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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 A6 `( X/ i3 U# [+ H/ pGONADOTROPIN
7 m0 N+ O1 X3 M k& f& P$ gRICHARD C. KLUGO* AND JOSEPH C. CERNY
% A) p9 v' J7 m4 O/ k3 r) cFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan0 `& o1 H/ X; R. R
ABSTRACT
' p# I: p4 m6 Q3 MFive patients were treated with gonadotropin and topical testosterone for micropenis associated# o7 J7 e2 h! m0 u% ?
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' e6 h3 W+ G& ]& ?5 }$ Ltropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
2 x" G* y% l. f( Q& \! {, ~0 ]2 l1 ]cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
/ h, Z) p" U3 j5 i% [for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% y! m' t( G6 E O# {" n- X* C* mincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average. r6 W5 }. I( ]7 u" z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" O. c7 k0 A z0 L' ^occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
* ^! n5 X8 b6 y5 E; V0 \study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 E) W3 ~/ ]9 i
growth. The response appears to be greater in younger children, which is consistent with previ-8 k, i. G3 r- x. L( W1 _! I
ously published studies of age-related 5 reductase activity.
" a8 y5 J7 Z( G( e8 q" Y8 [Children with microphallus regardless of its etiology will7 L/ `& G6 Z, a2 @" r' U
require augmentation or consideration for alteration of exter-
9 R/ N" g) D+ `! \* bnal genitalia. In many instances urethroplasty for hypo-
0 ]; {2 i! y2 H9 w0 |/ l, Zspadias is easier with previous stimulation of phallic growth.# H* g: u' i5 ]' b4 V9 k" L
The use of testosterone administered parenterally or topically
' [# ^5 D2 o( p" i8 N) mhas produced effective phallic growth. 1- 3 The mechanism of1 C3 e( M6 g- {
response has been considered as local or systemic. With this5 }' M. n! Z# r, k) _# Z
in mind we studied 5 children with microphallus for response. f: ?" O2 t$ c' G; g+ {% {$ L0 k
to gonadotropin and to topical testosterone independently.$ ~" r5 @8 W6 K) m1 g
MATERIALS AND METHODS
( H2 E3 J( r3 U V) j' z1 q$ DFive 46 XY male subjects between 3 and 17 years old were
C4 h$ s; I9 J* f2 k: n2 d: |evaluated for serum testosterone levels and hypothalamic+ z3 E$ r6 O( ~$ {
function. Of these 5 boys 2 were considered to have Kallmann's
5 ?, ?9 j. M2 x1 Qsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, P$ B8 E1 K4 i5 L, e# ilamic deficiency. After evaluation of response to luteinizing$ j2 D9 Z- Y% _ s0 a* S8 Y! d
hormone-releasing hormone these patients were treated with
w, z* i; ^/ }1 }; |# f: n1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 O, n! U) {( m" ]" @* C/ Aafter completion of gonadotropin therapy 10 per cent topical6 J$ \( W8 ?' w$ }! n) K+ G
testosterone was applied to the phallus twice daily for 3 weeks.& C; a& Z& @% ?, B
Serum testosterone, luteinizing hormone and follicle-stimulat-
& H! A! m* ~ P! f/ l1 King hormone were monitored before, during and after comple-
3 o, u7 t l( g" ?# ]& y% u& s7 ?" X! ~tion of each phase of therapy. Penile stretch length was7 L% B9 h# g+ |' ]" K9 {) ^
obtained by measuring from the symphysis pubis to the tip of
5 d6 G- ]" B" q% gthe glans. Penile circumferential (girth) measurements were
$ {9 i; p, v& q' ~/ Yobtained using an orthopedic digital measuring device (see
2 P; V9 l/ F7 `8 cfigure).
5 x% q4 Y6 z8 K" j* T9 m1 ?RESULTS
& ?7 v3 ^- D, n0 |" jSerum testosterone increased moderately to levels between
7 p: Z, o5 F7 H50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 L8 c1 x+ _/ t
terone levels with topical testosterone remained near pre-
: ?% k) R( W; C# \3 c3 ?7 d0 Q& P! ttreatment levels (35 ng./dl.) or were elevated to similar levels0 v: M, N& h& U! C# B
developed after gonadotropin therapy (96 ng./dl.). Higher
% v5 G2 e: [. t' g: e$ oserum levels were noted in older patients (12 and 17 years old),
. M r; y( ^0 ^$ L N+ a, `$ K/ Iwhile lower levels persisted in younger patients (4, 8, and 10
: F+ {# W* M! _; N: Oyears old) (see table). Despite absence of profound alterations# X. {3 l8 }4 Q( j9 c' s
of serum testosterone the topical therapy provided a greater- Z. ]% c# Q- z! r# e C7 q% x0 @6 ~
