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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 E1 N# B; V: E4 q! n$ P, _; I
GONADOTROPIN
6 _$ k! t) W$ N8 c" PRICHARD C. KLUGO* AND JOSEPH C. CERNY
8 o8 F) H) B' Q% M) MFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
- ?6 N w& a% S2 ~3 ^ABSTRACT
. z* J+ _( C+ c: IFive patients were treated with gonadotropin and topical testosterone for micropenis associated) p' u5 v( v. V& f& R# ?
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' p, ]+ @7 J& ktropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone9 i+ L$ K" P* W9 v7 ^
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 G3 K7 h+ U) Jfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 D7 ?; B# |% I3 U% b5 Q9 e8 Zincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average! e Y$ j' N$ R [% R, l- [
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response- j# k* v: u# \8 p
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ y4 ^# u0 T) z: \
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 }0 K- ]' H) _8 q% n R, ~* d
growth. The response appears to be greater in younger children, which is consistent with previ-
* }3 c; O2 z9 t. dously published studies of age-related 5 reductase activity.
% W9 W& _1 M* _Children with microphallus regardless of its etiology will
! o, B1 o2 O( _) G+ z: v+ rrequire augmentation or consideration for alteration of exter-
; S! B4 q( i# F8 A8 v+ R/ _+ I- j" _1 pnal genitalia. In many instances urethroplasty for hypo-
8 h1 p9 f1 F6 e8 m, D3 \/ rspadias is easier with previous stimulation of phallic growth." J, t$ v; o4 y+ W+ C
The use of testosterone administered parenterally or topically: k0 n: e2 @& k& F' b
has produced effective phallic growth. 1- 3 The mechanism of, b+ W7 N; Z6 O8 Z
response has been considered as local or systemic. With this/ I* i" f" d& K; r" ?+ O5 e* Y
in mind we studied 5 children with microphallus for response i0 b! A' W4 O
to gonadotropin and to topical testosterone independently.; f, x \3 z; `
MATERIALS AND METHODS4 j0 X: C, z5 x
Five 46 XY male subjects between 3 and 17 years old were
; {) H. ], W/ D ^( ]evaluated for serum testosterone levels and hypothalamic V3 j, |, x" X9 S0 @) l; [9 A1 H
function. Of these 5 boys 2 were considered to have Kallmann's
4 k3 a) W4 x- j8 V: U$ }0 {syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( C# h- u, j# E# C& hlamic deficiency. After evaluation of response to luteinizing
7 M# a* _3 X8 _3 d4 phormone-releasing hormone these patients were treated with1 O/ e3 Y: Z) I0 G: C9 L) |& m5 k
1,000 units of gonadotropin weekly for 3 weeks. Six weeks, i' y9 F2 O; s& S
after completion of gonadotropin therapy 10 per cent topical
+ ^- y% g0 T! Etestosterone was applied to the phallus twice daily for 3 weeks.
$ W3 A; J# ` t0 `Serum testosterone, luteinizing hormone and follicle-stimulat-
, h( K* r/ Q( H* ving hormone were monitored before, during and after comple-& V# Z. T. N# Q: T
tion of each phase of therapy. Penile stretch length was# s! e$ k0 r3 ~7 M2 |
obtained by measuring from the symphysis pubis to the tip of
4 f- n) m1 {7 a! Z/ f. Ithe glans. Penile circumferential (girth) measurements were
9 _ e+ g' a! U! B2 ~. [obtained using an orthopedic digital measuring device (see
$ X' k1 L- a8 N" Zfigure).9 U* \5 ?' U4 a2 a% x1 ]# w
RESULTS+ R3 \- h) s% L! ^! l7 ^% x% O* y
Serum testosterone increased moderately to levels between
/ I* y" D% m. m' C( c! c- [50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 o0 X- W0 {( h. Mterone levels with topical testosterone remained near pre-5 R* b7 q$ n1 R+ c0 U( T
treatment levels (35 ng./dl.) or were elevated to similar levels
6 O/ w: B6 ~) c& E" v" s9 J, K) edeveloped after gonadotropin therapy (96 ng./dl.). Higher9 T# Y3 S" X% @5 `( H) I
serum levels were noted in older patients (12 and 17 years old),
7 m$ A, y' U% dwhile lower levels persisted in younger patients (4, 8, and 10
9 J5 J, [1 t, \) e S' }years old) (see table). Despite absence of profound alterations3 y2 v! d' z3 b" |- c
of serum testosterone the topical therapy provided a greater/ b, o- l. h+ |1 j/ B3 U& m
Accepted for publication July 1, 1977. ·
" e3 A U0 b/ F0 F, K# }1 V, @Read at annual meeting of American Urological Association,
P4 H+ Z, `. q. BChicago, Illinois, April 24-28, 1977.
