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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* o# N! p& e; c4 V8 y! d! V9 H; F& i
GONADOTROPIN
; t4 y3 A3 v; z9 Z0 z! O; `5 ^# SRICHARD C. KLUGO* AND JOSEPH C. CERNY
3 N! z8 E! l6 H+ ^% i- w, eFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& D9 h6 d% J3 N5 x$ Y% I& }ABSTRACT
( T$ D( L( }2 v" t$ }7 PFive patients were treated with gonadotropin and topical testosterone for micropenis associated
* \6 a7 e0 g- S' R- y6 m- hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-9 p9 o$ t1 k# j& D7 C' N% ~
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. T( `# U) P* r2 _( o
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; S8 p5 y" t7 a0 ^for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% @1 w& F/ N( q, ?increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: @4 Q! M, B6 ^% K9 V; U7 kincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response& A8 Z4 o8 D6 \& |( k- |
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 b7 z- y4 |8 R' |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 M( \( I4 |9 Vgrowth. The response appears to be greater in younger children, which is consistent with previ-
, [$ V5 v3 Y5 w/ M3 kously published studies of age-related 5 reductase activity.
3 N2 X- |6 F5 a" p0 uChildren with microphallus regardless of its etiology will9 Q {& s* u% t$ {
require augmentation or consideration for alteration of exter-6 r* r0 c1 T/ Y1 f! [4 S# X& I
nal genitalia. In many instances urethroplasty for hypo-; f% @+ n4 J) n6 h$ p% p* J
spadias is easier with previous stimulation of phallic growth.$ n5 P9 d. F9 l1 a9 X4 E
The use of testosterone administered parenterally or topically* j8 ^ X F" L% Y9 E
has produced effective phallic growth. 1- 3 The mechanism of( m, J, v4 q: R9 Y1 M3 J) _% [
response has been considered as local or systemic. With this
+ F0 M- U0 P4 G7 I1 k0 D# \in mind we studied 5 children with microphallus for response
7 K7 W) i( x& Y7 S- K) ato gonadotropin and to topical testosterone independently.
% Y/ ]8 y* d) k$ V7 tMATERIALS AND METHODS; p/ C; V8 r- s3 D3 Z3 P+ b
Five 46 XY male subjects between 3 and 17 years old were
# L9 j5 O8 z: |9 \4 mevaluated for serum testosterone levels and hypothalamic
' i, l) n9 R# g' B& [function. Of these 5 boys 2 were considered to have Kallmann's
e/ i, G) ^ N/ ~syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
" ?& c, a. z+ X( H) D) A/ c; |! Zlamic deficiency. After evaluation of response to luteinizing
. ^3 U6 T8 C* j( shormone-releasing hormone these patients were treated with
: T' e/ a; g! @$ [1,000 units of gonadotropin weekly for 3 weeks. Six weeks
5 z1 @# t" f& y3 Qafter completion of gonadotropin therapy 10 per cent topical+ e# L' ^3 h% X9 M1 x1 G5 O* g" F2 m
testosterone was applied to the phallus twice daily for 3 weeks." ]$ ~) l$ J; J5 K3 _8 }' E
Serum testosterone, luteinizing hormone and follicle-stimulat-
+ n4 V3 K9 ~/ ?5 m' y; F% i' i5 ging hormone were monitored before, during and after comple-; H- V9 M/ o, G4 s6 B* X
tion of each phase of therapy. Penile stretch length was: `6 d; X3 K! l% \8 y, v
obtained by measuring from the symphysis pubis to the tip of
) Q4 Q# x! l4 K/ [! kthe glans. Penile circumferential (girth) measurements were0 L2 s3 `+ u8 Y) A7 [' }
obtained using an orthopedic digital measuring device (see& a+ t& {( W1 W
figure).9 I+ C, z7 J- H( {9 f# N
RESULTS
/ V' ]7 c% w$ `+ B! ?* ^; JSerum testosterone increased moderately to levels between
/ @, L3 R& T F" g Q6 F e6 M# X50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-2 X- e& G8 s$ X4 E
terone levels with topical testosterone remained near pre-
+ E5 ~/ p7 L* l* Ntreatment levels (35 ng./dl.) or were elevated to similar levels% I6 Q- V3 f9 B! T! X2 v+ V: R
developed after gonadotropin therapy (96 ng./dl.). Higher
6 E+ n1 f) X, }( \+ ~2 Hserum levels were noted in older patients (12 and 17 years old),
( @( R ] L5 e2 a( ]while lower levels persisted in younger patients (4, 8, and 10
" T9 Y7 j. {6 f) H6 F( h, Y* ?years old) (see table). Despite absence of profound alterations
+ J4 O0 t* `. d5 L; j! Eof serum testosterone the topical therapy provided a greater# y6 b$ _3 A( K1 k& w% d, b
