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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% Q! M6 z( o, c1 R5 f
GONADOTROPIN
% g3 H: W% Q x0 s2 Q- M& ARICHARD C. KLUGO* AND JOSEPH C. CERNY+ b# b: a5 x. A6 J2 O. ^* l
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan- Y1 Z/ {( G* Q1 R
ABSTRACT
# `, a% s7 `4 G5 b. W- q2 |& AFive patients were treated with gonadotropin and topical testosterone for micropenis associated3 O' ^' ^% P8 g+ k% J. U
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-# M. p/ R, g w |: V( X; S
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! S, [1 m' J3 H* M0 _; ^2 r3 V
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent0 w6 v6 ~, Y6 t0 I" h. M0 Q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% a8 t r! N' S1 \$ w. nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: E% y9 c3 N2 B; e" `% h0 r: e' Xincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ i* k- H7 [! hoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
6 F* ]: O. x1 N; u' J! Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 Q5 u* l- w( E0 |3 O7 m, O
growth. The response appears to be greater in younger children, which is consistent with previ-
7 d0 J6 c. V9 mously published studies of age-related 5 reductase activity.
& R- s: i5 Q3 R; _Children with microphallus regardless of its etiology will, h9 K/ e3 s' A- H5 H/ q. N
require augmentation or consideration for alteration of exter-
9 v0 `$ |* z2 B) m' A+ Znal genitalia. In many instances urethroplasty for hypo-
3 y* X) |! C' X& v5 R" i( Rspadias is easier with previous stimulation of phallic growth.
7 q `, n2 w/ GThe use of testosterone administered parenterally or topically
1 F4 k3 D4 l* Z% e& s1 _has produced effective phallic growth. 1- 3 The mechanism of/ l- [8 y* c5 O7 Q# |1 [9 P+ w% {' Q
response has been considered as local or systemic. With this
) w; }6 \8 D4 p% X. lin mind we studied 5 children with microphallus for response( [, W! P1 s8 K+ p" s8 v/ K S
to gonadotropin and to topical testosterone independently.* u% E! [3 c; j2 Q% K
MATERIALS AND METHODS
- E$ h, k" s5 {" s3 HFive 46 XY male subjects between 3 and 17 years old were, X. D4 e7 b# N8 Q: e
evaluated for serum testosterone levels and hypothalamic* R: [4 f5 Z8 N5 r
function. Of these 5 boys 2 were considered to have Kallmann's
- ]& U( v0 R; B2 T% {" `syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
e1 u9 B# U: U3 m5 olamic deficiency. After evaluation of response to luteinizing0 b' N0 x2 {6 a' y& N6 J" B' m
hormone-releasing hormone these patients were treated with' q# A: s/ s/ i) J V# O$ K
1,000 units of gonadotropin weekly for 3 weeks. Six weeks. N, h) q/ A9 I& Z
after completion of gonadotropin therapy 10 per cent topical
- w: S1 f- A+ }testosterone was applied to the phallus twice daily for 3 weeks.
6 U" P1 o, K$ Y1 x! q% XSerum testosterone, luteinizing hormone and follicle-stimulat-& u7 w1 B% Q9 c; a" s* w
ing hormone were monitored before, during and after comple-& s& E1 T* C6 h h. m
tion of each phase of therapy. Penile stretch length was
$ | G* H8 _& F* Iobtained by measuring from the symphysis pubis to the tip of
+ R4 y& U4 y* }! L9 L. L c- b3 athe glans. Penile circumferential (girth) measurements were
2 J& x, k5 H( dobtained using an orthopedic digital measuring device (see8 l# R1 q( d+ K( y8 q. R( B
figure).- Q \* ]8 R# M y8 e% K
RESULTS0 F! L! @# b3 |3 C# W
Serum testosterone increased moderately to levels between9 e" G7 i4 v$ T' e; \6 r
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ E6 A8 g7 {4 N- X1 \ D1 s
terone levels with topical testosterone remained near pre-
4 c+ J; c+ |9 F* W. wtreatment levels (35 ng./dl.) or were elevated to similar levels
Y) f: T" t4 T0 s, |developed after gonadotropin therapy (96 ng./dl.). Higher+ N. l' G* M1 F* F. ?
serum levels were noted in older patients (12 and 17 years old),
$ B- Y0 s9 e5 p$ Jwhile lower levels persisted in younger patients (4, 8, and 10
N; D. X$ n0 Gyears old) (see table). Despite absence of profound alterations9 f$ h K8 l1 w) P
of serum testosterone the topical therapy provided a greater& }8 s, c3 Z- T* J0 A7 I
Accepted for publication July 1, 1977. ·) Q& C) v7 s1 Q* ^5 x" w' t: @+ O
Read at annual meeting of American Urological Association,
, |5 G5 u5 O8 O9 `4 q6 E3 ]Chicago, Illinois, April 24-28, 1977.7 O) J+ j0 w4 [$ O* h
* Requests for reprints: Division of Urology, Henry Ford Hospital,# N/ W/ p# |& u; h
2799 W. Grand Blvd., Detroit, Michigan 48202.) t! O) |7 `' f# }& L9 s2 E
improvement in phallic growth compared to gonadotropin.
