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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" h) f- I/ ?8 P7 U) U
GONADOTROPIN* f, \6 G/ Q' h* r$ P3 Y- T
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 R: r* \7 X* `2 ~
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 o& @' i8 X2 S! bABSTRACT6 H9 l _8 D" ]/ V: ^
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
' ^* E) m4 _: A: @with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 `( ]" Q5 j* S& R2 S
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 U$ Z0 Z/ y( o- G: m
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, H$ P) u% h$ i1 ~0 b+ ^& q" \
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" f: e6 I) n: c
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
1 d2 A2 g8 M) H$ b" f9 l, Yincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response' w S0 d- c7 Q9 P1 e
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
$ ]) v5 `7 b$ z4 o3 A! P& j7 I0 x/ Sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile5 z, f4 U" Q' ?, P% i
growth. The response appears to be greater in younger children, which is consistent with previ-4 Z# m% ^1 m, _1 t- w( p0 A
ously published studies of age-related 5 reductase activity.
- e5 K& h1 W. n7 P/ h9 Q7 cChildren with microphallus regardless of its etiology will
; K7 b% \! F3 u* D" Yrequire augmentation or consideration for alteration of exter-
( R& S6 L0 ~2 J g0 onal genitalia. In many instances urethroplasty for hypo-. N' p. H! k. D8 C- n, q
spadias is easier with previous stimulation of phallic growth.
! d3 @* C4 d) m7 o) f8 L+ O7 M5 Q3 V/ iThe use of testosterone administered parenterally or topically
3 w3 C/ [" ~0 \0 Ehas produced effective phallic growth. 1- 3 The mechanism of
9 h; T. p+ O" M/ ^' A" lresponse has been considered as local or systemic. With this
M$ u. _# r9 @- x8 j6 Jin mind we studied 5 children with microphallus for response0 {9 N2 D6 V( t7 |
to gonadotropin and to topical testosterone independently.
! J6 k+ K# F, Z1 t7 p0 V# g, dMATERIALS AND METHODS
$ U/ i) }1 y. g2 m4 |6 UFive 46 XY male subjects between 3 and 17 years old were
# I5 f5 r) T. k+ [( t( s% mevaluated for serum testosterone levels and hypothalamic
( L& O' T; A) p8 Gfunction. Of these 5 boys 2 were considered to have Kallmann's
- ?! f9 I& x0 ]9 ~% ~* rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( k$ k- M& i& j R6 Slamic deficiency. After evaluation of response to luteinizing
) Y7 w4 ^$ B1 `3 X9 p$ D2 c' D9 Jhormone-releasing hormone these patients were treated with
e! ~7 J& W% K$ n: X4 w& i1,000 units of gonadotropin weekly for 3 weeks. Six weeks
) K6 I' T0 ]7 xafter completion of gonadotropin therapy 10 per cent topical/ `4 Q& I6 a6 }& U- D
testosterone was applied to the phallus twice daily for 3 weeks.
; p9 k K/ q3 y& ~& H! {$ `8 |Serum testosterone, luteinizing hormone and follicle-stimulat-6 _6 H- K$ h4 C! F1 X2 ^
ing hormone were monitored before, during and after comple-
- a" z) { F! m% t5 [* Ption of each phase of therapy. Penile stretch length was
. [$ ?; [% I( bobtained by measuring from the symphysis pubis to the tip of6 A" w7 q" y+ W6 U* e+ t% R: o1 o
the glans. Penile circumferential (girth) measurements were G# C3 Y! {8 ^& A6 n1 }9 U
