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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 T8 @: q0 x7 W0 _$ |8 T% GGONADOTROPIN
9 O! h+ R' W" _) y& NRICHARD C. KLUGO* AND JOSEPH C. CERNY
( I( ]+ K- h) }* z1 cFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan0 X1 S& g7 X4 X2 z3 d& A/ J2 y
ABSTRACT6 v$ E5 k1 k' e9 x k a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
: t2 Q0 }( j m1 ?; e _with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ ^+ C7 {! _& P- R8 Itropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 t x) k: q3 c6 Z% i7 I1 L" n
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! F: O" {, @7 \$ I6 z L3 S
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" W( c+ F" M1 k$ [+ W% A
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 C1 m4 a! E8 ~9 f% O4 n" Fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response& b8 q) v! P4 z P
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( a# E% G z0 g7 mstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile3 a j: k6 I2 q" a
growth. The response appears to be greater in younger children, which is consistent with previ-, s# [6 E f/ ]5 m. Y( Q: b
ously published studies of age-related 5 reductase activity.
* W& r$ ]0 ^% t+ AChildren with microphallus regardless of its etiology will
! b R) P8 f* l9 h" i. |6 Srequire augmentation or consideration for alteration of exter-
5 c; L3 c( J# ~nal genitalia. In many instances urethroplasty for hypo-
; t1 V9 \+ ^5 |/ _; b! Tspadias is easier with previous stimulation of phallic growth.
q& {3 B! ?/ m/ P ^) QThe use of testosterone administered parenterally or topically
4 b- q7 p/ s2 c3 P2 g1 F6 Zhas produced effective phallic growth. 1- 3 The mechanism of
6 _1 ^- T% ]: o, M1 x: \- I- N$ Uresponse has been considered as local or systemic. With this3 E5 c# D# g" U
in mind we studied 5 children with microphallus for response
$ G$ v6 c- |" ^. B, b( i' ~: `to gonadotropin and to topical testosterone independently.
. W% d5 V1 x1 _& eMATERIALS AND METHODS+ z3 T: I$ p% i, s! P# W; w& x
Five 46 XY male subjects between 3 and 17 years old were W0 w. g/ c. y$ C& p
evaluated for serum testosterone levels and hypothalamic
2 g( w$ j+ `! t. y2 d4 sfunction. Of these 5 boys 2 were considered to have Kallmann's
8 l: ]4 X! i0 h: y: Nsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; G% S2 l2 N" ?8 i0 ?* n
lamic deficiency. After evaluation of response to luteinizing
, j. p) [4 R+ e3 a0 f( Bhormone-releasing hormone these patients were treated with
% ~) `4 h3 @& I& Y: j' }8 {$ W: u% [# H1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 e- W; F% v* A- `8 j* V+ x
after completion of gonadotropin therapy 10 per cent topical
3 x0 Z2 \" \ A7 M1 ~testosterone was applied to the phallus twice daily for 3 weeks.
5 u% `- `+ \8 o, ~Serum testosterone, luteinizing hormone and follicle-stimulat-
4 u, x" d+ S1 ting hormone were monitored before, during and after comple-( n* \ p- d& O7 K" T3 M
tion of each phase of therapy. Penile stretch length was- o8 N; t6 H8 b- {7 N( }
obtained by measuring from the symphysis pubis to the tip of
& o5 E, z! j4 _* c# t8 Z, zthe glans. Penile circumferential (girth) measurements were; J$ d; W4 G; X6 `2 |0 O) P: B
obtained using an orthopedic digital measuring device (see
: e! N4 j0 ~& P0 b6 @8 G9 H: t3 Hfigure).0 F7 l1 e8 I' \, f. H1 V/ f
RESULTS
7 l' }% q+ K5 q4 ^5 d K) kSerum testosterone increased moderately to levels between/ u% @' X4 \) r2 }4 G+ m, G* d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
6 K! _6 }" @: H( B, u6 ]terone levels with topical testosterone remained near pre-0 N {% O9 F; o1 D l. |% j
treatment levels (35 ng./dl.) or were elevated to similar levels
3 p- x7 e `5 k7 ^/ ~developed after gonadotropin therapy (96 ng./dl.). Higher
* D( W: G: E+ Tserum levels were noted in older patients (12 and 17 years old),2 t: F0 c0 P6 o7 o! j
while lower levels persisted in younger patients (4, 8, and 10, _ v: ~3 [! h( H8 o
years old) (see table). Despite absence of profound alterations