" N% e4 ]4 X- D o* Requests for reprints: Division of Urology, Henry Ford Hospital,
5 K% W# V9 X( H5 g( _9 r2799 W. Grand Blvd., Detroit, Michigan 48202." a2 `. F3 y4 U+ n! D% f( k
improvement in phallic growth compared to gonadotropin.
) P9 P/ n1 `% M9 A4 a9 e+ vAverage phallic growth with gonadotropin was 14.3 per cent, D- ^+ M! X3 l$ P$ f
increase in length and 5.0 per cent increase of girth. Topical
1 Q, D' i0 `8 e) l' o' ztestosterone produced a 60.0 per cent increase of phallic length
2 ^: M2 n5 _! Rand 52.9 per cent increase of girth (circumference). The: C1 A7 {& d( \2 ]) w# W
response to topical testosterone was greatest in children be-8 g( k3 C0 s( K! G5 _
tween 4 and 8 years old, with a gradual decrease to age 17& x# g3 y; M! M8 Z
years (see table).: R3 ^) _. y+ {. R
DISCUSSION) X4 c( s& z: h; v) _3 p
Topical testosterone has been used effectively by other
' m5 Y8 G. \5 E2 g3 aclinicians but its mode of action remains controversial. Im-
/ f' n' ^9 i' N2 gmergut and associates reported an excellent growth response$ m: {) N1 I7 v( k+ R) W
to topical testosterone with low levels of serum testosterone,
8 Y- L/ A3 O" h7 p8 Nsuggesting a local effect.1 Others have obtained growth re-
& ~4 e4 G Y- j3 X( v8 b: d9 w' @2 ]sponse with high. levels of serum testosterone after topical- y. G2 H8 X. b8 b: p x, M$ w" q
administration, suggesting a systemic response. 3 The use of
/ K/ g+ K/ A8 }1 Wgonadotropin to obtain levels of serum testosterone compara-" J& R' o. A; X9 p4 ^! |# d
ble to levels obtained with topical testosterone would seem to9 E4 b2 q4 H: x. W I1 X% ~
provide a means to compare the relative effectiveness of# j7 o8 h# G( q. ^6 w; y0 Y1 M& I+ b
topical testosterone to systemic testosterone effect. It cer-" L5 Y4 H6 T# C& e! w
tainly has been established that gonadotropin as well as par-- i3 y" k! i0 ?# P
enteral testosterone administration will produce genital
6 \+ W) c& Y+ V8 Y8 S) ?growth. Our report shows that the growth of the phallus was
; t' T* g) r3 j; G; jsignificantly greater with topical applications than with go-
6 Z! P6 I l3 @# hnadotropin, particularly in children less than 10 years old.
" o/ a3 } `; E2 x9 GThe levels of serum testosterone remained similar or lower8 }9 B8 G) `- W9 y% n9 W5 M7 ^
than with gonadotropin during therapy, suggesting that topi-. H3 @7 ]9 q$ T1 M* F0 P/ w/ a
cal application produces genital growth by its local effect as2 U* T0 i# N4 q% ^4 @0 r
well as its systemic effect.
