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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
$ A5 g0 b3 U$ P2 T0 }9 uGONADOTROPIN
% U* @0 j( h- F% s8 k* PRICHARD C. KLUGO* AND JOSEPH C. CERNY
6 H; p; {: h! c ]: }, fFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
. N# e; {; E, K3 s3 M2 V+ iABSTRACT+ z S e, |. e H6 P* s* p3 p
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
7 X* u3 B5 N' m+ n! Q1 ^with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. H: A$ ~. l0 |/ p: @7 [tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone( J- ` c: u% S: V+ X
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( t+ j! ^- O/ c8 T7 b7 }" B$ g. rfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent- h- I1 s; U( s
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! z# i1 U5 `, y9 o' f% |& ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
- Y% Q5 |( S# X: m% s6 c2 Goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
/ x: B9 W& F9 ]$ Z; R/ P1 fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 d- [, h; u. rgrowth. The response appears to be greater in younger children, which is consistent with previ-
2 E2 y& H' c1 H1 p8 z; D8 b/ }ously published studies of age-related 5 reductase activity.
5 y+ Y! }, o9 Z, u/ A3 oChildren with microphallus regardless of its etiology will
- t1 M* `7 q% s brequire augmentation or consideration for alteration of exter-6 L/ W1 a* e1 f q7 a* U" D( s7 Z8 O# o
nal genitalia. In many instances urethroplasty for hypo-( M' z% Q( a' z& H% n# l
spadias is easier with previous stimulation of phallic growth.* \2 L/ T0 h- T6 i
The use of testosterone administered parenterally or topically F7 d a5 _: `. j. Y
has produced effective phallic growth. 1- 3 The mechanism of
9 R, y5 X$ A5 p8 ^- a9 p1 rresponse has been considered as local or systemic. With this m( ^: c. a* s
in mind we studied 5 children with microphallus for response
O. a3 E; M4 l }. P' q" Qto gonadotropin and to topical testosterone independently.
) T+ r1 U0 A: w( |/ |, ?MATERIALS AND METHODS
4 p1 G+ _ D$ g d0 x$ rFive 46 XY male subjects between 3 and 17 years old were
! D7 G8 o4 \7 N# P6 t4 Xevaluated for serum testosterone levels and hypothalamic" z6 v+ R# z* d1 t+ j& w5 i
function. Of these 5 boys 2 were considered to have Kallmann's
' c( d# S4 @; Psyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, J" E1 p% }# N; C; |# J
lamic deficiency. After evaluation of response to luteinizing
1 a: Q& S+ }) Xhormone-releasing hormone these patients were treated with
5 p9 c$ |2 S! r5 T1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# s; C% J" N8 q8 B5 k& aafter completion of gonadotropin therapy 10 per cent topical
0 f& q: \% b% N4 V2 `/ U3 @testosterone was applied to the phallus twice daily for 3 weeks.
$ E! q8 F' J! P/ WSerum testosterone, luteinizing hormone and follicle-stimulat-; F, `' e& [6 r
ing hormone were monitored before, during and after comple-
" p- s# u3 G8 P4 _3 n& ktion of each phase of therapy. Penile stretch length was6 d8 q4 V: k/ F" e, L2 M+ O, h
obtained by measuring from the symphysis pubis to the tip of/ _# u; x. l5 _# W9 v& P" a
the glans. Penile circumferential (girth) measurements were; K" G: j# ]* K+ J6 y% W8 e( m i
obtained using an orthopedic digital measuring device (see
, |9 \% t. ?% o( ffigure).: k+ A8 e6 {! P: T c: H+ X8 _# h
RESULTS
3 Z& Z4 r" j' ASerum testosterone increased moderately to levels between
