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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ B& S ^2 n8 A* A4 M* @, C1 S. b
GONADOTROPIN* q! \ z6 ]+ w ?; |7 n" t, q3 f
RICHARD C. KLUGO* AND JOSEPH C. CERNY0 K2 O' @1 c) v
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* G: z1 e3 |8 c8 d8 O; [% { FABSTRACT
* I' ]5 S$ U( ?' q! uFive patients were treated with gonadotropin and topical testosterone for micropenis associated
; U+ c2 J* _- ^9 }0 R% Fwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
0 V/ @; f% \: i$ L y( F- Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
; H5 |1 D. H, t% mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 l3 `2 ^$ [% g: L% w, H# b% u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
! ^! Q. T: ?# s: {5 L& pincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average" ]0 ], |" n3 B3 i
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
6 Z z6 ^0 |7 y! soccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
" u) g3 d- [6 a( }2 q4 [study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
: T' ~" c. `- i8 w' }& mgrowth. The response appears to be greater in younger children, which is consistent with previ-
& r6 k+ ^9 W2 P2 Lously published studies of age-related 5 reductase activity.$ J3 i+ g! i. _- J' F
Children with microphallus regardless of its etiology will* p8 g4 x3 i+ o& y. V0 F
require augmentation or consideration for alteration of exter-$ x1 s0 y* Y0 ~
nal genitalia. In many instances urethroplasty for hypo-
* Q* s, _ g% n Y, l) Z8 H2 sspadias is easier with previous stimulation of phallic growth.4 A8 d7 L+ j# b: ~# i; h7 l- s
The use of testosterone administered parenterally or topically
8 O5 e T1 I1 K0 L/ O4 ]8 j* ^% Vhas produced effective phallic growth. 1- 3 The mechanism of, j& L2 ^; M: i- I. a
response has been considered as local or systemic. With this
+ X: p6 b! U+ C2 ?" `& d2 |in mind we studied 5 children with microphallus for response! n. d1 |/ M6 S. C ^
to gonadotropin and to topical testosterone independently.6 Z" C7 E( p8 g. X: }
MATERIALS AND METHODS
* ~3 O* m0 q1 eFive 46 XY male subjects between 3 and 17 years old were
! a7 F; y& c$ Q' m& }evaluated for serum testosterone levels and hypothalamic: w5 S1 S3 k1 n* z: _8 T
function. Of these 5 boys 2 were considered to have Kallmann's+ ]5 U" T2 M6 D: d- H# d6 N
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' Y( t7 j# C/ {- v/ L5 ~lamic deficiency. After evaluation of response to luteinizing ?8 Y0 S2 a( R8 K$ @/ S5 ~7 ]0 @
hormone-releasing hormone these patients were treated with3 k% R# a* ?& T& y' x
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
+ S$ A' L. y8 m9 Z$ X8 |9 V5 fafter completion of gonadotropin therapy 10 per cent topical# A! {% j' W q3 j- }- F, H
testosterone was applied to the phallus twice daily for 3 weeks.6 a+ f4 o6 k1 \# L
Serum testosterone, luteinizing hormone and follicle-stimulat-9 h5 W% \& A V' K
ing hormone were monitored before, during and after comple-' B& M" S/ h# r$ w: U$ C
tion of each phase of therapy. Penile stretch length was$ r: _$ J. n0 H U. H: P
obtained by measuring from the symphysis pubis to the tip of* C8 ~! T/ t$ U$ e) T8 J' ]
the glans. Penile circumferential (girth) measurements were
" i/ }: H+ R: [! l/ ]! _1 o' s7 Aobtained using an orthopedic digital measuring device (see
: B3 Z) ?; t- r! {) i! ifigure).
" c2 o% o3 Q! N3 r; WRESULTS
$ X$ F( k8 s3 E' n' v* ]Serum testosterone increased moderately to levels between- J9 F; \8 |& D" B! M' C( |
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 r0 [2 Q0 Y; O$ |( B8 L
terone levels with topical testosterone remained near pre-9 w3 r9 Z: |1 |
treatment levels (35 ng./dl.) or were elevated to similar levels! i" n: ~' N, p& k. O# t! V x' N' B+ ]! m
developed after gonadotropin therapy (96 ng./dl.). Higher- P4 q# D% p4 m4 k k
serum levels were noted in older patients (12 and 17 years old),
5 f; l/ f! k; R" r+ i9 @! D8 O Bwhile lower levels persisted in younger patients (4, 8, and 10: }; d' ^7 F" |4 ~6 L
years old) (see table). Despite absence of profound alterations
" d3 v( r+ o% [: S( Nof serum testosterone the topical therapy provided a greater
u& T. E2 {- B6 J; PAccepted for publication July 1, 1977. ·' m5 ?- X) D" C; T$ L. ^! z7 x
Read at annual meeting of American Urological Association,. F! S7 }9 b( y. y& a
Chicago, Illinois, April 24-28, 1977.
