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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
! E, D! V) v/ v( f0 @1 EGONADOTROPIN" F5 }1 q% b+ C5 |' Y
RICHARD C. KLUGO* AND JOSEPH C. CERNY
' v8 `( H) r" u( XFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ ]" n6 H0 o) N
ABSTRACT0 O, C) D, o. r" r2 b, S
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
4 ^) b. s- K; E/ o0 Z5 @7 _with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# z2 f( U! l3 @+ Ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone6 o. `$ ^# b; j; x& a6 E
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent$ ^; W* z2 U- O: g* ]: E: `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent( [4 Q/ m" h7 |% }$ ?3 w" N
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
$ L2 e! ~" I* G/ ]2 Qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 n3 i7 L2 V$ {3 X7 K4 Ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, G# R; _: c. u4 t; j: O; Z# wstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% C- }) r) \" s6 H* q4 A" p4 L Bgrowth. The response appears to be greater in younger children, which is consistent with previ-" e2 n w) I0 @/ Y
ously published studies of age-related 5 reductase activity.* G3 N# d- m8 h- w/ B9 P5 B
Children with microphallus regardless of its etiology will
" O' G; c5 W/ L/ v8 \' frequire augmentation or consideration for alteration of exter-8 D/ v$ G$ h0 h. ?# p. ~& x
nal genitalia. In many instances urethroplasty for hypo-
+ S$ o8 B) b9 z0 }9 Ispadias is easier with previous stimulation of phallic growth.0 N6 S: s5 D) F( u2 g* D7 L8 M4 s
The use of testosterone administered parenterally or topically
0 f: n4 Y* x3 Hhas produced effective phallic growth. 1- 3 The mechanism of: M* J4 P( ^4 }% Z
response has been considered as local or systemic. With this
# Y6 m$ j9 f% iin mind we studied 5 children with microphallus for response' }: i6 ]* B. }! u; f
to gonadotropin and to topical testosterone independently." B9 A: z& _ F& D2 g# |$ F
MATERIALS AND METHODS
& B5 c4 g* x& t( S' |# D/ {1 qFive 46 XY male subjects between 3 and 17 years old were
0 z7 C7 R; A7 Pevaluated for serum testosterone levels and hypothalamic
. Q8 t0 x3 `& V7 d' i! gfunction. Of these 5 boys 2 were considered to have Kallmann's$ ?$ M% S/ u( c3 A. k
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-6 K' d; E" _8 P" |
lamic deficiency. After evaluation of response to luteinizing5 U" D" }2 f' h1 U3 D
hormone-releasing hormone these patients were treated with7 q S2 z# L+ z& T" P. y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
; c# _1 v9 U! E% {& s+ a; ~after completion of gonadotropin therapy 10 per cent topical3 p0 m u5 a# T* a+ m5 |
testosterone was applied to the phallus twice daily for 3 weeks./ D- `, M' m* o6 `8 w2 Y
Serum testosterone, luteinizing hormone and follicle-stimulat-* ]6 A4 k- ]- E4 U0 [' }
ing hormone were monitored before, during and after comple-
1 b6 r$ @, {" L3 P0 a7 |! }tion of each phase of therapy. Penile stretch length was
" Z e, m/ c6 o* `) ~& F: Y4 Qobtained by measuring from the symphysis pubis to the tip of: n7 y2 S/ B5 i
the glans. Penile circumferential (girth) measurements were4 B2 ?9 V9 c0 K% }( V* _
obtained using an orthopedic digital measuring device (see
# v4 H7 }2 V [: R b1 b* [figure).; i, w+ P4 ]4 y+ k! Z; T
RESULTS1 \$ b6 p& E8 J8 H
Serum testosterone increased moderately to levels between. ?5 \/ [7 |0 z8 h5 R" d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos- p( f* b+ l6 i$ L8 b6 c
terone levels with topical testosterone remained near pre-( B. S2 S0 } J4 [9 \1 K, A
treatment levels (35 ng./dl.) or were elevated to similar levels
2 c. I. W+ R9 A2 k: G, Q1 s: wdeveloped after gonadotropin therapy (96 ng./dl.). Higher9 W5 G2 H/ X+ L
serum levels were noted in older patients (12 and 17 years old),
6 N( f% F, m$ q+ m! m+ kwhile lower levels persisted in younger patients (4, 8, and 10
E* @5 k J% z! j* N: @ Oyears old) (see table). Despite absence of profound alterations
6 ]; s) q1 t0 M9 |# \of serum testosterone the topical therapy provided a greater( b1 ^* y2 N& U6 [4 H3 p+ R" J
Accepted for publication July 1, 1977. ·
' ~6 I% L! b5 t6 c% m" B* jRead at annual meeting of American Urological Association,
. X6 i8 `; X' ^0 bChicago, Illinois, April 24-28, 1977.: p! I3 `' B( A# Z& X X
* Requests for reprints: Division of Urology, Henry Ford Hospital,
$ ^. h6 M1 N$ Z: E. V2799 W. Grand Blvd., Detroit, Michigan 48202.
