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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND J, c6 @8 f; C% S. C
GONADOTROPIN
: h% t8 u* v5 M3 j, A8 m8 HRICHARD C. KLUGO* AND JOSEPH C. CERNY; ~/ o: m) N7 P
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! {5 A4 M- `" l7 Z* CABSTRACT
3 c! d2 r. b" }- SFive patients were treated with gonadotropin and topical testosterone for micropenis associated
4 I# J' z0 A0 ^% D/ v+ R( fwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! S: r H' y. O/ p1 f5 M' z/ o
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( x3 L: g+ g. S3 ]1 A; I7 s# acream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
$ \. J" I% p8 N2 q: q- J5 {for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
! F" ?2 e8 `4 l6 ?increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! m) D, j9 Q# r8 d8 F) @
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# j2 K3 x* a/ b+ @* B/ |occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This' y1 o- U- v7 k* m2 D- S0 J G' {
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile M- |4 i! H" Y: Z4 o: Z6 z
growth. The response appears to be greater in younger children, which is consistent with previ-
5 f6 C. W4 g! ?, n n9 Mously published studies of age-related 5 reductase activity.
) u0 p+ R9 B' D( ]& z) S, r6 eChildren with microphallus regardless of its etiology will+ ~4 N0 B% ^ H; C: b
require augmentation or consideration for alteration of exter-7 B- L6 C* i& V% r) R) `+ L
nal genitalia. In many instances urethroplasty for hypo-$ M2 `8 e- F( M+ S5 ]0 f: R
spadias is easier with previous stimulation of phallic growth., L4 y# X# O5 J, B" a
The use of testosterone administered parenterally or topically
9 D/ A+ x# P2 {" T% ihas produced effective phallic growth. 1- 3 The mechanism of" |" G6 S: o( ]6 `& @
response has been considered as local or systemic. With this
' I2 F. @, w8 B! B0 lin mind we studied 5 children with microphallus for response4 r& d7 v1 w! w* ]2 n
to gonadotropin and to topical testosterone independently.
5 u* o- C6 g' x$ ^: f8 xMATERIALS AND METHODS' v P5 h6 p. M" L$ W% m1 R
Five 46 XY male subjects between 3 and 17 years old were R( r% @+ }8 T% [1 d9 F
evaluated for serum testosterone levels and hypothalamic
! v7 {& s) }: T+ t3 ?1 ^- O8 kfunction. Of these 5 boys 2 were considered to have Kallmann's B; w2 P& X2 @+ f5 i& N
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-) y* z6 s) X" y2 S
lamic deficiency. After evaluation of response to luteinizing
# Z3 P4 G) Y+ n+ i% U7 b: }hormone-releasing hormone these patients were treated with
+ {8 R* {1 t7 T- T( ^0 E3 H1,000 units of gonadotropin weekly for 3 weeks. Six weeks
1 ~# C8 ^& H8 \2 `after completion of gonadotropin therapy 10 per cent topical
. B, ^- ?0 d6 Y, |testosterone was applied to the phallus twice daily for 3 weeks.
; n$ d A% s5 S8 I5 [0 WSerum testosterone, luteinizing hormone and follicle-stimulat-) T3 s# h" B* Z" ~ l
ing hormone were monitored before, during and after comple-
$ g7 z' F; Q! Y7 L- r. [tion of each phase of therapy. Penile stretch length was+ O+ f+ |+ @" Z7 f& g
obtained by measuring from the symphysis pubis to the tip of
# C; W8 X! n$ \& dthe glans. Penile circumferential (girth) measurements were1 s* n: ^$ A; ^ ^7 x6 x
obtained using an orthopedic digital measuring device (see
X' b7 t- b7 a0 [$ ofigure).
4 V3 A. {) m1 X* t. }4 _& Q2 W: LRESULTS
3 t7 Q4 Y4 f/ N2 I! aSerum testosterone increased moderately to levels between: l+ a3 R8 Z& ?/ p! w% ~
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
: |" m G) \4 _& K4 j2 Z1 W ?terone levels with topical testosterone remained near pre-
( N7 G) {$ G/ N2 L1 y* [treatment levels (35 ng./dl.) or were elevated to similar levels2 v* `' a n/ e: v
developed after gonadotropin therapy (96 ng./dl.). Higher
S+ I, S& W9 i) E* t) w+ c4 lserum levels were noted in older patients (12 and 17 years old),4 J- T8 m5 J7 E- O
while lower levels persisted in younger patients (4, 8, and 10
$ K6 X. O0 z& s4 \. Iyears old) (see table). Despite absence of profound alterations
9 _- y; }: w% d) |, Z) Eof serum testosterone the topical therapy provided a greater' O2 l8 s; g7 E, ~3 ~- B/ {/ b
Accepted for publication July 1, 1977. ·
, y+ C3 S5 F O3 m: nRead at annual meeting of American Urological Association,
. q2 A. n3 K. ?; d& `. ~Chicago, Illinois, April 24-28, 1977.* G. ?4 |- H6 v7 N8 Q1 W
* Requests for reprints: Division of Urology, Henry Ford Hospital,
; @# N- r7 B. x1 h2799 W. Grand Blvd., Detroit, Michigan 48202.
