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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; `( x) q7 _. Q! {' @GONADOTROPIN( |, u) i# w& M# s3 O. e7 N7 g
RICHARD C. KLUGO* AND JOSEPH C. CERNY
4 j% K* I( W" ^; D/ GFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% f; {" A/ Y9 X8 ?4 I( q. ^% xABSTRACT
6 Q7 m u$ v# L1 i, v" YFive patients were treated with gonadotropin and topical testosterone for micropenis associated
% @4 z9 i4 t$ Ewith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 s. A, n6 _' t" n9 M1 S2 X0 m
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone i: H/ [6 }: u% ~0 B
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: K6 l9 C5 Y5 Q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
`' t; H- D* G) e- S5 b( I: N. tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average2 j4 K& @: J; l4 f8 z1 s" J4 f
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 e8 u8 g, @0 D' ^) w/ Ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This' F; L' C" B: y2 x8 h" A" F# N+ Y( P
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile* }/ q5 G3 s3 M
growth. The response appears to be greater in younger children, which is consistent with previ- P, a1 H7 O. @ i
ously published studies of age-related 5 reductase activity.6 V" b3 N7 N5 b4 d# G( k
Children with microphallus regardless of its etiology will. G5 B/ N: B; U6 A' K! `( }5 j! P
require augmentation or consideration for alteration of exter-
" m' o5 G9 B! Inal genitalia. In many instances urethroplasty for hypo-
6 K9 n! \' p% t4 p6 M" y' d: w% n& wspadias is easier with previous stimulation of phallic growth.; o/ d. c A3 C3 _
The use of testosterone administered parenterally or topically8 \" O9 t& N6 J& O- Z2 Q9 U6 l/ D
has produced effective phallic growth. 1- 3 The mechanism of, D6 _7 S0 Y9 i+ Y2 ~& y, H
response has been considered as local or systemic. With this
% g7 t) K1 E$ `2 l( Zin mind we studied 5 children with microphallus for response
/ x- w/ j, w% Y# P R( rto gonadotropin and to topical testosterone independently.2 w: a2 | A5 e+ X4 f8 `
MATERIALS AND METHODS
3 Z- ]7 t/ H5 E* o7 }! X: L. P* M% PFive 46 XY male subjects between 3 and 17 years old were4 c6 B' f) i, B4 S2 p6 s
evaluated for serum testosterone levels and hypothalamic
7 |& L. s6 N3 D* A. M. yfunction. Of these 5 boys 2 were considered to have Kallmann's( v# e2 k$ F1 D
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-# \: S* Y* d, O2 c
lamic deficiency. After evaluation of response to luteinizing
' u7 n; k/ s0 t( Q1 e" Ihormone-releasing hormone these patients were treated with
4 D1 O% @9 Q5 F( k9 {1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ A: e1 t# P+ w0 F+ k2 C, [after completion of gonadotropin therapy 10 per cent topical
5 O: U X$ ?; ~2 ]; a( \6 Ktestosterone was applied to the phallus twice daily for 3 weeks.. B4 Y1 d' E- y$ t. x( }
Serum testosterone, luteinizing hormone and follicle-stimulat-
6 X- S2 P# y9 Aing hormone were monitored before, during and after comple-# Z7 q. d( `* ?
tion of each phase of therapy. Penile stretch length was
# E& f) a) W+ S* {; u1 | Nobtained by measuring from the symphysis pubis to the tip of* l1 M, H+ k, k1 y
the glans. Penile circumferential (girth) measurements were
$ |+ p$ H# ^8 O" X7 e# aobtained using an orthopedic digital measuring device (see* }* Z5 I2 @+ U& a* _2 b
figure).
- |' C% W& M/ ~0 j9 J% s6 ~% ?( M& KRESULTS' S! W; A9 m, A3 d" y7 g3 |
Serum testosterone increased moderately to levels between* p* B5 s3 i' n5 |6 x% M9 [# G+ g
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: W8 Y% H4 q. ?" r( v
terone levels with topical testosterone remained near pre-" e1 _; z" O' [2 Q: e" G
treatment levels (35 ng./dl.) or were elevated to similar levels; \; ?# H/ Y/ C- O) Z6 A
developed after gonadotropin therapy (96 ng./dl.). Higher
0 h/ \: U* J5 u0 B2 I9 u+ H5 aserum levels were noted in older patients (12 and 17 years old),
0 ~; `) a1 ~/ S9 F! E6 ?while lower levels persisted in younger patients (4, 8, and 10+ H( q7 J- g3 m7 ~ K" F; K/ j: I! @/ b
years old) (see table). Despite absence of profound alterations/ N7 y' B) Y8 D* @. ]" D8 d V
of serum testosterone the topical therapy provided a greater
( L0 k8 |1 P+ z) j: [Accepted for publication July 1, 1977. ·* v" H, t+ r" C) v- u4 j" k
Read at annual meeting of American Urological Association,
& t# p7 W- K7 {Chicago, Illinois, April 24-28, 1977.