obtained using an orthopedic digital measuring device (see8 `' m- h- C" i$ w
figure).' X( M$ J7 @: N) c8 Z+ H7 V
RESULTS
) @& `" R7 {) gSerum testosterone increased moderately to levels between4 w4 D1 e$ B2 }) ^( _9 Y& T! }
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-# L9 S- B8 \ [7 Z
terone levels with topical testosterone remained near pre-
, W3 Q9 Y0 X% ^9 S* ]treatment levels (35 ng./dl.) or were elevated to similar levels! s% d; j& b% `8 g# z: l
developed after gonadotropin therapy (96 ng./dl.). Higher. t, J/ g4 ?" y
serum levels were noted in older patients (12 and 17 years old),' P& A$ n+ g4 g" Q4 {6 k
while lower levels persisted in younger patients (4, 8, and 10
. V: d2 ^8 [+ i, Ayears old) (see table). Despite absence of profound alterations1 J* E. M2 a/ v" C
of serum testosterone the topical therapy provided a greater
7 W7 e* a0 G4 _" OAccepted for publication July 1, 1977. ·- b/ g. f8 ^; z$ R! k. v, p
Read at annual meeting of American Urological Association,- N# t' j- h) i/ }. x
Chicago, Illinois, April 24-28, 1977.$ z- u$ l3 T: R, _6 U- d; E! W
* Requests for reprints: Division of Urology, Henry Ford Hospital,0 H$ O) x) H7 v
2799 W. Grand Blvd., Detroit, Michigan 48202." `' R6 u- p ]) L' W9 Y
improvement in phallic growth compared to gonadotropin.; B" F" X$ ~* j) M4 ~9 w4 C2 ?; M
Average phallic growth with gonadotropin was 14.3 per cent8 s; ^: o; U5 @) U& m
increase in length and 5.0 per cent increase of girth. Topical! _/ U! {7 h. e7 O
testosterone produced a 60.0 per cent increase of phallic length& r* ~; w9 n" _* h
and 52.9 per cent increase of girth (circumference). The* P0 k% v( h* n$ Z; ?: \8 \$ p
response to topical testosterone was greatest in children be-
* u) }; B/ v. Otween 4 and 8 years old, with a gradual decrease to age 17
7 F9 @: S" h; ?' g% w# \years (see table).' q K+ }" N* y+ F9 y
DISCUSSION1 d, B6 D9 y. m* D4 R
Topical testosterone has been used effectively by other
# F+ y. f+ j3 ?7 ~clinicians but its mode of action remains controversial. Im-
( U( R% m) `8 vmergut and associates reported an excellent growth response5 X- E9 v+ D+ \9 @: b$ O# {
to topical testosterone with low levels of serum testosterone,$ Z+ V+ C! y( V1 `5 s
suggesting a local effect.1 Others have obtained growth re-. p9 c0 A0 R: f+ F
sponse with high. levels of serum testosterone after topical
& z0 J1 I1 F4 n! Y& i$ x7 ^' vadministration, suggesting a systemic response. 3 The use of
5 W2 b- }- a1 Sgonadotropin to obtain levels of serum testosterone compara-4 y) t5 l/ P$ L) o% `# ]
ble to levels obtained with topical testosterone would seem to/ n( x2 c% _$ O, s2 I& y
provide a means to compare the relative effectiveness of
: v7 v; U) ]) ?$ I( @- p3 P8 p* Utopical testosterone to systemic testosterone effect. It cer-; Y% E, I d) c+ U" X
tainly has been established that gonadotropin as well as par-
. l% R! ~ w) K9 r4 ^9 C/ Centeral testosterone administration will produce genital
$ j( h: c9 H# igrowth. Our report shows that the growth of the phallus was$ p0 w6 A8 q% V8 I
significantly greater with topical applications than with go-( r8 {% a# V0 p2 l
nadotropin, particularly in children less than 10 years old.# Z. C+ M0 {. S/ L# h3 Q& p
The levels of serum testosterone remained similar or lower( C$ D x- ]7 Z! I! ]