Accepted for publication July 1, 1977. ·% {+ s7 `8 R3 B: m3 E
Read at annual meeting of American Urological Association,
1 T/ d1 A8 G* B5 a7 h# A9 k* MChicago, Illinois, April 24-28, 1977.
! h/ N9 U/ {0 S: o! z' R* Requests for reprints: Division of Urology, Henry Ford Hospital,
/ ^1 q, d' Q Q" H2799 W. Grand Blvd., Detroit, Michigan 48202.( R# I) O/ g3 a$ B$ ?
improvement in phallic growth compared to gonadotropin.
" l2 g# h, e5 J. j2 }! T8 eAverage phallic growth with gonadotropin was 14.3 per cent
) R. J" U6 e/ n& u5 K$ |increase in length and 5.0 per cent increase of girth. Topical, U- m" X3 A4 P# [+ N+ c) y
testosterone produced a 60.0 per cent increase of phallic length
& P9 R; e( E# L. T& W) gand 52.9 per cent increase of girth (circumference). The
- X: R1 T- Z- h) Z) Qresponse to topical testosterone was greatest in children be-1 Q1 n& k$ c; I0 K+ H
tween 4 and 8 years old, with a gradual decrease to age 17& q5 y F# k, h9 Q' o, X7 S, w5 ~7 }3 F
years (see table).& R9 g; v+ c$ \9 ^8 Y8 K
DISCUSSION
' M( Y' t5 S- f" w ?Topical testosterone has been used effectively by other
0 l6 F0 i0 ^! Lclinicians but its mode of action remains controversial. Im-, ]) I* G# `0 T+ E
mergut and associates reported an excellent growth response
3 T6 j+ |* x- }# D& O- vto topical testosterone with low levels of serum testosterone,
* [* q1 I& D- w9 N" e# P% vsuggesting a local effect.1 Others have obtained growth re-
% @1 a: Q j! M$ p. x& Asponse with high. levels of serum testosterone after topical% g! d) m& @3 n D' W H& k- w% c1 f
administration, suggesting a systemic response. 3 The use of* V! \$ H2 |! e& }! g
gonadotropin to obtain levels of serum testosterone compara-! h }, }% h( U+ Z3 p4 q- d
ble to levels obtained with topical testosterone would seem to# ]; ~6 m( h* V/ r$ x7 f
provide a means to compare the relative effectiveness of7 n4 q) ~& \8 T
topical testosterone to systemic testosterone effect. It cer-
# ~6 V( t3 | y5 g, T- @; H qtainly has been established that gonadotropin as well as par-
# B8 M' ^) q. j- p: p# E7 A& @enteral testosterone administration will produce genital/ q; U* q" I1 w& U1 ^
growth. Our report shows that the growth of the phallus was
: \( k* } K- H: d, x5 f$ Nsignificantly greater with topical applications than with go-* D6 L( D o$ ^) C* k$ F
nadotropin, particularly in children less than 10 years old.# h& _ C6 Y! V1 `8 A
The levels of serum testosterone remained similar or lower
9 X$ I, A6 R- G$ {* b- k2 V" bthan with gonadotropin during therapy, suggesting that topi-
; i) t( Y! K/ F' B8 c3 q' S: bcal application produces genital growth by its local effect as
! s7 j% p$ Z6 i9 o( H7 ~) Y& qwell as its systemic effect.9 b( Q: c- {: I' d- W% I( I% T
Review of our patients and their growth response related to
. T! B/ W7 E$ X" Q2 Y( t4 Qage shows a greater growth response at an earlier age. This is6 {; G( N2 R( [' @# E
consistent with the findings of Wilson and Walker, who
' d4 j8 g* v' m9 _4 w5 `reported an increased conversion of testosterone to dihydrotes-
! {/ A1 _$ ~7 b% G6 O% N4 stosterone in the foreskin of neonates and infants.4 This activ-
! f; t! H. a6 v' M- P* p6 w) G! bity gradually decreases with age until puberty when it ap-
. p. W; P1 w5 I: f& x/ w% Uproaches the same level of activity as peripheral skin. It may, m3 ~5 w& p7 {3 Q6 ^7 ~ W# ^3 X% }
well be that absorption of testosterone is less when applied at
0 f% J+ A+ Q8 X! K# ^an earlier age as suggested by lower serum levels in children, p5 {) t; X; ~! r9 k5 M7 x% U
less than 10 years old. This fact may be explained by the
- r4 |% z. ]9 n3 |* ?# e+ b# jgreater ability of phallic skin to convert testosterone to dihy-1 [* U" t8 m: R" R |
drotestosterone at this age. Conversely, serum levels in older
, j' b5 L% X3 U1 Opatients were higher, possibly because of decreased local9 U! J$ r, h0 E. K5 M! |0 ]8 u
667
5 I) g& m# _: ]. d, P1 l" _/ J668 KLUGO AND CERNY" r# L2 r, N) I: I) Q
Pt. Age
% x8 x, c @" R( V' O(yrs.)
