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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
+ N6 q' Y" n6 R0 V V5 H! H% y9 }GONADOTROPIN5 k% l4 d# R( [: O4 z
RICHARD C. KLUGO* AND JOSEPH C. CERNY0 o; q$ V4 I+ } P
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan9 ]4 `8 o! l2 I$ N, e
ABSTRACT
* e2 l V7 @* H$ X# rFive patients were treated with gonadotropin and topical testosterone for micropenis associated/ z% x3 g: C% f2 ]2 w+ F# r
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* w/ A' H+ h; K8 Ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
; S% }* j% r6 `' \; lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 b3 L* p- }2 C0 i5 n( ]2 k$ M( g* Y5 ffor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
. s* n. q. S$ Q! l- ] Vincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
/ H6 j, C2 F/ s0 k, M" h fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 M: G6 J( t, {9 voccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
) E6 z* y' e8 L8 Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 S! \5 T& @: c# Agrowth. The response appears to be greater in younger children, which is consistent with previ-: s" }/ X) l" ~
ously published studies of age-related 5 reductase activity.
% k) ]0 _" Z2 o9 w8 QChildren with microphallus regardless of its etiology will9 @8 d8 [5 w! T. |" S" i
require augmentation or consideration for alteration of exter-2 C: a6 r5 p1 U, d" t, _9 A$ e
nal genitalia. In many instances urethroplasty for hypo-
6 Q* H5 r' g8 H: @spadias is easier with previous stimulation of phallic growth.
( M* r, {* B5 QThe use of testosterone administered parenterally or topically1 T0 n6 q# j* H5 C
has produced effective phallic growth. 1- 3 The mechanism of! f8 M: O& }. v, o' S1 d( e
response has been considered as local or systemic. With this' T! I1 [4 S( G2 ^1 a! A1 D
in mind we studied 5 children with microphallus for response! p$ R7 Y5 A5 k0 \& ]. V. ?( T* `
to gonadotropin and to topical testosterone independently.! V* Y Q# U8 Z& o2 o
MATERIALS AND METHODS
9 B1 P/ C: I. y- ~% WFive 46 XY male subjects between 3 and 17 years old were
* X* [% r7 p+ V; ^% I$ `evaluated for serum testosterone levels and hypothalamic
: l0 n1 c9 r0 J) v2 q. I9 ofunction. Of these 5 boys 2 were considered to have Kallmann's
$ J1 L$ m, V7 I: o' ?# vsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
9 v/ Z* @3 x* ylamic deficiency. After evaluation of response to luteinizing
7 Y9 h! O; ]8 F& b0 ]& T! y9 A ]hormone-releasing hormone these patients were treated with2 n* Z# i6 j; {( d+ \
1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ d+ h6 ^ B' o
after completion of gonadotropin therapy 10 per cent topical7 U' c/ w6 Y) Q: I& ~
testosterone was applied to the phallus twice daily for 3 weeks.
0 ]+ q3 {9 L! P ZSerum testosterone, luteinizing hormone and follicle-stimulat-4 m; p+ Y9 x" R; L& b6 Q; ~
ing hormone were monitored before, during and after comple-
( w9 U9 G3 ]8 _# K/ K4 [$ v& otion of each phase of therapy. Penile stretch length was0 q# a% `8 B' y* e* c" k
obtained by measuring from the symphysis pubis to the tip of
, W( _/ d7 i! ?* P% d2 }& u$ }# L5 tthe glans. Penile circumferential (girth) measurements were8 z& Z4 K( _( N7 y) ^, x
obtained using an orthopedic digital measuring device (see3 A7 P0 I. }7 |) }! }5 N2 ] l
figure).1 u3 Y- x$ d [+ t% L9 _ d
RESULTS
5 k7 e7 c1 _- ]& _" O, `2 Q nSerum testosterone increased moderately to levels between
" l s, K: R; U50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# n# S% P9 X3 v' j2 Gterone levels with topical testosterone remained near pre-
" P: e" M/ n& n8 X0 u9 A ~2 l: mtreatment levels (35 ng./dl.) or were elevated to similar levels
) @+ Y, a# V% V7 {3 sdeveloped after gonadotropin therapy (96 ng./dl.). Higher' x$ e) i6 q t- j9 R
serum levels were noted in older patients (12 and 17 years old),
4 N! }0 x% W+ o E; D3 Q* a/ o$ Gwhile lower levels persisted in younger patients (4, 8, and 10. `( q; |$ W0 `: q" O& m! Z7 a) l7 }
years old) (see table). Despite absence of profound alterations
7 v+ J) P" p* _1 g4 Iof serum testosterone the topical therapy provided a greater# m5 [2 p9 t, \
Accepted for publication July 1, 1977. ·" o1 ?( a( I+ D# k- O4 ?. o; c+ f3 h
Read at annual meeting of American Urological Association,
9 r: H" G3 b7 K6 d9 o) U; ^Chicago, Illinois, April 24-28, 1977.) u" |! Y* \" R2 t S: Z! g
* Requests for reprints: Division of Urology, Henry Ford Hospital,* Q% @4 s0 I6 {0 Y* @+ c
