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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND- b3 Y( B/ }' e$ E4 M
GONADOTROPIN
- I/ p) g% k: a- m- q5 W6 z$ a3 [1 SRICHARD C. KLUGO* AND JOSEPH C. CERNY" ?. Y. v& }' N+ k7 F6 N) y
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& L& P' A* w. o/ B, OABSTRACT
' F7 H1 _" H( n0 ?* y: [; ?1 w' f' a7 \; ?Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( s4 Y1 f5 y# ?, m. U' a) Mwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
: {% ?" g( o `tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' ?2 j) x3 }7 w$ W) G7 [3 X' z5 Q5 Y
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* E0 Q. P7 l, C
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
! P# z: S2 F# Y/ ]& H9 o2 sincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; d h& n" Q8 x0 T& K* Yincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
H: F X8 ]* j! i( d' D3 Y: foccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This, R4 C( f9 `( l- D# C* g* _
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile: D/ A1 d2 G" i0 @% v! {! I
growth. The response appears to be greater in younger children, which is consistent with previ-
8 ?5 D; @$ ^* h; d% }3 ?! J9 Y9 Vously published studies of age-related 5 reductase activity.+ O `- h' ?$ {( W
Children with microphallus regardless of its etiology will
n ?$ M2 F; b% m7 vrequire augmentation or consideration for alteration of exter-
. _" [' b8 I& [6 K$ ^) xnal genitalia. In many instances urethroplasty for hypo-
) }3 T( `( _& |3 _! ]spadias is easier with previous stimulation of phallic growth.
( w W) X6 C& `# o/ ZThe use of testosterone administered parenterally or topically: _, }: C* A! l% @+ ]- f9 K9 U
has produced effective phallic growth. 1- 3 The mechanism of$ Y1 ?+ K0 g7 b4 P( I7 W
response has been considered as local or systemic. With this
3 O C) l2 E, ?3 D: b& iin mind we studied 5 children with microphallus for response
* W0 S8 d' I' }( |; Zto gonadotropin and to topical testosterone independently.. A' p6 D$ G0 o# O
MATERIALS AND METHODS
) {6 g5 m& d6 u. h+ D# q% jFive 46 XY male subjects between 3 and 17 years old were# ^! U3 f; w1 f; P
evaluated for serum testosterone levels and hypothalamic% C7 N- U% t, I3 p# K
function. Of these 5 boys 2 were considered to have Kallmann's
6 ]* s1 f: R; e* jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-& C" p" G: l# P& h1 C+ ~* p& S
lamic deficiency. After evaluation of response to luteinizing# }1 s0 O" S, _- I9 t
hormone-releasing hormone these patients were treated with' H" t1 z' N& V$ E" |5 d9 m& K3 d
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: j0 C" O1 y1 r0 i- kafter completion of gonadotropin therapy 10 per cent topical, [3 Y5 U4 W' V. @0 G
testosterone was applied to the phallus twice daily for 3 weeks.+ w0 `! I/ Y, F0 v! S
Serum testosterone, luteinizing hormone and follicle-stimulat-
* r/ _ n, x( w- z! [ing hormone were monitored before, during and after comple-
: w, W+ W9 E( S* ?, btion of each phase of therapy. Penile stretch length was H7 L2 T) ~7 a9 j6 H
obtained by measuring from the symphysis pubis to the tip of- ?5 ]1 s; ]# g+ ~5 `- m
the glans. Penile circumferential (girth) measurements were6 C9 r- G. l: N% J3 T) t
obtained using an orthopedic digital measuring device (see
! h- H5 m" o. d. x0 I0 Q0 l! |figure).% `% ^; D' G' [; n$ e- z6 B; L
RESULTS
6 u% V; e! i+ K" W( TSerum testosterone increased moderately to levels between
: v# k7 q7 Q# m: `0 x2 O50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-/ A) @. d; p$ _1 e' |2 L
terone levels with topical testosterone remained near pre-2 N2 c( w# ^9 J
treatment levels (35 ng./dl.) or were elevated to similar levels
- k* `7 G b- h8 m2 Wdeveloped after gonadotropin therapy (96 ng./dl.). Higher
* O3 @! ~% o9 @' C! bserum levels were noted in older patients (12 and 17 years old),: c7 Z( o# }" Z% e2 P b9 e+ B( ^
while lower levels persisted in younger patients (4, 8, and 10
/ r1 M/ K: @2 ?. h, |years old) (see table). Despite absence of profound alterations/ M/ |% ^# f3 Y( r* S/ [! H/ k& F( b
of serum testosterone the topical therapy provided a greater
) p* i& y7 ~ L- M( q8 _( V) wAccepted for publication July 1, 1977. ·( r' S+ i* a6 W" n9 g: `
Read at annual meeting of American Urological Association,0 ], T; v' V5 I: w
Chicago, Illinois, April 24-28, 1977., p) D/ B3 g2 x- E3 ~2 q
* Requests for reprints: Division of Urology, Henry Ford Hospital,& O7 @0 a2 s: p+ z
2799 W. Grand Blvd., Detroit, Michigan 48202.
( T0 m9 Y% I7 ?8 pimprovement in phallic growth compared to gonadotropin.
