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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
/ k' v$ X) O2 w( y1 \, @) u1 @GONADOTROPIN! x Z6 f' W9 [
RICHARD C. KLUGO* AND JOSEPH C. CERNY
: T$ b$ p/ ?- {3 I5 \& @9 o; X8 I: dFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan0 [* |* }8 O( n" }( E5 r- {3 ^
ABSTRACT
5 C3 e' O# n* A1 lFive patients were treated with gonadotropin and topical testosterone for micropenis associated
# B! u" I; Y3 M7 Awith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 K3 z* z. {) M2 K/ E0 h. t* K
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 ?5 p7 O; ~3 j, |cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
# {9 u+ B; l, t6 T! zfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. L$ W a) V! D' Y( } e7 f
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average/ k. j& {1 e0 f) o8 ^
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
, q2 R0 g# [, U& roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
7 O0 h* N9 T5 [' A& q R, L& kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 L/ }) L( C P& P% A6 z4 ]
growth. The response appears to be greater in younger children, which is consistent with previ-
# K5 P2 V" @$ _2 sously published studies of age-related 5 reductase activity.7 s, m/ ^! H" q6 r7 Z }2 M
Children with microphallus regardless of its etiology will# t* m# V, y+ d, S& X. t2 e( N
require augmentation or consideration for alteration of exter-
9 A* B) @8 ~- ]' Onal genitalia. In many instances urethroplasty for hypo-. L( M) p$ V# ]' f. d1 t
spadias is easier with previous stimulation of phallic growth.
2 [% c& x; `/ j) }% TThe use of testosterone administered parenterally or topically
8 A. F+ S# s. \( j& S; Zhas produced effective phallic growth. 1- 3 The mechanism of# H9 M" \1 }# w* n( z
response has been considered as local or systemic. With this
$ L$ t. ~7 ]2 F3 x% ~in mind we studied 5 children with microphallus for response
* p) E1 {, `$ ]( X0 ` yto gonadotropin and to topical testosterone independently.
) |5 Y4 T: l9 w# D1 h o* ~( s% gMATERIALS AND METHODS
& q9 [& H4 r9 t: M7 _' OFive 46 XY male subjects between 3 and 17 years old were
; J8 ?3 T# e" m" j% wevaluated for serum testosterone levels and hypothalamic
; K7 d4 C. ]# C) I' f7 L3 C5 Z) {function. Of these 5 boys 2 were considered to have Kallmann's1 ?% }& W% _% { J' ?
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ Q0 E a% n5 `8 v5 d# y
lamic deficiency. After evaluation of response to luteinizing' z5 O& [; o/ v
hormone-releasing hormone these patients were treated with$ p& Q4 R5 w& V7 q8 z
1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ P3 K% B+ S4 j) T/ [7 |" }8 F
after completion of gonadotropin therapy 10 per cent topical/ A" O) y. ], t$ R# v7 D
testosterone was applied to the phallus twice daily for 3 weeks.) H% p$ Z; X$ S' [# p
Serum testosterone, luteinizing hormone and follicle-stimulat-+ w' l2 L" F+ c. O( c* S( c0 m
ing hormone were monitored before, during and after comple-; e# _* N+ \( R9 \
tion of each phase of therapy. Penile stretch length was4 L) N2 v1 Q; A. }: {% t
obtained by measuring from the symphysis pubis to the tip of
7 o4 h% f, {: z! G8 z( ]the glans. Penile circumferential (girth) measurements were/ M) b9 p% }" s, B2 U; J
obtained using an orthopedic digital measuring device (see! j, n' T a5 e r2 }: @
figure).
0 C7 R' i. A* i0 @1 [RESULTS( d" y4 k$ H2 ~, \' o
Serum testosterone increased moderately to levels between
- c0 C4 @2 H. E9 L f6 J50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-1 k0 r7 J4 X4 [7 J
terone levels with topical testosterone remained near pre-( D, p: s P! r' g
treatment levels (35 ng./dl.) or were elevated to similar levels
% t( i; z" z- E, i; Jdeveloped after gonadotropin therapy (96 ng./dl.). Higher
3 T( K+ k2 y# H# r+ O1 o# a' Qserum levels were noted in older patients (12 and 17 years old),
; X" t+ F- ]: q' p- Ewhile lower levels persisted in younger patients (4, 8, and 10
! \' ?$ a- ^1 d' [8 }years old) (see table). Despite absence of profound alterations
3 K8 h; o0 X3 ^# h1 bof serum testosterone the topical therapy provided a greater2 j; |; O8 E3 X3 ?1 Y% F
Accepted for publication July 1, 1977. ·
' K- r3 w; [* J# Z+ }6 O6 YRead at annual meeting of American Urological Association,
7 i8 J6 K9 o5 [5 k" X- iChicago, Illinois, April 24-28, 1977.8 t! _2 h9 U0 m6 p, {3 x9 E+ U
* Requests for reprints: Division of Urology, Henry Ford Hospital,
( E8 L% N( g4 y; D' b, t$ |2799 W. Grand Blvd., Detroit, Michigan 48202.2 |0 x: C* A/ f7 V5 y( Y, u g1 d5 D
improvement in phallic growth compared to gonadotropin.