2799 W. Grand Blvd., Detroit, Michigan 48202.
/ o$ P& v1 I& S1 C; C ?' Jimprovement in phallic growth compared to gonadotropin.
& W: E" q- U$ H$ H5 i4 LAverage phallic growth with gonadotropin was 14.3 per cent. V' P% |' z# T8 x
increase in length and 5.0 per cent increase of girth. Topical l) N' C3 q# k# L3 E' A5 _
testosterone produced a 60.0 per cent increase of phallic length
! x! D9 p1 S' w9 Jand 52.9 per cent increase of girth (circumference). The
4 A8 D: @& ^* _response to topical testosterone was greatest in children be-6 R) s6 G, }, Z% v6 f0 I; [" j/ g% u
tween 4 and 8 years old, with a gradual decrease to age 171 U, z/ N( A3 s+ g
years (see table).1 F4 B% C. `4 j. q2 }
DISCUSSION
) b& K6 U, C8 B3 aTopical testosterone has been used effectively by other' E6 A( n- s8 S' ~" F
clinicians but its mode of action remains controversial. Im-# J. }2 t5 H5 c X# i$ y9 e2 R
mergut and associates reported an excellent growth response
5 Z/ E5 ^# P4 n/ |0 |- K9 t" J- b$ Pto topical testosterone with low levels of serum testosterone,
/ x; f# h3 a# O, m9 z6 {3 xsuggesting a local effect.1 Others have obtained growth re-- @7 h/ b8 `* y4 Q4 {
sponse with high. levels of serum testosterone after topical6 a. i$ E: G9 l9 f' D' `" E4 L8 i
administration, suggesting a systemic response. 3 The use of. P( ]2 V; N4 ~8 w7 B
gonadotropin to obtain levels of serum testosterone compara-
* I# j( f" }5 o" ~$ L3 v5 yble to levels obtained with topical testosterone would seem to
1 B; O K. R" b- G) B% @$ R) C; iprovide a means to compare the relative effectiveness of5 K D# ~0 S7 P u! @6 J
topical testosterone to systemic testosterone effect. It cer-) [5 W4 P3 B$ v
tainly has been established that gonadotropin as well as par-0 e' J. H! O1 t+ ]1 _* U
enteral testosterone administration will produce genital
; m7 A# K% b( ogrowth. Our report shows that the growth of the phallus was) v& i( f9 u* E* ~9 d/ G$ ~, l4 n
significantly greater with topical applications than with go-
3 I- `/ @0 {9 H! K2 S" N0 |nadotropin, particularly in children less than 10 years old.' P& A' c' f/ q1 k2 e* F
The levels of serum testosterone remained similar or lower# J7 \2 |0 K- M
than with gonadotropin during therapy, suggesting that topi-7 m: j+ N7 I* ?
cal application produces genital growth by its local effect as7 k4 v2 m6 e5 G8 N
well as its systemic effect.
