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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND1 C. q7 e/ t! D/ `; `+ T- r
GONADOTROPIN
# Y( d6 f6 o- Q" hRICHARD C. KLUGO* AND JOSEPH C. CERNY. a) J) O& {& \4 c5 a6 @& T
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan* ^/ m' c- @: t+ d8 Z4 W
ABSTRACT
, S. [- |# v2 ~) }2 ]Five patients were treated with gonadotropin and topical testosterone for micropenis associated
/ @% ^- `% {% C) xwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 x/ c* o0 @9 J$ i& i0 K
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: R1 W r* v' F! ?) fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent7 w. h' B0 ?/ E
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 l0 u- N7 y* ?, x9 k7 k" Y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average, k2 H% t1 T' ]' s2 Z. t8 f
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response2 \% u$ C8 U0 a6 W7 S
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 m+ ^1 T. h& Q; ]( U: p
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% [5 Y& \! @# u2 t' A+ L: U6 wgrowth. The response appears to be greater in younger children, which is consistent with previ-
/ p# A: b" W) o4 [& {: Eously published studies of age-related 5 reductase activity.6 E. X* z) |8 J- i6 P
Children with microphallus regardless of its etiology will, _; v! e- w+ }8 @+ } o
require augmentation or consideration for alteration of exter-! e U& ?# i1 Y+ {5 @2 t
nal genitalia. In many instances urethroplasty for hypo-- n4 t* Q3 c7 J" d6 _& ~: M, T# y# F5 q! \
spadias is easier with previous stimulation of phallic growth.' h% U0 k+ T/ i5 Y( X
The use of testosterone administered parenterally or topically* Y f! w' e! y6 x
has produced effective phallic growth. 1- 3 The mechanism of9 V ?5 `( e& f/ ~1 y# X
response has been considered as local or systemic. With this
- a, A+ R8 q/ c0 zin mind we studied 5 children with microphallus for response
: }' y2 e/ q5 T8 P; H- {5 Ato gonadotropin and to topical testosterone independently.
7 C, |# K4 f5 c+ XMATERIALS AND METHODS
0 d7 a; l* D3 f3 ?* ~# t3 ]Five 46 XY male subjects between 3 and 17 years old were- Z& [! s* k0 B) r) ~( ~
evaluated for serum testosterone levels and hypothalamic% ?! C1 I) H Q3 o$ H
function. Of these 5 boys 2 were considered to have Kallmann's9 z- q: v# h( Y+ o+ u
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" K: j7 Z I4 i6 J& n4 e3 r9 E* K3 |
lamic deficiency. After evaluation of response to luteinizing0 _) N `" U( l) A8 ^! N$ P6 a+ u3 j
hormone-releasing hormone these patients were treated with( _3 w, @1 ^9 \; w$ ~5 Z9 D
1,000 units of gonadotropin weekly for 3 weeks. Six weeks; \8 v: u; V& R9 |/ n) t
after completion of gonadotropin therapy 10 per cent topical" a( i$ D" y$ [# z% G) Z& L' h5 b
testosterone was applied to the phallus twice daily for 3 weeks.7 L. g9 d% f; u' w" c
Serum testosterone, luteinizing hormone and follicle-stimulat-. u( {% a+ a3 |/ P3 s
ing hormone were monitored before, during and after comple-# C8 J: z1 e% z- V
tion of each phase of therapy. Penile stretch length was
+ z/ p0 O* Q3 c# C" f" R& nobtained by measuring from the symphysis pubis to the tip of7 a. u, b; k6 c. K& O
the glans. Penile circumferential (girth) measurements were
/ d2 H( q6 Q N, u0 ~* wobtained using an orthopedic digital measuring device (see
& H" N k* q0 Qfigure).& h9 H" L# o4 A) A+ G% q# v$ L
RESULTS
7 j5 g- F/ |. y ~+ n9 QSerum testosterone increased moderately to levels between
0 A9 R, c" h+ B! w: S50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-# ~3 I) U$ H9 C" P+ n
terone levels with topical testosterone remained near pre-
! h( h7 }0 n2 g k! ?$ Y- y5 \treatment levels (35 ng./dl.) or were elevated to similar levels
" W; v* ~$ T" e6 ddeveloped after gonadotropin therapy (96 ng./dl.). Higher8 d- x- J6 b% \- D1 b, o" u
serum levels were noted in older patients (12 and 17 years old),$ n, u' j" h" U e- O
while lower levels persisted in younger patients (4, 8, and 10
! Z$ E. p9 a% a% r9 Ryears old) (see table). Despite absence of profound alterations. E0 w* u# ^, f$ y$ D
of serum testosterone the topical therapy provided a greater
% z/ `! ~* q( T, S7 ^) R2 _, P, |Accepted for publication July 1, 1977. ·8 {" c/ v. ?: y T& x$ ~, m
Read at annual meeting of American Urological Association,! Q+ P& f$ m K6 S
Chicago, Illinois, April 24-28, 1977.0 E" c' O/ ^ }/ u) w) v% ~4 Z* D
* Requests for reprints: Division of Urology, Henry Ford Hospital,' G8 p/ B! Z# e, |