Accepted for publication July 1, 1977. ·
2 P+ r' h( H3 @ ]' L8 s9 mRead at annual meeting of American Urological Association,
1 B( |7 q. s }Chicago, Illinois, April 24-28, 1977.
' v2 M3 ]* @' ] L: u3 n% b* Requests for reprints: Division of Urology, Henry Ford Hospital,0 X+ E2 p6 ~% N4 z, T1 r' L3 Y6 s
2799 W. Grand Blvd., Detroit, Michigan 48202.' C, k J( J/ K4 l h" c$ J `
improvement in phallic growth compared to gonadotropin.
9 @; Y W& [# W9 [3 x3 s* k& oAverage phallic growth with gonadotropin was 14.3 per cent
7 }' J6 N$ i- ~ zincrease in length and 5.0 per cent increase of girth. Topical
. V0 u3 z# `7 etestosterone produced a 60.0 per cent increase of phallic length
+ @/ k/ d3 T2 A6 [$ gand 52.9 per cent increase of girth (circumference). The
" }& _8 `$ J- c; X2 x+ ~response to topical testosterone was greatest in children be-5 V6 r6 F( ]) ^" ]
tween 4 and 8 years old, with a gradual decrease to age 17
6 j* d7 Q$ }: e2 N- b. Lyears (see table).
! z# B! ]+ a, p8 ?2 w0 W4 c; lDISCUSSION
% I9 l1 h9 u. R9 pTopical testosterone has been used effectively by other+ o+ @0 _" f# [- K
clinicians but its mode of action remains controversial. Im-7 R; t) Q2 ^) A, i" h4 p
mergut and associates reported an excellent growth response
0 O7 n4 y, k2 @to topical testosterone with low levels of serum testosterone,8 x8 I q& O; _
suggesting a local effect.1 Others have obtained growth re-
8 ?! f7 ? O% b M2 m, Gsponse with high. levels of serum testosterone after topical' T$ s& \" X" k1 _! V
administration, suggesting a systemic response. 3 The use of
- v2 |4 p% S1 l" o' g( I( M; Vgonadotropin to obtain levels of serum testosterone compara-: p1 [' V* ^+ E7 i
ble to levels obtained with topical testosterone would seem to
0 ?5 c& g) k4 c3 {provide a means to compare the relative effectiveness of
9 t( v& a1 @2 vtopical testosterone to systemic testosterone effect. It cer-/ R! N }+ H' d2 O1 u3 J* X
tainly has been established that gonadotropin as well as par-
* r* B+ h% C; penteral testosterone administration will produce genital
* V! v. O3 ^$ P( B5 z4 Z ^. {% rgrowth. Our report shows that the growth of the phallus was3 A, X w$ r% a! d% h; f, Q
significantly greater with topical applications than with go-
[, C7 Z J O+ Vnadotropin, particularly in children less than 10 years old.
4 G' |( H" X0 S- v7 r% D0 @, h$ E) lThe levels of serum testosterone remained similar or lower) h- _- m7 ?+ J Q
than with gonadotropin during therapy, suggesting that topi-" B1 i( s' d7 y1 }, i2 ~( `
cal application produces genital growth by its local effect as3 L6 u1 l+ ~3 k) u
well as its systemic effect.