. O8 t) Q5 a$ W5 b! Z; rReview of our patients and their growth response related to
1 d9 R* u9 H6 R, A( Bage shows a greater growth response at an earlier age. This is
, ^7 G) t8 A1 ~, }# M; rconsistent with the findings of Wilson and Walker, who
1 o) _) n9 G- h8 a8 q( \! @- h9 _$ f3 Preported an increased conversion of testosterone to dihydrotes-7 Z& }+ h+ ]) f: |
tosterone in the foreskin of neonates and infants.4 This activ-: z. p( T0 I/ z! l* d4 q
ity gradually decreases with age until puberty when it ap-4 q( i% `2 z" R/ e+ J9 w) a) V; e2 b5 K
proaches the same level of activity as peripheral skin. It may
2 Q7 |, y6 _% [' I, P+ R- N7 awell be that absorption of testosterone is less when applied at* [* x* m" D1 H3 Y. D# e
an earlier age as suggested by lower serum levels in children
7 M6 H M. w5 X( Q4 ?less than 10 years old. This fact may be explained by the, I y% j. ?* \& n
greater ability of phallic skin to convert testosterone to dihy-
8 k9 s+ A* }0 Z5 e- \. gdrotestosterone at this age. Conversely, serum levels in older& R" e8 F% F% f& w. @1 g
patients were higher, possibly because of decreased local
+ X, b9 _9 T- T! P T5 a667: H' `4 J1 e' K
668 KLUGO AND CERNY
' ^$ t3 o0 \ w$ KPt. Age
5 a3 g6 G1 u0 L! a5 D: K$ e. l(yrs.)7 G: V2 f( x l5 a; q2 ^* l! e) k
Serum Testosterone Phallus (cm.) Change Length* z' l9 `$ H4 _
(ng./dl.) Girth x Length (%)) T& ^) q5 r: D; _- x
4
, ]% d! ]; F# d& ~88 D9 d, \1 j; Q1 _, z
10, I0 Z/ t8 P s6 g' C" f, W: V
125 [# r% ~- r9 Z
17
* S' z# h8 B% @6 j) G! b9 x( ]Gonadotropin
5 H ^+ _5 {; A$ E) s3 ], l71.6 2.0 X 3 16.6
, d; Z' J8 o4 T- p! j50.4 4.0 X 5.0 20.0
6 q3 {- q$ e. p6 } t% V5 W22.0 4.5 X 4.0 25.07 z) X8 t6 R$ y* c6 P$ \5 P7 q! ~
84.6 4.0 X 4.5 11.1
' Q/ ?; y [& R) i85.9 4.5 X 5.5 9.0, u1 g |; ~" ]# V
Av. 14.39 ^1 t, q& c5 \# N2 Q
4! g& s6 {8 W( p: c* g, n/ `
8- g: i- c. {/ Q0 n4 ~: j) Z
10
2 n2 N& Z+ D4 i. ?5 n+ ?/ m12# x, l& x& D6 t! c5 v$ d
17 O: j9 {1 M0 B4 P" o
Topical testosterone
: |( J- v6 v4 P6 j1 A2 w34.6 4.5 X 6.5 858 e A, G8 B% ]
38.8 6.0 X 8.5 70( K; }# V1 M& c
40.0 6.0 X 6.5 62.5
5 X& @) K& ]2 L+ b0 S93.6 6.0 X 7.0 55.52 `) X+ A9 E0 ~' s1 J3 |; c
95.0 6.5 X 7.0 27.29 x/ G/ O6 d; b
Av. 60.0& o8 d; V+ G: v# A2 h0 @
available testosterone. Again, emphasis should be placed on
" Z9 Y+ q9 I' ~# ]& r$ Mearly therapy when lower levels of testosterone appear to
1 `9 f5 ]5 `- S9 eprovide the best responses. The earlier therapy is instituted" |1 b/ C5 B `' x
the more likely there will be an excellent response with low
3 K: b9 w% ?6 q8 i# u6 g% w0 T+ lserum levels. Response occurs throughout adolescence as8 V3 G2 h1 j8 O
noted in nomograms of phallic growth. 7 The actual response7 Z# g# N' Y: s9 \% \' {
to a given serum level of testosterone is much greater at birth6 k8 N% J3 w6 v8 g0 Q
and gradually decreases as boys reach puberty. This is most( F7 x' W- m- d* @9 D$ C
likely related to the conversion of testosterone to dihydrotes-% ~+ |. B3 j3 w" X, v1 O3 i( B6 i! x
tosterone and correlates well with the studies of testosterone
3 e, q# V/ I1 D; |! @$ C1 Zconversion in foreskin at various ages.
0 x% M( ]: P# R1 S( c: aThe question arises regarding early treatment as to whether
) y' S* R! A- \$ tone might sacrifice ultimate potential growth as with acceler- s/ E; F, p: `/ D. i+ o5 ]. z" O! S
ated bone growth. The situation appears quite the reverse
! _$ m/ ^8 o" n* v6 Fwith phallic response. If the early growth period is not used0 a6 n4 n" }4 N. r- U; ^
when 5a reductase activity is greatest then potential growth$ Y$ h7 V8 X4 q" B" p
may be lost. We have not observed any regression of growth
/ m7 j/ w2 \, n, u$ Zattained with topical or gonadotropin therapy. It may well5 N. I5 _1 l1 j" u6 o
be that some patients will show little or no response to any
4 H- N3 O) E6 C4 {3 V8 D# _- Oform of therapy. This would suggest a defect in the ability to
$ x5 G# ^: I. ^/ S3 qconvert testosterone to dihydrotestosterone and indicate that, ]. z i2 z$ e+ J% ^9 L+ I# Q
phallic and peripheral skin, and subcutaneous tissue should: z, ^# l0 C m+ k' z" O. w
be compared for 5a reductase activity.% O* S6 C- J3 G8 h; [
A, loop enlarges to measure penile girth in millimeters. B,2 m P% u% i/ T4 A, F( ~
example of penile girth computed easily and accurately.
