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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* T0 H( }0 p3 ?! N
GONADOTROPIN
) `) }0 o& x P2 k' oRICHARD C. KLUGO* AND JOSEPH C. CERNY
2 `; d! v0 T3 x2 x; GFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! r/ T0 D$ y; a& nABSTRACT4 |1 X: F* B- ~$ Q$ v7 V
Five patients were treated with gonadotropin and topical testosterone for micropenis associated9 g! e' ]4 ^% z' G/ Y0 z$ n" g9 k
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" I* Y) \) P0 T- ~
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* s6 I* f+ w1 [# S' ]
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 O! f% d7 y' C ]
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent; V$ m2 ?- m4 V; L) `
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average1 \; `* C7 g7 b! _ X0 z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response& U; k4 o; n! h0 ~6 i
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, G! @) |7 U8 ~# m+ T" Ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* X R- H2 k9 H# n' \' Y. ngrowth. The response appears to be greater in younger children, which is consistent with previ-5 m9 [( \* Y0 X
ously published studies of age-related 5 reductase activity.
. V) I! t a- V8 \' T7 F! I6 k8 v% wChildren with microphallus regardless of its etiology will4 I. ] }* J7 [* i: }' r! C1 V
require augmentation or consideration for alteration of exter-" i `/ ?/ d7 L& J1 A6 l( a
nal genitalia. In many instances urethroplasty for hypo-# `, x3 E/ J. x- E
spadias is easier with previous stimulation of phallic growth.
( q0 U$ o0 y. F& O* qThe use of testosterone administered parenterally or topically
' T" z& E( r$ @9 w3 dhas produced effective phallic growth. 1- 3 The mechanism of1 E d5 q& \& n& }1 W
response has been considered as local or systemic. With this
% J+ {& ]2 j- d: a# c2 g% ^in mind we studied 5 children with microphallus for response
\# Y* _% A) ]$ h; C& eto gonadotropin and to topical testosterone independently.
n% p: O% j# p) g2 ZMATERIALS AND METHODS; k" c* ]/ A. D8 s6 B6 D
Five 46 XY male subjects between 3 and 17 years old were
/ X Q) C$ L' L4 Aevaluated for serum testosterone levels and hypothalamic5 W- M4 Y$ O4 W- B) X; @
function. Of these 5 boys 2 were considered to have Kallmann's/ j! s6 l& t1 a/ i
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
5 [0 W7 p* }# ?3 {# @3 ]% Dlamic deficiency. After evaluation of response to luteinizing% g& E9 ?! T3 E. V$ j' u, R" g2 V
hormone-releasing hormone these patients were treated with
: x) l( H' a+ i3 f; c1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. @) ]9 O3 E; m: S6 m' s' A; ]3 Tafter completion of gonadotropin therapy 10 per cent topical& k" j: g6 b5 [6 o# y
testosterone was applied to the phallus twice daily for 3 weeks.( [. ^" q1 [/ P0 ?- B
Serum testosterone, luteinizing hormone and follicle-stimulat-$ K$ r% H4 q4 K/ ^# T4 c( h
ing hormone were monitored before, during and after comple-
! _6 z: ~7 l) k5 u3 X9 wtion of each phase of therapy. Penile stretch length was
5 I# C+ P9 k4 N; T! _obtained by measuring from the symphysis pubis to the tip of
. i3 x1 M6 L, B+ N8 c* Othe glans. Penile circumferential (girth) measurements were* i: z3 f" i" L+ G! w! J+ x
obtained using an orthopedic digital measuring device (see) h( s. Y* q# ^/ S* N( q8 y
figure). i7 r/ S6 }$ {
RESULTS
" B7 o4 Z% f6 r2 b1 CSerum testosterone increased moderately to levels between
3 v: x) l8 R, f: Z, ~ u50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
5 ~' a8 I! L* Lterone levels with topical testosterone remained near pre-1 d! }1 X$ d1 V/ ~6 ^# U# p
treatment levels (35 ng./dl.) or were elevated to similar levels
0 @$ _: S0 \. J; r7 Udeveloped after gonadotropin therapy (96 ng./dl.). Higher7 D- R2 r4 g$ |/ v
serum levels were noted in older patients (12 and 17 years old),4 f) m4 W5 u" ], U% T. q
while lower levels persisted in younger patients (4, 8, and 10: b1 H% j! s4 k4 p
years old) (see table). Despite absence of profound alterations9 f- e( o7 p* `& e( E; v3 g
of serum testosterone the topical therapy provided a greater
- X: a# _; U$ p+ _) I4 H3 MAccepted for publication July 1, 1977. ·3 L* p; `6 ]- H k8 |% I6 D5 X& @% A
Read at annual meeting of American Urological Association,8 p3 }1 h8 Y6 L( X
Chicago, Illinois, April 24-28, 1977.- Z/ y6 f6 r2 S
* Requests for reprints: Division of Urology, Henry Ford Hospital,8 J/ D( m- r9 L5 N& W& J" M# G
2799 W. Grand Blvd., Detroit, Michigan 48202.1 F0 q4 M! t9 v, V; x' X% y; R, M' q
improvement in phallic growth compared to gonadotropin.