' ^! g. G) F7 e* Requests for reprints: Division of Urology, Henry Ford Hospital, @. Q1 M, L0 j$ n% u
2799 W. Grand Blvd., Detroit, Michigan 48202.; l L* J3 u7 ?5 J0 `
improvement in phallic growth compared to gonadotropin.
, D& c) j. h! R L% Q3 |Average phallic growth with gonadotropin was 14.3 per cent
( q$ o. Z) L2 V+ wincrease in length and 5.0 per cent increase of girth. Topical
/ ~/ i: R8 S: L8 A2 |testosterone produced a 60.0 per cent increase of phallic length
7 F: `& {: R3 k/ w( cand 52.9 per cent increase of girth (circumference). The
( h9 i: Z+ C' s- M" {, Dresponse to topical testosterone was greatest in children be-, a8 N" M+ C; y$ a( [& S- C
tween 4 and 8 years old, with a gradual decrease to age 17) O/ R% l9 d( o) y
years (see table).
* U2 l) o9 |, ^: m- yDISCUSSION
+ A# {' ^( K* i9 ITopical testosterone has been used effectively by other
% a* y1 X( F' Yclinicians but its mode of action remains controversial. Im-
- n9 ^7 k4 q$ q% q# i3 nmergut and associates reported an excellent growth response% `% `0 v* `/ l
to topical testosterone with low levels of serum testosterone,
+ z% { x4 ^2 }2 Fsuggesting a local effect.1 Others have obtained growth re-" C( k* z7 @, K3 w% T
sponse with high. levels of serum testosterone after topical& o4 b* \. L5 ?2 w& g( N" u! m
administration, suggesting a systemic response. 3 The use of
7 e& i1 a* U# e- Ogonadotropin to obtain levels of serum testosterone compara-
3 ]: r6 E c, y" z0 N% z' R0 kble to levels obtained with topical testosterone would seem to
7 [- H/ ^, b. {$ _/ @% uprovide a means to compare the relative effectiveness of) _' ~, x; q7 B* A% X& `: G
topical testosterone to systemic testosterone effect. It cer-
* Z! p$ h6 i% |tainly has been established that gonadotropin as well as par-+ I( [/ G! |- Q! B! p& h
enteral testosterone administration will produce genital
, g# C2 v* c- R- ?$ s; W5 ` ?growth. Our report shows that the growth of the phallus was
9 _2 }7 [% q% R8 Rsignificantly greater with topical applications than with go-
* t7 H4 K0 o# J: [nadotropin, particularly in children less than 10 years old.7 @7 Y3 [; }6 e- j7 h
The levels of serum testosterone remained similar or lower$ q% Z: K' h5 W( s
than with gonadotropin during therapy, suggesting that topi-
5 _2 O9 ]1 I% [7 P! G% ecal application produces genital growth by its local effect as/ V5 n+ _3 \' z, y0 G) Q1 Z6 y$ G
well as its systemic effect.! b$ x, _) s3 U* o, w; P5 d
Review of our patients and their growth response related to
: ^. x) S7 S2 f# e0 T. @8 zage shows a greater growth response at an earlier age. This is
- s# n/ [' z# N: ~. e- ]consistent with the findings of Wilson and Walker, who
5 n3 ~. d; D! rreported an increased conversion of testosterone to dihydrotes-
: p( y$ z6 F( K: C! h+ stosterone in the foreskin of neonates and infants.4 This activ-
! o4 o3 j e. d; Z+ G' ^ c& dity gradually decreases with age until puberty when it ap-
5 e8 V H# t& v6 d: C2 g/ H3 Mproaches the same level of activity as peripheral skin. It may* l3 y* a5 ]7 h
well be that absorption of testosterone is less when applied at
6 f3 c0 R9 O+ Ran earlier age as suggested by lower serum levels in children6 F$ L" l4 i2 J: e9 p" b) }
less than 10 years old. This fact may be explained by the
, w) d; {* ?+ S: k F6 a- w, @greater ability of phallic skin to convert testosterone to dihy-" G* [* m8 F; v( {) Z& y, q
drotestosterone at this age. Conversely, serum levels in older
( g1 K8 i. R1 Y$ H! K* cpatients were higher, possibly because of decreased local
+ n- F& ~' J9 a0 k/ C+ K0 T667% N7 R2 ~- R0 l; j" m+ K I
668 KLUGO AND CERNY
9 E# z R+ g5 q& l/ vPt. Age2 v& `$ D! `& [ C1 G
(yrs.)
