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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
4 f; p+ B2 N4 @4 }! d5 @+ FGONADOTROPIN5 a1 x* w& t& E: f3 ~5 R, H$ E
RICHARD C. KLUGO* AND JOSEPH C. CERNY
* t& B4 B8 j& h* w! P W& P8 T- RFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan. R- B' L' }' `, A: W# N: G8 Q
ABSTRACT) s# _$ j1 V' H2 x7 K! J' g. E
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
& l: f; Y7 h8 E/ R# a" l# nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
% y' H5 r$ O+ u4 ~$ u0 wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
/ f9 B, _ h C$ Hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent1 Z6 w0 N4 z. Y2 l
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent+ ]& i6 T E5 u' x* M8 [8 c
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average( t3 w* q4 r, ?7 Y6 n
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response9 R2 A3 H0 e" h
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This9 |2 s" k' e! @( L& q
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
& s$ q) N( E3 p( N' W7 J p+ L; mgrowth. The response appears to be greater in younger children, which is consistent with previ-
0 g) g5 m7 B% V. c3 u/ lously published studies of age-related 5 reductase activity.' C f5 Q! R- @3 d
Children with microphallus regardless of its etiology will$ d& b, R2 k: C6 w
require augmentation or consideration for alteration of exter-
. |) S# t8 n$ Hnal genitalia. In many instances urethroplasty for hypo-. m7 F& H w: B k, h
spadias is easier with previous stimulation of phallic growth.1 Z* f) t" j" b/ q5 u# P' j% M6 q
The use of testosterone administered parenterally or topically( Z7 \" i7 ?6 T1 A( r
has produced effective phallic growth. 1- 3 The mechanism of
& q, o& Y/ O# y7 M7 z iresponse has been considered as local or systemic. With this: @5 J" f! {0 [5 b" H
in mind we studied 5 children with microphallus for response- f2 ~9 s# L% V/ X% c
to gonadotropin and to topical testosterone independently.
- H$ j' m3 n# N( rMATERIALS AND METHODS K0 {( a: @/ B0 E+ {8 e7 |3 P( |
Five 46 XY male subjects between 3 and 17 years old were4 H9 Y% ~$ N6 g2 h7 X7 e
evaluated for serum testosterone levels and hypothalamic
+ }+ M( l, o Ffunction. Of these 5 boys 2 were considered to have Kallmann's1 y$ Y* D4 A. X; k. B. J* e
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 y9 ?4 f* X/ A( W5 Z
lamic deficiency. After evaluation of response to luteinizing
, ?2 A) s- S* \( V6 ]2 K# J" U2 Uhormone-releasing hormone these patients were treated with
P; @6 c9 {8 g- I: X; [. Z1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 _7 Z( v) ]- q: u9 b- Cafter completion of gonadotropin therapy 10 per cent topical/ \! b- r1 ?& V! w
testosterone was applied to the phallus twice daily for 3 weeks.
+ y! k+ l5 W6 S6 D3 b3 W VSerum testosterone, luteinizing hormone and follicle-stimulat- O5 L) D6 N& h" G7 Z
ing hormone were monitored before, during and after comple-8 z: p0 o: |; T9 N* a
tion of each phase of therapy. Penile stretch length was
* c* E2 u+ t6 v, a' W7 ]obtained by measuring from the symphysis pubis to the tip of) O; A) x+ L G
the glans. Penile circumferential (girth) measurements were
( d( [# i U7 t# d8 }9 X& }obtained using an orthopedic digital measuring device (see
- {0 W ?+ j* R( [) vfigure).% b3 n6 V9 n9 ?8 o y/ u6 J# V
RESULTS/ W" F1 p! a/ z
Serum testosterone increased moderately to levels between, B* f: L2 l b$ D; W/ i; k9 R7 g) k
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-" {1 Z. a6 i0 J* V* u
terone levels with topical testosterone remained near pre-: v5 T: M: a: P
treatment levels (35 ng./dl.) or were elevated to similar levels% G9 n6 K# |, \& l/ G# r; G% W, h
developed after gonadotropin therapy (96 ng./dl.). Higher
3 \# f8 ?% Z6 n- Jserum levels were noted in older patients (12 and 17 years old),
% q' j5 N s" P4 X7 |8 T! ]while lower levels persisted in younger patients (4, 8, and 10
# z. L8 g7 q: i6 xyears old) (see table). Despite absence of profound alterations
* X/ z- _" o% |+ l$ o, Y2 |of serum testosterone the topical therapy provided a greater
& k5 G) x5 `# G% ?3 \# uAccepted for publication July 1, 1977. ·
8 k( B% g! [, jRead at annual meeting of American Urological Association,
2 a( P0 B7 v2 c$ g0 I& OChicago, Illinois, April 24-28, 1977.& u1 Q7 ]( \$ ] v7 q, `5 p
* Requests for reprints: Division of Urology, Henry Ford Hospital,5 g4 G. \+ r; D$ H- ]9 R2 _6 S; E
2799 W. Grand Blvd., Detroit, Michigan 48202./ Q! B( e! [1 K/ N/ f5 \- Z
improvement in phallic growth compared to gonadotropin.) |. q( U* O H2 |8 }3 U& s
Average phallic growth with gonadotropin was 14.3 per cent4 b% s) |6 ^/ |, H0 B+ N5 C8 f
increase in length and 5.0 per cent increase of girth. Topical
7 w% X s/ w. y; [* l# U( k- ~testosterone produced a 60.0 per cent increase of phallic length( \' L9 t; V' A8 ?* j, j! K
and 52.9 per cent increase of girth (circumference). The2 {1 K" M! ^/ k* i9 o
response to topical testosterone was greatest in children be-1 |- B2 l, y3 Z8 J) i* U' s
tween 4 and 8 years old, with a gradual decrease to age 17
p0 L, z2 J- J5 y$ Syears (see table).
