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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* d: W/ v- x" V- e" U7 r
GONADOTROPIN
- `1 @ {! Z2 h' J# x( n0 x3 m1 QRICHARD C. KLUGO* AND JOSEPH C. CERNY
, m' g& r* e3 v- NFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan# a1 N5 D( o5 r( D0 Y- N0 r3 B
ABSTRACT
4 f. P3 X9 i3 v- ?$ oFive patients were treated with gonadotropin and topical testosterone for micropenis associated% o. Z4 v' `( F$ Q2 ^; Q
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-9 Z) i7 a! h/ L) U$ L1 L; p
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 R1 Z$ u! N' D2 l
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" C1 i0 h; ?! s, [+ Lfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 D3 ^; K8 m2 [0 Z3 N) W; { P( x$ cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
" j! h e* l. Aincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response, ~+ o3 [( c; s2 a
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 ?6 q: K3 b% j# ~( s ]% j+ S# z
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile# q9 U \7 R2 e8 e7 N; Q, l0 }/ p& C
growth. The response appears to be greater in younger children, which is consistent with previ-' ^3 P/ u0 k: G) n+ \7 \. q
ously published studies of age-related 5 reductase activity.3 a) h& |; @ J0 S% C: B/ a& A. ?
Children with microphallus regardless of its etiology will: O" @" Z$ O, ^. K$ W
require augmentation or consideration for alteration of exter-! Q% x* u$ e, H* v# [5 x
nal genitalia. In many instances urethroplasty for hypo-
% d+ h. H* r" D/ b1 Ospadias is easier with previous stimulation of phallic growth.
2 ~1 L3 f6 c: b6 v6 o4 iThe use of testosterone administered parenterally or topically$ w1 ?; ]& R4 F
has produced effective phallic growth. 1- 3 The mechanism of" `& A! w; K. B% h" `) Z
response has been considered as local or systemic. With this
8 b0 _( | X- {in mind we studied 5 children with microphallus for response- R1 z. c \( \$ F* O
to gonadotropin and to topical testosterone independently.& t. y1 B2 y$ Y% [, [7 e( ^
MATERIALS AND METHODS
4 X6 ?& h' F# v# }3 r2 d$ XFive 46 XY male subjects between 3 and 17 years old were
: z/ [. U* p5 Pevaluated for serum testosterone levels and hypothalamic
9 ~* g: G' Y& q8 N, ofunction. Of these 5 boys 2 were considered to have Kallmann's
4 a. E! g, i @% lsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-2 X* v! |: z }
lamic deficiency. After evaluation of response to luteinizing
# T" t0 y; q/ b% ahormone-releasing hormone these patients were treated with
7 T- v' V( P% h! o4 C( p2 \) L1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* y3 J0 t. a0 X6 H( v! Wafter completion of gonadotropin therapy 10 per cent topical" ^' {* z4 v6 S' b$ p$ Z( H
testosterone was applied to the phallus twice daily for 3 weeks.
7 J. h- q' z9 F2 B+ i/ m1 @Serum testosterone, luteinizing hormone and follicle-stimulat-
( w* \! r! X( g7 {ing hormone were monitored before, during and after comple-
7 s r! |: i6 l' _9 H; otion of each phase of therapy. Penile stretch length was
! f) k y1 }7 W& Uobtained by measuring from the symphysis pubis to the tip of* F& Z Q' F, _( \! J5 J8 v' m
the glans. Penile circumferential (girth) measurements were2 J! i n$ w {2 m" G' u8 B0 X H. x4 Z
obtained using an orthopedic digital measuring device (see
4 D& p$ p2 v3 m& h7 Y: sfigure).
- ?. d/ Z( ?% ORESULTS# c; f& ^7 i$ ^& u% I, ~. I
Serum testosterone increased moderately to levels between2 W5 ~+ v. Y1 `$ W. L" n
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ |, Y; h& F# t& E( Rterone levels with topical testosterone remained near pre-
4 B+ }0 m8 @5 t$ R2 V6 btreatment levels (35 ng./dl.) or were elevated to similar levels
7 j, j! x# V7 T6 Y9 @) x+ V( ndeveloped after gonadotropin therapy (96 ng./dl.). Higher, f# ]$ j3 f) a! K# [' m0 d! b: `
serum levels were noted in older patients (12 and 17 years old),: l2 y4 s9 ?/ w2 J' }
while lower levels persisted in younger patients (4, 8, and 10: _% n. g3 y+ q h' B" e
years old) (see table). Despite absence of profound alterations
1 O, q/ B. S2 A# hof serum testosterone the topical therapy provided a greater1 e, V' _* O! Z y8 k
Accepted for publication July 1, 1977. ·
/ q; Y5 N* O# n9 sRead at annual meeting of American Urological Association,* t5 |$ C b' q+ V6 k; U8 M
Chicago, Illinois, April 24-28, 1977.
