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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
2 p' \3 f& m0 [' j7 MGONADOTROPIN# c: Y' [% @* p: b- f9 A" R% T" Z
RICHARD C. KLUGO* AND JOSEPH C. CERNY
5 w- ?' J( L' O: x( E0 ]5 WFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 v* {0 d4 ^* y! U" \ABSTRACT
9 S; S% F; q4 C6 yFive patients were treated with gonadotropin and topical testosterone for micropenis associated; o. ~9 k# z6 r! z ?; O$ k
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-. `: n& Q- {0 x, ]$ u; o
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone- t9 e& _, d: Q; \$ P! r3 X
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 @6 S9 ^4 j5 M7 R; {: Ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
! ]8 k& D+ m* C( Z5 @ x, a9 `. L9 Cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average. ~7 i. X _8 S1 }: ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response( @5 M* G. i" A" f3 B* V' R
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# w5 Q% O# a+ n% n
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
9 H7 s2 ~1 \+ U' K$ |growth. The response appears to be greater in younger children, which is consistent with previ-
3 q# \$ u. C1 R. dously published studies of age-related 5 reductase activity./ p! e' Y% D0 D& X& W; ]5 [
Children with microphallus regardless of its etiology will8 E% w# z \! H* h
require augmentation or consideration for alteration of exter-
) n7 P+ G/ e! o; Pnal genitalia. In many instances urethroplasty for hypo-
2 y% }2 d$ A5 {) t* _( Uspadias is easier with previous stimulation of phallic growth.$ X- C# A2 C, u% L6 m- ~
The use of testosterone administered parenterally or topically
: e- P$ b) S$ l, I0 Nhas produced effective phallic growth. 1- 3 The mechanism of
) K* {+ d6 l( w! Cresponse has been considered as local or systemic. With this
6 k0 [% Y* Z5 c) y- D2 fin mind we studied 5 children with microphallus for response
# Q$ J, S5 U* I; R* @to gonadotropin and to topical testosterone independently.
1 N" A2 R( Z, G5 @MATERIALS AND METHODS$ y- Y( H% L: y
Five 46 XY male subjects between 3 and 17 years old were
: s' }, X/ p6 bevaluated for serum testosterone levels and hypothalamic
9 Y% E7 t2 A' e6 e2 H3 yfunction. Of these 5 boys 2 were considered to have Kallmann's
; _( ]/ N. ]( [. Usyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' P5 O) o: `1 F) K6 C9 L t
lamic deficiency. After evaluation of response to luteinizing
) C0 G& B8 B* C2 ehormone-releasing hormone these patients were treated with
/ [4 ?) j" F' _' Y+ M4 R3 w1,000 units of gonadotropin weekly for 3 weeks. Six weeks
9 n/ B3 A4 u. Y3 H" }% r1 iafter completion of gonadotropin therapy 10 per cent topical
! N( ?3 J# H0 Y' P5 utestosterone was applied to the phallus twice daily for 3 weeks.6 \3 H- {/ J% h% X
Serum testosterone, luteinizing hormone and follicle-stimulat-
' W$ _+ u' P: l& h; p2 E: Ming hormone were monitored before, during and after comple-
0 }3 {0 t9 p/ Etion of each phase of therapy. Penile stretch length was
0 P9 H7 K* h" Pobtained by measuring from the symphysis pubis to the tip of1 U' ^2 `, v% z' [
the glans. Penile circumferential (girth) measurements were
* q) }5 R" T$ N6 X- ^) gobtained using an orthopedic digital measuring device (see1 m7 F" c K2 C) S; l
figure).' Z: |) s' Q+ C' l0 _3 F
RESULTS
6 ^& |( H9 {/ p3 e; ]- l- z) uSerum testosterone increased moderately to levels between8 B8 e' N' f$ _( m) }. Q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 [' G- U7 d; o% t0 B" j2 c5 nterone levels with topical testosterone remained near pre-
; ~/ g5 L6 j* ftreatment levels (35 ng./dl.) or were elevated to similar levels
6 q) |/ D1 u j) Hdeveloped after gonadotropin therapy (96 ng./dl.). Higher, N4 ^! N9 q% F
serum levels were noted in older patients (12 and 17 years old),
3 J* }; k( E2 M4 ~6 h2 Uwhile lower levels persisted in younger patients (4, 8, and 10
7 q# z ]! e# G$ b( byears old) (see table). Despite absence of profound alterations* f Q7 H2 K6 Y: U/ G
of serum testosterone the topical therapy provided a greater
# `( ?8 T5 O' t) I) u c: P! vAccepted for publication July 1, 1977. ·1 j2 \% O& W# i, {# a- {# S, v
Read at annual meeting of American Urological Association,, `' |6 q- G) x! v
Chicago, Illinois, April 24-28, 1977.
