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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND5 ^* \ S# O7 c( Q
GONADOTROPIN
0 ?6 q4 v. y* m2 L8 WRICHARD C. KLUGO* AND JOSEPH C. CERNY) ~& f6 N* l: `: {$ t( k, \* H d
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 q. F4 U1 [- u& ^' f
ABSTRACT
) `7 i( G; ]( i+ r* [Five patients were treated with gonadotropin and topical testosterone for micropenis associated1 f# c5 w9 S7 f6 k
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
% W; u) Y$ p7 u8 c1 g( @tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: i6 j: t# L3 u# L6 j- Scream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 `- a, R9 ^; G( q# e) K9 L$ Gfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent5 n- _& w% N1 O u- m* l
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: g3 _, s) C9 U6 @1 k$ J& }
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 \3 x! I- F. m& P4 @( I# A
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
1 ^9 {. G" Q0 P+ Gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; c4 I- K& @6 e4 Z, Xgrowth. The response appears to be greater in younger children, which is consistent with previ-( j! a" J( O- I( b9 C0 z: j
ously published studies of age-related 5 reductase activity.
& _. B6 m" {: w0 m) J6 Q& rChildren with microphallus regardless of its etiology will: b! K, o8 F( T4 s, o. K" h8 @; g
require augmentation or consideration for alteration of exter-8 ~, R: j R' i P
nal genitalia. In many instances urethroplasty for hypo-: w. M; U3 C4 R4 Z, y: |% l
spadias is easier with previous stimulation of phallic growth.
+ J; {. V F) i1 ~) R+ j) RThe use of testosterone administered parenterally or topically$ X: L0 M+ K% h6 p8 M4 l( ]; r
has produced effective phallic growth. 1- 3 The mechanism of
+ m! ? `5 O5 B2 `9 @) `9 rresponse has been considered as local or systemic. With this' p4 l2 s$ X. T+ |, I$ i& S9 s) P
in mind we studied 5 children with microphallus for response# I: Z, B* l/ }: s2 R
to gonadotropin and to topical testosterone independently.
1 H: ^* |( r( h4 X" lMATERIALS AND METHODS: O. t' A9 b1 T4 ]2 F, ` M
Five 46 XY male subjects between 3 and 17 years old were3 T4 h8 \/ D0 c3 P' w
evaluated for serum testosterone levels and hypothalamic
8 L+ q3 H0 U/ n6 b; F- M% T, Y/ Xfunction. Of these 5 boys 2 were considered to have Kallmann's6 [& ~& _6 d9 u) u% V0 _
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; M A1 W9 f2 {8 K! K
lamic deficiency. After evaluation of response to luteinizing
+ ?; z. }; ~: X' z9 x2 Chormone-releasing hormone these patients were treated with
" f( C. [; {# W7 r! x9 T1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 J$ h' O, ^3 R' v' p& Fafter completion of gonadotropin therapy 10 per cent topical7 h1 m2 v# v: h2 M" N% |1 }
testosterone was applied to the phallus twice daily for 3 weeks.
6 I3 ]5 n& `* t! _( Y: v# G8 GSerum testosterone, luteinizing hormone and follicle-stimulat-9 s% W& A7 e, s7 _) P+ O: T) | C1 j
ing hormone were monitored before, during and after comple-
) j a* h1 Q4 P& J8 Ztion of each phase of therapy. Penile stretch length was
2 Z% A7 G4 o7 U1 n* }8 _obtained by measuring from the symphysis pubis to the tip of
l- n2 m2 W, r$ ]. r7 v9 l2 othe glans. Penile circumferential (girth) measurements were; ]0 G D, }7 B' `5 {, N
obtained using an orthopedic digital measuring device (see" n* u1 @& G8 P% l" ?
figure).
