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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 Q7 E: P3 A# i4 X9 F: m8 EGONADOTROPIN% ]9 y- l2 W3 A; s& y7 K* e0 B
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 X- u ?' u0 l! t) TFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
+ ~. A1 k* U; H) r( X8 B% ^ABSTRACT& W' J; X( i6 F; I
Five patients were treated with gonadotropin and topical testosterone for micropenis associated9 J, D( t* T$ |, t6 j$ l. o N) j
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; I% p0 X4 c2 D3 V$ |tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
* R- y4 F9 P0 V1 p1 Q: | Zcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ v5 v' c# C3 T1 x& K' d+ O, T
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ r0 E! {* ~ x2 I, Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average8 F# [( o6 |3 X% A) |) D
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ d/ h$ N o0 B2 M& [! b
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# A; y/ q* x6 l7 c1 _
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
5 x" }4 w- e! g+ w$ ]growth. The response appears to be greater in younger children, which is consistent with previ-. @/ U4 o" ~9 b2 F$ A3 ]7 D1 _5 R
ously published studies of age-related 5 reductase activity.
8 Y4 U1 U/ ^, _# z1 V# CChildren with microphallus regardless of its etiology will
' D. D1 D1 u0 k; i) srequire augmentation or consideration for alteration of exter-9 f1 l6 u' I! d( d0 ]
nal genitalia. In many instances urethroplasty for hypo-
2 Z. h4 Y9 O; [% L J. ]; d& [# L1 Ospadias is easier with previous stimulation of phallic growth.
y3 ^7 x( \3 Y( G9 y3 M1 D6 HThe use of testosterone administered parenterally or topically# T, B8 m F' y* f% p7 q Z
has produced effective phallic growth. 1- 3 The mechanism of" i5 l# V* d& U7 ~# i2 o
response has been considered as local or systemic. With this& d! H+ [) U$ l
in mind we studied 5 children with microphallus for response- k! z1 Y6 K3 ~! d9 E
to gonadotropin and to topical testosterone independently., [# l% T: ?; V" @
MATERIALS AND METHODS
( B( m! y' U+ A+ c7 U0 Z) E' {1 l3 @8 PFive 46 XY male subjects between 3 and 17 years old were6 O' t+ ~( Q8 l# T$ w s% C
evaluated for serum testosterone levels and hypothalamic
& ]3 d3 G$ p0 k& A/ H5 Mfunction. Of these 5 boys 2 were considered to have Kallmann's4 b {5 n5 ]* m. O
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 c2 F9 s+ I$ f& A' i1 I/ ~; L8 _8 j. L
lamic deficiency. After evaluation of response to luteinizing
% ?: K$ {! U& `" K rhormone-releasing hormone these patients were treated with3 M5 v5 W6 ?' x+ |' t) x
1,000 units of gonadotropin weekly for 3 weeks. Six weeks0 i6 G6 u% {" \7 T/ R, e
after completion of gonadotropin therapy 10 per cent topical0 P1 `& j% b: h0 ?& W, @
testosterone was applied to the phallus twice daily for 3 weeks.
% ?) h7 v: D" ]: H) uSerum testosterone, luteinizing hormone and follicle-stimulat-) V3 Z- |9 d" u, C$ ~, ?& ?
ing hormone were monitored before, during and after comple-, z7 I2 J. j% E# T' Q( n6 O- Z
tion of each phase of therapy. Penile stretch length was3 ^) @9 H" d; g p( s" X8 K
obtained by measuring from the symphysis pubis to the tip of4 r- ]' F; v6 @) \5 o8 {* E
the glans. Penile circumferential (girth) measurements were7 U- L, a+ h+ J9 f1 ~
obtained using an orthopedic digital measuring device (see) i8 \4 E8 p7 Q6 ?9 A4 t5 o
figure).
5 U& R( I0 u; z4 ^ M6 {9 dRESULTS
2 ]' R' K- F* [2 q, RSerum testosterone increased moderately to levels between- n# M8 @4 {' _# u; u$ Q6 o
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-1 J K. G0 |+ Q# u- _2 R
terone levels with topical testosterone remained near pre-* j7 L4 U$ I, ]+ G9 w* U
treatment levels (35 ng./dl.) or were elevated to similar levels5 N6 p( W" @0 y: Y3 u- i% N8 f# ^
developed after gonadotropin therapy (96 ng./dl.). Higher
5 d1 F! Q; F7 u j; cserum levels were noted in older patients (12 and 17 years old),; m) K4 E2 P! n, v7 }* u
while lower levels persisted in younger patients (4, 8, and 107 `9 \9 V- T! t( u9 _ ~
years old) (see table). Despite absence of profound alterations
+ [5 x: j5 }" L: l& B ^; ?of serum testosterone the topical therapy provided a greater
. K" _% i+ u9 C; GAccepted for publication July 1, 1977. ·
4 g" D/ r, ^, O4 t. W9 v% N9 bRead at annual meeting of American Urological Association,: z i& A" Y. B8 J5 B
Chicago, Illinois, April 24-28, 1977.
