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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
z/ L7 j1 G( K ?GONADOTROPIN
* X) k0 e( G0 x$ `' VRICHARD C. KLUGO* AND JOSEPH C. CERNY
) d+ a/ P3 o; V. h) I$ \+ H4 D: U! NFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, A- j8 c' q5 p2 E$ CABSTRACT6 M: I1 B+ h% G' ?( E5 ?
Five patients were treated with gonadotropin and topical testosterone for micropenis associated; A" y( m; @' L9 z: J
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-& |* K5 E+ M4 {0 W- t* @/ v' z3 M) e
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
& d4 ?+ n$ i, hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 @" x0 C2 M. }5 ~% ?for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ I V' a% o4 _5 c; Z
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: i! D: P+ R ?! } z5 a- v1 P f
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ a3 c; w3 E" U. c, w {0 N5 z2 q/ yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 I, m5 A) Q! rstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
3 }/ y3 o. Q- h, G* {9 @3 T1 Kgrowth. The response appears to be greater in younger children, which is consistent with previ-. k% O' k3 w6 Q* ~
ously published studies of age-related 5 reductase activity.
7 ]; Q" S6 p9 \: }2 F6 K UChildren with microphallus regardless of its etiology will
2 Z6 v7 d. Y. zrequire augmentation or consideration for alteration of exter-" o8 b) L7 j. N1 J( F4 V# M
nal genitalia. In many instances urethroplasty for hypo-
: q8 u3 E( E. P+ n8 b( l9 T5 Xspadias is easier with previous stimulation of phallic growth.$ n4 b4 E% s$ S$ y
The use of testosterone administered parenterally or topically1 G! A- t' D4 e, D& Q2 }) s# n2 {6 v. R
has produced effective phallic growth. 1- 3 The mechanism of# [; _2 Z5 T/ a2 L* {, ^
response has been considered as local or systemic. With this
P* m! r, h* d( \# `( Kin mind we studied 5 children with microphallus for response
: M8 N, _1 {6 ^" k8 H0 Yto gonadotropin and to topical testosterone independently.
" X) V( ]2 N3 N& QMATERIALS AND METHODS0 Q' c z& F; A3 x% O3 P: u; m
Five 46 XY male subjects between 3 and 17 years old were
/ w* w) s! c H2 a9 t6 w9 levaluated for serum testosterone levels and hypothalamic4 n9 Z. q) {: y7 {4 |
function. Of these 5 boys 2 were considered to have Kallmann's3 K/ s) h2 ^( Q, S- T1 S
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 `" Z- P1 c( E2 E$ _lamic deficiency. After evaluation of response to luteinizing
s1 ~5 j& j7 K! s' Z3 thormone-releasing hormone these patients were treated with) r6 B: {4 T1 y `+ o G7 y4 x" `2 e
1,000 units of gonadotropin weekly for 3 weeks. Six weeks% I: j% C& ]# Q* t6 k+ k8 D+ _
after completion of gonadotropin therapy 10 per cent topical" _! ^" i1 s. l7 e
testosterone was applied to the phallus twice daily for 3 weeks.
. J" z i3 G$ _. y* q; zSerum testosterone, luteinizing hormone and follicle-stimulat-* f# i6 n" Y+ P @4 T
ing hormone were monitored before, during and after comple-
+ M2 P; P3 U( R: k% \tion of each phase of therapy. Penile stretch length was
5 L) I: Q" q+ ?. s& tobtained by measuring from the symphysis pubis to the tip of$ Q% ?& T% I' F2 G. @) C( U0 u( R
the glans. Penile circumferential (girth) measurements were
) Y2 D( o) f. O% {- Tobtained using an orthopedic digital measuring device (see$ m8 z4 C: G9 ~3 w$ z6 r* y! c
figure).5 j) w% f3 _8 l3 n
RESULTS1 `2 L, X4 b9 F5 L
Serum testosterone increased moderately to levels between
7 a! `6 x: v6 k9 N50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* u3 ~6 h0 F7 A, ^( y' @
terone levels with topical testosterone remained near pre-! g q, P6 J7 j9 q
treatment levels (35 ng./dl.) or were elevated to similar levels
z. A5 m! D, _3 Sdeveloped after gonadotropin therapy (96 ng./dl.). Higher
# A: ?8 C; V1 W/ O# P' g9 R( ?4 vserum levels were noted in older patients (12 and 17 years old),$ s4 A* E+ a% T8 G
while lower levels persisted in younger patients (4, 8, and 108 f) ^- D" f7 j+ d, Q/ A3 V) X$ {/ G6 V
years old) (see table). Despite absence of profound alterations( v: @, B' t( F9 E* h; y. h- X
of serum testosterone the topical therapy provided a greater
$ e( V: g& d) ~% [* }8 M h# l8 zAccepted for publication July 1, 1977. ·1 E6 \, y7 y0 O( o+ D5 X0 {8 ?
