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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, c2 n6 N2 t; y3 f5 l5 T9 _
GONADOTROPIN$ b& p a+ ^! f
RICHARD C. KLUGO* AND JOSEPH C. CERNY8 ]0 X' x6 q6 `
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 X0 S4 X2 G! A0 `ABSTRACT+ _2 D! o, w" @7 A* ?& r* C
Five patients were treated with gonadotropin and topical testosterone for micropenis associated. k/ H* x$ P/ Z" s5 m5 n, L
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
& J* n. ~9 ~ }% ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
7 M( M# q: `: e7 T7 Vcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
. l, |8 i+ q* U$ l x- Kfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 }4 C2 U: ]; r! G
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average* u2 C4 N g B' ` ]$ e/ f+ h
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response) F r+ Z- J D) b$ [
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This) Y& ^+ @: A2 {1 C5 j r5 q
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile* L z4 F; `; }9 c n
growth. The response appears to be greater in younger children, which is consistent with previ-
& z. U0 _9 l4 Sously published studies of age-related 5 reductase activity.7 j& M7 H* z8 R
Children with microphallus regardless of its etiology will
; j- l1 d U& `require augmentation or consideration for alteration of exter-
1 _! U! L r9 I" r& K; \0 {nal genitalia. In many instances urethroplasty for hypo-5 h* u0 y0 h1 a( g, X6 g/ {& T o
spadias is easier with previous stimulation of phallic growth.& S+ K! Z z3 S: h: u/ d
The use of testosterone administered parenterally or topically
/ ^( p' h. {2 T4 ihas produced effective phallic growth. 1- 3 The mechanism of
0 L$ ^; R1 C# r2 X( @response has been considered as local or systemic. With this
! ?7 r) p1 @. [2 s! k% M% R! vin mind we studied 5 children with microphallus for response
R6 o% e* N: E1 G0 z1 V& Z# P# ?to gonadotropin and to topical testosterone independently.) B$ s* X$ D% n7 ?
MATERIALS AND METHODS
/ Z% O6 K5 j& O- aFive 46 XY male subjects between 3 and 17 years old were8 z1 e+ m5 j8 H2 p
evaluated for serum testosterone levels and hypothalamic. y6 v/ a+ `& u0 ~6 H
function. Of these 5 boys 2 were considered to have Kallmann's+ A7 j- b, D5 |9 i4 @) D
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-! B( L D0 A: ]0 K7 y
lamic deficiency. After evaluation of response to luteinizing
9 V9 K- ~2 A2 V3 o' B, Qhormone-releasing hormone these patients were treated with+ a3 w- D' x# s
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
' t% k. J( L+ {( Rafter completion of gonadotropin therapy 10 per cent topical$ c1 n/ @- `1 h1 G9 m
testosterone was applied to the phallus twice daily for 3 weeks.' n7 _( W/ N, D, h
Serum testosterone, luteinizing hormone and follicle-stimulat-
7 {( ?! |4 U2 z% [0 B o1 ?ing hormone were monitored before, during and after comple-
5 w5 e: ?) z7 h& b- _2 W) etion of each phase of therapy. Penile stretch length was
* L/ u/ z3 T% n3 g- Yobtained by measuring from the symphysis pubis to the tip of" }+ e* m1 Z2 a4 J( V2 d% S
the glans. Penile circumferential (girth) measurements were
$ z, s4 I [8 o6 p* |/ j: Hobtained using an orthopedic digital measuring device (see* e' U; i. B# E' ]8 U
figure).( W. \9 c: }) I4 ?7 g9 n5 C
RESULTS U! g9 |( C0 Z- H
Serum testosterone increased moderately to levels between
3 V, P3 B: v' u0 l( ~- @9 Z( ^50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
" l/ \8 a* Y/ E. Xterone levels with topical testosterone remained near pre-: w$ j) O. P8 }) U7 P. X
treatment levels (35 ng./dl.) or were elevated to similar levels
_" [$ \1 b$ {7 mdeveloped after gonadotropin therapy (96 ng./dl.). Higher
8 i( N c* h7 y9 j+ d# {- sserum levels were noted in older patients (12 and 17 years old),. T8 c, J( d8 y
while lower levels persisted in younger patients (4, 8, and 10
/ G% R& H9 A0 k% m) C3 `6 qyears old) (see table). Despite absence of profound alterations1 C# S! h( K2 f: {
of serum testosterone the topical therapy provided a greater; Z- L, c% D1 t+ z5 X' w
Accepted for publication July 1, 1977. ·
- G! b8 l3 c& L; }$ ~: k/ d# K: ~' J' sRead at annual meeting of American Urological Association,
t' D2 h6 N& {5 D& ?8 e% f) i- d) PChicago, Illinois, April 24-28, 1977.
