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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# ^- Y4 ~2 w% B8 ~+ y- w
GONADOTROPIN& M1 G) n5 K- ?0 [1 B: v
RICHARD C. KLUGO* AND JOSEPH C. CERNY8 A! Y7 J) F9 `2 m0 ^; z$ i: B* S' k
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan A* I2 v' l7 `* D" Q" @* X/ r
ABSTRACT
( y- `9 h) e* f( H% a' FFive patients were treated with gonadotropin and topical testosterone for micropenis associated
4 N& M5 @7 }! Z; W ^4 c7 ^0 @9 |with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
" ^) p$ }! q* {" Vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: k# W8 v* |- J4 T) S; S! }cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' K) V7 X0 J2 k1 [2 |8 [
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent7 u5 d7 x, ?( T5 \' M
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average. x. y5 g1 y; s$ x; O8 b
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: e. s( P O# t" a: M6 doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
$ e' q, D4 F0 `6 H9 C' estudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 h$ I/ ~/ V4 W% |growth. The response appears to be greater in younger children, which is consistent with previ-
: _, C! _1 V" N1 z5 B5 Lously published studies of age-related 5 reductase activity.( W$ n# f- M: g- \( s0 t5 G2 [
Children with microphallus regardless of its etiology will
' Y8 N1 w1 [" Hrequire augmentation or consideration for alteration of exter-2 d% [# u5 L9 K2 A8 P, H
nal genitalia. In many instances urethroplasty for hypo-# w$ x# t5 G( `( z* X' x
spadias is easier with previous stimulation of phallic growth., h- ]8 e5 `+ Z/ p' Y
The use of testosterone administered parenterally or topically
& z' g/ ?/ c0 w. ~1 t) ghas produced effective phallic growth. 1- 3 The mechanism of+ i' ]/ B1 b% O) {3 Z& y9 X
response has been considered as local or systemic. With this
1 ]) A- ]+ H; L$ P5 }( i2 u( ?in mind we studied 5 children with microphallus for response
7 _6 l8 f( y7 A7 D, }to gonadotropin and to topical testosterone independently.: g) U% y8 G+ J; G. g% ?4 N6 ^8 i
MATERIALS AND METHODS
) d& x3 Z* w1 g" v3 `, ]& OFive 46 XY male subjects between 3 and 17 years old were; i: f6 s0 s* c. t6 B: Q9 Y" f" Z
evaluated for serum testosterone levels and hypothalamic- K. {9 x9 h8 ?' d0 j6 Y4 U
function. Of these 5 boys 2 were considered to have Kallmann's6 B2 q4 z9 A) ~. h2 _0 |. @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& I' F4 N5 o, H* ?* [& I8 llamic deficiency. After evaluation of response to luteinizing/ y P! p; @+ W) B
hormone-releasing hormone these patients were treated with
5 L% Q8 ]' W/ F* B) F1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& @( `1 P# p, l% C9 uafter completion of gonadotropin therapy 10 per cent topical- ~3 u; B0 L* t+ O! a
testosterone was applied to the phallus twice daily for 3 weeks.0 L5 B& Y+ y, o$ H
Serum testosterone, luteinizing hormone and follicle-stimulat-
7 ]" |' v( x: ning hormone were monitored before, during and after comple-
$ o; j- @ |2 T; Gtion of each phase of therapy. Penile stretch length was
5 Y& _, F8 z' n( Vobtained by measuring from the symphysis pubis to the tip of
/ \3 W1 k5 j; u# [& X3 Uthe glans. Penile circumferential (girth) measurements were
) w4 ~$ T' ]( {' Uobtained using an orthopedic digital measuring device (see4 g# f: E7 s; v, c' t3 N
figure).
3 o+ m5 E0 h+ s! y5 H( ?) ZRESULTS
7 z1 S' |. g9 F" o" V( w' @" _8 R( ?Serum testosterone increased moderately to levels between
, R) v/ B8 `) ^9 I# Y. X' r, J# m50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
" D! }: S& g) j0 i& \; Uterone levels with topical testosterone remained near pre-2 Z* `( e# U$ ~ z$ J
treatment levels (35 ng./dl.) or were elevated to similar levels: o$ F6 a/ _9 F' A, B# x3 k: W
developed after gonadotropin therapy (96 ng./dl.). Higher
$ t+ Q# k8 n& C8 Sserum levels were noted in older patients (12 and 17 years old),% s- ^5 E7 d& h# x$ N5 b9 T6 H z
while lower levels persisted in younger patients (4, 8, and 10& ^( O: K4 \7 | a z* p' {8 S, \
years old) (see table). Despite absence of profound alterations' j+ u3 C7 |7 m, K9 l
of serum testosterone the topical therapy provided a greater- i- J6 N; ^% I: n# K: N/ @# H
Accepted for publication July 1, 1977. ·; z# O4 j, Q8 F" I0 `" Z" z2 c
Read at annual meeting of American Urological Association,6 X* `$ c V% N3 P8 ? K, b
Chicago, Illinois, April 24-28, 1977.