' k- d0 M0 t9 c; ~: pAverage phallic growth with gonadotropin was 14.3 per cent
8 Z# T4 r4 N$ q4 Z) w* aincrease in length and 5.0 per cent increase of girth. Topical
4 M0 T( ^! B* c, ]. ?* A6 e. N: Qtestosterone produced a 60.0 per cent increase of phallic length; B% G( g1 b+ x2 l1 ^
and 52.9 per cent increase of girth (circumference). The6 a2 C. j# h' k+ }
response to topical testosterone was greatest in children be-
* v# H3 @. e9 b& w. z/ y" ~tween 4 and 8 years old, with a gradual decrease to age 17
0 Z: A/ h2 T7 y5 Z6 Y4 Dyears (see table).
: a8 N& M: l$ h7 L8 b7 a2 @$ G4 MDISCUSSION$ u; w6 D; l" O$ q# g! f3 [
Topical testosterone has been used effectively by other
* q N5 F7 c' kclinicians but its mode of action remains controversial. Im-) i5 O. y1 t: }6 y
mergut and associates reported an excellent growth response
3 m7 ^" Y$ _" dto topical testosterone with low levels of serum testosterone,
7 A, P ]. Z' @9 s/ jsuggesting a local effect.1 Others have obtained growth re-
6 b% O9 c b2 Tsponse with high. levels of serum testosterone after topical
8 r# D/ n8 k. V9 E' cadministration, suggesting a systemic response. 3 The use of
( d5 z6 F' [# P4 L& |# dgonadotropin to obtain levels of serum testosterone compara-
: T7 d- X4 c1 J: A' Lble to levels obtained with topical testosterone would seem to
7 q5 K) S; G& ^# v2 f2 m3 Qprovide a means to compare the relative effectiveness of
; ^- [- a% L7 X5 P& A' o: jtopical testosterone to systemic testosterone effect. It cer-
F! r: |" p3 g" ]' A ztainly has been established that gonadotropin as well as par-
* r# A& J8 K# y8 wenteral testosterone administration will produce genital
2 l/ c5 A4 |+ D2 l% P& j$ v* Ggrowth. Our report shows that the growth of the phallus was m0 C1 w H! o/ ~
significantly greater with topical applications than with go-
6 v( v0 Y4 }2 _+ fnadotropin, particularly in children less than 10 years old.8 D5 N* R% n: L$ N: x* M
The levels of serum testosterone remained similar or lower1 [( V9 D$ K! T2 a1 ~. z: H" X
than with gonadotropin during therapy, suggesting that topi-
( L7 ]6 ^8 M1 ]! G3 X# f: fcal application produces genital growth by its local effect as2 M% U. y" H$ U
well as its systemic effect.
$ @; f1 N7 K8 ^% |+ K' AReview of our patients and their growth response related to2 B: F6 p6 \" M; ~! t1 J
age shows a greater growth response at an earlier age. This is* ^8 g0 L. N: n2 m; n
consistent with the findings of Wilson and Walker, who& t5 ~" ^# Y# K$ n% i# j% W- y. k
reported an increased conversion of testosterone to dihydrotes-& M$ \1 q6 E# Y& r
tosterone in the foreskin of neonates and infants.4 This activ-
# u6 Y( @* _9 H0 hity gradually decreases with age until puberty when it ap-
' G: q3 L0 Q4 Sproaches the same level of activity as peripheral skin. It may
8 j! n) ?: ?( Fwell be that absorption of testosterone is less when applied at
Z3 U" B7 m# X) x' I# ^an earlier age as suggested by lower serum levels in children
% i- K4 ^/ ~) l4 P' Uless than 10 years old. This fact may be explained by the
3 ]5 T' _( H/ x& ?' V: Rgreater ability of phallic skin to convert testosterone to dihy-! m. m$ S. X5 j/ l1 E, I
drotestosterone at this age. Conversely, serum levels in older: W4 z. m. _6 z" X4 u. S5 @