) q' K& Q4 n4 m9 }$ Bof serum testosterone the topical therapy provided a greater* z, D% u' t( ]7 y, ]+ d" j7 b5 {
Accepted for publication July 1, 1977. ·
" b) ^3 G# s4 N) W, _0 b( ^Read at annual meeting of American Urological Association,
$ K: k2 N2 s" n# D, \Chicago, Illinois, April 24-28, 1977.( D/ r' {' c6 ^
* Requests for reprints: Division of Urology, Henry Ford Hospital," Q$ `2 } B3 ~' }
2799 W. Grand Blvd., Detroit, Michigan 48202.' A2 o- B# h# W# M9 U6 W' H
improvement in phallic growth compared to gonadotropin.* u8 h& h, @+ @! ?- N
Average phallic growth with gonadotropin was 14.3 per cent0 ^: E5 k+ o% b0 `
increase in length and 5.0 per cent increase of girth. Topical
/ J0 G7 \' ` U0 b rtestosterone produced a 60.0 per cent increase of phallic length4 g! p, f/ V4 s1 J7 T# I
and 52.9 per cent increase of girth (circumference). The
9 r/ }- P5 g" W/ S! q' W. yresponse to topical testosterone was greatest in children be-: X1 N- T/ K: Q; F- F
tween 4 and 8 years old, with a gradual decrease to age 177 l0 l9 C- v3 m& F+ d/ i* R: I
years (see table).0 R# l% m0 c, q: M: L
DISCUSSION
* D1 T3 _) ]9 j% C9 |Topical testosterone has been used effectively by other( Q) ^7 y5 Z" u l3 ^! M
clinicians but its mode of action remains controversial. Im-
" r; {3 `. ]# i' y4 k% P' smergut and associates reported an excellent growth response3 v9 j4 y9 B, _3 j+ S6 ~5 U( `
to topical testosterone with low levels of serum testosterone,
) T' P4 {6 i* ?2 _" a4 {8 Z3 Msuggesting a local effect.1 Others have obtained growth re-+ e( b' `3 b: |: K( j e6 W
sponse with high. levels of serum testosterone after topical6 }% y8 [$ D' M# B1 K1 ?7 m
administration, suggesting a systemic response. 3 The use of
9 W6 _2 y% I8 @4 D" Wgonadotropin to obtain levels of serum testosterone compara-
& ^, ]0 r! Q8 t0 Ible to levels obtained with topical testosterone would seem to
; _& P9 L n" Y! r hprovide a means to compare the relative effectiveness of! \$ w, M; G V* X+ d8 o: Q
topical testosterone to systemic testosterone effect. It cer-
0 g* j7 ]7 d! m3 z7 `tainly has been established that gonadotropin as well as par-
: }# W0 C6 X2 A1 U- Renteral testosterone administration will produce genital2 `5 O' |+ c9 M0 H
growth. Our report shows that the growth of the phallus was0 \ _% l0 B( q7 t2 d' p' N0 d0 P
significantly greater with topical applications than with go-
# V/ n# P3 f6 A2 v6 V" J# Inadotropin, particularly in children less than 10 years old.# w$ T# p' d5 p) p
The levels of serum testosterone remained similar or lower/ B' T& a4 V- M- ~0 ]
than with gonadotropin during therapy, suggesting that topi-
: R0 B6 z3 s) t$ L* Acal application produces genital growth by its local effect as
/ S5 A, v- l9 s6 o6 e9 a) u% qwell as its systemic effect.- F' g; A$ H( p) I8 i9 u1 y* k
Review of our patients and their growth response related to+ N3 U3 U& L6 K" ~* Z) L" c7 X
age shows a greater growth response at an earlier age. This is
+ T0 W* |, P( Zconsistent with the findings of Wilson and Walker, who
7 @, i' X1 }# \( l) Greported an increased conversion of testosterone to dihydrotes-% _- f% w- M/ Z! p) O6 \
tosterone in the foreskin of neonates and infants.4 This activ- E; ~2 ^; p2 L) P; R" s4 @, |6 X
ity gradually decreases with age until puberty when it ap-5 i4 Z( j, i( H/ p4 R
proaches the same level of activity as peripheral skin. It may+ m( t' u! s, j% H) f" y6 w
well be that absorption of testosterone is less when applied at
7 T0 Y. `3 L4 k8 ?3 b2 uan earlier age as suggested by lower serum levels in children
& n2 ]# i* M1 A. F9 Yless than 10 years old. This fact may be explained by the
- ^( s4 |& u4 xgreater ability of phallic skin to convert testosterone to dihy-
0 W2 q' B8 x$ N$ h. P( a: S" x/ Rdrotestosterone at this age. Conversely, serum levels in older
, i" {6 W9 q/ l: P+ e3 b0 Vpatients were higher, possibly because of decreased local& x X, a' Q4 h7 X4 r' j
667
7 X3 _; {+ e' d$ q6 ~668 KLUGO AND CERNY
* W. ~ ^6 O- c3 q lPt. Age
% R1 `6 b3 [9 a$ C8 W(yrs.)