- c. F5 `6 i. t1 ~ \1 ]RESULTS$ Q3 [+ g' o( f% M* h8 Q: l
Serum testosterone increased moderately to levels between4 N! G0 ` R2 ^0 O8 Y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ d" N* i, I }' B$ V$ C; ~
terone levels with topical testosterone remained near pre-! H( E" r0 s- S% A
treatment levels (35 ng./dl.) or were elevated to similar levels
! t! t7 c. P; ?developed after gonadotropin therapy (96 ng./dl.). Higher- h& N5 {$ D8 [3 T6 V. M
serum levels were noted in older patients (12 and 17 years old),
( R6 v9 z) Y* ]! R- M( Q/ m. Vwhile lower levels persisted in younger patients (4, 8, and 106 K- j+ Q' H) L+ i v& F( l
years old) (see table). Despite absence of profound alterations7 Y o, R) ]* ]5 N, Z7 [6 H
of serum testosterone the topical therapy provided a greater3 T3 {% E' A3 E, v2 [0 u( Y+ y
Accepted for publication July 1, 1977. ·
( m1 Y; V# ^$ L# QRead at annual meeting of American Urological Association,; C0 V l- j6 \7 ]9 j
Chicago, Illinois, April 24-28, 1977.. R ~3 v0 T1 M0 \! o
* Requests for reprints: Division of Urology, Henry Ford Hospital," n! D7 C3 q& I7 B
2799 W. Grand Blvd., Detroit, Michigan 48202.4 s3 g; ~1 d9 z
improvement in phallic growth compared to gonadotropin./ ~* w" ~9 g- ?' v; }' A
Average phallic growth with gonadotropin was 14.3 per cent
) W8 U9 o7 @9 Bincrease in length and 5.0 per cent increase of girth. Topical
5 o9 j' s: @7 @( T0 ^testosterone produced a 60.0 per cent increase of phallic length! W# V& n" \; b
and 52.9 per cent increase of girth (circumference). The D O0 p! R6 b6 a e- @/ C5 _
response to topical testosterone was greatest in children be-
! d5 ^) P+ X; U6 L% i: ]tween 4 and 8 years old, with a gradual decrease to age 17. Q# [6 t+ `- P
years (see table).
( u3 U, E' \ \3 T" pDISCUSSION
& h2 s0 X4 h/ |- M$ n( E: b% u1 YTopical testosterone has been used effectively by other
% n/ j2 O1 Y7 f# zclinicians but its mode of action remains controversial. Im-
- G& v4 i8 {+ qmergut and associates reported an excellent growth response
7 Z& }/ p% N) o6 Y! e8 v) z2 oto topical testosterone with low levels of serum testosterone,' x9 `( Q3 j: m" q6 s
suggesting a local effect.1 Others have obtained growth re-$ n9 D4 @9 o( s- Y# u3 Z- b- [
sponse with high. levels of serum testosterone after topical, v* S+ X5 J7 M5 R {2 i' `
administration, suggesting a systemic response. 3 The use of
- r1 G( U5 Y8 c4 e4 dgonadotropin to obtain levels of serum testosterone compara-% r! o- c7 P6 z6 @; k
ble to levels obtained with topical testosterone would seem to
, d4 O6 D. }0 @5 \. wprovide a means to compare the relative effectiveness of+ `4 H3 R' [. H3 U: B) V
topical testosterone to systemic testosterone effect. It cer-6 K P1 p; J7 Q4 N5 q# m
tainly has been established that gonadotropin as well as par-! Q3 } m& }5 N Z) e0 F3 o& b
enteral testosterone administration will produce genital
- b/ C( J( F: Q3 t" `6 h" q6 b% Rgrowth. Our report shows that the growth of the phallus was
9 a' S5 J U: Q: D- @, L0 asignificantly greater with topical applications than with go-
8 J9 N. M5 b% ]5 ]nadotropin, particularly in children less than 10 years old.1 _& R; E6 l+ z- v4 D8 L
The levels of serum testosterone remained similar or lower: @7 W- [/ W! w, a
than with gonadotropin during therapy, suggesting that topi-
) Q, m0 R0 ~! r' Ncal application produces genital growth by its local effect as
) M$ i% d( A; ?! Awell as its systemic effect.5 R/ O6 M; ]% j& ~; J) k
Review of our patients and their growth response related to3 ?, V# F/ A2 g# W
age shows a greater growth response at an earlier age. This is+ e6 G' e! g2 P0 g4 K8 P2 V
consistent with the findings of Wilson and Walker, who
6 n1 g/ L+ J, Q0 Rreported an increased conversion of testosterone to dihydrotes-' E w. ^/ _- k8 m/ x' |
tosterone in the foreskin of neonates and infants.4 This activ-
& E4 P3 y. ?: D- _3 aity gradually decreases with age until puberty when it ap-* \- B% e$ S; j, Q/ ^. Z+ c% x
proaches the same level of activity as peripheral skin. It may
( C' `" @( o. Y: _well be that absorption of testosterone is less when applied at: [+ O0 u9 C+ K/ l* D2 p
an earlier age as suggested by lower serum levels in children1 h9 h# t4 i. [, @1 u
less than 10 years old. This fact may be explained by the
9 ^& ]/ a# I S, l2 @( r& j% wgreater ability of phallic skin to convert testosterone to dihy-- }8 Y/ r; a& ?
