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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 e2 R2 K# f' s) [7 B
GONADOTROPIN) ~& K. l8 d8 m D8 r) D
RICHARD C. KLUGO* AND JOSEPH C. CERNY
U; j+ U& D& [+ I! {From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
i4 x" `( Q/ k+ uABSTRACT# i3 G$ R8 v# C# H
Five patients were treated with gonadotropin and topical testosterone for micropenis associated& p& [, A" K4 W4 e: r) Z
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-( ]' d" l3 X1 q) i
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! I- ~) l+ {* W% R: p2 ?) m# P7 t6 ~( B icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& C3 Q: @$ ^+ P# m5 i( `; O4 L
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent3 f; q6 s; @' r; K+ E4 D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 s. g6 R# O U. d& Cincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ g, _$ s' ]. m) U3 Z9 voccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 h; M- x1 w7 R9 M/ g8 }9 J# Fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! f; x6 j% r; O7 J
growth. The response appears to be greater in younger children, which is consistent with previ-
7 V. U% B% P( J u; P- a2 {# O; wously published studies of age-related 5 reductase activity. d4 c/ G5 p. d% l# x
Children with microphallus regardless of its etiology will
& X/ n# y5 W" ^' b6 z g; Arequire augmentation or consideration for alteration of exter-- L% p4 z! B6 ]& l$ d2 {0 t0 p
nal genitalia. In many instances urethroplasty for hypo-1 K* D" x/ W6 Q- X8 \
spadias is easier with previous stimulation of phallic growth.
% }( w4 V6 l+ z/ m6 d* X( ]- P" q) wThe use of testosterone administered parenterally or topically4 G* ^. v& q8 r& T4 w& Q2 T+ B
has produced effective phallic growth. 1- 3 The mechanism of' M+ d# R- K. j0 R( U$ q% X
response has been considered as local or systemic. With this$ }* J& P( T( e# G( }/ g
in mind we studied 5 children with microphallus for response$ `7 h1 L' y; R( F/ ]
to gonadotropin and to topical testosterone independently.* f7 C9 c( F3 G: L( `
MATERIALS AND METHODS& H! G3 z+ `# N0 c( S' O4 r% [
Five 46 XY male subjects between 3 and 17 years old were2 u3 {+ M' y3 V% y
evaluated for serum testosterone levels and hypothalamic
; K5 E% S9 U$ _# [function. Of these 5 boys 2 were considered to have Kallmann's
) U' }: J& c1 n6 tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 b2 F- ~; D/ E5 ]" K$ j
lamic deficiency. After evaluation of response to luteinizing- p8 T$ R, B2 `
hormone-releasing hormone these patients were treated with
- I& q: g- m* c r1 v; c/ @. B1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* J7 f4 U0 g- |: C. X! {after completion of gonadotropin therapy 10 per cent topical
" @* Y, P# Q7 Rtestosterone was applied to the phallus twice daily for 3 weeks.
/ a$ D0 a; b* J3 A( }- ^* HSerum testosterone, luteinizing hormone and follicle-stimulat-, w7 X+ J3 M- L( N1 j& z: [7 t
ing hormone were monitored before, during and after comple-# [, r/ R4 Z. |% p1 B. F! s
tion of each phase of therapy. Penile stretch length was7 \( F5 a( D0 s; h3 x3 [1 x
obtained by measuring from the symphysis pubis to the tip of' [) G6 `. C. k7 p& I$ A
the glans. Penile circumferential (girth) measurements were
4 B! D) I' c6 [8 q: iobtained using an orthopedic digital measuring device (see0 J4 Z" s2 o0 Y
figure).) N# w3 k8 x/ G( g0 l
RESULTS
% B) b. t5 B2 p' {7 `Serum testosterone increased moderately to levels between
/ G5 k* j5 j/ Q1 A7 J* w50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-" N l: f- o( t. W+ A
terone levels with topical testosterone remained near pre-
, t& C7 _+ i+ J8 Mtreatment levels (35 ng./dl.) or were elevated to similar levels; a( N+ z% h; f$ l" H2 W9 y! T7 X
developed after gonadotropin therapy (96 ng./dl.). Higher
" ]( w$ V# p5 tserum levels were noted in older patients (12 and 17 years old),2 g, z$ g, q" M( g9 V
while lower levels persisted in younger patients (4, 8, and 10
- p0 E3 o5 t% F* k, F% Uyears old) (see table). Despite absence of profound alterations
* e |) K5 U, Q) [6 ^" ]+ rof serum testosterone the topical therapy provided a greater0 ?; [$ l4 T- A) h4 H: i
Accepted for publication July 1, 1977. ·: ^ s9 I& Z+ b, O
Read at annual meeting of American Urological Association,5 L' v# f0 i) R0 M
Chicago, Illinois, April 24-28, 1977.
