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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 d; ^5 c4 p8 D- p" ~GONADOTROPIN
" x( E U5 s1 `9 D+ iRICHARD C. KLUGO* AND JOSEPH C. CERNY7 b) ^) ]" t3 H$ ^
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 V1 o' T* |* A8 Z- K1 a4 i
ABSTRACT
$ O& v: P' n. D& m# SFive patients were treated with gonadotropin and topical testosterone for micropenis associated% {; B; f" T `. @6 L, U
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 x: P6 E- Z$ u5 M
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
3 g$ T- D$ {% M' O& M( Ccream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 x$ s4 `" y5 M5 t$ Q9 I8 J
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ v% O0 m! u0 lincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
7 E, {/ N: ^5 x/ N* d0 A1 Bincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% C* b; {& _% q, P' Woccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This9 [3 M! N) N5 B9 n
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 F% }( M2 ^; u4 F \
growth. The response appears to be greater in younger children, which is consistent with previ-
^, B/ ^3 G" O" ^' x: n, pously published studies of age-related 5 reductase activity.
3 g3 w8 X6 W8 s4 U7 X; ~/ DChildren with microphallus regardless of its etiology will
; N" w' M' Q( G" N5 _/ Frequire augmentation or consideration for alteration of exter-$ B8 U; X: Q1 l+ l# [# c9 x7 ~/ B
nal genitalia. In many instances urethroplasty for hypo-
) v2 m5 y. u& u8 O; F2 F# kspadias is easier with previous stimulation of phallic growth.
7 ~' _9 `# ]& \# B/ ?! U/ m/ ?; |The use of testosterone administered parenterally or topically
/ ?7 R6 Z' t& Y/ w. v- S( U& Xhas produced effective phallic growth. 1- 3 The mechanism of& N( D& n5 K) s# ^& z
response has been considered as local or systemic. With this }: o5 P* M" E5 k, |# {
in mind we studied 5 children with microphallus for response
0 a' Y- `. R8 h8 K0 E# ^# D! Lto gonadotropin and to topical testosterone independently.- e% H$ G! L" d) }) t+ v& t
MATERIALS AND METHODS$ q5 z& W1 J& d
Five 46 XY male subjects between 3 and 17 years old were
) u3 U9 {3 K0 Q3 ?% [) }3 [evaluated for serum testosterone levels and hypothalamic/ q. N/ }0 g) N- M& z7 t0 h9 p
function. Of these 5 boys 2 were considered to have Kallmann's6 U+ y+ q9 \, K- m, u; R l3 I
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 V; r) ^( s5 ]0 M
lamic deficiency. After evaluation of response to luteinizing
- C$ _3 j, Z; n6 c, e1 l1 f$ ~hormone-releasing hormone these patients were treated with
$ U! f. W! r Z/ v% C& ?1,000 units of gonadotropin weekly for 3 weeks. Six weeks
) B/ d3 @8 Y9 ^- uafter completion of gonadotropin therapy 10 per cent topical+ c# C) \8 z. E* j M
testosterone was applied to the phallus twice daily for 3 weeks.% [: V! ~( z( c9 D) R4 t$ b: {9 D5 E
Serum testosterone, luteinizing hormone and follicle-stimulat-$ X) ^: U8 v/ o
ing hormone were monitored before, during and after comple-
( @/ ~( J2 }; K6 v4 M) mtion of each phase of therapy. Penile stretch length was/ ]( T, t4 a4 \( S
obtained by measuring from the symphysis pubis to the tip of. X% R& V3 U7 G
the glans. Penile circumferential (girth) measurements were1 N0 u% x( R L) `1 Y& `; B. @