. E3 ?6 y2 H! ?" b# C/ y* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 _* J4 P; R4 l, R0 q2799 W. Grand Blvd., Detroit, Michigan 48202.6 `4 L& n3 u2 ?0 z4 I
improvement in phallic growth compared to gonadotropin.
" W/ Y, o( k0 l u7 W8 N# FAverage phallic growth with gonadotropin was 14.3 per cent
2 c3 b6 L) J5 R! h5 [, }* H* aincrease in length and 5.0 per cent increase of girth. Topical8 q/ g* b! S9 I4 t p( g
testosterone produced a 60.0 per cent increase of phallic length
) c2 a9 [% D& d' W) V- ?and 52.9 per cent increase of girth (circumference). The
) ]0 O; U. H. ~3 P k0 [7 F8 presponse to topical testosterone was greatest in children be-
- @" W+ D: S9 a+ X8 ?* ztween 4 and 8 years old, with a gradual decrease to age 17. L3 S- [- D: X# E9 q
years (see table).
/ O2 t6 e; a( k+ A9 RDISCUSSION4 L/ u# A7 V& U# V* ^% Q: t
Topical testosterone has been used effectively by other- Q8 V2 c% ]" C* ^6 i/ F o
clinicians but its mode of action remains controversial. Im-
, Y& B8 _" f/ e: Qmergut and associates reported an excellent growth response/ u! w0 A+ z- l2 s: E
to topical testosterone with low levels of serum testosterone,' F Y4 `; k k/ ~
suggesting a local effect.1 Others have obtained growth re-
' k" t- L! A; i; }sponse with high. levels of serum testosterone after topical5 {# V; I h$ F# F* Y- v, @
administration, suggesting a systemic response. 3 The use of
7 J K1 F) f9 z9 i( |8 G# R/ ?gonadotropin to obtain levels of serum testosterone compara-
! }0 ], }* p3 r! [$ C! p1 Sble to levels obtained with topical testosterone would seem to* A+ l; g3 B6 B3 c$ ^
provide a means to compare the relative effectiveness of5 X* `; |; `5 N, H# }+ J
topical testosterone to systemic testosterone effect. It cer-
' ~' ^8 z% O+ D! B1 E& q2 y+ Stainly has been established that gonadotropin as well as par-8 L6 K" b5 s4 o& G4 g$ b3 V
enteral testosterone administration will produce genital
& v. O' }! c4 E) D- Fgrowth. Our report shows that the growth of the phallus was
2 s& ]: j e& V5 K$ @5 [significantly greater with topical applications than with go-6 W" X' d c4 N0 [/ Q \: L
nadotropin, particularly in children less than 10 years old.
" P' L+ \3 ]. y5 y3 sThe levels of serum testosterone remained similar or lower
4 A/ m2 o( R" Q9 c, Cthan with gonadotropin during therapy, suggesting that topi-. e) o; {% U6 d1 \
cal application produces genital growth by its local effect as
4 u4 j" H) y" P+ p0 zwell as its systemic effect.3 U% C% e, Q. ?2 G% E/ M b" B
Review of our patients and their growth response related to* ?3 E- r# `1 k' y" Q: O
age shows a greater growth response at an earlier age. This is; s! |( a4 A' G! W: s; F' l9 c
consistent with the findings of Wilson and Walker, who9 |& U9 {& |$ K. e- _1 W
reported an increased conversion of testosterone to dihydrotes-
5 l5 R' x, x* @# K6 U0 x; S' J* s# V/ u1 qtosterone in the foreskin of neonates and infants.4 This activ-
& E' }# s) }# f# m& Iity gradually decreases with age until puberty when it ap-
* k3 e+ p9 I5 O5 e& j/ I3 Z5 Qproaches the same level of activity as peripheral skin. It may
6 N7 _) M$ g% n' h$ K# I8 M% Vwell be that absorption of testosterone is less when applied at
6 j/ V- @0 V/ `* {an earlier age as suggested by lower serum levels in children
~$ p5 p2 X5 G7 }$ U, @8 zless than 10 years old. This fact may be explained by the
0 |; B! m% Q, F8 G$ Wgreater ability of phallic skin to convert testosterone to dihy-6 b! D2 L- J1 P, q% w
drotestosterone at this age. Conversely, serum levels in older. n# K( Y3 U+ ?, E. R: T
patients were higher, possibly because of decreased local5 {* l+ N" t7 J1 P' P
667
! a) e+ |5 t5 [5 w668 KLUGO AND CERNY
2 W9 x7 c) `6 T1 O) ?& tPt. Age
: W7 {4 W2 R9 o/ \- V6 {! D( J9 r! j(yrs.)