- N+ Y0 e r9 `; B5 B9 `50 and 86 ng./dl. with gonadotropin stimulation. Serum testos- W" w$ ^/ t' v0 F5 [. T
terone levels with topical testosterone remained near pre-
' G# B. N) t: w: m: x6 Z4 H$ Mtreatment levels (35 ng./dl.) or were elevated to similar levels
! b) k% f9 H" J& Z9 y4 J: `developed after gonadotropin therapy (96 ng./dl.). Higher2 p& ^, c7 |5 V. M" V6 W8 f3 |
serum levels were noted in older patients (12 and 17 years old),
9 U( ], m( X2 E+ r6 w! b/ X4 h& Ywhile lower levels persisted in younger patients (4, 8, and 10
" ]/ q8 w7 H( k6 z8 |; ~& O4 ?0 Uyears old) (see table). Despite absence of profound alterations6 O1 ?2 s3 A1 p( w! J6 g
of serum testosterone the topical therapy provided a greater
3 _6 n" h. y# E$ A% iAccepted for publication July 1, 1977. ·/ X7 P8 T& {' [) C# J
Read at annual meeting of American Urological Association,
/ r0 z& V; {# E3 wChicago, Illinois, April 24-28, 1977.7 m3 `% g* s: s! |9 \1 |
* Requests for reprints: Division of Urology, Henry Ford Hospital,
# k: t+ ^& v3 Z8 B' L2799 W. Grand Blvd., Detroit, Michigan 48202.; W" R3 Y( M! k( N8 d( w
improvement in phallic growth compared to gonadotropin.- i- L: W9 J, Q
Average phallic growth with gonadotropin was 14.3 per cent9 b4 r* n! ]7 g: W' w; [
increase in length and 5.0 per cent increase of girth. Topical4 v( }# b2 c3 y4 h4 M8 ^! y
testosterone produced a 60.0 per cent increase of phallic length$ @$ I3 d; v' Z
and 52.9 per cent increase of girth (circumference). The; U+ }1 a# J+ g! y$ {
response to topical testosterone was greatest in children be-4 ^& U$ {( y. j% h4 W
tween 4 and 8 years old, with a gradual decrease to age 17
7 M! p$ o" D) p) k/ ~! O: H$ Ayears (see table).% A( B. w& o3 a6 _( R
DISCUSSION
2 M. Y2 y4 f: E& k9 Z3 kTopical testosterone has been used effectively by other
7 {6 B3 E) p9 @- a: [clinicians but its mode of action remains controversial. Im-
8 _2 y* t" p# p2 ~( `mergut and associates reported an excellent growth response
$ O) B" @ S Z1 Yto topical testosterone with low levels of serum testosterone,3 p7 s4 E. D8 x1 [! X
suggesting a local effect.1 Others have obtained growth re-
7 T- j5 |2 k! |sponse with high. levels of serum testosterone after topical
7 o+ X6 m. _0 `8 X8 Z, Fadministration, suggesting a systemic response. 3 The use of- _ e4 ?( l; n
gonadotropin to obtain levels of serum testosterone compara-9 ?" w% a. [1 z; u8 c2 z
ble to levels obtained with topical testosterone would seem to
! m. a& d9 P; s) A g; h$ ^& }provide a means to compare the relative effectiveness of8 J- f8 M7 R2 U+ K8 M
topical testosterone to systemic testosterone effect. It cer-
5 z K0 a% ^2 R# ttainly has been established that gonadotropin as well as par-+ |% `1 J& L! {4 }3 g J
enteral testosterone administration will produce genital
. @0 ^( O& A( d2 q: k6 D$ _6 I0 Igrowth. Our report shows that the growth of the phallus was+ w( q$ A0 [. h6 ^" g/ E
significantly greater with topical applications than with go-
3 P2 u6 M+ a7 [. z: _ w, X$ lnadotropin, particularly in children less than 10 years old.3 ]1 n2 s& _# n, g7 `1 b; X: I
The levels of serum testosterone remained similar or lower' y$ M6 q" e* ~ q& B
than with gonadotropin during therapy, suggesting that topi-- W& B$ t& |# [* l! _$ \3 U r
cal application produces genital growth by its local effect as
% P4 [0 J: |+ ^6 r6 kwell as its systemic effect.