: H4 {8 v! u0 K- qconversion of testosterone to dihydrotestosterone. It is in this+ z+ K2 J4 M+ H$ I/ p* R& h
older group that others have noted high levels of serum$ H& L9 i! S2 q/ A3 {, I, ^- Y
testosterone with topical application. It would also appear
* u& j1 j2 u+ t$ j: ~# [ xthat phallic response during puberty is related directly to the
( P K5 b5 y# [) _3 aserum testosterone level. There also is other evidence of local
- D- |! Y: G* z. S% Aresponse to testosterone with hair growth and with spermato- m" ]& K: A1 C* |* H
genesis. 5• 6! n- S& O& \0 _8 b; ]3 P( R, K6 X! t
Administration of larger doses of gonadotropin or systemic5 T& g5 s/ H) l# H0 w M3 M
testosterone, as well as topical applications that produce
6 \0 Q. P2 D# J. s: c& X, M1 bhigher levels of serum testosterone (150 to 900 ng./dl.), will
" J# S* U( R2 \9 \ `& C9 s* falso produce phallic growth but risks accelerated skeletal2 S8 J) H- h. ^
maturation even after stopping treatment. It would appear; D, H$ ^4 J% Z2 l: ]) v1 b+ d1 q
that this may be avoided by topical applications of testosterone5 U; Q6 b, a6 ~3 K: ?9 ]5 A) [+ [
and monitoring of serum testosterone. Even with this control& J/ V8 r0 M& ]: O1 ]- L$ ?
the duration of our therapy did not exceed 3 weeks at any; Y3 G" |, M3 l5 W6 x* T; V6 ^
time. It is apparent that the prepuberal male subject may2 _! F- Z% @7 Y- H8 Q. _2 m
suffer accelerated bone growth with testosterone levels near
9 T6 y5 `$ d0 M: |0 L+ K200 ng./dl. When skeletal maturation is complete the level of
# }6 ]" K. L" m0 f- z: }2 \serum testosterone can be maintained in the 700 to 1,300 ng./
" q$ Q# B' h1 ?& Edl. range to stimulate phallic growth and secondary sexual
6 r5 T9 }; M4 e( Q" T8 n8 Ochanges. Therefore, after skeletal maturation parenteral tes-2 Z+ G, J1 u: _* P0 N
tosterone may be used to advantage. Before skeletal matura-3 Z+ [ T- q; ~
tion care must be taken to avoid maintaining levels of serum* `2 O7 u# c, n, I5 e
testosterone more than 100 ng./dl. Low-dose gonadotropin5 r, o9 A1 y+ h1 J/ ^
depends upon intrinsic testicular activity and may require
& u1 X: a3 L) I3 m6 e! y- tprolonged administration for any response.
3 {; C7 m( I$ _' y; U' QAlternately, topical testosterone does not depend upon tes-( N7 y6 a: U0 {, x o
ticular function and may provide a more constant level of
: D: ]& j! V/ W* X* oREFERENCES
^( Z% n9 g# d: o; O1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 n _' e* q Z# Q
R.: The local application of testosterone cream to the prepub-
% ?7 u! O! ~, q. Wertal phallus. J. Urol., 105: 905, 1971.
8 a3 j) h d- H( w: ?# d e2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 ~7 H3 ?+ L% I0 Z" Ctreatment for micropenis during early childhood. J. Pediat.,
: H- H1 b, ^6 ]# @6 Y83: 247, 1973.
1 P: g, h2 \% n) \4 n+ z5 d3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* A1 ~0 B2 `1 J. Uone therapy for penile growth. Urology, 6: 708, 1975.
) v: d" E1 [* r6 a" o: N, d% w4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 U5 B! r) J* c; `$ Uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
8 @6 ~0 z% _( g0 Mskin slices of man. J. Clin. Invest., 48: 371, 1969.4 _$ b& Q9 U7 Z! O+ Z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 `1 q/ S7 R0 K: e6 w
by topical application of androgens. J.A.M.A., 191: 521, 1965.+ u* W/ e1 P% v
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 Q# d+ k- k6 G% Iandrogenic effect of interstitial cell tumor of the testis. J.
5 Y! T0 {( |+ A0 ]: w: k, qUrol., 104: 774, 1970.) h0 c5 Q& K4 Q8 _& L
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( X2 _9 l- Z% ~1 F& u
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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