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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 p5 X* o2 P/ @9 A$ [. ?GONADOTROPIN Q5 v s9 E9 `$ z' b* h
RICHARD C. KLUGO* AND JOSEPH C. CERNY. q; K6 Q: i6 i6 u
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ k* E/ a6 Z$ W1 u. c+ i7 P
ABSTRACT
6 C- b) R6 U; f. n# VFive patients were treated with gonadotropin and topical testosterone for micropenis associated
+ x4 E: p5 @+ D: e8 o. n6 zwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
1 B+ a3 o$ i# n+ @2 n+ B: ^% Stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* t1 ~' V# s, ^% ?: z, q2 j
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent% w' i( y2 `8 X
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 q; Y$ q8 s4 d! b7 ?3 fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
$ T, h; y1 p$ A1 S7 x* Eincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. l, \2 j- h8 G5 s3 goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( ~5 y- w8 ~: n1 J8 }( h
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) e. B6 _, F3 z% R; ]5 z) cgrowth. The response appears to be greater in younger children, which is consistent with previ-; C: D: g+ E3 y* q( H
ously published studies of age-related 5 reductase activity.
9 F1 c& Y5 s' q6 `Children with microphallus regardless of its etiology will. M5 l$ `, @: t; q$ n' A3 b
require augmentation or consideration for alteration of exter-2 ^/ Z, o" k, }1 ? a4 r. l2 J% _
nal genitalia. In many instances urethroplasty for hypo-$ {, g! ^3 _! W6 c! d
spadias is easier with previous stimulation of phallic growth." q8 N8 D1 I+ n
The use of testosterone administered parenterally or topically2 n' G3 [: x) i* A- P
has produced effective phallic growth. 1- 3 The mechanism of. l9 G; p3 G2 M7 r) q; w
response has been considered as local or systemic. With this( D( L) v$ i& g9 U b G
in mind we studied 5 children with microphallus for response0 Z- {7 m5 O) k& e$ E& b8 [# S
to gonadotropin and to topical testosterone independently.
& T6 j, c* }. l- f, ~# O' i: EMATERIALS AND METHODS
/ f' [1 q, W# J* @( gFive 46 XY male subjects between 3 and 17 years old were
# l8 e. T$ a, e% q& oevaluated for serum testosterone levels and hypothalamic% w2 z, q" U3 X5 H, Z. P$ o
function. Of these 5 boys 2 were considered to have Kallmann's
( Y; Q$ t$ a! d$ ?( K2 T% G& xsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 A2 N7 p2 i0 c2 ]6 @
lamic deficiency. After evaluation of response to luteinizing
- u: J' T6 |" ~8 zhormone-releasing hormone these patients were treated with X N6 B! j: M' ^
1,000 units of gonadotropin weekly for 3 weeks. Six weeks! ~6 U7 s8 k9 A) F
after completion of gonadotropin therapy 10 per cent topical
+ h; q8 y4 m4 F+ e& }0 Jtestosterone was applied to the phallus twice daily for 3 weeks./ p/ m0 I7 r3 z+ t6 Q
Serum testosterone, luteinizing hormone and follicle-stimulat-: }9 V: d8 m" J: Q# q! u
ing hormone were monitored before, during and after comple-
, V( R) @2 i. z' |( o5 Ption of each phase of therapy. Penile stretch length was. G" G0 n0 h1 Y$ ]& o- `
obtained by measuring from the symphysis pubis to the tip of
/ N: M, Y9 Q2 A( n0 Hthe glans. Penile circumferential (girth) measurements were: `5 k" ~9 U$ B. F( c/ w+ R! y
obtained using an orthopedic digital measuring device (see z o0 H; l9 Y3 \. {
figure).
" _; U" }4 X! n5 l; b& N! aRESULTS
5 x. }/ S6 e4 _* B \2 XSerum testosterone increased moderately to levels between
$ [) @+ l0 `3 N2 C2 N- f7 O50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: A" o6 s& @* {9 I0 E
terone levels with topical testosterone remained near pre-9 {6 q, ^ p3 |
treatment levels (35 ng./dl.) or were elevated to similar levels
. i: w) n& i- m" h. D. vdeveloped after gonadotropin therapy (96 ng./dl.). Higher
/ Y/ b; J/ J A5 Y4 a0 s. M$ fserum levels were noted in older patients (12 and 17 years old),5 `# J$ u0 b, p& U
while lower levels persisted in younger patients (4, 8, and 10
& |& e! z8 M8 `! G3 Ryears old) (see table). Despite absence of profound alterations% ?1 n+ s( y0 A5 W9 _
of serum testosterone the topical therapy provided a greater) X& ]7 t; Y/ g. y( ^$ g
Accepted for publication July 1, 1977. ·% h$ E% |- z, ^8 C" Z
Read at annual meeting of American Urological Association,1 L. j* O( b# |
Chicago, Illinois, April 24-28, 1977.+ g- X& ~0 g4 S! {) h
* Requests for reprints: Division of Urology, Henry Ford Hospital,- s! T2 o. {4 o2 F; w' f$ q( r" p
