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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 t3 U& W2 D+ }7 K2 ZGONADOTROPIN
* D5 g, ~4 [7 B- S% K8 H: @RICHARD C. KLUGO* AND JOSEPH C. CERNY+ C* Z/ z; S; t
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ ~" ?1 B: I5 i5 E0 l2 ]. ] H
ABSTRACT8 `2 g* Y$ q- r$ t+ f
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
/ b# D5 c8 C9 Y G+ e4 B" vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) l9 ?- W, A% j jtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 ~! q' U+ h) b4 w0 C, ~! A1 n2 ~
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent# }: y+ w* ]1 |
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) K; d, U# f* o8 ]% b% | X( K8 ~9 O
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: U$ v9 b0 X* @" X
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ H1 d; G g# h$ M0 s
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 Y. U# [8 |" X a' D# S+ m0 Tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile; X3 ?( Q ?; O" y) l3 u+ [/ V
growth. The response appears to be greater in younger children, which is consistent with previ-$ u( X$ H; K d) `; e
ously published studies of age-related 5 reductase activity.
/ u9 E* B1 ? I' K5 @( D/ ZChildren with microphallus regardless of its etiology will8 Q; H6 M% A7 |6 H
require augmentation or consideration for alteration of exter-+ J {9 n# ?0 ~8 D1 Y! w ?
nal genitalia. In many instances urethroplasty for hypo-" [ z( K$ M4 k1 E
spadias is easier with previous stimulation of phallic growth.- u3 G* G, e _, a, \1 Y4 D9 K
The use of testosterone administered parenterally or topically
7 E' S8 D( |0 X% S; ]' m. S" c% Ghas produced effective phallic growth. 1- 3 The mechanism of
8 f) g* J( @ B4 cresponse has been considered as local or systemic. With this
& P8 z: u9 ^/ t( x* t6 k- H: I) lin mind we studied 5 children with microphallus for response
( N( P9 e% a- K/ S) g# ~! {4 }7 Uto gonadotropin and to topical testosterone independently.; c/ w' P. u8 ?: W+ S
MATERIALS AND METHODS
- ]6 F3 A. E4 n3 y: _2 uFive 46 XY male subjects between 3 and 17 years old were+ [- `9 k3 Q2 \/ _4 L' p$ |
evaluated for serum testosterone levels and hypothalamic, c- p: {3 D: |
function. Of these 5 boys 2 were considered to have Kallmann's
! w4 O, }/ e s, v' tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-% E; G T" ~6 L/ m: Y! w
lamic deficiency. After evaluation of response to luteinizing
* W8 V+ x, x" ihormone-releasing hormone these patients were treated with' @7 Q8 u" e1 Y9 a8 _
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
1 u8 A+ Z+ S/ H% ]* N. H5 @3 Aafter completion of gonadotropin therapy 10 per cent topical x' H! C; T' Z6 L% X! f
testosterone was applied to the phallus twice daily for 3 weeks.6 `5 y' M8 ]4 w% k
Serum testosterone, luteinizing hormone and follicle-stimulat-, d u! t: ]0 \( V- G% \
ing hormone were monitored before, during and after comple-
8 k0 l% A- \6 H- K P5 jtion of each phase of therapy. Penile stretch length was% H* B" O w }
obtained by measuring from the symphysis pubis to the tip of
% ?; Y3 b8 L$ }1 z; A: Tthe glans. Penile circumferential (girth) measurements were
" [$ y \* v5 S& q3 d; k% {1 U% xobtained using an orthopedic digital measuring device (see h9 h7 d: ?& ]- ^, @( u0 ]
figure).) I) b) B! [7 @: B. j9 V% {; d
RESULTS# d( h9 _6 k7 a# B
Serum testosterone increased moderately to levels between! T! `9 ]* C: j E
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
8 J; i% H" y( S6 j( S$ a0 jterone levels with topical testosterone remained near pre-9 l' Y& u% h z- Y5 q" E
treatment levels (35 ng./dl.) or were elevated to similar levels7 ]6 b- r- p/ h7 C: ~0 \
developed after gonadotropin therapy (96 ng./dl.). Higher8 J4 ~7 `1 s* x. \/ G* I2 n9 H2 O( Q
serum levels were noted in older patients (12 and 17 years old),* r7 [1 F9 c/ o8 @( `4 }3 d1 |
while lower levels persisted in younger patients (4, 8, and 10
! ~* ~% A4 @8 j* b* `years old) (see table). Despite absence of profound alterations
# B5 ? o2 y9 `/ Y7 J. ?9 \of serum testosterone the topical therapy provided a greater
- _- _: h) Q) j7 U( _( x% IAccepted for publication July 1, 1977. ·
5 m% Y8 `$ N0 h( w/ e m/ s8 HRead at annual meeting of American Urological Association,
) c( l4 M, A% ]% V9 KChicago, Illinois, April 24-28, 1977.9 ~* w/ @% W$ G, o
* Requests for reprints: Division of Urology, Henry Ford Hospital,4 e# ? ^) |! p. z$ Z5 V+ Y
2799 W. Grand Blvd., Detroit, Michigan 48202.
4 _$ b& a* P Z) h0 Oimprovement in phallic growth compared to gonadotropin.
