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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
3 S/ u/ H+ ~, CGONADOTROPIN, S9 S2 j# U" S
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 v4 ~! y6 O- }& B6 g# LFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# B' H2 y: E1 r# X3 G2 CABSTRACT
( B1 X" c( N- w: w1 ^9 VFive patients were treated with gonadotropin and topical testosterone for micropenis associated
6 x8 g# F, j( B/ ]with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-4 X. o. A$ {$ z' }; V
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
3 f* _% K% j( O) L- V9 f: kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 r# _+ n- h& d2 z- f" q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent# O- G; }4 c( W. l7 F" Z& ]' D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 A* p: n) E/ q9 @" lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& g" V; q$ J' D6 toccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 E# a6 }6 a( n$ q
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile; i; [4 c/ X0 l5 c6 U
growth. The response appears to be greater in younger children, which is consistent with previ-: k3 a+ i( \* A0 }2 F9 w, P1 C9 o' e3 D% q
ously published studies of age-related 5 reductase activity.
3 Y# V2 ?5 n6 P0 FChildren with microphallus regardless of its etiology will
* Q$ ]/ ~7 Z5 }require augmentation or consideration for alteration of exter-, @& S# U2 w& h/ K( }, J
nal genitalia. In many instances urethroplasty for hypo-) q; A E; C/ X y2 x
spadias is easier with previous stimulation of phallic growth.
. A7 [' O# Y: }. SThe use of testosterone administered parenterally or topically) ^6 x, v- ^ |/ Q6 z7 i
has produced effective phallic growth. 1- 3 The mechanism of
( z5 t9 {- u0 X; J3 B; q" lresponse has been considered as local or systemic. With this
; W+ ?& W7 b' `- C3 ?- I. D |in mind we studied 5 children with microphallus for response
& e8 E# M3 N) T) d7 z- S8 @8 r- Qto gonadotropin and to topical testosterone independently.
9 G9 D' ~3 J6 P6 i) m8 Z& N: o" lMATERIALS AND METHODS) @ R/ r: A' r5 y* \* x' r
Five 46 XY male subjects between 3 and 17 years old were; [ Y$ T( i5 o' B( `
evaluated for serum testosterone levels and hypothalamic) N; W+ Y' |" p8 N p8 X
function. Of these 5 boys 2 were considered to have Kallmann's/ ?* V$ b3 C: X2 z" O0 L: \6 _
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, V# b" g' s- G. hlamic deficiency. After evaluation of response to luteinizing
; H6 _: T3 C, n: ]hormone-releasing hormone these patients were treated with
% v; I% C* t' k1,000 units of gonadotropin weekly for 3 weeks. Six weeks* x( t8 ~( s5 h% U
after completion of gonadotropin therapy 10 per cent topical
`4 H; [$ @, V4 f% L- m& \8 g1 G7 ttestosterone was applied to the phallus twice daily for 3 weeks.2 l9 f" c6 @6 w+ y/ J" w
Serum testosterone, luteinizing hormone and follicle-stimulat-
* u$ g. p2 s! r7 ]ing hormone were monitored before, during and after comple-
8 U$ p I! S" ~7 [tion of each phase of therapy. Penile stretch length was
' n& Z" A5 h+ uobtained by measuring from the symphysis pubis to the tip of
+ m1 v$ X5 s1 p/ l* G: R8 uthe glans. Penile circumferential (girth) measurements were& H5 v4 K4 i# e* M7 x# g( k
obtained using an orthopedic digital measuring device (see) H# z7 ?/ K1 p# S( v, \5 Y* L' g
figure).6 s8 U/ Y1 O* F6 _; ^" D
RESULTS, @* b( T* t) D+ Y% c: M
Serum testosterone increased moderately to levels between
C" @5 r. J# { X# v50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-% A2 V7 S% Z0 j5 Q$ f
terone levels with topical testosterone remained near pre-9 D' E8 Q& \3 ^: ^# N2 I
treatment levels (35 ng./dl.) or were elevated to similar levels1 I t5 ]. X4 t! b6 R8 N
developed after gonadotropin therapy (96 ng./dl.). Higher# e9 W) M6 C {+ d9 e- O3 r
serum levels were noted in older patients (12 and 17 years old),
`: |. I8 c2 Z9 ewhile lower levels persisted in younger patients (4, 8, and 10+ a3 T( }. h, m+ R( K/ K) I
years old) (see table). Despite absence of profound alterations
' d& r4 s4 M- N( {6 n5 H; Z Hof serum testosterone the topical therapy provided a greater& v9 Z! J. u% g( u6 Y
Accepted for publication July 1, 1977. ·
. h/ ~6 z* M- I x5 KRead at annual meeting of American Urological Association,! v; o" _- o3 j
Chicago, Illinois, April 24-28, 1977.. c$ O( W1 V& k; B, ^4 M" B' I; d" i+ Q
* Requests for reprints: Division of Urology, Henry Ford Hospital,
- p9 b r5 k4 L, j8 u8 h2799 W. Grand Blvd., Detroit, Michigan 48202.9 e' F9 V% n. A# [5 I
improvement in phallic growth compared to gonadotropin.