8 s9 }# f `3 c% _: zAverage phallic growth with gonadotropin was 14.3 per cent
/ Q/ b6 r: q# q% N- uincrease in length and 5.0 per cent increase of girth. Topical" u8 d7 G; l: B4 R2 ~! L
testosterone produced a 60.0 per cent increase of phallic length
/ G: o$ l3 d6 H$ ], m1 `and 52.9 per cent increase of girth (circumference). The+ k8 n0 y2 }6 L! d4 x5 q5 D" P! T$ u
response to topical testosterone was greatest in children be-. \" L* a. H; s- a
tween 4 and 8 years old, with a gradual decrease to age 179 ]: e/ k% W1 L
years (see table).& C5 a' B; Y! g+ x( r" ^. i4 P
DISCUSSION5 B- i: B) ]) c+ P
Topical testosterone has been used effectively by other
, o- U6 M; q+ E; Eclinicians but its mode of action remains controversial. Im-# M/ t% }6 n+ d" y
mergut and associates reported an excellent growth response5 f+ u' B: a$ x* C7 g
to topical testosterone with low levels of serum testosterone,8 D( S1 K" f6 r- R
suggesting a local effect.1 Others have obtained growth re-
7 R) Z" m7 a& o) x0 Xsponse with high. levels of serum testosterone after topical9 C2 \1 |0 D, ?9 k( ~) C% z; \; B7 B
administration, suggesting a systemic response. 3 The use of3 ?6 d9 g% l2 j. }7 C3 z! r7 F" ^( }
gonadotropin to obtain levels of serum testosterone compara-% A/ A" F2 p7 w
ble to levels obtained with topical testosterone would seem to
! f7 R+ b \+ s7 e3 U# C7 bprovide a means to compare the relative effectiveness of. u& ^3 ~. i: c r) W/ [ I4 m* o# V
topical testosterone to systemic testosterone effect. It cer-. }4 e+ o4 u+ B
tainly has been established that gonadotropin as well as par-) J+ a6 N. K2 ]6 i
enteral testosterone administration will produce genital+ O8 r+ M& o# ?: t4 W0 u3 S. \
growth. Our report shows that the growth of the phallus was
" P! u; u! b- C6 C. ^significantly greater with topical applications than with go-
! L c! v! x7 }: J( Mnadotropin, particularly in children less than 10 years old.
! I: R# B+ h! h" ^The levels of serum testosterone remained similar or lower- }$ n+ g) C$ T( |" @
than with gonadotropin during therapy, suggesting that topi-0 ^5 ~: B& w1 m6 {6 \
cal application produces genital growth by its local effect as7 C9 V$ L1 w v) i
well as its systemic effect.; E: n+ L6 w# Y {1 u
Review of our patients and their growth response related to1 q& ]8 B4 Q5 T! x
age shows a greater growth response at an earlier age. This is# L- Y& I- _6 s: x; z8 e/ d+ y+ Y
consistent with the findings of Wilson and Walker, who
1 D" }$ Z/ B. `1 h8 @reported an increased conversion of testosterone to dihydrotes-( f1 }, Y$ a2 ]1 R
tosterone in the foreskin of neonates and infants.4 This activ-) Y1 f3 N8 U) Z3 i8 v( o5 W% l8 h
ity gradually decreases with age until puberty when it ap-! w e6 u0 Z+ M0 W# J3 ^ ^
proaches the same level of activity as peripheral skin. It may
! T$ P" V& V, N$ ~well be that absorption of testosterone is less when applied at/ i$ C5 q9 b. N+ o( a7 o
an earlier age as suggested by lower serum levels in children- q5 m- L4 w* R8 T
less than 10 years old. This fact may be explained by the
/ H: M; R- }& ~2 F; dgreater ability of phallic skin to convert testosterone to dihy-( R t$ \8 {& l: p! M/ o
