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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND1 n/ V: ]+ y; _7 B
GONADOTROPIN, j5 R# }: N/ T
RICHARD C. KLUGO* AND JOSEPH C. CERNY
+ Z# C% T9 n: G& W: m; k8 WFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan) H( f. v4 b# ]. l! l7 D2 C% O/ O1 c
ABSTRACT# N9 R( {7 ]. U: `
Five patients were treated with gonadotropin and topical testosterone for micropenis associated# w* R: {4 h# i8 l: | Z0 b
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-7 _/ F1 e1 N; f, o7 b, }/ ]2 j
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone a; f) f! m4 O1 L) t- W
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent6 z( e/ F4 r1 a3 F, @. D5 `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* M. _7 U3 N+ q, y- m" oincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average* f7 U' T: a$ n& m
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 {" z. W( C' `9 M2 M
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( i3 q& ? x/ |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ N; i! L2 \( S! K4 x- l0 ^) b4 s' B# hgrowth. The response appears to be greater in younger children, which is consistent with previ-3 q- l. v, x8 w6 N
ously published studies of age-related 5 reductase activity.
, V3 M" y. q4 a4 V" Q x% xChildren with microphallus regardless of its etiology will8 J3 T6 c9 Z6 H h
require augmentation or consideration for alteration of exter-( `7 N- f5 ~2 V! z" B
nal genitalia. In many instances urethroplasty for hypo-
+ Q0 u4 P& x* rspadias is easier with previous stimulation of phallic growth.
. F: [* `4 f" J7 |# s; nThe use of testosterone administered parenterally or topically: M2 O! g X6 ~7 ~; f6 a9 S
has produced effective phallic growth. 1- 3 The mechanism of
: K6 v+ U" B# g8 @0 I# N6 presponse has been considered as local or systemic. With this" X% `5 `5 s3 X0 B
in mind we studied 5 children with microphallus for response
$ j1 r+ e$ p2 y! _1 |to gonadotropin and to topical testosterone independently.* o- I' A9 o* U, y
MATERIALS AND METHODS. A* {- f+ S+ r3 ^
Five 46 XY male subjects between 3 and 17 years old were1 H/ e9 v3 k' K: C: e
evaluated for serum testosterone levels and hypothalamic
! [0 a8 ^" {# m- d. ^function. Of these 5 boys 2 were considered to have Kallmann's/ @8 S3 _. L3 d
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' w- X" [4 K1 T: k, \lamic deficiency. After evaluation of response to luteinizing- E" W1 R: Z/ G- \1 @
hormone-releasing hormone these patients were treated with
" h' v) H) K$ H9 p1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! [' l3 o& V& rafter completion of gonadotropin therapy 10 per cent topical
9 F& O& Q8 |/ P8 y' @9 Z2 Otestosterone was applied to the phallus twice daily for 3 weeks.! D% r( V U( E. [
Serum testosterone, luteinizing hormone and follicle-stimulat-2 E. C: f- p% W# q0 N
ing hormone were monitored before, during and after comple-4 E% [3 e( ?5 @1 t- k( [
tion of each phase of therapy. Penile stretch length was" T/ l0 l* G& X h7 L
obtained by measuring from the symphysis pubis to the tip of
0 V* N1 a5 T0 A9 L7 ?0 [# Ethe glans. Penile circumferential (girth) measurements were' p G: }9 d$ X) a4 _/ r
obtained using an orthopedic digital measuring device (see
% e; t# ?+ B) X% D0 }8 Ffigure).2 N1 m# b# R# S5 d& `7 v
RESULTS
5 {, X9 H7 g7 p/ p! m; KSerum testosterone increased moderately to levels between& O" V8 j& C* e+ t: [
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
9 b& x) {: ?) D& e8 F4 E [terone levels with topical testosterone remained near pre-# F% x' F) P! y: J2 U$ b4 f+ t
treatment levels (35 ng./dl.) or were elevated to similar levels
+ {7 F8 _- Y+ F" Jdeveloped after gonadotropin therapy (96 ng./dl.). Higher
5 j4 U, ]* _, B% o! Qserum levels were noted in older patients (12 and 17 years old),
3 h2 y* R6 r9 W: [while lower levels persisted in younger patients (4, 8, and 10
* L- L A4 B9 m: n3 E) Gyears old) (see table). Despite absence of profound alterations( {, d3 [; D& b9 N1 P3 h; H
of serum testosterone the topical therapy provided a greater( ]0 X. N, _. K: \8 V
Accepted for publication July 1, 1977. ·
3 F3 F; K) H, v; v' QRead at annual meeting of American Urological Association,
, ~# N2 R( T" Z4 o9 H s/ P: G( SChicago, Illinois, April 24-28, 1977.