& k: D t- S2 B" ^7 j- H9 z3 q9 {Review of our patients and their growth response related to
* e3 W% z1 K) H& I& p6 A. bage shows a greater growth response at an earlier age. This is% Q, f+ m) P' f
consistent with the findings of Wilson and Walker, who& o* m b, {1 G5 X
reported an increased conversion of testosterone to dihydrotes-
: m! d3 r" _) vtosterone in the foreskin of neonates and infants.4 This activ-
5 G+ e5 ?; \; nity gradually decreases with age until puberty when it ap-, I' Y$ X# n3 d7 k4 m7 i
proaches the same level of activity as peripheral skin. It may, N5 F2 L' K! I/ v
well be that absorption of testosterone is less when applied at
v2 P0 c& P" k' q& ? U+ w/ Yan earlier age as suggested by lower serum levels in children8 l- O$ o) O, U$ D( |
less than 10 years old. This fact may be explained by the
4 A9 k: i7 a5 v0 U" ]greater ability of phallic skin to convert testosterone to dihy-
M) _& l6 M# `! u/ \drotestosterone at this age. Conversely, serum levels in older+ g% u, S, `6 v% p
patients were higher, possibly because of decreased local! g$ J. {2 v7 k
667( ` V+ q* s+ j1 e8 h7 F& I
668 KLUGO AND CERNY5 C. V! C$ B8 |4 U* q2 _
Pt. Age" j+ V8 K9 i% y5 E; Y3 {( D
(yrs.)/ o0 y i* i- k0 ?4 Y0 u; T
Serum Testosterone Phallus (cm.) Change Length( z' g, C- i) j( @+ x1 w" B
(ng./dl.) Girth x Length (%)
/ W% Q6 H K( T% G3 y1 A! M/ z4
4 b& _+ r6 D# Y8 s( d+ f; q87 [: _; S" I/ z% z
10
: L* J; d$ U& S, T+ |12( ^- u' ]0 _8 h7 \
17
& Y6 h) R+ F; X+ y/ fGonadotropin
$ S' G* c$ g$ }) U3 _71.6 2.0 X 3 16.61 l x. H3 }0 C) H
50.4 4.0 X 5.0 20.0
& K% w3 y: ^5 x) n8 H3 o6 \7 n" r22.0 4.5 X 4.0 25.0
% _' K4 D8 @; ~; M2 H$ a84.6 4.0 X 4.5 11.1
/ l0 W7 V2 t* @85.9 4.5 X 5.5 9.0
6 E$ D: H; `( S, _Av. 14.3
8 Q: i d) q% p6 R6 J4/ [6 g% b; j& I$ s9 H' u* r2 n
8$ a4 C% T, S' l! z% m
10 r6 ?& z7 p9 M$ F- x7 f
12) }& a0 L0 \3 ?% s" a, q2 m0 H
17' M1 ~+ P9 ~$ d v
Topical testosterone& q' h2 a9 c# g! g
34.6 4.5 X 6.5 85
( ^6 C% x5 M# ^9 `+ Q. V, @38.8 6.0 X 8.5 70
* d& ]. r- Q$ `40.0 6.0 X 6.5 62.5
. Z% V. ]9 ^! g93.6 6.0 X 7.0 55.5
' F% r. _' e3 ]% q2 u+ I4 `95.0 6.5 X 7.0 27.24 J' D+ {% y% m U' b2 }, T
Av. 60.07 c+ N8 Y* s' n
available testosterone. Again, emphasis should be placed on
" L* O( }2 R9 Yearly therapy when lower levels of testosterone appear to
6 _% M+ }) l% e7 @: {provide the best responses. The earlier therapy is instituted) Q$ F5 X; \; ]: a9 s( D$ O
the more likely there will be an excellent response with low7 D: A# o+ B) q7 k0 q4 z' h
serum levels. Response occurs throughout adolescence as( ~( B! `: U9 R7 m2 @4 V7 U
noted in nomograms of phallic growth. 7 The actual response% o9 u- o0 i# H2 c' p
to a given serum level of testosterone is much greater at birth
+ a$ G6 O, D+ x2 d4 w% B; F7 Sand gradually decreases as boys reach puberty. This is most
6 q9 V% Z4 x0 L( B0 L* L- n% Flikely related to the conversion of testosterone to dihydrotes-
) b2 a! p! B' p2 {* b3 Ctosterone and correlates well with the studies of testosterone4 \/ Y+ p7 ^5 B) y% {& h7 ~$ C
conversion in foreskin at various ages., ?5 ^+ L8 P8 ^5 G k8 {
The question arises regarding early treatment as to whether5 @; b$ X7 z, }% f- i* E* q
one might sacrifice ultimate potential growth as with acceler-
0 D) k3 M0 p% x; ^* r G. wated bone growth. The situation appears quite the reverse
( l8 Z* d$ I! Qwith phallic response. If the early growth period is not used7 d$ T# a* @" ~1 D9 }
when 5a reductase activity is greatest then potential growth. F, S& ^1 A2 B1 m# n, O [4 F
may be lost. We have not observed any regression of growth! J+ S3 w: S& D4 }4 H5 I7 _$ C
attained with topical or gonadotropin therapy. It may well( H' H @7 p b. X c0 m$ x
be that some patients will show little or no response to any
: p3 o3 G& k' R4 W+ Lform of therapy. This would suggest a defect in the ability to
4 j0 W4 F8 g( g. Hconvert testosterone to dihydrotestosterone and indicate that8 D: J0 `! `! O. w
phallic and peripheral skin, and subcutaneous tissue should' _! V/ H# f+ [& m9 E) V
