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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND2 w3 W, \) B$ q5 u& Q3 x) L
GONADOTROPIN9 y/ a/ ?1 _4 b# ?7 }* m
RICHARD C. KLUGO* AND JOSEPH C. CERNY& R6 a* _2 e/ ^% I6 @
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ W# \' c4 Q$ ZABSTRACT
: d' D. _! ?3 r+ H6 yFive patients were treated with gonadotropin and topical testosterone for micropenis associated
7 @2 ]6 ?% ]8 y" b+ G5 ~with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! B3 |8 z$ R) y' w/ |3 j; j& h
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ H5 T- W% a/ j, E
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" E3 W5 y* y9 k: _ Tfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent8 y3 A; n0 _8 }. I8 s
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
8 z1 j- s0 i; N, `- \increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% a* V" c3 n2 C6 toccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
7 A) x6 y# {- H& f5 n6 g; ?1 Qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# u1 ~8 l4 g1 x8 }growth. The response appears to be greater in younger children, which is consistent with previ-- `2 e* }6 }/ p* h
ously published studies of age-related 5 reductase activity.
% Q7 a5 ]# b% d; t. Q+ AChildren with microphallus regardless of its etiology will, X l: b; m9 v. s' o. @0 H" ]2 D
require augmentation or consideration for alteration of exter-2 M- S( x. Y" M( P% e3 J7 s% L
nal genitalia. In many instances urethroplasty for hypo-
/ ]+ @1 u8 N* M$ wspadias is easier with previous stimulation of phallic growth.
; S% P. [9 b) fThe use of testosterone administered parenterally or topically
; X7 n& G; Z5 b A2 hhas produced effective phallic growth. 1- 3 The mechanism of
* r( j- f# O3 g8 N& ^response has been considered as local or systemic. With this
. y5 F. v* V0 X @! ^in mind we studied 5 children with microphallus for response
7 F/ s& W# a: ^5 ~& B( S* z) \: Zto gonadotropin and to topical testosterone independently.
# h- U# W1 S( w6 NMATERIALS AND METHODS0 ]3 x1 Y% x) J1 m
Five 46 XY male subjects between 3 and 17 years old were. H l9 M, Z8 d' z1 j% `- w3 b
evaluated for serum testosterone levels and hypothalamic
4 D, z8 I+ x2 k; ifunction. Of these 5 boys 2 were considered to have Kallmann's' S3 J2 w6 ?3 C' C, ?
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& m: V" f/ h( I" Y" Hlamic deficiency. After evaluation of response to luteinizing" s/ A: `$ J; T. ^4 L0 e2 U
hormone-releasing hormone these patients were treated with+ ^3 n: M1 u/ s4 v- n: C9 T
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 G0 P0 y+ J, L, h: H' q& d" yafter completion of gonadotropin therapy 10 per cent topical
: |* ]; M0 w# E! w; ^. z( dtestosterone was applied to the phallus twice daily for 3 weeks.5 I# l* f/ G% ]: Q
Serum testosterone, luteinizing hormone and follicle-stimulat-
$ k8 H8 s+ m8 {9 @7 W0 |& t& }ing hormone were monitored before, during and after comple-
# N8 K. r' Q! L- ition of each phase of therapy. Penile stretch length was- ?& a& I1 |1 I% q# l8 b
obtained by measuring from the symphysis pubis to the tip of
: i. \/ } U6 f$ K. }# n2 rthe glans. Penile circumferential (girth) measurements were8 g& E2 I* w- U7 e; w5 s5 Z
obtained using an orthopedic digital measuring device (see2 P* o8 K" f' f- T/ }! M) L8 W
figure).
. b% B- G" V4 G2 \2 ?6 WRESULTS
. {. v5 g) ~* `# OSerum testosterone increased moderately to levels between( r# r g# l5 C# Q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
- e& ~' A0 |- _3 r' t$ p+ E" Lterone levels with topical testosterone remained near pre-
- T) b: f" k* Q7 M& Q0 _treatment levels (35 ng./dl.) or were elevated to similar levels
8 E7 T+ `- L* n8 j' b' x' R; \developed after gonadotropin therapy (96 ng./dl.). Higher$ y2 f( }# e; c4 T
serum levels were noted in older patients (12 and 17 years old),2 w& H: L4 R, k3 a4 C" Q
while lower levels persisted in younger patients (4, 8, and 10
! {" s1 `' z, \" vyears old) (see table). Despite absence of profound alterations
2 D- E) M+ l- m8 aof serum testosterone the topical therapy provided a greater
3 ?0 K8 S5 k: _" a* c( ]" f1 K# {Accepted for publication July 1, 1977. ·
: [9 _; _: m1 M: `8 } pRead at annual meeting of American Urological Association,& H! n, h+ ], k5 |% Y9 i
Chicago, Illinois, April 24-28, 1977.