' W5 K( x4 ]3 C4 O# Q6 X3 j: {* Requests for reprints: Division of Urology, Henry Ford Hospital,
# a; }2 E* Q1 P. n$ n0 e) f2 X2799 W. Grand Blvd., Detroit, Michigan 48202.
' T1 m5 s2 O2 Wimprovement in phallic growth compared to gonadotropin.. Z2 e% s j7 z& t# x, N
Average phallic growth with gonadotropin was 14.3 per cent
: @. w! i+ X) Q1 r% {7 I0 }( aincrease in length and 5.0 per cent increase of girth. Topical
8 V; k2 c: V Gtestosterone produced a 60.0 per cent increase of phallic length8 H l& M6 G" t8 b& P
and 52.9 per cent increase of girth (circumference). The
' Z) Z+ E8 j' S2 t; W; fresponse to topical testosterone was greatest in children be-
; G* i M4 j. X4 ]- Ttween 4 and 8 years old, with a gradual decrease to age 17
2 c6 z: a0 L7 O) ~ V- ~years (see table).- s* H$ ]4 l0 L& k7 k9 U, p( ^3 X
DISCUSSION
: Y4 ]; A; }/ @Topical testosterone has been used effectively by other
2 w) N& P* M7 a) b% ~clinicians but its mode of action remains controversial. Im-
' e6 @3 e0 t* B. `mergut and associates reported an excellent growth response
5 |4 x: u0 u: wto topical testosterone with low levels of serum testosterone,
1 h3 {9 c& k) Zsuggesting a local effect.1 Others have obtained growth re-) P% o: R! q: Q2 h1 m3 T9 i+ E
sponse with high. levels of serum testosterone after topical' a# L6 X8 [. d$ J2 K! x; D$ C
administration, suggesting a systemic response. 3 The use of
5 K1 V; a( \. G3 x, I3 t* v9 c: egonadotropin to obtain levels of serum testosterone compara-
$ c; T9 D1 e3 l9 b: tble to levels obtained with topical testosterone would seem to. Z* N" O3 |7 r" _0 @
provide a means to compare the relative effectiveness of6 T9 y* U5 }. H" W' r
topical testosterone to systemic testosterone effect. It cer-
1 t2 b/ L6 i3 t7 [0 gtainly has been established that gonadotropin as well as par- [3 p$ [. Q* f4 V4 I' s+ N% c
enteral testosterone administration will produce genital
6 Z" @' {! k( J* Agrowth. Our report shows that the growth of the phallus was ^( l) [* s, n+ ?1 U7 ^
significantly greater with topical applications than with go-
$ |( h& e# P5 Tnadotropin, particularly in children less than 10 years old.+ S0 T1 |+ F9 @$ {" B) y
The levels of serum testosterone remained similar or lower
* e( N/ K/ f/ V( ]' f& t/ Kthan with gonadotropin during therapy, suggesting that topi-
* t1 m% m y6 E# u2 {+ vcal application produces genital growth by its local effect as) t9 c6 u/ P1 y6 u
well as its systemic effect.
- Y$ P* q5 B: o, p! e4 J2 hReview of our patients and their growth response related to
" i& l( Z# q5 y5 }* N3 _age shows a greater growth response at an earlier age. This is# ]$ q( e3 g: I( o2 A! H
consistent with the findings of Wilson and Walker, who |' P3 ^) r/ f8 K9 b% G+ E
reported an increased conversion of testosterone to dihydrotes-
+ l7 Z; ~9 H* X/ rtosterone in the foreskin of neonates and infants.4 This activ-
# v) x# @* E3 o$ E# C' c& vity gradually decreases with age until puberty when it ap-
: Z3 I3 O7 R4 b: P) V+ j8 n$ q% Tproaches the same level of activity as peripheral skin. It may
2 Q# D( B9 A+ s3 J3 @% J, dwell be that absorption of testosterone is less when applied at# Q% a0 A- h* r9 v7 a
an earlier age as suggested by lower serum levels in children) A$ M& c, `2 _3 d" m
less than 10 years old. This fact may be explained by the5 F" e: S7 r' S# q1 Z
greater ability of phallic skin to convert testosterone to dihy-
7 T1 V$ X! ?7 I/ }+ v6 |+ pdrotestosterone at this age. Conversely, serum levels in older
1 |. Y& V3 w' |: y) S( |) R0 Ypatients were higher, possibly because of decreased local! R( ]0 u) b+ F$ i
667
: ~+ u4 @8 h* T$ F2 }668 KLUGO AND CERNY: C+ Y! K* G" ]. `" w( t# S
Pt. Age
; u3 r" ^+ [* S8 a l: d* ?( G(yrs.)