# i ]3 y* Y5 y/ |* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 c" [+ |5 @ ^- }9 Z5 l2799 W. Grand Blvd., Detroit, Michigan 48202.; r% Y) j8 J. h, [
improvement in phallic growth compared to gonadotropin.
( p) o) j- W% z T5 p- v8 N+ ~Average phallic growth with gonadotropin was 14.3 per cent6 s7 w3 c4 ~0 O) s0 i; M
increase in length and 5.0 per cent increase of girth. Topical
" d1 o& Q$ h; ^$ vtestosterone produced a 60.0 per cent increase of phallic length# K" [( j: x& P/ P- K) W" u) z2 ^. r
and 52.9 per cent increase of girth (circumference). The" R/ g2 m7 m6 D2 a& ]" K- k1 D
response to topical testosterone was greatest in children be-
+ ?( f- D/ ?( f; T& e& v. Xtween 4 and 8 years old, with a gradual decrease to age 17# y- ? k. _0 e( v2 x/ A
years (see table).
' a! ?% h5 O. D+ B* ^ f( a1 h! \5 tDISCUSSION
9 f- E4 Y7 x; @2 [: }Topical testosterone has been used effectively by other4 ~; r2 R+ T4 s" ~+ Z$ i, @
clinicians but its mode of action remains controversial. Im-
. `7 n# ]6 _& o. e5 |' tmergut and associates reported an excellent growth response% h- m: q, w$ q+ j. F, w
to topical testosterone with low levels of serum testosterone,
9 X0 D. M2 B$ U; k# l1 w0 hsuggesting a local effect.1 Others have obtained growth re-1 O- Y1 z: o& E9 b
sponse with high. levels of serum testosterone after topical3 Y' J; |' h0 g7 [9 B
administration, suggesting a systemic response. 3 The use of9 P' v6 {8 v. t: U! O
gonadotropin to obtain levels of serum testosterone compara-
7 a' v' T: |3 B2 \5 ?ble to levels obtained with topical testosterone would seem to
+ ^8 K5 A* ~% h; Sprovide a means to compare the relative effectiveness of
4 _0 _) O, w2 u+ B* r2 ]/ N2 @topical testosterone to systemic testosterone effect. It cer-7 P. j' w( O/ c" f
tainly has been established that gonadotropin as well as par-, y1 N$ X1 h; p. p9 n8 X
enteral testosterone administration will produce genital3 |6 \) Q( {: B; V0 z
growth. Our report shows that the growth of the phallus was
3 a2 t) H* s7 x- [2 Asignificantly greater with topical applications than with go-. n, i! Q0 z+ Y( V: i( u1 k6 o* r
nadotropin, particularly in children less than 10 years old.
! n! a* a; p) b- p. iThe levels of serum testosterone remained similar or lower
, Y& p" r8 P9 ?: [) i" ]# fthan with gonadotropin during therapy, suggesting that topi-
7 ~5 [. y( y; A7 a9 k0 }cal application produces genital growth by its local effect as/ h% M1 k) i* m) x: G0 r
well as its systemic effect.# v8 N7 }0 U4 b4 d
Review of our patients and their growth response related to1 I/ V+ c% w. ^+ R/ S# D
age shows a greater growth response at an earlier age. This is
' S( _6 k" W% Q3 g5 s# s/ ~( k8 o5 @consistent with the findings of Wilson and Walker, who) k' v: I1 _$ t; ]
reported an increased conversion of testosterone to dihydrotes-& ` D/ |1 b* m0 ?+ B
tosterone in the foreskin of neonates and infants.4 This activ-
1 A8 F5 [# z6 W* ~& }( rity gradually decreases with age until puberty when it ap-1 z' |& p% f' R. b# z
proaches the same level of activity as peripheral skin. It may
% b1 y0 B- T$ D: }1 B/ Swell be that absorption of testosterone is less when applied at i, @- ~0 e9 |7 R$ j, n
an earlier age as suggested by lower serum levels in children7 ~ w8 a, Q8 b8 \1 i& S8 v
less than 10 years old. This fact may be explained by the5 r* y6 F- S) z2 v: R, J8 f
greater ability of phallic skin to convert testosterone to dihy-
' u7 I* r4 {2 edrotestosterone at this age. Conversely, serum levels in older' l6 t; x) X. k7 t9 P7 M$ G1 P0 Q
patients were higher, possibly because of decreased local, n% u) k8 ]3 L3 }/ y# `
667 Z" [, v1 V1 [/ q% M$ c
668 KLUGO AND CERNY7 w4 D: _) O2 i7 K
Pt. Age) i; e: h% E F8 a- s# t7 z9 J
(yrs.)