) M$ G) `- q5 r, [+ v- ]( @9 P* Requests for reprints: Division of Urology, Henry Ford Hospital,, X: d. s+ W( h- L% z7 m# h: ?
2799 W. Grand Blvd., Detroit, Michigan 48202.3 O' L5 y% g6 {
improvement in phallic growth compared to gonadotropin.
4 L5 S" e6 W$ `% zAverage phallic growth with gonadotropin was 14.3 per cent4 {/ @/ W: i6 \3 a3 b5 @
increase in length and 5.0 per cent increase of girth. Topical! W; m6 ^' N$ C0 H. T3 G
testosterone produced a 60.0 per cent increase of phallic length
" t7 x( r' w( `' L: V3 ^5 aand 52.9 per cent increase of girth (circumference). The9 F$ z- {4 A+ x! l% X' |4 k# F+ K+ L
response to topical testosterone was greatest in children be-1 H6 T: ?0 [1 a8 R, r7 D: W7 i
tween 4 and 8 years old, with a gradual decrease to age 172 H+ o0 R; x3 u. Q8 h0 l* ~1 d2 a
years (see table).' g% |. x1 T. A. b7 F1 s, P) `
DISCUSSION1 X3 ~6 r& y- H. y6 a7 `* S
Topical testosterone has been used effectively by other* F/ S6 F% M' _9 V9 ?+ Q
clinicians but its mode of action remains controversial. Im-* k1 A* p. ^# u1 q; w
mergut and associates reported an excellent growth response
0 i g9 t8 i j, ?$ Uto topical testosterone with low levels of serum testosterone,' w5 t: q9 R/ i
suggesting a local effect.1 Others have obtained growth re-
* D, K( ?3 O$ l1 {sponse with high. levels of serum testosterone after topical$ ]+ B8 P9 ?5 e+ V0 P' K" G! _/ q: m
administration, suggesting a systemic response. 3 The use of: I5 H& S- D- s& [; O9 a& x* {
gonadotropin to obtain levels of serum testosterone compara-
6 y4 m1 {3 W. Z2 `, ^4 C' ?& n* p: lble to levels obtained with topical testosterone would seem to4 j% H3 z% P) P2 q5 t' [) X: B5 @
provide a means to compare the relative effectiveness of
+ w$ z0 n0 |# `topical testosterone to systemic testosterone effect. It cer-
. L5 L, E* u$ e; G, Z) Y/ {tainly has been established that gonadotropin as well as par-
5 N/ S) g- R1 e& E& ^- i' }enteral testosterone administration will produce genital% u' L9 K! m1 x0 i0 i" w
growth. Our report shows that the growth of the phallus was
3 H/ Y- `$ `( J+ tsignificantly greater with topical applications than with go-
1 a: m' ^$ B3 U$ `( X/ snadotropin, particularly in children less than 10 years old.
; R9 n+ ~& Q4 dThe levels of serum testosterone remained similar or lower' u! i& Z8 j2 D: q {! A4 O
than with gonadotropin during therapy, suggesting that topi-
3 e* _) S/ s! o3 w/ h2 F# U! C- j1 k6 Acal application produces genital growth by its local effect as ^2 _ H- D4 O: y+ @$ V
well as its systemic effect.9 N1 L6 l* Z* R3 K; X+ }
Review of our patients and their growth response related to) T3 _9 V9 v( A J/ Q. b
age shows a greater growth response at an earlier age. This is0 F) @/ h1 }% k$ `" [3 ~
consistent with the findings of Wilson and Walker, who2 [* ~% ^, @% U/ E( D
reported an increased conversion of testosterone to dihydrotes-7 p6 x8 K4 _, k3 P4 x
tosterone in the foreskin of neonates and infants.4 This activ-5 H5 _, s" o+ n- W) n; o" S8 g
ity gradually decreases with age until puberty when it ap-
" y, p2 e' \- y, `. Eproaches the same level of activity as peripheral skin. It may! Z' E+ O* {0 N3 A' F: ]3 q
well be that absorption of testosterone is less when applied at6 \; t" m: [) [) k8 s7 h. A) g+ o0 ]
an earlier age as suggested by lower serum levels in children' r! {# b4 Q' A9 S8 y4 G" F. r
less than 10 years old. This fact may be explained by the H# L# \# ?6 v6 w+ v8 a
greater ability of phallic skin to convert testosterone to dihy-" a3 E+ l! m" B
drotestosterone at this age. Conversely, serum levels in older) q3 S" i" O! R
patients were higher, possibly because of decreased local
2 ~" m6 _! m! q, b5 Z5 I3 ]! D667- ~9 X; {" Z3 m9 b. {+ o$ F! W
668 KLUGO AND CERNY2 z, D) N! O# B& V! {2 v% {
Pt. Age E6 _$ T9 u/ q% O) g
(yrs.)