" m; ]! z9 B7 ^5 v8 A* Requests for reprints: Division of Urology, Henry Ford Hospital,& `: @$ M! Q" Y8 H* b5 t' C7 ^' \7 H
2799 W. Grand Blvd., Detroit, Michigan 48202.( Q' c! p: R; b6 y
improvement in phallic growth compared to gonadotropin., r+ [, N; y$ L: e4 U( Y2 Y
Average phallic growth with gonadotropin was 14.3 per cent
) z4 [9 J7 G! a! s) K) lincrease in length and 5.0 per cent increase of girth. Topical
6 A$ O E/ h) h4 Atestosterone produced a 60.0 per cent increase of phallic length
4 u# l6 m) V* }+ R7 c4 Vand 52.9 per cent increase of girth (circumference). The3 A* c) h" D; G$ M
response to topical testosterone was greatest in children be-1 N. l& K& B! d- q3 P. t, g+ }
tween 4 and 8 years old, with a gradual decrease to age 17
. y, P6 g7 z+ |0 V7 cyears (see table).0 ]6 S$ x8 b% z' T8 J; G! x
DISCUSSION1 I/ a2 t% W; ?0 }
Topical testosterone has been used effectively by other$ J! O$ y. ]$ C. i/ X8 w ^8 i2 c$ D
clinicians but its mode of action remains controversial. Im-
3 U( `+ G* t1 hmergut and associates reported an excellent growth response
% G: ?5 e0 R# c( z! C* |to topical testosterone with low levels of serum testosterone,, ?: n; e3 I" H
suggesting a local effect.1 Others have obtained growth re-
# ?" L9 G; H2 g/ D5 m1 U. B3 Csponse with high. levels of serum testosterone after topical
6 r+ g, c# f9 B( l; u8 F6 yadministration, suggesting a systemic response. 3 The use of1 v5 ]$ I+ H6 ^
gonadotropin to obtain levels of serum testosterone compara-9 A! H) r0 `/ T3 [% ?9 j0 Y0 m
ble to levels obtained with topical testosterone would seem to
- l* O9 Z# q' K1 x6 x$ O9 Q& Sprovide a means to compare the relative effectiveness of& q9 ?# E2 r& o( C, F
topical testosterone to systemic testosterone effect. It cer-8 M' u ~! ?' a$ R4 L
tainly has been established that gonadotropin as well as par-
, _3 T" O: p5 Uenteral testosterone administration will produce genital$ q# `6 ^- m% v% V
growth. Our report shows that the growth of the phallus was2 ~* y) k: {% o7 L7 l$ y# Z- u
significantly greater with topical applications than with go-( w' I; [1 y" m9 e3 a9 I l
nadotropin, particularly in children less than 10 years old.( p1 L+ u6 l5 R, }8 O& y
The levels of serum testosterone remained similar or lower
! r. P# g& o* n+ G0 l' othan with gonadotropin during therapy, suggesting that topi-
9 D% j+ K$ f9 q& u6 Y9 lcal application produces genital growth by its local effect as* Z/ t6 k; c$ F, h2 P" A
well as its systemic effect.% e& }8 O8 _* M- F" [4 i/ M
Review of our patients and their growth response related to! \! A( _- l+ V, g [9 \
age shows a greater growth response at an earlier age. This is
) |' g8 L% [. s' l' U" }consistent with the findings of Wilson and Walker, who
% B& z3 D7 ]9 y2 r' c) Qreported an increased conversion of testosterone to dihydrotes-4 H# A. ~1 K9 s9 x
tosterone in the foreskin of neonates and infants.4 This activ-/ ]2 E& d3 D5 E4 p _' g
ity gradually decreases with age until puberty when it ap-
, L# U8 s) r8 jproaches the same level of activity as peripheral skin. It may
0 {: R+ ^5 P) j' L$ w1 x( Qwell be that absorption of testosterone is less when applied at0 I! K) n Q* L( W; ~+ N
an earlier age as suggested by lower serum levels in children
5 ~4 u+ h% Q2 F1 mless than 10 years old. This fact may be explained by the
