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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
% r4 }. Z% D8 wGONADOTROPIN
- s* _4 g6 C4 m$ w4 u& b0 ?% IRICHARD C. KLUGO* AND JOSEPH C. CERNY
3 h+ k: L! }+ {' q9 v L$ qFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* w( U4 I+ t4 S9 P" \, ]4 BABSTRACT
( E) i1 @; r# i/ A8 oFive patients were treated with gonadotropin and topical testosterone for micropenis associated# m" h& X/ Y0 K I C
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-8 H$ S% v/ q+ ]
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( y; V' A4 F% j2 f5 b! Mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent# n, j8 F) }3 t7 \( Z% {
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 i4 L$ i' |- l/ d/ p; L9 q- n/ M- h1 Wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, P: l ~+ f7 E) gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. O3 s. D6 G- o2 `; j9 d% x; c% ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( q9 s: ?+ c) s' L" y2 l4 ]: x
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 y$ s2 J4 L1 wgrowth. The response appears to be greater in younger children, which is consistent with previ-
9 {6 }0 {9 @* h& z9 fously published studies of age-related 5 reductase activity.! ~, |, `! v' E+ f' H
Children with microphallus regardless of its etiology will. m K9 _* l" V' F$ P6 T& k+ Z
require augmentation or consideration for alteration of exter-: U. A% y7 W6 U" l) K u% E) y
nal genitalia. In many instances urethroplasty for hypo-
, Z" [" O7 O6 b% z, l0 {spadias is easier with previous stimulation of phallic growth.
; w! z6 h: p% o; M2 |4 A0 ~The use of testosterone administered parenterally or topically
1 Y! I+ x" O% ^2 G' p7 Ahas produced effective phallic growth. 1- 3 The mechanism of, S& c1 b' N7 ~8 G
response has been considered as local or systemic. With this
" ^: \7 _3 c8 G* Y* F% A3 kin mind we studied 5 children with microphallus for response
+ X% P2 P* X6 q3 [, wto gonadotropin and to topical testosterone independently.9 g3 G4 V e v+ u) Z% H
MATERIALS AND METHODS
7 v! d# o- z5 r8 T$ {Five 46 XY male subjects between 3 and 17 years old were
2 S" a. ]# H% M/ g+ @# H: Kevaluated for serum testosterone levels and hypothalamic
- B3 i. p# n' u6 s2 E0 dfunction. Of these 5 boys 2 were considered to have Kallmann's9 l: w* m! t7 J6 y% s( e: n8 y; R& b
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
+ J' h1 a- P7 f- ulamic deficiency. After evaluation of response to luteinizing0 }% p' K! h9 T! `
hormone-releasing hormone these patients were treated with8 x! Y8 o" M' A; p- O3 s& K% J
1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 R. L. `8 q8 ?8 N* U5 \' b
after completion of gonadotropin therapy 10 per cent topical! W- p& h+ t" D5 J- l
testosterone was applied to the phallus twice daily for 3 weeks.
" W9 Q B2 R9 a) \( m }6 ]2 hSerum testosterone, luteinizing hormone and follicle-stimulat-) S8 a& _/ n5 s" ^, @
ing hormone were monitored before, during and after comple-
) p- F* {' b, S# U( z/ H- ytion of each phase of therapy. Penile stretch length was; i5 L/ Z6 j. |; x+ U' b
obtained by measuring from the symphysis pubis to the tip of* ?; C9 ]3 q$ A0 Q4 r7 H
the glans. Penile circumferential (girth) measurements were
; u) {6 a. T1 l( _4 ?0 ]obtained using an orthopedic digital measuring device (see
$ X6 h [$ V4 @, r4 dfigure).9 o( n+ w8 h1 ^$ I3 p* |
RESULTS* d1 I d" s w+ A
Serum testosterone increased moderately to levels between1 _# r" G4 g+ I
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 ^) D, N" d2 h C4 X* Vterone levels with topical testosterone remained near pre-
4 U" ]5 X. j8 t# I8 ltreatment levels (35 ng./dl.) or were elevated to similar levels
+ f; W" b v8 l" n) B' {8 n- m- vdeveloped after gonadotropin therapy (96 ng./dl.). Higher% u' U2 j* M! P* A1 T) o
serum levels were noted in older patients (12 and 17 years old),3 ^- |9 Z" H( I4 s! U" T
while lower levels persisted in younger patients (4, 8, and 10; ]' Y, O; {5 Y, u3 H5 X
years old) (see table). Despite absence of profound alterations+ B* ]7 i" j' Z4 W' k
of serum testosterone the topical therapy provided a greater2 P( {& |8 C0 B$ r6 k* j# Q7 A8 ?# V( a
Accepted for publication July 1, 1977. ·9 r. ^) H& D& j% F* K# h8 _5 T: ~& c
Read at annual meeting of American Urological Association,
; Z/ O* M6 o9 Q: M. `( I: NChicago, Illinois, April 24-28, 1977.
