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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# I) E% Y7 q5 v8 A. {6 T1 F" H: L2 j
GONADOTROPIN
3 [: \2 k/ F. M* ]2 u R7 QRICHARD C. KLUGO* AND JOSEPH C. CERNY* c# h6 e$ D$ u$ d" j* ^
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan% u+ y- A J, T7 a1 o+ I7 a
ABSTRACT
% Z: ]' a/ k6 H# V6 |$ zFive patients were treated with gonadotropin and topical testosterone for micropenis associated& M5 Y7 z8 m. v3 _: F: D: \
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ A; C9 i6 a/ `% N
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ t7 G e0 |& X
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 j! B' h c' J9 W2 M Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent( ~" z' @/ w& \8 \% Z- E
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average4 @. b* z6 m) V$ |- ?( ]5 n7 ^8 W
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ x- f, Y7 J1 w6 ?occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This9 G4 M9 V0 \1 N! B/ j- j' s
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile9 B0 @1 n# R8 c8 b- Z
growth. The response appears to be greater in younger children, which is consistent with previ-
* h1 E* ^1 b1 P' z4 _" w% Fously published studies of age-related 5 reductase activity.
0 d' D/ q7 s* r" S- O Z; q! GChildren with microphallus regardless of its etiology will" t* b# @ ]$ _) L6 b) D5 p1 ^
require augmentation or consideration for alteration of exter-
, Z) m+ E: |4 U9 h! I$ Tnal genitalia. In many instances urethroplasty for hypo-
6 s" ~& b/ l+ x6 f$ O |) N7 `- gspadias is easier with previous stimulation of phallic growth.* c* x$ Y2 b0 a# ^
The use of testosterone administered parenterally or topically. P0 x" Q- y2 |2 T1 c2 G
has produced effective phallic growth. 1- 3 The mechanism of
9 {4 M( ]( X2 y7 ^2 Sresponse has been considered as local or systemic. With this* Q; G' Q' L, _9 w" l. H
in mind we studied 5 children with microphallus for response% P) {/ N& B& w
to gonadotropin and to topical testosterone independently.9 E! }. F; \7 [1 T/ g; W5 u! o
MATERIALS AND METHODS
: l# e, j0 I% `Five 46 XY male subjects between 3 and 17 years old were1 A1 f) M$ l4 t# }; L" a
evaluated for serum testosterone levels and hypothalamic
9 l6 u2 K- @: m. D- }4 z# b: kfunction. Of these 5 boys 2 were considered to have Kallmann's
6 A1 J" c) y( w2 Isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 j# c5 G1 Z: O! o, S/ B' }
lamic deficiency. After evaluation of response to luteinizing4 v$ G& I8 P7 f1 w* P; A7 u( z9 _
hormone-releasing hormone these patients were treated with
5 H: Y' Y7 T! |$ S7 R% }( w1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# |; l9 Y- a l: e& qafter completion of gonadotropin therapy 10 per cent topical
4 ^9 ^5 c' D: Q! z1 b' Btestosterone was applied to the phallus twice daily for 3 weeks.2 H2 ]3 ?/ A- @2 |4 _+ \$ u; F# T
Serum testosterone, luteinizing hormone and follicle-stimulat-
* ]+ \) P. |5 C# m, a2 z/ fing hormone were monitored before, during and after comple-. R- @& e6 ]' F, F4 \; q! ^
tion of each phase of therapy. Penile stretch length was, m9 A6 `- B5 E% ?+ f/ T& h
obtained by measuring from the symphysis pubis to the tip of
( T6 |6 n9 R4 v7 T7 ythe glans. Penile circumferential (girth) measurements were
. p/ l$ a- v K5 u7 ]3 Cobtained using an orthopedic digital measuring device (see
! A) h! \* I/ }0 d2 g! }6 kfigure).2 c/ R6 k4 V% s
RESULTS
0 q k8 _2 R: G G# WSerum testosterone increased moderately to levels between) i9 _, B# g3 M! _7 b$ h9 N/ V
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
& A& f @) C7 [ d: [* q! ]terone levels with topical testosterone remained near pre-
2 H( n4 j4 u. U- Atreatment levels (35 ng./dl.) or were elevated to similar levels) n, I6 l A! G6 F1 Q+ T
developed after gonadotropin therapy (96 ng./dl.). Higher
; W9 ~, }1 n$ ~8 a) g' b+ Mserum levels were noted in older patients (12 and 17 years old),; [3 v: m! b* Z D
while lower levels persisted in younger patients (4, 8, and 10
7 ]8 |7 a4 m; C5 N- E! byears old) (see table). Despite absence of profound alterations
# K. r7 c9 k+ Z9 z$ x6 ?of serum testosterone the topical therapy provided a greater
) A( W6 ^& J0 E# y. B. r" sAccepted for publication July 1, 1977. ·0 z( H3 q4 m/ j/ b+ k
Read at annual meeting of American Urological Association,
9 e6 u, P/ m. R1 gChicago, Illinois, April 24-28, 1977.
