^; t0 N- xlamic deficiency. After evaluation of response to luteinizing+ O; a# l! w4 x4 n" }0 s# _! X
hormone-releasing hormone these patients were treated with$ b- v# t6 H- w: l$ U1 ] X6 g# F
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
; N5 x5 _+ S! O- ?& vafter completion of gonadotropin therapy 10 per cent topical+ S _0 l$ z: K( v
testosterone was applied to the phallus twice daily for 3 weeks.% n& J8 I1 y3 {. \
Serum testosterone, luteinizing hormone and follicle-stimulat-
' L q1 e9 |6 W2 _/ ping hormone were monitored before, during and after comple-( H; v- O1 V; ~$ ~) v& u
tion of each phase of therapy. Penile stretch length was' E5 L+ _. ?$ L3 {4 x, A
obtained by measuring from the symphysis pubis to the tip of) ?& l7 b# j1 d1 L/ Z
the glans. Penile circumferential (girth) measurements were" M8 d" A5 }2 t! k3 x+ S
obtained using an orthopedic digital measuring device (see
" m2 ]; T3 u9 W5 f8 H0 q* }figure).* _1 P" g2 }( a' P4 h: q
RESULTS
! Q: Y1 Y- }( A6 sSerum testosterone increased moderately to levels between
4 c8 ]9 S- w! _- W( O50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ R+ o: w8 s; i! pterone levels with topical testosterone remained near pre-6 M j- O, J1 k0 k J# r
treatment levels (35 ng./dl.) or were elevated to similar levels) a. z" V# y: s9 W
developed after gonadotropin therapy (96 ng./dl.). Higher* W4 e9 S& Q% z- }
serum levels were noted in older patients (12 and 17 years old),7 h u9 V: A- t- {8 L0 F
while lower levels persisted in younger patients (4, 8, and 10
- |5 W# z: G8 f& Hyears old) (see table). Despite absence of profound alterations1 e: K* C4 {) u0 r3 I
of serum testosterone the topical therapy provided a greater- D* v/ ?, M5 y# P, Y/ z
Accepted for publication July 1, 1977. ·9 ^* |) v5 M9 R# T' t |+ x
Read at annual meeting of American Urological Association,0 I9 s9 g$ N9 c- M/ j( d5 k0 t* h- E' e
Chicago, Illinois, April 24-28, 1977.
6 E) n/ E8 O+ F4 W* Requests for reprints: Division of Urology, Henry Ford Hospital, }1 e; v% c3 t5 |- \0 v( R
2799 W. Grand Blvd., Detroit, Michigan 48202.
6 f. ~0 a3 X% f8 G: ?# x; p$ himprovement in phallic growth compared to gonadotropin.+ R" b5 J2 U" o+ K g! }2 z
Average phallic growth with gonadotropin was 14.3 per cent! l7 X+ o2 \/ m
increase in length and 5.0 per cent increase of girth. Topical1 d- P* S( T2 W# X! G' T+ ]6 z! n7 r: U
testosterone produced a 60.0 per cent increase of phallic length
+ _# l( B! B& T5 aand 52.9 per cent increase of girth (circumference). The. F9 R7 h$ @4 D- f6 ~7 T
response to topical testosterone was greatest in children be-
7 {$ S9 Y# z8 } H1 vtween 4 and 8 years old, with a gradual decrease to age 17$ Q: H) P+ C; }+ W( }8 J
years (see table).1 L/ _# V& c8 F/ Y( m
DISCUSSION
- s1 O7 @/ B. i0 h% U7 sTopical testosterone has been used effectively by other
5 X3 H; N5 g5 ]% K/ p2 ]( T1 Qclinicians but its mode of action remains controversial. Im-- J; \( ^. a2 R2 s
mergut and associates reported an excellent growth response# ~: X* t* S0 p! m1 N" J; _
to topical testosterone with low levels of serum testosterone,
@& a: s9 S# S. X$ Wsuggesting a local effect.1 Others have obtained growth re-7 M, P" [% C0 [" v8 ]5 w2 @
sponse with high. levels of serum testosterone after topical& X& Y. [9 N; p& X0 d; M! E
administration, suggesting a systemic response. 3 The use of
8 F F: W3 ?1 ?! Ggonadotropin to obtain levels of serum testosterone compara-
; @0 G3 T; L( Hble to levels obtained with topical testosterone would seem to/ a* v. R1 n0 n c3 m
provide a means to compare the relative effectiveness of
7 u) |, T, H/ l4 f' E2 Dtopical testosterone to systemic testosterone effect. It cer-+ u2 a; D$ s+ L' N: h* ]0 y
tainly has been established that gonadotropin as well as par-
; M' _/ t% {+ Benteral testosterone administration will produce genital
" G% w7 Z$ U+ z* S& [/ Xgrowth. Our report shows that the growth of the phallus was
; H: O$ c+ }7 i( b, c. lsignificantly greater with topical applications than with go-( o+ F; \" V; Y; H
nadotropin, particularly in children less than 10 years old.