0 b2 |' j; Z: g0 V: [7 j! {+ ESerum Testosterone Phallus (cm.) Change Length& u2 R/ w7 y W* G* v
(ng./dl.) Girth x Length (%): U% S( Z3 `+ a s- Z
4/ D2 M/ Y; w: {( }
8
9 P# ^8 j% s/ s# _. T$ J) ?10
$ F" k' [3 }) E* {" ?/ R12% o4 p8 c1 v+ O( M% [3 v& k
17
) ]# ~" x: {7 ?; B: |/ o$ ZGonadotropin
9 t/ m o. t) c, @# P! B3 E71.6 2.0 X 3 16.66 z! {; {' W1 _- x& C3 h6 Y
50.4 4.0 X 5.0 20.0
& [, @# c' T6 ?22.0 4.5 X 4.0 25.0
' s# @/ H: |' ~84.6 4.0 X 4.5 11.1
8 F, M w* Z1 ]5 a. c2 L* F$ A85.9 4.5 X 5.5 9.0
r& V5 s: R9 R0 C& c2 fAv. 14.36 I/ z l$ B7 T
45 L2 J- D4 j5 J
8' F' \9 @7 k! U& n# e* n
10
4 K# `9 E: Q5 g7 n# e" ]: K12+ R5 a5 Z# s% x4 S4 T N6 V; e7 i
17
% s X' S: ]) E3 j# `: m) C" c6 kTopical testosterone( Y; Z2 j4 I- p
34.6 4.5 X 6.5 85
6 j& l, k. P+ W3 g38.8 6.0 X 8.5 70
% v! Y3 u4 r: d2 w @8 T40.0 6.0 X 6.5 62.5
# ~. L4 H& m/ V e3 G6 G93.6 6.0 X 7.0 55.5
7 A, B; b5 v/ Z95.0 6.5 X 7.0 27.2
& U) y/ g9 n1 g# f& |: W0 J' @Av. 60.08 { a6 m* s# Y+ C. r, z
available testosterone. Again, emphasis should be placed on# e9 `) y+ k$ i- f* m2 P
early therapy when lower levels of testosterone appear to
) e8 Y( v! G+ F: B9 }' ]; ~+ Yprovide the best responses. The earlier therapy is instituted
4 l' O( f D! @3 |: \' u) u8 w$ M3 dthe more likely there will be an excellent response with low
( k& ~* i7 |8 D" C2 e! hserum levels. Response occurs throughout adolescence as7 n1 e- w% c7 J7 C2 y) i7 d, [
noted in nomograms of phallic growth. 7 The actual response5 W* y" C& o: H+ ]
to a given serum level of testosterone is much greater at birth* c @6 r- Z7 O' R2 X2 g* F
and gradually decreases as boys reach puberty. This is most
8 X- x2 i' _5 g, P' `$ w, i, _likely related to the conversion of testosterone to dihydrotes-
) ~3 B9 F) l7 y7 J! p& S0 Btosterone and correlates well with the studies of testosterone) \5 Z) _' A2 q
conversion in foreskin at various ages.