1 m" h( s e$ J2 E8 DReview of our patients and their growth response related to
F, D3 R, R, R- E. @0 rage shows a greater growth response at an earlier age. This is5 [) g# J# e. f4 X9 x% t+ I
consistent with the findings of Wilson and Walker, who, V7 ?7 X4 _3 t2 ?/ w! l }! B' C
reported an increased conversion of testosterone to dihydrotes-8 g8 d" p9 {. D# {8 i
tosterone in the foreskin of neonates and infants.4 This activ-
5 T1 D2 G' _ M6 F; I# C X, u) Vity gradually decreases with age until puberty when it ap-
3 o7 T! c+ g) `proaches the same level of activity as peripheral skin. It may2 H2 {1 ^$ J3 n8 H2 [- Q* m
well be that absorption of testosterone is less when applied at* n! ~. O! d+ q/ U3 l/ J: X
an earlier age as suggested by lower serum levels in children* k1 W1 a9 T* F8 U# r) o p/ l
less than 10 years old. This fact may be explained by the
J6 u3 i# e+ K8 x$ T5 f# i# B) Bgreater ability of phallic skin to convert testosterone to dihy-
+ C% p+ x* x; @! Q" }drotestosterone at this age. Conversely, serum levels in older
1 [1 h# }$ w# T6 Z" |% ipatients were higher, possibly because of decreased local
4 r& U$ M& U# C( r- y667
2 r9 J3 X& W# U5 f* L! K668 KLUGO AND CERNY
* C- j+ U& [7 q; mPt. Age+ h8 D) I: Y3 F/ ^8 f# i, i2 T
(yrs.). W9 k$ L. p; A8 |$ ~( L" m
Serum Testosterone Phallus (cm.) Change Length6 M9 {/ H% P1 O6 U
(ng./dl.) Girth x Length (%)% F( K. |+ w) l: o0 C
4
; Z/ q4 k$ l& \# T$ B8
2 d5 `( K* O- @# c109 D; G7 M. Q; x, f3 Q
12% n! _& T# T8 A" _% k
17! \8 o/ f7 [: m7 y* D
Gonadotropin1 s$ m3 A9 T4 i" W" v; z
71.6 2.0 X 3 16.6' y" Y7 Z7 S/ f0 D
50.4 4.0 X 5.0 20.0
; T9 U+ y4 c( k, ?. }" r6 P22.0 4.5 X 4.0 25.0
. w$ y8 f- b9 ?% ]3 C84.6 4.0 X 4.5 11.1
2 J& m* o* C( G4 c' k85.9 4.5 X 5.5 9.0
( ?* P" |9 f0 l3 l7 ?; N* ~& t. wAv. 14.3
9 O6 Z6 x- C/ N; I42 d- t3 U6 M/ A4 h
8
) y+ R8 }+ ^* u! R7 N10
+ l5 ~' I6 K$ Y12
; z8 Y$ m* R$ u! H17
7 r" r1 g; j% L- U# N2 m: O. l* U, x2 ~Topical testosterone s l; s1 z( B; q+ ]
34.6 4.5 X 6.5 857 T- y& Y% b; A( I; B0 B+ ^
38.8 6.0 X 8.5 70
?' x! L* `% [+ p1 Z# a40.0 6.0 X 6.5 62.5& P5 |4 C# ^3 ?/ P7 [
93.6 6.0 X 7.0 55.5
$ y: I- T5 i( w, U95.0 6.5 X 7.0 27.2
2 z! j/ X" }! I% S. RAv. 60.0$ O' w0 f$ g1 `9 g+ d
available testosterone. Again, emphasis should be placed on
0 d% e' t7 D0 N4 C* Bearly therapy when lower levels of testosterone appear to
) Q7 w# k5 q& P6 x& oprovide the best responses. The earlier therapy is instituted
8 D$ [6 ~% t- _' a$ I5 b0 othe more likely there will be an excellent response with low3 D% x- ~- @, }2 _; P* w7 Y
serum levels. Response occurs throughout adolescence as
* A ~/ _4 u- D! Y6 w7 Fnoted in nomograms of phallic growth. 7 The actual response
- h% v# v7 E* I! {0 R5 gto a given serum level of testosterone is much greater at birth) [5 c; D7 G, s$ }/ f4 L- _9 I
and gradually decreases as boys reach puberty. This is most
, p) o- a( ?- [* Ulikely related to the conversion of testosterone to dihydrotes- k( i/ Q/ n5 X, `+ A5 [
tosterone and correlates well with the studies of testosterone- x& `8 T3 @& Q- v0 M" D6 e
conversion in foreskin at various ages., i5 Z% n, ?3 F) a# ]& A
The question arises regarding early treatment as to whether
3 c* Q0 J8 U* B# G; `: Cone might sacrifice ultimate potential growth as with acceler-
& z. ~$ v6 v( C/ sated bone growth. The situation appears quite the reverse# P/ F: I7 [3 A6 o, s0 C' G
with phallic response. If the early growth period is not used/ b* ` p+ D0 u8 Y* j, \$ P6 T
when 5a reductase activity is greatest then potential growth
. t3 z& X4 T* ^# Y m+ Z: amay be lost. We have not observed any regression of growth
( ]/ V6 b0 F+ E" U" A$ _attained with topical or gonadotropin therapy. It may well
4 |: ^6 o$ N, T2 k0 v3 b/ R1 D Mbe that some patients will show little or no response to any
2 \( l% z4 `. y! K( Jform of therapy. This would suggest a defect in the ability to
3 e; w( t9 T8 ]convert testosterone to dihydrotestosterone and indicate that
! E) f( T" ^) ^1 J3 ^; ]3 ~3 iphallic and peripheral skin, and subcutaneous tissue should
) W; n: `7 H1 hbe compared for 5a reductase activity.& ~2 W& b: F; W! I( X, _6 h
A, loop enlarges to measure penile girth in millimeters. B,
8 _* E' h9 |/ ?, l8 Z. ]example of penile girth computed easily and accurately.- a" ?0 Z9 o& @' a/ R7 x V
conversion of testosterone to dihydrotestosterone. It is in this
9 o+ p" G3 v* H7 g' O6 J: tolder group that others have noted high levels of serum) t+ D ~$ t9 k- ?0 W0 `
testosterone with topical application. It would also appear
1 F, x5 u& ]% m3 @/ qthat phallic response during puberty is related directly to the
. b0 u }0 z% ~# `% y3 kserum testosterone level. There also is other evidence of local n$ s1 e" F2 B; {* ~4 L$ k1 f
response to testosterone with hair growth and with spermato-5 f) c$ s0 w$ H4 V7 G
genesis. 5• 64 u2 Q4 b/ M* ?