( ]+ X* L8 z% m; q6 i$ I' mDISCUSSION
V( j! {2 N$ B6 OTopical testosterone has been used effectively by other
$ O. l6 ?: B! m/ Qclinicians but its mode of action remains controversial. Im-
! P6 h+ J2 @! |* i) n/ kmergut and associates reported an excellent growth response* f& R5 X1 w9 N" Y
to topical testosterone with low levels of serum testosterone,
% ]3 E/ Y! r& h5 ^! fsuggesting a local effect.1 Others have obtained growth re-
- h' t* V) n4 o9 \; W) X% Bsponse with high. levels of serum testosterone after topical
+ w8 K( }0 S5 q. a" uadministration, suggesting a systemic response. 3 The use of1 _0 _% W. L; m p
gonadotropin to obtain levels of serum testosterone compara-# }1 `' l2 _ ?, _* ^
ble to levels obtained with topical testosterone would seem to) E l% q( v5 P. U
provide a means to compare the relative effectiveness of
& s& V; F+ e+ B+ ?7 |8 ?7 f! Ytopical testosterone to systemic testosterone effect. It cer-
' b, P% X# p6 ?" Y1 H5 ttainly has been established that gonadotropin as well as par-
2 r1 O7 L4 V5 ?1 R# a: ~, l, [enteral testosterone administration will produce genital" X) H% z' {- c+ i- G% s" y
growth. Our report shows that the growth of the phallus was
+ {9 w7 f; F& x5 k9 Ksignificantly greater with topical applications than with go-' |* z5 P: t1 d& H4 s; T
nadotropin, particularly in children less than 10 years old.' H0 U$ q7 S$ I, m* H+ a- |& K& K1 \
The levels of serum testosterone remained similar or lower( z. \ H c* H# _% U
than with gonadotropin during therapy, suggesting that topi-
* s# ^; O- `% _+ I5 v7 p' Gcal application produces genital growth by its local effect as
7 ` H7 q+ L$ m [well as its systemic effect.+ m9 w; V3 P# h; T* y1 W! n, H1 U/ L
Review of our patients and their growth response related to
) D5 j' x2 U- Dage shows a greater growth response at an earlier age. This is4 T8 }# i, W- f) q0 {2 v2 s
consistent with the findings of Wilson and Walker, who- k$ T/ ]# x' x2 |1 ~% J* o5 ?
reported an increased conversion of testosterone to dihydrotes-
B5 o! }. [5 r. a6 wtosterone in the foreskin of neonates and infants.4 This activ-8 ^% a G, `0 L2 B- m
ity gradually decreases with age until puberty when it ap-9 {6 e/ o1 O0 N+ N0 x3 o" t
proaches the same level of activity as peripheral skin. It may- Y- C0 K: }9 |* s- U
well be that absorption of testosterone is less when applied at* V1 f2 o% D, g" A f( _
an earlier age as suggested by lower serum levels in children
) g. r" f0 c1 H6 k6 ?less than 10 years old. This fact may be explained by the
: a# _7 A- n; Igreater ability of phallic skin to convert testosterone to dihy-8 {( q: \5 h M
drotestosterone at this age. Conversely, serum levels in older
! B+ b! h6 p' ` zpatients were higher, possibly because of decreased local. {& Z% h) F* h2 U
667( q* Z9 o- x4 C" T! K
668 KLUGO AND CERNY
1 E5 V) C) F9 i2 k% PPt. Age
% K+ J$ Y6 R4 M ]+ O(yrs.)