2 \4 T( Q# x* p6 O* L* hSerum Testosterone Phallus (cm.) Change Length7 T* ?, y( O5 M' I
(ng./dl.) Girth x Length (%)
# Z4 Q- m# l# H2 a( ^3 |# J4
2 m% ^$ n& ~+ x Q. X8 }- X& a D8
8 N$ @; h' g5 ]9 ?2 w10
2 o# I3 `1 |3 k6 p123 Z% v1 ~0 m0 w7 n* b
17
3 N! @ z" U# m* d/ G A! D" NGonadotropin5 V$ B* @+ ~( K1 C# P! {
71.6 2.0 X 3 16.65 n4 U1 z# k9 u( O+ m/ d: n* U
50.4 4.0 X 5.0 20.0
( C* I# l! ^4 ^0 E4 I) n22.0 4.5 X 4.0 25.0! }/ v' s" F I. I5 J
84.6 4.0 X 4.5 11.1; j4 z% |) F, v* `% m
85.9 4.5 X 5.5 9.0
/ |1 c5 Y- Y ]+ aAv. 14.3
+ I! \+ F: n% X& v# i4
4 e4 k! K% y) d3 ]6 f3 A8* S4 I) j' g' |, d- E# v
10
" |4 W8 O- [ O" }4 E12
5 |4 x3 T j Z/ Z9 c17) w& o) ^: _& c7 c$ y4 k4 Q2 `# L4 u
Topical testosterone3 y! E4 G5 q8 C8 \ d0 G+ s# A
34.6 4.5 X 6.5 85
" c9 Y7 j# ^/ Q- ~; A3 }38.8 6.0 X 8.5 709 r) m+ G( x% Z
40.0 6.0 X 6.5 62.5
6 b$ a0 [/ H& y93.6 6.0 X 7.0 55.52 ?6 Z( {1 h% f5 Z7 R; C
95.0 6.5 X 7.0 27.2
; N5 P, i4 w) v# AAv. 60.0
& i0 O* M" t, a& e' B5 s+ \available testosterone. Again, emphasis should be placed on
' D' M0 p' [% E S0 }1 Tearly therapy when lower levels of testosterone appear to7 q8 N7 l$ X9 ?9 y% }& ~; K* f- u
provide the best responses. The earlier therapy is instituted
- z3 z) A3 O( M. R( S Pthe more likely there will be an excellent response with low
1 y3 c' e/ }+ `) B3 nserum levels. Response occurs throughout adolescence as
. Q& G, f7 n, U3 [9 b, ^noted in nomograms of phallic growth. 7 The actual response
B3 z! p5 ^2 z0 rto a given serum level of testosterone is much greater at birth( k H1 A' o$ A+ L1 d( R; M. S
and gradually decreases as boys reach puberty. This is most
2 g0 w6 S. C, u. S/ {: Olikely related to the conversion of testosterone to dihydrotes-
9 t1 e) }) r( N2 n. X5 Ptosterone and correlates well with the studies of testosterone
) p" D+ ^0 W8 v, A F% Q5 P, b- Yconversion in foreskin at various ages." E' ]& L9 x1 t- W: {* N% P. @
The question arises regarding early treatment as to whether
- a9 s8 ^7 U; xone might sacrifice ultimate potential growth as with acceler-* Y9 l) T1 ?4 {3 A- K
ated bone growth. The situation appears quite the reverse
; F8 q" u: w" w9 Jwith phallic response. If the early growth period is not used6 W+ Q$ F4 A+ _% G: \4 p
when 5a reductase activity is greatest then potential growth
$ [% Z9 O* ~' L& ?: ^/ P+ smay be lost. We have not observed any regression of growth- U$ L* U9 w+ a. }: e Y- a( l
attained with topical or gonadotropin therapy. It may well
8 a: y$ r5 d4 N9 H/ \& qbe that some patients will show little or no response to any
0 F6 H4 g# w) ?, Xform of therapy. This would suggest a defect in the ability to/ \! u7 a. H0 y
convert testosterone to dihydrotestosterone and indicate that- b; v" I+ T( L# y- C1 h
phallic and peripheral skin, and subcutaneous tissue should
7 E6 [2 |: ?# M3 f% Ube compared for 5a reductase activity.- g9 G% K/ A- h) y0 N2 E, o/ B
A, loop enlarges to measure penile girth in millimeters. B,
# S% {( I2 p! v% Z) r! fexample of penile girth computed easily and accurately.5 O' R7 n) h/ j; h5 {, [7 J6 f
conversion of testosterone to dihydrotestosterone. It is in this
/ o: z6 K9 V5 g) rolder group that others have noted high levels of serum
& l" \1 j/ x0 b- Ytestosterone with topical application. It would also appear- f Z0 V3 N; J; J3 n
that phallic response during puberty is related directly to the; J9 N. x* G+ Z; d