. h0 i4 m# g5 R3 i3 L+ j( ]; {The levels of serum testosterone remained similar or lower& W' l; ]+ o' l
than with gonadotropin during therapy, suggesting that topi-
# c1 D$ E1 J: @cal application produces genital growth by its local effect as' |1 f0 ]5 H% s l8 U4 V! @' a+ m& G
well as its systemic effect.; r! ^# P: J; g4 w: J( ?+ G2 R
Review of our patients and their growth response related to. w2 y- I" }+ @, R7 \% X/ v
age shows a greater growth response at an earlier age. This is
3 C3 \: s' p9 C) Mconsistent with the findings of Wilson and Walker, who9 v" P' K3 }+ s2 Q
reported an increased conversion of testosterone to dihydrotes-( o+ F, ]9 K, ]/ Q! U
tosterone in the foreskin of neonates and infants.4 This activ-. Z& d, e! d2 z
ity gradually decreases with age until puberty when it ap-! \; I$ ?: N Z0 f9 w
proaches the same level of activity as peripheral skin. It may
5 l' U% N2 }- swell be that absorption of testosterone is less when applied at
( Y+ D% l; L4 u4 H4 ian earlier age as suggested by lower serum levels in children
) ^- T/ [: }3 k m" Dless than 10 years old. This fact may be explained by the
" L# F# f8 o% r; q5 s( w0 jgreater ability of phallic skin to convert testosterone to dihy-
' V0 g' M N. p+ D7 ^# Xdrotestosterone at this age. Conversely, serum levels in older
9 M/ y0 o3 i+ v) b. M: Gpatients were higher, possibly because of decreased local8 K5 L$ L* n* L7 H# x) I0 c" l
667; Y6 g* X' q9 K: G
668 KLUGO AND CERNY# p6 s% Q; @, T3 q& ?
Pt. Age
) \! r0 i- G3 d% v- K1 _(yrs.) Y, d/ r! A8 R$ b0 [2 o
Serum Testosterone Phallus (cm.) Change Length; j5 P: G5 w' X# T6 k
(ng./dl.) Girth x Length (%)
X9 ~2 ~0 G _+ B: N7 s4% z/ ^9 i5 t! k; S; o5 l5 o
8" S* K: m' y1 E2 J
103 N; f2 Z9 ]$ J9 r
125 b$ C% ?; @% g( x( j
17
5 m7 w6 X8 T4 y/ Y @! yGonadotropin, E; G) O3 p/ Z1 R
71.6 2.0 X 3 16.62 @% x, H& ^% S) i+ S8 \
50.4 4.0 X 5.0 20.0. C9 [: p# O# `+ I! P7 w. ?