3 M8 v3 U0 X; k1 T+ S7 C0 tSerum Testosterone Phallus (cm.) Change Length
- A! c& [( I3 [( W; x2 I(ng./dl.) Girth x Length (%)- X# O: `2 G3 V/ V9 B2 l8 ~! @
4
9 p8 l8 c7 t( ]1 }4 Y81 ]& P/ K) H' n. r- a2 s5 t* c* b/ D8 X
101 Y# |% |( q1 e$ k* P
12- @9 \& c8 s! x/ s
17
1 C# R: N! m0 P$ k5 HGonadotropin
6 e# j# }8 |: U' L9 |# a$ B, y' g71.6 2.0 X 3 16.6
' _0 [9 k( _; t* T50.4 4.0 X 5.0 20.0
# X: v$ D! r' Z/ X; _22.0 4.5 X 4.0 25.08 a! p" g/ z8 }* w4 s3 O( l9 G
84.6 4.0 X 4.5 11.1
5 R' {8 [3 u6 y2 L$ C; p85.9 4.5 X 5.5 9.0& J: Z( @% a& F: m7 N. t
Av. 14.3- G. z' P( a* k% b; j# h
4
& K6 ?: l, L1 { I8
* G" r8 L8 z; @$ a9 ?$ i" G10* {$ i6 y2 ]% q, j
127 X3 i/ [9 a/ R! T$ C. b
17
- k u# M L- P. V) n& Q7 @Topical testosterone6 O: \: j [0 y
34.6 4.5 X 6.5 858 H8 |2 m& L+ ^/ s/ ]: G) A+ u
38.8 6.0 X 8.5 70
R( K2 N9 M4 H0 ]9 x% y40.0 6.0 X 6.5 62.5( h' C7 @- O' P
93.6 6.0 X 7.0 55.5: M7 C7 q D( T l/ p0 w# Y
95.0 6.5 X 7.0 27.2
. ?5 @ [0 X* v' kAv. 60.0
7 J- K& }+ E8 ^/ y6 O* Javailable testosterone. Again, emphasis should be placed on
$ y- E$ N) F/ D/ dearly therapy when lower levels of testosterone appear to
% Q3 q# w* M, C& X1 I, ~: Kprovide the best responses. The earlier therapy is instituted
# S2 p7 u0 B2 Zthe more likely there will be an excellent response with low
: |* c* ?1 N: X4 I0 Wserum levels. Response occurs throughout adolescence as* \0 R' U) M: d; ]
noted in nomograms of phallic growth. 7 The actual response
. r6 z, ?, u9 G$ Yto a given serum level of testosterone is much greater at birth
+ p8 K: o, h1 iand gradually decreases as boys reach puberty. This is most7 `! Z' o$ `4 F5 A& D/ Q% ?% _
likely related to the conversion of testosterone to dihydrotes-
3 i- n0 d* @$ x& Ytosterone and correlates well with the studies of testosterone9 \8 f9 q! ]. V: |: a
conversion in foreskin at various ages.