" o& h) x% i% e2 X- P* Requests for reprints: Division of Urology, Henry Ford Hospital,2 t. n. C0 F9 P; k5 {* n
2799 W. Grand Blvd., Detroit, Michigan 48202.+ y) g7 f1 i. ?; ]
improvement in phallic growth compared to gonadotropin.
: e4 U1 a! W; `( TAverage phallic growth with gonadotropin was 14.3 per cent
5 U# I& f) f/ H* T% l5 s, K0 Rincrease in length and 5.0 per cent increase of girth. Topical7 C5 _& \+ I9 d" e
testosterone produced a 60.0 per cent increase of phallic length
: @* H' `: U2 W dand 52.9 per cent increase of girth (circumference). The
! A! D3 M$ J9 l W5 dresponse to topical testosterone was greatest in children be-
1 V# j! E$ M4 ?- Z1 ltween 4 and 8 years old, with a gradual decrease to age 17
% o9 R' ]$ B' T, V( Uyears (see table).
) q7 j3 u& E( R( v9 W! e2 h2 V. ?* Z' cDISCUSSION
6 v' g2 x5 m! @# [ Z5 {" XTopical testosterone has been used effectively by other
% A% }" ]0 \( t0 |) E5 l; A: eclinicians but its mode of action remains controversial. Im-; V9 M% ]+ m) d3 S4 G
mergut and associates reported an excellent growth response4 r5 P$ w s+ V3 z8 r
to topical testosterone with low levels of serum testosterone,
8 b- X& Y2 Q- c2 g3 j$ Gsuggesting a local effect.1 Others have obtained growth re-+ ?) g+ x3 l' E5 M8 W+ I0 [4 t& o; C) z
sponse with high. levels of serum testosterone after topical
# j7 Q2 H8 i; g% B2 W% Iadministration, suggesting a systemic response. 3 The use of
4 d" t$ R# d) k; O7 x. ogonadotropin to obtain levels of serum testosterone compara-
! [3 T3 K3 K3 k m, @ble to levels obtained with topical testosterone would seem to
) |6 r, b1 f) [provide a means to compare the relative effectiveness of
/ @9 c0 W4 h' A3 ^topical testosterone to systemic testosterone effect. It cer-% k: i- m: W8 w+ a
tainly has been established that gonadotropin as well as par-9 N. ~2 A! h/ E8 O5 J
enteral testosterone administration will produce genital7 L1 v' E# m0 S0 N" I
growth. Our report shows that the growth of the phallus was
: Q4 G/ q# Z$ I7 h9 T7 fsignificantly greater with topical applications than with go-5 T! w& ]& f* q
nadotropin, particularly in children less than 10 years old., V, ], Y% i; A- y% a: b
The levels of serum testosterone remained similar or lower1 s& x, M5 p" [; I
than with gonadotropin during therapy, suggesting that topi-$ r) p& p5 L' d$ [ l ~
cal application produces genital growth by its local effect as
' {+ H) S& L: k1 c, Cwell as its systemic effect.+ p# ]" o- \$ j. Z
Review of our patients and their growth response related to
# |; q6 Y9 I) D) _8 @; ^age shows a greater growth response at an earlier age. This is
6 y/ \9 b& J4 Xconsistent with the findings of Wilson and Walker, who
; K( `: m7 u0 t" }: Q+ ^. N+ g7 zreported an increased conversion of testosterone to dihydrotes-3 ]) P/ F D9 k# U
tosterone in the foreskin of neonates and infants.4 This activ-% k" X9 O1 l( H! b, |" I. k% @+ n
ity gradually decreases with age until puberty when it ap-
. d& m% m; J3 e: g0 P$ y' Cproaches the same level of activity as peripheral skin. It may
; a) V7 f0 ~( Vwell be that absorption of testosterone is less when applied at
_9 \0 _# H1 B( b" ]# g8 ]8 I/ Xan earlier age as suggested by lower serum levels in children
' b7 m' I# O/ Vless than 10 years old. This fact may be explained by the
6 i( G5 y; h8 \! I/ v; C& Jgreater ability of phallic skin to convert testosterone to dihy-
p9 b3 ]# ~* ?+ H9 k# r& `2 i1 T6 ]9 |drotestosterone at this age. Conversely, serum levels in older
: w# F) G6 h+ |5 G. f" W' |patients were higher, possibly because of decreased local( Z0 a- l2 j* l! `1 k+ ? g1 x" D% c
667
, b# p, h* O+ v( x/ d/ R668 KLUGO AND CERNY
' }, |' n7 M6 b9 y( mPt. Age" F% ~6 c8 `3 Q* Z& |+ j7 L3 p3 q! O
(yrs.)