/ c" ~9 [& V( X- y( MSerum Testosterone Phallus (cm.) Change Length
. ?# w1 x3 S& t6 y1 h(ng./dl.) Girth x Length (%)* f# k) s4 s F. F3 M
4" G0 H. n, `3 n7 p
8
- ^, Z. P+ B8 R) X4 a- p, H109 i) ]% C: |4 ^# D9 L
122 y* ]% p4 ?6 n
17
% y/ v+ J1 H% AGonadotropin2 L( y. L% f) c: G
71.6 2.0 X 3 16.6& B/ G& X' s, C, M0 I
50.4 4.0 X 5.0 20.0" I* v9 H2 }% P+ v# S0 R- Z3 F
22.0 4.5 X 4.0 25.00 M1 j4 K" O1 g* c; R7 P
84.6 4.0 X 4.5 11.1& S: r5 t( z8 B& R
85.9 4.5 X 5.5 9.0
# f1 |; G7 x, h# C: s$ S7 \( }Av. 14.3
* ]; d: X6 |' J* A& b+ ]4
8 g* J) w$ k6 B2 U7 K8
# @8 \, C1 ?* s8 }6 |107 y0 u. \5 a9 t# }; t' T$ {
120 M5 y# b% A! W0 i& r( U
17
8 C( D2 S9 }+ w4 ]3 {+ W# GTopical testosterone
2 W! m& | O! ^5 i$ ~7 ~34.6 4.5 X 6.5 85
, |* R3 Z7 K, Z( F38.8 6.0 X 8.5 70
% ]' i: k$ y2 }- Z" P40.0 6.0 X 6.5 62.5* I# i/ e9 x, E% S W2 N4 C
93.6 6.0 X 7.0 55.5# P$ E8 h! V& |& c' a! Z" R K
95.0 6.5 X 7.0 27.2; E; N% m4 W6 B0 H
Av. 60.0
* X7 W7 Q% B% v# J5 `3 V, Yavailable testosterone. Again, emphasis should be placed on
4 H/ t9 h) P @$ e8 j- K" jearly therapy when lower levels of testosterone appear to
, K: e, K9 V8 Aprovide the best responses. The earlier therapy is instituted
2 G9 D# ~" T, i2 U! ^3 M& C; a: n, E6 pthe more likely there will be an excellent response with low- ?1 o. }: Z8 H
serum levels. Response occurs throughout adolescence as- e& B: k# K" u4 o8 O& q
noted in nomograms of phallic growth. 7 The actual response
$ n$ L3 R& F& K5 e4 oto a given serum level of testosterone is much greater at birth( K8 N+ }0 @8 e: {# u- H* W% K9 T
and gradually decreases as boys reach puberty. This is most
( q Y3 i- }# s$ E& z' Nlikely related to the conversion of testosterone to dihydrotes-
" X9 j8 f( n& y0 z a8 Ztosterone and correlates well with the studies of testosterone; f/ ^& o' {1 y3 d7 A) O
conversion in foreskin at various ages.
O( O5 {& o4 g; F$ y% JThe question arises regarding early treatment as to whether
# Q9 W8 F% C* I5 }( N8 ~; S- Done might sacrifice ultimate potential growth as with acceler-/ Z0 K' E. ?1 Q
ated bone growth. The situation appears quite the reverse
& U i/ j2 E2 q/ T/ A5 d7 jwith phallic response. If the early growth period is not used
* W( F7 S! p1 i; Z9 d3 Y- z, Twhen 5a reductase activity is greatest then potential growth( U5 V! w3 X) O& y. o( l3 D
may be lost. We have not observed any regression of growth( [4 u, i5 y' y% O$ j
attained with topical or gonadotropin therapy. It may well
# A( a1 I2 S, c. jbe that some patients will show little or no response to any
, T, u6 p+ t. |form of therapy. This would suggest a defect in the ability to
: J) C+ }" E+ }; Zconvert testosterone to dihydrotestosterone and indicate that c( k& [, F9 X& S: @0 e+ m
phallic and peripheral skin, and subcutaneous tissue should
" [+ a3 p8 k* Obe compared for 5a reductase activity., b' Z# V2 f$ g. t' l# y
A, loop enlarges to measure penile girth in millimeters. B,
4 @" }+ a3 X$ O* W. jexample of penile girth computed easily and accurately.