, n E- u: u c* q* g* R. Y8 O* Requests for reprints: Division of Urology, Henry Ford Hospital,9 b, x3 y! o' ?1 z
2799 W. Grand Blvd., Detroit, Michigan 48202.8 X" c3 J0 u' H
improvement in phallic growth compared to gonadotropin., d: G) I8 u. I& i& J
Average phallic growth with gonadotropin was 14.3 per cent
4 F9 C/ r( K/ O! E$ I* Y4 _- H; |increase in length and 5.0 per cent increase of girth. Topical
; u' E, [; Y) ^+ S9 B$ t, Otestosterone produced a 60.0 per cent increase of phallic length
9 i0 \7 c3 p3 G- J5 {" J+ [and 52.9 per cent increase of girth (circumference). The) T& Y/ }9 [0 [" H
response to topical testosterone was greatest in children be-" g. H- o) f" D: I
tween 4 and 8 years old, with a gradual decrease to age 17) y* D8 n0 t* }1 }' B
years (see table).2 ], \$ `+ ^7 Q; ]
DISCUSSION( W, ?) z/ o6 a6 w
Topical testosterone has been used effectively by other
5 k8 D/ [! `8 L6 ]9 @2 I+ j9 ]) ]clinicians but its mode of action remains controversial. Im-
. |2 n% g* {+ b/ w+ y( Hmergut and associates reported an excellent growth response
7 [( \3 f8 e1 P# F$ Tto topical testosterone with low levels of serum testosterone,
) x! K2 P! M6 D. Csuggesting a local effect.1 Others have obtained growth re-+ Y3 V8 Q4 _. |% ~% w
sponse with high. levels of serum testosterone after topical
+ U! H' c; l, ]' p Q! W! Zadministration, suggesting a systemic response. 3 The use of
! Q4 N# u$ ^) f/ `9 E/ a0 w# Sgonadotropin to obtain levels of serum testosterone compara-" a Z! M- _) F8 J
ble to levels obtained with topical testosterone would seem to% L, a; c5 D% O) z" e/ t
provide a means to compare the relative effectiveness of2 L+ p4 p/ U N+ W; Q
topical testosterone to systemic testosterone effect. It cer- r0 Z" [( s3 k' o& A
tainly has been established that gonadotropin as well as par-% [: F: @* z5 a5 }9 d
enteral testosterone administration will produce genital; }9 j8 Z7 P# |3 ]
growth. Our report shows that the growth of the phallus was
7 t6 T, ^1 l8 Ysignificantly greater with topical applications than with go-1 H6 f/ `( l2 g' h& Z
nadotropin, particularly in children less than 10 years old.
; V, F% f+ Y. w" b8 W0 tThe levels of serum testosterone remained similar or lower
5 ~; w5 r2 M6 O2 z) k# G T0 G2 x- T1 p7 ?than with gonadotropin during therapy, suggesting that topi-
, s9 r5 t; {. I& ^# g fcal application produces genital growth by its local effect as# c7 k' C" \' i: @- A+ o0 ?
well as its systemic effect.
0 I9 d$ J/ l; B. GReview of our patients and their growth response related to% c. @2 k" O% f' H0 |) d0 g& L
age shows a greater growth response at an earlier age. This is
0 X$ q/ o' I5 Wconsistent with the findings of Wilson and Walker, who
1 R* ]& P. `2 }! Hreported an increased conversion of testosterone to dihydrotes-
) r3 M0 M: I4 A" H7 ltosterone in the foreskin of neonates and infants.4 This activ-5 m% d, k2 K4 r& N3 R' ?
ity gradually decreases with age until puberty when it ap-
# d9 j7 `# @9 q' hproaches the same level of activity as peripheral skin. It may
# |8 E: I% H8 }- i3 l+ ^$ _well be that absorption of testosterone is less when applied at
. ]$ B+ P+ V4 `" can earlier age as suggested by lower serum levels in children$ @6 X, U# ?- ~
less than 10 years old. This fact may be explained by the9 y. s F& i4 |0 ]1 G9 j$ M& Z, N
greater ability of phallic skin to convert testosterone to dihy-9 O/ t% Z6 o* _2 V1 H& u- s
drotestosterone at this age. Conversely, serum levels in older) f2 x* y3 J- i' S0 h# _
patients were higher, possibly because of decreased local
! z; V4 b: I3 p$ F- ~. y- R667& h7 H1 B( H: b( h
668 KLUGO AND CERNY3 @% @7 s8 Y1 \0 a/ i; A
Pt. Age/ U1 Q8 A( }5 |
(yrs.)