' f7 R' q) F( \# {/ EAverage phallic growth with gonadotropin was 14.3 per cent
( D* C! [- g! L7 A6 M$ R- B# A) p$ cincrease in length and 5.0 per cent increase of girth. Topical7 N$ s j# @6 U5 e. c) Z5 z( p; h
testosterone produced a 60.0 per cent increase of phallic length; S0 U5 O8 O4 n7 I4 F
and 52.9 per cent increase of girth (circumference). The- c7 r4 Y0 |( x
response to topical testosterone was greatest in children be-
+ [. {4 p- v$ z- g* Y! Y/ `* s! k1 \tween 4 and 8 years old, with a gradual decrease to age 17& X# u. Z# G7 X6 Z5 l! \8 W$ ^
years (see table).; D( P% L0 t# V6 V5 a3 t( n7 t& W
DISCUSSION
2 {1 |, ^9 V: p4 @8 m) ]! F* aTopical testosterone has been used effectively by other* ]: t* ]2 H+ L2 e! e+ G
clinicians but its mode of action remains controversial. Im-7 P* o: Y, b V$ m
mergut and associates reported an excellent growth response% g' i* x1 c9 O( M) h
to topical testosterone with low levels of serum testosterone,/ p4 k. _) q; Z5 Y' Z2 T1 v
suggesting a local effect.1 Others have obtained growth re-. D0 Z9 a% R+ u; W" g0 V; n3 Y+ y7 L
sponse with high. levels of serum testosterone after topical
9 v. M( z! N( Nadministration, suggesting a systemic response. 3 The use of
: b8 x, z/ A1 c; u& ]gonadotropin to obtain levels of serum testosterone compara-9 G. X: G$ \( t( e* N
ble to levels obtained with topical testosterone would seem to7 }/ o1 B8 b9 B2 I6 {
provide a means to compare the relative effectiveness of( L! v5 k9 ?" t2 K' e& z) m
topical testosterone to systemic testosterone effect. It cer-3 _% c: H: R0 h; {( m
tainly has been established that gonadotropin as well as par-
' e' o. r. j, q" b" m' l2 ]2 t. ]enteral testosterone administration will produce genital
- D @* F5 r3 k% L1 Qgrowth. Our report shows that the growth of the phallus was1 b- h# b, b: P
significantly greater with topical applications than with go-
. x2 g5 j1 {. u6 p+ l; B/ o" knadotropin, particularly in children less than 10 years old." ^" [# {. V8 A* ]5 r. B5 N
The levels of serum testosterone remained similar or lower
1 D6 g( k9 y- Z8 v% ithan with gonadotropin during therapy, suggesting that topi-: Y' T' ~! J9 B- v) z v( N
cal application produces genital growth by its local effect as! J g- r0 d8 c$ s' e: C
well as its systemic effect.( g- W8 S2 M. B+ J! a& U8 Z2 F4 Y
Review of our patients and their growth response related to) Z) r T: Z7 X8 E; Q& ~/ z& k
age shows a greater growth response at an earlier age. This is. N4 U2 g3 v7 [3 s |
consistent with the findings of Wilson and Walker, who6 Q, k6 Z5 L, a/ u
reported an increased conversion of testosterone to dihydrotes-
/ z9 i- U. N5 g. i5 jtosterone in the foreskin of neonates and infants.4 This activ-
/ R, F9 s* @! `0 r9 t# d" uity gradually decreases with age until puberty when it ap-6 D7 k- F3 `; x( T/ Q1 ~% |, c% }
proaches the same level of activity as peripheral skin. It may3 W9 a/ g. J9 b- P# ~; o! ^
well be that absorption of testosterone is less when applied at6 T9 I: I) t1 m: ]
an earlier age as suggested by lower serum levels in children+ I2 z& ?9 w' L4 w' u
less than 10 years old. This fact may be explained by the/ T% p( c: m [$ o4 U. [4 M8 \- ?' @
greater ability of phallic skin to convert testosterone to dihy-: s, ~4 D7 R) N' P
drotestosterone at this age. Conversely, serum levels in older
( C4 u/ j% a( F$ D$ W, epatients were higher, possibly because of decreased local) e5 }5 I# g, e2 Z5 Z
667
3 u$ e1 i/ P6 D3 h( \- G! \. R668 KLUGO AND CERNY
$ P. z6 u7 K; k) L$ t" k; ~; pPt. Age$ {' ^1 ? }, G- k0 u( P( S
(yrs.)