2799 W. Grand Blvd., Detroit, Michigan 48202.
9 V8 w v+ Q2 b/ wimprovement in phallic growth compared to gonadotropin.
# {; S0 ] y0 v' P. r! lAverage phallic growth with gonadotropin was 14.3 per cent' Z! g1 p% M5 A& o3 X& u* U `
increase in length and 5.0 per cent increase of girth. Topical
" |- z( y% t6 C7 gtestosterone produced a 60.0 per cent increase of phallic length
" D0 M/ g7 l4 }+ ]& W% ?8 Band 52.9 per cent increase of girth (circumference). The: N1 N! M0 W. l0 m& s g. J# L1 N
response to topical testosterone was greatest in children be-
! S+ q. b3 d: V) g; Itween 4 and 8 years old, with a gradual decrease to age 17
0 ~) v* x) e+ I% h4 w% E8 D0 Dyears (see table).
7 B [- E9 }1 |1 h, ~& B. YDISCUSSION
% T! {% k# T# z/ ~, z( i- W+ fTopical testosterone has been used effectively by other9 ^8 [$ L) }2 F# V9 j
clinicians but its mode of action remains controversial. Im-
. Y2 W$ d+ g. i5 V9 Vmergut and associates reported an excellent growth response( Z: m( b8 H" E8 H& O' \# d" {. Y' E
to topical testosterone with low levels of serum testosterone,
" _: W; s! Z, b" [suggesting a local effect.1 Others have obtained growth re-
% L# v) E9 x+ A3 M9 \+ Msponse with high. levels of serum testosterone after topical& S8 h* y! M9 N! ]6 Y3 B! v
administration, suggesting a systemic response. 3 The use of
5 h8 N; [* R" `& pgonadotropin to obtain levels of serum testosterone compara-
, z) w" p& c. ^; B+ W4 W5 eble to levels obtained with topical testosterone would seem to, n! s5 W A$ s9 u$ O5 p$ @
provide a means to compare the relative effectiveness of
6 ?1 M8 s8 g2 b# M; D# htopical testosterone to systemic testosterone effect. It cer-
: W7 o3 C8 q0 L3 c3 qtainly has been established that gonadotropin as well as par-% d5 f4 S5 e; w3 p, [5 m f, q
enteral testosterone administration will produce genital \% q* X! [$ Y, [/ g
growth. Our report shows that the growth of the phallus was& A6 e4 t) Y- Z% J) a( v
significantly greater with topical applications than with go-
# E: L3 s7 J7 n! [- \$ Mnadotropin, particularly in children less than 10 years old. |+ d2 \# R4 y0 \- N
The levels of serum testosterone remained similar or lower! V5 ?1 G# Z0 e
than with gonadotropin during therapy, suggesting that topi-2 i- i6 g0 l$ X0 c: W, Q
cal application produces genital growth by its local effect as- ]/ o: [! S7 u$ h
well as its systemic effect.0 E8 H7 f# `! c% `" E$ @
Review of our patients and their growth response related to
5 t& _! x. w9 H# O) h& E mage shows a greater growth response at an earlier age. This is
5 G9 @& \( g/ Jconsistent with the findings of Wilson and Walker, who% r; C; i2 ?8 U" i( F, M
reported an increased conversion of testosterone to dihydrotes-" e3 O" B) B7 F' z# W
tosterone in the foreskin of neonates and infants.4 This activ-
# t+ p; y B4 C6 w# R4 z0 Tity gradually decreases with age until puberty when it ap-- l( a" ~( l1 m
proaches the same level of activity as peripheral skin. It may
6 v6 V; F( w5 Wwell be that absorption of testosterone is less when applied at- a* e2 e. z% M9 A0 ^3 }: L
an earlier age as suggested by lower serum levels in children- i* J# Y& ?8 D" d: _1 B+ R. P
less than 10 years old. This fact may be explained by the" Q4 B; t- Y! M
greater ability of phallic skin to convert testosterone to dihy-
6 D4 m- p4 {% J0 Zdrotestosterone at this age. Conversely, serum levels in older
& l, E# b! s$ L5 i" L; J2 ]patients were higher, possibly because of decreased local
8 k& x( K; b8 J: T$ ?: Y667
* T1 {( G& y: n4 j: [$ g/ Q668 KLUGO AND CERNY
$ @) ]9 j; Z% V9 o* ZPt. Age. M L8 q: r3 @$ W- S
(yrs.)