Read at annual meeting of American Urological Association,
5 X$ a" `4 ]# BChicago, Illinois, April 24-28, 1977.& h$ t2 D& } a
* Requests for reprints: Division of Urology, Henry Ford Hospital,; M! Q- m# ]# c5 ~9 B K% N( y* o
2799 W. Grand Blvd., Detroit, Michigan 48202.
- {: J8 M" H5 x% Pimprovement in phallic growth compared to gonadotropin.
. S% v! @" ~+ d h8 NAverage phallic growth with gonadotropin was 14.3 per cent0 ?1 W5 Y% f3 W3 V6 E/ o
increase in length and 5.0 per cent increase of girth. Topical/ s) u/ T- F9 t6 R
testosterone produced a 60.0 per cent increase of phallic length8 d- V; G2 E! e# S1 V9 Q8 f
and 52.9 per cent increase of girth (circumference). The
6 I& C* D$ a4 Z: a# _" w1 Dresponse to topical testosterone was greatest in children be-
% Q# x2 x# b" b- Ftween 4 and 8 years old, with a gradual decrease to age 17
. R0 u1 V2 T; B# ~: W/ w# \years (see table).
* b. ]2 |) N7 F, aDISCUSSION0 [: o# k- i: f! I9 g
Topical testosterone has been used effectively by other% V1 m& @: U9 h
clinicians but its mode of action remains controversial. Im-( M) X; W7 h. `0 ?& w2 {; j
mergut and associates reported an excellent growth response
! P" Q- A$ X7 lto topical testosterone with low levels of serum testosterone,
* W" ~$ M2 S; i6 B. [- Csuggesting a local effect.1 Others have obtained growth re-
) J% P7 A- ?; u2 ~3 Asponse with high. levels of serum testosterone after topical8 i% L4 o7 @6 d! F8 ^3 @
administration, suggesting a systemic response. 3 The use of
5 a4 Z0 U }( \4 b8 f9 sgonadotropin to obtain levels of serum testosterone compara-$ y; ]$ o! K2 L
ble to levels obtained with topical testosterone would seem to
- \: j" _. X/ W6 U" _5 Vprovide a means to compare the relative effectiveness of) `' O: ?; [; W+ [* w( k" }
topical testosterone to systemic testosterone effect. It cer-
7 B" I& Z2 l. F' O+ Q! Vtainly has been established that gonadotropin as well as par-3 G; E5 e% @$ y
enteral testosterone administration will produce genital) o, @1 r2 z8 l5 O3 U
growth. Our report shows that the growth of the phallus was- w$ p" e F/ c
significantly greater with topical applications than with go-/ P) H; ]/ N1 P) ]" D/ o' T: r* k
nadotropin, particularly in children less than 10 years old.! @3 E; }1 w h4 P
The levels of serum testosterone remained similar or lower
3 f9 G. R) B) C" I9 ithan with gonadotropin during therapy, suggesting that topi-: C6 M$ O, E6 Z5 V* A5 T
cal application produces genital growth by its local effect as
& y% d1 X. X. R5 ^& q# Pwell as its systemic effect.
- b. U: A* h5 G; [7 b& lReview of our patients and their growth response related to& H* J* v" Z7 V" u7 \
age shows a greater growth response at an earlier age. This is" n9 ^- {5 @5 P$ y9 [9 y; x! j
consistent with the findings of Wilson and Walker, who
7 o* J% m0 G# Y0 B# H* m3 u: preported an increased conversion of testosterone to dihydrotes-2 j8 `% @7 R" ]$ I
tosterone in the foreskin of neonates and infants.4 This activ-
* a1 ]+ b2 d& O" `ity gradually decreases with age until puberty when it ap-* c% Y6 y B$ g7 ~, J K
proaches the same level of activity as peripheral skin. It may
, u: Y* m# F1 W$ U/ Hwell be that absorption of testosterone is less when applied at
# q) X% C. E! s4 h! V+ Wan earlier age as suggested by lower serum levels in children m$ f# J/ R. @6 t3 ]& f I |
less than 10 years old. This fact may be explained by the, f/ O! Y" I7 P
greater ability of phallic skin to convert testosterone to dihy-6 P4 n7 e- c0 l- s6 o
drotestosterone at this age. Conversely, serum levels in older
% |& k! k5 P" Apatients were higher, possibly because of decreased local( {' V5 y5 o* _ [2 @; h; M
667' f1 T( M3 z% g9 o; }7 M
668 KLUGO AND CERNY$ _% O4 i# ?; e& X& r
Pt. Age
! V& y7 v- {) n" R' i+ I# |(yrs.)" }7 W( o! H6 N5 x: W
Serum Testosterone Phallus (cm.) Change Length* z, d. h6 @% L, z H
(ng./dl.) Girth x Length (%): u' J9 f+ \$ `0 _2 ?