; V L' f4 P! s* Requests for reprints: Division of Urology, Henry Ford Hospital,
' g3 ?) [8 {2 A2799 W. Grand Blvd., Detroit, Michigan 48202.7 ^: `/ t4 {. Y
improvement in phallic growth compared to gonadotropin.
, J& U; ~# ?2 g5 O( {( X) h2 [Average phallic growth with gonadotropin was 14.3 per cent( v) V7 h' C. Z
increase in length and 5.0 per cent increase of girth. Topical# ?, o" X+ i) K( g2 D, l
testosterone produced a 60.0 per cent increase of phallic length t- `; n* \! J x6 b9 i3 J
and 52.9 per cent increase of girth (circumference). The
2 i* x3 h7 c/ t% Tresponse to topical testosterone was greatest in children be-
0 a$ g# x. f% y |tween 4 and 8 years old, with a gradual decrease to age 170 ^9 q; y! }1 q+ A& f7 P! A6 ^. C& J
years (see table).
# n5 }: F$ M/ wDISCUSSION2 R% T5 S; m4 k- G
Topical testosterone has been used effectively by other
+ [ X$ [# k2 T9 }0 Eclinicians but its mode of action remains controversial. Im-' u) N, {/ t# R6 l! u/ ]9 \# L
mergut and associates reported an excellent growth response1 L6 S* U. J2 U
to topical testosterone with low levels of serum testosterone,
. D- D4 r# j; u" L/ Csuggesting a local effect.1 Others have obtained growth re-
, }7 [# I3 U5 n Esponse with high. levels of serum testosterone after topical
" w* E# g1 N7 B: s. Z0 g1 _# Kadministration, suggesting a systemic response. 3 The use of" `$ y3 l0 S Y; ]8 {
gonadotropin to obtain levels of serum testosterone compara-9 c' B2 }9 a1 T
ble to levels obtained with topical testosterone would seem to6 {% E" V3 m/ l! x9 J% o# A2 T
provide a means to compare the relative effectiveness of
0 h, D, N# U: N2 e6 x6 h8 W. ptopical testosterone to systemic testosterone effect. It cer-
0 \7 K4 A& u! `6 ftainly has been established that gonadotropin as well as par-
! ~; n5 x: z1 p7 benteral testosterone administration will produce genital
' a O$ d) b4 |9 j6 Z; b/ ?3 `growth. Our report shows that the growth of the phallus was
" l5 Q" n( n& h/ `! F6 Zsignificantly greater with topical applications than with go-: v; Z. ]9 k( o( b/ A
nadotropin, particularly in children less than 10 years old.# [5 L) o+ P; D9 E" m* f5 W8 k
The levels of serum testosterone remained similar or lower1 S) B) Y& m, I2 ]: E( N4 P! p
than with gonadotropin during therapy, suggesting that topi-
3 \9 _% G Q1 {& zcal application produces genital growth by its local effect as6 o; O" s9 g/ E/ D! s& a
well as its systemic effect.
