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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 X; _4 V o- b# g5 T
GONADOTROPIN
1 i, a9 N+ j) qRICHARD C. KLUGO* AND JOSEPH C. CERNY
: O( L$ X! ~$ B; AFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan+ x/ F J0 X3 v$ o8 W3 q3 o
ABSTRACT
% r, m6 R4 h* J' E" _Five patients were treated with gonadotropin and topical testosterone for micropenis associated; g4 @0 b" p' F
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 o6 ]' D) I6 i3 P( U1 X
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, s4 A% @# z+ \! N. O/ e- bcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 |& ]& M0 V! c# B7 k
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* Z* v- c9 Q% Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 S/ e! K( n2 c6 J% Vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 E$ ~* @0 |) ?# e7 `occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ B; `* O" p2 R, i/ S0 I, ystudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ Z* M- v! [* I
growth. The response appears to be greater in younger children, which is consistent with previ-; t1 V8 z- N, P/ p; Q+ G
ously published studies of age-related 5 reductase activity.
! A! b K4 R7 F7 O2 @Children with microphallus regardless of its etiology will
; Y' ]- i7 Y2 Arequire augmentation or consideration for alteration of exter-
, L: T1 k w% H, H7 [nal genitalia. In many instances urethroplasty for hypo-
% H2 J$ e: }) y/ x1 yspadias is easier with previous stimulation of phallic growth.3 ^# q- w- B: B- G3 S* [ h
The use of testosterone administered parenterally or topically* P* L1 |, a: o3 |0 G- I
has produced effective phallic growth. 1- 3 The mechanism of
: z2 H% x& i3 P; n) `, l: Kresponse has been considered as local or systemic. With this+ {& G% Q( f( ^/ q$ g
in mind we studied 5 children with microphallus for response, k5 ?$ ~1 J% C/ ~* k" V: w
to gonadotropin and to topical testosterone independently.
" L# M# y6 W" ~0 S l l. m4 EMATERIALS AND METHODS
* j3 M2 u1 _3 FFive 46 XY male subjects between 3 and 17 years old were3 v) d2 H- I1 q( q
evaluated for serum testosterone levels and hypothalamic% u% I# M8 G( t2 f, J0 E/ @
function. Of these 5 boys 2 were considered to have Kallmann's2 w3 p ~- a/ q) R
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ w& [& |! d; p6 r
lamic deficiency. After evaluation of response to luteinizing+ c. R! Q( ]2 G( p7 q
hormone-releasing hormone these patients were treated with
: C$ S5 o' _# M2 f1,000 units of gonadotropin weekly for 3 weeks. Six weeks4 v& J' l+ M; m9 |( e4 s
after completion of gonadotropin therapy 10 per cent topical
" i' w+ ^0 h: w2 T0 `testosterone was applied to the phallus twice daily for 3 weeks.0 S2 Q Q; R2 O/ h. u7 t6 y
Serum testosterone, luteinizing hormone and follicle-stimulat-+ ~# ?# q0 M' S5 `' o
ing hormone were monitored before, during and after comple-
% z! i/ m' S$ \0 H( ktion of each phase of therapy. Penile stretch length was, c% z9 N6 R0 \* j
obtained by measuring from the symphysis pubis to the tip of s7 T' a& h9 k% H& m: j. b/ ?
the glans. Penile circumferential (girth) measurements were
4 }7 U+ x4 _7 qobtained using an orthopedic digital measuring device (see8 }0 E! u4 Z2 u: t2 y
figure).: O! h" W$ Q3 f
RESULTS! @- U! o' K+ }/ ~2 o
Serum testosterone increased moderately to levels between/ f- w% S' C" i: a# i$ t5 O
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
\* l4 y. Q9 U' dterone levels with topical testosterone remained near pre-
$ U& c: Y% o H8 c% t# ytreatment levels (35 ng./dl.) or were elevated to similar levels
& d6 A# g6 V# b# Pdeveloped after gonadotropin therapy (96 ng./dl.). Higher' C7 o3 o) v# C! L% M, |7 D
serum levels were noted in older patients (12 and 17 years old),1 n6 C0 G9 R5 a
while lower levels persisted in younger patients (4, 8, and 10
& D; {/ l5 O" G% Z% v4 ]) Ryears old) (see table). Despite absence of profound alterations' A& e- F% l( v! k: Q
of serum testosterone the topical therapy provided a greater
" W9 @, R! W# ]/ X6 u; lAccepted for publication July 1, 1977. ·
' U( s8 p, l" R0 j' U5 ~% bRead at annual meeting of American Urological Association,
: a4 L- O8 w! jChicago, Illinois, April 24-28, 1977.