9 E. V8 e) L% aimprovement in phallic growth compared to gonadotropin.& V! ~0 X& z9 @9 S/ W
Average phallic growth with gonadotropin was 14.3 per cent2 _. }" V8 k! i3 ?
increase in length and 5.0 per cent increase of girth. Topical7 L& [) m6 W* L- ]# j$ \0 `
testosterone produced a 60.0 per cent increase of phallic length, ?( O6 O6 }5 d5 e- [+ [
and 52.9 per cent increase of girth (circumference). The
8 z2 K5 E$ r! gresponse to topical testosterone was greatest in children be-/ s1 |8 [- d5 L" ^
tween 4 and 8 years old, with a gradual decrease to age 17
. x, A+ f) ]0 p y [years (see table).
! |, ~9 s( l9 |: EDISCUSSION
9 W! Z e- s# ]- B9 UTopical testosterone has been used effectively by other+ O* ? `( P' N4 U
clinicians but its mode of action remains controversial. Im-
9 x: S$ [2 W! Z: d& i' Q0 V8 R1 Vmergut and associates reported an excellent growth response
# e5 ~( s7 A' L0 }to topical testosterone with low levels of serum testosterone,: f# R' @9 u' z0 a6 N! W+ |& U! n% I
suggesting a local effect.1 Others have obtained growth re-+ N9 a4 V" L- g( X$ |# K5 ]
sponse with high. levels of serum testosterone after topical3 @8 ?5 r* v8 Q; t A
administration, suggesting a systemic response. 3 The use of8 ^9 R! _$ l7 {2 [/ o0 n
gonadotropin to obtain levels of serum testosterone compara-
5 l6 B" I8 G/ k. Vble to levels obtained with topical testosterone would seem to9 F$ `1 u3 r" \( {- R; ~% j
provide a means to compare the relative effectiveness of8 M% l6 x/ d8 X u% l. O! B
topical testosterone to systemic testosterone effect. It cer-) Z: _& K1 W0 o+ _' ]" I3 {( }, @
tainly has been established that gonadotropin as well as par-4 a- E" K$ X3 d9 B# ~
enteral testosterone administration will produce genital
2 G2 @3 z, S- I9 agrowth. Our report shows that the growth of the phallus was
4 Y- Q' K' R E6 S- n9 usignificantly greater with topical applications than with go-6 I& V( y2 [: M9 U. d+ B
nadotropin, particularly in children less than 10 years old.. ^ r' K- |- o; h1 g6 A; X
The levels of serum testosterone remained similar or lower
1 X; [, S3 m3 K5 Sthan with gonadotropin during therapy, suggesting that topi-; G- Y, \( s ?: w; A7 y' N5 ]" @
cal application produces genital growth by its local effect as
" Y8 g) G8 {8 R- U5 _/ r4 }well as its systemic effect.
/ D4 j& D+ `- K7 d: t- G8 zReview of our patients and their growth response related to
+ V+ n$ C* @! }- j6 x I+ F# @age shows a greater growth response at an earlier age. This is4 f# L9 ~' K2 H( ]4 s$ P* L. V
consistent with the findings of Wilson and Walker, who4 w- q9 r! a" s5 F- ]3 R
reported an increased conversion of testosterone to dihydrotes-, L3 q8 Y' R7 j( q+ e
tosterone in the foreskin of neonates and infants.4 This activ-: m- E* L0 l6 V
ity gradually decreases with age until puberty when it ap-$ M' F* n4 A( C9 `. e
proaches the same level of activity as peripheral skin. It may
" W, c$ e" D# V- ywell be that absorption of testosterone is less when applied at
" Y$ N( C. F" I, w6 D1 W. S) Aan earlier age as suggested by lower serum levels in children/ ^8 G! E5 f' g' C! P
less than 10 years old. This fact may be explained by the& b! |; P' Z$ @7 B* Q; H
greater ability of phallic skin to convert testosterone to dihy-/ b& k4 x1 s1 T
drotestosterone at this age. Conversely, serum levels in older& G/ a( v( S% C) }/ f
patients were higher, possibly because of decreased local
: x7 o2 ?" u0 Q J, d/ f% ?+ S. v667) {" ~# { b6 r& X5 w, B. t
668 KLUGO AND CERNY' P0 f* j9 L, u) i' M
Pt. Age
- c* o3 y7 L: D) a' g$ {& ^: E- Z3 B(yrs.)