0 P( c `6 L ]4 y |Average phallic growth with gonadotropin was 14.3 per cent
# u2 t# r9 L8 r2 n5 m" Jincrease in length and 5.0 per cent increase of girth. Topical" u j# R6 t! L+ [
testosterone produced a 60.0 per cent increase of phallic length. K7 ?4 _6 A5 _3 x+ R4 F8 J" k( ?
and 52.9 per cent increase of girth (circumference). The
" N4 G u$ |. C3 tresponse to topical testosterone was greatest in children be-$ z& L9 k; ]: Q0 O, F6 |9 A
tween 4 and 8 years old, with a gradual decrease to age 17
2 p- S$ D1 X5 y/ u* zyears (see table).. C, f' ?, X. c& k( O7 Z) f. i, H
DISCUSSION
( [3 y' P3 R. H' f2 dTopical testosterone has been used effectively by other8 {& m% k! a# e# r
clinicians but its mode of action remains controversial. Im-5 i) N# r0 z* U
mergut and associates reported an excellent growth response+ S( h2 u5 u t0 Q
to topical testosterone with low levels of serum testosterone,
7 Q; o$ B0 [2 y. fsuggesting a local effect.1 Others have obtained growth re-
! @ v$ W1 A) A$ lsponse with high. levels of serum testosterone after topical
$ K$ g) o7 ~" I" H4 [1 p# l: Xadministration, suggesting a systemic response. 3 The use of i+ |6 s1 D1 h- ~. U2 t% m
gonadotropin to obtain levels of serum testosterone compara-
( w ]# {6 m6 T A& Rble to levels obtained with topical testosterone would seem to: d. G6 S* u# H4 h
provide a means to compare the relative effectiveness of0 G& f" o8 ?8 C h0 Q7 u1 m6 [* k4 @
topical testosterone to systemic testosterone effect. It cer-
3 \& q. A: c: f# J7 w6 Rtainly has been established that gonadotropin as well as par-
* h! y% r6 h( w- `9 W4 lenteral testosterone administration will produce genital- @+ F: y R5 X" O, W6 \
growth. Our report shows that the growth of the phallus was
6 l+ v k! M8 M4 Z, m/ j( r, Isignificantly greater with topical applications than with go-
& E; x0 [' J3 V2 U: Z0 snadotropin, particularly in children less than 10 years old.1 O1 R+ X# N* v: z" T
The levels of serum testosterone remained similar or lower
% g. b* L6 ?; P% _ X' I$ @6 V4 ^than with gonadotropin during therapy, suggesting that topi-, |7 ?4 e$ Z# F" B+ E# S1 G9 k
cal application produces genital growth by its local effect as3 b& A' n2 J K2 H, m) [' u
well as its systemic effect.* K& m/ W6 u4 i% t8 w2 e0 c- g
Review of our patients and their growth response related to6 {- u" Q- o4 ]* ?* K" U: U" Y8 ?
age shows a greater growth response at an earlier age. This is, `0 {; E- x, o% ^4 F* O
consistent with the findings of Wilson and Walker, who
0 ?$ ~0 b4 `. u( m H* _6 wreported an increased conversion of testosterone to dihydrotes-7 e/ D( r! F9 ]- B% }
tosterone in the foreskin of neonates and infants.4 This activ-
4 C W5 y3 H0 ?+ \5 rity gradually decreases with age until puberty when it ap-! d2 m6 d; p% Y$ J) Q& Y
proaches the same level of activity as peripheral skin. It may' f, U4 U7 o1 n1 o
well be that absorption of testosterone is less when applied at& l+ A2 s- T: D& b
an earlier age as suggested by lower serum levels in children
! a/ u) H8 U/ u1 x; b% @less than 10 years old. This fact may be explained by the
6 W8 h/ w6 N' F ]; Y+ T5 T8 Y6 ]greater ability of phallic skin to convert testosterone to dihy-
" W, S9 U4 H# P( L Vdrotestosterone at this age. Conversely, serum levels in older
1 j2 u8 R7 u+ d u4 h- Rpatients were higher, possibly because of decreased local
. w. j7 ^/ U9 [8 M6 F9 q667% g7 ^( N9 g: @) @
668 KLUGO AND CERNY3 Y' @/ I* u5 ]3 { O6 A4 E
Pt. Age4 O, |0 F8 j7 r A) n$ J' ]% g
(yrs.)