3 k4 V1 |: h( j) ^- a- M# ?conversion of testosterone to dihydrotestosterone. It is in this
7 T3 [2 O+ O, W3 Wolder group that others have noted high levels of serum
3 _' h) B1 [& q. @( A7 ]testosterone with topical application. It would also appear5 q" k5 e, {% p9 o. |1 U& {
that phallic response during puberty is related directly to the& P3 v8 y% `! ^
serum testosterone level. There also is other evidence of local
/ C& _& g7 H* V" _response to testosterone with hair growth and with spermato-
( m: m ~" S0 z3 B- Dgenesis. 5• 6
, j1 D! W! \* B* |Administration of larger doses of gonadotropin or systemic
3 |9 H* n( p3 Ytestosterone, as well as topical applications that produce7 J7 ^* j& I( w) T2 E* C; I
higher levels of serum testosterone (150 to 900 ng./dl.), will
0 l2 U4 i8 y" M$ d( talso produce phallic growth but risks accelerated skeletal
% e& Y( T- O& z) O3 |maturation even after stopping treatment. It would appear7 s+ T8 |/ A- _/ C3 y, }
that this may be avoided by topical applications of testosterone7 y$ o! T0 N' ?7 \) H! b
and monitoring of serum testosterone. Even with this control
: |! @; v% t( f- Y/ q/ k, qthe duration of our therapy did not exceed 3 weeks at any
1 ^) h4 s; r5 _1 D7 N) w! ytime. It is apparent that the prepuberal male subject may
. w' V* M4 l. `& B6 M7 i/ msuffer accelerated bone growth with testosterone levels near( V& M: b9 s. \. X' O8 k8 a4 B z
200 ng./dl. When skeletal maturation is complete the level of5 D& \& ~8 S' J/ d
serum testosterone can be maintained in the 700 to 1,300 ng./2 T# t) E' |, k
dl. range to stimulate phallic growth and secondary sexual
_; k/ L% O9 _1 x0 g3 ]changes. Therefore, after skeletal maturation parenteral tes-
7 U' a( Q6 l8 X4 v w: ztosterone may be used to advantage. Before skeletal matura-$ {/ Y+ r# I8 _& F
tion care must be taken to avoid maintaining levels of serum
" o: s* c: H/ S6 vtestosterone more than 100 ng./dl. Low-dose gonadotropin
4 }! l/ h2 k! x8 h: [" wdepends upon intrinsic testicular activity and may require
+ T& i5 G$ Z, |' _9 a6 dprolonged administration for any response.4 W* x% P4 E" _. _) O! L
Alternately, topical testosterone does not depend upon tes-
: f5 _/ F" O9 V" B1 u8 gticular function and may provide a more constant level of* G/ p6 m* n+ o
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/ V/ C4 }- E: q3 s/ U" a( r( k5 I1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; }2 _9 g; P* y7 I8 m9 N/ d" j7 F1 S! kR.: The local application of testosterone cream to the prepub-2 ^: v; |4 b3 J. O% d' X
ertal phallus. J. Urol., 105: 905, 1971.
+ W! |% I/ u0 ~1 w2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 e" G+ l$ w* N0 Streatment for micropenis during early childhood. J. Pediat.,
- k& C4 y* u2 g- t% J3 T$ J7 w9 Z83: 247, 1973.6 i+ y X8 f$ d
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( m2 [& {7 I' g5 D0 H; P
one therapy for penile growth. Urology, 6: 708, 1975.. v( Y' @; w# a/ x2 o1 f
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: a$ A7 \8 F3 ~- C2 } Bto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 U3 O; K" `0 s1 h6 ]
skin slices of man. J. Clin. Invest., 48: 371, 1969.
7 L4 N* Z; r; W ?; z4 O4 P5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
& N$ d& ^8 a0 \9 N: w/ s* x! ?by topical application of androgens. J.A.M.A., 191: 521, 1965.
. S6 E3 Z. A" U% Z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 i8 o( j$ q/ o" I
androgenic effect of interstitial cell tumor of the testis. J.- |% o x6 p4 G. c9 g, `$ K
Urol., 104: 774, 1970.) B" E6 `; W1 T | P( ?
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
) f% {5 H8 m, P$ {5 |tion in the male genitalia from birth to maturity. J. Urol., 48: |
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