2 G3 Z3 P2 \- IAverage phallic growth with gonadotropin was 14.3 per cent
( Q$ x5 s" W. @& ?( Eincrease in length and 5.0 per cent increase of girth. Topical
9 W6 J' i3 L/ F( g9 [9 |. ktestosterone produced a 60.0 per cent increase of phallic length. Q5 s4 z8 X7 v$ l5 S" ]
and 52.9 per cent increase of girth (circumference). The
* h) a. E) u m+ ?$ c) f- Yresponse to topical testosterone was greatest in children be-" a# `7 U8 s: Q- o+ y
tween 4 and 8 years old, with a gradual decrease to age 17
7 ~7 d+ S6 P$ L5 byears (see table)./ t6 A. ?+ r$ x. }9 i! p
DISCUSSION _4 D( d5 G4 M+ h; W7 K
Topical testosterone has been used effectively by other
V' q/ [3 b9 `6 Dclinicians but its mode of action remains controversial. Im-( }9 t/ H" T0 A0 @( n g
mergut and associates reported an excellent growth response
& N/ \2 A" _9 `% e2 Kto topical testosterone with low levels of serum testosterone,
; I" G! ]1 g9 E7 c" G0 w$ D# nsuggesting a local effect.1 Others have obtained growth re-+ g) G) R. I" z
sponse with high. levels of serum testosterone after topical
7 |4 L0 e5 e5 R* {; d3 Radministration, suggesting a systemic response. 3 The use of* H" o% A L8 W. S+ H1 \7 ~
gonadotropin to obtain levels of serum testosterone compara-( l7 H( J6 b7 l% S' M
ble to levels obtained with topical testosterone would seem to
' x$ M3 q. u9 ?) ?% D5 \provide a means to compare the relative effectiveness of
# ~& y) s* Q9 Q8 {topical testosterone to systemic testosterone effect. It cer-
/ o% b3 i$ d6 A4 I/ qtainly has been established that gonadotropin as well as par-
! |+ `. H% }4 T; m4 H1 {" Senteral testosterone administration will produce genital6 R# H4 M# ^1 l1 D$ n, Q3 J
growth. Our report shows that the growth of the phallus was4 I; h6 J9 I$ n: O, |! y
significantly greater with topical applications than with go-$ ]. I9 G: ~3 W( T6 p8 n5 l" {9 ^" Z
nadotropin, particularly in children less than 10 years old.: ~2 e% S' g% |% @
The levels of serum testosterone remained similar or lower* f) J2 A# c% i5 C
than with gonadotropin during therapy, suggesting that topi-. _+ |5 U" O/ J% H# ~4 n4 f8 E `0 W
cal application produces genital growth by its local effect as# c5 Y6 {% K- C2 k4 u: G
well as its systemic effect.
5 y7 D0 A$ O& U! t- k1 b+ l. NReview of our patients and their growth response related to/ }' k4 I# w" ?6 D2 k. T# q& `
age shows a greater growth response at an earlier age. This is# h) `' I+ A) ~' G, B! c k3 M
consistent with the findings of Wilson and Walker, who
5 f9 K+ H. v- X& ]3 [& x" treported an increased conversion of testosterone to dihydrotes-0 z( }) q8 W2 W- Y% _1 b
tosterone in the foreskin of neonates and infants.4 This activ-
X( D3 v! o) o2 P; ]! Y6 s7 tity gradually decreases with age until puberty when it ap-
# d0 R" B+ [8 R: A' s7 i3 jproaches the same level of activity as peripheral skin. It may
. f- O/ M2 S5 u4 A3 v' x1 iwell be that absorption of testosterone is less when applied at; r0 w# G) l0 C1 x p4 H2 I, C
an earlier age as suggested by lower serum levels in children' O, L5 x! V/ D2 ^ [8 S
less than 10 years old. This fact may be explained by the, y. _9 S5 F5 K# A
greater ability of phallic skin to convert testosterone to dihy-
* d/ W3 O) _+ S8 n6 K3 Sdrotestosterone at this age. Conversely, serum levels in older
t3 P9 r' b9 T$ l7 r, F; gpatients were higher, possibly because of decreased local: M+ M" L! x- b2 A
667
( o' F# P: r ?( }! i668 KLUGO AND CERNY
+ A0 S7 K5 p$ m A. K# [% I, y: [Pt. Age
* {3 M8 o/ M$ o) j(yrs.)