, A& D* h+ K$ J$ YSerum Testosterone Phallus (cm.) Change Length
; C& Y$ ]5 _5 u(ng./dl.) Girth x Length (%)
! }* |+ \5 a. M3 V/ V4) o. L7 N$ K# n: `; w6 i$ E, S @
8
7 `0 H1 J6 @" O% Z104 G7 M; y! f" h
12
+ C. w( ~6 [" g$ `, D; G7 A& @17
! G! y6 v& x; t) ^Gonadotropin; E6 I/ \5 X. x) M
71.6 2.0 X 3 16.6
& C0 H& t" T! C6 V3 t8 G50.4 4.0 X 5.0 20.0
0 V% L# H( } T; h, P w- D" c: ?# T22.0 4.5 X 4.0 25.0$ N; I, I# c* k" m) b% L3 Z
84.6 4.0 X 4.5 11.1! F. a& S$ V5 _( G2 z& N; i
85.9 4.5 X 5.5 9.03 i% }' m- ]) c1 M5 X" f: I- P6 e
Av. 14.3+ g; d, F- l% I
4
+ R; j% q7 a& G6 s; D, }% Z8" b: C3 }3 ^& {7 s- i
10
* V3 D+ n: C3 U+ F* p120 v( f$ ^1 q+ v1 @0 \. H/ l9 t5 h, L
17
4 V, L$ c$ J* v! H& k# g0 @Topical testosterone* p9 }7 N6 x6 V5 G
34.6 4.5 X 6.5 85
* L6 _( D9 l3 f9 q4 t! w& N38.8 6.0 X 8.5 70
* T# D3 Z: L% j( I& o' Y# ?40.0 6.0 X 6.5 62.5
# v" w9 U: H+ d' ]6 `$ S93.6 6.0 X 7.0 55.52 S1 f6 ~. O" l& g; m9 ]8 ]
95.0 6.5 X 7.0 27.2
# D, O% T7 C9 }: LAv. 60.0
, X- @: K, \$ Cavailable testosterone. Again, emphasis should be placed on, B" Q4 E; T! I2 Y
early therapy when lower levels of testosterone appear to! [* S. w+ T" S
provide the best responses. The earlier therapy is instituted7 x) O' r/ q: H4 D \; R) L0 l6 M
the more likely there will be an excellent response with low! o! k" d4 Q& i. D/ c' k/ [0 b
serum levels. Response occurs throughout adolescence as% }. n0 ~2 x7 K5 v( [6 `" z+ N: e
noted in nomograms of phallic growth. 7 The actual response
1 i* m3 A1 S5 Vto a given serum level of testosterone is much greater at birth2 Q$ Q% _& Z: S- S) ?9 i
and gradually decreases as boys reach puberty. This is most9 r% {! t* ` {# h6 q$ _3 ~
likely related to the conversion of testosterone to dihydrotes-* _7 L3 `& {/ d3 f/ X. m
tosterone and correlates well with the studies of testosterone
8 h6 v0 i9 u4 a1 ]6 k/ E8 kconversion in foreskin at various ages.+ I( d1 l8 Y) q# n% f
The question arises regarding early treatment as to whether) S* M; c2 s0 j: p0 Q
one might sacrifice ultimate potential growth as with acceler-
( {; ~$ n0 b$ q0 L6 @$ dated bone growth. The situation appears quite the reverse
+ ?2 Z5 H# N: p$ swith phallic response. If the early growth period is not used
3 }0 Q; B& Z1 u/ T: k+ D0 [" e. Uwhen 5a reductase activity is greatest then potential growth; |2 M/ z! Y5 F# p3 l# M: M* n" S
may be lost. We have not observed any regression of growth' b- ~; Q* }8 h% c
attained with topical or gonadotropin therapy. It may well
3 x3 ?9 i- [1 [* @: wbe that some patients will show little or no response to any4 b: X7 i9 J- Y& ^7 T) W. g. f0 D; u
form of therapy. This would suggest a defect in the ability to
' k7 h4 {1 q6 F- Fconvert testosterone to dihydrotestosterone and indicate that: V& n7 |$ `8 ` Q4 y' I( e/ u4 f
phallic and peripheral skin, and subcutaneous tissue should
$ ^. m t; G; J& f9 l6 v+ p. rbe compared for 5a reductase activity.