" b; A: F# X" g; M* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 g0 j, y8 s6 L: y' F3 T2799 W. Grand Blvd., Detroit, Michigan 48202.2 e6 R9 ]3 |5 W& J9 Q
improvement in phallic growth compared to gonadotropin.* W4 }5 C5 c" t2 z$ W9 M
Average phallic growth with gonadotropin was 14.3 per cent& @# l; ] | |& w
increase in length and 5.0 per cent increase of girth. Topical+ S: O, g) T! |( m. U* O
testosterone produced a 60.0 per cent increase of phallic length& l( h. N# n" A1 o& I
and 52.9 per cent increase of girth (circumference). The' F' T6 t, y) q. |( z
response to topical testosterone was greatest in children be-: \, O3 K8 ]" h1 k6 \' l
tween 4 and 8 years old, with a gradual decrease to age 179 d4 {( ]6 H' [0 _) C
years (see table).
- G' b8 X6 N% L# m# n; I( ]DISCUSSION
+ B% g4 E2 l4 ]% A* j7 w! m8 @; Q/ g) ATopical testosterone has been used effectively by other% R4 R* q6 o% I9 A$ q
clinicians but its mode of action remains controversial. Im-3 T1 T u4 b* ^! S
mergut and associates reported an excellent growth response
8 Y; A: i$ c; ?) a- ^to topical testosterone with low levels of serum testosterone,2 |- Y. L' [5 c/ ?2 D: W1 q* N
suggesting a local effect.1 Others have obtained growth re-
6 y- k5 l2 Y' E6 @1 b2 ]3 x i' `sponse with high. levels of serum testosterone after topical
3 F. H7 m! d, p( \4 e4 W/ m0 uadministration, suggesting a systemic response. 3 The use of: b" |9 g* C3 d' U
gonadotropin to obtain levels of serum testosterone compara-& h4 e1 {% \4 G8 S& |
ble to levels obtained with topical testosterone would seem to
2 s% c; _. ?% a, n& m9 a. m5 R `provide a means to compare the relative effectiveness of
7 K( Z0 C9 s! G3 N6 c* h- i0 [topical testosterone to systemic testosterone effect. It cer-3 x s E$ _0 k! t+ K
tainly has been established that gonadotropin as well as par-4 f2 d& O0 Q: h% w! H6 W/ e6 F o
enteral testosterone administration will produce genital, J9 @. g2 }7 C2 X
growth. Our report shows that the growth of the phallus was) G9 j& U, X6 U
significantly greater with topical applications than with go-
- L8 O- D! L* e2 F7 O9 {nadotropin, particularly in children less than 10 years old.% k1 z$ M0 `9 X9 ?2 \8 p
The levels of serum testosterone remained similar or lower9 `) r# [" y/ m! N% V5 }
than with gonadotropin during therapy, suggesting that topi-& P6 B- `. ]2 q! C! n
cal application produces genital growth by its local effect as
1 f5 X3 {6 E8 M6 @2 I6 twell as its systemic effect.
+ v' F. G5 n+ T/ T* AReview of our patients and their growth response related to9 p3 q# I# ?) {2 T4 ]) N
age shows a greater growth response at an earlier age. This is' { M. d: D. d, x# K5 N$ Z8 k. g
consistent with the findings of Wilson and Walker, who
% [ l8 E/ r/ \: O1 jreported an increased conversion of testosterone to dihydrotes-
8 J# ]" d, n( m @tosterone in the foreskin of neonates and infants.4 This activ-, }, b" H. W$ N5 P. k4 P
ity gradually decreases with age until puberty when it ap-, F7 y/ f& S* h$ Y$ e1 g
proaches the same level of activity as peripheral skin. It may
7 u% _# `+ K+ E& c4 B/ k, b# ]well be that absorption of testosterone is less when applied at7 P, i j; `0 U8 ~1 } d
an earlier age as suggested by lower serum levels in children5 S7 w6 B1 n0 t" `$ R/ Z' C7 k2 e
less than 10 years old. This fact may be explained by the; |5 |; v* C+ b4 J, @7 B3 P3 U5 q
greater ability of phallic skin to convert testosterone to dihy-! u/ e. u9 s4 X
drotestosterone at this age. Conversely, serum levels in older& ], r$ W2 J; t0 q5 r% n
patients were higher, possibly because of decreased local
4 C2 G" U1 ~& p9 N K* o" d6 Z667
$ r- V! r, [0 P( G% ^668 KLUGO AND CERNY. r% n, n' h$ Q
Pt. Age
: L# L2 Y. V7 T2 u7 M! O3 b(yrs.)
