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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ e) n, k2 v) t+ ]; p6 u
GONADOTROPIN
* i9 J! p* |5 p3 S6 l1 uRICHARD C. KLUGO* AND JOSEPH C. CERNY
' w) K3 R+ B3 K7 lFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
7 ]; P1 Q; I0 BABSTRACT/ l; c0 V# ?- s" S$ O* ]7 H
Five patients were treated with gonadotropin and topical testosterone for micropenis associated: Z3 b- J, `" m' w" x m3 H+ V" ?
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! I$ v1 u9 _* [& f4 [
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
' o( T0 l8 M5 }. U8 ?: I d6 ncream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 W2 t" J7 C2 j
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 w7 C4 c" s: s' D- f
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average' ?/ e! N5 K3 _1 e" ]9 y9 N
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 X" L7 C" c! Q' y5 H; u% i) Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This4 L& H, |% y- j, S
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ w3 C% D* D1 F9 U
growth. The response appears to be greater in younger children, which is consistent with previ- u/ z& |" F* L2 N7 g" }) Y
ously published studies of age-related 5 reductase activity./ E) t) t# t4 g7 _+ G; T+ E
Children with microphallus regardless of its etiology will
8 v% M- G3 g7 x9 l' [' {9 k/ Wrequire augmentation or consideration for alteration of exter-) V+ U- G2 X' s, U& b/ w
nal genitalia. In many instances urethroplasty for hypo-3 w- S& a3 J6 h4 [& k5 _
spadias is easier with previous stimulation of phallic growth.) L) c- q8 v3 @ F
The use of testosterone administered parenterally or topically
: h0 B3 T, h A; {: c, S8 O- {/ fhas produced effective phallic growth. 1- 3 The mechanism of
" Q7 I# Y2 W- H% n% Kresponse has been considered as local or systemic. With this" \2 ]( }& v `3 b
in mind we studied 5 children with microphallus for response; _' E/ C0 {' T" X$ S* G
to gonadotropin and to topical testosterone independently.( [7 Z5 Y1 C5 s
MATERIALS AND METHODS6 H% \, t/ ^* j0 }1 i
Five 46 XY male subjects between 3 and 17 years old were
9 D0 ?& M1 |; pevaluated for serum testosterone levels and hypothalamic
# G" p/ U2 [! E) Zfunction. Of these 5 boys 2 were considered to have Kallmann's
; r. g/ i5 A) M/ C2 U1 Jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
" ?/ D1 v Z C5 F- L A: alamic deficiency. After evaluation of response to luteinizing
: x. T$ C$ k5 N# uhormone-releasing hormone these patients were treated with7 A6 T" Y# k2 ?. u+ [( d
1,000 units of gonadotropin weekly for 3 weeks. Six weeks: n/ L0 ]* H' m# d0 [
after completion of gonadotropin therapy 10 per cent topical
h0 }5 I$ Q) V3 |' C* \$ z2 Otestosterone was applied to the phallus twice daily for 3 weeks.
, o. C/ h! D8 t; I. WSerum testosterone, luteinizing hormone and follicle-stimulat-
2 q1 F" A8 k a% ling hormone were monitored before, during and after comple-1 f1 a" i; {% j! w) L2 Q, }
tion of each phase of therapy. Penile stretch length was- u: y! ^9 q" ^/ ~0 `$ K k7 m) P
obtained by measuring from the symphysis pubis to the tip of
! u. G$ Q9 a! @4 b9 P( Sthe glans. Penile circumferential (girth) measurements were; `0 b, M4 z# {( h5 M& i, [, Y
obtained using an orthopedic digital measuring device (see9 l- C! _+ {9 \" @- I! n4 l) M
figure).% t# r- g# g/ N: R% y+ K
RESULTS0 q& W0 a; h2 @/ i
Serum testosterone increased moderately to levels between
1 K7 W6 ]9 ?. Z1 X% S50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-2 o. S& s+ R& w( Y
terone levels with topical testosterone remained near pre-3 `8 r: \; Z4 X% T7 ?+ T k- [
treatment levels (35 ng./dl.) or were elevated to similar levels+ ^0 `3 e3 q) A) ~* O4 a( w1 N
developed after gonadotropin therapy (96 ng./dl.). Higher
2 z v; F5 V0 hserum levels were noted in older patients (12 and 17 years old),
6 y3 V6 @5 m s; e/ ^while lower levels persisted in younger patients (4, 8, and 10 f1 H. h1 ` U* t' o/ E$ Z
years old) (see table). Despite absence of profound alterations
3 v/ d2 Z( T- ~& ]$ s4 ~2 X; Lof serum testosterone the topical therapy provided a greater
: c7 j8 o O0 Y# zAccepted for publication July 1, 1977. ·2 z+ T! O3 H0 Y* s
Read at annual meeting of American Urological Association,+ |2 P6 A5 X# F' b) u8 |
Chicago, Illinois, April 24-28, 1977." ?; k/ d4 d3 G5 O
* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 f& z/ e$ f) I' K# l6 [" G5 v0 g2799 W. Grand Blvd., Detroit, Michigan 48202.: }7 O. {- N! p! i2 f3 f
improvement in phallic growth compared to gonadotropin.