" o2 T9 E1 h" f+ s( w# G' Q% pSerum Testosterone Phallus (cm.) Change Length( O5 D, W( U( \5 q
(ng./dl.) Girth x Length (%)" t7 L; U9 t6 w# m2 i
4
0 {0 ?3 g- Q4 ^3 O% e* G83 V/ _$ ?: z0 B0 x& c2 j
10( ^% F+ I- Y# G' q+ b* i* Z
128 v Y. w: w/ f8 w4 @3 g# v
17
8 D* H$ Y6 Z) f' y/ V- I( K0 i5 P9 _Gonadotropin' F1 O9 B4 I; c. z2 L5 ?/ }' U
71.6 2.0 X 3 16.6
, @: c) N8 e0 n4 Y50.4 4.0 X 5.0 20.0
- @, C$ P8 \; M) A* j22.0 4.5 X 4.0 25.0/ r& i; Q* Y- o+ @" k) N
84.6 4.0 X 4.5 11.1
9 R6 N* J; ?% s7 l: u85.9 4.5 X 5.5 9.0: ?9 N; C: z" @
Av. 14.3- n: P; p: @3 d
48 ]$ _7 a1 k5 M6 V2 v
8
# r% C0 [2 v4 I( [" n108 l! m. b- E$ X S( o
12
: s2 p% V% G8 I3 M17# E1 Y4 q( F4 }4 v M
Topical testosterone. }! {, D2 z7 j. t7 v
34.6 4.5 X 6.5 85$ ~" i5 r( X2 u. F& @
38.8 6.0 X 8.5 70
/ K' x2 X. z" H! l; f8 k40.0 6.0 X 6.5 62.5
* t; _# z# o* q% X, T% A3 w93.6 6.0 X 7.0 55.5
1 l6 d e- a8 G: B s95.0 6.5 X 7.0 27.2
( h1 w; E% ^9 B" M& K, DAv. 60.0
) H8 r! [9 J* B" s9 qavailable testosterone. Again, emphasis should be placed on. A/ `( Z& I* L* s# H
early therapy when lower levels of testosterone appear to
# Q g( ]' S0 m: |provide the best responses. The earlier therapy is instituted
# r) t: C/ B S8 a0 @) |& K2 p; c- r3 Ythe more likely there will be an excellent response with low
) e$ G9 ?" S# `6 {serum levels. Response occurs throughout adolescence as
. h( d+ L$ Z* D2 Q" N% snoted in nomograms of phallic growth. 7 The actual response
, i, p3 p/ e& B( v8 N1 _4 q R" W2 @to a given serum level of testosterone is much greater at birth
5 c6 G$ ~5 U( f$ `9 ?$ `and gradually decreases as boys reach puberty. This is most5 E% B' L; O% {- x2 }" T
likely related to the conversion of testosterone to dihydrotes-
1 r# b( g" _4 v. z+ O5 ^tosterone and correlates well with the studies of testosterone
, t8 N( U: G5 v9 Q x' aconversion in foreskin at various ages.