22.0 4.5 X 4.0 25.0) {0 w# C9 @1 a: y! z9 ]
84.6 4.0 X 4.5 11.1
# M S4 P9 t; Q) q! V85.9 4.5 X 5.5 9.0
: {2 ^7 Z4 g. l+ g) {Av. 14.3
" P W: X4 i8 P( N+ _6 B42 Z' `# ]* ?) N: k% t
8
$ C- y0 O* F; g3 x- ~10
; f$ R" p8 \. A* N6 P3 V12
0 @ y1 r& z, F* u- C2 Q6 l17
* o4 l4 b: Q- S3 F |% {4 aTopical testosterone+ O8 m2 `: E$ ?& F Q+ U9 v
34.6 4.5 X 6.5 85, f, \5 m( o0 o9 m# ~' V( j! W
38.8 6.0 X 8.5 70
+ h# H: ?0 r0 i6 k40.0 6.0 X 6.5 62.5
* C0 S7 L1 Y4 _; X, a93.6 6.0 X 7.0 55.5
& U- o* N' r) q9 w- G" b6 ]4 u95.0 6.5 X 7.0 27.2: ^# T$ \7 K( t3 m
Av. 60.0
( N( `+ T2 j% r2 yavailable testosterone. Again, emphasis should be placed on2 ]+ F! g5 a8 O: `
early therapy when lower levels of testosterone appear to4 v7 w9 z2 G b5 T
provide the best responses. The earlier therapy is instituted
5 I+ \9 l1 L1 Mthe more likely there will be an excellent response with low
) `3 s6 k3 T" T% M" q, w9 ?serum levels. Response occurs throughout adolescence as
4 k. Q4 I4 k" Y6 {3 R! S( ~noted in nomograms of phallic growth. 7 The actual response
/ r. e+ j; F1 Y) N# m) `! eto a given serum level of testosterone is much greater at birth
' @+ I: X1 o* E! x: \, \and gradually decreases as boys reach puberty. This is most6 d- l8 R. x8 M
likely related to the conversion of testosterone to dihydrotes-
4 N6 M% d5 J+ Z1 t6 e* k: n. S _tosterone and correlates well with the studies of testosterone3 ^6 X; K% h4 C8 v, |) q: U d
conversion in foreskin at various ages., _3 L5 K6 P) P' J9 p- F- D
The question arises regarding early treatment as to whether
# J6 a. _) Y; `8 H0 u) xone might sacrifice ultimate potential growth as with acceler-/ I, s& D: t# D# w+ {. n' L+ v7 G
ated bone growth. The situation appears quite the reverse
$ G, o- O, s8 Y; o9 c! g4 Gwith phallic response. If the early growth period is not used4 T' n- u% s3 z, D$ N7 F
when 5a reductase activity is greatest then potential growth9 _+ F& \) t/ q& J1 f1 Q% ~6 E3 p* p
may be lost. We have not observed any regression of growth
9 z7 p0 [/ v7 k5 o: L# Zattained with topical or gonadotropin therapy. It may well$ a# J* y! U( x$ p
be that some patients will show little or no response to any- @) e% C) E+ w$ ^8 r
form of therapy. This would suggest a defect in the ability to
" F- G, Q. A" Jconvert testosterone to dihydrotestosterone and indicate that5 c; d" j }+ c7 f
phallic and peripheral skin, and subcutaneous tissue should
. b4 @ y- s3 @# Z3 X8 Tbe compared for 5a reductase activity. r, S. e- Q( n. t/ b# n
A, loop enlarges to measure penile girth in millimeters. B,0 ?; B: n V7 k [5 H% p& ~7 @
example of penile girth computed easily and accurately.9 c4 P1 g3 ?- ~1 ^' J+ v6 P
conversion of testosterone to dihydrotestosterone. It is in this
' S3 s3 B) s. L% f! R. K8 molder group that others have noted high levels of serum; K8 o6 @+ s; j) b
testosterone with topical application. It would also appear
6 `9 {8 Q+ L9 p% J8 sthat phallic response during puberty is related directly to the
/ ~2 n; S; i+ cserum testosterone level. There also is other evidence of local
( N' O: a, U2 z# gresponse to testosterone with hair growth and with spermato-( q9 e7 V* J1 ~! F4 i5 w
genesis. 5• 6# G! u/ @7 n7 t$ Z/ [