be compared for 5a reductase activity.8 [: ]8 J7 o% i7 A
A, loop enlarges to measure penile girth in millimeters. B,
, m/ e9 F5 J7 F8 y. hexample of penile girth computed easily and accurately.; S4 \; I: B6 ^' q' t5 a0 X! C( M+ G
conversion of testosterone to dihydrotestosterone. It is in this
" ^$ m) h% A9 n' folder group that others have noted high levels of serum2 L5 b) G) C, U( n
testosterone with topical application. It would also appear
9 r* x/ C3 g5 a9 R2 K, @& nthat phallic response during puberty is related directly to the* e/ a' G% d" c+ `
serum testosterone level. There also is other evidence of local
3 o1 S j. A& b" aresponse to testosterone with hair growth and with spermato-/ n! g; G1 P7 A0 A& L
genesis. 5• 6) m$ \# a( u4 i% [3 e
Administration of larger doses of gonadotropin or systemic
6 R. Y4 c# R7 \ a; V. [ _testosterone, as well as topical applications that produce" U4 a9 z- @0 w0 \8 |& o0 J+ Z
higher levels of serum testosterone (150 to 900 ng./dl.), will3 C+ u7 r8 o$ S1 C/ ^/ M7 T$ H, |
also produce phallic growth but risks accelerated skeletal& Y: s, J- T4 E" Z
maturation even after stopping treatment. It would appear
' L( j n! I% y0 E3 W* X+ Mthat this may be avoided by topical applications of testosterone# s% E9 p# f8 b7 }
and monitoring of serum testosterone. Even with this control
6 Y6 [4 A2 x2 l1 athe duration of our therapy did not exceed 3 weeks at any
$ h$ k0 H, p7 l$ y6 h( X: S; F+ ftime. It is apparent that the prepuberal male subject may
6 K0 Q$ t8 S6 a/ y4 f" ^# Y" [suffer accelerated bone growth with testosterone levels near8 t5 P0 s' t! M% [3 t* X* G
200 ng./dl. When skeletal maturation is complete the level of
& a3 W/ I2 ]1 V8 I, \7 q: qserum testosterone can be maintained in the 700 to 1,300 ng./& y) n$ T% l" F, S+ B: _& A
dl. range to stimulate phallic growth and secondary sexual" p- ^* i) ] s6 H3 I4 ~) B6 m1 L
changes. Therefore, after skeletal maturation parenteral tes-( L- ]9 N4 ~/ a" p. [: _) |
tosterone may be used to advantage. Before skeletal matura-
; \; E2 d0 }: I) {9 c% Ption care must be taken to avoid maintaining levels of serum
: d3 u/ @6 O! htestosterone more than 100 ng./dl. Low-dose gonadotropin
3 x0 z& H. @9 odepends upon intrinsic testicular activity and may require
! D' b) M1 Q7 ^8 t, K3 {prolonged administration for any response.( a. Q' C# Z& ?% s+ l7 E
Alternately, topical testosterone does not depend upon tes-
; `, j$ M; Z! K5 Xticular function and may provide a more constant level of! X. A- c# @! F1 c' u
REFERENCES
" Y2 H. \" H( G4 ?6 N1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
( B Q8 T. S" q# DR.: The local application of testosterone cream to the prepub-7 s8 R1 W) B8 p& N9 `3 s" ]
ertal phallus. J. Urol., 105: 905, 1971.
( ?- l4 }" g- N5 L& \9 J8 p2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( i' d q; T; R
treatment for micropenis during early childhood. J. Pediat.,
5 U- S2 v2 I. K2 N" V) d83: 247, 1973.
3 i# @9 ~& B" ], Y3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% t5 s" p! X. }5 n% O G+ S9 t& K
one therapy for penile growth. Urology, 6: 708, 1975.+ F5 t$ {- x( a
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- L1 X3 N: W7 s1 J* ^' g% {to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by& v, b ~& E8 F& o' m
skin slices of man. J. Clin. Invest., 48: 371, 1969.! S$ ~' x' A! M2 f) i
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth/ v% f8 F/ p- i9 B. ?
by topical application of androgens. J.A.M.A., 191: 521, 1965.8 z; G3 ?2 w: K- K1 z
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; n; t, D0 E$ v0 }! _1 A. l1 W' `androgenic effect of interstitial cell tumor of the testis. J.
W- R# w* \( r( Q" d8 WUrol., 104: 774, 1970.
. s' M) v0 f8 f! L7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
! y" E; q2 k% |$ j! J+ j! Ytion in the male genitalia from birth to maturity. J. Urol., 48: |
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