3 e+ h3 S/ O& [0 [/ \& ?Serum Testosterone Phallus (cm.) Change Length
# q6 r3 v8 }: J0 I+ S(ng./dl.) Girth x Length (%)$ m. {2 Z/ T' O4 ^) \
4
6 o4 q2 r. P/ i) n) ~82 l; y: w2 t% ~+ s
10: e! O; k6 ~) _! d+ l8 h6 F
12
- l5 Q! g5 X" b+ J, q% a# t# e) g7 T17
6 {' ] C) o3 C% b/ G% SGonadotropin' v: ^& g D7 a/ I7 H- n' _2 N# K5 m
71.6 2.0 X 3 16.68 q v. D. b' s
50.4 4.0 X 5.0 20.0. E- x9 K) T- H9 }* a3 y
22.0 4.5 X 4.0 25.0
0 { H, { a6 }/ \' ~; x! U84.6 4.0 X 4.5 11.1+ K0 i" \0 p2 X# w f
85.9 4.5 X 5.5 9.0
! D( b; v3 J9 d) M! w) l# IAv. 14.3
7 C4 p; \3 W z2 A8 M4, Q7 K1 N- X W% h3 {: [3 S
8! m2 q1 y5 L3 F9 k
10( S0 ? h2 X! S x0 _
12
" y6 ^& p4 \! e$ M- r7 w1 z17! E, q" b; E6 H8 c
Topical testosterone
; {, x: N3 c, Y/ f* O, m. t; Y34.6 4.5 X 6.5 85% G; C: ^, }, |; A
38.8 6.0 X 8.5 70
+ A, m' a8 p$ m40.0 6.0 X 6.5 62.53 N! h3 s$ B# d; v
93.6 6.0 X 7.0 55.5
0 f J& ~" H4 P3 h u95.0 6.5 X 7.0 27.2# r1 \5 V) {) a# y: X1 i. v# j
Av. 60.0
2 v# Z% t& {3 D- l/ E$ yavailable testosterone. Again, emphasis should be placed on
* M' N4 c7 j: o4 X( r6 x; nearly therapy when lower levels of testosterone appear to; ^' M$ |) ]8 _. {7 q7 j
provide the best responses. The earlier therapy is instituted
8 C# B) ?! w) M- H; u2 h c0 fthe more likely there will be an excellent response with low7 o# S* a2 W) L/ k
serum levels. Response occurs throughout adolescence as! [' ]3 f- d7 `! w' u+ _
noted in nomograms of phallic growth. 7 The actual response
2 _3 `! c" ?4 e+ Cto a given serum level of testosterone is much greater at birth% {# a% V/ ^4 _6 Y+ i. V3 b* t
and gradually decreases as boys reach puberty. This is most9 U4 w6 U7 n4 V% h
likely related to the conversion of testosterone to dihydrotes-* \. U& Q1 o) U: d) c. a
tosterone and correlates well with the studies of testosterone- E1 z9 M4 K2 @ F% F
conversion in foreskin at various ages.8 X6 ~4 c1 M5 c' d7 B! j
The question arises regarding early treatment as to whether
6 z: y5 E0 z* t! F) s6 s7 Done might sacrifice ultimate potential growth as with acceler-; D) R d) y6 i0 B$ k, C
ated bone growth. The situation appears quite the reverse
$ ]2 D7 m5 E" e7 _1 ^$ }with phallic response. If the early growth period is not used2 _. o6 m- j5 w s; F
when 5a reductase activity is greatest then potential growth _$ h# j0 g$ x+ m# r
may be lost. We have not observed any regression of growth+ p) k$ @/ u& ~; G8 Y- A- z
attained with topical or gonadotropin therapy. It may well- `0 n3 z m7 L g/ c* ]
be that some patients will show little or no response to any
9 Z7 X% ~2 Z3 X7 F- C, y! C# `form of therapy. This would suggest a defect in the ability to+ W$ \9 Q6 m0 K( i5 r
convert testosterone to dihydrotestosterone and indicate that) j; F3 ~3 b" y6 p4 A( \7 l1 Z4 {
phallic and peripheral skin, and subcutaneous tissue should( d$ F% ]& Q: |! K; b0 B/ o; s* t