( h5 {9 J3 E% s9 [Serum Testosterone Phallus (cm.) Change Length
2 ]0 b6 v- |2 x* ?% V% }) ](ng./dl.) Girth x Length (%)* [$ ^; p% x* {6 p' P* w9 u
4
]$ f9 s! B( m0 l B8
! p% F2 t5 p2 w# z+ [/ y10
4 s! E. Y# o5 {9 ?# z, o12
( g5 ~0 X4 Q+ a17) s9 e/ S) \3 Q% C( [
Gonadotropin' D4 M2 C, B+ @5 o0 h C6 S( w
71.6 2.0 X 3 16.6
; N8 y0 t; q8 i) S& y( a' C50.4 4.0 X 5.0 20.0
8 x; y0 E9 X& y4 I22.0 4.5 X 4.0 25.0) g% C) u3 b5 @% S/ g9 v
84.6 4.0 X 4.5 11.1
* \- o: q5 H+ x! h# X85.9 4.5 X 5.5 9.0
2 r8 n( h( h; @6 ~1 y3 M6 nAv. 14.3
# W7 x% b2 F5 o) ]1 \/ g4
: k9 M6 G* U& |( |. U1 R8
/ ~( V+ S0 Z1 e/ |9 m p Q/ ?4 r10
4 S& _: M4 M* F8 p( B$ F12
7 Y3 R% F0 k4 ?- b' j2 Y+ q17$ Z) D1 r* a9 s- G6 u0 o5 O7 Z
Topical testosterone
/ ]- E7 l6 G" P3 ~9 j34.6 4.5 X 6.5 85
: E* y4 g# g+ f4 o4 N38.8 6.0 X 8.5 70
" R% O3 _* p; A$ I) P2 g+ G5 y0 b7 B40.0 6.0 X 6.5 62.5, P# |4 x k2 G0 v2 E+ L
93.6 6.0 X 7.0 55.5
* u# ]; B% o% m4 c95.0 6.5 X 7.0 27.27 e7 _. y/ B a5 M5 d3 ?
Av. 60.01 F* i8 y. k1 n5 ]$ _
available testosterone. Again, emphasis should be placed on8 f4 t( z8 v6 h. @% K1 W: b
early therapy when lower levels of testosterone appear to
' S" J0 t: ^* W* C" X* t V+ aprovide the best responses. The earlier therapy is instituted& I/ _6 i" z4 a( e: j
the more likely there will be an excellent response with low$ }* i. @" j) g; e- |
serum levels. Response occurs throughout adolescence as
: ?% z4 i7 S( |noted in nomograms of phallic growth. 7 The actual response
8 Q2 ~' n3 D. @5 B7 G; rto a given serum level of testosterone is much greater at birth9 `9 [: ]7 o- i3 z# s" N
and gradually decreases as boys reach puberty. This is most
8 h9 i# {$ `5 L( k1 ?likely related to the conversion of testosterone to dihydrotes-
" N1 ?( }6 T( Y% P2 O* qtosterone and correlates well with the studies of testosterone, h7 w9 ]2 d; E
conversion in foreskin at various ages.& s5 Q2 ]0 C$ Y+ a9 h
The question arises regarding early treatment as to whether. k/ {* K8 p: ~4 t$ |' ^6 ?( o
one might sacrifice ultimate potential growth as with acceler-
f# V4 F w$ Z. P5 |4 Dated bone growth. The situation appears quite the reverse2 ~" c T% I4 Q3 Y) k( ~9 v% N2 e
with phallic response. If the early growth period is not used
1 b7 ^3 U8 i# X4 A4 bwhen 5a reductase activity is greatest then potential growth
, L7 _: u+ o0 S; j+ ^may be lost. We have not observed any regression of growth
# Y# G/ F. x! \ Q* vattained with topical or gonadotropin therapy. It may well
9 ?/ D" a& J# ]4 h% Z2 L+ @be that some patients will show little or no response to any& ?6 r3 Y3 U& `0 K. `1 l6 A3 k
form of therapy. This would suggest a defect in the ability to
1 z. J8 ~* A' V1 a3 Fconvert testosterone to dihydrotestosterone and indicate that
/ V* Q' z) f" s$ i) G5 Cphallic and peripheral skin, and subcutaneous tissue should4 H# h( X% I2 u! u
be compared for 5a reductase activity.' \: C3 m/ ]* t" J. {5 U4 t
A, loop enlarges to measure penile girth in millimeters. B,% ~7 i+ v& U9 [2 o
example of penile girth computed easily and accurately.9 L2 p5 _2 N& d: q
conversion of testosterone to dihydrotestosterone. It is in this
; ~# ?5 z, v- j/ uolder group that others have noted high levels of serum& j) ~# u' M0 G3 @) q, N+ N% }
testosterone with topical application. It would also appear
" p$ {. O! B C( Mthat phallic response during puberty is related directly to the7 c3 h( b8 K. C3 T& B