patients were higher, possibly because of decreased local
% } i J; @9 G! b667- B+ n$ q9 A x+ k7 I
668 KLUGO AND CERNY
# k# ^" s) n2 n& _ @Pt. Age
# U; F9 A3 F1 Q1 Z(yrs.)
( _* z0 h/ H4 E7 ~Serum Testosterone Phallus (cm.) Change Length" g1 ~+ o# t/ u
(ng./dl.) Girth x Length (%)$ Y A4 i$ g, J! ~3 u
42 _. i- F& S* Y% y
8
9 K" a. l4 H" j* B10$ H! p" F1 ^. O* Q
125 w8 u& x% ]0 U8 y+ q
17! Y5 s o: j" i) }
Gonadotropin
, N3 j& R$ ?4 a0 b1 J2 e1 b3 [8 v. r71.6 2.0 X 3 16.6
1 A/ l, |# l5 |: |& W50.4 4.0 X 5.0 20.08 [# L. s6 n0 ~5 A5 Y+ T
22.0 4.5 X 4.0 25.0
, h3 f g4 W, S! W1 _# V: ]1 J4 g84.6 4.0 X 4.5 11.16 d/ b: j0 B% Q J' M/ o( D( @
85.9 4.5 X 5.5 9.03 C) m% n3 g d, l8 o. Z( t5 _# l
Av. 14.3
; |7 p+ V. l4 C! b) [" u$ D1 [: L4
0 `" o# ] V$ l) @6 H8 }2 a2 @! I8
2 G/ P% B1 `: j* i4 r10% d1 c4 A4 U) A" g
12
! `, \4 A+ G7 }, P3 v8 p7 M; R; M# v0 Z17
4 y; y) }* T- N% CTopical testosterone
h9 ] T5 V, ~34.6 4.5 X 6.5 85( f$ R* f& _8 P
38.8 6.0 X 8.5 709 N5 F3 F J- | S7 ~2 ^* l/ z- x
40.0 6.0 X 6.5 62.5) q* x: q# t8 I7 s5 S' M/ |/ h
93.6 6.0 X 7.0 55.5
' |* M5 k8 U( B S95.0 6.5 X 7.0 27.2$ o$ W9 [5 ?: K. M9 M- k- v
Av. 60.04 [# A3 P0 L$ S/ W3 P0 h6 h9 h
available testosterone. Again, emphasis should be placed on
2 S8 K1 u. _4 W) m4 T+ i iearly therapy when lower levels of testosterone appear to
/ [: g$ q: c3 l$ g5 [! u! `provide the best responses. The earlier therapy is instituted
2 `. B# c( e6 K- P- \the more likely there will be an excellent response with low1 [0 g) o* _; a* r
serum levels. Response occurs throughout adolescence as
( f L+ c9 o# l: unoted in nomograms of phallic growth. 7 The actual response, @+ j" ]- U* n4 q
to a given serum level of testosterone is much greater at birth0 F, C1 c, T. h% o% j0 R* ?
and gradually decreases as boys reach puberty. This is most
6 m B7 w8 W7 s- f; C4 O9 Hlikely related to the conversion of testosterone to dihydrotes-
# \; ?8 T0 P7 w; b2 b) O. btosterone and correlates well with the studies of testosterone* ^3 s. y. U7 T% l+ Q
conversion in foreskin at various ages.- ~: w/ ?1 [: u
The question arises regarding early treatment as to whether
% q% n# A6 A6 o3 P1 u7 }+ Uone might sacrifice ultimate potential growth as with acceler-
$ o1 b g$ Q: F( |8 Y+ Xated bone growth. The situation appears quite the reverse* X; }8 B* [# G, C9 ?$ r" O/ L/ f
with phallic response. If the early growth period is not used# w- p* ~5 f7 g7 L
when 5a reductase activity is greatest then potential growth3 }: ^( U' c& v; |) b
may be lost. We have not observed any regression of growth5 B+ y% q% v1 s8 O
attained with topical or gonadotropin therapy. It may well
2 \& h p k" J4 }4 L7 Vbe that some patients will show little or no response to any
/ k- B" V8 }/ q8 y3 _form of therapy. This would suggest a defect in the ability to W8 z! ^7 H3 \' X+ Q8 X/ c3 ]
convert testosterone to dihydrotestosterone and indicate that
& R- o! K9 |2 k4 Gphallic and peripheral skin, and subcutaneous tissue should# Q$ k% \& ^- v1 |: g
be compared for 5a reductase activity.# j2 ~* G; p& g$ O L! O9 P/ x
A, loop enlarges to measure penile girth in millimeters. B,
5 e" `% ~/ ~- U# P% _( |example of penile girth computed easily and accurately.9 r) l5 M; d, G& W# {! Q
conversion of testosterone to dihydrotestosterone. It is in this
4 L- @- W# ^' F0 t6 Solder group that others have noted high levels of serum: l0 R E; X2 v; S. \
testosterone with topical application. It would also appear
, y$ r* p% L! N/ i3 o5 M- v5 fthat phallic response during puberty is related directly to the