1 k$ P* J0 B) g: AA, loop enlarges to measure penile girth in millimeters. B,
4 Q1 v( F& w, R- ^8 F; ]3 texample of penile girth computed easily and accurately.
3 |' L' u& r# C. p$ @# Tconversion of testosterone to dihydrotestosterone. It is in this# U. ? U1 U8 x9 @( q
older group that others have noted high levels of serum
8 [9 ~( [! ^4 |- S& [4 Etestosterone with topical application. It would also appear8 h8 }+ \! l. k- `
that phallic response during puberty is related directly to the
! W! K1 h& T; l2 gserum testosterone level. There also is other evidence of local, \: o+ h1 D0 `
response to testosterone with hair growth and with spermato-/ n' r' g& Y0 E# D+ _
genesis. 5• 6
! X* z* R3 y: L6 U0 i4 s4 MAdministration of larger doses of gonadotropin or systemic
, k7 V Z) B$ q1 c9 P o& b8 Itestosterone, as well as topical applications that produce! r" b6 A3 M, ^. t) M' E
higher levels of serum testosterone (150 to 900 ng./dl.), will
7 [# B$ c: N$ s4 t6 Ralso produce phallic growth but risks accelerated skeletal
+ o& x8 _) _8 Y. {# z: amaturation even after stopping treatment. It would appear
9 t5 P. P* ]# y9 _0 t% r% sthat this may be avoided by topical applications of testosterone
, A- @! v: X) n8 ?4 P- aand monitoring of serum testosterone. Even with this control0 f* H3 e/ u) J1 G, p, |& t- p
the duration of our therapy did not exceed 3 weeks at any
& P" k9 R4 }, T0 I+ ?9 g. m4 ytime. It is apparent that the prepuberal male subject may. t+ ?( R* M. k) N3 R% M
suffer accelerated bone growth with testosterone levels near4 _$ W& ~0 M( j
200 ng./dl. When skeletal maturation is complete the level of
- x, H6 w0 X& O- R9 o& r) Fserum testosterone can be maintained in the 700 to 1,300 ng./, i. ~7 C7 U2 n0 b
dl. range to stimulate phallic growth and secondary sexual* c' t! k9 V4 l& R, r
changes. Therefore, after skeletal maturation parenteral tes-/ D% k. Z! {* @! S4 G
tosterone may be used to advantage. Before skeletal matura-
5 R" K& w% x+ E4 M. Ption care must be taken to avoid maintaining levels of serum4 v, e" A. W# G8 P9 ?( {' X
testosterone more than 100 ng./dl. Low-dose gonadotropin
& z4 L+ P* {; d4 E/ c- x: Fdepends upon intrinsic testicular activity and may require. ~. v. N9 |1 r6 T" O
prolonged administration for any response.1 F4 @9 ~$ N! x3 ~" ^+ C' `& l
Alternately, topical testosterone does not depend upon tes-- `3 K& T7 t8 u* ?4 i0 ~
ticular function and may provide a more constant level of4 T5 q3 H: L0 X
REFERENCES
! }( h3 i. O8 k) h( c; x1 e1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 |5 T$ P& p9 ]5 _! Y; X
R.: The local application of testosterone cream to the prepub-
" l8 G+ p c4 J2 b. {$ _- xertal phallus. J. Urol., 105: 905, 1971.* q+ c8 h# J. j) Q7 E* ?7 X
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% {7 V, W- A! N4 Ptreatment for micropenis during early childhood. J. Pediat.,
: ?) _ a/ U3 n" [# Y G( w83: 247, 1973.
4 |# C% E7 q* s3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 m* {; E" X/ ^5 j
one therapy for penile growth. Urology, 6: 708, 1975.* V3 v+ r3 h, x
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 c+ t$ P4 A! sto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- i* \$ } [/ F# _2 M5 fskin slices of man. J. Clin. Invest., 48: 371, 1969.5 C/ Q) F) p1 }8 G) q$ H) V3 [# C
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ y& e! Y8 X y
by topical application of androgens. J.A.M.A., 191: 521, 1965.7 \0 R# H0 P8 O. \, ^* {
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local# M: \" E. \- @/ ?, p
androgenic effect of interstitial cell tumor of the testis. J.
) |! E" Y4 K2 Q7 |, T4 ~( E5 RUrol., 104: 774, 1970.! j8 ?- [% R. Q* l8 \ q
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
! j3 {% F' c0 s' T- Ytion in the male genitalia from birth to maturity. J. Urol., 48: |
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