: F' _2 [' R. S- D! ]* Requests for reprints: Division of Urology, Henry Ford Hospital,8 |9 I; Q* ^0 ?2 [: U+ t6 H
2799 W. Grand Blvd., Detroit, Michigan 48202.
' \7 `- P: Z& b3 Pimprovement in phallic growth compared to gonadotropin.9 Z# D5 N$ [# b9 ?
Average phallic growth with gonadotropin was 14.3 per cent
7 R J5 b- |* Y ~2 V* Lincrease in length and 5.0 per cent increase of girth. Topical4 y, Z2 _% ^1 R8 B" V2 A& H
testosterone produced a 60.0 per cent increase of phallic length6 \+ @' ?" T/ E! h# X K$ c9 B& [
and 52.9 per cent increase of girth (circumference). The
# f2 k8 i$ O5 t# B( ?5 n" \response to topical testosterone was greatest in children be-
* K8 F# I& H- w& e9 N+ }# ftween 4 and 8 years old, with a gradual decrease to age 17: B; I+ f% K! M: O& o+ v& t) ~2 y
years (see table). J4 O) J1 L( N! H, D6 h
DISCUSSION% M) n$ \3 I/ C& A% A! E8 [
Topical testosterone has been used effectively by other
$ N5 K5 t! t' r) m: j! Q6 K+ eclinicians but its mode of action remains controversial. Im-5 H$ g+ a6 U6 N# g, s1 C5 G3 I5 n
mergut and associates reported an excellent growth response
% r' W* X; T2 F9 A7 [to topical testosterone with low levels of serum testosterone,& j- ~6 V+ \; V5 `. O) N
suggesting a local effect.1 Others have obtained growth re-' v0 s! n" A7 I- ?
sponse with high. levels of serum testosterone after topical
* q! X$ z8 r1 p+ w4 k2 X M- L% qadministration, suggesting a systemic response. 3 The use of. M, x; s7 c5 ]$ r q4 q( e( v
gonadotropin to obtain levels of serum testosterone compara-
) p* f9 ^9 m+ x# Lble to levels obtained with topical testosterone would seem to4 M1 N' A4 [1 u# Y) G# [
provide a means to compare the relative effectiveness of1 e" s8 e- [- n, v
topical testosterone to systemic testosterone effect. It cer-( H) |; A2 a* l1 d
tainly has been established that gonadotropin as well as par-* ~2 F, z$ @% `4 C" n
enteral testosterone administration will produce genital. I8 Y* e. j" B4 \& Z- W! V0 z# |
growth. Our report shows that the growth of the phallus was
8 w% G7 b6 h* K4 Msignificantly greater with topical applications than with go-
! R5 ` a0 H Jnadotropin, particularly in children less than 10 years old.
, E2 W2 @' @. Y& `The levels of serum testosterone remained similar or lower8 D8 y( |( h; v- \- ]5 y: l
than with gonadotropin during therapy, suggesting that topi-
. e$ L, p& a2 ~6 Hcal application produces genital growth by its local effect as
- {- z* @! r p: wwell as its systemic effect.