% P. c, ~$ U8 ]- ?. T, @- h% qReview of our patients and their growth response related to* j; F5 Q6 Z1 o4 Z- N
age shows a greater growth response at an earlier age. This is7 u* Z t8 C* w& c; u# [$ f9 p
consistent with the findings of Wilson and Walker, who
, [. s* S5 Y9 E4 rreported an increased conversion of testosterone to dihydrotes-, ?0 S5 }. E9 o* t5 h& l
tosterone in the foreskin of neonates and infants.4 This activ-5 w; E0 V3 H; u; [1 y, H X
ity gradually decreases with age until puberty when it ap-
6 j+ ^: @- T8 B. x' N$ v( \# ], ^proaches the same level of activity as peripheral skin. It may
/ e- c; r" p! T! J- F ?well be that absorption of testosterone is less when applied at! r2 x1 w2 I# Z8 E0 ]- {; w6 R! M
an earlier age as suggested by lower serum levels in children
; K" }0 z9 Q7 _* u# L. {5 Hless than 10 years old. This fact may be explained by the1 i! T) H* v$ v" ^ ^7 G
greater ability of phallic skin to convert testosterone to dihy-
# b$ J/ `& q; T8 f8 e4 ^drotestosterone at this age. Conversely, serum levels in older
% y8 ]$ Z3 J. \" mpatients were higher, possibly because of decreased local
% g, g- K* N: A9 a) C6678 l# B8 t0 _+ Q" {; F
668 KLUGO AND CERNY' u4 E' H6 n p+ ~/ C# B3 Z0 X$ A' l
Pt. Age7 n; b. r5 \+ i7 z
(yrs.)/ z3 _1 {( t1 y. L, O% S2 p
Serum Testosterone Phallus (cm.) Change Length$ g5 }4 }9 ]- K6 C. G" p h0 y
(ng./dl.) Girth x Length (%)
- t8 S6 P4 ^- N, z4- E- p ?" S C
8' }' J' a0 f0 I
10* U$ |2 I1 x* L% _7 l: ^1 ]# o
12" |% n3 W* u( N% b b( D9 | G
17
& P/ g6 t4 K: aGonadotropin4 R) Q+ m1 v5 U6 k: Z
71.6 2.0 X 3 16.6( I2 c# G% N# a/ H
50.4 4.0 X 5.0 20.0; K, ~' l3 H# Q. _6 ]& ~
22.0 4.5 X 4.0 25.0
6 h2 F6 ^/ f9 {+ J7 S4 ]7 r7 R84.6 4.0 X 4.5 11.1
: H! l3 W) {: c85.9 4.5 X 5.5 9.08 u# _1 u6 f3 b" U$ ^* {* `
Av. 14.3
7 b* u6 U8 t& k4* z1 ]. F% y9 x
8# a' E6 |; a# R7 N' w9 z2 R2 i
10- l7 l# D* a$ F; v; A9 }
12 ]8 u* b) K2 S5 V! Z& _
17% H3 ?4 ]4 j6 ] ?7 r5 N5 {
Topical testosterone' \7 X! Y# r) i# Q
34.6 4.5 X 6.5 85
" i9 d1 @' \, B38.8 6.0 X 8.5 70
. v+ y# y- e4 W* [& A; N40.0 6.0 X 6.5 62.5* |# j( @1 q1 V% T, u
93.6 6.0 X 7.0 55.5
% U0 r# m f+ e95.0 6.5 X 7.0 27.28 p3 V) q* ?) [4 k3 y! z% t
Av. 60.0
) ]# x/ m7 u: X2 K' p6 Cavailable testosterone. Again, emphasis should be placed on
2 z! w' x* D3 e2 Pearly therapy when lower levels of testosterone appear to
* e! `2 l( X! |+ V+ A4 Vprovide the best responses. The earlier therapy is instituted
( X7 j( d- a P9 N( _( \the more likely there will be an excellent response with low
5 ^0 g8 l X5 G+ j; X! userum levels. Response occurs throughout adolescence as
* O+ X8 o5 L- `: i- O: anoted in nomograms of phallic growth. 7 The actual response
) [% b& l6 O; V) c! Q* ^1 _to a given serum level of testosterone is much greater at birth; ~. G. p: ~' M, b" D
and gradually decreases as boys reach puberty. This is most7 F4 ]% O7 q/ w0 _5 d' A/ f
likely related to the conversion of testosterone to dihydrotes-: [& L/ _3 P- C) q- ^, H
tosterone and correlates well with the studies of testosterone
* Q6 |8 g) P4 l2 u, Y& {, zconversion in foreskin at various ages.5 X: l+ g, Z3 Q- C! o) Q3 W2 \9 G- R6 x, ?
The question arises regarding early treatment as to whether
8 C; O3 h* @" W7 V' Pone might sacrifice ultimate potential growth as with acceler-8 M' E) j# ]5 ~7 r
ated bone growth. The situation appears quite the reverse
d0 Y3 T9 g2 c2 E& Pwith phallic response. If the early growth period is not used, ]; O( | A6 A' @
when 5a reductase activity is greatest then potential growth8 c' C/ [6 Y* |# O& b* o
may be lost. We have not observed any regression of growth/ r8 R/ _9 |/ c* `. c p
attained with topical or gonadotropin therapy. It may well
/ [7 g) z( h5 O' _be that some patients will show little or no response to any% E% Q" X. O9 q2 i) f
form of therapy. This would suggest a defect in the ability to
) m0 g# O7 n$ a7 M3 A/ A* Jconvert testosterone to dihydrotestosterone and indicate that
" h: B: S- ]$ A" |! }& jphallic and peripheral skin, and subcutaneous tissue should; F9 b. F, F7 U
be compared for 5a reductase activity.