* ^0 s- q. @2 Y2 ESerum Testosterone Phallus (cm.) Change Length
. M7 ]- b! m: k; W8 V" _5 B(ng./dl.) Girth x Length (%)
: ^9 p- T/ @# X4
' ^, Z7 @/ X0 R8 |8" B3 N$ v N# g7 a
101 J* a2 \, C# s/ k) b7 }( E1 `
12
. l2 _+ L9 H; G+ p) f! g4 R17+ q z: q5 t6 h0 t X( q7 ^. d
Gonadotropin, j3 v8 y F9 d5 B" Q& ]
71.6 2.0 X 3 16.69 X( A z$ ?# _9 H
50.4 4.0 X 5.0 20.0
1 r8 {+ v9 @2 T8 o% v- a/ M22.0 4.5 X 4.0 25.09 E, X; G+ R H# j+ H
84.6 4.0 X 4.5 11.1
K! K. [0 o( m4 L85.9 4.5 X 5.5 9.0* } j' H. U8 o* D' @; X% r/ q) e
Av. 14.3
. [5 n: Z, |- y* L1 i$ a4% Q3 s: K# z$ a" N& Y; H' C
8" W# m, T- q) w( h
106 h3 j" Q. f. H5 l% r
12
8 x9 r) ^) e- Y17
" ~9 K6 a6 ^. D" GTopical testosterone4 ?' S- R, \/ j
34.6 4.5 X 6.5 85
/ l0 e6 a2 b) G. e7 F38.8 6.0 X 8.5 70
% Q+ p7 F( v* P4 k- U8 i40.0 6.0 X 6.5 62.5
1 ~7 I7 z5 @3 T# h4 C! p$ `93.6 6.0 X 7.0 55.5
# z' T% X2 c& F, M! j95.0 6.5 X 7.0 27.2
/ {* E0 r4 v! P/ g, `; OAv. 60.0* k/ R6 ]# r* t$ ~) c+ i
available testosterone. Again, emphasis should be placed on3 l9 A, G% r% X) m, _. j8 h" u# F
early therapy when lower levels of testosterone appear to% g% I7 D1 M) R- }7 a8 R% p
provide the best responses. The earlier therapy is instituted t) K1 j# b$ S5 P+ t
the more likely there will be an excellent response with low; q. d$ l! J4 o1 O
serum levels. Response occurs throughout adolescence as
- S# ^. E" I0 m+ t3 _& ynoted in nomograms of phallic growth. 7 The actual response
5 C* g5 c! m8 [9 Dto a given serum level of testosterone is much greater at birth8 P% J3 \* v; I) X0 J8 x# E
and gradually decreases as boys reach puberty. This is most& ~' v" J* l- |4 Q& q5 e# O
likely related to the conversion of testosterone to dihydrotes-
. A; t2 K G) g5 vtosterone and correlates well with the studies of testosterone
! W. p5 g, h; U% ?: ~9 }* T1 cconversion in foreskin at various ages. y- P0 F7 K5 \' z1 N, Q1 A
The question arises regarding early treatment as to whether
! V( v/ r2 H1 l2 t* ~8 z- zone might sacrifice ultimate potential growth as with acceler-
' V; _1 \5 L! ] m# h) cated bone growth. The situation appears quite the reverse
" S1 \5 g8 J- F9 H$ h4 B4 bwith phallic response. If the early growth period is not used
* w- W# v1 u. L& u" M9 u1 jwhen 5a reductase activity is greatest then potential growth
7 S0 C2 G; y- lmay be lost. We have not observed any regression of growth% f) @, ~& b7 V; ~5 n
attained with topical or gonadotropin therapy. It may well
. H! Y/ i8 p/ e) ^, ^3 W& X6 Kbe that some patients will show little or no response to any
! m# }: E. [, }form of therapy. This would suggest a defect in the ability to0 J4 W7 l: G% r/ a8 a
convert testosterone to dihydrotestosterone and indicate that- T ~) S- W0 n4 V8 y
phallic and peripheral skin, and subcutaneous tissue should
8 \9 c b' [+ V: _3 ^* Obe compared for 5a reductase activity./ E( Q* o- j1 v; m# n/ V* m5 n
A, loop enlarges to measure penile girth in millimeters. B,
, p- h, N' _3 J; ]example of penile girth computed easily and accurately.