+ _& H4 o! D2 WReview of our patients and their growth response related to
2 T! z2 v& Y9 B% x% Lage shows a greater growth response at an earlier age. This is
& d4 V" ^- l" u; \9 nconsistent with the findings of Wilson and Walker, who
( [- [: I! d* ~5 [; e% Rreported an increased conversion of testosterone to dihydrotes-2 k% v5 w3 B( y+ \! j2 e1 _% p+ n
tosterone in the foreskin of neonates and infants.4 This activ-
( b. n# a5 ] ^/ uity gradually decreases with age until puberty when it ap-' E0 Y0 f$ o- E9 D6 E4 o
proaches the same level of activity as peripheral skin. It may
# @( H" J5 H. nwell be that absorption of testosterone is less when applied at. e i; Q. S6 C- e
an earlier age as suggested by lower serum levels in children
7 O& P$ C j- k$ X% G5 bless than 10 years old. This fact may be explained by the: P& G* j Y' u- X5 f5 L0 y; u
greater ability of phallic skin to convert testosterone to dihy-
+ q, v/ W6 w8 c8 f1 t/ H& |! |drotestosterone at this age. Conversely, serum levels in older
6 s2 G. }2 G7 F2 r/ _2 Gpatients were higher, possibly because of decreased local
3 u. R4 U1 i0 G! g# _6 c667
+ K! b* Q3 u4 F0 u( T& y* T668 KLUGO AND CERNY5 N j6 ?8 \, x, S9 Z5 g: a
Pt. Age8 b) j9 W Q z4 x6 p+ {
(yrs.). c* ^0 C/ \0 Q3 ]7 `6 Y" `
Serum Testosterone Phallus (cm.) Change Length
" m5 |# [- ?% L5 v' l; K' z(ng./dl.) Girth x Length (%)
4 i7 J0 z- q" T' X0 |41 n0 U5 Y1 O* Z, S1 R/ b: f N: h
8
( V/ e* z# i; L/ ^! p104 P0 ^+ G1 b' e5 Q
12
/ ?% w3 N5 a8 W) G Y) t17/ V; R& l8 g% w% y" g/ J
Gonadotropin
; M6 k6 }3 w- L4 }/ R7 R71.6 2.0 X 3 16.6% C m6 I4 K5 k' N: s L1 r
50.4 4.0 X 5.0 20.0. |+ N1 ?! K' f7 ^
22.0 4.5 X 4.0 25.0, _. C' [. ]; l3 f4 h5 A
84.6 4.0 X 4.5 11.1
- A& f8 Y# f' H: x# M7 P0 |85.9 4.5 X 5.5 9.0; R: G3 H# z8 t* E$ A2 }, v% m
Av. 14.3
1 E0 k9 n! a7 ]( x- _4 ]4- Q, F2 ]( k p6 ]& F. I
88 J. D5 B) n; J/ J @4 g+ l5 l
108 X/ V" r9 v: v5 F+ `
12% l; \9 u& C0 ~ T
17& o8 z: [7 w( t" f7 \$ f
Topical testosterone/ D1 U, z' p( b
34.6 4.5 X 6.5 851 {4 L' ~8 o0 R% e9 ^; o
38.8 6.0 X 8.5 70
. b9 M$ |# Z+ k: |2 i* o40.0 6.0 X 6.5 62.5% b0 w4 v; L) i
93.6 6.0 X 7.0 55.57 d( A) o( s2 B9 E$ j: R1 a3 T
95.0 6.5 X 7.0 27.2
2 e; J" Y) s4 uAv. 60.0% i# g. ?' F3 O) X+ U
available testosterone. Again, emphasis should be placed on0 l* m4 I% q/ w% y! O
early therapy when lower levels of testosterone appear to
* g% m0 X( R+ G0 R1 {! ^% Q u9 [provide the best responses. The earlier therapy is instituted- C/ Z* ^6 _# M0 g5 l9 I
the more likely there will be an excellent response with low
( a: d* K8 f# r- D; Iserum levels. Response occurs throughout adolescence as
: Z/ \/ V* |( nnoted in nomograms of phallic growth. 7 The actual response8 z A" T7 Z& M8 f! o
to a given serum level of testosterone is much greater at birth
0 B" B, I6 ^( K8 uand gradually decreases as boys reach puberty. This is most
0 z& l8 u. N$ i5 flikely related to the conversion of testosterone to dihydrotes-6 g% F% O5 E# j0 Y, {0 B) X: W
tosterone and correlates well with the studies of testosterone
" s* i6 }. \, ]% ~conversion in foreskin at various ages.7 z/ m. Y9 I( A' z
The question arises regarding early treatment as to whether- e0 Q2 U) k; T! N. y4 S
one might sacrifice ultimate potential growth as with acceler-' X3 P! w' x8 N5 m) ^; Q
ated bone growth. The situation appears quite the reverse- i) E' `' g! t+ I! {( \9 J$ k1 c* n
with phallic response. If the early growth period is not used' q( m4 ]2 J1 E
when 5a reductase activity is greatest then potential growth
. B7 C3 L( d! l. Umay be lost. We have not observed any regression of growth
0 h- _ P" t) V1 G1 dattained with topical or gonadotropin therapy. It may well
2 G' F- q8 ^7 T) Vbe that some patients will show little or no response to any" n) s+ g* x% w7 g, T3 |; T
form of therapy. This would suggest a defect in the ability to) H) i9 ~# n3 I, X4 U% v2 O) Y
convert testosterone to dihydrotestosterone and indicate that
' f3 ~& a1 C! V% o' Lphallic and peripheral skin, and subcutaneous tissue should) [1 Y9 v8 r$ P: C+ u2 @
be compared for 5a reductase activity.