4 B. {1 ~! j5 ?/ Y3 ?3 C i3 RReview of our patients and their growth response related to
u7 V" o: u7 v# m' R) E6 p0 Eage shows a greater growth response at an earlier age. This is
. i: l0 k) N4 X3 d0 vconsistent with the findings of Wilson and Walker, who0 E: U: v$ K. o7 Z- h0 B( a
reported an increased conversion of testosterone to dihydrotes-
8 n' z& A$ g: t) b- Rtosterone in the foreskin of neonates and infants.4 This activ-
7 u1 _# ^" ~- u Y6 z: `ity gradually decreases with age until puberty when it ap-
2 V3 I1 O) n0 t+ k4 {proaches the same level of activity as peripheral skin. It may& W+ F. r( D* v- f G6 P+ } A
well be that absorption of testosterone is less when applied at) z: n9 V) D7 v4 j1 v$ u
an earlier age as suggested by lower serum levels in children& [7 ~9 q, N% N2 S5 h
less than 10 years old. This fact may be explained by the* b' m4 }9 Z& k ~- i
greater ability of phallic skin to convert testosterone to dihy-' y% H5 B5 M- y# s
drotestosterone at this age. Conversely, serum levels in older
' Y1 k$ x8 o% k9 }% `, ~patients were higher, possibly because of decreased local* k; Y4 C7 b( b0 R8 t
6674 i6 E- w8 j t. V
668 KLUGO AND CERNY
' Y4 X, ~( b) R7 w! m! pPt. Age. e5 b5 B% }/ N7 n* M. Q; d7 B2 M
(yrs.)( H# z8 \# U. h$ T3 Q, e* c
Serum Testosterone Phallus (cm.) Change Length+ e: ^& s0 K* F: p p* I
(ng./dl.) Girth x Length (%)
z& ^# N7 K1 l4
3 n0 m8 B- \+ G% h% ~& ]+ @83 P! N+ q5 v! l. o% v* u2 D
10
' v* t9 ^6 f" p2 x12( ^4 _5 o* V' O9 E6 C; b
17$ f% a+ \0 \: j1 C/ X; \- z3 \( R
Gonadotropin
/ v5 q" f! ?7 u6 x4 g; J3 J71.6 2.0 X 3 16.6
0 q6 C+ u3 Q# I, f+ B50.4 4.0 X 5.0 20.00 P; f o0 I2 M* D4 L
22.0 4.5 X 4.0 25.0
/ B- e" o* y: {/ [" S84.6 4.0 X 4.5 11.1
0 q. o Q g' H4 h; z" F85.9 4.5 X 5.5 9.0: G1 r: x8 c7 T3 y
Av. 14.38 }. |# v, I! V' A7 X
4
- g4 j. Z) G4 V5 H8
8 D" L" A5 L8 y: b7 C3 D2 `106 k% J0 N! C ^) }3 m
12
6 z1 ]5 o# Z3 w! K! v17 i/ u4 s7 k1 v
Topical testosterone4 }3 c# q5 S3 T4 Z" r g
34.6 4.5 X 6.5 85
+ D* {: ~6 y, V. ?5 O5 l4 R38.8 6.0 X 8.5 70
: t6 K' j7 N1 P40.0 6.0 X 6.5 62.5
; D0 M+ t) V) ^- r5 I93.6 6.0 X 7.0 55.5/ |* ]% _, Z/ g
95.0 6.5 X 7.0 27.2
2 {8 q5 n5 t0 L! c% z c5 CAv. 60.01 D1 ]+ n1 ]3 B! p
available testosterone. Again, emphasis should be placed on
& `! Q! X+ g0 C( I1 w! C4 @early therapy when lower levels of testosterone appear to0 a) R" g: e! [- B4 L* @% N
provide the best responses. The earlier therapy is instituted
3 H. {% a# @1 t# A. V- Hthe more likely there will be an excellent response with low% E& Y$ j& k& X! o% ^9 G
serum levels. Response occurs throughout adolescence as0 |) M2 [& I, J7 [ z
noted in nomograms of phallic growth. 7 The actual response$ d( {" a& J# t6 c" b5 e
to a given serum level of testosterone is much greater at birth
# m* ^+ g2 e: ~3 A2 Cand gradually decreases as boys reach puberty. This is most
% F6 r. S1 o: a1 b9 [3 rlikely related to the conversion of testosterone to dihydrotes-- l) l3 ~ O6 h$ w% ^( v3 X
tosterone and correlates well with the studies of testosterone
: q6 t- A7 E% j4 ^& X" j( [conversion in foreskin at various ages.4 W$ R" L, C# [. Y$ d1 {9 d0 F
The question arises regarding early treatment as to whether2 s. E( z( `/ N* N7 f" {# n/ B: F6 @
one might sacrifice ultimate potential growth as with acceler-
8 M& b ~+ k$ i( H4 dated bone growth. The situation appears quite the reverse0 [" ~1 c4 \3 @
with phallic response. If the early growth period is not used
8 v" H8 r5 r/ T. C" n0 B9 bwhen 5a reductase activity is greatest then potential growth ]+ p$ Q- x( g) }! V' N* g
may be lost. We have not observed any regression of growth" ~) `( b9 o, Z% E5 Q
attained with topical or gonadotropin therapy. It may well0 p5 _* R) k2 ]: M$ v4 u3 K
be that some patients will show little or no response to any
, P ]& d& d! O& C0 tform of therapy. This would suggest a defect in the ability to
# e% _( F9 g! \% lconvert testosterone to dihydrotestosterone and indicate that
# S5 M" E0 ] A4 L- e9 sphallic and peripheral skin, and subcutaneous tissue should! o# R/ y! O0 K. R* C: P" R5 a6 N; E
be compared for 5a reductase activity.
