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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
* ^" u( `# s4 D" a2 ?5 t7 HGONADOTROPIN4 y( ^% G7 b1 @( a5 V2 l. x
RICHARD C. KLUGO* AND JOSEPH C. CERNY; o/ T0 z. W+ G. U
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan5 U& M& m9 T- c
ABSTRACT" E4 ]4 U: Y* Q; K Z# y
Five patients were treated with gonadotropin and topical testosterone for micropenis associated, w* _2 Q* R7 f; b8 F/ c, r! w
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
`9 U8 a- b* ytropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
f' s/ w- ]8 d, c9 ~. \, A. Vcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
- r, P0 Z# p3 S( x! wfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
M0 [. N* @/ y* S; \/ Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average: i- F9 ?- ]' v: E. J7 d( z; M
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response4 h5 F% t; H, C# N, N
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 I6 ^5 a( e" ^1 i% b! Kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# q+ F/ p5 k8 {; n/ B: `growth. The response appears to be greater in younger children, which is consistent with previ-% [7 W, u' \9 }6 ~
ously published studies of age-related 5 reductase activity.
/ ~, B* d5 }1 n" e R* _Children with microphallus regardless of its etiology will' Q/ f" K% X/ N6 T+ O. Y' Y
require augmentation or consideration for alteration of exter-( X9 w6 N0 u5 W: a
nal genitalia. In many instances urethroplasty for hypo-
( [3 @" ~" X& ?# [( c3 L2 ?spadias is easier with previous stimulation of phallic growth.1 |6 H, o P) l4 \$ t
The use of testosterone administered parenterally or topically# J* ]1 M/ ^* `1 n" Y. f' L
has produced effective phallic growth. 1- 3 The mechanism of/ ~! B! C8 _6 x
response has been considered as local or systemic. With this( L8 s7 ]( Q. z, u( M. E0 x3 F* Q
in mind we studied 5 children with microphallus for response( ~- P0 ^- c" i- u- x, A
to gonadotropin and to topical testosterone independently.9 ^" d1 x$ F# t% r5 j
MATERIALS AND METHODS
* c* \% E; u7 K% X$ `Five 46 XY male subjects between 3 and 17 years old were
: M' f+ i6 _) Wevaluated for serum testosterone levels and hypothalamic6 O0 x5 {" `5 c6 u; H9 i) n% y8 `1 N
function. Of these 5 boys 2 were considered to have Kallmann's* y0 q5 K0 a' Y% f
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
* \7 U: q9 N$ l+ tlamic deficiency. After evaluation of response to luteinizing) j# ?; S9 s& |
hormone-releasing hormone these patients were treated with5 M1 z0 _& p2 k; H* m9 ]
1,000 units of gonadotropin weekly for 3 weeks. Six weeks8 x& F+ S5 g- x, G7 Q
after completion of gonadotropin therapy 10 per cent topical
6 D3 y6 Q: M! G: Q3 j' i; atestosterone was applied to the phallus twice daily for 3 weeks.1 p$ s8 {3 \% S% O6 ~
Serum testosterone, luteinizing hormone and follicle-stimulat-
' j! G* W8 E5 j% X% V7 K# king hormone were monitored before, during and after comple-
2 s5 R' N% K; ?0 O5 h# J9 \tion of each phase of therapy. Penile stretch length was
/ Y: M+ n* E8 i# Y+ uobtained by measuring from the symphysis pubis to the tip of
8 D7 n' ]9 o7 M3 wthe glans. Penile circumferential (girth) measurements were
$ g8 M$ i0 q: N. \) Q( [ xobtained using an orthopedic digital measuring device (see8 M- l6 Q0 Y+ H9 v2 Z; s
figure).
9 T. r6 s5 J8 zRESULTS
5 |# p6 u/ v! i2 N# r- o$ LSerum testosterone increased moderately to levels between4 w- d6 p( B# i& k5 w+ r/ a
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' Z S( S8 e+ U" b# Kterone levels with topical testosterone remained near pre-
9 w' s+ D9 b- E- otreatment levels (35 ng./dl.) or were elevated to similar levels3 B3 J. W6 _$ z' v$ g* Q
developed after gonadotropin therapy (96 ng./dl.). Higher
& a3 @5 @0 ~; ]9 g9 W7 J7 Xserum levels were noted in older patients (12 and 17 years old),
5 L% T; O3 H/ f( {3 N. y7 Pwhile lower levels persisted in younger patients (4, 8, and 10
6 D& q# B. t2 J6 |! g0 |years old) (see table). Despite absence of profound alterations0 X, w+ A3 T* b0 L7 h! n
of serum testosterone the topical therapy provided a greater
2 ~2 Y& `- @! C) f4 Y* A0 \Accepted for publication July 1, 1977. ·
, h6 S1 a9 d' K5 G1 \7 xRead at annual meeting of American Urological Association,% d' Z2 V0 x) _, f9 T" ^- [
Chicago, Illinois, April 24-28, 1977.8 w; W3 o9 a! h, P
* Requests for reprints: Division of Urology, Henry Ford Hospital,3 Z0 H5 E' u1 {" o: d4 e0 S