1 D. S! ^! G/ H- s# u( CA, loop enlarges to measure penile girth in millimeters. B,
, f" Z3 X) F1 cexample of penile girth computed easily and accurately.5 E9 }1 `+ V0 ^ D, B, p0 ^
conversion of testosterone to dihydrotestosterone. It is in this
9 g: |5 F- W; Y: Wolder group that others have noted high levels of serum
. ^; L) G* z2 t' e2 Ttestosterone with topical application. It would also appear
" S3 _! M1 a+ y! z p* B6 Pthat phallic response during puberty is related directly to the. s9 T$ ?* L0 ~+ x8 Z3 |; S, o! E# u
serum testosterone level. There also is other evidence of local
" S' }' b& j8 f0 ~5 }response to testosterone with hair growth and with spermato-4 Y O! w0 }5 J# D+ v$ k: [
genesis. 5• 69 V9 C) e$ f) p! }
Administration of larger doses of gonadotropin or systemic
& L: ]/ J7 U+ D1 N6 q5 ytestosterone, as well as topical applications that produce
2 @& q8 n+ \" c- e' V: o" ihigher levels of serum testosterone (150 to 900 ng./dl.), will
; g& G4 i4 d/ L2 K5 q' X' w/ {also produce phallic growth but risks accelerated skeletal8 a1 h3 w6 C" ^ @: M! M
maturation even after stopping treatment. It would appear2 |8 F9 e5 f A3 {- p
that this may be avoided by topical applications of testosterone3 U/ I0 ]4 c! ?" @
and monitoring of serum testosterone. Even with this control6 h+ Y0 T, {6 T7 Y9 ?8 X5 p! f; ]
the duration of our therapy did not exceed 3 weeks at any
3 V$ ^; H$ c. s ptime. It is apparent that the prepuberal male subject may6 r' n$ ^" _) n3 n/ V3 s$ k) ^) J
suffer accelerated bone growth with testosterone levels near
/ J5 L) e" `2 d2 `: S" W% s200 ng./dl. When skeletal maturation is complete the level of
, N7 I8 @6 d/ a3 qserum testosterone can be maintained in the 700 to 1,300 ng./( L! {; m; y! [' |
dl. range to stimulate phallic growth and secondary sexual
' s8 N ]# ^2 a8 z: G1 ?changes. Therefore, after skeletal maturation parenteral tes-
, B q3 E, \, Y, t; Stosterone may be used to advantage. Before skeletal matura-) \: A% ?% |5 x/ \+ K |. C- l9 f4 T
tion care must be taken to avoid maintaining levels of serum
0 Z0 i- f9 z' w9 gtestosterone more than 100 ng./dl. Low-dose gonadotropin2 ~* T4 L# c1 p: ^
depends upon intrinsic testicular activity and may require
* Z( r( q" N3 h/ A- S. P! `prolonged administration for any response.' f( A1 _0 K w
Alternately, topical testosterone does not depend upon tes-! S6 _1 v0 P' Y- e! ]/ L
ticular function and may provide a more constant level of
( H; T4 O8 l5 k4 f, d% ]# BREFERENCES1 w+ I8 W/ r2 q4 J
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
. L5 r9 [: H+ zR.: The local application of testosterone cream to the prepub-3 |3 [7 [! H/ R5 ^
ertal phallus. J. Urol., 105: 905, 1971.$ J4 x5 t2 Q3 C! S6 [
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
- D- E N2 G. q4 @treatment for micropenis during early childhood. J. Pediat.,
; i: c6 k. Q5 k j! y83: 247, 1973.) B9 {7 O( n; y4 e5 W, j' b5 o
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; |- y1 x% d8 X9 g8 l9 U6 Z/ n
one therapy for penile growth. Urology, 6: 708, 1975.
+ o$ Y y1 c! E' M4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& @! ]) K8 P5 R% P) q
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% x0 r# K, S, O0 P# L
skin slices of man. J. Clin. Invest., 48: 371, 1969.( M8 @# ?5 d1 I: N
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) U! o; d% ^7 {4 F0 s hby topical application of androgens. J.A.M.A., 191: 521, 1965.
- k o9 j4 I2 u# `6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& L5 C/ v. S$ M6 X! g) g
androgenic effect of interstitial cell tumor of the testis. J.
" G6 i5 X& X) U4 }. AUrol., 104: 774, 1970.
$ F1 Y5 h% L9 ?9 r7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ g; P0 a% J7 Ition in the male genitalia from birth to maturity. J. Urol., 48: |
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