' E z! h3 V1 m% ]9 bThe question arises regarding early treatment as to whether
) N7 o! i: N4 O/ T& Zone might sacrifice ultimate potential growth as with acceler-
$ l/ r# y; M" Vated bone growth. The situation appears quite the reverse8 c. Y7 S5 \& z
with phallic response. If the early growth period is not used! i! L# t+ _" U3 S' O
when 5a reductase activity is greatest then potential growth
% `# A2 P, I8 U* O u$ k; U1 Bmay be lost. We have not observed any regression of growth
! v/ R1 @8 D( }9 X$ k$ }attained with topical or gonadotropin therapy. It may well! G* j5 I6 L/ a& C9 i$ q" z- [5 \3 F5 P
be that some patients will show little or no response to any
' F/ O% h! b3 e* O; J2 ?4 kform of therapy. This would suggest a defect in the ability to
' B3 }. f9 O5 F1 W: i( w" ?3 v1 bconvert testosterone to dihydrotestosterone and indicate that1 ?$ p1 Y$ q: s6 w5 ?' c" C4 \* M
phallic and peripheral skin, and subcutaneous tissue should
2 P3 ^& T5 H& l, S c! ^be compared for 5a reductase activity.$ u" D0 b% L0 a, ]
A, loop enlarges to measure penile girth in millimeters. B,9 u2 D1 E* i( U2 U: n
example of penile girth computed easily and accurately.$ u6 x# w; C/ @# j6 _
conversion of testosterone to dihydrotestosterone. It is in this
3 i) K* n$ R( G* c% _older group that others have noted high levels of serum
+ z# n- W/ u: f7 L- Ytestosterone with topical application. It would also appear. \& T6 ]) Y* d
that phallic response during puberty is related directly to the
) E& O* N5 H% r: Mserum testosterone level. There also is other evidence of local5 B i8 N8 R; f t
response to testosterone with hair growth and with spermato-& |" d: n. i; P: u$ O& x8 V
genesis. 5• 6
# H& v4 [7 L s$ v! f8 cAdministration of larger doses of gonadotropin or systemic, m( ?/ U9 x8 O! @( I
testosterone, as well as topical applications that produce
2 Y' p6 {$ M4 d0 W6 o- Z, V5 bhigher levels of serum testosterone (150 to 900 ng./dl.), will
$ q9 q# B/ I4 E6 p1 w8 oalso produce phallic growth but risks accelerated skeletal2 P5 R) g4 G$ {+ X% j
maturation even after stopping treatment. It would appear5 X: p8 H& w% j' d
that this may be avoided by topical applications of testosterone& B7 x& G! L, i5 C6 g5 f
and monitoring of serum testosterone. Even with this control
& o* |5 f6 l p( W' w" H, R* ]the duration of our therapy did not exceed 3 weeks at any8 H9 w) y/ m( Z/ n2 O' Z8 g0 E
time. It is apparent that the prepuberal male subject may
9 Q, E$ V$ I2 d" zsuffer accelerated bone growth with testosterone levels near0 ^3 `9 c% q' y( t' y5 q/ ]% t3 Z
200 ng./dl. When skeletal maturation is complete the level of, k) j8 c) P6 T* D t# z, n# ^1 u
serum testosterone can be maintained in the 700 to 1,300 ng./6 G/ s3 R2 `. m7 ]1 b9 u
dl. range to stimulate phallic growth and secondary sexual
3 E) @% U6 c, c, l; i# O) \changes. Therefore, after skeletal maturation parenteral tes-
# ^8 D6 t& X, W: G. V% htosterone may be used to advantage. Before skeletal matura-/ K! X4 d5 n1 V! \( i9 T% K# X
tion care must be taken to avoid maintaining levels of serum
7 {4 {0 |/ o' M. D% d' n+ f+ g, Ptestosterone more than 100 ng./dl. Low-dose gonadotropin' N# P. F6 ^$ g& Q/ K0 n
depends upon intrinsic testicular activity and may require9 U' `# `6 C; Z8 R) i
prolonged administration for any response.
& A" s: [. {- U6 d; Q& tAlternately, topical testosterone does not depend upon tes-
, x# F$ I9 Y; ?0 R. Dticular function and may provide a more constant level of
% L' S9 g3 L6 S( ?& [# I4 ZREFERENCES
! `" |) M$ V$ K! n+ d1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; C$ E- J" e: S1 o7 K( m* [2 FR.: The local application of testosterone cream to the prepub-# m7 }* _ ?& G. j/ |6 M
ertal phallus. J. Urol., 105: 905, 1971.: m/ v9 Y: Z' J4 c, M
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 U8 {+ l* g6 h2 B
treatment for micropenis during early childhood. J. Pediat.,# u& L6 g+ n( Y1 [
83: 247, 1973.& m( I7 n# \3 ~, @5 L9 [% L* E
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" o4 H) u" J9 O' Xone therapy for penile growth. Urology, 6: 708, 1975.
3 T$ B+ a' e& E6 n- f4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 g6 X; ]: Y! G2 j* M
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( ?0 J; i8 {& o0 w: E: p
skin slices of man. J. Clin. Invest., 48: 371, 1969.0 L' I' j+ Z( w5 s& _* |& R
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
% w4 O) {5 h: A! H# J% c% w5 xby topical application of androgens. J.A.M.A., 191: 521, 1965.
; A+ ~ b* F9 B0 p/ b' U# p: D6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
9 Z* A0 A& Y' ^) i3 wandrogenic effect of interstitial cell tumor of the testis. J.2 u. B! @6 A9 i" x# u) w* c0 J
Urol., 104: 774, 1970.+ ^3 Z7 H" P: o, ^
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ |* q5 q$ S1 D* o% t
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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