2799 W. Grand Blvd., Detroit, Michigan 48202.
. [: V6 I# j: H6 H8 P* F* ?improvement in phallic growth compared to gonadotropin.& `8 n, I4 r( l) ]! E- S! }% [
Average phallic growth with gonadotropin was 14.3 per cent, Z3 S1 U# a% O$ f, b
increase in length and 5.0 per cent increase of girth. Topical+ o2 |9 o4 x2 C: u
testosterone produced a 60.0 per cent increase of phallic length
1 S& V3 b- X* R$ uand 52.9 per cent increase of girth (circumference). The
1 j$ d! a/ g4 N& y/ Wresponse to topical testosterone was greatest in children be-4 ?0 h( n4 U0 N0 @
tween 4 and 8 years old, with a gradual decrease to age 17& Q# a0 M6 j% r# N- M" F
years (see table).$ I. s( I9 ?( |; j- }! f5 p- Z1 A
DISCUSSION
5 G" S9 ?, J+ |; J0 c8 uTopical testosterone has been used effectively by other2 [# l8 f3 s2 ^ N- i
clinicians but its mode of action remains controversial. Im-
' A% q, o- V/ |' G8 t1 jmergut and associates reported an excellent growth response
) _ [) @# ~7 p! u3 T0 k/ {to topical testosterone with low levels of serum testosterone,
9 K8 J3 a8 i0 l% [' Ssuggesting a local effect.1 Others have obtained growth re-
3 J9 H$ T2 U9 ]) T" o+ gsponse with high. levels of serum testosterone after topical
7 j$ a9 s/ r8 E6 Uadministration, suggesting a systemic response. 3 The use of% S% p2 G& r% J D5 Q3 T
gonadotropin to obtain levels of serum testosterone compara-
- j5 p5 H6 C7 l5 W5 Gble to levels obtained with topical testosterone would seem to }: |4 p6 ]5 V; e9 o
provide a means to compare the relative effectiveness of; K- g7 B/ B5 @. C
topical testosterone to systemic testosterone effect. It cer-" a2 f9 ^; o$ c+ E6 D6 c& n* C/ O
tainly has been established that gonadotropin as well as par-# Q' s% |8 y1 M1 C$ _
enteral testosterone administration will produce genital
) G9 ?* t' O! }) s; V; egrowth. Our report shows that the growth of the phallus was
9 I2 Q2 u. F% d$ n1 Y, W9 ^significantly greater with topical applications than with go-& S* e- Y. Z5 w* }
nadotropin, particularly in children less than 10 years old.% U+ ^% h" j4 |9 }4 |2 W O
The levels of serum testosterone remained similar or lower6 c+ ` f/ I/ ] {5 K* o0 N% e5 c1 A- s
than with gonadotropin during therapy, suggesting that topi-
9 e/ S1 J X6 r# Qcal application produces genital growth by its local effect as+ X$ I/ T' x9 ?4 u; `3 r' z
well as its systemic effect.; b5 B- u. C+ C$ ?