obtained using an orthopedic digital measuring device (see
5 A" Q, X6 X1 d& m5 x: U- Bfigure).
3 a/ V* p3 v, }RESULTS
" n& D' t% w, e, O. r' dSerum testosterone increased moderately to levels between7 f; x7 u3 Q* z& u5 R
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 J: t5 `2 O' U( U5 {" a3 t rterone levels with topical testosterone remained near pre-
. i2 _0 m9 g1 b7 [0 [8 h. Q+ Ctreatment levels (35 ng./dl.) or were elevated to similar levels# c4 d/ x, |+ F9 K$ u; d& Y; I
developed after gonadotropin therapy (96 ng./dl.). Higher
6 d- A% O# y6 {6 P. v" zserum levels were noted in older patients (12 and 17 years old),3 P' t' e) e J X4 a
while lower levels persisted in younger patients (4, 8, and 10
0 V6 ?+ k5 ~+ Y2 q" cyears old) (see table). Despite absence of profound alterations$ t* r# c0 s; |3 P: E+ R
of serum testosterone the topical therapy provided a greater
0 w3 M" U# S8 ]4 T8 I2 U* W" I' |Accepted for publication July 1, 1977. ·3 c: Q1 i1 S% H* k3 l8 B
Read at annual meeting of American Urological Association,) E# `9 r T( q) V
Chicago, Illinois, April 24-28, 1977.8 a' F: T4 Y7 }0 q( l7 J
* Requests for reprints: Division of Urology, Henry Ford Hospital,
p$ [3 }) x$ M7 s2 O* T) k9 A, n2799 W. Grand Blvd., Detroit, Michigan 48202.+ u3 g! x0 q, q) y0 L1 d- e1 O9 v
improvement in phallic growth compared to gonadotropin.# X- {1 ^6 Q/ W
Average phallic growth with gonadotropin was 14.3 per cent
' @7 T0 n* o1 ^! `1 O$ b* T- Yincrease in length and 5.0 per cent increase of girth. Topical
& I. N6 l9 t8 j$ atestosterone produced a 60.0 per cent increase of phallic length
( m! e% T; B. d4 o% Yand 52.9 per cent increase of girth (circumference). The; ]# Z6 p: J7 s
response to topical testosterone was greatest in children be-
" k7 |7 b/ H3 E xtween 4 and 8 years old, with a gradual decrease to age 17
& J( F# n9 \- X9 Dyears (see table).
6 Q& A- D* R9 `* ^! N! U- xDISCUSSION
; w# H6 ?& _* ]! S7 p3 o( c3 dTopical testosterone has been used effectively by other
\8 n$ X. I, o! Yclinicians but its mode of action remains controversial. Im-
1 ?+ u k& G9 W' u- \6 q' Mmergut and associates reported an excellent growth response
, r- h; E' j0 `+ S" Bto topical testosterone with low levels of serum testosterone,( W5 u$ Z1 Y2 r4 e# C9 _0 p
suggesting a local effect.1 Others have obtained growth re-
2 K/ X% @" ]: P8 csponse with high. levels of serum testosterone after topical# N% h$ M ?: F' R
administration, suggesting a systemic response. 3 The use of7 @( ]' [. b" i6 L
gonadotropin to obtain levels of serum testosterone compara- X& E5 Q3 a: ?1 q( r. y
ble to levels obtained with topical testosterone would seem to
8 _! @5 J; X, X+ o: F1 dprovide a means to compare the relative effectiveness of4 f+ d, d) I0 `1 ?
topical testosterone to systemic testosterone effect. It cer-7 T# a9 f/ p1 r3 E1 l! V2 X
tainly has been established that gonadotropin as well as par-
: Y3 g; }+ J7 y5 n2 D, p! ]% wenteral testosterone administration will produce genital4 c! g$ j3 }5 Q/ R" T1 c2 u: Y% {0 I4 r
growth. Our report shows that the growth of the phallus was
! V: e+ H, p+ z4 n& Bsignificantly greater with topical applications than with go-
g b8 D' s6 P( J7 {nadotropin, particularly in children less than 10 years old.
u2 |2 I4 {( s$ f3 t) QThe levels of serum testosterone remained similar or lower7 P" j6 u* |+ u3 c# _5 Z
than with gonadotropin during therapy, suggesting that topi-
( f6 L$ s O& a8 ?1 Q- L( p6 n* ^cal application produces genital growth by its local effect as
/ x C% E5 ~; pwell as its systemic effect.
, |2 Z- q, Z$ c* a' uReview of our patients and their growth response related to, A* L6 K8 L6 `
age shows a greater growth response at an earlier age. This is
$ T! ^9 U9 l4 T8 c) N7 T( Vconsistent with the findings of Wilson and Walker, who
* Y# N7 Q. C; Z. \- A3 greported an increased conversion of testosterone to dihydrotes-
8 C$ ~( r) G3 t! O$ \/ v6 k+ J7 l3 A# }tosterone in the foreskin of neonates and infants.4 This activ-
/ W! Z o. L9 U! eity gradually decreases with age until puberty when it ap-4 O$ z7 y( h6 _4 c9 S% s
proaches the same level of activity as peripheral skin. It may
- @9 l: \* s# w! pwell be that absorption of testosterone is less when applied at
4 ] x: l. H) Y4 pan earlier age as suggested by lower serum levels in children8 P8 B$ k8 m$ X% v: o
less than 10 years old. This fact may be explained by the
1 U7 y" j2 @2 ygreater ability of phallic skin to convert testosterone to dihy-
# Y0 @/ h# K# s$ B1 N6 J; Edrotestosterone at this age. Conversely, serum levels in older' \$ `' c. T5 F( r
patients were higher, possibly because of decreased local% ]9 e# p Z9 R0 c9 i: f2 ?
