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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" D. ?) j( q0 e2 n& ?0 LGONADOTROPIN: B1 {8 d1 G5 W0 Z' ^5 @
RICHARD C. KLUGO* AND JOSEPH C. CERNY
2 C# o6 H5 b! |7 U7 b2 qFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan" \# h x" T6 K: p- _ }
ABSTRACT
+ p( G2 B4 _ E- vFive patients were treated with gonadotropin and topical testosterone for micropenis associated
2 @% a* }8 S) v" j. `0 rwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-. p5 X+ B) i9 i3 ]0 `' H# x0 V
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone; b+ }) M- [: D! ^0 ^
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
% i( x$ i6 `1 S" G9 N# G- @for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 ?6 L# Y( m& P1 k
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
$ C$ P- ~- p6 l) U; n8 u! Sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 @& W5 V: N( Y, {1 D& r$ |7 F4 L
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 i7 w* T8 @! l+ K" \) T# i
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
. r/ X: c6 Y. b4 |+ Vgrowth. The response appears to be greater in younger children, which is consistent with previ-
9 P- Y% Z6 x+ q: w4 R1 x5 nously published studies of age-related 5 reductase activity.1 m0 F/ ]% Z0 r# r+ n
Children with microphallus regardless of its etiology will! [$ j6 y. M& b, C O, C
require augmentation or consideration for alteration of exter-
+ q" F$ a7 z" w* T% I# j" c0 Ynal genitalia. In many instances urethroplasty for hypo-
6 [! }1 W6 }! aspadias is easier with previous stimulation of phallic growth.; e7 ]* X B% S {% M
The use of testosterone administered parenterally or topically* i+ @0 t! k) l8 ?" A# v1 Q
has produced effective phallic growth. 1- 3 The mechanism of
% d# |: k$ A9 Yresponse has been considered as local or systemic. With this
) I! w9 \( v+ ]1 L5 bin mind we studied 5 children with microphallus for response' J8 N# ~. a4 ` g. g0 J4 h
to gonadotropin and to topical testosterone independently.$ [3 T7 q3 g+ w6 P
MATERIALS AND METHODS
; W9 X# H& b, K. f8 |' K6 fFive 46 XY male subjects between 3 and 17 years old were) \ o* V' E+ o. N8 _$ }. J2 p- o
evaluated for serum testosterone levels and hypothalamic0 `' W' I9 D9 ^' [1 n
function. Of these 5 boys 2 were considered to have Kallmann's; V4 \ Z+ O; W/ ~3 l
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
# u. C$ m% j! X! Qlamic deficiency. After evaluation of response to luteinizing& c" N" l% D& v7 q, T
hormone-releasing hormone these patients were treated with
1 ]; l# r/ L$ x \; T1,000 units of gonadotropin weekly for 3 weeks. Six weeks: t& F+ {% E$ O4 C# D0 E* }" r
after completion of gonadotropin therapy 10 per cent topical/ s4 _7 X/ Z! `) L
testosterone was applied to the phallus twice daily for 3 weeks.
) {2 e% {' \- M9 j" \Serum testosterone, luteinizing hormone and follicle-stimulat-
! H- K1 w3 w+ {: X `1 |0 D* ning hormone were monitored before, during and after comple-
) P* c; y' R4 U2 z; h3 Jtion of each phase of therapy. Penile stretch length was5 x8 Q( X! s4 v
obtained by measuring from the symphysis pubis to the tip of7 p2 ~5 N2 m* I5 V3 `3 V
the glans. Penile circumferential (girth) measurements were, b0 |" t, N0 _6 F. k/ U