9 u) x Z) e: F' Zimprovement in phallic growth compared to gonadotropin.3 X$ k1 l" J/ K6 W) n5 I5 f- o% Y
Average phallic growth with gonadotropin was 14.3 per cent, @: G9 {6 K" }/ e
increase in length and 5.0 per cent increase of girth. Topical
: r* }+ n% c- z, gtestosterone produced a 60.0 per cent increase of phallic length4 U m' D- L6 {4 [9 Y
and 52.9 per cent increase of girth (circumference). The
# G- U0 K6 m6 C! V0 ^response to topical testosterone was greatest in children be-2 t3 x' s7 D( K2 `1 f& u0 f
tween 4 and 8 years old, with a gradual decrease to age 179 e6 W9 D' R7 ^' d
years (see table).; t+ ?5 S% G% E) J8 Y. }6 J% ]
DISCUSSION# Y' W% G$ X4 i: @
Topical testosterone has been used effectively by other
% f0 |3 ]) s( j9 T- Mclinicians but its mode of action remains controversial. Im-' D, @9 j5 y {1 w2 K ^7 D: o8 A) u! y
mergut and associates reported an excellent growth response) ?& d& v9 ` a( [2 _# ^; R
to topical testosterone with low levels of serum testosterone,
5 [) s7 `# w0 R" n0 k7 _( H1 K1 w2 M+ wsuggesting a local effect.1 Others have obtained growth re-$ L& O2 C4 k) I
sponse with high. levels of serum testosterone after topical
& X6 S, T- Y& f# P# W, tadministration, suggesting a systemic response. 3 The use of
! j% }8 C1 g( y* q$ x3 `5 z" x9 | tgonadotropin to obtain levels of serum testosterone compara-
9 U( m- X6 e+ Dble to levels obtained with topical testosterone would seem to6 \: A7 s3 e0 ]" `$ ^
provide a means to compare the relative effectiveness of) ]5 J' W# ~$ E0 g% A
topical testosterone to systemic testosterone effect. It cer-
/ S- p+ f8 j7 b7 L+ g) s! Xtainly has been established that gonadotropin as well as par-
0 Q8 L) q* V1 tenteral testosterone administration will produce genital
7 k! I' _/ s0 S$ D& M \growth. Our report shows that the growth of the phallus was
- }* h% J; j8 |# Z: y; Asignificantly greater with topical applications than with go-
. O) V+ \! d. Anadotropin, particularly in children less than 10 years old.( {5 q. t/ v6 o& C
The levels of serum testosterone remained similar or lower, \4 h7 j8 A4 W7 I3 [
than with gonadotropin during therapy, suggesting that topi-
, f3 R/ X& o% x+ ]cal application produces genital growth by its local effect as' B1 Q" v7 W" \
well as its systemic effect., n6 X5 V. u. G( h A' V
Review of our patients and their growth response related to8 e9 [. W% N% Q
age shows a greater growth response at an earlier age. This is
: j2 h" \0 P- }( _$ f+ Zconsistent with the findings of Wilson and Walker, who( O- r0 s4 D& k
reported an increased conversion of testosterone to dihydrotes-
/ y: |. C8 h9 D% c, Stosterone in the foreskin of neonates and infants.4 This activ-: P0 H: C. g* e" V" O' i& e, v' l
ity gradually decreases with age until puberty when it ap-$ n6 S$ y* U: |; J: k* I
proaches the same level of activity as peripheral skin. It may) t' b8 ~6 Z/ c4 F# b) n: o
well be that absorption of testosterone is less when applied at
6 u3 R. l2 q& V, W v' nan earlier age as suggested by lower serum levels in children6 h5 M2 _9 \) t
less than 10 years old. This fact may be explained by the8 X \% N$ Z- j, k9 \2 _2 f
greater ability of phallic skin to convert testosterone to dihy-5 E) Q2 p4 ?5 M: q