1 G0 Q; X. }* |# u; z* Requests for reprints: Division of Urology, Henry Ford Hospital,# m- r. m6 |9 M" s. [7 d( ^
2799 W. Grand Blvd., Detroit, Michigan 48202.6 l$ M. k* ~$ m" z) r- Q" G
improvement in phallic growth compared to gonadotropin.) p1 \( [* e6 s# R2 y5 z; E
Average phallic growth with gonadotropin was 14.3 per cent% h" M1 M. h* f" N: P/ o
increase in length and 5.0 per cent increase of girth. Topical) k) ~; Y2 h1 H# Q9 ^$ E6 X
testosterone produced a 60.0 per cent increase of phallic length h# J7 Q# h$ j. {
and 52.9 per cent increase of girth (circumference). The9 D* A6 b3 L8 q- C. v9 D( [+ C q
response to topical testosterone was greatest in children be-1 U7 T- P0 M/ i8 n5 s
tween 4 and 8 years old, with a gradual decrease to age 174 ?4 t& X! h. Z" Z4 X
years (see table).
, p. o! _+ |, _9 q4 UDISCUSSION
2 z% v" N9 k5 u* S' uTopical testosterone has been used effectively by other2 `3 J8 H! u0 e" C2 v* R
clinicians but its mode of action remains controversial. Im-
$ [$ \- a% v( i, N4 z& V- Imergut and associates reported an excellent growth response) j7 B u# t1 _; Y; M% n3 G
to topical testosterone with low levels of serum testosterone,
5 P' Y: ~) d7 I) u( K( E2 G9 Jsuggesting a local effect.1 Others have obtained growth re-
& K1 n% e0 \# a0 P9 |: e4 Ysponse with high. levels of serum testosterone after topical
; \8 J% l- I6 ] k1 j* Vadministration, suggesting a systemic response. 3 The use of2 _: Q# @- w! p5 C: N4 X
gonadotropin to obtain levels of serum testosterone compara-
/ z- w5 F/ y0 L- K- S& ]8 I" e Kble to levels obtained with topical testosterone would seem to) g% [2 @& D/ p, o/ s7 V$ V
provide a means to compare the relative effectiveness of
( B4 S8 q, M/ m ^7 R7 u6 x. Gtopical testosterone to systemic testosterone effect. It cer-
! \1 X5 H9 c$ {) X0 Q" _tainly has been established that gonadotropin as well as par-
: i/ b6 Y, j) j. Uenteral testosterone administration will produce genital
% x2 M2 Y* [) N! A4 X6 kgrowth. Our report shows that the growth of the phallus was
! k# z' @3 }; |& X& W1 X; z( Asignificantly greater with topical applications than with go-
% }9 j7 k, C0 \, J! T! Jnadotropin, particularly in children less than 10 years old.) B: c2 g$ B2 x8 E6 ?3 B2 j" J
The levels of serum testosterone remained similar or lower
- r* b4 ~4 `) m" d8 s B$ ^& ]% s; Kthan with gonadotropin during therapy, suggesting that topi-
1 U$ m+ k/ p7 I7 y8 [cal application produces genital growth by its local effect as
; w9 O1 X$ c" Bwell as its systemic effect.% E# d, F1 G$ G* g3 S
Review of our patients and their growth response related to
' T; P) V1 p; o2 [& S+ zage shows a greater growth response at an earlier age. This is
% F# g, o8 _# T' e! d! oconsistent with the findings of Wilson and Walker, who9 ~4 y. O' c0 l% J b1 N2 G/ _
reported an increased conversion of testosterone to dihydrotes-
+ c# D! r) N- `( L4 G6 R: N etosterone in the foreskin of neonates and infants.4 This activ-8 G9 u) G1 ~; Z. `2 q
ity gradually decreases with age until puberty when it ap-
: r: e1 j' f2 Fproaches the same level of activity as peripheral skin. It may! d. F5 ^; w1 u) C/ C- p" E
well be that absorption of testosterone is less when applied at1 j/ X% x Y( }4 U* J
an earlier age as suggested by lower serum levels in children