' u' \0 Q8 X6 M" @: g2 N! uSerum Testosterone Phallus (cm.) Change Length
( V3 V& k. K% A/ x2 n8 v/ q7 [- e(ng./dl.) Girth x Length (%)
# M/ z, }" ?0 T. n+ W4
! k: b) h; |) k) C8; N2 G' T: i* j/ S4 m9 {+ @7 ]$ [9 c
10$ D2 s9 [& ^2 A. A; \' [- t
12& ], C; e5 q+ B# ] f6 z/ [+ t
17
2 N/ a% n8 q4 K9 V2 `Gonadotropin
6 r7 c1 s1 \. U, R% }( U4 B7 k71.6 2.0 X 3 16.6
: ~8 X: s8 O0 u3 F. a9 z" o' \50.4 4.0 X 5.0 20.0
' I! Z/ c Q0 p* O2 L! b8 S22.0 4.5 X 4.0 25.0
* W# U2 g1 n: B. d( G# F) q+ R84.6 4.0 X 4.5 11.10 x7 ?2 M5 m+ @2 o2 s
85.9 4.5 X 5.5 9.0
* A/ @" O" M0 b% g& _! g$ }Av. 14.30 n; L- U0 E3 a$ K4 J0 G
4# i* ~9 e) ?5 C: G! M# l3 p
83 ?3 E( q; _3 H
10
) u: m9 E# ? L! X4 J12
( V m: m5 r5 L' a+ o5 x. o" ~17
9 e, [! B/ I5 N; _5 J) p# Q ?Topical testosterone. a/ I; C+ A9 J- s
34.6 4.5 X 6.5 85
2 {% P4 f0 H' ~8 Y% Z+ i I6 V38.8 6.0 X 8.5 70; c8 W" g1 C: q+ H- P# ^1 v. K
40.0 6.0 X 6.5 62.5# c& H! W2 Q, U- q0 W# D4 |& }
93.6 6.0 X 7.0 55.5
0 T+ Q* p5 J; K! I0 U95.0 6.5 X 7.0 27.2
8 K! q+ X! B; UAv. 60.0
2 F7 s% p1 T) f0 Mavailable testosterone. Again, emphasis should be placed on+ V' [8 ^% m# f! l# W0 f
early therapy when lower levels of testosterone appear to" J8 H0 s& B# ?: ?% G
provide the best responses. The earlier therapy is instituted, s7 W2 ^ L9 i5 F. f
the more likely there will be an excellent response with low
1 u, F7 H) a; H2 f- zserum levels. Response occurs throughout adolescence as% s P8 L9 K/ B+ ]$ D) c' t8 d
noted in nomograms of phallic growth. 7 The actual response
" {4 j7 _1 R& r7 w' X. O; g0 I4 oto a given serum level of testosterone is much greater at birth6 G5 R7 }; h! g# j" `
and gradually decreases as boys reach puberty. This is most
; T2 {$ ^* ~; K% U# y. Jlikely related to the conversion of testosterone to dihydrotes-- J0 `* C5 P) d( f
tosterone and correlates well with the studies of testosterone
1 y* P K) S# qconversion in foreskin at various ages., J @# C2 A8 @+ j+ r
The question arises regarding early treatment as to whether
; G) E- E8 H- ~3 Tone might sacrifice ultimate potential growth as with acceler-
4 J1 @, b1 c# n! h( O2 o7 n9 |3 ~ gated bone growth. The situation appears quite the reverse
) K) i, ~0 t2 x+ y" `& dwith phallic response. If the early growth period is not used9 |7 n K" t. J$ ?
when 5a reductase activity is greatest then potential growth& o- e8 G$ n- Z7 @
may be lost. We have not observed any regression of growth, }, n1 o0 h8 |& r
attained with topical or gonadotropin therapy. It may well
6 u7 L( x2 a) b$ B" e5 ~$ ^) W& A& Rbe that some patients will show little or no response to any
3 P% D% @7 R* f1 gform of therapy. This would suggest a defect in the ability to* _8 D1 \% `- \
convert testosterone to dihydrotestosterone and indicate that
4 X; S) ~1 u! G8 b, K3 j z1 Qphallic and peripheral skin, and subcutaneous tissue should
+ a, U7 _6 @9 V' Q: Qbe compared for 5a reductase activity.