0 `5 w, v" j9 s$ {1 g1 pAverage phallic growth with gonadotropin was 14.3 per cent/ u# X1 b* x6 i: o d
increase in length and 5.0 per cent increase of girth. Topical' d/ m8 @; |' O' {# k( p1 {+ E$ K
testosterone produced a 60.0 per cent increase of phallic length
1 v/ K$ Y! k. g% _and 52.9 per cent increase of girth (circumference). The
: w2 }- E5 A; L) P1 J3 _, Presponse to topical testosterone was greatest in children be-0 y! o& L6 y: T% g- d. J: q
tween 4 and 8 years old, with a gradual decrease to age 17( j \9 n y$ d) O9 x0 n
years (see table).
: I9 x) l$ l( {4 ]% B0 U" bDISCUSSION
4 t( e7 H$ I9 [" f8 b. wTopical testosterone has been used effectively by other4 }+ F$ } b- x+ U' {
clinicians but its mode of action remains controversial. Im-
1 X n+ q- j) y. J- s0 [' `mergut and associates reported an excellent growth response# h* X$ d1 ?; i
to topical testosterone with low levels of serum testosterone,/ ^* d" K- G! L
suggesting a local effect.1 Others have obtained growth re-
8 v3 A; l& V* u+ G3 {7 |8 Gsponse with high. levels of serum testosterone after topical
9 \ o* c- S8 @8 W! u( m) zadministration, suggesting a systemic response. 3 The use of0 F6 C; d9 C( N; n9 U7 \2 r9 C
gonadotropin to obtain levels of serum testosterone compara-
/ @0 a. B' i9 r* a. P1 pble to levels obtained with topical testosterone would seem to
8 W, ]" h6 d0 W0 oprovide a means to compare the relative effectiveness of
! {3 T6 D7 }% Q- [) rtopical testosterone to systemic testosterone effect. It cer-! h% P; W3 D6 t$ C; E
tainly has been established that gonadotropin as well as par-$ q5 i; Q& `* t6 [! V# c; w# `+ e
enteral testosterone administration will produce genital
C% b* M* _5 j( q, pgrowth. Our report shows that the growth of the phallus was% T5 c& P" _# M: }9 g2 c
significantly greater with topical applications than with go-
& p: F1 @6 I8 ]) inadotropin, particularly in children less than 10 years old.
* O% Z) V; u* \1 _6 j% u2 TThe levels of serum testosterone remained similar or lower' S6 Q1 f+ w+ @) V- B% {! b
than with gonadotropin during therapy, suggesting that topi-' u, E6 c" U0 p7 F) s. \
cal application produces genital growth by its local effect as* {+ v/ ^3 p7 ]; [2 k6 P- n4 M3 Z
well as its systemic effect.
1 s' X" U6 M2 z* R8 qReview of our patients and their growth response related to
9 l4 O7 Y" Q, S% L# u: ?8 F. Uage shows a greater growth response at an earlier age. This is+ I! ~- ]7 I Y* i, W3 _; ?+ c
consistent with the findings of Wilson and Walker, who
# N Q+ L4 k; p, L! xreported an increased conversion of testosterone to dihydrotes-1 d) y+ L) E/ x k: v
tosterone in the foreskin of neonates and infants.4 This activ-/ ?# q+ s# F7 ]0 A2 L
ity gradually decreases with age until puberty when it ap-8 K! B+ B: }' X' j. I3 v# o5 f3 {
proaches the same level of activity as peripheral skin. It may
' Z1 a$ [0 B" P: }; C. \well be that absorption of testosterone is less when applied at
( y- D; T) ?. Wan earlier age as suggested by lower serum levels in children% ]4 X( w& q) n" z% i
less than 10 years old. This fact may be explained by the
- b4 a: x+ L* ?) Dgreater ability of phallic skin to convert testosterone to dihy-3 z7 y2 ]( p/ N+ ~/ H
drotestosterone at this age. Conversely, serum levels in older4 ?. W, A: p6 A5 ?3 F3 ]* j! ^