1 S) @3 z' H. a0 w$ ]& X5 n+ K8 O8 QAverage phallic growth with gonadotropin was 14.3 per cent a3 E. W, `" I. ^* k3 {3 n
increase in length and 5.0 per cent increase of girth. Topical/ C' j. p1 N4 S
testosterone produced a 60.0 per cent increase of phallic length
4 X9 t3 |$ ^" J8 }% }and 52.9 per cent increase of girth (circumference). The
B, o, B6 y. i: nresponse to topical testosterone was greatest in children be- @ x `8 U/ H" Y3 H$ l$ n
tween 4 and 8 years old, with a gradual decrease to age 17/ ?! B8 W* V C P1 j# l
years (see table).
: D: i; z5 n3 H7 J$ hDISCUSSION
4 W! ?/ f& m0 S8 o/ g- V/ d8 gTopical testosterone has been used effectively by other( R4 n5 S' _2 N" q! ]* N
clinicians but its mode of action remains controversial. Im-% N: x6 i" A3 ^5 q8 ]
mergut and associates reported an excellent growth response
9 ~( W9 P2 D/ Z4 R6 F: gto topical testosterone with low levels of serum testosterone,) r6 i% ^7 l' Y" o* h4 W# C* m& ~
suggesting a local effect.1 Others have obtained growth re-" f( H4 H. b/ o7 ~
sponse with high. levels of serum testosterone after topical
( u8 Q" q& i( y! F0 Z& t# N9 Wadministration, suggesting a systemic response. 3 The use of
( x m. S7 B3 W3 tgonadotropin to obtain levels of serum testosterone compara-* @3 _; \; F4 x% Y- ^
ble to levels obtained with topical testosterone would seem to' S5 e9 j6 f! v% Z& \" h
provide a means to compare the relative effectiveness of! Q0 q# Z5 K, ~
topical testosterone to systemic testosterone effect. It cer-* f7 E- t+ o4 d* `4 t6 R
tainly has been established that gonadotropin as well as par-
! k, n$ J3 c- [$ j2 Genteral testosterone administration will produce genital
w$ v! a3 a! E" u; p; r2 qgrowth. Our report shows that the growth of the phallus was* o3 O/ u6 \ E1 L/ d
significantly greater with topical applications than with go-
* V$ }: d# i4 I6 ]2 | t) znadotropin, particularly in children less than 10 years old.
) s& J/ J6 b! M1 U: _The levels of serum testosterone remained similar or lower* ?" i/ p% B% D. y Z& O: Q6 C6 D
than with gonadotropin during therapy, suggesting that topi-
6 T' o4 o7 p, D9 Kcal application produces genital growth by its local effect as
; v. g* |. k/ v( U5 ewell as its systemic effect.
% }) }. t+ h4 o% e0 o2 MReview of our patients and their growth response related to# p) K) }9 v$ B. v/ x
age shows a greater growth response at an earlier age. This is+ N' P. e, m; P7 h3 n
consistent with the findings of Wilson and Walker, who
; U2 v$ l# l" Jreported an increased conversion of testosterone to dihydrotes-8 @* i1 ?8 O2 H2 P# ]* k
tosterone in the foreskin of neonates and infants.4 This activ-
2 s8 t5 M1 [; h; s1 |( l4 Rity gradually decreases with age until puberty when it ap-
$ O* W! v- S3 r# N% Aproaches the same level of activity as peripheral skin. It may7 \' t2 I2 h& N1 y8 L
well be that absorption of testosterone is less when applied at
6 q4 g0 I4 Q6 @3 e, _$ g+ j8 ]an earlier age as suggested by lower serum levels in children
. u. B8 ]3 H9 f4 k2 kless than 10 years old. This fact may be explained by the. |3 h. I* O% o: F# z
greater ability of phallic skin to convert testosterone to dihy-' |& B8 p g. Y: @ J5 W4 e
drotestosterone at this age. Conversely, serum levels in older) r: \) @0 w: L f7 d
patients were higher, possibly because of decreased local1 `; \4 ?) k7 v% g- a+ u0 p9 G* f
667+ q; M1 A& i) ]9 e# h
668 KLUGO AND CERNY7 T' N- ^# H. X' W/ t3 k
Pt. Age I u K# z7 J- x% h F
(yrs.)