2 S3 q, t. g8 i1 S$ ^1 `" qgreater ability of phallic skin to convert testosterone to dihy-$ {3 @( @& ~) l5 N( }+ S
drotestosterone at this age. Conversely, serum levels in older
8 S8 y8 e S! Y% Y+ }# h3 tpatients were higher, possibly because of decreased local& R+ s" T. U0 x$ x, G8 s' ?" h
667 L. G l) x! q2 A! i
668 KLUGO AND CERNY
; m8 x4 {- y# E SPt. Age# F b/ U) O) d' K
(yrs.)8 I7 Z2 E% o: N, y2 S! b
Serum Testosterone Phallus (cm.) Change Length
9 a6 P- l# O* V* U8 }$ S(ng./dl.) Girth x Length (%)- c- c3 `. H5 N6 k- f( n
41 P1 u/ b6 [% J4 _, l2 B: ~
8
3 w# N7 n6 ^. P& L10
# ]% b6 Y3 V: j& ^121 _1 X4 } G! {8 H1 y3 `
17# Y% s* Y. v% e5 I
Gonadotropin" `! ~' h8 k, t; V) A
71.6 2.0 X 3 16.62 ^3 d; q/ T: I: c
50.4 4.0 X 5.0 20.06 G3 R+ X w6 ?7 l1 u
22.0 4.5 X 4.0 25.0
6 r! q4 U" o) c: J3 M- Y- n84.6 4.0 X 4.5 11.1
: V; z H- i) u( H3 w85.9 4.5 X 5.5 9.0( x' i+ l" s2 k3 c9 T F' L V8 H) ~
Av. 14.3
6 b! g5 `7 `) K5 N Q4* H. j! A+ F, G; ^; n; `* Z
8
' L0 a0 h; m3 p102 R# {2 x0 d( r1 r1 L- z0 N
12
% o3 j" k1 P. M) O1 C r17
8 E) |! T" W, X4 fTopical testosterone1 X' Z' v9 o9 F+ X+ M7 _5 N# e
34.6 4.5 X 6.5 85% j, v' w# \; r' k. g1 B* Y2 W
38.8 6.0 X 8.5 70
0 x# y8 {3 Z ^( O40.0 6.0 X 6.5 62.5
8 u% v3 f6 ~5 @% W; f93.6 6.0 X 7.0 55.5
& k, x7 N$ i8 K2 j9 }4 z! W( g/ @5 X95.0 6.5 X 7.0 27.2
2 F3 D8 C( Q# Z4 q5 v6 aAv. 60.0
$ Q7 C0 \8 C2 _, b8 lavailable testosterone. Again, emphasis should be placed on
0 L- `- X$ H% }" J; O* g# Vearly therapy when lower levels of testosterone appear to
7 S' d% M# U( i% a# r# _6 x1 cprovide the best responses. The earlier therapy is instituted
" A* _ g$ A& Z8 a1 h2 z( L) vthe more likely there will be an excellent response with low
2 e0 i6 |" ]9 p4 ` ^; q) lserum levels. Response occurs throughout adolescence as9 L1 U+ S7 x& O, d
noted in nomograms of phallic growth. 7 The actual response
5 t& v4 V" W* s1 Wto a given serum level of testosterone is much greater at birth9 I. @, W, C/ X* I3 r, M
and gradually decreases as boys reach puberty. This is most
' n+ p/ f; D# C( A2 p. f% s) K% o( mlikely related to the conversion of testosterone to dihydrotes-
; h h! y' d: b. X T+ Wtosterone and correlates well with the studies of testosterone
4 }* X$ c# t9 C7 G; W, p$ Rconversion in foreskin at various ages.# m9 O% [/ x8 K' g3 n# }0 w7 j) G6 u
The question arises regarding early treatment as to whether! T3 \. x: @7 W* i, o
one might sacrifice ultimate potential growth as with acceler-
. K% R8 i& \. z) A) Kated bone growth. The situation appears quite the reverse
) Q0 r: {0 Q" r9 Xwith phallic response. If the early growth period is not used
) F; S6 ], r7 h2 e0 x' L }when 5a reductase activity is greatest then potential growth
" J8 ~- I$ r* \- @8 k4 `may be lost. We have not observed any regression of growth* [: y% }. z; z$ v: ^% `# a
attained with topical or gonadotropin therapy. It may well
7 Z' i9 T( G Y; y- i4 Rbe that some patients will show little or no response to any
2 O X- ~- B/ i- T: z! sform of therapy. This would suggest a defect in the ability to R- o# N8 X c( E/ s
convert testosterone to dihydrotestosterone and indicate that
+ p& F3 c+ ?$ |. \6 Y# L2 `: ^phallic and peripheral skin, and subcutaneous tissue should. c8 ~$ i3 M8 a$ Y: k
be compared for 5a reductase activity.