& K: i) Z/ t7 [0 i. p; Y! EThe question arises regarding early treatment as to whether+ R5 {$ w" }6 R" X. I
one might sacrifice ultimate potential growth as with acceler-5 A, o) l1 n( C$ {9 s1 X: d H
ated bone growth. The situation appears quite the reverse
, [; k3 n, w, n! Y' u( bwith phallic response. If the early growth period is not used3 R& d) q7 Y! F' L1 M& t
when 5a reductase activity is greatest then potential growth
4 r9 M# X0 q) Q M' q! ~may be lost. We have not observed any regression of growth
6 P2 q6 ~& I5 v; E9 w5 ?3 }5 j# p" k/ Lattained with topical or gonadotropin therapy. It may well$ T6 x g$ M- Z1 r. h
be that some patients will show little or no response to any
4 h. r# D$ @3 I# l p3 Q. Xform of therapy. This would suggest a defect in the ability to
6 e1 b5 F4 `% [* {0 m9 }* t* S/ }convert testosterone to dihydrotestosterone and indicate that
/ o- v/ g* X. y9 `' H3 Q' Cphallic and peripheral skin, and subcutaneous tissue should i2 e f: h! W6 b5 e) w- X
be compared for 5a reductase activity.( ~8 A/ `1 j8 K6 P2 D2 S
A, loop enlarges to measure penile girth in millimeters. B,
" O8 o# }- ^* i# M( Q7 Y5 [/ Xexample of penile girth computed easily and accurately.' L, i/ `' b5 Y( R2 K
conversion of testosterone to dihydrotestosterone. It is in this
8 e5 N% s3 G- U+ k* B: W( {" {older group that others have noted high levels of serum' Z5 S7 U% h4 |; a, \- t
testosterone with topical application. It would also appear
a$ W6 d% p1 i8 f+ h3 i* ?2 }2 ]that phallic response during puberty is related directly to the% ^% w0 f" m$ ^
serum testosterone level. There also is other evidence of local- S) u0 M; Y) k& M3 g1 u9 S' k
response to testosterone with hair growth and with spermato-5 |9 n n8 J$ _5 h+ u0 g
genesis. 5• 67 _# ]" A; o2 W8 r! V
Administration of larger doses of gonadotropin or systemic( K/ j V8 T/ k) `- A3 q
testosterone, as well as topical applications that produce
+ x- v- H. d( o# B$ Dhigher levels of serum testosterone (150 to 900 ng./dl.), will
1 q) p+ z2 J! [$ w) Palso produce phallic growth but risks accelerated skeletal5 u5 N1 A1 R4 E j* P4 {- [# |
maturation even after stopping treatment. It would appear }1 G m. R/ g
that this may be avoided by topical applications of testosterone
0 f# a7 J4 L9 Q. L6 e0 H+ Jand monitoring of serum testosterone. Even with this control. {4 h& a! t. N9 {' j, n
the duration of our therapy did not exceed 3 weeks at any
0 s! }* S+ S& _. Q2 [/ ptime. It is apparent that the prepuberal male subject may s# m1 A- K9 t* u6 ^
suffer accelerated bone growth with testosterone levels near
+ u1 u6 E% m6 R3 _9 u% p6 a200 ng./dl. When skeletal maturation is complete the level of
' _) ^9 V! g8 sserum testosterone can be maintained in the 700 to 1,300 ng./: t4 r. ?5 A" Q4 F$ w6 h
dl. range to stimulate phallic growth and secondary sexual$ m4 p# \, v! ~ [
changes. Therefore, after skeletal maturation parenteral tes-& ~8 F) ^# M# }0 _7 i4 z z0 z
tosterone may be used to advantage. Before skeletal matura-) Q. Y3 T& a$ e, X
tion care must be taken to avoid maintaining levels of serum: K5 D: m/ T. ^! p+ Q5 `' I$ ^* c& f ]
testosterone more than 100 ng./dl. Low-dose gonadotropin
1 A( }4 Q: m. O' H1 idepends upon intrinsic testicular activity and may require% I, ^2 M" h# }/ f+ Q$ s
prolonged administration for any response., y/ ~: ~1 B3 W. H: [# n, [$ P: C
Alternately, topical testosterone does not depend upon tes-
1 k% _3 a" I' S& r/ v) j- O+ Qticular function and may provide a more constant level of
, {" c9 S6 k5 c8 q0 f" u" FREFERENCES
! T7 ], ?( U# G5 u+ p( r7 \) Q1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& p0 `. _4 A! Q3 r" Y9 D+ s
R.: The local application of testosterone cream to the prepub-4 h# `. g1 s0 Y* l8 G7 p" c
ertal phallus. J. Urol., 105: 905, 1971. R1 a& ?0 K7 P: m) ~2 |) y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, p6 ]" _- F! [; J
treatment for micropenis during early childhood. J. Pediat.,
; q4 u* X I# L0 a& Q83: 247, 1973.
; {0 u/ l0 N' H- {' c E3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
/ E5 P `5 z8 `0 W. S4 P: R O' H+ Yone therapy for penile growth. Urology, 6: 708, 1975.
6 g( b& ?( \6 M1 T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone o5 J1 A7 E7 b# Q1 _, _
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' z* |% [$ _, _5 m) pskin slices of man. J. Clin. Invest., 48: 371, 1969.
8 c9 l4 _# E. R. a& m; v1 z5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth4 x- K" D/ C9 o w
by topical application of androgens. J.A.M.A., 191: 521, 1965.0 X& M! _; ?' R& ~
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
: ^$ h0 d' h: n1 n/ y, k- d5 Oandrogenic effect of interstitial cell tumor of the testis. J.
( R( @. S! b) l3 ?9 w# @Urol., 104: 774, 1970.% z+ z" r2 w! F9 t
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
h0 H3 f( }- t) U% V) A" Wtion in the male genitalia from birth to maturity. J. Urol., 48: |
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