! ^, ~+ E9 A/ e. C6 oSerum Testosterone Phallus (cm.) Change Length0 P! L6 }/ d7 e3 a7 P2 p
(ng./dl.) Girth x Length (%)
* y( D$ D5 {/ M* C# V4
8 N; x$ @. n* w' Z$ g% z- E; P. X$ f81 O9 B2 y0 c' E+ o% i
106 \" G1 b5 S8 ~; w6 i
12
- S) p: l! n" P9 u$ p17) W) A! x/ Y- T/ H
Gonadotropin: f! U3 W" E, P4 h1 j1 e" t2 T
71.6 2.0 X 3 16.6$ W/ Y' {+ s8 e" g
50.4 4.0 X 5.0 20.0
+ i6 V3 O8 A; t5 P& \22.0 4.5 X 4.0 25.07 z1 I, E4 d" y6 X" s7 t
84.6 4.0 X 4.5 11.16 \. E7 G7 t* u9 x1 s! k9 v
85.9 4.5 X 5.5 9.0
6 [& W0 d, D$ K' [0 X( ]Av. 14.3
; u' ~' R/ }- s& K1 F0 a, `4
* J: F( H. n3 u4 q82 t: L7 l& w. W- p3 _
10
0 [+ K$ f2 H( I- R128 ?! n$ b8 H* F9 ]1 C4 g
17
6 m" q$ e& Q+ vTopical testosterone4 B5 h9 D7 F$ C: M4 y \/ r5 F! t
34.6 4.5 X 6.5 85 \0 G9 N( i/ V! G h
38.8 6.0 X 8.5 70
& P* E, G0 j7 w. d- g$ S, W; y40.0 6.0 X 6.5 62.52 { H; A |$ v6 l% B% X
93.6 6.0 X 7.0 55.5/ d+ T0 u- U9 }* N Z& M) h
95.0 6.5 X 7.0 27.2
, s4 r6 ?0 n) w# W8 c! {( MAv. 60.06 V6 c- U: s' [. e V6 X
available testosterone. Again, emphasis should be placed on& y3 z! u) h% R! z, G; [
early therapy when lower levels of testosterone appear to# ^7 a3 R0 s' v# C1 p. L3 z
provide the best responses. The earlier therapy is instituted: V4 P: \3 Z: ?' }/ }$ B
the more likely there will be an excellent response with low6 n- P/ w# r7 U6 O
serum levels. Response occurs throughout adolescence as
# \1 z' f4 _; unoted in nomograms of phallic growth. 7 The actual response
& S# n; D% R% B7 m- D8 Gto a given serum level of testosterone is much greater at birth: g2 R3 C- |- c% b/ y
and gradually decreases as boys reach puberty. This is most0 U+ C0 q- P/ z1 N
likely related to the conversion of testosterone to dihydrotes-
, Z" e! J }$ g; ^$ d' Ftosterone and correlates well with the studies of testosterone
3 [$ u8 O$ j' W1 ^9 z/ tconversion in foreskin at various ages.
% R4 B! I& Y1 }9 T+ R4 lThe question arises regarding early treatment as to whether
$ W- y+ @1 \2 ^. _9 K0 H& L6 N- N2 Xone might sacrifice ultimate potential growth as with acceler-
; S- F1 [1 n5 Hated bone growth. The situation appears quite the reverse/ Q$ \8 w0 c; |4 [
with phallic response. If the early growth period is not used
$ ?0 a2 S( _8 b( w0 nwhen 5a reductase activity is greatest then potential growth) o& @9 J" z$ D, E) x
may be lost. We have not observed any regression of growth) ^# g: w4 y8 [2 |( |" i6 \# o/ P
attained with topical or gonadotropin therapy. It may well
( V/ ]6 E7 T# ~$ u% T! `be that some patients will show little or no response to any5 B% g ?, Z) E" o F, }# U
form of therapy. This would suggest a defect in the ability to
/ U4 V2 ~9 G* n, R) |convert testosterone to dihydrotestosterone and indicate that
* W1 q4 O0 G- B6 Jphallic and peripheral skin, and subcutaneous tissue should7 K& h' g) T, t/ g* e& p; L
be compared for 5a reductase activity.