than with gonadotropin during therapy, suggesting that topi-
& N. Y& ^0 ?/ f6 xcal application produces genital growth by its local effect as
3 Z2 x7 x3 g6 {$ Iwell as its systemic effect.
" g3 ]* O! A% jReview of our patients and their growth response related to
% p5 @, X$ b6 c3 a$ w6 [. g. {5 L: Sage shows a greater growth response at an earlier age. This is
! ^. e" Y& D# W4 i) [/ P* t2 Mconsistent with the findings of Wilson and Walker, who J* L# W9 c+ c* }/ a
reported an increased conversion of testosterone to dihydrotes-
6 c: F% @- Z8 u9 K. Ptosterone in the foreskin of neonates and infants.4 This activ-
% q* o% C; r- B( Z9 e. m1 Vity gradually decreases with age until puberty when it ap-7 E5 Z' Y$ |$ c7 r# J. X
proaches the same level of activity as peripheral skin. It may
: E& b+ S- f; z* H+ o" F& xwell be that absorption of testosterone is less when applied at, i* G7 ], v( N4 r1 t
an earlier age as suggested by lower serum levels in children# u, P5 v9 @# Y$ h( C0 l
less than 10 years old. This fact may be explained by the) j- d& K5 C- @0 D2 L0 n) E
greater ability of phallic skin to convert testosterone to dihy-
" A* |" K1 E+ y6 ] Q9 w; u/ Qdrotestosterone at this age. Conversely, serum levels in older
' m- @0 O' t/ L* _ C- _6 Opatients were higher, possibly because of decreased local
8 D9 S# E7 c) E* t) |667
/ Z/ G) X, Y4 W5 s# b7 i, h8 s2 c( G668 KLUGO AND CERNY
! ^# g- u h1 Q2 W: K" v1 APt. Age
% i6 d: B! |. V) X4 F% L7 W; t/ l(yrs.)# {: |: I* D$ G
Serum Testosterone Phallus (cm.) Change Length
+ r3 @& G+ K H8 k" D(ng./dl.) Girth x Length (%)
7 i( ^/ K d, ]) n5 ?1 E5 M+ ~40 `# w! n4 ?( `! [3 q5 _6 {( f
8
; K8 D2 F, U$ {/ E- R& b! i10
. s- W) d+ i5 M) W! [, v127 v6 r* T7 v% p$ G. W
17
7 i i) X8 Z, b- ]Gonadotropin, B1 h* J. B! Y; \( h) R$ i
71.6 2.0 X 3 16.6
J, a8 h, n! G2 G2 l50.4 4.0 X 5.0 20.0
+ c* r" e2 J( o( Q/ A. O( _22.0 4.5 X 4.0 25.0, [3 ?1 N! B t4 Z& A
84.6 4.0 X 4.5 11.1$ [6 U+ [$ s" U6 @9 B) q
85.9 4.5 X 5.5 9.0
. ~9 d# x+ E# {, _+ L7 hAv. 14.3) x( \( A) e# I5 v" j
4* d) p& }$ s* y/ W, S6 ?, R; B
8( ~! \2 a% h4 j4 _
10
( f- ~' @! S. T6 |12
' \" G, _; y/ u, e2 ~3 J172 q S: N; E: B* W4 }! W# |
Topical testosterone
8 {; |. t d3 q- w34.6 4.5 X 6.5 85
/ ~) O9 P5 o; ]) ~. W o5 x' f9 e38.8 6.0 X 8.5 70& v9 d6 }0 U3 D9 ?: b% o$ i
40.0 6.0 X 6.5 62.59 r* w% s* C2 e7 k( j; G
93.6 6.0 X 7.0 55.5
& y y$ C8 ]0 ^+ z$ W8 ~0 a) k! i95.0 6.5 X 7.0 27.22 s+ G5 B0 G/ a0 U* y& J
Av. 60.05 ^2 F' r3 t/ x* h- J0 g
available testosterone. Again, emphasis should be placed on. i' f! @( i" p6 y
early therapy when lower levels of testosterone appear to
/ Z; ]' o& k" z# ^provide the best responses. The earlier therapy is instituted; }5 S; y' R, c
the more likely there will be an excellent response with low$ Z2 Q. [4 Z H& N3 v3 _3 Z
serum levels. Response occurs throughout adolescence as
0 h$ [! i6 |7 b Onoted in nomograms of phallic growth. 7 The actual response
- R$ |7 e- ?8 R5 Vto a given serum level of testosterone is much greater at birth9 r2 h* Q& [8 V T2 [1 O
and gradually decreases as boys reach puberty. This is most
# ^/ c7 h+ ]9 M; F% Clikely related to the conversion of testosterone to dihydrotes-
; U6 M8 N) ^9 o. _' j( A& k ytosterone and correlates well with the studies of testosterone9 Z) F9 {& g/ K4 j( A: E
conversion in foreskin at various ages.
1 }: O6 p( i7 L- XThe question arises regarding early treatment as to whether4 A2 ~0 K7 e6 f B
one might sacrifice ultimate potential growth as with acceler-
2 `8 _: M8 @* }, G3 ^ated bone growth. The situation appears quite the reverse! A' g; I8 k, `6 M) z& L- t
with phallic response. If the early growth period is not used
. M) b% Y9 A, ^8 ?; [5 x) Zwhen 5a reductase activity is greatest then potential growth
n8 C! D7 B. ]9 E" b0 nmay be lost. We have not observed any regression of growth
( P: e, B! ?7 h- J. iattained with topical or gonadotropin therapy. It may well
! e) v0 J. M, \ W3 [be that some patients will show little or no response to any% e+ f, v% C! E+ Q
form of therapy. This would suggest a defect in the ability to3 |, M6 \. v4 z7 y& r. f
convert testosterone to dihydrotestosterone and indicate that
9 p! S) m+ q x0 nphallic and peripheral skin, and subcutaneous tissue should
6 M7 H3 K0 \& J1 dbe compared for 5a reductase activity.$ ~5 P$ |& \2 r! l# P
A, loop enlarges to measure penile girth in millimeters. B,
4 {9 O. i e' F0 X* |example of penile girth computed easily and accurately.