obtained using an orthopedic digital measuring device (see
8 P9 W" X0 {! @( \figure).
* X3 q0 k5 m' ]/ \( X4 aRESULTS* H$ F& o/ _6 F' p) k1 E, b& A
Serum testosterone increased moderately to levels between+ L, _' I/ S2 \! ?- |! d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 t7 @5 j% w0 ^1 x/ t& ~
terone levels with topical testosterone remained near pre-( d; g. y% S+ d% a" s
treatment levels (35 ng./dl.) or were elevated to similar levels: L3 }+ K, E: c% a3 C9 @
developed after gonadotropin therapy (96 ng./dl.). Higher
! |+ Z8 w; }9 g; ~4 e8 R: eserum levels were noted in older patients (12 and 17 years old),
" i; {) A6 b) }2 C, V( t/ q. G2 vwhile lower levels persisted in younger patients (4, 8, and 10$ q9 p+ b3 L) M, s. I5 @4 J
years old) (see table). Despite absence of profound alterations
5 ~ H8 e( K( }+ ^- kof serum testosterone the topical therapy provided a greater4 F% c: p7 q C* Y1 O) p
Accepted for publication July 1, 1977. ·
) s0 x, z: M6 h. iRead at annual meeting of American Urological Association,% }. \( c$ z" `! t9 P
Chicago, Illinois, April 24-28, 1977.3 ]" k9 v f. k* G1 Y) U
* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 O' L3 B$ Z# t: A2799 W. Grand Blvd., Detroit, Michigan 48202.9 | v( n/ `- B% J$ _; ?7 C e; Y
improvement in phallic growth compared to gonadotropin.+ P9 d- Z I ^% h) h
Average phallic growth with gonadotropin was 14.3 per cent
. ~: D; c, K7 N/ U+ U( Jincrease in length and 5.0 per cent increase of girth. Topical
- @9 t+ f3 y" d* ~3 Ktestosterone produced a 60.0 per cent increase of phallic length
; \9 A& k' i, Z+ T0 ?2 dand 52.9 per cent increase of girth (circumference). The
2 ?, z j$ A* _8 Lresponse to topical testosterone was greatest in children be-! d) @, T4 X! o0 I) ^2 N0 }
tween 4 and 8 years old, with a gradual decrease to age 17/ z" K3 _$ ~1 p+ Y, U
years (see table).7 d* T5 s4 v7 K% y
DISCUSSION: o! Y8 w9 }9 x( r4 z2 i. H- e" p; r
Topical testosterone has been used effectively by other, b3 U! h5 q+ G1 h
clinicians but its mode of action remains controversial. Im-
* A6 S, I3 o, q: o$ }mergut and associates reported an excellent growth response5 v' G4 ^/ F$ {7 h4 e
to topical testosterone with low levels of serum testosterone,
. _& z P/ [& @! p' K6 @suggesting a local effect.1 Others have obtained growth re-* c2 T+ u# `4 {% u% y7 n# ^+ j' o6 O$ b2 c
sponse with high. levels of serum testosterone after topical
7 b+ ^( y0 G5 C1 o* n4 [, Cadministration, suggesting a systemic response. 3 The use of6 P( q6 o+ d4 w/ j* i+ L
gonadotropin to obtain levels of serum testosterone compara-8 Z$ D+ `! R f% ?1 b
ble to levels obtained with topical testosterone would seem to$ s; x* j+ S6 ^1 U3 R5 `
provide a means to compare the relative effectiveness of9 \/ A) q! y+ u4 h7 Q L
topical testosterone to systemic testosterone effect. It cer-
9 J9 _5 @% p) q y3 _, Q; I+ Wtainly has been established that gonadotropin as well as par-, H9 h1 o. f8 K8 G
enteral testosterone administration will produce genital
8 @9 M; I7 k$ y# W* j6 k: y. z+ ?* ngrowth. Our report shows that the growth of the phallus was
^2 n& L, z/ i9 C& [significantly greater with topical applications than with go-9 V; t- G8 V" E* O y
nadotropin, particularly in children less than 10 years old.
7 r# y, C' }& ?' [The levels of serum testosterone remained similar or lower