; C9 A" y# V6 C3 l% [A, loop enlarges to measure penile girth in millimeters. B,0 j2 @& z5 k f
example of penile girth computed easily and accurately.; ?$ [7 Q; p/ w9 e5 U
conversion of testosterone to dihydrotestosterone. It is in this
# X7 J) T& v7 K. rolder group that others have noted high levels of serum
+ }- t5 P W# X0 vtestosterone with topical application. It would also appear5 x$ p9 E$ r8 @& u: W
that phallic response during puberty is related directly to the
8 _! B1 F+ C. `' Qserum testosterone level. There also is other evidence of local( x: ~$ \" I0 m& ?
response to testosterone with hair growth and with spermato-- F9 F1 b; n1 o+ t7 Y
genesis. 5• 68 E6 T5 D4 U# ]+ a2 i( b
Administration of larger doses of gonadotropin or systemic5 ~- E5 O# K$ ?5 p. v1 m9 Y
testosterone, as well as topical applications that produce, o0 p+ ^6 D8 k1 J+ p- o, y9 Z, V
higher levels of serum testosterone (150 to 900 ng./dl.), will( K) N& k9 F! y \, s
also produce phallic growth but risks accelerated skeletal/ X) ]& Y4 s' J3 h: N! Z
maturation even after stopping treatment. It would appear
( J# X$ j$ G0 D, @; Lthat this may be avoided by topical applications of testosterone0 _3 c3 M5 m+ J2 z( W% q
and monitoring of serum testosterone. Even with this control' w" j+ j! v: W8 I/ Q0 u2 c
the duration of our therapy did not exceed 3 weeks at any
, A" o" S, z3 @2 z# stime. It is apparent that the prepuberal male subject may! @: z# h# m$ x) b9 s5 y- @
suffer accelerated bone growth with testosterone levels near
7 \( j+ o3 N; O) U5 S3 ?200 ng./dl. When skeletal maturation is complete the level of
3 d3 _8 ?0 J" A1 u0 Z" ^' M4 Sserum testosterone can be maintained in the 700 to 1,300 ng./
1 p0 M8 H0 b* h1 k3 rdl. range to stimulate phallic growth and secondary sexual
7 B0 V' C- M2 b) |! g' P( r) M6 Achanges. Therefore, after skeletal maturation parenteral tes-
' l* y1 {& k" e+ Ztosterone may be used to advantage. Before skeletal matura-/ q$ X+ d3 L, ?6 \( m( r/ x
tion care must be taken to avoid maintaining levels of serum
$ M" Y3 F6 N9 @1 U: Z Itestosterone more than 100 ng./dl. Low-dose gonadotropin
, B; G! }+ j. B3 vdepends upon intrinsic testicular activity and may require
9 P$ y5 ]8 F! _1 x) Hprolonged administration for any response.3 ^( V/ H! a* K l1 {8 @
Alternately, topical testosterone does not depend upon tes-
! B* u6 z9 b) g& H6 i( L# ?& Vticular function and may provide a more constant level of' f' n% `3 L) f1 `
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6 b7 B( W: \3 ^& k+ [- m& H1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 i3 Z" m" m8 L+ HR.: The local application of testosterone cream to the prepub-
1 _" D* H4 a: p* I, tertal phallus. J. Urol., 105: 905, 1971.
. h; M0 T3 ^: T8 v3 ~2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
; m3 L" j3 k _! k! t$ Ctreatment for micropenis during early childhood. J. Pediat.,
! @- x- W3 D3 w/ F6 E* L83: 247, 1973.
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one therapy for penile growth. Urology, 6: 708, 1975.
. C% M6 g# k8 w7 V' z7 e4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
4 i; r% U4 e2 l6 l) A1 rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 [1 a) K: d+ n2 h4 Wskin slices of man. J. Clin. Invest., 48: 371, 1969. b; e8 e$ H% ~+ A# z9 E
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
9 M3 `3 I4 u1 F; gby topical application of androgens. J.A.M.A., 191: 521, 1965.
( d( b" k1 u* i+ s; b6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 ~$ j9 {0 d4 i& \ T8 @
androgenic effect of interstitial cell tumor of the testis. J.
, B# t/ B: `8 J- E4 ]; r. qUrol., 104: 774, 1970.2 K5 }. Q) ^4 p. E) ~/ d
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
# a7 p3 D3 |' q+ c ^tion in the male genitalia from birth to maturity. J. Urol., 48: |
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