8 P$ x7 B8 w$ IA, loop enlarges to measure penile girth in millimeters. B,4 w& I+ ~7 }- w2 g, W! Z1 ~
example of penile girth computed easily and accurately.
/ Z% D% ?/ ]4 Y6 N ?conversion of testosterone to dihydrotestosterone. It is in this5 f2 P$ b' J( d3 y& S+ Z5 s/ m. R" n
older group that others have noted high levels of serum- q- E, K! d m: x3 w& i9 Z
testosterone with topical application. It would also appear# w* \. f* k7 y5 Q8 |$ g
that phallic response during puberty is related directly to the3 F9 m+ v5 q0 x) `. z# x; b
serum testosterone level. There also is other evidence of local
4 n9 t- v6 T7 J8 n) P) [% Jresponse to testosterone with hair growth and with spermato-
& P. P! A7 F6 o# z: S# q9 K% ugenesis. 5• 6' M: E: U6 S P8 _& m
Administration of larger doses of gonadotropin or systemic
5 G2 ? n' K' O6 [2 l8 Atestosterone, as well as topical applications that produce, e- o0 O, D) X9 N
higher levels of serum testosterone (150 to 900 ng./dl.), will% M( G9 j2 ]* w" @" A9 w& W, i
also produce phallic growth but risks accelerated skeletal
% o0 Z( Q5 d: z5 x& }. bmaturation even after stopping treatment. It would appear
3 i! z. u' u. @, z' ithat this may be avoided by topical applications of testosterone2 A0 R( ~" K0 x) S7 v
and monitoring of serum testosterone. Even with this control
' |" ~9 r" G/ q l- p6 \4 Xthe duration of our therapy did not exceed 3 weeks at any* p/ e5 e5 n; G
time. It is apparent that the prepuberal male subject may
& ^0 z1 Y- l: v9 c/ T7 \5 ^0 ysuffer accelerated bone growth with testosterone levels near9 c- m3 f7 p8 `3 ^
200 ng./dl. When skeletal maturation is complete the level of) Q5 `4 U; D6 j7 u: `' L% T
serum testosterone can be maintained in the 700 to 1,300 ng./+ f9 E7 C4 l$ r8 X% U+ f1 w
dl. range to stimulate phallic growth and secondary sexual" v! b. B& l+ O/ @
changes. Therefore, after skeletal maturation parenteral tes-1 [2 S" R) G! @) C' W
tosterone may be used to advantage. Before skeletal matura-
( z* e2 [" @; f5 B7 |& Ttion care must be taken to avoid maintaining levels of serum
z3 Z# d/ u" L' htestosterone more than 100 ng./dl. Low-dose gonadotropin
+ A0 Z! s( p; N4 T1 ndepends upon intrinsic testicular activity and may require
8 U. S3 f: H K- Z" J. m. O6 Oprolonged administration for any response. k5 q% ?; v/ |5 n% }
Alternately, topical testosterone does not depend upon tes-* D9 D' g& H' R& C3 B. w ]3 G
ticular function and may provide a more constant level of2 d1 \7 {6 t# d% a. E0 Z
REFERENCES
- }2 ]! \3 f; O7 b; v& C; m1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& c1 [$ l. [; j" S$ }5 C4 V7 F" k
R.: The local application of testosterone cream to the prepub-
3 @+ }1 v8 ^2 Q) vertal phallus. J. Urol., 105: 905, 1971.; } N3 [2 I/ E% i4 r+ D8 H
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' M/ \* z2 a3 V' \ Htreatment for micropenis during early childhood. J. Pediat.,
5 ?3 [9 t1 D4 d1 a0 q( W83: 247, 1973., l/ x- b4 B& L( f" X) f, P
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-" E) m0 }1 v4 s6 q; w
one therapy for penile growth. Urology, 6: 708, 1975.
s4 \9 B/ l7 D! B& z$ q4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) p) f, R! q) t' Q6 i
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: ~: r0 w( u& y; f& p
skin slices of man. J. Clin. Invest., 48: 371, 1969.
7 J6 [- o+ v9 o2 {( U+ x6 S" [5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 O% ]0 n$ K6 t3 R. X# [$ j- jby topical application of androgens. J.A.M.A., 191: 521, 1965.
9 a H7 [+ C4 |2 S/ O& K* S; L; x6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
% j3 j0 [/ I' A, k8 k( S( yandrogenic effect of interstitial cell tumor of the testis. J.* ~5 }( B! c; s: g' o7 p Y' a# w' ^
Urol., 104: 774, 1970.
8 B( e+ l+ ?. ?7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 F/ e5 ?1 e8 G8 Y- C/ Jtion in the male genitalia from birth to maturity. J. Urol., 48: |
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