drotestosterone at this age. Conversely, serum levels in older) w' \- R" F* f7 q5 i
patients were higher, possibly because of decreased local [% q$ D: r/ ^% Z' y
667+ G, A U& p) S% ]( W
668 KLUGO AND CERNY5 r e/ `0 n; {' n& |* g; Q
Pt. Age' B* t- V6 q C8 h1 D
(yrs.)4 j2 v7 j6 c$ u% l
Serum Testosterone Phallus (cm.) Change Length; Z: x. | w2 L
(ng./dl.) Girth x Length (%)1 K- Z# E9 q$ G y! B9 y
4
" @; m& J- c# n' ^4 T7 t* K. n4 o8% w: o. v) x, O# n, I
10
. n r& @" z* d" b, U9 K! q) m8 T12
7 D/ q4 k- w. m/ N: f+ M+ k170 b/ L) o+ u6 J. o0 ~6 B& c
Gonadotropin
3 w% F: C0 W( e' ?% N5 s71.6 2.0 X 3 16.6" b7 v' D% Y) `! N" h. P
50.4 4.0 X 5.0 20.0' t9 A4 C1 \( d
22.0 4.5 X 4.0 25.0
3 K& n+ c7 k0 f( R* }/ W7 m84.6 4.0 X 4.5 11.1
8 Y. R9 C) j: u& T85.9 4.5 X 5.5 9.0 c( Q X6 ~) K, c
Av. 14.3
! ]5 G8 T# a# X8 K$ |/ e46 O3 ]+ T& `0 i+ i, X$ L( e
8
5 r k" ^5 X" f8 g1 r$ v c10
- {- b |: _% W7 V- H, b126 \9 C% S: I) b0 j4 k
17" {! g6 _. @' C7 R" k
Topical testosterone* t) X- Q' U8 Z4 `5 Y: I+ O, y
34.6 4.5 X 6.5 859 }9 b9 d- o6 F
38.8 6.0 X 8.5 70 s7 m) s' F1 G2 G8 N8 y0 i
40.0 6.0 X 6.5 62.5
8 Y9 R+ ~3 V1 E% b93.6 6.0 X 7.0 55.5: f1 v6 K6 X8 x
95.0 6.5 X 7.0 27.2
5 o' V' s. R% ~Av. 60.0
$ Y8 W" Z) s( c9 Oavailable testosterone. Again, emphasis should be placed on
$ G; H. q* ^5 t8 v# y6 j+ u9 _! Vearly therapy when lower levels of testosterone appear to
5 r7 Q# h i' }# @: mprovide the best responses. The earlier therapy is instituted7 q0 e7 F1 Q; q4 i' N% [7 r% u( {
the more likely there will be an excellent response with low
4 O, I3 R) v0 \0 S5 [' Y! ?3 t0 @serum levels. Response occurs throughout adolescence as
* J' Z( n4 P4 C# I& tnoted in nomograms of phallic growth. 7 The actual response& ]% B3 N Z+ z! T
to a given serum level of testosterone is much greater at birth% F& K% q# T( v( r* e; z- m9 z$ h
and gradually decreases as boys reach puberty. This is most0 y( ?: E2 [& w9 }- t% F
likely related to the conversion of testosterone to dihydrotes-
7 K& v7 {6 D3 h0 y! e% etosterone and correlates well with the studies of testosterone0 k$ `# u* ~3 \% ~
conversion in foreskin at various ages.5 M! a5 Q; u- ]
The question arises regarding early treatment as to whether( ^6 G, h/ N u# ?4 J
one might sacrifice ultimate potential growth as with acceler-
, b' _/ z6 Q; B5 F( [' x& n5 qated bone growth. The situation appears quite the reverse
& R! H$ o/ a( g% m8 Lwith phallic response. If the early growth period is not used/ z2 w2 F; e# y% s
when 5a reductase activity is greatest then potential growth
7 A, `2 R7 Q" l+ r& ?may be lost. We have not observed any regression of growth
' v7 v6 W& K$ L8 t2 S. |. Eattained with topical or gonadotropin therapy. It may well
* L* m3 j" k& q5 Hbe that some patients will show little or no response to any
- C& K0 c r+ H0 tform of therapy. This would suggest a defect in the ability to/ _* g/ g: m9 ^! X
convert testosterone to dihydrotestosterone and indicate that
$ i. @# j4 L% C5 V3 w' ?- p4 hphallic and peripheral skin, and subcutaneous tissue should' v- G" s h) Z* X6 G; ~( v' U9 p
be compared for 5a reductase activity.$ ]$ L: h/ e- I7 O6 ?5 Q