' V% Y% H% E t9 pSerum Testosterone Phallus (cm.) Change Length/ I' W. a. d5 f3 H# c
(ng./dl.) Girth x Length (%)
I) ~9 H0 m j4
- |4 e" Y- U$ v! b. [8
5 j$ O3 P3 S' m( F. A10
8 r4 J3 e- k3 b' S$ ?1 p+ E$ ^12. K- Q9 B0 ?- H1 ^: K/ D
17
2 _. W1 h1 t9 g/ m! uGonadotropin7 @+ F4 H! _* y2 j! v2 K9 y
71.6 2.0 X 3 16.6 x/ J0 G6 c* n3 J0 X
50.4 4.0 X 5.0 20.0$ A K0 N' h/ J Q1 O/ G
22.0 4.5 X 4.0 25.0
0 z, b9 e0 N( \9 n' k2 N) F84.6 4.0 X 4.5 11.1
# b7 W5 K& v; w3 T, q; O& F4 `( O85.9 4.5 X 5.5 9.0
' ^/ u' M' R2 Y6 FAv. 14.3
: s6 D; Z! d; l3 k& \) ]4
# ^3 w2 ?8 x5 U# _& t8
& q2 U) _- T& i# N+ i' B10
- I y: p" q7 H3 k12
6 r& R* W( v2 F6 I17" ~4 q: F d: |! E
Topical testosterone
1 A/ W. _: ~+ _6 g34.6 4.5 X 6.5 850 E9 m @6 ~/ z& i2 R
38.8 6.0 X 8.5 706 ]: s: I, a$ `* R' v) f
40.0 6.0 X 6.5 62.57 g4 i# K- f: N0 o' h
93.6 6.0 X 7.0 55.5
5 H8 f3 ?0 j+ a5 W95.0 6.5 X 7.0 27.29 x; c% H1 q x/ Z( M
Av. 60.0
W) o* E6 C& R. havailable testosterone. Again, emphasis should be placed on5 F; Q: `( h% l: i! M8 g+ `! w I9 b
early therapy when lower levels of testosterone appear to5 P8 Y# T& Q7 S
provide the best responses. The earlier therapy is instituted
2 d3 e. I9 w- i6 P, c9 ?the more likely there will be an excellent response with low
7 [! m1 Y! T% ]! O8 {. Z% Zserum levels. Response occurs throughout adolescence as
- Y0 e! u2 Q: ~! r4 {5 i% m! D9 ~noted in nomograms of phallic growth. 7 The actual response
3 y4 X6 S, Z& \3 xto a given serum level of testosterone is much greater at birth
3 j) o$ i. E( Sand gradually decreases as boys reach puberty. This is most
, h$ a4 b1 a; {: o1 G( t, f$ {6 @" ylikely related to the conversion of testosterone to dihydrotes-3 ^* B; @6 c# o
tosterone and correlates well with the studies of testosterone9 G3 S9 B8 f2 l1 b; f6 x* a
conversion in foreskin at various ages." Y! Z, k% Y5 K5 w; @& J9 C0 ?