& g- S$ d) [7 u% mSerum Testosterone Phallus (cm.) Change Length
. F3 G4 C- v# f5 ?(ng./dl.) Girth x Length (%)8 F% v3 x0 O7 D; H: z6 P* U
4
+ ?7 Q. z8 G6 w7 {3 w1 p8
! D2 b5 J& d( _/ J$ {$ b2 {10
( t6 ?$ N+ W$ e1 S' \12- M. `. e$ O9 W3 ` g+ D
17# {& ?4 h# b/ O. I8 C5 V( L& u1 x
Gonadotropin
. E/ L% ^! P* }# U9 @- Q71.6 2.0 X 3 16.6
8 u+ b/ ?4 i/ _2 k1 }& x50.4 4.0 X 5.0 20.0
& u9 `7 N6 {' v" y; u* a22.0 4.5 X 4.0 25.0+ n/ r% h! Q5 v* J, [$ G
84.6 4.0 X 4.5 11.1
- U6 l: E- o- P+ g" ~8 E5 {, T85.9 4.5 X 5.5 9.0
5 I1 D) c9 s+ z7 `7 g0 A$ I( GAv. 14.3
. P# @" r. U3 { @4 u; {7 a% K4
- o' D* J8 J9 n8
+ Q) }# B$ S' }. F; j10
- s' O1 z7 W' L# ^12
9 } E: X9 r6 H/ m6 K# H17
4 k& I" H% |# O$ p9 G# E, bTopical testosterone
/ F( r- N# w6 e$ g" a6 I# W1 d# `34.6 4.5 X 6.5 85
" u0 d- f6 ~8 w- h F0 N# K38.8 6.0 X 8.5 70
! J& A5 x& G! U. X$ X40.0 6.0 X 6.5 62.5/ s: ^5 a# U% y2 P2 d% c- E
93.6 6.0 X 7.0 55.5
3 i5 S+ F, ^2 v95.0 6.5 X 7.0 27.20 {6 Y& M: Q' P/ o
Av. 60.0- ?) t) ~" \* \8 k, x. Y
available testosterone. Again, emphasis should be placed on0 J( q% z7 {1 ^& L, o
early therapy when lower levels of testosterone appear to; z* b0 ?2 |' C2 F: E
provide the best responses. The earlier therapy is instituted
3 e+ f" C# ?6 |+ }: ~9 w1 w# Ethe more likely there will be an excellent response with low
# i* z" _' D. e. l& K; _+ t0 t; F/ Sserum levels. Response occurs throughout adolescence as- z$ o# o5 I( P
noted in nomograms of phallic growth. 7 The actual response/ _! S W8 _8 ^4 c9 I
to a given serum level of testosterone is much greater at birth, s" @! m" y: r J; |" Q7 _
and gradually decreases as boys reach puberty. This is most9 n- B8 O5 i0 p& p* j a
likely related to the conversion of testosterone to dihydrotes-
" S7 H* |9 }, N9 a% \$ ytosterone and correlates well with the studies of testosterone4 I" z0 i4 H6 t w* J( u- ?/ a. }0 |
conversion in foreskin at various ages.
- y! B: ~) u: hThe question arises regarding early treatment as to whether# z5 X2 d+ Y, R% ^
one might sacrifice ultimate potential growth as with acceler-) h( O B _8 l+ Y
ated bone growth. The situation appears quite the reverse/ g: M1 I: O) e0 I5 B( `
with phallic response. If the early growth period is not used& ^2 W9 m, W, Y1 X
when 5a reductase activity is greatest then potential growth' V5 Z. e0 R+ F- r
may be lost. We have not observed any regression of growth
9 ^9 R* X3 _& d1 i' f& A2 Eattained with topical or gonadotropin therapy. It may well& F* S) N6 D# e/ p5 o; g
be that some patients will show little or no response to any
, R2 Z$ f* z. b- P. Xform of therapy. This would suggest a defect in the ability to
# W1 A5 _2 Z/ ~, O+ k* x$ \convert testosterone to dihydrotestosterone and indicate that' }3 S$ [% Z5 b: e" P& [
phallic and peripheral skin, and subcutaneous tissue should( Q! a6 f$ @, t% Y# d! ~& j3 q
be compared for 5a reductase activity.