drotestosterone at this age. Conversely, serum levels in older6 k- ~. n# r/ ~& |' h% Z0 K( |0 [- o
patients were higher, possibly because of decreased local
V- m# P+ D! P# D667
2 d h) J7 {. W0 {668 KLUGO AND CERNY
! f) h( k+ i. R3 G3 APt. Age
) N6 B" o i. Z" ](yrs.)' v( w) y+ T0 G
Serum Testosterone Phallus (cm.) Change Length
/ I( J+ c- j5 o; i# M$ s$ {& K(ng./dl.) Girth x Length (%)
! w# o, [% i/ P4
- g$ d F8 R3 M' m$ J1 E9 ]6 E8
. K* t; c# S2 z( }/ q10: w7 r1 k, y$ G# n7 J2 p( h
12
1 t2 R2 X8 L5 z% h9 A* L4 r17' P8 d3 \7 i5 d6 Q0 }2 h/ v2 z
Gonadotropin4 a) B7 `" W# D
71.6 2.0 X 3 16.6
& j) V8 X0 }1 }2 w50.4 4.0 X 5.0 20.0
6 a: q" ^. o6 w$ W22.0 4.5 X 4.0 25.0' Q( i, @, F1 A! ]$ y3 _
84.6 4.0 X 4.5 11.1* x1 t( V/ o' b+ v: o& y
85.9 4.5 X 5.5 9.0
5 v+ C2 `4 N* D) q9 FAv. 14.3
# K: p2 D. `9 p! q3 A O47 v+ D0 ~% W! ?
89 a% j3 d- M' }/ e7 y3 Q# _
10! e" Q: O5 t$ Q/ }
12
; p# H5 D3 A9 a/ ]5 ^3 \178 x7 b1 H7 J i$ P# x5 W9 ~" u1 j
Topical testosterone D1 s( X: V2 T2 i7 K+ {! h- Z
34.6 4.5 X 6.5 852 ]- P- ]- ~) Z. h8 I& q
38.8 6.0 X 8.5 70
j3 P* }/ e @2 E40.0 6.0 X 6.5 62.5
7 v) K+ G& y1 }1 w& C93.6 6.0 X 7.0 55.5
; P" U' I+ D$ x95.0 6.5 X 7.0 27.2+ F' U% q% m* @
Av. 60.0
3 s3 l/ b# o) }7 iavailable testosterone. Again, emphasis should be placed on
& |3 U# D7 W. B$ Iearly therapy when lower levels of testosterone appear to9 d/ M8 m8 j! [- x; C
provide the best responses. The earlier therapy is instituted
! {9 h& Y+ o) G+ |8 E8 q5 nthe more likely there will be an excellent response with low' Q2 ~' Z; K6 E) R2 u: F
serum levels. Response occurs throughout adolescence as" k, S2 h, D! U8 h2 p- t
noted in nomograms of phallic growth. 7 The actual response7 K9 x/ u* }$ p( Q/ n) b" B
to a given serum level of testosterone is much greater at birth% R, H0 v$ T, g. R- a
and gradually decreases as boys reach puberty. This is most
5 L! r% q' C3 Llikely related to the conversion of testosterone to dihydrotes-
8 r; c5 u' Y4 b- c/ G: m- {- ]tosterone and correlates well with the studies of testosterone
% r: f, X( M& n0 hconversion in foreskin at various ages.
- c, D5 g/ j0 @2 J @$ C* QThe question arises regarding early treatment as to whether
- J9 C ^( R! _2 Wone might sacrifice ultimate potential growth as with acceler-8 F3 D# {2 s" Q1 F
ated bone growth. The situation appears quite the reverse
& v2 E& K3 _* d& @8 v0 [with phallic response. If the early growth period is not used
+ l) L; F' }7 u/ ^* Kwhen 5a reductase activity is greatest then potential growth/ R3 d$ W7 R: I o+ ~( M6 U
may be lost. We have not observed any regression of growth
( c: s# e. V+ E7 Zattained with topical or gonadotropin therapy. It may well6 q/ D' r3 ^9 Q8 N
be that some patients will show little or no response to any% Y. u2 q c1 A. I9 r* L' I P8 Q% M
form of therapy. This would suggest a defect in the ability to$ \0 a. W* N0 x
convert testosterone to dihydrotestosterone and indicate that7 k( h% x2 P$ D3 E! T' t V
phallic and peripheral skin, and subcutaneous tissue should
) r$ E" B$ M5 \! wbe compared for 5a reductase activity.8 q; F+ E5 l, C/ a4 i
A, loop enlarges to measure penile girth in millimeters. B,- l$ G {. B: N+ _
example of penile girth computed easily and accurately.