667# |/ W: E" D5 w1 m3 n1 C( Z6 [# E7 X
668 KLUGO AND CERNY
4 d3 N6 v4 |2 j3 }Pt. Age
: ^7 _" z8 \( R(yrs.)
4 n4 r- C4 D" `! O0 h; NSerum Testosterone Phallus (cm.) Change Length" N; D. b3 |& X
(ng./dl.) Girth x Length (%)
" ~" O$ Z/ F& Z43 t* e" y* ^" x6 ]* s
8
- u2 k9 t7 v2 n' z( h& \( ^- ~10
9 [2 h% U3 t3 l8 ?4 D120 l$ B5 u" s( X8 ~3 E+ ?" O
17/ P# c0 t9 i( S( v6 P1 N
Gonadotropin: ]! L$ B8 A* n
71.6 2.0 X 3 16.6* L% W% b8 n% G
50.4 4.0 X 5.0 20.0" e6 I# j/ j. [# O6 H2 s
22.0 4.5 X 4.0 25.0
/ l& |! H7 i3 ?" G: c+ `" Y84.6 4.0 X 4.5 11.1
+ T1 k5 r8 j a8 }% q85.9 4.5 X 5.5 9.05 V* c0 W% M! f# n- T a2 N0 g
Av. 14.3$ K ^5 {; d8 c0 h
4
* i+ _" d+ R( _0 A9 r3 N4 W/ a" }8
" `/ c6 J2 b& m+ r9 m N5 `& P10
$ y/ i7 c7 P$ P( m8 m12; ~7 i* x2 f4 u; C( T, P; _; \
17
* J* i( O) P5 R9 ]Topical testosterone
! Z) m- e2 w o* @9 D8 |% G m34.6 4.5 X 6.5 850 r( p' P7 P l
38.8 6.0 X 8.5 70
2 B) S! h. ?! h0 J! u+ G4 T, f8 P7 l40.0 6.0 X 6.5 62.5
" w" c# X( c. S93.6 6.0 X 7.0 55.5: |$ |- L1 |5 p5 ?' `1 w' W8 }
95.0 6.5 X 7.0 27.27 S9 w6 B3 H8 U
Av. 60.0
+ }6 u! q9 t8 J2 }7 ~; savailable testosterone. Again, emphasis should be placed on+ q% D2 f: o) R+ m# l; _
early therapy when lower levels of testosterone appear to
Z. Q+ Z+ }+ Q# sprovide the best responses. The earlier therapy is instituted
}7 D+ z9 g- o9 O% N& X |the more likely there will be an excellent response with low
. w: _1 k/ U$ |0 ?! x5 W% j5 Bserum levels. Response occurs throughout adolescence as& I; S: u+ K9 W7 W& v
noted in nomograms of phallic growth. 7 The actual response+ x: Z7 M5 e8 M9 M
to a given serum level of testosterone is much greater at birth. t, @5 y% n, W: c0 @ x3 o# u6 C
and gradually decreases as boys reach puberty. This is most7 e9 `9 Q5 G4 B2 U9 X
likely related to the conversion of testosterone to dihydrotes-
& C2 Q- d5 {/ G5 O. Mtosterone and correlates well with the studies of testosterone
% O4 _, g6 C. l/ {conversion in foreskin at various ages.
* {8 [. s- e3 B I4 \3 s# n1 eThe question arises regarding early treatment as to whether1 e) z* }. x* ~: C
one might sacrifice ultimate potential growth as with acceler-2 l6 q/ e, p4 k, a' E
ated bone growth. The situation appears quite the reverse
$ x) H0 d' {. r, o, T% s0 i6 s" lwith phallic response. If the early growth period is not used" l6 X* b- i" h# G+ l, W
when 5a reductase activity is greatest then potential growth
6 X n$ d6 E9 k; N5 }2 dmay be lost. We have not observed any regression of growth
$ z: S4 F. \) o6 O9 K' F# gattained with topical or gonadotropin therapy. It may well
% M4 W- c/ T# A# Xbe that some patients will show little or no response to any
7 Z3 _; X1 a$ A7 k1 yform of therapy. This would suggest a defect in the ability to
8 M" S; {4 ?3 e7 P: A% H: K' r- Vconvert testosterone to dihydrotestosterone and indicate that
- i, h( l) q L( [. z) S" Uphallic and peripheral skin, and subcutaneous tissue should
1 v+ g& Q- L3 T7 ]/ @& y# F# Obe compared for 5a reductase activity.% [* m8 c8 D) K& L4 f
A, loop enlarges to measure penile girth in millimeters. B,
! x, V K" x0 F; F% ]example of penile girth computed easily and accurately.