Review of our patients and their growth response related to3 }/ v9 I8 \ j, _* K8 l5 ]
age shows a greater growth response at an earlier age. This is
* J7 v$ a* t6 Gconsistent with the findings of Wilson and Walker, who3 V) V1 B# {6 |/ E* J% C4 P
reported an increased conversion of testosterone to dihydrotes-, L6 S5 F8 [ ?- B
tosterone in the foreskin of neonates and infants.4 This activ-
+ K. [* A& x4 h" i5 eity gradually decreases with age until puberty when it ap-
- ~! C5 ?$ J2 \proaches the same level of activity as peripheral skin. It may9 Q# W, k% `, o: s' Q
well be that absorption of testosterone is less when applied at5 Z+ Y/ f N/ i' I
an earlier age as suggested by lower serum levels in children5 t* G- [0 z% Q
less than 10 years old. This fact may be explained by the
f8 s; S; S2 l, V2 @ I _greater ability of phallic skin to convert testosterone to dihy-3 f/ k" N r. a/ b( }8 Q) }( }& X p
drotestosterone at this age. Conversely, serum levels in older' f: |$ ~ |: B7 T) K
patients were higher, possibly because of decreased local
: @) h @9 ^: L# L8 U3 a' L667
1 I7 z" K& D, O0 F" \; E668 KLUGO AND CERNY. X. F6 K4 C0 j" W- |; z4 D Z
Pt. Age
0 Q0 w8 l- y1 M1 F. h' B* V(yrs.)" b! `4 H3 l( L* u
Serum Testosterone Phallus (cm.) Change Length
$ W, J+ T% T+ K6 _0 u$ r8 n(ng./dl.) Girth x Length (%)
( q n: \! h( d( U2 b3 o6 e$ L; e! M: B4
& D8 K3 }7 e( A7 V8
9 K1 n( V r" G4 J! k10
! Y9 Q; `6 V& v5 ~) c12
; v" R2 v* E# A" z8 @4 T R176 h& s3 R) p/ W' b: _7 s8 O
Gonadotropin
) K. M' o0 D! W8 y) ]71.6 2.0 X 3 16.6! _ Y) c2 {: E7 C; |
50.4 4.0 X 5.0 20.0: M/ ^2 r# j* K: M3 c# C
22.0 4.5 X 4.0 25.0
7 |9 W2 n, t! t9 D5 U+ \ A84.6 4.0 X 4.5 11.11 B- h$ D$ O+ Z. `
85.9 4.5 X 5.5 9.0! ?8 X5 X( }5 x/ r9 Q! K
Av. 14.3
- Y) b2 C! a# l% M4
4 u( S. X$ ^: B8 Q `+ a6 b' H8/ [4 @7 {& f0 i
10
& R7 B. ?% B9 j: O# k9 l, `12" Z: k, W" n( ^
17" I1 [; Q0 j* N( Y: E) e% N& m
Topical testosterone, B- Z1 {* T9 z8 T# L; k+ O) _+ w
34.6 4.5 X 6.5 85$ d( ^' K8 m: ?+ k0 o" `( K
38.8 6.0 X 8.5 70
* [* w9 W+ H& m2 j$ |4 D40.0 6.0 X 6.5 62.5
@$ {* p) A0 `5 v$ A4 o$ W( Y93.6 6.0 X 7.0 55.51 }& `2 v( w8 b1 D- t& K3 Y
95.0 6.5 X 7.0 27.2
1 K* O, V x3 n7 m7 T5 `Av. 60.0/ [) h" o; O f g4 E: ^3 L
available testosterone. Again, emphasis should be placed on
' k( n' B& O- ?6 m/ R! Iearly therapy when lower levels of testosterone appear to# q& f. p, I1 g7 q# `, y
provide the best responses. The earlier therapy is instituted7 G5 D, `9 s- J5 z' t8 b+ S$ }* F
the more likely there will be an excellent response with low" G+ |7 ~. ^% d% m% N) I2 a. O
serum levels. Response occurs throughout adolescence as
9 V2 Y6 P) x3 k Inoted in nomograms of phallic growth. 7 The actual response
' ?, o1 u# u' r# H4 O+ c; ], Yto a given serum level of testosterone is much greater at birth# ?7 L8 l+ I! M
and gradually decreases as boys reach puberty. This is most
" W( H d$ v E) j) h& i" n0 v( I: Z3 K7 Tlikely related to the conversion of testosterone to dihydrotes-( C6 b l- p6 {; [( o7 `
tosterone and correlates well with the studies of testosterone
' t- i; N `; I& V5 y5 `conversion in foreskin at various ages." A% J/ ]. A' \
The question arises regarding early treatment as to whether- R# r- g, ^3 e8 C/ J2 J e3 G" C4 i7 B+ C
one might sacrifice ultimate potential growth as with acceler-
7 ^: p& P6 e" ~* G/ mated bone growth. The situation appears quite the reverse
; ^6 E3 B4 x3 L9 r6 Pwith phallic response. If the early growth period is not used$ J5 m: w' X3 W5 h
when 5a reductase activity is greatest then potential growth
2 {0 `7 ?* B7 w5 r a- Pmay be lost. We have not observed any regression of growth
+ D$ z& @5 [* w' oattained with topical or gonadotropin therapy. It may well7 ^; a. e3 b1 p: A
be that some patients will show little or no response to any
& m$ {5 G/ i( y6 S2 p2 G2 cform of therapy. This would suggest a defect in the ability to5 G) P( E$ I% m
convert testosterone to dihydrotestosterone and indicate that; z! ^: L- n* y6 F$ z9 y
phallic and peripheral skin, and subcutaneous tissue should
' P- ?1 H( B' ibe compared for 5a reductase activity.