( [+ N5 x$ _$ wconversion of testosterone to dihydrotestosterone. It is in this
) V! V5 @% A7 x7 q' K( eolder group that others have noted high levels of serum
) o. I6 u5 R% a, t3 B/ Vtestosterone with topical application. It would also appear% n0 F8 }( @! _6 ?
that phallic response during puberty is related directly to the
2 @8 {8 y8 Q0 G( \- G: z3 r' Z2 y) Pserum testosterone level. There also is other evidence of local# v9 {9 _' O. M7 @
response to testosterone with hair growth and with spermato-8 Q9 S* T) P3 _5 v4 P; `0 h, T
genesis. 5• 61 x# ?4 _7 I% n/ K5 p) A
Administration of larger doses of gonadotropin or systemic
. w2 M. H6 m% N. d: dtestosterone, as well as topical applications that produce
. G* ~! o: ~* B" D J" x! |higher levels of serum testosterone (150 to 900 ng./dl.), will% ?9 }( T: A8 U/ L/ j) ]4 m
also produce phallic growth but risks accelerated skeletal T! U: P9 v3 A# Y* U& m
maturation even after stopping treatment. It would appear; o( D( _6 {8 n8 A, Y
that this may be avoided by topical applications of testosterone3 v% Y3 ]& o. V+ P% H l
and monitoring of serum testosterone. Even with this control
. c/ L- s4 K6 \) Wthe duration of our therapy did not exceed 3 weeks at any) B. A8 M. x: f2 Y: \* R9 {
time. It is apparent that the prepuberal male subject may
9 }: a! G* l2 t8 Ssuffer accelerated bone growth with testosterone levels near
! @! r+ G6 _- E* J6 m( [200 ng./dl. When skeletal maturation is complete the level of
8 A/ `, U9 S9 L# M0 O$ t* zserum testosterone can be maintained in the 700 to 1,300 ng./
4 j6 J- [9 P1 I" p: K1 [: pdl. range to stimulate phallic growth and secondary sexual0 r: ? F# I9 M% Q
changes. Therefore, after skeletal maturation parenteral tes-. [% K3 U- p& |( y3 U/ k
tosterone may be used to advantage. Before skeletal matura-
$ `0 w# d3 t5 p/ jtion care must be taken to avoid maintaining levels of serum; \$ [' V. ?( i$ G' Y7 h2 p+ g
testosterone more than 100 ng./dl. Low-dose gonadotropin
W# ?/ }9 q; U; R" N& k0 |depends upon intrinsic testicular activity and may require" `: T; ~) L) M) k# |
prolonged administration for any response.
. V9 N" k: g. g$ J% L6 P+ E! cAlternately, topical testosterone does not depend upon tes-0 q# {# `) D6 k: T4 \' W( W
ticular function and may provide a more constant level of5 Y, D$ w! X6 W+ R9 @) W; s
REFERENCES
4 q K/ @! ?8 x9 J2 I4 v1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,1 o2 V! W0 K4 r* T0 m" U, X: i
R.: The local application of testosterone cream to the prepub-# V. f' c( L2 }# z7 j' l: |
ertal phallus. J. Urol., 105: 905, 1971.2 z2 }* D5 v9 _- M2 b( D' o) I
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
/ P8 [+ A8 O; s$ r3 ]4 {treatment for micropenis during early childhood. J. Pediat.,
, d9 J9 ~! k5 b% x: Q9 B83: 247, 1973.4 P1 j* \ n4 r% i; c
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
: t j1 o+ e# K: |7 W: Bone therapy for penile growth. Urology, 6: 708, 1975.
, c# R! Z3 K3 p# k, h( l4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! i; K6 ~# j: x o3 Eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: Z0 s+ p9 n% y" u% u$ V
skin slices of man. J. Clin. Invest., 48: 371, 1969.: t6 Z. j7 K# Y' X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 G) \$ M. u! y: [1 x: E' Y
by topical application of androgens. J.A.M.A., 191: 521, 1965.
: s' L# R5 b+ L, e/ v1 V S6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 d& g5 ~- Z' L9 v/ p
androgenic effect of interstitial cell tumor of the testis. J.: {/ P5 v4 k2 W5 i
Urol., 104: 774, 1970.% [ S% N+ }" Z3 `2 L
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 ?/ {' }0 i3 Y8 E3 ~# k7 W; q( c
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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