+ r3 `, C, L: [ p G0 ]9 R0 X6 w* Requests for reprints: Division of Urology, Henry Ford Hospital,# h5 C" `% O0 M: j" {
2799 W. Grand Blvd., Detroit, Michigan 48202.
" `! c, o0 i" ?. |2 i9 Zimprovement in phallic growth compared to gonadotropin.
. `3 z7 e- s+ l1 b, h/ E3 IAverage phallic growth with gonadotropin was 14.3 per cent' X# {0 x0 G" B7 r7 S
increase in length and 5.0 per cent increase of girth. Topical7 S2 X* q( i9 y9 n% p
testosterone produced a 60.0 per cent increase of phallic length
3 t: X$ u# `/ K3 R, E! hand 52.9 per cent increase of girth (circumference). The
: A1 \9 B+ d W7 |5 H+ M9 Q+ L9 \response to topical testosterone was greatest in children be-( @8 r; D. W2 C( k! t6 j/ f
tween 4 and 8 years old, with a gradual decrease to age 17" @6 o% f0 P+ d% l* g
years (see table).
0 G) ^4 I2 s1 U2 j8 M3 ?DISCUSSION# J) R/ x1 v- x& u4 s+ i' J
Topical testosterone has been used effectively by other Y: N0 p7 k5 O: h& G" b" U4 M: b
clinicians but its mode of action remains controversial. Im-
f% m' q g% J' t. L7 ^( nmergut and associates reported an excellent growth response
' j1 `& A6 l% T! bto topical testosterone with low levels of serum testosterone,' \6 t. ]6 J* Q
suggesting a local effect.1 Others have obtained growth re-6 e& B a( r- ]9 F" n! e! F
sponse with high. levels of serum testosterone after topical
: D, \3 f& @0 A) f! _8 jadministration, suggesting a systemic response. 3 The use of
+ }+ _; n2 U* n3 q- R$ s) T7 v$ }gonadotropin to obtain levels of serum testosterone compara-
8 d o& e2 W+ r2 F) `- L1 Bble to levels obtained with topical testosterone would seem to9 m. p3 Y. H; W
provide a means to compare the relative effectiveness of ]3 T5 W# n# T, Q
topical testosterone to systemic testosterone effect. It cer-
5 n+ F- L' D# c& R2 M. atainly has been established that gonadotropin as well as par-/ {6 I" W; l9 r. s$ _
enteral testosterone administration will produce genital
1 N! ~+ ^8 i. _. ?growth. Our report shows that the growth of the phallus was) R1 h1 v( {9 ~6 t
significantly greater with topical applications than with go-
3 Z" ]" E4 G8 p3 j% znadotropin, particularly in children less than 10 years old.# K" C9 N! `4 z6 m- j: }
The levels of serum testosterone remained similar or lower
& a0 H) G8 [0 Lthan with gonadotropin during therapy, suggesting that topi-5 F# @% H9 b' |2 ?2 x9 P* L
cal application produces genital growth by its local effect as" [0 w7 @: L9 q: @$ V
well as its systemic effect." W( v3 M( S7 Z9 _# Q0 Q
Review of our patients and their growth response related to
0 A# X, v& q" e$ C# Jage shows a greater growth response at an earlier age. This is1 f: m/ N; a3 R: X
consistent with the findings of Wilson and Walker, who
+ i' b" u. J* g" Z9 Xreported an increased conversion of testosterone to dihydrotes-: d( I/ K# b. L6 B% t