+ y1 G' W9 i6 E5 D4 D* H# Aserum testosterone level. There also is other evidence of local
! ?5 R: |; ~8 F* `: T2 h/ S8 Nresponse to testosterone with hair growth and with spermato-9 j8 y9 W2 f& D' A( g
genesis. 5• 6: G) p7 M, j' \8 D" d/ q/ c! `
Administration of larger doses of gonadotropin or systemic7 Y1 \5 q# M% M0 W- V) x" R% b
testosterone, as well as topical applications that produce
7 O' C1 ~ N3 n4 u! j- F: w8 Thigher levels of serum testosterone (150 to 900 ng./dl.), will
6 C1 ~! {( P) e- F6 D- i. dalso produce phallic growth but risks accelerated skeletal1 R7 s v2 H* ^! M# v! F
maturation even after stopping treatment. It would appear, d+ o0 _% K& F/ B% K, z
that this may be avoided by topical applications of testosterone8 O9 y/ B3 P; }( I: o
and monitoring of serum testosterone. Even with this control' l- u; o1 Z# a/ E$ a; ?4 B: X
the duration of our therapy did not exceed 3 weeks at any6 u- I$ G# T( R' ]5 d# s! X& t
time. It is apparent that the prepuberal male subject may3 D8 C& K& I6 W- E8 a' C
suffer accelerated bone growth with testosterone levels near2 n6 ~) K# p. `5 h$ `+ Y& {
200 ng./dl. When skeletal maturation is complete the level of! H2 c4 m1 {3 K3 ]( w
serum testosterone can be maintained in the 700 to 1,300 ng./
: c4 X2 u; a0 v, sdl. range to stimulate phallic growth and secondary sexual5 i3 S4 N( u' `; m1 X
changes. Therefore, after skeletal maturation parenteral tes-
2 Y: \+ l7 Y8 |& q5 M4 e. J7 n+ a5 otosterone may be used to advantage. Before skeletal matura-# e1 d# W- t! u) v
tion care must be taken to avoid maintaining levels of serum/ u- ?$ J* a- X: C, S7 B; w0 \2 _
testosterone more than 100 ng./dl. Low-dose gonadotropin
2 w& O( v5 {! l7 C6 x bdepends upon intrinsic testicular activity and may require
7 h7 N, p' d1 }. U7 d7 Lprolonged administration for any response.1 r. e/ O+ m- V* v/ \% x" S
Alternately, topical testosterone does not depend upon tes-" \% k; W Y+ }8 t% a' Z
ticular function and may provide a more constant level of8 x5 ~0 U8 P' F! v
REFERENCES
' m' f9 K8 a2 D% v, z; D1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 H6 |& x' f; }
R.: The local application of testosterone cream to the prepub-
* m% R, L: X8 H8 R6 \ |! {2 e7 G- \ertal phallus. J. Urol., 105: 905, 1971.
' V* Y- g* X9 T* A2 Z1 l) M2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 V( C* D+ B$ n. q
treatment for micropenis during early childhood. J. Pediat.,
$ ^* L2 N* ?, a. B3 l0 M$ G83: 247, 1973.
2 r+ ~* l9 r2 E2 W$ S3 p0 W. r2 I3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 s7 ~, G0 @. M# M1 c; t/ Q# J6 Jone therapy for penile growth. Urology, 6: 708, 1975.
9 c( {8 G/ d# x! m; Z6 ~! ]) A4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
Y$ H9 h$ n3 A$ ~to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 D) c# g" {2 ^: q/ `
skin slices of man. J. Clin. Invest., 48: 371, 1969.
% O8 Y+ u. U9 n- c7 w0 L5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. |( z: m: ?1 |1 |# M
by topical application of androgens. J.A.M.A., 191: 521, 1965./ k; D. C) R; Y) K7 K' d0 c: M
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ t* u& Y+ i5 D
androgenic effect of interstitial cell tumor of the testis. J., `5 J8 k9 g% ?. j3 e
Urol., 104: 774, 1970.
% E- f$ m$ L: W' W) i, q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ Q* p$ D; G$ U9 ~/ e. {! Btion in the male genitalia from birth to maturity. J. Urol., 48: |
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