! s. V9 J5 p, z! {7 ~" U# RSerum Testosterone Phallus (cm.) Change Length
. D3 p# T$ j! ^( |3 I(ng./dl.) Girth x Length (%)4 l7 q3 \0 r I: X, Z
41 t/ a) U) R# O2 R" g5 B8 J
8; \3 ^( \/ `' y6 S) C
103 D( n `0 M3 n
12
" m: c5 ], h* b$ B/ F9 T174 j1 z+ h( r2 f
Gonadotropin
: v6 T8 h$ x5 f/ J5 i! j3 v3 K! }71.6 2.0 X 3 16.6
( Q3 ^1 J& f2 B+ K50.4 4.0 X 5.0 20.06 [) C8 J% L+ ?) @7 F
22.0 4.5 X 4.0 25.08 B6 V2 W# x- a. B2 F
84.6 4.0 X 4.5 11.1
9 I& k3 ?( M% d85.9 4.5 X 5.5 9.0
$ G+ X& q6 ]* N0 Y/ MAv. 14.3
$ `% q( T9 i, K+ c2 W" G48 j4 ]- l5 [1 G8 f! {
8* C# t1 h5 ^! B; H# b. s
10
( m4 M( @& @* c6 ~, e12/ e/ _: B, Z5 D8 M9 z1 E" _
17
, p, ^5 w' F; z; }, U# Y9 STopical testosterone4 Y& x" T6 t- }4 @* P
34.6 4.5 X 6.5 85: {; }' ?- K1 ~6 p* H
38.8 6.0 X 8.5 70
1 I Y4 w% v# x9 G+ n( s1 I8 `40.0 6.0 X 6.5 62.54 y* R& B- O, X# ?" ~( ^! [
93.6 6.0 X 7.0 55.5, z0 W4 _8 ~- L9 X2 a
95.0 6.5 X 7.0 27.2' ]! E, @/ t: L) M: Y
Av. 60.0- k; E) b6 S+ G* y# W; h
available testosterone. Again, emphasis should be placed on. a* U$ ^/ G) }# n4 J* W
early therapy when lower levels of testosterone appear to
# C: O# X6 f L; T: kprovide the best responses. The earlier therapy is instituted
5 g* Q& O2 D) uthe more likely there will be an excellent response with low
5 |" f& y8 l7 nserum levels. Response occurs throughout adolescence as
- I3 |! v6 Q) [- knoted in nomograms of phallic growth. 7 The actual response
9 M" _0 n3 C! E' Z* ]1 Kto a given serum level of testosterone is much greater at birth
1 T5 L2 P; K* x9 B8 ~and gradually decreases as boys reach puberty. This is most
3 p: Q& z! L& c1 m* A. j3 {likely related to the conversion of testosterone to dihydrotes-
! ~& L0 e$ o, {& P7 k& P5 {tosterone and correlates well with the studies of testosterone
& Q# g0 g/ n+ [- u2 h x: fconversion in foreskin at various ages.
7 O6 _2 ~, R u" e% IThe question arises regarding early treatment as to whether) d4 T" N9 z" r0 G8 [
one might sacrifice ultimate potential growth as with acceler-) d9 N" E! g# c$ g$ l
ated bone growth. The situation appears quite the reverse
# A! D( y$ f0 A6 t% `3 swith phallic response. If the early growth period is not used9 q2 c3 [3 U9 y# S: N
when 5a reductase activity is greatest then potential growth
" k5 j% x! F, N% L6 }( |8 ~' C/ x5 Qmay be lost. We have not observed any regression of growth4 ] U Z: l* u
attained with topical or gonadotropin therapy. It may well
: P9 s1 ]: ~+ xbe that some patients will show little or no response to any
& e% T" B3 u+ b# R* Gform of therapy. This would suggest a defect in the ability to7 k; {8 `% N, ~, [ @( D
convert testosterone to dihydrotestosterone and indicate that+ A3 S: p- v% H9 u7 g6 z- X) \+ t
phallic and peripheral skin, and subcutaneous tissue should' e( j$ W1 h2 h9 _6 ^
be compared for 5a reductase activity.