+ i( p3 m' \+ c+ X: d* S8 e( SA, loop enlarges to measure penile girth in millimeters. B,
. y1 L* Y! I7 g. }example of penile girth computed easily and accurately.
" |& r3 R' i2 ~conversion of testosterone to dihydrotestosterone. It is in this
# u- i5 [! J) C8 b$ |' B. |older group that others have noted high levels of serum2 n) I! R; V& V: a. C" f
testosterone with topical application. It would also appear
3 v f4 N! ?& E7 |% ~) s6 }7 Tthat phallic response during puberty is related directly to the @7 W4 g! x" @+ r9 j/ `# w8 V
serum testosterone level. There also is other evidence of local2 ~6 _1 D8 T6 n- A# V
response to testosterone with hair growth and with spermato-
4 G; g! t6 V# A |1 q8 k/ R$ ?genesis. 5• 6
3 f: q6 p( s6 mAdministration of larger doses of gonadotropin or systemic2 \; S6 M/ v* `, [3 p& I! }
testosterone, as well as topical applications that produce
5 }5 r$ t4 x, I# c, }3 a' ^higher levels of serum testosterone (150 to 900 ng./dl.), will
8 M% q/ p0 g4 b. E" w. a t, s. x& Galso produce phallic growth but risks accelerated skeletal
, X3 K! R2 ]$ ematuration even after stopping treatment. It would appear3 X" e$ A$ a& w- |: Z
that this may be avoided by topical applications of testosterone
6 h5 k7 g& h* I+ `$ f. [# [and monitoring of serum testosterone. Even with this control
& [1 h* p/ b2 V* L/ |the duration of our therapy did not exceed 3 weeks at any, c5 ^( R; k4 b/ y0 X6 s
time. It is apparent that the prepuberal male subject may
. F6 r2 L5 N) [. E/ J# ?2 |suffer accelerated bone growth with testosterone levels near& F0 _6 J% j$ y3 M2 v' s
200 ng./dl. When skeletal maturation is complete the level of' q" |4 D; C0 D% V: N& k [
serum testosterone can be maintained in the 700 to 1,300 ng./
6 a& l0 m1 M% pdl. range to stimulate phallic growth and secondary sexual
& _8 i$ f; r( schanges. Therefore, after skeletal maturation parenteral tes-
$ m1 C5 r) e0 w$ ~tosterone may be used to advantage. Before skeletal matura-. Q# m v0 q* P- B6 W: P+ f- m
tion care must be taken to avoid maintaining levels of serum
$ S7 G/ e6 b8 E0 v5 J; ntestosterone more than 100 ng./dl. Low-dose gonadotropin
+ X G; s/ b. A4 S( rdepends upon intrinsic testicular activity and may require, \ V- E0 o9 _3 Q& K' D3 A
prolonged administration for any response.5 O* H& ^7 s. a) G9 }
Alternately, topical testosterone does not depend upon tes-
& F( c( y3 V2 B/ d! ]ticular function and may provide a more constant level of
2 k/ X2 U/ }1 }) }1 P& B/ \- c( HREFERENCES
1 x* `3 b$ `: u. b6 c1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( @0 g, d9 D/ F5 l8 U
R.: The local application of testosterone cream to the prepub-# C0 m( H$ u2 W9 x7 [9 e, C' L
ertal phallus. J. Urol., 105: 905, 1971.% v5 E% N9 G- d' M {
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- E2 j- _% Y' k- N% i i# L! N
treatment for micropenis during early childhood. J. Pediat.,
8 g0 d8 Y" u6 \; \ n83: 247, 1973.
& s3 A1 `+ y4 m W( U& G+ B8 Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( L: P$ M" L( R; ]' A" i8 R# wone therapy for penile growth. Urology, 6: 708, 1975. d6 A8 Y& b# V. `+ y9 ^# z5 g1 Z' ]
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone S. }. t+ i" f2 Y+ J
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 D/ I# x& {& ~- A' a' Eskin slices of man. J. Clin. Invest., 48: 371, 1969.$ A* W, Q; [2 @9 A5 H
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth& H. ?1 I" C: P7 ]
by topical application of androgens. J.A.M.A., 191: 521, 1965.# A0 Z+ s6 u4 u+ O, D- Q- O
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) t1 g" j4 k! q. F
androgenic effect of interstitial cell tumor of the testis. J.
! {$ k2 \$ i, a# Q& ` W" ?: q' qUrol., 104: 774, 1970.2 M; T4 n6 S% X* I! }
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" r9 J' ?" \9 `
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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