tosterone in the foreskin of neonates and infants.4 This activ-
6 `1 i- `% e0 q& c- M& Bity gradually decreases with age until puberty when it ap-5 x& z* H s8 k6 K1 E1 L2 \
proaches the same level of activity as peripheral skin. It may) ^) u- f; j% e
well be that absorption of testosterone is less when applied at
9 \$ Z/ C& M: N% \9 R y+ ~an earlier age as suggested by lower serum levels in children5 a4 U: S# Y7 S5 F: T1 k) M
less than 10 years old. This fact may be explained by the
" B/ V8 @: B1 [* F$ p! Rgreater ability of phallic skin to convert testosterone to dihy-7 x7 u D# }( I: |- Q
drotestosterone at this age. Conversely, serum levels in older0 u+ @- ~8 [" {$ l- B
patients were higher, possibly because of decreased local: P, y5 z7 o* {( t. U4 }6 G
6676 O6 z( H* }6 A ?( u2 |+ c5 P' e
668 KLUGO AND CERNY' C% t/ E8 R0 E* w& w% X6 d
Pt. Age# v, P( `1 E6 ]+ `$ ]6 p( ^& u( }+ c
(yrs.)7 j( B/ I/ Q) y* U5 v; r, M5 M7 X
Serum Testosterone Phallus (cm.) Change Length0 ?1 y1 @4 |: V! z3 F: y
(ng./dl.) Girth x Length (%)) W4 A6 k: O9 w0 D
4
: [6 z& q' R+ r }. b. D8; B$ E! V, h \8 o
10+ L! ?2 t+ h, F
12
7 F& k8 ~3 T7 R9 K' U17- Z# t) m! C/ r6 b& F
Gonadotropin1 t! W8 v; H# Z. }7 U' p% X
71.6 2.0 X 3 16.67 V# ] e4 y% M% V6 a
50.4 4.0 X 5.0 20.0: _2 [. K/ t& P/ ^ i: w
22.0 4.5 X 4.0 25.0; M- x, F" w. W
84.6 4.0 X 4.5 11.1. ?! n7 r' ^: l3 @6 f4 I0 m
85.9 4.5 X 5.5 9.0
& H/ i6 R/ K. AAv. 14.3
, W; ]8 v' p: y) }! `4
, w$ N+ \; n: w" T0 U8
) v$ v$ X- a" S) d) w10
6 q3 v+ c% @& \+ S# o% R128 S1 e. l. Z+ B7 k8 w
17
5 u/ I/ l, P) WTopical testosterone
" W! D$ U+ ^+ c% `5 d5 s34.6 4.5 X 6.5 858 p n0 x5 y0 C5 T! `
38.8 6.0 X 8.5 70* _7 ^6 x! X f0 O* u* u$ F
40.0 6.0 X 6.5 62.5
- Z8 b1 x9 \+ F& w1 h- p93.6 6.0 X 7.0 55.5
# v+ ]4 E2 K3 y95.0 6.5 X 7.0 27.2% m: @2 ~1 p& T4 j: x
Av. 60.0
8 `( x- g: l! D4 _5 s$ zavailable testosterone. Again, emphasis should be placed on
! t3 [: I+ d2 x9 v+ y8 @$ E2 Dearly therapy when lower levels of testosterone appear to
- r$ c R( ~' A. s$ s! U. Rprovide the best responses. The earlier therapy is instituted
: U- g) [# u' E7 e- Bthe more likely there will be an excellent response with low4 |$ G& h) y# J, @! |
serum levels. Response occurs throughout adolescence as9 N: i1 T, Y/ ^( g6 d
noted in nomograms of phallic growth. 7 The actual response8 p2 R4 N) C% C
to a given serum level of testosterone is much greater at birth
* g( H" E( i9 E: `( j, O: Pand gradually decreases as boys reach puberty. This is most$ T2 n. C" }" p! r5 i0 k
likely related to the conversion of testosterone to dihydrotes-
# P4 H( x; b& n! X4 h" m0 O+ utosterone and correlates well with the studies of testosterone+ K. r+ U% L3 z7 Q! d
conversion in foreskin at various ages.