serum testosterone level. There also is other evidence of local/ v D; Q0 Z1 Z$ r9 ^% t8 p/ w! e5 i
response to testosterone with hair growth and with spermato-% L) F5 d) n2 q( P9 ?5 f
genesis. 5• 6! D$ @/ f7 m5 r
Administration of larger doses of gonadotropin or systemic
5 b1 R# r5 Q- x8 B* [& `; Rtestosterone, as well as topical applications that produce. _; Q }6 h. {! W7 S" b
higher levels of serum testosterone (150 to 900 ng./dl.), will# d1 Y$ h% c' G
also produce phallic growth but risks accelerated skeletal2 o5 R; ^7 V, q6 y: {
maturation even after stopping treatment. It would appear
# b4 T) V1 y9 O+ S: u4 a) X uthat this may be avoided by topical applications of testosterone
4 c* p- h& { Tand monitoring of serum testosterone. Even with this control% D4 J( H! l: N1 X6 D. q
the duration of our therapy did not exceed 3 weeks at any. }) g. y7 @4 e5 \9 [3 f
time. It is apparent that the prepuberal male subject may, Y" ~& V( F3 z6 J) d
suffer accelerated bone growth with testosterone levels near5 ~5 t( {! C; u6 Y6 G- P
200 ng./dl. When skeletal maturation is complete the level of
/ L; c* R$ ?1 y" y4 [0 userum testosterone can be maintained in the 700 to 1,300 ng./8 N3 C5 D) \8 q6 C6 L4 U/ \4 J
dl. range to stimulate phallic growth and secondary sexual
* E" v6 ]) }. O0 Echanges. Therefore, after skeletal maturation parenteral tes-: Q; `0 D9 o H$ `
tosterone may be used to advantage. Before skeletal matura-7 X! J* M/ P) t8 C2 m& O
tion care must be taken to avoid maintaining levels of serum
. k7 Q' W: g6 q6 Ztestosterone more than 100 ng./dl. Low-dose gonadotropin; s3 E& M$ X% Q9 H8 D
depends upon intrinsic testicular activity and may require q; ?+ J5 A8 H9 z4 ~' w9 H
prolonged administration for any response.
) e% I6 r; K6 s2 gAlternately, topical testosterone does not depend upon tes-) R# d, X* A d6 w N
ticular function and may provide a more constant level of
& x4 }0 I" q/ B& f0 lREFERENCES! O; P" c/ |+ c
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,1 j0 l5 M& {6 l: B( y
R.: The local application of testosterone cream to the prepub-- I6 v1 h1 x) ^. \
ertal phallus. J. Urol., 105: 905, 1971.) c( W: u4 N! m
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 K( h; H) ^0 ^
treatment for micropenis during early childhood. J. Pediat.,/ o6 q; Z; T& D+ ?% i
83: 247, 1973.
4 G! w5 q, v) q. \3 L3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-/ @3 r7 J0 l% F5 ?4 |& X
one therapy for penile growth. Urology, 6: 708, 1975.
1 j9 I* w' c) R! ]" y/ J/ U8 f4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
% W, {* x7 K! \: |; sto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
2 z; o( ]# q0 k: Y4 X) E+ sskin slices of man. J. Clin. Invest., 48: 371, 1969., v( j: c; U+ O {- _; Y
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
5 U2 w/ z# z/ V. `by topical application of androgens. J.A.M.A., 191: 521, 1965.5 H" V: S5 j {6 Y
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ z; F* g8 h$ R/ m' j
androgenic effect of interstitial cell tumor of the testis. J.; H) y4 U) |- A: c7 [. k. n& J# B6 t
Urol., 104: 774, 1970.) \3 H r9 a+ }& {3 n' P" [+ H
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-/ G2 E" Q# T1 M9 l. k! z
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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