+ a5 [4 [% {# fSerum Testosterone Phallus (cm.) Change Length
7 |; O) n8 W+ Q2 V& v A p(ng./dl.) Girth x Length (%)
# }* D8 f6 F+ o+ V# h/ \$ F4, z2 c0 F* N* W" s
80 y7 Z( e* A& ? s; @& |& ] c3 j
10# C- t8 \5 v; [
122 p/ a" [: z5 X8 v2 }# W3 l& a- l
175 x- }. G( Y9 h: p
Gonadotropin
" o% r4 R/ W: }; T9 |, p" I71.6 2.0 X 3 16.6: ~1 C2 R' u" a. d" v3 g2 c
50.4 4.0 X 5.0 20.0
9 H: d1 X. g1 t2 T. m6 w22.0 4.5 X 4.0 25.0
! b& q- h+ ^: f6 P7 d84.6 4.0 X 4.5 11.1
+ `, ?/ L) T0 Y- W) w3 K9 f# q85.9 4.5 X 5.5 9.0
. [* J0 u _6 X5 p9 S. Z l0 b9 c* Z" ?Av. 14.3& ]9 T" R' `# J) Z
4% \2 W! K I) X& B" I: ?" ~% }5 Q
8
. x. N! M$ i" E% p10+ Z# z2 [+ k$ H4 W) s. c
12
b) q! q& k' K9 F, w17
! J: {+ t* l4 C% g( q2 STopical testosterone( _2 `7 b: l: b k: c$ e1 k
34.6 4.5 X 6.5 85- r8 w$ {9 Y0 m+ \2 I' F
38.8 6.0 X 8.5 700 b; K* c6 `4 J2 a, S* G, P ~
40.0 6.0 X 6.5 62.5
2 i" c! t3 m6 G93.6 6.0 X 7.0 55.5
8 I! `2 b3 W g3 m/ v& w6 ]95.0 6.5 X 7.0 27.2
" i4 W7 K% {) t. H9 x( SAv. 60.0
8 |: {) U' p9 O/ ?3 R4 Ravailable testosterone. Again, emphasis should be placed on, p+ F. [) p+ ` W" {) Z' X2 f
early therapy when lower levels of testosterone appear to
5 F) \( Y+ G7 Kprovide the best responses. The earlier therapy is instituted
* V" ?4 a* {+ R# q1 b: W6 cthe more likely there will be an excellent response with low
+ K- _2 U& c" p& |4 C7 userum levels. Response occurs throughout adolescence as
, e. F5 ^ H7 }noted in nomograms of phallic growth. 7 The actual response$ Z+ T% P8 ^/ X
to a given serum level of testosterone is much greater at birth
% n4 H) R% @# n# Hand gradually decreases as boys reach puberty. This is most4 _, \6 m, I/ P, t" A
likely related to the conversion of testosterone to dihydrotes-3 ^7 n3 c4 y; ~* h. Q6 C5 n
tosterone and correlates well with the studies of testosterone
; R, i/ j4 i+ \8 Z% B7 j2 I5 _conversion in foreskin at various ages.
( t& f5 a5 c% n7 JThe question arises regarding early treatment as to whether
! l+ e1 j/ V' r- } tone might sacrifice ultimate potential growth as with acceler-' }" \# t! ~+ y9 D7 P
ated bone growth. The situation appears quite the reverse
! u- T- t/ X: y: j3 pwith phallic response. If the early growth period is not used. _+ H, R, H/ G% j
when 5a reductase activity is greatest then potential growth# N% V3 e3 `' \+ l. i% @$ Z; ?" }
may be lost. We have not observed any regression of growth
* t8 v0 y1 U E! F6 u" u$ [attained with topical or gonadotropin therapy. It may well
$ P& I3 g5 u8 i6 L8 Obe that some patients will show little or no response to any
( O# A, O5 O. O, l: j2 b! Tform of therapy. This would suggest a defect in the ability to
4 j$ h( z* c4 H. b% @convert testosterone to dihydrotestosterone and indicate that
k3 |" C6 I E4 Aphallic and peripheral skin, and subcutaneous tissue should
: f$ w8 F6 C; i6 obe compared for 5a reductase activity.