patients were higher, possibly because of decreased local& j- G- H2 V2 q' e/ i
667
9 m( q+ @3 _- [7 h4 }! ?( ?668 KLUGO AND CERNY
" L$ _1 W6 o. `# ?$ jPt. Age
2 A9 |; a& R4 ~(yrs.)
6 R6 {' B' r G# u+ c) ASerum Testosterone Phallus (cm.) Change Length+ R' B% h3 g% ]/ n, u
(ng./dl.) Girth x Length (%)
. Z- O; @) t7 o" {% d$ n. i4/ O/ Z& C. y# X
8
* F7 ^, }1 ^2 d$ ]. o103 Q7 b/ {# P' ?2 ]* @
124 n, N/ n# }: _% d# L" q+ B$ q: G7 H
17- O' |# Z! O$ C3 F- M
Gonadotropin+ _3 u5 X4 N. ^" z2 e m
71.6 2.0 X 3 16.6
R0 s* x! w; x! u# g50.4 4.0 X 5.0 20.01 ~- r- i) ~1 j& o
22.0 4.5 X 4.0 25.0
3 K- W0 a! c' ^84.6 4.0 X 4.5 11.17 o" L% o5 p! R% a9 M b
85.9 4.5 X 5.5 9.0
% d( E( x0 x0 e/ T7 a/ v" D/ S5 F- W gAv. 14.3- I# O. i' o! A7 u$ V( a
44 g; |1 Y" U H; J% a; q( e
81 S2 p* c5 C; V6 M2 F
10
' S: i# b" v, p( q12% s4 X( Z$ O% G: \
173 j: w) r6 l) c9 j/ k+ I+ w$ U& k- g4 ?
Topical testosterone. S" N5 i/ _* M0 `4 K
34.6 4.5 X 6.5 85
& t/ h; P; r8 \. w# {3 |# Q38.8 6.0 X 8.5 70
- C! E9 ^6 X0 f) G1 K% O40.0 6.0 X 6.5 62.57 y& Y0 ]% t* s9 C% ~7 W" P( u! n
93.6 6.0 X 7.0 55.5
6 s, j. ~# h+ k5 J/ ?$ X3 q95.0 6.5 X 7.0 27.2
- D$ w8 K; F- lAv. 60.07 ^# {, S1 h# G/ U( D1 w
available testosterone. Again, emphasis should be placed on
- r/ Q1 ~" z: ?/ q) s2 hearly therapy when lower levels of testosterone appear to
. l' i' l/ P p/ s. E# i7 ^provide the best responses. The earlier therapy is instituted
* h; m! m9 n* _2 {* Wthe more likely there will be an excellent response with low- {7 f' Y; A) l) X5 v+ }
serum levels. Response occurs throughout adolescence as
b2 E1 }& a' a h% Gnoted in nomograms of phallic growth. 7 The actual response
# _8 y& h# w; A! Q4 G) Dto a given serum level of testosterone is much greater at birth4 i N1 z/ Z0 a
and gradually decreases as boys reach puberty. This is most: s$ E0 m, y2 Z c
likely related to the conversion of testosterone to dihydrotes-
M5 I1 [' _4 Y3 a; n `tosterone and correlates well with the studies of testosterone" O% U$ r# R0 d) v# n
conversion in foreskin at various ages.* ~: i; W8 A( f' ]. r7 {; k) A/ j
The question arises regarding early treatment as to whether
% k& |; Y. W1 O7 H( [2 R+ uone might sacrifice ultimate potential growth as with acceler-7 n2 Y6 H3 @$ h$ I& m* J
ated bone growth. The situation appears quite the reverse
- u4 c% V+ M9 v5 r: twith phallic response. If the early growth period is not used% w$ N# y1 c# a' [( w+ R7 J
when 5a reductase activity is greatest then potential growth
0 Y: V- \, j" k+ T3 [may be lost. We have not observed any regression of growth
4 `6 }) q+ H9 G: oattained with topical or gonadotropin therapy. It may well, T' W& H" J: T, f! a5 u, c
be that some patients will show little or no response to any" {& P$ R0 v2 f# c0 b
form of therapy. This would suggest a defect in the ability to4 g9 N7 {: u& S1 u2 Q: h7 c
convert testosterone to dihydrotestosterone and indicate that
; s9 F" Q& U) F+ E3 Z- gphallic and peripheral skin, and subcutaneous tissue should4 f$ y# C8 {5 ^6 f3 v) b
be compared for 5a reductase activity.4 \, ]7 Y* P# r
A, loop enlarges to measure penile girth in millimeters. B,8 s/ c( j8 {+ R
example of penile girth computed easily and accurately.) I& x3 ]' {1 V$ V7 B9 A0 C
conversion of testosterone to dihydrotestosterone. It is in this. d, y# P _* _2 a& T" O
older group that others have noted high levels of serum: H! @/ W! W! m+ s `* a1 R% ~. L6 p8 P
testosterone with topical application. It would also appear