* v4 i2 l1 P9 w/ T' f( f' P/ mA, loop enlarges to measure penile girth in millimeters. B,; {3 f; B Z4 \2 s4 r( d* M0 K
example of penile girth computed easily and accurately.
0 _) ?, n2 X. l p& }/ g3 X) lconversion of testosterone to dihydrotestosterone. It is in this
8 G* Z' f' ?' j' G$ f) a) Iolder group that others have noted high levels of serum) L4 l! D( ?- T; W1 S* H: u
testosterone with topical application. It would also appear
( a# p6 [1 |0 R1 d/ n" Lthat phallic response during puberty is related directly to the
' O7 G. I* |+ h2 H, ?6 q! b4 }serum testosterone level. There also is other evidence of local) b0 f$ V1 R, N
response to testosterone with hair growth and with spermato-
! F ]6 O2 E) rgenesis. 5• 64 e- T. b- @1 p
Administration of larger doses of gonadotropin or systemic
' Z% d5 Q! O: F4 h0 n: Itestosterone, as well as topical applications that produce
* L4 Z9 R5 \4 D% ~1 nhigher levels of serum testosterone (150 to 900 ng./dl.), will% V( m1 t8 h- ~# Q
also produce phallic growth but risks accelerated skeletal5 R2 r2 m6 d& R$ x' m
maturation even after stopping treatment. It would appear
P$ h0 g V! g1 t3 G3 L/ O$ Bthat this may be avoided by topical applications of testosterone6 ^9 N5 A9 c! p/ o- j
and monitoring of serum testosterone. Even with this control
; l5 Y0 G4 p- [! l u [/ lthe duration of our therapy did not exceed 3 weeks at any& j# z* B- W" w1 `
time. It is apparent that the prepuberal male subject may( V; ]7 F& q$ N, v: [
suffer accelerated bone growth with testosterone levels near) @4 ?6 I8 P3 D& d( K
200 ng./dl. When skeletal maturation is complete the level of
0 c1 t; }- Y% mserum testosterone can be maintained in the 700 to 1,300 ng./" c) }' X* U) n) ^; o
dl. range to stimulate phallic growth and secondary sexual
- Y+ \ h& x7 B$ `changes. Therefore, after skeletal maturation parenteral tes-7 M: h) J3 l/ {
tosterone may be used to advantage. Before skeletal matura-4 Y0 I \0 J; w, }; a0 ^1 t' Y$ _
tion care must be taken to avoid maintaining levels of serum* r+ C; M& ?! v2 `
testosterone more than 100 ng./dl. Low-dose gonadotropin% O4 |9 _% i; ?
depends upon intrinsic testicular activity and may require
* u5 [+ B c' ^$ p' n$ hprolonged administration for any response.
, `" R9 S1 ? [9 JAlternately, topical testosterone does not depend upon tes-8 m4 `. q. p. c
ticular function and may provide a more constant level of
0 A- d3 T; h( W! ~REFERENCES" }4 a) x0 l2 ?0 z+ X9 \1 P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; |/ Y& z Q# i3 F5 T- H/ J9 @. F
R.: The local application of testosterone cream to the prepub-; U6 _* S! f( Q% ?+ l, r
ertal phallus. J. Urol., 105: 905, 1971.
: n: D( |# a# V2 V, V6 u" }2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
# r( s$ T$ _. b1 C( t# Otreatment for micropenis during early childhood. J. Pediat.,
/ Z& s- {( L: ~. S3 p83: 247, 1973.
- u) L+ Z) a3 Y' ?3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-7 t; s1 d! ]8 o0 j. }& J; D" n
one therapy for penile growth. Urology, 6: 708, 1975.2 B3 C, q3 h; G! k5 L2 q
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' _5 [/ L; ~& R( w
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by4 c. E, \# ^8 V. m N
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ m8 S4 T# M& Z$ H
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
( [* D; t2 r7 v; J# c; j, y- mby topical application of androgens. J.A.M.A., 191: 521, 1965.
, M+ S! e" ~, Z) r9 V B* p6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- M# B* _ s" I% `
androgenic effect of interstitial cell tumor of the testis. J.
; X! t/ N5 ] Q2 D/ {; H0 M# T# \2 FUrol., 104: 774, 1970.+ P, M% t) y! L" ~9 B9 ]
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-' n E3 n/ z5 S! H
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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