8 l5 W( |" I1 B- l7 b& K2 N; @! V+ XA, loop enlarges to measure penile girth in millimeters. B,6 u5 B9 _4 S$ y9 B
example of penile girth computed easily and accurately.
8 ~6 K9 |4 b, |% T2 n1 V/ Lconversion of testosterone to dihydrotestosterone. It is in this
% O. W* `6 k' d9 l7 \older group that others have noted high levels of serum. k$ u- G% |* V7 g* V; q H
testosterone with topical application. It would also appear
: D) C3 c6 Z5 p# P5 I" o) ethat phallic response during puberty is related directly to the" w' | S6 c4 [8 R5 H! C
serum testosterone level. There also is other evidence of local
9 p6 X& F! ]6 w* Z* @response to testosterone with hair growth and with spermato-
) h6 a/ y: d K, b& g+ vgenesis. 5• 6" m" y2 @4 E$ D4 h+ N- z' p
Administration of larger doses of gonadotropin or systemic
# v' y1 i* t# R Jtestosterone, as well as topical applications that produce
$ m, x7 U) w9 U( ghigher levels of serum testosterone (150 to 900 ng./dl.), will+ @+ Y; a% G" T8 G0 C- U
also produce phallic growth but risks accelerated skeletal
. z, L3 F) f$ D! h) Amaturation even after stopping treatment. It would appear
+ D9 H2 Z9 N6 V' _that this may be avoided by topical applications of testosterone
! E9 V4 _" A/ K0 j: J# f4 l; nand monitoring of serum testosterone. Even with this control) I9 E2 E. J6 t V
the duration of our therapy did not exceed 3 weeks at any
! z, c5 i. ]9 p* Ytime. It is apparent that the prepuberal male subject may* h* p8 M9 Y% s/ L' p& [; @
suffer accelerated bone growth with testosterone levels near, g1 K* H9 w- H8 M, C+ j8 v' c
200 ng./dl. When skeletal maturation is complete the level of
9 b4 s. h. }! h" d4 J9 A" Yserum testosterone can be maintained in the 700 to 1,300 ng./; g0 U9 o; U I8 A
dl. range to stimulate phallic growth and secondary sexual& ]& v8 g8 C) i" _+ h) @2 d# P
changes. Therefore, after skeletal maturation parenteral tes-
7 D s8 M8 w. c6 [& O1 c) ?# Ltosterone may be used to advantage. Before skeletal matura-
" |$ m, ^' c Q& J2 mtion care must be taken to avoid maintaining levels of serum# k( H N+ B+ p* w5 {- J
testosterone more than 100 ng./dl. Low-dose gonadotropin
O7 D' I& a" ] T! I: k0 e! Rdepends upon intrinsic testicular activity and may require" Q0 ^) {; f9 O5 K$ I
prolonged administration for any response.: g" d/ k' m( h+ E* E! l
Alternately, topical testosterone does not depend upon tes-
0 G. Q# \) c3 ^1 ~ticular function and may provide a more constant level of
1 {8 P7 N' D( ]0 RREFERENCES }& o! l, ~, }/ F% a8 }1 \- Z8 V/ l
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 A; [* e" h* ]9 V3 N" q( e" _
R.: The local application of testosterone cream to the prepub-
, T, k/ Z+ Q8 o* C. Iertal phallus. J. Urol., 105: 905, 1971.# Q, J. E" C! M K" S- F2 n
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% S6 R0 U/ C! u- L
treatment for micropenis during early childhood. J. Pediat.,9 k1 h4 r! X6 W$ l0 ^4 U
83: 247, 1973.! v( l0 \. f U8 v4 T9 v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-$ |. B3 d% C% C
one therapy for penile growth. Urology, 6: 708, 1975.
* u- V/ b$ m9 ]: @! q5 ]4 G4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, B; R/ a& [: Rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: i1 V2 h* o! o
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ [5 w! ]- \* d9 k) T+ ^
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
$ Z! _6 J) P0 t- ^6 d; P0 d8 K5 Yby topical application of androgens. J.A.M.A., 191: 521, 1965.
( h& ^! v" |! t6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 g* \7 e2 m% W" }3 [androgenic effect of interstitial cell tumor of the testis. J.& Y& i6 {/ r( ?) a% I
Urol., 104: 774, 1970.
( N2 S: B% b2 d8 P; v7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-: u% F- y0 ?3 i, k
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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