9 X {9 L4 x& x; c4 T; _that phallic response during puberty is related directly to the
2 m4 ~1 w" E; z. Hserum testosterone level. There also is other evidence of local! K( L4 P1 \4 N- [! p2 D$ j
response to testosterone with hair growth and with spermato-& o; T- X+ p+ H% k3 F1 z; x
genesis. 5• 6
2 } v3 o1 f. L4 n0 p; M+ `& k, ?Administration of larger doses of gonadotropin or systemic- U2 v5 A k2 t A# s
testosterone, as well as topical applications that produce9 Y7 J# K! C# n* d. A7 y+ x* a
higher levels of serum testosterone (150 to 900 ng./dl.), will
/ S9 w3 C" f. ^$ C7 [' R& k( Valso produce phallic growth but risks accelerated skeletal/ Q* |, G9 ?# k0 ~/ B+ ]
maturation even after stopping treatment. It would appear7 O, D# S; W) V9 A* M/ Q
that this may be avoided by topical applications of testosterone
! T" K& j+ y- O& V" ~and monitoring of serum testosterone. Even with this control8 O0 h& n( B8 T$ P" x( w7 E
the duration of our therapy did not exceed 3 weeks at any& ^6 Y8 A, Y5 e* D0 z" R3 y V) T
time. It is apparent that the prepuberal male subject may, p5 Y0 x, `$ S1 l
suffer accelerated bone growth with testosterone levels near1 t3 ~0 J7 p( [* h0 r& f& G( Z
200 ng./dl. When skeletal maturation is complete the level of! ^6 C1 r% i% M/ {8 I
serum testosterone can be maintained in the 700 to 1,300 ng./
N) e- d2 D' c7 Adl. range to stimulate phallic growth and secondary sexual
2 C0 ?) ?: M; h2 `6 d; M: Q) f$ }) ~) n- Kchanges. Therefore, after skeletal maturation parenteral tes-
/ M! Z, Z# ~7 J2 O! Ytosterone may be used to advantage. Before skeletal matura-
2 e( E" L0 X' z4 vtion care must be taken to avoid maintaining levels of serum
- i1 |5 U" ~5 C7 h5 p8 Etestosterone more than 100 ng./dl. Low-dose gonadotropin% E6 B6 Z9 S j% B
depends upon intrinsic testicular activity and may require8 ^! P+ W- `4 A' e9 T& k
prolonged administration for any response.
) c9 E3 w: D; U$ I% `! S cAlternately, topical testosterone does not depend upon tes-
7 d- Z$ {" R) |ticular function and may provide a more constant level of
. E; Y" s* b5 ^7 }REFERENCES4 y/ z3 S8 Y4 B" Z- O) [% o# d
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; i4 j) r9 z2 \. Q" i) i
R.: The local application of testosterone cream to the prepub-; ]1 `8 v1 L( z3 f1 q& k! F q
ertal phallus. J. Urol., 105: 905, 1971.
; b, _0 k9 [6 m U$ a7 u2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( _/ r% L& S% V; O% M# e9 X5 r" H
treatment for micropenis during early childhood. J. Pediat.,4 R# x5 T5 y* ]
83: 247, 1973." y6 U: x; B5 ?- L D" k% I2 w
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* K' f6 u3 V" Y! \' A; S1 t" r' ?
one therapy for penile growth. Urology, 6: 708, 1975.; C: R0 M n& B3 ?" P, l, Y
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone# q9 ]; E7 D9 ^: V! Z9 w& {
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& f& _# n# p* [& F# v8 Zskin slices of man. J. Clin. Invest., 48: 371, 1969.! K) k$ \5 i+ D
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
0 b) M5 y- a- h- d Z+ w2 Hby topical application of androgens. J.A.M.A., 191: 521, 1965.
9 Z+ y1 C4 Q# W6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 ^: X3 `) y; J7 X
androgenic effect of interstitial cell tumor of the testis. J.
2 i1 k+ Z T) g2 U: l# D% W$ CUrol., 104: 774, 1970.
1 V" f7 t% P4 J( a* i+ R7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
Y( Z: C. p/ \tion in the male genitalia from birth to maturity. J. Urol., 48: |
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