& G& w: n% E/ cA, loop enlarges to measure penile girth in millimeters. B,
( w b6 V, Y" L- a, a6 Fexample of penile girth computed easily and accurately.( z& K6 q" B4 l
conversion of testosterone to dihydrotestosterone. It is in this+ k1 h3 q: P; O+ _# x: s
older group that others have noted high levels of serum" r0 ]( U+ P7 }" F. E. s
testosterone with topical application. It would also appear, k8 B+ K2 e7 Y* U' k4 f& H
that phallic response during puberty is related directly to the
/ C, w: p# Q* I9 d- f4 z5 Vserum testosterone level. There also is other evidence of local
. h7 y) P8 U0 z# S; wresponse to testosterone with hair growth and with spermato- M& p, P) O! B2 i9 u7 N
genesis. 5• 6
& l' B' o/ O) }3 d1 y1 XAdministration of larger doses of gonadotropin or systemic1 ^# P( C: f; H) j
testosterone, as well as topical applications that produce
/ Q5 ]3 ?9 X8 dhigher levels of serum testosterone (150 to 900 ng./dl.), will
) \# p, x2 o; {0 [9 E2 Oalso produce phallic growth but risks accelerated skeletal1 R2 [6 Y0 Z& p6 ^# h
maturation even after stopping treatment. It would appear$ n6 o. j! h! G* ~
that this may be avoided by topical applications of testosterone
2 S3 D( V" R, p5 {9 d- W3 {" ^' rand monitoring of serum testosterone. Even with this control; q9 ]0 X0 u. i3 l' k f
the duration of our therapy did not exceed 3 weeks at any1 z% a0 S8 `- K' D- O
time. It is apparent that the prepuberal male subject may+ x A3 \2 Z- t
suffer accelerated bone growth with testosterone levels near& [: L( R+ V6 ]" y# C. i I0 }
200 ng./dl. When skeletal maturation is complete the level of3 h; D% |& F& {+ { d
serum testosterone can be maintained in the 700 to 1,300 ng./
8 m& S) R; v) }4 L9 H$ Edl. range to stimulate phallic growth and secondary sexual% M' z8 D- d1 {7 a( z
changes. Therefore, after skeletal maturation parenteral tes-
$ b0 G* J! e. u, c) o) D8 f' v& R$ ytosterone may be used to advantage. Before skeletal matura-; G" H+ S2 g2 ?5 \/ V. k
tion care must be taken to avoid maintaining levels of serum; Q% F* m! J, H) m. `4 C5 {; u
testosterone more than 100 ng./dl. Low-dose gonadotropin8 y& e( l$ e4 c+ t4 H
depends upon intrinsic testicular activity and may require
/ O7 K# c4 |- ^' L7 bprolonged administration for any response.: G& B" @9 Q2 _; {
Alternately, topical testosterone does not depend upon tes-' y' Z/ Q J( I. |4 B( w3 \
ticular function and may provide a more constant level of
1 d- n# s3 I [4 b+ ^4 d% PREFERENCES7 \& U4 M: ^1 _$ Z
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
# w g$ S4 V& n" }$ L. VR.: The local application of testosterone cream to the prepub-! r0 m. s- B6 m9 Q r9 P
ertal phallus. J. Urol., 105: 905, 1971.
" T2 i/ h2 y& {% R. m' f2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 s1 z4 g3 Z5 O# I% f
treatment for micropenis during early childhood. J. Pediat.,6 \; c' V# T! ]
83: 247, 1973.. i4 O7 Z9 M R+ e/ k0 g5 a
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ q5 H. w- E8 t- r( t: s. kone therapy for penile growth. Urology, 6: 708, 1975.7 g' k8 |5 q$ `
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( Q1 ?8 m' ]; g$ i ^6 e$ }to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
( u, I; H8 g2 c* Q8 u" W/ [5 A* Tskin slices of man. J. Clin. Invest., 48: 371, 1969.: ~, A3 H. @+ H
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth9 z6 _ t) g+ d- J, w7 `8 ~
by topical application of androgens. J.A.M.A., 191: 521, 1965., j7 }, B) L6 H- p* R, A
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ `( k4 t- t: F; j. tandrogenic effect of interstitial cell tumor of the testis. J.
3 Y. s. n7 \5 z- x/ Z- ^Urol., 104: 774, 1970." Y+ M( ]3 v/ D% p
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( ~. a9 s9 x+ ^) g5 j9 `; Vtion in the male genitalia from birth to maturity. J. Urol., 48: |
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