drotestosterone at this age. Conversely, serum levels in older
; m- a( P' t) N& u, Vpatients were higher, possibly because of decreased local7 y% @/ e" _: ]9 M+ V
667* s3 Z5 u8 |& u* d; @+ S
668 KLUGO AND CERNY
0 j3 R; l# f8 D2 C/ MPt. Age5 Q" O: ]3 p6 q( g
(yrs.)+ B" d) T. W) Z- w/ O/ I6 |
Serum Testosterone Phallus (cm.) Change Length1 V' Q7 T% |3 I7 p$ N
(ng./dl.) Girth x Length (%)
" w7 D5 C% T8 R5 A! F4. b x# V3 D) }& X$ @/ y2 n3 G
8
# y( ~( j2 R! J% z8 O10; Y" ? {! @. k3 p
126 {# s: [' Q2 i3 E
17$ R/ g* v" v7 y2 V0 [/ G
Gonadotropin
( u2 q: c( y8 ~( `/ y8 J( W7 x7 B71.6 2.0 X 3 16.65 S' V% n8 n2 M/ j. O
50.4 4.0 X 5.0 20.0! P9 y4 ]4 }- }2 x
22.0 4.5 X 4.0 25.0
8 z( D# f( o7 J# a$ U- L- T84.6 4.0 X 4.5 11.1
# h, i V# A, {( |7 S" w% r+ r85.9 4.5 X 5.5 9.0! g- C- f& u+ t
Av. 14.3
; q3 p6 u& |1 i" C4
6 o. s) ^) z9 i# ^- X8 V) i; Z T8* S2 m8 N3 N5 |4 E+ `* f
10
' I# ^3 N7 E- H0 A12
2 c# R% c; J. Q; X: N C17
, N: V4 }: M2 F8 VTopical testosterone+ f7 Q; l6 l* [/ S
34.6 4.5 X 6.5 85% A" O% _ j a& N+ z p; _) A* W4 V
38.8 6.0 X 8.5 70 ^$ t8 \9 E2 K" [; M0 E
40.0 6.0 X 6.5 62.5
& N; Q' \% I/ ?9 s' D$ N4 b( t93.6 6.0 X 7.0 55.51 ]/ O- L+ u6 b/ a
95.0 6.5 X 7.0 27.2
% e4 \; [, p# \1 X1 HAv. 60.07 K( L5 {1 P( i( z5 n
available testosterone. Again, emphasis should be placed on
% t" z0 a0 o% x8 _- l9 Cearly therapy when lower levels of testosterone appear to/ }0 ] Y( d- ]# M2 P) ^
provide the best responses. The earlier therapy is instituted. E0 L) O5 b% n. R+ V5 `5 x
the more likely there will be an excellent response with low
% @4 I( J, V2 G& F+ C; {serum levels. Response occurs throughout adolescence as
/ N. R2 C. B6 s6 k# l8 I. Anoted in nomograms of phallic growth. 7 The actual response
* V6 B' q7 _3 @to a given serum level of testosterone is much greater at birth; m2 g v5 o/ F9 I& C) f: q3 ?4 z% a
and gradually decreases as boys reach puberty. This is most
5 f( o8 S, [. L# r olikely related to the conversion of testosterone to dihydrotes-% u5 `. O; ]1 i0 }- Z' s8 n, Q: ?8 R
tosterone and correlates well with the studies of testosterone
2 m9 G" u. K% S9 S1 T/ J! u% Pconversion in foreskin at various ages.1 I0 @. Q6 ~* N( E2 g
The question arises regarding early treatment as to whether8 w' ^- V5 H3 Q2 C# {! Z8 v# H
one might sacrifice ultimate potential growth as with acceler-
, P$ x8 }/ _- Y1 a& b9 R2 Qated bone growth. The situation appears quite the reverse
0 S* R% ^5 Z- ^with phallic response. If the early growth period is not used- U1 u2 M% s X3 b. M* @) ~
when 5a reductase activity is greatest then potential growth' U7 o; R+ ^, ]/ ^$ y; ^# Z0 Q( \
may be lost. We have not observed any regression of growth
P, ]1 Y# d2 K; |attained with topical or gonadotropin therapy. It may well
& x { U" c5 ~be that some patients will show little or no response to any
- }5 L8 {/ V. _! K3 x8 uform of therapy. This would suggest a defect in the ability to0 z& c1 M( }8 h6 F1 m( U
convert testosterone to dihydrotestosterone and indicate that
: a$ T6 d) y3 g! W. c2 M Yphallic and peripheral skin, and subcutaneous tissue should
% L6 h {/ A" ~/ L& ]( [1 Hbe compared for 5a reductase activity.