" F$ t3 g# J9 H2 Yconversion of testosterone to dihydrotestosterone. It is in this; Y1 m) i! n! m% i6 L6 k
older group that others have noted high levels of serum) `* I0 D: w, e/ _/ m1 t
testosterone with topical application. It would also appear
, u4 u/ q5 i6 R6 k6 L. c7 R tthat phallic response during puberty is related directly to the
% K6 w. L8 Q: P t( `serum testosterone level. There also is other evidence of local' S7 u ^/ Q! r
response to testosterone with hair growth and with spermato-
, Q: Y( r6 v3 E/ ?3 ]! M$ jgenesis. 5• 6
/ [1 y; f0 H. H z/ X5 {7 ^1 Q. }Administration of larger doses of gonadotropin or systemic: {1 \! p& V6 L0 Z* D" Y
testosterone, as well as topical applications that produce
a, l6 B9 A3 W! `+ q+ Q; yhigher levels of serum testosterone (150 to 900 ng./dl.), will% g, g8 F: C8 [: a% p1 t$ J
also produce phallic growth but risks accelerated skeletal
, v4 f l9 G# e5 hmaturation even after stopping treatment. It would appear
5 K3 l7 w: r5 v g& G6 i) qthat this may be avoided by topical applications of testosterone' J/ \$ i* [, Y% N/ m
and monitoring of serum testosterone. Even with this control+ k9 u0 d9 n0 W0 ^
the duration of our therapy did not exceed 3 weeks at any1 ]$ S" h* L: `4 X: @) T8 `6 f- i
time. It is apparent that the prepuberal male subject may
& k% s0 f& b4 x1 [# G' f; Csuffer accelerated bone growth with testosterone levels near
7 o* `9 x e, k# Q5 r E+ h1 ~200 ng./dl. When skeletal maturation is complete the level of6 v0 C& W1 z/ O" k# m q
serum testosterone can be maintained in the 700 to 1,300 ng./. N0 B2 ]- P6 }+ ^. a* q' z4 I
dl. range to stimulate phallic growth and secondary sexual
4 P8 i/ c1 K, O. Uchanges. Therefore, after skeletal maturation parenteral tes-
$ E, A0 P& J% c- c, {/ Ntosterone may be used to advantage. Before skeletal matura-
. e3 m( Z; V' K% {# dtion care must be taken to avoid maintaining levels of serum
0 x. K# \# D1 c9 l l" Itestosterone more than 100 ng./dl. Low-dose gonadotropin2 A1 D" R% E# _1 e
depends upon intrinsic testicular activity and may require0 c" A8 |7 F+ I: ]2 [8 e
prolonged administration for any response.+ H( d; Y0 e, o7 K" J
Alternately, topical testosterone does not depend upon tes-& `2 M" b8 G. o" M& d: z
ticular function and may provide a more constant level of8 w: R& Y; O1 ^& B4 ]' g
REFERENCES: _( Q O2 `& U2 F( B8 W% g5 J' [
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
& {! `0 }! {" |* {# V6 YR.: The local application of testosterone cream to the prepub-& y C* @* W0 r, @- ^: R) s2 Z
ertal phallus. J. Urol., 105: 905, 1971./ j/ I$ w- h, g3 v- J9 k
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. S" |8 C J: E5 k+ |* [4 P# q8 v
treatment for micropenis during early childhood. J. Pediat.,
- G" `) U! C( y4 ?83: 247, 1973.
, |. h6 E, ?/ v) @. `6 L3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' `2 {1 R% v) ^
one therapy for penile growth. Urology, 6: 708, 1975. y- S% e& |' c6 a
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) l8 _2 `9 Z& Zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by9 c; B/ R7 }! d- e' L4 q% a# a
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 a1 i Z9 f4 g- G
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 B; u7 z" L2 O* W3 l. ?
by topical application of androgens. J.A.M.A., 191: 521, 1965.
; u! |( J3 u& g6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
' }3 C7 B! R p0 R0 l; wandrogenic effect of interstitial cell tumor of the testis. J.
9 x. U9 m5 e5 R# RUrol., 104: 774, 1970.8 U2 k+ s; w0 N: N! y6 ^
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 E) ]" k6 m J U d
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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