7 }, T0 o1 Z9 k) x5 m: F1 Nthan with gonadotropin during therapy, suggesting that topi-/ `$ d! P2 t/ i2 z# C% K7 |5 i) p
cal application produces genital growth by its local effect as
3 c3 |# x! j* s7 M: { owell as its systemic effect.# N# [. W W5 o y# r( @% L2 S
Review of our patients and their growth response related to& M) [/ Q- g% P" W, A
age shows a greater growth response at an earlier age. This is5 i2 H) q) p3 D. D/ p: C' R2 M
consistent with the findings of Wilson and Walker, who) l: }8 W- d* x3 N. b. n3 r1 ~
reported an increased conversion of testosterone to dihydrotes-' _& J, ]& C1 `9 Q$ Z
tosterone in the foreskin of neonates and infants.4 This activ-
% F) b% `7 G& b: X6 o! ^ity gradually decreases with age until puberty when it ap-
' h5 Y( X$ X G. `6 {+ q3 Mproaches the same level of activity as peripheral skin. It may
, c j( [3 p6 @; T6 Pwell be that absorption of testosterone is less when applied at' P6 p$ l V0 V8 V; }* l6 @/ S* E
an earlier age as suggested by lower serum levels in children! W; \3 b; l2 `% r
less than 10 years old. This fact may be explained by the7 O* U- n% f1 {' a
greater ability of phallic skin to convert testosterone to dihy-
3 q N, l4 M9 c) M% V1 rdrotestosterone at this age. Conversely, serum levels in older
( [! \) w; X6 g6 h% p$ `patients were higher, possibly because of decreased local. B! |9 F8 g. q9 b* h
667
8 z$ o6 M5 K$ V3 ~9 f$ h668 KLUGO AND CERNY5 e& A" l% x, M7 ]) ?+ S9 n0 |* W
Pt. Age
8 E+ C, k2 H0 c3 Y8 m0 M: [(yrs.)% o5 i9 t+ Y1 \5 {5 ~2 I
Serum Testosterone Phallus (cm.) Change Length
8 u/ n: Q! T/ X+ t( T5 d(ng./dl.) Girth x Length (%)
9 i. b6 a7 h! G7 I4/ M$ S* V L8 P. }( ~2 X: E
8) F9 [* k4 h8 L2 Z
106 ^4 J: m7 c& g
120 m, P8 f# }, d) q) W4 Y* j
17
2 \$ H; ?8 O+ ]% [) R% H( bGonadotropin
) C4 V/ {) ^: S1 J, H8 X& a% W71.6 2.0 X 3 16.6" _1 \ E c- t/ }3 A5 x0 y
50.4 4.0 X 5.0 20.0! Y5 P& n, [" _
22.0 4.5 X 4.0 25.0
' R3 W: _) W3 y) n/ x( e84.6 4.0 X 4.5 11.1! L/ O C+ B8 u4 s( b: }% F
85.9 4.5 X 5.5 9.09 e* z5 e& x9 S# D
Av. 14.3
5 n( y' _: B; c: x4
b9 R9 O! d& d85 E; P) E" S9 n
105 `( Z* B% e: i$ s" X* s* @
12
* |. a# K/ [- k( p17
+ |7 [: y/ P# t. a4 Y* c5 [Topical testosterone7 f( T" v# L2 }7 h; R: \3 c
34.6 4.5 X 6.5 85
" E* |" w" v; h% h I4 U6 J& `38.8 6.0 X 8.5 70# W$ F7 N1 M) R8 ]% y' F
40.0 6.0 X 6.5 62.5) g: w* {$ R5 H
93.6 6.0 X 7.0 55.5& r6 K" ]2 G1 S! h" U. ~- O
95.0 6.5 X 7.0 27.2
) c" q# e" p) ~Av. 60.0
3 {4 P* n/ w2 I0 j/ m1 c' savailable testosterone. Again, emphasis should be placed on6 R% m7 e( { E& N7 s \% m o
early therapy when lower levels of testosterone appear to7 \, W6 ~: d( D% }$ K |
provide the best responses. The earlier therapy is instituted; ], t8 r, N& ]% M P# C: h
the more likely there will be an excellent response with low
8 d( L% |3 b1 X z1 V4 oserum levels. Response occurs throughout adolescence as
% c$ w4 c. D# ?) [# k( h. ?6 W" |noted in nomograms of phallic growth. 7 The actual response
! K6 x1 ?5 |- p5 ], E6 ato a given serum level of testosterone is much greater at birth& m$ {6 B) \( e, U7 [% g0 L: k6 r9 j0 p
and gradually decreases as boys reach puberty. This is most
* F @: H. G! I/ O! ]. P, qlikely related to the conversion of testosterone to dihydrotes-# x& e( Z( n* c2 x7 z
tosterone and correlates well with the studies of testosterone
& i* ]: t0 L3 R% _- rconversion in foreskin at various ages.