1 a$ W$ a+ O1 Z \6 h; `/ ?8 qThe question arises regarding early treatment as to whether: O4 L& D8 U9 @- |8 o5 O
one might sacrifice ultimate potential growth as with acceler-
" c* N0 r, m5 |3 u- z! v2 F- G; g, qated bone growth. The situation appears quite the reverse
7 B( B+ f* }5 r8 |) nwith phallic response. If the early growth period is not used3 c5 v$ O M* E. Z
when 5a reductase activity is greatest then potential growth
* U# \; G* y; c) m) @may be lost. We have not observed any regression of growth
7 y8 {, B; s% p" G Wattained with topical or gonadotropin therapy. It may well
5 A% g6 c9 w, x. A( ebe that some patients will show little or no response to any! I/ w3 g$ L/ N( e( ~$ L
form of therapy. This would suggest a defect in the ability to
% L) Q4 N% I( k5 Yconvert testosterone to dihydrotestosterone and indicate that
& e/ V: \5 I, }3 |phallic and peripheral skin, and subcutaneous tissue should
, ]8 f ~% W5 m; ?3 r( Tbe compared for 5a reductase activity." R e y2 P1 f
A, loop enlarges to measure penile girth in millimeters. B,, D5 |* p! ^0 s$ o" M* n* W9 J* d
example of penile girth computed easily and accurately.& o9 f* g: W' r
conversion of testosterone to dihydrotestosterone. It is in this( C4 J; U2 i& b3 p8 m
older group that others have noted high levels of serum0 }8 O- W2 g& s7 b8 r
testosterone with topical application. It would also appear
& Q. F: s5 {8 ^: X: Cthat phallic response during puberty is related directly to the
; P; m/ y v: P$ g* Sserum testosterone level. There also is other evidence of local8 d0 m' J6 C, |8 [% p
response to testosterone with hair growth and with spermato-
$ F" N; Z/ Q ?" C, ^2 Agenesis. 5• 6
0 A4 G& P, V: h9 UAdministration of larger doses of gonadotropin or systemic
8 v& N2 R8 f# `; ~$ v9 w0 d1 `! p( stestosterone, as well as topical applications that produce1 r( L, p+ U+ P+ C; V. `
higher levels of serum testosterone (150 to 900 ng./dl.), will
' p( J1 S6 P( \ E4 Palso produce phallic growth but risks accelerated skeletal9 i; Y' @/ ~) m3 A9 j: R% _
maturation even after stopping treatment. It would appear! R( K9 g5 F% M1 N& y! b
that this may be avoided by topical applications of testosterone; v* J3 L4 w/ l' e, S @" o
and monitoring of serum testosterone. Even with this control: N3 R- I8 u( p
the duration of our therapy did not exceed 3 weeks at any/ }5 J9 C2 j! V$ a8 v* r4 P
time. It is apparent that the prepuberal male subject may: x/ \6 ]( j1 N; g( K
suffer accelerated bone growth with testosterone levels near
1 D" h& L% q+ Q2 ]6 l. c200 ng./dl. When skeletal maturation is complete the level of
, D7 C! e, `3 O I/ userum testosterone can be maintained in the 700 to 1,300 ng./- G4 P/ J' r$ ^
dl. range to stimulate phallic growth and secondary sexual
% R" ^' `5 K# Nchanges. Therefore, after skeletal maturation parenteral tes-
8 f7 a0 Y' [' z% _7 U- z7 Wtosterone may be used to advantage. Before skeletal matura-7 q$ E9 z% c# c- I$ h
tion care must be taken to avoid maintaining levels of serum! I* V$ [5 q& u8 g" d
testosterone more than 100 ng./dl. Low-dose gonadotropin# ^; F. @0 T) O5 S- n! [
depends upon intrinsic testicular activity and may require
2 s; T& ]8 u5 X: |1 e) Lprolonged administration for any response.! v2 c$ X: W6 A C" q% \5 Y2 [
Alternately, topical testosterone does not depend upon tes-
3 V: c) M4 T( ?4 D2 b) Dticular function and may provide a more constant level of, W& |5 m8 D: [5 {# \ y
REFERENCES' D% a5 W O/ q# x
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
2 g" a2 f3 W: Y5 B+ b2 \R.: The local application of testosterone cream to the prepub-7 y- Y* L8 l5 O2 B: @ w9 `
ertal phallus. J. Urol., 105: 905, 1971.5 X+ x* v) ^. Z' ^0 ^8 @
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 l7 S) r W1 Y6 qtreatment for micropenis during early childhood. J. Pediat.,
: x5 B* g$ Q# D- @8 w83: 247, 1973.
0 Q5 a1 Q. p) x5 W" o+ _3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, \' b- z( g4 e, gone therapy for penile growth. Urology, 6: 708, 1975.1 O; a$ p- v- d9 a" n! C
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
5 ^. }9 i P) U* N5 N! q' F) Nto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
5 k' k# V0 x; O% P! |' Dskin slices of man. J. Clin. Invest., 48: 371, 1969." g# i6 M x S$ m/ A; {
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 V7 l8 N2 ]% @9 o5 g
by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ W- Z1 P' x4 D! m2 s) @" T' w6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local' M5 t2 ^* g. O3 A5 ~
androgenic effect of interstitial cell tumor of the testis. J.
+ `$ o+ G. y- A2 E* PUrol., 104: 774, 1970.
( z! D/ |0 I8 k4 n/ ~7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ T2 F# I% z7 y
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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