% }! H; G6 d, u: u4 Y; j! Dconversion of testosterone to dihydrotestosterone. It is in this
; [+ S( }7 `7 R4 q; u- Polder group that others have noted high levels of serum
+ x3 o. i) n6 {4 Ftestosterone with topical application. It would also appear
1 q1 z0 S% Y/ v [/ sthat phallic response during puberty is related directly to the6 d4 G" C! `( J. d7 i3 W
serum testosterone level. There also is other evidence of local9 L+ G1 f6 I4 f7 W2 W
response to testosterone with hair growth and with spermato-. W; C' J* s- T( b
genesis. 5• 63 Z* h4 D# g2 {( N8 U
Administration of larger doses of gonadotropin or systemic* O( E" u5 W# U7 m. k. O
testosterone, as well as topical applications that produce; t8 M: W! ?8 F& {6 ~7 F# R, s
higher levels of serum testosterone (150 to 900 ng./dl.), will+ V1 P" E6 q; [) p" v6 v
also produce phallic growth but risks accelerated skeletal( M& ?# T: x$ l* }, O
maturation even after stopping treatment. It would appear
8 F @7 U2 g+ w' lthat this may be avoided by topical applications of testosterone
' r+ l# g; u9 d& @and monitoring of serum testosterone. Even with this control
. @5 k7 `1 p0 }$ j0 wthe duration of our therapy did not exceed 3 weeks at any
: P; K" K" d) I/ a* i4 mtime. It is apparent that the prepuberal male subject may
8 B6 j( \9 i1 V6 D' @% a! h3 \suffer accelerated bone growth with testosterone levels near
4 \9 H1 i4 {+ h0 R; p! k200 ng./dl. When skeletal maturation is complete the level of
6 P/ M, g h$ k+ R8 J3 G& l1 @- hserum testosterone can be maintained in the 700 to 1,300 ng./
' m( X: g1 e& c) ^* Z( Adl. range to stimulate phallic growth and secondary sexual
* S# z# T# [" e2 u. Gchanges. Therefore, after skeletal maturation parenteral tes-
3 t' |, R0 z& V$ T+ ltosterone may be used to advantage. Before skeletal matura-
& j7 m1 p$ @! R) e Xtion care must be taken to avoid maintaining levels of serum
# w# P5 T; B1 N: f7 jtestosterone more than 100 ng./dl. Low-dose gonadotropin: e/ @5 g1 i2 @1 N; Q
depends upon intrinsic testicular activity and may require6 K( Y- `. I" q- E* D
prolonged administration for any response.
3 B- p0 v5 O& T9 kAlternately, topical testosterone does not depend upon tes-
8 _. x9 W: @/ N. w) f# d4 {- Pticular function and may provide a more constant level of+ X" V1 m' \. W2 H" V
REFERENCES
) A4 x! t x- p+ ], Z5 s! @; w1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,1 M9 k5 f# a4 f$ K
R.: The local application of testosterone cream to the prepub-$ m8 G( V+ o, a, k6 k
ertal phallus. J. Urol., 105: 905, 1971.2 A4 a+ k: S! F7 N" g {
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
. A( g+ e/ [+ Dtreatment for micropenis during early childhood. J. Pediat.,/ m' S8 V$ [. c8 |) M% K
83: 247, 1973.
4 Y5 r' d N( N3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-7 A2 ~5 d, y( ?2 e
one therapy for penile growth. Urology, 6: 708, 1975.
/ y! c' a! \2 p& O- T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone" a" s! a7 H+ a& f$ j! ^% X
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ R/ g% X }2 V% _
skin slices of man. J. Clin. Invest., 48: 371, 1969.2 {$ b% O/ C1 H9 l& C
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth6 n: {8 J7 I3 L3 r
by topical application of androgens. J.A.M.A., 191: 521, 1965.: Q4 `& m8 d3 p5 r- j
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 O- x9 K# Q+ }' l5 Candrogenic effect of interstitial cell tumor of the testis. J.) E4 c6 j" P) |: P3 U
Urol., 104: 774, 1970.
1 q& e' p( B' ~: u& H7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, R9 y0 h S9 I& u" x
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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