* S: h2 G1 t9 d+ e/ a4 sless than 10 years old. This fact may be explained by the/ T" j b" I$ o& W+ \
greater ability of phallic skin to convert testosterone to dihy-
1 C' D. U+ ~5 {- k& Xdrotestosterone at this age. Conversely, serum levels in older
9 {+ Y w2 Z D' S6 Y, t+ ^; K) qpatients were higher, possibly because of decreased local% e4 ]. t- K: }3 Z+ m" p
667" J9 `( R* w. `: x( E4 k* X* \
668 KLUGO AND CERNY$ W8 e, c7 q4 [1 \' Y$ W, V g- o
Pt. Age
; p" M# A$ ~5 T# C0 j2 \, ?# G(yrs.)) u8 z) W! B! n5 Z
Serum Testosterone Phallus (cm.) Change Length
" E$ p" e- p7 p; S(ng./dl.) Girth x Length (%)
4 h# b! T- l* q5 r; {+ d49 p5 E% r6 I C8 L
8
$ r# K1 P7 ^4 f! H0 V* ~10
3 Y3 l- w! \) i) ?12
6 c; K* A2 O# p# r4 z+ p% l17
% |2 ?) j9 t0 ~& D" pGonadotropin/ d3 v* ]/ R( A
71.6 2.0 X 3 16.6& W7 Q; r& c5 A5 p4 c
50.4 4.0 X 5.0 20.08 E" f8 l* n( N; _' U) T+ [ {
22.0 4.5 X 4.0 25.0
3 g/ B: Y, Y" M S' b M84.6 4.0 X 4.5 11.1/ U$ L5 L' o+ [ N8 o& a
85.9 4.5 X 5.5 9.0
6 d8 k3 ]3 f9 D {9 U: @Av. 14.35 u. {5 d, n, U/ c. M
4
- R; r, t L/ @0 Q$ g$ I8% @3 u6 H( i' W, P
10, v4 f; U% N$ s
12
# f- U4 D! [6 z+ d17* ~+ F7 o1 ~ [3 e
Topical testosterone4 v+ k8 M# d6 }, ~; b, Z
34.6 4.5 X 6.5 85
% r% s2 _. w: L/ C' O5 ~38.8 6.0 X 8.5 70$ z) a2 B) ~) d$ e4 p' U
40.0 6.0 X 6.5 62.5
. H( T% ^) q4 l4 X: L93.6 6.0 X 7.0 55.5
5 n Y( Q& p2 W7 G& N4 G95.0 6.5 X 7.0 27.2
2 f6 ?0 a1 g; ^" o, [Av. 60.0
4 }' n% ` M% ravailable testosterone. Again, emphasis should be placed on2 x y" ^+ h2 t! F0 r m9 r
early therapy when lower levels of testosterone appear to5 A2 Y* D% B7 l# W3 f' V1 V5 ~
provide the best responses. The earlier therapy is instituted6 A6 s% F% O, q z
the more likely there will be an excellent response with low
* N% b& n8 l. c$ q! @) @serum levels. Response occurs throughout adolescence as
4 r5 ~& G$ y4 znoted in nomograms of phallic growth. 7 The actual response+ D, P: j/ z9 D. N( @2 q
to a given serum level of testosterone is much greater at birth
d5 f) w' c! N9 rand gradually decreases as boys reach puberty. This is most4 \) e% ~. H! p- c: X! q9 I$ h
likely related to the conversion of testosterone to dihydrotes-
4 |5 e5 ~$ g( [3 ^tosterone and correlates well with the studies of testosterone
* u- ?, {2 |3 @3 I" Zconversion in foreskin at various ages.
/ J- P4 X7 f* e2 @, BThe question arises regarding early treatment as to whether5 A9 n( B# w. P- T' W8 M' m! C
one might sacrifice ultimate potential growth as with acceler-
8 {$ ^0 q' A: t0 ]/ \7 c" Sated bone growth. The situation appears quite the reverse
( L0 A9 f7 k: Swith phallic response. If the early growth period is not used
3 i- G4 b* b# d' swhen 5a reductase activity is greatest then potential growth0 b3 D( @( q9 h5 r6 {0 Z! {9 A$ s
may be lost. We have not observed any regression of growth! _1 K: N' t# Y0 H2 i
attained with topical or gonadotropin therapy. It may well
7 R9 k6 L" Y# C6 z) l- Lbe that some patients will show little or no response to any6 J% @8 {* O3 ]) }3 e+ \; Q
form of therapy. This would suggest a defect in the ability to
1 }2 D7 Z" u9 s* sconvert testosterone to dihydrotestosterone and indicate that
5 O1 v+ y0 G4 q3 d7 Vphallic and peripheral skin, and subcutaneous tissue should
/ Z. U9 Z0 D4 x' j! }be compared for 5a reductase activity.