$ c2 j+ Y2 b/ y' a4 V V ?! C0 ZSerum Testosterone Phallus (cm.) Change Length1 [+ [! F7 [8 `5 i- V2 E+ O2 F
(ng./dl.) Girth x Length (%)% s: j7 F+ I; A4 X
49 v' L5 [6 g, [+ ?+ Q
8 [: X# o$ b; k2 e/ x2 }( }
10
% f+ P0 R5 m0 f. n/ U129 q0 n( }4 X# J9 n2 n% M- g
17. v# x x2 R! u% Q
Gonadotropin
0 o9 Z5 Q5 F2 s" o4 O( B71.6 2.0 X 3 16.6/ V: Z: z& e. w! m j/ o
50.4 4.0 X 5.0 20.02 }4 m) f1 r: v2 `4 L
22.0 4.5 X 4.0 25.0% `! f9 b7 d, h0 ^ I4 h0 a
84.6 4.0 X 4.5 11.1* s2 _& `6 }) G0 O! l
85.9 4.5 X 5.5 9.0% k/ g/ W9 e. L% n4 A/ {4 `
Av. 14.3
2 f) \5 Z1 O" u' w7 W3 ^# s4
; [5 {: E* v: @8/ {. J |' m: i. y6 i" ]# H$ K! Z
10+ K; M8 n8 _" M0 S# _
12
' V( t3 R: i% j) q& v4 D17" Z# ?( D4 f8 H3 M5 U4 ?$ d
Topical testosterone0 E _) R$ P7 I: y4 ]; ~$ m3 ?
34.6 4.5 X 6.5 853 W! o5 ]5 g" |: [
38.8 6.0 X 8.5 70
/ x" `7 ~# S7 p! ?- j) P& V1 K40.0 6.0 X 6.5 62.5$ f: x k7 V7 b$ m: t
93.6 6.0 X 7.0 55.5
; p& ]. ~# d9 r+ M95.0 6.5 X 7.0 27.2
; z$ B0 G% F" D) R0 QAv. 60.0) ]/ R8 q) @0 }$ a0 G, k
available testosterone. Again, emphasis should be placed on
4 j) ]+ R1 Z7 F/ s, f+ Pearly therapy when lower levels of testosterone appear to/ ~; P* @$ o$ T3 F6 l% m7 h
provide the best responses. The earlier therapy is instituted/ z E% [6 w+ k, i& }+ i
the more likely there will be an excellent response with low
4 @$ d* }& v; P9 C$ o/ Jserum levels. Response occurs throughout adolescence as1 u! S" C) P8 n6 }& s2 ?- ]8 O
noted in nomograms of phallic growth. 7 The actual response
4 G% j. f* d2 e1 O) bto a given serum level of testosterone is much greater at birth
. |; ]7 }. f+ t1 j# Gand gradually decreases as boys reach puberty. This is most
$ D p/ ]* t& X' L5 Y! i3 I$ M6 y3 O; C1 Zlikely related to the conversion of testosterone to dihydrotes-
- }2 Y7 u$ M R2 stosterone and correlates well with the studies of testosterone0 B$ F6 |: ^* K, r5 ~( D
conversion in foreskin at various ages.