# z' W# j( h4 J- K4 Uconversion of testosterone to dihydrotestosterone. It is in this
% E( D) @9 m$ q4 }/ E3 _. Uolder group that others have noted high levels of serum
7 ^- c; O; I+ w/ b8 Ntestosterone with topical application. It would also appear5 `" z$ ^, U. P! I
that phallic response during puberty is related directly to the9 W: t* u# H* B
serum testosterone level. There also is other evidence of local4 ?8 X8 k6 P w0 H
response to testosterone with hair growth and with spermato-
1 Z4 {8 Z3 R v2 J7 r0 R# pgenesis. 5• 6) w: E+ N. b$ P. R4 J
Administration of larger doses of gonadotropin or systemic
8 s& w# o- ]" e' ]% I. R2 htestosterone, as well as topical applications that produce* y0 r. z* \- _) p
higher levels of serum testosterone (150 to 900 ng./dl.), will
4 m2 Z. e5 B8 d5 h v1 P# Salso produce phallic growth but risks accelerated skeletal
3 u- S ?3 ?6 A+ t9 Ymaturation even after stopping treatment. It would appear
( w" D/ v5 U3 Wthat this may be avoided by topical applications of testosterone8 D, T0 F$ l O" Z2 |
and monitoring of serum testosterone. Even with this control* l+ l" ~2 a2 n" w' s" C& q' M
the duration of our therapy did not exceed 3 weeks at any% y6 z% j3 ^8 e2 h' F9 `; D$ l9 z. N
time. It is apparent that the prepuberal male subject may+ [. [3 M2 y! e3 s/ l
suffer accelerated bone growth with testosterone levels near
3 j1 B0 {0 w# q7 s$ j& n200 ng./dl. When skeletal maturation is complete the level of
2 _' i) K7 h; w* b0 u+ \serum testosterone can be maintained in the 700 to 1,300 ng./5 X7 y( K2 q( @1 B4 P" }
dl. range to stimulate phallic growth and secondary sexual
6 b5 {6 i( _5 G7 [3 F/ Zchanges. Therefore, after skeletal maturation parenteral tes-
' ], ?0 t# m7 H4 _" Gtosterone may be used to advantage. Before skeletal matura-
; J0 S5 z) V0 ~4 }tion care must be taken to avoid maintaining levels of serum
& O/ \5 g: j" X; itestosterone more than 100 ng./dl. Low-dose gonadotropin1 v# @; ]% Y$ k
depends upon intrinsic testicular activity and may require3 N$ P7 M0 g$ `& a5 C3 y$ x
prolonged administration for any response.' L/ O$ y [' R/ F# v& A7 k
Alternately, topical testosterone does not depend upon tes-
- [; e- T( C, @- r9 u( T2 ^ticular function and may provide a more constant level of5 m$ O8 |' _5 c, W, P
REFERENCES
' i0 p# j% _& b+ o% t4 j9 |) v+ q1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 V. k* S+ [3 q. W& \" M
R.: The local application of testosterone cream to the prepub-4 K& |# M% q \3 I! k
ertal phallus. J. Urol., 105: 905, 1971.
6 w" a. s2 H; F7 d J2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, c! C# ?; O/ K3 M+ b) {
treatment for micropenis during early childhood. J. Pediat.,
3 D6 W2 X% I* Y& _83: 247, 1973.
* u. \2 t# C9 ^. J) `- x7 V! c5 ]3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, A" r, X0 d7 p( zone therapy for penile growth. Urology, 6: 708, 1975.
- ]2 W9 G4 \9 b: E3 d. ]% l/ {2 L6 o0 D2 T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 y4 o, T; e. \to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 _( X2 G1 Q5 H1 U3 iskin slices of man. J. Clin. Invest., 48: 371, 1969.
/ X }/ r2 ]. O7 ]5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) L% u c# K9 k! @! Z# w& rby topical application of androgens. J.A.M.A., 191: 521, 1965.
' }5 j& P: N7 `' [6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# b4 `$ |9 p" d* ^" xandrogenic effect of interstitial cell tumor of the testis. J.
3 k/ |- w* M5 PUrol., 104: 774, 1970.
* ^6 F" g& B8 r$ z0 v7 q4 H( L7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
* M4 Q& F1 x2 I; A2 ition in the male genitalia from birth to maturity. J. Urol., 48: |
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