2799 W. Grand Blvd., Detroit, Michigan 48202.
- h. I: } W& a. a: `& b# _improvement in phallic growth compared to gonadotropin.+ H" T$ I3 E: Z- Z: u% G' F
Average phallic growth with gonadotropin was 14.3 per cent0 F I2 p% ^5 U
increase in length and 5.0 per cent increase of girth. Topical% u, e: T3 s5 O0 Q$ r
testosterone produced a 60.0 per cent increase of phallic length
9 [. A. R) c x' Rand 52.9 per cent increase of girth (circumference). The/ k: H- N5 _; j. H
response to topical testosterone was greatest in children be-2 q' ]) h' ~8 f6 m' u3 `
tween 4 and 8 years old, with a gradual decrease to age 17. a; ?$ M5 y, j. m; R) g
years (see table).
/ s$ }, Y) c2 W1 a' r5 q$ Z. D4 LDISCUSSION
, n9 f/ B7 q" w) r8 HTopical testosterone has been used effectively by other
6 t1 T! Q3 S! Z3 Y( ]clinicians but its mode of action remains controversial. Im-
7 L9 k& Y& n* h2 h0 U( T2 `" Wmergut and associates reported an excellent growth response" X) }; Q p3 F
to topical testosterone with low levels of serum testosterone,
6 O; b# ^! a3 x" R/ S+ i3 xsuggesting a local effect.1 Others have obtained growth re-" |3 q6 f7 ~) }; S2 n" H5 A# P
sponse with high. levels of serum testosterone after topical( V% e+ d1 i: {7 T
administration, suggesting a systemic response. 3 The use of! v% h, e) [( l, Z5 W: J7 {- }
gonadotropin to obtain levels of serum testosterone compara-5 R. H) g8 |, w& A7 Q6 k
ble to levels obtained with topical testosterone would seem to! \4 T) m4 a- `2 Z7 q
provide a means to compare the relative effectiveness of
, a0 I7 j Q8 G: Ctopical testosterone to systemic testosterone effect. It cer-& N8 q( S* ?: V+ m! k; o0 @( m
tainly has been established that gonadotropin as well as par-1 d! o. P3 `9 ]# F3 N# J! R6 N
enteral testosterone administration will produce genital+ c( K" B, O% m S0 S
growth. Our report shows that the growth of the phallus was
, m; \) T3 L- u4 q3 @5 I0 _/ Msignificantly greater with topical applications than with go-
( Q* T3 a" N" Gnadotropin, particularly in children less than 10 years old.
2 ~& |; \+ l: A* F0 J G$ K$ sThe levels of serum testosterone remained similar or lower
2 ]# R7 ~4 M+ x nthan with gonadotropin during therapy, suggesting that topi-
! ?0 W- [& L1 z" l; ccal application produces genital growth by its local effect as
+ r q3 B. Q* N6 c3 |% e8 a+ jwell as its systemic effect.* {* N% R) B+ O4 ]7 d& j; J' d
Review of our patients and their growth response related to
7 t. U9 z7 C" d+ j. p+ hage shows a greater growth response at an earlier age. This is
, O! r2 V( b& |3 e, q0 nconsistent with the findings of Wilson and Walker, who! u! K7 z0 j- A; ?; w
reported an increased conversion of testosterone to dihydrotes-$ F9 L9 t' _6 H- {1 U5 R
tosterone in the foreskin of neonates and infants.4 This activ-
/ {5 b2 c$ U1 d6 z8 G1 {8 [3 A3 }/ J% H4 o+ vity gradually decreases with age until puberty when it ap-* ~3 [! e( r0 ?$ o: x" ]
proaches the same level of activity as peripheral skin. It may- w0 \9 L- L- V L* V9 A
well be that absorption of testosterone is less when applied at
8 a% Q/ ~5 t7 I. i( I- r( d$ Jan earlier age as suggested by lower serum levels in children
. p5 r, r3 Q2 D: j( d7 ?less than 10 years old. This fact may be explained by the! X2 ?+ }! o1 L# e: |
greater ability of phallic skin to convert testosterone to dihy-
# ]# ^1 }$ _$ Z: Tdrotestosterone at this age. Conversely, serum levels in older W5 M2 d3 H* e3 U/ I7 O2 X& o
patients were higher, possibly because of decreased local
1 T+ m% b2 S: ~% C. D, j667
+ T; `, m! h- {8 B z668 KLUGO AND CERNY
$ b3 z- s! ?* ?Pt. Age0 }7 O7 d5 _' J9 V# x k
(yrs.)