be compared for 5a reductase activity./ p# H2 _( f$ t# Q) R
A, loop enlarges to measure penile girth in millimeters. B,
# F: `9 c1 ]# jexample of penile girth computed easily and accurately.
& m e- \7 P9 Uconversion of testosterone to dihydrotestosterone. It is in this; G6 N8 V9 c) m! V6 L: z/ o7 u' n! Z2 {
older group that others have noted high levels of serum1 ^; {% k3 F& ?" c5 x6 @2 [
testosterone with topical application. It would also appear& d. W/ \0 R( ~4 K
that phallic response during puberty is related directly to the) x: C) e2 z2 J/ A4 Y
serum testosterone level. There also is other evidence of local
: @+ R- R+ d7 J, H' I9 wresponse to testosterone with hair growth and with spermato-
$ U% ^( B2 ?8 |9 `' [genesis. 5• 6
8 K! \2 ]5 T) a! t' f k: v8 RAdministration of larger doses of gonadotropin or systemic" K M% Z* v j
testosterone, as well as topical applications that produce; u. \# A, u x- p, _
higher levels of serum testosterone (150 to 900 ng./dl.), will6 [' x# U0 ^7 z
also produce phallic growth but risks accelerated skeletal
; Z/ k8 ?# L6 R- k6 mmaturation even after stopping treatment. It would appear+ e, c M) j0 U0 e; [. G
that this may be avoided by topical applications of testosterone# L+ f1 B p) K! b4 \7 C
and monitoring of serum testosterone. Even with this control8 s& m# Z( x" l
the duration of our therapy did not exceed 3 weeks at any
1 W; j4 ^5 T. k) L: O1 Ztime. It is apparent that the prepuberal male subject may
" n( y3 R8 G8 T- Qsuffer accelerated bone growth with testosterone levels near# |* g& z% D- I' p( J5 j
200 ng./dl. When skeletal maturation is complete the level of3 k6 ?" \+ J# `1 p0 _- r* ~6 C
serum testosterone can be maintained in the 700 to 1,300 ng./( j6 O6 i2 V' ^6 R/ e
dl. range to stimulate phallic growth and secondary sexual; v) [ k. z) @- r/ v: v
changes. Therefore, after skeletal maturation parenteral tes-
$ u- g, F* Q, J- Dtosterone may be used to advantage. Before skeletal matura-8 }: |9 ~1 S: [: t
tion care must be taken to avoid maintaining levels of serum3 `. {: ^. ]" n$ v' k/ K
testosterone more than 100 ng./dl. Low-dose gonadotropin
) V$ Q5 T$ l. S; T( z, @ ldepends upon intrinsic testicular activity and may require
# g% M* n: [3 z# r+ [& ^; Y+ kprolonged administration for any response.
5 a. C+ |, }4 J/ hAlternately, topical testosterone does not depend upon tes-
; h/ H% A% o4 `) O7 dticular function and may provide a more constant level of, q, j$ a0 f v
REFERENCES" [- Z" P @% O. C, ^) ^
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; i3 `$ k( ^5 T2 u
R.: The local application of testosterone cream to the prepub-
* l8 |8 c2 X0 E9 K6 oertal phallus. J. Urol., 105: 905, 1971.
~2 O. m% `3 u/ ^! E( a2 s2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
0 M& N" v5 M- q+ Atreatment for micropenis during early childhood. J. Pediat.,5 ^( w3 u# n# P0 V) S
83: 247, 1973.
, Z# I; ]. V* `# A+ I3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* k% W4 X8 [, _5 b) _8 ^! o
one therapy for penile growth. Urology, 6: 708, 1975.
1 Q% Y1 f+ T. i4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 \% P$ I3 X+ p: C# b9 b( w; u0 ?2 R4 y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 }& H( _( O! l6 c4 [
skin slices of man. J. Clin. Invest., 48: 371, 1969.0 K: q9 l" R& q- P0 v; n) ^
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
c3 \2 x8 A% \; o; M5 C2 q* Jby topical application of androgens. J.A.M.A., 191: 521, 1965.5 Q7 ?$ d- ?6 |
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local# F& b5 h. Z( f8 X; Z( k7 s5 \
androgenic effect of interstitial cell tumor of the testis. J.* v, I* [9 P: g3 q5 c1 H
Urol., 104: 774, 1970.' d! o; {/ E% d4 t9 I
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' V2 w7 K5 b6 q9 M9 [tion in the male genitalia from birth to maturity. J. Urol., 48: |
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