. ~5 p$ `- J% f9 F: w& xThe question arises regarding early treatment as to whether
1 a5 q+ ?" |/ s3 E! c/ Eone might sacrifice ultimate potential growth as with acceler-
) U* q6 {' g9 x% l: u( Lated bone growth. The situation appears quite the reverse
9 q5 e7 _- j4 u) B% [5 D2 |6 V# xwith phallic response. If the early growth period is not used
4 v7 Y% ~' s6 r) ewhen 5a reductase activity is greatest then potential growth
8 b, H$ `9 n0 K2 Z( W7 rmay be lost. We have not observed any regression of growth
; z# d9 w% }3 mattained with topical or gonadotropin therapy. It may well
" l' W8 F" b! y8 J4 Wbe that some patients will show little or no response to any
( B+ x8 |2 X1 A/ v+ O0 nform of therapy. This would suggest a defect in the ability to2 g+ Z7 i$ y5 E; m, [9 g
convert testosterone to dihydrotestosterone and indicate that d. {' K! @9 E% O' }3 I2 d+ X
phallic and peripheral skin, and subcutaneous tissue should
; b1 w6 e3 g$ Lbe compared for 5a reductase activity.( ~. s: Q# i0 n. O
A, loop enlarges to measure penile girth in millimeters. B,
3 s' H% ?! ~, f' q- E. e& |example of penile girth computed easily and accurately.4 ]" }, X1 M' A. h& K: Z
conversion of testosterone to dihydrotestosterone. It is in this
! r: M3 H/ s( r$ K) eolder group that others have noted high levels of serum/ l1 v* u7 n" I
testosterone with topical application. It would also appear
2 [* F, v$ d6 h3 N! a6 q/ ~that phallic response during puberty is related directly to the+ [1 _3 F3 ^! w% h+ f, m ]
serum testosterone level. There also is other evidence of local
L/ S1 g2 b1 b% Uresponse to testosterone with hair growth and with spermato- u; R- \+ ]3 I L( c' h
genesis. 5• 66 W1 I- w" j1 w# ?- P* |) x3 O$ X: u
Administration of larger doses of gonadotropin or systemic
$ |5 Y4 B5 j8 [( v3 J; o" q0 N& Ttestosterone, as well as topical applications that produce
% o- Q4 \% i0 khigher levels of serum testosterone (150 to 900 ng./dl.), will& u0 K) B4 D4 r6 b. c% Z- f0 m
also produce phallic growth but risks accelerated skeletal
" \+ y" T0 @: o# K' b5 w2 `4 o# ^maturation even after stopping treatment. It would appear
, M$ q* {' ?6 l+ L; Y. hthat this may be avoided by topical applications of testosterone& a ?( l3 U( b4 x5 T
and monitoring of serum testosterone. Even with this control0 {) P8 W6 x% R. c: G" c# C
the duration of our therapy did not exceed 3 weeks at any! x/ f0 ?" Y1 B! o9 u- k6 V
time. It is apparent that the prepuberal male subject may
( C# i% ^/ E: }: [suffer accelerated bone growth with testosterone levels near
9 T; i$ [3 g p7 s4 W+ u4 K" U, `' `) A200 ng./dl. When skeletal maturation is complete the level of
! z: }1 g ]- Q R l) S: Oserum testosterone can be maintained in the 700 to 1,300 ng./6 d0 M) l) D: {. ?5 T+ F3 M
dl. range to stimulate phallic growth and secondary sexual
! H/ y5 o5 J7 B7 L9 c3 a9 tchanges. Therefore, after skeletal maturation parenteral tes-
( u( f. s# S& B- B5 F3 q2 L& Ntosterone may be used to advantage. Before skeletal matura-& @* }. n- M- z; h$ O. i' C
tion care must be taken to avoid maintaining levels of serum
# M2 ^2 J0 L9 Ttestosterone more than 100 ng./dl. Low-dose gonadotropin
" w. D+ a4 v$ zdepends upon intrinsic testicular activity and may require# O @+ [8 @- a4 E
prolonged administration for any response.+ ?) s* Y. y% T! Y4 H: n
Alternately, topical testosterone does not depend upon tes-
% @3 h. N# l rticular function and may provide a more constant level of* [7 h+ X7 S4 i( }. ]
REFERENCES0 c5 T7 {! q. Q C4 Y; S
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,! i; U$ L" r: y6 h% X9 I5 P
R.: The local application of testosterone cream to the prepub-8 J, d) ?3 B& e0 l( t2 {5 N3 k/ \
ertal phallus. J. Urol., 105: 905, 1971.
+ ^0 P( y0 ~4 P* J2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, U. ]8 v* y- ?6 S$ j( Ktreatment for micropenis during early childhood. J. Pediat.,* J4 {1 `) U: @( L9 @) J
83: 247, 1973.2 a( I4 r$ o3 h, h
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-/ K" L' o: w4 N9 E1 I
one therapy for penile growth. Urology, 6: 708, 1975.
" L5 w; h3 G3 I& ]* \5 d: m# ^3 N4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* y: E3 }( Y" P' fto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
0 z. z- b, E) h4 p! Vskin slices of man. J. Clin. Invest., 48: 371, 1969.$ m: P6 X1 R0 A! _0 w# J& p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 I! g. d. V5 |) ~; Q
by topical application of androgens. J.A.M.A., 191: 521, 1965.
$ [+ O! N, B/ v6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local; @! K8 S* h5 T1 Z
androgenic effect of interstitial cell tumor of the testis. J.
& c! H7 j$ T3 r/ m& sUrol., 104: 774, 1970.2 v8 h) a- v* S: F) J9 k
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" g( i! @' s; q! L8 @
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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