; y2 i4 Y' P2 eThe question arises regarding early treatment as to whether: N0 n( k5 w) h% F
one might sacrifice ultimate potential growth as with acceler-; h- q. ?1 ]7 j! d; J& {4 C9 Y% a% U
ated bone growth. The situation appears quite the reverse: Q9 k) y. q# f; z
with phallic response. If the early growth period is not used( C- `2 I b% c0 f. d
when 5a reductase activity is greatest then potential growth" p+ U' g' `6 e R% c
may be lost. We have not observed any regression of growth, _' l. M5 x+ O* \
attained with topical or gonadotropin therapy. It may well
4 z: d$ `. m: T9 X- r% o! nbe that some patients will show little or no response to any
. ^# ]3 c \! Z9 [" K" qform of therapy. This would suggest a defect in the ability to# m+ o, u8 ~) P! r/ m) _ q2 {
convert testosterone to dihydrotestosterone and indicate that
: o) {0 L! O% v: G; {+ }: }phallic and peripheral skin, and subcutaneous tissue should: `5 J9 Z$ U: m6 v# J% m3 o: c8 B
be compared for 5a reductase activity.) W7 C2 L9 I6 P8 ^1 E- g7 y- i# W% k
A, loop enlarges to measure penile girth in millimeters. B,* y$ x4 k1 q" k: `! |2 ?" {# {2 n
example of penile girth computed easily and accurately.1 u% |5 K6 X1 i2 i6 d
conversion of testosterone to dihydrotestosterone. It is in this, ^4 D/ |( s1 a2 y/ G
older group that others have noted high levels of serum
9 h2 |3 M# t: n* Z U. t0 Ltestosterone with topical application. It would also appear
- Z, a8 Q, M; N' L( o5 Lthat phallic response during puberty is related directly to the
" p- S4 Q% E6 h3 W( Lserum testosterone level. There also is other evidence of local- |. v9 V' e7 [5 s J0 L- B
response to testosterone with hair growth and with spermato-1 Q0 E/ T/ w0 x( e
genesis. 5• 6
, M% x/ T, \# q2 B3 d. C( jAdministration of larger doses of gonadotropin or systemic% i9 r/ V1 K) L0 M4 R, E- y
testosterone, as well as topical applications that produce
: P. f- ]% f) u7 L, o$ Zhigher levels of serum testosterone (150 to 900 ng./dl.), will
2 I2 r) L& K! D: s; M' Lalso produce phallic growth but risks accelerated skeletal& Y B) F$ [" P& L/ X9 N
maturation even after stopping treatment. It would appear
G8 t! f6 S* }( \; Wthat this may be avoided by topical applications of testosterone
9 p1 v) t1 L" S7 [4 Wand monitoring of serum testosterone. Even with this control
$ q1 n7 H: S! [0 i4 cthe duration of our therapy did not exceed 3 weeks at any
2 d; H; H# `9 ltime. It is apparent that the prepuberal male subject may1 |, B6 C g3 Z I) U. o3 k' m
suffer accelerated bone growth with testosterone levels near3 X' ^; \- P0 F- @/ i# B
200 ng./dl. When skeletal maturation is complete the level of
P) i4 Y8 ]4 f. zserum testosterone can be maintained in the 700 to 1,300 ng./
+ s0 h% n* q' K& w' U* {/ `3 @dl. range to stimulate phallic growth and secondary sexual0 b' z: Y+ |) W" L" h% S9 k
changes. Therefore, after skeletal maturation parenteral tes-
9 T, G8 H& _5 {9 Y0 d, L3 btosterone may be used to advantage. Before skeletal matura-# M0 D7 c: J7 Y9 d" F5 `1 b' d# w
tion care must be taken to avoid maintaining levels of serum
, D$ o9 W( x; Z* U; itestosterone more than 100 ng./dl. Low-dose gonadotropin1 \; J& C+ g6 g3 [! I) J; x
depends upon intrinsic testicular activity and may require
U" R: k! A* Sprolonged administration for any response.
" _! B3 U3 ?: iAlternately, topical testosterone does not depend upon tes-
# A, L# i3 p" }3 Pticular function and may provide a more constant level of M( a9 l/ A$ c: V# @& n
REFERENCES
2 J" r3 j" T( H- y# z) c2 A+ H1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
9 |; B9 g4 W7 Q! S5 b. aR.: The local application of testosterone cream to the prepub-
# J6 A3 _. J' c% R% Z$ N7 S+ p0 lertal phallus. J. Urol., 105: 905, 1971.5 x( c& u& W% \, s, a$ q7 k
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, L+ t" B& _8 H* S3 N3 z
treatment for micropenis during early childhood. J. Pediat.,. S5 R) P: ?) O( p
83: 247, 1973.
6 c% N2 b* W$ \, f3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-! O* }1 R; O- p/ Y: O
one therapy for penile growth. Urology, 6: 708, 1975.: ]+ S/ o* F5 f: ?1 W
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! y F/ E3 _8 E5 y9 m8 I( Oto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
7 P$ R/ @6 d' o. g4 u1 uskin slices of man. J. Clin. Invest., 48: 371, 1969.( W/ A r% |3 I9 n' U* [7 }8 I3 j
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# s* f" z( B# J$ x8 Wby topical application of androgens. J.A.M.A., 191: 521, 1965.
+ X8 t0 N, [, z0 p* I0 E6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) |$ H- K0 h3 P/ E0 `
androgenic effect of interstitial cell tumor of the testis. J.
. t/ G7 |7 \9 N; x0 v) zUrol., 104: 774, 1970.
4 }- G2 ~0 x4 R7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-: i7 Z3 a6 D- Y& i- Q. I
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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