; X( W9 b/ N; Y) YSerum Testosterone Phallus (cm.) Change Length
# D3 s! b5 w1 l5 n! Q) O. ^(ng./dl.) Girth x Length (%)
9 ^9 m1 g5 z0 d+ J' _0 Z4$ S. A. ]) T5 S/ h7 j
88 o# [/ P1 o$ P; h+ E% y
10
0 d% T) o/ Z; O; |! \127 R& n; M- ~. T0 n" a9 K% c- O
17
% Q/ P& K2 P" D5 k& O7 oGonadotropin. t* C7 _6 j+ `* H5 x
71.6 2.0 X 3 16.6
! l. r1 F! ]8 d% R$ t2 o50.4 4.0 X 5.0 20.0: P6 D0 d; k# X* z5 m' h3 Y/ r
22.0 4.5 X 4.0 25.01 ^+ G8 O+ {" E! ]% f7 h
84.6 4.0 X 4.5 11.16 ?% o C- k' N7 P1 @4 m5 Y
85.9 4.5 X 5.5 9.0
* U/ z6 e. J0 ^$ L1 t B5 KAv. 14.3' N4 T. G6 d3 c( p( C( k
4
$ L8 `5 D; D/ s$ J1 O8) U1 i1 D1 \1 |- K# d) h$ J
10
2 z g+ x" b2 ^) k# w# E6 E5 J, b( `12
7 m- w! @6 \8 u+ X$ j17$ M! E' I' v3 w3 y3 R
Topical testosterone$ c( u: r; Z5 J: T' U
34.6 4.5 X 6.5 85/ i. l* p8 E) ?. z' H* L
38.8 6.0 X 8.5 70
: z4 ?9 U4 S7 e" ^4 x40.0 6.0 X 6.5 62.5
' g @9 u" e3 w9 F9 n93.6 6.0 X 7.0 55.5
' S& ?& b% R2 B9 O" N95.0 6.5 X 7.0 27.2
' O$ q4 o# O! [. u( Y& v. hAv. 60.0
$ b$ \5 L. B) F6 _ z1 Q) j( m( uavailable testosterone. Again, emphasis should be placed on
7 t& m% r( J) a% m( Kearly therapy when lower levels of testosterone appear to
- l: F' w, ^4 a" G: ]8 Yprovide the best responses. The earlier therapy is instituted
- j6 |/ K/ `" [the more likely there will be an excellent response with low) v j: e' X( {, J/ i0 c
serum levels. Response occurs throughout adolescence as
9 J$ ^1 k" [( V' Tnoted in nomograms of phallic growth. 7 The actual response: n) T1 ?/ J2 |0 {7 I0 w7 z
to a given serum level of testosterone is much greater at birth
$ ?6 Z/ @) g1 T- E5 w" Land gradually decreases as boys reach puberty. This is most
4 Q4 T' e9 A, X2 S" u1 {( d9 ilikely related to the conversion of testosterone to dihydrotes-. q5 y7 H; o2 S
tosterone and correlates well with the studies of testosterone
9 f" Z8 s4 X% G |4 fconversion in foreskin at various ages.& R4 D5 Q& L- O# z, z% h e; m
The question arises regarding early treatment as to whether3 V8 ]5 ^; N0 n. B6 @/ w
one might sacrifice ultimate potential growth as with acceler-3 ?, R$ ^1 b$ d* b# h) W3 f; h
ated bone growth. The situation appears quite the reverse
5 M. i/ R c6 a& h/ \! Mwith phallic response. If the early growth period is not used
0 w- t2 a3 A5 M, ?3 Ewhen 5a reductase activity is greatest then potential growth) p% c8 K- n5 i9 u' A, L
may be lost. We have not observed any regression of growth
9 Z& h v0 S6 d1 G, Mattained with topical or gonadotropin therapy. It may well$ H, [* x* V# M# w$ _
be that some patients will show little or no response to any, q5 A h; Y5 \2 P+ P
form of therapy. This would suggest a defect in the ability to
9 |9 Q; R5 v# T; @& Aconvert testosterone to dihydrotestosterone and indicate that7 O$ i& L) ~. G' o; [; a! N
phallic and peripheral skin, and subcutaneous tissue should' U2 {! M) A# d
be compared for 5a reductase activity.6 M& [, a8 ]" B" u
A, loop enlarges to measure penile girth in millimeters. B,( n7 B4 p! Y1 I! u: R
example of penile girth computed easily and accurately.) j7 e1 w. N4 c; Y* F! P% ^$ J
conversion of testosterone to dihydrotestosterone. It is in this7 c! r! H/ w( V( u) G
older group that others have noted high levels of serum( t; c% ^0 a, Q
testosterone with topical application. It would also appear
+ t6 |7 x' h' n! p" _: Y/ Qthat phallic response during puberty is related directly to the