& M# L8 Q9 ^* F! FA, loop enlarges to measure penile girth in millimeters. B,+ @0 [4 i9 u b; }
example of penile girth computed easily and accurately.+ p/ i. o$ w( Q! u
conversion of testosterone to dihydrotestosterone. It is in this# u1 f! B* W$ X6 p
older group that others have noted high levels of serum# n5 `5 B& A6 Z* n
testosterone with topical application. It would also appear8 Y% m* y* Q. X$ `. i/ O9 p H
that phallic response during puberty is related directly to the
% \( b- ^# _: X9 gserum testosterone level. There also is other evidence of local/ q3 O* ^! e* s6 M% m: Q
response to testosterone with hair growth and with spermato-, c9 k3 R0 i& H6 @0 L3 c# Y% V
genesis. 5• 6
) f2 x! W1 w! a/ n. q; J( bAdministration of larger doses of gonadotropin or systemic& Q4 i" s n/ h- U4 A) o
testosterone, as well as topical applications that produce/ Y$ ~* C: q5 U, M
higher levels of serum testosterone (150 to 900 ng./dl.), will) g+ D9 [5 ^+ O: p( n* s
also produce phallic growth but risks accelerated skeletal
8 I/ x+ [8 A( fmaturation even after stopping treatment. It would appear
( T1 Z6 S, N" N. I9 Lthat this may be avoided by topical applications of testosterone
4 j) ^# C5 w$ I4 Y& M' P* `$ Fand monitoring of serum testosterone. Even with this control- m5 t/ r1 n0 e% d1 P
the duration of our therapy did not exceed 3 weeks at any
6 e# h0 {9 i6 g2 o- ~1 h& vtime. It is apparent that the prepuberal male subject may
4 P* N2 b' |5 ~# dsuffer accelerated bone growth with testosterone levels near
+ C# d* O( |1 _: ~* T7 k$ P3 s, b# \200 ng./dl. When skeletal maturation is complete the level of
) {. e. c: z2 i* p9 \serum testosterone can be maintained in the 700 to 1,300 ng./3 Y* {( X$ p. K
dl. range to stimulate phallic growth and secondary sexual6 z. z) }( H& D0 W; y3 g
changes. Therefore, after skeletal maturation parenteral tes-3 z; J M; f+ ~1 X8 l+ |5 I
tosterone may be used to advantage. Before skeletal matura-; y' Z' s& k4 }+ Q+ v. x
tion care must be taken to avoid maintaining levels of serum" i* U) l2 l6 w
testosterone more than 100 ng./dl. Low-dose gonadotropin! k, O7 l" b. a! r1 k, K
depends upon intrinsic testicular activity and may require+ s9 r4 [+ e; X2 L# S. h
prolonged administration for any response.
! V2 a4 c( u" d0 `+ @. zAlternately, topical testosterone does not depend upon tes-% T+ @" d$ Z& Z' D
ticular function and may provide a more constant level of
5 A( J* _: ~; QREFERENCES
1 ^/ Q' j7 y1 s! G, J d+ u, n1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,9 x5 F# X$ z/ ?5 J6 P
R.: The local application of testosterone cream to the prepub-
. _: n* L* U0 z) [6 M+ G0 Nertal phallus. J. Urol., 105: 905, 1971.
7 ^4 U" A1 `# J9 s! B* v' g' q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone; c7 V( L5 \# R" K5 C
treatment for micropenis during early childhood. J. Pediat.,2 i: u; n6 E* g) f+ ^: c- T
83: 247, 1973.0 q# ]5 j, Z3 o7 M1 q( u& p
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( j+ @5 F+ R6 m9 [+ [, none therapy for penile growth. Urology, 6: 708, 1975.
! q- l" B" Y5 o+ z6 \4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- F- L, _/ O$ A7 Xto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by& {! K6 ~$ N( y0 Y$ A
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 e: B% L" i3 C% s% w; d6 L5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth9 }) J! e5 J V6 `
by topical application of androgens. J.A.M.A., 191: 521, 1965.! ^( f+ U$ ]7 |8 P
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
( y& u6 m" C( u" c& O/ s0 [) zandrogenic effect of interstitial cell tumor of the testis. J.; l4 L, @8 X& y' _5 |+ B+ k- z
Urol., 104: 774, 1970.
- v d! U- y3 J9 A7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' \ Z3 r6 V2 n; P% S9 Btion in the male genitalia from birth to maturity. J. Urol., 48: |
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