6 n8 Y, U- n w. e; e' Z' MA, loop enlarges to measure penile girth in millimeters. B,; M0 D% _6 j0 [9 x, B7 j
example of penile girth computed easily and accurately.
- W4 Z: O q1 y: v7 }6 @conversion of testosterone to dihydrotestosterone. It is in this
3 j% T# j" F# m4 `& Aolder group that others have noted high levels of serum( k; e" Q; W2 g6 U
testosterone with topical application. It would also appear/ d U% R8 l0 M. @/ |' ?
that phallic response during puberty is related directly to the
0 ^; {' h# z- y% @+ Cserum testosterone level. There also is other evidence of local) b$ S) t/ l3 C8 R5 N0 k
response to testosterone with hair growth and with spermato-
* K& P5 O' J: Y& B* y& M( ` B: [genesis. 5• 65 e* V& G4 T, u
Administration of larger doses of gonadotropin or systemic* S2 e, `5 P3 O; H9 G& y- r4 E6 }
testosterone, as well as topical applications that produce( R( P6 b0 _! ]4 `6 V
higher levels of serum testosterone (150 to 900 ng./dl.), will
/ E( L) P& Z; _also produce phallic growth but risks accelerated skeletal; E- o7 l$ y3 C8 y; m$ I; `& Z
maturation even after stopping treatment. It would appear
. B* q4 R- P, P& jthat this may be avoided by topical applications of testosterone4 D' ^$ V# w$ t/ Y! ~ U6 h
and monitoring of serum testosterone. Even with this control; c+ ?/ c2 k: J$ a( w' o
the duration of our therapy did not exceed 3 weeks at any1 i. t" x- N' h" R
time. It is apparent that the prepuberal male subject may" C+ P+ `# H3 b3 D1 j+ |
suffer accelerated bone growth with testosterone levels near
* W" j2 M9 m6 Z5 C& T+ |, R& C200 ng./dl. When skeletal maturation is complete the level of
; d9 a& `! Z3 g' bserum testosterone can be maintained in the 700 to 1,300 ng./
" V* a3 C$ B O* {# l& adl. range to stimulate phallic growth and secondary sexual
) w5 e o k2 s8 U( @changes. Therefore, after skeletal maturation parenteral tes-# Q+ K! R! U$ D0 W' Q( E
tosterone may be used to advantage. Before skeletal matura-
% i/ c6 t: x" Dtion care must be taken to avoid maintaining levels of serum5 H. S* _8 t' e+ C
testosterone more than 100 ng./dl. Low-dose gonadotropin
; s+ D; Y2 L6 _) qdepends upon intrinsic testicular activity and may require9 T4 b8 }" G8 {1 {. f) d2 B3 t
prolonged administration for any response." s7 l; @1 ]& x# d
Alternately, topical testosterone does not depend upon tes-- D( b) L1 ^" G5 p* H2 e
ticular function and may provide a more constant level of+ q5 _+ J5 {9 Z
REFERENCES
' E# D: `- M" E: ^% ]' m; Z4 v1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& h4 X: b: I, Y6 e3 i
R.: The local application of testosterone cream to the prepub-- M4 F. c3 b2 N9 b& m! r: y: u( A
ertal phallus. J. Urol., 105: 905, 1971.
. G8 M& [: Y- y2 G) z2 d T2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, ]* M) y4 T# r' f" s9 m" H
treatment for micropenis during early childhood. J. Pediat.,
* x/ ?3 Q& E) x4 x83: 247, 1973.
) C |7 v6 g2 Q. E3 Y2 ~ n3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* E9 W4 R0 r# G% n& Vone therapy for penile growth. Urology, 6: 708, 1975.' L$ f: f8 {. a
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
$ n2 b' }( Y" u3 @to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. a1 \% V @) F1 o4 J# xskin slices of man. J. Clin. Invest., 48: 371, 1969.
* @* X' p9 D! K# O) J4 v5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. i+ m5 m+ W) I$ Aby topical application of androgens. J.A.M.A., 191: 521, 1965.
+ C( w' b" Z2 e; n6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! F% L; Q" \2 w J, Gandrogenic effect of interstitial cell tumor of the testis. J.# w6 I3 z" i ~- t8 T' }+ h" s
Urol., 104: 774, 1970.9 }" ]: |# ^+ P; o$ l. e0 j
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-% t e! _, J5 f+ Y/ x9 ~& _
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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