4. ?# f" z' g1 V9 p, H# c- J
8; R) Z- b! h( k, |9 g/ c" M4 o1 T
10
' ?* g! \. u: |" H12
+ j; J N" t# d! N6 O17
w1 ]+ P3 g& PGonadotropin
4 z- g$ `# b9 p5 F71.6 2.0 X 3 16.6
( X D& _$ F( Z1 v7 c" G50.4 4.0 X 5.0 20.0
. p# Q, _5 R9 U6 g8 K22.0 4.5 X 4.0 25.0
- z" J7 ?' G" b [84.6 4.0 X 4.5 11.1 Y- Z) {# Q% U( t
85.9 4.5 X 5.5 9.0
" L& C3 k+ z6 f$ H$ JAv. 14.3
# `% Q' D+ M' |) o% d" v49 F* w. H, f! o' D$ O
8
* s0 ^' v: d/ A" }. s3 E10
; l( [7 n! L# S C! x12
) h- F3 V# c* v4 w+ U17
/ i t: S0 E K% w% M/ {Topical testosterone- C/ L4 J: g0 ~' L5 X
34.6 4.5 X 6.5 856 l8 I# O9 C: K
38.8 6.0 X 8.5 70
; _: ?- e6 B; o' l6 _% _40.0 6.0 X 6.5 62.5
$ c8 i! d9 j" `( U% }93.6 6.0 X 7.0 55.5
9 i9 N3 y# Y' H" @95.0 6.5 X 7.0 27.2
: K' }& L# N5 n9 N. w* [+ NAv. 60.0# g2 Q$ f( Z8 G* ^! }$ [
available testosterone. Again, emphasis should be placed on
' c) W* \, f8 Q: B2 Learly therapy when lower levels of testosterone appear to z) {* _" ~4 _$ ^2 B
provide the best responses. The earlier therapy is instituted" s$ s" d) O" j$ l2 O
the more likely there will be an excellent response with low4 J7 k1 G3 f4 ^ W2 E% o
serum levels. Response occurs throughout adolescence as/ j$ J, |" J/ C2 x0 m; N
noted in nomograms of phallic growth. 7 The actual response
* ~8 H0 s; R1 G/ gto a given serum level of testosterone is much greater at birth, ~3 U- R0 q: o3 L( T
and gradually decreases as boys reach puberty. This is most7 R0 o5 w4 y2 d* W
likely related to the conversion of testosterone to dihydrotes-& u0 p$ C" Y2 i8 D
tosterone and correlates well with the studies of testosterone
- \' ~; S) S& C' Vconversion in foreskin at various ages.