The question arises regarding early treatment as to whether! J) y" Z/ c# w$ s$ b
one might sacrifice ultimate potential growth as with acceler-
5 T4 x/ U& L" B; g: X. z3 Wated bone growth. The situation appears quite the reverse0 k5 F+ E, C# a
with phallic response. If the early growth period is not used
0 U: X7 X6 k' Q$ r4 swhen 5a reductase activity is greatest then potential growth
# C5 t; y6 j$ \may be lost. We have not observed any regression of growth# d7 T, s' [' K3 E6 G3 _/ q" j
attained with topical or gonadotropin therapy. It may well
/ F, v. V, b6 nbe that some patients will show little or no response to any- H& L& u( _! {7 e
form of therapy. This would suggest a defect in the ability to* r& I0 L2 Z; X2 i
convert testosterone to dihydrotestosterone and indicate that
- R% D2 |) A7 Sphallic and peripheral skin, and subcutaneous tissue should
1 |) b( z$ b9 H4 V y# Rbe compared for 5a reductase activity.0 q/ L( A5 K# Z* U) v. [
A, loop enlarges to measure penile girth in millimeters. B,
$ V3 G; q+ l9 Nexample of penile girth computed easily and accurately.) w1 x1 V0 u z# m) y& q! `
conversion of testosterone to dihydrotestosterone. It is in this
$ a0 a1 Q: o3 x( [6 kolder group that others have noted high levels of serum
/ M3 B9 z, K8 k- g% Y# H$ T7 D; ~testosterone with topical application. It would also appear
+ \" F3 s. s- l |that phallic response during puberty is related directly to the/ z4 u7 F& n# ?; J6 }, M
serum testosterone level. There also is other evidence of local
7 \: x8 {$ {2 P. K' @( Lresponse to testosterone with hair growth and with spermato-
# S8 \; X5 [) Hgenesis. 5• 6
$ T$ y% w, D G3 m6 h( y- EAdministration of larger doses of gonadotropin or systemic8 Z/ }7 G$ B: C& f2 H5 {* T" j, Z
testosterone, as well as topical applications that produce9 r' Q' ~6 P! X5 F8 N1 w1 }- M+ @
higher levels of serum testosterone (150 to 900 ng./dl.), will9 L6 W/ f. @5 z
also produce phallic growth but risks accelerated skeletal2 G+ ^' g- O8 Q0 N5 k' U' l
maturation even after stopping treatment. It would appear7 p3 y- D, D# c/ {3 z$ x
that this may be avoided by topical applications of testosterone
' I6 i K1 I' @$ `and monitoring of serum testosterone. Even with this control2 s. N; O( P0 a; X3 w# G j* a' R
the duration of our therapy did not exceed 3 weeks at any
: C& o: O2 n, Vtime. It is apparent that the prepuberal male subject may
, n. _' ~( }: g! l* n Qsuffer accelerated bone growth with testosterone levels near. P4 Y1 q$ r$ g
200 ng./dl. When skeletal maturation is complete the level of! |: a0 t, f. y% F. U- E0 o/ g
serum testosterone can be maintained in the 700 to 1,300 ng./
v4 X( s( U5 ^( E" Ddl. range to stimulate phallic growth and secondary sexual
& Q8 @% @( ~4 t8 jchanges. Therefore, after skeletal maturation parenteral tes-" E/ m/ L% g s0 e
tosterone may be used to advantage. Before skeletal matura-
8 J# B# b4 |$ J* X' Q2 qtion care must be taken to avoid maintaining levels of serum3 d9 k5 n' C$ k
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ a3 ~( X- R, X, E0 ~depends upon intrinsic testicular activity and may require
1 [3 r& w1 C- S" Kprolonged administration for any response.
9 W: k, l! r/ l7 mAlternately, topical testosterone does not depend upon tes- A/ y, _ E m" |
ticular function and may provide a more constant level of
# ~5 b+ M" m& B! u4 T. mREFERENCES& ~1 {4 n; w- j, Q( J* b8 }7 V
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 W$ A) [! p4 j5 g$ d7 |8 TR.: The local application of testosterone cream to the prepub-. F' B$ C. T: B
ertal phallus. J. Urol., 105: 905, 1971.
, I5 U# \/ T ^9 r% c2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 L/ V9 I' u5 H+ Y4 V! U! ]treatment for micropenis during early childhood. J. Pediat.,
. O! ~- @8 }; m! m! h/ W& c9 S: F83: 247, 1973.
. ]" u; W, r1 M$ h3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster- K1 }3 P- x9 x* g) ^
one therapy for penile growth. Urology, 6: 708, 1975.
, D' ?5 M- E/ l b4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone6 G: ~! I' E2 A$ U: |& J
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
+ a" I t7 _" rskin slices of man. J. Clin. Invest., 48: 371, 1969.
: G) z8 g& K2 N5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth( K" O1 Z) B+ T7 c4 o' @, n* @
by topical application of androgens. J.A.M.A., 191: 521, 1965.
, D$ c( F% l( Q, o& `4 a6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
& R8 x/ }, P% m6 h xandrogenic effect of interstitial cell tumor of the testis. J.
3 P" v4 ~' b, fUrol., 104: 774, 1970. K) S) J% ]. d$ d- s5 @, v* n
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 W0 F! S1 f/ P! n& Rtion in the male genitalia from birth to maturity. J. Urol., 48: |
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