Administration of larger doses of gonadotropin or systemic$ Y# d4 f* j, o7 _# v
testosterone, as well as topical applications that produce1 W+ c( Q6 Q4 }* n8 ], B
higher levels of serum testosterone (150 to 900 ng./dl.), will
a7 Q; C k/ b% O7 malso produce phallic growth but risks accelerated skeletal
: B4 d3 S% {- ~maturation even after stopping treatment. It would appear
0 {: _7 M5 r! s/ C/ h+ uthat this may be avoided by topical applications of testosterone
U' t' D# c0 ~# K( aand monitoring of serum testosterone. Even with this control
7 f R2 B' `" q( Vthe duration of our therapy did not exceed 3 weeks at any
/ Y7 E4 a) H3 e2 i2 Rtime. It is apparent that the prepuberal male subject may
3 m; X8 f/ Z/ {, j. {: [2 Zsuffer accelerated bone growth with testosterone levels near
' o V* Z/ y/ W9 [200 ng./dl. When skeletal maturation is complete the level of
, e+ B( V5 _, U3 ]5 R. |serum testosterone can be maintained in the 700 to 1,300 ng./
y3 T: {! y2 E$ Q" I, Vdl. range to stimulate phallic growth and secondary sexual
. v" j. \$ u5 M0 ?" D# R& Ychanges. Therefore, after skeletal maturation parenteral tes-
M+ G$ x c- j+ `: i1 i& ttosterone may be used to advantage. Before skeletal matura-6 E) L- s/ U: O! Z' h, F/ o* Q
tion care must be taken to avoid maintaining levels of serum* ^, i% l0 O( O# L1 _. v7 e& e
testosterone more than 100 ng./dl. Low-dose gonadotropin0 V9 P. m# U' F$ ]
depends upon intrinsic testicular activity and may require6 u8 T1 z+ B6 C5 p( a6 X: K D: T
prolonged administration for any response.6 f3 g! V/ C5 Y
Alternately, topical testosterone does not depend upon tes-& W' z: g" Y/ c- D% y+ r6 s* O
ticular function and may provide a more constant level of
6 J: a; B# E( z- jREFERENCES
) Z5 Q' X, }! I) ^7 z3 U1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ S& g) b3 e) T
R.: The local application of testosterone cream to the prepub-
+ x. `: f0 k: G! A& F- Aertal phallus. J. Urol., 105: 905, 1971.9 z. `$ q" u, M' x
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
: G! s3 Y+ ~- W' D1 C# Streatment for micropenis during early childhood. J. Pediat.,
% L q7 i; z$ v8 S2 ]83: 247, 1973.
7 p. N# |( ?- K% H7 g5 s: ?3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# F7 l. l" e; U; I8 o) t
one therapy for penile growth. Urology, 6: 708, 1975.
+ m- t6 o, Z& E0 }' C4 V/ O7 ^, l4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) A9 B8 N7 e$ S; B8 ]+ ~
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by1 o- {0 S& H' c* i" \& C
skin slices of man. J. Clin. Invest., 48: 371, 1969.* g, j/ B0 A3 l
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 |$ U. A" {: F* a8 C, P! a
by topical application of androgens. J.A.M.A., 191: 521, 1965.
) t) t* c& |# x6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
& I+ B3 N: G2 K" m0 V- landrogenic effect of interstitial cell tumor of the testis. J.
. G7 n0 C E ?! `Urol., 104: 774, 1970.$ K& Y! w4 l( X
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 l- u' B. Y6 p0 R# ^$ ? ]9 \6 Ttion in the male genitalia from birth to maturity. J. Urol., 48: |
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