: O. N+ B6 S( x2 i4 P& ]A, loop enlarges to measure penile girth in millimeters. B,
* d+ ~; Z( N$ S( E3 N+ b7 _+ [example of penile girth computed easily and accurately.& u# f9 E# B% w6 P: _+ L) z: z* V
conversion of testosterone to dihydrotestosterone. It is in this: t$ W7 L7 N- F! f1 ]) \
older group that others have noted high levels of serum- M) z# N5 ]- J! D7 G
testosterone with topical application. It would also appear
" C- F' R/ m. g- nthat phallic response during puberty is related directly to the0 A* @ n# v8 c
serum testosterone level. There also is other evidence of local
1 Q5 ~/ k* C9 {0 y; kresponse to testosterone with hair growth and with spermato-
* v/ h% | \+ F0 E4 |genesis. 5• 6
9 W5 o; ]$ V# X) @0 dAdministration of larger doses of gonadotropin or systemic& Y8 e4 C* b) q) i; i% Z0 Y/ v
testosterone, as well as topical applications that produce7 t" j) i+ N+ h8 p, a- M
higher levels of serum testosterone (150 to 900 ng./dl.), will( `' O8 P0 _* e7 k' w1 v/ M+ A
also produce phallic growth but risks accelerated skeletal
2 c# d' E0 u! z: X/ { s3 Bmaturation even after stopping treatment. It would appear/ a6 q* p! Y* a4 g' q
that this may be avoided by topical applications of testosterone) v; R! [' @' E% T% k
and monitoring of serum testosterone. Even with this control+ L% t( N* _% Q" M8 ^# `5 h5 G6 ^
the duration of our therapy did not exceed 3 weeks at any
/ j9 \& t/ e% Q( I# | Stime. It is apparent that the prepuberal male subject may
" i- m1 C+ Z2 Q" E7 Lsuffer accelerated bone growth with testosterone levels near' Q1 M/ q- T% t5 m
200 ng./dl. When skeletal maturation is complete the level of
$ d9 J" Q# _. f; q0 Rserum testosterone can be maintained in the 700 to 1,300 ng./
9 R H& H0 A9 y! k M* j ?# Zdl. range to stimulate phallic growth and secondary sexual5 c G' i" ?9 Y0 b, J6 P
changes. Therefore, after skeletal maturation parenteral tes-
1 f- g! y. }% \. T* J0 H( Qtosterone may be used to advantage. Before skeletal matura-
% u5 Q5 b& T/ ?6 Htion care must be taken to avoid maintaining levels of serum( l: U0 X3 l& {5 c6 P
testosterone more than 100 ng./dl. Low-dose gonadotropin j( }, D* [ `/ S2 i
depends upon intrinsic testicular activity and may require: d; z" O& _4 {* n# W/ h
prolonged administration for any response.2 k3 ~4 a% i9 u J- F
Alternately, topical testosterone does not depend upon tes- Y4 K9 _& T( ~# R
ticular function and may provide a more constant level of
: L+ B; ?6 _' q' I, xREFERENCES3 l+ E+ B& m" `+ Q3 L! B
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 Q! a. Y' U4 r% B* w! CR.: The local application of testosterone cream to the prepub-& c. G" F) W$ V \% s; H
ertal phallus. J. Urol., 105: 905, 1971.1 t7 e$ e: k, f7 U: b2 T
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
; u8 ^) b4 a6 u* s5 Btreatment for micropenis during early childhood. J. Pediat.,5 F1 o( Z- Z" Z& i* Q6 u; |. ]5 |4 c
83: 247, 1973.
: F( `) |, ~+ k- x* [3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
2 V* `! J/ M4 x0 J9 cone therapy for penile growth. Urology, 6: 708, 1975.: C$ b9 _5 p* |! {0 w
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone6 ~) Y& J" I; @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by# k/ l- f" c2 J/ ?# C1 K: b R
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 g+ v$ |$ v# B
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
0 P; T, \7 ?0 \$ M6 ~5 F$ G+ rby topical application of androgens. J.A.M.A., 191: 521, 1965.
3 g1 O& ?0 H/ H/ l6 z5 i, e6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 e* o; y6 ?' B( vandrogenic effect of interstitial cell tumor of the testis. J.6 M5 w4 v! G5 o4 w3 b! M8 N, g* d
Urol., 104: 774, 1970.
2 u& L7 o+ C9 [4 _( M7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
# @) @# L0 C8 E I/ G% |tion in the male genitalia from birth to maturity. J. Urol., 48: |
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