Administration of larger doses of gonadotropin or systemic
( R; A$ `9 {$ ~# T' V# j4 _/ u- ]1 ctestosterone, as well as topical applications that produce. a ^# n7 X; x. C# y( C
higher levels of serum testosterone (150 to 900 ng./dl.), will4 R e1 j' j A C D
also produce phallic growth but risks accelerated skeletal
7 O% a1 `6 n. @# B4 b( ]1 [% Amaturation even after stopping treatment. It would appear7 _8 e: `% ]! ~( k* |2 G# q$ P
that this may be avoided by topical applications of testosterone( Z9 p5 b, D+ i7 h
and monitoring of serum testosterone. Even with this control' |# u* m; q; T" Z' S b( Q
the duration of our therapy did not exceed 3 weeks at any' _4 l6 r+ o. o' \( Q5 Y3 _
time. It is apparent that the prepuberal male subject may
! m$ q; S7 ]( {! a, r: e" Isuffer accelerated bone growth with testosterone levels near
7 m3 O5 Y, y$ d0 h200 ng./dl. When skeletal maturation is complete the level of
6 d! T# t$ y5 t, m" Q( I7 M+ a- r6 rserum testosterone can be maintained in the 700 to 1,300 ng./
% V7 }6 k6 Z; v) b, Jdl. range to stimulate phallic growth and secondary sexual n! f6 T5 B7 v, ?3 q9 r
changes. Therefore, after skeletal maturation parenteral tes-
. L. @# Q: h0 L1 Ntosterone may be used to advantage. Before skeletal matura-
+ |) |+ B) v0 x. m& F; |tion care must be taken to avoid maintaining levels of serum
) a# W) o% b' J. W* Xtestosterone more than 100 ng./dl. Low-dose gonadotropin
/ w' }# z$ j( R$ W3 qdepends upon intrinsic testicular activity and may require: {% q, t/ B6 V, h3 }# x
prolonged administration for any response.
) `$ f4 M9 d( f, AAlternately, topical testosterone does not depend upon tes-6 ]6 l- ^% T# t4 L) }; b+ a
ticular function and may provide a more constant level of) z1 P4 K3 D. `5 J7 P
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1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' N* S. g% H8 A( l7 W) `; D
R.: The local application of testosterone cream to the prepub-* ^. M$ \8 W, E' B4 _' g2 ]' ^1 l
ertal phallus. J. Urol., 105: 905, 1971.
7 L2 v9 a: v0 q) U ~! z; d1 i4 X; {2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, Q) W3 Q+ t; C% E4 Btreatment for micropenis during early childhood. J. Pediat.,
! w0 H! @$ w* X/ q83: 247, 1973.$ h$ L+ B4 |7 K4 m
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-8 H" ?3 F% q+ y1 H( d
one therapy for penile growth. Urology, 6: 708, 1975.' W; ]1 F! b- ]3 @0 d3 B3 w
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone" E+ o: |& U# r8 L0 J0 k9 N0 A+ F J3 }
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
A ] X2 _0 |skin slices of man. J. Clin. Invest., 48: 371, 1969.1 F9 C2 E3 y3 [4 L( H' _
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
% A% K: J8 u& ^$ u# ~by topical application of androgens. J.A.M.A., 191: 521, 1965.0 P( F! |7 _; U' D) y
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ b9 _( G- |: }5 D: y9 J0 N
androgenic effect of interstitial cell tumor of the testis. J.# w2 F( G; T5 i# b5 K" \
Urol., 104: 774, 1970.% j% F& U! Z; G# O, y, a
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' h1 h9 `/ i. i$ `- u3 Ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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