|$ @6 G6 P8 r: @0 U, P: fserum testosterone level. There also is other evidence of local
3 Z" p9 r3 B" Y3 gresponse to testosterone with hair growth and with spermato-& [" J2 a- `0 l9 ^
genesis. 5• 6% i% x7 V2 m+ L: k
Administration of larger doses of gonadotropin or systemic& u o F6 X8 }, Z' l/ ~+ Q: @- j
testosterone, as well as topical applications that produce
! ^: l J. N' \' T+ p3 S& jhigher levels of serum testosterone (150 to 900 ng./dl.), will0 P4 h( H; Y8 n0 H B# \# R: ^
also produce phallic growth but risks accelerated skeletal8 @" K3 U6 f/ x$ ~" Y7 `
maturation even after stopping treatment. It would appear
" B/ l6 r# M- I% p; X& W5 othat this may be avoided by topical applications of testosterone
% ]2 x; n4 y" g8 rand monitoring of serum testosterone. Even with this control
4 y& _ F8 D: M) lthe duration of our therapy did not exceed 3 weeks at any* G; V% m, U, m& ~- ^( L
time. It is apparent that the prepuberal male subject may
+ @- `9 f; g4 Psuffer accelerated bone growth with testosterone levels near
. A4 U ~) _" `0 |& ^200 ng./dl. When skeletal maturation is complete the level of
4 v2 ~/ T; a; M; a6 c) S |& y5 fserum testosterone can be maintained in the 700 to 1,300 ng./+ Z5 Y6 {0 w1 T i; ]' G0 ^; `
dl. range to stimulate phallic growth and secondary sexual
+ k% @6 L% ?- Mchanges. Therefore, after skeletal maturation parenteral tes-, }# W4 ]/ a0 n( ^
tosterone may be used to advantage. Before skeletal matura-
$ Y7 \5 }/ d5 w Ution care must be taken to avoid maintaining levels of serum
# E" ~& E% H1 c6 xtestosterone more than 100 ng./dl. Low-dose gonadotropin
! [. d3 B' Q0 G6 w& K }depends upon intrinsic testicular activity and may require0 L5 }4 \" f: E \
prolonged administration for any response.5 W) Z# K. p, T) H; u
Alternately, topical testosterone does not depend upon tes-) n4 {1 p; ~+ J! b- U" q& B# ?
ticular function and may provide a more constant level of8 @. H8 M, |5 L: R1 y5 h2 V
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1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 z2 O6 j9 @# e; T( x' W$ cR.: The local application of testosterone cream to the prepub-
. M8 u b! J" b% C: Zertal phallus. J. Urol., 105: 905, 1971." y5 n% J% \# ^. {7 T) T: q
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone+ C1 l- ~ P' G6 @
treatment for micropenis during early childhood. J. Pediat.,* d$ h! R7 T* f1 D
83: 247, 1973.
& m7 L# D+ x3 T' U" R, U8 f6 [; q! Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' o, R' H! Y! H$ [# [one therapy for penile growth. Urology, 6: 708, 1975./ W: Q9 D& n1 [( ~ u
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
% d2 H( y l% p- B/ g: rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# [6 m% K7 D- Jskin slices of man. J. Clin. Invest., 48: 371, 1969.
( m7 |9 r% v/ R" D3 `5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 R; H( q- G" n! @% e
by topical application of androgens. J.A.M.A., 191: 521, 1965.
; C0 i* M7 j# a# l' a9 M6 h6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ I4 O: R6 w1 E. f
androgenic effect of interstitial cell tumor of the testis. J.$ l5 B* g3 X7 j1 ~( u
Urol., 104: 774, 1970.
- h3 H" c, q0 n, C0 M; d# d" W7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 a9 W @+ Q7 G% R% d
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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