" |$ [' [+ g- I$ J7 jSerum Testosterone Phallus (cm.) Change Length0 _' U( p3 ~$ X% y
(ng./dl.) Girth x Length (%)
) `: M* v4 e+ T6 c: P4' A# k' Y# Z( o$ {
8
' O9 \( B0 x( a) i10- y' C, O: w& \
12
2 O6 y$ U" }! _" \7 \3 v+ z6 m" E17
3 H0 d" u/ N1 k2 PGonadotropin
& c, P x i# I) Y4 f71.6 2.0 X 3 16.65 G- q+ h8 q" Z( }/ `6 a1 x
50.4 4.0 X 5.0 20.0 r0 ^0 U1 v/ b4 h" b8 S4 n
22.0 4.5 X 4.0 25.0* M& u! r% ~% k" X' U, y9 V; r
84.6 4.0 X 4.5 11.1 D$ n& A% ~# t. x; z) g
85.9 4.5 X 5.5 9.0
w2 D/ }; @1 M8 U8 ^+ k; ~) AAv. 14.3: K5 `" j6 A& h9 {, W( K. \% V
4
, ? j7 b% A4 Q# k& M% V8$ m- i% N- |3 T
10
* x4 p; @5 m( V! v3 Y" u) F2 Y122 F7 J5 t. n. n9 S: x0 X
17! ~9 I6 _. a) F2 H! `; M7 G
Topical testosterone
) X" D) d" O. i9 c34.6 4.5 X 6.5 855 c. i* \. s4 n! n/ Q$ y5 T( m
38.8 6.0 X 8.5 70
& q, @) ]7 C, J+ x40.0 6.0 X 6.5 62.5
# D0 c( _: L+ B/ {93.6 6.0 X 7.0 55.5
* U7 [5 V, y6 t6 b5 x- e% u95.0 6.5 X 7.0 27.23 s! Q0 U* q! r0 K% P
Av. 60.0
+ m# Y9 g V# aavailable testosterone. Again, emphasis should be placed on
. h& I+ t V& Bearly therapy when lower levels of testosterone appear to2 I0 g4 N8 G2 M* {- W8 m
provide the best responses. The earlier therapy is instituted
`" b2 @4 P( e( jthe more likely there will be an excellent response with low# `$ y- b9 d' g* k; t! Y
serum levels. Response occurs throughout adolescence as9 Q5 T: F% e. r1 R+ |
noted in nomograms of phallic growth. 7 The actual response
1 \) P, [2 X' u9 i& x* w1 jto a given serum level of testosterone is much greater at birth
& j# E9 m. H j# e2 M2 i1 D2 M% |and gradually decreases as boys reach puberty. This is most, D* f( P0 I$ ]6 I8 A
likely related to the conversion of testosterone to dihydrotes-
% l( L3 ] Z/ S! Ptosterone and correlates well with the studies of testosterone4 ]) o6 V9 ?. c- G
conversion in foreskin at various ages.+ H5 l F, ~; i& p/ K2 {. N
The question arises regarding early treatment as to whether
L; ^1 D f- @/ S$ V2 {one might sacrifice ultimate potential growth as with acceler-
0 ^/ q; z$ P& o% Q3 iated bone growth. The situation appears quite the reverse5 Y% M8 M& y! d+ P. W v
with phallic response. If the early growth period is not used
4 F: N D5 J; a! Swhen 5a reductase activity is greatest then potential growth
. u' w2 h4 u, [$ p+ T/ |4 ^6 ?may be lost. We have not observed any regression of growth: c$ w" l0 M0 g9 g6 K
attained with topical or gonadotropin therapy. It may well
8 i& K4 Y2 [4 {& C. bbe that some patients will show little or no response to any
; x2 ?# \+ @, W- c S) sform of therapy. This would suggest a defect in the ability to4 |( o$ I. \. g6 U8 A7 t4 n
convert testosterone to dihydrotestosterone and indicate that' i" ?" ]1 f7 z
phallic and peripheral skin, and subcutaneous tissue should
: O5 E8 K1 p [$ _. z, hbe compared for 5a reductase activity.+ r! k9 n$ c4 C0 H0 G+ T+ ]6 e
A, loop enlarges to measure penile girth in millimeters. B,' E" q5 W) f: x# h5 ^" o
example of penile girth computed easily and accurately.