. G! e q- |# Z/ gThe question arises regarding early treatment as to whether% h& ]0 T! o& s
one might sacrifice ultimate potential growth as with acceler-
- H( G! p7 `! h: p$ S. Hated bone growth. The situation appears quite the reverse: C$ u" n- h9 D5 d# w
with phallic response. If the early growth period is not used
' @: n- O) z* E1 W, [6 M# ?" fwhen 5a reductase activity is greatest then potential growth% e9 A$ ]: R! _+ a
may be lost. We have not observed any regression of growth+ d0 u" W0 F" H- w6 g
attained with topical or gonadotropin therapy. It may well
' a9 ?( o5 G8 K! r: v V: qbe that some patients will show little or no response to any
3 W# f, O H! d) ~form of therapy. This would suggest a defect in the ability to5 C% \) a8 h2 z% V; Q9 G
convert testosterone to dihydrotestosterone and indicate that
4 m7 i; V0 g- Aphallic and peripheral skin, and subcutaneous tissue should
7 y5 x5 w' e, |8 z2 r! s! lbe compared for 5a reductase activity.# \. g" O. u; l, A; P. b! ]) X
A, loop enlarges to measure penile girth in millimeters. B,
4 b6 X/ K7 e' h9 O- A8 lexample of penile girth computed easily and accurately.. }9 r( k0 p- n5 J
conversion of testosterone to dihydrotestosterone. It is in this' E& [4 K+ w T
older group that others have noted high levels of serum
) ?& d/ z* n' Y2 }$ |testosterone with topical application. It would also appear6 {5 q$ \7 y. p3 S$ S) E) E- o0 J
that phallic response during puberty is related directly to the
o8 H' A4 o2 K1 Qserum testosterone level. There also is other evidence of local: L0 W0 O* R. {/ R5 g
response to testosterone with hair growth and with spermato-0 x4 } L( F7 @1 C
genesis. 5• 65 w3 J" ]) u4 L* [2 V4 ]- H" p
Administration of larger doses of gonadotropin or systemic
' C) S1 C" O' D ftestosterone, as well as topical applications that produce
5 \: `5 y0 h- c2 l2 j4 G C8 i# ohigher levels of serum testosterone (150 to 900 ng./dl.), will
W! A( @+ |' H) e9 v+ E3 k# Y& }1 J3 galso produce phallic growth but risks accelerated skeletal; z9 |3 @! P) H; Z* e, D
maturation even after stopping treatment. It would appear
! W2 D3 x) P0 {that this may be avoided by topical applications of testosterone+ q6 N0 D) }1 O- t# P1 v
and monitoring of serum testosterone. Even with this control x& M1 A1 n" d5 o& U" y
the duration of our therapy did not exceed 3 weeks at any, K) _6 C: `6 i
time. It is apparent that the prepuberal male subject may# Q: G4 B6 _; Y! o4 a, F6 d
suffer accelerated bone growth with testosterone levels near: _5 x, c3 B$ a7 ?9 e! y3 p
200 ng./dl. When skeletal maturation is complete the level of
, m, M3 r1 r; K# Q) |serum testosterone can be maintained in the 700 to 1,300 ng./6 p8 s- @& O6 L+ i
dl. range to stimulate phallic growth and secondary sexual; f) i3 X) v/ p8 L4 w0 Y& @# w
changes. Therefore, after skeletal maturation parenteral tes-
" w, W4 `- W4 o q7 Q* G- v! ctosterone may be used to advantage. Before skeletal matura-0 Q+ H" v B/ f9 V9 c
tion care must be taken to avoid maintaining levels of serum
( o2 [% W. N$ V' J2 x0 jtestosterone more than 100 ng./dl. Low-dose gonadotropin+ J! N) g1 O1 R1 z3 B. d% ]
depends upon intrinsic testicular activity and may require5 t. q# b+ M. p0 S8 ^& Z( R" P
prolonged administration for any response.
+ C# p6 ]; N' w7 yAlternately, topical testosterone does not depend upon tes-
2 U' c5 D8 f# Iticular function and may provide a more constant level of
9 Z3 R5 S% u2 h7 N5 d7 [5 HREFERENCES) f2 `: n9 Y- r
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
, u& I1 V; ]; u- a7 A* |9 FR.: The local application of testosterone cream to the prepub-+ X* Z6 F6 T# V9 @
ertal phallus. J. Urol., 105: 905, 1971.
! b, Q8 d& N5 g; C: o+ X* w- |2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone9 e7 Q; Y! Z& h$ u9 E- F+ ?
treatment for micropenis during early childhood. J. Pediat.,
. l4 y7 {0 N4 \" g5 e" G. H83: 247, 1973.
+ S. ]3 m O$ `: d6 e& R3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 D; |/ h: O& v8 Gone therapy for penile growth. Urology, 6: 708, 1975.' F7 g9 Z4 t5 m+ d) r; @* J+ A
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone8 O; W& q& n8 N4 p, {- C
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 z" Z' X8 W* }
skin slices of man. J. Clin. Invest., 48: 371, 1969.9 X' A" b) L2 Q) W" H- O# p/ R$ u S% z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
$ y! m3 }* Q2 m& F: Gby topical application of androgens. J.A.M.A., 191: 521, 1965.
3 l) X% m2 V% T( ]6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local6 _' j: V. J' k
androgenic effect of interstitial cell tumor of the testis. J.: Y0 @( T+ y: P# v+ x4 t
Urol., 104: 774, 1970.& G% P. x$ R/ S5 Q
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
6 Z1 {+ j; ^4 Ttion in the male genitalia from birth to maturity. J. Urol., 48: |
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