( x8 H8 H4 f. s, ?! P, n* D6 [A, loop enlarges to measure penile girth in millimeters. B,1 W: B6 i' t" v7 n
example of penile girth computed easily and accurately.
7 Y; b; q$ \( U' o6 {conversion of testosterone to dihydrotestosterone. It is in this
& ]0 V" n( V' K) \9 polder group that others have noted high levels of serum
7 _( }. ?; |; S* k6 R1 t( {8 Rtestosterone with topical application. It would also appear1 V D* j2 V! l+ h5 o3 i& u8 \
that phallic response during puberty is related directly to the
& n9 [; }+ p8 X. L |2 w( dserum testosterone level. There also is other evidence of local$ s0 r3 O) a6 j; `- T
response to testosterone with hair growth and with spermato-
* |9 L# x2 h5 `- Hgenesis. 5• 69 A3 O6 z+ H8 O( q/ G6 p6 ?
Administration of larger doses of gonadotropin or systemic5 A$ ?( o8 \0 D
testosterone, as well as topical applications that produce
C: t+ i p: E {3 C# k# t `higher levels of serum testosterone (150 to 900 ng./dl.), will
" u* y7 [, D$ E0 Jalso produce phallic growth but risks accelerated skeletal
, l) ^# E' N! H% Amaturation even after stopping treatment. It would appear; I: [1 N/ o1 k/ H
that this may be avoided by topical applications of testosterone
0 o& ~$ Y- I4 K B( H; Fand monitoring of serum testosterone. Even with this control6 E6 x( u/ y* e Y# z
the duration of our therapy did not exceed 3 weeks at any
) Z1 @6 r3 q% ~5 |time. It is apparent that the prepuberal male subject may, X3 T. r p' K8 m* V6 X$ \
suffer accelerated bone growth with testosterone levels near+ g4 l" H0 c; @
200 ng./dl. When skeletal maturation is complete the level of
5 f a6 i, h9 [: w& y+ Eserum testosterone can be maintained in the 700 to 1,300 ng./
7 w) j; p1 T& D" b3 K& I) W: udl. range to stimulate phallic growth and secondary sexual T' Q2 M3 {' J- ?, @
changes. Therefore, after skeletal maturation parenteral tes-
2 m9 ~9 p2 {. _' v/ g" [ P( Wtosterone may be used to advantage. Before skeletal matura-
' |4 C \3 J* [tion care must be taken to avoid maintaining levels of serum3 M( M) K+ g/ \
testosterone more than 100 ng./dl. Low-dose gonadotropin K5 N0 S8 p/ F2 i% K4 T. h. ]6 M2 K
depends upon intrinsic testicular activity and may require
/ ~2 r8 R) [5 o& kprolonged administration for any response.* }6 V7 c' @5 ?0 C
Alternately, topical testosterone does not depend upon tes-
1 ?7 p/ l8 n* F% l: c( Rticular function and may provide a more constant level of& q3 Q1 @0 _ l$ i! v4 `: ^
REFERENCES
8 h0 [/ i4 Q' `4 r' k+ p$ d D1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,3 K: j1 l& K; h
R.: The local application of testosterone cream to the prepub-* \8 T* T' J5 l- g
ertal phallus. J. Urol., 105: 905, 1971., |6 c( D9 c. `# p; O3 P
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. ]5 Y) ]2 R0 A5 B$ j8 m
treatment for micropenis during early childhood. J. Pediat.,
7 o/ G7 ]; p% i83: 247, 1973.* G5 p! s% _" e y% f' J) \
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# |* V4 C: Z% y, oone therapy for penile growth. Urology, 6: 708, 1975./ \' F$ M% c/ [' n4 t T$ e
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone; A5 R# t! {" |/ c" F" L' e4 R9 O
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' l( R4 N7 P2 m: a) ~' Qskin slices of man. J. Clin. Invest., 48: 371, 1969.% t3 x& Z9 y; H( m
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth! Y" p1 }/ p! V
by topical application of androgens. J.A.M.A., 191: 521, 1965., ?4 N0 q) S7 {! B' H+ k. R# [
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ O2 c; _1 v" C- a% Q# \androgenic effect of interstitial cell tumor of the testis. J.
& X0 b1 ?* E, VUrol., 104: 774, 1970.5 c# W# S0 k' T2 X& R" V
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
3 l( n4 ?% m7 k+ Ktion in the male genitalia from birth to maturity. J. Urol., 48: |
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