! s; L' C- W) a7 E2 A3 [The question arises regarding early treatment as to whether
5 j$ c( n% N" V' s& M: Lone might sacrifice ultimate potential growth as with acceler-
; D( E( D7 G8 O, U6 [. H2 Vated bone growth. The situation appears quite the reverse5 G* X0 t( p9 \) P I9 z
with phallic response. If the early growth period is not used& H" M, }! }5 w: L
when 5a reductase activity is greatest then potential growth0 ]: S {6 E$ Z" y( z; C( C
may be lost. We have not observed any regression of growth
0 Y3 D, T- F% S8 i# P+ \9 y3 N* Vattained with topical or gonadotropin therapy. It may well3 T0 Q; Z2 j% t3 f9 _
be that some patients will show little or no response to any
6 M4 M, f3 n3 d, M5 L, sform of therapy. This would suggest a defect in the ability to( _, p9 b( Z6 r& W
convert testosterone to dihydrotestosterone and indicate that' K: }( P$ E' G2 V: k: k
phallic and peripheral skin, and subcutaneous tissue should, R: h- ~- X$ v0 u, ~* i8 u
be compared for 5a reductase activity.# {6 W+ z( ]% O/ K
A, loop enlarges to measure penile girth in millimeters. B,4 {7 }9 p- b% @8 t2 q% [; R7 |
example of penile girth computed easily and accurately.3 ~ O: ]2 U, l% U8 j+ Z5 c5 b
conversion of testosterone to dihydrotestosterone. It is in this
- P3 r0 H# |' w2 Z% z, rolder group that others have noted high levels of serum, f6 j3 _ M; R7 |
testosterone with topical application. It would also appear9 Y8 a4 B( \+ B
that phallic response during puberty is related directly to the) b2 V) \" y9 p) r
serum testosterone level. There also is other evidence of local5 O( j u5 v+ B/ Q
response to testosterone with hair growth and with spermato- I" m, I7 B( _; S# d6 r
genesis. 5• 6* f2 }8 P' B/ O4 H8 \/ p6 W
Administration of larger doses of gonadotropin or systemic
5 K, C7 B' Y# w* o( i; i1 s2 btestosterone, as well as topical applications that produce W" Y# J& j" O5 v% B
higher levels of serum testosterone (150 to 900 ng./dl.), will4 b7 S- z7 F; {! c8 h5 h. v
also produce phallic growth but risks accelerated skeletal
6 a7 ?3 @, F4 r7 G4 x% J+ a9 o4 }maturation even after stopping treatment. It would appear
4 L$ K: u8 a1 r* }7 V) Vthat this may be avoided by topical applications of testosterone
& d" P; W- I- E) Vand monitoring of serum testosterone. Even with this control
2 Z+ N5 w" _$ r' |# j, q0 C5 Zthe duration of our therapy did not exceed 3 weeks at any8 J$ k1 K+ ^! I& J' t) F+ I" w& l
time. It is apparent that the prepuberal male subject may, j0 g$ O) E- ?5 l( V: X
suffer accelerated bone growth with testosterone levels near6 H$ ^; S) P I; Q
200 ng./dl. When skeletal maturation is complete the level of) Z n5 T0 u8 `" o' j# g; C
serum testosterone can be maintained in the 700 to 1,300 ng./; n8 H6 `6 G9 C! y7 \
dl. range to stimulate phallic growth and secondary sexual
* h* r& ?) V. X, qchanges. Therefore, after skeletal maturation parenteral tes-
7 Y( I r& u ptosterone may be used to advantage. Before skeletal matura-
& ^: g3 I" P3 E: k% K$ f) }( vtion care must be taken to avoid maintaining levels of serum
; ^* N4 N, K* d% f" ^" T- Vtestosterone more than 100 ng./dl. Low-dose gonadotropin, h6 y+ t6 q4 j
depends upon intrinsic testicular activity and may require
l: K1 r) H, Z# n' ]4 F1 `prolonged administration for any response.4 S; E( |3 @& j
Alternately, topical testosterone does not depend upon tes-+ E8 @, N3 S) E2 r
ticular function and may provide a more constant level of. c; O, ^3 A- x. _9 ?
REFERENCES
6 u2 S# V$ e0 h' W3 Q8 K) ~1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,, E4 \; h) b; J/ |8 u
R.: The local application of testosterone cream to the prepub- `/ u9 V, n7 Q( o# [
ertal phallus. J. Urol., 105: 905, 1971.
$ [$ e2 u( Q G1 k/ e2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 O8 ~/ v7 h( ptreatment for micropenis during early childhood. J. Pediat.,( B$ L& U( b6 o' ~$ u, A) S
83: 247, 1973.
& k% u. j8 k! { X5 o# ~3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, Y) P; V9 ], U- N+ s3 q
one therapy for penile growth. Urology, 6: 708, 1975.& p' g# ]: c3 e$ T3 `+ F/ F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone( g. Y& J+ `% ~3 i( E* h; k
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 S4 T0 H6 ?5 W4 v2 y% t& j) F! n1 wskin slices of man. J. Clin. Invest., 48: 371, 1969.
9 W) c" g7 v; @5 V/ t! j' n2 ^; J5 U5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, y. l( F/ q7 p! _/ f
by topical application of androgens. J.A.M.A., 191: 521, 1965. D8 P6 m$ ?% Y/ i+ P5 q: `# G
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 H5 Y( g: u4 i$ A7 dandrogenic effect of interstitial cell tumor of the testis. J.
/ W* e! i: g6 e- L. O* hUrol., 104: 774, 1970.; j4 k* i& w0 H, k
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( d. N. k! U7 w$ Mtion in the male genitalia from birth to maturity. J. Urol., 48: |
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