' n3 c8 Y% M& H/ b5 yconversion of testosterone to dihydrotestosterone. It is in this
' l9 u/ H: }" N7 s3 tolder group that others have noted high levels of serum
) U! ? B/ \* ~testosterone with topical application. It would also appear
' ?. j4 |: f# O- mthat phallic response during puberty is related directly to the3 z+ D1 x" l8 K# g! C8 ?2 b
serum testosterone level. There also is other evidence of local
, [% z2 j* s9 ~: G! j4 \response to testosterone with hair growth and with spermato-
( A) m1 ]* @$ T1 ^0 Egenesis. 5• 6; q# h; x+ }6 ?
Administration of larger doses of gonadotropin or systemic: [# S( H1 X. ?" I' J
testosterone, as well as topical applications that produce, k9 B) v- X H7 J5 G5 {7 i, N
higher levels of serum testosterone (150 to 900 ng./dl.), will; R# ~7 j- T2 M; ?8 ~9 j
also produce phallic growth but risks accelerated skeletal
/ }( s# D5 b& x6 U) Jmaturation even after stopping treatment. It would appear( F( d$ ~5 W" ?. j: r
that this may be avoided by topical applications of testosterone
/ T! C- q, Q7 `+ ], ]! d% ~and monitoring of serum testosterone. Even with this control
' ~5 I% X6 Y& l9 F1 ~the duration of our therapy did not exceed 3 weeks at any
; n3 D! w* s' d1 }& k' Ltime. It is apparent that the prepuberal male subject may
$ f8 }, H2 z+ |1 X0 d9 ssuffer accelerated bone growth with testosterone levels near
/ J, H5 l( e- O3 v200 ng./dl. When skeletal maturation is complete the level of/ O8 b/ S2 i- S! C M
serum testosterone can be maintained in the 700 to 1,300 ng./' n- f/ s5 @. [ R, T
dl. range to stimulate phallic growth and secondary sexual' X. g& Y0 g% r z, _
changes. Therefore, after skeletal maturation parenteral tes-
* u4 @) i# c/ A7 A4 z( Otosterone may be used to advantage. Before skeletal matura-
) _/ V5 s5 {* S7 p) r9 M3 dtion care must be taken to avoid maintaining levels of serum% E" c- U6 i- U+ B- j$ E
testosterone more than 100 ng./dl. Low-dose gonadotropin B; @) |6 B4 \! K3 j, q
depends upon intrinsic testicular activity and may require
8 q5 v3 N4 L Z6 O/ P2 dprolonged administration for any response.
1 q- B, h3 N) _% A5 yAlternately, topical testosterone does not depend upon tes-
# i/ \( u. Q9 z5 j7 Wticular function and may provide a more constant level of+ L0 ^9 s8 H/ D r* L
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1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; z; U) P2 T( i# |6 F9 K
R.: The local application of testosterone cream to the prepub-
|$ Y q) q4 \0 h7 Y! Hertal phallus. J. Urol., 105: 905, 1971.
: q8 \' b& ^( J: W% e2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 S7 S$ |! X( Rtreatment for micropenis during early childhood. J. Pediat., h( |1 l1 M. t* u( V U
83: 247, 1973.
) p' w& Q# p0 P8 O- n3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
2 r/ ?( S- M# Y; Done therapy for penile growth. Urology, 6: 708, 1975.
2 ]4 O# s/ w( K9 `' F% \$ `' q) S4 z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
$ c3 g: i" w- v" @2 u& Ato 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# v# h! l2 w$ W/ T- f6 Lskin slices of man. J. Clin. Invest., 48: 371, 1969.9 C, ?9 o3 G y8 b) @2 u1 H* @
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth1 s6 h3 X3 u$ ?* }5 s
by topical application of androgens. J.A.M.A., 191: 521, 1965.
3 o4 m6 \2 i% W( @6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- g! e, [- Q+ {4 i$ U f0 B9 q
androgenic effect of interstitial cell tumor of the testis. J. g d7 A4 Q4 F/ ~% {1 z
Urol., 104: 774, 1970.
( x0 g2 U3 |/ I, F3 P/ q6 U7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 _# T' }: Z) ~0 ]8 ]' ~
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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