! `! `& M+ O n( i$ \A, loop enlarges to measure penile girth in millimeters. B,5 ^2 N; f. k$ z& u) H
example of penile girth computed easily and accurately.6 T6 U0 Z R5 @% K
conversion of testosterone to dihydrotestosterone. It is in this
" z i4 ?1 a+ colder group that others have noted high levels of serum8 \7 ]3 ~% {4 W8 E' {
testosterone with topical application. It would also appear& b# R7 b# C* G, n( M y9 G( s
that phallic response during puberty is related directly to the+ a& P7 _7 a$ ?
serum testosterone level. There also is other evidence of local% y) D1 a( [8 B3 W) @# `' \
response to testosterone with hair growth and with spermato-
; w+ y! T- o6 a1 c8 hgenesis. 5• 6
' D3 U, A" r# }, t1 Z9 r5 D7 i1 lAdministration of larger doses of gonadotropin or systemic/ v. T- V9 w( L6 L! ? O
testosterone, as well as topical applications that produce; o) ]; C1 O; L; [& y
higher levels of serum testosterone (150 to 900 ng./dl.), will
- f% i) C( ]' a, B+ lalso produce phallic growth but risks accelerated skeletal4 m+ N+ i3 x8 a8 \
maturation even after stopping treatment. It would appear; u* p+ o$ \$ s) n# R3 f% z) Z
that this may be avoided by topical applications of testosterone
0 a6 z0 ^2 f4 | vand monitoring of serum testosterone. Even with this control/ K8 |) Q g/ u( r/ f/ ?5 o: u
the duration of our therapy did not exceed 3 weeks at any# ]2 L6 ^. Q9 Z9 O3 w; C
time. It is apparent that the prepuberal male subject may
' p- p$ \6 Q0 k- Ksuffer accelerated bone growth with testosterone levels near
# R1 b) `4 j3 R# z" d8 H200 ng./dl. When skeletal maturation is complete the level of$ A6 \# M1 T, a9 d# Y, w& D
serum testosterone can be maintained in the 700 to 1,300 ng./" q4 H: O) e c" s$ X% r* l' w( b
dl. range to stimulate phallic growth and secondary sexual p# V! O! l6 ]8 z9 Q: d7 T
changes. Therefore, after skeletal maturation parenteral tes-' J5 {" B6 b* U( g. H F5 a q
tosterone may be used to advantage. Before skeletal matura-5 ~) c% t9 A% e! C! U
tion care must be taken to avoid maintaining levels of serum
& O* p* z9 V3 U, t, f0 ctestosterone more than 100 ng./dl. Low-dose gonadotropin
& S5 f) N z9 G" M1 q/ I! R" V! ydepends upon intrinsic testicular activity and may require
3 i* r" k+ x6 ~: M& tprolonged administration for any response.+ y+ K+ G; K/ E) U2 b( |/ u2 e
Alternately, topical testosterone does not depend upon tes-1 j9 P$ Y* Q2 v
ticular function and may provide a more constant level of) s; i- u9 `# [1 R I' h* y
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1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' F# y6 {8 \- |0 a8 T( H3 d+ c
R.: The local application of testosterone cream to the prepub-
% M0 T* T. }6 i0 C4 f8 W# C6 |* v eertal phallus. J. Urol., 105: 905, 1971.
7 ~; G, S$ M, j C# u2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 B8 ~+ ?9 F- B, V8 i" l7 J
treatment for micropenis during early childhood. J. Pediat.,3 i+ }0 n3 v6 w3 o, M3 n
83: 247, 1973.
8 I: ?( J6 X3 l. k3 V6 W3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
4 _3 h: E1 w2 P# }- Q; W: u* g' c' q& ?one therapy for penile growth. Urology, 6: 708, 1975.
6 V9 U S4 G. B/ }/ G& y [4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 l4 ?& }: A# }5 H1 b3 ^# s
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. r* {: h! @2 D& W
skin slices of man. J. Clin. Invest., 48: 371, 1969.
J% c+ V d9 O- y0 K, q% r5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
/ Y5 e t* Y8 {! m. tby topical application of androgens. J.A.M.A., 191: 521, 1965.
4 _- j& y* H3 r, y v2 A. B6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, d; U( d; Y$ z$ v. I
androgenic effect of interstitial cell tumor of the testis. J.
5 f7 Y, X: p. M# ?; X" V9 ? i* qUrol., 104: 774, 1970.
* v0 q6 z! S+ b7 u4 v7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 X2 q2 M, @6 h
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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