A, loop enlarges to measure penile girth in millimeters. B,' i, ^( a* ^- b- A1 W6 }
example of penile girth computed easily and accurately." i2 L% O) S5 W" o& y5 V
conversion of testosterone to dihydrotestosterone. It is in this
0 M' U& P" J) ?; }9 b1 ^older group that others have noted high levels of serum
" |) e/ v8 }" atestosterone with topical application. It would also appear
+ o0 K$ S2 _9 G+ E& y' r5 xthat phallic response during puberty is related directly to the
( r+ ~+ a) e( x' _7 k& vserum testosterone level. There also is other evidence of local7 `5 v* x6 s& k: f0 \. `" X
response to testosterone with hair growth and with spermato-5 w) U7 w+ {& z0 o
genesis. 5• 6
6 ]- Q% C! q. A$ b- g: |Administration of larger doses of gonadotropin or systemic9 c2 L) h2 M0 x& l9 ]
testosterone, as well as topical applications that produce
/ S/ I# s P2 x+ n/ H% G- jhigher levels of serum testosterone (150 to 900 ng./dl.), will
4 O# s$ E8 d. r+ T8 J/ falso produce phallic growth but risks accelerated skeletal' ?+ z8 ~ Z5 _, R6 Q3 O I, v
maturation even after stopping treatment. It would appear
, r1 g X- Y( ?% C2 b Zthat this may be avoided by topical applications of testosterone5 A! C9 f" g4 k6 K5 I
and monitoring of serum testosterone. Even with this control
2 J8 c& z( X1 e6 c6 dthe duration of our therapy did not exceed 3 weeks at any
1 S, k. c2 J* S' U7 X+ S% Q8 ntime. It is apparent that the prepuberal male subject may$ u5 X- u( I' _9 @2 Z7 }+ K+ p0 |
suffer accelerated bone growth with testosterone levels near( w4 l2 `$ L) J+ ?) ^/ v- M( F
200 ng./dl. When skeletal maturation is complete the level of6 {4 W* ]" C4 v0 b) f
serum testosterone can be maintained in the 700 to 1,300 ng./
9 o, p9 J0 x2 j0 V. a+ |dl. range to stimulate phallic growth and secondary sexual# t) |' T3 _9 ]. B
changes. Therefore, after skeletal maturation parenteral tes-
: s1 V4 X% N+ Ntosterone may be used to advantage. Before skeletal matura-
7 o( Z& r+ H+ [; C, `, N) u7 ftion care must be taken to avoid maintaining levels of serum. |# j) a3 Y8 I
testosterone more than 100 ng./dl. Low-dose gonadotropin8 Z" C0 p; o5 J; H4 p& Y
depends upon intrinsic testicular activity and may require1 } ~* e$ {; T x& ]0 S) j
prolonged administration for any response.9 {' m. B5 G' m6 E i9 c Z
Alternately, topical testosterone does not depend upon tes-
$ o; J. U/ s$ a+ q# Jticular function and may provide a more constant level of6 }' T0 Q6 D0 \
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" \1 r, [ w9 d$ D6 f+ OR.: The local application of testosterone cream to the prepub-/ x g, L/ U3 I2 ]' N
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& ]* w: V1 [' _$ `% }; t# wone therapy for penile growth. Urology, 6: 708, 1975., i) a/ D9 T/ N! l! a
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* e- t2 {+ W+ L m9 Nskin slices of man. J. Clin. Invest., 48: 371, 1969.
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' o% `: e7 n/ a9 F0 Rby topical application of androgens. J.A.M.A., 191: 521, 1965.
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tion in the male genitalia from birth to maturity. J. Urol., 48: |
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