serum testosterone level. There also is other evidence of local! T" } S+ I3 ?% O6 Q: V( V6 b" l0 }
response to testosterone with hair growth and with spermato-6 o" M0 p$ a+ `0 \* |7 x
genesis. 5• 6! r8 h1 r+ `' N% A) I& y
Administration of larger doses of gonadotropin or systemic2 r% F8 i. J( w3 r5 f' T
testosterone, as well as topical applications that produce& \% J1 q3 U9 G- \, r
higher levels of serum testosterone (150 to 900 ng./dl.), will8 b2 W8 ~- X2 [+ {+ b. C
also produce phallic growth but risks accelerated skeletal
2 t, b" t9 P) w4 t: ?" Jmaturation even after stopping treatment. It would appear! D$ B( L! [2 W
that this may be avoided by topical applications of testosterone
- N( o M8 q5 V- \8 I9 o/ Eand monitoring of serum testosterone. Even with this control: U$ b* w- W0 x
the duration of our therapy did not exceed 3 weeks at any+ a! H% c5 o Z( O3 q) M, a" ?, ~
time. It is apparent that the prepuberal male subject may/ s2 \7 l' W/ {" H2 F5 n) E
suffer accelerated bone growth with testosterone levels near
7 j: Q- _. x, G- h. u; X1 A. e1 ~200 ng./dl. When skeletal maturation is complete the level of+ b) Q4 ]7 O6 m. W' R8 ~( }
serum testosterone can be maintained in the 700 to 1,300 ng./
: `) n2 O" G9 ~" o4 P Rdl. range to stimulate phallic growth and secondary sexual
; c5 w) Y7 c/ N0 Kchanges. Therefore, after skeletal maturation parenteral tes-. x* D$ d) R9 d2 x% M9 M- o9 J
tosterone may be used to advantage. Before skeletal matura-
0 G: o: N" e3 F' Rtion care must be taken to avoid maintaining levels of serum( o0 L6 c- s8 Y' [: ^" g
testosterone more than 100 ng./dl. Low-dose gonadotropin& J* Q3 x1 ~" h, X, @4 r
depends upon intrinsic testicular activity and may require1 f$ d+ g5 ~" W- e" E- A/ e. ?
prolonged administration for any response.
2 G# l. T& p, u# \7 f% T/ D% qAlternately, topical testosterone does not depend upon tes-
6 F4 J$ `1 i3 Nticular function and may provide a more constant level of
. X0 K$ f: _: @. v- t4 O+ W- lREFERENCES9 Z( M4 J* J# b" n. K& w0 \
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,. V9 t6 G* ~8 C z. Q/ Z
R.: The local application of testosterone cream to the prepub-
( B% }" ^# {+ Q* m- t' dertal phallus. J. Urol., 105: 905, 1971.# k" N+ u3 h: e% K' ~
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 ^3 i, W& R9 Ltreatment for micropenis during early childhood. J. Pediat.,0 m' {6 h ?" z
83: 247, 1973.; B3 N# M" I5 v! w9 V& J
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 u! Q7 F2 v3 n9 |. Tone therapy for penile growth. Urology, 6: 708, 1975.* V4 G' b l7 @0 ~
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone% w5 l; ]1 [) u, `& O7 _) P7 E
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. q- v. R/ N m. |- ]4 b8 B7 `% Dskin slices of man. J. Clin. Invest., 48: 371, 1969.
, Q( c5 d" Y, j+ o5 I; a) b7 D1 [5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth" d P: y( R1 y! g0 _+ H
by topical application of androgens. J.A.M.A., 191: 521, 1965.) }# v; V. C8 ~) o! B" r; c9 h
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local7 c4 i& V9 B& H9 K
androgenic effect of interstitial cell tumor of the testis. J.9 t$ n, V- r) \' H% J7 B
Urol., 104: 774, 1970.
+ {- ~) H5 I- N! f7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, P2 V) e2 p( m9 W$ ?% X. U' W
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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